Gareri Pietro, Condorelli Daniele, Belluardo Natale, Gratteri Santo, Ferreri Guido, Donato Di Paola Eugenio, De Sarro Angela, De Sarro Giovambattista
Department of Experimental and Clinical Medicine, Faculty of Medicine and Surgery, University of Catanzaro, School of Medicine at Catanzaro, Policlinico Mater Domini, Via T. Campanella, 88100, Catanzaro, Italy.
Eur J Pharmacol. 2004 Jan 19;484(1):49-56. doi: 10.1016/j.ejphar.2003.10.047.
Carbenoxolone, the succinyl ester of glycyrrhetinic acid, is an inhibitor of 11beta-hydroxy steroid dehydrogenase and gap junctional intercellular communication. It is currently used in clinical treatment of ulcer diseases. Systemic administration of carbenoxolone (1-40 mg/kg, intraperitoneally (i.p.)) was able to produce a dose-dependent decrease in DBA/2 audiogenic seizure severity score. Glycyrrhizin, an analogue of carbenoxolone inactive at the gap-junction level, was unable to affect audiogenic seizures at doses up to 30 mg/kg. In combination with conventional antiepileptic drugs, carbenoxolone, 0.5 mg/kg, i.p., which per se did not significantly affect the occurrence of audiogenic seizures in DBA/2 mice, potentiated the anticonvulsant activity of carbamazepine, diazepam, felbamate, gabapentin, lamotrigine, phenytoin, phenobarbital and valproate against sound-induced seizures in DBA/2 mice. This effect was not observed after the combination of glycyrrhizin (10 mg/kg, i.p.) with some conventional antiepileptic drugs. The degree of potentiation induced by carbenoxolone was greater for diazepam, felbamate, gabapentin, phenobarbital and valproate, less for lamotrigine, phenytoin and carbamazepine. This increase was associated with a comparable impairment in motor activity; however, the therapeutic index of combined treatment of antiepileptic drugs with carbenoxolone was more favourable than the combination with glycyrrhizin or saline. Since carbenoxolone did not significantly influence the total and free plasma levels of diazepam, felbamate, gabapentin, lamotrigine, phenytoin, phenobarbital, valproate and carbamazepine, pharmacokinetic interactions are not likely. However, the possibility that carbenoxolone can modify the brain clearance of the anticonvulsant drugs studied may not be excluded. In addition, carbenoxolone did not significantly affect the hypothermic effects of the anticonvulsants tested. In conclusion, carbenoxolone showed an additive anticonvulsant effect when administered in combination with some classical anticonvulsants, most notably diazepam, felbamate, gabapentin, phenobarbital, and valproate, implicating a possible therapeutic relevance of such drug combinations.
甘草次酸的琥珀酸酯——生胃酮，是11β-羟基类固醇脱氢酶和间隙连接细胞间通讯的抑制剂。它目前用于溃疡疾病的临床治疗。腹腔注射（i.p.）生胃酮（1 - 40毫克/千克）能够使DBA/2听源性癫痫严重程度评分呈剂量依赖性降低。甘草甜素是生胃酮在间隙连接水平无活性的类似物，在剂量高达30毫克/千克时无法影响听源性癫痫发作。与传统抗癫痫药物联合使用时，腹腔注射0.5毫克/千克的生胃酮本身对DBA/2小鼠听源性癫痫发作的发生没有显著影响，但能增强卡马西平、地西泮、非氨酯、加巴喷丁、拉莫三嗪、苯妥英、苯巴比妥和丙戊酸对DBA/2小鼠声音诱发癫痫发作的抗惊厥活性。在甘草甜素（10毫克/千克，腹腔注射）与一些传统抗癫痫药物联合使用后未观察到这种效果。生胃酮诱导的增强程度在地西泮、非氨酯、加巴喷丁、苯巴比妥和丙戊酸方面更大，在拉莫三嗪、苯妥英和卡马西平方面较小。这种增加与运动活动的类似损害有关；然而，抗癫痫药物与生胃酮联合治疗的治疗指数比与甘草甜素或生理盐水联合更有利。由于生胃酮对DBA/2小鼠体内地西泮、非氨酯、加巴喷丁、拉莫三嗪、苯妥英、苯巴比妥、丙戊酸和卡马西平的总血浆水平和游离血浆水平没有显著影响，因此不太可能存在药代动力学相互作用。然而，不能排除生胃酮可以改变所研究抗癫痫药物脑清除率的可能性。此外，生胃酮对所测试抗癫痫药物的降温作用没有显著影响。总之，生胃酮与一些经典抗癫痫药物联合使用时显示出相加的抗惊厥作用，最显著的是地西泮、非氨酯、加巴喷丁、苯巴比妥和丙戊酸，这表明这种药物组合可能具有治疗相关性。
