K. Na Bangchang

Comparison of oral artemether and mefloquine in acute uncomplicated falciparum malaria

Plasmodium falciparum malaria in Thailand is highly resistant to available antimalarials, and alternative drugs are needed urgently. Artemether is effective against falciparum malaria but associated with a high recrudescence rate. The proper dosage regimen remains to be defined. We have done a clinical trial comparing mefloquine 1250 mg in divided doses with oral artemether at 700 mg total dose given over 5 days in acute uncomplicated falciparum malaria. 46 patients, admitted to the Bangkok Hospital for Tropical Diseases, were randomised to receive either mefloquine (12) or artemether (34). Hospital follow-up was 28 days for the artemether group and 42 days for the mefloquine group. Oral artemether gave a significantly faster parasite clearance time than mefloquine (30 vs 64 h), and a significantly better cure rate (97 vs 64%) with fewer episodes of dizziness and vomiting. Oral artemether at 700 mg given over 5 days is effective and well tolerated. The cure rate with this regimen is higher than that reported by previous studies with 600 mg intramuscular artemether given over 5 days. Oral artemether can be considered as an alternative drug for multiple-drug-resistant falciparum malaria.

Mefloquine pharmacokinetics in pregnant women with acute falciparum malaria

Mefloquine has an established place in the treatment of chloroquine-resistant falciparum malaria. To investigate mefloquine pharmacokinetics in pregnancy, 9 untreated pregnant women aged 16-33 years and 8 non-pregnant females aged 16-38 years received an average of 15 (range 13-19) mg mefloquine/kg body-weight as single-dose treatment for uncomplicated falciparum malaria. Regular blood samples were taken during the subsequent 48 h and then intermittently for 3-26 d after treatment. Whole blood mefloquine concentrations were analysed by high-performance liquid chromatography and a one-compartment open pharmacokinetic model was fitted to the data. Peak mefloquine concentrations were significantly lower in the pregnant patients (median [range]; 1257 [650-1584] vs. 1617 [1051-3111] ng/mL) and the total apparent volume of distribution (Vd/f) was larger (10.8 [8.3-26.1] vs. 10.0 [4.8-13.9] L/kg; P < 0.05 in each case), consistent with an expanded circulating blood volume and increased tissue binding in pregnancy. There was no significant difference between the 2 groups in half-times of absorption or elimination (P > 0.1), and systemic clearance rates were also similar. These results suggest that pregnant patients need larger doses of mefloquine than non-pregnant women to achieve comparable blood levels, an important consideration in areas where multi-drug resistant falciparum malaria is emerging.

Effect of ampicillin on mefloquine pharmacokinetics in thai males

SummaryThe kinetics of a single oral dose of mefloquine given either alone or with ampicillin has been studied in 8 healthy Thai male volunteers.There was a significantly higher maximum whole blood mefloquine concentration after coadministration with ampicillin (1648 vs 1228 ng·ml−1), as well as a significantly reduced terminal half life (15.3 vs 17.7 days), mean residence time (20.1 vs 23.4 days) and volume of distribution at steady state (14.1 vs 19.4 l·kg−1). Although there was no significant change in the AUC from zero time to infinity, the AUC from zero time to 5 days was significantly increased by ampicillin (4.86 vs 3.27 μg·ml−1 day).These changes in mefloquine disposition after antibiotic treatment may be due both to an increase in fractional bioavailability and a reduction in the enterohepatic recycling of mefloquine.

Effect of tetracycline on mefloquine pharmacokinetics in Thai males

SummaryThe kinetics of a single oral dose of mefloquine given either alone or with tetracycline has been studied in 20 healthy Thai male volunteers.There was a significantly higher maximum whole blood mefloquine concentration after coadministration with tetracycline (1600 vs 1160 ng · ml−1), as well as a significantly reduced terminal half-life (14.4 vs 19.3 days), mean residence time (11.9 vs 16.0 days) and volume of distribution at steady state (13.3 vs 19.91 · kg−1). Although there was no significant change in the AUC from zero time to infinity, the AUC from zero time to 7 days was significantly increased by tetracycline (6.18 vs 4.76 μg · ml−1 · day).The changes in mefloquine disposition after tetracycline treatment are probably due to a reduction in enterohepatic recycling. The initial increase in mefloquine AUC without an apparent increase in side-effects suggests that this combination may have a place in the treatment of multi-drug resistant falciparum malaria.

Pharmacokinetics of mefloquine in the presence of primaquine

In the c h e m o t h e r a p y of malar ia the ach ievement of radical t r ea tmen t requires antimalarial drugs that act on various stages of the parasi te cycle. As there is no single drug which can affect radical t reatment , a combina t ion o f a fast-acting b lood schizonticide and a gametocytoc ida l drug has been advoca ted [1, 2]. The role of p r imaqu ine as a gametocy toc ida l drug in P.falciparum infections is controversial . Mef loquine has been shown to be effective in the prophylaxis and treatmen t of infections with mul t i -drug resistant P.falciparum [3, 4] and its use in combina t ion with the gametocytoc ida l drug pr imaquine could be of great value in the control of malaria, p rov ided that there was no adverse effect due to a drug interaction. Pr imaquine does inhibit hepat ic microsomal enzymes, bo th in vitro and in vivo [5, 6], and since mef loquine is metabol ized in the liver to a carboxylic acid [7, 8], perhaps via isozyme(s) of cy toch rome P450 (Na Bangchang , unpubl i shed observat ions) , it was impor tan t to ascertain if the co-adminis t ra t ion of p r imaquine would alter the pharmacokine t ics of mefloquine. The present study was conduc ted to examine this pharmacok ine t i c possibility.

Paracetamol disposition in Thai patients during and after treatment of falciparum malaria

Investigations in animals have suggested that conjugation of paracetamol may be reduced in malaria. We have measured plasma concentrations and the urinary excretion of paracetamol and its phase II metabolites in eight Thai patients during uncomplicated falciparum malaria and in convalescence, following a 1000 mg single oral dose.The apparent oral clearance (Malaria, 3.6; Convalescence, 3.9; ml·min−1·kg−1), the elimination half-life (Malaria, 3.8; Convalescence, 3.7 h) and apparent volume of distribution (Malaria, 1.2; Convalescence, 1.2; l·kg−1) of paracetamol were similar during malaria and convalescence. In addition, the urinary excretion of paracetamol and its major phase II metabolites and their formation clearances from paracetamol were not significantly different between the two study phases.These data show that clinical malaria infection has no effect on the conjugation of paracetamol in man.