The effect of diazepam in the recovery of rabbits from acute acetaminophen intoxication.
We have recently shown that diazepam can reduce mortality of acute iron overdose in rats. The mechanism for that effect is not yet defined. Our objective in the present study was to assess whether diazepam can similarly reduce mortality of experimental acute acetaminophen intoxication. Survival of rabbits was compared among four groups receiving 3 g/kg (body weight) of acetaminophen (LD40) orally each, followed by: 1) nothing (group I), 2) one oral dose of 140 mg/kg N-acetylcystein (NAC) an hour later (group II), 3) intramuscular injection of 7 mg/kg diazepam (group III), 4) intramuscular injection of 7 mg/kg diazepam and one oral dose of 140 mg/kg NAC an hour later (group IV). 37.5% of rabbits in group I died after 16 hours, whereas none of the rabbits in group III died, (p = 0.04). No animal died during the 96-hour observation period in groups II and IV. Two and four hours post drug administration, acetaminophen plasma concentrations (APC) were significantly lower among rabbits in group III than in group I (p = 0.0007 and 0.01, respectively) and significantly lower among rabbits in group IV than in those in group II (p<0.0001 and p = 0.03, respectively). Acetaminophen plasma concentrations 2 hours after drug administration were also significantly lower among rabbits in group III than in those in group II (p = 0.0002). Seven and 24 hours after dosage, APC tended to be higher among rabbits in group III than in those in group I, but not significantly so. Administration of diazepam without NAC did not prevent liver and renal dysfunction. We conclude that early administration of diazepam in acute experimental acetaminophen overdose in rabbits reduced APC and mortality, probably by slowing intestinal motility, which resulted in delayed acetaminophen absorption from the gastrointestinal tract.
Berkovitch
M
M
Department of Pediatrics, Assaf Harofeh Medical Center, Zerifin, Israel.
Eshel
G
G
Lushkov
G
G
Reznik
S
S
Chen-Levy
Z
Z
Pinto
O
O
Koren
G
G
D000082:Acetaminophen / Q000097:blood / Q000506:poisoning*; D000208:Acute Disease; D000284:Administration, Oral; D000410:Alanine Transaminase / Q000097:blood; D018712:Analgesics, Non-Narcotic / Q000097:blood / Q000627:therapeutic use*; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D003404:Creatinine / Q000097:blood; D003975:Diazepam / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical; D008297:Male; D011817:Rabbits; D015996:Survival Rate; D016896:Treatment Outcome; D014508:Urea / Q000097:blood
D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen; D014508:Urea; D003404:Creatinine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D003975:Diazepam