Pharmacology and pharmacokinetics of new antimalarials

Chloroquine-resistant Plasmodium falciparum is now widespread in Africa, requiring new drugs for the control of both non-severe and severe forms of the disease. For non-severe malaria, pyrimethamine-sulphadoxine, an antifolate combination antimalarial, is at present efficacious, single-dose and cheap; important characteristics for treatments in Africa. However, alternative combinations are being investigated which are intrinsically more active, less toxic and with shorter elimination half-lives. In theory, short half-life compounds reduce the selective pressure for resistance, which may be a major determinant of the useful therapeutic life of an antimalarial drug. The potential advantages/disadvantages of alternative antifolates is discussed. While the use of mefloquine and halofantrine in Africa is at present limited by cost, these drugs are likely replacements for the antifolates when parasite resistance arises. For severe, life-threatening falciparum malaria, quinine remains the treatment of choice. In contrast to quinine, artemether rapidly reduces the viability of circulating, ring-stage parasites, produces more rapid parasite clearance and may reduce the length of coma, but does not significantly reduce the mortality of severe malaria which remains at about 15% even with optimal management. It seems unlikely that chemotherapy, even with "new" antimalarials, will reduce this high figure. Other strategies are required.