Hayase T, Yamamoto Y, Yamamoto K, Fukui Y
Department of Legal Medicine, Faculty of Medicine, Kyoto University Graduate School of Medicine, Yoshidakonoe-cho, Sakyo-ku, 606-8501, Kyoto, Japan.
Pharmacol Biochem Behav. 2000 Sep;67(1):151-9. doi: 10.1016/s0091-3057(00)00297-5.
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.
在雄性ICR小鼠中检测了心血管（CV）药物对抗惊厥药（AC药物）或乙醇（EtOH）修饰的可卡因（COCA）诱导毒性的作用。使用无毒剂量的CV药物尼莫地平（NIMO）、哌唑嗪（PRA）、酚妥拉明（PHEN）、普萘洛尔（PRO）和依那普利（ENA），同时使用或不使用AC药物地西泮（DZP）、苯巴比妥（PHB）、苯妥英（PHY）和EtOH。在腹腔注射75mg/kg COCA前5分钟，将每种CV药物与或不与每种AC药物联合腹腔注射（IP）。在所检测的CV药物中，5mg/kg的PRA和5mg/kg的PHEN可预防COCA诱导的惊厥，但只有α1肾上腺素能阻断剂PRA可预防COCA诱导的死亡。在所检测的AC药物中，5mg/kg的DZP和50mg/kg的PHB以及3g/kg的EtOH可减轻COCA诱导惊厥的严重程度，但只有PHB可预防COCA诱导的死亡。当适当的CV药物与AC药物联合使用时，与仅使用COCA的组相比，总死亡率显著降低，且常常具有协同作用：在EtOH联合治疗组中为5mg/kg的PRA，在DZP联合治疗组中为5mg/kg的PRA、5mg/kg的PHEN或10mg/kg的ENA，在PHB联合治疗组中为5mg/kg的NIMO、5mg/kg的PRA、5mg/kg的PHEN或10mg/kg的PRO。血液和/或脑中COCA浓度的降低并不总是伴随着死亡率的降低。然而，单一PRA、PHEN、DZP或PHB联合治疗减轻严重惊厥的同时，脑COCA浓度会降低。
