Influence of ethacrynic acid on the anticonvulsant activity of conventional antiepileptic drugs in the mouse maximal electroshock seizure model

The aim of this study was to determine whether ethacrynic acid (EA), a loop diuretic with anticonvulsant activity, would affect the protective action of the conventional antiepileptics (AEDs) carbamazepine (CBZ), phenytoin (PHT), valproate (VPA) and phenobarbital (PB) in the mouse maximal electroshock seizure (MES) model. The effects of acute and chronic treatment with EA on these AEDs were examined. At a single dose of 100 mg/kg ip, EA enhanced the antielectroshock activity of VPA, decreasing its ED₅₀ value from 225.6 to 146.6 mg/kg (p < 0.05), but enhancement was not observed following continuous administration of EA (12.5 mg/kg) for seven days. Combined treatment of EA with other AEDs had no effect on their ED₅₀ values. The observed interaction between EA and VPA was pharmacodynamic in nature as EA did not alter free plasma (non-protein-bound) and total brain concentrations of VPA. Taking into consideration the clinical use of both drugs, this interaction between EA and VPA can be important for patients receiving these drugs.     

Trazodone reduces the anticonvulsant action of certain classical antiepileptics in the mouse maximal electroshock model

BackgroundThe aim of the study was to examine effects of an acute and chronic treatment with trazodone, a serotonin antagonist and reuptake inhibitor (SARI), on the protective activity of four classical antiepileptic drugs provided in the maximal electroshock test in mice.MethodsElectroconvulsions were produced in mice by means of an alternating current (50 Hz, 25 mA, 0.2 s) and delivered via earclip electrodes. Motor impairment in animals were assessed in the chimney test, and long-term memory deficits were quantified in the passive-avoidance task. Brain concentrations of antiepileptic drugs were analyzed by fluorescence polarization immunoassay.ResultsThe obtained results showed that a single administration of trazodone (up to 40 mg/kg) did not influence the electroconvulsive threshold. In contrast, chronic treatment with the antidepressant (40 mg/kg) significantly increased this parameter. Furthermore, both single and chronic administration of trazodone reduced the anticonvulsant effect of phenytoin and carbamazepine against the maximal electroshock. However, the antidepressant remained without effect on the anticonvulsant action of valproate and phenobarbital. Some interactions between trazodone and antiepileptic drugs may have a pharmacodynamic background. Both, acute and chronic treatment with the antidepressant diminished the brain concentration of phenytoin. Chronic trazodone lowered the brain levels of carbamazepine and phenobarbital. Moreover, acute and chronic trazodone increased the valproate concentration in the brain. As regards undesired effects, acute and chronic trazodone (40 mg/kg), alone and in combination with phenytoin, significantly impaired long-term memory in tested animals, evaluated in the passive avoidance task. Acute trazodone (40 mg/kg) alone and combined with phenytoin produced also significant motor deficits in mice, as measured in the chimney test.ConclusionThe obtained results allow to conclude that trazodone is not a good candidate for an antidepressant drug in epileptic patients.     

Interactions between ACE inhibitors and classical antiepileptic drugs in the mouse maximal electroshock seizures

This study evaluated the effect of two angiotensin-converting enzyme (ACE) inhibitors, enalapril and cilazapril, commonly used antihypertensive drugs, on the protective efficacy of the classical antiepileptics — carbamazepine (CBZ), phenytoin (PHT), valproate (VPA) and phenobarbital (PB). For this purpose, we used the maximal electroshock seizure (MES) test in mice. Additionally, adverse effects of combined treatment with ACE inhibitors and antiepileptic drugs in the passive avoidance task and chimney test were assessed. All drugs were administered intraperitoneally. Neither enalapril (10, 20 and 30 mg/kg) nor cilazapril (5, 10 and 20 mg/kg) affected the threshold for electroconvulsions. Enalapril (30 mg/kg) but not cilazapril (20 mg/kg), enhanced the protective action of VPA, decreasing its ED₅₀ value from 249.5 to 164.9 mg/kg (p < 0.01). Free plasma (non-protein-bound) and total brain concentrations of VPA were not significantly influenced by enalapril. Therefore, the observed interaction could be pharmacodynamic in nature. The combinations of ACE inhibitors with other antiepileptics (CBZ, PHT, and PB) were ineffective in that their ED₅₀ values against MES were not significantly changed. Enalapril and cilazapril remained ineffective as regards memory retention in the passive avoidance task or motor performance in the chimney test. The current study suggests that there are no negative interactions between the studied ACE inhibitors and classical antiepileptic drugs. Enalapril was even documented to enhance the anticonvulsant activity of VPA.     

Enalapril enhances the anticonvulsant activity of lamotrigine in the test of maximal electroshock

BackgroundThe aim of this study was to find out whether angiotensin-converting enzyme (ACE) inhibitors, enalapril and cilazapril, affect the anticonvulsant action of some second-generation antiepileptics, lamotrigine (LTG), topiramate (TPM) and oxcarbazepine (OXC).MethodsThe effects of ACE inhibitors on antiepileptic drugs were examined in the mouse model of maximal electroshock.ResultsEnalapril (30 mg/kg ip) potentiated the anticonvulsant action of LTG, decreasing its ED50 value from 5.3 to 3.6 mg/kg (p < 0.01). The anticonvulsant activity of TPM or OXC was not modified by enalapril. Cilazapril did not affect the protective activity of the studied antiepileptics. The interaction between enalapril and LTG could be pharmacodynamic in nature because enalapril did not change plasma and total brain concentrations of LTG.ConclusionsThis study shows that there are no negative interactions between the studied antiepileptic drugs and enalapril or cilazapril. Enalapril even enhanced the anticonvulsant activity of LTG in the MES test in mice that is thought to be a predictive model of human generalized tonic-clonic seizures.     

Influence of orphenadrine upon the protective activity of various antiepileptics in the maximal electroshock-induced convulsions in mice

Orphenadrine is an anticholinergic drug used in the treatment of Parkinson’s disease, and is also known to exert nonspecific antagonistic activity at the phencyclidine binding site of the N-methyl-D-aspartate (NMDA) receptor. The aim of this study was to assess the anticonvulsant properties of orphenadrine and to evaluate its effect on the anticonvulsant activity of antiepileptic drugs against maximal electroshock-induced seizures in mice. Orphenadrine given at a dose of 5.65 mg/kg elevated the electrical seizure threshold from 5.7 (5.4 – 6.1) to 6.8 (6.3–7.3) mA, while a dose of 2.8 mg/kg was ineffective. The ED₅₀ values of orphenadrine administered 10,30 and 120 min before maximal electroshock-induced convulsions were 16.8 (11.3–25.1), 17.8 (15.7–20.0) and 25.6 (23.3–28.3) mg/kg, respectively. Orphenadrine at a sub-threshold dose of 2.8 mg/kg significantly enhanced the anticonvulsant activity of valproate by reducing its ED₅₀ value from 315.8 (270.0–369.4) to 245.9 (207.1–292.0) mg/kg without affecting the free plasma levels of valproate. However, orphenadrine failed to enhance the protective activity of carbamazepine, phenytoin, phenobarbital, lamotrigine, topiramate, or oxcarbazepine against maximal electroshock-induced seizures.     

Effect of acute and chronic tianeptine on the action of classical antiepileptics in the mouse maximal electroshock model

BackgroundThe aim of the study was to analyze the influence of acute and chronic treatment with tianeptine, an antidepressant selectively accelerating presynaptic serotonin reuptake, on the protective activity of classical antiepileptic drugs in the maximal electroshock test in mice.MethodsElectroconvulsions were produced by means of an alternating current (50 Hz, 25 mA, 0.2 s) delivered via ear-clip electrodes. Motor impairment and long-term memory deficits in animals were quantified in the chimney test and in the passive-avoidance task, respectively. Brain concentrations of antiepileptic drugs were measured by fluorescence polarization immunoassay.ResultsAcute and chronic treatment with tianeptine (25–50 mg/kg) did not affect the electroconvulsive threshold. Furthermore, tianeptine applied in both acute and chronic protocols enhanced the anticonvulsant action of valproate and carbamazepine, but not that of phenytoin. Neither acute nor chronic tianeptine changed the brain concentrations of valproate, carbamazepine or phenytoin. On the other hand, both single and chronic administration of tianeptine diminished the brain concentration of phenobarbital. In spite of this pharmacokinetic interaction, the antidepressant enhanced the antielectroshock action of phenobarbital. In terms of adverse effects, acute/chronic tianeptine (50 mg/kg) and its combinations with classic antiepileptic drugs did not impair motor performance or long-term memory in mice.ConclusionThe obtained results justify the conclusion that tianeptine may be beneficial in the treatment of depressive disorders in the course of epilepsy.     

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.     

Nefopam enhances the protective activity of antiepileptics against maximal electroshock-induced convulsions in mice

Nefopam is a centrally acting non-opioid analgesic with a mechanism of action that is not completely understood. Adverse effects associated with the therapeutic use and overdose of nefopam are mainly associated with the central nervous system, such as hallucinations, cerebral edema and convulsions. The aim of this study was to assess the effect of nefopam on the electrical threshold and its influence on the protective activity of antiepileptic drugs in the maximal electroshock test in mice. A 5 mg/kg dose of nefopam significantly elevated the electric seizure threshold, while a dose of 1 mg/kg failed to protect mice against electroconvulsion. At a subthreshold dose of 1 mg/kg, nefopam significantly enhanced the anticonvulsant activity of valproate against electroconvulsions. The protective activity of phenobarbital and phenytoin was significantly enhanced by co-administration of nefopam at the 5 mg/kg dose, but this same dose of nefopam failed to affect the protective activity of carbamazepine. In conclusion, nefopam exerts an anticonvulsive effect when given alone and significantly enhances the protective activity of certain antiepileptic agents against electroconvulsions induced in mice.     

Acute and chronic treatment with mianserin differentially affects the anticonvulsant activity of conventional antiepileptic drugs in the mouse maximal electroshock model

Rationale Epilepsy often coexists with depression. Therefore, the probability of simultaneous treatment with antiepileptics and antidepressants and the possibility of interactions between them are relatively high. Objective The effects of acute and chronic administration of mianserin on the protective activity of valproate (VPA), carbamazepine, phenytoin, and phenobarbital were evaluated in the maximal electroshock in mice. Materials and methods Animals were subjected to electroconvulsions. Undesired effects were evaluated in the chimney test (motor impairment) and passive-avoidance task (memory deficit). Brain concentrations of antiepileptic drugs were assessed by immunofluorescence. Results When given acutely, mianserin (at doses greater than or equal to 20 mg/kg) significantly raised the electroconvulsive threshold. The antidepressant, at the subanticonvulsant doses, enhanced the anticonvulsant action of carbamazepine, phenytoin, and VPA. Mianserin administered chronically at 30 mg/kg significantly decreased the electroconvulsive threshold. In contrast to acute treatment, the antidepressant at subeffective doses diminished the anticonvulsant activity of VPA and phenytoin. Mianserin given either acutely or chronically did not affect the brain concentrations of antiepileptic drugs, so a pharmacokinetic contribution to the observed interactions is not probable. Acute and chronic treatment with mianserin and its combinations with antiepileptic drugs did not impair either motor coordination or long-term memory. Conclusion Although acute application of mianserin may potentiate the anticonvulsant action of some antiepileptics, its chronic administration can lead to the opposite effect. Therefore, as far as the presented results can be transferred to clinical conditions, the antidepressant therapy with mianserin should be limited or even avoided in epileptic patients.     

Influence of salbutamol on the anticonvulsant potency of the antiepileptic drugs in the maximal electroshock-induced seizures in mice

Backgroundβ₂-Adrenergic receptor agonists are widely used agents in the treatment of asthma or preterm labor. Since prevalence of asthma was shown to be higher in patients with epilepsy and modulation of noradrenergic system activity may modify epilepsy course, the aim of the present study was to examine the effect of salbutamol (SALB), one of the most commonly used β₂-adrenergic receptor agonist on the anticonvulsant potency of four classical antiepileptic drugs (AEDs): valproate (VPA), carbamazepine (CBZ), phenytoin (DPH) and phenobarbital (PB) in mice subjected to the maximal electroshock (MES)-induced seizures.MethodsSeizures were caused by a current delivered through ear-clip electrodes. The influence of AEDs and SALB on animals’ motor coordination and memory processes was also evaluated.ResultsSingle SALB injection did not change, whereas 7 days SALB administration decreased seizure threshold in the MES-induced seizures in mice. Moreover, SALB injected ip for 1 day and for 7 days lowered the antiepileptic activity of PB in the MES-induced seizures in mice, but did not change the effect of other analyzed AEDs: VPA, CBZ or DPH. Butoxamine, a selective β₂-adrenergic receptor antagonist, reversed SALB influence on the activity of PB. SALB given alone or in combination with the tested AEDs did not affect animals’ motor performance and memory after both single and 7 days administration.ConclusionsPresented results show that SALB may decrease the antiepileptic efficacy of PB. A special caution is advised to patients with epilepsy receiving β₂-adrenergic receptors agonists in the pharmacotherapy of pulmonary and obstetrical disorders.     

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

BackgroundThe aim of this study was to determine the effects of 5-(3-chlorophenyl)-4-(4-methylphenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (TP10) on the protective action of 4 classical antiepileptic drugs – carbamazepine, phenobarbital, phenytoin and valproate – against maximal electroshock-induced seizures in mice.MethodsTonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by an electric current (sine-wave, 25 mA, 500 V, 50 Hz, 0.2 s stimulus duration) delivered via auricular electrodes. Acute adverse-effect profiles with respect to motor performance, long-term memory and skeletal muscular strength were measured, together with total brain antiepileptic drug concentrations.ResultsTP10 administered intraperitoneally at 10 mg/kg significantly elevated the threshold for electroconvulsions in mice. TP10 at doses of 2.5 and 5 mg/kg had no impact on the threshold for electroconvulsions in mice. Moreover, TP10 (5 mg/kg) significantly enhanced the anticonvulsant activity of valproate, but not that of carbamazepine, phenobarbital or phenytoin in the maximal electroshock seizure test in mice. Pharmacokinetic experiments revealed that TP10 significantly elevated total brain concentrations of valproate in mice.ConclusionThe enhanced anticonvulsant action of valproate by TP10 in the mouse maximal electroshock-induced seizure model was associated with a pharmacokinetic increase in total brain valproate concentrations in mice. The combinations of TP10 with carbamazepine, phenobarbital and phenytoin were neutral from a preclinical viewpoint.     

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.     

Caffeine and the anticonvulsant potency of antiepileptic drugs: experimental and clinical data

Caffeine (1,3,7-trimethylxanthine) is the most commonly ingested stimulant in the world. The daily consumption of this methylxanthine in coffee, tea and soft drinks is approximately 200 mg per person, which yields a pharmacologically active blood concentration. Experimental data indicate that caffeine may either lower the convulsive threshold in experimental models of epilepsy or induce seizure activity in doses over 400 mg/kg in rodents. Interestingly, animal data have demonstrated that caffeine, at doses far below its convulsive potential, diminishes the protective effects of conventional antiepileptic drugs (AEDs--carbamazepine, phenobarbital, phenytoin, valproate) and the newer AED, topiramate against electroconvulsions in mice. However, in contrast to these AEDs, caffeine did not impair the anticonvulsant efficacy of other newer AEDs, lamotrigine, tiagabine, and oxcarbazepine in this experimental model of epileptic seizure. Although limited, the clinical data generally confirm the experimental findings, suggesting increased seizure frequency in epileptic patients who began ingesting caffeine in high quantities. Thus far, no analysis has been performed in epileptic patients to determine whether the hazardous effects of caffeine are dependent upon individual antiepileptic treatments. These data clearly indicate that methylxanthines should be avoided in epileptic patients.     

Cholecalciferol enhances the anticonvulsant effect of conventional antiepileptic drugs in the mouse model of maximal electroshock

The interactions between cholecalciferol, a precursor of the active form of Vitamin D(3), and conventional antiepileptic drugs (valproate, carbamazepine, phenytoin, and phenobarbital) were studied in the maximal electroshock test in mice. Vitamin D(3) applied i.p. at doses of 37.5 and 75 mug/kg, but not at 18.75 mug/kg, significantly raised the electroconvulsive threshold. Furthermore, cholecalciferol (at its highest subthreshold dose of 18.75 mug) potentiated the anticonvulsant activity of phenytoin and valproate. The action of carbamazepine and phenobarbital was also enhanced by Vitamin D(3), but when it was given at the higher dose of 37.5 mug/kg. Cholecalciferol, 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). Cholecalciferol did not significantly increase the brain concentrations of conventional antiepileptics, indicating a pharmacodynamic nature of revealed interactions. Our findings show that cholecalciferol may play an anticonvulsant role in the brain and can influence the efficacy of antiepileptic drugs, at least in experimental conditions.     

1-Methyl-1,2,3,4-tetrahydroisoquinoline enhances the anticonvulsant action of carbamazepine and valproate in the mouse maximal electroshock seizure model

1-Methyl-1,2,3,4-tetrahydroisoquinoline (1-MeTHIQ - an endogenous parkinsonism-preventing substance) administered intraperitoneally at a dose of 20 mg/kg considerably elevated the threshold for electroconvulsions in mice from 6.4 to 8.4 mA (P < 0.05). In contrast, the agent administered at 5 and 10 mg/kg had no significant impact on the electroconvulsive threshold in mice. Moreover, 1-MeTHIQ (at a subthreshold dose of 10 mg/kg) potentiated the anticonvulsant action of valproate (VPA) against maximal electroshock (MES)-induced seizures in mice, reducing its median effective dose (ED50) from 232 to 170 mg/kg (P < 0.001). Similarly, 1-MeTHIQ (at 10 mg/kg) enhanced the antielectroshock activity of carbamazepine (CBZ) in mice, decreasing its ED50 from 10.8 to 7.8 mg/kg (P < 0.05). In contrast, 1-MeTHIQ (at 10 mg/kg) did not affect the anticonvulsant action of phenytoin and phenobarbital against MES-induced seizures in mice. The evaluation of acute neurotoxic effects of the studied antiepileptic drugs (AEDs) in combination with 1-MeTHIQ, as regards motor coordination impairment in the chimney test, revealed no significant changes in median toxic doses (TD50) of conventional AEDs after systemic administration of 1-MeTHIQ (up to 10 mg/kg). Pharmacokinetic characterization of interactions between 1-MeTHIQ (10 mg/kg) and VPA (170 mg/kg) or CBZ (7.8 mg/kg) revealed no significant changes in total brain concentrations of CBZ and VPA, indicating that the observed enhancement of antiseizure effects of CBZ and VPA by 1-MeTHIQ was pharmacodynamic in nature. Based on our preclinical study, it may be concluded that 1-MeTHIQ exerts the anticonvulsant effects increasing the threshold for electroconvulsions and potentiating the antiseizure action of CBZ and VPA against maximal electroshock. The antiseizure properties of 1-MeTHIQ (an endogenous parkinsonism-preventing substance) and its exact physiological role in the brain need extensive examination in further neuropharmacological studies.     

Effect of p-isopropoxyphenylsuccinimide monohydrate on the anticonvulsant action of carbamazepine,phenobarbital, phenytoin and valproate in the mouse maximal electroshock-induced seizure model

This study was designed to determine the effects of p-isopropoxyphenylsuccinimide monohydrate (IPPS) on the protective action of four classical antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) in the mouse maximal electroshock seizure model.Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (sine-wave, 25 mA, 500 V, 50 Hz, 0.2 s stimulus duration) delivered via auricular electrodes. Acute 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 indicate that IPPS administered intraperitoneally (ip) at doses of 75 and 150 mg/kg significantly elevated the threshold for electroconvulsions in mice. IPPS at lower doses of 18.75 and 37.5 mg/kg had no impact on the threshold for electroconvulsions in mice. Moreover, 37.5 mg/kg IPPS significantly enhanced the anticonvulsant activity of phenytoin and valproate, but not that of carbamazepine or phenobarbital, in the maximal electroshock seizure test in mice. IPPS (18.75 mg/kg) had no impact on the antiseizure action of phenytoin and valproate against maximal electroshock-induced seizures in mice. Pharmacokinetic experiments revealed that IPPS did not alter total brain concentrations of phenytoin or valproate in mice.In conclusion, the enhanced anticonvulsant action of phenytoin and valproate by IPPS in the mouse maximal electroshock-induced seizure model and lack of pharmacokinetic interactions make the combinations of IPPS with phenytoin and valproate of pivotal importance for further experimental and clinical studies. The combinations of IPPS with carbamazepine and phenobarbital are neutral from a preclinical viewpoint.     

Isobolographic analysis of interactions between loreclezole and conventional antiepileptic drugs in the mouse maximal electroshock-induced seizure model

This study examined the interaction characteristics between loreclezole (LCZ) and various conventional antiepileptic drugs (phenytoin - PHT, carbamazepine - CBZ, valproate - VPA and phenobarbital - PB) in the mouse maximal electroshock (MES)-induced seizure model using isobolographic analysis. Drug-related adverse effects were ascertained by use of the chimney test (motor impairment) and the step-through passive avoidance task (learning and retrieval). It was observed that the combination of LCZ with VPA or PB, at the fixed ratio of 1:1, was supra-additive (synergistic) and the combination of LCZ with CBZ, at all fixed ratios tested (1:3, 1:1 and 3:1), was supra-additive against electroconvulsions. The remaining combinations evaluated, i.e., LCZ with PB or VPA at fixed ratios of 1:3 and 3:1, as well as all fixed-ratio combinations between LCZ and PHT, were additive in the MES test in mice. Pharmacokinetic characterization revealed that LCZ significantly increased both free plasma and brain concentrations of CBZ and PHT, but was without effect on PB. Moreover, a bi-directional pharmacokinetic interaction between LCZ and VPA was observed in that while LCZ increased free plasma, but not total brain VPA concentrations, VPA increased the total brain, but not free plasma LCZ concentrations. Adverse-effect testing revealed that for all antiepileptic drug combinations neither motor performance nor long-term memory was altered. Of the drug combinations investigated, only that of LCZ and PB at the fixed ratio of 1:1 was not associated with any pharmacokinetic interactions, and thus it may be concluded that the supra-additive (synergistic) isobolographic interaction was pharmacodynamic in nature. Furthermore, the fact that LCZ and PB have similar mechanisms of action would suggest that drugs with similar mechanisms of action may provide rational polytherapy regimens.The results of this study were presented in part at the 8th Congress of the European Federation of Neurological Societies, held in Paris, France, on 4--7 September 2004 [Abstract available in Eur J Neurol 11(Suppl 2): 227, 2004].     

Influence of agmatine on the protective action of numerous antiepileptic drugs against pentetrazole-induced seizures in miceA

The aim of this study was to assess the influence of agmatine (an endogenous neuromodulator/neurotransmitter in the brain) on the protective action of numerous classical and second-generation antiepileptic drugs (clonazepam, ethosuximide, gabapentin, phenobarbital, tiagabine, vigabatrin, and valproate) in the mouse pentetrazole-induced clonic seizure model.The results indicate that agmatine (up to 100 mg/kg, ip, 45 min before the test) did not alter the threshold for pentetrazole-induced clonic seizures in mice. However, agmatine (100 mg/kg, ip) significantly attenuated the anticonvulsant effects of vigabatrin against pentetrazole-induced clonic seizures by elevating the ED₅₀ value of vigabatrin from 517.5 to 790.3 mg/kg (p < 0.01). In contrast, agmatine at a dose of 50 mg/kg did not significantly affect the anticonvulsant action of vigabatrin, although a reduction in the ED₅₀ value of the antiepileptic drug from 517.5 to 629.1 mg/kg was documented. Moreover, agmatine at doses of 50 and 100 mg/kg (ip) had no significant impact on the anticonvulsant action of clonazepam, ethosuximide, gabapentin, phenobarbital, tiagabine, or valproate in pentetrazole-induced seizures in mice.In conclusion, the combination of agmatine with vigabatrin seems to be unfavorable due to the reduction of the anticonvulsant effect of vigabatrin after concomitant administration of agmatine in the pentetrazole-induced seizure model. Therefore, the utmost caution is advised when combining agmatine with vigabatrin in further clinical settings.     

2-Methyl-6-phenylethynyl-pyridine (MPEP), a non-competitive mGluR5 antagonist,differentially affects the anticonvulsant activity of four conventional antiepileptic drugs against amygdala-kindled seizures in rats

2-Methyl-6-phenylethynyl-pyridine (MPEP), a selective noncompetitive mGluR5 antagonist, influences the action of conventional antiepileptic drugs in amygdala-kindled seizures in rats. MPEP alone (up to 40 mg/kg) did not affect any seizure parameter. Moreover, the common treatment of MPEP with either carbamazepine or phenytoin (administered at subeffective doses) did not result in any anticonvulsant action in kindled rats. However, when combined with subprotective doses of valproate or phenobarbital, MPEP significantly shortened seizure and afterdischarge durations. Importantly, combinations of MPEP with the two antiepileptics did not have the adverse effects of impaired motor performance or long-term memory in rats. Our data indicate that MPEPmay positively interact with some conventional antiepileptic drugs in the amygdala-kindling model of complex partial seizures.     

Low-affinity kainate receptor-mediated events reduce the protective activity of phenobarbital and diphenylhydantoin against maximal electroshock in mice

(2S,2R)-4-Methylglutamic acid (SYM 2081), a potent selective agonist of GluR5 and GluR6 kainate receptor subtypes, applied at the dose of 15.5 mg/kg, equal to its CD(16) value (i.e., a dose required to induce convulsions in 16% of mice), significantly decreased the electroconvulsive threshold from 7.0 to 5.8 mA. When administered at the dose of 11.5 mg/kg, equal to 75% of its CD(16), it markedly attenuated the protective activity of phenobarbital and diphenylhydantoin, but not that of valproate, carbamazepine, or diazepam against maximal electroshock-induced seizures in mice. The respective ED(50) values were increased from 18.5 to 23.8 mg/kg for phenobarbital, and from 11.7 to 14.7 mg/kg for diphenylhydantoin. Since the free plasma levels of both antiepileptic drugs were not influenced by SYM 2081, the pharmacokinetic interaction does not seem to be involved in the observed results.In conclusion, low-affinity kainate receptor-mediated events might be a factor reducing the protective efficacy of some antiepileptic drugs. Furthermore, the activation of GluR5 and GluR6 kainate receptor subtypes by endogenous glutamate during seizures may be associated with the drug-resistance phenomenon.