Assessment of the sub-acute and delayed toxicity of artemether-lumefantrine combination in rats

Abstract

Considering the current surge in the use of artemether-lumefantrine combination (AL), as a treatment regimen for malaria infection, this research elucidated its sub-acute and delayed toxicity profile. Adult albino wistar rats were randomly placed in 7 groups (n=8). Groups 1-3 received oral AL 14, 28 and 56 mg/kg and were used for the sub-acute toxicity study. Groups 4-6 equally received oral AL 14, 28 and 56 mg/kg and were used for the delayed toxicity study. Animals in group 7 served as control. Treatment was given for 7 days; animals for the sub-acute tests were sacrificed on day 8, while animals for the delayed toxicity test were sacrificed on day 15. Parameters evaluated include random blood sugar levels, alanine transaminase, aspartate transaminase, alkaline phosphatase, bilirubin, cholesterol, serum electrolytes and hematological indices. The liver, kidney and heart were also subjected to histopathological evaluation. The random blood sugar level was only significantly (P<0.05) elevated in the sub-acute phase but not in the delayed phase. The AL treated rats had a marginal but non-significant increments in Na+, serum cholesterol, urea and liver enzymes in both the sub-acute and delayed phases. The AL had no effect on total and conjugated bilirubin, but reduced K+, Cl- and HCO3 -. There was mild increase in hemoglobin, packed cell volume, reticulocyte, total white blood cell and lymphocyte, and a decrease in neutrophil counts. Histology sections showed dose-related increase in severity of hepatic congestion and inflammation. Renal sections showed no significant changes. However, about 25% of animals that received 14, 28 and 56 mg/kg of AL respectively had granular and eosinophilic hyaline casts in renal tubules. There were no remarkable histopathologic changes in the heart in both sub-acute and delayed phases. However, one animal that received 56 mg/kg in the sub-acute phase had organizing fibrinous pericarditis, with intense lymphocytic infiltration and tubular coagulative necrosis. Though oral administration of normal to quadruple strength of AL affected vital organs and clinical parameters, no significant deleterious toxic effect was observed.