Arteriopathy induced by an adenosine agonist-antihypertensive in monkeys.
An adenosine agonist, designated chemically as (R)-N-(2,3-dihydro-1H-inden-1-yl) adenosine or CI-947, was administered orally to 2 males and 2 female cynomolgus monkeys each at 5, 10, 20, and 50 mg/kg of body weight for 2 wk. One male and 1 female given 50 mg/kg were euthanatized on days 10 and 8, respectively, because of poor clinical condition. Emesis was present at 10, 20, and 50 mg/kg. Decreased heart rate and QT prolongation were present at 50 mg/kg. Extramural coronary arterial lesions consisting of medial necrosis with cellular debris and mixed inflammatory cell response in the intima, media, and adventitia were present in 1 male at 20 mg/kg and 1 male at 50 mg/kg at study termination. Similar arterial lesions were present in the small and large intestines and testis of the male at 50 mg/kg. Colonic mucosal erosions with mixed inflammatory cell infiltrates in the lamina propria were seen in this male and in all CI-947 treated females at 10, 20, and 50 mg/kg. Myocardial degeneration and necrosis of myocardial fibers with mononuclear cell infiltrates in the interstititum were noted in the left ventricle of 1 female at 20 mg/kg and in all animals at 50 mg/kg. Renal cortical tubular dilatation with increases in serum creatinine and/or blood urea nitrogen were noted in a control female and animals at 10 and 50 mg/kg. Plasma CI-947 concentration increased with increasing dose. Coronary vascular injury in the monkey was similar to the arterial lesion in CI-947-treated dogs and may relate to the pharmacologic/hemodynamic effects induced by CI-947. When compared with the dog, the monkey appears to be less sensitive to development of arteriopathy, as indicated by lower incidence, at similar systemic exposure levels.
Albassam
M A
MA
Parke-Davis Research Institute, Mississauga, Ontario, Canada. albassm@aa.wl.com
Smith
G S
GS
Macallum
G E
GE
D000241:Adenosine / Q000819:agonists / Q000031:analogs & derivatives* / Q000097:blood / Q000633:toxicity; D000818:Animals; D000959:Antihypertensive Agents / Q000633:toxicity*; D003331:Coronary Vessels / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D007422:Intestines / Q000098:blood supply / Q000473:pathology; D008252:Macaca fascicularis; D008297:Male; D009206:Myocardium / Q000473:pathology; D013737:Testis / Q000098:blood supply / Q000473:pathology; D014652:Vascular Diseases / Q000097:blood / Q000139:chemically induced / Q000473:pathology*
D000959:Antihypertensive Agents; C071201:N-(2,3-dihydro-1H-inden-1-yl)adenosine; D000241:Adenosine