Delayed calcium channel blockade with diltiazem reduces paracetamol hepatotoxicity in mice.
1. Diltiazem (30 mg kg-1 body weight, intraperitoneally) given to mice 9 h after paracetamol (450 mg kg-1, orally) reduced liver damage, as judged by plasma aspartate aminotransferase activity (median 186, range 6-602 IU 1(-1), n = 18 vs 466, range 23-3872 IU 1(-1) in 18 saline-treated controls; P less than 0.05) with comparable reductions in mortality (14% vs 33%, respectively; NS). 2. Regenerative activity, as judged by mitotic figures in tissue removed at 30 h after paracetamol, was significantly higher in mice treated at 9 h with diltiazem (median 0.83 per high power field vs 0.1 in saline-treated controls; P less than 0.05). 3. Diltiazem administered earlier or later than 9 h showed reduced efficacy and in some cases potentiated toxicity, as did nifedipine (40 mg kg-1 in divided doses up to 9 h).
Deakin
C D
CD
Institute of Liver Studies, King's College Hospital and School of Medicine and Dentistry, London, UK.
Gove
C D
CD
Fagan
E A
EA
Tredger
J M
JM
Williams
R
R
D000082:Acetaminophen / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury; D004110:Diltiazem / Q000494:pharmacology*; D004334:Drug Administration Schedule; D008107:Liver Diseases / Q000201:enzymology / Q000517:prevention & control*; D008115:Liver Regeneration / Q000187:drug effects; D008297:Male; D051379:Mice; D009543:Nifedipine / Q000494:pharmacology
D000082:Acetaminophen; D001219:Aspartate Aminotransferases; D004110:Diltiazem; D009543:Nifedipine