register interest

Emeritus Professor David A Warrell FMedSci FRCP

Research Area: Global Health
Technology Exchange: Drug discovery and Vaccine production and evaluation
Scientific Themes: Tropical Medicine & Global Health
Keywords: tropical medicine, snake bite, neglected tropical diseases, clinical toxinology and venomous bites and stings
Web Links:
Figure 3: Estimated deaths and standardized death rates in states with high
prevalence of snakebite deaths, 2005 Death rates are standardised to 2005 UN population estimates for India. The vertical bars represent the state wise estimated deaths (in thousands). Total snakebite deaths for the 13 states with high-prevalence of snakebite death are 42,800 or 93% of the national total (these states have about 85% of the total
estimated population of India). States where the snakebite death rate was below 3/100,000 or where populations are less than 10 million are not shown. The states with high-prevalence of snakebite deaths are: AP-Andhra Pradesh, BR-Bihar, CG559 Chhattisgarh, GJ-Gujarat, JH-Jharkhand, KA-Karnataka, MP Madhya Pradesh, MH560 Maharashtra, OR-Orissa, RJ- Rajasthan, TN-Tamil Nadu, UP-Uttar Pradesh, WB561 West Bengal.

Source: Mohapatra B, Warrell DA, Suraweera W, Bhatia P, Dhingra N, et al. (2011) Snakebite Mortality in India: A Nationally Representative Mortality Survey. PLoS Negl Trop Dis 5(4): e1018. doi:10.1371/journal.pntd.0001018

Figure 3: Estimated deaths and standardized death rates in states with high prevalence of ...

Faiz MA, Ghose A, Ahsan MF, Rahman MR, Amin MR, Hassan MM, Chowdhury MA, Kuch U, Rocha T, Harris JB, Theakston RD, Warrell DA. The greater black krait (Bungarus niger), a newly recognized cause of neuro-myotoxic snake bite envenoming in Bangladesh. Brain. 2010 Nov;133(11):3181-93

Faiz MA, Ghose A, Ahsan MF, Rahman MR, Amin MR, Hassan MM, Chowdhury MA, Kuch U, Rocha T, Harris ...

Scott A. Weinstein, David A. Warrell, Julian White, Daniel E. Keyler. “Venomous” Bites from Non-Venomous Snakes: A Critical Analysis of Risk and Management of “Colubrid” Snake Bites. Burlington, USA, Elsevier, 2011 (in press)

Scott A. Weinstein, David A. Warrell, Julian White, Daniel E. Keyler. “Venomous” Bites from ...

WHO SEARO Guidelines for the management of snake-bites. WHO Regional Office for South-East Asia, 2nd Ed 2010.

WHO SEARO Guidelines for the management of snake-bites. WHO Regional Office for South-East Asia, ...

WHO AFRO Guidelines: Prevention and Clinical Management of Snakebite in Africa. WHO Regional Office for Africa Brazzaville, 2010.

WHO AFRO Guidelines: Prevention and Clinical Management of Snakebite in Africa. WHO Regional Office ...

WHO Recommendations on Rabies Post-Exposure Treatment and the Correct technique of Intradermal Immunization against Rabies

WHO Recommendations on Rabies Post-Exposure Treatment and the Correct technique of Intradermal ...

Rabies and Envenomings A Neglected Public Health Issue Report of a Consultative Meeting WHO Geneva 10 January 2007

Rabies and Envenomings A Neglected Public Health Issue Report of a Consultative Meeting WHO Geneva ...

Research on the incidence, morbidity and mortality of snake bites in Africa, Asia, Oceania and Latin America; and on the clinical presentation, pathophysiology, treatment and prevention of envenoming by snakes and other venomous animals. Current sites of active research are Nepal, Bangladesh and Papua New Guinea. The key component of snake bite treatment is provision of specific antivenom. New antivenoms for treatment of saw-scaled viper bites in Nigeria and of taipan bites in Papua New Guinea have been developed and have or are being clinically tested. Recent findings in India give support to the belief that snake bite is the most neglected of all neglected tropical diseases and deserves reprioritisation. This programme is aimed at producing evidence relevant to establishing the true status of snake bite as a public health problem.

Name Department Institution Country
Dr Sanjib K Sharma Medicine B.P. Koirala Institute of Health Sciences, Dharan Nepal
Professor M Abul Faiz FRCP Medicine Sir Salimullah Medical College Bangladesh
Professor Sir Isi Kevau KBE Medical School University of Papua New Guinea, Port Moresby Papua New Guinea
Mr David J Williams Pharmacology University of Melbourne Australia
Dr Abdulrazaq G Habib FRCP Medicine Bayero University, Kano Nigeria
Keyler DE, Richards DP, Warrell DA, Weinstein SA. 2016. Local envenomation from the bite of a juvenile false water cobra (Hydrodynastes gigas; Dipsadidae). Toxicon, 111 pp. 58-61. | Show Abstract | Read more

The false water cobra (Hydrodynastes gigas) is a non-front-fanged colubroid snake frequently exhibited in zoos, and maintained by amateur collectors. Little detailed documentation regarding the time-course of symptoms development and the consequences of their bites to humans has been published. Reported here is a case of envenoming in a 25 yo male that occurred after the bite of a juvenile H. gigas. The victim was bitten on the fourth digit of the left hand while processing the snake for sex determination, and the snake remained attached to the digit for approximately 30 s; there was no jaw advancement. Within 5 min, intense local pain developed, and at 4hr post bite the entire dorsal aspect of the hand was significantly edematous, The local effects progressed and involved the entire forearm, and the local pain referred to the axillary region. Mild paresthesia and local blanching ("pallor") were noted in the affected digit, but resolved within 7 days. The clinical course in the patient showed that moderate localized symptoms may result from the bite of a juvenile H.gigas.

Warrell DA. 2016. Venomous animals Medicine, 44 (2), pp. 120-124. | Show Abstract | Read more

© 2015 Elsevier Ltd. All rights reserved.Every year, snake-bites kill more than 100,000 people, while survivors suffer physical and mental sequelae; insects cause over 5000 anaphylactic deaths, scorpion-stings kill more than 1000 and spiders and jellyfish kill hundreds. Aquatic venomous animals include sea-snakes, fish, jellyfish, corals, cone shells, blue-ringed octopuses and sea urchins. Specific antidotes - hyperimmune serum antivenoms - are manufactured for serious envenoming. Adrenaline (epinephrine) is essential treatment for anaphylaxis. Cardiorespiratory and kidney failure require supportive treatment. Surgical intervention is rarely needed. Prevention is all important; community education can reduce risk by encouraging the use of protective clothing, lights after dark, bed nets and urgent medical treatment rather than traditional remedies.

Habib AG, Kuznik A, Hamza M, Abdullahi MI, Chedi BA, Chippaux JP, Warrell DA. 2015. Snakebite is Under Appreciated: Appraisal of Burden from West Africa. PLoS Negl Trop Dis, 9 (9), pp. e0004088. | Show Abstract | Read more

BACKGROUND: Snakebite envenoming (SBE) is a major problem in rural areas of West Africa (WA). Compared to other Neglected Tropical Diseases (NTD), the public health burden of SBE has not been well characterized. We estimated the impact of snakebite mortality and morbidity using the Disability Adjusted Life Years (DALYs) metrics for 16 countries in WA. METHODS: We used the reported annual number of SB deaths and mean age at time of SB and converted these into years of life lost (YLL). Similarly, the years of life lived with disability (YLD) were estimated by multiplying the number of amputations by the respective disability weight of 0.13. RESULTS: In WA, the annual cases of SB mortality and amputations ranged from 24 (95% Confidence Interval: 19-29) and 28 (17-48) respectively in Guinea-Bissau with the highest estimates of 1927 (1529-2333) and 2368 (1506-4043) respectively in Nigeria. We calculated that the annual DALYs associated with a SB death ranged from 1550 DALYs (95%CI: 1227-1873 DALYs) in Guinea Bissau to 124,484 DALYs (95%CI: 98,773-150,712 DALYs) in Nigeria. The annual DALYs associated with amputation for the two countries were 149 DALYs (95%CI: 91-256 DALYs) and 12,621 DALYs (95%CI: 8027-21,549 DALYs) respectively. The total burden of SBE was estimated at 319,874 DALYs (95% CI: 248,357-402,654 DALYs) in the 16 countries in WA. These estimates are similar, and in some instances even higher, than for other NTDs encountered in WA (e.g., Buruli ulcer, Echinococcosis, Intestinal Nematode Infections, Leishmaniasis, Onchocerchiasis, Trachoma and Trypanosomiasis) as reported in the Global Burden of Diseases 2010 (GBD). CONCLUSIONS: The public health burden of SBE in WA is very substantial and similar to other more widely recognized NTDs. Efforts and funding commensurate with its burden should be made available for the control of snakebite in the sub-region.

Gutiérrez JM, Burnouf T, Harrison RA, Calvete JJ, Brown N, Jensen SD, Warrell DA, Williams DJ, Global Snakebite Initiative. 2015. A Call for Incorporating Social Research in the Global Struggle against Snakebite. PLoS Negl Trop Dis, 9 (9), pp. e0003960. | Read more

Warrell MJ, Warrell DA. 2015. Rabies: the clinical features, management and prevention of the classic zoonosis. Clin Med (Lond), 15 (1), pp. 78-81. | Show Abstract | Read more

The diagnosis of rabies encephalitis relies on awareness of the varied clinical features and eliciting a history of unusual contact with a mammal throughout the endemic area. The diagnosis is easily missed. Laboratory tests are not routine and only confirm clinical suspicion. Rabies infection carries a case fatality exceeding 99.9%. Palliation is appropriate, except for previously-vaccinated patients or those infected by American bats, for whom intensive care is probably indicated. However, as rabies vaccines are outstandingly effective, no one should die of dog-transmitted infection. Vaccines and rabies immunoglobulin are expensive and usually scarce in Asia and Africa. All travellers to dog rabies enzootic areas should be strongly encouraged to have pre-exposure immunisation before departure. There is no contraindication to vaccination but the cost can be prohibitive. Intradermal immunisation, using 0.1 ml and sharing vials of vaccine, is cheaper and is now permitted by UK regulations. Returning travellers may need post-exposure prophylaxis. Economical intradermal post-exposure vaccination is practicable and should be introduced into rural areas of Africa and Asia immediately. Eliminating rabies in dogs is now feasible and would dramatically reduce human mortality, if funds were made available. The high current economic burden of human prophylaxis would then be largely relieved.

Gutiérrez JM, Burnouf T, Harrison RA, Calvete JJ, Kuch U, Warrell DA, Williams DJ, Global Snakebite Initiative. 2014. A multicomponent strategy to improve the availability of antivenom for treating snakebite envenoming. Bull World Health Organ, 92 (7), pp. 526-532. | Show Abstract | Read more

Snakebite envenoming is a common but neglected public health problem, particularly in impoverished rural regions of sub-Saharan Africa, Asia and Latin America. The only validated treatment for this condition is passive immunotherapy with safe and effective animal-derived antivenoms. However, there is a long-lasting crisis in the availability of these life-saving medications, particularly in sub-Saharan Africa and parts of Asia. We herein advocate a multicomponent strategy to substantially improve the availability of safe and effective antivenoms at the global level. This strategy is based on: (i) preparing validated collections of representative venom pools from the most medically dangerous snakes in high-risk regions of the world; (ii) strengthening the capacity of national antivenom manufacturing and quality control laboratories and their regulatory authorities and establishing new facilities in developing countries through technology transfer, as an integral part of efforts to develop their biological products industry; (iii) getting established laboratories to generate antivenoms for various regions of the world; and (iv) getting governments and relevant organizations to give snakebite envenoming due recognition within national and international public health policy frameworks. These ways of making antivenom available should be complemented by actions to improve health information systems, the accessibility of antivenoms, the training of medical and nursing staff, and community-based education. Such a multicomponent strategy involving stakeholders on many levels could help consolidate sustainable improvements in antivenom availability worldwide.

Cited:

20

Scopus

Warrell DA, Gutiérrez JM, Calvete JJ, Williams D. 2013. New approaches & technologies of venomics to meet the challenge of human envenoming by snakebites in India Indian Journal of Medical Research, 138 (JUL 2013), pp. 38-59. | Show Abstract

The direct estimate of 46,000 snakebite deaths in India in 2005 (1 for every 2 HIV/AIDS deaths), based on verbal autopsies, renders unrealistic the total of only 47,000 snakebite deaths in the whole world in 2010, obtained indirectly as part of the "Global Burden of Disease 2010" study. Persistent underestimation of its true morbidity and mortality has made snakebite the most neglected of all the WHO's "neglected tropical diseases", downgrading its public health importance. Strategies to address this neglect should include the improvement of antivenom, the only specific antidote to envenoming. To accommodate increased understanding of geographical intraspecific variation in venom composition and the range of snake species that are medically important in India, the design of antivenoms (choice of venom sources and species coverage) should be reconsidered. Methods of preclinical and clinical testing should be improved. The relatively new science of venomics involves techniques and strategies for assessing the toxin composition of snake venoms directly through proteomics-centred approaches or indirectly via high-throughput venom gland transcriptomics and bioinformatic analysis. Antivenomics is translational venomics: a proteomics-based protocol to quantify the extent of cross-reactivity of antivenoms against homologous and heterologous venoms. These approaches could revolutionize the preclinical assessment of antivenom efficacy, leading to a new generation of antivenoms that are clinically more effective.

Warrell DA, Maria Gutierrez J, Calvete JJ, Williams D. 2013. New approaches & technologies of venomics to meet the challenge of human envenoming by snakebites in India INDIAN JOURNAL OF MEDICAL RESEARCH, 138 pp. 37-58.

Warrell DA, Gutiérrez JM, Calvete JJ, Williams D. 2013. New approaches & technologies of venomics to meet the challenge of human envenoming by snakebites in India. Indian J Med Res, 138 pp. 38-59. | Show Abstract

The direct estimate of 46,000 snakebite deaths in India in 2005 (1 for every 2 HIV/AIDS deaths), based on verbal autopsies, renders unrealistic the total of only 47,000 snakebite deaths in the whole world in 2010, obtained indirectly as part of the "Global Burden of Disease 2010" study. Persistent underestimation of its true morbidity and mortality has made snakebite the most neglected of all the WHO's "neglected tropical diseases", downgrading its public health importance. Strategies to address this neglect should include the improvement of antivenom, the only specific antidote to envenoming. To accommodate increased understanding of geographical intraspecific variation in venom composition and the range of snake species that are medically important in India, the design of antivenoms (choice of venom sources and species coverage) should be reconsidered. Methods of preclinical and clinical testing should be improved. The relatively new science of venomics involves techniques and strategies for assessing the toxin composition of snake venoms directly through proteomics-centred approaches or indirectly via high-throughput venom gland transcriptomics and bioinformatic analysis. Antivenomics is translational venomics: a proteomics-based protocol to quantify the extent of cross-reactivity of antivenoms against homologous and heterologous venoms. These approaches could revolutionize the preclinical assessment of antivenom efficacy, leading to a new generation of antivenoms that are clinically more effective.

Habib AG, Warrell DA. 2013. Antivenom therapy of carpet viper (Echis ocellatus) envenoming: Effectiveness and strategies for delivery in West Africa Toxicon, 69 pp. 82-89. | Show Abstract | Read more

In West Africa, response to specific, geographically appropriate, antivenom is often dramatic following carpet viper (Echis ocellatus) envenoming with rapid restoration of blood coagulability and resolution of spontaneous haemorrhage. Envenoming from Australasian snakes causing similar coagulopathies may respond less dramatically and the effectiveness of antivenom is being questioned. Here we have reviewed and re-analysed all published preclinical and clinical studies on envenoming and antivenom therapy conducted in West Africa to determine the effectiveness of antivenom. 22 studies provided relevant information: 12 observational studies, 4 RCTs and 6 preclinical studies. Four comparative studies confirmed statistically significant protection against mortality ranging from 57 to 87% using specific antivenoms compared to non-specific or no antivenoms. Meta-analysis estimated combined Odds Ratio (95% CI) of 0.25 (0.14-0.45) of dying among those treated with specific antivenom or 75% (95% CI: 55-86%) protection against death. Mortality more than doubled during times when stocks of reliable antivenoms ran out, with Relative Risk (95% CI)] of 2.33 (1.26-4.06). Serum kinetics of venom antigen/antivenom levels also confirmed that decline of venom antigen levels coincided with resolution of coagulopathy while decline of antivenom levels was associated with venom antigen reappearance and recurrence of coagulopathy. Preclinical and antivenomics analysis confirmed efficacy of regionally appropriate antivenoms against E. ocellatus and related species' venoms in Sub-Saharan Africa but not against Asian Echis carinatus venom. Antivenoms raised against E. carinatus were ineffective in human studies. In West Africa, specific antivenom is effective in managing carpet viper envenoming. A centralized hub-and-spoke strategy is suggested for broadening antivenom access to endemic rural areas together with instituting quality assurance, standardization and manpower training. Benefits, risks, cost-effectiveness and feasibility of the approach should be formally assessed. © 2013 Elsevier Ltd.

Weinstein SA, White J, Keyler DE, Warrell DA. 2013. Non-front-fanged colubroid snakes: A current evidence-based analysis of medical significance Toxicon, 69 pp. 103-113. | Show Abstract | Read more

Non-front-fanged colubroid snakes (NFFC; formerly and artificially taxonomically assembled as " colubrids" ) comprise about 70% of extant snake species and include several taxa now known to cause lethal or life threatening envenoming in humans. Although the medical risks of bites by only a handful of species have been documented, a growing number of NFFC are implicated in medically significant bites. The majority of these snakes have oral products (Duvernoy's secretions, or venoms) with unknown biomedical properties and their potential for causing harm in humans is unknown. Increasingly, multiple NFFC species are entering the commercial snake trade posing an uncertain risk. Published case reports describing NFFC bites were assessed for evidence-based value, clinical detail and verified species identification. These data were subjected to meta-analysis and a hazard index was generated for select taxa. Cases on which we consulted or personally treated were included and subjected to the same assessment criteria. Cases involving approximately 120 species met the selection criteria, and a small subset designated Hazard Level 1 (most hazardous), contained 5 species with lethal potential. Recommended management of these cases included antivenom for 3 species, Dispholidus typus, Rhabdophis tiginis, Rhabdophis subminiatus, whereas others in this subset without commercially available antivenoms (Thelotornis spp.) were treated with plasma/erythrocyte replacement therapy and supportive care. Heparin, antifibrinolytics and/or plasmapheresis/exchange transfusion have been used in the management of some Hazard Level 1 envenomings, but evidence-based analysis positively contraindicates the use of any of these interventions. Hazard Level 2/3 species were involved in cases containing mixed quality data that implicated these taxa (e.g. Boiga irregularis, Philodryas olfersii, Malpolon monspessulanus) with bites that caused rare systemic effects. Recommended management may include use of acetylcholinesterase inhibitors (e.g. neostigmine) and wound care on a case-by-case basis. Hazard level 3 species comprised a larger group capable of producing significant local effects only, often associated with a protracted bite (eg Heterodon nasicus, Borikenophis (Alsophis) portoricensis, Platyceps (Coluber) rhodorachis). Management is restricted to wound care. Bites by Hazard level 4 species comprised the majority of surveyed taxa and these showed only minor effects of no clinical importance. This study has produced a comprehensive evidence-based listing of NFFC snakes tabulated against medical significance of bites, together with best-practice management recommendations. This analysis assumes increasing importance, as there is growing exposure to lesser-known NFFC snakes, particularly in captive collections that may uncover further species of significance in the future. Careful and accurate documentation of bites by verified species of NFFC snakes is required to increase the evidence base and establish the best medical management approach for each species. © 2013.

Warrell DA. 2013. Redi award lecture: Clinical studies of snake-bite in four tropical continents Toxicon, 69 pp. 3-13. | Show Abstract | Read more

Research is discussed in the areas of venomous snake taxonomy, epidemiology, species diagnosis, defining the clinical phenotype of human envenoming, pathophysiological mechanisms of envenoming, clinical testing of antivenoms and prevention of snake-bite through community education. This work was carried out over the past 40 years in many countries in four tropical continents. The help and friendship of a large number of collaborators is gratefully acknowledged. © 2012 Elsevier Ltd.

Gutiérrez JM, Warrell DA, Williams DJ, Jensen S, Brown N, Calvete JJ, Harrison RA, Global Snakebite Initiative. 2013. The need for full integration of snakebite envenoming within a global strategy to combat the neglected tropical diseases: the way forward. PLoS Negl Trop Dis, 7 (6), pp. e2162. | Read more

Weinstein SA, White J, Westerström A, Warrell DA. 2013. Anecdote vs. substantiated fact: The problem of unverified reports in thetoxinological and herpetological literature describing non-front-fanged colubroid ("colubrid") snakebites Herpetological Review, 44 (1), pp. 23-29.

Weinstein SA, White J, Keyler DE, Warrell DA. 2013. Non-front-fanged colubroid snakes: a current evidence-based analysis of medical significance. Toxicon, 69 pp. 103-113. | Show Abstract | Read more

Non-front-fanged colubroid snakes (NFFC; formerly and artificially taxonomically assembled as "colubrids") comprise about 70% of extant snake species and include several taxa now known to cause lethal or life threatening envenoming in humans. Although the medical risks of bites by only a handful of species have been documented, a growing number of NFFC are implicated in medically significant bites. The majority of these snakes have oral products (Duvernoy's secretions, or venoms) with unknown biomedical properties and their potential for causing harm in humans is unknown. Increasingly, multiple NFFC species are entering the commercial snake trade posing an uncertain risk. Published case reports describing NFFC bites were assessed for evidence-based value, clinical detail and verified species identification. These data were subjected to meta-analysis and a hazard index was generated for select taxa. Cases on which we consulted or personally treated were included and subjected to the same assessment criteria. Cases involving approximately 120 species met the selection criteria, and a small subset designated Hazard Level 1 (most hazardous), contained 5 species with lethal potential. Recommended management of these cases included antivenom for 3 species, Dispholidus typus, Rhabdophis tiginis, Rhabdophis subminiatus, whereas others in this subset without commercially available antivenoms (Thelotornis spp.) were treated with plasma/erythrocyte replacement therapy and supportive care. Heparin, antifibrinolytics and/or plasmapheresis/exchange transfusion have been used in the management of some Hazard Level 1 envenomings, but evidence-based analysis positively contraindicates the use of any of these interventions. Hazard Level 2/3 species were involved in cases containing mixed quality data that implicated these taxa (e.g. Boiga irregularis, Philodryas olfersii, Malpolon monspessulanus) with bites that caused rare systemic effects. Recommended management may include use of acetylcholinesterase inhibitors (e.g. neostigmine) and wound care on a case-by-case basis. Hazard level 3 species comprised a larger group capable of producing significant local effects only, often associated with a protracted bite (eg Heterodon nasicus, Borikenophis (Alsophis) portoricensis, Platyceps (Coluber) rhodorachis). Management is restricted to wound care. Bites by Hazard level 4 species comprised the majority of surveyed taxa and these showed only minor effects of no clinical importance. This study has produced a comprehensive evidence-based listing of NFFC snakes tabulated against medical significance of bites, together with best-practice management recommendations. This analysis assumes increasing importance, as there is growing exposure to lesser-known NFFC snakes, particularly in captive collections that may uncover further species of significance in the future. Careful and accurate documentation of bites by verified species of NFFC snakes is required to increase the evidence base and establish the best medical management approach for each species.

Habib AG, Warrell DA. 2013. Antivenom therapy of carpet viper (Echis ocellatus) envenoming: effectiveness and strategies for delivery in West Africa. Toxicon, 69 pp. 82-89. | Show Abstract | Read more

In West Africa, response to specific, geographically appropriate, antivenom is often dramatic following carpet viper (Echis ocellatus) envenoming with rapid restoration of blood coagulability and resolution of spontaneous haemorrhage. Envenoming from Australasian snakes causing similar coagulopathies may respond less dramatically and the effectiveness of antivenom is being questioned. Here we have reviewed and re-analysed all published preclinical and clinical studies on envenoming and antivenom therapy conducted in West Africa to determine the effectiveness of antivenom. 22 studies provided relevant information: 12 observational studies, 4 RCTs and 6 preclinical studies. Four comparative studies confirmed statistically significant protection against mortality ranging from 57 to 87% using specific antivenoms compared to non-specific or no antivenoms. Meta-analysis estimated combined Odds Ratio (95% CI) of 0.25 (0.14-0.45) of dying among those treated with specific antivenom or 75% (95% CI: 55-86%) protection against death. Mortality more than doubled during times when stocks of reliable antivenoms ran out, with Relative Risk (95% CI)] of 2.33 (1.26-4.06). Serum kinetics of venom antigen/antivenom levels also confirmed that decline of venom antigen levels coincided with resolution of coagulopathy while decline of antivenom levels was associated with venom antigen reappearance and recurrence of coagulopathy. Preclinical and antivenomics analysis confirmed efficacy of regionally appropriate antivenoms against E. ocellatus and related species' venoms in Sub-Saharan Africa but not against Asian Echis carinatus venom. Antivenoms raised against E. carinatus were ineffective in human studies. In West Africa, specific antivenom is effective in managing carpet viper envenoming. A centralized hub-and-spoke strategy is suggested for broadening antivenom access to endemic rural areas together with instituting quality assurance, standardization and manpower training. Benefits, risks, cost-effectiveness and feasibility of the approach should be formally assessed.

Harris J, Flecknell P, Thomas A, Warrell DA. 2013. On the use of analgesia in experimental toxinology. Toxicon, 64 pp. 36-37. | Read more

Bates NS, Warrell DA. 2013. Treatment of adder bites in dogs. Vet Rec, 172 (1), pp. 23-24. | Read more

Jeevagan V, Katulanda P, Gnanathasan CA, Warrell DA. 2013. Acute pituitary insufficiency and hypokalaemia following envenoming by Russell's viper (Daboia russelii) in Sri Lanka: Exploring the pathophysiological mechanisms. Toxicon, 63 (1), pp. 78-82. | Show Abstract | Read more

Russell's viper envenoming is associated with a high incidence of morbidity and mortality. Hypopituitarism following envenoming by Russell's vipers is a well recognized sequel in Burma and parts of India but has been reported only once in Sri Lanka. Hypokalaemia following envenoming by Russell's viper has not been described. Here we describe the association of acute pituitary insufficiency and hypokalaemia following Russell's viper envenoming in Sri Lanka and review the literature in order to understand its pathophysiological basis. A previously healthy 21-year-old man was envenomed by a Russell's viper and treated with antivenom. Ten hours after the bite, he developed persistent hypotension, which responded promptly to intravenous dexamethasone. His hormone profiles were consistent with hypocortisolism secondary to acute pituitary insufficiency. He also developed hypokalaemia. Analysis of urine and serum electrolytes suggested redistribution of potassium in to the cells rather than renal loss. Hypotension and hypoglycaemic coma are life-threatening manifestations of acute pituitary insufficiency. Therefore prompt steroid administration in these setting is life saving. Awareness of these complications among physicians would help to make prompt diagnosis and initiate immediate life saving treatment.

Herrera C, Rucavado A, Warrell DA, Gutiérrez JM. 2013. Systemic effects induced by the venom of the snake Bothrops caribbaeus in a murine model. Toxicon, 63 (1), pp. 19-31. | Show Abstract | Read more

Snakebite envenoming by Bothrops caribbaeus, an endemic viperid from the Lesser Antillean island of Saint Lucia, is clinically characterized by local tissue damage and systemic thrombosis that can lead to cerebral, myocardial or pulmonary infarctions and venous thromboses. Systemic effects (lethality, pulmonary hemorrhage, thrombocytopenia and coagulopathy) induced by intravenous (i.v.) administration of B. caribbaeus venom were studied in mice. The role of snake venom metalloproteinases (SVMPs) in these systemic alterations was assessed by inhibition with the chelating agent calcium disodium ethylenediaminetetraacetic acid (CaNa(2)EDTA). A snake C-type lectin-like (snaclec) and a type P-III hemorrhagic SVMP were isolated and characterized from this venom, and the effect of venom and the isolated snaclec on human platelet aggregation was studied in vitro. Results indicate that SVMPs play an important role in the overall toxicity of B. caribbaeus venom, being responsible for systemic hemorrhage and lethality, but not thrombocytopenia, whereas the isolated snaclec is involved in the thrombocytopenic effect. Both venom and snaclec induce platelet aggregation/agglutination. Moreover, the snaclec binds directly to glycoprotein Ib (GPIb) and induces agglutination in washed fixed platelets. On the other hand, B. caribbaeus venom hydrolyzed fibrinogen in vitro and induced a partial drop of fibrinogen levels with an increase in fibrin/fibrinogen degradation products (FDP) levels in vivo. The negative result for D-dimer (DD) in plasma is consistent with the lack of microscopic evidence of pulmonary thrombosis and endothelial cell damage. Likewise, no increments in plasma sE-selectin levels were detected. The absence of thrombosis in this murine model suggests that this effect may be species-specific.

Warrell DA. 2013. Redi award lecture: clinical studies of snake-bite in four tropical continents. Toxicon, 69 pp. 3-13. | Show Abstract | Read more

Research is discussed in the areas of venomous snake taxonomy, epidemiology, species diagnosis, defining the clinical phenotype of human envenoming, pathophysiological mechanisms of envenoming, clinical testing of antivenoms and prevention of snake-bite through community education. This work was carried out over the past 40 years in many countries in four tropical continents. The help and friendship of a large number of collaborators is gratefully acknowledged.

Warrell MJ, Warrell DA. 2012. Viral CNS Infections: Rabies and Related Viruses pp. 344-348. | Read more

Warrell DA. 2012. Poisonous Plants and Aquatic Animals: Poisonous Aquatic Animals pp. 923-924. | Read more

Warrell DA. 2012. Injurious Arthropods pp. 969-985. | Read more

Warrell DA. 2012. Poisonous Plants and Aquatic Animals: Fish Poisoning: Gastrointestinal and Neurotoxic Syndromes pp. 925-927. | Read more

Warrell DA. 2012. Animals Hazardous to Humans pp. 938-965. | Read more

Warrell DA. 2012. Pentastomiasis pp. 966-968. | Read more

Suraweera W, Morris SK, Kumar R, Warrell DA, Warrell MJ, Jha P, Million Death Study Collaborators. 2012. Deaths from symptomatically identifiable furious rabies in India: a nationally representative mortality survey. PLoS Negl Trop Dis, 6 (10), pp. e1847. | Show Abstract | Read more

BACKGROUND: It is estimated that India has more deaths from rabies than any other country. However, existing estimates are indirect and rely on non-representative studies. METHODS AND PRINCIPAL FINDINGS: We examined rabies deaths in the ongoing Million Death Study (MDS), a representative survey of over 122,000 deaths in India that uses enhanced types of verbal autopsy. We estimated the age-specific mortality rates of symptomatically identifiable furious rabies and its geographic and demographic distributions. A total of 140 deaths in our sample were caused by rabies, suggesting that in 2005 there were 12,700 (99% CI 10,000 to 15,500) symptomatically identifiable furious rabies deaths in India. Most rabies deaths were in males (62%), in rural areas (91%), and in children below the age of 15 years (50%). The overall rabies mortality rate was 1.1 deaths per 100,000 population (99%CI 0.9 to 1.4). One third of the national rabies deaths were found in Uttar Pradesh (4,300) and nearly three quarters (8,900) were in 7 central and south-eastern states: Chhattisgarh, Uttar Pradesh, Odisha, Andhra Pradesh, Bihar, Assam, and Madhya Pradesh. CONCLUSIONS AND SIGNIFICANCE: Rabies remains an avoidable cause of death in India. As verbal autopsy is not likely to identify atypical or paralytic forms of rabies, our figure of 12,700 deaths due to classic and clinically identifiable furious rabies underestimates the total number of deaths due to this virus. The concentrated geographic distribution of rabies in India suggests that a significant reduction in the number of deaths or potentially even elimination of rabies deaths is possible.

Warrell DA. 2012. Venomous bites, stings, and poisoning. Infect Dis Clin North Am, 26 (2), pp. 207-223. | Show Abstract | Read more

This article discusses the epidemiology, prevention, clinical features, first aid and medical treatment of venomous bites by snakes, lizards, and spiders; stings by fish, jellyfish, echinoderms, and insects; and poisoning by fish and molluscs, in all parts of the world. Of these envenoming and poisonings, snake bite causes the greatest burden of human suffering, killing 46,000 people each year in India alone and more than 100,000 worldwide and resulting in physical handicap in many survivors. Specific antidotes (antivenoms/antivenins) are available to treat envenoming by many of these taxa but supply and distribution is inadequate in many tropical developing countries.

Warrell DA. 2012. Mechanisms of Envenoming: An Overview of their Relevance in Treating Patients CLINICAL TOXICOLOGY, 50 (4), pp. 279-280.

Warrell DA. 2012. Venomous animals Medicine, 40 (3), pp. 159-163. | Show Abstract | Read more

Bites by venomous snakes cause more than 100,000 deaths and many permanent sequelae each year, while scorpion stings kill thousands of children. Hypersensitization to bee, wasp and ant venoms is a common cause of anaphylaxis but mass attacks by African killer bees can kill by direct envenoming. Aquatic venomous animals include sea snakes, stinging fish, jellyfish, corals, cone shells, blue-ringed octopuses and sea urchins. Treatment of severe envenoming by all these groups of animals requires specific antivenom, supportive treatment for cardiorespiratory and renal failure, and surgical management of wounds. Animal bites and stings can be prevented by learning about local venomous fauna, wearing protective clothing, using a light after dark, and sleeping off the ground or under a bed net. © 2011 Published by Elsevier Ltd.

Mohapatra B, Warrell DA, Suraweera W, Bhatia P, Dhingra N, Jotkar RM, Rodriguez PS, Mishra K, Whitaker R, Jha P, Million Death Study Collaborators. 2011. Snakebite mortality in India: a nationally representative mortality survey. PLoS Negl Trop Dis, 5 (4), pp. e1018. | Show Abstract | Read more

BACKGROUND: India has long been thought to have more snakebites than any other country. However, inadequate hospital-based reporting has resulted in estimates of total annual snakebite mortality ranging widely from about 1,300 to 50,000. We calculated direct estimates of snakebite mortality from a national mortality survey. METHODS AND FINDINGS: We conducted a nationally representative study of 123,000 deaths from 6,671 randomly selected areas in 2001-03. Full-time, non-medical field workers interviewed living respondents about all deaths. The underlying causes were independently coded by two of 130 trained physicians. Discrepancies were resolved by anonymous reconciliation or, failing that, by adjudication. A total of 562 deaths (0.47% of total deaths) were assigned to snakebites. Snakebite deaths occurred mostly in rural areas (97%), were more common in males (59%) than females (41%), and peaked at ages 15-29 years (25%) and during the monsoon months of June to September. This proportion represents about 45,900 annual snakebite deaths nationally (99% CI 40,900 to 50,900) or an annual age-standardised rate of 4.1/100,000 (99% CI 3.6-4.5), with higher rates in rural areas (5.4/100,000; 99% CI 4.8-6.0), and with the highest state rate in Andhra Pradesh (6.2). Annual snakebite deaths were greatest in the states of Uttar Pradesh (8,700), Andhra Pradesh (5,200), and Bihar (4,500). CONCLUSIONS: Snakebite remains an underestimated cause of accidental death in modern India. Because a large proportion of global totals of snakebites arise from India, global snakebite totals might also be underestimated. Community education, appropriate training of medical staff and better distribution of antivenom, especially to the 13 states with the highest prevalence, could reduce snakebite deaths in India.

Petras D, Sanz L, Segura A, Herrera M, Villalta M, Solano D, Vargas M, León G et al. 2011. Snake venomics of African spitting cobras: toxin composition and assessment of congeneric cross-reactivity of the pan-African EchiTAb-Plus-ICP antivenom by antivenomics and neutralization approaches. J Proteome Res, 10 (3), pp. 1266-1280. | Show Abstract | Read more

Venomic analysis of the venoms of Naja nigricollis, N. katiensis, N. nubiae, N. mossambica, and N. pallida revealed similar compositional trends. The high content of cytotoxins and PLA(2)s may account for the extensive tissue necrosis characteristic of the envenomings by these species. The high abundance of a type I α-neurotoxin in N. nubiae may be responsible for the high lethal toxicity of this venom (in rodents). The ability of EchiTAb-Plus-ICP antivenom to immunodeplete and neutralize the venoms of African spitting cobras was assessed by antivenomics and neutralization tests. It partially immunodepleted 3FTx and PLA(2)s and completely immunodepleted SVMPs and CRISPs in all venoms. The antivenom neutralized the dermonecrotic and PLA(2) activities of all African Naja venoms, whereas lethality was eliminated in the venoms of N. nigricollis, N. mossambica, and N. pallida but not in those of N. nubiae and N. katiensis. The lack of neutralization of lethality of N. nubiae venom may be of medical relevance only in relatively populous areas of the Saharan region. The impaired activity of EchiTAb-Plus-ICP against N. katiensis may not represent a major concern. This species is sympatric with N. nigricollis in many regions of Africa, although very few bites have been attributed to it.

Weinstein SA, Warrell DA, White J, Keyler DE. 2011. "Venomous" Bites from Non-Venomous Snakes "Venomous" Bites from Non-Venomous Snakes, | Show Abstract

This book is the first significant contribution to thoroughly examine the potential hazards associated with snakes of the former family, Colubridae. This family contained >65% of living snake species (approximately 3,000 taxa) and has recently been split into multiple families. Many of these snakes produce oral secretions that contain toxins and other biologically-active substances. A large variety of these snakes figure in the pet industry, yet little documented information or formal study of their potential medical importance has been published. Therefore, although the possible medical importance of many of these species has been subjected to speculation since the mid-nineteenth century, there is a limited amount of useful descriptive information regarding the real hazard (or lack thereof) of snakes belonging to this diverse, artificial family. There is a need for "one-stop shopping" offering information regarding their possible toxicity and clinical relevance as well as recommendations for medical management of their bites. This book is the first synthesis of this information and includes evidence-based risk assessment, hazard rankings and specific recommendations regarding important species, many common in captivity. Fills a gap in the toxinological, medical and herpetological literature by providing a comprehensive review of this entire assemblage of snakes, with particular attention given to their capacity, real or rumored, to cause harm to humans A patient-centered, evidence-based approach is applied to analyzing documented case reports of bites inflicted by approximately 100 species. Clinical management of medically significant bites from non-front-fanged colubroids is methodically reviewed, and specific recommendations are provided. © 2011 Elsevier Inc. All rights reserved.

Warrell DA. 2011. Snake bite: a neglected problem in twenty-first century India. Natl Med J India, 24 (6), pp. 321-324.

Williams DJ, Gutiérrez JM, Calvete JJ, Wüster W, Ratanabanangkoon K, Paiva O, Brown NI, Casewell NR et al. 2011. Ending the drought: new strategies for improving the flow of affordable, effective antivenoms in Asia and Africa. J Proteomics, 74 (9), pp. 1735-1767. | Show Abstract | Read more

The development of snake antivenoms more than a century ago should have heralded effective treatment of the scourge of snakebite envenoming in impoverished, mostly rural populations around the world. That snakebite still exists today, as a widely untreated illness that maims, kills and terrifies men, women and children in vulnerable communities, is a cruel anachronism. Antivenom can be an effective, safe and affordable treatment for snakebites, but apathy, inaction and the politicisation of public health have marginalised both the problem (making snakebite arguably the most neglected of all neglected tropical diseases) and its solution. For lack of any coordinated approach, provision of antivenoms has been pushed off the public health agenda, leading to an incongruous decline in demand for these crucial antidotes, excused and fed by new priorities, an absence of epidemiological data, and a poor regulatory framework. These factors facilitated the infiltration of poor quality products that degrade user confidence and undermine legitimate producers. The result is that tens of thousands are denied an essential life-saving medicine, allowing a toll of human suffering that is a summation of many individual catastrophes. No strategy has been developed to address this problem and to overcome the intransigence and inaction responsible for the global tragedy of snakebite. Attempts to engage with the broader public health community through the World Health Organisation (WHO), GAVI, and other agencies have failed. Consequently, the toxinology community has taken on a leadership role in a new approach, the Global Snakebite Initiative, which seeks to mobilise the resources, skills and experience of scientists and clinicians for whom venoms, toxins, antivenoms, snakes and snakebites are already fields of interest. Proteomics is one such discipline, which has embraced the potential of using venoms in bio-discovery and systems biology. The fields of venomics and antivenomics have recently evolved from this discipline, offering fresh hope for the victims of snakebites by providing an exciting insight into the complexities, nature, fundamental properties and significance of venom constituents. Such a rational approach brings with it the potential to design new immunising mixtures from which to raise potent antivenoms with wider therapeutic ranges. This addresses a major practical limitation in antivenom use recognised since the beginning of the 20th century: the restriction of therapeutic effectiveness to the specific venom immunogen used in production. Antivenomic techniques enable the interactions between venoms and antivenoms to be examined in detail, and if combined with functional assays of specific activity and followed up by clinical trials of effectiveness and safety, can be powerful tools with which to evaluate the suitability of current and new antivenoms for meeting urgent regional needs. We propose two mechanisms through which the Global Snakebite Initiative might seek to end the antivenom drought in Africa and Asia: first by establishing a multidisciplinary, multicentre, international collaboration to evaluate currently available antivenoms against the venoms of medically important snakes from specific nations in Africa and Asia using a combination of proteomic, antivenomic and WHO-endorsed preclinical assessment protocols, to provide a validated evidence base for either recommending or rejecting individual products; and secondly by bringing the power of proteomics to bear on the design of new immunising mixtures to raise Pan-African and Pan-Asian polyvalent antivenoms of improved potency and quality. These products will be subject to rigorous clinical assessment. We propose radically to change the basis upon which antivenoms are produced and supplied for the developing world. Donor funding and strategic public health alliances will be sought to make it possible not only to sustain the financial viability of antivenom production partnerships, but also to ensure that patients are relieved of the costs of antivenom so that poverty is no longer a barrier to the treatment of this important, but grossly neglected public health emergency.

Williams DJ, Gutiérrez J-M, Calvete JJ, Wüster W, Ratanabanangkoon K, Paiva O, Brown NI, Casewell NR et al. 2011. Ending the drought: New strategies for improving the flow of affordable, effective antivenoms in Asia and Africa Journal of Proteomics,

Antonypillai CN, Wass JA, Warrell DA, Rajaratnam HN. 2011. Hypopituitarism following envenoming by Russell's vipers (Daboia siamensis and D. russelii) resembling Sheehan's syndrome: first case report from Sri Lanka, a review of the literature and recommendations for endocrine management. QJM, 104 (2), pp. 97-108. | Show Abstract | Read more

Russell's vipers (Daboia russelii and D. siamensis) inhabit 10 South and South East Asian countries. People envenomed by these snakes suffer coagulopathy, bleeding, shock, neurotoxicity, acute kidney injury and local tissue damage leading to severe morbidity and mortality. An unusual complication of Russell's viper bite envenoming in Burma (D. siamensis) and southern India (D. russelii) is hypopituitarism but until now it has not been reported elsewhere. Here, we describe the first case of hypopituitarism following Russell's viper bite in Sri Lanka, review the literature on this subject and make recommendations for endocrine investigation and management. A 49-year-old man was bitten and seriously envenomed by D. russelii in 2005. He was treated with antivenom but although he recovered from the acute effects he remained feeling unwell. Hypopituitarism, with deficiencies of gonadal, steroid and thyroid axes, was diagnosed 3 years later. He showed marked improvement after replacement of anterior pituitary hormones. We attribute his hypopituitarism to D. russelii envenoming. Russell's viper bite is known to cause acute and chronic hypopituitarism and diabetes insipidus, perhaps through deposition of fibrin microthrombi and haemorrhage in the pituitary gland resulting from the action of venom procoagulant enzymes and haemorrhagins. Forty nine cases of hypopituitarism following Russell's viper bite have been described in the English language literature. Patients with acute hypopituitarism may present with hypoglycaemia and hypotension during the acute phase of envenoming. Those with chronic hypopituitarism seem to have recovered from envenoming but present later with features of hypopituitarism. Over 85% of these patients had suffered acute kidney injury immediately after the bite. Steroid replacement in acute hypopituitarism is life saving. All 11 patients with chronic hypopituitarism in whom the outcome of treatment was reported, showed marked improvement with hormone replacement. Unrecognized acute hypopituitarism is potentially fatal while chronic hypopituitarism can be debilitating. Physicians should therefore be aware of this complication of severe envenoming by Russell's vipers, especially in Burma and South India, so that the diagnosis may be made without delay and replacement started with essential hormones such as hydrocortisone and thyroxine.

Aslam A, Lloyd-Lavery A, Warrell DA, Misbah S, Ogg GS. 2011. Common filaggrin null alleles are not associated with hymenoptera venom allergy in Europeans. Int Arch Allergy Immunol, 154 (4), pp. 353-355. | Show Abstract | Read more

The association of filaggrin mutations with atopic eczema (atopic dermatitis, AD) is well established and it is thought that filaggrin dysfunction impairs the skin's barrier function allowing allergen penetration and subsequent cutaneous sensitisation and inflammation. However, as most forms of barrier dysfunction are not associated with allergic sensitisation to common allergens, the possibility that filaggrin itself is involved in Th1/Th2 polarisation remains. We tested the hypothesis that allergen delivered to the skin independently of the stratum corneum is not associated with filaggrin mutations. Wasp stings bypass the stratum corneum and deliver antigen to the dermis. We found that European individuals with AD (n = 32) have an increased frequency of the 2 commonest filaggrin null mutations (R501X and 2282del4) compared to those with vespid allergy (n = 56) and healthy controls (n = 30). Thus, filaggrin does not appear to have a downstream effect on the development of allergic disease, and it is indeed filaggrin's role in the epithelial function that is likely to determine the link between filaggrin mutations and allergic sensitisation.

Faiz A, Ghose A, Ahsan F, Rahman R, Amin R, Hassan MU, Chowdhury AW, Kuch U et al. 2010. The greater black krait (Bungarus niger), a newly recognized cause of neuro-myotoxic snake bite envenoming in Bangladesh. Brain, 133 (11), pp. 3181-3193. | Show Abstract | Read more

Prospective studies of snake bite patients in Chittagong, Bangladesh, included five cases of bites by greater black kraits (Bungarus niger), proven by examination of the snakes that had been responsible. This species was previously known only from India, Nepal, Bhutan and Burma. The index case presented with descending flaccid paralysis typical of neurotoxic envenoming by all Bungarus species, but later developed generalized rhabdomyolysis (peak serum creatine kinase concentration 29,960 units/l) with myoglobinuria and acute renal failure from which he succumbed. Among the other four patients, one died of respiratory paralysis in a peripheral hospital and three recovered after developing paralysis, requiring mechanical ventilation in one patient. One patient suffered severe generalized myalgia and odynophagia associated with a modest increase in serum creatine kinase concentration. These are the first cases of Bungarus niger envenoming to be reported from any country. Generalized rhabdomyolysis has not been previously recognized as a feature of envenoming by any terrestrial Asian elapid snake, but a review of the literature suggests that venoms of some populations of Bungarus candidus and Bungarus multicinctus in Thailand and Vietnam may also have this effect in human victims. To investigate this unexpected property of Bungarus niger venom, venom from the snake responsible for one of the human cases of neuro-myotoxic envenoming was injected into one hind limb of rats and saline into the other under buprenorphine analgesia. All animals developed paralysis of the venom-injected limb within two hours. Twenty-four hours later, the soleus muscles were compared histopathologically and cytochemically. Results indicated a predominantly pre-synaptic action (β-bungarotoxins) of Bungarus niger venom at neuromuscular junctions, causing loss of synaptophysin and the degeneration of the terminal components of the motor innervation of rat skeletal muscle. There was oedema and necrosis of extrafusal muscle fibres in envenomed rat soleus muscles confirming the myotoxic effect of Bungarus niger venom, attributable to phospholipases A₂. This study has demonstrated that Bungarus niger is widely distributed in Bangladesh and confirms the risk of fatal neuro-myotoxic envenoming, especially as no specific antivenom is currently manufactured. The unexpected finding of rhabdomyolysis should prompt further investigation of the venom components responsible. The practical implications of having to treat patients with rhabdomyolysis and consequent acute renal failure, in addition to the more familiar respiratory failure associated with krait bite envenoming, should not be underestimated in a country that is poorly equipped to deal with such emergencies.

Chu ER, Weinstein SA, White J, Warrell DA. 2010. Venom ophthalmia caused by venoms of spitting elapid and other snakes: Report of ten cases with review of epidemiology, clinical features, pathophysiology and management. Toxicon, 56 (3), pp. 259-272. | Show Abstract | Read more

Venom ophthalmia caused by venoms of spitting elapid and other snakes: report of ten cases with review of epidemiology, clinical features, pathophysiology and management. Chu, ER, Weinstein, SA, White, J and Warrell, DA. Toxicon XX:xxx-xxx. We present ten cases of ocular injury following instillation into the eye of snake venoms or toxins by spitting elapids and other snakes. The natural history of spitting elapids and the toxinology of their venoms are reviewed together with the medical effects and management of venom ophthalmia in humans and domestic animals including both direct and allergic effects of venoms. Although the clinical features and management of envenoming following bites by spitting elapids (genera Naja and Hemachatus) are well documented, these snakes are also capable of "spraying" venom towards the eyes of predators, a defensive strategy that causes painful and potentially blinding ocular envenoming (venom ophthalmia). Little attention has been given to the detailed clinical description, clinical evolution and efficacy of treatment of venom ophthalmia and no clear management guidelines have been formulated. Knowledge of the pathophysiology of ocular envenoming is based largely on animal studies and a limited body of clinical information. A few cases of ocular exposure to venoms from crotaline viperids have also been described. Venom ophthalmia often presents with pain, hyperemia, blepharitis, blepharospasm and corneal erosions. Delay or lack of treatment may result in corneal opacity, hypopyon and/or blindness. When venom is "spat" into the eye, cranial nerve VII may be affected by local spread of venom but systemic envenoming has not been documented in human patients. Management of venom ophthalmia consists of: 1) urgent decontamination by copious irrigation 2) analgesia by vasoconstrictors with weak mydriatic activity (e.g. epinephrine) and limited topical administration of local anesthetics (e.g. tetracaine) 3) exclusion of corneal abrasions by fluorescein staining with a slit lamp examination and application of prophylactic topical antibiotics 4) prevention of posterior synechiae, ciliary spasm and discomfort with topical cycloplegics and 5) antihistamines in case of allergic kerato-conjunctivitis. Topical or intravenous antivenom and topical corticosteroids are contraindicated. Clinical outcome of venom ophthalmia is largely dependent on prompt treatment and appropriate follow-up.

Trinh KX, Khac QL, Trinh LX, Warrell DA. 2010. Hyponatraemia, rhabdomyolysis, alterations in blood pressure and persistent mydriasis in patients envenomed by Malayan kraits (Bungarus candidus) in southern Viet Nam. Toxicon, 56 (6), pp. 1070-1075. | Show Abstract | Read more

Between 1998 and 2007, 42 patients admitted to Choray hospital, Ho Chi Minh City, and to two hospitals in adjacent regions in southern Viet Nam brought the Malayan kraits (Bungarus candidus) that had been responsible for biting them. Half of the patients had been bitten while they were asleep. Fang marks and numbness were the only local features of the bites. Common signs of neurotoxic envenoming included bilateral ptosis, persistently dilated pupils, limb weakness, breathlessness, hypersalivation, dysphonia and dysphagia. Thirty patients (71.4%) required endotracheal intubation of whom all but one were mechanically ventilated. Fourteen patients (33.3%) developed hypertension, 13 (31.0%) shock, 31 (73.8%) hyponatraemia (plasma sodium concentration < 130 mEq/l) and 30 (71.4%) showed evidence of mild rhabdomyolysis (peak plasma creatine kinase concentration 1375 +/- 140 micro/l). None developed acute kidney injury. All the patients were treated with a new monospecific B. candidus antivenom. There were no fatalities. Hyponatraemia has been reported previously in victims of Chinese kraits (Bungarus multicinctus) in northern Viet Nam and rhabdomyolysis in patients envenomed by B. niger in Bangladesh. These features of envenoming pose new problems for the management of krait bite cases in South east Asia and should stimulate a search for the causative venom toxins.

Krudsood S, Tangpukdee N, Wilairatana P, Pothipak N, Duangdee C, Warrell DA, Looareesuwan S. 2010. Intravenous ibuprofen (IV-ibuprofen) controls fever effectively in adults with acute uncomplicated Plasmodium falciparum malaria but prolongs parasitemia. Am J Trop Med Hyg, 83 (1), pp. 51-55. | Show Abstract | Read more

Because some febrile patients are unable to swallow or retain oral antipyretic drugs, we carried out a double-blind, placebo-controlled trial in which intravenous ibuprofen (IV-ibuprofen) was given to adults hospitalized with fever associated with acute uncomplicated falciparum malaria treated with oral artesunate plus mefloquine. Thirty patients received IV-ibuprofen 400 mg and 30 received placebo every 6 hours for 72 hours. Reduction in the area above 37.0 degrees C versus time curve was significantly greater for IV-ibuprofen than for placebo during the first 72 hours after first administration. No patients developed severe malaria; parasite clearance was delayed in the patients whose fevers were controlled by IV-ibuprofen (median 37.3 hours versus 23.7 hours in the placebo group [P = 0.0024]). This difference did not appear to be clinically important Adverse events, none considered severe, occurred equally in both groups. IV-ibuprofen was effective and well tolerated in reducing fever in febrile inpatients with malaria.

Habib AG, Nasidi A, Alder N, Juszczak E, David R, Theakston G, Warrell DA, UK ESGN. 2010. Response to a letter from J-P Chippaux and L Boyer entitled: "The 3+3 dose escalation design is not appropriate for antivenom dose finding." TOXICON, 55 (7), pp. 1410-1411. | Read more

Calvete JJ, Cid P, Sanz L, Segura A, Villalta M, Herrera M, León G, Harrison R et al. 2010. Antivenomic assessment of the immunological reactivity of EchiTAb-Plus-ICP, an antivenom for the treatment of snakebite envenoming in sub-Saharan Africa. Am J Trop Med Hyg, 82 (6), pp. 1194-1201. | Show Abstract | Read more

The immunoreactivity of EchiTAb-Plus-ICP, an antivenom developed for the treatment of snakebite envenoming in sub-Saharan Africa, to venoms of seven Echis and Bitis species, was assessed by "antivenomics." This proteomic approach is based on the ability of an antivenom to immunodeplete homologous or heterologous venom proteins. Our results show an extensive cross-reactivity of this antivenom against all Echis and Bitis venoms studied, as revealed by the complete immunodepletion of the majority of venom components, including metalloproteinases, serine proteinases, C-type lectin-like proteins, some phospholipases A(2) and L-amino acid oxidase. However, some phospholipases A(2), disintegrins and proteinase inhibitors were immunodepleted to only a partial extent. These results support the hypothesis that immunizing horses with a mixture of the venoms of Echis ocellatus, Bitis arietans, and Naja nigricollis generates antibodies capable of recognizing the majority of components of medically-relevant homologous and heterologous viperid venoms of the genera Bitis and Echis from sub-Saharan Africa.

Karlson-Stiber CB, Persson HE, Warrell DA. 2010. Use of antivenom in Vipera berus Bites--a comment. Wilderness Environ Med, 21 (2), pp. 180. | Read more

Harris JB, Faiz MA, Rahman MR, Jalil MM, Ahsan MF, Theakston RD, Warrell DA, Kuch U. 2010. Snake bite in Chittagong Division, Bangladesh: a study of bitten patients who developed no signs of systemic envenoming. Trans R Soc Trop Med Hyg, 104 (5), pp. 320-327. | Show Abstract | Read more

The demographics, epidemiology, first aid, clinical management, treatment and outcome of snake bites causing no significant signs of systemic envenoming were documented in Chittagong Medical College Hospital, Bangladesh, between May 1999 and October 2002. Among 884 patients admitted, 350 were systemically envenomed and 534 were without signs of either systemic or significant local envenoming. The average age of patients with physical evidence of snake bite but no systemic envenoming was 26.4 years. Most had been bitten on their feet or hands. Ligatures had been applied proximal to the bite site in >95% of cases and the bite site had been incised in 13%. Patients were typically discharged at 24h. Those with clinical signs of systemic envenoming resembled the non-envenomed cases demographically and epidemiologically except that they arrived at hospital significantly later than non-envenomed patients, having spent longer with traditional healers. No non-envenomed patient was treated with antivenom and none went on to develop symptoms of systemic envenoming after discharge. The potential complications and confusing signs caused by ligatures and incision demand that all patients admitted with a history of snake bite be kept under observation for 24h after admission even if they have no signs of systemic envenoming.

Abubakar SB, Abubakar IS, Habib AG, Nasidi A, Durfa N, Yusuf PO, Larnyang S, Garnvwa J et al. 2010. Pre-clinical and preliminary dose-finding and safety studies to identify candidate antivenoms for treatment of envenoming by saw-scaled or carpet vipers (Echis ocellatus) in northern Nigeria. Toxicon, 55 (4), pp. 719-723. | Show Abstract | Read more

The aim of this study was to identify candidate antivenoms with specific activity against the venom of the saw-scaled or carpet viper (Echis ocellatus) in northern Nigeria, where bites by this species cause great morbidity and mortality but where effective antivenoms have become scarce and unaffordable. Selected antivenoms were destined to be compared by randomised controlled clinical trials (RCTs). Standard pre-clinical neutralisation assays were carried out in rodents. We included two licensed antivenoms of established clinical efficacy and 6 candidate antivenoms. Although 6 of the tested antivenoms showed promising efficacy, all but 3 were excluded from further study because of inadequate pre-clinical efficacy or because they were unavailable or unaffordable for the anticipated RCTs. Median effective doses (ED(50)) of the remaining three candidate antivenoms suggested that the following doses might neutralise the maximum observed venom yield of 24.8 mg (dry weight) of venom milked from captive E. ocellatus: 10 ml of MicroPharm "EchiTAb G" (ET-G) antivenom; 30 ml of Instituto Clodomiro Picado "EchiTAb-Plus-ICP" (ET-Plus) antivenom; 50 ml of VacSera, Cairo "EgyVac" antivenom. A preliminary clinical dose-finding and safety study of these three antivenoms was carried out in 24 patients with incoagulable blood after E. ocellatus bites who were not severely envenomed. A 3+3 dose escalation design was employed. Initial doses of 10 ml ET-G and 30 ml ET-Plus restored blood coagulability in groups of 6 patients with early mild reactions (pruritus only) in not more than one third of them. EgyVac antivenom did not fulfil efficacy or safety criteria in 12 patients. On the basis of these results, ET-G and ET-Plus were selected for comparison in a RCT.

Ahmed N, Pinkham M, Warrell DA, Verdez J-M. 2010. Symptom in search of a toxin: muscle spasms following bites by Old World tarantula spiders (Lampropelma nigerrimum, Pterinochilus murinus, Poecilotheria regalis) with review (vol 102, pg 851, 2009) QJM-AN INTERNATIONAL JOURNAL OF MEDICINE, 103 (3), pp. 203-204. | Read more

Warrell DA. 2010. Snake bite (vol 375, pg 77, 2010) LANCET, 375 (9715), pp. 640-640.

Segura A, Villalta M, Herrera M, León G, Harrison R, Durfa N, Nasidi A, Calvete JJ, Theakston RD, Warrell DA, Gutiérrez JM. 2010. Preclinical assessment of the efficacy of a new antivenom (EchiTAb-Plus-ICP) for the treatment of viper envenoming in sub-Saharan Africa. Toxicon, 55 (2-3), pp. 369-374. | Show Abstract | Read more

A preclinical assessment was performed on the neutralizing efficacy of a whole IgG polyspecific antivenom (EchiTAb-Plus-ICP), designed for the treatment of snakebite envenomings in Nigeria. It was generated by immunizing horses with the venoms of Echis ocellatus, Bitis arietans and Naja nigricollis, the most medically important species in Nigeria. Antivenom was tested against the venoms of E. ocellatus, Echis leucogaster, Echis pyramidum leakeyi, B. arietans, Bitis gabonica, Bitis rhinoceros and Bitis nasicornis. The neutralization of the venom toxins responsible for the lethal, hemorrhagic, coagulant and local necrotizing activities was assessed, since these are the most significant effects that characterize envenoming by these species. Echis sp venoms exerted lethal, hemorrhagic, coagulant and necrotizing effects, whereas the Bitis sp venoms tested induced lethality, hemorrhage and necrosis, but were devoid of coagulant activity. The antivenom was effective in the neutralization of all effects tested in all venoms. Highest neutralization was achieved against the venoms of E. ocellatus and B. arietans, and the lowest neutralizing potency was against the venom of B. nasicornis, a species that has a low clinical relevance. It is concluded that EchiTAb-Plus-ICP, whilst specifically designed for Nigeria, has a good preclinical neutralizing profile against homologous and heterologous viperid venoms from other sub-Saharan African locations. It therefore constitutes a promising therapeutic option for the treatment of snakebite envenoming in this region.

Williams D, Gutiérrez JM, Harrison R, Warrell DA, White J, Winkel KD, Gopalakrishnakone P, Global Snake Bite Initiative Working Group, International Society on Toxinology. 2010. The Global Snake Bite Initiative: an antidote for snake bite. Lancet, 375 (9708), pp. 89-91. | Read more

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Scopus

Abubakar SB, Abubakar IS, Habib AG, Nasidi A, Durfa N, Yusuf PO, Larnyang S, Garnvwa J et al. 2010. Pre-clinical and preliminary dose-finding and safety studies to identify candidate antivenoms for treatment of envenoming by saw-scaled or carpet vipers (Echis ocellatus) in northern Nigeria Toxicon, 55 (4), pp. 719-723. | Show Abstract | Read more

The aim of this study was to identify candidate antivenoms with specific activity against the venom of the saw-scaled or carpet viper (Echis ocellatus) in northern Nigeria, where bites by this species cause great morbidity and mortality but where effective antivenoms have become scarce and unaffordable. Selected antivenoms were destined to be compared by randomised controlled clinical trials (RCTs). Standard pre-clinical neutralisation assays were carried out in rodents. We included two licensed antivenoms of established clinical efficacy and 6 candidate antivenoms. Although 6 of the tested antivenoms showed promising efficacy, all but 3 were excluded from further study because of inadequate pre-clinical efficacy or because they were unavailable or unaffordable for the anticipated RCTs. Median effective doses (ED 50) of the remaining three candidate antivenoms suggested that the following doses might neutralise the maximum observed venom yield of 24.8mg (dry weight) of venom milked from captive E. ocellatus: 10ml of MicroPharm " EchiTAb G" (ET-G) antivenom; 30ml of Instituto Clodomiro Picado " EchiTAb-Plus-ICP" (ET-Plus) antivenom; 50ml of VacSera, Cairo " EgyVac" antivenom. A preliminary clinical dose-finding and safety study of these three antivenoms was carried out in 24 patients with incoagulable blood after E. ocellatus bites who were not severely envenomed. A 3+3 dose escalation design was employed. Initial doses of 10ml ET-G and 30ml ET-Plus restored blood coagulability in groups of 6 patients with early mild reactions (pruritus only) in not more than one third of them. EgyVac antivenom did not fulfil efficacy or safety criteria in 12 patients. On the basis of these results, ET-G and ET-Plus were selected for comparison in a RCT. © 2009 Elsevier Ltd.

Warrell DA, Theakston RDG, Wuester W. 2010. Destruction of the collection of reptiles and arthropods at Butantan Institute: a view from the United Kingdom JOURNAL OF VENOMOUS ANIMALS AND TOXINS INCLUDING TROPICAL DISEASES, 16 (4), pp. 534-536.

Aslam A, Chan H, Ogg GS, Warrell DA, Misbah S. 2010. Tracking Antigen-Specific T-Cells during Clinical Tolerance Induction in Humans PLoS ONE, 5 (6), | Show Abstract | Read more

Allergen immunotherapy presents an opportunity to define mechanisms of induction of clinical tolerance in humans. Significant progress has been made in our understanding of changes in T cell responses during immunotherapy, but existing work has largely been based on functional T cell assays. HLA-peptide-tetrameric complexes allow the tracking of antigen-specific T-cell populations based on the presence of specific T-cell receptors and when combined with functional assays allow a closer assessment of the potential roles of T-cell anergy and clonotype evolution. We sought to develop tools to facilitate tracking of antigen-specific T-cell populations during wasp-venom immunotherapy in people with wasp-venom allergy. We first defined dominant immunogenic regions within Ves v 5, a constituent of wasp venom that is known to represent a target antigen for T-cells. We next identified HLA-DRB1*1501 restricted epitopes and used HLA class II tetrameric complexes alongside cytokine responses to Ves v 5 to track T-cell responses during immunotherapy. In contrast to previous reports, we show that there was a significant initial induction of IL-4 producing antigen-specific T-cells within the first 3-5 weeks of immunotherapy which was followed by reduction of circulating effector antigen-specific T-cells despite escalation of wasp-venom dosage. However, there was sustained induction of IL-10-producing and FOXP3 positive antigen-specific T cells. We observed that these IL-10 producing cells could share a common precursor with IL-4-producing T cells specific for the same epitope. Clinical tolerance induction in humans is associated with dynamic changes in frequencies of antigenspecific T-cells, with a marked loss of IL-4-producing T-cells and the acquisition of IL-10-producing and FOXP3-positive antigen-specific CD4+ T-cells that can derive from a common shared precursor to pre-treatment effector T-cells. The development of new approaches to track antigen specific T-cell responses during immunotherapy can provide novel insights into mechanisms of tolerance induction in humans and identify new potential treatment targets. © 2010 Aslam et al.

Aslam A, Chan H, Warrell DA, Misbah S, Ogg GS. 2010. Tracking antigen-specific T-cells during clinical tolerance induction in humans. PLoS One, 5 (6), pp. e11028. | Show Abstract | Read more

Allergen immunotherapy presents an opportunity to define mechanisms of induction of clinical tolerance in humans. Significant progress has been made in our understanding of changes in T cell responses during immunotherapy, but existing work has largely been based on functional T cell assays. HLA-peptide-tetrameric complexes allow the tracking of antigen-specific T-cell populations based on the presence of specific T-cell receptors and when combined with functional assays allow a closer assessment of the potential roles of T-cell anergy and clonotype evolution. We sought to develop tools to facilitate tracking of antigen-specific T-cell populations during wasp-venom immunotherapy in people with wasp-venom allergy. We first defined dominant immunogenic regions within Ves v 5, a constituent of wasp venom that is known to represent a target antigen for T-cells. We next identified HLA-DRB1*1501 restricted epitopes and used HLA class II tetrameric complexes alongside cytokine responses to Ves v 5 to track T-cell responses during immunotherapy. In contrast to previous reports, we show that there was a significant initial induction of IL-4 producing antigen-specific T-cells within the first 3-5 weeks of immunotherapy which was followed by reduction of circulating effector antigen-specific T-cells despite escalation of wasp-venom dosage. However, there was sustained induction of IL-10-producing and FOXP3 positive antigen-specific T cells. We observed that these IL-10 producing cells could share a common precursor with IL-4-producing T cells specific for the same epitope. Clinical tolerance induction in humans is associated with dynamic changes in frequencies of antigen-specific T-cells, with a marked loss of IL-4-producing T-cells and the acquisition of IL-10-producing and FOXP3-positive antigen-specific CD4+ T-cells that can derive from a common shared precursor to pre-treatment effector T-cells. The development of new approaches to track antigen specific T-cell responses during immunotherapy can provide novel insights into mechanisms of tolerance induction in humans and identify new potential treatment targets.

Abubakar IS, Abubakar SB, Habib AG, Nasidi A, Durfa N, Yusuf PO, Larnyang S, Garnvwa J et al. 2010. Randomised controlled double-blind non-inferiority trial of two antivenoms for saw-scaled or carpet viper (Echis ocellatus) envenoming in Nigeria. PLoS Negl Trop Dis, 4 (7), pp. e767. | Show Abstract | Read more

BACKGROUND: In West Africa, envenoming by saw-scaled or carpet vipers (Echis ocellatus) causes great morbidity and mortality, but there is a crisis in supply of effective and affordable antivenom (ISRCTN01257358). METHODS: In a randomised, double-blind, controlled, non-inferiority trial, "EchiTAb Plus-ICP" (ET-Plus) equine antivenom made by Instituto Clodomiro Picado was compared to "EchiTAb G" (ET-G) ovine antivenom made by MicroPharm, which is the standard of care in Nigeria and was developed from the original EchiTAb-Fab introduced in 1998. Both are caprylic acid purified whole IgG antivenoms. ET-G is monospecific for Echis ocellatus antivenom (initial dose 1 vial) and ET-Plus is polyspecific for E. ocellatus, Naja nigricollis and Bitis arietans (initial dose 3 vials). Both had been screened by pre-clinical and preliminary clinical dose-finding and safety studies. Patients who presented with incoagulable blood, indicative of systemic envenoming by E. ocellatus, were recruited in Kaltungo, north-eastern Nigeria. Those eligible and consenting were randomly allocated with equal probability to receive ET-Plus or ET-G. The primary outcome was permanent restoration of blood coagulability 6 hours after the start of treatment, assessed by a simple whole blood clotting test repeated 6, 12, 18, 24 and 48 hr after treatment. Secondary (safety) outcomes were the incidences of anaphylactic, pyrogenic and late serum sickness-type antivenom reactions. FINDINGS: Initial doses permanently restored blood coagulability at 6 hours in 161/194 (83.0%) of ET-Plus and 156/206 (75.7%) of ET-G treated patients (Relative Risk [RR] 1.10 one-sided 95% CI lower limit 1.01; P = 0.05). ET-Plus caused early reactions on more occasions than did ET-G [50/194 (25.8%) and 39/206 (18.9%) respectively RR (1.36 one-sided 95% CI 1.86 upper limit; P = 0.06). These reactions were classified as severe in 21 (10.8%) and 11 (5.3%) of patients, respectively. CONCLUSION: At these doses, ET-Plus was slightly more effective but ET-G was slightly safer. Both are recommended for treating E. ocellatus envenoming in Nigeria. TRIAL REGISTRATION: Current Controlled Trials ISRCTN01257358.

Ahmed N, Pinkham M, Warrell DA. 2009. Symptom in search of a toxin: muscle spasms following bites by Old World tarantula spiders (Lampropelma nigerrimum, Pterinochilus murinus, Poecilotheria regalis) with review. QJM, 102 (12), pp. 851-857. | Show Abstract | Read more

BACKGROUND: Tarantula spiders are widely kept and bred in captivity by both adults and children. Their bites are generally considered harmless. AIM: To explore the effects of envenoming by Old World tarantulas. DESIGN AND METHODS: Clinical studies and review of conventional literature and hobbyist web sites. RESULTS: Two men bitten on their index fingers by pet Old World tarantula spiders, Lampropelma nigerrimum (Ornithoctoninae) and Pterinochilus murinus (Harpactirinae) in England, developed intense local pain, swelling and episodic, agonising, generalised muscle cramps. In one of them, cramps persisted for 7 days and serum creatine kinase concentration was mildly elevated. A third man bitten on a finger by Poecilotheria regalis (Poecilotheriinae), suffered persistent local cramps in the affected hand. Reports since 1803, including recent ones on hobbyist web-sites, have been largely overlooked. They mentioned muscle spasms after bites by these and other genera of Old World tarantulas, including Eumenophorus, Selenocosmia and Stromatopelma. The severe muscle spasms seen in two of our patients were a challenge to medical treatment and might, under some circumstances, have been life threatening. They demand a toxinological explanation. CONCLUSION: Bites by several genera of African, Asian and Australasian tarantulas can cause systemic neurotoxic envenoming. In the absence of available antivenom, severe persistent muscle spasms, reminiscent of latrodectism, pose a serious therapeutic challenge. Discovery of the toxin responsible would be of scientific and potential clinical benefit. Tarantula keepers should be warned of the danger of handling these animals incautiously.

Gutiérrez JM, Williams D, Fan HW, Warrell DA. 2010. Snakebite envenoming from a global perspective: Towards an integrated approach. Toxicon, 56 (7), pp. 1223-1235. | Show Abstract | Read more

Snakebite envenoming is a neglected public health challenge of compelling importance in many regions of the world, particularly sub-Saharan Africa, Asia, Latin America and Papua-New Guinea. Addressing the problem of snakebite effectively demands an integrated multifocal approach, targeting complex problems and involving many participants. It must comprise: (a) Acquisition of reliable information on the incidence and mortality attributable to snakebite envenoming, and the number of people left with permanent sequelae. (b) Improvements in production of effective and safe antivenoms, through strategies aimed at strengthening the technological capacity of antivenom manufacturing laboratories. (c) Increasing the capacity of low-income countries to produce specific immunogens(snake venoms) locally, and to perform their own quality control of antivenoms. (d) Commitments from regional producers to manufacture antivenoms for countries where antivenom production is not currently feasible. (e) Implementation of financial initiatives guaranteeing the acquisition of adequate volumes of antivenom at affordable prices in low-income countries. (f) Performance of collaborative studies on the safety and effectiveness of antivenoms assessed preclinically and by properly designed clinical trials. (g) Development of antivenom distribution programmes tailored to the real needs and epidemiological situations of rural areas in each country. (h) Permanent training programmes for health staff, particularly in rural areas where snakebites are frequent.(i) Implementation of programmes to support those people whose snakebites resulted in chronic disabilities. (j) Preventive and educational programmes at the community level, with the active involvement of local organizations and employing modern methods of health promotion. Such an integrated approach, currently being fostered by the Global Snake Bite Initiative of the International Society on Toxinology and by the World Health Organization, will help to alleviate the enormous burden of human suffering inflicted by snakebite envenoming.

Caron EJ, Manock SR, Maudlin J, Koleski J, Theakston RD, Warrell DA, Smalligan RD. 2009. Apparent marked reduction in early antivenom reactions compared to historical controls: was it prophylaxis or method of administration? Toxicon, 54 (6), pp. 779-783. | Show Abstract | Read more

OBJECTIVE: Serious morbidity and mortality following snakebite injuries are common in tropical regions of the world. Although antivenom administration is clinically effective, it carries an important risk of early anaphylactic reactions, ranging from relatively benign nausea, vomiting, and urticaria to life-threatening angioedema, bronchospasm and hypotension. Currently, no adequately powered study has demonstrated significant benefit from the use of any prophylactic drug. A high rate of anaphylactic reactions observed during a trial of three different antivenoms in Ecuador prompted adoption of premedication with intravenous (i.v.) hydrocortisone and diphenhydramine together with dilution and slower administration of antivenom. DESIGN: In a rural mission hospital in Eastern Ecuador, 53 consecutive snakebite victims received a new antivenom regimen in 2004-2006, comprising prophylactic drugs and i.v. infusion of diluted antivenom over 60 min. They were compared to an historical control cohort of 76 patients treated in 1997-2002 without prophylactic drugs and with i.v. "push" injection of undiluted antivenom over 10 min. All these patients had incoagulable blood on admission and all were treated with Brazilian Instituto Butantan polyspecific antivenom. RESULTS: Baseline characteristics of the historical control and premedicated groups were broadly similar. In the historical group, early reaction rates were as follows: 51% of patients had no reaction; 35% had mild reactions; 6% moderate; and 6% severe. In the premedicated/slow i.v. group, 98% of patients had no reaction; 0 mild; 0 moderate; and 2% severe. The difference in reaction rates was statistically significant (p<0.001). CONCLUSIONS: Premedication with intravenous hydrocortisone and diphenhydramine together with dilution of antivenom and its administration by i.v. infusion over 60 min appeared to reduce both the frequency and severity of anaphylactic reactions. A randomized blinded controlled trial is needed to confirm these encouraging preliminary findings.

Ariaratnam CA, Sheriff MH, Arambepola C, Theakston RD, Warrell DA. 2009. Syndromic approach to treatment of snake bite in Sri Lanka based on results of a prospective national hospital-based survey of patients envenomed by identified snakes. Am J Trop Med Hyg, 81 (4), pp. 725-731. | Show Abstract | Read more

Of 860 snakes brought to 10 hospitals in Sri Lanka with the patients they had bitten, 762 (89%) were venomous. Russell's vipers (Daboia russelii) and hump-nosed pit vipers (Hypnale hypnale) were the most numerous and H. hypnale was the most widely distributed. Fifty-one (6%) were misidentified by hospital staff, causing inappropriate antivenom treatment of 13 patients. Distinctive clinical syndromes were identified to aid species diagnosis in most cases of snake bite in Sri Lanka where the biting species is unknown. Diagnostic sensitivities and specificities of these syndromes for envenoming were 78% and 96% by Naja naja, 66% and 100% by Bungarus caeruleus, 14% and 100% by Daboia russelii, and 10% and 97% by Hypnale hypnale, respectively. Although only polyspecific antivenoms are used in Sri Lanka, species diagnosis remains important to anticipate life-threatening complications such as local necrosis, hemorrhage and renal and respiratory failure and to identify likely victims of envenoming by H. hypnale who will not benefit from existing antivenoms. The technique of hospital-based collection, labeling and preservation of dead snakes brought by bitten patients is recommended for rapid assessment of a country's medically-important herpetofauna.

Warrell DA. 2009. Researching nature's venoms and poisons. Trans R Soc Trop Med Hyg, 103 (9), pp. 860-866. | Show Abstract | Read more

Our environment hosts a vast diversity of venomous and poisonous animals and plants. Clinical toxinology is devoted to understanding, preventing and treating their effects in humans and domestic animals. In Sri Lanka, yellow oleander (Thevetia peruviana, Sinhala 'kaneru'), a widespread and accessible ornamental shrub, is a popular means of self-harm. Its toxic glycosides resemble those of foxglove, against which therapeutic antibodies have been raised. A randomised placebo-controlled trial proved that this treatment effectively reversed kaneru cardiotoxicity. There are strong scientific grounds for the use of activated charcoal, but encouraging results with multiple-dose activated charcoal were not confirmed by a recent more powerful study. Venom of Russell's viper (Daboia siamensis) in Burma (Myanmar) produces lethal effects in human victims. The case of a 17-year-old rice farmer is described with pathophysiological interpretations. During the first 9 days of hospital admission he suffered episodes of shock, coagulopathy, bleeding, acute renal failure, local tissue necrosis, generally increased capillary permeability and acute symptomatic hypoglycaemia with evidence of acute pituitary/adrenal insufficiency. Antivenom rapidly restored haemostatic function but failed to correct other effects of venom toxins incurred during the 3h before he could be treated.

Warrell DA. 2009. Commissioned article: management of exotic snakebites. QJM, 102 (9), pp. 593-601. | Show Abstract | Read more

Exotic (foreign or non-native) snakes, including venomous species, are becoming increasingly popular pets in Western countries. Some of them are kept illegally (as defined by the UK Dangerous Wild Animals Act of 1976). There is a large international market for such animals, with contraventions of the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES). In the UK, several other European countries and the USA the reported numbers of bites by venomous exotic snakes, although small, are increasing but still underestimate the occurrence of these occasionally fatal events because of the victims' reluctance to seek medical care. Victims are predominantly young men who have been drinking alcohol. Bites may be intentionally provoked. In Europe, the species most often involved are cobras, green mambas, American pit vipers particularly rattlesnakes, African adders, vipers and Asian green pit vipers. To illustrate the special problems involved, case histories are presented of bites by exotic species in the UK and of bites abroad, where patients were repatriated for treatment. In view of the relative rarity and diversity of these cases, expert advice must usually be sought. These requests should include information about the species thought to have been responsible and the history and timing of the evolution of envenoming. Sources of advice and antivenom are discussed together with recommendations for appropriate first aid and emergency treatment while this is being awaited. Respiratory and cardiovascular resuscitation may be required and when systemic or severe local envenoming develops, specific (equine or ovine) antivenom is indicated.

Warrell DA, Williams D. 2009. Response to comment on: Failure of a new antivenom to treat Echis ocellatus snake bite in rural Ghana: the importance of quality surveillance TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE, 103 (9), pp. 965-966. | Read more

Lalloo DG, Shingadia D, Pasvol G, Chiodini PL, Whitty CJ, Beeching NJ, Hill DR, Warrell DA, Bannister BA, Preventi HPAACM. 2009. UK malaria treatment guidelines (vol 54, pg 111, 2007) JOURNAL OF INFECTION, 59 (1), pp. 73-73. | Read more

Warrell DA. 2009. Venomous Exotic Snakes: Global Overview Warrell DA CLINICAL TOXICOLOGY, 47 (5), pp. 461-461.

Lalloo DG, Shingadia D, Pasvol G, Chiodini PL, Whitty CJ, Beeching NJ, Hill DR, Warrell DA, Bannister BA. 2009. Corrigendum to “UK malaria treatment guidelines” [Journal of Infection 54 (2007) 111–121] Journal of Infection, 59 (1), pp. 73-73. | Read more

Warrell DA. 2008. Proatheris superciliaris: the deadly venom of a rare and elusive snake revealed. Toxicon, 52 (8), pp. 833-835. | Read more

Lamb L, Ross DA, Lalloo DG, Green A, Morgan ER, Warrell DA. 2008. Management of venomous bites and stings in British Military Personnel deployed in Iraq, Afghanistan and Cyprus. J R Army Med Corps, 154 (4 Suppl), pp. 2-40.

Ariaratnam CA, Thuraisingam V, Kularatne SA, Sheriff MH, Theakston RD, de Silva A, Warrell DA. 2008. Frequent and potentially fatal envenoming by hump-nosed pit vipers (Hypnale hypnale and H. nepa) in Sri Lanka: lack of effective antivenom. Trans R Soc Trop Med Hyg, 102 (11), pp. 1120-1126. | Show Abstract | Read more

In a prospective study of snake bites involving 10 hospitals in Sri Lanka, 302 (35%) of 860 patients with bites by identified snakes proved to have been bitten by hump-nosed pit vipers (301 by Hypnale hypnale and 1 by H. nepa). Most victims were males aged between 11 years and 50 years who had been bitten on their feet or ankles while walking at night close to their homes. There was local swelling in 276 (91%) and local necrosis in 48 (16%). Eleven (4%) required amputation of fingers or toes and 12 (4%) received skin grafts. In 117 patients (39%) blood incoagulability was first detected between 15 min and 48 h after the bite, and in 116 of them this was present on admission to hospital. Spontaneous systemic bleeding was observed in 55 patients (18%). Acute renal failure developed in 10%, five of whom died to give an overall case fatality rate of 1.7%. Thus, bites by hump-nosed pit vipers can cause debilitating local and fatal systemic envenoming. In Sri Lanka and southwestern India where bites by these snakes are common, the only available antivenoms (raised against cobra, krait, Russell's viper and saw-scaled viper venoms) are ineffective and carry a high risk of reactions.

Manock SR, Suarez G, Graham D, Avila-Aguero ML, Warrell DA. 2008. Neurotoxic envenoming by South American coral snake (Micrurus lemniscatus helleri): case report from eastern Ecuador and review. Trans R Soc Trop Med Hyg, 102 (11), pp. 1127-1132. | Show Abstract | Read more

A man bitten by a large coral snake (Micrurus lemniscatus helleri) in the Amazon basin of Ecuador developed persistent excruciating pain in the bitten arm. On admission to hospital less than 30 min later, he had a polymorphonuclear leucocytosis, thrombocytopenia and mildly prolonged prothrombin time/partial thromboplastin time. Not until 14 h after the bite did he develop the first signs of neurotoxicity. Despite treatment with specific antivenom 50 h after the bite, he required oxygen for respiratory failure 60 h, and 6 h of mechanical ventilation 72 h, after the bite. Over the next 38 h, he required two further intubations and periods of assisted ventilation before being airlifted to a tertiary referral hospital. Complications included bacterial pneumonia, pneumothorax, bronchial obstruction by mucus plugs and mild rhabdomyolysis. He was discharged from hospital 15 days after the bite with persistent limb weakness and urinary incontinence but eventually recovered. The interesting and unusual features of this case (severe local pain, very slow evolution of neurotoxic envenoming, persistent thrombocytopenia and mild coagulopathy) are discussed in the context of what is known of the composition of Micrurus venoms and the small clinical literature on envenoming from their bites.

Malina T, Krecsak L, Warrell DA. 2008. Neurotoxicity and hypertension following European adder (Vipera berus berus) bites in Hungary: case report and review. QJM, 101 (10), pp. 801-806. | Read more

Gutiérrez JM, Sanz L, Escolano J, Fernández J, Lomonte B, Angulo Y, Rucavado A, Warrell DA, Calvete JJ. 2008. Snake venomics of the Lesser Antillean pit vipers Bothrops caribbaeus and Bothrops lanceolatus: correlation with toxicological activities and immunoreactivity of a heterologous antivenom. J Proteome Res, 7 (10), pp. 4396-4408. | Show Abstract | Read more

The venom proteomes of the snakes Bothrops caribbaeus and Bothrops lanceolatus, endemic to the Lesser Antillean islands of Saint Lucia and Martinique, respectively, were characterized by reverse-phase HPLC fractionation, followed by analysis of each chromatographic fraction by SDS-PAGE, N-terminal sequencing, MALDI-TOF mass fingerprinting, and collision-induced dissociation tandem mass spectrometry of tryptic peptides. The venoms contain proteins belonging to seven ( B. caribbaeus) and five ( B. lanceolatus) types of toxins. B. caribbaeus and B. lanceolatus venoms contain phospholipases A 2, serine proteinases, l-amino acid oxidases and zinc-dependent metalloproteinases, whereas a long disintegrin, DC-fragments and a CRISP molecule were present only in the venom of B. caribbaeus, and a C-type lectin-like molecule was characterized in the venom of B. lanceolatus. Compositional differences between venoms among closely related species from different geographic regions may be due to evolutionary environmental pressure acting on isolated populations. The venoms of these two species differed in the composition and the relative abundance of their component toxins, but they exhibited similar toxicological and enzymatic profiles in mice, characterized by lethal, hemorrhagic, edema-forming, phospholipase A 2 and proteolytic activities. The venoms of B. caribbaeus and B. lanceolatus are devoid of coagulant and defibrinogenating effects and induce only mild local myotoxicity in mice. The characteristic thrombotic effect described in human envenomings by these species was not reproduced in the mouse model. The toxicological profile observed is consistent with the abundance of metalloproteinases, PLA 2s and serine proteinases in the venoms. A polyvalent (Crotalinae) antivenom produced in Costa Rica was able to immunodeplete approximately 80% of the proteins from both B. caribbaeus and B. lanceolatus venoms, and was effective in neutralizing the lethal, hemorrhagic, phospholipase A 2 and proteolytic activities of these venoms.

Habib AG, Abubakar SB, Abubakar IS, Larnyang S, Durfa N, Nasidi A, Yusuf PO, Garnvwa J et al. 2008. Envenoming after carpet viper (Echis ocellatus) bite during pregnancy: timely use of effective antivenom improves maternal and foetal outcomes. Trop Med Int Health, 13 (9), pp. 1172-1175. | Show Abstract | Read more

The report describes successful management of 10 women in 2nd and 3rd pregnancy trimesters with EchiTab IgG antivenom after carpet viper (Echis ocellatus) envenoming. All women survived but foetal loss in a victim with delayed presentation and a case of mild hypersensitivity reaction were recorded. Excellent outcomes can be achieved in rural and semi-nomadic populations without specialized care and immediate access and provision of effective antivenoms is paramount in curtailing snakebite maternal morbidity, mortality and foetal loss.

Ariaratnam CA, Sheriff MH, Theakston RD, Warrell DA. 2008. Distinctive epidemiologic and clinical features of common krait (Bungarus caeruleus) bites in Sri Lanka. Am J Trop Med Hyg, 79 (3), pp. 458-462. | Show Abstract

A prospective study was designed to define epidemiologic and clinical features of krait bites to improve diagnosis, management, and prevention. Among 762 cases of venomous snake bites admitted to 10 Sri Lankan hospitals in which the snake responsible was brought and identified, 88 (11.5%) were caused by common kraits (Bungarus caeruleus). Bites were: most frequent in September through November. Distinctive features of B. caeruleus bites (compared with bites by other species in parentheses) were bitten while sleeping on the ground, 100% (1%); indoors, 100% (49%); between 2300 and 0500 hours, 100% (3%). Only 13% of krait victims were bitten on their lower limbs (82%), only 9% had local swelling (in all cases mild) at the site of the bite (93%), 64% developed respiratory paralysis (2%), and 91% experienced (often severe) abdominal pain (10%). Case fatality was 6% (3%). This distinctive pattern of epidemiology and symptoms will aid clinical recognition (syndromic diagnosis) and prevention of krait bite envenoming.

Santoro ML, Sano-Martins IS, Fan HW, Cardoso JL, Theakston RD, Warrell DA, Butantan Institute Antivenom Study Group. 2008. Haematological evaluation of patients bitten by the jararaca, Bothrops jararaca, in Brazil. Toxicon, 51 (8), pp. 1440-1448. | Show Abstract | Read more

Complete blood counts are used frequently by physicians to assess and manage the development of complications of diseases. We studied 100 patients bitten by Bothrops jararaca snakes, and correlated their haematological values with the severity of envenoming and the development of complications. Patients who developed both local and systemic bleeding showed a greater drop in packed cell volume, red blood cell (RBC) count and haemoglobin concentration than those with who did not bleed. No morphological changes in RBCs were seen in blood films. Total white blood cell (WBC) counts were significantly higher in the clinically "more severe" group than in the "less severe" group on admission. Neutrophilic leucocytosis with left shift was present on admission, concurrently with a decrease in eosinophil and lymphocyte counts. These changes tend to become more marked 6h after antivenom therapy, and are greatest in "more severe" envenoming. Thrombocytopenia on admission is positively associated with the development of systemic bleeding and the severity of envenoming. Thrombocytopenia may also be a useful prognostic indicator for the development of local complications, such as necrosis. The intensity of neutrophilia and eosinopenia might be used to follow the progression of necrosis in victims of snake bite.

Malbranque S, Piercecchi-Marti MD, Thomas L, Barbey C, Courcier D, Bucher B, Ridarch A, Smadja D, Warrell DA. 2008. Fatal diffuse thrombotic microangiopathy after a bite by the "Fer-de-Lance" pit viper (Bothrops lanceolatus) of Martinique. Am J Trop Med Hyg, 78 (6), pp. 856-861. | Show Abstract

In Martinique, a man bitten two days earlier by a pit viper (Bothrops lanceolatus) was hospitalized with impaired consciousness and tetraplegia. Investigations confirmed cerebral and myocardial infarctions. Resolving thrombocytopenia was associated with virtually normal blood prothrombin time/activated partial thromboplastin time but increasing hyperfibrinogenemia. Despite specific antivenom treatment, he developed fatal left ventricular failure six days after the bite. At autopsy, multiple cerebral, myocardial and mesenteric infarctions were found. Rupture of mitral chordae tendinae was the likely cause of death. Histopathologic examination showed multi-focal thrombotic microangiopathy with intimal-medial dissection by thrombi extending from foci of endothelial damage in small cerebral, myocardial, pulmonary, mesenteric, and interlobular renal arteries and arterioles. These findings were the causes of infarctions. There was intense angiogenesis in organizing cerebral infarcts. Immunohistochemical analysis showed platelet aggregates and endothelial cells within microthrombi. Viperidae venoms contain vascular endothelial toxins, notably metalloproteinase hemorrhagins, but von Willebrand factor activators or vascular endothelial growth factor-type factors are more likely to have been implicated in this case.

Eddleston M, Juszczak E, Buckley NA, Senarathna L, Mohamed F, Dissanayake W, Hittarage A, Azher S et al. 2008. A randomised controlled trial of multiple dose activated charcoal in acute self-poisoning CLINICAL TOXICOLOGY, 46 (5), pp. 380-380.

Warrell DA. 2008. Unscrupulous marketing of snake bite antivenoms in Africa and Papua New Guinea: choosing the right product--'what's in a name?'. Trans R Soc Trop Med Hyg, 102 (5), pp. 397-399. | Show Abstract | Read more

Snake bite envenoming, mainly caused by the saw-scaled or carpet viper (Echis ocellatus), is a neglected disease of West Africa. Specific antivenoms can save life and limb but, for various reasons, supply of these essential drugs to Africa has dwindled to less than 2% of estimated requirements. Other problems include maldistribution, inadequate conservation and inappropriate clinical use of antivenoms. In the face of this crisis, several promising new antivenoms have been developed. However, some dangerously inappropriate products of Indian origin are being marketed by unscrupulous manufacturers or distributors in Africa and Papua New Guinea, with disastrous results. A major source of confusion is labelling antivenom with ambiguous snake names that fail to distinguish the Asian species whose venoms are used in their production from the local snakes whose venoms are antigenically dissimilar.

Eddleston M, Juszczak E, Buckley NA, Senarathna L, Mohamed F, Dissanayake W, Hittarage A, Azher S et al. 2008. Multiple-dose activated charcoal in acute self-poisoning: a randomised controlled trial. Lancet, 371 (9612), pp. 579-587. | Show Abstract | Read more

BACKGROUND: The case-fatality for intentional self-poisoning in the rural developing world is 10-50-fold higher than that in industrialised countries, mostly because of the use of highly toxic pesticides and plants. We therefore aimed to assess whether routine treatment with multiple-dose activated charcoal, to interrupt enterovascular or enterohepatic circulations, offers benefit compared with no charcoal in such an environment. METHODS: We did an open-label, parallel group, randomised, controlled trial of six 50 g doses of activated charcoal at 4-h intervals versus no charcoal versus one 50 g dose of activated charcoal in three Sri Lankan hospitals. 4632 patients were randomised to receive no charcoal (n=1554), one dose of charcoal (n=1545), or six doses of charcoal (n=1533); outcomes were available for 4629 patients. 2338 (51%) individuals had ingested pesticides, whereas 1647 (36%) had ingested yellow oleander (Thevetia peruviana) seeds. Mortality was the primary outcome measure. Analysis was by intention to treat. The trial is registered with controlled-trials.com as ISRCTN02920054. FINDINGS: Mortality did not differ between the groups. 97 (6.3%) of 1531 participants in the multiple-dose group died, compared with 105 (6.8%) of 1554 in the no charcoal group (adjusted odds ratio 0.96, 95% CI 0.70-1.33). No differences were noted for patients who took particular poisons, were severely ill on admission, or who presented early. INTERPRETATION: We cannot recommend the routine use of multiple-dose activated charcoal in rural Asia Pacific; although further studies of early charcoal administration might be useful, effective affordable treatments are urgently needed.

Warrell MJ, Riddell A, Yu LM, Phipps J, Diggle L, Bourhy H, Deeks JJ, Fooks AR et al. 2008. A simplified 4-site economical intradermal post-exposure rabies vaccine regimen: a randomised controlled comparison with standard methods. PLoS Negl Trop Dis, 2 (4), pp. e224. | Show Abstract | Read more

BACKGROUND: The need for economical rabies post-exposure prophylaxis (PEP) is increasing in developing countries. Implementation of the two currently approved economical intradermal (ID) vaccine regimens is restricted due to confusion over different vaccines, regimens and dosages, lack of confidence in intradermal technique, and pharmaceutical regulations. We therefore compared a simplified 4-site economical PEP regimen with standard methods. METHODS: Two hundred and fifty-four volunteers were randomly allocated to a single blind controlled trial. Each received purified vero cell rabies vaccine by one of four PEP regimens: the currently accepted 2-site ID; the 8-site regimen using 0.05 ml per ID site; a new 4-site ID regimen (on day 0, approximately 0.1 ml at 4 ID sites, using the whole 0.5 ml ampoule of vaccine; on day 7, 0.1 ml ID at 2 sites and at one site on days 28 and 90); or the standard 5-dose intramuscular regimen. All ID regimens required the same total amount of vaccine, 60% less than the intramuscular method. Neutralising antibody responses were measured five times over a year in 229 people, for whom complete data were available. FINDINGS: All ID regimens showed similar immunogenicity. The intramuscular regimen gave the lowest geometric mean antibody titres. Using the rapid fluorescent focus inhibition test, some sera had unexpectedly high antibody levels that were not attributable to previous vaccination. The results were confirmed using the fluorescent antibody virus neutralisation method. CONCLUSIONS: This 4-site PEP regimen proved as immunogenic as current regimens, and has the advantages of requiring fewer clinic visits, being more practicable, and having a wider margin of safety, especially in inexperienced hands, than the 2-site regimen. It is more convenient than the 8-site method, and can be used economically with vaccines formulated in 1.0 or 0.5 ml ampoules. The 4-site regimen now meets all requirements of immunogenicity for PEP and can be introduced without further studies. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN 30087513.

Tsai IH, Tsai HY, Wang YM, Tun-Pe, Warrell DA. 2007. Venom phospholipases of Russell's vipers from Myanmar and eastern India--cloning, characterization and phylogeographic analysis. Biochim Biophys Acta, 1774 (8), pp. 1020-1028. | Show Abstract | Read more

Venoms of Russell's vipers (genus Daboia) are known for their deadly coagulopathic and other effects. We herein studied various isoforms of venom phospholipases A(2) (PLAs) from two Daboia species at their geographic boundary. From Myanmar Daboia siamensis venom (designated as DsM), four PLAs (designated DsM-aI, aI', aII' and bI') were purified, and the cDNAs encoding two acidic (DsM-aI and aII) and two basic PLAs (DsM-bI and S1) were also cloned from its venom-glands. DsM-S1 is identical to the major venom PLA of southern India Daboia russelii, but the protein is absent from the venom. Additionally, four PLAs (designated DrK-aI, aII, bI and bII) were cloned from cDNA obtained from venom glands of a Kolkata D. russelii, and the PLAs were purified from the pooled venom (designated as DrK). The acidic DrK-aI is the most neurotoxic and lethal among these PLAs; DsM-aI which differs from DrK-aI by only the Phe2 substitution shows greatly reduced enzymatic activity and lethality. Both acidic PLAs do not form dimeric complex with basic PLAs in the same venoms. DsM-bI' is neurotoxic and lethal but its orthologous DrK-bI (97% identical to DsM-bI') is a much weaker toxin. Given the fact that most of the orthologous PLAs of DrK and DsM share 97-100% sequence identity, Daboia vipers of Myanmar and Kolkata must be closely related. Molecular phylogenetic analyses on 30 venom PLAs of Eurasian vipers' revealed co-evolution of five subtypes of venom PLAs in both Daboia and Vipera genera. Our results shed light on the intra- and inter-species variations and structure-function relationships of viperid venom PLAs.

Warrell DA. 2007. Advances in clinical toxinology TROPICAL MEDICINE & INTERNATIONAL HEALTH, 12 pp. 24-24.

Warrell DA. 2007. Bent Einer Juel-Jensen - Obituary BRITISH MEDICAL JOURNAL, 334 (7589), pp. 373-373. | Read more

Lalloo DG, Shingadia D, Pasvol G, Chiodini PL, Whitty CJ, Beeching NJ, Hill DR, Warrell DA, Bannister BA, HPA Advisory Committee on Malaria Prevention in UK Travellers. 2007. UK malaria treatment guidelines. J Infect, 54 (2), pp. 111-121. | Show Abstract | Read more

Malaria is the tropical disease most commonly imported into the UK, with 1500-2000 cases reported each year, and 10-20 deaths. Approximately three-quarters of reported malaria cases in the UK are caused by Plasmodium falciparum, which is capable of invading a high proportion of red blood cells and rapidly leading to severe or life-threatening multi-organ disease. Most non-falciparum malaria cases are caused by Plasmodium vivax; a few cases are caused by the other two species of Plasmodium: Plasmodium ovale or Plasmodium malariae. Mixed infections with more than 1 species of parasite can occur; they commonly involve P. falciparum with the attendant risks of severe malaria. Management of malaria depends on awareness of the diagnosis and on performing the correct diagnostic tests: the diagnosis cannot be excluded until 3 blood specimens have been examined by an experienced microscopist. There are no typical clinical features of malaria, even fever is not invariably present. The optimum diagnostic procedure is examination of thick and thin blood films by an expert to detect and speciate the malarial parasites; P. falciparum malaria can be diagnosed almost as accurately using rapid diagnostic tests (RDTs) which detect plasmodial antigens or enzymes, although RDTs for other Plasmodium species are not as reliable. The treatment of choice for non-falciparum malaria is a 3-day course of oral chloroquine, to which only a limited proportion of P. vivax strains have gained resistance. Dormant parasites (hypnozoites) persist in the liver after treatment of P. vivax or P. ovale infection: the only currently effective drug for eradication of hypnozoites is primaquine. This must be avoided or given with caution under expert supervision in patients with glucose-6-phosphate dehydrogenase deficiency (G6PD), in whom it may cause severe haemolysis. Uncomplicated P. falciparum malaria can be treated orally with quinine, atovaquone plus proguanil (Malarone) or co-artemether (Riamet); quinine is highly effective but poorly tolerated in prolonged dosage and is always supplemented by additional treatment, usually with oral doxycycline. ALL patients treated for P. falciparum malaria should be admitted to hospital for at least 24 h, since patients can deteriorate suddenly, especially early in the course of treatment. Severe falciparum malaria, or infections complicated by a relatively high parasite count (more than 2% of red blood cells parasitized), should be treated with intravenous therapy until the patient is well enough to continue with oral treatment. In the UK, the treatment of choice for severe or complicated malaria is currently an infusion of intravenous quinine. This may exacerbate hypoglycaemia that can occur in malaria; patients treated with intravenous quinine therefore require careful monitoring. Intravenous artesunate reduces high parasite loads more rapidly than quinine and is more effective in treating severe malaria in selected situations. It can also be used in patients with contra-indications to quinine. Intravenous artesunate is unlicensed in the EU. Assistance in obtaining artesunate may be sought from specialist tropical medicine centres, on consultation, for named patients. Patients with severe or complicated malaria should be managed in a high dependency or intensive care environment. They may require haemodynamic support and management of acute respiratory distress syndrome, disseminated intravascular coagulation, renal impairment/failure, seizures, and severe intercurrent infections including gram-negative bacteraemia/septicaemia. Falciparum malaria in pregnancy is more likely to be severe and complicated: the placenta contains high levels of parasites. Stillbirth or early delivery may occur and diagnosis can be difficult if parasites are concentrated in the placenta and scanty in the blood. The treatment of choice for falciparum malaria in pregnancy is quinine; doxycycline is contraindicated in pregnancy but clindamycin can be substituted for it, and is equally effective. Primaquine (for eradication of P. vivax or P. ovale hypnozoites) is contraindicated in pregnancy; after treatment for these infections a pregnant woman should take weekly chloroquine prophylaxis until after delivery when hypnozoite eradication can be considered. Children are over-represented in the incidence of malaria in the UK, probably because completely susceptible UK-born children accompany their overseas-born parents on visits to family and friends in endemic areas. Malaria in children (and sometimes in adults) may present with misleading symptoms such as gastrointestinal features, sore throat or lower respiratory complaints; the diagnosis must always be sought in a feverish or very sick child who has visited malaria-endemic areas. Children can be treated with most of the antimalarial regimens which are effective in adults, with appropriate dosage adjustment. Doxycycline plus quinine should not be given to children under 12 years as doxycycline is contraindicated in this age group, but clindamycin can be substituted for doxycycline, and pyrimethamine-sulfadoxine (Fansidar) may also be an effective substitute. An acute attack of malaria does not confer protection from future attacks: individuals who have had malaria should take effective anti-mosquito precautions and chemoprophylaxis during future visits to endemic areas.

Joseph JK, Simpson ID, Menon NC, Jose MP, Kulkarni KJ, Raghavendra GB, Warrell DA. 2007. First authenticated cases of life-threatening envenoming by the hump-nosed pit viper (Hypnale hypnale) in India. Trans R Soc Trop Med Hyg, 101 (1), pp. 85-90. | Show Abstract | Read more

In Kerala, south-western India, five patients developed systemic envenoming after bites by hump-nosed pit vipers (Hypnale hypnale), proved by identification of the snakes responsible. Two of the dead snakes had been misidentified as saw-scaled vipers (Echis carinatus), while three had remained unidentified. Symptoms of local envenoming were pain, swelling, haemorrhagic blistering, bruising and regional lymphadenopathy. Systemic symptoms included headache, nausea, vomiting and abdominal and chest pain. There was evidence of haemostatic dysfunction (coagulopathy, fibrinolysis, thrombocytopenia or spontaneous systemic haemorrhage) in all cases and of microangiopathic haemolysis in two. Two patients were haemodialysed for acute renal failure, one of whom developed pulmonary oedema requiring mechanical ventilation. In India, H. hypnale has not previously been regarded as a cause of frequent or potentially dangerous envenoming. Its medical importance has been overlooked throughout its geographical range, probably because of confusion with other small species. No specific antivenom exists, yet most patients are treated with non-specific antivenoms, risking reactions without hope of benefit. An effective antivenom is urgently needed in south India and in Sri Lanka, where this species is also a common cause of bites.

Eddleston M, Haggalla S, Reginald K, Sudarshan K, Senthilkumaran M, Karalliedde L, Ariaratnam A, Sheriff MH, Warrell DA, Buckley NA. 2007. The hazards of gastric lavage for intentional self-poisoning in a resource poor location. Clin Toxicol (Phila), 45 (2), pp. 136-143. | Show Abstract | Read more

OBJECTIVE: The 10-20% case fatality found with self-poisoning in the developing world differs markedly from the 0.5% found in the West. This may explain in part why the recent movement away from the use of gastric lavage in the West has not been followed in the developing world. After noting probable harm from gastric lavage in Sri Lanka, we performed an observational study to determine how lavage is routinely performed and the frequency of complications. CASE SERIES: Fourteen consecutive gastric lavages were observed in four hospitals. Lavage was given to patients unable or unwilling to undergo forced emesis, regardless of whether they gave consent or the time elapsed since ingestion. It was also given to patients who had taken non-lethal ingestions. The airway was rarely protected in patients with reduced consciousness, large volumes of fluid were given for each cycle (200 to more than 1000 ml), and monitoring was not used. Serious complications likely to be due to the lavage were observed, including cardiac arrest and probable aspiration of fluid. Health care workers perceived lavage as being highly effective and often life-saving; there was peer and relative pressure to perform lavage in self-poisoned patients. CONCLUSIONS: Gastric lavage as performed for highly toxic poisons in a resource-poor location is hazardous. In the absence of evidence for patient benefit from lavage, (and in agreement with some local guidelines), we believe that lavage should be considered for few patients - in those who have recently taken a potentially fatal dose of a poison, and who either give their verbal consent for the procedure or are sedated and intubated. Ideally, a randomized controlled trial should be performed to determine the balance of risks and benefits of safely performed gastric lavage in this patient population.

Eddleston M, Juszczak E, Buckley NA, Senarathna L, Mohammed F, Allen S, Dissanayake W, Hittarage A et al. 2007. Study protocol: a randomised controlled trial of multiple and single dose activated charcoal for acute self-poisoning. BMC Emerg Med, 7 (1), pp. 2. | Show Abstract | Read more

BACKGROUND: The case fatality for intentional self-poisoning in rural Asia is 10-30 times higher than in the West, mostly due to the use of highly toxic poisons. Activated charcoal is a widely available intervention that may - if given early - bind to poisons in the stomach and prevent their absorption. Current guidelines recommend giving a single dose of charcoal (SDAC) if patients arrive within an hour of ingestion. Multiple doses (MDAC) may increase poison elimination at a later time by interrupting any enterohepatic or enterovascular circulations. The effectiveness of SDAC or MDAC is unknown. Since most patients present to hospital after one hour, we considered MDAC to have a higher likelihood of clinical benefit and set up a study to compare MDAC with no charcoal. A third arm of SDAC was added to help determine whether any benefit noted from MDAC resulted from the first dose or all doses. METHODS/DESIGN: We set up a randomised controlled trial assessing the effectiveness of superactivated charcoal in unselected adult self-poisoning patients admitted to the adult medical wards of three Sri Lankan secondary hospitals. Patients were randomised to standard treatment or standard treatment plus either a single 50 g dose of superactivated charcoal dissolved in 300 ml of water or six doses every four hours. All patients with a history of poison ingestion were approached concerning the study and written informed consent taken from each patient, or their relative (for unconscious patients or those <16 yrs), recruited to the study. The exclusion criteria were: age under 14 yrs; prior treatment with activated charcoal during this poisoning episode; pregnancy; ingestion of a corrosive or hydrocarbon; requirement for oral medication; inability of the medical staff to intubate the patient with a Glasgow Coma Score <13; presentation >72 hrs post-ingestion, and previous recruitment. The primary outcome was in-hospital mortality; secondary outcomes included the occurrence of serious complications (need for intubation, time requiring assisted ventilation, fits, cardiac dysrhythmias). Analysis will be on an intention-to-treat basis; the effects of reported time to treatment after poisoning and status on admission will also be assessed. DISCUSSION: This trial will provide important information on the effectiveness of both single and multiple dose activated charcoal in the forms of poisoning commonly seen in rural Asia. If charcoal is found to be effective, it should be possible to make it widely available across rural Asia in an affordable formulation. TRIAL REGISTRATION: Current Controlled Trials ISRCTN02920054.

Otero R, León G, Gutiérrez JM, Rojas G, Toro MF, Barona J, Rodríguez V, Díaz A et al. 2006. Efficacy and safety of two whole IgG polyvalent antivenoms, refined by caprylic acid fractionation with or without beta-propiolactone, in the treatment of Bothrops asper bites in Colombia. Trans R Soc Trop Med Hyg, 100 (12), pp. 1173-1182. | Show Abstract | Read more

The efficacy and safety of two whole IgG polyvalent antivenoms (A and B) were compared in a randomised, blinded clinical trial in 67 patients systemically envenomed by Bothrops asper in Colombia. Both antivenoms were fractionated by caprylic acid precipitation and had similar neutralising potencies, protein concentrations and aggregate contents. Antivenom B was additionally treated with beta-propiolactone to lower its anticomplementary activity. Analysing all treatment regimens together, there were no significant differences between the two antivenoms (A=34 patients; B=33 patients) in the time taken to reverse venom-induced bleeding and coagulopathy, to restore physiological fibrinogen concentrations and to clear serum venom antigenaemia. Blood coagulability was restored within 6-24 h in 97% of patients, all of whom had normal coagulation and plasma fibrinogen levels 48 h after the start of antivenom treatment. Two patients (3.0%) had recurrent coagulopathy and eight patients suffered recurrence of antigenaemia within 72 h of treatment. None of the dosage regimens of either antivenom used guaranteed resolution of venom-induced coagulopathy within 6 h, nor did they prevent recurrences. A further dose of antivenom at 6 h also did not guarantee resolution of coagulopathy within 12-24 h in all patients. The incidence of early adverse reactions (all mild) was similar for both antivenoms (15% and 24%; P>0.05).

Warrell DA. 2006. Australian toxinology in a global context. Toxicon, 48 (7), pp. 718-725. | Read more

Aslam A, Kessler B, Batycka M, O'Callaghan CA, Misbah SA, Warrell DA, Ogg G. 2006. Defining the T cell antigen proteome of wasp venom. Clin Exp Allergy, 36 (10), pp. 1274-1280. | Show Abstract | Read more

BACKGROUND: While modulation of T cell function is believed to be important in the successful acquisition of clinical tolerance during venom immunotherapy, little is known of the role of wasp venom specific T cell antigens. OBJECTIVE: We sought comprehensively to characterize the T cell proteome for wasp venom to facilitate the future development of T cell-based immunotherapeutic approaches. METHODS: Using peripheral blood mononuclear cells from wasp venom-allergic individuals and IL-4 ELISPOT analysis, we characterized T cell responses to whole venom and gel filtration/ion exchange-fractionated venom. Reactive fractions were purified and identified using highly sensitive electrospray ion-trap mass spectrometry. RESULTS: Wasp venom-allergic individuals have detectable whole wasp venom-specific T cells directly ex vivo, which show rapid IL-4 effector function. T cell responses to gel filtration/ion exchange fractionated venom were dominated by responses to phospholipase A(1), hyaluronidase and antigen 5. CONCLUSION: Although it is likely that there are many T cell antigens within wasp venom, the main responses are to proteins coincident with the known IgE-binding proteins.

Eddleston M, Dissanayake M, Sheriff MH, Warrell DA, Gunnell D. 2006. Physical vulnerability and fatal self-harm in the elderly. Br J Psychiatry, 189 (3), pp. 278-279. | Show Abstract | Read more

Although the high rate of suicide in elderly people is conventionally explained as being due to greater intent to die, we have noted elderly Sri Lankans dying after relatively mild poisoning. Using data from cases of yellow oleander poisoning, we investigated the effect of age on outcome in 1697 patients, controlling for gender and amount ingested. In fully adjusted models, people over 64 years old were 13.8 (95% CI 3.6-53.0) times more likely to die than those less than 25 years old. The high number of suicides in elderly people globally is likely to be due, in part, to the difficulty they face in surviving the effects of both the poisoning and its treatment.

Gutiérrez JM, Theakston RD, Warrell DA. 2006. Confronting the neglected problem of snake bite envenoming: the need for a global partnership. PLoS Med, 3 (6), pp. e150. | Read more

Turner MR, Madkhana A, Ebers GC, Clover L, Vincent A, McGavin G, Sarrigiannis P, Kennett R, Warrell DA. 2006. Wasp sting induced autoimmune neuromyotonia. J Neurol Neurosurg Psychiatry, 77 (5), pp. 704-705. | Read more

Senis YA, Kim PY, Fuller GL, García A, Prabhakar S, Wilkinson MC, Brittan H, Zitzmann N et al. 2006. Isolation and characterization of cotiaractivase, a novel low molecular weight prothrombin activator from the venom of Bothrops cotiara. Biochim Biophys Acta, 1764 (5), pp. 863-871. | Show Abstract | Read more

In this study, we isolated a novel prothrombin activator from the venom of Bothrops cotiara, a Brazilian lance-headed pit viper (Cotiara, Jararaca preta, Biocotiara), which we have designated "cotiaractivase" (prefix: cotiar- from B. cotiara; suffix: -activase, from prothrombin activating activity). Cotiaractivase was purified using a phenyl-Superose hydrophobic interaction column followed by a Mono-Q anion exchange column. It is a single-chain polypeptide with a molecular weight of 22,931 Da as measured by mass spectroscopy. Cotiaractivase generated active alpha-thrombin from purified human prothrombin in a Ca2+-dependent manner as assessed by S2238 chromogenic substrate assay and SDS-PAGE. Cotiaractivase cleaved prothrombin at positions Arg271-Thr272 and Arg320-Ile321, which are also cleaved by factor Xa. However, the rate of thrombin generation by cotiaractivase was approximately 60-fold less than factor Xa alone and 17 x 10(6)-fold less than the prothrombinase complex. The enzymatic activity of cotiaractivase was inhibited by the chelating agent EDTA, whereas the serine protease inhibitor PMSF had no effect on its activity, suggesting that it is a metalloproteinase. Interestingly, S2238 inhibited cotiaractivase activity non-competitively, suggesting that this toxin contains an exosite that allows it to bind prothrombin independently of its active site. Tandem mass spectrometry and N-terminal sequencing of purified cotiaractivase identified peptides that were identical to regions of the cysteine-rich and disintegrin-like domains of known snake venom metalloproteinases. Cotiaractivase is a unique low molecular weight snake venom prothrombin activator that likely belongs to the metalloproteinase family of proteins.

Warrell DA. 2006. Treatment of bites by adders and exotic venomous snakes (vol 331, pg 1244, 2005) BRITISH MEDICAL JOURNAL, 332 (7534), pp. 151-151.

Warrell DA. 2006. Foreword Tropical Infectious Diseases, | Read more

Cited:

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Gutiérrez JM, Theakston RDG, Warrell DA. 2006. Confronting the neglected problem of snake bite envenoming: The need for a global partnership PLoS Medicine, 3 (6), pp. 0727-0731. | Read more

Warrell DA. 2005. Treatment of bites by adders and exotic venomous snakes. BMJ, 331 (7527), pp. 1244-1247. | Read more

Gutiérrez JM, Rojas E, Quesada L, León G, Núñez J, Laing GD, Sasa M, Renjifo JM et al. 2005. Pan-African polyspecific antivenom produced by caprylic acid purification of horse IgG: an alternative to the antivenom crisis in Africa. Trans R Soc Trop Med Hyg, 99 (6), pp. 468-475. | Show Abstract | Read more

A polyspecific Pan-African antivenom has been produced from the plasma of horses immunized with a mixture of the venoms of Echis ocellatus, Bitis arietans and Naja nigricollis, the three most medically important snakes in sub-Saharan Africa. The antivenom is a whole IgG preparation, obtained by caprylic acid precipitation of non-IgG plasma proteins. The antivenom effectively neutralizes the most important toxic activities of the three venoms used in the immunization in standard assays involving preincubation of venom and antivenom before testing. This antivenom compares favourably with other antivenoms designed for use in Africa with respect to neutralization of the toxins present in the venom of E. ocellatus. Caprylic acid fractionation of horse hyperimmune plasma is a simple, convenient and cheap protocol for the manufacture of high quality whole IgG antivenoms. It constitutes a potentially valuable technology for the alleviation of the critical shortage of antivenom in Africa.

Isbister GK, White J, Currie BJ, Bush SP, Vetter RS, Warrell DA. 2005. Spider bites: addressing mythology and poor evidence. Am J Trop Med Hyg, 72 (4), pp. 361-364.

Warrell DA. 2005. Rabies on the doorstep. Adv Exp Med Biol, 568 pp. 145-160. | Read more

Warrell MJ, Warrell DA. 2004. Rabies and other lyssavirus diseases. (vol 363, pg 959, 2004) LANCET, 364 (9451), pp. 2096-2096.

Smalligan R, Cole J, Brito N, Laing GD, Mertz BL, Manock S, Maudlin J, Quist B et al. 2004. Crotaline snake bite in the Ecuadorian Amazon: randomised double blind comparative trial of three South American polyspecific antivenoms. BMJ, 329 (7475), pp. 1129. | Show Abstract | Read more

OBJECTIVE: To compare the efficacy and safety of three polyspecific antivenoms for bites by pit vipers. DESIGN: Randomised double blind comparative trial of three antivenoms. SETTING: Shell, Pastaza, southeastern Ecuador. PARTICIPANTS: 210 patients with incoagulable blood were recruited from 221 consecutive patients admitted with snake bite between January 1997 and December 2001. INTERVENTION: One of three antivenoms manufactured in Brazil, Colombia, and Ecuador, chosen for their preclinical potency against Ecuadorian venoms. MAIN OUTCOME MEASURES: Permanent restoration of blood coagulability after 6 and 24 hours. RESULTS: The snakes responsible for the bites were identified in 187 cases: 109 patients (58%) were bitten by Bothrops atrox, 68 (36%) by B bilineatus, and 10 (5%) by B taeniatus, B brazili, or Lachesis muta. Eighty seven patients (41%) received Colombian antivenom, 82 (39%) received Brazilian antivenom, but only 41 (20%) received Ecuadorian antivenom because the supply was exhausted. Two patients died, and 10 developed local necrosis. All antivenoms achieved the primary end point of permanently restoring blood coagulability by 6 or 24 hours after the start of treatment in > 40% of patients. Colombian antivenom, however, was the most effective after initial doses of 20 ml (two vials), < 70 ml, and any initial dose at both 6 and 24 hours. An initial dose of 20 ml of Colombian antivenom permanently restored blood coagulability in 64% (46/72) of patients after 6 hours (P = 0.054 compared with the other two antivenoms) and an initial dose of < 70 ml was effective at 6 hours (65%, P = 0.045) and 24 hours (99%, P = 0.06). Early anaphylactoid reactions were common (53%, 73%, and 19%, respectively, for Brazilian, Colombian, and Ecuadorian antivenoms, P < 0.0001) but only three reactions were severe and none was fatal. CONCLUSIONS: All three antivenoms can be recommended for the treatment of snakebites in this region, though the reactogenicity of Brazilian and Colombian antivenoms is a cause for concern.

Schneemann M, Cathomas R, Laidlaw ST, El Nahas AM, Theakston RD, Warrell DA. 2004. Life-threatening envenoming by the Saharan horned viper (Cerastes cerastes) causing micro-angiopathic haemolysis, coagulopathy and acute renal failure: clinical cases and review. QJM, 97 (11), pp. 717-727. | Show Abstract | Read more

BACKGROUND: The desert horned vipers (Cerastes cerastes and C. gasperettii) are the most familiar snakes of the great deserts of North Africa and the Middle East, including the plains of Iraq. They are responsible for many human snake bites. In Western countries, they are popular among exotic-snake keepers. AIM: To investigate mechanisms of life-threatening envenoming and treatment. DESIGN: Clinical investigation. METHODS: Clinical and laboratory studies with measurement of serum venom antigen concentrations by enzyme immunoassay. RESULTS: Two men bitten while handling captive Saharan horned vipers (Cerastes cerastes) in Europe developed extensive local swelling and life-threatening systemic envenoming, characterized by coagulopathy, increased fibrinolysis, thrombocytopenia, micro-angiopathic haemolytic anaemia and acute renal failure. The clinical picture is explicable by the presence in C. cerastes venom of several thrombin-like, Factor-X-activating, platelet-aggregating, haemorrhagic and nephrotoxic components. In one case, prophylactic use of subcutaneous epinephrine may have contributed to intracranial haemorrhage. The roles in treatment of heparin (rejected) and specific antivenom (recommended) are discussed. DISCUSSION: Cerastes cerastes is capable of life-threatening envenoming in humans. Optimal treatment of envenoming is by early administration of specific antivenom, and avoidance of ineffective and potentially-dangerous ancillary methods.

Jorge MT, Malaque C, Ribeiro LA, Fan HW, Cardoso JL, Nishioka SA, Sano-Martins IS, França FO, Kamiguti AS, Theakston RD, Warrell DA. 2004. Failure of chloramphenicol prophylaxis to reduce the frequency of abscess formation as a complication of envenoming by Bothrops snakes in Brazil: a double-blind randomized controlled trial. Trans R Soc Trop Med Hyg, 98 (9), pp. 529-534. | Show Abstract | Read more

Bites by many species of venomous snake may result in local necrosis at, or extending from, the site of the bite. The use of prophylactic antibiotics to prevent infection as a complication of local necrotic envenoming is controversial. A double-blind randomized controlled trial was carried out to assess whether antibiotic therapy is effective in this situation. Two hundred and fifty-one patients, with proven envenoming by snakes of the genus Bothrops, admitted to two hospitals in Brazil, between 1990 and 1996, were randomized to receive either oral chloramphenicol (500 mg every six hours for five days) or placebo. One hundred and twenty-two of these patients received chloramphenicol (group 1) and 129 were given placebo (group 2). There were no significant differences between the groups at the time of admission. Necrosis developed in seven (5.7%) patients in group 1 and in five (3.9%) patients in group 2 (P>0.05) while abscesses occurred in six patients (4.9%) in group 1 and in six (4.7%) patients in group 2 (P>0.05). In conclusion, the use of orally-administered chloramphenicol for victims of Bothrops snake bite with signs of local envenoming on admission, is not effective for the prevention of local infections.

Laing GD, Yarleque A, Marcelo A, Rodriguez E, Warrell DA, Theakston RD. 2004. Preclinical testing of three south American antivenoms against the venoms of five medically-important Peruvian snake venoms (vol 44, pg 103, 2004) TOXICON, 44 (3), pp. 337-338. | Read more

Laing GD, Yarleque A, Marcelo A, Rodriguez E, Warrell DA, Theakston RD. 2004. Preclinical testing of three South American antivenoms against the venoms of five medically-important Peruvian snake venoms. Toxicon, 44 (1), pp. 103-106. | Show Abstract | Read more

World Health Organization (WHO)-recommended preclinical in vivo and in vitro studies were carried out to compare the efficacy of Brazilian, Peruvian and Colombian antivenoms in neutralizing the venom toxins responsible for the lethal, haemorrhagic, necrotizing, coagulant and defibrinogenating effects of five medically-important Peruvian snake venoms. Overall, the Brazilian antivenom was found to be the most effective followed by the Peruvian and Colombian antivenoms. However, it was concluded that all three antivenoms would be acceptable for use in a randomised clinical trial in envenomed humans in Peru.

Warrell MJ, Warrell DA. 2004. Rabies and other lyssavirus diseases. Lancet, 363 (9413), pp. 959-969. | Show Abstract | Read more

The full scale of the global burden of human rabies is unknown, owing to inadequate surveillance of this fatal disease. However, the terror of hydrophobia, a cardinal symptom of rabies encephalitis, is suffered by tens of thousands of people each year. The recent discovery of enzootic European bat lyssavirus infection in the UK is indicative of our expanding awareness of the Lyssavirus genus. The main mammalian vector species vary geographically, so the health problems created by the lyssaviruses and their management differ throughout the world. The methods by which these neurotropic viruses hijack neurophysiological mechanisms while evading immune surveillance is beginning to be unravelled by, for example, studies of molecular motor transport systems. Meanwhile, enormous challenges remain in the control of animal rabies and the provision of accessible, appropriate human prophylaxis worldwide.

Laing GD, Yarleque A, Marcelo A, Rodriguez E, Warrell DA, Theakston RD. 2004. Erratum: Preclinical testing of three south American antivenoms against the venoms of five medically-important Peruvian snake venoms (Toxicon (2004) 44 (103-106) DOI: 10.1016/j.toxcon.2004.03.020) Toxicon, 44 (3), pp. 337-338. | Read more

Pardal PP, Souza SM, Monteiro MR, Fan HW, Cardoso JL, França FO, Tomy SC, Sano-Martins IS et al. 2004. Clinical trial of two antivenoms for the treatment of Bothrops and Lachesis bites in the north eastern Amazon region of Brazil. Trans R Soc Trop Med Hyg, 98 (1), pp. 28-42. | Show Abstract | Read more

The efficacies of specific Bothrops atrox-Lachesis and standard Bothrops-Lachesis antivenoms were compared in the north eastern Amazon region of Brazil. The main aim was to investigate whether a specific antivenom raised against the venom of B. atrox, the most important Amazon snake species from a medical point of view, was necessary for the treatment of patients in this region. Seventy-four patients with local and systemic effects of envenoming by Bothrops or Lachesis snakes were randomly allocated to receive either specific (n = 38) or standard (n = 36) antivenoms. In 46 cases (24 in the standard antivenom group, 22 in the other) the snake was identified either by enzyme immunoassay or by examination of the dead snake, as B. atrox in 45, L. muta in one. Patients were similar in all clinical and epidemiological respects before treatment. Results indicated that both antivenoms were equally effective in reversing all signs of envenoming detected both clinically and in the laboratory. Venom-induced haemostatic abnormalities were resolved within 24 h after the start of antivenom therapy in most patients. The extent of local complications, such as local skin necrosis and secondary infection, was similar in both groups. There were no deaths. The incidence of early anaphylactic reactions was 18% and 19%, respectively for specific and standard antivenoms; none was life-threatening. Measurement of serum venom concentrations by enzyme immunoassay (EIA) confirmed that both antivenoms cleared venom antigenaemia effectively. EIA also revealed that one patient had been bitten by Lachesis muta, although the clinical features in this case were not distinctive.

Theakston RDG, Warrell DA, Griffiths E. 2003. Erratum to Report of WHO workshop on the standardization and control on antivenoms (vol 41, pg 541, 2003) TOXICON, 42 (2), pp. 223-223. | Read more

Laing GD, Renjifo JM, Ruiz F, Harrison RA, Nasidi A, Gutierrez JM, Rowley PD, Warrell DA, Theakston RD. 2003. A new Pan African polyspecific antivenom developed in response to the antivenom crisis in Africa. Toxicon, 42 (1), pp. 35-41. | Show Abstract | Read more

Currently there is a crisis in the supply of antivenom for treatment of snake bite in sub-Saharan Africa. Commercial pressures have resulted in the reduction or even cessation of production of antivenom by European manufacturers while continued production of antivenom in Africa has been threatened by the privatisation of the only remaining company based in Africa. As a consequence, there has been an increase in snake bite morbidity and mortality in many African countries. Two Latin American antivenom manufacturers have agreed to produce antivenom suitable for Africa, using venoms from the species which are of the greatest medical importance in sub-Saharan Africa. Preclinical in vivo assays of neutralising potency demonstrated that a new Pan African antivenom produced in Colombia compared favourably with the existing commercial monospecific and polyspecific antivenoms. This new antivenom, and a similar product being manufactured in Costa Rica, are now candidates for clinical testing at an appropriate site in Africa.

Makani J, Matuja W, Liyombo E, Snow RW, Marsh K, Warrell DA. 2003. Admission diagnosis of cerebral malaria in adults in an endemic area of Tanzania: implications and clinical description. QJM, 96 (5), pp. 355-362. | Show Abstract | Read more

BACKGROUND: Cerebral malaria is commonly diagnosed in adults in endemic areas in Africa, both in hospitals and in the community. This presents a paradox inconsistent with the epidemiological understanding that the development of immunity during childhood confers protection against severe disease in adult life. AIM: To establish the contribution of Plasmodium falciparum infection in adults admitted with neurological dysfunction in an endemic area, to assess the implications of an admission clinical diagnosis of 'cerebral malaria' on the treatment and clinical outcome, and to describe the clinical features of patients with malaria parasitaemia. DESIGN: Prospective observational study. METHODS: We studied adult patients admitted with neurological dysfunction to Muhimbili National Hospital, Dar-es-Salaam, Tanzania from October 2000 to July 2001. A full blood count was done and serum creatinine, blood glucose and P. falciparum parasite load were measured. RESULTS: Of 199 patients (median age 34.6 years), 38% were diagnosed as 'cerebral malaria' on admission, but only 7.5% had detectable parasitaemia, giving a positive predictive value of 13.3%. Only 1% fulfilled the WHO criteria for cerebral malaria. The prevalence of parasitaemia (7.5%) was less than that observed in a group of asymptomatic controls (9.3%), but distribution of parasite densities was higher in the patients. Mortality was higher in patients with no parasitaemia (22.3%) than in those with parasitaemia (13%). DISCUSSION: Cerebral malaria was grossly overdiagnosed, resulting in unnecessary treatment and insufficient investigation of other possible diagnoses, which could lead to higher mortality. Extension of this misperception to the assessment of cause of death in community surveys may lead to an overestimation of the impact of malaria in adults.

França FO, Barbaro KC, Fan HW, Cardoso JL, Sano-Martins IS, Tomy SC, Lopes MH, Warrell DA, Theakston RD, Butantan Institute Antivenom Study Group. 2003. Envenoming by Bothrops jararaca in Brazil: association between venom antigenaemia and severity at admission to hospital. Trans R Soc Trop Med Hyg, 97 (3), pp. 312-317. | Show Abstract | Read more

The association between the clinical severity of Bothrops jararaca envenoming at admission and serum venom and plasma fibrinogen concentrations before antivenom administration is reported in 137 patients admitted to Hospital Vital Brazil, Instituto Butantan, São Paulo, Brazil, between 1989 and 1990. Other variables such as age, gender, site of the bite, use of tourniquet and the time interval between the bite and start of antivenom therapy, spontaneous systemic bleeding, and the 20 minute whole blood clotting test (20WBCT) at admission showed no association with either severity or serum venom antigen concentration (SVAC). Mean SVAC in patients with mild envenoming was significantly lower than in the group with moderate envenoming (P = 0.0007). Patients with plasma fibrinogen concentrations > 1.5 g/L had a lower mean SVAC than patients with plasma fibrinogen concentrations < or = 1.5 g/L (P = 0.02). Those admitted with a tourniquet in place had significantly higher plasma fibrinogen concentrations than those without a tourniquet (P = 0.002). A multiple logistic regression model showed independent risk factors for severity: bites at sites other than legs or forearms, SVACs > or = 400 ng/mL, and the use of a tourniquet. Rapid quantification of SVAC before antivenom therapy might improve initial evaluation of severity in B. jararaca bites.

Theakston RD, Warrell DA, Griffiths E. 2003. Report of a WHO workshop on the standardization and control of antivenoms. Toxicon, 41 (5), pp. 541-557. | Show Abstract | Read more

A workshop to discuss progress in the standardization and control of antivenoms, organized by the Quality Assurance and Safety of Biologicals Unit of WHO, was held at the National Institute for Biological Standards and Control, Potters Bar, England, 7-9 February 2001. This was the first meeting convened by the WHO on this subject since 1979 and it brought together experts from academic institutions, antivenom manufacturers and national regulatory authorities from 21 countries. The meeting reviewed antivenom production and quality control measures and special consideration was given to the current crisis in antivenom production and supply in sub-Saharan Africa. The importance of snake bite and scorpion stings as public health issues was re-emphasised. The majority of commercial antivenoms are raised against snake or scorpion venoms.The review of antivenom production methods indicated that the vast majority of commercial antivenoms were still produced by traditional technology in horses, although some antisera were raised in sheep and rabbits. Methods used for plasma fractionation included salt and heat coagulation, caprylic acid stabilization or ion exchange chromatography, as well as immunoglobulin digestion with pepsin to produce F(ab')(2) or with papain to produce Fab fragments. The meeting agreed that there was much room for improving the production, quality control and safety profile of these products and that lessons could be learnt from the experience gained with the preparation of human immunoglobulins. Many basic assumptions, such as the need to remove Fc fragments by enzyme digestion and to freeze-dry antivenom preparations, required critical re-examination and more attention should be given to clinical trials as a means of assessing efficacy and safety and of defining the average initial dose. The Workshop also discussed concerns about the risks of transmitting infectious agents to humans via animal blood products, especially those posed by viruses or prions and it was agreed that this aspect needed attention. However, there was no documented or even suspected example of this ever having occurred in the case of antivenom treatment. Current WHO Requirements for the production and control of antivenoms and for immune sera of animal origin date from the late 1960s. The Workshop recommended that these be updated to take account of the progress that had taken place in the production and quality control of biologicals in recent years. In addition, the Workshop discussed the need for better standardization of both the venoms and antivenoms, but concluded that international standards and reference materials were not appropriate in the antivenom field due to the considerable variation in venom characteristics from the same species from region to region. Instead, it was recommended that national or regional standards be prepared and used.

Warrell DA. 2003. Taking the sting out of ant stings: venom immunotherapy to prevent anaphylaxis. Lancet, 361 (9362), pp. 979-980. | Read more

Laing GD, Harrison RA, Theakston RD, Renjifo JM, Nasidi A, Gutierrez JM, Warrell DA. 2003. Polyspecific snake antivenom may help in antivenom crisis. BMJ, 326 (7386), pp. 447. | Read more

Laing GD, Harrison RA, Theakston RDG, Renjifo JM, Nasidi A, Gutierrez JM, Warrell DA. 2003. Polyspecific snake antivenom may help in antivenom crisis BRITISH MEDICAL JOURNAL, 326 (7386), pp. 447-448.

Warrell DA. 2002. Bites of venomous snakes. N Engl J Med, 347 (22), pp. 1804-1805. | Read more

Warrell MJ, Warrell DA. 2002. Intradermal regimens for rabies postexposure prophylaxis: more confusion. Clin Infect Dis, 35 (2), pp. 213-215. | Read more

Lalloo DG, Theakston RDG, Warrell DA. 2002. The African challenge LANCET, 359 (9316), pp. 1527-1527. | Read more

Stienstra Y, van der Graaf WT, Teelken MA, Ellen DE, van der Werf TS. 2002. The African challenge. Lancet, 359 (9316), pp. 1527-1528. | Read more

Warrell DA. 2001. "To search and Studdy out the secrett of Tropical Diseases by way of Experiment". Lancet, 358 (9297), pp. 1983-1988. | Read more

Warrell DA. 2001. 'To search and studdy out the secrett of tropical diseases by way of experiment'. Clin Med (Lond), 1 (6), pp. 485-494. | Show Abstract | Read more

William Harvey wrote about malaria, snake bite and rabies, three diseases now having their greatest impact in tropical developing countries. Global malarial mortality has not declined for 50 years. The most effective control measure would be a vaccine. Temporary immunity in humans, through hundreds of bites by irradiated infected mosquitoes, was achieved in the 1970s. A promising current strategy is effector T-cell vaccination directed at infected hepatocytes. RTS,S/(SB)ASO2, an adjuvanted fusion protein, produced transient protection in 70% of vaccines. Prime (DNA vaccine) boost (poxvirus recombinant) is particularly immunogenic. Pyrethroid-treated bed nets reduce childhood mortality and deplete the mosquito population, interrupting transmission. Chlorproguanil-dapsone is more effective than pyrimethamine-sulfadoxine in treating uncomplicated chloroquine-resistant malaria. Artemisinin derivatives are as effective as quinine in severe disease. Snake bite is an underestimated and neglected cause of morbidity and mortality in rural communities in tropical countries. Sutherland's pressure-immobilisation technique is recommended first-aid for victims of neurotoxic elapid snakes. Rabies post-exposure prophylaxis, using new generation cell culture vaccines, is now feasible in developing countries, employing an economical 8-site intradermal regimen. This Harveian Oration, the first in 350 years to be devoted to tropical medicine, emphasises the importance of this speciality in the twenty-first century.

Sano-Martins IS, Tomy SC, Campolina D, Dias MB, de Castro SC, de Sousa-e-Silva MC, Amaral CF, Rezende NA, Kamiguti AS, Warrell DA, Theakston RD. 2001. Coagulopathy following lethal and non-lethal envenoming of humans by the South American rattlesnake (Crotalus durissus) in Brazil. QJM, 94 (10), pp. 551-559. | Show Abstract | Read more

The South American tropical rattlesnake (Crotalus durissus subspp) is responsible for approximately 10% of bites from venomous snakes in Brazil. We studied 24 victims of bites by this species over 3 years, in south-eastern Brazil, particularly investigating haemostatic alterations. Thirteen patients were defined as moderately envenomed and 11 as severe. There were two deaths, which were not attributed to venom-induced haemostatic disturbances. However, envenoming by C. durissus is frequently associated with haemostatic disorders, which are probably attributable mainly to the action of the thrombin-like enzyme, with possible additional effects secondary to the powerful myotoxic activity of the venom.

Sundell IB, Theakston RD, Kamiguti AS, Harris RJ, Treweeke AT, Laing GD, Fox JW, Warrell DA, Zuzel M. 2001. The inhibition of platelet aggregation and blood coagulation by Micropechis ikaheka venom. Br J Haematol, 114 (4), pp. 852-860. | Show Abstract | Read more

Uncoagulable blood and life-threatening bleeding can result from the action of some snake venom toxins on haemostatic components of blood and vessel walls. Although envenoming by Micropechis ikaheka primarily affects neurones and muscle cells causing post-synaptic neuromuscular blockade and rhabdomyolysis, disturbances of haemostasis also occur. Therefore, the present study explored the effects of M. ikaheka venom on platelets and endothelium, which are important components of the haemostatic mechanism. The venom inhibited platelet aggregation in response to ADP and collagen, and also delayed clotting dependent on platelet activation or endothelial cell tissue factor expression. Some of these effects were reduced by the incubation of venom with a phospholipase A2 (PLA2) inhibitor and could be reproduced by a 17 kDa venom fraction containing a PLA2. In addition, an 11 kDa fraction containing a long-chain neurotoxin reduced ADP-induced aggregation. The venom was also found to reduce endothelial cell adherence to vitronectin-, fibronectin- and collagen-coated surfaces. These results suggest that, by inhibiting procoagulant activities of platelets and endothelial cells, a 17 kDa PLA2 plays an important role in the anticoagulant action of M. ikaheka venom.

Warrell DA. 2001. Chagas' disease. Lancet, 358 (9279), pp. 424. | Read more

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Puorto G, Salomao MD, Theakston RDG, Thorpe RS, Warrell DA, Wuster W. 2001. Combining mitochondrial DNA sequences and morphological data to infer species boundaries: phylogeography of lanceheaded pitvipers in the Brazilian Atlantic forest, and the status of Bothrops pradoi (Squamata : Serpentes : Viperidae) JOURNAL OF EVOLUTIONARY BIOLOGY, 14 (4), pp. 527-538. | Read more

Warrell DA. 2001. Chagas' disease [6] Lancet, 358 (9279), pp. 424.

Ariaratnam CA, Sjöström L, Raziek Z, Kularatne SA, Arachchi RW, Sheriff MH, Theakston RD, Warrell DA. 2001. An open, randomized comparative trial of two antivenoms for the treatment of envenoming by Sri Lankan Russell's viper (Daboia russelii russelii). Trans R Soc Trop Med Hyg, 95 (1), pp. 74-80. | Show Abstract | Read more

Russell's viper (Daboia russelii russelii) is an important cause of morbidity and mortality in Sri Lanka. In a study in 1985, Haffkine equine polyspecific antivenom in doses up to 20 g proved ineffective in clearing antigenaemia and caused a high incidence of anaphylactoid reactions. A new, monospecific ovine Fabantivenom (Polonga TAb) has been developed against the venom of Sri Lankan Russell's viper and, to assess its safety and efficacy, we carried out (in 1997) an open, randomized comparison of this with the Haffkine antivenom currently in use in the country. Patients with systemic envenoming following Russell's viper bite were randomized to receive an initial intravenous dose of either 1 g of Polonga TAb (n = 23) or 10 g of Haffkine antivenom (n = 20). One dose of Polonga TAb permanently restored blood coagulability in only 9 (41%) of 22 patients and 13 needed repeated doses, whereas the majority (14/20; 70%) had restored coagulability after 1 dose of Haffkine antivenom. There was a tendency towards more rapid resolution of local swelling and systemic manifestations in the Haffkine group. Venom antigenaemia was eliminated more quickly in the Haffkine group and ovine Fab was cleared from the circulation more rapidly than equine F(ab')2. To evaluate safety, patients were closely observed for adverse reactions. Following a severe reaction with Haffkine antivenom all subsequent patients in this group were treated prophylactically with hydrocortisone and chlorpheniramine. Despite this, the incidence of adverse reactions was significantly higher in the Haffkine group compared with the PolongaTAb group (81% compared with 48%) and 4 patients had a severe anaphylactic reaction in the former group. In conclusion, the new antivenom is safer than Haffkine antivenom but, to avoid repeated doses, an initial dose higher than 1 g is needed in the treatment of Sri Lankan Russell's viper envenoming. The safety of this larger dose is the subject of further studies.

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Theakston RDG, Warrell DA. 2000. Crisis in snake antivenom supply for Africa LANCET, 356 (9247), pp. 2104-2104. | Read more

Warrell MJ, Warrell DA. 2000. Intradermal postexposure rabies vaccine regimens. Clin Infect Dis, 31 (3), pp. 844-845. | Read more

Ledingham JG, Warrell DA, Weatherall D. 2000. Asymptomatic haematuria. Oxford textbook of medicine might have helped author. BMJ, 320 (7249), pp. 1599.

Ledingham JGG, Warrell DA, Weatherall D. 2000. Asymptomatic haematuria - Oxford Textbook of Medicine might have helped author BRITISH MEDICAL JOURNAL, 320 (7249), pp. 1599-1599.

Eddleston M, Rajapakse S, Rajakanthan, Jayalath S, Sjöström L, Santharaj W, Thenabadu PN, Sheriff MH, Warrell DA. 2000. Anti-digoxin Fab fragments in cardiotoxicity induced by ingestion of yellow oleander: a randomised controlled trial. Lancet, 355 (9208), pp. 967-972. | Show Abstract | Read more

BACKGROUND: Severe cardiac glycoside cardiotoxicity after ingestion of yellow oleander seeds is an important problem in rural areas of Sri Lanka. Currently, patients must be transferred to the capital for temporary cardiac pacing. We did a randomised controlled trial to investigate whether anti-digoxin Fab could reverse serious oleander-induced arrhythmias. METHODS: After a preliminary dose-finding study, 66 patients who presented to hospital with a serious cardiac arrhythmia were randomised to receive either 1200 mg of anti-digoxin Fab or a saline placebo. A 12-lead electrocardiogram, 3 min rhythm strip, and blood sample for measurement of electrolytes and cardiac glycosides were taken before treatment and at 12 timepoints thereafter. FINDINGS: 34 patients received anti-digoxin Fab and 32 received placebo. The presenting arrhythmia had resolved completely after 2 h in 15 antibody-treated patients and two controls (p<0.001); 24 and five patients, respectively, were in sinus rhythm at 8 h (p<0.001). Kaplan-Meier analysis of time to first reversal showed a significant response to anti-digoxin Fab. The heart rate increased in cases, from 49.1 per min at baseline to 66.8 at 2 h, but not in controls (50.6 per min at baseline to 51.5; p<0.001). Mean serum potassium concentrations decreased from 4.9 mmol/L to 4.1 mmol/L at 2 h in cases; no such decrease occurred in controls. INTERPRETATION: Anti-digoxin Fab fragments are a safe and effective treatment for serious cardiac arrhythmias induced by yellow oleander. Their use in small rural hospitals in Sri Lanka should minimise costly transfer of patients and reduce the numbers of deaths; however, further study will be required to confirm this reduction.

Eddleston M, Ariaratnam CA, Sjöström L, Jayalath S, Rajakanthan K, Rajapakse S, Colbert D, Meyer WP et al. 2000. Acute yellow oleander (Thevetia peruviana) poisoning: cardiac arrhythmias, electrolyte disturbances, and serum cardiac glycoside concentrations on presentation to hospital. Heart, 83 (3), pp. 301-306. | Show Abstract | Read more

OBJECTIVE: To describe the cardiac arrhythmias, electrolyte disturbances, and serum cardiac glycoside levels seen in patients presenting to hospital with acute yellow oleander (Thevetia peruviana) poisoning and to compare these with published reports of digitalis poisoning. DESIGN: Case series. SETTING: Medical wards of Anuradhapura District General Hospital, Sri Lanka, and coronary care unit of the Institute of Cardiology, National Hospital of Sri Lanka, Colombo, the national tertiary referral centre for cardiology. PATIENTS: 351 patients with a history of oleander ingestion. MEASUREMENTS: ECG and blood sample analysis on admission. RESULTS: Most symptomatic patients had conduction defects affecting the sinus node, the atrioventricular (AV) node, or both. Patients showing cardiac arrhythmias that required transfer for specialised management had significantly higher mean serum cardiac glycoside and potassium but not magnesium concentrations. Although there was considerable overlap between groups, those with conduction defects affecting both sinus and AV nodes had significantly higher mean serum cardiac glycoside levels. CONCLUSIONS: Most of these young previously healthy patients had conduction defects affecting the sinus or AV nodes. Relatively few had the atrial or ventricular tachyarrhythmias or ventricular ectopic beats that are typical of digoxin poisoning. Serious yellow oleander induced arrhythmias were associated with higher serum cardiac glycoside concentrations and hyperkalaemia but not with disturbances of magnesium.

Beales PF, Brabin B, Dorman E, Gilles HM, Loutain L, Marsh K, Molyneux ME, Olliaro P et al. 2000. Severe falciparum malaria. World Health Organization, Communicable Diseases Cluster. Trans R Soc Trop Med Hyg, 94 Suppl 1 (SUPPL.1), pp. S1-90.

Cutler SJ, Akintunde CO, Moss J, Fukunaga M, Kurtenbach K, Talbert A, Zhang H, Wright DJ, Warrell DA. 1999. Successful in vitro cultivation of Borrelia duttonii and its comparison with Borrelia recurrentis. Int J Syst Bacteriol, 49 Pt 4 (4), pp. 1793-1799. | Show Abstract | Read more

Borrelia duttonii, the cause of East African tick-borne relapsing fever, has until now been refractory to growth in laboratory media. This spirochaete has only be propagated in mice or by tissue culture, restricting both yield and purity of cells available for research. The successful isolation of five clinical isolates of B. duttonii from patients in Central Tanzania and their comparison with Borrelia recurrentis is reported. Electron microscopy revealed spirochaetal cells with pointed ends, a mean wavelength of 1.8 microns with an amplitude of 0.8 micron, similar to the findings for B. recurrentis. Cells contained 10 periplasmic flagella inserted at each end of the spirochaete, again comparable with the counts of 8-10 flagella found in B. recurrentis. PFGE revealed a chromosome of approximately 1 Mb, a large plasmid of approximately 200 kb, and a small plasmid of 11 kb in all strains of B. duttonii and in B. recurrentis. B. duttonii possessed a further 7-9 plasmids with sizes ranging from 20 to 90 kb. In two isolates of B. duttonii, the profiles were identical. In contrast, all 18 isolates of B. recurrentis fell into one of five plasmid patterns with 3-4 plasmids ranging from 25 to 61.5 kb in addition to those of 11 and 200 kb described above. Analysis of the SDS-PAGE profiles of B. duttonii strains revealed a high-molecular-mass band of 33.4-34.2 kDa in four strains (variable large protein, VLP) and a low-molecular-mass band of 22.3 kDa in the remaining strain (variable small protein, VSP). This resembles the protein profiles found in B. recurrentis. The G + C ratio of B. duttonii was 27.6 mol%. Nucleotide sequence of the rrs gene (16S rRNA) from four B. duttonii isolates revealed 100% identity among these strains and 99.7% homology with three strains deposited by others in GenBank. The rrs gene of eight representative clinical isolates of B. recurrentis confirmed their close similarity with B. duttonii.

Eddleston M, Warrell DA. 1999. Management of acute yellow oleander poisoning. QJM, 92 (9), pp. 483-485. | Read more

Warrell DA. 1999. Management of severe malaria. Parassitologia, 41 (1-3), pp. 287-294. | Show Abstract

The case fatality of WHO-defined 'severe falciparum malaria' remains unacceptably high, at 10-20%. However, a gradual decline in case fatality in adults and children treated in hospitals may reflect use of improved regimens of antimalarial chemotherapy and increased awareness of important complications of the disease. The development of severe, perhaps inevitably-fatal, malaria might be prevented by early appropriate chemotherapy of uncomplicated disease. At the most peripheral levels of the health service, suppository formulations of artemisinin derivatives can be administered even to patients who are vomiting or prostrated. At dispensaries, clinics or hospitals, where intramuscular or intravenous administration of antimalarial drugs is possible, quinine and artemisinin derivatives are the treatments of choice. There is growing evidence of the safety and efficacy of the quinine loading dose and of the use of artemether and artesunate, based on large, randomised, controlled clinical studies. No safe and effective form of prophylactic ancillary treatment has yet emerged. Results of studies of antipyretics, anticonvulsants (phenobarbitone), anticytokine/anti-inflammatory agents (anti-TNF antibodies, pentoxifylline, dexamethasone), iron chelators and hyperimmune sera have been disappointing. Only blood transfusion and treatment of respiratory, circulatory and renal failure are of obvious benefit. New ideas are needed, based on what is known of the pathophysiology of severe disease.

Wüster W, Golay P, Warrell DA. 1999. Synopsis of recent developments in venomous snake systematics, No. 3. Toxicon, 37 (8), pp. 1123-1129. | Show Abstract | Read more

We present recent findings in the systematics of venomous snakes, with emphasis on those which affect the nomenclature and our understanding of species limits in these animals. Changes in systematics reviewed here include particularly the genera Acanthophis, Elapsoidea, Bitis, Lachesis, Porthidium, Trimeresurus/Tropidolaemus and Vipera. Other new publications of more general interest to toxinologists are also presented.

Ariaratnam CA, Meyer WP, Perera G, Eddleston M, Kuleratne SA, Attapattu W, Sheriff R, Richards AM, Theakston RD, Warrell DA. 1999. A new monospecific ovine Fab fragment antivenom for treatment of envenoming by the Sri Lankan Russell's viper (Daboia Russelii Russelii): a preliminary dose-finding and pharmacokinetic study. Am J Trop Med Hyg, 61 (2), pp. 259-265. | Show Abstract

Russell's viper is the most important cause of life-threatening snake bite and acute renal failure in Sri Lanka. Only equine polyspecific antivenoms imported from India are available. They have not proved effective clinically or in clearing venom antigenemia and they frequently cause reactions. In an attempt to reduce mortality and morbidity, a new monospecific ovine Fab fragment antivenom (PolongaTab; Therapeutic Antibodies, Inc., London, United Kingdom) was raised against Sri Lankan Russell's viper venom. In a preliminary dose-finding study in 35 patients, an initial dose of 3-4 g restored blood coagulability permanently and stopped systemic bleeding, even in severely envenomed patients. Venom antigenemia disappeared within 1 hr of antivenom treatment but recurred, probably as a result of continued absorption of venom from the site of the bite, after the rapid clearance of therapeutic antibody. Twelve patients (34%) experienced early reactions that were usually mild and always responded to epinephrine.

Looareesuwan S, Sjostrom L, Krudsood S, Wilairatana P, Porter RS, Hills F, Warrell DA. 1999. Polyclonal anti-tumor necrosis factor-alpha Fab used as an ancillary treatment for severe malaria. Am J Trop Med Hyg, 61 (1), pp. 26-33. | Show Abstract

Single doses (250, 500, 1,000, or 2,000 units/kg) of an ovine polyclonal-specific Fab fragment directed against tumor necrosis factor-alpha (TNF-alpha) were given to 17 adult patients with severe falciparum malaria immediately before treatment with artesunate in a pilot study to assess safety and optimal dosage with a view to future studies. Clinical and laboratory variables were compared with 11 controls. In the groups given Fab, there was a tendency for a faster resolution of clinical manifestations and reduction of fever but also a tendency towards longer parasite clearance times. Adverse events were more common in the control group and no early anaphylactic or late serum sickness reactions occurred in the Fab treated patients. On admission all patients had markedly elevated levels of TNF-alpha (85-1,532 ng/L) and interleukin-6 (IL-6) (30-27,500 ng/L). Also, 86% had elevated interferon-gamma (IFN-gamma) levels, 75% had increased IL-2 levels, 36% had increased IL-8 levels, and 21% had increased IL-1beta levels. Antibody treatment reduced IFN-gamma concentrations in a dose-related manner, but had no obvious effects on levels of other cytokines in this small study, although unbound TNF-alpha was undetectable after Fab treatment. Circulating concentrations of soluble E-selectin, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 were not affected by Fab treatment. The Fab exhibited a two-compartment, dose-proportional kinetics with an average elimination half-life of 12.0 hr, with about 20% being excreted renally. These results encourage a randomized, placebo-controlled trial in patients with cerebral malaria and provide some guidance about dosage.

Fan HW, Marcopito LF, Cardoso JL, França FO, Malaque CM, Ferrari RA, Theakston RD, Warrell DA. 1999. Sequential randomised and double blind trial of promethazine prophylaxis against early anaphylactic reactions to antivenom for bothrops snake bites. BMJ, 318 (7196), pp. 1451-1452. | Show Abstract | Read more

OBJECTIVE: To investigate the efficacy of the H1 antihistamine promethazine against early anaphylactic reactions to antivenom. DESIGN: Sequential randomised, double blind, placebo controlled trial. SETTING: Public hospital in a venom research institute, São Paulo, Brazil. PARTICIPANTS: 101 patients requiring antivenom treatment after being bitten by bothrops snakes. INTERVENTION: Intramuscular injection of promethazine (25 mg for adults and 0.5/kg for children) or placebo given 15-20 min before starting intravenous infusion of antivenom. MAIN OUTCOME MEASURES: Incidence and severity of anaphylactic reactions occurring within 24 hours after antivenom. RESULTS: Reactions occurred in 12 of 49 patients treated with promethazine (24%) and in 13 of 52 given placebo (25%); most were mild or moderate. Continuous sequential analysis indicated that the study could be interrupted at the 22nd untied pair, without preference for promethazine or placebo. CONCLUSION: Prophylaxis with promethazine does not prevent early reactions. Patients should be observed carefully during antivenom infusion and the subsequent few hours.

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Fan HW, Marcopito LF, Cardoso JLC, Franca FOS, Malaque CMS, Ferrari RA, Theakston RDG, Warrell DA. 1999. Sequential randomised and double blind trial of promethazine prophylaxis against early anaphylactic reactions to antivenom for bothrops snake bites BRITISH MEDICAL JOURNAL, 318 (7196), pp. 1451-1453. | Show Abstract

Objective. To investigate the efficacy of the H1 antihistamine promethazine against early anaphylactic reactions to antivenom. Design. Sequential randomised, double-blind, placebo controlled trial. Setting. Public hospital in a venom research institute, Sao Paulo, Brazil. Participants. 101 patients requiring antivenom treatment after being bitten by bothrops snakes. Intervention. Intramuscular injection of promethazine (25 mg for adults and 0.5/kg for children) or placebo given 15-20 min before starting intravenous infusion of antivenom. Main outcome measures. Incidence and severity of anaphylactic reaction occurring within 24 hours after antivenom. Results. Reactions occurred in 12 of 49 patients treated with promethazine (24%) and in 13 of 52 given placebo (25%); most were mild or moderate. Continuous sequential analysis indicated that the study could be interrupted at the 22nd united pair, without preference for promethazine or placebo. Conclusion. Prophylaxis with promethazine does not prevent early reactions. Patients should be observed carefully during antivenom infusion and the subsequent few hours.

Eddleston M, Ariaratnam CA, Meyer WP, Perera G, Kularatne AM, Attapattu S, Sheriff MH, Warrell DA. 1999. Epidemic of self-poisoning with seeds of the yellow oleander tree (Thevetia peruviana) in northern Sri Lanka. Trop Med Int Health, 4 (4), pp. 266-273. | Show Abstract | Read more

Deliberate self-harm is an important problem in the developing world. Ingestion of yellow oleander seeds (Thevetia peruviana) has recently become a popular method of self-harm in northern Sri Lanka -- there are now thousands of cases each year. These seeds contain cardiac glycosides that cause vomiting, dizziness, and cardiac dysrhythmias such as conduction block affecting the sinus and AV nodes. This paper reports a study of the condition's mortality and morbidity conducted in 1995 in Anuradhapura General Hospital, a secondary referral centre serving 750 000 people in Sri Lanka's north central province. 415 cases were admitted to the hospital during 11 months; 61% were women and 46% were less than 21 years old. A prospective study of 79 patients showed that 6% died soon after admission. 43% presented with marked cardiac dysrhythmias which necessitated ther transfer to the coronary care unit in Colombo for prophylactic temporary cardiac pacing. The reasons for the acts of self-harm were often relatively trivial, particularly in children; most denied that they wished to die. Unfortunately, the case fatality rate for oleander poisoning in Sri Lanka is at least 10%. This epidemic is not only causing many unnecessary deaths, it is also putting immense stress on the already stretched Sri Lankan health services. There is an urgent need for an intervention which could be used in rural hospitals, thus preventing the hazardous and expensive emergency transfer of patients to the capital.

Warrell MJ, Warrell DA. 1999. Equine antirabies serum treatment during an epizootic outbreak in the city of Ribeirão Preto, Brazil. Trans R Soc Trop Med Hyg, 93 (1), pp. 106.

Warrell MJ, Warrell DA. 1999. Equine antirabies serum treatment during an epizootic outbreak in the city of Ribeirao Preto, Brazil TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE, 93 (1), pp. 106-106. | Read more

Vidal V, Scragg IG, Cutler SJ, Rockett KA, Fekade D, Warrell DA, Wright DJ, Kwiatkowski D. 1998. Variable major lipoprotein is a principal TNF-inducing factor of louse-borne relapsing fever. Nat Med, 4 (12), pp. 1416-1420. | Show Abstract | Read more

Massive release of tumor necrosis factor is responsible for the potentially fatal larisch-Herxheimer reaction that follows antibiotic treatment of relapsing fever due to Borrelia recurrentis. We have undertaken the quantitative purification of the components of B. recurrentis that stimulate human monocytes to produce tumor necrosis factor. We show that the predominant factor inducing tumor necrosis factor is a variable lipoprotein homologous to the variable major protein of B. hermsii. We found antibodies to different forms of variable major protein in two patients with louse-borne relapsing fever. The three purified variable major proteins studied here differ in their ability to induce tumor necrosis factor production, which may partly explain the variable clinical severity of borrelial infection. These results may be of considerable relevance for the pathogenesis of Lyme disease and other forms of human borreliosis.

Bhetwal BB, O'Shea M, Warrell DA. 1998. Snakes and snake bite in Nepal. Trop Doct, 28 (4), pp. 193-195.

Gilks CF, Floyd K, Otieno LS, Adam AM, Bhatt SM, Warrell DA. 1998. Some effects of the rising case load of adult HIV-related disease on a hospital in Nairobi. J Acquir Immune Defic Syndr Hum Retrovirol, 18 (3), pp. 234-240. | Show Abstract | Read more

Increasing numbers of HIV-infected adults in Africa need hospital care. It remains unclear what impact this has on health care services or on how hospitals respond. The aim of this study was to describe the effects of a rising case load of adult HIV-related disease by comparing results from a prospective cross-sectional study of acute adult medical admissions to a government hospital in Nairobi conducted in 1992 with results from a previous study done in 1988 and 1989 in the same hospital, using the same study design and protocol. Data on age, gender, number admitted, length of stay, HIV status, clinical AIDS, final diagnosis, case mix, and outcome were compared. In 1992, 374 consecutive patients were admitted in 15 24-hour periods (24.9 patients/period) compared with the 1988 to 1989 study, which enrolled 506 patients in 22 24-hour periods (23.0 patients/period). Patients' age, gender, and length of hospital stay were similar in both studies. In 1992, 39% of patients were HIV-positive compared with 19% in 1988 to 1989 (p < 10(-6)); whereas seropositive admissions rose 123% between the two periods (p < .0001), HIV-negative admissions declined 18% (p < .05). Clinical surveillance for AIDS consistently identified <40% of HIV-positive patients. Irrespective of HIV status, tuberculosis and pneumococcal pneumonia were the leading diagnoses in both surveys. No change was found in the diagnoses recorded for HIV-positive patients, but in HIV-negative patients, reductions were significant in the case mix (p < .00001) and range of diagnoses (p < .001) seen in 1992. Outcome remained unchanged for HIV-positive patients with approximately 35% mortality in both surveys. Outcome significantly worsened, in relative and absolute terms, for HIV-negative patients: in 1992, mortality was 23%, compared with 13.9% in 1988 to 1989 (p < .005), with 3.5 deaths per 24-hour period in 1992 compared with 2.6 deaths per 24-hour period in 1988 to 1989 (p < .05, one-tailed). These data suggest that increasing selection for admission is taking place as demand for care increases because of HIV/AIDS. This process appears to favor HIV-positive patients at the expense of HIV-negative patients who seem to be crowded out and, once admitted, experience higher mortality rates. The true social costs of the HIV epidemic are underestimated by not including the effects on HIV-negative people.

Newton CR, Warrell DA. 1998. Neurological manifestations of falciparum malaria. Ann Neurol, 43 (6), pp. 695-702. | Show Abstract | Read more

Plasmodium falciparum remains one of the most common causes of central nervous system infection worldwide. Recently, differences between the pathophysiology of cerebral malaria in African children and nonimmune adults have been discovered, new syndromes occurring after malaria infection described, and mechanisms for the pathogenesis proposed. In addition, new antimalarial agents have been examined worldwide and initial studies on supportive studies conducted. This paper reviews these new advances, putting them into the perspective of the more established knowledge.

Seaton RA, Trevett AJ, Wembri JP, Nwokolo N, Naraqi S, Black J, Laurenson IF, Kevau I, Saweri A, Lalloo DG, Warrell DA. 1998. Randomized comparison of intramuscular artemether and intravenous quinine in adult, Melanesian patients with severe or complicated, Plasmodium falciparum malaria in Papua New Guinea. Ann Trop Med Parasitol, 92 (2), pp. 133-139. | Show Abstract | Read more

An open-label, randomized, controlled trial was used to compare the safety and efficacy of intramuscular artemether (a loading dose of 3.2 mg/kg, followed by 1.6 mg/kg daily for 4 days) and intravenous quinine (a loading dose of 20 mg quinine dihydrochloride/kg, followed first by 10 mg/kg every 8 h, each injection taking 4 h, for at least 48 h, and then oral quinine for a total of 7 days) in the management of strictly defined severe/complicated malaria in Melanesian adults. Four (12%) of the 33 patients who enrolled and completed follow-up died (one of the 15 who received artemether and three of the 18 who received quinine). Overall, cerebral malaria was uncommon (6%) whilst jaundice was common (76%). The time taken to clear 50% of parasites was less in those treated with artemether (median = 8 h; range = 2-24 h) than in the patients given quinine (median = 14 h; range = 2-25 h; P = 0.05). Temperature defervescence was also quicker in those treated with artemether (median = 32 hours; range = 20-112 h) than in those in the quinine group (median = 48 h; range = 28-88 h; P = 0.034). Hypoglycaemia was not observed in any patient treated with artemether but complicated therapy in 11 (79%) of the 14 patients given quinine who had not had pre-treatment spontaneous hypoglycaemia. No serious adverse effects were attributable to artemether. The Plasmodium falciparum infections observed during the 1 month of follow-up, in three patients who had received artemether and two who had been given quinine, were probably due to recrudescence. Plasmodium vivax parasitaemias were also observed during follow-up, in one or two patients in each treatment group. Artemether appears safe in Melanesian adults and is probably as effective as intravenous quinine in the treatment of severe or complicated falciparum malaria.

Wüster W, Golay P, Warrell DA. 1998. Synopsis of recent developments in venomous snake systematics, No. 2. Toxicon, 36 (2), pp. 299-307. | Show Abstract | Read more

Developments in our understanding of the systematics of venomous snakes since the beginning of 1996 are discussed and reviewed with special emphasis on their relevance and implications for toxinologists and clinicians. Groups of snakes affected by recent developments include the genera Elapomorphus, Rhabdophis, Vermicella, Atheris, Daboia, Agkistrodon/Gloydius, Bothrops/Bothriopsis and Trimeresurus. Other important publications on venomous snakes are noted.

Warrell DA. 1998. Introduction British Medical Bulletin, 54 (2), pp. 265-267. | Read more

Warrell DA. 1998. Antivenoms and treatment of snake-bite Prescribers' Journal, 38 (1), pp. 10-18.

Moran NF, Newman WJ, Theakston RD, Warrell DA, Wilkinson D. 1998. High incidence of early anaphylactoid reaction to SAIMR polyvalent snake antivenom. Trans R Soc Trop Med Hyg, 92 (1), pp. 69-70. | Show Abstract | Read more

During a prospective study of 147 patients with snakebite presenting to a rural South African hospital, 13 of 17 patients (76%) treated with South African Institute for Medical Research (SAIMR) polyvalent antivenom experienced potentially severe early (anaphylactoid) reactions. The most common reaction was generalized urticaria (12; 71%), but 3 cases of angio-oedema (18%), 2 of bronchospasm (12%), and 2 of hypotension (12%) were also observed. Reactions were controlled with adrenaline, antihistamines, and resuscitation. All patients fully recovered from envenoming although the full dose of antivenom was not given to most. Indications for the use of this antivenom should be reconsidered and patients should be given antivenom in a high care setting if possible. Use of antivenom by lay people outside hospital should be discouraged and antivenom manufacturing processes could usefully be reviewed.

Warrell DA. 1998. Tropical medicine: achievements and prospects. Introduction. Br Med Bull, 54 (2), pp. 265-267.

Newman WJ, Moran NF, Theakston RD, Warrell DA, Wilkinson D. 1997. Traditional treatments for snake bite in a rural African community. Ann Trop Med Parasitol, 91 (8), pp. 967-969. | Read more

Wuster W, Warrell DA, Cox MJ, Jintakune P, Nabhitabhata J. 1997. Redescription of Naja siamensis (Serpentes : Elapidae), a widely overlooked spitting cobra from SE Asia: geographic variation, medical importance and designation of a neotype JOURNAL OF ZOOLOGY, 243 (4), pp. 771-788. | Read more

Eddleston M, Peacock S, Juniper M, Warrell DA. 1997. Ganciclovir therapy for severe cytomegalovirus infection in immunocompetent patients - Reply CLINICAL INFECTIOUS DISEASES, 25 (6), pp. 1487-1488. | Read more

Warrell DA. 1997. Cerebral malaria: clinical features, pathophysiology and treatment. Ann Trop Med Parasitol, 91 (7), pp. 875-884. | Show Abstract | Read more

Herbert Gilles played an important role in the establishment of the Wellcome-Mahidol University, Oxford Tropical Medicine Research Programme in Thailand in 1979. The randomized, placebo-controlled trial of dexamethasone in cerebral malaria that was carried out in Chantaburi in 1980 yielded results which led to the abandonment of ancillary corticosteroid therapy in this disease and contributed to a rejection of the 'permeability hypothesis'. The clinical manifestations of strictly defined cerebral malaria have not been described both in non-immune adults in Thailand and Vietnam and in African children. Clinical and histopathological studies in human patients, together with laboratory studies of cyto-adherence, malaria 'toxin' and cytokine production have provided some evidence for both the 'mechanical' and 'toxin-cytokine' hypotheses to explain the pathophysiology of this condition. Chemotherapy is challenged by the continuing evolution of antimalarial resistance. Recently, the most powerful studies ever carried out with antimalarial drugs have demonstrated that artemether and quinine achieve similar case fatalities, in the range 11%-21%, and that both drugs have some advantages and disadvantages. Further studies are needed to define the efficacy and safety of prophylactic anticonvulsants and exchange transfusion in cerebral malaria. Cerebral malaria remains a major cause of mortality and, in African children, morbidity.

Warrell DA. 1997. Venom and antivenom SAUDI MEDICAL JOURNAL, 18 (5), pp. 447-452. | Show Abstract

The fauna of Saudi Arabia comprises a large number of venomous species of snakes, fish, scorpions, insects, coelenterates and molluses. The venoms of these animals show a remarkable diversity of actions on human tissues. Neurotoxins (for example, from the Arabian cobra Naja haje arabica) interrupt transmission at peripheral neuromuscular junctions or (for example scorpion neurotoxins) stimulate voltage sensitive synaptic sodium and potassium channels with release of acetylcholine and catecholamines. The venoms of Red Sea carnivorous marine snails (genus Conus) contain 'conotoxins' which have effects on voltage sensitive calcium and sodium channels, acetylcholine receptors, the vasopressin receptor and N-methyl-D-aspartate receptors. Of particular interest are sarafotoxins from the venom of the burrowing asp (Atractaspis engaddensis, Atractaspididae), which cause coronary artery vasoconstriction and atrioventricular block. They are homologous with human endogenous endothelins. Human victims of bites by this species may die very rapidly after developing anaphylactic/autonomic symptoms, shock and atrioventricular conduction abnormalities. Improved ovine Fab fragment antivenoms are being developed for treatment of envenoming by Saudi Arabian snakes and scorpions. These Fab antivenoms have the pharmacological advantage of more rapid tissue distribution, a larger apparent volume of distribution and less risk of Fc or aggregate-induced complement activation than conventional F (ab1)2 antivenoms.

Lalloo DG, Trevett AJ, Warrell DA. 1997. Severe envenomation by the taipan (Oxyuranus scutellatus) Med J Aust, 167 (1), pp. 54-55.

Warrell DA. 1997. Debate: Tropical Medicine as a formal discipline is dead and should be buried - Opposing the motion .1. TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE, 91 (4), pp. 374-374.

Warrell DA. 1997. Travel medicine SAUDI MEDICAL JOURNAL, 18 (4), pp. 331-337. | Show Abstract

Most of the infectious diseases to which travellers are exposed can now be prevented by immunization, chemoprophytaxis protection against insect bites, strict food and water hygiene and avoidance of unprotected sexual activity. Some basic childhood immunizations (tetanus, diphtheria, poliomyelitis) may need to be boosted. Special vaccines are available for regional disease problems such as Japanese encephalitis in Asia and tick- borne encephalitis in Central Europe. Yellow Fever vaccination is statutory in endemic areas of Africa and Latin America. Pre-exposure immunization against rabies is increasingly advocated for travellers. When advising travellers it is important to obtain up-to-date information about recent epidemics. This is provided by Morbidity and Mortality Weekly Report (MMWR) and WHO epidemiological reports. Annual epidemics of meningococcal meningitis are predictable in some areas such as the 'meningitis' belt of Africa. Traveller's diarrhea remains the commonest of diseases of travellers, with an incidence of >50% in some countries, while malaria is the most likely to prove fatal. However, most deaths in travellers are caused by trauma, including road traffic accidents, and chronic conditions not directly related to travel (for example, cardiovascular disease).

Gilks CF, Godfrey-Faussett P, Batchelor BI, Ojoo JC, Ojoo SJ, Brindle RJ, Paul J, Kimari J et al. 1997. Recent transmission of tuberculosis in a cohort of HIV-1-infected female sex workers in Nairobi, Kenya. AIDS, 11 (7), pp. 911-918. | Show Abstract | Read more

OBJECTIVES: To describe the epidemiological and clinical characteristics of HIV-related tuberculosis in a female cohort, and to investigate the relative importance of recently transmitted infection and reactivation in the pathogenesis of adult HIV-related tuberculosis. DESIGN: Members of an established cohort of female sex workers in Nairobi were enrolled in a prospective study. Women were followed up regularly and seen on demand when sick. METHODS: Between October 1989 and September 1992 we followed 587 HIV-infected and 132 HIV-seronegative women. Standard protocols were used to investigate common presentations. Cases of tuberculosis were identified clinically or by culture. All available Mycobacterium tuberculosis strains underwent DNA fingerprint analysis. RESULTS: Forty-nine incident and four recurrent episodes of tuberculosis were seen in HIV-infected women; no disease was seen in seronegative sex workers (P = 0.0003). The overall incidence rate of tuberculosis was 34.5 per 1000 person-years amongst HIV-infected participants. In purified protein derivative (PPD) skin test-positive women the rate was 66.7 per 1000 person-years versus 18.1 per 1000 person-years in PPD-negative women. Twenty incident cases (41%) were clinically compatible with primary disease. DNA fingerprint analysis of strains from 32 incident cases identified two clusters comprising two and nine patients; allowing for index cases, 10 patients (28%) may have had recently transmitted disease. Three out of 10 (30%) patients who were initially PPD skin test-negative became PPD-positive. Taken together, 26 incident cases (53%) may have been recently infected. DNA fingerprint analysis also identified two (50%) of the four recurrent tuberculosis episodes as reinfection. CONCLUSIONS: Substantial recent transmission of tuberculosis appears to be occurring in Nairobi amongst HIV-infected sex workers. It may be incorrect to assume in other regions of high tuberculosis transmission that active HIV-related tuberculosis usually represents reactivation of latent infection.

Faux JA, Moffatt MF, Lalvani A, Dekker J, Warrell DA, Cookson WO. 1997. Sensitivity to bee and wasp venoms: association with specific IgE responses to the bee and wasp venom and HLA DRB1 and DPB1. Clin Exp Allergy, 27 (5), pp. 578-583. | Show Abstract | Read more

BACKGROUND: Stings from bees and wasps can cause systemic reactions which can be fatal in some individuals. In these venom-sensitive patients, specific IgE to the venom is produced and is considered to participate in the adverse reactions. This immune response requires antigen presentation by human leucocyte antigens (HLA) class II molecules, which includes DR and DP, which are present on antigen presenting cells. OBJECTIVE: To test for associations between HLA class II DRB1 and DPB1 alleles and life-threatening sensitivity to both bee and wasp venoms. To establish further whether any associations are independent of the atopy phenotype. METHODS: A total of 33 bee- and 44 wasp-venom-sensitive patients was studied. DRB1 genotypes were determined by single stranded oligonucleotide (SSO) probing of PCR products, and DPB1 genotypes by amplified fragment length polymorphism (AFLP) analysis. Total and specific IgE were measured using the Pharmacia Immunocap, FEIA. Patients with specific IgE to the venom antigens only were termed monosensitive and those with additional specific IgE to HDM and/or GP were termed polysensitive. RESULTS: Allele frequencies were compared to an unrelated control population. The 33 bee-sensitive patients had a greater prevalence of DRB1*07 alleles than the control subjects, 26% vs 14%, with an odds ratio (OR) of 2.1 (95% CI, 1.2-3.7, P = 0.015, corrected for multiple comparisons, Pc = ns). This association was confined to the 15 monosensitive bee patients, who had a 43% DRB1*07 allele frequency when compared with 11% in the 18 polysensitive bee patients, OR 6.1 (95% CI, 1.73-22, P = 0.004, Pc = 0.05), and when compared with a control group of non-venom subjects, 43% vs 16%, OR 3.9 (95% CI, 1.72-9.0, P = 0.002, Pc = 0.02). The 44 wasp-sensitive patients had an increase in the DRB1*11 allele when compared with the control subjects, 13% vs 6%, with an OR 2.2 (95% CI, 1.0-4.6, P = 0.04, Pc = NS), and a decreased prevalence of DRB1*04 alleles, 10% vs 19%, with an OR 0.33 (95% CI, 0.24-0.99, P = 0.04, Pc = NS), but these were not significant when multiple comparisons were taken into account. The DPB1 alleles were not significantly different between the venom sensitive patients and the controls. CONCLUSION: Patients monosensitive to bee venom had a significantly greater prevalence of DRB1*07 alleles than the non-venom, control population suggesting that IgE responses in these patients may, in part be controlled by immune response HLA class II genes. These results are also suggestive of wasp-sensitive patients having a higher prevalence of DRB1*11 and a lower prevalence of DRB1*04 than the control population.

Milani Júnior R, Jorge MT, de Campos FP, Martins FP, Bousso A, Cardoso JL, Ribeiro LA, Fan HW et al. 1997. Snake bites by the jararacuçu (Bothrops jararacussu): clinicopathological studies of 29 proven cases in São Paulo State, Brazil. QJM, 90 (5), pp. 323-334. | Show Abstract | Read more

The jararacuçu, one of the most dreaded snakes of Brazil, southern Bolivia, Paraguay and northeastern Argentina, is a heavily-built pit viper which may grow to a length of 2.2 m. Up to 1000 mg (dry weight) of highly-lethal venom may be milked from its venom glands on a single occasion. It has accounted for 0.8% to 10% of series of snake bites in São Paulo State, Brazil. We examined 29 cases of proven jararacuçu bites recruited over a 20-year period in two São Paulo hospitals. Severe signs of local and systemic envenoming, (local necrosis, shock, spontaneous systemic bleeding, renal failure) were seen only in patients bitten by snakes longer than 50 cm; bites by shorter specimens were more likely to cause incoagulable blood. Fourteen patients developed coagulopathy, six local necrosis (requiring amputation in one) and five local abscesses. Two became shocked and four developed renal failure. Three patients, aged 3, 11 and 65 years, died 18.75, 27.75 and 83 h after being bitten, with respiratory and circulatory failure despite large doses of specific antivenom and intensive-care-unit management. In two patients, autopsies revealed acute renal tubular necrosis, cerebral oedema, haemorrhagic rhabdomyolysis at the site of the bite and disseminated intravascular coagulation. In one survivor with chronic renal failure, renal biopsy showed bilateral cortical necrosis; the patient remains dependent on haemodialysis. Effects of polyspecific Bothrops antivenom were not impressive, and it has been suggested that anti-Bothrops and anti-Crotalus antivenoms should be given in combination.

Coombs MD, Dunachie SJ, Brooker S, Haynes J, Church J, Warrell DA. 1997. Snake bites in Kenya: a preliminary survey of four areas. Trans R Soc Trop Med Hyg, 91 (3), pp. 319-321. | Show Abstract | Read more

Primary data were collected on the incidence, severity and species responsible for snake bites in 4 areas of Kenya: (i) Kakamega and western Kenya, (ii) Lake Baringo and Laikipia, (iii) Kilifi and Malindi, and (iv) northern Kenya. The overall average frequency of snake bite was 13.8 per 100,000 population per year (range 1.9-67.9). The minimum rate of snake bite mortality was 0.45/100,000/year. Thirty-four of the 50 units visited reported no knowledge of death from snake bite in the last 5 years. Possible reasons for the low estimates are discussed. Traditional treatments were common, especially the use of herbal remedies and incisions at the wound site.

Warrell DA. 1997. The 1996 Runme Shaw Memorial Lecture: malaria--past, present and future. Ann Acad Med Singapore, 26 (3), pp. 380-387. | Show Abstract

Falciparum malaria may have infected Homo sapiens (and perhaps H erectus) in the Asia Pacific region for more than 100,000 years. This estimate is based on the gene frequency of alpha-thalassaemia, the protection it affords against falciparum malaria and assumptions of untreated mortality from the infection. Up until the end of the 19th century, there was a high mortality from malaria in the coastal parts of Malaya, but the malaria control campaign, begun in 1901 at Klang, was described by Sir Ronald Ross as the first successful antimalarial work in the (then) British Empire. This was extended to Singapore in 1911. When the Far Eastern Association of Tropical Medicine held its Fifth Biennial Congress in Singapore in 1923, malaria was still a major killing disease in parts of Malaya and Sarawak. The mechanism of life-threatening malaria involves cytoadherence of parasitised erythrocytes in microvascular beds, a process enhanced by the products of macrophage activation induced by malarial pyrogen. Improvements in the chemotherapy of life-threatening falciparum malaria with chloroquine and quinine have been countered by the emergence of resistant strains. Artemisinin derivatives may become the treatment of choice during the coming decade. Apart from traditional anti-mosquito methods, control of malaria now involves the use of insecticide-impregnated bed nets, new entomological strategies, including genetic manipulation of mosquitoes and selective chemoprophylaxis. Antigenic diversity and antigenic variation of the malaria parasite have so far defeated attempts to produce an effective vaccine.

Jorge MT, Sano-Martins IS, Tomy SC, Castro SC, Ferrari RA, Ribeiro LA, Warrell DA. 1997. Snakebite by the bushmaster (Lachesis muta) in Brazil: case report and review of the literature. Toxicon, 35 (4), pp. 545-554. | Show Abstract | Read more

The bushmaster (Lachesis muta) of Central and South America, the world's longest pit viper, is capable of injecting a large dose of potent venom when it bites. A 28-year-old man, bitten by a 1.82 m long L. m. muta in Brazil, developed pain and oedema at the bite site, nausea, vomiting, diarrhoea and sweating. There was peripheral neutrophil leucocytosis and evidence of fibrinogen consumption with secondary activation of the fibrinolytic system. Two hours after the bite, eight ampoules of Instituto Butantan Lachesis antivenom was administered, and haemostasis was normal 24 hr later. A review of reports of 20 cases of bites in humans reliably attributed to this snake in Costa Rica, French Guiana, Brazil, Colombia and Venezuela confirms a syndrome of nausea, vomiting, abdominal colic, diarrhoea, sweating, hypotension, bradycardia and shock, possibly autopharmacological or autonomic in origin, not seen in victims of other American crotaline snakes. These, and other symptoms of bushmaster envenoming, are explained by haemorrhagic, coagulant and neurotoxic venom activities. The therapeutic efficacy of non-specific Bothrops/Crotalus polyvalent antivenoms in these cases has been unimpressive. For the treatment of bites by a snake which potentially injects a large dose (> 300 mg dry weight) of venom with a range of life-threatening activities, there is an urgent need to develop more potent specific antivenoms and to treat the dramatic and life-threatening cardiovascular symptoms.

Wüster W, Golay P, Warrell DA. 1997. Synopsis of recent developments in venomous snake systematics. Toxicon, 35 (3), pp. 319-340. | Show Abstract | Read more

Changes to our understanding of venomous snake systematics, and the consequent changes in the nomenclature of these animals, have traditionally been a great source of confusion among biomedical researchers. This paper aims to facilitate access to the taxonomic literature by presenting a synopsis of the changes in venomous snake systematics that have taken place recently (primarily since 1992), together with some comments on the implications of these changes for toxinologists and clinicians. Some long-standing problems in venomous snake taxonomy receive special attention. This includes Asiatic Naja, Asiatic Agkistrodon/Gloydius, Bothrops and related genera, Trimeresurus, Echis, Daboia (including Daboia russellii) and Vipera. It is hoped that this synopsis will result in the use of a more up-to-date and interpretable nomenclature for venomous snakes in the toxinological literature.

Coxon RE, Fekade D, Knox K, Hussein K, Melka A, Daniel A, Griffin GG, Warrell DA. 1997. The effect of antibody against TNF alpha on cytokine response in Jarisch-Herxheimer reactions of louse-borne relapsing fever. QJM, 90 (3), pp. 213-221. | Show Abstract | Read more

Severe Jarisch Herxheimer reaction (J-HR) precipitated by antibiotic treatment of louse-borne relapsing fever (LBRF) is associated with a transient, marked rise in circulating tumour necrosis factor alpha (TNF alpha), interleukin 6 (IL-6) and interleukin 8 (IL-8). Ovine polyclonal anti-TNF alpha antibody fragments (Fab) were used in a randomized double blind placebo controlled trial in an attempt to prevent this reaction. Within 4 h after penicillin, in controls (n = 29), a several-fold rise in cytokines occurred, concomitant with a fall in spirochaetes and maximal clinical manifestations of the J-HR. An intravenous infusion of anti-TNF alpha Fab, 30 min before penicillin in 20 patients reduced peak plasma levels of IL-6 and IL-8 (but not IL-1 beta) compared with controls (p = 0.01 and < 0.001, respectively) and the incidence of the J-HR, indicating some neutralization of TNF alpha. An apparent fall in TNF alpha reflected interference of anti-TNF alpha in the immunoassay.

Meyer WP, Habib AG, Onayade AA, Yakubu A, Smith DC, Nasidi A, Daudu IJ, Warrell DA, Theakston RD. 1997. First clinical experiences with a new ovine Fab Echis ocellatus snake bite antivenom in Nigeria: randomized comparative trial with Institute Pasteur Serum (Ipser) Africa antivenom. Am J Trop Med Hyg, 56 (3), pp. 291-300. | Show Abstract

During the past decade, effective snake antivenoms have become scarce in northern Nigeria. As a result, many patients severely envenomed by the saw-scaled or carpet viper (Echis ocellatus), which is responsible for more than 95% of the snake bites in the region, did not receive effective treatment and mortality and morbidity increased. To combat this crisis, a new monospecific ovine Fab antivenom (EchiTab) is being developed. Its theoretical advantages over conventional equine F(ab')2 antivenom are a more rapid tissue penetration and larger apparent volume of distribution (the volume of [tissue] fluid in which the the antivenom would be uniformly distributed to achieve the observed plasma concentration). In a preliminary study, two vials (20 ml; 1.0 g of protein) of EchiTab rapidly and permanently restored blood coagulability and cleared venom antigenemia in seven envenomed patients. Four experienced early reactions that responded to epinephrine. In a randomized comparative trial of one vial (10 ml; 0.5 g protein) of EchiTab or four ampules (40 ml; 2.12 g of protein) of Institute Pasteur Serum (Ipser) Africa polyspecific F(ab')2 antivenom, there were fewer reactions, but only 36% and 35% of patients, respectively, showed permanent restoration of coagulability, with the remainder requiring further doses. This suggests that 0.5 g (one vial) of EchiTab is approximately equivalent to 2.12 g (four ampules) of Ipser Africa antivenom, and that a higher initial dose will be required for most patients. Measurements of circulating venom and antivenom levels reflected the clinical events.

Seaton RA, Naraqi S, Wembri JP, Warrell DA. 1997. Cell-mediated immunity in HIV seronegative patients recovered from Cryptococcus neoformans var. gattii meningitis Medical Mycology, 35 (1), pp. 7-11. | Show Abstract | Read more

Cell-mediated immunity was assessed in 37 HIV seronegative healthy patients cured of Cryptococcus neoformans var. gattii meningitis and compared with matched controls using a multitest device which simultaneously injects seven standardized common antigens intradermally. Responses in patients and controls were similar; however, male patients had significantly higher compound (average) scores than controls (P = 0·041). Male scores were higher than female scores in both patient (P = 0·002) and control (P = 0·017) groups. In eight patients with acute cryptococcal meningitis, seven were anergic to challenge with 5 IU of tuberculin on admission. Two of these patients had positive reactions after treatment. Three of four patients tested prior to treatment with the multitest device were anergic to all seven antigens but all three survivors showed improved responsiveness following cure. These data suggest that patients are immunosuppressed on presentation (due to overwhelming var. gattii infection) but that following cure, cell-mediated immunity improves to its premorbid state. A transient state of immunosuppression prior to the development of the disease cannot be excluded. © 1997 Informa UK Ltd All rights reserved.

Warrell DA. 1997. The success of vaccination in tropical countries. Proc R Coll Physicians Edinb, 27 (1), pp. 22-29.

Warrell DA. 1997. Prazosin: scorpion envenoming and the cardiovascular system. Trop Doct, 27 (1), pp. 1.

Seaton RA, Naraqi S, Wembri JP, Warrell DA. 1997. Cell-mediated immunity in HIV seronegative patients recovered from Cryptococcus neoformans var. gattii meningitis. J Med Vet Mycol, 35 (1), pp. 7-11. | Show Abstract

Cell-mediated immunity was assessed in 37 HIV seronegative healthy patients cured of Cryptococcus neoformans var. gattii meningitis and compared with matched controls using a multitest device which simultaneously injects seven standardized common antigens intradermally. Responses in patients and controls were similar: however, male patients had significantly higher compound (average) scores than controls (P = 0.041). Male scores were higher than female scores in both patient (P = 0.002) and control (P = 0.017) groups. In eight patients with acute cryptococcal meningitis, seven were anergic to challenge with 5 IU of tuberculin on admission. Two of these patients had positive reactions after treatment. Three of four patients tested prior to treatment with the multitest device were anergic to all seven antigens but all three survivors showed improved responsiveness following cure. These data suggest that patients are immunosuppressed on presentation (due to overwhelming var. gattii infection) but that following cure, cell-mediated immunity improves to its premorbid state. A transient state of immunosuppression prior to the development of the disease cannot be excluded.

Trevett AJ, Mavo B, Warrell DA. 1997. Tetrodotoxic poisoning from ingestion of a porcupine fish (Diodon hystrix) in Papua New Guinea: nerve conduction studies. Am J Trop Med Hyg, 56 (1), pp. 30-32. | Show Abstract

Near Port Moresby in Papua New Guinea, three of four adult family members who ate a porcupine fish (Diodon hystrix) were severely poisoned. Within one hour of the meal, both the mother and her older daughter had developed paraesthesiae, ataxia, hypersalivation, sweating, and had collapsed and died. The younger daughter developed similar symptoms with progressive paralysis requiring mechanical ventilation for 24 hr, but she made a complete recovery 10 days after the poisoning. In this patient, nerve conduction studies showed reduced sensory and motor conduction velocities and evoked amplitudes with gradual improvement in parallel with the patient's clinical condition, consistent with the known action of tetrodotoxin on voltage-gated sodium channels.

Seaton RA, Verma N, Naraqi S, Wembri JP, Warrell DA. 1997. Visual loss in immunocompetent patients with Cryptococcus neoformans var. gattii meningitis. Trans R Soc Trop Med Hyg, 91 (1), pp. 44-49. | Show Abstract | Read more

In Papua New Guinea cryptococcal meningitis occurs predominantly in immunocompetent patients in whom Cryptococcus neoformans var, gattii is implicated in 95% of cases. Ocular complications are common. We have reviewed ophthalmic findings in 82 immunocompetent patients and have attempted to identify those features of the disease that predict an unfavourable visual outcome. Visual loss occurred in 52.6% of survivors and was associated with optic atrophy following optic disc swelling in 60.9%. Progression of disc swelling to optic atrophy was predicted by the presence of an abducens palsy (P = 0.049) and cerebrospinal fluid (CSF) cryptococcal antigen titres > 1:1024 (P = 0.036). Raised intracranial pressure (defined as opening CSF pressure > or = 300 mm on admission) was not associated with visual loss. Vision deteriorated in 17.3% of patients despite anticryptococcal therapy and in 3.7% it followed curative therapy. The high rate of visual loss in immunocompetent patients with C. neoformans var. gattii infection contrasts with others' experience of immunosuppressed patients with C. neoformans var. neoformans infection, in whom visual loss was rare. This difference may reflect immune mediated optic nerve dysfunction in C. neoformans var. gattii meningitis caused by either compression due to arachnoid adhesions or oedema and inflammatory cell-mediated damage.

Seaton RA, Verma N, Naraqi S, Wembri JP, Warrell DA. 1997. The effect of corticosteroids on visual loss in Cryptococcus neoformans var. gattii meningitis. Trans R Soc Trop Med Hyg, 91 (1), pp. 50-52. | Show Abstract | Read more

In Papua New Guinea visual loss is a frequent sequal to Cryptococcus neoformans var. gattii meningitis in immunocompetent patients. We have previously postulated that visual loss may occur as a result of the immunological response to infection around the optic nerve. This retrospective study set out to explore the effect of corticosteroids on visual outcome. Sixteen patients received varying doses of corticosteroid (mainly 100-250 mg of hydrocortisone daily for the prevention of febrile reactions to amphotericin) and 10 received anticryptococcal therapy alone. Visual deterioration occurred less frequently in those treated with corticosteroids (2/16 [12.5%] vs. 7/10 [70%], P = 0.007), blindness was less frequent (1/16 [5.3%] vs. 5/10 [50%], P = 0.018), and in 3 patients vision improved. Corticosteroids may have a role in preventing or halting visual loss in C. neoformans var. gattii meningitis in immunocompetent patients.

Warrell DA. 1997. Herbal remedies for malaria. Trop Doct, 27 Suppl 1 (SUPPL. 1), pp. 5-6.

Warrell DA. 1997. Prazosin: Scorpion envenoming and the cardiovascular system TROPICAL DOCTOR, 27 (1), pp. 1-1.

White NJ, Warrell DA. 1996. Dosage for malaria treatment LANCET, 348 (9037), pp. 1312-1312. | Read more

White NJ, Warrell DA. 1996. Dosage for malaria treatment. Lancet, 348 (9037), pp. 1312.

Seaton RA, Hamilton AJ, Hay RJ, Warrell DA. 1996. Exposure to Cryptococcus neoformans var. gattii--a seroepidemiological study. Trans R Soc Trop Med Hyg, 90 (5), pp. 508-512. | Show Abstract | Read more

An enzyme-linked immunosorbent assay was developed to study prevalence of immunoglobulin G (IgG) antibody to non-capsular Cryptococcus neoformans var. gattii antigen in a population of healthy Papua New Guinea (PNG) controls and patients. Patients with acute C. neoformans var. gattii meningitis had elevated levels of IgG which declined significantly following treatment (P = 0.034). Levels in the sera of convalescent patients were significantly higher than those in PNG controls (P < 0.001), which in turn were significantly higher than in a UK control group (P < 0.001). Clear differences were observed amongst the PNG controls. Adults had significantly higher levels than children (P = 0.002) and men had significantly higher levels than women (P = 0.047). No difference was observed between levels in patient-related and unrelated controls. IgG responses in PNG controls mirror the prevalence of disease in this population. It is postulated that exposure to C. neoformans var. gattii is less common in children and women due to some as yet unidentified behavioural difference and that exposure occurs away from the home environment.

Warrell MJ, Warrell DA. 1996. Economical use of rabies vaccine. Lancet, 348 (9027), pp. 614.

Warrell MJ, Warrell DA. 1996. Economical use of rabies vaccine LANCET, 348 (9027), pp. 614-615. | Read more

Fekade D, Knox K, Hussein K, Melka A, Lalloo DG, Coxon RE, Warrell DA. 1996. Prevention of Jarisch-Herxheimer reactions by treatment with antibodies against tumor necrosis factor alpha. N Engl J Med, 335 (5), pp. 311-315. | Show Abstract | Read more

BACKGROUND: In patients with louse-borne relapsing fever (Borrelia recurrentis infection), antimicrobial treatment is often followed by sudden fever, rigors, and persistent hypotension (Jarisch-Herxheimer reactions) that are associated with increases in plasma concentrations of tumor necrosis factor alpha (TNF-alpha), interleukin-6, and interleukin-8. We attempted to determine whether sheep polyclonal Fab antibody fragments against TNF-alpha (anti-TNF-alpha Fab) could suppress the Jarisch-Herxheimer reaction. METHODS: We conducted a randomized, double-blind, placebo-controlled trial in 49 patients with proven louse-borne relapsing fever. Immediately before the intramuscular injection of penicillin, the patients received an intravenous infusion of either anti-TNF-alpha Fab or a control solution. RESULTS: Ten of the 20 patients given anti-TNF-alpha Fab had Jarisch-Herxheimer reactions with rigors, as compared with 26 of the 29 control patients (P = 0.006). The controls had significantly greater mean maximal increases in temperature (1.5 vs. 0.8 degrees C, P < 0.001), pulse rate (31 vs. 13 per minute, P < 0.001), and systolic blood pressure (25 vs. 15 mm Hg, P < 0.003), as well as higher mean peak plasma concentrations of interleukin-6 (50 vs. 17 micrograms per liter) and interleukin-8 (2000 vs 205 ng per liter) (P < 0.001 for both comparisons). Levels of TNF-alpha were undetectable after treatment with anti-TNF-alpha Fab. CONCLUSIONS: Pretreatment with sheep anti-TNF-alpha Fab suppresses Jarisch-Herxheimer reactions that occur after penicillin treatment for louse-borne relapsing fever, reduces the associated increases in plasma concentrations of interleukin-6 and interleukin-8, and may be useful in other forms of sepsis.

Lalloo DG, Trevett AJ, Paul M, Korinhona A, Laurenson IF, Mapao J, Nwokolo N, Danga-Christian B et al. 1996. Severe and complicated falciparum malaria in Melanesian adults in Papua New Guinea. Am J Trop Med Hyg, 55 (2), pp. 119-124. | Show Abstract

Severe falciparum malaria usually occurs in children, but also occurs in nonimmune migrants or partially immune adults in areas of unstable transmission. We have studied prospectively 70 adult patients with strictly defined severe malaria from the south coast of Papua New Guinea where malaria transmission is not intense. Only 19 (27.1%) were migrants from areas where malaria transmission does not occur; many other patients were periurban dwellers who had become infected after visits to their home villages. The most common clinical features were jaundice or hepatic dysfunction, impaired consciousness, renal failure, cerebral malaria, and anemia. Hypoglycemia was common following treatment with quinine. The overall case fatality rate was 18.6%; renal failure and cerebral malaria in particular were associated with a poor outcome. Reduction in mortality might be achieved by aggressive therapy of renal failure with earlier institution of dialysis; the use of preventive measures for immigrants or urban dwellers returning to high transmission areas might reduce the incidence of this dangerous disease.

Warrell DA, Hudson BJ, Lalloo DG, Trevett AJ, Whitehead P, Bamler PR, Ranaivoson M, Wiyono A et al. 1996. The emerging syndrome of envenoming by the New Guinea small-eyed snake Micropechis ikaheka. QJM, 89 (7), pp. 523-530. | Show Abstract | Read more

The New Guinea small-eyed or ikaheka snake, Micropechis ikaheka, which occurs throughout New Guinea and some adjacent islands, is feared by the indigenes. The first proven human fatality was in the 1950s and this species has since been implicated in many other cases of severe and fatal envenoming. Reliable attribution of envenoming to this species in victims unable to capture or kill the snake recently became possible by the use of enzyme immunoassay. Eleven cases of proven envenoming by M. ikaheka, with two fatalities, were identified in Papua New Guinea and Irian Jaya. Five patients showed no clinical signs of envenoming. The other six patients showed symptoms typical of envenoming by other Australasian elapids: mild local swelling, local lymphadenopathy, neurotoxicity, generalized myalgia, spontaneous systemic bleeding, incoagulable blood and passage of dark urine (haemoglobinuria or myoglobinuria). Two patients developed hypotension and two died of respiratory paralysis 19 and 38 h after being bitten. In vitro studies indicate that the venom is rich in phospholipase A2, is indirectly haemolytic, anticoagulant and inhibits platelets, but is not procoagulant or fibrinolytic. It shows predominantly post-synaptic neurotoxic and myotoxic activity. Anecdotally, Commonwealth Serum Laboratories' (CSL) death adder antivenom has proved ineffective whereas CSL polyvalent antivenom may be beneficial. Anticholinesterase drugs might prove effective in improving neuromuscular transmission and should be tested in patients with neurotoxic envenoming.

Seaton RA, Naraqi S, Wembri JP, Warrell DA. 1996. Predictors of outcome in Cryptococcus neoformans var. gattii meningitis. QJM, 89 (6), pp. 423-428. | Show Abstract | Read more

In Papua New Guinea, Cryptococcus neoformans var. gattii meningitis has a high fatality rate even in immunocompetent patients. Our retrospective study attempted to identify marker of poor prognosis. Of 88 immunocompetent patients, 30 (34.1%) died, usually soon after admission, and mortality was higher in men (p = 0.025) and older patients (p = 0.039). Death was associated with altered consciousness (p < 0.001), a history of convulsions prior to treatment (p = 0.002) and a maximum systolic blood pressure of > 150 mmHg (p = 0.017). These data suggest that death results from raised intracranial pressure and subsequent tentorial herniation. However, CSF opening pressure measured on admission was raised in 29/36 (81%) patients and did not predict outcome. In survivors, relapse was uncommon and was not predicted by discharge serum cryptococcal antigen titres, which were frequently raised on completion of therapy in asymptomatic patients. Mortality may be reduced if efforts are made to lower intracranial pressure in those patients who present with markers of poor prognosis.

Wuster W, Thorpe RS, Puorto G, Furtado MFD, Hoge SA, Salomao MG, Theakston RDG, Warrell DA. 1996. Systematics of the Bothrops atrox complex (Reptilia: Serpentes: Viperidae) in Brazil: A multivariate analysis HERPETOLOGICA, 52 (2), pp. 263-271.

Lucas SB, Hounnou A, Bell J, Peacock C, Andoh J, Honde M, DeCock KM, Warrell DA. 1996. Severe cerebral swelling is not observed in children dying with malaria QJM-AN INTERNATIONAL JOURNAL OF MEDICINE, 89 (5), pp. 351-353. | Show Abstract

In an autopsy study in Abidjan, Cote d'lvoire, 14/155 brains of children <13 years had malaria parasites within cerebral blood vessels. This was associated with cerebral swelling (57% of brains), ventricular compression (86%) and mild basal grooving (43%), but not with coning of the medulla and cerebellum. The pathophysiology of cerebral malaria does not culminate in severe raised intracranial pressure and herniation, and over-concern over the safety of lumbar puncture in malaria may not be warranted.

Warrell DA, White NJ, Nosten F, Day N. 1996. Tropical medicine in and out of the tropics. Lancet, 347 (9008), pp. 1111-1112. | Read more

Gilks CF, Ojoo SA, Ojoo JC, Brindle RJ, Paul J, Batchelor BI, Kimari JN, Newnham R, Bwayo J, Plummer FA. 1996. Invasive pneumococcal disease in a cohort of predominantly HIV-1 infected female sex-workers in Nairobi, Kenya. Lancet, 347 (9003), pp. 718-723. | Show Abstract | Read more

BACKGROUND: HIV infection is a major risk factor for pneumococcal disease in industrialised countries. Although both are common infections in sub-Saharan Africa, few studies have investigated the importance of this interaction. We have followed up a cohort of female sex-workers in Nairobi and report here on the extent of invasive pneumococcal disease. METHODS: A well-established cohort of low-class female sex-workers, based around a community clinic, was followed up from October, 1989, to September, 1992. 587 participants were HIV positive and 132 remained HIV negative. Set protocols were used to investigate common presentations. Cases were identified clinically and radiographically. Streptococcus pneumoniae and other pathogens were diagnosed by culture. FINDINGS: Seventy-nine episodes of invasive pneumococcal disease were seen in the 587 HIV-positive women compared with one episode in the 132 seronegative women (relative risk 17.8, 95% CI 2.5 to 126.5). In seropositive women the incidence rate was 42.5 per 1000 person-years and the recurrence rate was 264 per 1000 person-years. By serotyping, most recurrent events were re-infection. A wide spectrum of HIV-related pneumococcal disease was seen: only 56% of cases were pneumonia; sinusitis was seen in 30% of cases, and occult bacteraemia, a novel adult presentation, in 11%. Despite forty-two bacteraemic episodes, no deaths were attributable to Strep pneumoniae. At first presentation the mean CD4 cell count was 302/microL(SD 191) and was 171/microL (105) for recurrent episodes. During acute Strep pneumoniae infection the CD4 cell count was reversibly suppressed (mean fall in sixteen episodes, 105/microL [123]). The neutrophil response to acute infection was blunted and was correlated with CD4 count (r=0.50, 95% CI 0.29 to 0.66). Strep pneumoniae caused more disease, at an earlier stage of HIV immunosuppression, than Mycobacterium tuberculosis or non-typhi salmonellae. INTERPRETATION: Our study highlights the importance of the pneumococcus as an early but readily treatable complication of HIV infection in sub-Saharan Africa.

Pierini SV, Warrell DA, de Paulo A, Theakston RD. 1996. High incidence of bites and stings by snakes and other animals among rubber tappers and Amazonian Indians of the Juruá Valley, Acre State, Brazil. Toxicon, 34 (2), pp. 225-236. | Show Abstract | Read more

Among forest-dwelling Amazonian Indians and rubber tappers (seringueiros) of the Juruá valley in Acre State, north-western Brazil, snakebite is an important cause of morbidity and death. Overall, 13% of a surveyed population had been bitten during their lifetime. Seventeen per cent of Katukina Indians, but only 8% of Ashaninkas, had been bitten by snakes reflecting, perhaps, different levels of traditional knowledge of the forest and its dangers. Most bites occurred in the jungle or on jungle trails (56%), while people were working (41%) or walking (26%), and were inflicted on the feet (54%). Ninety per cent of bite victims received treatment, usually traditional (93%); the majority (80%) recovered fully. Mortality was estimated at about 400 deaths per 100,000 population per lifetime. Bites and stings from other venomous forest and river animals, especially the freshwater sting ray (Potamotrygon sp.), were also extremely common. One death from an ant bite was recorded.

Laurenson IF, Trevett AJ, Lalloo DG, Nwokolo N, Naraqi S, Black J, Tefurani N, Saweri A, Mavo B, Igo J, Warrell DA. 1996. Meningitis caused by Cryptococcus neoformans var. gattii and var. neoformans in Papua New Guinea. Trans R Soc Trop Med Hyg, 90 (1), pp. 57-60. | Show Abstract | Read more

Eleven cases of cryptococcal meningitis were diagnosed and biotyped from September 1991 to August 1992 in Papua New Guinea (PNG). Seven isolates were Cryptococcus neoformans var. gattii from paediatric and adult patients, one with diabetes mellitus and 4 were C. neoformans var. neoformans from adults, of whom 2 had human immunodeficiency virus type 1 (HIV-1) infection, and one each had tuberculosis and Plasmodium vivax malaria. Significant clinical findings were headache, fever, meningism, vomiting, photophobia, papilloedema and cranial nerve lesions. Five patients (45.5%) died; 3 of these were adults with var. gattii and 2 were men with both var. neoformans and HIV-1 infections. This prospective tropical study documents the emergence of C. neoformans var. neoformans in patients with HIV-1 infection in a country where previously var. gattii had predominated in the immunocompetent. There has been no earlier report of cryptococcosis in an HIV-1 seropositive patient in PNG. Despite presumed exposure to both varieties of C. neoformans, var. gattii infections had been most frequent. As HIV-1 spreads, the proportion of hosts infected with var. neoformans may rise. The course of meningitis caused by the 2 varieties of C. neoformans may differ, with mortality in the tropics remaining particularly high. In PNG the environmental source of C. neoformans remains elusive.

Lalloo DG, Trevett AJ, Black J, Mapao J, Saweri A, Naraqi S, Owens D, Kamiguti AS, Hutton RA, Theakston RD, Warrell DA. 1996. Neurotoxicity, anticoagulant activity and evidence of rhabdomyolysis in patients bitten by death adders (Acanthophis sp.) in southern Papua New Guinea. QJM, 89 (1), pp. 25-35. | Show Abstract | Read more

Thirty-two patients with enzyme-immunoassay-proven death adder (Acanthophis sp.) bites were studied in Port Moresby, Papua New Guinea. Eighteen were envenomed; local signs were rare and none had incoagulable blood, but all except one had signs of neurotoxicity. Five (27.7%) envenomed patients required intubation and ventilation. One patient developed renal failure, previously undescribed following death adder bites. Laboratory investigations showed mild prolongation of prothrombin and partial thromboplastin times in some patients. In vitro studies showed that the venom contains anticoagulant activity, but does not cause fibrinogenolysis. In contrast to taipan envenoming, neurotoxicity did not progress after antivenom administration, and there was reversal of neurotoxicity, evident within 6 h, in three severely envenomed patients treated less than 12 h after the bite. One patient treated with antivenom and anticholinesterases had the most dramatic response to treatment; the optimum management of bites by this species may include prompt treatment with both antivenom and anticholinesterases in addition to effective first aid.

Connolly S, Trevett AJ, Nwokolo NC, Lalloo DG, Naraqi S, Mantle D, Schofield IS, Fawcett PR, Harris JB, Warrell DA. 1995. Neuromuscular effects of Papuan Taipan snake venom. Ann Neurol, 38 (6), pp. 916-920. | Show Abstract | Read more

Snakebite is a cause of significant morbidity in Central Province, Papua New Guinea. Three adult patients with clinical evidence of neurotoxicity following envenomation by the Papuan taipan had serial neurophysiological examinations over the course of their subsequent hospitalization. All required artificial ventilation for 2.5 to 5 days. The compound muscle action potential (CMAP) amplitudes declined over the first 2 to 4 days after envenoming and then gradually increased in parallel with clinical recovery. Repetitive stimulation studies revealed a distinctive pattern of abnormality. Activation resulted in brief potentiation of the CMAP followed by significantly greater decrement than observed at rest. This effect lasted up to 30 minutes and was not altered after intravenous edrophonium. Single-fiber electromyographic recordings during the recovery phase of the illness were abnormal with marked blocking and increased jitter. All patients were able to return home.

Chiodini PL, Conlon CP, Hutchinson DB, Farquhar JA, Hall AP, Peto TE, Birley H, Warrell DA. 1995. Evaluation of atovaquone in the treatment of patients with uncomplicated Plasmodium falciparum malaria. J Antimicrob Chemother, 36 (6), pp. 1073-1078. | Show Abstract | Read more

The activity of atovaquone in patients with oligosymptomatic Plasmodium falciparum malaria was assessed in an open, non-comparative clinical study. The patients showed a good clinical response, but there was a high rate of recrudescence. The activity of atovaquone in combination with another antimalarial agent should be investigated.

Theakston RD, Warrell DA. 1995. 1st International Congress on Envenomations and their Treatments Institut Pasteur, Paris, 7-9 June, 1995. Biologicals, 23 (4), pp. 327-330. | Read more

Theakston RD, Laing GD, Fielding CM, Lascano AF, Touzet JM, Vallejo F, Guderian RH, Nelson SJ, Wüster W, Richards AM. 1995. Treatment of snake bites by Bothrops species and Lachesis muta in Ecuador: laboratory screening of candidate antivenoms. Trans R Soc Trop Med Hyg, 89 (5), pp. 550-554. | Show Abstract | Read more

Bothrops xanthogrammus/asper, B. atrox and Lachesis muta are probably responsible for most cases of severe envenoming in Ecuador. In recent years, the most widely used antivenom ('Myn' Ronti, imported from Mexico) has proved clinically ineffective. There is an urgent need to identify an effective alternative for clinical testing. Five antivenoms with activity against Bothrops venoms were compared using standard World Health Organization rodent and in vitro assays: (i) 'Myn', Ronti Mexico SA ('B. atrox', 'Crotalus terrificus'), (ii) Instituto Butantan (Bothrops polyvalent, Brazil), (iii) Instituto Nacional de Hygiene y Medicina Tropical (Bothrops polyvalent, Ecuador), (iv) Instituto Nacional de Salud (B. asper, C. durissus and Lachesis muta, Colombia), and (v) Laboratorios Probiol (Bothrops, Lachesis and Crotalus, Colombia). The venoms against which these antivenoms were tested were Ecuadorian B. atrox, B. asper and B. xanthogrammus. Brazilian antivenom proved to be the most effective, followed by the Ecudorian and Colombian antivenoms. Mexican antivenom was completely ineffective in neutralizing the lethal effects of Ecuadorian Bothrops venoms. Monospecific Brazilian L. muta antivenom (Instituto Butantan) proved effective against Ecuadorian L. muta venom, but the Colombian polyspecific antivenoms did not. Clinical trials of Brazilian and Ecuadorian antivenoms are planned in the Amazon region of Ecuador in the near future.

Weatherall DJ, Ledingham JG, Warrell DA. 1995. On dinosaurs and medical textbooks. Lancet, 346 (8966), pp. 4-5. | Read more

Trevett AJ, Lalloo DG, Nwokolo NC, Naraqi S, Kevau IH, Theakston RD, Warrell DA. 1995. Electrophysiological findings in patients envenomed following the bite of a Papuan taipan (Oxyuranus scutellatus canni). Trans R Soc Trop Med Hyg, 89 (4), pp. 415-417. | Show Abstract | Read more

Electrophysiological studies were done on patients with systemic neurotoxicity following the bite of a Papuan taipan (Oxyuranus scutellatus canni). Evoked compound muscle action potentials decreased and increased in tandem with clinical deterioration and recovery. Nerve conduction velocities did not change in envenomed patients and were consistent with control studies. Repetitive nerve stimulation studies showed decremental responses in envenomed patients with post-tetanic potentiation followed by post-tetanic exhaustion. The findings are consistent with studies in vitro which suggested that the major action of neurotoxins in Australian taipan venom is at the synapse. The observation that electrophysiological data correlate closely with the clinical condition of the patient has potential application in the assessment of interventions in the management of snake bite victims.

Trevett AJ, Lalloo DG, Nwokolo NC, Naraqi S, Kevau IH, Theakston RD, Warrell DA. 1995. Failure of 3,4-diaminopyridine and edrophonium to produce significant clinical benefit in neurotoxicity following the bite of Papuan taipan (Oxyuranus scutellatus canni). Trans R Soc Trop Med Hyg, 89 (4), pp. 444-446. | Show Abstract | Read more

Progressive systemic neurotoxicity is a common feature in patients envenomed following the bite of a Papuan taipan (Oxyuranus scutellatus canni). Respiratory paralysis, which commonly results, accounts for considerable morbidity and mortality. Established neurotoxicity does not respond to antivenom. In this study, a combination of clinical and electrophysiological variables was used to assess the effect of edrophonium and 3,4-diaminopyridine in patients with significant neurotoxicity. Both drugs produced minor electrophysiological and clinical changes in envenomed patients. This effect was maximal when the 2 drugs were used in combination, but was insufficient to be of significant clinical benefit. Neither drug can be recommended for use in the management of Papuan taipan bite.

Lalloo DG, Trevett AJ, Korinhona A, Nwokolo N, Laurenson IF, Paul M, Black J, Naraqi S, Mavo B, Saweri A. 1995. Snake bites by the Papuan taipan (Oxyuranus scutellatus canni): paralysis, hemostatic and electrocardiographic abnormalities, and effects of antivenom. Am J Trop Med Hyg, 52 (6), pp. 525-531. | Show Abstract

One hundred sixty-six patients with enzyme immunoassay-proven bites by taipans (Oxyuranus scutellatus canni) were studied in Port Moresby, Papua New Guinea. One hundred thirty-nine (84%) showed clinical evidence of envenoming: local signs were trivial, but most developed hemostatic disorders and neurotoxicity. The blood of 77% of the patients was incoagulable and 35% bled spontaneously, usually from the gums. Fifty-one per cent had microscopic hematuria. Neurotoxic signs (ptosis, ophthalmoplegia, bulbar paralysis, and peripheral muscular weakness) developed in 85%. Endotracheal intubation was required in 42% and mechanical ventilation in 37%. Electrocardiographic abnormalities (sinus bradycardia and septal T wave inversion) were found in 52% of a group of 69 unselected patients. Specific antivenom raised against Australian taipan venom was effective in stopping spontaneous systemic bleeding and restoring blood coagulability but, in most cases, it neither reversed nor prevented the evolution of paralysis even when given within a few hours of the bite. However, early antivenom treatment was associated statistically with decreased incidence and severity of neurotoxic signs. The low case fatality rate of 4.3% is attributable mainly to the use of mechanical ventilation, a technique rarely available in Papua New Guinea. Earlier use of increased doses of antivenoms of improved specificity might prove more effective.

Warrell DA, Warrell MJ. 1995. Human rabies: a continuing challenge in the tropical world. Schweiz Med Wochenschr, 125 (18), pp. 879-885. | Show Abstract

More than 99% of all human rabies deaths in the world occur in tropical developing countries. In India alone, 30,000 to 50,000 people may die of rabies each year. The Lyssaviruses (Family Rhabdoviridae) include rabies and rabies-related viruses, 3 of which have caused human disease. Rabies is a zoonosis, principally affecting domestic and stray dogs in most parts of Africa, Asia and Latin America. In North America, southern Africa, parts of the Caribbean and Europe, the principal mammalian reservoir species are wild carnivores. The pathogenesis, clinical features and differential diagnosis of rabies are discussed. The planning of rabies control strategies requires background information on the distribution and incidence of rabies in animals and the species involved. In some parts of the world, such as Latin American cities, most domestic dogs, even apparent strays, have an owner and can be immunized with conventional canine vaccines during well publicized campaigns. However, in areas such as India, where there may be a high proportion of stray domestic dogs without owners, and in those areas where wild mammals are the principal reservoir species, immunization may be possible using live attenuated or recombinant oral vaccines distributed in baits. In the poor tropical developing countries, unsatisfactory nervous tissue vaccines are still widely used. However, economical multisite intradermal regimens using tissue culture vaccines have proved effective and have begun to replace nervous tissue vaccines in some countries.

Watt G, Warrell DA. 1995. Leptospirosis and the Jarisch-Herxheimer reaction. Clin Infect Dis, 20 (5), pp. 1437-1438. | Read more

Warrell DA, Harvey AL. 1995. Clinical reports in Toxicon. Toxicon, 33 (5), pp. 583-584. | Read more

Trevett AJ, Lalloo DG, Nwokolo NC, Theakston DG, Naraqi S, Warrell DA. 1995. Venom detection kits in the management of snakebite in Central province, Papua New Guinea. Toxicon, 33 (5), pp. 703-705. | Show Abstract | Read more

The bites of six species of venomous elapid snakes in Central Province Papua New Guinea produce similar clinical syndromes. Optimal management of envenomed patients involves the use of monospecific antivenom. In this study, Venom Detection Kits (VDKs) (CSL Diagnostics, Melbourne) were used to try to make a specific diagnosis in envenomed patients at their admission. VDKs detected venom in admission bite site swabs from 39 to 46 patients (85%). Thirty-eight of these patients were shown to have been bitten by taipans. In all cases where venom was detected by the VDK, this correlated with subsequent laboratory enzyme immunoassay results. Selective use of VDKs in Central Province could allow more widespread use of monospecific antivenoms and produce considerable financial savings.

Trevett AJ, Lalloo DG, Nwokolo NC, Naraqi S, Kevau IH, Theakston RD, Warrell DA. 1995. The efficacy of antivenom in the treatment of bites by the Papuan taipan (Oxyuranus scutellatus canni). Trans R Soc Trop Med Hyg, 89 (3), pp. 322-325. | Show Abstract | Read more

A prospective series of 156 patients systemically envenomed following the bite of a Papuan taipan (Oxyuranus scutellatus canni) were studied. All patients were treated with appropriate antivenom and clinical course and outcome were compared. The proportion of patients requiring intubation was significantly smaller, and the time to resolution of neurotoxicity and discharge from hospital significantly shorter, in patients receiving antivenom no more than 4 h after the bite. No significant difference in outcome was demonstrated between patients receiving antivenom at various times after 4 h. No difference was demonstrated in the times to restoration of coagulability between the 2 groups. The only significant difference between a small number of patients given 2 vials of antivenom and patients given a single vial at the same time after envenoming was a marginally shorter duration of intubation in those who required it. The study suggests that, to achieve significant clinical benefit in Papuan taipan bite, antivenom must be given as early as possible.

Tun-Pe, Aye-Aye-Myint, Warrell DA, Tin-Myint. 1995. King cobra (Ophiophagus hannah) bites in Myanmar: venom antigen levels and development of venom antibodies. Toxicon, 33 (3), pp. 379-382. | Show Abstract | Read more

Venom, venom IgG and IgM antibody and total serum IgG levels following king cobra bites in two reptile handlers were measured by enzyme immunoassay. The patient in case 1 received antivenom while the patient in case 2 did not. Case 1 made a complete recovery following the bite and produced a high titre short-lived antibody. Venom antigen was not detected in the sample taken 11 hr after antivenom. Case 2 had experienced two recent minor king cobra bites and had received traditional immunization 4 weeks before the accident reported here. He had developed only local swelling and suffered no neurological symptoms. Venom antigen measured at 1.45 hr after the bite was 132 ng/ml; this rapidly fell to 45 ng/ml over the next 30 min, and was no longer detectable 14 hr after the bite. The pattern of venom IgG and IgM antibody responses in both cases was comparable, except that in case 2 the venom IgG peak was maintained for 13 days, compared with 1 day in case 1; in case 2 it subsequently fell to low levels 8 weeks after the bite. Venom IgM appeared 1 day after the bite, peaked at day 7-9, rapidly tailed off on day 12-16 and was then undetectable from day 20 onwards in both. Total IgG level remained within normal limits in both. It is possible that previous bites and recent immunization contributed to the boosting of the venom IgG response in case 2.

Lalloo DG, Trevett AJ, Saweri A, Naraqi S, Theakston RD, Warrell DA. 1995. The epidemiology of snake bite in Central Province and National Capital District, Papua New Guinea. Trans R Soc Trop Med Hyg, 89 (2), pp. 178-182. | Show Abstract | Read more

Snake bite is an important medical problem in some areas of Papua New Guinea and appears to be most common in the Central Province and National Capital District. The overall incidence for Central Province is 215.5 per 100,000 population, but Kairuku subprovince has an incidence of 526 per 100,000, which is amongst the highest in the world. The clinical pattern of envenoming also varies within the Province, suggesting that different species of snake may be responsible for bites in different areas. Most envenomed patients are bitten during daylight on the lower limb and are rarely able to describe the snake. The mortality rate in Central Province is 7.9 per 100,000; most patients die from ventilatory failure due to severe neurotoxicity. Mortality might be reduced by increased use of compression bandaging as a first aid measure, earlier treatment with antivenom and earlier referral to hospital.

Lalloo DG, Trevett AJ, Owens D, Minei J, Naraqi S, Saweri A, Hutton RA, Theakston RD, Warrell DA. 1995. Coagulopathy following bites by the Papuan taipan (Oxyuranus scutellatus canni). Blood Coagul Fibrinolysis, 6 (1), pp. 65-72. | Show Abstract | Read more

The mechanisms of haemostatic failure were studied in 87 patients bitten by the Papuan taipan (Oxyuranus scutellatus canni). Eighty (92%) had evidence of a coagulopathy on laboratory testing; 36 (41.4%) developed spontaneous systemic bleeding, although this was rarely of clinical significance. Coagulation assays in 48 completely defibrinated patients showed marked reductions in factors V and VIII and reductions in factors II, IX, XI, XII and XIIIA. There was a reduction in plasminogen and alpha 2-antiplasmin levels and both total and cross-linked fibrin(ogen) degradation products (FDP) levels were elevated. The mean platelet count was initially decreased and fell further during admission. Similar but less severe changes were seen in patients who were mildly defibrinated. Following treatment with antivenom, fibrinogen levels rose rapidly and coagulability was restored within 6-12 h in 93% of patients. These abnormalities may be primarily attributable to the prothrombin activator present in taipan venom, but it is likely that other uncharacterized venom components contributed.

Jorge MT, Cardoso JL, Castro SC, Ribeiro L, França FO, de Almeida ME, Kamiguti AS, Santo-Martins IS, Santoro ML, Mancau JE. 1995. A randomized 'blinded' comparison of two doses of antivenom in the treatment of Bothrops envenoming in São Paulo, Brazil. Trans R Soc Trop Med Hyg, 89 (1), pp. 111-114. | Show Abstract | Read more

An earlier study in São Paulo state suggested that the dose for patients with mild or moderate envenoming by Bothrops snakes (mainly Bothrops jararaca) could be effectively decreased to 4 ampoules (40 mL) of Brazilian Brothrops polyspecific antivenom. The present 'blinded' study examined the lowest dose studied in the first trial (equivalent to 4 x 10 mL ampoules) and half that dose of antivenom (equivalent to 2 x 10 mL ampoules) in 2 similar groups of 170 patients who were comparable in all respects before treatment. The majority of patients showed rapid clinical improvement after treatment with either dose regimen and rapid restoration of blood coagulability and cessation of bleeding. There was no apparent difference between the 2 groups of patients in any respect. The study confirmed that, in such patients, the dose of antivenom can be decreased from 4 ampoules to 2 ampoules without reduction of therapeutic efficacy, and it is highly likely that this reduction will result in a decrease of early anaphylactic reactions caused by the antivenom.

Sells PG, Theakston RD, Warrell DA. 1994. Development of alpha-neurotoxin antibodies in patients envenomed by the monocellate Thai cobra (Naja kaouthia). Toxicon, 32 (12), pp. 1667-1671. | Show Abstract | Read more

Serum samples from 50 patients envenomed by the Thai cobra (Naja kaouthia) were tested by enzyme immune assay for the presence of antibodies against the principal neurotoxin. Samples were taken between 1 month and 19 years after the bite. Only 16% (8/50) of the samples were positive for antibodies against neurotoxin, while 76% (38/50) were positive for antibodies against whole venom. There was no clear correlation between the presence of antibodies against neurotoxin and clinical features.

Miller JH, Warrell DA. 1994. Imported falciparum malaria. BMJ, 309 (6963), pp. 1233-1234. | Read more

Miller JH, Byers M, Whiteoak R, Warrell DA. 1994. Imported falciparum malaria in British troops returning from Kenya. J R Army Med Corps, 140 (3), pp. 119-123. | Show Abstract | Read more

The objective of this study was to report on a breakthrough of Plasmodium falciparum infection following a military exercise in central Kenya and the treatment regimens used. A series of case reports are presented from the three UK hospitals involved. Among 150 British soldiers who had been on exercises for five weeks in central Kenya, taking proguanil/chloroquine anti-malarial prophylaxis, seven developed symptomatic falciparum malaria. Initial symptoms, which started between 2 and 10 days before their return to England, included faintness, sweating, shivering, diarrhoea, headache and myalgia. Diagnosis was delayed from between 5 and 13 days after the first symptom. One patient was severely ill with 50% parasitaemia: he required intensive care, exchange blood transfusion and haemofiltration for acute renal failure. Compliance with chemoprophylaxis was not measured and anti-mosquito measures were not generally practised. However, British Army policy was amended in June 1993 so that mefloquine will be used in future rather than proguanil/chloroquine. It was concluded therefore that even in an educated and motivated population simple preventive measures are not observed. Chemoprophylactic compliance could be improved by changing to a simpler regime. Falciparum malaria is a medical emergency that requires urgent admission for confirmation of diagnosis, supportive and curative treatment. Its presence should be suspected in any ill traveller.

Sano-Martins IS, Fan HW, Castro SC, Tomy SC, Franca FO, Jorge MT, Kamiguti AS, Warrell DA, Theakston RD. 1994. Reliability of the simple 20 minute whole blood clotting test (WBCT20) as an indicator of low plasma fibrinogen concentration in patients envenomed by Bothrops snakes. Butantan Institute Antivenom Study Group. Toxicon, 32 (9), pp. 1045-1050. | Show Abstract

Reliability of the simple 20 minute whole blood clotting test (WBCT20) as an indicator of low plasma fibrinogen concentration in patients envenomed by Bothrops snakes. Toxicon 32, 1045-1050, 1994.--A simple whole blood clotting test (WBCT20) was assessed for its efficacy in determination of severe defibrinogenation in patients envenomed by Bothrops snakes in Brazil. There was a close relationship between the results of the WBCT20 and plasma fibrinogen levels in 69 moderately envenomed patients. The advantage of the WBCT20 over estimation of plasma fibrinogen concentrations in patients is that it is a simpler, faster and more reliable test. It is also of use in assessing the effectiveness of antivenom therapy in relation to the restoration of blood coagulability.

Trevett AJ, Lalloo DG, Nwokolo N, Kevau IH, Warrell DA. 1994. Analysis of referral letters to assess the management of poisonous snake bite in rural Papua New Guinea. Trans R Soc Trop Med Hyg, 88 (5), pp. 572-574. | Show Abstract | Read more

A prospective series of patients envenomed after snake bite was seen at Port Moresby General Hospital (PMGH), Papua New Guinea, between January 1991 and December 1992. Referral letters were received with 60 of the patients who had been initially seen at a health centre. These letters were analysed in conjunction with our own clinical observations. The importance of non-clotting blood and local lymphadenopathy as early signs of systemic poisoning did not appear to be universally recognized by staff in health centres. In some cases, no attempt was made to transfer the patient to hospital until signs of neurotoxicity were established with potentially dangerous delay. Analysis of both hospital and health centre records suggests that the majority of deaths which occurred in Central Province, Papua New Guinea, during the period of the study were due to delay in transfer to hospital. We suggest that all patients with unequivocal signs of envenoming in Central Province, Papua New Guinea, should be transferred to PMGH as soon as possible. Antivenom should also be given as soon as possible, but this does not remove the need for immediate transfer.

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SANOMARTINS I, FAN H, CASTRO S, TOMY S, FRANCA F, JORGE M, KAMIGUTI A, WARRELL D et al. 1994. RELIABILITY OF THE SIMPLE 20-MINUTE WHOLE-BLOOD CLOTTING TEST (WBCT20) AS AN INDICATOR OF LOW PLASMA-FIBRINOGEN CONCENTRATION IN PATIENTS ENVENOMED BY BOTHROPS SNAKES TOXICON, 32 (9), pp. 1045-1050. | Show Abstract | Read more

A simple whole blood clotting test (WBCT20) was assessed for its efficacy in determination of severe defibrinogenation in patients envenomed by Bothrops snakes in Brazil. There was a close relationship between the results of the WBCT20 and plasma fibrinogen levels in 69 moderately envenomed patients. The advantage of the WBCT20 over estimation of plasma fibrinogen concentrations in patients is that it is a simpler, faster and more reliable test. It is also of use in assessing the effectiveness of antivenom therapy in relation to the restoration of blood coagulability. © 1994.

Kamiguti AS, Laing GD, Lowe GM, Zuzel M, Warrell DA, Theakston RD. 1994. Biological properties of the venom of the Papuan black snake (Pseudechis papuanus): presence of a phospholipase A2 platelet inhibitor. Toxicon, 32 (8), pp. 915-925. | Show Abstract | Read more

The whole venom of Pseudechis papuanus, in addition to its anticoagulant activity, powerfully inhibited platelet aggregation induced by ADP, adrenaline, collagen, ristocetin and thrombin. High levels of phospholipase A2 (PLA2) activity were detected. A mild procoagulant activity was also observed. Following exposure of platelets to P. papuanus venom, platelet factor 3 (procoagulant platelet phospholipid) showed decreased cofactor activity in factor X activation by Russell's viper, venom suggesting that the venom PLA2 plays a major role in the inhibition of the coagulation mechanism. In vivo rodent assays confirmed the inhibitory effect on platelets and the haemorrhagic and neurotoxic activities. It is possible that PLA2 is responsible for anticoagulation and that this, combined with the effect on platelet aggregation, a mild procoagulant and a moderately potent haemorrhagin, is responsible for the haemorrhagic diathesis observed in systemically envenomed patients. Polyvalent (Australia-Papua New Guinea) Commonwealth Serum Laboratories antivenom, currently used for clinical treatment of snakebite in Papua New Guinea, proved highly effective against P. papuanus venom in rodent and in vitro assays, despite the absence of this particular venom from the immunising mixture.

Lalloo D, Trevett A, Black J, Mapao J, Naraqi S, Owens D, Hutton R, Theakston RD, Warrell DA. 1994. Neurotoxicity and haemostatic disturbances in patients envenomed by the Papuan black snake (Pseudechis papuanus). Toxicon, 32 (8), pp. 927-936. | Show Abstract | Read more

Among 335 patients presenting with snakebites in Central Province, Papua New Guinea, nine were proved by enzyme immunoassay to have been bitten by Papuan black snakes (Pseudechis papuanus). Seven showed clinical evidence of envenoming. Early symptoms included vomiting and tender local lymph nodes. Five patients had neurotoxic signs and one required mechanical ventilation. Spontaneous systemic bleeding occurred in two patients. Coagulation studies in four patients showed thrombocytopenia, prolongation of prothrombin time, mild defibrination and depletion of other clotting factors with elevated fibrin(ogen) degradation products and other evidence of fibrinolysis. One patient developed mild renal dysfunction. There was no evidence of intravascular haemolysis or rhabdomyolysis. These clinical observations, which do not distinguish victims of P. papuanus from those of taipans (Oxyuranus scutellatus canni), suggest that the venom contains neurotoxic, haemorrhagic and mild procoagulant activities. Only two other cases of proven envenoming by this species have been reported. There appears to have been a decline in the abundance of this species, and hence its medical importance, over the last 25 years.

Gillissen A, Theakston RD, Barth J, May B, Krieg M, Warrell DA. 1994. Neurotoxicity, haemostatic disturbances and haemolytic anaemia after a bite by a Tunisian saw-scaled or carpet viper (Echis 'pyramidum'-complex): failure of antivenom treatment. Toxicon, 32 (8), pp. 937-944. | Show Abstract | Read more

A young man in Germany was bitten by a large captive saw-scaled viper (Echis 'pyramidum'-complex) of Tunisian origin. During the first few hours after the bite he developed evidence of disseminated intravascular coagulation and fibrinolysis, and bled spontaneously. Despite being given a total of 310 ml of three different Echis-specific antivenoms (together with large amounts of fresh frozen plasma and concentrated clotting factors), venom antigenaemia (measured by enzyme immunoassay) and coagulopathy persisted for more than 10 days, and he developed a haemolytic anaemia and mild renal dysfunction. Transient bilateral ptosis was attributed to envenoming. The venom of the snake responsible for the bite was immunologically distinct from that of Nigerian E. ocellatus and was clearly not neutralised by the three monospecific antivenoms which had been administered. This case is another illustration of the geographical variation in snake venoms and the need for pooling venoms from snakes from different parts of the geographical range in the preparation of antivenoms. Envenoming by North African Echis species may not be reversible by available antivenoms.

CONNOLLY S, TREVETT A, FAWCETT P, WARRELL D. 1994. NEUROPHYSIOLOGICAL ASSESSMENT FOLLOWING SNAKEBITE - SERIAL STUDIES OF PATIENTS ENVENOMED BY THE PAPUAN TAIPAN SNAKE ANNALS OF NEUROLOGY, 36 (2), pp. 283-283.

França FO, Benvenuti LA, Fan HW, Dos Santos DR, Hain SH, Picchi-Martins FR, Cardoso JL, Kamiguti AS, Theakston RD, Warrell DA. 1994. Severe and fatal mass attacks by 'killer' bees (Africanized honey bees--Apis mellifera scutellata) in Brazil: clinicopathological studies with measurement of serum venom concentrations. Q J Med, 87 (5), pp. 269-282. | Show Abstract | Read more

In São Paulo State, Brazil, five males, aged between 8 and 64 years, were attacked by 'Africanized' honey bees (Apis mellifera scutellata). The estimated number of stings received by each patient ranged from > 200 to > 1000. All five were transferred to intensive care units in São Paulo City. Clinical features included intravascular haemolysis, respiratory distress with ARDS, hepatic dysfunction, rhabdomyolysis (with myoglobinaemia and myoglobinuria), hypertension and myocardial damage (perhaps explained by release of endogenous catecholamines by venom phospholipase A2 and mellitin), shock, coma, acute renal failure and bleeding. Laboratory findings included gross neutrophil leucocytosis, elevated serum enzymes [AST, ALT, LDH, CPK (predominantly CPK-MM)] and creatinine. Clotting times were slightly prolonged. Despite treatment with antihistamines, corticosteroids, bronchodilators, vasodilators, bicarbonate, mannitol and mechanical ventilation, three of the patients died between 22 and 71 h after the attacks, with histopathological features of ARDS, hepatocellular necrosis, acute tubular necrosis, focal subendocardial necrosis and disseminated intravascular coagulation. Whole bee venom and phospholipase A2 (PLA2) antigen concentrations were measured in serum and urine for the first time, using enzyme immunoassay. High venom and PLA2 concentrations were detected in serum and urine for more than 50 h after the stings in two fatal cases, in one of which the total circulating unbound whole venom was estimated at 27 mg, one hour after the attack. An antivenom should be developed to treat the increasing numbers of victims of mass attacks by Africanized 'killer' bees in USA, Middle and South America.

SELIGMANN M, WARRELL D, ABOULKER J, CARBON C, DARBYSHIRE J, DORMONT J, ESCHWEGE E, GIRLING D et al. 1994. Concorde: MRC/ANRS randomised double-blind controlled trial of immediate and deferred zidovudine in symptom-free HIV infection. Concorde Coordinating Committee. Lancet, 343 (8902), pp. 871-881. | Show Abstract | Read more

Concorde is a double-blind randomised comparison of two policies of zidovudine treatment in symptom-free individuals infected with human immunodeficiency virus (HIV): (a) immediate zidovudine from the time of randomisation (Imm); and (b) deferred zidovudine (Def) until the onset of AIDS-related complex (ARC) or AIDS (CDC group IV disease) or the development of persistently low CD4 cell counts if the clinician judged that treatment was indicated. Between October, 1988, and October, 1991, 1749 HIV-infected individuals from centres in the UK, Ireland, and France were randomly allocated to zidovudine 250 mg four times daily (877 Imm) or matching placebo (872 Def). Follow-up was to death or Dec 31, 1992 (total 5419 person-years; median 3.3 years) and only 7% of the 1749 had not had a full clinical assessment after July 1, 1992. Of those allocated to the Def group, 418 started zidovudine at some time during the trial, 174 (42%) of them at or after they were judged by the clinician to have developed ARC or AIDS (nearly all confirmed subsequently) and most of the remainder on the basis of low CD4 cell counts. Those in the Imm group spent 81% of the time before ARC or AIDS on zidovudine compared with only 16% for those in the Def group. Despite the large difference in the amount of zidovudine between the two groups and the fact that the number of clinical endpoints (AIDS and death) in Concorde (347) outnumbers the total of those in all other published trials in symptom-free and early symptomatic infection, there was no statistically significant difference in clinical outcome between the two therapeutic policies. The 3-year estimated survival probabilities were 92% (95% CI 90-94%) in Imm and 94% (92-95%) in Def (log-rank p = 0.13), with no significant differences overall or in subgroup analyses by CD4 cell count at baseline. Similarly, there was no significant difference in progression of HIV disease: 3-year progression rates to AIDS or death were 18% in both groups, and to ARC, AIDS, or death were 29% (Imm) and 32% (Def) (p = 0.18), although there was an indication of an early but transient clinical benefit in favour of Imm in progression to ARC, AIDS, or death. However, there was a clear difference in changes in CD4 cell count over time in the two groups.(ABSTRACT TRUNCATED AT 400 WORDS)

de Silva A, Wijekoon AS, Jayasena L, Abeysekera CK, Bao CX, Hutton RA, Warrell DA. 1994. Haemostatic dysfunction and acute renal failure following envenoming by Merrem's hump-nosed viper (Hypnale hypnale) in Sri Lanka: first authenticated case. Trans R Soc Trop Med Hyg, 88 (2), pp. 209-212. | Show Abstract | Read more

A five years old boy was bitten by a Merrem's hump-nosed viper (Hypnale hypnale) in Central Province, Sri Lanka. He developed local swelling, incoagulable blood, thrombocytopenia, bleeding into the gastrointestinal tract, and acute renal failure. Treatment with Serum Institute of Indian polyspecific antivenom (specific for venoms of cobra, common krait, Russell's viper and saw-scaled viper) had no effect on the coagulopathy, which persisted for more than a week. The boy recovered after 27 d in hospital, during which he was treated with peritoneal dialysis for renal failure. Laboratory studies demonstrated that the venom of H. hypnale was procoagulant, fibrinolytic and aggregated platelets. This first authenticated case of life-threatening acute renal failure and haemostatic disturbances caused by H. hypnale, a species responsible for 27% of snake bites in Sri Lanka, demonstrates the need for a new antivenom with specific activity against the venom of this species.

Cutler SJ, Fekade D, Hussein K, Knox KA, Melka A, Cann K, Emilianus AR, Warrell DA, Wright DJ. 1994. Successful in-vitro cultivation of Borrelia recurrentis. Lancet, 343 (8891), pp. 242. | Read more

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CUTLER S, FEKADE D, HUSSEIN K, KNOX K, MELKA A, CANN K, EMILIANUS A, WARRELL D, WRIGHT D. 1994. SUCCESSFUL IN-VITRO CULTIVATION OF BORRELIA-RECURRENTIS LANCET, 343 (8891), pp. 242-242. | Read more

Warrell DA. 1993. Venomous bites and stings in the tropical world. Med J Aust, 159 (11-12), pp. 773-779. | Show Abstract

Snakes of the families Viperidae and Elapidae are responsible for the high incidence of morbidity and mortality after snake bites in countries of West Africa, the Indian subcontinent, South-East Asia, New Guinea and Latin America. Envenoming can cause local effects, notably tissue necrosis; and systemic effects, including paralysis, haemostatic disturbances, shock, increased capillary permeability, myocardial damage, rhabdomyolysis and acute renal failure. Specific hyperimmune serum (antivenom) is the mainstay of medical treatment for severe envenoming. Ancillary treatments such as assisted ventilation, repletion of circulating volume, renal dialysis and surgical debridement of necrotic tissues are needed in some cases. Scorpion stings are a common medical problem in middle and southern America, North Africa and the Middle East. Vasodilator drugs are important to counter the effects of massive catecholamine release. Bites by spiders and stings by hymenoptera and marine animals are responsible for deaths and morbidity in some tropical countries.

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WARRELL D. 1993. TROPICAL HEALTH .23. VENOMOUS BITES AND STINGS IN THE TROPICAL WORLD MEDICAL JOURNAL OF AUSTRALIA, 159 (11-12), pp. 773-779.

Tin-Nu-Swe, Tin-Tun, Myint-Lwin, Thein-Than, Tun-Pe, Robertson JI, Leckie BJ, Phillips RE, Warrell DA. 1993. Renal ischaemia, transient glomerular leak and acute renal tubular damage in patients envenomed by Russell's vipers (Daboia russelii siamensis) in Myanmar. Trans R Soc Trop Med Hyg, 87 (6), pp. 678-681. | Show Abstract | Read more

Fifty-two patients who had been bitten by Russell's vipers in Myanmar developed acute renal failure (serum creatinine exceeding 1.3 mg/dL). Thirty-four of them (65%) became oliguric, but the other 18 (35%) maintained a urine output of more than 400 mL/24 h. In oliguric patients, gastrointestinal haemorrhages, renal angle tenderness and conjunctival oedema occurred more commonly, and peak serum creatinine, blood urea nitrogen and the fractional excretion of sodium were significantly higher (P < 0.01) than in non-oliguric patients, indicating a greater degree of renal damage. Urinary concentrations of beta 2 microglobulin and retinol binding protein were raised in most of the patients indicating failure of proximal tubular reabsorption of these proteins, while high urinary N-acetyl glucosaminidase concentrations were consistent with renal tubular damage. Plasma concentrations of active renin were very high, suggesting that renal ischaemia, associated with activation of the renin-angiotensin system, was involved in the development of renal dysfunction.

de Silva A, Mendis S, Warrell DA. 1993. Neurotoxic envenoming by the Sri Lankan krait (Bungarus ceylonicus) complicated by traditional treatment and a reaction to antivenom. Trans R Soc Trop Med Hyg, 87 (6), pp. 682-684. | Show Abstract | Read more

A 30 year old woman bitten by a large Sri Lankan krait (Bungarus ceylonicus) developed progressive paralytic symptoms within one hour of the bite. After seeking traditional treatment her condition deteriorated and when she arrived at hospital 6 h after the bite she was drowsy, with bilateral ptosis and signs of aspiration pneumonia (a complication of traditional treatment). She developed an anaphylactic reaction after antivenom treatment and, despite treatment, had a cardio-respiratory arrest. She was resuscitated and mechanically ventilated, but remained deeply unconscious until her death 90 h after the bite. B. ceylonicus is endemic in Sri Lanka, is common in some areas, and could be mistaken for the common krait (B. caeruleus). It is doubtful whether any existing antivenom is effective against its venom.

Hutton RA, Warrell DA. 1993. Action of snake venom components on the haemostatic system. Blood Rev, 7 (3), pp. 176-189. | Show Abstract | Read more

Among the components in snake venom are a number which have profound effects (either stimulatory or inhibitory) on haemostatic mechanisms, including coagulation, fibrinolysis, platelet function and vascular integrity. As a consequence, human victims of snakebite may suffer severe and sometimes fatal haemorrhagic and/or thrombotic sequelae. Many of these venom components have been isolated and their precise mechanisms of action established. Apart from direct fibrinolysins, procoagulants predominate, most of these exerting their effect late in the clotting cascade, activating factor X or prothrombin or directly converting fibrinogen to fibrin. Some of the procoagulants are, or have the potential to be, used as therapeutic agents. Some venom components have been put to use as laboratory reagents for diagnostic purposes or for characterising molecular defects of haemostasis, although because they often have unphysiological actions, results must be interpreted with caution. These and other useful constituents e.g. protein C activator and platelet aggregating agents are discussed.

Trevett AJ, Warrell DA, Lalloo DG, Nwokolo N. 1993. Disorders of neuromuscular transmission due to natural environmental toxins. J Neurol Sci, 118 (1), pp. 101.

TREVETT A, WARRELL D, LALLOO D, NWOKOLO N. 1993. DISORDERS OF NEUROMUSCULAR-TRANSMISSION DUE TO NATURAL ENVIRONMENTAL TOXINS JOURNAL OF THE NEUROLOGICAL SCIENCES, 118 (1), pp. 101-101. | Read more

Warrell DA. 1993. Snake bite and snake venoms. Q J Med, 86 (6), pp. 351-353. | Read more

WARRELL D. 1993. VENOMOUS BITES AND STINGS IN SAUDI-ARABIA SAUDI MEDICAL JOURNAL, 14 (3), pp. 196-202.

WARRELL D. 1993. LEISHMANIASIS, MALARIA AND SCHISTOSOMIASIS IN SAUDI-ARABIA SAUDI MEDICAL JOURNAL, 14 (3), pp. 203-208.

Cardoso JL, Fan HW, França FO, Jorge MT, Leite RP, Nishioka SA, Avila A, Sano-Martins IS, Tomy SC, Santoro ML. 1993. Randomized comparative trial of three antivenoms in the treatment of envenoming by lance-headed vipers (Bothrops jararaca) in São Paulo, Brazil. Q J Med, 86 (5), pp. 315-325. | Show Abstract | Read more

In São Paulo City, Brazil, 121 patients with moderately severe envenoming by Bothrops snakes (principally B. jararaca) were randomized for treatment with Brazilian polyspecific Bothrops antivenoms: Instituto Butantan (39 patients), Instituto Vital Brazil (41), Fundação Ezequiel Dias (FUNED) (41). The initial dose was four ampoules (40 ml) in 89 patients with less severe envenoming and eight ampoules (80 ml) in 32 patients with more severe envenoming. A second dose of four ampoules was required in 20 patients. Patients receiving the three antivenoms were comparable in all respects before treatment. There were no deaths. The majority showed rapid clinical improvement, resolution of local envenoming, cessation of bleeding and restoration of blood coagulability. No differences in the efficacy of the three antivenoms were revealed by clinical or laboratory observations, including measures of haematological, haemostatic and biochemical abnormalities. Twelve patients developed abscesses (Butantan 1, Vital Brazil 6, FUNED 5) and seven developed local necrosis (3,1,3). Of 88 patients followed up 20-30 days after the bite 33 (37.5%) still had symptoms or signs of local envenoming, especially swelling. Early (anaphylactic) reactions were unexpectedly frequent after all three antivenoms but were significantly more frequent with Butantan (87%) than with Vital Brazil (37%) or FUNED (56%) antivenoms (p < 0.001). A possible explanation was the higher total protein content and percentage immunoglobulin of Butantan antivenom. The doses of antivenom recommended in Brazil and used in this study may be unnecessarily high, resulting in an unacceptably high incidence of reactions. Results of the study should prompt a critical re-evaluation of antivenom production techniques and dosage recommendations in Brazil.

Phillips RE, Looareesuwan S, Molyneux ME, Hatz C, Warrell DA. 1993. Hypoglycaemia and counterregulatory hormone responses in severe falciparum malaria: treatment with Sandostatin. Q J Med, 86 (4), pp. 233-240. | Show Abstract | Read more

The mechanism and response to treatment of severe life-threatening hypoglycaemia (plasma glucose 1.15 +/- 0.73 mM/l [+/- SD]) was studied in eight Thai patients with falciparum malaria. Plasma insulin concentrations were inappropriately high (range 1.0-21.8 mU/l), lactic acidosis was common (arterial blood lactic acid concentration 1.44-17.8 mM/l), but the glucose counterregulatory response, indicated by plasma cortisol, growth hormone, catecholamines and glucagon concentrations, was intact. Hyperinsulinaemia was successfully treated in five patients by a continuous intravenous infusion of the long-acting somatostatin analogue Sandostatin (SMS 201-995), 50 micrograms/h. In volunteer studies a single intramuscular injection of Sandostatin (100 micrograms) suppressed quinine-induced hyperinsulinaemia within 15 min; this effect was maintained for 6 h. These results suggest that Sandostatin may be a safe and effective way of correcting the hyperinsulinaemic hypoglycaemia complicating quinine treatment of falciparum malaria. This treatment could be particularly useful in fluid-overloaded patients with recurrent hypoglycaemia despite dextrose infusions.

Warrell DA, Fenner PJ. 1993. Venomous bites and stings. Br Med Bull, 49 (2), pp. 423-439. | Show Abstract

Travellers to tropical countries are often extremely concerned about the risk of bites and stings by venomous animals. This fear prompts many enquiries, usually at the last moment before departure, about the possibility of carrying first aid kits and antivenoms. In fact, these accidents are extremely rare because most travellers wear shoes and are far less exposed to venomous animals than indigenous peoples for whom bites and stings may be important causes of death or morbidity.

Warrell MJ, Warrell DA. 1993. Rabies vaccine: economical regimens. Trop Doct, 23 (2), pp. 95-96.

WARRELL M, WARRELL D. 1993. RABIES VACCINE - ECONOMICAL REGIMENS - REPLY TROPICAL DOCTOR, 23 (2), pp. 95-96.

Luzzi GA, Brindle R, Sockett PN, Solera J, Klenerman P, Warrell DA. 1993. Brucellosis: imported and laboratory-acquired cases, and an overview of treatment trials. Trans R Soc Trop Med Hyg, 87 (2), pp. 138-141. | Show Abstract | Read more

Following the successful eradication of Brucella abortus infection in cattle, human brucellosis in England and Wales has become an uncommon imported disease. Culture of the organism presents a major laboratory hazard, and difficulties in identification may occur using a biochemical test-strip method. An overview of recent treatment trials of brucellosis indicates that regimens combining streptomycin and doxycycline are associated with a higher success rate (judged by the frequency of treatment failure and relapse following therapy) than combinations of rifampicin and doxycycline.

McNally T, Conway GS, Jackson L, Theakston RD, Marsh NA, Warrell DA, Young L, Mackie IJ, Machin SJ. 1993. Accidental envenoming by a Gaboon viper (Bitis gabonica): the haemostatic disturbances observed and investigation of in vitro haemostatic properties of whole venom. Trans R Soc Trop Med Hyg, 87 (1), pp. 66-70. | Show Abstract | Read more

We report the successful treatment of envenoming by the Gaboon viper (Bitis gabonica) and include results of in vitro investigations of the haemostatic properties of the whole venom. The patient was admitted to casualty soon after the bite with chest tightness, dizziness, nausea and swelling at the site of the bite and was treated immediately with polyspecific antivenom, hydrocortisone, chlorpheniramine and antibiotics. Results of haemostatic investigations were essentially normal on admission but on day 3 the thrombin time became prolonged and was associated with significant hypofibrinogenaemia and elevated D-dimers. Factors V and VIII, antithrombin III and protein C levels and platelet number were not significantly reduced. The haemostatic disturbances persisted for more than 24 h despite treatment with blood products (16 units of cryoprecipitate, 2 units of fresh frozen plasma and 6 units of platelet concentrate). Resolution of the abnormalities occurred only after administration of a further dose of antivenom. The period of hypofibrinogenaemia occurred at a time when venom antigen was undetectable in plasma by enzyme-linked immunosorbent assay. Studies in vitro with whole venom and a panel of amidolytic substrates commonly employed for measurement of haemostatic proteins revealed significant activity of venom with substrates sensitive to kallikrein and plasmin. The venom inhibited washed platelet aggregation induced by collagen, thrombin, arachidonic acid and the calcium ionophore A23187 in a dose-dependent manner.

Warrell DA. 1992. Pathophysiology of severe falciparum malaria. P N G Med J, 35 (4), pp. 229-232.

Theakston RD, Fan HW, Warrell DA, Da Silva WD, Ward SA, Higashi HG. 1992. Use of enzyme immunoassays to compare the effect and assess the dosage regimens of three Brazilian Bothrops antivenoms. The Butantan Institute Antivenom Study Group (BIASG). Am J Trop Med Hyg, 47 (5), pp. 593-604. | Show Abstract

The effect of the three main Brazilian polyspecific antivenoms on venom clearance was assessed in 118 moderately envenomed victims of bites by Bothrops species (mainly B. jararaca) in Sao Paulo State, Brazil. Serum samples taken from patients at intervals during their stay in the hospital and at followup approximately four weeks later were tested by enzyme immunoassay for the presence of whole venom and therapeutic antivenom. Results indicated that in patients treated with the standard regimen of either four (40 ml) or eight (80 ml) ampules of each antivenom, venom was cleared from the circulation within four days of antivenom administration. However, high concentrations of antivenom persisted for approximately 10 days and remained detectable until 30-50 days after administration. This suggests that patients may be being treated with excessive amounts of antivenom in Brazil. This practice increases the national cost of antivenom therapy and may contribute to the high frequency of antivenom reactions. Clinically, there was no obvious difference in the efficacy between the three antivenoms.

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THEAKSTON R, FAN H, WARRELL D, DASILVA W, WARD S, HIGASHI H. 1992. USE OF ENZYME IMMUNOASSAYS TO COMPARE THE EFFECT AND ASSESS THE DOSAGE REGIMENS OF 3 BRAZILIAN BOTHROPS ANTIVENOMS AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 47 (5), pp. 593-604.

Laing GD, Theakston RD, Leite RP, da Silva WD, Warrell DA. 1992. Comparison of the potency of three Brazilian Bothrops antivenoms using in vivo rodent and in vitro assays. BIASG (Butantan Institute Antivenom Study Group). Toxicon, 30 (10), pp. 1219-1225. | Show Abstract | Read more

Three Brazilian polyspecific Bothrops antivenoms were compared using standard W.H.O. rodent in vivo and in vitro assays of their ability to neutralize the principal venom activities of pooled whole Bothrops jararaca venom. On a volume basis, the antivenoms were equally effective in neutralizing lethal activity in mice, and there were only minor differences in their ability to neutralize venom-induced haemorrhage, necrosis and procoagulant activity. Antivenom efficacy in neutralizing defibrinogenation varied. However, when equal amounts of antivenom IgG were compared, it was found that the FUNED antivenom best neutralized lethality, haemorrhage, necrosis and fibrinogen clotting activity. Vital Brazil and FUNED antivenoms were equally effective in neutralizing plasma coagulant activity but Vital Brazil antivenom was the more effective in neutralizing defibrinogenation.

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LAING G, THEAKSTON R, LEITE R, DASILVA W, WARRELL D. 1992. COMPARISON OF THE POTENCY OF 3 BRAZILIAN BOTHROPS ANTIVENOMS USING INVIVO RODENT AND INVITRO ASSAYS TOXICON, 30 (10), pp. 1219-1225. | Read more

Luzzi GA, Warrell DA, Barnes AJ, Dunbar EM. 1992. Treatment of primaquine-resistant Plasmodium vivax malaria. Lancet, 340 (8814), pp. 310. | Read more

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LUZZI G, WARRELL D, BARNES A, DUNBAR E. 1992. TREATMENT OF PRIMAQUINE-RESISTANT PLASMODIUM-VIVAX MALARIA LANCET, 340 (8814), pp. 310-310. | Read more

Warrell DA. 1992. Cerebral malaria. Schweiz Med Wochenschr, 122 (23), pp. 879-886. | Show Abstract

Cerebral malaria is the most important manifestation of severe Plasmodium falciparum infection. The clinical picture in South East Asian adults differs from that in African children. The children are more likely to have abnormal brain stem reflexes, signs suggestive of cerebral herniation, and raised CSF opening pressure, and to suffer persistent neurological sequelae. The mortality remains high at about 20%. The diagnosis must be considered in all patients with fever and impaired consciousness who may have been exposed to the infection. The pathophysiology of cerebral malaria may involve mechanical obstruction of the cerebral circulation by parasitized erythrocytes which have adhered to the vascular endothelium. Cytokines such as tumor necrosis factor may also contribute. The most important element of treatment is early, optimal chemotherapy with quinine, but artemisinine derivatives may prove even more effective.

Winstanley PA, Watkins WM, Newton CR, Nevill C, Mberu E, Warn PA, Waruiru CM, Mwangi IN, Warrell DA, Marsh K. 1992. The disposition of oral and intramuscular pyrimethamine/sulphadoxine in Kenyan children with high parasitaemia but clinically non-severe falciparum malaria. Br J Clin Pharmacol, 33 (2), pp. 143-148. | Show Abstract | Read more

1. H.p.l.c. methods are described for the measurement of pyrimethamine and sulphadoxine in small volumes of plasma dried on filter paper strips. 2. Pyrimethamine/sulphadoxine (Fansidar, Hoffman LaRoche) was given by mouth and by intramuscular injection to children with uncomplicated falciparum malaria but with high parasitaemia (n = 8 for both routes; pyrimethamine 1.25 mg kg-1, sulphadoxine 25 mg kg-1). 3. Plasma concentrations of pyrimethamine and sulphadoxine associated with synergistic effects against pyrimethamine-resistant strains of Plasmodium falciparum in vitro were achieved within 1 h of administration and were maintained beyond the end of sampling. 4. After both oral and parenteral administration the plasma concentrations of both compounds were lower than those predicted by data from healthy subjects. 5. Areas under the plasma concentration-time curves of sulphadoxine after oral and i.m. administration did not differ significantly, although maximum plasma drug concentrations were higher after the i.m. route (P = 0.03). 6. The AUC values of pyrimethamine did not differ significantly between the two routes of administration. However, after i.m. administration AUC(0,24 h) values were smaller (P = 0.03), and the time to maximum plasma drug concentration (tmax) was longer (P = 0.004) than when the drug was given orally.

Winstanley PA, Newton CR, Pasvol G, Kirkham FJ, Mberu E, Peshu N, Ward SA, Were JB, Warrell DA, Marsh K. 1992. Prophylactic phenobarbitone in young children with severe falciparum malaria: pharmacokinetics and clinical effects. Br J Clin Pharmacol, 33 (2), pp. 149-154. | Show Abstract | Read more

1. A method is described for the measurement of phenobarbitone (PB) by reversed phase high performance liquid chromatography (h.p.l.c.) from small samples of whole blood dried onto filter paper strips. 2. The disposition of PB given prophylactically to young children with severe malaria on parenteral quinine is contrasted with that in aparasitaemic Kenyan children on no antimalarial drugs. There were no differences in the disposition of PB between the two groups. 3. Peak blood PB concentrations were equal to or greater than 15 mg l-1 in 27% of the patients on quinine and 23% of those not on quinine; a concentration of 10 mg l-1 was achieved or exceeded by 100% and 92% of each group, respectively, and was maintained for 39 +/- 24 h (mean +/- s.d.), and 33 +/- 21 h, respectively. 4. In an open, dose-finding study, the progress of young children with cerebral malaria given prophylactic PB (10 mg kg-1), was contrasted with that of controls given no seizure prophylaxis. 5. The drug had no apparent effect on depth or duration of coma, but neither was the incidence of seizures reduced. 6. A controlled trial of prophylactic PB in young children with cerebral malaria is needed, but a larger dose than 10 mg kg-1 should be studied.

Viravan C, Looareesuwan S, Kosakarn W, Wuthiekanun V, McCarthy CJ, Stimson AF, Bunnag D, Harinasuta T, Warrell DA. 1992. A national hospital-based survey of snakes responsible for bites in Thailand. Trans R Soc Trop Med Hyg, 86 (1), pp. 100-106. | Show Abstract | Read more

Snakes which had been killed and brought to hospital with the patients they had bitten were collected in 80 district and provincial hospitals throughout 67 provinces in Thailand in order to establish the geographical distribution and relative medical importance of the venomous species. Of the 1631 snakes collected, 1145 were venomous: Malayan pit vipers (Calloselasma rhodostoma), green pit vipers (Trimeresurus albolabris) and Russell's vipers (Daboia russelii) were the most numerous, while T. albolabris, C. rhodostoma and spitting cobras ('Naja atra') were the most widely distributed. In 22 cases, non-venomous species were mistaken for venomous ones and antivenom was used unnecessarily. The Malayan krait (Bungarus candidus) was confused with B. fasciatus in 5 cases and B. fasciatus antivenom was used inappropriately. The study extended the known ranges of most of the medically-important venomous species in Thailand. Correct identification of venomous snakes is especially important in Thailand because the locally-produced antivenoms are monospecific. The technique of hospital-based collection, labelling and preservation of dead snakes brought by bitten patients is recommended when rapid assessment of a country's medically important herpetofauna is required.

Warrell DA, Looareesuwan S, Stimson AF, Hutton RA. 1992. Rediscovery and redefinition of Malcolm Smith's Trimeresurus kanburiensis in Thailand, with a report of envenoming. Trans R Soc Trop Med Hyg, 86 (1), pp. 95-99. | Show Abstract | Read more

Three specimens of an apparently rare pit viper, Trimeresurus kanburiensis, previously known only from the holotype collected in 1928, were found near Kanchanaburi in western Thailand. One of the snakes had bitten a young woman on the foot. She experienced severe local pain, swelling that involved the whole of the bitten limb and beyond, local bruising, recurrent shock, peripheral leucocytosis and a mild coagulopathy, but she recovered despite the lack of specific treatment. The severity of envenoming augurs ill for a young or debilitated patient bitten by this species. During the last 20 years, the name T. kanburiensis has been used incorrectly for the medically more important species, T. purpureomaculatus. Conversely, the name T. purpureomaculatus has been misapplied to specimens of a species of viper from southern Thailand which we consider very similar to T. kanburiensis, but for which a new specific name, 'T. venustus', has been suggested recently. The rediscovery and redefinition of T. kanburiensis should prevent further confusion.

Gilks CF, Otieno LS, Brindle RJ, Newnham RS, Lule GN, Were JB, Simani PM, Bhatt SM, Okelo GB, Waiyaki PG. 1992. The presentation and outcome of HIV-related disease in Nairobi. Q J Med, 82 (297), pp. 25-32. | Show Abstract

The range of clinical presentations of HIV-related disease in Africa has not been adequately described, despite the fact that many hospitals have to rely heavily on clinical diagnosis. Six hundred adult medical patients seen in the Casualty Department of the main Government hospital in Nairobi were enrolled in a study of the presentation and outcome of HIV-related disease: 506 of these patients were admitted, of whom 19 per cent (95) were HIV seropositive. The remaining 94 were dealt with as outpatients: 11 percent (10) of these were seropositive. A history of prior treatment for sexually transmitted disease and, if male, being uncircumcised, were associated with being seropositive. Three presentations were strongly associated with HIV infection: acute fever with no focus except the gastrointestinal tract (enteric fever-like illness), acute cough with fever (community-acquired pneumonia) and chronic diarrhoea with wasting. The WHO clinical case definition (CCD) for AIDS missed a substantial amount of HIV-related morbidity (sensitivity 39 per cent) and misidentified many seronegative patients (positive predictive value 59 per cent). In comparison with the Centers for Disease Control surveillance definition for AIDS, the CCD was specific (91 per cent) and sensitive (79 per cent) but only had a positive predictive values of 30 per cent: the CCD may therefore be a poor surveillance tool for AIDS. Seropositive patients were much more likely to die than were seronegative patients (39 per cent vs. 15 per cent mortality). Enteric fever-like illness was the presentation which most commonly proved fatal. A wider spectrum of disease is associated with underlying HIV immunosuppression than has previously been described in Africa.

Pasvol G, Newton CR, Winstanley PA, Watkins WM, Peshu NM, Were JB, Marsh K, Warrell DA. 1991. Quinine treatment of severe falciparum malaria in African children: a randomized comparison of three regimens. Am J Trop Med Hyg, 45 (6), pp. 702-713. | Show Abstract

The pharmacokinetics and effectiveness of three dosage regimens of quinine were studied in a group of 59 children with severe malaria. The children were randomized to receive high-dose intravenous or intramuscular quinine (20 mg salt/kg loading, then 10 mg salt/kg every 12 hr), or low-dose intravenous quinine (10 mg salt/kg loading, then 5 mg salt/kg every 12 hr). In the group receiving the high-dose intravenous regimen, mean high and low quinine concentrations were consistently greater than 10 and 6.5 mg/l, respectively. Peak concentrations as well as the time required to achieve them were similar in the intramuscular and high-dose intravenous groups. The low-dose intravenous quinine regimen resulted in mean peak concentrations greater than 6 mg/l and mean low concentrations greater than 3.5 mg/l. All blood concentrations exceeded the 99% in vitro inhibitory concentration (EC99) of 0.89 mg/l or less of quinine for 60 isolates of Plasmodium falciparum, which were taken from children with malaria during the same period. Judged by a number of clinical criteria, the response was better in patients receiving the high-dose than the low-dose intravenous regimen. The time taken to clear parasites with both the high-dose intravenous and intramuscular regimens were significantly shorter than those obtained in the low-dose group. We have also shown for the first time that the rate of parasite clearance can be directly related to the area under the quinine concentration versus time curve. This applied to all three quinine regimens (r = 0.4252, P less than 0.02; n less than or equal to 35). Five patients, two on the low-dose regimen, two on the intramuscular regimen, and one on the high-dose regimen, developed hypoglycemia after admission, but in these cases, insulin concentrations were correspondingly low. No significant quinine toxicity was observed in any of the cases. The high-dose intravenous quinine regimen described here may be optimal for treatment of severe falciparum malaria in areas of chloroquine resistance in Africa. Our data provide no justification for reducing the dose of quinine in the treatment of severe malaria in Africa. The intramuscular regimen could provide a satisfactory alternative in areas where intravenous administration might be delayed or is impossible.

Tun-Pe, Ba-Aye, Aye-Aye-Myint, Tin-Nu-Swe, Warrell DA. 1991. Bites by Russell's vipers (Daboia russelii siamensis) in Myanmar: effect of the snake's length and recent feeding on venom antigenaemia and severity of envenoming. Trans R Soc Trop Med Hyg, 85 (6), pp. 804-808. | Show Abstract | Read more

An improved enzyme immunoassay technique (EIA) was used in the diagnosis of 311 suspected Russell's viper bite cases in Myanmar [Burma], 181 of whom (58%) had systemic envenoming. Russell's viper venom was detected in the sera of 175 (56.3%), cobra or green pit viper venoms in 4 (1.3%), and no venom in the remaining 132 (42.4). Among 175 of these patients who failed to bring the dead snake, EIA achieved a specific diagnosis of Russell's viper envenoming in 101 (58%). The serum venom antigen concentration was higher in patients with systemic envenoming than in those with local or no envenoming and it increased with the development of coagulopathy. Stomach contents were examined in 101 Russell's vipers responsible for bites. The presence of prey, usually a rodent, in the snake's stomach, indicating that it had eaten recently, did not influence the severity of envenoming, the initial venom level, or the percentage circumference increase and the extent of local swelling in the bitten limb. One hundred and fifty-five Russell's vipers responsible for bites showed a bimodal distribution of total lengths. The smaller snakes had probably been born that year. Longer snakes were responsible for more severe envenoming, a shorter interval between the bite and the detection of incoagulable blood, and more extensive local swelling with a greater percentage circumference increase of the bitten limb; but their bites were not associated with higher initial venom antigenaemia or a greater risk of developing acute renal failure.

Theakston RD, Warrell DA. 1991. Facial swelling in cattle. Vet Rec, 129 (17), pp. 392.

THEAKSTON R, WARRELL D. 1991. FACIAL SWELLING IN CATTLE VETERINARY RECORD, 129 (17), pp. 392-392. | Read more

Tin-Myint, Rai-Mra, Maung-Chit, Tun-Pe, Warrell DA. 1991. Bites by the king cobra (Ophiophagus hannah) in Myanmar: successful treatment of severe neurotoxic envenoming. Q J Med, 80 (293), pp. 751-762. | Show Abstract

Three patients bitten by the world's largest species of venomous snake, the king cobra (Ophiophagus hannah), were observed in Myanmar (Burma). All three were involved in the famous snake dance in Yangon (Rangoon) Zoological Gardens. One patient showed no signs of envenoming despite a sustained bite, another developed only signs of local envenoming, but in a third there was severe neurotoxic envenoming requiring mechanical ventilation for 64 1/2 hours, episodes of hypotension and massive swelling of the bitten limb. This patient showed some signs of recovery before delayed treatment with specific antivenom. It is possible that all three patients had some immunity to king cobra venom resulting from traditional 'immunization' achieved by scratching venom into the skin. The literature on king cobra bites is reviewed and recommendations given for antivenom and ancillary treatments.

KIRKHAM F, NEWTON C, WINSTANLEY P, PASVOL G, PESHU N, WARRELL D, MARSH K. 1991. CEREBRAL MALARIA - REPLY LANCET, 337 (8752), pp. 1282-1283.

Thein-Than, Tin-Tun, Hla-Pe, Phillips RE, Myint-Lwin, Tin-Nu-Swe, Warrell DA. 1991. Development of renal function abnormalities following bites by Russell's vipers (Daboia russelii siamensis) in Myanmar. Trans R Soc Trop Med Hyg, 85 (3), pp. 404-409. | Show Abstract | Read more

Renal function was monitored in 24 patients with systemic envenoming following proven Russell's viper bite. In all patients, blood clotted within 20 min on admission. In 15 cases severe defibrination (systemic envenoming) developed during the next 3-5 d. None of the patients received antivenom before admission but enzyme-refined monospecific antivenom was given to those who developed signs of systemic envenoming. Specific antigen was detected by enzyme immuno-assay in all 21 subjects tested. Nine patients whose renal function remained normal did not develop systemic envenoming, and recovered without any treatment even though venom antigen was detectable in their serum. Ten patients developed mild renal dysfunction and systemic envenoming, but recovered after treatment with antivenom alone. The remaining 5 patients, all of whom were oliguric from admission, developed acute renal failure despite treatment with antivenom, but some recovered after peritoneal dialysis. Serum venom antigen levels were high in the last 2 groups, but there was some overlap. Albuminuria, found only in patients who became systemically envenomed, was associated with high fractional sodium excretion in those who developed acute oliguric renal failure. Albuminuria may appear before a gross clotting defect is detectable. It is an indication for antivenom and spot measurements might prove a useful early predictor of outcome.

WARRELL D. 1991. ANTIVENOM TREATMENT FOR SCORPION STINGS - REPLY TROPICAL DOCTOR, 21 (2), pp. 78-79.

Newton CR, Kirkham FJ, Winstanley PA, Pasvol G, Peshu N, Warrell DA, Marsh K. 1991. Intracranial pressure in African children with cerebral malaria. Lancet, 337 (8741), pp. 573-576. | Show Abstract | Read more

Opening lumbar cerebrospinal fluid (CSF) pressure was measured with a paediatric spinal fluid manometer in 26 of 61 Kenyan children (mean age 39 months) with cerebral malaria. In all cases pressure was above normal (mean [SD]22.6 [7.4] cm CSF, range 10.5-36). Clinical features of our patients suggest that intracranial hypertension is important in the pathogenesis of cerebral malaria in children, especially as a cause of death. We suggest that raised intracranial pressure is secondary to increased cerebral blood volume. Lowering intracranial pressure may significantly reduce the mortality and morbidity of cerebral malaria. The potential risks and benefits of lumbar puncture should be considered carefully in patients with suspected cerebral malaria.

Friedland JS, Warrell DA. 1991. The Jarisch-Herxheimer reaction in leptospirosis: possible pathogenesis and review. Rev Infect Dis, 13 (2), pp. 207-210. | Show Abstract

The importance of treating leptospirosis with penicillin is emphasized by two case reports and a review documenting the occurrence of the Jarisch-Herxheimer reaction (JHR) in patients with this bacterial infection. The JHR is significant both as a cause of morbidity and mortality and as an indication of the therapeutic efficacy of penicillin. The possible etiology of the JHR is discussed, and comparisons with the changes occurring in septic shock are made; a study of either condition facilitates the understanding of the other. Tumor necrosis factor is hypothesized to play a key role in both. Current treatment of the JHR consists of general clinical support. Specific measures such as oxpentifylline therapy may play a role in the future.

Warrell DA, Shaheen J, Hillyard PD, Jones D. 1991. Neurotoxic envenoming by an immigrant spider (Steatoda nobilis) in southern England. Toxicon, 29 (10), pp. 1263-1265. | Show Abstract | Read more

A young woman was bitten on the shoulder by a female Steatoda nobilis spider, in Worthing on the south coast of England. She noticed intense radiating pain, local sweating (indicating parasympathetic stimulation) and feverishness. This immigrant species from the Canary Islands has established itself along the south coast of England in recent years. Like the related Mediterranean species S. paykulliana, S. nobilis may be of medical importance and deserves further study.

Theakston RD, Warrell DA. 1991. Antivenoms: a list of hyperimmune sera currently available for the treatment of envenoming by bites and stings. Toxicon, 29 (12), pp. 1419-1470. | Read more

Kamiguti AS, Cardoso JL, Theakston RD, Sano-Martins IS, Hutton RA, Rugman FP, Warrell DA, Hay CR. 1991. Coagulopathy and haemorrhage in human victims of Bothrops jararaca envenoming in Brazil. Toxicon, 29 (8), pp. 961-972. | Show Abstract | Read more

Thirty-four patients envenomed by Bothrops jararaca in Brazil were studied. Of these, 20 (59%) had incoagulable blood associated with local and/or systemic bleeding and 10 of the 20 were thrombocytopenic. Among 14 patients with coagulable blood, 6 (43%) had bleeding symptoms and 3 (21%) were thrombocytopenic. High levels of von Willebrand factor (vWF), plasminogen activator inhibitor type 1 (PAI-1) and tissue type plasminogen activator (t-PA) antigens were also recorded in some patients with systemic bleeding with or without incoagulable blood. These substances may have been released from endothelial cells. Admission serum venom antigen levels were similar in both groups. The study indicated that systemic haemorrhage may occur in patients with coagulable blood and thrombocytopenia and that coagulopathy is not therefore the primary cause of haemorrhage.

Warrell DA, Phillips RE, Garrard CS. 1991. Intensive care unit management of severe malaria Clinical Intensive Care, 2 (2), pp. 86-96.

Theakston RD, Phillips RE, Looareesuwan S, Echeverria P, Makin T, Warrell DA. 1990. Bacteriological studies of the venom and mouth cavities of wild Malayan pit vipers (Calloselasma rhodostoma) in southern Thailand. Trans R Soc Trop Med Hyg, 84 (6), pp. 875-879. | Show Abstract | Read more

Venom and oropharyngeal swabs from freshly captured Malayan pit vipers (Calloselasma rhodostoma) in southern Thailand and captive specimens in England were cultured aerobically and anaerobically to identify the bacterial flora which might contaminate wounds inflicted by bites of this species. The snakes' mouths contained a wider range of organisms than their venoms, especially gut-related Gram-negative rods such as Enterobacter and Pseudomonas species and some staphylococci and clostridia. There were fewer positive cultures from captive snakes. C. rhodostoma venom inhibited the growth of group A streptococci and, to a lesser extent, that of Staphylococcus aureus and Clostridium perfringens but not that of 2 Gram-negative organisms. Secondary bacterial infection is an important complication of snake bite, especially of necrotic wounds. A combination of gentamicin with benzyl penicillin would have prevented infection with, or treated, most of the bacteria isolated from snake venoms and mouths in Thailand.

Hutton RA, Looareesuwan S, Ho M, Silamut K, Chanthavanich P, Karbwang J, Supanaranond W, Vejcho S, Viravan C, Phillips RE. 1990. Arboreal green pit vipers (genus Trimeresurus) of South-East Asia: bites by T. albolabris and T. macrops in Thailand and a review of the literature. Trans R Soc Trop Med Hyg, 84 (6), pp. 866-874. | Show Abstract | Read more

In Thailand 29 patients were proved to have been bitten by arboreal green pit vipers: 24 by Trimeresurus albolabris and 5 by T. macrops. They were studied in order to define the clinical effects of envenoming, to characterize the haemostatic abnormalities and assess the efficacy of Thai Red Cross antivenom. T. macrops caused only local painful swelling, neutrophil leucocytosis and thrombocytopenia. T. albolabris caused more severe envenoming with local blistering and necrosis, shock, spontaneous systemic bleeding, defibrination, thrombocytopenia and leucocytosis. There was no evidence of disseminated intravascular coagulation, but fibrinolytic activity was increased. Platelet function was normal. The product of admission venom antigen concentration and the delay between bite and admission was significantly higher in defibrinated patients than in those without severe coagulopathy. Antivenom (5 ampoules intravenously) restored blood coagulability, but there was persistent venom antigenaemia, associated in some cases with recurrent coagulopathy. The literature on bites by south Asian green pit vipers of the genus Trimeresurus is reviewed; these bites are common medical problems and causes of morbidity. The identification of individual species is difficult, but may be important if antivenom is to be improved and used appropriately.

Gilks CF, Brindle RJ, Otieno LS, Bhatt SM, Newnham RS, Simani PM, Lule GN, Okelo GB, Watkins WM, Waiyaki PG. 1990. Extrapulmonary and disseminated tuberculosis in HIV-1-seropositive patients presenting to the acute medical services in Nairobi. AIDS, 4 (10), pp. 981-985. | Show Abstract | Read more

We studied 506 consecutive adult acute medical admissions to hospital in Nairobi; 95 (18.8%) were seropositive for HIV-1, and 43 new cases of active tuberculosis (TB) were identified. TB was clearly associated with HIV infection, occurring in 17.9% of seropositive patients compared with 6.3% of seronegatives [odds ratio (OR) 3.2; 95% confidence limits (CL) 1.6-6.5]. Extrapulmonary disease was more common in seropositive than seronegative TB patients (nine out of 17 versus five out of 26; OR 4.7; 95% CL 1.01-23.6); this accounted for most of the excess cases of TB seen in seropositive patients. Mycobacteraemia was demonstrated in two of eight seropositive TB patients but in none of 11 seronegative TB patients. No atypical mycobacteria were isolated. The World Health Organization (WHO) clinical case definition for African AIDS did not discriminate well between seropositive and seronegative TB cases. Five out of seven seropositive women with active tuberculosis had delivered children in the preceding 6 months and were lactating, compared with only one out of eight seronegative tuberculous women. An association between recent childbirth, HIV immunosuppression and the development of TB is suggested.

Gilks CF, Brindle RJ, Otieno LS, Simani PM, Newnham RS, Bhatt SM, Lule GN, Okelo GB, Watkins WM, Waiyaki PG. 1990. Life-threatening bacteraemia in HIV-1 seropositive adults admitted to hospital in Nairobi, Kenya. Lancet, 336 (8714), pp. 545-549. | Show Abstract | Read more

During 6 months, 506 consecutive adult emergency admissions to hospital in Nairobi were enrolled in a study of bacteraemia and HIV infection. 19% were HIV-1 antibody positive. Significantly more HIV-seropositive than seronegative patients had bacteraemia (26% vs 6%). The predominant organisms isolated from the seropositive patients were Salmonella typhimurium and Streptococcus pneumoniae. Mortality was higher in the seropositive than in the seronegative bacteraemic patients. The findings suggest that non-opportunistic bacteria are important causes of morbidity and mortality in HIV-infected individuals in Africa.

Cardoso JL, Wen FH, França FO, Warrell DA, Theakston RD. 1990. Detection by enzyme immunoassay of Loxosceles gaucho venom in necrotic skin lesions caused by spider bites in Brazil. Trans R Soc Trop Med Hyg, 84 (4), pp. 608-609. | Read more

Pukrittayakamee S, Nontprasert A, White NJ, Warrell DA, Bunnag D. 1990. Characterization of a monoclonal antibody that neutralizes the hyaluronidase activity of Russell's viper venom. Southeast Asian J Trop Med Public Health, 21 (2), pp. 231-237. | Show Abstract

Three monoclonal antibodies (WPN1, WPN2 and WPN3) raised against a partially purified fraction of Russell's viper venom (RVV) were characterized. All three monoclonal antibodies reacted with crude RVV when tested by ELISA, but only two (WPN1, WPN2) neutralized its hyaluronidase activity. WPN1 was the more potent and was effective at an antigen: antibody ratio of 1:3. Furthermore, WPN1 was shown to recognize only the 14,000 MW component of crude RVV. This has been identified in a previous study to be hyaluronidase. This antibody was also found to recognize some components of Calloselasma rhodostoma venom which also possesses potent hyaluronidase activity. The potential therapeutic role of antibodies that neutralize the hyaluronidase component of snake venoms should be investigated further.

Warrell DA. 1990. Bites by dark green pit vipers in Bangkok. Am J Trop Med Hyg, 42 (6), pp. 623-624.

Looareesuwan S, Phillips RE, Karbwang J, White NJ, Flegg PJ, Warrell DA. 1990. Plasmodium falciparum hyperparasitaemia: use of exchange transfusion in seven patients and a review of the literature. Q J Med, 75 (277), pp. 471-481. | Show Abstract | Read more

During the last 15 years, at least 35 patients with severe falciparum malaria or babesiosis have recovered following treatment by exchange of up to 10 l of blood. In a patient treated in Manchester, a parasitaemia of 2.10 X 10(6) microliters (42 per cent) was virtually eliminated over eight hours by a 3.5 litre exchange blood transfusion. However, the equipment and amounts of compatible blood required for total exchange are rarely available in areas endemic for malaria and the risks of the procedure, including transfusion-related infections, are high. Partial exchange transfusion with one to two litres of blood carried out over two to seven hours, reduced Plasmodium falciparum parasitaemias of 0.33-1.48 X 10(6)/microliters (13-38 per cent) to 0.11-0.81 X 10(6) (4-17 per cent) in six Thai patients who were receiving intravenous quinine. The reduction in parasitaemia ranged from 0.13-0.67 X 10(6) microliters (9-12 per cent) within six hours. During the same period, parasitaemia in 13 patients with cerebral malaria treated with chemotherapy alone showed little reduction from initial levels of 0.20-1.74 X 10(6)/microliters (11-42 per cent). One of the patients who were treated with exchange transfusion died with intractable hypotension before the procedure could be completed and two others developed oliguric renal failure which was controlled by peritoneal dialysis. Partial exchange transfusion is a promising and practical alternative to total exchange where facilities are limited. It deserves further assessment in the rural tropics.

Ho M, Silamut K, White NJ, Karbwang J, Looareesuwan S, Phillips RE, Warrell DA. 1990. Pharmacokinetics of three commercial antivenoms in patients envenomed by the Malayan pit viper, Calloselasma rhodostoma, in Thailand. Am J Trop Med Hyg, 42 (3), pp. 260-266. | Show Abstract

The pharmacokinetics of 3 monospecific antivenoms were compared in patients envenomed by the Malayan pit viper, Calloselasma rhodostoma. There was a biphasic decline in serum concentrations following intravenous administration. The initial rapid decline was attributable to the formation of venom-antivenom complexes, as the fall in antivenom during this phase was positively correlated with the initial venom concentration (P = 0.045). The total apparent volume of distribution for each antivenom was 1.5-3 times larger than that of the central compartment, which suggests some tissue distribution in addition to complex formation. This was marked for antivenom from the Government Pharmaceutical Organization of Thailand which contained mostly F(ab)2 fragments. The terminal elimination half time was shorter for Twyford antivenom of caprine origin. Systemic clearance was lower for Thai Red Cross antivenom. In 8 of the 26 patients who experienced recurrence of non-clotting blood after initial response to antivenom, serial measurements of plasma venom and antivenom concentrations revealed that recurrence of venom antigenemia and non-clotting blood bore no direct relation to the elimination half-life of the antivenom used, but non-clotting blood recurred when serum antivenom levels fell below 10-20% of the total given. There is no substitute for close monitoring of envenomed patients so that indications for further antivenom can be detected promptly.

Theakston RD, Phillips RE, Warrell DA, Galagedera Y, Abeysekera DT, Dissanayaka P, de Silva A, Aloysius DJ. 1990. Envenoming by the common krait (Bungarus caeruleus) and Sri Lankan cobra (Naja naja naja): efficacy and complications of therapy with Haffkine antivenom. Trans R Soc Trop Med Hyg, 84 (2), pp. 301-308. | Show Abstract | Read more

In Anuradhapura, Sri Lanka, 5 patients proved to have been bitten by common kraits (Bungarus caeruelus) and 2 by Sri Lankan cobras (Naja naja naja) were investigated. In all the cases of krait bite the patients were bitten while they were asleep: local signs were negligible but 4 developed symptoms of systemic envenoming including paralysis, muscle pain and tenderness and abdominal pain. Mild myoglobinaemia was found in one case. Of the 2 patients bitten by cobras, one developed severe local swelling which progressed to necrosis and the other local swelling and respiratory paralysis. Response to polyspecific antivenom (Haffkine, India) was neither rapid nor convincing. Venom antigenaemia became undetectable within 2 h of the start of antivenom treatment, but recurred 25 and 65 h later in 2 cases. Among a group of 27 patients treated with this antivenom (including 21 bitten by Russell's vipers), the incidence of early anaphylactic and pyrogenic reactions was high at 52% and 65% respectively. Anticholinesterase did not improve paralysis in 2 patients bitten by kraits. The respiratory failure in 2 patients was successfully treated by mechanical ventilation for 8 and 30 h. These observations confirm the importance of neurotoxic symptoms following bites by these species but also suggest a contributory role of generalized rhabdomyolysis in krait victims and emphasize the problem of severe local tissue necrosis in cobra victims. There is a need for safer and more potent antivenoms for use in Sri Lanka.

Newton CR, Pasvol G, Winstanley PA, Warrell DA. 1990. Cerebral malaria: what is unarousable coma? Lancet, 335 (8687), pp. 472.

NEWTON C, PASVOL G, WINSTANLEY P, WARRELL D. 1990. CEREBRAL MALARIA - WHAT IS UNAROUSABLE COMA LANCET, 335 (8687), pp. 472-472. | Read more

Warrell DA. 1990. A Letter to the editor (I) American Journal of Tropical Medicine and Hygiene, 42 (6), pp. 623.

Warrell DA. 1989. Snake venoms in science and clinical medicine. 1. Russell's viper: biology, venom and treatment of bites. Trans R Soc Trop Med Hyg, 83 (6), pp. 732-740. | Show Abstract | Read more

Russell's viper, Vipera russelli (Shaw), is distributed erratically in 10 south Asian countries and is a leading cause of fatal snake bite in Pakistan, India, Bangladesh, Sri Lanka, Burma and Thailand. In Burma it has been the 5th most important cause of death. Its venom is of great interest to laboratory scientists and clinicians. The precoagulant activity of the venom was used by Macfarlane and others to elucidate the human clotting cascade. Up to 70% of the protein content is phospholipase A2, present in the form of at least 7 isoenzymes. Possible clinical effects of the enzyme include haemolysis, rhabdomyolysis, pre-synaptic neurotoxicity, vasodilatation and shock, release of endogenous autacoids and interaction with monoamine receptors. Russell's viper bite is an occupational hazard of rice farmers throughout its geographical range. Defibrination, spontaneous haemorrhage, shock and renal failure develop with frightening rapidity. In several countries, Russell's viper bite is the commonest cause of acute renal failure. There is a fascinating geographical variation in the clinical manifestations, doubtless reflecting differences in venom composition. Conjunctival oedema is unique to Burma, acute pituitary infarction to Burma and south India, and rhabdomyolysis and neurotoxicity to Sri Lanka and south India. Treatment with potent specific antivenom rapidly controls bleeding and clotting disorders, but may not reverse nephrotoxicity and shock. Causes of death include shock, pituitary and intracranial haemorrhage, massive gastrointestinal haemorrhage and acute tubular necrosis or bilateral renal cortical necrosis. The paddy farmer and the Russell's viper coexist in fragile symbiosis. The snake controls rodent pests but inevitably interacts with man, often with mutually disastrous results.

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WARRELL M, WHITE N, LOOAREESUWAN S, PHILLIPS R, SUNTHARASAMAI P, CHANTHAVANICH P, RIGANTI M, FISHERHOCH S et al. 1989. FAILURE OF INTERFERON ALFA AND TRIBAVIRIN IN RABIES ENCEPHALITIS BRITISH MEDICAL JOURNAL, 299 (6703), pp. 830-833. | Read more

WARRELL D. 1989. CORRECTION LANCET, 2 (8664), pp. 696-696.

WARRELL D. 1989. CEREBRAL CONSUMPTION OF GLUCOSE - REPLY LANCET, 1 (8647), pp. 1142-1142.

Molyneux ME, Looareesuwan S, Menzies IS, Grainger SL, Phillips RE, Wattanagoon Y, Thompson RP, Warrell DA. 1989. Reduced hepatic blood flow and intestinal malabsorption in severe falciparum malaria. Am J Trop Med Hyg, 40 (5), pp. 470-476. | Show Abstract

We have studied intestinal function and liver blood flow in Thai adults with complicated and uncomplicated falciparum malaria. The absorption of 3 orally administered test sugars, D-xylose, 3-O-methyl-D-glucose, and L-rhamnose, was greatly reduced in complicated malaria, while the lactulose/rhamnose absorption ratio was significantly increased. Hepatic blood flow was concomitantly reduced in severe malaria. These deviations reverted to normal in convalescence. Neither sugar absorption nor liver blood flow was reduced in uncomplicated falciparum malaria.

Warrell DA. 1989. Cerebral malaria. Q J Med, 71 (265), pp. 369-371. | Read more

Ratcliffe PJ, Pukrittayakamee S, Ledingham JG, Warrell DA. 1989. Direct nephrotoxicity of Russell's viper venom demonstrated in the isolated perfused rat kidney. Am J Trop Med Hyg, 40 (3), pp. 312-319. | Show Abstract

Envenoming by Russell's Viper (Vipera russelli) is an important cause of acute renal failure. The mechanism of renal damage is unresolved. It is difficult to obtain evidence of a direct nephrotoxic action because of the coincidental disturbance to the systemic circulation. We studied the action of Russell's Viper venom on the function of the isolated perfused rat kidney. Direct nephrotoxic action was indicated by a dose dependent decrease in inulin clearance and an increase in fractional excretion of sodium seen at venom concentrations down to 50 ng/ml, a concentration likely to be achieved in the human circulation after envenoming. The isolated perfused kidney was also used to assess the efficiency of antivenom and for a comparison with snake venoms from the Thai cobra (Naja kauothia) and the Nigerian Saw-Scaled Viper (Echis ocellatus).

Than-Than, Francis N, Tin-Nu-Swe, Myint-Lwin, Tun-Pe, Soe-Soe, Maung-Maung-Oo, Phillips RE, Warrell DA. 1989. Contribution of focal haemorrhage and microvascular fibrin deposition to fatal envenoming by Russell's viper (Vipera russelli siamensis) in Burma. Acta Trop, 46 (1), pp. 23-38. | Show Abstract | Read more

In Burma, clinicopathological studies were carried out in three young farmers who died 15, 52 and 36 h after being bitten by Russell's vipers. Clinical features included local swelling, spontaneous systemic bleeding, defibrination, shock, cardiac arrhythmia, hypoglycaemia, coma and oliguria. On admission to hospital, 15, 48 and 21 h after the bites, serum venom antigen concentrations ranged from 50 to 130 ng/ml. Autopsies revealed widespread congestion and bleeding in the lungs, gastrointestinal and renal tracts, adrenals, heart, brain and anterior pituitary. There was histopathological evidence of focal haemorrhage and fibrin deposition at the site of the bite and in the pituitary, lungs and kidneys and acute tubular necrosis. Deposition of fibrin microthrombi results from the action of venom procoagulants. Shock was attributed to increased capillary permeability, revealed clinically by conjunctival oedema. Acute pituitary/adrenal failure in one case was explained by fibrin deposition and haemorrhage in the anterior pituitary--resembling Sheehan's syndrome. Acute tubular necrosis resulted from ischaemia caused by fibrin deposition and to prerenal factors. An intractable cardiac tachyarrhythmia may have been caused by subendocardial and myocardial haemorrhages.

Warrell DA. 1989. Treatment of severe malaria. J R Soc Med, 82 Suppl 17 (17), pp. 44-50. | Show Abstract

In the treatment of severe Plasmodium falciparum infection antimalarial drugs should, ideally, be given by controlled rate intravenous infusion until the patient is able to swallow tablets. In cases where infection has been acquired in a chloroquine resistant area, and where it has broken through chloroquine prophylaxis or where the geographical origin or species are uncertain, quinine is the treatment of choice. When access to parenteral quinine is likely to be delayed, parenteral quinidine is an effective alternative. A loading dose of quinine is recommended in order to achieve therapeutic plasma concentrations as quickly as possible. In the case of chloroquine sensitive P. falciparum infection, chloroquine, which can be given safely by slow intravenous infusion, may be more rapidly effective and has fewer toxic effects than quinine. There is limited experience with parenteral administration of pyrimethamine sulphonamide combinations such as Fansidar, and resistance to these drugs has developed in South East Asia and elsewhere. Mefloquine and halofantrine cannot be given parenterally. Qinghaosu derivatives are not readily available and have not been adequately tested outside China. Supportive treatment includes the prevention or early detection and treatment of complications, strict attention to fluid balance, provision of adequate nursing for unconscious patients and avoidance of harmful ancillary treatments. Anaemia is inevitable and out of proportion to detectable parasitaemia. Hypotension and shock ('algid malaria') are often attributable to secondary gram-negative septicaemia requiring appropriate antimicrobial therapy and haemodynamic resuscitation. Many patients with severe falciparum malaria are hypovolaemic on admission to hospital and require cautious fluid replacement. Failure to rehydrate these patients may lead to circulatory collapse, lactic acidosis, renal failure and severe hyponatraemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Warrell DA, Warrell MJ. 1988. Human rabies and its prevention: an overview. Rev Infect Dis, 10 Suppl 4 (Supplement 4), pp. S726-S731. | Show Abstract | Read more

Human rabies is underreported, but it clearly is still a frequent medical problem that is virtually confined to tropical countries. Rabies encephalitis remains essentially incurable, and most patients die at home, their terrible symptoms unpalliated by sedatives or analgesics. Recent attempts to cure rabies in well-equipped intensive care units have failed, a situation reemphasizing the importance of preventive measures. The great advances that have been made in understanding the rabies virus and the associated improvements in rabies vaccines have had little or no impact in the tropical endemic zone. Most patients who have been exposed to rabies are still given nervous tissue vaccines for postexposure prophylaxis. An urgent priority is the development of a regimen using tissue culture vaccine that is sufficiently economical to replace nervous tissue vaccine. This has been achieved in China with primary hamster kidney cell vaccine.

WARRELL D. 1988. CORRECTION LANCET, 2 (8612), pp. 698-698.

Warrell DA, White NJ, Veall N, Looareesuwan S, Chanthavanich P, Phillips RE, Karbwang J, Pongpaew P, Krishna S. 1988. Cerebral anaerobic glycolysis and reduced cerebral oxygen transport in human cerebral malaria. Lancet, 2 (8610), pp. 534-538. | Show Abstract | Read more

In 12 patients comatose with cerebral malaria, cerebral blood flow was 52.2 (SE 4.0) ml/100 g per min, within the reported range for healthy controls, but cerebral vascular resistance was raised at 1.66 (0.19) mm Hg/ml per 100 g per min. Cerebral oxygen consumption (1.90 [0.23] ml/100 g per min), and cerebral arteriovenous oxygen content difference (3.5 [0.43] ml/dl) were subnormal, while cerebral venous pO2 (5.7 [0.2] kpA) was raised. After recovery of consciousness there were significant decreases in arterial lactate concentration (2.44 [0.45] to 1.19 [0.45] mumol/l) and cerebral lactate production (17.4 [7.9] to 5.6 [1.1] mmol/100 g per minute). These results provide evidence of cerebral anaerobic glycolysis associated with inadequate oxygen delivery to the brain consistent with either inhibition of cerebral oxidative metabolism or the microcirculatory obstruction envisaged in the "mechanical" hypothesis for cerebral malaria.

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PHILLIPS R, THEAKSTON R, WARRELL D, GALIGEDARA Y, ABEYSEKERA D, DISSANAYAKA P, HUTTON R, ALOYSIUS D. 1988. PARALYSIS, RHABDOMYOLYSIS AND HEMOLYSIS CAUSED BY BITES OF RUSSELLS VIPER (VIPERA-RUSSELLI-PULCHELLA) IN SRI-LANKA - FAILURE OF INDIAN (HAFFKINE) ANTIVENOM QUARTERLY JOURNAL OF MEDICINE, 68 (257), pp. 691-716.

Phillips RE, Theakston RD, Warrell DA, Galigedara Y, Abeysekera DT, Dissanayaka P, Hutton RA, Aloysius DJ. 1988. Paralysis, rhabdomyolysis and haemolysis caused by bites of Russell's viper (Vipera russelli pulchella) in Sri Lanka: failure of Indian (Haffkine) antivenom. Q J Med, 68 (257), pp. 691-715. | Show Abstract | Read more

In Sri Lanka, Russell's viper, Vipera russelli pulchella, kills more people than any other species of snake. At Anuradhapura in the dry central zone of the island we studied 23 patients with systemic envenoming after proven bites. Seventy-three per cent had swelling at the bite site. Neurotoxicity was the commonest sign of systemic envenoming: 82 per cent had external ophthalmoplegia and 77 per cent had ptosis. Incoagulable blood was found in 59 per cent but only 36 per cent had spontaneous bleeding. Other signs included generalized muscle tenderness (32 per cent), black urine (27 per cent) and persistent oliguria (9 per cent). Laboratory studies showed evidence of a severe clotting disorder: fibrinogen was often depleted as were factors V and X. Fibrin degradation products, including cross-linked moieties, were grossly elevated, clear evidence for enhanced fibrinolysis. Intravascular haemolysis, unrelated to G6PD deficiency, was often present. Myoglobin was detected in the plasma of all 19 patients tested (range 100- greater than 8000 ng/ml) and in the urine in 14 of 18 patients (110- greater than 16,000 ng/ml). Venom antigen (16.5-702 ng/ml) was detected by specific ELISA in the serum of all patients. Its concentration fell with the administration of 50-200 ml of Haffkine polyspecific antivenom raised against Indian venoms. Complete permanent clearance of venom antigen from the circulation was seen in only one of 21 patients who were followed until discharge. Blood coagulability was restored between one and 25 h (mean 8.8) after the first dose of antivenom in the 12 surviving patients whose clotting defect could be followed; no dramatic reversal of neuromyotoxic signs was seen. Haffkine antivenom thus has limited efficacy against systemic poisoning by Russell's viper in Sri Lanka.

Than-Than, Hutton RA, Myint-Lwin, Khin-Ei-Han, Soe-Soe, Tin-Nu-Swe, Phillips RE, Warrell DA. 1988. Haemostatic disturbances in patients bitten by Russell's viper (Vipera russelli siamensis) in Burma. Br J Haematol, 69 (4), pp. 513-520. | Show Abstract | Read more

Patients who are severely envenomed by Russell's viper develop DIC which is frequently associated with spontaneous bleeding and incoagulable blood. These haemostatic disturbances may be responsible for death or organ/tissue damage both through haemorrhage and microvascular occlusion by fibrin thrombi. The most striking laboratory features of the coagulopathy developing after Russell's viper bite in the 42 patients studied were depletion of fibrinogen (mean 0.09 g/l, range 0-0.6), factor V (6.5 u/dl, range 0-17), factor X (35 u/dl, range 1-85), factor XIIIa (57 u/dl, range 15-82), plasminogen (61 u/dl, range 10-92), antiplasmin (36 u/dl, range 14-62). Protein C (49 u/dl, range 15-100) and platelets (104 x 10(9)/l, range 25-197). Intense fibrinolytic activity was detected in all cases with marked elevation of FDPs (1614 micrograms/ml, range 350-3000), a large proportion of which were cross-linked (1058 micrograms/ml, range 38-3000). The monospecific Burmese antivenom appeared to be very effective in neutralizing the venom procoagulants and in restoring blood coagulability. Moreover, the unexpectedly normal level of AT III provides a theoretical basis for the use of heparin to enhance the inactivation of those serine proteases present before antivenom administration.

White NJ, Looareesuwan S, Phillips RE, Chanthavanich P, Warrell DA. 1988. Single dose phenobarbitone prevents convulsions in cerebral malaria. Lancet, 2 (8602), pp. 64-66. | Show Abstract | Read more

48 patients over 6 years of age with strictly defined cerebral malaria were randomised to receive either a single intramuscular injection of phenobarbitone (3.5 mg/kg) or placebo in a double-blind, placebo-controlled study. Phenobarbitone significantly reduced the incidence of subsequent convulsions from 54% to 12.5%, without adverse effects. A single intramuscular injection of phenobarbitone is a simple, cheap, and effective method for prevention of convulsions in cerebral malaria.

Davis TM, White NJ, Looareesuwan S, Silamut K, Warrell DA. 1988. Quinine pharmacokinetics in cerebral malaria: predicted plasma concentrations after rapid intravenous loading using a two-compartment model. Trans R Soc Trop Med Hyg, 82 (4), pp. 542-547. | Show Abstract | Read more

To investigate the toxic potential of rapid intravenous quinine administration in severe malaria, the pharmacokinetic properties of low-dose quinine dihydrochloride injection (4 mg/kg body weight, equivalent to 3.3 mg base/kg) followed one hour later by infusion of 16 mg/kg over 3 h were studied in 7 patients with cerebral malaria. Plasma quinine concentrations closely followed a bi-exponential decline. Both the volumes of the central compartment (mean +/- SD: 0.17 +/- 0.10 litre/kg) and total volumes of distribution (0.74 +/- 0.30 litre/kg) were significantly smaller than those previously reported for healthy subjects. Based on the derived pharmacokinetic parameters, predicted plasma quinine concentrations following intravenous injection of the standard therapeutic dose (10 mg salt/kg) over 10-20 min are potentially toxic in severe malaria. Further reductions in administration time would produce disproportionately higher plasma quinine concentrations, especially as the distribution half-time (2.3 +/- 3.2 min) is approached. A theoretical regimen designed to achieve therapeutic, non-toxic plasma quinine concentrations promptly would be 7.0 mg quinine dihydrochloride/kg over 30 min. A subsequent maintenance infusion of 10 mg/kg over 4 h would allow for drug elimination and acute changes in pharmacokinetic parameters due to resuscitation and rehydration.

Looareesuwan S, Phillips RE, Edwards G, Rodick CL, Chanthavanich P, Supanaranond W, Warrell DA. 1988. Mepacrine accumulation during treatment of chloroquine-resistant falciparum malaria. Ann Trop Med Parasitol, 82 (2), pp. 107-112. | Show Abstract

Oral mepacrine dihydrochloride, 200 mg (158 mg of the base) six-hourly for five doses followed by 100 mg (79 mg of the base) eight-hourly for six days (half dosage for those less than or equal to 50 kg) was given to 21 patients with high-grade chloroquine-resistant falciparum malaria in eastern Thailand. Fifteen patients (71%) had a clinical response [fever clearance time of 81 +/- 35 hours (mean +/- S.D.)] and 13 (62%) had complete clearance of parasitaemia (clearance time 92 +/- 42 hours). Two patients were cured, but 11 patients returned with recurrent parasitaemia between 11 and 40 days after starting treatment. Five patients had an R2 response and three had an R3 response. Mepacrine retains some activity against chloroquine-resistant falciparum malaria but it cannot be recommended for use in Thailand. The doses used, which are those also recommended for giardiasis, led to progressive and potentially toxic mepacrine accumulation. Further evaluation of regimens which produce safer plasma concentration profiles is needed.

Edwards G, Looareesuwan S, Davies AJ, Wattanagoon Y, Phillips RE, Warrell DA. 1988. Pharmacokinetics of chloroquine in Thais: plasma and red-cell concentrations following an intravenous infusion to healthy subjects and patients with Plasmodium vivax malaria. Br J Clin Pharmacol, 25 (4), pp. 477-485. | Show Abstract | Read more

1. Chloroquine diphosphate (15 mg base kg-1) was given by constant rate intravenous infusion to two groups of Thai subjects. Eleven were patients with malaria (10 with Plasmodium vivax and one case with Plasmodium malariae) and 10 were healthy normal volunteers. 2. Plasma and packed red-cell concentrations of chloroquine, electrocardiographic intervals, arterial blood pressure and pulse were measured at frequent intervals. 3. Peak plasma concentrations at the end of the infusion ranged from 979 to 2,900 ng ml-1 in the malaria patients. In the group of healthy subjects the range was 550-2,200 ng ml-1. Values for terminal elimination rate constant, (lambda z) plasma clearance (CL), initial volume of distribution (V1) and volume of distribution at steady state (Vss) were calculated. For the healthy subjects, mean estimates of these parameters were lambda z = 0.062 +/- 0.030 day-1, CL = 597 +/- 238 ml min-1, V1 = 0.66 +/- 0.71 l kg-1 and Vss = 132 +/- 50 l.kg-1 For the group of malaria patients, the corresponding values were lambda z = 0.055 +/- 0.032 day-1, CL = 535 +/- 246 ml min-1, V1 = 0.74 +/- 0.75 l kg-1 and Vss = 136 +/- 64 l kg-1 There was no statistically significant difference in the estimates for any parameter between groups (P less than or equal to 0.05). 4. Chloroquine concentrations in packed red blood cells consistently exceeded those in plasma and showed no consistent change with time throughout the period of study in either group. The median value for the red cell to plasma ratio was between 3 and 4 in each group.(ABSTRACT TRUNCATED AT 250 WORDS)

Singh B, Ho M, Looareesuwan S, Mathai E, Warrell DA, Hommel M. 1988. Plasmodium falciparum: inhibition/reversal of cytoadherence of Thai isolates to melanoma cells by local immune sera. Clin Exp Immunol, 72 (1), pp. 145-150. | Show Abstract

The effect of sera on the cytoadherence in vitro of Plasmodium falciparum-infected erythrocytes to melanoma cells was examined. Sera from 19 healthy individuals living in endemic malarious areas in Thailand and 24 patients with P. falciparum malaria were tested against four local P. falciparum isolates. Out of 57 sera examined, 12 (21%) showed significant inhibition (greater than 50%) of cytoadherence for at least one isolate. Anti-malarial IgG antibody titres were determined for all 57 sera and although 11 of the 12 inhibitory sera had relatively high titres, 36 out of 47 sera with similarly high titres showed no significant inhibitory activity. Convalescent sera were no more effective than corresponding acute sera in inhibiting the cytoadherence of erythrocytes infected with any of the four heterologous isolates examined. Sera which significantly inhibited cytoadherence were also capable of reversing cytoadherence, and pooled plasma, from healthy individuals living in malarious areas, was effective in significantly reversing the in vitro cytoadherence of all the five parasite isolates examined. The results confirm the antibody mediated strain-specific nature of the inhibition of cytoadherence and stress the difficulty in selecting immune sera potentially useful for the immunotherapy of cerebral malaria patients in Thailand.

WARRELL D. 1988. TREATMENT OF MALARIA LANCET, 1 (8583), pp. 466-467. | Read more

Warrell MJ, Looareesuwan S, Manatsathit S, White NJ, Phuapradit P, Vejjajiva A, Hoke CH, Burke DS, Warrell DA. 1988. Rapid diagnosis of rabies and post-vaccinal encephalitides. Clin Exp Immunol, 71 (2), pp. 229-234. | Show Abstract

In an attempt to establish the diagnoses of rabies post-vaccinal encephalitis (PVE) and early rabies encephalitis, paired serum and CSF levels of rabies neutralizing antibody (Rab) and rabies specific-IgM (RIgM) were compared in 12 PVE, 10 rabies and five control patients with similar presenting clinical features. Rapid methods of rabies antigen detection were evaluated in 17 patients. All 12 PVE patients had Rab in their serum and in eight it was also present in the CSF. These same eight had RIgM in the serum, and in seven also in the CSF. The CSF antibodies may have originated in the plasma since six patients had a high albumin quotient indicating leakage across the blood-brain barrier. Among the rabies patients, only the two vaccinated ones had serum Rab; this was also detected in the CSF of one and RIgM was in the CSF of the other. A raised IgG Index, indicating intrathecal synthesis of IgG was seen in five of 12 PVE patients. This did not correlate with the presence of CSF rabies antibody, suggesting production of antibody to other vaccine antigens of neural origin. The diagnosis of rabies encephalitis in life was made by antigen detection in a skin biopsy. No false positive results occurred and the method was as efficient as immunofluorescence of a post-mortem brain biopsy.

THAN T, KHIN E, HUTTON R, SOE S, SWE T, LWIN M, PHILLIPS R, WARRELL D. 1988. HEMOSTATIC DEFECTS AND THEIR RESPONSE TO SPECIFIC ANTIVENOM THERAPY IN SEVERELY ENVENOMATED RUSSELL VIPER BITE VICTIMS TOXICON, 26 (1), pp. 43-43.

Pukrittayakamee S, Warrell DA, Desakorn V, McMichael AJ, White NJ, Bunnag D. 1988. The hyaluronidase activities of some Southeast Asian snake venoms. Toxicon, 26 (7), pp. 629-637. | Show Abstract | Read more

The hyaluronidase activities of venoms of snakes indigenous to Southeast Asia were investigated. With the exception of the venom of the Malayan krait Bungarus candidus, the elapid venoms had either little or no hyaluronidase activities, whereas the viperid venoms possessed considerable activity. A component of Russell's viper venom with hyaluronidase activities had a mol. wt of approximately 14,000. Neither MP4, a monoclonal antibody raised against the purified Russell's viper venom hyaluronidase toxin, nor a monospecific polyclonal antivenom neutralized the hyaluronidase activities of this purified hyaluronidase component of crude Russell's viper venom. The Russell's viper venom hyaluronidase activities was labile on heating and storage. The significance of these observations to envenomation and antivenom production is discussed.

Looareesuwan S, Viravan C, Warrell DA. 1988. Factors contributing to fatal snake bite in the rural tropics: analysis of 46 cases in Thailand. Trans R Soc Trop Med Hyg, 82 (6), pp. 930-934. | Show Abstract | Read more

Records of 46 cases of fatal bites by identified snakes from 15 provincial hospitals throughout Thailand contained sufficient information for detailed analysis. Bungarus candidus and Calloselasma rhodostoma were each responsible for 13 deaths, Naja kaouthia for 12, Vipera russelli for 7 and B. fasciatus for one. Major causes of death among elapid victims were respiratory failure (26) and complications of prolonged mechanical ventilation (10), and among viper victims shock (12), intracranial haemorrhage (9), complications of local wound necrosis (7) including tetanus (2), and renal failure (2). Factors contributing to fatal outcome included inadequate dose of antivenom (15 cases), misidentification of the snake leading to use of the wrong antivenom (12), problems associated with mechanical ventilation (10), and delayed arrival in hospital after traditional (herbal) treatment (10). Similar problems have been identified in other tropical countries. Education of medical staff and the patient population at highest risk could reduce snake bite mortality.

Webster HK, Ho M, Looareesuwan S, Pavanand K, Wattanagoon Y, Warrell DA, Hockmeyer WT. 1988. Lymphocyte responsiveness to a candidate malaria sporozoite vaccine (R32tet32) of individuals with naturally acquired Plasmodium falciparum malaria. Am J Trop Med Hyg, 38 (1), pp. 37-41. | Show Abstract

Lymphocyte proliferative responses to the candidate malaria sporozoite vaccine antigen R32tet32 were evaluated in 29 patients with acute Plasmodium falciparum malaria, 20 convalescent patients, 11 nonimmune individuals, and 22 healthy residents of two endemic malarious areas in Thailand. The results indicate that 14 of 20 (70%) convalescent patients and 14 of 22 (64%) residents of endemic areas responded to the R32tet32 antigen. However, only 8 of 29 (28%) patients with acute P. falciparum malaria responded. When 4 of the convalescent patients who remained in a malaria-free area were restudied 5-10 months after the acute infection, they were either not responsive or their responses had greatly diminished. These findings show that sensitization to R32tet32 occurs following a natural P. falciparum infection, but the cellular immune response to sporozoite antigens may be short-lived and may be suppressed during acute P. falciparum malaria.

Looareesuwan S, Merry AH, Phillips RE, Pleehachinda R, Wattanagoon Y, Ho M, Charoenlarp P, Warrell DA, Weatherall DJ. 1987. Reduced erythrocyte survival following clearance of malarial parasitaemia in Thai patients. Br J Haematol, 67 (4), pp. 473-478. | Show Abstract | Read more

Erythrocyte survival times were measured in healthy Thai controls and in patients following clearance of asexual P. falciparum or P. vivax parasitaemia. In five controls the mean cell life (MCL) of compatible donor erythrocytes was 89.6 d (mean range 73-101 d) compared with a mean MCL of 56.8 d (range 30-66 d) for autologous erythrocytes in 12 falciparum patients. In one of these patients the survival curve was biphasic with a rapid loss of some labelled cells. The survival of compatible donor erythrocytes was also studied in 10 patients and two types of survival curve could be distinguished. In five patients the cells had a mean MCL of 64.4 d (range 42-90 d). In the others survival curves were curvilinear, suggesting a complex mechanism of cell clearance or the presence of more than one cell population. There was initially a more rapid rate of destruction. In P. vivax malaria the MCL of autologous erythrocytes in seven patients was a mean of 67.2 d (range 34-74 d) and that of compatible donor cells in six patients was 66.8 d (range 54-76 d). In all except one of these patients both autologous and donor cell survival curves could be fitted to straight lines. No increase in cell-bound IgG or C3 was evident in 12 patients tested. The differences between the mean MCL in all the groups of patients and the controls were statistically significant at the 5% level. This indicates an increased rate of erythrocyte destruction following clearance of P. falciparum or P. vivax parasites which is not antibody or complement mediated. The mechanism is unknown, but appears to be extrinsic to the erythrocytes themselves and may result from nonspecific activation of the reticuloendothelial function associated with the parasitic infection.

Suntharasamai P, Warrell MJ, Viravan C, Chanthavanich P, Looareesuwan S, Supapochana A, Supanaranond JK, Chittamas S, Bijok U, Warrell DA. 1987. Purified chick embryo cell rabies vaccine: economical multisite intradermal regimen for post-exposure prophylaxis. Epidemiol Infect, 99 (3), pp. 755-765. | Show Abstract | Read more

The standard six-dose intramuscular (i.m.) rabies post-exposure vaccine regimen using a new purified chick embryo cell (PCEC) vaccine was compared with two economical multisite intradermal (i.d.) PCEC regimens, a multisite i.m. PCEC schedule and a subcutaneous regimen using a suckling mouse brain (SMB) rabies vaccine manufactured in Thailand. The neutralizing antibody results for the four-site and eight-site i.d. and the standard i.m. PCEC regimens were similar over 3 months. A three-site i.m. PCEC regimen had no advantage. The SMB vaccine gave the lowest antibody levels. Human rabies immune globulin therapy significantly increased the GMT of all groups on day 7, unlike equine antirabies serum (EARS). Both antisera suppressed antibody responses to PCEC on days 14 and 28. Three generalized reactions probably related to EARS were the only serious side effects. An eight-site i.d. PCEC vaccine regimen proved as immunogenic as the routine i.m. schedule and, if implemented as post-exposure prophylaxis, would be the cheapest widely available tissue culture vaccine regimen. The protective efficiency should now be tested in patients bitten by rabid animals.

Tun-Pe, Phillips RE, Warrell DA, Moore RA, Tin-Nu-Swe, Myint-Lwin, Burke CW. 1987. Acute and chronic pituitary failure resembling Sheehan's syndrome following bites by Russell's viper in Burma. Lancet, 2 (8562), pp. 763-767. | Show Abstract | Read more

Pituitary function was investigated in 9 patients in shock after Russell's viper bites and in 24 individuals who had been severely envenomed 2 weeks to 24 years previously. 3 out of 9 patients had hypoglycaemia and inappropriately low serum cortisol, plasma growth hormone, and plasma prolactin concentrations. 4 who died had pituitary haemorrhage and 1 had adrenal haemorrhage as well. Of the 24 who had apparently recovered from bites, 7 had clinical features of hypopituitarism and no response in plasma growth hormone or prolactin concentrations to symptom-producing insulin-induced hypoglycaemia. 4 of these 7 had a sluggish serum cortisol response to 'Synacthen Depot' and 5 had an abnormal cortisol response to hypoglycaemia. 4 men with symptoms who were tested had low serum testosterone concentrations; serum thyroxine was also low in these men but not in 2 women with menstrual disturbances and impaired insulin responses. Of the 17 individuals without clinical evidence of endocrine disease, 4 had pituitary hormonal abnormalities. Russell's viper envenoming may thus produce a disorder resembling Sheehan's syndrome.

Looareesuwan S, Ho M, Wattanagoon Y, White NJ, Warrell DA, Bunnag D, Harinasuta T, Wyler DJ. 1987. Dynamic alteration in splenic function during acute falciparum malaria. N Engl J Med, 317 (11), pp. 675-679. | Show Abstract | Read more

Plasmodium-infected erythrocytes lose their normal deformability and become susceptible to splenic filtration. In animal models, this is one mechanism of antimalarial defense. To assess the effect of acute falciparum malaria on splenic filtration, we measured the clearance of heated 51Cr-labeled autologous erythrocytes in 25 patients with acute falciparum malaria and in 10 uninfected controls. Two groups of patients could be distinguished. Sixteen patients had splenomegaly, markedly accelerated clearance of the labeled erythrocytes (clearance half-time, 8.4 +/- 4.4 minutes [mean +/- SD] vs. 62.5 +/- 36.5 minutes in controls; P less than 0.001), and a lower mean hematocrit than did the patients without splenomegaly (P less than 0.001). In the nine patients without splenomegaly, clearance was normal. After institution of antimalarial chemotherapy, however, the clearance in this group accelerated to supernormal rates similar to those in the patients with splenomegaly, but without the development of detectable splenomegaly. Clearance was not significantly altered by treatment in the group with splenomegaly. Six weeks later, normal clearance rates were reestablished in most patients in both groups. We conclude that splenic clearance of labeled erythrocytes is enhanced in patients with malaria if splenomegaly is present and is enhanced only after treatment if splenomegaly is absent. Whether this enhanced splenic function applies to parasite-infected erythrocytes in patients with malaria and has any clinical benefit will require further studies.

Wickramasinghe SN, Phillips RE, Looareesuwan S, Warrell DA, Hughes M. 1987. The bone marrow in human cerebral malaria: parasite sequestration within sinusoids. Br J Haematol, 66 (3), pp. 295-306. | Show Abstract | Read more

Bone marrow aspirates from patients with cerebral malaria were studied with the light and electron microscopes. Various abnormalities were found including: (1) an increase in plasma cells and macrophages, sometimes to a marked degree; (2) phagocytosis of parasitized red cells by macrophages and of merozoites by neutrophil metamyelocytes, neutrophil granulocytes and macrophages; (3) an increase in the proportion of eosinophil granulocytes and their precursors; (4) the presence of giant metamyelocytes; and (5) morphological abnormalities of erythroblasts, particularly irregularly-shaped nuclei and karyorrhexis. A high percentage of the red cells within marrow sinusoids were parasitized and the parasitized cells were attached to the endothelium. Some marrow sinusoids were packed with and completely obstructed by parasitized cells. Strands of electron-dense material were sometimes found connecting the knobs of parasitized red cells to endothelial cells or to the knobs of adjacent parasitized red cells. A striking finding was a complex interdigitation between cytoplasmic processes developed by some of the parasitized red cells and those developed by the endothelial cells to which they were attached. Occasionally, cytoplasmic processes arising from marginated parasitized red cells completely penetrated the endothelial cell and emerged extravascularly. Several parasitized red cells were also found extravascularly between haemopoietic cells. Sequestration of parasitized red cells within small blood vessels may play a part in the pathogenesis not only of the encephalopathy of cerebral malaria but also of the bone marrow dysfunction in severe malaria.

Looareesuwan S, White NJ, Warrell DA, Forgo I, Dubach UG, Ranalder UB, Schwartz DE. 1987. Studies of mefloquine bioavailability and kinetics using a stable isotope technique: a comparison of Thai patients with falciparum malaria and healthy Caucasian volunteers. Br J Clin Pharmacol, 24 (1), pp. 37-42. | Show Abstract | Read more

1 A mefloquine hydrochloride tablet (250 mg base equivalent to 4.8 +/- 0.6 mg kg-1; mean +/- s.d.) and deuterium labelled mefloquine hydrochloride solution (250 mg base) were given to six adult male Thai patients with acute falciparum malaria and six healthy Swiss adult male volunteers (equivalent to 3.5 +/- 0.1 mg kg-1). 2 The relative bioavailability of the tablet formulation derived from comparison of the areas under the plasma concentration-time curves was similar in both groups; 87 +/- 11% and 89 +/- 10% (mean +/- s.d.). 3 The rate of drug absorption appeared to be similar in the two groups but peak plasma mefloquine concentrations were approximately three times higher in the Thai patients (1004 +/- 276 ng ml-1 for the tablet and 1085 +/- 280 ng ml-1 for the suspension) compared with the Swiss volunteers (319 +/- 73 ng ml-1 for the tablet, and 369 +/- 121 ng ml-1 for the suspension). 4 Estimates of the oral clearance CLpo of unlabelled mefloquine were significantly lower (17.5 +/- 4.4 ml h-1 kg-1) in the Thai patients compared with 28.8 +/- 3.5 ml h-1 kg-1 in the Swiss volunteers; P less than 0.05). Terminal elimination half-lives were significantly shorter in the patients (10.3 +/- 2.5 days) than in the volunteers (16.7 +/- 1.9 days; P less than 0.005). Differences of a similar magnitude were observed when comparing the pharmacokinetic parameters derived from the deuteromefloquine plasma concentrations. 5 Both genetic and disease related factors are likely to account for the large pharmacokinetic differences between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Karbwang J, Looareesuwan S, Phillips RE, Wattanagoon Y, Molyneux ME, Nagachinta B, Back DJ, Warrell DA. 1987. Plasma and whole blood mefloquine concentrations during treatment of chloroquine-resistant falciparum malaria with the combination mefloquine-sulphadoxine-pyrimethamine. Br J Clin Pharmacol, 23 (4), pp. 477-481. | Show Abstract | Read more

Mefloquine-sulphadoxine-pyrimethamine (MSP) in combination has proved effective against multiple-drug-resistant falciparum malaria, but nothing is known about mefloquine absorption when it is given in this formulation. Nine Thai patients, aged 15-51 years with uncomplicated chloroquine-resistant falciparum malaria, took 11.2-16.7 mg of mefloquine base per kilogram bodyweight as MSP tablets. All patients responded to treatment with fever and parasite clearance times of 61 +/- 29 h (mean +/- s.d.) and 52 +/- 24 h, respectively. The mean apparent absorption half-time (t1/2abs) of mefloquine was 4.89 h (range 2.25-9.72) and mean peak plasma concentration was 1815 ng ml-1 (range 725-3368). Peak plasma mefloquine concentrations in three patients who vomited within 2 h of treatment were 725, 956 and 1972 ng ml-1. There was no significant difference between plasma and whole blood mefloquine concentrations during the first 48 h of treatment. Based on the elimination of parasitaemia, the plasma mefloquine concentrations are adequate for therapy of uncomplicated falciparum malaria although the relationship between plasma concentrations and therapeutic efficacy of mefloquine requires further study.

Edwards G, Davies AJ, Phillips RE, Looareesuwan S, Karbwang J, White NJ, Warrell DA. 1987. Plasma concentrations and toxicity of chloroquine after slow intravenous infusion in patients with falciparum malaria. Ann Trop Med Parasitol, 81 (2), pp. 79-84. | Show Abstract

Five male patients with acute Plasmodium falciparum or Plasmodium vivax infections were infused with chloroquine diphosphate (15 mg kg-1) over four hours. Further does of chloroquine diphosphate (5 mg kg-1) were given at 12, 24, 36 and 60 hours. Plasma chloroquine concentrations were determined before and four hours after each dose and then daily until discharge. No serious cardiovascular toxicity was observed, and plasma chloroquine concentrations exceeding the putative minimum inhibitory concentration (MIC) of sensitive P. falciparum strains were reached within four hours of starting treatment. Further doses produced plasma concentrations which were sustained above the putative MIC, but showed no rapid increase into the range associated with toxicity.

Chapel HM, Warrell DA, Looareesuwan S, White NJ, Phillips RE, Warrell MJ, Supawanta V, Tharavanij S. 1987. Intrathecal immunoglobulin synthesis in cerebral malaria. Clin Exp Immunol, 67 (3), pp. 524-530. | Show Abstract

Local synthesis of immunoglobulin within the central nervous system has been evaluated in 37 patients with acute cerebral malaria; seven patients were also studied in the convalescent phase. There was evidence in the cerebrospinal fluid (CSF) of 21 patients that intrathecal IgG synthesis occurs in the acute phase. There were raised IgG: albumin ratios in 43% of acute patients. Oligoclonal IgG bands or cathodal IgG was seen in the CSF of 43% of patients tested by polyacrylamide electrophoresis. Only eight out of 37 acute patients (22%) had no evidence of intrathecal IgG synthesis by either method. The serial studies showed that most patients had IgG-CSF abnormalities when tested in convalescence. These studies suggest that an immune stimulus (perhaps malarial antigens or mitogens) may be present in the brain in acute cerebral malaria.

Silamut K, Ho M, Looareesuwan S, Viravan C, Wuthiekanun V, Warrell DA. 1987. Detection of venom by enzyme linked immunosorbent assay (ELISA) in patients bitten by snakes in Thailand. Br Med J (Clin Res Ed), 294 (6569), pp. 402-404. | Show Abstract | Read more

The ability of an enzyme linked immunosorbent assay (ELISA) to detect venom was evaluated in 251 patients bitten by four of the commonest poisonous snakes in Thailand. Serum was tested only from patients who brought the snakes that had bitten them. About one third of all bitten patients had detectable venom antigenaemia, though a smaller proportion were symptomatic. Serum venom concentrations on admission correlated with the severity of clinical manifestations. The test was sensitive and specific even for specimens that had been collected and stored under suboptimal conditions. The technique is suitable for forensic use in cases of suspected snakebite. The combination of snake identification and venom antigen detection should be a more reliable means of studying the epidemiology of snakebite than the measurement of venom antibodies in a population.

White NJ, Looareesuwan S, Edwards G, Phillips RE, Karbwang J, Nicholl DD, Bunch C, Warrell DA. 1987. Pharmacokinetics of intravenous amodiaquine. Br J Clin Pharmacol, 23 (2), pp. 127-135. | Show Abstract | Read more

Amodiaquine hydrochloride (3 mg base kg-1) was given by constant rate intravenous injection over 10 min to seven healthy adult male volunteers, and by constant rate infusion (10 mg base kg-1) over 4 h to 10 adult patients admitted to hospital with falciparum malaria. After intravenous injection in volunteers there was considerable variation in plasma concentration profiles between subjects; peak plasma concentrations ranged between 65 and 1921 ng ml-1. A biexponential equation was fitted to the plasma concentration time data and the following estimated pharmacokinetic parameters (geometric mean; range) were derived; lambda 1 = 24.4 (7.6-95.0) h-1, lambda 2 = 0.33 (0.12-0.79) h-1, V1:1.1 (0.3-3.6) 1 kg-1, Vss: 17.4 (2.3-95.9) 1 kg-1 and systemic clearance 13.0 (4.7-56.6) 1 kg-1 h-1. After intravenous infusion there was also considerable variability between patients with post-infusion plasma concentrations ranging between 82 and 836 ng ml-1. The plasma concentration-time profiles were biphasic with the following estimated pharmacokinetic parameters (geometric mean; range) alpha = 1.87 (0.60-8.52) h-1, beta = 0.069 (0.021-0.265) h-1, V1: 4.6 (0.5-29.3) 1 kg-1, Vss: 38.3 (3.7-127.9) 1 kg-1 and systemic clearance CL (1.6-17.3) 1 kg-1 h-1. There was no measurable long terminal elimination phase, and the principal metabolite desethyl amodiaquine was not detected in the plasma samples. There was no serious toxicity in either group. During intravenous injection there was a significant fall in systolic blood pressure in four subjects (mean fall 16 mm Hg) but there was no significant change in heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Than Than, Khin Ei Han, Hutton RA, Myint Lwin, Tin Nu Swe, Phillips RE, Warrell DA. 1987. Evolution of coagulation abnormalities following Russell's viper bite in Burma. Br J Haematol, 65 (2), pp. 193-198. | Show Abstract | Read more

The evolution of coagulation abnormalities was studied in Russell's viper bite victims who, on admission to hospital, showed no clinical signs of systemic envenoming. Based on the laboratory results and subsequent clinical course, three groups were distinguished. The first group, consisting of five cases, showed no activation of coagulation at any stage. The second group, consisting of six cases, developed mild to moderate abnormalities in some tests, particularly in the aPTT and factor V assay, which corrected to normal without treatment. The third group, consisting of nine patients, developed haemostatic abnormalities as early as 1-2 h after the bite, which progressed to severe defibrination 4-8 h later at which time antivenom was given. Comparison of the haemostatic abnormalities in the three groups suggested that serial monitoring of the serum FDP concentration may be of value in predicting the likelihood of systemic envenoming and progression to complete defibrination.

Chapel HM, Warrell DA, Looareesuwan S, White NJ, Phillips RE, Supawanta V, Tharavanij S. 1987. Intrathecal immunoglobulin synthesis in cerebral malaria Clinical and Experimental Immunology, 67 (3), pp. 524-530. | Show Abstract

Local synthesis of immunoglobulin within the central nervous system has been evaluated in 37 patients with acute cerebral malaria; seven patients were also studied in the convalescent phase. There was evidence in the cerebrospinal fluid (CSF) of 21 patients that intrathecal IgG synthesis occurs in the acute phase. There was raised IgG: albumin ratios in 43% of acute patients. Oligoclonal IgG bands or cathodal IgG was seen in the CSF of 43% of patients tested by polyacrylamide electrophoresis. Only eight out of 37 acute patients (22%) had no evidence of intrathecal IgG synthesis by either method. The serial studies showed that most patients had IgG-CSF abnormalities when tested in convalescence. These studies suggest that an immune stimulus (perhaps malarial antigens or mitogens) may be present in the brain in acute cerebral malaria.

Pukrittayakamee S, Ratcliffe PJ, McMichael AJ, Warrell DA, Bunnag D. 1987. A competitive radioimmunoassay using a monoclonal antibody to detect the factor X activator of Russell's viper venom. Toxicon, 25 (7), pp. 721-729. | Show Abstract | Read more

A radioimmunoassay (RIA) has been developed for the detection of Russell's viper venom in body fluids. This is a competitive binding technique using a monoclonal antibody directed against the factor X activator of Russell's viper venom. The sensitivity of the test in urine was 4 ng/ml, in 0.1% bovine serum albumin-phosphate buffered saline it was 20 ng/ml and in serum it was 5 micrograms/ml. This was adequate to detect venom in the serum of four patients bitten by Russell's viper. Urine from an isolated kidney preparation perfused with Russell's viper venom contained coagulant activity and was positive using the competitive RIA. Testing of sera from other envenomated patients and pure venom from seven other species of snake indigenous to Thailand revealed RIA cross reactivity between cobra venom and Russell's viper venom. In practice, the absence of coagulant activity in cobra venom clearly distinguishes between the two. Although further development is required to elucidate the serum factors interfering with this assay, this is a promising technique, which is of potential value in the diagnosis and investigation of the pathophysiology of Russell's viper envenomation.

Chanthavanich P, Suntharasamai P, Warrell MJ, Viravan C, Looareesuwan S, Supanaranond W, Karbwang J, Warrell DA, Phillips RE, Sinhaseni A. 1987. Antibody response to suckling mouse brain rabies vaccines for post exposure treatment. Trans R Soc Trop Med Hyg, 81 (2), pp. 260-263. | Show Abstract | Read more

A new suckling mouse brain vaccine (SMBV) against rabies, produced by the Thai Red Cross Society, was compared with the well established Institut Pasteur SMBV in patients with very low risk rabies contact. The 4 regimens used were the standard daily injections with booster doses of Thai Red Cross vaccine (TRCV) and Institut Pasteur Vaccine (IPV), and a reduced dose scheme of 6 injections as used for tissue culture vaccines. The effect of 20 IU/kg of human rabies immune globulin (HRIG) was tested on each regimen, making 8 groups, a total of 122 patients. Blood samples taken on days 0, 7, 14, 28 and 91 were tested for neutralizing antibody. Only the standard IPV regimen produced antibody in every patient; all had levels greater than 0.5 IU at some stage. Two people (13%) given the standard TRCV produced no detectable antibody (less than or equal to 0.1 IU) throughout the study. The reduced dose regimens gave very low antibody levels. 7% of the IPV and 76% of the TRCV groups failed to produce antibody on any occasion. The antibody response was significantly suppressed by the administration of HRIG. Compared to the original South American SMBV, the vaccines tested induced low levels of short lived antibody. No reduction in the dosage of SMBV should be considered unless the potency of the product is adequate.

Tun-Pe, Tin-Nu-Swe, Myint-Lwin, Warrell DA, Than-Win. 1987. The efficacy of tourniquets as a first-aid measure for Russell's viper bites in Burma. Trans R Soc Trop Med Hyg, 81 (3), pp. 403-405. | Show Abstract | Read more

The efficacy of the tourniquets commonly used by Russell's viper bite victims in retarding venom movement from the bite was studied in 37 cases by measuring venom antigen levels by enzyme-linked immunosorbent assay in venous samples taken proximal and distal to the tourniquets and also before and after release of tourniquets. In most cases, the tourniquet did not prevent proximal spread of venom. In 8/37 cases, however, venom antigen assays suggested but did not prove that venom absorption was being delayed by the tourniquet.

Warrell DA. 1987. Pathophysiology of severe falciparum malaria in man. Parasitology, 94 Suppl (S1), pp. S53-S76. | Read more

Looareesuwan S, White NJ, Silamut K, Phillips RE, Warrell DA. 1987. Quinine and severe falciparum malaria in late pregnancy. Acta Leiden, 55 pp. 115-120.

Warrell DA. 1987. Clinical management of severe falciparum malaria. Acta Leiden, 55 pp. 99-113.

Suntharasamai P, Warrell MJ, Warrell DA, Chanthavanich P, Looareesuwan S, Supapochana A, Phanuphak P, Jittapalapongsa S, Yager PA, Baer GM. 1987. Early antibody responses to rabies post-exposure vaccine regimens. Am J Trop Med Hyg, 36 (1), pp. 160-165. | Show Abstract

The aim of post-exposure rabies vaccine treatment is to induce immunity, measured as neutralizing antibody, as fast as possible. This is especially important in the tropical rabies-endemic areas where simultaneous passive prophylaxis with hyperimmune serum is not practicable in the majority of cases. We compared the rate of production of antibody during the first two weeks, by six vaccine regimens in 118 subjects using two tissue culture vaccines, human diploid cell strain vaccine (HDCSV) and purified Vero cell rabies vaccine (PVRV). No antibody was detected on day 5. On day 7, the highest seroconversion rate was seen in subjects given HDCSV intramuscularly at two sites on days 0 and 3 (7 of 15), but this was not significantly different from the group with the lowest rate: the conventional single-site intramuscular regimen. All subjects had antibody by day 14, at which time the highest geometric mean titer was in the group vaccinated with 0.25 ml doses of diploid cell vaccine given subcutaneously at eight sites. This regimen, together with the standard single-site diploid cell vaccine and an eight-site intradermal regimen of the same product gave significantly higher titers than the two-site intramuscular regimens of either product. No single immunization schedule emerges as best, so the speed of antibody response, economy, and the skill needed for intradermal injection should be considered when deciding on the optimum regimen for use in a particular geographic area.

LOOAREESUWAN S, WARRELL D. 1987. TREATMENT OF FALCIPARUM-MALARIA ISI ATLAS OF SCIENCE-PHARMACOLOGY, 1 (4), pp. 303-306. | Show Abstract

The treatment of falciparum malaria, one of the world's major killing diseases, has been complicated by development of resistance to a number of antimalarial drugs, principally chloroquine. Quinine and quinidine are the only widely available drugs which are effective against chloroquine-resistant falciparum malaria and can be given by injection. Three new synthetic antimalarial drugs, mefloquine, halofantrine, and enpiroline, are also effective against chloroquine-resistant strains, but rare cases of resistance to these drugs have already been encountered. Qinghaosu, an ancient Chinese herbal remedy, may prove to be the most rapidly effective drug for treating severe falciparum malaria.

Watt G, Theakston RD, Hayes CG, Yambao ML, Sangalang R, Ranoa CP, Alquizalas E, Warrell DA. 1986. Positive response to edrophonium in patients with neurotoxic envenoming by cobras (Naja naja philippinensis). A placebo-controlled study. N Engl J Med, 315 (23), pp. 1444-1448. | Show Abstract | Read more

To study the ability of anticholinesterase drugs to reverse the potentially fatal paralytic effects of cobra venom, we conducted a placebo-controlled, double-blind crossover trial of intravenous edrophonium (Tensilon) in 10 adults with neurotoxic envenoming caused by bites of the Philippine cobra (Naja naja philippinensis). There was significantly more improvement in ptosis and endurance of upward gaze after edrophonium than after placebo. Five minutes after injection, the mean difference (+/- SD) in the percentage of the iris that was uncovered was 39 +/- 5.47 (70 vs. 31 percent; P less than 0.01), and the mean difference in the number of seconds of upward gaze was 33.1 +/- 9.29 (39.7 vs. 6.6 seconds; P less than 0.01). The expiratory and inspiratory pressures, forced vital capacity, and ability to cough, speak, and swallow also improved after edrophonium. In both the patients who were studied electromyographically, pretreatment and postplacebo responses were typical of myasthenia gravis and became normal after edrophonium. We conclude that anticholinesterases are beneficial in the management of neurotoxic envenoming by Asian cobras (Naja naja), and we recommended a test of edrophonium in any patient with signs of neurotoxic envenoming after snakebite.

Sriwanthana B, Phanuphak P, Thaweepathomwat M, Warrell MJ, Warrell DA, Suntharasamai P, Baer GM. 1986. Effect of inosiplex on the humoral and cell-mediated immune responses to intradermal human diploid cell rabies vaccine. Southeast Asian J Trop Med Public Health, 17 (4), pp. 543-549. | Show Abstract

Antigen-stimulated lymphocyte transformation was studied in recipients of intradermal human diploid cell rabies vaccine (HDCV). HDCV was administered intradermally at 8 different anatomical sites, 0.1 ml each, on day 0; followed by another 4-site injection on day 7. Rabies antigen-stimulated in vitro proliferative response was evident as early as 7 days after starting immunization. It reached a peak on day 14 and had declined by day 28. The cellular proliferative response preceded and roughly correlated with the antirabies antibody response. Simultaneous administration of inosiplex, an antiviral and immunopotentiating drug, during the first 10 days of intradermal HDCV immunization did not result in heightened antibody titres or cell-mediated immune response to the vaccine. The number of T cells and the lymphocyte proliferative response to phytohaemagglutinin in inosiplex-treated vaccinees were similarly not significantly different from untreated controls. Our results confirm other previous findings that a specific cell-mediated immune response can be consistently and rapidly induced by an intradermal regimen of HDCV immunization. The addition of inosiplex to this regimen did not enhance the humoral or cell-mediated immune responses to the vaccine. The apparent lack of immunostimulating effect of inosiplex in this setting may be the result of several factors such as the immunization schedule and the immunologic parameters examined.

Warrell DA, Looareesuwan S, Theakston RD, Phillips RE, Chanthavanich P, Viravan C, Supanaranond W, Karbwang J, Ho M, Hutton RA. 1986. Randomized comparative trial of three monospecific antivenoms for bites by the Malayan pit viper (Calloselasma rhodostoma) in southern Thailand: clinical and laboratory correlations. Am J Trop Med Hyg, 35 (6), pp. 1235-1247. | Show Abstract

Three monospecific antivenoms for Malayan pit viper (MPV) (Calloselasma rhodostoma) were compared in Southern Thailand, where this species is the most common cause of snake bite morbidity. Forty-six patients with proved MPV bites and incoagulable blood, indicating systemic envenoming, were randomly allocated for treatment with Thai Red Cross (TRC), Thai Government Pharmaceutical Organization (GPO), or Twyford Pharmaceutical monospecific antivenoms. Both GPO and Twyford antivenoms produced rapid and permanent restoration of blood coagulability, but TRC antivenom failed in 2/15 cases. Patients in the GPO group showed the greatest increase in plasma fibrinogen concentration during the first 24 hr and had fewer early anaphylactic reactions (6/15) compared with Twyford 8/16 and with TRC 13/15. Pyrogenic reactions occurred more frequently after TRC antivenom (8/15) than GPO (1/15) or Twyford (0/16). Patients requiring more than one dose of antivenom were identifiably more severely envenomed on admission. In an accompanying laboratory study the antivenoms were assessed in rodents using five WHO standard tests of neutralizing activity. Compared with the other two antivenoms TRC was significantly inferior in anti-lethal potency, GPO was superior in anti-hemorrhagic and anti-necrotic potency and Twyford was superior in anti-procoagulant and anti-defibrinogenating potency. The clinical efficacy of these antivenoms against local necrosis remains equivocal. GPO and Twyford antivenoms are recommended for the treatment of systemic envenoming by MPV in an initial dose of 5 ampoules.

Phillips RE, Warrell DA. 1986. The pathophysiology of severe falciparum malaria. Parasitol Today, 2 (10), pp. 271-282. | Show Abstract | Read more

By the end of the 1940s, the clinical and pathological features of severe falciparum malaria had been well described by military physicians and pathologists working in theatres of war where the disease was endemic. From that time serious efforts were made to discover the pathophysiology of the severe manifestations of malaria because an understanding of these mechanisms forms an important basis for the clinical management of affected patients. Recently, after a period of neglect, there has been a revival of interest in malaria as a subject for clinical and laboratory research. In this article, Rodney Phillips and David Warrell review aspects of that work and attempt to unravel the mysteries of the pathophysiology of severe malaria in man.

Warrell DA, Looareesuwan S, Phillips RE, White NJ, Warrell MJ, Chapel HM, Areekul S, Tharavanij S. 1986. Function of the blood-cerebrospinal fluid barrier in human cerebral malaria: rejection of the permeability hypothesis. Am J Trop Med Hyg, 35 (5), pp. 882-889. | Show Abstract

We tested the hypothesis that cerebral malaria is caused by blood-brain barrier inflammation and cerebral edema. In a group of 157 Thai patients with strictly defined cerebral malaria, cerebrospinal fluid (CSF) opening pressures were normal in 79% and were lower in fatal cases than in survivors (means +/- 1 SD, 144 +/- 58 and 167 +/- 51 mm CSF, respectively, P = 0.051). CSF: serum albumin ratios (X 10(3)) in 39 of them were significantly higher than in 61 British controls (medians 8.5 and 5.5, respectively, P = 0.04), but were no higher in 7 fatal cases. In a group of 12 patients this ratio was not significantly higher during coma than after full recovery (means +/- 1 SD, 9.0 +/- 6.2 and 6.7 +/- 4.2, respectively, P greater than 0.1). CSF alpha 2-macroglobulin concentrations were always normal. CSF : serum 77Br- ratios were elevated in 11/19 comatose cases but fell to normal 4 to 9 days later in 11/11 cases. Dexamethasone treatment had no significant effect on bromide partition. The percentage of an intravenously administered dose of 125I-human serum albumin detectable per ml of CSF 6 hr after intravenous injection was 2.4 +/- 1.3 X 10(-5) in 14 comatose patients and 4.4 +/- 4.0 X 10(-5) in 9 of them during convalescence (P greater than 0.1). These results demonstrate that the blood-CSF barrier is essentially intact in patients with cerebral malaria and give no support to the idea that cerebral edema is the cause of coma.

Merry AH, Looareesuwan S, Phillips RE, Chanthavanich P, Supanaranond W, Warrell DA, Weatherall DJ. 1986. Evidence against immune haemolysis in falciparum malaria in Thailand. Br J Haematol, 64 (1), pp. 187-194. | Show Abstract | Read more

Evidence of immune mediated haemolysis was sought in 83 patients with P. falciparum malaria in eastern Thailand. Amongst 73 patients with uncomplicated infection 12 (16.4%) had a weakly positive direct antiglobulin test (DAT). The incidence in 32 children aged 8-16 years was similar to that in adults. Of 10 patients with cerebral malaria, six adults, all of whom were in unrousable coma, had a positive DAT. Erythrocyte-bound IgG1 accounted for the positive DAT in all cases; sensitization with complement or other IgG subclasses was not found. Patients with uncomplicated malaria had a median value of 70 IgG molecules per erythrocyte compared with 65 molecules per cell in 67 healthy controls. This difference was not statistically significant but could account for the lower incidence of a positive DAT in control subjects (4.5%). There was no correlation between the number of IgG molecules per cell and the degree of anaemia during the acute or convalescent phases of the infection. There is no evidence from this study that an immunohaemolytic process contributes to the anaemia of falciparum malaria in eastern Thailand.

Suntharasamai P, Warrell MJ, Warrell DA, Viravan C, Looareesuwan S, Supanaranond W, Chanthavanich P, Supapochana A, Tepsumethanon W, Pouradier-Duteil X. 1986. New purified Vero-cell vaccine prevents rabies in patients bitten by rabid animals. Lancet, 2 (8499), pp. 129-131. | Show Abstract | Read more

The protective effect of a new, potentially economical tissue-culture rabies vaccine, purified vero-cell rabies vaccine (PVRV), was tested in 106 patients bitten by animals with proven rabies. 0.5 ml PVRV was given intramuscularly on days 0, 3, 7, 14, 28, and 91; 47 patients with severe exposure were also given 20 IU/kg human rabies immune globulin (HRIG). All patients are alive and well after 1 year. Side-effects of treatment were negligible. Rabies neutralising antibody (greater than or equal to 1.6 IU) was demonstrated on day 14 and persisted for 1 year in every case. There was no significant suppression of the antibody response by HRIG. If the untreated mortality is 15%, PVRV is 81% efficient in protecting patients against rabies encephalitis (95% confidence limit). PVRV is likely to replace human diploid-cell strain vaccine as the most widely used tissue-culture rabies vaccine.

Phillips RE, Warrell DA, Edwards G, Galagedera Y, Theakston RD, Abeysekera DT, Dissanayaka P. 1986. Divided dose intramuscular regimen and single dose subcutaneous regimen for chloroquine: plasma concentrations and toxicity in patients with malaria. Br Med J (Clin Res Ed), 293 (6538), pp. 13-16. | Show Abstract | Read more

Adults with malaria in Sri Lanka were treated with parenteral chloroquine diphosphate, either 2.5 mg base/kg intramuscularly at 0, 1, 12, 13, 24, and 25 hours or 5 mg base/kg subcutaneously at 0, 12, and 24 hours. Both regimens were completed with oral chloroquine phosphate, 5 mg base/kg, at 36 and 48 hours. Mean peak chloroquine concentrations in the first 12 hours, which were 0.5 (range 0.3-0.6) mg/l (1.4 (0.9-1.7) mu mol/l) [corrected] with the intramuscular regimen and 0.3 (0.2-0.4) mg/l (1.0 (0.7-1.3) mu mol/l) [corrected] with the subcutaneous regimen (p less than 0.05), were reached in median times of 90 (65-90) minutes and 30 (30-60) minutes respectively (p less than 0.05) after the start of treatment. The mean area under the plasma concentration curve for the first 12 hours was 1.4 (0.9-2.1) mg/l.h (4.5 (2.8-6.4) mu mol/l.h) [corrected] after intramuscular administration and 1.8 (0.8-2.3) mg/l.h (5.7 (2.7-7.2) mu mol/l.h) [corrected] after subcutaneous administration (p greater than 0.1). Mean maximum plasma concentrations were higher after intramuscular administration (0.6 (0.4-0.8) mg/l (1.7 (1.3-2.5) mu mol/l)) [corrected] than after subcutaneous administration (0.4 (0.4-0.5) mg/l (1.3 (1.3-1.5) mu mol/l)) [corrected] (p less than 0.05), but both regimens produced satisfactory plasma profiles. Chloroquine resistance was found in the only case of Plasmodium falciparum malaria. Chloroquine is absorbed rapidly after divided dose intramuscular injection and single dose subcutaneous injection and does not cause hypotension or neurotoxicity in adults. Similar regimens should be evaluated in children before the parenteral use of this drug is abandoned.

Wattanagoon Y, Phillips RE, Warrell DA, Silamut K, Looareesuwan S, Nagachinta B, Back DJ. 1986. Intramuscular loading dose of quinine for falciparum malaria: pharmacokinetics and toxicity. Br Med J (Clin Res Ed), 293 (6538), pp. 11-13. | Show Abstract | Read more

In a study of intramuscular injection of quinine eight adults with moderately severe falciparum malaria resistant to chloroquine were treated with quinine dihydrochloride, being given a loading dose of 20 mg salt (16.7 mg base)/kg followed by three or four eight hourly maintenance doses of 10 mg salt (8.3 mg base)/kg injected into the anterior thigh. All patients responded to treatment. Fever and parasite clearance times (mean (SD) 60 (23) h and 53 (22) h respectively) were comparable with those obtained with intravenous quinine. The mean peak plasma quinine concentration of 11.0 mg/l (34.4 mu mol/l) [corrected] was reached a median of five hours after administration of the loading dose. In all patients plasma quinine concentrations exceeded the high minimum inhibitory concentration for Plasmodium falciparum malaria prevalent in Thailand within four hours of the start of treatment but did not cause toxicity other than mild cinchonism. When intravenous infusion is not possible an intramuscular quinine loading dose is an effective means of starting treatment in patients with moderately severe falciparum malaria who cannot swallow tablets.

Looareesuwan S, White NJ, Chanthavanich P, Edwards G, Nicholl DD, Bunch C, Warrell DA. 1986. Cardiovascular toxicity and distribution kinetics of intravenous chloroquine. Br J Clin Pharmacol, 22 (1), pp. 31-36. | Show Abstract | Read more

Chloroquine diphosphate (3 mg base kg-1) was given by constant rate intravenous injection over 10 min to 12 healthy adult male volunteers. Plasma concentrations of chloroquine and the principal metabolite desethylchloroquine, electrocardiograph intervals, and arterial blood pressure were measured at frequent intervals to determine the relationship between cardiovascular effects and plasma concentrations. Peak plasma concentrations ranged between 784 and 6649 (mean 2913) ng ml-1. The decline in plasma concentrations was multiexponential with an initial rapid distribution phase; mean (+/- s.d.) first order rate constant 0.65 +/- 0.14 min-1, and an estimated apparent volume of the central compartment of 0.18 +/- 0.15 l kg-1. There was no serious toxicity, but subjective side effects were reported in all patients and there was a significant fall in systolic blood pressure (110 +/- 9.5 to 101 +/- 12.5 mm Hg; P = 0.03) and rise in heart rate which paralleled the change in plasma chloroquine concentrations. Coincident with changes in blood pressure, there was a significant prolongation of the electrocardiograph QRS interval; 81 +/- 15 to 92 +/- 13 ms (P less than 0.01) but no change in the QTc interval. These findings suggest that the cardiovascular toxicity of parenteral chloroquine is related to transiently high plasma concentrations occurring early in the distribution phase. This results from incomplete distribution from a central compartment that is approximately one thousand times smaller than the eventual total apparent volume of distribution at steady state. Rate of administration is therefore a major determinant of toxicity.

Phillips RE, Looareesuwan S, White NJ, Silamut K, Kietinun S, Warrell DA. 1986. Quinine pharmacokinetics and toxicity in pregnant and lactating women with falciparum malaria. Br J Clin Pharmacol, 21 (6), pp. 677-683. | Show Abstract | Read more

Quinine dihydrochloride (10 mg or, in two patients, a loading dose of 20 mg kg-1) was infused intravenously over 4 h in ten severely ill but conscious women with falciparum malaria complicating the third trimester of pregnancy. Plasma quinine concentrations, measured spectrophotofluorimetrically after benzene extraction, fitted closely a single exponential decline after the intravenous infusion. These data were therefore fitted to a one compartment model: total apparent volume of distribution, V, 0.96 +/- 0.27 l kg-1 (+/- s.d.), elimination half-time (t1/2,z), 11.3 +/- 4.3 h, total clearance, 1.22 +/- 0.77 ml min-1 kg-1. There was no relationship between arterial blood pressure and plasma quinine concentrations. Eight women delivered of live infants while taking quinine, had placental cord plasma quinine concentrations from 1.0 to 4.6 mg l-1 (mean 2.4) which correlated significantly with maternal plasma quinine concentrations (r = 0.78, t = 3.06, P less than 0.05). The mean (+/- s.d.) ratio of cord plasma to maternal plasma quinine concentration was 0.32 +/- 0.14. Heart blood from a foetus aborted at term had a plasma quinine concentration of 2.8 mg l-1; simultaneous maternal plasma quinine was 7.1 mg l-1 (ratio 0.39). Breast milk quinine concentrations and milk to plasma ratios were 0.5-3.6 mg l-1 (mean 2.6) and 0.11-0.53 (mean 0.31) in twenty-five women who were breast-feeding and had taken oral quinine sulphate for 1-10 days (mean 4.0). Five women with more serious infections received intravenous quinine; breast milk quinine concentrations ranged between 0.5 and 8.0 mg l-1 (mean 3.4).(ABSTRACT TRUNCATED AT 250 WORDS)

Suntharasamai P, Chanthavanich P, Warrell MJ, Looareesuwan S, Karbwang J, Supanaranond W, Phillips RE, Jansawan W, Xueref C, Pouradier-Duteil X. 1986. Purified Vero cell rabies vaccine and human diploid cell strain vaccine: comparison of neutralizing antibody responses to post-exposure regimens. J Hyg (Lond), 96 (3), pp. 483-489. | Show Abstract | Read more

Neutralizing antibody responses to conventional rabies post-exposure regimens of human diploid cell strain vaccine (HDCSV) and the new purified Vero cell rabies vaccine (PVRV) were compared in 58 healthy Thai veterinary students. The geometric mean titres (GMTs) of the group given HDCSV were slightly higher than those given PVRV, but on day 28 the peak GMTs of the two groups were statistically similar. The early antibody response to PVRV was unaffected by the addition of passive immunization, whereas the level of HDCSV response was reduced on day 14, so that there was no difference on that day between the GMTs of the two vaccine groups given HRIG. However, by day 91 the GMT of those given PVRV and HRIG was lower than in those given HDCSV alone or with HRIG. The appearance of antibody was less rapid than was observed in previous studies using multiple-site intradermal vaccination. Side effects were trivial. Our results confirm the promise of this new, potentially more economical tissue culture vaccine, but they suggest that the regimen could be improved.

Phillips RE, Looareesuwan S, White NJ, Chanthavanich P, Karbwang J, Supanaranond W, Turner RC, Warrell DA. 1986. Hypoglycaemia and antimalarial drugs: quinidine and release of insulin. Br Med J (Clin Res Ed), 292 (6531), pp. 1319-1321. | Show Abstract | Read more

Life threatening hypoglycaemia has been closely associated with the use of quinine, but the effect of quinidine and the synthetic antimalarials on the homoeostasis of glucose has not been investigated. In volunteers given a fixed dose of 500 mg base and patients with malaria given a quinidine loading dose (15 mg base/kg) mean (SEM) plasma insulin concentrations rose from 6.1 (1.5) mU/l to 10.9 (4.4) mU/l (p less than 0.02) and 10.4 (2.0) mU/l to 18.5 (5.3) mU/l (p less than 0.04), respectively. Plasma glucose concentrations fell from 4.5 (1.1) mmol/l (81 (20) mg/100 ml) to 4.0 (0.3) mmol/l (72 (5) mg/100 ml) in volunteers (p less than 0.04) and from 5.7 (1.3) mmol/l (102 (23) mg/100 ml) to 4.8 (1.6) mmol/l (86 (29) mg/100 ml) in patients (p less than 0.05). One of two patients with cerebral malaria and acute renal failure became profoundly hypoglycaemic (plasma glucose concentration 1.4 mmol/l (25 mg/100 ml), plasma insulin concentration 3.1 mU/l). Hypoglycaemia may occur in any severely ill fasting patient given parenteral quinidine. The other antimalarials tested, chloroquine, amodiaquine, mefloquine, and halofantrine, did not stimulate the release of insulin, an important advantage that should be taken into account when treatment is chosen for Plasmodium falciparum malaria.

Ho M, Warrell DA, Looareesuwan S, Phillips RE, Chanthavanich P, Karbwang J, Supanaranond W, Viravan C, Hutton RA, Vejcho S. 1986. Clinical significance of venom antigen levels in patients envenomed by the Malayan pit viper (Calloselasma rhodostoma). Am J Trop Med Hyg, 35 (3), pp. 579-587. | Show Abstract

Serial venom antigen levels were measured by enzyme-linked immunosorbent assay (ELISA) in 46 patients with systemic envenoming by the Malayan pit viper (Calloselasma rhodostoma), a major cause of snake bite in Southeast Asia. The principal effects of the venom are defibrination, hemorrhage and local tissue necrosis. Admission venom levels, which varied between 0 and 595 ng/ml, correlated with the incidence of spontaneous systemic bleeding, blood incoagulability and concentrations of plasma fibrinogen and serum fibrin degradation products. The presence or absence of nonclotting blood also correlated with the time elapsed between the bite and hospital admission. The development of nonclotting blood may be delayed by up to 72 hr after the bite even though circulating venom and raised FDP may be detected at presentation. This is probably explained by a temporary equilibrium between synthesis and consumption of fibrinogen. Venom antigenemia recurred in 12 patients (26%) suggesting continuous absorption of venom from the wound or saturation of extravascular binding sites. Admission venom levels also correlated with the extent of local swelling and the occurrence of tissue necrosis at the site of the bite. Venom was detected in 87% of wound aspirates and 88% of urine specimens taken on admission. Tourniquets, of the type used in rural Thailand, did not delay the absorption of venom into the circulation.

EDWARDS G, DAVIES A, LOOAREESUWAN S, PHILLIPS R, WARRELL D, ORME M, BRECKENRIDGE A. 1986. THE DISPOSITION OF A SINGLE INFUSION OF CHLOROQUINE IN PATIENTS WITH VIVAX MALARIA BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, 21 (5), pp. P600-P601.

Ho M, Webster HK, Looareesuwan S, Supanaranond W, Phillips RE, Chanthavanich P, Warrell DA. 1986. Antigen-specific immunosuppression in human malaria due to Plasmodium falciparum. J Infect Dis, 153 (4), pp. 763-771. | Show Abstract | Read more

Proliferative responses of T lymphocytes to antigens specific and not specific for malaria were investigated in 32 adult patients in eastern Thailand during acute infection with Plasmodium falciparum malaria and during their convalescence. Immune unresponsiveness to malarial antigen, which persisted for more than four weeks in 37.5% of the individuals, was present in all patients, irrespective of parasitemia or severity of clinical illness. Suppression of responses to nonspecific antigens was less profound and observed only in patients with moderately severe or cerebral malaria. The depressed functional responses were associated with a loss of T lymphocytes--both helper and suppressor subsets--from the peripheral blood; these responses were recovered once parasites were cleared. These results indicate that blood-stage plasmodial infections may suppress responses important for immunity to malaria and so allow the parasite to survive. They further suggest that patients acutely or even recently infected with P. falciparum may not respond as well to a malaria vaccine as would uninfected individuals.

Warrell MJ, Warrell DA, Suntharasamai P, Chanthavanich P. 1986. Intradermal post-exposure rabies vaccination. Trop Doct, 16 (2), pp. 57.

Phillips RE, Warrell DA, Looareesuwan S, Turner RC, Bloom SR, Quantrill D, Moore AR. 1986. Effectiveness of SMS 201-995, a synthetic, long-acting somatostatin analogue, in treatment of quinine-induced hyperinsulinaemia. Lancet, 1 (8483), pp. 713-716. | Show Abstract | Read more

SMS 201-995, a new long-acting, synthetic somatostatin analogue, dose 50 micrograms/h, given as a continuous intravenous infusion, completely abolished quinine-induced insulin release in 9 healthy Thai volunteers. Hyperinsulinaemia, which caused sustained hypoglycaemia in a 32-year-old post-partum Thai patient who was receiving intravenous quinine for falciparum malaria, was suppressed within 30 min of starting SMS 201-995, and the patient became fully conscious. This octapeptide antagonises the stimulatory effect of quinine on the pancreatic beta cell and is a specific therapy for life-threatening hyperinsulinaemic hypoglycaemia complicating falciparum malaria.

Phillips RE, Looareesuwan S, Warrell DA, Lee SH, Karbwang J, Warrell MJ, White NJ, Swasdichai C, Weatherall DJ. 1986. The importance of anaemia in cerebral and uncomplicated falciparum malaria: role of complications, dyserythropoiesis and iron sequestration. Q J Med, 58 (227), pp. 305-323. | Show Abstract | Read more

Ninety-four per cent of 169 patients with cerebral malaria developed anaemia (haematocrit less than 35 per cent) and 30 per cent required blood transfusion to maintain the haematocrit at more than 21 per cent. Anaemia was at its worst on admission in 58 patients (34 per cent); in the rest the haematocrit fell further, reaching its nadir one to 17 days later (mean 2.3 days). The mean lowest haematocrit was 24.3 +/- 7.2 per cent (+/- 1 SD) and the mean maximum fall was 7.9 +/- 5.6 per cent. Anaemia was more severe in patients with bacterial infection, retinal haemorrhages, schizontaemia and in pregnancy. The lowest haematocrit correlated with admission parasitaemia (r = -0.33, p less than 0.001), total serum bilirubin (r = -0.25, p less than 0.01) and serum creatinine (r = -0.22, p less than 0.01). In 23 patients with uncomplicated falciparum malaria the mean serum iron on admission was 53 micrograms/dl (range 16-157) and the mean serum ferritin 1773 ng/ml (range 170-10 000). There was a significant (p less than 0.001) rise in serum iron 96 h after starting antimalarial treatment; the serum ferritin declined slowly over several weeks. Stainable iron was present in all marrows examined and in eight patients the characteristic pattern of the anaemia of chronic disorders was seen. Seventy-three per cent of patients had dyserythropoiesis which was moderate to gross in 36 per cent. Dyserythropoiesis and erythrophagocytosis were often present on admission but sometimes appeared after the parasitaemia had cleared and persisted for at least three weeks into convalescence. These disturbances in iron metabolism and haemopoiesis are not completely explicable by red blood cell parasitisation. They may contribute more to the anaemia than has previously been recognised.

Malasit P, Warrell DA, Chanthavanich P, Viravan C, Mongkolsapaya J, Singhthong B, Supich C. 1986. Prediction, prevention, and mechanism of early (anaphylactic) antivenom reactions in victims of snake bites. Br Med J (Clin Res Ed), 292 (6512), pp. 17-20. | Show Abstract

Victims of snake bites are often subjected to cutaneous or conjunctival hypersensitivity testing before being given antivenom. None of 12 early (anaphylactic) reactions was predicted by these tests in 25 Nigerian and Thai patients. The incidence and severity of early reactions was the same whether antivenom was given by intravenous injection over 10 minutes or diluted and given as an intravenous infusion over 30 minutes. Although antivenom activated complement in vitro, there was no evidence of complement activation or formation of immune complexes in patients bitten by snakes who were treated with antivenom, whether or not they developed early reactions. Higher doses of antivenom might induce the complement activation and formation of immune complexes (aggregates) that have been observed during the clinically more severe reactions associated with homologous immunoglobulin treatment.

Looareesuwan S, White NJ, Karbwang J, Turner RC, Phillips RE, Kietinun S, Rackow C, Warrell DA. 1986. Quinine and severe falciparum malaria in late pregnancy Obstetrical and Gynecological Survey, 41 (3), pp. 157-158.

Ho M, Warrell MJ, Warrell DA, Bidwell D, Voller A. 1986. A critical reappraisal of the use of enzyme-linked immunosorbent assays in the study of snake bite. Toxicon, 24 (3), pp. 211-221. | Show Abstract | Read more

The enzyme-linked immunosorbent assay (ELISA) has been the most widely used serological test in snake bite immunodiagnosis and epidemiology. The technique has been applied, however, without due consideration of the many factors which would affect an inherently sensitive test system, especially in tropical rural areas where large scale snake bite studies are usually carried out. This review discusses the effects of non-specific reactivity, cross reactivity and the quality of reagents on both the sensitivity and specificity of venom antigen and antibody detection assays. Simple laboratory modifications to optimize the assays are described. The importance of using the predictive value to assess the validity of applying the same test system in different circumstances is stressed. To fulfil its potential as the most versatile immunoassay technique in snake bite research, the test conditions of the ELISA will have to be much more stringently controlled in future.

Viravan C, Veeravat U, Warrell MJ, Theakston RD, Warrell DA. 1986. ELISA confirmation of acute and past envenoming by the monocellate Thai cobra (Naja kaouthia). Am J Trop Med Hyg, 35 (1), pp. 173-181. | Show Abstract

The monocellate Thai cobra (Naja kaouthia) is a major cause of snake bite mortality and morbidity throughout Thailand, but neither the local nor the systemic effects of its venom are diagnostic. Species diagnosis is important because only monospecific antivenoms are available for treatment in Thailand. We tested the ability of the ELISA technique to detect venom antigen in the sera of 58 acute snake bite cases including 4 fatalities, and venom antibody in 51 patients bitten between 1 month and 19 years previously. N. kaouthia venom antigen was found in 8 of 33 patients with only local envenoming and in 14 of 20 with local plus systemic (neurotoxic) envenoming, but the mean venom concentration was 33 times greater in the latter group. The serum of 1 fatal case contained banded krait (Bungarus fasciatus) but no cobra venom antigen. N. kaouthia venom antibody was present in sera of patients bitten between 1 month and 7 years previously. Antibody was found in 6 of 8 patients who had had local envenoming alone but in only 19 of 41 who had had systemic envenoming treated by antivenom. The titer of antibody declined with an approximate half time of 2-3 years. One patient had a significant titer of B. fasciatus venom antibody. This study confirms the value of ELISA-immunodiagnosis and the predominance of N. kaouthia as a cause of neurotoxic envenoming in the Bang Phli area. However, the attribution of 1 fatal case to B. fasciatus bite suggests that patients with neurotoxic signs should be given B. fasciatus antivenom if they fail to respond to cobra antivenom.

CHONGSUPHAJAISIDDHI T, GILLES C, KROGSTAD D, SALAKO L, WARRELL D, WHITE N, BEALES P, NAJERA J, SHETH U, SPENCER H, WERNSDORFER W. 1986. SEVERE AND COMPLICATED MALARIA - WORLD-HEALTH-ORGANIZATION MALARIA ACTION PROGRAM TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE, 80 pp. 3-50.

Chanthavanich P, Warrell MJ, Looareesuwan S, Karbwang J, Phillips RE, Supanaranond W, Vejcho S, Rollin PE, Sureau P, Warrell DA. 1985. Lack of interferon induction in man by two rabies tissue culture vaccines. Southeast Asian J Trop Med Public Health, 16 (4), pp. 521-524. | Show Abstract

Both neutralising antibody and interferon play a part in protection of animals against death from rabies virus infection. Interferon induction was therefore sought in 53 volunteers within 24 hours of receiving human diploid cell strain vaccine or fetal bovine kidney cell vaccine given either intramuscularly or intradermally. Repeat observations were made in 18 subjects following a second dose of vaccine seven days later. No interferon was detected in any sample tested although no subject had any detectable rabies neutralising antibody on day 0. The sensitivity of the interferon assay, and comparison with other studies are discussed. An interferon inducer suitable for human use should be sought as an alternative to, or a replacement for, passive rabies immunization.

Usawattanakul W, Tharavanij S, Warrell DA, Looareesuwan S, White NJ, Supavej S, Soikratoke S. 1985. Factors contributing to the development of cerebral malaria. II. Endotoxin. Clin Exp Immunol, 61 (3), pp. 562-568. | Show Abstract

Limulus amoebocyte lysate test (LALT) was used to detect endotoxin-like substances in the plasma of 15 patients with cerebral malaria, 28 patients with uncomplicated falciparum malaria and 30 healthy controls. On admission, 67% of cerebral malaria patients were positive, whereas only 21.4% of uncomplicated malaria patients and none of controls were positive. Among uncomplicated malaria cases, four of eight patients with parasitaemia over 90,000/mm3 were LALT positive whereas only two of 20 patients with parasitaemia of less than 90,000/mm3 were positive. A follow-up study in cerebral malaria patients showed some variation in LALT positivity rate from day to day (85.7% on day 1, 53.3% on day 3 and all negative on discharge from hospital). LALT positivity bore no relationship to gram negative bacteraemia. Leucocytosis and elevated serum enzymes were more frequently found in LALT-positive patients. Our results suggest that endotoxin (LALT positivity) of the plasma of malaria patients is derived from either the parasites themselves or from the gut. It relates to parasitaemia, leucocytosis and elevated serum enzymes, but not to the clinical syndrome of cerebral malaria.

Ward SA, Mihaly GW, Edwards G, Looareesuwan S, Phillips RE, Chanthavanich P, Warrell DA, Orme ML, Breckenridge AM. 1985. Pharmacokinetics of primaquine in man. II. Comparison of acute vs chronic dosage in Thai subjects. Br J Clin Pharmacol, 19 (6), pp. 751-755. | Show Abstract | Read more

We have investigated the pharmacokinetics of primaquine after acute and chronic administration of the drug to five healthy Thai volunteers. After acute dosage (15 mg p.o.) mean (+/- s.d.) peak plasma concentrations of 65.0 +/- 34.7 ng ml-1 were achieved within 2 +/- 1h. Thereafter plasma drug concentrations declined monoexponentially with a mean elimination half life of 4.4 +/- 1.4 h. The mean (+/- s.d.) oral clearance was 37.6 +/- 15.5 1 h-1. These values are in broad agreement with values obtained in healthy Caucasians after administration of an equivalent dose of primaquine. Repeated dosing with primaquine had no effect on the mean pharmacokinetic parameters calculated for this drug. In contrast, individual pharmacokinetic parameters for some subjects exhibited gross and unpredictable changes after chronic dosage. The carboxylic acid metabolite of primaquine accumulated in plasma after repeated dosing such that by day 14 of chronic dosing the mean AUC (0,24) for this metabolite was 74% greater than that obtained after acute administration of primaquine.

Warrell MJ, Nicholson KG, Warrell DA, Suntharasamai P, Chanthavanich P, Viravan C, Sinhaseni A, Chiewbambroongkiat MK, Pouradier-Duteil X, Xueref C. 1985. Economical multiple-site intradermal immunisation with human diploid-cell-strain vaccine is effective for post-exposure rabies prophylaxis. Lancet, 1 (8437), pp. 1059-1062. | Show Abstract | Read more

An economical post-exposure regimen of Mérieux human diploid-cell-strain vaccine (HDCSV) was compared with Semple vaccine (SV), the most widely used vaccine in Asia. 155 patients bitten by animals proved to be rabid received either conventional courses of SV (34 severe and 43 mild cases) or HDCSV, 0.1 ml intradermally, at eight sites on day 0, at four sites on day 7, and at one site on days 28 and 91 (36 severe and 42 mild cases). All severely bitten patients were given equine anti-rabies serum (EARS), 80 IU/kg on day 0. There were no deaths from rabies in either group. Follow-up was 97.5% at 1 year and 93% at 2 years. 88% of patients given HDCSV alone had detectable neutralising antibody on day 7 in contrast to 2% given SV alone. Antibody persisted until 1 year in all sera tested from HDCSV patients in contrast to only 48% of SV sera. The high dose of EARS resulted in pronounced suppression of response to HDCSV. There were no serious systemic side-effects but local side-effects were significantly more common in the SV group. The multiple-site intradermal HDCSV regimen was at least as effective as SV. The amount of HDCSV used was 30% of the conventional dose.

Phuapradit P, Manatsathit S, Warrell MJ, Warrell DA. 1985. Paralytic rabies: some unusual clinical presentations. J Med Assoc Thai, 68 (2), pp. 106-110.

Mihaly GW, Nicholl DD, Edwards G, Ward SA, Orme ML, Warrell DA, Breckenridge AM. 1985. High-performance liquid chromatographic analysis of amodiaquine in human plasma. J Chromatogr, 337 (1), pp. 166-171. | Read more

Teklu B, Habte-Mlchael A, White NJ, Warrell DA, Wright DJM, Turner RC. 1985. Glucose and insulin homeostasis during the Jarisch-Herxheimer reaction Transactions of the Royal Society of Tropical Medicine and Hygiene, 79 (1), pp. 78-79. | Show Abstract | Read more

Plasma concentrations of glucose and insulin were measured in ten patients during the Jarisch-Herxheimer reaction of tetracycline-treated louse-borne relapsing fever. Plasma glucose fell significantly in eight of the ten patients associated with the peak of the reaction, but plasma insulin remained low. Glucoregulation by insulin was therefore normal. This evidence questions the role of macrophage mediator-induced pancreatic insulin release in causing hypoglycaemia in borreliosis or bacterial endotoxicosis. © 1985.

Phillips RE, Warrell DA, White NJ, Looareesuwan S, Karbwang J. 1985. Intravenous quinidine for the treatment of severe falciparum malaria. Clinical and pharmacokinetic studies. N Engl J Med, 312 (20), pp. 1273-1278. | Show Abstract | Read more

Quinidine has proved more effective than quinine against chloroquine-resistant Plasmodium falciparum both in vitro and in patients with uncomplicated disease. To examine the effectiveness and pharmacokinetics of quinidine for this use, we treated 14 patients who had severe falciparum malaria with intravenous quinidine gluconate; a loading dose of 15 mg of the base per kilogram of body weight was followed by 7.5 mg per kilogram every eight hours. Two of the five patients with cerebral malaria died, but parasitemia was eliminated in the 12 survivors. Two patients had recurrent parasitemia on Days 25 and 28. Times required for parasite clearance and elimination of fever (49.4 +/- 17.8 and 69.5 +/- 18.7 hours, respectively) were comparable to those in earlier studies with a loading dose of quinine. Quinidine appears to have a larger volume of distribution than quinine. The elimination half-life was 12.8 hours, the volume of distribution was 1.68 liters per kilogram, total clearance was 1.75 ml per kilogram per minute, and urinary clearance was 0.62 ml per kilogram per minute. Electrocardiographic changes were common but there were no dysrhythmias. In two patients, blood pressure fell during the initial infusion of quinidine. Quinidine gluconate is more widely available than quinine in many countries, and our findings show that it is effective in severe falciparum malaria.

MacPherson GG, Warrell MJ, White NJ, Looareesuwan S, Warrell DA. 1985. Human cerebral malaria. A quantitative ultrastructural analysis of parasitized erythrocyte sequestration. Am J Pathol, 119 (3), pp. 385-401. | Show Abstract

For investigation of the pathogenesis of cerebral malaria, immediate postmortem samples from brain and other tissues of patients dying with Plasmodium falciparum malaria, with (CM) or without (NCM) cerebral malaria, were processed for electron microscopy. Counts of parasitized erythrocytes (PRBCs) in cerebral and other vessels showed that the proportion of PRBCs was higher in CM than in NCM, and also that the proportion of PRBCs was higher in the brain than in other organs examined in both CM and NCM. Cerebral vessels from CM patients were more tightly packed with RBCs than those from NCM patients, but there was no significant difference in the amount or degree of endothelial damage or numbers of vessels with endothelial pseudopodia. Fibrillar (fibrin) deposits were present in a small proportion of vessels, but no thrombosis was present. There was neither acute nor chronic inflammation, and leukocytes were absent within or outside cerebral vessels. There was no immune complex deposition in cerebral vessels. Parasites in cerebral vessels were mainly trophozoites or schizonts. Occasional RBC remnants following parasite release were seen. Some parasites were degenerate, resembling crisis forms. PRBCs adhered to endothelium via surface knobs. It is concluded that there is no evidence for an inflammatory or immune pathogenesis for human cerebral malaria and that the clinical effects probably relate to anoxia and the metabolic activities of the parasites.

PHILLIPS R, LOOAREESUWAN S, WARRELL D, LEE S, MERRY A, WEATHERALL D. 1985. ANEMIA AND P-FALCIPARUM MALARIA QUARTERLY JOURNAL OF MEDICINE, 57 (223), pp. 803-803.

Looareesuwan S, Phillips RE, White NJ, Karbwang J, Benjasurat Y, Attanath P, Warrell DA. 1985. Intravenous amodiaquine and oral amodiaquine/erythromycin in the treatment of chloroquine-resistant falciparum malaria. Lancet, 2 (8459), pp. 805-808. | Show Abstract | Read more

In eastern Thailand, 14 adults with moderately severe falciparum malaria were treated with intravenous amodiaquine dihydrochloride, loading dose 10 mg base/kg infused over 4 h followed by three further intravenous infusions of 5 mg base/kg at 24, 48, and 72 h. All patients were clinically cured--mean fever clearance time 37.8 h (range 24-60), mean parasite clearance time 64.9 h (18-164). There were no serious toxic effects. 33 patients aged over 5 years with uncomplicated falciparum malaria were given oral amodiaquine dihydrochloride (mean total dose 41 mg base/kg over 3 days) combined with erythromycin estolate (mean dose 48 mg base/kg daily for 5 days). 2 patients failed to respond. In the other 31 patients mean fever clearance time was 55.9 h (range 10-104) and mean parasite clearance time was 65.4 h (40-120). In both studies, more than half the patients followed-up had recurrent parasitaemia but reinfection could not be excluded. Parasites isolated from 18 patients were highly resistant to chloroquine in vitro.

Myint-Lwin, Warrell DA, Phillips RE, Tin-Nu-Swe, Tun-Pe, Maung-Maung-Lay. 1985. Bites by Russell's viper (Vipera russelli siamensis) in Burma: haemostatic, vascular, and renal disturbances and response to treatment. Lancet, 2 (8467), pp. 1259-1264. | Show Abstract | Read more

Of 123 patients with proved Russell's viper bite, 28% showed no evidence of envenoming, 28% had local swelling alone, but 44% had systemic envenoming manifested by incoagulable blood (100% of those admitted before treatment), thrombocytopenia (26%), spontaneous systemic bleeding (20%), hypotension (35%), evidence of increased capillary permeability (24%), and oliguria (44%). Patients with systemic envenoming usually had more local swelling than those without, but 5 had no local signs. Snake length correlated with the amount of local swelling, but snakes causing systemic envenoming were no longer than those causing local or no envenoming. Burma Pharmaceutical Industry monospecific antivenom was rapidly effective in restoring blood coagulability but did not prevent the development of renal failure even when given within 4 h of the bite. Hypotension responded to volume expanders (11/19 cases) and dopamine (6/7 cases) but not to naloxone (0/3) or high-dose methylprednisolone (0/5). The 10 deaths (8%) were attributed to hypotension, pituitary haemorrhage, and renal failure.

White NJ, Warrell DA, Looareesuwan S, Chanthavanich P, Phillips RE, Pongpaew P. 1985. Pathophysiological and prognostic significance of cerebrospinal-fluid lactate in cerebral malaria. Lancet, 1 (8432), pp. 776-778. | Show Abstract | Read more

Cerebrospinal-fluid (CSF) lactate concentrations were elevated in all but 1 of 45 patients with cerebral malaria. They were significantly higher in patients who died (9.0 +/- 5.3 mmol/l, mean +/- SD) than in survivors (3.4 +/- 1.1 mmol/l, p = 0.0002) and had returned to normal values in each of 9 patients studied after recovery of consciousness. There was a significant negative correlation between CSF lactate and CSF glucose. All 11 patients with CSF lactate concentrations above 6 mmol/l died. CSF lactate is thus an important prognostic indicator in cerebral malaria and these findings suggest that hypoxia contributes to the pathogenesis of this disorder.

Looareesuwan S, Phillips RE, White NJ, Kietinun S, Karbwang J, Rackow C, Turner RC, Warrell DA. 1985. Quinine and severe falciparum malaria in late pregnancy. Lancet, 2 (8445), pp. 4-8. | Show Abstract | Read more

Quinine dihydrochloride was given intravenously to 12 women with severe falciparum malaria in the third trimester of pregnancy. The initial dose consisted of 10 or 20 mg salt/kg over 4 h and was followed by 10 mg salt/kg every 8 h until patients were fit to swallow, when quinine sulphate tablets were given. Uterine activity showed little or no change despite rising quinine concentrations. Of 3 patients in labour, 2 proceeded normally while a third had a successful caesarean section for fetal distress. Late (type II) decelerations of the fetal heart rate were recorded in 6 patients before treatment but in most patients signs of fetal distress diminished as the maternal temperature fell. Hypoglycaemia and hyperinsulinaemia developed in 7 patients, in 2 before quinine was started. The important toxic effect of quinine in late pregnancy is not an oxytocic action but rather its capacity to release insulin.

Teklu B, Habte-Michael A, White NJ, Warrell DA, Wright DJ, Turner RC. 1985. Glucose and insulin homeostasis during the Jarisch-Herxheimer reaction. Trans R Soc Trop Med Hyg, 79 (1), pp. 74-77. | Show Abstract | Read more

Plasma concentrations of glucose and insulin were measured in ten patients during the Jarisch-Herxheimer reaction of tetracycline-treated louse-borne relapsing fever. Plasma glucose fell significantly in eight of the ten patients associated with the peak of the reaction, but plasma insulin remained low. Glucoregulation by insulin was therefore normal. This evidence questions the role of macrophage mediator-induced pancreatic insulin release in causing hypoglycaemia in borreliosis or bacterial endotoxicosis.

Chanthavanich P, Looareesuwan S, White NJ, Warrell DA, Warrell MJ, DiGiovanni JH, von Bredow J. 1985. Intragastric mefloquine is absorbed rapidly in patients with cerebral malaria. Am J Trop Med Hyg, 34 (6), pp. 1028-1036. | Show Abstract

Mefloquine has proved effective in chloroquine- and quinine-resistant falciparum malaria, but it cannot be given parenterally. We have measured the absorption of mefloquine hydrochloride suspension (mean 15.6, range 9.7-28.6 mg/kg) given by nasogastric tube to 19 cerebral malaria patients already receiving intravenous quinine. Absorption was rapid with both dose schedules used; mean absorption half-times were 1.5 and 1.8 hr, and plasma mefloquine concentrations exceeded 200 ng/g within 3 hr of completing administration in all but one exceptionally ill patient who died 40 hr later. Steady state plasma concentrations over 7 days ranged from 300 to 1,050 (mean 561) ng/g. Bioavailability of mefloquine suspension in cerebral malaria therefore appears to be adequate for treatment in all but the most severely ill patients. Although intragastric mefloquine cannot now be recommended as an alternative to intravenous quinine for the treatment of severe chloroquine-resistant falciparum malaria, this situation could change if quinine resistance increases further.

Silamut K, White NJ, Looareesuwan S, Warrell DA. 1985. Binding of quinine to plasma proteins in falciparum malaria. Am J Trop Med Hyg, 34 (4), pp. 681-686. | Show Abstract

Plasma protein binding of quinine was measured in 12 patients with cerebral malaria on the first and seventh day of treatment, and in 7 patients with uncomplicated falciparum malaria on admission and also one month later. Binding was significantly higher and therefore the proportion of free drug was lower in cerebral malaria patients (free: total quinine concentration; 7.2 +/- 3.5%, mean +/- SD, on admission; 7.4 +/- 5.3% on day 7) compared with uncomplicated malaria patients on admission (10.2 +/- 5.8%) or following recovery (11.0 +/- 5.5%, n = 6) P = 0.011. Binding was significantly correlated with the red cell/total concentration ratio r = 0.56, P less than 0.0001. The ratio of cerebrospinal fluid to free (unbound) plasma quinine was 0.55 +/- 0.33 which suggests that quinine does not freely cross the blood brain barrier. These findings are relevant to the interpretation of total plasma or serum concentration, and may explain the rarity of serious quinine toxicity in severe falciparum malaria.

WARRELL D, WHITE N, LOOAREESUWAN S, PHILLIPS R, WARRELL M, BUNNAG D, HARINASUTA K. 1985. THE TREATMENT OF SEVERE FALCIPARUM-MALARIA BRITISH MEDICAL JOURNAL, 291 (6508), pp. 1573-1573. | Read more

WARRELL D. 1985. TROPICAL SNAKEBITE - CLINICAL-STUDIES IN SOUTH EAST-ASIA TOXICON, 23 (4), pp. 543-543.

VIRAVAN C, WARRELL D, WARRELL M, THEAKSTON R, VIRAWATANA U. 1985. PAST AND PRESENT ENVENOMING OF MAN BY THE THAI COBRA DETECTED BY ELISA TOXICON, 23 (4), pp. 627-628.

WARRELL D. 1985. THE IMPORTANCE OF CLINICAL-STUDIES OF SNAKE BITE TOXICON, 23 (4), pp. 628-628.

WARRELL D. 1985. EARLY (ANAPHYLACTOID) ANTIVENOM REACTIONS - ABSENCE OF COMPLEMENT ACTIVATION AND IMMUNE-COMPLEX FORMATION IN HUMAN PATIENTS TOXICON, 23 (4), pp. 628-628. | Read more

Hall A. 1985. Dangers of high-dose quinine and overhydration in severe malaria. Lancet, 1 (8443), pp. 1453-1454. | Read more

Warrell DA, White NJ. 1984. Complications of malaria. Trop Doct, 14 (4), pp. 191. | Read more

Warrell MJ, Suntharasamai P, Nicholson KG, Warrell DA, Chanthavanich P, Viravan C, Sinhaseni A, Phanfung R, Xueref C, Vincent-Falquet JC. 1984. Multi-site intradermal and multi-site subcutaneous rabies vaccination: improved economical regimens. Lancet, 1 (8382), pp. 874-876. | Show Abstract | Read more

Neutralising antibody responses to six post-exposure regimens of human diploid cell strain rabies vaccine with or without human rabies immune globulin (HRIG) were studied in 98 patients. The total amount of vaccine used was 22-34% of that required by conventional regimens. Vaccine was given at multiple sites intradermally or subcutaneously with or without adjuvant. Antibody was detectable within 7 days of the first dose in all subjects only in the groups given 0.1 ml intradermally at 8 sites. From day 14 onwards all groups showed an excellent antibody response; there was little difference between the various regimens. Suppression of the response to 8-site intradermal vaccination by a large dose of HRIG could be prevented by giving the second dose of vaccine on day 7 rather than day 14.

Phillips RE, Looareesuwan S, Karbwang J, Warrell DA, White NJ, Kasemsarn P, Warhurst DC. 1984. Failure of chloroquine-erythromycin and chloroquine-tetracycline combinations in treatment of chloroquine-resistant falciparum malaria in eastern Thailand. Lancet, 1 (8372), pp. 300-302. | Show Abstract | Read more

In Eastern Thailand the increasing resistance of Plasmodium falciparum to all available antimalarial drugs prompted a reassessment of chloroquine in combination with either erythromycin or tetracycline. Both combinations had produced encouraging results in vitro, in experimental animal models, or in preliminary clinical trials. In patients with uncomplicated falciparum malaria presenting with moderate parasitaemia the trial of chloroquine and tetracycline was abandoned after RIII resistance with clinical deterioration was encountered in 2 out of the first 5 patients studied. Of 16 patients treated with chloroquine+erythromycin, 11 showed resistance (RI-RIII). These regimens appear ineffective and potentially dangerous in Eastern Thailand.

WARRELL D, WHITE N. 1984. COMPLICATIONS OF MALARIA TROPICAL DOCTOR, 14 (4), pp. 191-191.

VEALL N, WARRELL D, WHITE N. 1984. CEREBRAL PERFUSION IN MALARIA BRITISH JOURNAL OF RADIOLOGY, 57 (679), pp. 659-659.

White NJ, Warrell DA. 1983. Clinical management of chloroquine-resistant Plasmodium falciparum malaria in Southeast Asia. Trop Doct, 13 (4), pp. 153-158. | Read more

Warrell DA. 1983. Notes on the use of antivenom. Ceylon Med J, 28 (3), pp. 186.

Warrell MJ, Warrell DA, Suntharasamai P, Viravan C, Sinhaseni A, Udomsakdi D, Phanfung R, Xueref C et al. 1983. An economical regimen of human diploid cell strain anti-rabies vaccine for post-exposure prophylaxis. Lancet, 2 (8345), pp. 301-304. | Show Abstract | Read more

Vaccine regimens using 0.1 ml human diploid cell strain vaccine (HDCSV) given intradermally (id) in single and multiple sites, or with aluminum hydroxide adjuvant given subcutaneously (sc), were compared with the regimens of HDCSV and Semple vaccine currently suggested by WHO. Some groups were also given human rabies-immune globulin (HRIG). Neutralising antibody titres were monitored for 3 months. Antibody was detected earliest in subjects given 0.1 ml HDCSV id at each of eight sites. The highest antibody titres from day 14 onwards were found after intramuscular (im) administration of HDCSV, but the multiple-site id regimen, which requires only one quarter of the volume of vaccine required for the im regimen, gave similar results, provided that a booster was given on day 91. This finding suggests that a treatment schedule based on this regimen would be suitable for post-exposure prophylaxis. Adjuvanted vaccine gave similar results to the same amount of antigen given id. Semple vaccine produced the lowest titres. HRIG, given at the high dose of 40 IU per kg, suppressed the antibody response to some of the regimens.

Warrell DA, Perine PL, Krause DW, Bing DH, MacDougal SJ. 1983. Pathophysiology and immunology of the Jarisch-Herxheimer-like reaction in louse-borne relapsing fever: comparison of tetracycline and slow-release penicillin. J Infect Dis, 147 (5), pp. 898-909. | Show Abstract | Read more

Twelve men with louse-borne relapsing fever were treated with single doses of procaine penicillin plus aluminum monostearate (PAM) intramuscularly or of tetracycline intravenously. All patients experienced a definite Jarisch-Herxheimer-like reaction. Fever and spirochetemia were significantly prolonged and peak temperature was lower and occurred later in the PAM-treated group. Peak pulmonary ventilation, metabolic rate, and arterial PO2 were significantly higher in the tetracycline-treated group. Circulatory changes were similar in the two groups but were prolonged in the PAM-treated patients. Thus, tetracycline is recommended for treatment because it is more rapidly effective in eliminating Borrelia spirochetes and produces a reaction no more stressful physiologically than the one after PAM. There was no evidence of complement activation, and there was no change in immunoglobulin levels throughout the reaction. Immune complexes were detected in serum of five patients before treatment, but in fewer patients at the peak of the reaction and subsequently.

Warrell DA, Looareesuwan S, White NJ, Theakston RD, Warrell MJ, Kosakarn W, Reid HA. 1983. Severe neurotoxic envenoming by the Malayan krait Bungarus candidus (Linnaeus): response to antivenom and anticholinesterase. Br Med J (Clin Res Ed), 286 (6366), pp. 678-680. | Show Abstract

Five patients were bitten by the Malayan krait Bungarus candidus (Linnaeus) in eastern Thailand or north western Malaya. Two patients were not envenomed but the other three developed generalised paralysis which progressed to respiratory paralysis in two cases, one of which ended fatally. One patient showed parasympathetic abnormalities. Anticholinesterase produced a dramatic improvement in one patient. Another patient probably benefited from paraspecific antivenom. The efficacy of antivenoms and adjuvants such as anticholinesterases in patients with neurotoxic envenoming requires further study.

Teklu B, Habte-Michael A, Warrell DA, White NJ, Wright DJ. 1983. Meptazinol diminishes the Jarisch-Herxheimer reaction of relapsing fever. Lancet, 1 (8329), pp. 835-839. | Show Abstract | Read more

Naloxone, an opioid antagonist, and meptazinol, an opioid antagonist with agonist properties, were tested in a double-blind placebo-controlled trial in 24 Ethiopian patients with louse-borne relapsing fever. The potentially fatal Jarisch-Herxheimer reaction (J-HR), which invariably follows tetracycline treatment of the disease, was unaffected by naloxone, 30-40 mg intravenously, but was diminished by meptazinol, 300-500 mg intravenously. Compared with naloxone and placebo, meptazinol reduced the clinical severity of the reaction, significantly delayed and shortened its chill phase, delayed the rise in temperature, and reduced peak temperature and changes in pulse and respiratory rates and leucocyte count. High-dose corticosteroids given before or at the time of tetracycline treatment failed to alter the reaction, which is thought to result from release of endotoxin-like substances. Meptazinol is the first effective treatment for the J-HR of louse-borne relapsing fever. This finding suggests a role for endogenous opioids in the pathogenesis of the J-HR.

White NJ, Looareesuwan S, Warrell DA. 1983. Quinine and quinidine: a comparison of EKG effects during the treatment of malaria. J Cardiovasc Pharmacol, 5 (2), pp. 173-175. | Show Abstract | Read more

We recorded electrocardiograms from 31 patients receiving quinine and 14 patients receiving quinidine for the treatment of Plasmodium falciparum malaria. Despite plasma quinine concentrations of up to 20 mg/L, there was no evidence of cardiotoxicity. QT prolongation was considerably greater in the quinidine-treated patients. The mean ratio of change in corrected QT interval to change in plasma concentration (delta QTc%/delta CQ) was 3.2% . mg-1 . L-1 for quinidine, compared to 0.74% . mg-1 . L-1 for quinine (p less than 0.001). T-wave flattening was observed in both groups. Plasma concentrations of quinine cannot be predicted from the EKG, because concentrations within the therapeutic range produced only minor and unpredictable abnormalities.

TEKLU B, HABTEMICHAEL A, WHITE N, WARRELL D, WRIGHT D. 1983. OPIATE ANTAGONISTS IN THE JARISCH-HERXHEIMER REACTION IN BORRELIAL INFECTIONS POSTGRADUATE MEDICAL JOURNAL, 59 pp. 67-67.

Looareesuwan S, Warrell DA, White NJ, Sutharasamai P, Chanthavanich P, Sundaravej K, Juel-Jensen BE, Bunnag D, Harinasuta T. 1983. Do patients with cerebral malaria have cerebral oedema? A computed tomography study. Lancet, 1 (8322), pp. 434-437. | Show Abstract | Read more

Computed tomography of the brain in 10 patients with severe cerebral malaria, 5 of whom died, showed evidence of cerebral oedema in only 2 fatal cases. Small areas of altered density were seen in 4 cases; these were not associated with focal neurological signs and were still visible in convalescent scans in 2 survivors. 4 patients, including 1 of the fatalities, had completely normal scans. Cerebral oedema may occur in severe cerebral malaria but is not a consistent feature of living patients and cannot, therefore, always be the cause of their coma.

White NJ, Looareesuwan S, Warrell DA, Warrell MJ, Chanthavanich P, Bunnag D, Harinasuta T. 1983. Quinine loading dose in cerebral malaria. Am J Trop Med Hyg, 32 (1), pp. 1-5. | Show Abstract

In cerebral malaria, the use of currently recommended doses of intravenous quinine may result in subtherapeutic plasma concentrations during the critical first 24 hours of treatment. A loading dose of quinine (20 mg/kg quinine dihydrochloride, equivalent to 16.7 mg/kg base, infused over 4 hours) proved a rapid and safe method of achieving plasma concentrations above the high minimum inhibitory concentrations for Plasmodium falciparum prevalent in Eastern Thailand.

Looareesuwan S, Warrell DA, White NJ, Chanthavanich P, Warrell MJ, Chantaratherakitti S, Changswek S, Chongmankongcheep L, Kanchanaranya C. 1983. Retinal hemorrhage, a common sign of prognostic significance in cerebral malaria. Am J Trop Med Hyg, 32 (5), pp. 911-915. | Show Abstract

Retinal hemorrhages were seen in 21 patients among a group of 144 with strictly-defined cerebral malaria. Hemorrhages were multiple in 17 cases and bilateral in 14. There was subhyaloid extension in two. Soft exudates were seen in two, the retinae were considered edematous in four and in one there was bilateral papilledema. Retinal hemorrhages were significantly associated with several indices of severity of Plasmodium falciparum infection: high parasitemia with schizontemia, anemia, elevated serum creatinine and reduced plasma antithrombin III. Only two patients with hemorrhages were both severely anemic and thrombocytopenic. It is suggested that retinal hemorrhages, a frequent finding in cerebral malaria, may be visible evidence of vascular lesions involved in the pathogenesis of this condition.

White NJ, Warrell DA, Chanthavanich P, Looareesuwan S, Warrell MJ, Krishna S, Williamson DH, Turner RC. 1983. Severe hypoglycemia and hyperinsulinemia in falciparum malaria. N Engl J Med, 309 (2), pp. 61-66. | Show Abstract | Read more

We studied the occurrence, clinical manifestations, and mechanism of hypoglycemia in patients with falciparum malaria in eastern Thailand. Hypoglycemia, which was often severe and recurrent, occurred in 17 patients, including 12 in a series of 151 patients with cerebral malaria. Thirty episodes were investigated. Plasma concentrations of insulin and C peptide were inappropriately high, and lactate and alanine concentrations were significantly higher than in patients with falciparum malaria who were normoglycemic (P less than 0.05). Sixteen patients had received quinine; plasma quinine and insulin concentrations were correlated at the time of hypoglycemia (P = 0.007). In seven healthy fasting volunteers intravenous quinine increased the mean plasma insulin concentration (+/- S.D.) from 8.9 +/- 3.1 to 17.1 +/- 8.4 mU per liter (P = 0.02) and reduced the mean plasma glucose concentration from 88 +/- 20 to 68 +/- 23 mg per deciliter (P = 0.002). Our observations indicate that in falciparum malaria quinine-induced insulin secretion may precipitate hypoglycemia, but other factors, including the large glucose requirements of the malaria parasites may also contribute. This important complication, associated with pregnancy and severe disease, must be excluded in all patients with falciparum malaria who have impaired or deteriorating consciousness.

TEKLU B, HABTEMICHAEL A, WHITE N, WARRELL D, WRIGHT D. 1983. OPIATE ANTAGONISTS IN THE JARISCH-HERXHEIMER REACTION (J-HR) IN BORRELIAL INFECTIONS CIRCULATORY SHOCK, 10 (3), pp. 260-260.

WARRELL D. 1983. CORRECTION BRITISH MEDICAL JOURNAL, 286 (6378), pp. 1652-1652.

WARRELL D, WHITE N, WARRELL M. 1983. Is dexamethasone deleterious in cerebral malaria? Br Med J (Clin Res Ed), 286 (6374), pp. 1355.

Warrell DA, White NJ, Warrell MJ. 1982. Dexamethasone deleterious in cerebral malaria. Br Med J (Clin Res Ed), 285 (6355), pp. 1652.

White NJ, Warrell DA. 1982. Managing cerebral malaria. Br Med J (Clin Res Ed), 285 (6339), pp. 439.

Harinasuta T, Dixon KE, Warrell DA, Doberstyn EB. 1982. Recent advances in malaria with special reference to Southeast Asia. Southeast Asian J Trop Med Public Health, 13 (1), pp. 1-34.

Warrell DA, Looareesuwan S, Warrell MJ, Kasemsarn P, Intaraprasert R, Bunnag D, Harinasuta T. 1982. Dexamethasone proves deleterious in cerebral malaria. A double-blind trial in 100 comatose patients. N Engl J Med, 306 (6), pp. 313-319. | Show Abstract | Read more

High-dose dexamethasone was compared with placebo in a double-blind trial involving 100 comatose patients with strictly defined cerebral malaria. The two treatment groups, whose members were six to 70 years old, proved comparable on admission. There were eight deaths in the dexamethasone group and nine in the placebo group (no significant difference; P = 0.8); at post-mortem examination the brain showed features diagnostic of cerebral malaria in all but one patient who died. Dexamethasone prolonged coma among the survivors: the interval between the start of treatment and the full recovery of consciousness was 63.2 +/- 5.9 hours (mean +/- S.E.M.) in the dexamethasone group, as compared with 47.4 +/- 3.2 hours in the placebo group (P = 0.02). Complications, including pneumonia and gastrointestinal bleeding, occurred in 26 patients given dexamethasone and 11 given placebo (P = 0.004). Only five patients had neurologic sequelae. Results were similar in a subgroup of 28 children six to 14 years old. Dexamethasone is deleterious in cerebral malaria and should no longer be used.

White NJ, Looareesuwan S, Warrell DA, Warrell MJ, Bunnag D, Harinasuta T. 1982. Quinine pharmacokinetics and toxicity in cerebral and uncomplicated Falciparum malaria. Am J Med, 73 (4), pp. 564-572. | Show Abstract | Read more

Acute pharmacokinetics of intravenously infused quinine were studied in 25 patients with cerebral malaria and 13 with uncomplicated falciparum malaria. In patients with cerebral malaria receiving the standard dose of 10 mg/kg every eight hours, plasma quinine concentrations consistently exceeded 10 mg/liter, reaching a peak 60 +/- 25 hours (mean +/- 1 S.D.) after treatment was begun and then declining. Quinine total clearances (Cl) and total apparent volumes of distribution (Vd) were significantly lower than in uncomplicated malaria (Cl, 0.92 +/- 0.42 compared with 1.35 +/- 0.6 ml/min/kg, p = 0.03; Vd, 1.18 +/- 0.37 compared with 1.67 +/- 0.34 liter/kg, p = 0.0013). There was no significant difference between the two groups in elimination half-times (t/2) or renal clearances (Cu) (t/2, 18.2 +/- 9.7 compared with 16 +/- 7.0 hours; Cu, 0.21 +/- 0.16 compared with 0.21 +/- 0.08 ml/min/kg). In nine patients studied following recovery, Cl (3.09 +/- 1.18 ml/min), Vd (2.74 +/- 0.47 liter/kg), and Cu (0.53 +/- 0.22 ml/min/kg) were significantly greater (p less than or equal to 0.0004), and t/2 was significantly shorter (11.1 +/- 4.1 hours, p = 0.006) than during the acute illness. Cu accounted for approximately 20 percent of Cl in all groups. Renal failure did not alter the disposition kinetics in cerebral malaria. There was no clinical or electrocardiographic evidence of cardiotoxicity and no permanent neurotoxicity. Quinine toxicity in cerebral malaria has probably been overemphasized. The benefits of high plasma concentrations in the acute phase of this life-threatening disease appear to outweigh the risks, particularly in view of the increasing resistance of Plasmodium falciparum to quinine in Southeast Asia.

WARRELL D, WHITE N, WARRELL M. 1982. DEXAMETHASONE DELETERIOUS IN CEREBRAL MALARIA BRITISH MEDICAL JOURNAL, 285 (6355), pp. 1652-1652.

WHITE N, WARRELL D. 1982. MANAGING CEREBRAL MALARIA BRITISH MEDICAL JOURNAL, 285 (6339), pp. 439-439.

WARRELL D, LOOAREESUWAN S, WARRELL M, BUNNAG D, HARINASUTA T. 1982. DEXAMETHASONE IN CEREBRAL MALARIA - REPLY NEW ENGLAND JOURNAL OF MEDICINE, 307 (5), pp. 319-319.

White NJ, Looareesuwan S, Warrell DA, Chongsuphajaisiddhi T, Bunnag D, Harinasuta T. 1981. Quinidine in falciparum malaria. Lancet, 2 (8255), pp. 1069-1071. | Show Abstract | Read more

Fourteen patients with falciparum malaria were successfully treated with oral quinidine. Twelve of these patients were followed for 35 days without recrudescence. In six patients the infection had already recrudesced after antimalarial treatment, which in two cases had included a full course of quinine. Quinidine caused no cardiotoxicity, although the electrocardiogram QTc interval was prolonged by more than 25% in four patients. In-vitro cultures from nine of these patients and a further seven patients with falciparum malaria showed that the minimum inhibitory concentration was consistently lower for quinidine than for quinine. Quinidine is an effective antimalarial drug for Plasmodium falciparum infections and may be more potent than quinine.

Warrell DA, Warrell MJ, Edgar W, Prentice CR, Mathison J, Mathison J. 1980. Comparison of Pasteur and Behringwerke antivenoms in envenoming by the carpet viper (Echis carinatus). Br Med J, 280 (6214), pp. 607-609. | Show Abstract | Read more

Bites and envenoming by the carpet viper Echis carinatus are common medical emergencies in parts of Nigeria, but the most effective use of the various commercially produced antivenoms in treatment has not been established. Pasteur Paris Echis monospecific and Behringwerke West and North Africa Bitis-Echis-Naja polyspecific antivenoms were compared in two groups of seven patients with incoagulable blood after E carinatus bites. In both groups spontaneous bleeding stopped within a few hours and local swelling subsided within two weeks after the initial antivenom injection. Pasteur antivenom (20-40 ml) restored blood coagulability within 12 hours in all cases, but 60--180 ml of Behringwerke antivenom was effective in only four cases. Persisting venom procoagulant activity was observed in the remaining three cases. Despite its potency in the mouse protection test, Behringwerke antivenom is unreliable and unpredictable in neutralising venom procoagulant in humans bitten by E carinatus.

Edgar W, Warrell MJ, Warrell DA, Prentice CR. 1980. The structure of soluble fibrin complexes and fibrin degradation products after Echis carinatus bite. Br J Haematol, 44 (3), pp. 471-481. | Show Abstract | Read more

Studies on the concentration and structure of fibrinogen, fibrinogen-fibrin soluble complexes, and fibrinogen-fibrin degradation products were made on 11 patients in Nigeria who suffered defibrination following Echis carinatus bite. Following admission, before treatment with antivenom, all patients had reduced or zero fibrinogen levels, and increased concentrations of soluble complexes and degradation products. The fibrin component of the soluble complexes, separated by fibrinogen-sepharose chromatography, consisted of both intact fibrin and fibrin degraded at the alpha-chain. After isolation by Biogel chromatography the soluble complexes were also found to contain gamma-dimer chains. The fibrinogen-fibrin degradation products consisted of several X species, Y, D and D-dimer, as well as fragment E. The major fragment in all patients was D, but a few samples contained significant quantities of D-dimer, indicating in vivo activation of factor XIII. There was evidence of degraded fibrinogen, as well as fibrin, in the soluble complexes and degradation products, suggesting that fibrinogenolysis, in addition to fibrinolysis, had occurred, probably as a result of secondary endogenous activation of the fibrinolytic system in response to defibrination.

Warrell DA. 1979. Bites and stings by venomous animals in Britain Prescribers' Journal, 19 (6), pp. 190-199.

Warrell DA, Tobin JO, Tomlinson AH. 1978. Infection with Epstein-Barr virus. Br Med J, 2 (6139), pp. 774.

Warrell DA. 1978. Snakes and snake bite. Br Med J, 2 (6133), pp. 352-353. | Read more

WARRELL D, TOBIN J, TOMLINSON A. 1978. INFECTION WITH EPSTEIN-BARR VIRUS BRITISH MEDICAL JOURNAL, 2 (6139), pp. 774-774. | Read more

WARRELL D, WARRELL M, EDGAR W, PRENTICE C. 1978. CLINICAL PHYSIOLOGY AND TREATMENT OF ECHIS-CARINATUS VICTIMS TOXICON, 16 (5), pp. 430-430.

Bryceson AD, Warrell DA, Pope HM. 1977. Dangerous reactions to treatment of onchocerciasis with diethylcarbamazine. Br Med J, 1 (6063), pp. 742-744. | Show Abstract | Read more

Nine Nigerians with severe onchocerciasis who were treated with diethylcarbamazine developed clinical changes, ranging in severity from mild itching to distress, cough, and syncope. Physiological changes (fever, tachypnoea, tachycardia, or hypotension) were seen in eight. In five patients the systolic blood pressure fell by more than 25 mm Hg, and one patient collapsed on attempting to sit up. Circulating eosinophils decreased profoundly in all cases, reaching their lowest levels just before or during the clinical and physiological changes. A fall in serum complement (c3) accompanied the reaction but there was no fall in antibody titre. Diethylcarbamazine probably acts on the parasite's cuticle, thus exposing it to the body's defence mechansims. The reaction coincides with the death of microfilariae, and the accompanying physiological changes may be so severe, even in generally healthy patients, the treatment should perferably be started in hospital.

Warrell DA. 1977. The threat of rabies. J R Coll Physicians Lond, 11 (2), pp. 171-180. | Show Abstract

Rabies encephalitis in man cannot be cured and so must be prevented. Rabies can be kept out of Britain by enforcing quarantine regulations and preventing the smuggling of pet animals. If rabies were reintroduced there would be a severe risk of the virus becoming established in wild foxes. The traditional methods of dealing with fox rabies should be critically reexamined. They have proved largely unsuccessful in Europe, they are indiscriminate and fail to take into account what is known about fox ecology. If rabies were to become endemic in Britain, the post exposure treatment of patients bitten by animals would become a major medical problem. Even if rabies can be kept out, a designated centre is needed for the treatment of imported rabies patients. This unit would be run by a staff fully protected against rabies by preexposure vaccination.

Warrell DA, Davidson NMcD, Greenwood BM, Ormerod LD, Pope HM, Watkins BJ, Prentice CR. 1977. Poisoning by bites of the saw-scaled or carpet viper (Echis carinatus) in Nigeria. Q J Med, 46 (181), pp. 33-62. | Show Abstract

The Saw-scaled or Carpet Viper (Echis carinatus) whose range extends from Senegal to Bengal probably bites and kills more people than any other species of snake. One hundred and fifteen patients with poisoning caused by its bite were studied in the savanna region of Nigeria, where victims of this snake may occupy 10 per cent of hospital beds. Patients showing no signs of envenoming were excluded. All patients had local swelling at the site of the bite. Other features included local blistering (13 per cent), local necrosis (11 per cent), incoagulable blood (93 per cent), and spontaneous systemic bleeding (57 per cent). There was evidence of disseminated intravascular coagulation in all cases; fibrinogen was severely depleted, fibrin degradation products were increased (mean 1711 +/- 904 micron per ml), but significant thrombocytopenia (less than 103 000 per mm3) was seen in only ten severe cases. Clotting factors V, VIII, II and XIII were depleted, while X and VII were usually normal. Fibrinolytic activity was rarely increased, so it seems likely that a procoagulant action (direct activation of prothrombin) is principal effect of E. carinatus venom on blood coagulation in man. Development of the haemostatic defect was observed as early as 75 minutes and as late as 27 hours after the bite. Spontaneous haemorrhage is clinically the most important effect of E. carinatus venom, causing the five deaths in this series. The relative importance of procoagulant and haemorrhagic components of the venom in causing haemorrhage is discussed. Complement activation via the classical and alternative pathways may have contributed to vascular damage. Mortality was reduced from the untreated level of between 10 and 20 per cent to 2.8 per cent in a group of 107 patients treated with 10 to 110 ml of specific antivenom. The dose was controlled using a simple clotting test. Blood coagulability was restored in two to 39 (mean 12) hours after the first dose of antivenom. Immediate-type serum reactions were observed in 21 per cent of cases. Additional treatment included blood transfusion for patients in haemorrhagic shock and ealry surgical débridement of necrotic tissue at the site of the bite.

Tugwell P, Greenwood BM, Warrell DA. 1976. Pneumococcal meningitis: a clinical and laboratory study. Q J Med, 45 (180), pp. 583-601. | Show Abstract

Forty-two patients who were admitted consecutively with pneumococcal meningitis during an 18-month period were studied in Ahmadu Bello University Hospital, Zaria, Nigeria. The disease was seen most frequently in older children and young adults. A predisposing condition was found in only four patients. Counter-current immunoelectrophoresis was found to be a rapid and effective method of diagnosis: pneumococcal polysaccharide antigen was found in the initial cerebrospinal fluid (CSF) sample from all but one of the patients. Detailed physiological studies carried out in two patients showed profound disturbances of cerebral carbohydrate metabolism and an increase in cerebral vascular resistance. Twenty patients died (48 per cent) in spite of treatment with large doses of penicillin. A fatal outcome was associated with impairment of consciousness on admission, a low CSF white cell count and a high CSF antigen titre. It is suggested that marked changes in cerebral carbohydrate metabolism, and perhaps vascular damage, play important roles in producing severe brain damage in patients with pneumococcal meningitis and that defective CSF polymorphoneutrophil leukocyte function may contribute to the failure of the infection to respond satisfactorily to antibiotic therapy.

Payne T, Warrell DA. 1976. Effects of venom in eye from spitting cobra. Arch Ophthalmol, 94 (10), pp. 1803.

Warrell DA, Pope HM, Prentice CR. 1976. Disseminated intravascular coagulation caused by the carpet viper (Echis carinatus): trial of heparin. Br J Haematol, 33 (3), pp. 335-342. | Show Abstract | Read more

Heparin has been advocated for the treatment of poisoning by Echis carinatus, a snake whose venom causes disseminated intravascular coagulation. Fourteen patients with proven E. carinatus bite who had incoagulable blood were treated with specific Echis antivenom. Seven of them were also given low-dose heparin, initially 50 units/kg body weight by i.v. injection, followed by 10 units/kg/h by i.v. infusion for 22 h. Response to treatment was assessed clinically and by repeated tests of blood coagulation. All patients showed a rapid return to normal blood coagulability after treatment and the heparinized group were not significantly different in any respect from the group given antivenom alone. Heparin did not reduce the local effects of envenoming. There appears to be no place for heparin in the treatment of E. carinatus poisoning provided that potent antivenom is available. The in vivo results were supported by in vitro studies in which it was found that Echis-induced thrombin was less sensitive to the inhibitory effect of heparin than physiological thrombin.

Warrell DA, Ormerod LD. 1976. Snake venom ophthalmia and blindness caused by the spitting cobra (Naja nigricollis) in Nigeria. Am J Trop Med Hyg, 25 (3), pp. 525-529. | Show Abstract

Venom entered the eyes of 9 patients spat at by the spitting cobra, Naja nigricollis. In 5 the only effect was a simple conjunctivitis but 4 had corneal ulceration, 1 developed anterior uveitis indicating absorption of venom in the anterior chamber, and 2 were permanently blinded. Treatment of this rare emergency is discussed: immediate irrigation of the eye with water, careful examination for corneal abrasion, and prevention of secondary infection are recommended. The value of local specific antivenom is unproven.

Warrell DA, Ormerod LD, Davidson NM. 1976. Bites by the night adder (Causus maculatus) and burrowing vipers (genus Atractaspis) in Nigeria. Am J Trop Med Hyg, 25 (3), pp. 517-524. | Show Abstract

Nineteen patients proven to have been bitten by the small African adders Causus maculatus, Atractapis dahomeyensis and A. microlepidota were studied in the Nigerian savanna region. One of the patients bitten by C. maculatus was drowsy, hypotensive and flaccid on admission but recovered without treatment. Mild or moderate local swelling, local lymphadenitis and mild fever were the only other features in this group. None of the patients bitten by Atractaspis had signs of systemic envenoming apart from moderate fever. Local blistering appeared in two cases but did not progress to necrosis. No patient showed any disturbance of blood coagulation, or evidence of spontaneous hemorrhage or of cranial nerve lesions. The small literature on the effects of Causus and Atractaspis venoms in man and in laboratory animals is reviewed. It appears that bites by these species are very unlikely to cause serious ill effects. A few deaths from Atractaspis bites have been reported, but the danger from these species has been exaggerated.

Warrell DA, Davidson NM, Pope HM, Bailie WE, Lawrie JH, Ormerod LD, Kertesz A, Lewis P. 1976. Pathophysiologic studies in human rabies. Am J Med, 60 (2), pp. 180-190. | Show Abstract | Read more

Six patients with proved rabies were studied with a combination of clinical, physiologic and pathologic technics. Three were given a type of intensive care but died with evidence of respiratory failure. Although circulatory failure did not develop in any of the six patients, three had supraventricular arrhythmias: interstitial myocarditis was found in one of these and rabies virus was isolated from the myocardium of another. Inspiratory muscle spasm was the dominant clinical feature in all cases. This occurred as part of the hydrophobic response and followed stimulation of the upper respiratory tract and skin. Hydrophobia may represent an exaggerated respiratory tract irritant reflex with associated arousal. Later in the course of the disease, various patterns of periodic and ataxic breathing were observed. Widespread brain stem encephalitis was discovered at autopsy, with particular involvement of the neighborhood of the nucleus ambiguous in two of three patients examined. In one patient cerebral metabolism was grossly abnormal, with greatly reduced cerebral oxygen consumption suggesting irreversible brain damage. Respiratory and circulatory disturbances may well be immediate causes of death in patients with rabies, but the present studies reemphasize the severity of the encephalitis which remains the ultimate barrier to survival. In the developing countries in which rabies is still a major problem and in which the cost precludes intensive care, the clinical management of rabies can aim only to reduce suffering by heavy sedation.

Warrell DA, Barnes HJ, Piburn MF. 1976. Neurotoxic effects of bites by the Egyptian cobra (Naja haje) in Nigeria. Trans R Soc Trop Med Hyg, 70 (1), pp. 78-79. | Show Abstract | Read more

Two patients were bitten by Egyptian cobra (Naja haje). One became drowsy and developed transient ptosis 24 hours later. The other lost consciousness and died within two hours of the bite, but no cause was revealed by autopsy. A third patient developed severe transient neurological signs after being bitten by an unidentified snake. The small literature on bites by this species is discussed.

Warrell DA, Arnett C. 1976. The importance of bites by the saw-scaled or carpet viper (Echis carinatus): epidemiological studies in Nigeria and a review of the world literature. Acta Trop, 33 (4), pp. 307-341. | Show Abstract

The incidence of Echis carinatus (saw-scaled or carpet viper) bite and its mortality have been investigated in the Nigerian savanna region. A geographical area was defined in which the snake was particularly abundant and bites were frequent. Perennial and seasonal fluctuations in incidence and mortality, the circumstances in which bites occurred and the types of people bitten were studied at Bambur, Zaria, Kaltungo and Gombe hospitals. Peak incidence coincided with the increase in farming during the rains whereas percentage mortality seemed to be greatest during the cold dry season. The majority of the patients were young males bitten on the foot while walking or farming. A review of the world literature indicated that E. carinatus was the principal cause of snake bite morbidity wherever data were available throughout its wide geographical range. Official statistics have seriously underestimated this important rural health problem.

Warrell DA, Greenwood BM, Davidson NM, Ormerod LD, Prentice CR. 1976. Necrosis, haemorrhage and complement depletion following bites by the spitting cobra (Naja nigricollis). Q J Med, 45 (177), pp. 1-22. | Show Abstract

The Spitting Cobra, Naja nigricollis, is widely and densely distributed in Africa. Fourteen patients with proven N. nigricollis bites, who were seen in the savanna region of Nigeria, did not exhibit the neurological signs, such as cranial nerve lesions and respiratory paralysis, expected following Elapid poisoning. All had local swelling, in eight cases involving the entire limb, and ten developed local tissue necrosis. Spontaneous haemorrhage was detected in three cases and was the probable cause of death in one of them; the other death in this series was unexplained. Haematological abnormalities included prolonged clot lysis anf failure of clot retraction due to a platelet defect. There was no specific deficit in clotting factors and a delayed rise in fibrin degradation products was attributed to extensive tissue damage at the site of the bit. Most patients showed depletion of complement component C3 and glycine-rich beta-glycoprotein (GBG), suggesting activation of the alternative pathway of complement fixation. There was evidence of hepatocellular damage in two out of six patients investigated. There was no evidence that specific polyvalent antivenoms, used in doses of up to 80 ml, prevented any of the effects of N. nigricollis venom. Clinical laboratory diagnosis is discussed. In the past many bites were wrongly classified as viper bites on the basis of clinical findings. Immunodiagnosis is a promising method for assessing the true importance of N. nigricollis bite in West Africa.

Warrell DA. 1976. The clinical picture of rabies in man. Trans R Soc Trop Med Hyg, 70 (3), pp. 188-195. | Show Abstract | Read more

After an incubation period of one to two months rabies presents with non-specific prodromal symptoms and often with paraesthesiae of the bitten area. As in canine rabies there are furious and dumb forms of the disease. In man, furious rabies is characterised by hydrophobia: terror and excitation with spasms of inspiratory muscles, larynx and pharynx precipitated by attempts to drink and by a variety of other stimuli. Hydrophobia may represent an exaggerated respiratory tract irritant reflex with associated arousal potentiated by the selective destruction of brain stem inhibitory systmes. Also typical of furious rabies are intermittent episodes of excitement, hallucinations and maniacal behaviour. Focal neurological abnormalities are surprisingly uncommon. Other signs include hypersalivation, tachycardia and hyperpyrexia. Paralysis and coma supervene after a few days: survival rarely exceeds seven days. Dumb or paralytic rabies is an ascending flaccid paralysis with sphincter involvement and sensory disturbances. Death from respiratory and bulbar paralysis occurs after a longer illness than furious rabies. In a minority of cases hydrophobia develops before the terminal coma. Complications include respiratory arrest, pneumonitis, cardiac arrhythmias and interstitial myocarditis, posterior pituitary disorders, and gastrointestinal bleeding. Differential diagnoses of furious rabies include hysterical pseudo hydrophobia, tetanus, other encephalitides, delirium tremens and various other intoxications. Paralytic rabies may have to be distinguished from postvaccinal encephalomyelitis, poliomyelitis and other causes of Landry-type ascending paralysis. Intensive care has produced some promising results: life-threatening complications can be prevented but there is some evidence that the severity of the encephalitis is the ultimate barrier to survival.

PAYNE T, WARRELL D. 1976. EFFECTS OF VENOM IN EYE FROM SPITTING COBRA ARCHIVES OF OPHTHALMOLOGY, 94 (10), pp. 1803-1803. | Read more

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WARRELL D, ORMEROD L, DAVIDSON N. 1976. BITES BY NIGHT ADDER (CAUSUS-MACULATUS) AND BURROWING VIPERS (GENUS-ATRACTASPIS) IN NIGERIA AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, 25 (3), pp. 517-523.

Warrell DA, Ormerod LD, Davidson NM. 1975. Bites by puff-adder (Bitis arietans) in Nigeria, and value of antivenom. Br Med J, 4 (5998), pp. 697-700. | Show Abstract | Read more

Ten patients bitten by the puff-adder (Bitis arietans) were studied in the North of Nigeria. Six showed severe local signs, and four also had evidence of systemic envenoming, including spontaneous bleeding with thrombocytopenia, hypotension, and bradycardia. Two patients died after developing circulatory collapse and renal failure. Antivenom and intravenous fluid restored blood pressure in two hypotensive patients, and antivenom probably prevented the development of local necrosis in four others with massive local swelling. Victims of B arietans who have swelling of more than half the bitten limb or show signs of systemic envenoming should be given at least 80 ml of specific polyvalent antivenom and watched carefully for signs of circulatory collapse. Debridement of necrotic tissue may be necessary.

Warrell DA. 1975. Respiratory-tract infections in the tropics. Practitioner, 215 (1290), pp. 740-744.

Prentice CR, Warrell DA, Forbes CD, Edgar W. 1975. Proceedings: Haemostatic changes following snake bite by Echis carinatus; trial of heparin. Thromb Diath Haemorrh, 34 (1), pp. 350-351.

Warrell DA, Harrison BD, Fawcett IW, Mohammed Y, Mohammed WS, Pope HM, Watkins BJ. 1975. Silicosis among grindstone cutters in the north of Nigeria. Thorax, 30 (4), pp. 389-398. | Show Abstract | Read more

Many of the grindstones used in Nigerian homes are quarried from sandstone in a small group of villages near Kano in the extreme north of the country. Of an unselected group of 126 stonecutters from two of these villages 49 were found to have radiographic evidence of silicosis, with progressive massive fibrosis in 17. Those with silicosis had worked longer in the quarries than 77 whose radiographs showed no evidence of silicosis. Sixty-three per cent of the silicotics had respiratory symptoms, the commonest being breathlessness on moderate exertion. Cough was the earliest symptom in 42%. Only 35% had abnormal physical signs in the cardiorespiratory system, 18% had clearly reduced ventilatory capacity, and airways obstruction was evident in 16%. The prevalence of silicosis in these open-cast sandstone quarriers is unexpectedly high. This is probably explained by the intensity of exposure and the particular kind of sandstone being worked. Reduction of dust exposure in these quarries raises severe practical problems, but the inhabitants of this drought-ridden area can scarcely be expected to abandon their traditional livelihood.

Whittle HC, Greenwood BM, Davidson N, Tomkins A, Tugwell P, Warrell DA, Zalin A, BRYCESON AD et al. 1975. Meningococcal antigen in diagnosis and treatment of group A meningococcal infections. Am J Med, 58 (6), pp. 823-828. | Show Abstract | Read more

Meningococcal antigen was measured by countercurrent immunoelectrophoresis in the blood and cerebrospinal fluid of 200 patients with group A meningococcal meningitis. Antigen was detected in the blood of 27 (13.5 per cent) patients. These patients had a worse prognosis and a higher incidence of allergic complications, such as arthritis and vasculitis, about 5 days after the start of antibiotic treatment. Antigen was found in the CSF of 129 (67.5 per cent) patients); antigen often persisted in the cerebrospinal fluid despite antibiotic treatment before admission. A combination of immunoelectrophoresis and routine bacteriologic study was used in the diagnosis of 162 (84.8 per cent) patients with meningococcal meningitis. High levels of antigen and a slow antigen disappearance were associated with neurologic damage. The antigen is stable and may be detected from specimens of cerebrospinal fluid dried on filter paper.

Warrell DA, Fawcett IW, Harrison BD, Agamah AJ, Ibu JO, Pope HM, Maberly DJ. 1975. Bronchial asthma in the Nigerian savanna region. A clinical and laboratory study of 106 patients with a review of the literature on asthma in the tropics. Q J Med, 44 (174), pp. 325-347. | Show Abstract

One hundred and six asthma patients were studied in Zaria in the Nigerian savanna region. This group resembled hospital attenders in general in containing a disproportionately large number of immigrants from southern Nigeria and students undergoing higher education. Childhood asthma was rare. Asthma started after the age of 19 years in 69 per cent of patients. Twenty-seven per cent gave a history of rhinitis but none had had eczema. Twenty-two per cent gave a family history of asthma. Cutaneous hypersensitivity to house dust supported by a history of attacks being precipitated by dust was found in 41 per cent of patients. Asthma was worst in the rainy season in 45 per cent of patients. Mites were found in mattress dust samples; the mean count was 243 mites per g dust; Dermatophagoides farinae formed 86-6 per cent of the total mite population. The variability of airways obstruction averaged 50 per cent of maximum values for forced expiratory volume in the first second (FEV1) and peak expiratory flow (PEF). The median severity of airways obstruction measured as FEV1/VC per cent was four standard deviations below predicted normal. Eighty-seven per cent of patients were positive to prick skin tests with one or more allergens. The commonest reactions were to house dust (58 per cent), house dust mite (45 per cent) and Dermatophagoides farinae (44 per cent). Fifty-one per cent of a group of controls were also positive on skin testing but the pattern of responses was different from the asthmatic patients. This high proportion of reactors is explained by high allergen load. Serum IgE levels were lower in the asthmatics than in a group of healthy controls who showed the very high levels characteristic of some African populations. We suggest that the controls were protected from atopic disease by developing high blocking levels of non-specific IgE, perhaps in response to gut helminths. The clinical pattern of asthma in Zaria is compared with other countries in the tropical and temperate zones. The particular problems of treating asthma in developing tropical countries are discussed.

Bryceson AD, Greenwood BM, Warrell DA, Davidson NM, Pope HM, Lawrie JH, Barnes HJ, Bailie WE, Wilcox GE. 1975. Demonstration during life of rabies antigen in humans. J Infect Dis, 131 (1), pp. 71-74. | Show Abstract | Read more

In three cases of human rabies, in which the diagnosis was proved postmortem, rabies antigen was detected by direct immunofluorescence of frozen sections of facial skin. The antigen was thought to be in nerve fibers in association with hair follicles. Development of this technique might enable the establishment of a method for the diagnosis of human rabies during life.

WARRELL D. 1975. RESPIRATORY-TRACT INFECTIONS IN TROPICS PRACTITIONER, 215 (1290), pp. 740-746.

WARRELL D, DAVIDSON N, GREENWOOD B, ORMEROD L, POPE H, WATKINS B, PRENTICE C, REID H. 1975. DISSEMINATED INTRAVASCULAR COAGULATION CAUSED BY CARPET VIPER (ECHIS CARINATUS) QUARTERLY JOURNAL OF MEDICINE, 44 (176), pp. 643-643.

PRENTICE C, WARRELL D, FORBES C, EDGAR W. 1975. HEMOSTATIC CHANGES FOLLOWING SNAKE BITE BY ECHIS CARINATUS - TRIAL OF HEPARIN THROMBOSIS ET DIATHESIS HAEMORRHAGICA, 34 (1), pp. 350-351.

WARRELL D, DAVIDSON N, POPE H, LEWIS P. 1975. RESPIRATORY DISTURBANCES ASSOCIATED WITH RABIES ENCEPHALITIS THORAX, 30 (5), pp. 597-597.

VEALL N, BELL J, WARRELL D, REEVE J. 1975. OBSERVATIONS ON USE OF A SINGLE INJECTION IODO-I-125-ANTIPYRINE TECHNIQUE FOR STUDIES OF CEREBRAL BLOOD-FLOW AND METABOLISM IN COMATOSE PATIENTS BRITISH JOURNAL OF RADIOLOGY, 48 (570), pp. 505-505.

Greenwood BM, Warrell DA, Davidson NM, Ormerod LD, Reid HA. 1974. Immunodiagnosis of snake bite. Br Med J, 4 (5947), pp. 743-745. | Show Abstract | Read more

Management of a patient with snake bite is influenced by the nature of the offending snake. Species diagnosis based on the patient's history and physical signs is often unreliable and the possibility of making a species diagnosis by immunological means has therefore been investigated. Wound aspirates, blister fluids, sera, and urine samples from patients with snake bite were examined for the presence of species-specific venoms using immunodiffusion. A positive species diagnosis was made in 40 out of 101 patients. Immunodiagnosis was especially successful in patients bitten by the puff adder, Bitis arietans, and the African spitting cobra, Naja nigricollis. A higher success rate could probably be achieved using more specific antisera and more sensitive assay techniques.

Warrell DA, Davidson NM, Omerod LD, Pope HM, Watkins BJ, Greenwood BM, Ried HA. 1974. Bites by the saw-scaled or carpet viper (Echis carinatus): trial of two specific antivenoms. Br Med J, 4 (5942), pp. 437-440. | Show Abstract | Read more

Echis carinatus is the most important cause of morbidity and mortality from snake bite in Nigeria and in many other parts of the world. Forty-six patients with systemic poisoning by this snake were given echis antivenom made either by the South African Institute for Medical Research (S.A.I.M.R.) or by Behringwerke (North and West African polyvalent antivenom). A simple test of blood coagulability was used to assess whether an adequate neutralizing dose of antivenom had been given. An average of 15.2 ml S.A.I.M.R. antivenom restored normal coagulability permanently in all 23 patients in one group, but in the other group receiving an average dose of 37.9 ml Behringwerke antivenom normal clotting resulted in only 18 out of 23 patients. Local tissue swelling was similar in both groups, but local necrosis occurred in three patients treated with Behringwerke antivenom and in none given S.A.I.M.R. antivenom.

Fleming AF, Warrell DA, Dickmeiss H. 1974. Letter: Co-trimoxazole and the blood. Lancet, 2 (7875), pp. 284-285.

HARRISON B, WARRELL D, FAWCETT I, MOHAMMED Y, MOHAMMED W, POPE H, WATKINS B. 1974. SILICOSIS IN GRIND-STONE CUTTERS IN NIGERIA THORAX, 29 (5), pp. 613-613.

FLEMING A, WARRELL D, DICKMEIS H. 1974. CO-TRIMOXAZOLE AND BLOOD LANCET, 2 (7875), pp. 284-285. | Read more

Whittle HC, Davidson NM, Greenwood BM, Warrell DA, Tomkins A, Tugwell P, Zalin A, Bryceson AD et al. 1973. Trial of chloramphenicol for meningitis in northern savanna of Africa. Br Med J, 3 (5876), pp. 379-381. | Show Abstract | Read more

In a controlled trial chloramphenicol proved as effective and much cheaper than penicillin for the treatment of group A meningococcal meningitis in Zaria, Nigeria. A short course of five days cured most patients. Adults and older children were soon able to take chloramphenicol by mouth, which reduced the cost and simplified treatment.It is suggested that chloramphenicol is a suitable alternative to sulphonamides for the treatment of meningococcal meningitis in those parts of Africa where the organism is sulphonamide-resistant.

Gibson GJ, Warrell DA. 1972. Hypertensive crises and phenylpropanolamine. Lancet, 2 (7775), pp. 492-493. | Read more

Bryceson AD, Cooper KE, Warrell DA, Perine PL, Parry EH. 1972. Studies of the mechanism of the Jarisch-Herxheimer reaction in louse-borne relapsing fever: evidence for the presence of circulating Borrelia endotoxin. Clin Sci, 43 (3), pp. 343-354.

Scheich H, Honegger HW, Warrell DA, Kennedy G. 1972. Capillary dilatation in response to hypoxia in the brain of a gobiid fish. Respir Physiol, 15 (1), pp. 87-95. | Read more

Warrell DA, Evans JW, Clarke RO, Kingaby GP, West JB. 1972. Pattern of filling in the pulmonary capillary bed. J Appl Physiol, 32 (3), pp. 346-356.

GIBSON G, WARRELL D. 1972. HYPERTENSIVE CRISES AND PHENYLPROPANOLAMINE LANCET, 2 (7775), pp. 492-&.

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BRYCESON A, WARRELL D, COOPER K, PERINE P, PARRY E. 1972. STUDIES OF MECHANISM OF JARISCH-HERXHEIMER REACTION IN LOUSE-BORNE RELAPSING FEVER - EVIDENCE FOR PRESENCE OF CIRCULATING BORRELIA-ENDOTOXIN CLINICAL SCIENCE, 43 (3), pp. 343-&.

SCHEICH H, WARRELL D, HONEGGER H, KENNEDY G. 1972. CAPILLARY DILATATION IN RESPONSE TO HYPOXIA IN BRAIN OF A GOBIID FISH RESPIRATION PHYSIOLOGY, 15 (1), pp. 87-&. | Read more

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WARRELL D, WEST J, KINGABY G, CLARKE R, EVANS J. 1972. PATTERN OF FILLING IN PULMONARY CAPILLARY BED JOURNAL OF APPLIED PHYSIOLOGY, 32 (3), pp. 346-&.

Prather JW, Bowes DN, Warrell DA, Zweifach BW. 1971. Comparison of capsule and wick techniques for measurement of interstitial fluid pressure. J Appl Physiol, 31 (6), pp. 942-945.

Denison DM, Warrell DA, West JB. 1971. Airway structure and alveolar emptying in the lungs of sea lions and dogs. Respir Physiol, 13 (3), pp. 253-260. | Read more

Warrell DA, Perine PL, Bryceson AD, Parry EH, Pope HM. 1971. Physiologic changes during the Jarisch-Herxheimer reaction in early syphilis. A comparison with louse-borne relapsing fever. Am J Med, 51 (2), pp. 176-185.

Conolly ME, Warrell DA, Howes JA, Paterson JW, Beilin LJ, Robertson DG, Dollery CT. 1971. A comparison of the cardiorespiratory effects of isoprenaline and salbutamol in patients with bronchial asthma. Postgrad Med J, 47 pp. Suppl:77-81.

PERINE P, KIDAN T, WARRELL D, BRYCESON A, PARRY E. 1971. BLEEDING IN LOUSE-BORNE RELAPSING FEVER .2. FIBRINOLYSIS FOLLOWING TREATMENT TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE, 65 (6), pp. 782-&. | Read more

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PRATHER J, BOWES D, WARRELL D, ZWEIFACH B. 1971. COMPARISON OF CAPSULE AND WICK TECHNIQUES FOR MEASUREMENT OF INTERSTITIAL FLUID PRESSURE JOURNAL OF APPLIED PHYSIOLOGY, 31 (6), pp. 942-&.

WARRELL D, PERINE P, BRYCESON A, PARRY E, POPE H. 1971. PHYSIOLOGIC CHANGES DURING JARISCH-HERXHEIMER REACTION IN EARLY SYPHILIS - COMPARISON WITH LOUSE-BORNE RELAPSING FEVER AMERICAN JOURNAL OF MEDICINE, 51 (2), pp. 176-&. | Read more

CONOLLY M, WARRELL D, NEWTONHO J, PATERSON J, BEILIN L, ROBERTSO D, DOLLERY C. 1971. COMPARISON OF CARDIORESPIRATORY EFFECTS OF ISOPRENALINE AND SALBUTAMOL IN PATIENTS WITH BRONCHIAL ASTHMA POSTGRADUATE MEDICAL JOURNAL, 47 pp. 77-&.

Perine PL, Parry EH, Vukotich D, Warrell DA, Bryceson AD. 1971. Bleeding in louse-borne relapsing fever. I. Clinical studies in 37 patients. Trans R Soc Trop Med Hyg, 65 (6), pp. 776-781. | Read more

Perine PL, Kidan TG, Warrell DA, Bryceson AD, Parry EH. 1971. Bleeding in louse-borne relapsing fever. II. Fibrinolysis following treatment. Trans R Soc Trop Med Hyg, 65 (6), pp. 782-787. | Read more

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DENISON D, WARRELL D, WEST J. 1971. AIRWAY STRUCTURE AND ALVEOLAR EMPTYING IN LUNGS OF SEA LIONS AND DOGS RESPIRATION PHYSIOLOGY, 13 (3), pp. 253-&. | Read more

PERINE P, PARRY E, VUKOTICH D, WARRELL D, BRYCESON A. 1971. BLEEDING IN LOUSE-BORNE RELAPSING FEVER .1. CLINICAL STUDIES IN 37 PATIENTS TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE, 65 (6), pp. 776-&. | Read more

Parry EH, Warrell DA, Perine PL, Vukotich D, Bryceson AD. 1970. Some effects of louse-borne relapsing fever on the function of the heart. Am J Med, 49 (4), pp. 472-479. | Read more

Warrell DA, Hughes JM, Rosenzweig DY. 1970. Cardiopulmonary performance at rest and during exercise in seven patients with increased transradiancy of one lung ("Macleod's syndrome"). Thorax, 25 (5), pp. 587-597. | Read more

Warrell DA, Pope HM, Parry EH, Perine PL, Bryceson AD. 1970. Cardiorespiratory disturbances associated with infective fever in man: studies of Ethiopian louse-borne relapsing fever. Clin Sci, 39 (1), pp. 123-145.

Warrell DA, Edwards RH, Godfrey S, Jones NL. 1970. Effect of controlled oxygen therapy on arterial blood gases in acute respiratory failure. Br Med J, 1 (5707), pp. 452-455. | Show Abstract | Read more

Seven patients in acute exacerbation of chronic respiratory failure were given 24.5% and later 28% oxygen through Ventimasks. The mean increases in arterial PO(2) were 11 and 21 mm. Hg while breathing 24.5% and 28% oxygen respectively compared with control values while breathing air. Associated increases in arterial PCO(2) were 4 and 8 mm. Hg, respectively. In five of the patients these increases in inspired oxygen concentration resulted in useful increases in tissue oxygen supply without significant deterioration in ventilation, but in two patients arterial PCO(2) rose excessively and artificial ventilation was required.

Edwards RH, Kristinsson A, Warrell DA, Goodwin JF. 1970. Effects of propranolol on response to exercise in hypertrophic obstructive cardiomyopathy. Br Heart J, 32 (2), pp. 219-225. | Show Abstract

The circulatory, respiratory, and metabolic responses to steady state submaximal exercise have been studied in four women and two men with hypertrophic obstructive cardiomyopathy, before treatment, after intravenous, and after three months of oral propranolol. The physical working capacity was significantly lower than in normal subjects, and the response to exercise was characterized by a tachycardia, low cardiac output and stroke volume, and high ventilation and blood lactate concentration. After propranolol there was a significant reduction in heart rate, but changes in most other measurements were slight and there was no improvement in effort tolerance though angina was relieved in the two patients in whom it was present. The possible causes of breathlessness and effort intolerance in hypertrophic obstructive cardiomyopathy are discussed in relation to known effects of propranolol. It is concluded that further trial of propranolol and other beta-adrenergic blocking agents is warranted.

Warrell DA, Robertson DG, Howes JN, Conolly ME, Paterson JW, Beilin LJ, Dollery CT. 1970. Comparison of cardiorespiratory effects of isoprenaline and salbutamol in patients with bronchial asthma. Br Med J, 1 (5688), pp. 65-70. | Show Abstract | Read more

The effects of isoprenaline and salbutamol administered orally, by inhalation, or by intravenous infusion were compared in 13 asthmatic patients. Bronchodilator activity was assessed by serial measurement of specific airways conductance (SGaw). Log-dose response curves were obtained for both drugs and showed them to be equipotent as bronchodilators. Cardiovascular effects were variable, but in general, isopenaline caused greater rise in pulse rate and a greater change in blood pressure than the same dose of salbutamol.Cardiorespiratory measurements during continuous intravenous infusion of increasing doses of both drugs suggested a greater effect of isoprenaline than the same dose of salbutamol on metabolic rate, pulmonary ventilation, pulmonary gas exchange, cardiac output, and heart rate. The effect of salbutamol on the heart rate was about 10 times less than that of isoprenaline but lasted longer.

Bryceson AD, Parry EH, Perine PL, Warrell DA, Vukotich D, Leithead CS. 1970. Louse-borne relapsing fever. Q J Med, 39 (153), pp. 129-170.

Epstein SW, Warrell DA, Robertson DG, Newton-Howes J, Fletcher CM. 1970. The effect of intravenous histamine on specific airway conductance in patients with airway obstruction and in normal subjects. Respiration, 27 (3), pp. 201-211. | Read more

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WARRELL D, ROBERTSO D, HOWES J, CONOLLY M, PATERSON J, BEILIN L, DOLLERY C. 1970. COMPARISON OF CARDIORESPIRATORY EFFECTS OF ISOPRENALINE AND SALBUTAMOL IN PATIENTS WITH BRONCHIAL ASTHMA BRITISH MEDICAL JOURNAL, 1 (5688), pp. 65-&.

PARRY E, WARRELL D, PERINE P, VUKOTICH D, BRYCESON A. 1970. SOME EFFECTS OF LOUSE-BORNE RELAPSING FEVER ON FUNCTION OF HEART AMERICAN JOURNAL OF MEDICINE, 49 (4), pp. 472-&. | Read more

WARRELL D, ROSENZWE D, HUGHES J. 1970. CARDIOPULMONARY PERFORMANCE AT REST AND DURING EXERCISE IN 7 PATIENTS WITH INCREASED TRANSRADIANCY OF ONE LUNG (MACLEODS-SYNDROME) THORAX, 25 (5), pp. 587-&. | Read more

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WARRELL D, POPE H, PARRY E, PERINE P, BRYCESON A. 1970. CARDIORESPIRATORY DISTURBANCES ASSOCIATED WITH INFECTIVE FEVER IN MAN - STUDIES OF ETHIOPIAN LOUSE-BORNE RELAPSING FEVER CLINICAL SCIENCE, 39 (1), pp. 123-&.

EPSTEIN S, WARRELL D, ROBERTSO D, NEWTONHO J, FLETCHER D. 1970. EFFECT OF INTRAVENOUS HISTAMINE ON SPECIFIC AIRWAY CONDUCTANCE IN PATIENTS WITH AIRWAY OBSTRUCTION AND IN NORMAL SUBJECTS RESPIRATION, 27 (3), pp. 201-&.

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WARRELL D, EDWARDS R, GODFREY S, JONES N. 1970. EFFECT OF CONTROLLED OXYGEN THERAPY ON ARTERIAL BLOOD GASES IN ACUTE RESPIRATORY FAILURE BRITISH MEDICAL JOURNAL, 2 (5707), pp. 452-&.

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EDWARDS R, KRISTINS A, WARRELL D, GOODWIN J. 1970. EFFECTS OF PROPRANOLOL ON RESPONSE TO EXERCISE IN HYPERTROPHIC OBSTRUCTIVE CARDIOMYOPATHY BRITISH HEART JOURNAL, 32 (2), pp. 219-&.

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BRYCESON A, PARRY E, PERINE P, WARRELL D, VUKOTICH D, LEITHEAD C. 1970. LOUSE-BORNE RELAPSING FEVER - A CLINICAL AND LABORATORY STUDY OF 62 CASES IN ETHIOPIA AND A RECONSIDERATION OF LITERATURE QUARTERLY JOURNAL OF MEDICINE, 39 (153), pp. 129-&.

Warrell DA, Pope H, Bryceson AD, Parry EH, Perine LL. 1969. Respiratory and acid-base changes during the crises in relapsing fever. Clin Sci, 37 (2), pp. 567.

Robertson DG, Warrell DA, Newton-Howes JS, Fletcher CM. 1969. Bronchial reactivity to cigarette and cigar smoke. Br Med J, 3 (5665), pp. 269-271. | Show Abstract | Read more

The change in specific airway conductance produced by smoking a cigarette under standard conditions was measured in 91 heavy smokers. Subsequently 19 of the most reactive subjects smoked two cigarettes with different filters and another containing cigar tobacco. The results indicated that reactivity to cigarette smoke was reduced significantly by increasing the retention efficiency of the filter and that reactivity to inhaled cigar-tobacco smoke was no less than that to cigarette smoke.

Edwards RH, Kristinsson A, Warrell DA. 1969. Integrated response to exercise in patients with hypertrophic obstructive cardiomyopathy and effect of beta-adrenergic blockade on oxygen transport. Br Heart J, 31 (3), pp. 390.

Godfrey S, Edwards RH, Warrell DA. 1969. The influence of lung shrinkage on breath holding time. Q J Exp Physiol Cogn Med Sci, 54 (2), pp. 129-140.

Robertson DG, Epstein SW, Warrell DA. 1969. Trial of disodium cromoglycate in bronchial asthma. Br Med J, 1 (5643), pp. 552-554. | Show Abstract | Read more

In a double-blind cross-over trial of disodium cromoglycate on 11 patients nine were symptomatically improved, and in all of these daily measurements of peak expiratory flow increased. The forced expiratory volume in the first second and specific airway conductance did not increase in all patients. In most cases the average values for residual volume and functional residual capacity fell; exercise capacity and ventilation did not change, but the pulse rate on exercise was lower. It is suggested that the changes produced by disodium cromoglycate are worth while.

ROBERTSO D, WARRELL D, NEWTONHO J, FLETCHER C. 1969. BRONCHIAL REACTIVITY TO CIGARETTE AND CIGAR SMOKE BRITISH MEDICAL JOURNAL, 3 (5665), pp. 269-&.

EDWARDS R, KRISTINS A, WARRELL D. 1969. INTEGRATED RESPONSE TO EXERCISE IN PATIENTS WITH HYPERTROPHIC OBSTRUCTIVE CARDIOMYOPATHY AND EFFECT OF BETA-ADRENERGIC BLOCKADE ON OXYGEN TRANSPORT BRITISH HEART JOURNAL, 31 (3), pp. 390-&.

GODFREY S, EDWARDS R, WARRELL D. 1969. INFLUENCE OF LUNG SHRINKAGE ON BREATH HOLDING TIME QUARTERLY JOURNAL OF EXPERIMENTAL PHYSIOLOGY AND COGNATE MEDICAL SCIENCES, 54 (2), pp. 129-&.

ROBERTSO D, WARRELL D. 1969. DISODIUM CROMOGLYCATE IN BRONCHIAL ASTHMA BRITISH MEDICAL JOURNAL, 2 (5650), pp. 188-&.

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ROBERTSO D, EPSTEIN S, WARRELL D. 1969. TRIAL OF DISODIUM CROMOGLYCATE IN BRONCHIAL ASTHMA BRITISH MEDICAL JOURNAL, 1 (5643), pp. 552-&.

SCADDING J, OLSEN E, BOOTH C, WRONG O, STEINER R, DARRELL J, WARRELL D, GOODWIN J. 1969. A CASE OF SARCOIDOSIS WITH CRYPTOCOCCAL MENINGITIS BRITISH MEDICAL JOURNAL, 4 (5685), pp. 729-&.

WARRELL D, POPE H, BRYCESON A, PARRY E, PERINE L. 1969. RESPIRATORY AND ACID-BASE CHANGES DURING CRISES IN RELAPSING FEVER CLINICAL SCIENCE, 37 (2), pp. 567-&.

WARRELL D, PARRY E. 1969. CARDIORESPIRATORY COMPLICATIONS OF HIGH FEVER . A PHYSIOLOGICAL STUDY OF FEBRILE REACTION FOLLOWING TETRACYCLINE IN PATIENTS WITH LOUSE-BORNE RELAPSING FEVER QUARTERLY JOURNAL OF MEDICINE, 38 (152), pp. 522-&.

Warrell DA, Godfrey S, Olsen EG. 1968. Giant-cell arteritis with peripheral neuropathy. Lancet, 1 (7550), pp. 1010-1013. | Read more

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WARRELL D, GODFREY S, OLSEN E. 1968. GIANT-CELL ARTERITIS WITH PERIPHERAL NEUROPATHY LANCET, 1 (7550), pp. 1010-&.

Mohapatra B, Warrell DA, Suraweera W, Bhatia P, Dhingra N, Jotkar RM, Rodriguez PS, Mishra K, Whitaker R, Jha P, Million Death Study Collaborators. 2011. Snakebite mortality in India: a nationally representative mortality survey. PLoS Negl Trop Dis, 5 (4), pp. e1018. | Show Abstract | Read more

BACKGROUND: India has long been thought to have more snakebites than any other country. However, inadequate hospital-based reporting has resulted in estimates of total annual snakebite mortality ranging widely from about 1,300 to 50,000. We calculated direct estimates of snakebite mortality from a national mortality survey. METHODS AND FINDINGS: We conducted a nationally representative study of 123,000 deaths from 6,671 randomly selected areas in 2001-03. Full-time, non-medical field workers interviewed living respondents about all deaths. The underlying causes were independently coded by two of 130 trained physicians. Discrepancies were resolved by anonymous reconciliation or, failing that, by adjudication. A total of 562 deaths (0.47% of total deaths) were assigned to snakebites. Snakebite deaths occurred mostly in rural areas (97%), were more common in males (59%) than females (41%), and peaked at ages 15-29 years (25%) and during the monsoon months of June to September. This proportion represents about 45,900 annual snakebite deaths nationally (99% CI 40,900 to 50,900) or an annual age-standardised rate of 4.1/100,000 (99% CI 3.6-4.5), with higher rates in rural areas (5.4/100,000; 99% CI 4.8-6.0), and with the highest state rate in Andhra Pradesh (6.2). Annual snakebite deaths were greatest in the states of Uttar Pradesh (8,700), Andhra Pradesh (5,200), and Bihar (4,500). CONCLUSIONS: Snakebite remains an underestimated cause of accidental death in modern India. Because a large proportion of global totals of snakebites arise from India, global snakebite totals might also be underestimated. Community education, appropriate training of medical staff and better distribution of antivenom, especially to the 13 states with the highest prevalence, could reduce snakebite deaths in India.

Faiz A, Ghose A, Ahsan F, Rahman R, Amin R, Hassan MU, Chowdhury AW, Kuch U et al. 2010. The greater black krait (Bungarus niger), a newly recognized cause of neuro-myotoxic snake bite envenoming in Bangladesh. Brain, 133 (11), pp. 3181-3193. | Show Abstract | Read more

Prospective studies of snake bite patients in Chittagong, Bangladesh, included five cases of bites by greater black kraits (Bungarus niger), proven by examination of the snakes that had been responsible. This species was previously known only from India, Nepal, Bhutan and Burma. The index case presented with descending flaccid paralysis typical of neurotoxic envenoming by all Bungarus species, but later developed generalized rhabdomyolysis (peak serum creatine kinase concentration 29,960 units/l) with myoglobinuria and acute renal failure from which he succumbed. Among the other four patients, one died of respiratory paralysis in a peripheral hospital and three recovered after developing paralysis, requiring mechanical ventilation in one patient. One patient suffered severe generalized myalgia and odynophagia associated with a modest increase in serum creatine kinase concentration. These are the first cases of Bungarus niger envenoming to be reported from any country. Generalized rhabdomyolysis has not been previously recognized as a feature of envenoming by any terrestrial Asian elapid snake, but a review of the literature suggests that venoms of some populations of Bungarus candidus and Bungarus multicinctus in Thailand and Vietnam may also have this effect in human victims. To investigate this unexpected property of Bungarus niger venom, venom from the snake responsible for one of the human cases of neuro-myotoxic envenoming was injected into one hind limb of rats and saline into the other under buprenorphine analgesia. All animals developed paralysis of the venom-injected limb within two hours. Twenty-four hours later, the soleus muscles were compared histopathologically and cytochemically. Results indicated a predominantly pre-synaptic action (β-bungarotoxins) of Bungarus niger venom at neuromuscular junctions, causing loss of synaptophysin and the degeneration of the terminal components of the motor innervation of rat skeletal muscle. There was oedema and necrosis of extrafusal muscle fibres in envenomed rat soleus muscles confirming the myotoxic effect of Bungarus niger venom, attributable to phospholipases A₂. This study has demonstrated that Bungarus niger is widely distributed in Bangladesh and confirms the risk of fatal neuro-myotoxic envenoming, especially as no specific antivenom is currently manufactured. The unexpected finding of rhabdomyolysis should prompt further investigation of the venom components responsible. The practical implications of having to treat patients with rhabdomyolysis and consequent acute renal failure, in addition to the more familiar respiratory failure associated with krait bite envenoming, should not be underestimated in a country that is poorly equipped to deal with such emergencies.

Warrell DA. 2010. Snake bite (vol 375, pg 77, 2010) LANCET, 375 (9715), pp. 640-640.

Abubakar IS, Abubakar SB, Habib AG, Nasidi A, Durfa N, Yusuf PO, Larnyang S, Garnvwa J et al. 2010. Randomised controlled double-blind non-inferiority trial of two antivenoms for saw-scaled or carpet viper (Echis ocellatus) envenoming in Nigeria. PLoS Negl Trop Dis, 4 (7), pp. e767. | Show Abstract | Read more

BACKGROUND: In West Africa, envenoming by saw-scaled or carpet vipers (Echis ocellatus) causes great morbidity and mortality, but there is a crisis in supply of effective and affordable antivenom (ISRCTN01257358). METHODS: In a randomised, double-blind, controlled, non-inferiority trial, "EchiTAb Plus-ICP" (ET-Plus) equine antivenom made by Instituto Clodomiro Picado was compared to "EchiTAb G" (ET-G) ovine antivenom made by MicroPharm, which is the standard of care in Nigeria and was developed from the original EchiTAb-Fab introduced in 1998. Both are caprylic acid purified whole IgG antivenoms. ET-G is monospecific for Echis ocellatus antivenom (initial dose 1 vial) and ET-Plus is polyspecific for E. ocellatus, Naja nigricollis and Bitis arietans (initial dose 3 vials). Both had been screened by pre-clinical and preliminary clinical dose-finding and safety studies. Patients who presented with incoagulable blood, indicative of systemic envenoming by E. ocellatus, were recruited in Kaltungo, north-eastern Nigeria. Those eligible and consenting were randomly allocated with equal probability to receive ET-Plus or ET-G. The primary outcome was permanent restoration of blood coagulability 6 hours after the start of treatment, assessed by a simple whole blood clotting test repeated 6, 12, 18, 24 and 48 hr after treatment. Secondary (safety) outcomes were the incidences of anaphylactic, pyrogenic and late serum sickness-type antivenom reactions. FINDINGS: Initial doses permanently restored blood coagulability at 6 hours in 161/194 (83.0%) of ET-Plus and 156/206 (75.7%) of ET-G treated patients (Relative Risk [RR] 1.10 one-sided 95% CI lower limit 1.01; P = 0.05). ET-Plus caused early reactions on more occasions than did ET-G [50/194 (25.8%) and 39/206 (18.9%) respectively RR (1.36 one-sided 95% CI 1.86 upper limit; P = 0.06). These reactions were classified as severe in 21 (10.8%) and 11 (5.3%) of patients, respectively. CONCLUSION: At these doses, ET-Plus was slightly more effective but ET-G was slightly safer. Both are recommended for treating E. ocellatus envenoming in Nigeria. TRIAL REGISTRATION: Current Controlled Trials ISRCTN01257358.

Eddleston M, Juszczak E, Buckley NA, Senarathna L, Mohamed F, Dissanayake W, Hittarage A, Azher S et al. 2008. A randomised controlled trial of multiple dose activated charcoal in acute self-poisoning CLINICAL TOXICOLOGY, 46 (5), pp. 380-380.

Warrell MJ, Riddell A, Yu LM, Phipps J, Diggle L, Bourhy H, Deeks JJ, Fooks AR et al. 2008. A simplified 4-site economical intradermal post-exposure rabies vaccine regimen: a randomised controlled comparison with standard methods. PLoS Negl Trop Dis, 2 (4), pp. e224. | Show Abstract | Read more

BACKGROUND: The need for economical rabies post-exposure prophylaxis (PEP) is increasing in developing countries. Implementation of the two currently approved economical intradermal (ID) vaccine regimens is restricted due to confusion over different vaccines, regimens and dosages, lack of confidence in intradermal technique, and pharmaceutical regulations. We therefore compared a simplified 4-site economical PEP regimen with standard methods. METHODS: Two hundred and fifty-four volunteers were randomly allocated to a single blind controlled trial. Each received purified vero cell rabies vaccine by one of four PEP regimens: the currently accepted 2-site ID; the 8-site regimen using 0.05 ml per ID site; a new 4-site ID regimen (on day 0, approximately 0.1 ml at 4 ID sites, using the whole 0.5 ml ampoule of vaccine; on day 7, 0.1 ml ID at 2 sites and at one site on days 28 and 90); or the standard 5-dose intramuscular regimen. All ID regimens required the same total amount of vaccine, 60% less than the intramuscular method. Neutralising antibody responses were measured five times over a year in 229 people, for whom complete data were available. FINDINGS: All ID regimens showed similar immunogenicity. The intramuscular regimen gave the lowest geometric mean antibody titres. Using the rapid fluorescent focus inhibition test, some sera had unexpectedly high antibody levels that were not attributable to previous vaccination. The results were confirmed using the fluorescent antibody virus neutralisation method. CONCLUSIONS: This 4-site PEP regimen proved as immunogenic as current regimens, and has the advantages of requiring fewer clinic visits, being more practicable, and having a wider margin of safety, especially in inexperienced hands, than the 2-site regimen. It is more convenient than the 8-site method, and can be used economically with vaccines formulated in 1.0 or 0.5 ml ampoules. The 4-site regimen now meets all requirements of immunogenicity for PEP and can be introduced without further studies. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN 30087513.

Warrell MJ, Warrell DA. 2004. Rabies and other lyssavirus diseases. Lancet, 363 (9413), pp. 959-969. | Show Abstract | Read more

The full scale of the global burden of human rabies is unknown, owing to inadequate surveillance of this fatal disease. However, the terror of hydrophobia, a cardinal symptom of rabies encephalitis, is suffered by tens of thousands of people each year. The recent discovery of enzootic European bat lyssavirus infection in the UK is indicative of our expanding awareness of the Lyssavirus genus. The main mammalian vector species vary geographically, so the health problems created by the lyssaviruses and their management differ throughout the world. The methods by which these neurotropic viruses hijack neurophysiological mechanisms while evading immune surveillance is beginning to be unravelled by, for example, studies of molecular motor transport systems. Meanwhile, enormous challenges remain in the control of animal rabies and the provision of accessible, appropriate human prophylaxis worldwide.

Warrell DA. 2001. "To search and Studdy out the secrett of Tropical Diseases by way of Experiment". Lancet, 358 (9297), pp. 1983-1988. | Read more

Eddleston M, Rajapakse S, Rajakanthan, Jayalath S, Sjöström L, Santharaj W, Thenabadu PN, Sheriff MH, Warrell DA. 2000. Anti-digoxin Fab fragments in cardiotoxicity induced by ingestion of yellow oleander: a randomised controlled trial. Lancet, 355 (9208), pp. 967-972. | Show Abstract | Read more

BACKGROUND: Severe cardiac glycoside cardiotoxicity after ingestion of yellow oleander seeds is an important problem in rural areas of Sri Lanka. Currently, patients must be transferred to the capital for temporary cardiac pacing. We did a randomised controlled trial to investigate whether anti-digoxin Fab could reverse serious oleander-induced arrhythmias. METHODS: After a preliminary dose-finding study, 66 patients who presented to hospital with a serious cardiac arrhythmia were randomised to receive either 1200 mg of anti-digoxin Fab or a saline placebo. A 12-lead electrocardiogram, 3 min rhythm strip, and blood sample for measurement of electrolytes and cardiac glycosides were taken before treatment and at 12 timepoints thereafter. FINDINGS: 34 patients received anti-digoxin Fab and 32 received placebo. The presenting arrhythmia had resolved completely after 2 h in 15 antibody-treated patients and two controls (p<0.001); 24 and five patients, respectively, were in sinus rhythm at 8 h (p<0.001). Kaplan-Meier analysis of time to first reversal showed a significant response to anti-digoxin Fab. The heart rate increased in cases, from 49.1 per min at baseline to 66.8 at 2 h, but not in controls (50.6 per min at baseline to 51.5; p<0.001). Mean serum potassium concentrations decreased from 4.9 mmol/L to 4.1 mmol/L at 2 h in cases; no such decrease occurred in controls. INTERPRETATION: Anti-digoxin Fab fragments are a safe and effective treatment for serious cardiac arrhythmias induced by yellow oleander. Their use in small rural hospitals in Sri Lanka should minimise costly transfer of patients and reduce the numbers of deaths; however, further study will be required to confirm this reduction.

Vidal V, Scragg IG, Cutler SJ, Rockett KA, Fekade D, Warrell DA, Wright DJ, Kwiatkowski D. 1998. Variable major lipoprotein is a principal TNF-inducing factor of louse-borne relapsing fever. Nat Med, 4 (12), pp. 1416-1420. | Show Abstract | Read more

Massive release of tumor necrosis factor is responsible for the potentially fatal larisch-Herxheimer reaction that follows antibiotic treatment of relapsing fever due to Borrelia recurrentis. We have undertaken the quantitative purification of the components of B. recurrentis that stimulate human monocytes to produce tumor necrosis factor. We show that the predominant factor inducing tumor necrosis factor is a variable lipoprotein homologous to the variable major protein of B. hermsii. We found antibodies to different forms of variable major protein in two patients with louse-borne relapsing fever. The three purified variable major proteins studied here differ in their ability to induce tumor necrosis factor production, which may partly explain the variable clinical severity of borrelial infection. These results may be of considerable relevance for the pathogenesis of Lyme disease and other forms of human borreliosis.

Newton CR, Warrell DA. 1998. Neurological manifestations of falciparum malaria. Ann Neurol, 43 (6), pp. 695-702. | Show Abstract | Read more

Plasmodium falciparum remains one of the most common causes of central nervous system infection worldwide. Recently, differences between the pathophysiology of cerebral malaria in African children and nonimmune adults have been discovered, new syndromes occurring after malaria infection described, and mechanisms for the pathogenesis proposed. In addition, new antimalarial agents have been examined worldwide and initial studies on supportive studies conducted. This paper reviews these new advances, putting them into the perspective of the more established knowledge.

Fekade D, Knox K, Hussein K, Melka A, Lalloo DG, Coxon RE, Warrell DA. 1996. Prevention of Jarisch-Herxheimer reactions by treatment with antibodies against tumor necrosis factor alpha. N Engl J Med, 335 (5), pp. 311-315. | Show Abstract | Read more

BACKGROUND: In patients with louse-borne relapsing fever (Borrelia recurrentis infection), antimicrobial treatment is often followed by sudden fever, rigors, and persistent hypotension (Jarisch-Herxheimer reactions) that are associated with increases in plasma concentrations of tumor necrosis factor alpha (TNF-alpha), interleukin-6, and interleukin-8. We attempted to determine whether sheep polyclonal Fab antibody fragments against TNF-alpha (anti-TNF-alpha Fab) could suppress the Jarisch-Herxheimer reaction. METHODS: We conducted a randomized, double-blind, placebo-controlled trial in 49 patients with proven louse-borne relapsing fever. Immediately before the intramuscular injection of penicillin, the patients received an intravenous infusion of either anti-TNF-alpha Fab or a control solution. RESULTS: Ten of the 20 patients given anti-TNF-alpha Fab had Jarisch-Herxheimer reactions with rigors, as compared with 26 of the 29 control patients (P = 0.006). The controls had significantly greater mean maximal increases in temperature (1.5 vs. 0.8 degrees C, P < 0.001), pulse rate (31 vs. 13 per minute, P < 0.001), and systolic blood pressure (25 vs. 15 mm Hg, P < 0.003), as well as higher mean peak plasma concentrations of interleukin-6 (50 vs. 17 micrograms per liter) and interleukin-8 (2000 vs 205 ng per liter) (P < 0.001 for both comparisons). Levels of TNF-alpha were undetectable after treatment with anti-TNF-alpha Fab. CONCLUSIONS: Pretreatment with sheep anti-TNF-alpha Fab suppresses Jarisch-Herxheimer reactions that occur after penicillin treatment for louse-borne relapsing fever, reduces the associated increases in plasma concentrations of interleukin-6 and interleukin-8, and may be useful in other forms of sepsis.

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