Antimalarial and toxic effects of the acyclic nucleoside phosphonate (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine in Plasmodium berghei-infected mice.
Plasmodium berghei-infected mice died with low levels of parasitemia after repeated intraperitoneal administration (five times at 15 mg kg of body weight-1 every other day) of the in vitro active antimalarial acyclic nucleoside phosphonate (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [(S)-HPMPA]. Toxicological studies showed that the main cause of death resulted from (S)-HPMPA-induced nephrotoxicity. Although concomitant intraperitoneal administration of the tubular epithelium transport blocker probenecid prevented (S)-HPMPA-induced toxicity, mice eventually died with a high level of parasitemia, despite repeated administration of high doses of (S)-HPMPA. The short half-life of (S)-HPMPA in plasma combined with the insusceptibility of the nonreplicative stages of the parasite to (S)-HPMPA could explain this failure to eradicate all parasites. Indeed, a low but sustained (calculated) level of 200 nM (S)-HPMPA in plasma completely cured P. berghei-infected mice. However, these mice, which received a total dose of only 28 mg kg-1 administered via osmotic pumps for 7 days, died because of the toxicity of the drug. These findings indicate that nephrotoxicity hinders the use of (S)-HPMPA as a drug against blood stage parasites. An alternative application of (S)-HPMPA as a potent prophylactic drug is discussed.
Smeijsters
L J
LJ
Department of Parasitology, Faculty of Veterinary Medicine, University of Ultrecht, The Netherlands.
Nieuwenhuijs
H
H
Hermsen
R C
RC
Dorrestein
G M
GM
Franssen
F F
FF
Overdulve
J P
JP
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology* / Q000633:toxicity*; D003692:Delayed-Action Preparations; D008288:Malaria / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000494:pharmacology* / Q000633:toxicity*; D010962:Plasmodium berghei; D011339:Probenecid / Q000494:pharmacology
D000962:Antimalarials; D003692:Delayed-Action Preparations; D063065:Organophosphonates; D009943:Organophosphorus Compounds; C050127:9-(S)-(3-hydroxy-2-(phosphonomethoxy)propyl)adenine; D000225:Adenine; D011339:Probenecid