Safety evaluation and antimalarial effect of mechanochemically synthesized trimethoprim-copper in Plasmodium berghei infected mice

Abstract

Combating malaria especially in the sub-Saharan Africa was identified by the World Health Organization (WHO) and United Nations in the Millennium Development Goals as an objective. Antimalarial medicines are central to any strategy for effective reduction of mortality related to malaria. Efficacy and safety of antimalarial medicines, as measured by their quality, are therefore essential in mitigating morbidity and reducing deaths. The mechanochemical synthesis and characterization of trimethoprim - copper complex and its antimalarial efficacy on Plasmodium berghei infected mice and toxicity evaluation were investigated by evaluating percentage parasitemia and chemosuppresive effect of the drugs on Plasmodium berghei infected mice, status of some serum enzymes and hematological indices.  Derivatization of trimethoprim with copper enhanced the activity of the drug by significantly (p<0.05) improving the suppression of parasitemia in established infection when compared with the controls. Trimethoprim-copper complex demonstrated to be more efficacious than pure trimethoprim while chloroquine was most efficacious in malaria parasite clearance. Administration of trimethoprim, trimethoprim-copper complex and chloroquine to mice for seven days caused significant increase (p<0.05) in the activities of alkaline and acid phosphatases in the liver, kidney and small intestine when compared with the control while a significant reduction (p<0.05) in the activities of alanine and aspartate aminotransferases, and lactate dehyrogenase were observed in the liver, kidney and small intestine when compared with the control. Also there was a significant decrease (p<0.05) in the levels of PCV, Hb, RBC and lymphocytes and a significant increase (p<0.05) in WBC and neutrophil concentrations in all the treatment groups when compared with control. The result indicates that coordination of copper to trimethoprim by mechanical induction improved its antimalarial activity while the alterations in the investigated biochemical parameters suggest functional and structural toxicity. Thus, trimethoprim-copper complex may not be completely safe as antimalarial oral remedy.

Keywords: Mechanochemical synthesis, antimalarial activity, mice, trimethoprim, safety