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Two selective excitatory amino acid antagonists, DL-(E)-2-amino-4-methyl- 5-phosphono-3-pentenoic acid (CGP 37849) and its carboxyethylester (CGP 39551), were studied against audiogenic seizures in genetically epilepsy-prone rats following oral administration. Acute administration of CGP 37849 attenuated the clonic and tonic phases of the audiogenic seizures (109 dB, 12-16 kHz) 120 min after pretreatment (ED50 19.7 and 11.2 mumol kg-1, respectively). Similarly, CGP 39551 attenuated the clonic and tonic phases of audiogenic seizures 120 min after acute treatment with ED50 values of 17.2 and 8.8 mumol kg-1, respectively. For chronic studies animals were treated orally once daily (at 10 h) for 4 weeks with CGP 37849 (20 or 40 mumol kg-1) or CGP 39551 (15 or 30 mumol kg-1). In order to assess anticonvulsant activity, rats were subjected to auditory stimulation 120 min after drug administration on days 1, 3 and 5 and then every 3 or 4 days. Following 2 and 4 weeks of repeated drug administration with CGP 37849 (20 and 40 mumol kg-1) the ED50 values against clonic and tonic seizures were not significantly different from those observed following an acute administration. Similarly, 2 and 4 weeks after repeated treatment CGP 39551 (15 and 30 mumol kg-1) the ED50 values against clonic and tonic seizures were not significantly different from those observed following an acute administration. There was no significant difference between the ED50 values following either acute or repeated treatment of the two excitatory amino acid antagonists suggesting a lack of development tolerance. The duration of anticonvulsant activity observed between 0.5 and 24 h following administration of CGP 37849- and CGP 39551 was similar in acute and chronic treatment. The effects of CGP 37849 and CGP 39551 on motor behaviour was also evaluated following acute and repeated treatment by a rotarod apparatus 110 min following drug administration. The TD50 values for CGP 37849 and CGP 39551-induced impairment of locomotor performance recorded 2 or 4 weeks of repeated administration were not significantly different from those observed following an acute administration. The TD50 values for CGP 37849- and CGP 39551-induced impairment of locomotor performance were 87.6 and 70.8 mumol kg-1 i.p. respectively following 2 weeks treatment and 92.9 and 76.9 mumol kg-1 i.p. respectively following 4 weeks treatment. The doses of CGP 37849 and CGP 39551 required to elicit motor impairment were at least an order of magnitude above required for anticonvulsant activity. Since these compounds showed anticonvulsant properties after oral administration and lack of development of tolerance after repeated treatment, a potential use for antiepileptic therapy in man is suggested.

1. The effects of some anticonvulsant drugs against seizures induced by a combined treatment with aminophylline and quinolone in genetically epilepsy-prone rat have been investigated. 2. Animals were intraperitoneally pretreated with carbamazepine, diazepam, phenobarbital, CPPene and dizocilpine or saline and 15 min later administered orally with 51.86 mumol/kg b. wt of either cinoxacin or ciprofloxacin. 60 min after quinolones, rats received intraperitoneally aminophylline (100, 120, 140, 160 or 180 mg/kg b. wt). 3. Ciprofloxacin showed to be more effective than cinoxacin in potentiating the aminophylline convulsant effects. 4. Neither carbamazepine nor diazepam and phenobarbital, at the lowest dose used, elicited any effect in reducing the aminophylline-induced seizures in both cinoxacin- and ciprofloxacin-treated animals. Whereas, diazepam and phenobarbital when administered i.p. at 2.5 and 60 mg/kg b. wt respectively demonstrated protective properties. 5. CPPene and dizocilpine, two excitatory amino acid antagonists, were both very effective in antagonizing the seizures produced by concomitant treatment with cinoxacin or ciprofloxacin plus aminophylline. 6. The present results suggest an involvement of the excitatory amino acid receptors in mediating the seizures induced by the combined treatment with quinolones and aminophylline.

1. The effects of a chronic treatment with several quinolone derivatives on on the aminophylline-induced convulsions in the genetically epilepsy-prone rat have been investigated. 2. Two series of experiments have been performed: in the first one animals received the quinolone twice a day for 5 days, then were given aminophylline (80-140 mg.kg-1, i.p.); in the second series of experiments the rats were treated once a day with the quinolone plus 120 mg.kg-1 of aminophylline for 5 days. The changes induced by both treatment protocols on electrocortical activity and on the occurrance of seizures have been evaluated. 3. Enoxacin reduced the dose of aminophylline necessary for the induction of seizures in a higher degree with respect to the other quinolone derivatives. The derivatives which showed minor proconvulsant properties were ofloxacin, ciprofloxacin and cinoxacin. The potentiation of seizures induced by quinolones appeared a dose-dependent phenomenon which was more evident when high doses of quinolones were used. 4. The chronic treatment carried out daily with quinolones and aminophylline suggests that additive neurotoxic effects of both classes of drugs may contribute to the increase of severity of seizure scores. 5. The possible role of GABA-benzodiazepine, excitatory amino acid, purinergic mechanisms as well as the role of pharmacokynetic factors are discussed.