Randomised trial of pyronaridine versus chloroquine for acute uncomplicated falciparum malaria in Africa

Ringwald, Pascal; Bickii, Jean; Basco, L. K.

doi:10.1016/s0140-6736(96)91558-5

Cited by 125 publications

(97 citation statements)

References 10 publications

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“…In our previous studies, we have shown that the proportion of chloroquine-resistant P. falciparum infections is about 50%, in vitro and in vivo. 21,25,26 In contrast, amodiaquine is highly effective, in vitro and in vivo, against the clinical isolates obtained in Yaoundé. 27 Approximately 40% of the clinical isolates obtained in Yaoundé are resistant in vitro to pyrimethamine and have the mutant asparagine-108 allele in the dihydrofolate reductase gene, a genetic marker for pyrimethamine resistance.…”

Section: Discussionmentioning

confidence: 99%

“…31,32 Clinical trials in Yaoundé have also shown that pyronaridine, mefloquine, halofantrine, and artemether are highly effective (Ringwald P, unpublished data). 25,26,33 In view of our data on the epidemiology of drug-resistant P. falciparum, artemisinin derivatives are currently not essential for malaria control in Yaoundé. We have nevertheless assessed the in vitro activity of dihydroartemisinin since artemether and artesunate are commercially available in Cameroon.…”

Section: Discussionmentioning

confidence: 99%

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

Ringwald¹,

Bickii²,

Basco³

1999

The American Journal of Tropical Medicine and Hygiene

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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...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Ringwald¹,

Bickii²,

Basco³

1999

The American Journal of Tropical Medicine and Hygiene

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“…17,18 A total of 273 venous blood samples from malaria-infected Cameroonian patients residing in Yaounde were analyzed. The results of 136 samples collected in 1994-1995 were presented in our earlier work.…”

Section: Patientsmentioning

confidence: 99%

Molecular epidemiology of malaria in Yaounde, Cameroon IV. Evolution of pyrimethamine resistance between 1994 and 1998.

Basco¹,

Ringwald²

1999

The American Journal of Tropical Medicine and Hygiene

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Abstract. Pyrimethamine, in combination with sulfadoxine, is currently one of the major alternative drugs used for the treatment of chloroquine-resistant Plasmodium falciparum malaria infections in Africa. The mechanism of pyrimethamine resistance has been strongly associated with a single, key point mutation in the dihydrofolate reductase-thymidylate synthase gene, resulting in the substitution of the wild-type allele Ser-108 by either Asn-108 or Thr-108. The pyrimethamine-resistant phenotype and/or genotype were determined in 273 Cameroonian clinical isolates obtained in Yaounde by in vitro assays and polymerase chain reaction-restriction fragment length polymorphism over a 5-year period. The in vitro assays showed that 42% (18 of 43) and 63% (69 of 110) of the isolates obtained in 1994-1995 and 1997-1998, respectively, were resistant to pyrimethamine (50% inhibitory concentration [IC 50 ] Ͼ 100 nM). The polymerase chain reaction showed that 43% (55 of 127) and 59% (50 of 85) of the isolates in 1994-1995 and 1997-1998, respectively, had the mutant Asn-108 allele. The pyrimethamine-resistant genotype (Asn-108) corresponded with the pyrimethamine-resistant phenotype (IC 50 Ն 100 nM) in a large majority (Ͼ 95%) of the isolates. The results of our study suggest an increasing prevalence of pyrimethamine resistance in Yaounde. Our study further suggests that pyrimethamine resistance can be monitored by a technique that can be adopted by malaria research centers in Africa.Pyrimethamine, in combination with sulfadoxine, is one of the major antimalarial drugs currently used in Africa.

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“…12 Pyronaridine was also shown to be more effective than chloroquine in Cameroon. 13 In vivo activities of Mannich base antimalarials, including pyronaridine, have been explored against rodent malaria parasites 14 and against simian malaria. 15 However, clinical and field evaluation of pyronaridine is not yet complete.…”

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In vitro susceptibility of African isolates of Plasmodium falciparum from Gabon to pyronaridine.

Pradines

Mamfoumbi²,

Parzy³

et al. 1999

The American Journal of Tropical Medicine and Hygiene

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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.

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Randomised trial of pyronaridine versus chloroquine for acute uncomplicated falciparum malaria in Africa

Cited by 125 publications

References 10 publications

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

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

Molecular epidemiology of malaria in Yaounde, Cameroon IV. Evolution of pyrimethamine resistance between 1994 and 1998.

In vitro susceptibility of African isolates of Plasmodium falciparum from Gabon to pyronaridine.

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