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Safe and effective antimalarial drugs are required for the treatment of pregnant women. We report a 3-day regimen of artesunate (4 mg/kg/day)-azithromycin (25 mg/kg/day) (ASAZ) to be efficacious (polymerase chain reaction-corrected cure rate of 96.7%) and well tolerated in the treatment of Plasmodium falciparum malaria in children (N = 11) and adults (N = 19), in Vietnam in 2010. In comparison, the cure rate for artesunate (4 mg/kg on day 0, 2 mg/kg on days 1-6) was 90.0% in children (N = 7) and adults (N = 23). Because azithromycin is considered safe in pregnancy, our findings provide further evidence that ASAZ should be evaluated for the treatment of pregnant women with malaria.

We evaluated whether sex affects the steady-state pharmacokinetics of the antimalarial drugs, primaquine and doxycycline, in healthy subjects. Seventeen male and 17 female healthy Vietnamese subjects were administered 30 mg (base) of primaquine daily for 14 days. After a 2-week washout period, 14 male and 14 female subjects were administered 100 mg (base) of doxycycline daily for 14 days. Women had significantly higher median values of C(max) (212 versus 122 ng/mL, P< 0.001) and AUC(0-24) (1,909 versus 917 ng . h/mL, P < 0.001) of primaquine compared with men. Other than a longer t(max) in women, no sex-related differences were seen in the pharmacokinetics of doxycycline. The primaquine pharmacokinetic data suggest that women have increased exposure to primaquine, which may put them at increased risk for toxicity when administered the same maintenance dose as men. The similar pharmacokinetics of doxycycline between the two sexes justifies the same maintenance dose.

Aims To evaluate the effects of gender, food and grapefruit juice on the pharmacokinetics of primaquine in healthy subjects. Methods In a randomized, two-phase cross-over study, 10 male and 10 female healthy Vietnamese subjects were administered 30 mg primaquine in the fasting state or with food, followed by administration of primaquine with grapefruit juice. Results The pharmacokinetics of primaquine were comparable between male and female subjects, with geometric mean ratios of Cmax = 0.89 [95% confidence interval (CI) 0.65, 1.22] and AUC = 0.80 (95% CI 0.56, 1.15). The mean CL/F of primaquine was slightly higher in males than in females [0.52 l h−1 kg−1vs. 0.43 l h−1 kg−1, mean difference of 0.09 (95% CI –0.10, 0.28), P = 0.32]. When compared with fasting state values, food increased the geometric mean Cmax of primaquine by 26% (95% CI 12, 40) and the AUC by 14% (95% CI 3, 27). Similarly, grapefruit juice increased the geometric mean Cmax by 23% (95% CI 4, 45) and the AUC by 19% (95% CI 4, 37). Conclusions The disposition of primaquine was comparable between genders, suggesting no need to modify the dose of primaquine for malaria treatment or prophylaxis. Food increased the oral bioavailability of primaquine, which may lead to higher antimalarial efficacy. Grapefruit juice increased the bioavailability of primaquine, with marked interindividual differences suggesting that people should not take primaquine with grapefruit juice.

Food has been reported to increase the bioavailability of mefloquine in healthy volunteers, but its role in increasing blood mefloquine concentrations in malaria patients treated with mefloquine is unclear. In this study, we compared blood mefloquine concentrations after the administration of artesunate (8 mg/kg) and mefloquine (15 mg/kg) over 12h with either a low-fat (approximately 3g of fat) or high-fat (approximately 30 g of fat) meal for the treatment of Plasmodium falciparum malaria in 12 Vietnamese patients. No statistical differences were detected in the following kinetic parameters between the low-fat (n=6) and high-fat (n=6) groups, respectively: maximum blood mefloquine concentrations (2838+/-531 ng/ml and 2556+/-657 ng/ml, 95% CI -486 to 1050 ng/ml, P=0.43) and the area under the blood mefloquine concentration versus time curves (246.8+/-58.3 microg.h/ml and 238.3+/-28.4 microg.h/ml, 95% CI -50.5 to 67.5 microg.h/ml, P=0.75). A fatty meal does not appear to increase the bioavailability of mefloquine in malaria patients and should not affect the response of malaria infections to treatment.

Background In Vietnam, the artemisinin-based combination therapy (ACT) of dihydroartemisinin-piperaquine is currently used for first-line treatment of uncomplicated Plasmodium falciparum malaria. However, limited efficacy and tolerability data are available on alternative forms of ACT in Vietnam in case there is a reduction in the susceptibility of dihydroartemisinin-piperaquine. A study was conducted to compare the efficacy and tolerability of two fixed-dose formulations of ACT, artemisinin–piperaquine (Artequick®, ARPQ) and artesunate-amodiaquine (Coarsucam™, ASAQ) for the treatment of P. falciparum malaria in south-central Vietnam. Methods A randomized, open-label trial was conducted comparing the efficacy of a two-day regimen of ARPQ (~2.8 mg/kg artemisinin plus ~17.1 mg/kg of piperaquine per day) and a three-day regimen of ASAQ (~4.7 mg/kg of artesunate plus ~12.6 mg/kg of amodiaquine per day) for the treatment of children and adults with uncomplicated falciparum malaria. Primary efficacy endpoint was day 42, PCR-corrected, parasitological cure rate. Secondary endpoints were parasite and fever clearance times and tolerability. Results Of 128 patients enrolled, 63 were administered ARPQ and 65 ASAQ. Of the patients who completed the 42 days follow-up period or had a recurrence of malaria, 55 were on ARPQ (30 children, 25 adults) and 59 were on ASAQ (31 children, 28 adults). Recrudescent parasitaemia was PCR-confirmed for one patient in each treatment group, with cure rates at day 42 of 98% (95% CI: 88–100) for both forms of ACT. The median parasite clearance time was significantly slower in the ARPQ group compared with the ASAQ group (48 h vs. 36 h, Pvs. 24 h, P = 0.07). The two forms of ACT were well tolerated with no serious adverse events. Conclusion Both forms of ACT were highly efficacious in the treatment of uncomplicated P. falciparum malaria. Although the two-day course of ARPQ was equally as effective as the three-day course of ASAQ, parasite and fever clearance times were shorter with ASAQ. Further studies are warranted in different regions of Vietnam to determine the nationwide efficacy of ASAQ. Trial registration Australian New Zealand Clinical Trials Registry Number, ACTRN12609000816257

In 18 male healthy subjects, artesunate (200 mg)-azithromycin (1,500 mg) daily for 3 days was found to be well tolerated, with only mild gastrointestinal disturbances reported. The pharmacokinetic properties of artesunate-azithromycin given in combination are comparable to those of the drugs given alone. Artesunate and its major active metabolite, dihydroartemisinin, are responsible for most of the ex vivo antimalarial activity, with a delayed contribution by azithromycin.

Artesunate-amodiaquine (AAQ) is efficacious for the treatment of uncomplicated Plasmodium falciparum malaria in Africa, but little is known about its efficacy in Southeast Asia. We compared the efficacy of dihydroartemisinin-piperaquine (DHP) and AAQ against falciparum malaria in central Vietnam.Open, randomized clinical trial of 116 patients (36 children aged 6-14 years, 80 adults aged 15-60 years) were randomly allocated a 3-day course of either DHP (approximately 2.3 mg/kg dihydroartemisinin plus approximately 18.5 mg/kg of piperaquine per day) or AAQ (approximately 4.4 mg/kg of artesunate plus approximately 10.6 mg/kg of amodiaquine per day). The follow-up period was 42 days.The two drug combinations were well tolerated by all age groups with no obvious drug associated adverse events. Of the patients who completed 42 days of follow-up, 49 were on DHP (15 children, 34 adults) and 49 were on AAQ (14 children, 35 adults). The 42 day cure rates adjusted for reinfection identified by PCR genotyping for the two groups were similar [100% (49/49) and 98% (48/49) for DHP and AAQ, respectively]. With fewer reinfections, DHP appears to possess greater post-treatment prophylactic activity than AAQ.AAQ, an inexpensive artemisinin-based combination, could be an additional option to DHP for the treatment of multidrug-resistant falciparum malaria in Vietnam.

The two fixed-dose combinations of dihydroartemisinin and piperaquine (Artekin and Arterakine) were found to be bioinequivalent in healthy Vietnamese subjects. However, because the peak plasma concentrations and areas under the concentration-time curves of dihydroartemisinin and piperaquine were only marginally different between the two formulations, similar therapeutic efficacies are expected in the treatment of malaria infections.

We compared plasma maximum concentration (Cmax) and area under the concentration-time curve (AUC) of the antimalarial drug piperaquine in 26 healthy Vietnamese subjects after treatment with either a single oral dose of 500 mg (n = 6) or 1,000 mg (n = 6) of piperaquine phosphate and a three-day course of 500 mg of piperaquine/ day in the fasting state (n = 7) or with food (approximately 17 g fat) (n = 7). The geometric mean plasma Cmax and AUC((0-28)) was 2.8-fold (200 ng/mL versus 70 ng/mL) and 1.9-fold (5,736 ng x h/mL versus 2,999 ng x h/mL), respectively, and higher in subjects receiving the 1,000-mg dose than in those receiving the 500-mg dose. The geometric mean Cmax and AUC((0-28)) was 1.7-fold (198 ng/mL versus 119 ng/mL) and 1.4-fold (11,187 ng x h/mL versus 7,954 ng x h/mL) higher in the fed state than in the fasting state. Piperaquine AUC was proportional to the two doses tested and a moderate-fat meal enhanced the bioavailability of piperaquine by 41%, which should improve the therapeutic efficacy of this drug.

Summary The standard adult treatment regimen for Plasmodium vivax malaria is chloroquine (1500 mg over 3 d) plus primaquine (15 or 30 mg daily for 14 d), but patient compliance tends to be poor with the lengthy course. Preliminary observations are reported on the efficacy of a shorter treatment course – artesunate (200 mg twice a day for 2 d) plus primaquine (22.5 mg base twice a day for 7 d) – given to 28 adult patients infected with P. vivax in Viet Nam. All patients responded quickly to treatment with mean (SD) parasite and fever clearance times of 14.2 (4.0) and 18.6 (8.4) h, respectively. The high dose of primaquine was generally well tolerated, and only one patient (3.6%) had a recurrence of parasitaemia during 28 d of follow-up. As most patients infected with Southeast Asian strains of P. vivax have their first relapse within 28 d after treatment with rapidly eliminated blood schizonticides, the absence of parasitaemia in the remaining 27 patients suggests that this drug regimen was active against both blood and liver stages. Further studies are needed to confirm that this rapidly acting, short artesunate–primaquine regimen can result in better patient compliance and treatment outcomes than the chloroquine–primaquine regimen.

Micronutrient deficiencies remain common in preschool children in developing countries. Interventions focus on single micronutrients and often lack effectiveness. Weekly instead of daily supplementation may improve effectiveness.The efficacy of weekly and daily supplementation in reducing anemia prevalence and in improving the zinc, vitamin A, and growth status of 6-24-mo-old Vietnamese children was investigated.In this double-blind, placebo-controlled trial, the daily group (n = 55) received 8 mg elemental Fe (as iron sulfate), 5 mg elemental Zn (as zinc sulfate), 333 microg retinol, and 20 mg vitamin C 5 d/wk for 3 mo. The weekly group (n = 54) received 20 mg Fe, 17 mg Zn, 1700 microg retinol, and 20 mg vitamin C once a week. A third group (n = 54) received a placebo only. Venous blood samples were collected at the start and end of the supplementation period and anthropometric measurements were taken at the start and 3 mo after the end of supplementation.At baseline, 45.6% of subjects had hemoglobin concentrations110 g/L, 36.3% had zinc concentrations10.71 micromol/L, and 45.6% had retinol concentrations0.70 micromol/L. Hemoglobin, retinol, and zinc concentrations of both the weekly and daily groups increased similarly compared with the placebo group (P0.001). There was no significant difference in growth between the supplemented groups and the placebo group. However, the height-for-age of subjects stunted at baseline increased with z scores of 0.48 (P0.001) and 0.37 (P0.001) for the daily and weekly groups, respectively.Weekly and daily supplementation improved hemoglobin, zinc, and retinol concentrations similarly. Neither intervention affected growth of the overall population, but growth of children stunted at baseline was improved through both types of supplementation.