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PURPOSE: To characterize the interaction between tiagabine (TGB) and valproate (VPA)--two antiepileptic drugs in the mouse pentylenetetrazole (PTZ)-induced clonic seizure model, type I isobolographic analysis for non-parallel dose-response relationship curves (DRRCs) was used. MATERIAL AND METHODS: Clonic seizures were evoked in albino Swiss mice by subcutaneous injection of PTZ at its CD97 (100 mg/ kg). To ascertain the nature of interaction between TGB and VPA administered in combination, total brain concentrations of TGB and VPA were estimated by using high-performance liquid chromatography (HPLC) and fluorescence polarization immunoassay (FPIA). RESULTS: TGB and VPA produced clear-cut anticonvulsant effects against PTZ-induced clonic seizures in mice and their DRRCs were not parallel to one another. The type I isobolographic analysis for non-parallel DRRCs revealed that the combination of TGB with VPA at the fixed-ratio of 1:1 exerted additive interaction against PTZ-induced clonic seizures in mice. With FPIA, it was found that TGB did not affect total brain VPA concentrations in experimental animals. Moreover, VPA had no significant impact on total brain concentrations of TGB in mice, as measured with HPLC. CONCLUSION: The additive interaction between TGB and VPA at the fixed-ratio of 1:1 in the mouse PTZ model was pharmacodynamic in nature.

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7-Acetyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-1,3-dioxolo-4,5H-2,3-benzodiazepine hydrochloride (LY 300164; a selective noncompetitive AMPA/kainate antagonist; 2 mg/kg) and N(6)-2-(4-aminophenyl)ethyl-adenosine (APNEA; a nonselective adenosine A(1)/A(3) receptor agonist; 2 and 3 mg/kg) significantly raised the threshold for electroconvulsions in mice. In contrast, 5'-N-ethylcarboxamidoadenosine (NECA; a nonselective adenosine A(1)/A(2) receptor agonist; up to 1 mg/kg) did not affect the electroconvulsive threshold. The combined treatment of LY 300164 with NECA or APNEA was superior to single-drug medication as regards their protective action in this seizure model. Moreover, the combinations of LY 300164 with either NECA or APNEA were devoid of motor impairment, although they produced a significant long-term memory deficit. Measurement of the plasma levels of LY 300164 alone and in combination with APNEA or NECA did not suggest pharmacokinetic phenomena as an explanation for the interaction between these drugs. APNEA did not influence the plasma concentration of LY 300164. Moreover, NECA even significantly decreased the plasma levels of the AMPA/kainate antagonist. The present study clearly indicates a strong positive interaction in terms of anticonvulsant activity between LY 300164 and the drugs acting via adenosine receptors.

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PURPOSE: The aim of this study was to evaluate the influence of LY300164 (an AMPA/kainate receptor antagonist) administered alone or in combination with valproate (VPA) or phenobarbital (PB) on body temperature in mice. MATERIAL AND METHODS: The temperature measurements were performed in Albino Swiss mice injected with the respective drugs by using a rectal thermistor thermometer. RESULTS: LY300164, at the dose of 2 mg/kg, did not affect the body temperature of the examined animals. However, the combination of LY300164 (2 mg/kg) with VPA (165 mg/kg) resulted in a significant decrease in body temperature within 60-180 min after their peak of maximum anticonvulsant activity. Moreover, VPA (269 mg/kg) administered alone, evidently produced hypothermic effects at the times between 120-180 min after the peak of the maximum antiseizure effect. In contrast, phenobarbital administered alone or in combination with LY300164 did not affect the body temperature in the mice. CONCLUSIONS: Hypothermia induced by LY 300164 combined with VPA may be useful in various central nervous system disease treatments.

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Aminophylline (50-100 mg/kg) and strychnine (0.125-0.5 mg/kg) significantly raised the ED50 values of LY 300164 against maximal electroshock in mice, from 4 to 8 mg/kg (aminophylline 100 mg/kg) and from 3.6 to 11.5 mg/kg (strychnine 0.5 mg/kg). Also, aminophylline (25-50 mg/kg) and strychnine (0.125-0.25 mg/kg) increased the ED50 value of lamotrigine in this test, for instance from 5.5 to 8.0 mg/kg (aminophylline 50 mg/kg) and from 5.2 to 8.9 mg/kg (strychnine 0.25 mg/kg). Moreover, the ED50S values of aminophylline and strychnine for the reduction of the anticonvulsant effect of LY 300164 (7 mg/kg, the dose equal to its ED97 value against maximal electroshock) were 79.9 and 0.2 mg/kg, respectively. The respective ED50 values for the inhibition of the antiseizure action of lamotrigine were 40.9 and 0.2 mg/kg. Neither bicuculline nor picrotoxin affected the protective action of LY 300164 or lamotrigine. Strychnine significantly lowered the plasma concentrations of LY 300164 and this my point to a pharmacokinetic mechanism of the observed interaction. Aminophylline did not affect the plasma concentrations of the studied anticonvulsant drugs and strychnine - that of lamotrigine, so a pharmacokinetic interaction does not seem probable. The present results indicate that the potential of aminophylline and strychnine to attenuate the anticonvulsant activity of conventional antiepileptics is extended to LY 300164 and lamotrigine.

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A series of benzylamides of N-alkylated, N-acylated or free nine cyclic and one linear amino acids as potential anticonvulsants have been synthesized. The structures of the obtained compounds were designed on the basis of the previously determined structure and physicochemical properties/anticvonvulsant activity relationship of the formerly synthesized compounds of this type. The obtained compounds were evaluated in mice after intraperitoneal (i.p.) administration, by maximal electroshock seizure test (MES test), subcutaneous (s.c.) pentylenetetrazol test (s.c. PTZ test) and by the rotarod neurotoxicity test (Tox test). The results were the basis for their classification into one of three classes of the Anticonvulsant Screening Project (ASP) of the Antiepileptic Drug Development Program (ADDP) of the NIH. Three selected compounds were tested quantitatively in rats after oral administration. The MES ED50, s.c. PTZ ED50, Tox TD50 were determined and their protective index (PI) values were calculated. Anticonvulsant activity of the most promising compound (15) was examined in different seizure models. The respective ED50 and PI values of this compound were as follows: against bicuculline, 73 and 1.4; against PTZ, 47 and 2.2; against strychnine, 73 and 1.4; against pilocarpine 156, and 0.7; against kainic acid (2-carboxy-4-isopropenyl-3-pyrrolidineacetic acid), 39 and 2.6; against AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid), 10 and 10.3 and against NMDA (N-methyl-D-Aspartic acid), 114 and 0.9.

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Valproate and baclofen dose-dependently inhibited both phases of the formalin test. Combination of valproate and baclofen exerted the additive antinociceptive effect on both phases of the formalin test.

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The aim of this study was to evaluate the effects of chronic astemizole and ketotifen administration on the anticonvulsant activity of antiepileptic drugs against maximal electroshock-induced convulsions in mice. Adverse effects were evaluated in the chimney test (motor performance) and passive avoidance task (long-term memory). Brain and plasma levels of antiepileptics were measured by immunofluorescence. Astemizole (2 mg/kg) and ketotifen (8 mg/kg) significantly diminished the electroconvulsive threshold, being without effect upon this parameter at lower doses. Astemizole significantly reduced the anticonvulsant action of phenobarbital and diphenylhydantoin, but it did not affect that of carbamazepine and valproate. Moreover, ketotifen (at the subprotective dose of 4 mg/kg) remained without effect upon the protective activity of valproate, diphenylhydantoin or phenobarbital, but significantly diminished the anticonvulsant effect of carbamazepine. Histamine receptor antagonists combined with antiepileptic drugs, did not alter their brain and free plasma levels. Also, they did not influence adverse potential of carbamazepine, diphenylhydantoin and valproate while that of phenobarbital was significantly enhanced. Valproate, phenobarbital and diphenylhydantoin alone at their ED50s against maximal electroshock or combined with the histamine receptor antagonists disturbed long-term memory. The results of this study indicate that H1 receptor antagonists, should be used with caution in epileptic patients.

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Topiramate [2,3:4, 5-bis-O-(1-methyl-ethylidene-)-beta-D-fructopyranose sulfamate], administered intraperitoneally (i.p.) up to 5 mg/kg, did not influence the threshold for electroconvulsions. In doses of 10-30 mg/kg, topiramate significantly raised the threshold. This novel antiepileptic drug, in subprotective doses, enhanced the protective activity of i.p. given valproate, carbamazepine, dihenylhydantoin and phenobarbital against maximal electroshock-induced convulsions in mice. The potentiation induced by topiramate (2.5-5 mg/kg) was most profound for carbamazepine and phenobarbital. The anticonvulsive activity of valproate and diphenylhydantoin was potentiated by topiramate only at 5 mg/kg. Topiramate (5 mg/kg) combined with valproate, phenobarbital and diphenylhydantoin did not alter their free plasma levels but its combination with carbamazepine resulted in an increased free plasma level of this antiepileptic drug. Treatment with topiramate (5 mg/kg) alone or in combination with the studied antiepileptics (providing 50% protection against maximal electroshock) resulted in no adverse effects, as measured in the chimney test (motor coordination) or passive avoidance task (long-term memory). In contrast, valproate administered alone at its ED(50) against maximal electroshock impaired motor coordination. It is noteworthy that valproate and carbamazepine at their respective ED(50) values of 248 and 11.2 mg/kg disturbed long-term memory. The results provide an experimental basis for rational polytherapy.

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Evidence suggests that metabotropic glutamate receptors (mGluR) are involved in mediating seizures and epileptogenesis. In the present experiments, the selective, group II mGluR agonist (+)-2-aminobicyclo-[3.1.0]hexane-2,6-dicarboxylic acid (LY354740, 0.1-1.0 microM) inhibited spontaneous epileptiform discharges which developed in rat cortical slices in Mg2+-free medium. LY354740 (4-16 mg/kg) administered prior to an injection of pentylenetetrazol (80 mg/kg) or picrotoxin (3.2 mg/kg) produced a dose-dependent decrease in the number of mice exhibiting clonic convulsions, but had no effect on N-methyl-D-aspartate (NMDA, 150 mg/kg)-induced convulsions. LY354740 (4-16 mg/kg) did not affect lethality induced in mice by pentylenetetrazol, picrotoxin or NMDA. LY354740 potentiated the anticonvulsant activity of the conventional antiepileptic drug diazepam, significantly decreasing the ED50 for that drug's effect on pentylenetetrazol-induced convulsions by 30%, but had no influence on anticonvulsant activity of ethosuximide and valproic acid. A pharmacokinetic interaction between LY354740 and diazepam, leading to the lowering of the plasma level of free diazepam, was also demonstrated. Our data suggest that the group II mGluR agonist LY354740 possesses anti-seizure activity and may modify the effects of some conventional antiepileptic drugs.

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The anticonvulsant action of chlormethiazole was evaluated with the use of subthreshold doses of convulsants affecting the purinergic, glycinergic and gamma-aminobutyric acid (GABA)-mediated transmission, i.e. aminophylline, strychnine, bicuculline and picrotoxin in the model of generalized tonic-clonic convulsions. Chlormethiazole protected mice against maximal electroshock-induced seizures with an ED50 of 130.8 mg/kg. Aminophylline (100 mg/kg) and strychnine (0.4 mg/kg) reversed the protective action of chlormethiazole against electroconvulsions raising the ED50 values of this drug to 218.6 and 208.6 mg/kg, respectively. In contrast, GABA antagonists, bicuculline and picrotoxin, neither affected the protection provided by chlormethiazole nor did they alter the protective activity of valproate, phenobarbital, diphenylhydantoin and carbamazepine against electroconvulsions. Our results indicate that (a) the anticonvulsant activity of chlormethiazole might be related to its interaction with strychnine-sensitive glycinergic as well as purinergic neurotransmission, (b) purinergic and strychnine-sensitive glycinergic events contribute more prominently than GABAergic ones to the anticonvulsant activity of the drugs providing protection against maximal electroshock-induced convulsions.

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L-Lysine (250-2,000 mg/kg) and L-histidine (1,000-2,000 mg/kg) significantly raised the electroconvulsive threshold. D-Histidine (1,000 mg/kg) was completely ineffective in this regard. Both amino acids were generally inactive in pentetrazole-, picrotoxin- and aminophylline-induced seizures, though L-histidine (2,500 mg/kg) significantly reduced the number of mice with clonic convulsions in the pentetrazole test. Also, L-lysine (2,500 and 3,000 mg/kg) significantly diminished mortality rate in aminophylline-induced seizures. In addition, L-lysine (2,500-3,000 mg/kg) and L-histidine (2,000-2,500 mg/kg) delayed the onset of aminophylline- and picrotoxin-evoked convulsions. L-Lysine and L-histidine (both up to 1,000 mg/kg) did not affect amygdala-kindled seizures in rats. The results indicate that some of indispensable amino acids may play a role in the inhibitory transmission in the central nervous system. A possibility arises that appropriate diet may be an important supportive factor in the treatment of some epileptic patients, probably suffering from generalized tonic-clonic seizures.

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LY 300164 [7-acetyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-1,3-dioxolo(4, 5H)-2,3-benzodiazepine], administered intraperitoneally up to 2 mg/kg, did not influence the threshold for electroconvulsions. In doses of 2.5-4 mg/kg, LY 300164 significantly raised the threshold. In subprotective doses against electroconvulsions, this excitatory amino acid receptor antagonist enhanced the protective activity of intraperitoneally given valproate, carbamazepine and diphenylhydantoin against maximal electroshock-induced convulsions in mice. The anticonvulsive action of phenobarbital was potentiated by LY 300164 only at 2 mg/kg. The non-N-methyl-D-aspartate receptor antagonist did not affect the plasma levels of the antiepileptic drugs, so a pharmacokinetic interaction is not probable. Combined treatment with LY 300164 (2 mg/kg) and the antiepileptics studied (providing 50% protection against maximal electroshock) did not impair the motor performance of mice, evaluated in the chimney test. Valproate, at its ED50 of 280 mg/kg against maximal electroshock, produced motor impairment. As shown in the passive avoidance task, combination of LY 300164 (2 mg/kg) with valproate or diphenylhydantoin resulted in impairment of long-term memory. Alone among the antiepileptics, valproate (280 mg/kg) and phenobarbital (28.5 mg/kg) disturbed long-term memory. The results suggest that blockade of glutamate-mediated events via non-NMDA receptors leads to enhancement of the anticonvulsive activity of conventional antiepileptics. Some combinations of LY 300164 with antiepileptic drugs were superior to these antiepileptics alone in terms of their lack of adverse effects.

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The aim of this study was to determine the interaction potential of the new antiepileptic drug felbamate (2-phenyl-1,3-propanediol dicarbamate) with three Ca2+ channel blockers (nicardipine, nifedipine, and flunarizine), one Ca2+ channel activator (Bay K 8644; 1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)-phenyl]-3-pyridi ne carboxylic acid), and two methylxanthines (caffeine and aminophylline (theophylline2 . ethylenediamine)) which are all known to markedly change protective effects of conventional antiepileptic drugs. To do so, the maximal electroshock seizure test in mice (an experimental model predicting drug efficacy in the treatment of human generalized tonic-clonic seizures) was employed to (1) quantify changes in the protective efficacy and potency of felbamate produced by adjunct drugs and (2) assess the ability of aminophylline and caffeine to affect protective efficacy afforded by a submaximal protective dose of felbamate against maximal electroshock-induced seizures. Doses of adjunct drugs were selected based on their effects on the threshold for electroconvulsions and on appropriate literature. Nicardipine (10-30 mg/kg), nifedipine (5-20 mg/kg), flunarizine (2.5-10 mg/kg), Bay K 8644 (2.5-5 mg/kg), and aminophylline (50-75 mg/kg) did not change the protective efficacy and potency of felbamate against maximal electroshock-induced tonic convulsions. Aminophylline in the dose of 100 mg/kg, however, diminished the protective potency of felbamate as evidenced by a statistically significant increase in the protective ED50 value of felbamate (a dose, in mg/kg, predicted to protect 50% of mice against convulsive stimulus) from 79.6 to 118 mg/kg; P < 0.05). Aminophylline and caffeine only at high doses (100 and 161.7 mg/kg, respectively) significantly diminished the protective efficacy of felbamate (110 mg/kg) from 96% to 27% and 40% (P < 0.05), respectively. In conclusion, felbamate shows low interaction potential with Ca2+ channel modulators and methylxanthines. Such low interaction potential clearly differentiates felbamate from conventional antiepileptic drugs where protective effects are readily altered by the compounds tested in the present study.

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