Academic journal article Bulletin of the World Health Organization

Pharmacokinetics and Pharmacodynamics of Mefloquine in Thai Patients with Acute Falciparum Malaria

Academic journal article Bulletin of the World Health Organization

Pharmacokinetics and Pharmacodynamics of Mefloquine in Thai Patients with Acute Falciparum Malaria

Article excerpt

Introduction

From the pharmacokinetic point of view, mefloquine, one of the most successful drugs to have emerged from the U.S. Army's antimalarial drug programme, is an ideal medicament [1-6]. A single oral dose had proved to be safe and active against all malaria species in humans, including multidrug-resistant falciparum malaria [7].

Despite encouraging data on the activity of mefloquine, evidence of the resistance of falciparum malaria to the drug has been increasing. For example, in a recent clinical trial at Bangkok Hospital for Tropical Diseases, the "S"-type response with a 750-mg dose of mefloquine (a) was 85% (T. Harinasuta, personal communication, 1990), compared with a 95% cure rate in 1983 [7]. The risk of mefloquine resistance developing in human malaria must be taken seriously. Administration of a higher dose of mefloquine, e.g., 1250 mg, may improve the cure rate of clinical falciparum malaria; however, it could also result in more adverse effects, and the balance between the risks and benefits should be considered. Such adverse effects, i.e., nausea and vomiting, which have been reported to affect up to 51% in patients with falciparum malaria [8-12], are the most important factor limiting the use of mefloquine. These effects are dose-related, being more likely in patients who receive higher doses, i.e., > 15 mg/kg body weight [11], and in conjunction with the nausea and vomiting caused by malaria itself can result in low plasma drug concentrations and treatment failure.

We have carried out a comparative study of the pharmacokinetics and pharmacodynamics of mefloquine (a) given as a single oral dose of 750 or 1250 mg to Thai patients with falciparum malaria.

Materials and methods

Patients

A total of 20 male patients with acute uncomplicated falciparum malaria (asexual form, parasitaemia < 5%), aged 16-42 years and weight 45-60 kg, with no history of liver or kidney diseases, volunteered for the study. Written informed consent was obtained from all the patients, and during the study the only drug they took was mefloquine.

Each volunteer received a physical examination, routine blood tests, investigations of blood chemistry, chest X-ray, urine analysis, and an electrocardiogram (ECG), and was admitted to the Bangkok Hospital for Tropical Disease for 42 days.

Drug administration

The patients were randomly assigned to a regimen of either 1250 mg mefloquine (five tablets) or 750 ,g (three tablets). The drug was administered with a glass of water under supervision.

Blood collection for pharmacokinetic study

A 4-ml sample of whole blood was collected in heparinized tubes, 0, 0.5, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 14 18 24, 28, and 36 hours as well as 2, 3, 4, 5, 7, 14, 21, 28, 35 and 42 days after the dose had been taken (28 samples per volunteer).

Parasite count

The parasite count was performed twice daily until negative, then once daily until day 42 of the study.

Blood tests and blood biochemistry

Blood tests and investigations of blood biochemistry were carried out weekly until day 42 of the study.

Adverse effects

All adverse reactions during the study were recorded together with the date and time when they occurred and disappeared. These reactions included gastrointestinal, central nervous system, cardiovascular, skin, and blood signs as well as any other changes that could be attributed to mefloquine.

The frequency of vomiting and of diarrhoea (number of minutes or hourse after dosing) were recorded on days 0, 1, 2, 3, and 4.

A history of itching or skin rashes after taking any drugs or after taking mefloquine was noted. The intensity and duration of rashes were recorded.

ECGs and blood pressure determinations were performed at intervals when samples of blood were being taken and also weekly until day 42. …

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