Interaction of pregabalin with carbamazepine in the mouse maximal electroshock-induced seizure model: a type I isobolographic analysis for non-parallel dose-response relationship curves.

PURPOSE: To characterize the anticonvulsant effects of pregabalin (PGB - a third-generation antiepileptic drug) in combination with carbamazepine (CBZ - a classical antiepileptic drug) in the mouse maximal electroshock (MES)-induced seizure model by using the type I isobolographic analysis for non-parallel dose-response relationship curves (DRRCs). MATERIAL/METHODS: Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (sine-wave, 25mA, 500V, 50Hz, 0.2s stimulus duration) delivered via auricular electrodes. Potential adverse-effect profiles of interaction of PGB with CBZ at the fixed-ratio of 1:1 in the MES test with respect to motor performance, long-term memory, skeletal muscular strength and antinociceptive activity were measured along with total brain CBZ concentrations. RESULTS: In the mouse MES model, PGB administered singly had its DRRC non-parallel to that for CBZ. With type I isobolographic analysis for non-parallel DRRCs, the combination of PGB with CBZ at the fixed-ratio of 1:1 exerted additive interaction. In the combination, neither motor coordination, long-term memory nor muscular strength were affected. PGB administered alone and in combination with CBZ exerted antinociceptive effects, whereas CBZ administered alone produced no antinociceptive activity in mice subjected to the acute thermal pain model. Pharmacokinetic estimation of total brain antiepileptic drug concentrations revealed that PGB had no impact on total brain concentrations of CBZ in experimental animals. CONCLUSIONS: In conclusion, the additive interaction between PGB and CBZ is worthy of consideration while extrapolating the results from this study to clinical settings.

Interaction of tiagabine with valproate in the mouse pentylenetetrazole-induced seizure model: an isobolographic analysis for non-parallel dose-response relationship curves.

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.

Indapamide enhances the protective action of carbamazepine, phenobarbital, and valproate against maximal electroshock-induced seizures in mice.

PURPOSE: To determine the influence of indapamide on the protective action of numerous conventional and second-generation antiepileptic drugs (carbamazepine, lamotrigine, oxcarbazepine, phenobarbital, topiramate and valproate) in the mouse maximal electroshock seizure model. MATERIAL AND METHODS: Electroconvulsions were evoked in Albino Swiss mice by a current (sine-wave, 0.2 s stimulus duration) delivered via auricular electrodes. Adverse-effect profiles with respect to motor performance, long-term memory and skeletal muscular strength were measured along with total brain antiepileptic drug concentrations. RESULTS: Indapamide (up to 3 mg/kg, i.p., 120 min before the test) neither altered the threshold for maximal electroconvulsions, nor protected the animals against maximal electroshock-induced seizures in mice. Moreover, indapamide (3 mg/kg, i.p.) significantly enhanced the anticonvulsant action of carbamazepine, phenobarbital and valproate, but not that of lamotrigine, oxcarbazepine or topiramate in the maximal electroshock seizure test in mice. Indapamide (1.5 mg/kg) had no impact on the anticonvulsant action of all studied antiepileptic drugs in the maximal electroshock seizure test in mice. Estimation of total brain antiepileptic drug concentrations revealed that the observed interaction between indapamide and phenobarbital was complicated by a significant pharmacokinetic increase in total brain concentrations of phenobarbital. In contrast, indapamide had no impact on the total brain concentrations of carbamazepine and valproate in mice. CONCLUSIONS: The selective potentiation of the anticonvulsant action of carbamazepine and valproate by indapamide and lack of any pharmacokinetic interactions between drugs, make the combinations of indapamide with carbamazepine or valproate of pivotal importance for epileptic patients taking these drugs together.

Interactions between tiagabine and conventional antiepileptic drugs in the rat model of complex partial seizures.

This study evaluated the interactions between tiagabine (TGB) and three conventional antiepileptic drugs (AEDs): valproate (VPA), carbamazepine (CBZ), and phenobarbital (PB) in amygdala-kindled rats, a reliable model of complex partial seizures in humans. Isobolographic analysis of interactions revealed that TGB interacted additively with all tested conventional AEDs for the fixed-ratio combinations of 1:3, 1:1, and 3:1. Evaluation of pharmacokinetic interactions between AEDs revealed that the observed additivity was pharmacodynamic in nature. TGB did not affect the plasma and brain concentrations of VPA, CBZ and PB. Similarly, none of the studied conventional AEDs changed the plasma or brain levels of TGB. Also, TGB, VPA, CBZ, and PB administered alone (at their median effective doses) and in combinations at the fixed-ratio of 1:1 did not impair motor performance evaluated in the chimney test. In conclusion, additivity between TGB and conventional AEDs in amygdala-kindled rats and lack of bidirectional pharmacokinetic interactions suggest that TGB appears to be a valuable drug for an add-on therapy of refractory complex partial seizures in humans.

Influence of aminophylline on the anticonvulsive action of gabapentin in the mouse maximal electroshock seizure threshold model.

Accumulating evidence indicates that aminophylline [theophylline(2) x ethylenediamine] markedly attenuates the anticonvulsant action of conventional antiepileptic drugs in experimental animal models of epilepsy and evokes severe seizure activity in patients treated with this methylxanthine. The objective of this study was to determine the influence of acute (single) and chronic (twice daily for 14 consecutive days) treatments with aminophylline on the anticonvulsant potential of gabapentin (a second-generation antiepileptic drug) in the mouse maximal electroshock seizure threshold model. Additionally, the effects of acute and chronic administration of aminophylline on the adverse effect potential of gabapentin in terms of motor coordination impairment were assessed in the chimney test. To evaluate pharmacokinetic characteristics of interaction between drugs, total brain concentrations of gabapentin and theophylline were estimated with high-pressure liquid chromatography and fluorescence polarization immunoassay, respectively. Results indicated that gabapentin (at doses of 75 and 100 mg/kg, i.p.) increased the threshold for electroconvulsions in mice. Aminophylline in non-convulsive doses of 50 and 100 mg/kg (i.p.), both in acute and chronic experiments, did not attenuate the anticonvulsant potential of gabapentin in the maximal electroshock seizure threshold test in mice. Similarly, aminophylline at a dose of 100 mg/kg had no impact on the adverse effect potential of gabapentin in the chimney test. Pharmacokinetic evaluation of total brain concentrations of gabapentin and theophylline revealed no significant changes in total brain concentrations of the drugs after both, acute and chronic applications of aminophylline in combination with gabapentin. The data show that aminophylline did not alter the ability of gabapentin to protect mice against seizures induced by electroconvulsive shock. The observed interaction between gabapentin and aminophylline in both acute and chronic experiments was pharmacodynamic in nature.

7-Nitroindazole potentiates the anticonvulsant action of some second-generation antiepileptic drugs in the mouse maximal electroshock-induced seizure model.

The effects of 7-nitroindazole (7NI, a preferential neuronal nitric oxide synthase inhibitor) on the anticonvulsant activity of four second-generation antiepileptic drugs (AEDs: felbamate [FBM], lamotrigine [LTG], oxcarbazepine [OXC] and topiramate [TPM]) were studied in the mouse maximal electroshock-induced seizure (MES) model. Moreover, the influence of 7NI on the acute neurotoxic (adverse-effect) profiles of the studied AEDs, with regard to motor coordination, was determined in the chimney test in mice. Results indicate that 7NI (50 mg/kg; i.p.) significantly potentiated the anticonvulsant activity of OXC, but not that of FBM, LTG and TPM against MES-induced seizures and, simultaneously, it enhanced the acute neurotoxic effects of TPM, but not those of FBM, LTG and OXC in the chimney test in mice. 7NI at the lower dose of 25 mg/kg had no effect on the antiseizure activity and acute neurotoxic profiles of all investigated AEDs. Pharmacokinetic evaluation of interactions between 7NI and LTG, OXC and TPM against MES-induced seizures revealed no significant changes in free (non-protein bound) plasma AED concentrations following 7NI administration. Moreover, none of the examined combinations of 7NI with AEDs from the MES test were associated with long-term memory impairment in mice subjected to the step-through passive avoidance task. Based on our preclinical study, it can be concluded that only the combination of 7NI with OXC was beneficial, when considering its both anticonvulsant and acute neurotoxic effects. Moreover, the lack of impairment of long-term memory and no pharmacokinetic interactions in plasma of experimental animals make the combination of 7NI with OXC worthy of consideration for the treatment of patients with refractory epilepsy. The other combinations tested between 7NI and LTG, FBM and TPM were neutral, when considering their both anticonvulsant effects and acute neurotoxic profiles, therefore, no useful recommendation can be made for their clinical application.

Is a hypothermic effect of LY300164, valproate and phenobarbital evident in mice?

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.