Antimalarials

Publication Title: 
The Journal of Antibiotics

In the course of our screening program for artemisinin-like antimalarial compounds from microorganisms, seven fungal metabolites such as radicicol and heptelidic acid were identified as active compounds. Some of them exhibited antimalarial activity in vitro against the human malaria parasite Plasmodium falciparum to the extent of approximately 1/10 as potent as artemisinin. Radicicol was moderately active in vivo against Plasmodium berghei in mice.

Author(s): 
Tanaka, Y.
Shiomi, K.
Kamei, K.
Sugoh-Hagino, M.
Enomoto, Y.
Fang, F.
Yamaguchi, Y.
Masuma, R.
Zhang, C. G.
Zhang, X. W.
Omura, S.
Publication Title: 
The American Journal of Tropical Medicine and Hygiene

The effect of pentoxifylline (PTX) was tested for its capacity to modulate cytokine responses during therapy of severe Plasmodium falciparum malaria in a placebo-controlled, randomized study in 45 adult patients in Bangkok, Thailand. The patients received standard antimalarial treatment with artesunate (120 mg intravenously given immediately, then 60 mg every 12 hr for a total dose of 600 mg). The patients received either low-dose PTX (20 mg/kg/day, n = 15), high-dose PTX (40 mg/kg/day, n = 15), or placebo (n = 15) as continuous infusion for the first three days of antimalarial treatment.

Author(s): 
Wenisch, C.
Looareesuwan, S.
Wilairatana, P.
Parschalk, B.
Vannapann, S.
Wanaratana, V.
Wernsdorfer, W.
Graninger, W.
Publication Title: 
The American Journal of Tropical Medicine and Hygiene

Pentoxifylline, an inhibitor of tumor necrosis factor, has been evaluated as an antimalarial agent in combination with artesunate in 45 patients with severe falciparum malaria. Patients were admitted to the intensive care unit at the Hospital for Tropical Diseases in Bangkok, Thailand, and randomly assigned to treatment for 72 hr with a combination of intravenously administered artesunate and 1) placebo, 2) low-dose pentoxifylline (0.83 mg/kg/hr), or 3) high-dose pentoxifylline (1.67 mg/kg/hr).

Author(s): 
Looareesuwan, S.
Wilairatana, P.
Vannaphan, S.
Wanaratana, V.
Wenisch, C.
Aikawa, M.
Brittenham, G.
Graninger, W.
Wernsdorfer, W. H.
Publication Title: 
The American Journal of Tropical Medicine and Hygiene

The in vitro activity of artemether against 56 African isolates of Plasmodium falciparum from Senegal was evaluated using an isotope-based drug susceptibility semi-microtest. The 50% inhibitory concentration (IC50) values for artemether were in a narrow range from 0.8 to 15.2 nM (mean IC50 = 3.43 nM) and the 95% confidence interval (CI) was 2.50-4.36 nM. Artemether was equally effective on chloroquine-sensitive and chloroquine-resistant isolates (mean IC50 = 346 nM, 95% CI = 2.08-4.84 nM versus mean IC50 = 2.80 nM, 95% CI = 2.00-3.60 nM).

Author(s): 
Pradines, B.
Rogier, C.
Fusai, T.
Tall, A.
Trape, J. F.
Doury, J. C.
Publication Title: 
The American Journal of Tropical Medicine and Hygiene

A thermostable suppository of artesunate (artesunic acid) has been developed. In Gabon, 12 children with Plasmodium falciparum malaria received two administrations of this suppository in a 4-hr interval. Parasitemia and fever were then measured and the plasma levels of artesunate and its active metabolite, dihydroartemisinin, were determined by means of a reversed phase high-pressure liquid chromatography method using reductive electrochemical detection.

Author(s): 
Halpaap, B.
Ndjave, M.
Paris, M.
Benakis, A.
Kremsner, P. G.
Publication Title: 
British Journal of Clinical Pharmacology

AIMS: To investigate the pharmacokinetics of the antimalarial artemisinin in the field setting using sparsely collected data. METHODS: Artemisinin concentrations were determined by h.p.l.c. in a total of 107 capillary plasma samples collected on the first day and in 33 samples on the last day of a 5-day oral artemisinin regimen of 10 mg kg(-1) day(-1) in 23 paediatric (aged 2-12 years) and 31 adult (aged 16-45 years) Vietnamese patients with uncomplicated falciparum malaria.

Author(s): 
Sidhu, J. S.
Ashton, M.
Huong, N. V.
Hai, T. N.
Karlsson, M. O.
Sy, N. D.
Jonsson, E. N.
Cong, L. D.
Publication Title: 
Drug Metabolism and Disposition: The Biological Fate of Chemicals

beta-Arteether (AE) is an endoperoxide sesquiterpene lactone derivative currently being developed for the treatment of severe, complicated malaria caused by multidrug-resistant Plasmodium falciparum. Studies were undertaken to determine which form(s) of human cytochrome P-450 catalyze the conversion of beta-arteether to its deethylated metabolite, dihydroqinghaosu (DQHS), itself a potent antimalarial compound. In human liver microsomes, AE was metabolized to DQHS with a Km of 53.7 +/- 29.5 microM and a Vmax of 1.64 +/- 1. 78 nmol DQHS/min/mg protein.

Author(s): 
Grace, J. M.
Aguilar, A. J.
Trotman, K. M.
Peggins, J. O.
Brewer, T. G.
Publication Title: 
The American Journal of Tropical Medicine and Hygiene

The sensitivity of Plasmodium falciparum to chloroquine, mefloquine, quinine, quinidine, halofantrine, artemisinin, and sulfadoxine/pyrimethamine was investigated in Lambarene, Gabon in 1994. The development of in vitro susceptibility has been traced from 1983 or 1992 to 1994 for chloroquine, mefloquine, halofantrine, and quinine. Standard in vitro microtests according to World Health Organization methodology were performed.

Author(s): 
Philipps, J.
Radloff, P. D.
Wernsdorfer, W.
Kremsner, P. G.
Publication Title: 
The American Journal of Tropical Medicine and Hygiene

We report here the results of a randomized double blind trial comparing coartemether (CGP56697), a combination of artemether and benflumetol, with pyrimethamine/sulfadoxine (P/S). Two hundred eighty-seven children 1-5 years of age with uncomplicated falciparum malaria were enrolled at two centers in The Gambia between July 1996 and December 1996. Following treatment, children were visited at home every 24 hr until a blood film free of asexual parasites was obtained. Genotyping of parasites was used to distinguish recrudescence from new infections.

Author(s): 
von Seidlein, L.
Bojang, K.
Jones, P.
Jaffar, S.
Pinder, M.
Obaro, S.
Doherty, T.
Haywood, M.
Snounou, G.
Gemperli, B.
Gathmann, I.
Royce, C.
McAdam, K.
Greenwood, B.
Publication Title: 
The Journal of Biological Chemistry

Artemisinin and its derivatives are important new antimalarial drugs. When Plasmodium falciparum-infected erythrocytes are incubated with [10-3H]dihydroartemisinin, several malaria-specific proteins become labeled. One of these proteins is the P. falciparum translationally controlled tumor protein (TCTP) homolog. In vitro, dihydroartemisinin reacts covalently with recombinant TCTP in the presence of hemin. The association between drug and protein increases with increasing drug concentration, plateauing at approximately 1 drug/TCTP molecule.

Author(s): 
Bhisutthibhan, J.
Pan, X. Q.
Hossler, P. A.
Walker, D. J.
Yowell, C. A.
Carlton, J.
Dame, J. B.
Meshnick, S. R.

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