Intracerebroventricular injection of the antibiotic cefoselis produces convulsion in mice via inhibition of GABA receptors.

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.

Effect of experimental renal failure on the pharmacodynamics of cefoselis-induced seizures in rats.

We investigated the effect of infusion rate and experimental renal failure on the pharmacodynamics of cefoselis (CFSL)-induced seizures. As an animal model of CFSL-induced seizures, male Wistar rats received an intravenous infusion of CFSL at one of three different rates (1.4-5.8 g/h/rat) until the onset of maximal seizures (which occurred after 8.0 to 36.0 min of infusion). Samples of cerebrospinal fluid (CSF), blood (for serum), and brain were obtained immediately after stopping infusion of CSFL. The serum concentration of CFSL at the onset of seizures increased with increasing infusion rate, but brain and CSF concentrations of CFSL at the onset of seizures were not affected by the infusion rate. Ureter-ligated (UL) and control rats received an intravenous infusion of CFSL at 1.4 g/h/rat until the onset of seizures. Then the same procedure as used to determine the effect of infusion rate on the concentrations of CFSL was carried out. Renal failure was associated with a significant decrease in the amount of CFSL required to induce seizures. Serum, brain, and CSF concentrations of CFSL in UL rats were significantly lower than those in control rats. These results indicate that the experimental strategy and animal model in this investigation would be useful to assess the effects of diseases and other variables on the pharmacodynamics of CFSL-induced seizures and that renal failure is one of the risk factors for neurotoxicity of CFSL.

Evaluation of glutathione and ascorbic acid as suppressors of drug-induced lipid peroxidation.

In different sets of experiment lipid peroxidation induction capacity of two drugs, viz., ceftizoxime sodium, a third generation cephalosporin antibiotic, and acyclovir, an antiviral agent, was studied using goat whole blood as the lipid source. Ceftizoxime sodium caused significant extent of lipid peroxidation. Lipid peroxidation being a toxicity mediating process, such observation may be related to the toxic potential of the drug. Insignificant induction of lipid peroxidation was found in case of acyclovir and this is in good agreement with the safety record of the drug. Glutathione and ascorbic acid could significantly reduce ceftizoxime sodium induced lipid peroxidation, suggesting that free radical scavenging action of antioxidants may be exploited by possible antioxidant co-therapy to reduce iatrogenicity of the drug in persons with impaired endogenous antioxidant defence. Glutathione and ascorbic acid appear to be promising candidates for further investigation in this regard.

Non-toxic concentrations of cephem antibiotics for intravitreal application--evaluation by in vitro electroretinogram.

Non-toxic concentrations of ceftazidime (CAZ), cefuzonam sodium (CZON) and cefmetazole sodium (CMZ) for intravitreal use were assessed by the electroretinogram in in vitro perfused eyecups of albino rabbits. None of the a-wave, the b-wave and the oscillatory potentials deteriorated with 300 microM CAZ, 300 microM CZON or 500 microM CMZ. The oscillatory potentials were delayed and/or diminished at the concentration which did not change the a- and b-waves (500 microM and 1.0 mM for CAZ and CZON, 1.0 mM for CMZ). Thus, the oscillatory potentials were more vulnerable to these chemicals than the a- and b-waves. Not only the classical a- and b-waves, but also the oscillatory potentials should be examined in retinal toxicology studies by the electroretinogram.