Comparison of effect of ethanol and anticonvulsants on cardiovascular drug-modified cocaine toxicity.
The anticonvulsant (AC drug)- or ethanol (EtOH)-modified effects of cardiovascular (CV) drugs against cocaine (COCA)-induced toxicity were examined in male ICR mice. Nontoxic doses of the CV drugs nimodipine (NIMO), prazosin (PRA), phentolamine (PHEN), propranolol (PRO), and enalapril (ENA) were used with or without the AC drugs diazepam (DZP), phenobarbital (PHB), phenytoin (PHY), and EtOH. Each CV drug combined with or without each AC drug was administered intraperitoneally (IP) 5 min before an IP injection of COCA 75 mg/kg. Of the CV drugs examined, PRA 5 mg/kg and PHEN 5 mg/kg protected against COCA-induced seizures, but only the alpha1-adrenergic blocking agent PRA protected against COCA-induced deaths. Of the AC drugs examined, DZP 5 mg/kg and PHB 50 mg/kg, as well as EtOH 3 g/kg, attenuated the severity of the COCA-induced seizures, but only PHB protected against COCA-induced deaths. The total mortality rate was significantly, often synergistically, decreased compared to the COCA-only group when the appropriate CV drugs were combined with the AC drugs: PRA 5 mg/kg in the EtOH-cotreated groups, PRA 5 mg/kg, PHEN 5 mg/kg or ENA 10 mg/kg in the DZP-cotreated groups, and NIMO 5 mg/kg, PRA 5 mg/kg, PHEN 5 mg/kg, or PRO 10 mg/kg in the PHB-cotreated groups. The decrease in the COCA concentration in the blood and/or brain was not always accompanied by an attenuation of the mortality rate. However, the attenuation of severe seizures by a single PRA, PHEN, DZP, or PHB cotreatment was accompanied by a decrease in the brain COCA concentration.
Hayase
T
T
Department of Legal Medicine, Faculty of Medicine, Kyoto University Graduate School of Medicine, Yoshidakonoe-cho, Sakyo-ku, 606-8501, Kyoto, Japan. hayaselab@jweb.co.jp
Yamamoto
Y
Y
Yamamoto
K
K
Fukui
Y
Y
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002317:Cardiovascular Agents / Q000494:pharmacology*; D003042:Cocaine / Q000493:pharmacokinetics / Q000633:toxicity*; D003975:Diazepam / Q000494:pharmacology; D004656:Enalapril / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010634:Phenobarbital / Q000494:pharmacology; D010646:Phentolamine / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D012640:Seizures / Q000517:prevention & control
D000927:Anticonvulsants; D002317:Cardiovascular Agents; D000431:Ethanol; D004656:Enalapril; D011433:Propranolol; D003042:Cocaine; D003975:Diazepam; D010634:Phenobarbital; D010646:Phentolamine