Effects of ethanol and/or cardiovascular drugs on cocaine- and methamphetamine-induced fatal toxicities in mice.
The antidotal effects of antihypertensive cardiovascular (CV) drugs against cocaine (COCA)- and methamphetamine (MA)-induced fatal toxicities were examined in mice. Considering the previously-reported favorable interactions, the effects of CV drugs against combined COCA-ethanol (EtOH) or MA-EtOH toxicities were also evaluated. COCA (75 mg/kg) or MA (18 mg/kg) was administered 5 min after an injection of CV drugs, with or without EtOH (3 g/kg); all drugs were injected intraperitoneally. The CV drugs used were 10 mg/kg diltiazem (DIL), 5 mg/kg nimodipine (NIMO) and 5 mg/kg nitrendipine (NITRE) as calcium channel blockers, 5 mg/kg prazosin (PRA) and 5 mg/kg phentolamine (PHEN) as alpha-adrenergic blocking agents, 10 mg/kg propranolol (PRO) as a beta-adrenergic blocking agent, and 10 mg/kg enalapril (ENA) as an angiotensin converting-enzyme inhibitor. In both the COCA (n = 10) and MA (n = 6) groups, regardless of EtOH or CV drug cotreatment, the fatalities could be divided into the early and late deaths, depending on the survival times, the presence of a temporary recovery from acute toxic symptoms such as observable respiratory and locomotive symptoms, and the presence of the drugs (COCA or MA) in blood samples. The acute toxic symptoms included seizures in both the COCA and MA groups, but they were generally suppressed by EtOH regardless of the mortality rate. Some of the CV drugs, such as PRA and PHEN in the COCA groups and DIL, NIMO, NITRE, PRA and PHEN in the MA groups, also suppressed the seizures. The mortality rate was attenuated by PRA in the COCA groups, and by NIMO, NITRE, PRA and PHEN in the MA groups. In the groups cotreated with EtOH, which has been reported to exacerbate the COCA- and MA-induced cardiotoxicity, the frequency of late deaths was increased. Nevertheless, antidotal effects due to NIMO, NITRE, PRA and ENA in the COCA-EtOH groups, and NIMO, NITRE and PRA in the MA-EtOH groups were observed.
Hayase
T
T
Department of Legal Medicine, Kyoto University Graduate School of Medicine, Faculty of Medicine, Japan.
Yamamoto
Y
Y
Yamamoto
K
K
Abiru
H
H
Nishitani
Y
Y
Fukui
Y
Y
D000818:Animals; D000931:Antidotes / Q000494:pharmacology*; D002317:Cardiovascular Agents / Q000494:pharmacology*; D003042:Cocaine / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D000431:Ethanol / Q000494:pharmacology*; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D051379:Mice; D008813:Mice, Inbred ICR; D018675:Toxicity Tests
D000931:Antidotes; D002317:Cardiovascular Agents; D000431:Ethanol; D008694:Methamphetamine; D003042:Cocaine