Relationship between structure and convulsant properties of some beta-lactam antibiotics following intracerebroventricular microinjection in rats

Abstract

The epileptogenic activities of several ␤-lactam antibiotics were compared following their intracerebroventricular administration in rats. Different convulsant potencies were observed among the various ␤-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 ␤-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 mol 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 suggests that the ␤-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 ␤-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 ␤-lactam antibiotics exert their convulsant effects or may demonstrate a reduced affinity for the relevant site(s).

Retracted: Convulsant activity and pharmacokinetic–pharmacodynamic modeling of the electroencephalogram effect of gemifloxacin in rats

“…20,21 However, this approach does not take into consideration the CNS diffusion characteristics of these drugs, which may have major impacts on their convulsant activity. 17 The proconvulsive activity of antibiotics on pentylenetetrazol has also been investigated, 22,23 but many parameters may contribute to the observed proconvulsant effects, making data interpretation complex and potentially misleading.…”

Tautomer Selective Photochemistry in 1-(Tetrazol-5-yl)ethanol

“…[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] From a fundamental point of view, tetrazoles are also particularly interesting systems, especially because of the tautomerism they may exhibit and their diversified photochemistry. 1,[21][22][23][24][25][26][27][28][29] Unsubstituted tetrazole, for example, was found to exist exclusively in the crystalline phases as the 1H-tautomer, [30][31][32] whereas in solution and gas phase 1H-and 2H-tautomers coexist, the population of the most polar 1H form increasing with the polarity of the solvent.…”

Penetration of Drugs through the Blood-Cerebrospinal Fluid/Blood-Brain Barrier for Treatment of Central Nervous System Infections

“…for bacterial meningitis (263). After intraventricular injection in rats, cefazolin, imipenem, and aztreonam were most potent in inducing epileptic seizures (49). For this reason, meropenem instead of imipenem is recommended for the therapy of CNS infections.…”