In vitro activity of dihydroartemisinin against clinical isolates of Plasmodium falciparum in Yaounde, Cameroon.

Abstract

Abstract. The in vitro activities of dihydroartemisinin (the biologically active metabolite of artemisinin derivatives), chloroquine, monodesethylamodiaquine (the biologically active metabolite of amodiaquine), quinine, mefloquine, halofantrine, and pyrimethamine were assessed in 65 African isolates of Plasmodium falciparum from Yaoundé, Cameroon using an isotopic microtest. The 50% inhibitory concentration (IC 50 ) values for dihydroartemisinin were within a narrow range from 0.25 to 4.56 nM, with a geometric mean of 1.11 nM (95% confidence interval ϭ 0.96-1.28 nM). Dihydroartemisinin was equally active (P Ͼ 0.05) against the chloroquine-sensitive isolates (geometric mean IC 50 ϭ 1.25 nM, 95% confidence interval ϭ 0.99-1.57 nM) and the chloroquine-resistant isolates (geometric mean IC 50 ϭ 0.979 nM, 95% confidence interval ϭ 0.816-1.18 nM). A significant positive correlation was observed between the responses to dihydroartemisinin and mefloquine (r ϭ 0.662) or halofantrine (r ϭ 0.284), suggesting in vitro crossresistance. There was no correlation between the responses to dihydroartemisinin and other antimalarial drugs.Artemisinin (qinghaosu) has been used for centuries in traditional Chinese medicine for antimalarial treatment. 1 In 1972, Chinese scientists isolated the active principle from the plant Artemisia annua. 2 Artemisinin is a sesquiterpene lactone characterized by the presence of an endoperoxide that is associated with a potent antimalarial activity. Because artemisinin is chemically unstable and poorly soluble in water or oil, the carbonyl group at C-10 of the parent compound was reduced to obtain dihydroartemisinin. Several derivatives have been developed by adding an ether, ester, or other substituents to the hydroxyl group of dihydroartemisinin. These semi-synthetic derivatives include the water-soluble derivatives, sodium artesunate and artelinic acid, and the oilsoluble derivatives, artemether and arteether. With the exception of arteether and artelinic acid, these compounds are used to treat malarial infections in endemic countries, mainly in Southeast Asia and, to a lesser extent, in Africa and South America.Artemisinin derivatives are available in different formulations for oral, parenteral, and rectal administration. Clinical studies have shown that artemisinin derivatives are highly potent, rapidly acting, and well-tolerated blood schizontocides, resulting in shorter parasite clearance times than other antimalarial drugs. 3,4 Artemisinin derivatives are highly effective against Plasmodium falciparum isolates that are resistant to other drugs. These derivatives are indicated for the emergency treatment of severe and complicated falciparum malaria by parenteral administration and for the oral treatment of uncomplicated multidrug-resistant malaria. 5 So far, resistance to artemisinin derivatives has not been reported in clinical studies. However, because of the high recrudescence rate when used as monotherapy, many current therapeutic regimens used in Southeast Asia include a combination of o...

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

“…26 Our previous in vitro studies on African isolates have suggested that cross-resistance may occur between chloroquine and quinine and between amino alcohols and artemisinin derivatives. [27][28][29][30] A similar trend of cross-resistance patterns was observed in the present study. In vitro cross-resistance between these drugs has also been confirmed in other independent studies in Senegal and Thailand.…”

“…34 However, the extent to which multiple parasite populations in a given isolate influence in vitro response to amino alcohols and artemisinin derivatives is probably limited in Yaoundé, where regular in vitro monitoring of drug response has shown their high activity. 23,29,30 In conclusion, it does not seem to be clear at present whether there is a distinct set of pfmdr1 mutations that are strongly associated with resistance to amino alcohols and artemisinin derivatives in field isolates in Africa. The main reason may be related to the high clinical efficacy of these drugs in Africa, in contrast to Southeast Asia where clinical failure is frequently observed when monotherapy with quinine, mefloquine, or halofantrine is administered.…”

Molecular epidemiology of malaria in Yaounde, Cameroon V. analysis of the omega repetitive region of the plasmodium falciparum CG2 gene and chloroquine resistance.

“…25,[29][30][31] We have also demonstrated that a similar proportion of Cameroonian patients, including adults and children Ն 5 years old, failed to clear asexual parasitemia and symptoms associated with malaria infection within 14 days after the standard chloroquine therapy. 18,19,27 Thus, our in vitro and in vivo data are concordant and support the observation that a relatively high proportion of P. falciparum isolates in Yaounde are chloroquine-resistant.…”

Methods for monitoring artemisinin-based combination therapies efficacy

“…Classical isotopic (48-h) method was used for in vitro DHA monitoring (Desjardins et al, 1979). DHA was the most potent drug (geometric mean IC50 = 1.11 nM, 95% confidence interval = 0.96-1.28 nM, range = 0.25-4.56 nM, n = 65) among the panel of drug compounds tested (Ringwald et al, 1999).…”