De Sarro A, Ammendola D, Zappala M, Grasso S, De Sarro G B
Chair of Chemotherapy, School of Medicine, University of Messina, Italy.
Antimicrob Agents Chemother. 1995 Jan;39(1):232-7. doi: 10.1128/AAC.39.1.232.
The epileptogenic activities of several beta-lactam antibiotics were compared following their intracerebroventricular administration in rats. Different convulsant potencies were observed among the various beta-lactam antibiotics tested, but the epileptogenic patterns were similar. The patterns consisted of an initial phase characterized by wet-dog shakes followed by head tremor, nodding, and clonic convulsions. After the largest doses of beta-lactam antibiotics injected, clonus of all four limbs and/or the trunk, rearing, jumping, falling down, escape response, transient tonic-clonic seizures, and sometimes generalized seizures were observed, followed by a postictal period with a fatal outcome. At a dose of 0.033 mumol per rat, cefazolin was the most powerful epileptogenic compound among the drugs tested. It was approximately three times more potent than benzylpenicillin in generating a response and much more potent than other cephalosporins, such as ceftriaxone, cefoperazone, and cefamandole. No epileptogenic signs were observed with equimolar doses of cefotaxime, cefonicid, cefixime, and ceftizoxime in this model. The more convulsant compounds (i.e., cefazolin and ceftezole) are both characterized by the presence of a tetrazole nucleus at position 7 and show a marked chemical similarity to pentylenetetrazole. Imipenem and meropenem, the two carbapenems tested, also showed epileptogenic properties, but imipenem was more potent than meropenem, with a convulsant potency similar to those of ceftezole and benzylpenicillin. In addition, the monobactam aztreonam possessed convulsant properties more potent than those of cefoperazone and cefamandole. This suggest that the beta-lactam ring is a possible determinant of production of epileptogenic activity, with likely contributory factors in the substitutions at the 7-aminocephalosporanic or 6-aminopenicillanic acid that may increase or reduce the epileptogenic properties of the beta-lactam antibiotics. While the structure-activity relationship was also investigated, there seem to be no convincing correlations among the rank order of lipophilicities and the convulsant potencies of the compounds studied. The lack of marked convulsant properties of cefixime, cefonicid, cefuroxime, and cephradine suggests that these antibiotics may interact with a binding site which is different from that by which the beta-lactam antibiotics exert their convulsant effects or may demonstrate a reduced affinity for the relevant site(s).
在大鼠脑室内注射几种β-内酰胺类抗生素后，比较了它们的致痫活性。在所测试的各种β-内酰胺类抗生素中观察到了不同的惊厥效力，但致痫模式相似。这些模式包括一个初始阶段，其特征为湿狗样抖动，随后是头部震颤、点头和阵挛性惊厥。注射最大剂量的β-内酰胺类抗生素后，观察到四肢和/或躯干的阵挛、站立、跳跃、跌倒、逃避反应、短暂的强直-阵挛性发作，有时还会出现全身性发作，随后是一个伴有致命后果的发作后期。在每只大鼠0.033μmol的剂量下，头孢唑林是所测试药物中最强的致痫化合物。在引发反应方面，它的效力约为苄青霉素的三倍，比其他头孢菌素如头孢曲松、头孢哌酮和头孢孟多要强得多。在该模型中，等摩尔剂量的头孢噻肟、头孢尼西、头孢克肟和头孢唑肟未观察到致痫迹象。惊厥性更强的化合物（即头孢唑林和头孢替唑）都具有7位四氮唑核，并且与戊四氮显示出明显的化学相似性。所测试的两种碳青霉烯类药物亚胺培南和美罗培南也显示有致痫特性，但亚胺培南比美罗培南更有效，惊厥效力与头孢替唑和苄青霉素相似。此外，单环β-内酰胺类药物氨曲南的惊厥特性比头孢哌酮和头孢孟多更强。这表明β-内酰胺环可能是致痫活性产生的一个决定因素，7-氨基头孢烷酸或6-氨基青霉烷酸上的取代可能是增加或降低β-内酰胺类抗生素致痫特性的可能因素。虽然也研究了构效关系，但在所研究化合物的亲脂性排序和惊厥效力之间似乎没有令人信服的相关性。头孢克肟、头孢尼西、头孢呋辛和头孢拉定缺乏明显的惊厥特性，这表明这些抗生素可能与β-内酰胺类抗生素发挥惊厥作用的结合位点不同，或者可能对相关位点的亲和力降低。
