ACTIVITY OF PS-15 AND ITS METABOLITE, WR99210, AGAINST PLASMODIUM-FALCIPARUM IN AN IN-VIVO IN-VITRO MODEL

An in vivo-in vitro model was used to assess the antimalarial activity of PS-15 and its metabolite, WR99210, against Plasmodium falciparum. WR99210, an antifolate triazine compound, was given as a single oral d ose of 30 mg/kg to 8 Saimiri sciureus monkeys and, 3 months later, the parent compound, PS-15, was given similarly to the same monkeys. Seru m samples were collected at various times after drug administration, s erially diluted with control serum, and their antimalarial activity in vitro was determined against the multidrug-resistant K1 isolate of P. falciparum. Serum concentrations of PS-15 and WR99210 were esimated b y high performance liquid chromatography. The maximum dilutions of ser um that inhibited parasite growth were 20- to 86-fold higher 3 and 6 h after administration of PS-15 than following WR99210 administration. Substantial serum antimalarial activity was observed even at 48 h afte r medication with PS-15. Serum drug concentrations provided further ev idence that PS-15 was absorbed far better from the gastrointestinal tr act than WR99210. The substantial and sustained activity of PS-15 sugg ests that a single dose, or several smaller doses given once a day, sh ould be effective in curing drug-resistant infections of P. falciparum .