Document 0971
 DOCN  M95A0971
 TI    Preclinical toxicity evaluation of beta-F-ddA in the rat and dog
       (Meeting abstract).
 DT    9510
 AU    Tomaszewski JE; Schweikart KM; Wilkinson GE; Graves S; Mahon C; Toft J;
       Yarrington J; Placke ME; NCI, Bethesda, MD 20892
 SO    Proc Annu Meet Am Assoc Cancer Res; 36:A2184 1995. Unique Identifier :
       AIDSLINE ICDB/95609959
 AB    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.
 DE    Animal  Antiviral Agents/*TOXICITY  Deoxyadenosines/*TOXICITY
       Dideoxyadenosine/*ANALOGS & DERIVATIVES/*TOXICITY  Dogs  Dose-Response
       Relationship, Drug  Drug Screening  Rats  MEETING ABSTRACT

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       protected by Copyright Law (Title 17, U.S.Code).