Dose Of Mefloquine Research Articles

Malaria, Mefloquine, Madness, and Mosquito Nets-Reply

In Reply. — Choosing a drug for prophylaxis against malaria requires weighing the risk of malaria infection against the effectiveness and tolerance of the drug. Mefloquine is the most effective drug available to prevent infections with chloroquine-resistant Plasmodium falciparum malaria, a potentially fatal infection. Available data indicate that the drug is well tolerated when used for prophylaxis at doses of 250 mg. The frequency and type of mild or moderate adverse events reported by users of mefloquine for prophylaxis do not differ from those reported by users of chloroquine for prophylaxis. 1,2 Anecdotal case reports suggest that serious neurological and psychiatric events, such as convulsions or hallucinations, are possible with mefloquine for prophylaxis; however, such events have not been reported from prophylactic drug trials or from surveys of users of mefloquine for prophylaxis. 1-4 These studies included a total of 18 591 persons. 2 In contrast, therapeutic doses of mefloquine,

Effect of ampicillin on mefloquine pharmacokinetics in thai males

The 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 micrograms.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.

Effects of Mefloquine on the Release of Marker Enzymes from the Rat Liver Crude Lysosomal Fraction

The effects of the antimalarial agent mefloquine on the release of marker enzymes, acid phosphatase and beta glucuronidase, from the rat liver lysosomes in a crude lysosomal preparation were investigated and compared with that of chloroquine whose membrane effects have been well-documented in the literature. At 10 aM, mefloquine decreased significantly the release of marker enzymes when compared to the control, but at the higher concentrations of 100 μM and 500 aM, it markedly accelerated the release of enzymes. This suggested that mefloquine exerted a concentration-dependant biphasic effect of membrane stabilization and labilization. In comparison, chloroquine diminished the release of enzymes over the concentration range of 10-500 μM, that is showing a membrane stabilizing effect similar to other reports. Since serum levels of 1.6-3.2 μM are reported after a weekly dose of mefloquine, the present results suggest that a predominant stabilization effect should prevail under these conditions. However, higher drug concentrations may result in labilization with undesirable consequences.

A stable, oligosymptomatic malaria focus in Thailand

Blood from most of the 250 residents of a nonmigratory farming village in south-eastern Thailand was visually examined for malaria parasites monthly for 2 years. Nearly 97% of the population had at least one (median = 5) patent Plasmodium falciparum infection per year; 72% had one due to P. vivax (median = 1). This contrasted with a slide positivity rate of 17% calculated from 12 months of passive case detection before the study began. Children 1–9 years old had the highest mean monthly prevalence (51%) and highest geometric mean density ( 10 500 white blood cells) of P. falciparum. Fewer than half the expected number of mixed infections were found but these were more common at high densities of P. falciparum. Individuals over 19 years old comprised 52% of the population but accounted for only 18% of P. vivax and 32% of P. falciparum gametocytaemias. Fever rates were marginally higher in those below 10 years old (8%) but occurred with equal frequency in those with patent infections or negative. The spleen rate (89% stage 1) was 24% in those under 15 years old and 7% in those older. No malaria mortality was seen. P. falciparum cases treated for 10 d with quinine + tetracycline (QT) cleared the infection as often as those given one dose of mefloquine + sulfadoxine + pyrimethamine (MSP); both treatments reduced densities in cases not cured. Apparently unsupervised compliance was no better with MSP than with QT. The role played by hyperendemic, cryptic foci in Asian epidemics of malaria may have been underestimated.

Double-blind dose finding study of mefloquine-sulfadoxine-pyrimethamine in children with acute falciparum malaria

Three different doses of a combination of mefloquine-sulfadoxine-pyrimethamine (MSP), given double-blind as a single dose to 60 children, were evaluated for efficacy and tolerance. The children, 42 boys and 18 girls aged between 5 and 15 years, received a mefloquine dose equivalent to 1, 1 · 5, or 2 standard MSP (Fansimef ®) tablets. Radical cure was obtained in all patients with only mild to moderate side effects of nausea and vomiting, which were not worse in the higher dose groups. For children living in an endemic malarious area, a single dose of mefloquine 7 · 1–12 · 5 mg/kg, given in combination with sulfadoxine (14 · 3–25 · 0 mg/kg) and pyrimethamine (0 · 7-1 · 3 mg/kg), is a safe and effective treatment for uncomplicated chloroquine-resistant Plasmodium falciparum malaria. This dose of MSP is approximately 10 mg/kg, 20 mg/kg and 1 · 0 mg/kg respectively of mefloquine, sulfadoxine and pyrimethamine, which is equivalent to a single standard tablet of Fansimef ® (mefloquine, 250 mg; sulfadoxine, 500 mg; pyrimethamine, 25 mg) given to a child weighing 20–30 kg.

Disposition of the antimalarial, mefloquine, in the isolated perfused rat liver

The disposition of mefloquine has been investigated in the isolated perfused rat liver (IPRL) preparation after the administration of [ 14C]mefloquine HCl (3.8 mg, 4 μCi, quinoline ring labeled). Mefloquine underwent avid hepatic uptake within 10 min of dosing. Also at this point, hepatic oxygen consumption was reduced markedly in four of the six IPRL preparations, but was restored completely by approximately 30 min post-dose. The drug concentration profile underwent a biexponential decline over the 4-hr study period, with a terminal T 1 2 of 1.0 ± 0.3 hr. The area under the perfusate plasma concentration/time curve (AUC 0-∞) was 4.0 ± 1.8 μg·hr·ml −1. Mefloquine was a high clearance compound (956.0 ± 390 ml/hr) with a large apparent volume of distribution (1416 ± 819 ml) in the IPRL. Biliary excretion accounted for 7.5 ± 6.5% of the dose. Mefloquine was quantitated by HPLC analysis as approximately half (3.3 ± 1.8%) of biliary label, the remainder consisting of highly polar metabolites of mefloquine. By 4 hr, a total of 64.8 ± 4.4% of the [ 14C] dose was recovered from the livers. Subsequent HPLC analysis revealed this to be mostly unchanged mefloquine. Subcellular fractionation of the homogenized livers revealed that 50.6 ± 6.8% of the dose of mefloquine was located in the 10,000 g pellet. In summary, mefloquine was cleared rapidly from the IPRL and underwent avid hepatic uptake into the lipid-rich fractions of rat liver.

Excretion of mefloquine in human breast milk.

Concentrations of mefloquine in plasma and breast milk were measured in 2 women following the administration of one Lariam tablet (250 mg mefloquine). The milk-to-plasma ratio of mefloquine based on the area under the plasma and milk concentration curves was 0.13 and 0.16. After a maternal mefloquine dose of 3.73 mg/kg and assuming a daily milk ingestion of 1 litre over a week, the maximum amount of drug ingested by an infant would be 0.14 mg/kg. During lactation the plasma clearance and apparent volume of distribution of mefloquine were about 50% less than the same parameters calculated after lactation had ceased.

Loss of infectivity for Swiss mice of a mefloquine-resistant strain of Plasmodium berghei

A strain of Plasmodium berghei made resistant to a 244 mg/kg daily dose of mefloquine by interrupted subcurative therapy in successive passages in weanling rats, was maintained for more than six months under drug pressure and was cryopreserved. Experiments with this strain have shown its loss of virulence for intact mice. In splenectomized Swiss mice infection with this resistant strain is transient. The mefloquine resistance of this line was unstable and the strain became sensitive to mefloquine after 10 serial drug-free passages but did not recover its infectivity to mice.

The treatment of malaria.

At least four doses of quinine followed by a single dose of mefloquine or by a single dose of sulfadoxine-pyrimethamine are two highly effective regimens for chloroquine-resistant falciparum malaria. Mefloquine alone is valuable in ambulant patients. Chloroquine-sensitive falciparum malaria can be treated with a course of chloroquine. Vivax and all other types of malaria should be treated with sequential chloroquine and primaquine. Quinine, by intravenous infusion, is the most effective drug for severe falciparum malaria. The optimum intravenous dose varies between 5 mg/kg and 10 mg/kg administered over four hours. Intravenous or oral quinine should be administered about every 12 hours and the total daily dose of quinine should rarely exceed 20 mg/kg. Intravenous fluid input should be controlled in falciparum malaria to prevent pulmonary oedema. Established renal failure is best treated by dialysis. The value of adrenocortical steroids for falciparum coma has not been established. Fresh blood transfusion may be helpful in small doses for severe anaemia and to replace clotting factors. Anticoagulants, such as heparin, should not be used in falciparum malaria.