Enhancement of acute myocardial lesions by asthma drugs in rats.
Asthma morbidity and mortality have risen significantly in the last 10 years. The reasons for the increase are multifactorial. One proposed explanation is possible myocardial toxicity arising from the use of beta-agonists alone or in combination with methylxanthines. Previous studies have shown that beta-agonists given alone and beta-agonist/methylxanthine combinations given at higher than recommended clinical doses induced dose-related cardiotoxicity and sudden death in rats. The objective of the present study was to determine whether or not beta-agonists given alone and in combination with methylxanthines at recommended clinical doses also induce cardiotoxicity and sudden death in rats. The beta-agonists, isoproterenol hydrochloride (15 micrograms/kg), fenoterol hydrobromide (40 micrograms/kg), and terbutaline hemisulfate (0.4 mg/kg) were given in single sc doses separately and concurrently with the methylxanthines aminophylline hydrate (20 mg/kg) and caffeine (40 mg/kg), which were given up to a susceptible animal model, the heavy Sprague-Dawley rat. beta-agonist-induced myocardial toxicity (necrosis) was observed. The toxicity was enhanced by aminophylline resulting in the sudden death (most likely due to ventricular fibrillation) of some animals. A decrease in serum iron levels was observed in rats of all beta-agonist and/or methylxanthine-treated groups.
Whitehurst
V E
VE
Center for Drug Evaluation and Research, Food and Drug Administration, Washington, D.C. 20204.
Joseph
X
X
Alleva
F R
FR
Vick
J A
JA
Whittaker
P
P
Zhang
J
J
Fry
B E
BE
Balazs
T
T
D000208:Acute Disease; D000318:Adrenergic beta-Agonists / Q000633:toxicity; D000818:Animals; D001249:Asthma / Q000188:drug therapy*; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000473:pathology; D016757:Death, Sudden, Cardiac / Q000473:pathology; D004347:Drug Interactions; D007501:Iron / Q000097:blood; D008297:Male; D009206:Myocardium / Q000473:pathology; D009336:Necrosis / Q000473:pathology; D011241:Prednisone / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D014970:Xanthines / Q000633:toxicity
D000318:Adrenergic beta-Agonists; D014970:Xanthines; D007501:Iron; D011241:Prednisone