A new primaquine analogue, tafenoquine (WR 238605), for prophylaxis against Plasmodium falciparum malaria.

We tested tafenoquine (WR 238605), a new long-acting 8-aminoquinoline, for its ability to prevent malaria in an area that is holoendemic for Plasmodium falciparum. In a double-blinded, placebo-controlled, randomized clinical trial in western Kenya, adult volunteers received a treatment course of 250 mg halofantrine per day for 3 days, to effect clearance of preexisting parasites. The volunteers were then assigned to 1 of 4 drug regimens: placebo throughout; 3 days of 400 mg (base) of tafenoquine per day, followed by placebo weekly; 3 days of 200 mg of tafenoquine per day, followed by 200 mg per week; and 3 days of 400 mg of tafenoquine per day, followed by 400 mg per week. Prophylaxis was continued for up to 13 weeks. Of the evaluable subjects (223 of 249 randomized subjects), volunteers who received 400 mg tafenoquine for only 3 days had a protective efficacy of 68% (95% confidence interval [CI], 53%-79%), as compared with placebo recipients; those who received 200 mg per day for 3 days followed by 200 mg per week had a protective efficacy of 86% (95% CI, 73%-93%); and those who received 400 mg for 3 days followed by 400 mg per week had a protective efficacy of 89% (95% CI, 77%-95%). A similar number of volunteers in the 4 treatment groups reported adverse events. Prophylactic regimens of 200 mg or 400 mg of tafenoquine, taken weekly for < or =13 weeks, are highly efficacious in preventing falciparum malaria and are well tolerated.

Efficacy and safety of atovaquone/proguanil as suppressive prophylaxis for Plasmodium falciparum malaria.

Currently recommended prophylactic regimens for Plasmodium falciparum malaria are associated with a high incidence of adverse events and/or suboptimal efficacy. In a double-blind, placebo-controlled, randomized clinical trial in western Kenya, adult volunteers received a treatment course of atovaquone/proguanil hydrochloride (250 mg/100 mg per tablet) to eliminate preexisting infection. Immediately thereafter, subjects were randomized to one of the three prophylactic regimens to receive one atovaquone/proguanil tablet daily (n = 68), two atovaquone/proguanil tablets daily (n = 65), or placebo (n = 65) for 10 weeks. The study endpoint for any subject was the development of parasitemia, evident on blood smear, during prophylaxis. Of the evaluable subjects, all in the low-dose (54 of 54) and high-dose (54 of 54) atovaquone/proguanil groups remained malaria-free during the 10-week prophylaxis period, in contrast to only 48% (26 of 54) in the placebo group (P < .001). Both atovaquone/proguanil prophylactic regimens were as well tolerated as placebo. Thus, atovaquone/proguanil appears to be highly efficacious and safe as prophylaxis for P. falciparum malaria.

Successful double-blinded, randomized, placebo-controlled field trial of azithromycin and doxycycline as prophylaxis for malaria in western Kenya.

Azithromycin prevents malaria in animal models and early clinical trials. We determined the prophylactic efficacy of three antibiotic regimens given for 10 weeks (azithromycin, 250 mg daily; azithromycin, 1,000 mg weekly; and doxycycline, 100 mg daily) relative to that of placebo for 232 adult volunteers residing in an area of intense malaria transmission. Any confirmed parasitemia during the study was considered a prophylactic failure. Two hundred thirteen volunteers (92%) completed the study. The prophylactic efficacies were as follows: daily azithromycin, 82.7% (95% confidence interval [CI], 68.5%-91.1%); weekly azithromycin, 64.2% (95% CI, 47.1%-77.1%); and daily doxycycline, 92.6% (95% CI, 79.9%-97.5%). All regimens were well tolerated. We concluded that both 100 mg of doxycycline and 250 mg of azithromycin, given daily, were effective as prophylaxis for malaria in this setting. If studies with nonimmune volunteers confirm these results for semi-immune volunteers, a daily azithromycin regimen may have special utility for individuals with contraindications to treatment with doxycycline or other antimalarial agents.

Determination of fifty percent inhibitory concentrations (IC50) of antimalarial drugs against Plasmodium falciparum parasites in a serum-free medium.

Plasmodium falciparum chemosensitivity to the various antimalarial drugs is presently determined in the laboratory by setting up multiple microcultures of the parasite and estimating the amount of growth inhibition caused by known concentrations of drug. Parasite growth inhibition is assessed either by microscopy, radiolabeled substrate uptake, or calorimetrically. The obligate requirement for serum in this assay presents difficulties in the direct comparison of results among laboratories. We now have evidence that antimalarial drug sensitivity assays can be reliably performed in a serum-free medium. The overall comparison of 50% inhibitory concentration (IC50) values obtained with serum-free media (bovine albumin, Cohn fraction V [BAM] and BAM combined with glucose and lipids-cholesterol-rich mixture) and those obtained in serum-supplemented medium was r = 0.56; n = 60; P < 0.01.