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|
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.
|Prof Nicholas PJ Day FMedSci FRCP||Tropical Medicine||Oxford University||UK|
|Prof François H Nosten||Tropical Medicine||Oxford University||UK|
|Prof Adrianus Dondorp||Tropical Medicine||Oxford University||UK|
|Prof Jeremy Farrar||Tropical Medicine||Oxford University||UK|
|Dr Paul Newton||Tropical Medicine||Oxford University||UK|
|Prof Dominic Kwiatkowski||Wellcome Trust Centre for Human Genetics||Oxford University||UK|
|Dr Olivo Miotto||Tropical Medicine||Oxford University||UK|
|Dr Philippe Guerin||Tropical Medicine||Oxford University||UK|
|Prof Gareth Turner||Tropical Medicine||Oxford University||UK|
|Dr Paul Turner||Tropical Medicine||Oxford University||UK|
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
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
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
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
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
Lancet, 353 (9168), pp. 1965-1967. | Read more1999. Averting a malaria disaster.
Antimicrob Agents Chemother, 41 (7), pp. 1413-1422.1997. Assessment of the pharmacodynamic properties of antimalarial drugs in vivo.
Lancet, 2 (8665), pp. 697-701. Read abstract1989. Halving of mortality of severe melioidosis by ceftazidime.
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
Am J Trop Med Hyg, 32 (1), pp. 1-5. Read abstract1983. Quinine loading dose in cerebral malaria.
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
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
Improving the treatment of malaria
Infections still account for over half the preventable deaths in developing countries. The majority of these deaths are in young children. Anti-infective drug treatment remains the mainstay of medical management. Inappropriate use of these valuable medicines in both the public and private sector has accelerated the emergence and spread of resistance. Dosing strategies have been developed in richer countries and then extrapolated to tropical countries, usually without further pharmacokinetic ...
Molecular-dynamic correlates of oxidant haemolysis in glucose-6-phosphate dehydrogenase (G6PD) deficiency
Glucose -6-phosphate dehydrogenase (G6PD) deficiency, the most common human enzyme deficiency (>180 different genotypes), affects approximately 400 million people worldwide (1). Deficiency reduces production of NADPH, and lowers intraerythrocytic stores of reduced glutathione –a major defence against oxidant damage. Oxidant drugs and foods cause haemolysis in G6PD deficiency, which can be severe. Enzyme deficiency protects against severe malaria and so the abnormality is prevalent mainly in ...
Understanding the biology of Plasmodium vivax relapse
Vivax malaria affects hundreds of millions of people each year in tropical countries. Relapse is an important cause of morbidity in vivax malaria and explains why P.vivax is so difficult to eliminate. Relapse arises from the activation of dormant forms of the parasite in the liver (hypnozoites). The biology of relapse is fascinating but poorly understood, and as a consequence, treatment of vivax malaria is unsatisfactory
Development of novel approaches to model large series of heterogenous pharmacological data
Clinical Pharmacology is essential to ensure optimal dosing with currently available and newly introduced antimalarial drugs. This requires two key questions to be answered: Firstly, what drug exposure (concentrations over time) is necessary to ensure the required therapeutic effect? Secondly, do dosing recommendations need to be modified in important target populations including infants, pregnant women, and those with prevalent co-morbid diseases (especially HIV/AIDS, malnutrition) to ensure ...