Effect of 1-methyl-1,2,3,4-tetrahydroisoquinoline on the protective action of various antiepileptic drugs in the maximal electroshock-induced seizure model: a type II isobolographic analysis.

The aim of this study was to characterize the interaction between 1-methyl-1,2,3,4-tetrahydroisoquinoline (1-MeTHIQ-an endogenous parkinsonism-preventing substance) and various antiepileptic drugs [AEDs: clonazepam (CZP), ethosuximide (ETS), gabapentin (GBP), levetiracetam (LEV), tiagabine (TGB) and vigabatrin (VGB)] in the mouse maximal electroshock (MES)-induced seizure model. Results indicate that 1-MeTHIQ in combination with CZP (at the fixed ratios of 50:1 and 25:1), ETS (1:10) and GBP (1:1, 1:2, 1:5 and 1:10) exerted supra-additive (synergistic) interactions in the mouse MES model. In contrast, 1-MeTHIQ in combination with CZP (200:1 and 100:1), ETS (1:1, 1:2 and 1:5), LEV and VGB (1:1, 1:2, 1:5 and 1:10), and TGB (200:1, 100:1, 50:1 and 25:1) produced additive interaction in the mouse MES model. Total brain AED concentrations were unaffected by 1-MeTHIQ, and inversely, CZP, ETS and GBP had no impact on total brain concentrations of 1-MeTHIQ, indicating pharmacodynamic nature of synergistic interactions between 1-MeTHIQ and the tested AEDs in the mouse MES model. In conclusion, the supra-additive interactions of 1-MeTHIQ with CZP (at the fixed ratios of 50:1 and 25:1), ETS (1:10) and GBP (1:1, 1:2, 1:5 and 1:10) in the mouse MES model appear to be particularly favorable combinations from a clinical viewpoint. The additive combinations of 1-MeTHIQ with CZP (100:1, 50:1), ETS (1:1, 1:2 and 1:5), LEV and VGB (1:1, 1:2, 1:5, and 1:10), and TGB (200:1, 100:1, 50:1 and 25:1) seem to be neutral and worthy of consideration in further clinical practice.

Effects of three calcium channel antagonists (amlodipine, diltiazem and verapamil) on the protective action of lamotrigine in the mouse maximal electroshock-induced seizure model.

The aim of this study was to assess the effect of three calcium channel antagonists (amlodipine, diltiazem and verapamil) on the anticonvulsant action of lamotrigine (a second generation antiepileptic drug) against maximal electroshock-induced seizures in mice. Results indicated that all three calcium channel antagonists when administered alone [amlodipine (up to 20 mg/kg, ip), diltiazem (up to 10 mg/kg, ip) and verapamil (up to 20 mg/kg, ip)], did not significantly affect the threshold for maximal electroconvulsions in mice. However, amlodipine at a non-protective dose of 20 mg/kg, ip significantly enhanced the anticonvulsant activity of lamotrigine in the maximal electroshock-induced seizure test in mice by reducing its ED(50) value from 6.33 to 2.87 mg/kg (p < 0.05). In contrast, amlodipine at lower doses of 5 and 10 mg/kg, ip, diltiazem (at doses up to 10 mg/kg, ip) and verapamil (at doses up to 20 mg/kg, ip) had no significant impact on the antiseizure action of lamotrigine in the maximal electroshock-induced seizure test in mice. In conclusion, one can ascertain that the favorable combination of lamotrigine with amlodipine deserves more attention from a clinical viewpoint because of the enhanced antiseizure action of lamotrigine.

Characterization of acute adverse-effect profiles of selected antiepileptic drugs in the grip-strength test in mice.

The aim of this study was to assess the acute adverse effects (neurotoxic) of several antiepileptic drugs (clonazepam, lamotrigine, oxcarbazepine, phenytoin, phenobarbital and topiramate) by measuring skeletal muscular strength in mice using the grip-strength test. Linear regression analysis of grip-strength in relation to drug dose-response allowed us to determine D(50) values, the dosages of antiepileptic drugs that reduced grip-strength in mice by 50% compared to control animals. Each of the antiepileptic drugs studied reduced skeletal muscular strength in mice in a dose-dependent manner. The D(50) for clonazepam was 31.7 mg/kg, lamotrigine -47.7 mg/kg, oxcarbazepine -87.3 mg/kg, phenobarbital -128.7 mg/kg, phenytoin -69.7 mg/kg, and topiramate -509.5 mg/kg. In conclusion, the grip-strength test can aid in evaluating acute adverse effects of drugs with respect to their influence on muscular strength in experimental animals.

Effects of amlodipine, diltiazem, and verapamil on the anticonvulsant action of topiramate against maximal electroshock-induced seizures in mice.

To assess the effect of 3 calcium channel antagonists (amlodipine, diltiazem, and verapamil) on the anticonvulsant action of topiramate (a new generation antiepileptic drug) in the mouse maximal electroshock seizure (MES) model. Amlodipine (20 mg/kg) significantly enhanced the anticonvulsant activity of topiramate in the MES test in mice, reducing its ED50 value from 54.83 to 33.10 mg/kg (p < 0.05). Similarly, diltiazem (5 and 10 mg/kg) markedly potentiated the antiseizure action of topiramate against MES, lowering its ED50 value from 54.83 to 32.48 mg/kg (p < 0.05) and 28.68 mg/kg (p < 0.01), respectively. In contrast, lower doses of amlodipine (5 and 10 mg/kg) and diltiazem (2.5 mg/kg) and all doses of verapamil (5, 10, and 20 mg/kg) had no significant impact on the antiseizure action of topiramate. Pharmacokinetic verification of the interaction of topiramate with amlodipine and diltiazem revealed that neither amlodipine nor diltiazem affected total brain topiramate concentration in experimental animals, and thus, the observed interactions were concluded to be pharmacodynamic in nature. The favorable combinations of topiramate with amlodipine or diltiazem deserve more attention from a clinical viewpoint because the enhanced antiseizure action of topiramate was not associated with any pharmacokinetic changes in total brain topiramate concentration.