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Pharmacol Biochem Behav. 2002 Dec;74(1):53-9.
Intracerebroventricular injection of the antibiotic cefoselis produces convulsion in mice via inhibition of GABA receptors.
Yamazaki S, Mochizuki Y, Terai T, Sugimoto M, Uchida I, Matsuoka N, Mutoh S.
Department of Neuroscience, Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 2-1-6 Kashima, Yodogawa-ku, 532-8514, Osaka, Japan. shunji_yamazako.fujisawa.co.jp
A majority of beta-lactam antibiotics (e.g., cephalosporins and penicillins) have convulsive activity to a greater or lesser extent. (6R,7R)-3-[[3-Amino-2-(2-hydroxyethyl)-2H-pyrazol-1-ium-1-yl]methyl]-7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetylamino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate monosulfate (cefoselis), a newly developed injectable beta-lactam antibiotic with activity against methicillin-resistant Staphylococcus aureus (MRSA), might induce convulsions if cerebral concentrations become highly elevated. In the present study, we examined whether or not cefoselis had convulsive activity after direct brain administration, and we attempted to clarify the pharmacological mechanism of action. When cefoselis was injected into the lateral ventricle of the mouse brain at doses higher than 20 microg/animal, it produced convulsions dose-dependently. Cefoselis (50 microg/animal)-induced convulsions were prevented by pretreatment with 5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801), diazepam and phenobarbital (ED(50) values (mg/kg) of 0.78, 1.59 and 33.0, respectively), but not by carbamazepine or phenytoin. When the effects of these anticonvulsants on the convulsions induced by intracerebral injection of bicuculline methiodide (BMI) or N-methyl-D-aspartate (NMDA) were investigated, the inhibitory profile of anticonvulsants on cefoselis-induced convulsions was similar to those induced by BMI (125 ng/animal) but differed markedly in their inhibitory activity on NMDA (100 ng/animal)-induced convulsions, which were not inhibited by diazepam. These results suggest that cefoselis may be convulsive at higher concentrations through a mechanism involving inhibition of gamma-aminobutyric acid (GABA)(A) receptors.
online pharmacy ref. source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12376152&dopt=Abstract
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