In vitro activity of artemether against African isolates (Senegal) of Plasmodium falciparum in comparison with standard antimalarial drugs.

Abstract

Abstract. 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 (IC 50 ) values for artemether were in a narrow range from 0.8 to 15.2 nM (mean IC 50 ϭ 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 IC 50 ϭ 346 nM, 95% CI ϭ 2.08-4.84 nM versus mean IC 50 ϭ 2.80 nM, 95% CI ϭ 2.00-3.60 nM). There was a significant positive correlation between responses to artemether and mefloquine (r 2 ϭ 0.36, P Ͻ 0.001), artemether and quinine (r 2 ϭ 0.085, P Ͻ 0.05), artemether and halofantrine (r 2 ϭ 0.075, P Ͻ 0.05), quinine and mefloquine (r 2 ϭ 0.205, P Ͻ 0.01), quinine and halofantrine (r 2 ϭ 0.124, P Ͻ 0.05), and mefloquine and halofantrine (r 2 ϭ 0.801, P Ͻ 0.001). A positive correlation between these drugs suggests in vitro cross-resistance or at least in vitro cross-susceptibility.In the absence of effective and practical preventive measures, the only current options for reducing the morbidity and mortality of malaria especially in Africa are chemoprophylaxis and chemotherapy. For this reason, the increasing prevalence of strains of Plasmodium falciparum resistant to chloroquine and other antimalarial drugs poses a serious problem for control of malaria. 1 There is an urgent need to find and develop alternative drugs against chloroquine-resistant P. falciparum.One group of alternative antimalarial drugs comprises artemisinin (qinghaosu) and its derivatives. Artemisinin is a traditional Chinese medicinal herb derived from Artemisia annua. It has a sesquiterpene lactone with a peroxide bridge and antimalarial activity has been attributed to the peroxide moiety 2 by a mechanism involving production of free radicals that damage the parasite membrane. 3 Artemether (an oilsoluble artemisinin derivative) has shown effectiveness against chloroquine-resistant strains of P. falciparum in China and Thailand. 4,5 However, little information is available concerning the in vitro activity of artemisinin and its derivatives against isolates of P. falciparum from Africa other than reference strains. 6,7 The two-fold aim of this in vitro study was to evaluate the activity of artemether against fresh isolates of P. falciparum from Senegal, and to analyze cross-susceptibility between artemether, chloroquine, quinine, mefloquine, and halofantrine. MATERIALS AND METHODSIsolates of P. falciparum. All programs were reviewed and approved by the Conseil de Perfectionnement of the Institut de Dakar, which is presided over by the Senegalese Health Secretary. Informed oral consent was obtained from the patients and/or their parents before collection of blood samples. Only oral consent was obtained because only 5% of the people in Dielmo, Ndiop, and Toubakouta can read and write. Between October 1995 and January 1996, 56 fresh P. falciparum isolates were prepared from samples obtaine...

Molecular epidemiology of malaria in Cameroon. X. Evaluation of PFMDR1 mutations as genetic markers for resistance to amino alcohols and artemisinin derivatives.

“…In vitro cross-resistance between these drugs has also been confirmed in other independent studies in Senegal and Thailand. 26,31 In the present study, the resistant phenotype was not correlated with the pfmdr1 polymorphisms. In our earlier studies based on the determination of codon 86 of the pfmdr1 gene, we have already observed the predominance of Tyr-86 allele (110 of 129 isolates, 85%) in the clinical isolates obtained in Yaoundé in 1994-1996.…”

Analysis of Pfcrt, Pfmdr1, Dhfr, and DHPS Mutations and Drug Sensitivities in Plasmodium Falciparum Isolates From Patients in Vietnam Before and After Treatment With Artemisinin

“…39,40 This suggests that there may be genetic alterations that can confer differential sensitivity to artemisinin. Transfection of mutations into the pfmdr1 gene has altered the level of sensitivity to artemisinin, suggesting that the gene is a factor in determining the level of artemisinin sensitivity; 8 this agrees with other studies showing that mutations in pfmdr1 confer increased sensitivity to artemisinin in the progeny of a genetic cross of P. falciparum.…”

“…41 The differences in artemisinin sensitivity that might be expected between the primary isolates and those isolated after artemisinin treatment would be quite small. 39,40 Consequently, it may be difficult to quantitate the differences accurately enough to observe a slight decrease in artemisinin sensitivity. It will be interesting to follow artemisinin sensitivity in Vietnam over time to determine whether decreased sensitivity, and perhaps resistance, to this drug is developing.…”

In vitro susceptibility of Plasmodium falciparum isolates from Myanmar to antimalarial drugs.

“…9,20 Earlier, this was thought to be the result of some overlapping in the mechanisms of action of the 2 drug groups rather than true cross-reactivity. 21,22 Recently, an experimental study of pfmdr1 polymorphisms demonstrated that level of artemisinin sensitivity is modulated by mutations in Pgh1 (P-glycoprotein homologue 1 protein of P. falciparum, which is encoded by pfmdr1 gene) and this pfmdr1 effect parallels that observed with mefloquine in a strain-specific manner.…”