Background. Dihydroartemisinin-piperaquine (DP) is a fixed-combination antimalarial drug increasingly deployed in Southeast Asia. The current regimen involves 4 doses given over 3 days. Simplification of the dose regimen should facilitate treatment adherence and thereby increase effectiveness.Methods. In a randomized, controlled, 3-arm trial conducted along the northwestern border of Thailand, the standard 4-dose course of DP (DP4) was compared to an equivalent dose given as a once-daily regimen (DP3) and to the standard treatment of mefloquine-artesunate (MAS3).Results. A total of 499 patients were included in the study. Times to fever and parasite clearance were similar in all groups. The PCR genotyping-adjusted cure rates at day 63 after treatment initiation were 95.7% (95% confidence interval [95% CI], 92.2%-98.9%) for MAS3, 100% for DP4, and 99.4% (95% CI, 98.1%-100%) for DP3. The DP4 and DP3 cure rates were significantly higher than that for MAS3 ( and , respectively). P p .008 P p .03 All regimens were well tolerated. There were 3 deaths (1 in the MAS3 group and 2 in the DP3 group), all of which were considered to be unrelated to treatment. Rates of other adverse events were comparable between the groups, except for diarrhea, which was more common in the DP4 group ( vs. the MAS3 group). P p .05 Conclusions. A once-daily, 3-dose regimen of DP is a highly efficacious treatment for multidrug-resistant falciparum malaria. This simple, safe, and relatively inexpensive fixed combination could become the treatment of choice for falciparum malaria.

An open, randomized comparison of artemether-benflumetol (CGP 56 697; Novartis) with artesunate-mefloquine was conducted in 617 patients with acute uncomplicated multidrug-resistant falciparum malaria on the western border of Thailand. Both treatments rapidly and reliably cleared fever and parasitemia, and there was no significant difference in the initial therapeutic response parameters. Parasite genotyping was used to distinguish recrudescences from new infections. The 63-day cure rate for artesunate-mefloquine (94%) was significantly higher than the cure rate for artemether-benflumetol (81%) (P < 0.001). Both regimens were well tolerated. Nausea, vomiting, dizziness, sleep disorders, and other neurological side effects were between two and four times more common in the artesunate-mefloquine group than in the artemether-benflumetol group (P < 0.001). Artemether-benflumetol is effective and very well tolerated in the treatment of multidrug-resistant falciparum malaria. A higher dose than that used in the present study may improve efficacy.

In an open-label trial carried out on the northwest border of Thailand, 1596 patients with uncomplicated multidrug-resistant falciparum malaria were randomly assigned to receive atovaquone-proguanil, atovaquone-proguanil-artesunate, or artesunate-mefloquine and were followed up for 42 days. All 3 regimens were highly effective and well tolerated. Fever duration and parasite clearance times were significantly shorter among patients who received artesunate (P<.001). Polymerase chain reaction genotyping confirmed that recrudescence occurred in 13 patients who received artesunate-mefloquine (2.4%), 5 who received atovaquone-proguanil-artesunate (0.9%), and 15 who received atovaquone-proguanil (2.8%). Adding artesunate to atovaquone-proguanil reduced the risk of failure 3-fold (95% confidence interval [CI], 1.1-8.2) and subsequent gametocyte carriage 21-fold (95% CI, 14-30). Gastrointestinal complaints in the first 48 h after initiation of treatment were more common among artesunate recipients, but after day 2, dizziness, sleep disturbance, nausea, vomiting, and anorexia were more common among mefloquine recipients (P< or =.014). Artesunate-atovaquone-proguanil is a highly effective and well-tolerated treatment for multidrug-resistant falciparum malaria.

Plasma antimalarial activity following oral artesunate or dihydroartemisinin (DHA) treatment was measured by a bioassay in 18 patients with uncomplicated falciparum malaria. The mean antimalarial activity in terms of the bioavailability of DHA relative to that of artesunate did not differ significantly from 1, suggesting that DHA can be formulated to be an acceptable oral alternative to artesunate.Drug resistance to Plasmodium falciparum is a growing problem in Southeast Asia (14). The artemisinin derivatives are effective, safe, and widely used alternative treatments. Artesunate is the most commonly prescribed derivative (1, 7). Each artesunate treatment for adults costs at least $1 (U.S.). Nearly all the antimalarial activity of artesunate results from the activity of its main metabolite, dihydroartemisinin (DHA) (1, 2, 6). DHA has also been formulated as an oral antimalarial drug and could be easier and cheaper to produce than artesunate. Clinical trials on the treatment of acute, uncomplicated falciparum malaria have demonstrated that oral DHA is a safe, effective oral treatment that achieves cure rates similar to those achieved with oral artesunate (8,9,15).A recent study with eight patients with uncomplicated falciparum malaria, in which high-performance liquid chromatography (HPLC) and UV detection (UVD) were used to determine the plasma DHA concentration, gave an estimated mean oral bioavailability of DHA relative to that of oral artesunate of 0.88 (4). Chemical methods for the assay of the artemisinin derivatives have a limit of accurate quantitation above the range of concentrations which provide a significant antimalarial effect. Bioassay gives an alternative and considerably more sensitive measure but does not distinguish between parent drugs and their active metabolites (12). We therefore compared the bioavailabilities of the two most widely used formulations of oral artesunate and oral DHA given at the same milligram doses to patients with uncomplicated malaria in a randomized crossover trial with bioassay measurements of antimalarial activity obtained with serial plasma samples (3,10,11,12).Nonpregnant, febrile (temperature, Ͼ37.5°C) adults (age, Ͼ14 years) hospitalized at the Mae Sot Hospital or the Mae La Camp of displaced Karen People, Tak Province, western Thailand, with uncomplicated acute P. falciparum malaria (defined as the presence of asexual stages of P. falciparum in peripheral blood and not fulfilling the World Health Organization [16] criteria for severe malaria) were included in the study, provided that they gave fully informed consent and they had not previously received significant antimalarial treatment. The study was approved by the ethical and scientific review subcommittee of the Thai Ministry of Public Health and by the Karen Refugee Committee. In the first 48 h the patients were given both artesunate (200 mg as 50-mg tablets; Guilin No. 1 Factory, Guangxi, People's Republic of China) and dihydroartemisinin (200 mg as 20-mg tablets; Cotecxin; Cotec New Technology Corp., Beijin...

Combinations are set to become the mainstay in treatment and prophylaxis of malaria due to Plasmodium falciparum. Various antimalarials have been implicated in cardiotoxicity via prolongation of the QTc interval. Atovaquone-proguanil is an effective and increasingly popular antimalarial choice when used alone or with artesunate in areas of drug resistance. We report the results of an investigation carried out on the Thai-Burmese border in 42 patients randomized to receive either atovaquone-proguanil or atovaquone-proguanil-artesunate for three days. Electrocardiographic recordings were made at baseline and one hour after each dose. There was no statistically significant change in QTc interval between baseline and any subsequent readings in either treatment group or the cohort as a whole. We conclude that atovaquone-proguanil shows no evidence of cardiotoxicity either alone or when combined with artesunate.

No abstract