Acute cardiotoxicity of nucleoside analogs FddA and FddI in rats.
The acute cardiotoxic potential of single dosages of FddA (2'-fluoro-2',3'-dideoxyadenosine) and FddI (2'-fluoro-2',3'-dideoxyinosine) was investigated in 6- to 9-week-old rats. Both nucleoside analogs were administered orally at 1000 and 2000 mg/kg and intravenously at 500 or 1000 mg/kg. For comparative purposes, additional groups of rats received 2'-deoxyadenosine or the 2-fluororibose moiety common to both the FddA and FddI molecules. The effects of two adenosine receptor antagonists, caffeine and theophylline, on the cardiotoxicity induced by FddA were also investigated. Deaths occurred within a few hours to a few days in FddA-treated rats given 2000 mg/kg orally or 500 mg/kg intravenously and in FddI-treated rats given 1000 mg/kg intravenously. Microscopic examination of the hearts revealed myocardial degeneration and necrosis for all rats that died and myocardial fibrosis for many survivors. No deaths or cardiac lesions were observed after administration of 2'-deoxyadenosine or the 2-fluororibose moiety. FddA was more cardiotoxic than FddI in rats at equivalent dosages administered either orally or intravenously. Based on the anatomic findings, all deaths were attributed to cardiac lesions. The administration of high, oral dosages of caffeine and theophylline accentuated the acute cardiotoxicity of FddA in rats.
Department of Investigative Toxicology, Bristol-Myers Squibb Pharmaceutical Research Institute, Syracuse, New York 13221-4755.
C R
CR
Comereski
W A
WA
Kelly
T J
TJ
Davidson
W A
WA
Warner
L D
LD
Hopper
F B
FB
Oleson
D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000633:toxicity*; D001522:Behavior, Animal / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D016049:Didanosine / Q000031:analogs & derivatives* / Q000633:toxicity*; D016048:Dideoxyadenosine / Q000031:analogs & derivatives* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D006331:Heart Diseases / Q000139:chemically induced* / Q000473:pathology; D007275:Injections, Intravenous; D008297:Male; D009206:Myocardium / Q000473:pathology; D009336:Necrosis / Q000139:chemically induced; D051381:Rats; D017207:Rats, Sprague-Dawley; D014970:Xanthines / Q000633:toxicity
D000998:Antiviral Agents; D014970:Xanthines; C055502:2-fluoro-2',3'-dideoxyadenosine; C008514:methylxanthine; D016048:Dideoxyadenosine; D016049:Didanosine