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Antimalarial and toxic effects of the acyclic nucleoside phosphonate (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine in Plasmodium berghei-infected mice.

Abstract
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.
AuthorsL J Smeijsters, H Nieuwenhuijs, R C Hermsen, G M Dorrestein, F F Franssen, J P Overdulve
JournalAntimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 40 Issue 7 Pg. 1584-8 (Jul 1996) ISSN: 0066-4804 [Print] United States
PMID8807044 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antimalarials
  • Delayed-Action Preparations
  • Organophosphonates
  • Organophosphorus Compounds
  • 9-(S)-(3-hydroxy-2-(phosphonomethoxy)propyl)adenine
  • Adenine
  • Probenecid
Topics
  • Adenine (analogs & derivatives, pharmacology, toxicity)
  • Animals
  • Antimalarials (pharmacology, toxicity)
  • Delayed-Action Preparations
  • Malaria (drug therapy)
  • Mice
  • Mice, Inbred BALB C
  • Organophosphonates
  • Organophosphorus Compounds (pharmacology, toxicity)
  • Plasmodium berghei
  • Probenecid (pharmacology)

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