Prof Nicholas J White FRS

Research Area: Global Health
Technology Exchange: Mass spectrometry
Scientific Themes: Tropical Medicine & Global Health and Immunology & Infectious Disease
Keywords: malaria, drug discovery and therapeutics
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Proposed mechanism of periodic Plasmodium vivax relapse activation

Proposed mechanism of periodic Plasmodium vivax relapse activation

Professor White’s diverse interests include the epidemiology, pathophysiology and management of uncomplicated and severe malaria, meliodosis, enteric fever, tetanus, dengue haemorrhagic fever, Japanese encephalitis and tuberculosis. His particular interests at present include the pathophysiology and treatment of severe malaria,  the prevention of antimalarial drug resistance using artemisinin-based combinations. and the biology of relapse in vivax malaria.

Name Department Institution Country
Prof Nicholas PJ Day FMedSci FRCP Mahidol Oxford Tropical Medicine Research Unit Thailand
Prof François H Nosten Tropical Medicine University of Oxford United Kingdom
Prof Adrianus Dondorp Tropical Medicine University of Oxford United Kingdom
Prof Jeremy Farrar Tropical Medicine University of Oxford United Kingdom
Dr Paul Newton Tropical Medicine University of Oxford United Kingdom
Prof Dominic Kwiatkowski Wellcome Trust Centre for Human Genetics University of Oxford United Kingdom
Dr Olivo Miotto Tropical Medicine University of Oxford United Kingdom
Prof Philippe J Guerin Tropical Medicine University of Oxford United Kingdom
Dr Gareth Turner Tropical Medicine University of Oxford United Kingdom
Dr Paul Turner Tropical Medicine University of Oxford United Kingdom

Dondorp AM, Fanello CI, Hendriksen IC, Gomes E, Seni A, Chhaganlal KD, Bojang K, Olaosebikan R et al. 2010. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet, 376 (9753), pp. 1647-1657. Read abstract | Read more

Severe malaria is a major cause of childhood death and often the main reason for paediatric hospital admission in sub-Saharan Africa. Quinine is still the established treatment of choice, although evidence from Asia suggests that artesunate is associated with a lower mortality. We compared parenteral treatment with either artesunate or quinine in African children with severe malaria. Hide abstract

Dondorp AM, Nosten F, Yi P, Das D, Phyo AP, Tarning J, Lwin KM, Ariey F et al. 2009. Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med, 361 (5), pp. 455-467. Read abstract | Read more

Artemisinin-based combination therapies are the recommended first-line treatments of falciparum malaria in all countries with endemic disease. There are recent concerns that the efficacy of such therapies has declined on the Thai-Cambodian border, historically a site of emerging antimalarial-drug resistance. Hide abstract

Dondorp A, Nosten F, Stepniewska K, Day N, White N, South East Asian Quinine Artesunate Malaria Trial (SEAQUAMAT) group. 2005. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet, 366 (9487), pp. 717-725. Read abstract | Read more

In the treatment of severe malaria, intravenous artesunate is more rapidly acting than intravenous quinine in terms of parasite clearance, is safer, and is simpler to administer, but whether it can reduce mortality is uncertain. Hide abstract

Stepniewska K, Taylor WR, Mayxay M, Price R, Smithuis F, Guthmann JP, Barnes K, Myint HY et al. 2004. In vivo assessment of drug efficacy against Plasmodium falciparum malaria: duration of follow-up. Antimicrob Agents Chemother, 48 (11), pp. 4271-4280. Read abstract | Read more

To determine the optimum duration of follow-up for the assessment of drug efficacy against Plasmodium falciparum malaria, 96 trial arms from randomized controlled trials (RCTs) with follow-up of 28 days or longer that were conducted between 1990 and 2003 were analyzed. These trials enrolled 13,772 patients, and participating patients comprised 23% of all patients enrolled in RCTs over the past 40 years; 61 (64%) trial arms were conducted in areas where the rate of malaria transmission was low, and 58 (50%) trial arms were supported by parasite genotyping to distinguish true recrudescences from reinfections. The median overall failure rate reported was 10% (range, 0 to 47%). The widely used day 14 assessment had a sensitivity of between 0 and 37% in identifying treatment failures and had no predictive value. Assessment at day 28 had a sensitivity of 66% overall (28 to 100% in individual trials) but could be used to predict the true failure rate if either parasite genotyping was performed (r(2) = 0.94) or if the entomological inoculation rate was known. In the assessment of drug efficacy against falciparum malaria, 28 days should be the minimum period of follow-up. Hide abstract

White NJ, Pongtavornpinyo W. 2003. The de novo selection of drug-resistant malaria parasites. Proc Biol Sci, 270 (1514), pp. 545-554. Read abstract | Read more

Antimalarial drug resistance emerges de novo predominantly in areas of low malaria transmission. Because of the logarithmic distribution of parasite numbers in human malaria infections, inadequately treated high biomass infections are a major source of de novo antimalarial resistance, whereas use of antimalarial prophylaxis provides a low resistance selection risk. Slowly eliminated antimalarials encourage resistance largely by providing a selective filter for resistant parasites acquired from others, and not by selecting resistance de novo. The de novo emergence of resistance can be prevented by use of antimalarial combinations. Artemisinin derivative combinations are particularly effective. Ensuring adequate treatment of the relatively few heavily infected patients would slow the emergence of resistance. Hide abstract

White NJ, Nosten F, Looareesuwan S, Watkins WM, Marsh K, Snow RW, Kokwaro G, Ouma J et al. 1999. Averting a malaria disaster. Lancet, 353 (9168), pp. 1965-1967. | Read more

White NJ. 1997. Assessment of the pharmacodynamic properties of antimalarial drugs in vivo. Antimicrob Agents Chemother, 41 (7), pp. 1413-1422.

White NJ, Dance DA, Chaowagul W, Wattanagoon Y, Wuthiekanun V, Pitakwatchara N. 1989. Halving of mortality of severe melioidosis by ceftazidime. Lancet, 2 (8665), pp. 697-701. Read abstract | Read more

An open randomised trial was conducted to compare ceftazidime (120 mg/kg/day) with "conventional therapy" (chloramphenicol 100 mg/kg/day, doxycycline 4 mg/kg/day, trimethoprim 10 mg/kg/day, and sulphamethoxazole 50 mg/kg/day) in the treatment of severe melioidosis. A paired restricted sequential trial designed to detect a reduction in mortality from 80 to 40% in culture-positive patients surviving greater than 48 hours was stopped after 22 months. Of the 161 patients entered into the study, 65 had bacteriologically confirmed melioidosis and 54 of these were septicaemic. Ceftazidime treatment was associated with a 50% (95% CI 19-81%) lower overall mortality than conventional treatment (74% vs 37%; p = 0.009) and should now become the treatment of choice for severe melioidosis. Hide abstract

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. Read 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. Hide abstract

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. Read 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. Hide abstract

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