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 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 50 346 nM, 95% CI 2.08-4.84 nM versus mean IC 50 2.80 nM, 95% CI 2.00-3.60 nM). There was a significant positive correlation between responses to artemether and mefloquine (r 2 0.36, P 0.001), artemether and quinine (r 2 0.085, P 0.05), artemether and halofantrine (r 2 0.075, P 0.05), quinine and mefloquine (r 2 0.205, P 0.01), quinine and halofantrine (r 2 0.124, P 0.05), and mefloquine and halofantrine (r 2 0.801, P 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 chemopro-phylaxis 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 ar-temisinin (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 oil-soluble 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 twofold aim of this in vitro study was to evaluate the activity of artemether against fresh isolates of P. falcip-arum from Senegal, and to analyze cross-susceptibility between artemether, chloroquine, quinine, mefloquine, and hal-ofantrine. MATERIALS AND METHODS Isolates 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 obtained after oral consent in Diel-mo, Ndi...

Abstract. The in vitro activity of pyronaridine was evaluated against 62 isolates of Plasmodium falciparum from Libreville, Gabon using an isotopic, drug susceptibility microtest and was compared with amodiaquine, chloroquine, quinine, and halofantrine activities. The mean 50% inhibitory concentration (IC 50 ) values of the 62 isolates from Gabon to pyronaridine was 3.0 nM (95% confidence interval [CI] ϭ 2.1-3.9). Pyronaridine was less potent against chloroquine-resistant isolates than chloroquine-susceptible isolates but more potent than chloroquine against chloroquine-resistant parasites. The cut-off value for in vitro reduced susceptibility to pyronaridine was an IC 50 Ͼ 15 nM. Two isolates (3%) showed an IC 50 Ͼ 15 nM. A significant positive correlation was found between the activities of pyronaridine and chloroquine (r 2 ϭ 0.26, P Ͻ 0.001), pyronaridine and quinine (r 2 ϭ 0.36, P Ͻ 0.001), pyronaridine and amodiaquine (r 2 ϭ 0.55, P Ͻ 0.001), and pyronaridine and halofantrine (r 2 ϭ 0.50, P Ͻ 0.001). This correlation suggests in vitro cross-resistance or at least in vitro cross-susceptibility, which is not necessarily predictive of crossresistance in vivo. The present in vitro findings require comparison with those of clinical studies.The only current options for reducing the morbidity and mortality of malaria, especially in Africa, are chemoprophylaxis and chemotherapy. Therefore, the increasing prevalence of strains of Plasmodium falciparum resistant to chloroquine and other antimalarial drugs poses a serious problem for control of malaria.

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...

The in vitro activity of artemether against 63 African isolates of Plasmodium falciparum from Libreville, Gabon was evaluated using an isotopic drug susceptibility semi-microtest. The 50% inhibitory concentration (IC50) values for artemether were in a narrow range from 0.8 to 34.8 nM (mean IC50 5.0 nM) and the 95% confidence interval (CI95%) was 3.6-6.3 nM. In vitro decreased susceptibility or resistance were observed with artemether (14%), to chloroquine (90%), to quinine (32%). Isolate susceptibility to amodiaquine and halofantrine was high i.e. 100% and 98%, respectively. There was a significant positive correlation between responses to artemether and amodiaquine (r2 = 0.45, P < 0.001), artemether and chloroquine (r2 = 0.36, P < 0.001), artemether and quinine (r2 = 0.31, P < 0.001), and artemether and halofantrine (r2 = 0.19, P < 0.01). Positive correlation between these drugs suggests in vitro cross-resistance or at least common features in drug uptake and/or mode of action or resistance.

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Fluoroalkyl ethers (4) of dihydroartemisinin (2) have been prepared by reaction of fluoroalkyl alcohols with dihydroartemisinin by different methods (BF3,Et2O or TMSCl catalysis or Mitsunobu reaction). Ethers 4a-d derived from primary fluoroalkyl alcohols were obtained in moderate to good yields by these methods. Ethers 4e-j have been prepared from fluoroalkyl secondary and tertiary alcohols and phenol using the Mitsunobu reaction. Although in vitro antimalarial activities of ethers toward Plasmodium falciparum W-2 asiatic strain are moderate, in vivo activities against Plasmodium berghei (NT 173) are excellent.

SUMMARYTwenty-one monoclonal antibodies, obtained after immunization of mice with erythrocytic stages ofPlasmodium falciparum, produced a double dot image in IFA. Immunoelectronmicroscopy indicated that the mAbs reacted with the rhoptries. Rhoptries are pear-shaped apical organelles, believed to be involved in invasion of the host cell by the parasite. The mAbs all immunoprecipitated the high molecular weight antigen complex. Some mAbs recognized on immunoblots only 1 protein of this complex, whereas others reacted with RhopH1 and RhopH3, or RhopH2 and RhopH3 or with the 3 proteins. An additional antigen of 52 kDa was also recognized by some of the mAbs. The epitopes defined by the mAbs were present in most of the 40P. falciparumstrains or isolates studied by IFA. Interestingly, the mAbs also reacted with high titres onP. vivaxandP. ovale, but produced images that did not indicate an apical location. The mAbs failed to react on the non-human malaria parasites studied,P. cynomolgiandP. inui. OnP. bergheiorP. chabaudiparasites, only 5 mAbs gave a positive reaction, labelling a large network outside the parasite. Finally, the mAbs did not react withP. falciparumsporozoites, indicating that the rhoptries of merozoites and sporozoites, the two invasive stages of the malaria life-cycle are equipped with distinct sets of proteins.

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