Randomized trials of artemisinin-piperaquine, dihydroartemisinin-piperaquine phosphate and artemether-lumefantrine for the treatment of multi-drug resistant falciparum malaria in Cambodia-Thailand border area.

BACKGROUND: Drug resistance of falciparum malaria is a global problem. Sulphadoxine/pyrimethamine-resistant and mefloquine-resistant strains of falciparum malaria have spread in Southeast Asia at lightning speed in 1980s-1990s, and the Cambodia-Thailand border is one of the malaria epidemic areas with the most severe forms of multi-drug resistant falciparum malaria. METHODS: Artemisinin-piperaquine (AP), dihydroartemisinin-piperaquine phosphate (DHP) and artemether-lumefantrine (AL) were used to treat 110, 55 and 55 uncomplicated malaria patients, respectively. The total dosage for adults is 1,750 mg (four tablets, twice over 24 hours) of AP, 2,880 mg (eight tablets, four times over two days) of DHP, and 3,360 mg (24 tablets, six times over three days) of AL. The 28-day cure rate, parasite clearance time, fever clearance time, and drug tolerance of patients to the three drugs were compared. All of the above methods were consistent with the current national guidelines. RESULTS: The mean parasite clearance time was similar in all three groups (66.7 ± 21.9 hrs, 65.6 ± 27.3 hrs, 65.3 ± 22.5 hrs in AP, DHP and AL groups, respectively), and there was no remarkable difference between them; the fever clearance time was also similar (31.6 ± 17.7 hrs, 34.6 ± 21.8 hrs and 36.9 ± 15.4 hrs, respectively). After following up for 28-days, the cure rate was 95.1%(97/102), 98.2%(54/55) and 82.4%(42/51); and the recrudescence cases was 4.9%(5/102), 1.8%(1/55) and 17.6%(9/51), respectively. Therefore, the statistical data showed that 28-day cure rate in AP and DHP groups was superior to AL group obviously.The patients had good tolerance to all the three drugs, and some side effects (anoxia, nausea, vomiting, headache and dizziness) could be found in every group and they were self-limited; patients in control groups also had good tolerance to DHP and AL, there was no remarkable difference in the three groups. CONCLUSIONS: AP, DHP and AL all remained efficacious treatments for the treatment of falciparum malaria in Cambodia-Thailand border area. However, in this particular setting, the AP regimen turned out to be favourable in terms of efficacy and effectiveness, simplicity of administration, cost and compliance. TRIAL REGISTRATION: The trial was registered at Chinese Clinical Trial Register under identifier 2005L01041.

Rapid and effective malaria control in Cambodia through mass administration of artemisinin-piperaquine.

BACKGROUND: Previous efforts to eradicate malaria parasites, particularly Plasmodium falciparum, have failed in part due to the emergence of drug resistant parasites and mosquitoes resistant to insecticides. Using an artemisinin-based combination therapy (ACT) that kills parasites quickly, a strategy was designed to eliminate the source of transmission by mass treatment of human populations in malaria-endemic areas Cambodia. METHODS: A combination drug of artemisinin and piperaquine given with low doses of primaquine was used to eliminate all stages of parasites from human carriers. RESULTS: In a pilot study, mass administration of artemisinin-piperaquine (two tablets of 62.5 mg artemisinin and 375 mg piperaquine for adults aged > or =16 years at 0 and 24 hrs; 1.5 tablet for children aged 11-15 years; and one tablet for children aged 6-10 years) and primaquine (9 mg for adults, at 10 day intervals for 6 months) was carried out in 17 villages (3,653 individuals). Parasite rates were dramatically reduced from 52.3% to 2.6% after three years. The P. falciparum rate in children decreased from 37.0% to 1.4%, reaching 0% in eight of 17 villages. In a second field study, that included one additional mass treatment of artemisinin-piperaquine, the P. falciparum rate in children was reduced from 20.8% to 0% within six months. No major adverse effects were observed. CONCLUSIONS: Mass administration of artemisinin-piperaquine and low doses of primaquine can be an effective, safe, and affordable strategy for efficiently eliminating malaria parasites in human carriers and interrupting parasite transmission. This study provides important information for future strategies for the eradication of malaria.

[Artesunate in interrupting the transmission of Plasmodium falciparum].

OBJECTIVE: To observe the effect of artesunate (ATS) on the infectivity of Plasmodium falciparum gametocytes (PFG). METHODS: 31 volunteers with falciparum malaria and gametocytaemia were randomly divided into 3 groups: artesunate (ATS) group (15 cases), quinine (QN) group (10 cases) and placebo group (6 cases). Each case in ATS group received 6-day course of oral artesunate (200 mg at 0, 6 and 24 hours then 100 mg daily for 4 days). Cases in QN group each received 21-dose course of quinine sulfate (500 mg/time) over seven days. Cases in placebo group took 2 tablets of vitamin B composites, three times per day for seven days. Peripheral PFG were counted daily in all cases until the clearance of PFG. Mosquitoes (Anopheles dirus) were fed with venous blood of patients on the 1st, 7th, 14th, 21st and 28th day, respectively. RESULTS: All cases in placebo group were PFG positive at the whole course by blood smear examinations. The PFG relative density in ATS group were (12.5+/-3.3)%, (1.2+/-0.4)%, (0.3+/-0.1)% on 7th, 14th, 21st day respectively, and the mean PFG clearance time was (22.0+/-1.4) d. The PFG relative density in QN group were (173.9+/-47.0)%, (112.5+/-45.4)%, (32.5+/-17.8)% at 7th, 14th, 21st day respectively, and the mean clearance time of PFG was (32.5+/-2.1) d (t=4.731, P<0.01). PFG remained positive on the 28th day in placebo group. The infectivity test to mosquitoes showed on 14th day the positive rate in ATS group, QN group and placebo group were 0, 35.0% and 48.7% respectively. In ATS group, the sporozoite rate of anopheline mosquitoes were 14.8% and 0 at 7th, 14th day, while in QN group, 142.0%, 98.6% and 20.3% at 7th, 14th, 21st day respectively. In placebo group, the infection rate of sporozoites remained stable. CONCLUSION: Oral administration of artesunate with a total dosage of 1000 mg in 6 days inhibits the infectivity of PFG.

[A randomized comparative study of naphtoquine, mefloquine and artsunate in the treatment of falciparum malaria].

OBJECTIVE: To evaluate the efficacy and safety of naphtoquine, compared with mefloquine and artesunate in the treatment of falciparum malaria. METHOD: Ninety patients with falciparum malaria were randomly allocated to 3 groups, including naphtoquine, mefloquine and artesunate group. In the naphtoquine group, thirty patients were prescribed single daily dosage of 1,000 mg for one day. In the mefloquine group, equal patients were treated with single dosage of 750 mg. Another thirty patients in the artesunate group were given total dosage of 600 mg for five days and doubling dosage on the first day. RESULT: In all three groups, symptoms were well controlled. The average fever-subsidence time in naphtoquine group was 30 h +/- 16 h and approximate that in mefloquine group (24 h +/- 15 h, P>0.05), but was longer than that in naphtoquine group (18 h +/- 9 h, P<0.01). The average parasite-clearance time in naphtoquine group (98 h +/- 28 h) is longer than that in mefloquine group (57 h +/- 20 h, P<0.01) and that in artesunate group (43 h +/- 17 h, P<0.01). At the end of 28-day clinical trail, the curative ratio in naphtoquine group was the highest (96.7%), and was significantly higher than that in mefloquine group (76.7%, P<0.05) and artesunate group (73.3%, P<0.05). Slight nausea and vomiting were observed in few patient in three groups. CONCLUSION: Although the average fever-subsidence time and the parasite-clearance time of naphtoquine at single 24-hour dosage of 1,000 mg were longer than those of mefloquine and artesunate, the 28-day curative ratio of naphtoquine was higher than that of mefloquine and artesunate. So we recommend that the combination of artemisinin, which is a rapid action antimalarial, and naphtoquine or mefloquine, which are longterm action antimalarial, would contribute to promoting efficacy, shorting the period of treatment and delaying occurrence of drug resistance.

Plasmodium falciparum genome-wide scans for positive selection, recombination hot spots and resistance to antimalarial drugs.

Antimalarial drugs impose strong selective pressure on Plasmodium falciparum parasites and leave signatures of selection in the parasite genome; screening for genes under selection may suggest potential drug or immune targets. Genome-wide association studies (GWAS) of parasite traits have been hampered by the lack of high-throughput genotyping methods, inadequate knowledge of parasite population history and time-consuming adaptations of parasites to in vitro culture. Here we report the first Plasmodium GWAS, which included 189 culture-adapted P. falciparum parasites genotyped using a custom-built Affymetrix molecular inversion probe 3K malaria panel array with a coverage of approximately 1 SNP per 7 kb. Population structure, variation in recombination rate and loci under recent positive selection were detected. Parasite half-maximum inhibitory concentrations for seven antimalarial drugs were obtained and used in GWAS to identify genes associated with drug responses. This study provides valuable tools and insight into the P. falciparum genome.