Preclinical toxicity evaluation of beta-F-ddA in the rat and dog (Meeting abstract). NLM AIDSLINE Important note: Information in this article was accurate in 1995. The state of the art may have changed since the publication date.

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Preclinical toxicity evaluation of beta-F-ddA in the rat and dog (Meeting abstract).

Proc Annu Meet Am Assoc Cancer Res; 36:A2184 1995. Unique Identifier : AIDSLINE ICDB/95609959
Tomaszewski JE; Schweikart KM; Wilkinson GE; Graves S; Mahon C; Toft J; Yarrington J; Placke ME; NCI, Bethesda, MD 20892

Abstract: The safety and toxicity of beta-F-ddA, an anti-HIV, acid-stable, purine dideoxynucleoside was evaluated in preclinical studies. When beta-F-ddA was administered orally on a bid schedule to the rat, 1000 mg/kg/day produced mild cardiotoxicity. Oral doses up to 500 mg/kg/day were nontoxic in the dog when administered on a bid schedule. Plasma levels associated with these dose levels were 300-539 uM in the rat and 200-262 uM in the dog. The relevance of the cardiotoxicity produced in the rat to man is unknown and seems to indicate a species sensitivity rather than a true dose-limiting toxicity. In the studies performed to date, there is no indication that cardiotoxicity was produced due to a cumulative effect, but appeared to be related to high peak plasma levels of the parent compound, beta-F-ddA. Since the in vitro IC50 is only 10 uM, beta-F-ddA appears to have a wide therapeutic index and should be considered for Phase I clinical trials.
Keywords: Animal Antiviral Agents/*TOXICITY Deoxyadenosines/*TOXICITY Dideoxyadenosine/*ANALOGS & DERIVATIVES/*TOXICITY Dogs Dose-Response Relationship, Drug Drug Screening Rats ABSTRACTKWDanimalantiviralagents/KWDtoxicitydeoxyadenosines/KWDtoxicitydideoxyadenosine/KWDanalogs&derivatives/KWDtoxicitydogsdose-responserelationship,drugdrugscreeningratsabstract
951030
M95A0972

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