Jin, C Jung, I Ku, HJ Yook, J Kim, DH Kim, M Cho, JH Oh, CH 2024-01-21T14:45:11Z 2024-01-21T14:45:11Z 2021-09-05 1999-11-05 0300-483X https://pubs.kist.re.kr/handle/201004/141839 Since carbapenems and cephalosporins have been suggested to induce convulsive side effects through an inhibitory action on the central gamma-aminobutyric acid (GABA)-mediated inhibitory transmission, the present study evaluated the convulsive activity of a new carbapenem antibiotic (1R,5S,6S)-6[(R)-1-hydroxyethyl]-2-[(3S,5S)-5(S-methyl-4-thiomorpholinylcarbonyl)pyrrolidin-3-thio]-1-methylcarbapen-2-em-3-carboxylic acid (DK-35C) in in vitro and in vivo experiments, in comparison with cefazolin, imipenem and meropenem. In in vitro experiments, their abilities to inhibit [H-3]muscimol (5 nM) binding to GABA, receptors were measured using crude synaptic membranes prepared from the rat cerebral cortex. The concentrations (mM) of the antibiotics which inhibit 50% of the specific binding, were 0.6 for imipenem, 1.8 for cefazolin, 15.4 for DK-35C and 27.6 for meropenem. In in vivo experiments, intracerebroventricular (i.c.v.) injections of cefazolin, imipenem and DK-35C induced convulsions in a dose-dependent manner in rats. The doses (nmol/rat) of the antibiotics which induce convulsions in 50% of rats, were 57 for imipenem, 96 for cefazolin, 377 for DK-35C and > 3000 for meropenem. In the mouse pentyienetetrazole (PTZ) convulsive model, intravenous pretreatment with cefazolin (800 mg/kg) or imipenem (200 mg/kg) shifted the dose-response curve of PTZ (i.p.) to the left, indicating enhancement of the convulsive activity of PTZ. However, pretreatment with cefazolin, meropenem or DK-35C at a dose of 400 mg/kg did not produce any marked effects on the convulsive activity of PTZ compared with the saline vehicle-pretreated control. The results clearly demonstrate a good correlation between in vitro GABA(A) receptor binding assay and in vivo i.c.v. convulsive model using rats, and suggest that DK-35C may possess a relatively weak convulsive activity mediated through an interaction with GABA, receptors. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved. English ELSEVIER SCI IRELAND LTD BETA-LACTAM ANTIBIOTICS CENTRAL-NERVOUS-SYSTEM IMIPENEM-CILASTATIN RECEPTOR-BINDING SEIZURES PENICILLIN MICE BENZODIAZEPINE NEUROTOXICITY DERIVATIVES Low convulsive activity of a new carbapenem antibiotic, DK-35C, as compared with existing congeners Article 10.1016/S0300-483X(99)00078-5 1 TOXICOLOGY, v.138, no.2, pp.59 - 67 TOXICOLOGY 138 2 59 67 scie scopus 000083457300001 2-s2.0-0032848515 Pharmacology & Pharmacy Toxicology Pharmacology & Pharmacy Toxicology Article BETA-LACTAM ANTIBIOTICS CENTRAL-NERVOUS-SYSTEM IMIPENEM-CILASTATIN RECEPTOR-BINDING SEIZURES PENICILLIN MICE BENZODIAZEPINE NEUROTOXICITY DERIVATIVES carbapenem antibiotics DK-35C cefazolin GABA(A) receptors convulsions