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.