Drug Development Through Blood Schizontocidal Efficacy against rodent Malaria Parasite of Arteether (a/b) by Oral Formulation

Drug resistant malaria is a major worldwide public health problem. Artemisinin based drugs, derived from an ancient Chinese herbal remedy, are the most promising available antimalarials that offer hope in fight against drug resistant malaria. However, since several semi-synthetic derivatives of artemisinin viz. artemether, arteether and artesunate have been employed to cure life threatening infections with Plasmodium falciparum, resistance is likely to occur in future. A strain of rodent malaria parasite Plasmodium vinckei showing >12 fold resistance to arteether has been selected after exposure to sub-curative doses of drug in 50 sequential passages over a period of 700 days. Experimentally induced resistance was found to be stable after drug free maintenance of parasites for 11 serial passages over a period of 100 days. Cross sensitivity studies have shown that apart form resistance to related derivatives like artemether and artesunic acid, the derived parasites also show resistance to quinine and mefloquine. The present communication reports the development of a 43-arteether (30:70 mixtures of enantiomers) as a fast-acting blood schizontocide. This compound exertscurative blood schizontocidal action against P. berghei (sensitive strain), P. yoelii nigeriensis (chloroquine, quinine and mefloquine resistant line), P. knowlesi (resistant to mefloquine) and P. cynomolgi B (sensitive strain). In addition, arteether has shown no adverse pharmaco-logical effect in animal models, is safe in subacute toxicity, and has no teratogenic effect in rats and rabbits. The drug arteether (a/f3) has also completed multicentric clinical trials in P. falciparum endemic areas and was found to be effective and marketed as E. Mal. This drug is specifically useful in the control of drug-resistant malaria and asa potential compound for the treatment of severe complicated malaria including cerebral malaria. Arteether has higher safety margin compared to other artemisinin derivatives, has longer halflife, and produces high cure rates when administered in a short 3-dose (intramuscular) regimen.