Reversal of acute theophylline toxicity by calcium channel blockers in dogs and rats.
Theophylline, widely used in the treatment of pulmonary diseases, has a narrow therapeutic index; the recommended plasma levels being 10-20 micrograms/ml in humans. The misuse or abuse of theophylline can cause life-threatening central nervous system and cardiovascular effects. Increased intracellular Ca2+ levels are thought to play an important role in theophylline toxicity and death. The objective of this study was to determine whether Ca2+ channel blockers, e.g. verapamil, nifedipine, or diltiazem, prevent sudden death caused by theophylline treatment in rats and dogs. Groups of Sprague-Dawley rats were treated with theophylline alone (150 mg/kg i.p.) or with theophylline pretreatment followed by administration of verapamil (0.25 to 0.5 mg/kg i.p.), nifedipine (0.25 to 1.0 mg/kg i.p.), or diltiazem (0.5 to 1.0 mg/kg i.p.), 2.5 to 15 min later. The rats were observed for toxic signs and survival over a period of 15 days. All three calcium channel blockers significantly reduced the theophylline-induced sudden death in rats. In a separate study, neither verapamil (0.5 mg/kg i.p.) nor nifedipine (1.0 mg/kg i.p.) prevented the theophylline-induced myocardial necrosis in the rat. In beagle dogs, verapamil (0.5 mg/kg i.v.) prevented theophylline (15 mg/kg/min i.v. for 10 min)-induced hypotension, arrhythmias, and sudden death. Our results support previously reported findings that calcium plays a major role in theophylline-induced toxicity and death.
Whitehurst
V E
VE
Division of Oncology and Pulmonary Drug Products, Food and Drug Administration, Washington, DC 20204, USA.
Joseph
X
X
Vick
J A
JA
Alleva
F R
FR
Zhang
J
J
Balazs
T
T
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000401:mortality / Q000517:prevention & control; D001794:Blood Pressure / Q000187:drug effects; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D016757:Death, Sudden, Cardiac / Q000517:prevention & control; D004110:Diltiazem / Q000008:administration & dosage / Q000494:pharmacology; D004195:Disease Models, Animal; D004285:Dogs; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D007022:Hypotension / Q000401:mortality / Q000517:prevention & control; D007262:Infusions, Intravenous; D007274:Injections, Intraperitoneal; D008297:Male; D009543:Nifedipine / Q000008:administration & dosage / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012119:Respiration / Q000187:drug effects; D013806:Theophylline / Q000008:administration & dosage / Q000633:toxicity*; D014700:Verapamil / Q000008:administration & dosage / Q000494:pharmacology
D001993:Bronchodilator Agents; D002121:Calcium Channel Blockers; D010726:Phosphodiesterase Inhibitors; D013806:Theophylline; D014700:Verapamil; D004110:Diltiazem; D009543:Nifedipine; D002118:Calcium