       Document 0423
 DOCN  M9640423
 TI    Acute cardiotoxicity of the Anti-HIV dideoxynucleoside, F-ddA, in the
       rat.
 DT    9604
 AU    Donzanti BA; Kelley JA; Tomaszewski JE; Roth JS; Tosca P; Placke M;
       Singer A; Yarrington JT; Driscoll JS; Battelle Memorial Institute,
       Columbus, Ohio 43201, USA.
 SO    Fundam Appl Toxicol. 1995 Sep;27(2):167-76. Unique Identifier : AIDSLINE
       MED/96077634
 AB    2'-beta-Fluoro-2',3'-dideoxyadenosine (F-ddA), an acid-stable, purine
       dideoxynucleoside with in vitro anti-HIV activity, has been selected by
       the NCI as a clinical trial candidate. A recent report that high, single
       doses of F-ddA produce cardiotoxicity in rats prompted the present
       investigation whose objective was to quantitate this effect and
       establish a relationship between this toxicity and F-ddA plasma
       concentrations. Microscopic examination of cardiac tissues for
       degenerative lesions established the effects of F-ddA and ddA on three
       iv schedules [daily x 1(2.5-250 mg/kg); daily x 5(125, 250 mg/kg), and
       BID x 1 (250 mg/kg)] as well as one oral schedule [BID x 1 (500 mg/kg)
       using 8- to 12-week old female Sprague-Dawley rats. For both F-ddA and
       ddA, the group mean severity of the cardiac lesions was dose-dependent
       and proportional to the measured plasma concentrations of the
       undeaminated parent drugs. F-ddI and ddI, were essentially nontoxic in
       this study (iv, 250 mg/kg, daily x 1 and daily x 5), since plasma
       concentrations exceeding 2 mM produced only minimal cardiac lesions. The
       cardiomyopathy of F-ddA was minimal to mild for all iv doses except 250
       mg/kg (daily x 1) and usually was greater than that of ddA at any given
       dose. This is a consequence of the fact that F-ddA is deaminated 20
       times more slowly than ddA, resulting in higher plasma concentrations of
       F-ddA relative to ddA at any given time for any given dose. Neither
       F-ddA nor ddA was more cardiotoxic on a repeated iv schedule (daily x 5)
       than when administered only once, suggesting that rat cardiotoxicity is
       related Cmax rather than total exposure. In this most sensitive species,
       the formation of cardiac lesions above the background level is
       associated with i.v. F-ddA administration when the F-ddA plasma
       concentration approaches 300 microM, 30-50 times the anticipated
       therapeutic level in humans.
 DE    Administration, Oral  Animal  Antiviral
       Agents/PHARMACOKINETICS/*TOXICITY  Chromatography, High Pressure Liquid
       Dideoxyadenosine/*ANALOGS & DERIVATIVES/PHARMACOKINETICS/TOXICITY
       Female  Heart Diseases/*CHEMICALLY INDUCED/PATHOLOGY  HIV/*DRUG EFFECTS
       Injections, Intravenous  Myocardium/PATHOLOGY  Rats  Rats,
       Sprague-Dawley  Support, U.S. Gov't, P.H.S.  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

