RESUMO
The aims of this study were to determine the pharmacokinetic parameters of a single dose of 200 mg oral and rectal artesunate in healthy volunteers, and to suggest a rational dosage regimen for rectal administration. The study design was a randomized open cross-over study of 12 healthy volunteers; the analytical method used was a reversed phase high performance liquid chromatography with post column derivatization and subsequent ultraviolet detection. Pharmacokinetic parameters were derived from the main metabolite alpha-dihydroartemisinin data due to the rapid disappearance of artesunate from the plasma. Dihydroartemisinin following oral administration of artesunate had a significantly higher AUC(0-infinity) (P<0.05 95% confidence interval (CI) -1168.73, -667.61 ng x h/mL(-1)) and Cmax (P<0.05; 95% CI -419.73, -171.44 ng/mL(-1)), and had shorter tmax (P<0.05; 95% CI -0.97, -0.10 h) than that following rectal artesunate. There was no statistically significant difference in the elimination half-life between both routes of administration (P>0.05; 95% CI -0.14, 0.53 h). The relative bioavailability of rectal artesunate was [mean (coefficient of variation %) 54.9 (24.8%) %]. On the basis of these data an 8 hourly dosing regimen per day with rectal artesunate is proposed.
Assuntos
Antimaláricos/farmacocinética , Artemisininas/farmacocinética , Sesquiterpenos/farmacocinética , Administração Oral , Administração Retal , Adulto , Antimaláricos/administração & dosagem , Antimaláricos/sangue , Área Sob a Curva , Artemisininas/administração & dosagem , Artemisininas/sangue , Artesunato , Estudos Cross-Over , Feminino , Humanos , Masculino , Valores de Referência , Sesquiterpenos/administração & dosagem , Sesquiterpenos/sangueRESUMO
Documentation on the efficacy of artesunate in Africa is limited, and no experience of artesunate use in Sudan is documented. Severe malaria in rural areas of Sudan, where facilities for the safe and effective use of parenteral quinine are lacking, is a frequent problem. Early treatment with artesunate suppositories would provide a simple method for use by unskilled staff and would be an alternative approach to treat malaria in settings with poor resources. We describe a hospital-based study of rectal artesunate in 100 adult patients with severe falciparum malaria with a dose derived from pharmacokinetic data (200 mg every 8 hours) over 3 days, which halted progression of severe disease and had a low fatality rate. The dosage schedule led to a rapid clinical response and reduced parasite clearance and fever subsidence times of (31.5 +/- 10.1 hours) and (31.4 +/- 11.1 hours). The sequential treatment of rectal artesunate with either doxycycline or pyrimethamine/sulfadoxine or mefloquine resulted in similar clinical cure rates of around 100%, and the combination of artesunate with either doxycycline or pyrimethamine/sulfadoxine was equally effective as mefloquine in preventing recrudescence. There were no significant adverse effects or signs of toxicity related to the treatment observed during the 28-day follow-up. The combination regimens could be used in areas where there is limited access to parenteral therapy for malaria.