Philip J. Rosenthal

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NATURE REVIEWS | DRUG DISCOVERY VOLUME 3 | JUNE 2004 | 509 Malaria remains one of the most important diseases of the developing world, killing 1–3 million people and causing disease in 300–500 million people annually. Most severe malaria is caused by the blood-borne APICOMPLEXAN parasite Plasmodium falciparum and occurs in children in sub-Saharan Africa.(More)
Trophozoites of the malaria parasite Plasmodium falciparum hydrolyze erythrocyte hemoglobin in an acidic food vacuole to provide amino acids for parasite protein synthesis. Cysteine protease inhibitors block hemoglobin degradation, indicating that a cysteine protease plays a key role in this process. A principal trophozoite cysteine protease was purified by(More)
Erythrocytic malaria parasites utilize proteases for a number of cellular processes, including hydrolysis of hemoglobin, rupture of erythrocytes by mature schizonts, and subsequent invasion of erythrocytes by free merozoites. However, mechanisms used by malaria parasites to control protease activity have not been established. We report here the(More)
Metabolism of the antimalarial drug amodiaquine (AQ) into its primary metabolite, N-desethylamodiaquine, is mediated by CYP2C8. We studied the frequency of CYP2C8 variants in 275 malaria-infected patients in Burkina Faso, the metabolism of AQ by CYP2C8 variants, and the impact of other drugs on AQ metabolism. The allele frequencies of CYP2C8*2 and CYP2C8*3(More)
In the malaria parasite Plasmodium falciparum, erythrocytic trophozoites hydrolyse haemoglobin to provide amino acids for parasite protein synthesis. Cysteine protease inhibitors block parasite haemoglobin hydrolysis and development, indicating that cysteine proteases are required for these processes. Three papain-family cysteine protease sequences have(More)
CONTEXT Combination therapy is now widely advocated as first-line treatment for uncomplicated malaria in Africa. However, it is not clear which treatment regimens are optimal or how to best assess comparative efficacies in highly endemic areas. OBJECTIVE To compare the efficacy and safety of 3 leading combination therapies for the treatment of(More)
Plasmodium falciparum parasites that are resistant to artemisinins have been detected in Southeast Asia. Resistance is associated with several polymorphisms in the parasite's K13-propeller gene. The molecular epidemiology of these artemisinin resistance genotypes in African parasite populations is unknown. We developed an assay to quantify rare(More)
Protozoan parasites are among the most prevalent pathogens worldwide. Diseases like malaria, leishmaniasis, amebiasis, and trypanosomiasis affect hundreds of millions of people. Recent advances in our understanding of the biochemistry and molecular biology of these organisms has focused attention on specific parasite molecules that are key to the parasite(More)
Quinine remains an important anti-malarial drug almost 400 years after its effectiveness was first documented. However, its continued use is challenged by its poor tolerability, poor compliance with complex dosing regimens, and the availability of more efficacious anti-malarial drugs. This article reviews the historical role of quinine, considers its(More)
OBJECTIVES To compare the efficacy and safety of artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP) for treating uncomplicated falciparum malaria in Uganda. DESIGN Randomized single-blinded clinical trial. SETTING Apac, Uganda, an area of very high malaria transmission intensity. PARTICIPANTS Children aged 6 mo to 10 y with(More)