Clinical Studies of Atovaquone, Alone or in Combination with other Antimalarial Drugs, for Treatment of Acute Uncomplicated Malaria in Thailand

Looareesuwan, S; Viravan, C; Hk, Webster; Kyle, Dennis E.; Hutchinson, David; Canfield, Craig J.

doi:10.4269/ajtmh.1996.54.62

Cited by 353 publications

(262 citation statements)

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“…Both SP and CD have been shown to select for mutations at Ile51, Arg59, and Asn108 of dihydrofolate reductase, which are associated with in vitro resistance to pyrimethamine and cycloguanil. 31 Atovaquone plus proguanil has been found to be an extremely effective treatment for uncomplicated falciparum malaria, [32][33][34][35] but the cost per treatment is prohibitive for most subSaharan African countries. Recent studies have shown the combination of SP and artesunate to be an effective therapy FIGURE 2.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of mefloquine and sulfadoxine-pyrimethamine for the treatment of uncomplicated Plasmodium falciparum infection in Machinga District, Malawi, 1998.

MacArthur

Stennies²,

Macheso³

et al. 2001

The American Journal of Tropical Medicine and Hygiene

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Abstract. In response to the spread of chloroquine-resistant Plasmodium falciparum, Malaŵ i changed its first-line antimalarial drug in 1993 from chloroquine to sulfadoxine-pyrimethamine (SP). Surveillance data has suggested that resistance to SP may be increasing. We compared the efficacy of SP with a potential successor, mefloquine (MQ). By use of a modified World Health Organization in vivo protocol, children infected with P. falciparum were randomized to receive SP (sulfadoxine 25 mg/kg) or MQ (15 mg/kg). We observed combined RII and RIII parasitologic failures of 20.0 and 22.0% in the SP and MQ arms, respectively. Among those in the MQ arm, the relative hazard of failing with a Day 2 drug level Ͻ 500 ng/mL was 10.6 times higher than those with levels Ն 500 ng/mL. Given the decreased efficacy of the first-line antimalarial drug and the high failure rates of MQ at this lower dosage, Malaŵ i should consider assessing the efficacy and feasibility of alternative drugs to treat uncomplicated falciparum malaria.

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Section: Discussionmentioning

confidence: 99%

Efficacy of mefloquine and sulfadoxine-pyrimethamine for the treatment of uncomplicated Plasmodium falciparum infection in Machinga District, Malawi, 1998.

MacArthur

Stennies²,

Macheso³

et al. 2001

The American Journal of Tropical Medicine and Hygiene

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“…[1][2][3][4][5][6][7][8][9][10] These studies enrolled 1,395 patients with Plasmodium falciparum malaria and 32 patients with non-falciparum malaria, including 278 females and 200 children Յ 12 years of age. Four uncontrolled studies evaluated 397 patients.…”

Section: Methodsmentioning

confidence: 99%

Malarone (atovaquone and proguanil hydrochloride): a review of its clinical development for treatment of malaria. Malarone Clinical Trials Study Group.

Looareesuwan¹,

Chulay²,

Canfield³

et al. 1999

Am J Trop Med Hyg

185

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Abstract. The continuing spread of drug-resistant malaria emphasizes the need for new antimalarial drugs. Atovaquone is a broad-spectrum antiprotozoal drug with a novel mechanism of action, via inhibition of parasite mitochondrial electron transport, and a favorable safety profile. Early studies with atovaquone alone for treatment of malaria demonstrated good initial control of parasitemia but an unacceptable rate of recrudescent parasitemia. Parasites isolated during recrudescence after treatment with atovaquone alone were resistant to atovaquone in vitro. The combination of atovaquone and proguanil is synergistic in vitro, and clinical studies demonstrated enhanced efficacy of the combination compared to either drug alone for treatment of malaria. Malarone, a fixed-dose combination of 250 mg of atovaquone and 100 mg of proguanil hydrochloride, is available in many countries for treatment of acute, uncomplicated malaria caused by Plasmodium falciparum. At the recommended dose (in adults, four tablets once a day for three days), the overall cure rate was Ͼ 98% in more than 500 patients with falciparum malaria. In four randomized, controlled clinical trials, treatment with atovaquone and proguanil hydrochloride was significantly more effective than mefloquine (Thailand), amodiaquine (Gabon), chloroquine (Peru and the Philippines) or chloroquine plus pyrimethamine/sulfadoxine (Philippines). In clinical trials where the comparator drug was highly effective, treatment with atovaquone and proguanil hydrochloride was equally effective. Parasites isolated during recrudescence after treatment with the combination of atovaquone and proguanil were not resistant to atovaquone in vitro. The most commonly reported adverse events in clinical trials (abdominal pain, anorexia, nausea, vomiting, diarrhea and coughing) occurred with similar frequency in patients treated with a comparator drug. Malarone is a safe and effective new agent for treatment of malaria.

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“…Notable examples include chloroquine (1), atovaquone (2), and pyrimethamine (3,4). Both chloroquine resistance and pyrimethamine resistance are associated with multiple amino acid replacements in the target protein (5,6).…”

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confidence: 99%

Stepwise acquisition of pyrimethamine resistance in the malaria parasite

Lozovsky

Chookajorn

Brown

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

266

328

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The spread of high-level pyrimethamine resistance in Africa threatens to curtail the therapeutic lifetime of antifolate antimalarials. We studied the possible evolutionary pathways in the evolution of pyrimethamine resistance using an approach in which all possible mutational intermediates were created by site-directed mutagenesis and assayed for their level of drug resistance. The coding sequence for dihydrofolate reductase (DHFR) from the malaria parasite Plasmodium falciparum was mutagenized, and tests were carried out in Escherichia coli under conditions in which the endogenous bacterial enzyme was selectively inhibited. We studied 4 key amino acid replacements implicated in pyrimethamine resistance: N51I, C59R, S108N, and I164L. Using empirical estimates of the mutational spectrum in P. falciparum and probabilities of fixation based on the relative levels of resistance, we found that the predicted favored pathways of drug resistance are consistent with those reported in previous kinetic studies, as well as DHFR polymorphisms observed in natural populations. We found that 3 pathways account for nearly 90% of the simulated realizations of the evolution of pyrimethamine resistance. The most frequent pathway (S108N and then C59R, N51I, and I164L) accounts for more than half of the simulated realizations. Our results also suggest an explanation for why I164L is detected in Southeast Asia and South America, but not at significant frequencies in Africa.adaptive landscape ͉ drug resistance ͉ evolution

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Clinical Studies of Atovaquone, Alone or in Combination with other Antimalarial Drugs, for Treatment of Acute Uncomplicated Malaria in Thailand

Cited by 353 publications

References 0 publications

Efficacy of mefloquine and sulfadoxine-pyrimethamine for the treatment of uncomplicated Plasmodium falciparum infection in Machinga District, Malawi, 1998.

Efficacy of mefloquine and sulfadoxine-pyrimethamine for the treatment of uncomplicated Plasmodium falciparum infection in Machinga District, Malawi, 1998.

Malarone (atovaquone and proguanil hydrochloride): a review of its clinical development for treatment of malaria. Malarone Clinical Trials Study Group.

Stepwise acquisition of pyrimethamine resistance in the malaria parasite

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