Topiramate potentiates the antiseizure activity of some anticonvulsants in DBA/2 mice

Topiramate (1-50 mg/kg, intraperitoneally (i.p.)) was able to antagonize audiogenic seizures in DBA/2 mice in a dose-dependent manner. Topiramate at dose of 2.5 mg/kg i.p., which per se did not significantly affect the occurrence of audiogenic seizures in DBA/2 mice, potentiated the anticonvulsant activity of carbamazepine, diazepam, felbamate, lamotrigine, phenytoin, phenobarbital and valproate against sound-induced seizures in DBA/2 mice. The degree of potentiation induced by topiramate was greatest for diazepam, phenobarbital and valproate, less for lamotrigine and phenytoin and not significant for carbamazepine and felbamate. The increase in anticonvulsant activity was associated with a comparable increase in motor impairment. However, the therapeutic index of the combination of all drugs+topiramate was more favourable than that of antiepileptics+ saline, with the exception of carbamazepine or felbamate+topiramate. Since topiramate did not significantly influence the total and free plasma levels of the anticonvulsant drugs studied, we suggest that pharmacokinetic interactions, in terms of total or free plasma levels, are not probable. However, the possibility that topiramate can modify the clearance from the brain of the anticonvulsant drugs studied cannot be excluded. In addition, topiramate did not significantly affect the hypothermic effects of the anticonvulsants tested. In conclusion, topiramate showed an additive effect when administered in combination with some classical anticonvulsants, most notably diazepam, phenobarbital, lamotrigine, phenytoin and valproate.     

Influence of retigabine on the anticonvulsant activity of some antiepileptic drugs against audiogenic seizures in DBA/2 mice

Retigabine (D-2319, 0.5-20 mg/kg i.p.) antagonised dose dependently audiogenic seizures in DBA/2 mice. Retigabine at 0.5 mg/kg i.p., a dose that per se did not affect the occurrence of audiogenic seizures significantly, potentiated the anticonvulsant activity of carbamazepine, diazepam, felbamate, lamotrigine, phenytoin, phenobarbital and valproate against sound-induced seizures in DBA/2 mice. The degree of additivity for the effect induced by retigabine was greatest for diazepam, phenobarbital, phenytoin and valproate, less for carbamazepine and lamotrigine and least for felbamate. The increase in anticonvulsant activity was usually associated with a comparable increase in motor impairment. However, the therapeutic index of combined treatment (drugs plus retigabine), was more favourable than the same drug plus vehicle. Since retigabine had no significant influence on the total and free plasma levels of the anticonvulsant drugs, pharmacokinetic interactions, in terms of total or free plasma levels, are not probable. However, the possibility that retigabine modifies the clearance of the anticonvulsant drugs from the brain cannot be excluded. Retigabine had no significant effect on the hypothermic effects of the anticonvulsants tested. In conclusion, retigabine showed an additive effect when administered in combination with classical anticonvulsants, most notably diazepam, phenobarbital, phenytoin and valproate.     

7-Nitroindazole potentiates the antiseizure activity of some anticonvulsants in DBA/2 mice

7-Nitroindazole, a selective neuronal nitric oxide synthase inhibitor (25-200 mg kg(-1), intraperitoneally (i.p.)) antagonized audiogenic seizures in DBA/2 mice in a dose-dependent manner. We investigated the effects of 7-nitroindazole at a dose of 25 mg kg(-1) i.p., which per se did not show anticonvulsant activity against audiogenic seizures in DBA/2 mice, on the antiseizure activity of some conventional antiepileptic drugs. 7-Nitroindazole sometimes potentiated the anticonvulsant activity of carbamazepine, diazepam, lamotrigine, phenytoin, phenobarbital and valproate against audiogenic seizures in DBA/2 mice. The degree of potentiation by 7-nitroindazole was greatest for phenobarbital and diazepam, less for valproate and least for carbamazepine, lamotrigine and phenytoin. The increase in anticonvulsant activity was associated with a comparable increase in motor impairment. However, the therapeutic index of combined treatment with diazepam+7-nitroindazole, phenobarbital+7-nitroindazole or valproate+7-nitroindazole was more favourable than that of the diazepam+vehicle, phenobarbital+vehicle or valproate+vehicle treatment. The results indicate that 7-nitroindazole is able to increase the protective activity of some conventional antiepileptics and this effect appears not to result only from the impaired synthesis of nitric oxide. In fact, mice receiving 7-nitroindazole (25 mg kg(-1), i.p.) and L-arginine (30 microg/mouse, intracerebroventricularly (i.c.v.) did not show significant changes of ED(50) values in comparison to those of related groups of animals treated with 7-nitroindazole and anticonvulsants. 7-Nitroindazole was able to increase the brain levels of dopamine and noradrenaline and its anticonvulsant effects and changes in catecholamine content were antagonized by pretreatment with alpha-methyl-paratyrosine, an agent inhibiting the synthesis of catecholamines. The fact that alpha-methyl-paratyrosine reverses concomitantly both the increase in brain levels of dopamine and noradrenaline and the anticonvulsant properties of 7-nitroindazole strongly suggests an important role of catecholamines in the antiseizure activity of 7-nitroindazole. Since 7-nitroindazole did not significantly influence the total and free plasma levels of the anticonvulsant drugs studied, we suggest that pharmacokinetic interactions, in terms of total or free plasma levels, are not probable. 7-Nitroindazole did not significantly affect the hypothermic effects of the anticonvulsant compounds studied. 7-Nitroindazole showed an additive effect when administered in combination with some classical anticonvulsants, most notably diazepam, phenobarbital and valproate and its activity could be, in part, due to an increase of monoamine levels.     

Fosinopril and zofenopril, two angiotensin-converting enzyme (ACE) inhibitors, potentiate the anticonvulsant activity of antiepileptic drugs against audiogenic seizures in DBA/2 mice

The renin-angiotensin system (RAS) exists in the brain and it may be involved in pathogenesis of neurological and psychiatric disorders including seizures. The aim of the present research was to evaluate the effects of some angiotensin-converting enzyme inhibitors (ACEi; captopril, enalapril, fosinopril and zofenopril), commonly used as antihypertensive agents, in the DBA/2 mice animal model of generalized tonic-clonic seizures. Furthermore, the co-administration of these compounds with some antiepileptic drugs (AEDs; carbamazepine, diazepam, felbamate, gabapentin, lamotrigine, phenobarbital, phenytoin, topiramate and valproate) was studied in order to identify possible positive interactions in the same model. All ACEi were able to decrease the severity of audiogenic seizures with the exception of enalapril up to the dose of 100mg/kg, the rank order of activity was as follows: fosinopril>zofenopril>captopril. The co-administration of ineffective doses of all ACE inhibitors with AEDs, generally increased the potency of the latter. Fosinopril was the most active in potentiating the activity of AEDs and the combination of ACEi with lamotrigine and valproate was the most favorable, whereas, the co-administrations with diazepam and phenobarbital seemed to be neutral. The increase in potency was generally associated with an enhancement of motor impairment, however, the therapeutic index of combined treatment of AEDs with ACEi was predominantly more favorable than control. ACEi administration did not influence plasma and brain concentrations of the AEDs studied excluding pharmacokinetic interactions and concluding that it is of pharmacodynamic nature. In conclusion, fosinopril, zofenopril, enalapril and captopril showed an additive anticonvulsant effect when co-administered with some AEDs, most notably carbamazepine, felbamate, lamotrigine, topiramate and valproate, implicating a possible therapeutic relevance of such drug combinations.     

Influence of some beta-adrenoceptor antagonists on the anticonvulsant potency of antiepileptic drugs against audiogenic seizures in DBA/2 mice

The two enantiomers of propranolol antagonize generalized tonic-clonic seizures in DBA/2 mice with the (-)-enantiomer being about 1.5 times more potent than the (+)-enantiomer. Metoprolol was less active and atenolol was unable to affect audiogenic seizures. In combination with conventional antiepileptic drugs, both propranolol enantiomers tested in doses not affecting the occurrence of audiogenic seizures increased the anticonvulsant activity of diazepam, phenobarbital, valproate and lamotrigine and tended to increase that of carbamazepine and phenytoin. The effect was more pronounced with the (-)-enantiomer. This increase was associated with an enhancement of motor impairment, however, the therapeutic index of combined treatment of the antiepileptic drugs with both propranolol enantiomers was more favourable than the combination with saline alone. Metoprolol was also able to decrease the ED(50) values of the antiepileptic drugs, whereas atenolol showed no effects. Since neither enantiomer of propranolol significantly influenced the total and free plasma levels of the antiepileptics, pharmacokinetic interactions are not likely. In addition, (+)- and (-)-propranolol did not significantly affect the hypothermic effects of the antiepileptics tested. In conclusion, both enantiomers of propranolol and metoprolol showed an additive anticonvulsant effect when co-administered with some conventional antiepileptic drugs, most notably diazepam, phenobarbital, lamotrigine and valproate, implicating a possible therapeutic relevance of such drug combinations.     

Effects of some calcium antagonists upon the activity of common antiepileptic compounds on sound-induced seizures in DBA/2 mice.

1. Flunarizine (2.65 mumol/kg, i.p.) and nimodipine (5.25 mumol/kg, i.p.) potentiated the anticonvulsant properties of phenytoin, phenobarbital and valproate against audiogenic seizures in DBA/2 mice. 2. Diltiazem (5.25 mumol/kg, i.p.) was able to potentiate the antiseizure activity of phenytoin but was not effective against the anticonvulsant action of phenobarbital and valproate. 3. Verapamil (5.25 mumol/kg, i.p.) was unable to potentiate the anticonvulsant properties of all antiepileptic drugs studied. 4. Bay K 8644 (1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluorophenyl)-pyridine- 5-carboxylic acid), a calcium agonist at a dose of 2.65 mumol/kg, i.p., induced a reduction of anticonvulsant potency of phenytoin, phenobarbital and valproate. 5. None of the calcium antagonists used significantly increased the plasma levels of antiepileptic compounds or significantly affected the body temperature changes induced by anticonvulsant drugs. 6. It may be concluded that some calcium antagonists enhance the anticonvulsant properties of some antiepileptic drugs against audiogenic seizures. A pharmacokinetic interaction does not seem responsible for these effects.     

Synthetic cannabinoid WIN 55,212-2 mesylate enhances the protective action of four classical antiepileptic drugs against maximal electroshock-induced seizures in mice

The aim of this study was to determine the effect of WIN 55,212-2 mesylate (WIN — a non-selective cannabinoid CB1 and CB2 receptor agonist) on the protective action of four classical antiepileptic drugs (carbamazepine, phenytoin, phenobarbital, and valproate) in the mouse maximal electroshock seizure (MES) model. The results indicate that WIN (10 mg/kg, i.p.) significantly enhanced the anticonvulsant action of carbamazepine, phenytoin, phenobarbital and valproate in the MES test in mice. WIN (5 mg/kg) potentiated the anticonvulsant action of carbamazepine and valproate, but not that of phenytoin or phenobarbital in the MES test in mice. However, WIN administered alone and in combination with carbamazepine, phenytoin, phenobarbital and valproate significantly reduced muscular strength in mice in the grip-strength test. In the passive avoidance task, WIN in combination with phenobarbital, phenytoin and valproate significantly impaired long-term memory in mice. In the chimney test, only the combinations of WIN with phenobarbital and valproate significantly impaired motor coordination in mice. In conclusion, WIN enhanced the anticonvulsant action of carbamazepine, phenytoin, phenobarbital and valproate in the MES test. However, the utmost caution is advised when combining WIN with classical antiepileptic drugs due to impairment of motor coordination and long-term memory and/or reduction of skeletal muscular strength that might appear during combined treatment.     

Effect of felbamate and its combinations with conventional antiepileptics in amygdala-kindled rats

We investigated the effect of felbamate, administered singly and in combination with carbamazepine, phenobarbital, phenytoin or clonazepam, on various behavioral and electrographic correlates of seizures in amygdala-kindled rats. Felbamate (5 or 10 mg/kg) significantly increased afterdischarge threshold, shortened seizure and afterdischarge durations but remained without effect on seizure severity. Furthermore, the combination of felbamate (2.5 mg/kg) with carbamazepine (7.5 mg/kg; both drugs at their subeffective doses), was associated with the reduction in seizure severity and afterdischarge duration. In relation to the afterdischarge duration, the antiseizure potency of felbamate and carbamazepine, in combination, was comparable with that of carbamazepine (10 mg/kg) administered alone. Neither carbamazepine (7.5 and 10 mg/kg) nor felbamate (2.5-10 mg/kg) affected seizure severity, whereas the combined administration of felbamate (2.5 mg/kg) with carbamazepine (7.5 mg/kg) led to significant reduction in seizure severity from the fifth to the third stage of Racine's scale. Among the conventional antiepileptic drugs evaluated in this study, only valproate (100 mg/kg) and clonazepam (0.1 mg/kg) exerted similar action on seizure severity. However, the combinations of felbamate (2.5 mg/kg), with subeffective doses of valproate, phenobarbital, phenytoin or clonazepam, were not associated with any protective action. As blood and brain felbamate and carbamazepine concentrations were unaffected, a pharmacokinetic interaction can be excluded and a pharmacodynamic interaction concluded. These data suggest that felbamate and carbamazepine, administered in combination, may be useful in patients with drug-resistant partial epilepsy.     

Effect of 4-(4-bromophenyl)-5-(3-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione on the anticonvulsant action of different classical antiepileptic drugs in the mouse maximal electroshock-induced seizure model

The aim of this study was to determine the effects of 4-(4-bromophenyl)-5-(3-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (TP4-a new S-triazole derivative possessing anticonvulsant properties in preclinical studies) on the protective action of four different classical antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) against maximal electroshock-induced seizures in mice. Results indicate that TP4 administered intraperitoneally at doses of 75 and 100 mg/kg significantly elevated the threshold for electroconvulsions in mice. TP4 at doses of 12.5, 25, 37.5 and 50 mg/kg had no impact on the threshold for electroconvulsions in mice. Moreover, TP4 (50 mg/kg) significantly enhanced the anticonvulsant activity of carbamazepine, phenobarbital and valproate, but not that of phenytoin in the maximal electroshock seizure test in mice. TP4 at 25 mg/kg significantly potentiated the anticonvulsant action of carbamazepine, but not that of phenobarbital, phenytoin and valproate in the mouse maximal electroshock-induced seizure model. Pharmacokinetic experiments revealed that TP4 significantly elevated total brain concentrations of carbamazepine and valproate, having no impact on total brain concentrations of phenobarbital in mice. In conclusion, the enhanced anticonvulsant action of phenobarbital by TP4 was probably pharmacodynamic in nature and, therefore, the combination of TP4 with phenobarbital is worthy of consideration while extrapolating the results from this study into clinical settings. The enhanced anticonvulsant action of carbamazepine and valproate by TP4 in the mouse maximal electroshock-induced seizure model was associated with pharmacokinetic increases in total brain concentrations of the antiepileptic drugs in mice. The combination of TP4 with phenytoin was neutral from a preclinical point of view.     

Chronically administered fluoxetine enhances the anticonvulsant activity of conventional antiepileptic drugs in the mouse maximal electroshock model

Interactions between chronically administered fluoxetine and valproate, carbamazepine, phenytoin, or phenobarbital were studied in the maximal electroshock test in mice. Fluoxetine administered for 14 days at doses up to 20 mg/kg failed to affect the electroconvulsive threshold. Nevertheless the drug (at 15 and 20 mg) enhanced the anticonvulsant activity of valproate, carbamazepine, and phenytoin. When applied at 20 mg/kg, it potentiated the protective action of phenobarbital. Fluoxetine, antiepileptic drugs, and their combinations did not produce significant adverse effects evaluated in the chimney test (motor coordination) and passive-avoidance task (long-term memory). Chronically applied fluoxetine significantly increased the brain concentrations of valproate, carbamazepine, phenobarbital and phenytoin, indicating a pharmacokinetic contribution to the observed pharmacodynamic interactions. In conclusion, long-term treatment with fluoxetine exhibited some favorable effects on the anticonvulsant properties of conventional antiepileptic drugs, resulting, however, from pharmacokinetic interactions.     

Anticonvulsants and breast feeding: a critical review

Progress in the diagnosis and management of seizure disorders and the availability of effective anticonvulsive medications has enabled increasing numbers of epileptic women of child-bearing age to raise families. Breast feeding, which these women may wish to choose, provides health, nutritional, immunological, developmental, social, economic and environmental benefits. The traditional anticonvulsants, such as phenytoin, carbamazepine and valproic acid (valproate sodium), are generally considered safe for use during breast feeding; however, observation for adverse effects is recommended. The use of phenobarbital while breast feeding is controversial because of its slow elimination by the nursing infant. The newer anticonvulsants, such as clobazam, felbamate, gabapentin, lamotrigine, oxcarbazepine, tiagabine, topiramate, and vigabatrin, are used mainly as adjunctive therapy. Data on the use of these drugs in pregnancy and lactation, and regarding long term effects on cognition and behaviour, are sparse. Weighing the benefits of breast feeding against the potential risk to the nursing infant, breast feeding is considered to be safe when the mother is taking carbamazepine, valproic acid or phenytoin. Infant monitoring for potential adverse effects is advisable when the mother is taking phenobarbital, clobazam, gabapentin, lamotrigine, oxcarbazepine or vigabatrin. Monitoring of infant serum drug concentrations is advisable but not compulsory. The use of felbamate, tiagabine and topiramate during breast feeding should await further study.     

Felbamate, gabapentin and topiramate as adjuvant antiepileptic drugs in experimental models of epilepsy.

Newly diagnosed epileptic patients start their medication with monotherapy. Around 30% of epileptic patients require more than one antiepileptic drug. Results from experimental studies provide evidence that administration of two antiepileptic drugs may result in antagonistic, additive, or supra-additive (synergistic) anticonvulsant effects. If adverse effects of a synergistic combination also show supra-additive summation then the protective index may not change. In this context, drug combinations, possessing synergistic anticonvulsant effects and additive (or infra-additive) toxicity, are of clinical interest. Recent experimental data indicate that topiramate and gabapentin generally potentiate the protective activity of conventional antiepileptic drugs against maximal electroshock-induced convulsions in mice. The anticonvulsant action of carbamazepine, diphenylhydantoin, phenobarbital, and valproate was not modified in this test by felbamate at subprotective doses against threshold electroconvulsions. Interestingly, conventional antiepileptics (at subeffective doses) enhanced the protection offered by felbamate. It may indicate that beneficial effects of a drug combination may be observed at only some drug ratios.     

Imperatorin enhances the protective activity of conventional antiepileptic drugs against maximal electroshock-induced seizures in mice

The effects of imperatorin (8-isopentenyloxypsoralen; 9-(3-methylbut-2-enyloxy)-7H-furo[3,2-g]chromen-7-one) on the anticonvulsant activity of four conventional antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) were studied in the mouse maximal electroshock seizure model. Results indicate that imperatorin (30 and 40 mg/kg, i.p.) significantly potentiated the anticonvulsant activity of carbamazepine against maximal electroshock-induced seizures by reducing its median effective dose (ED(50)) from 10.3 to 6.8 (by 34%; P<0.05) and 6.0 mg/kg (by 42%; P<0.01), respectively. Similarly, imperatorin (40 mg/kg, i.p.) markedly enhanced the antielectroshock action of phenobarbital and phenytoin, by lowering their ED(50) values from 19.6 to 12.2 mg/kg (by 38%; P<0.05-phenobarbital) and from 12.8 to 8.5 mg/kg (by 34%; P<0.05-phenytoin) in the maximal electroshock seizure test. In contrast, imperatorin (40 mg/kg, i.p.) did not affect the protective action of valproate against maximal electroshock-induced seizures in mice. Imperatorin at lower doses of 20 and 30 mg/kg had no significant effect on the anticonvulsant activities of conventional antiepileptic drugs in the mouse maximal electroshock seizure model. Pharmacokinetic evaluation of interaction between imperatorin (30 mg/kg, i.p.) and carbamazepine (6.8 mg/kg, i.p.) revealed a significant increase in total brain carbamazepine concentration after imperatorin administration, indicating a pharmacokinetic nature of interaction between these drugs. In cases of phenobarbital and phenytoin, imperatorin (40 mg/kg, i.p.) did not alter significantly total brain concentrations of phenytoin and phenobarbital in mice, and thus, the observed interactions in the maximal electroshock seizure test between imperatorin and phenobarbital or phenytoin were pharmacodynamic in nature. The present study demonstrates that imperatorin enhanced the antiseizure effects of carbamazepine, phenobarbital and phenytoin in the mouse maximal electroshock seizure model. However, the combination of imperatorin with carbamazepine, despite its beneficial effects in terms of seizure suppression in mice, was complicated by a pharmacokinetic increase in total brain carbamazepine concentration in experimental animals. In contrast, the combinations of imperatorin with phenytoin and phenobarbital, due to their beneficial antiseizure effects and no pharmacokinetic interactions between drugs in the brain compartment of experimental animals, deserve more attention and are of pivotal importance for epileptic patients as advantageous combinations from a clinical viewpoint.     

Effect of caffeine on the anticonvulsant effects of oxcarbazepine,lamotrigine and tiagabine in a mouse model of generalized tonic-clonic seizures

Caffeine has been reported to be proconvulsant and to reduce the anticonvulsant efficacy of a variety of antiepileptic drugs (carbamazepine, phenobarbital, phenytoin, valproate and topiramate) in animal models of epilepsy and to increase seizure frequency in patients with epilepsy. Using the mouse maximal electroshock model, the present study was undertaken so as to ascertain whether caffeine affects the anticonvulsant efficacy of the new antiepileptic drugs lamotrigine, oxcarbazepine and tiagabine. The results indicate that neither acute nor chronic caffeine administration (up to 46.2 mg/kg) affected the ED₅₀ values of oxcarbazepine or lamotrigine against maximal electroshock. Similarly, caffeine did not modify the tiagabine electroconvulsive threshold. Furthermore, caffeine had no effect on oxcarbazepine, lamotrigine and tiagabine associated adverse effects such as impairment of motor coordination (measured by the chimney test) or long-term memory (measured by the passive avoidance task). Concurrent plasma concentration measurements revealed no significant effect on lamotrigine and oxcarbazepine concentrations. For tiagabine, however, chronic caffeine (4 mg/kg) administration was associated with an increase in tiagabine concentrations. In conclusion, caffeine did not impair the anticonvulsant effects of lamotrigine, oxcarbazepine, or tiagabine as assessed by electroconvulsions in mice. Also, caffeine was without effect upon the adverse potential of the studied antiepileptic drugs. Thus caffeine may not necessarily adversely affect the efficacy of all antiepileptic drugs and this is an important observation.     

Effect of acutely and chronically administered venlafaxine on the anticonvulsant action of classical antiepileptic drugs in the mouse maximal electroshock model

The influence of acute and chronic treatments with intraperitoneal venlafaxine, a selective serotonin/norepinephrine reuptake inhibitor, on the anticonvulsant activity of selected antiepileptic drugs was studied in the maximal electroshock test in mice. Venlafaxine (12.5 and 25 mg/kg), given either acutely or chronically, significantly increased the electroconvulsive threshold. Moreover, both acute and chronic venlafaxine, applied at the highest subprotective dose of 6.25 mg/kg, enhanced the anticonvulsant effect of valproate, without affecting the protective action of carbamazepine, phenobarbital and phenytoin. The antidepressant did not affect brain concentration of valproate, indicating that the interaction between the two drugs seems pharmacodynamic in nature. Despite the lack of effect on the antielectroshock action of the remaining antiepileptics, acute venlafaxine increased the brain concentration of phenobarbital, while chronic venlafaxine reduced the brain level of phenytoin. In terms of adverse effects, acute/chronic venlafaxine and antiepileptic drugs alone, as well as their combinations, did not produce significant motor or long-term memory deficits in mice. Summing up, it seems that venlafaxine may be considered as a safe drug for the clinical use in patients with epilepsy and depressive disorders.     

Assessment of drug–drug interactions between moxonidine and antiepileptic drugs in the maximal electroshock seizure test in mice

Hypertension is a common comorbid condition with epilepsy, and drug interactions between antihypertensive and antiepileptic drugs (AEDs) are likely in patients. Experimental studies showed that centrally active imidazoline compounds belonging to antihypertensive drugs can affect seizure susceptibility. The purpose of this study was to assess the effect of moxonidine, an I₁-imidazoline receptor agonist, on the anticonvulsant efficacy of numerous AEDs (carbamazepine, phenobarbital, valproate, phenytoin, oxcarbazepine, topiramate and lamotrigine) in the mouse model of maximal electroshock. Besides, the combinations of moxonidine and AEDs were investigated for adverse effects in the passive avoidance task and the chimney test. Drugs were administered intraperitoneally (ip). Moxonidine at doses of 1 and 2 mg/kg ip did not affect the convulsive threshold. Among tested AEDs, moxonidine (2 mg/kg) potentiated the protective effect of valproate against maximal electroshock. This interaction could be pharmacodynamic because the brain concentration of valproate was not significantly changed by moxonidine. The antihypertensive drug did not cause adverse effects when combined with AEDs. This study shows that moxonidine may have a neutral or positive effect on the anticonvulsant activity of AEDs in patients with epilepsy. The enhancement of the anticonvulsant action of valproate by moxonidine needs further investigations to elucidate potential mechanisms involved.     

Cytisine inhibits the anticonvulsant activity of phenytoin and lamotrigine in mice

BackgroundCytisine (CYT), the most commonly used drug for smoking cessation in Poland, was experimentally found to induce convulsions. There is a lack of studies on the influence of CYT on the anticonvulsant activity of antiepileptic drugs (AEDs).MethodsThe effects of CYT on the anticonvulsant activity of six AEDs were examined in maximal electroshock (MES)-induced seizures in mice.ResultsSingle intraperitoneal (ip) administration of CYTin a subthreshold dose of 2 mg/kg antagonized the protective activity of ip phenytoin and lamotrigine against MES-induced seizures in mice. Adose of 1 mg/kg did not reverse the protective activity of phenytoin and lamotrigine. CYT in a dose of 2 mg/kg had no effect on the anticonvulsive activity of carbamazepine, oxcarbazepine, phenobarbital, and valproate magnesium.ConclusionCYT ability to antagonize the anticonvulsive activity of phenytoin and lamotrigine can be of serious concern for epileptic smokers, who might demonstrate therapeutic failure to these drugs resulting in possible breakthrough seizure attacks.     

Potentiation by glycine of anticonvulsant drugs in maximal electroshock seizures in rats

This study evaluated the potentiation by glycine of anticonvulsant drugs in maximal electroshock seizures in rats. Administered alone, glycine (40 mmol/kg, p.o.) induced no anticonvulsant effect or neurotoxicity. Administered together with the anticonvulsants, glycine significantly enhanced the anticonvulsant potency of phenobarbital and carbamazepine. Glycine also potentiated the anticonvulsant actions of MK-801 and diazepam but did not improve the selectivity of the drugs, as effective doses were still associated with neurotoxicity. Glycine did not potentiate phenytoin or sodium divalproate. Administration together with glycine had no significant effect on the concentrations of phenobarbital or carbamazepine in the brain. Administration together with phenobarbital had no relevant effect on the concentration of glycine in the brain but administration of glycine and carbamazepine together resulted in an increased concentration of glycine in the hippocampus and brainstem. These findings indicate a possible glycine-sensitive component in the mechanism of action of phenobarbital, carbamazepine and diazepam in maximal electroshock seizures. Although the mechanism may not be mediated by a glycine-GABA interaction, the evidence does implicate a possible interaction between glycine and anticonvulsant drugs at NMDA receptors.     

2-phosphonomethyl-pentanedioic acid (glutamate carboxypeptidase II inhibitor) increases threshold for electroconvulsions and enhances the antiseizure action of valproate against maximal electroshock-induced seizures in mice

This study examined the effect of 2-(phosphonomethyl)-pentanedioic acid (2-PMPA), a potent and selective inhibitor of glutamate carboxypeptidase II (GCP II), an enzyme releasing glutamate and N-acetyl-aspartate from synaptical terminals, on the electroconvulsive threshold in mice. Moreover, the influence of 2-PMPA on the anticonvulsant activities of four conventional antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) was evaluated in the maximal electroshock-induced seizure test in mice. Results indicated that 2-PMPA (at a dose range of 50-200 mg/kg, i.p.) raised the electroconvulsive threshold in mice dose-dependently. Linear regression analysis of dose-response relationship between the doses of 2-PMPA and their corresponding threshold values allowed the calculation of threshold increasing dose by 20% (TID20), which was 109.2 mg/kg. Moreover, 2-PMPA administered i.p. at a constant dose of 150 mg/kg (the dose increasing the threshold for electroconvulsions) enhanced significantly the anticonvulsant action of valproate, by reducing its median effective dose (ED50) from 281.4 to 230.1 mg/kg (P<0.05). In contrast, 2-PMPA at the lower dose of 100 mg/kg (i.p.) had no impact on the antiseizure activity of valproate in the maximal electroshock-induced seizure test. Likewise, 2-PMPA at 100 and 150 mg/kg did not affect the antiseizure action of carbamazepine, phenobarbital and phenytoin against maximal electroshock-induced seizures in mice. Additionally, none of the combinations investigated between 2-PMPA (150 mg/kg, i.p.) and carbamazepine, phenobarbital, phenytoin and valproate (at their ED50 values) produced motor coordination impairment in the chimney test. Pharmacokinetic evaluation of interaction between 2-PMPA and valproate revealed that 2-PMPA at 150 mg/kg selectively increased total brain concentrations of valproate, remaining simultaneously without any effect on free plasma concentrations of valproate, indicating a pharmacokinetic nature of observed interaction in the maximal electroshock-induced seizures in mice. Based on our preclinical data, it may be concluded that 2-PMPA possesses a seizure modulating property by increasing the electroconvulsive threshold. The reduction of glutamate neurotransmission in the brain, as a consequence of inhibition of GCP II activity by 2-PMPA, was however insufficient to enhance the anticonvulsant activity of conventional antiepileptic drugs, except for valproate, whose antiseizure action against maximal electroconvulsions was potentiated by 2-PMPA. Unfortunately, the favourable interaction between 2-PMPA and valproate was associated with a pharmacokinetic increase in total brain valproate concentrations.     

Influence of antazoline and ketotifen on the anticonvulsant activity of conventional antiepileptics against maximal electroshock in mice.

Experimental studies have indicated that the central histaminergic system plays an important role in the inhibition of seizures through the stimulation of histamine H1 receptors. H1 receptor antagonists, including classical antiallergic drugs, occasionally may induce convulsions in healthy children and patients with epilepsy. The purpose of this study was to investigate the effects of antazoline and ketotifen (two H1 receptor antagonists) on the anticonvulsant activity of antiepileptic drugs against maximal electroshock (MES)-induced convulsions in mice. The following antiepileptic drugs were used: valproate, carbamazepine, diphenylhydantoin and phenobarbital. In addition, the effects of antiepileptic drugs alone or in combination with antazoline or ketotifen were studied on long-term memory (tested in the passive avoidance task) and motor performance (evaluated in the chimney test), acutely and after 7-day treatment with these H1 receptor antagonists. The influence of antazoline and ketotifen on the free plasma and brain levels of the antiepileptics was also evaluated. Antazoline (at 0.5 mg/kg), given acutely and after 7-day treatment, significantly diminished the electroconvulsive threshold. Similarly, ketotifen, after acute and chronic doses of 8 mg/kg markedly reduced the threshold for electroconvulsions. In both cases, antazoline and ketotifen were without effect upon this parameter at lower doses. Antazoline (0.25 mg/kg) significantly raised the ED50 value of carbamazepine against MES (both, acutely and after 7-day treatment). Furthermore antazoline (0.25 mg/kg) also reduced the anticonvulsant activity of diphenylhydantoin, but only after repeated administration, without modifying the brain and free plasma level of this drug. Moreover, valproate and phenobarbital did not change their protective activity when combined with antazoline. Ketotifen (4 mg/kg) possessed a biphasic action, acutely it enhanced the anticonvulsant action of carbamazepine and phenobarbital while, following 7-day treatment, reduced the antiseizure activity of carbamazepine. Ketotifen did not affect the free plasma or brain levels of antiepileptics tested. Only acute antazoline (0.25 mg/kg) applied with valproate impaired the performance of mice evaluated in the chimney test. Ketotifen (4 mg/kg) co-administered with conventional antiepileptic drugs impaired motor coordination in mice treated with valproate, phenobarbital or diphenylhydantoin. Acute and chronic antazoline (0.25 mg/kg) alone or in combination with antiepileptic drugs did not disturb long-term memory, tested in the passive avoidance task. Similarly, ketotifen (4 mg/kg) did not impair long-term memory, acutely and after 7-day treatment. However, valproate alone or in combination with chronic ketotifen (4 mg/kg) worsened long-term memory. The results of this study indicate that H1 receptor antagonists, crossing the blood brain barrier, should be used with caution in epileptic patients. This is because antazoline reduced the protective potential of diphenylhydantoin and carbamazepine. Also, ketotifen reduced the protection offered by carbamazepine and elevated the adverse activity of diphenylhydantoin, phenobarbital and valproate.