Activity Of Conventional Antiepileptic Drugs Research Articles

Acute and chronic treatment with moclobemide, a reversible MAO-inhibitor, potentiates the antielectroshock activity of conventional antiepileptic drugs in mice

BackgroundDue to enhancing serotonergic and noradrenergic neurotransmission, moclobemide may influence seizure phenomena. In this study, we examined the effect of both acute and chronic treatment with moclobemide on seizures and the action of first-generation antiepileptic drugs: valproate, carbamazepine, phenobarbital and phenytoin. MethodsThe effect of moclobemide on seizures was assessed in the electroconvulsive threshold test, while its influence on antiepileptic drugs was estimated in the maximal electroshock test in mice. Undesired effects were evaluated in the chimney test (motor impairment) and step-through passive-avoidance task (long-term memory deficits). Finally, brain concentrations of antiepileptics were determined by fluorescence polarization immunoassay. ResultsGiven acutely, moclobemide at 62.5 and 75 mg/kg increased the electroconvulsive threshold. In contrast, chronic treatment with moclobemide up to 75 mg/kg did not influence this parameter. Acute moclobemide applied at subthreshold doses (up to 50 mg/kg) enhanced the antielectroshock effects of carbamazepine, valproate and phenobarbital. Chronic moclobemide (37.5‐75 mg/kg) increased the action of all four antiepileptic drugs. All revealed interactions, except these between moclobemide and phenobarbital, seem to have pharmacokinetic nature, because the antidepressant drug, either in acute or in chronic treatment, increased the brain concentrations of respective antiepileptic drugs. In terms of undesired neurotoxic effects, acute and chronic moclobemide, antiepileptic drugs, and their combinations did not produce significant motor or long-term memory impairment. ConclusionsAcute and chronic therapy with moclobemide can increase the effectiveness of some antiepileptic drugs against the maximal electroshock test. In mice, this effect was, at least partially, due to pharmacokinetic interactions. So far as the results of experimental studies can be transferred to clinical conditions, moclobemide seems safe for the application in patients with epilepsy and depression. Possibly, in the case of certain antiepileptic drugs combined with moclobemide, their doses should be adjusted downwards.

Effect of aliskiren, a direct renin inhibitor, on the protective action of antiepileptic drugs against pentylenetetrazole-induced clonic seizures in mice.

It has been demonstrated that certain angiotensin-converting enzyme (ACE) inhibitors and angiotensin AT1 receptor antagonists can possess anticonvulsant activity. The purpose of the current study was to examine the effect of aliskiren, a direct renin inhibitor and a novel antihypertensive drug, against pentylenetetrazole (PTZ)-induced clonic seizures in mice and on the protective activity of conventional antiepileptic drugs (AEDs) in this seizure model. Effects of aliskiren on the PTZ threshold and the protective efficacy of AEDs, such as clonazepam (CLO), phenobarbital (PB), valproate (VPA), and ethosuximide (ETX) in the PTZ test, were evaluated in adult Swiss mice. Aliskiren and AEDs were administered intraperitoneally (i.p.) while PTZ (50-100 mg/kg) was injected subcutaneously (s.c.). The rota-rod and passive avoidance test were used to assess the adverse effects of the combined treatment with aliskiren and AEDs. Aliskiren, at the dose of 75 mg/kg, significantly raised the PTZ threshold (P < 0.05). Furthermore, aliskiren, at the subthreshold dose of 50 mg/kg, significantly enhanced the protective action of CLO (P < 0.01), PB (P < 0.01), and VPA (P < 0.05) but not ETX (P > 0.05) in the s.c. PTZ test. Motor coordination in the rota-rod test and long-term memory in the passive avoidance task were not impaired by the combined treatment of the drugs. This study suggests that treatment with aliskiren can be useful in hypertensive patients with myoclonic seizures. Certainly, a clinical verification of using aliskiren in such patients would be necessary.

An experimental study to investigate the effects of venlafaxine and escitalopram on anticonvulsant activity of conventional antiepileptic drugs in mice

Background: Depression is a common psychiatric comorbidity in patients with epilepsy which remains often untreated, due to concern of antidepressant induced seizures. The safety status of selective serotonin reuptake inhibitors (SSRIs) in epileptics is controversial.Methods: Phase I acute effect of venlafaxine and escitalopram on the seizure threshold was studied. Phase II, the acute effects of test ADDs on the effective dose of AEDs viz valproate, phenobarbitone and phenytoin were studied in maximal electroshock (MES). Phase III- same study design as in phase II except that AEDs and ADDs were administered daily for 28 days.Results: Venlafaxine raised the electroconvulsive threshold in a dose dependant manner in phase I, however it was significant at a dose of 25mg/kg. In phase II, a significant reduction in ED50 of valproate was observed when it was co-administered with venlafaxine at dose of 12.5 and 25mg/kg, whereas ED50 of phenobarbitone was significantly reduced at a dose of 25mg/kg. Chronic administration of venlafaxine at 12.5mg/kg daily reduced ED50 of valproate. At 25mg/kg daily ED50 of all the three studied AEDs was reduced, Escitalopram 8mg/kg significantly raised the electroconvulsive threshold value in phase 1, Escitalopram administered in the dose of 8mg/kg reduced the ed50 value of valproate. Escitalopram given in dose of 4 and 8mg/kg reduced the ED50 value of valproate.Conclusions: From this finding, it may be concluded that venlafaxine and escitalopram administered either alone or in combination with AEDs acutely or chronically, exhibit anticonvulsant action.

The effects of cimetidine chronic treatment on conventional antiepileptic drugs in mice

The aim of this study was to evaluate the effects of 1-day, 7-day and 14-day administrations of cimetidine on the anticonvulsant activity of conventional antiepileptic drugs (AEDs; valproate, carbamazepine, phenytoin and phenobarbital) against maximal electroshock (MES)-induced convulsions in mice. Electroconvulsions were evoked in Albino Swiss mice by a current delivered via ear-clip electrodes. In addition, the effects of cimetidine, AEDs alone and their combinations were studied on performance and long-term memory tests. Pharmacokinetic changes in plasma and brain concentrations of AEDs after cimetidine administration were evaluated with immunofluorescence. Cimetidine (up to 100mg/kg) after 1-day administration did not affect the electroconvulsive threshold in animals. Moreover, in the 14-day treatment, cimetidine administered at a dose of 40mg/kg did not significantly change the electroconvulsive threshold in the MES-test, cimetidine administered 14-day (at 20mg/kg) significantly increased the anticonvulsant activity of carbamazepine, staying without effects after a 1-day and 7-day studies. In contrast, both the 7-day and 14-day administrations of cimetidine resulted in significant reductions of protective efficacy of the phenobarbital. Only valproate and phenytoin were not affected by cimetidine (20mg/kg) in all experimental period. Cimetidine administered 1-day, did not alter total brain concentrations and free plasma levels of all AEDs tested, whilst the 14-day study elevated carbamazepine plasma and brain concentration and reduced phenobarbital brain concentration. Cimetidine co-applied with AEDs did not impair performance of mice evaluated in the chimney test however, it worsened long-term memory in animals. Based on this preclinical study, a special caution is advised when treating epileptic patients with combinations of phenobarbital or carbamazepine with cimetidine.

Interaction of famotidine, an H2 histamine receptor antagonist, with conventional antiepileptic drugs in mice

H2 histamine receptors are localized postsynaptically in the CNS. The aim of this study was to evaluate the effects of acute (1 day) and prolonged (7 day) administration of the H2 histamine receptor antagonist, famotidine, on the anticonvulsant activity of conventional antiepileptic drugs (AEDs; valproate, carbamazepine, diphenylhydantoin and phenobarbital) against maximal electroshock (MES)-induced seizures in mice. In addition, the effects of these drugs alone or in combination with famotidine were studied on motor performance and long-term memory. The influence of H2 receptor antagonist on brain concentrations and free plasma levels of the antiepileptic drugs was also evaluated. After acute or prolonged administration of famotidine (at dose of 10mg/kg) the drug raised the threshold for electroconvulsions. No effect was observed on this parameter at lower doses. Famotidine (5mg/kg), given acutely, significantly enhanced the anticonvulsant activity of valproate, which was expressed by a decrease in ED50. After the 7-day treatment, famotidine (5mg/kg) increased the anticonvulsant activity of diphenylhydantoin against MES. Famotidine (5mg/kg), after acute and prolonged administration, combined with valproate, phenobarbital, diphenylhydantoin and carbamazepine did not alter their free plasma levels. In contrast, brain concentrations of valproate were elevated for 1-day treatment with famotidine (5mg/kg). Moreover, famotidine co-applied with AEDs, given prolonged, worsened motor coordination in mice treated with carbamazepine or diphenylhydantoin. In contrast this histamine antagonist, did not impair the performance of mice evaluated in the long-term memory task. The results of this study indicate that famotidine modifies the anticonvulsant activity of some antiepileptic drugs.

Influence of selective A2 adenosine receptor antagonist, DMPX, on the anticonvulsant activity of conventional antiepileptic drugs

Influence of selective A2 adenosine receptor antagonist, DMPX, on the anticonvulsant activity of conventional antiepileptic drugs

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 100mg/kg ip, EA enhanced the antielectroshock activity of VPA, decreasing its ED50 value from 225.6 to 146.6mg/kg (p<0.05), but enhancement was not observed following continuous administration of EA (12.5mg/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.

Angiotensin AT 1 receptor antagonists enhance the anticonvulsant action of valproate in the mouse model of maximal electroshock

Angiotensin AT 1 receptor antagonists, drugs affecting the renin–angiotensin system, are commonly used in the treatment of hypertension and congestive heart failure. It is also known that the renin–angiotensin system exists in the brain and therefore it may be involved in the regulation of seizure susceptibility. The aim of the current study was to evaluate the effects of losartan (2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2′(1H-tetrazol-5-yl)-biphenil-4-yl)methyl]imidazole) and telmisartan (49-[(1,49-dimethyl-29-propyl[2,69-bi-1 H-benzimidazo]-19-yl)methyl]-[1,19-biphenyl]-2-carboxylic acid), the angiotensin AT 1 receptor antagonists which are widely used in clinical practice, on the protective action of conventional antiepileptic drugs (carbamazepine, phenytoin, valproate and phenobarbital) against maximal electroshock-induced seizures in mice. Losartan (10, 20 and 50 mg/kg i.p.) and telmisartan (5, 10 and 30 mg/kg i.p.) did not influence the threshold for electroconvulsions. However, both drugs potentiated the anticonvulsant activity of valproate. Losartan (50 mg/kg i.p.) decreased its ED 50 value from 249.8 to 194.6 mg/kg while telmisartan (30 mg/kg i.p.) lowered the ED 50 value for valproate from 249.8 to 190.6 mg/kg. The antiseizure action of the remaining antiepileptics was not affected by losartan or telmisartan. The observed interactions between tested angiotensin AT 1 receptor antagonists and valproate were pharmacodynamic in nature as either losartan or telmisartan did not alter total brain concentrations of valproate. This finding can be important for epileptic patients receiving valproate and also angiotensin AT 1 receptor antagonists due to other medical causes.

Effect of acute and chronic treatment with milnacipran potentiates the anticonvulsant activity of conventional antiepileptic drugs in the maximal electroshock-induced seizures in mice

Depression often coexists with epilepsy. Simultaneous therapy of the two diseases may be associated with pharmacodynamic and/or pharmacokinetic interactions between antiepileptic and antidepressant drugs. The aim of this study was to investigate the influence of acute and chronic treatment with intraperitoneal milnacipran (MLN), a selective serotonin/noradrenaline reuptake inhibitor, on the protective activity of valproate, carbamazepine (CBZ), phenytoin, or phenobarbital (PB) in the maximal electroshock (MES) test in mice. Electroconvulsions were produced by an alternating current (50 Hz, 25 mA) delivered via ear-clip electrodes. Motor coordination and long-term memory were evaluated in the chimney test and passive-avoidance task, respectively. Brain concentrations of antiepileptic drugs (AEDs) were assessed by immunofluorescence. Given acutely, MLN at 10 mg/kg increased the convulsive threshold. Acute MLN applied at the subprotective dose of 5 mg/kg enhanced the anticonvulsant effects of CBZ and PB. Chronic treatment with MLN (5-30 mg/kg once daily for 2 weeks) did not affect either the electroconvulsive threshold or the anticonvulsant action of all studied conventional antiepileptic drugs. Since the antidepressant did not affect brain concentrations of antiepileptics used in the study, the revealed interactions seem to be of pharmacodynamic nature. Moreover, acute and chronic MLN, AEDs, and their combinations did not produce significant motor and long-term memory impairment. Acute, but not chronic, treatment with MLN can increase the effectiveness of some AEDs against MES-induced seizures in mice. It seems that MLN may also be considered as a candidate drug for clinical trials in patients with epilepsy and depressive disorders.

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 40mg/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.

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.

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

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. 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. 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. 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. 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.

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.

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.

Valproic acid induced encephalopathy – 19 new cases in Germany from 1994 to 2003 – A side effect associated to VPA-therapy not only in young children

Valproic acid (VPA) is a broad-spectrum antiepileptic drug and is usually well-tolerated. Rare serious complications may occur in some patients, including haemorrhagic pancreatitis, bone marrow suppression, VPA-induced hepatotoxicity and VPA-induced encephalopathy. The typical signs of VPA-induced encephalopathy are impaired consciousness, sometimes marked EEG background slowing, increased seizure frequency, with or without hyperammonemia. There is still no proof of causative effect of VPA in patients with encephalopathy, but only of an association with an assumed causal relation. We report 19 patients with VPA-associated encephalopathy in Germany from the years 1994 to 2003, none of whom had been published previously.

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% (TID 20), 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 (ED 50) 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 ED 50 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.

Seizure-induced oxidative stress in rat brain regions: blockade by nNOS inhibition

Free radicals have been implicated in the pathogenesis of various neurological disorders including epilepsy. Experimental seizures are often accompanied by the generation of free radicals that cause lipid peroxidation (LPO), which may subsequently cause neurodegeneration observed in certain types of human epilepsy. We recently reported a trigger role for nitric oxide (NO) derived by activation of neuronal isoform of nitric oxide synthase (nNOS) and that the action of conventional antiepileptic drugs (AEDs) was potentiated by inhibition of nNOS. In the present study, we extend our observations to understand the significance of blockade of the nNOS pathway on seizure-induced oxidative stress. Increased NO and LPO levels was observed at the time that corresponded to the onset of generalized seizures in rat brain regions following administration of GABA A receptor antagonist, picrotoxin (PCT). Treatment with the selective nNOS inhibitor, 7-nitroindazole (7-NI), decreased NO and LPO levels. The AEDs, diazepam and phenobarbitone also prevented seizure-induced increase in NO and LPO levels. Seizures resulted in a significant increase in the activity of antioxidant enzymes, superoxide dismutase in the frontal cortex and hippocampus. On the other hand, the activity of glutathione peroxidase was decreased in the hippocampus and midbrain. Whereas treatment with 7-NI could minimize the effects of PCT, the AEDs per se did not have any significant impact on the activity of the antioxidant enzymes, though co-treatment with 7-NI and AEDs could significantly decrease seizure-induced alterations in antioxidant enzyme activities. These observations suggest that the AEDs may not have a significant role in modulating the activities of antioxidant enzymes and that their ability to decrease LPO is realized more likely by their ability to prevent free radical formation. In conclusion, the present study demonstrates that NO contributes to LPO observed following seizures induced by PCT. The study also provides evidence for the ability of the AEDs to inhibit seizure-induced increase in LPO levels, the effect being enhanced by co-treatment with 7-NI suggesting that 7-NI and the AEDs together could prevent the neurotoxic cascade induced by oxidative stress.

Isobolographic and subthreshold analysis of interactions among felbamate and four conventional antiepileptic drugs in pentylenetetrazole-induced seizures in mice.

Despite possibility of idiosyncratic reaction development, felbamate (FBM) is recommended in Lennox-Gastaut syndrome and partial refractory epilepsy. The aim of this study was to evaluate the profile of interactions between FBM and four conventional antiepileptic drugs (AEDs): clonazepam (CZP), ethosuximide (ESM), phenobarbital (PB), and valproate (VPA), in pentylenetetrazole (PTZ)-induced convulsions in mice, a model of myoclonic seizures in humans. Data obtained from PTZ-evoked seizures were compared by use of two basic procedures, the subthreshold method and isobolographic analysis. Results of the chimney test (evaluating motor coordination) also were elaborated isobolographically. Thus it was possible to determine both median toxic dose (TD50) and protective index (PI) for each drug combination. FBM reduced the clonic seizure activity [with an ED50 of 9.7 mg/kg; TD50, 439.1 mg/kg; and PI, 45.3]. FBM at the dose of 10 mg/kg, but not 7.5 mg/kg, significantly reduced PTZ-induced convulsions in mice. In the subthreshold method, FBM (7.5 mg/kg) did not affect the protective activity of conventional AEDs used in the study. However, when applied at 10 mg/kg, it enhanced the protective activity of PB and ESM, but not that of VPA or CZP. The nature of these interactions could not be precisely estimated with this method. The exact profile of drug interactions was determined with the use of isobolography. In terms of seizure inhibition, antagonism was found between FBM and VPA applied at the fixed-dose ratio of 3:1. Synergy was detected between FBM and PB (1:3). Combinations of FBM with VPA (1:3, 1:1), PB (1:1, 3:1), and ESM or CZP (1:3, 1:1, 3:1) led to additive interactions. As regards motor impairment, the combinations of FBM with VPA (1:3) or CZP (1:1, 3:1) were synergistic. Remaining combinations exhibited pure additivity. Pharmacokinetic events may influence FBM/ESM and FBM/CZP interactions, because FBM lowered the brain concentration of ESM and increased that of CZP. The profitable benefit index was found only for the combination of FBM with PB (1:3). Conversely, the combinations of FBM with either VPA (1:3) or CZP (1:1, 3:1) do not seem promising for the therapy of refractory myoclonic convulsions. Isobolographic analysis provides more reliable clues to be considered by the clinicians willing to introduce AED combinations for the therapy of epilepsy.

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

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

Influence of sexual hormone antagonists on the anticonvulsant action of conventional antiepileptic drugs against electrically- and pentylenetetrazol-induced seizures in mice

The present results refer to the action of three gonadal steroid antihormones, tamoxifen (TXF, an estrogen antagonist), cyproterone acetate (CYP, an antiandrogen) and mifepristone (MIF, a progesterone antagonist) on seizure phenomena in mice. TXF and CYP at their lowest protective dose in the electroconvulsive threshold test, enhanced the antiseizure efficacy of some antiepileptic drugs. TXF (20 mg/kg) potentiated the protective activity of valproate, diphenylhydantoin and clonazepam, but not that of carbamazepine or phenobarbital, against maximal electroshock-induced convulsions in female mice. CYP (40 mg/kg) enhanced the anticonvulsant action of valproate, carbamazepine, diphenylhydantoin and clonazepam, but not that of phenobarbital, against maximal electroshock in male animals. MIF failed to affect the electroconvulsive threshold or the efficacy of antiepileptic drugs in maximal electroshock. The effect of TXF or CYP upon the electroconvulsive threshold and on the action of antiepileptics was not reversed by sex steroid hormones (estradiol, testosterone, progesterone). However, the TXF-induced elevation of the electroconvulsive threshold was abolished by bicuculline, N-methyl- d-aspartic acid and kainic acid, and partially reversed by aminophylline, strychnine being ineffective in this respect. The action of CYP on the threshold for electroconvulsions was partially reversed by bicuculline and aminophylline. Both glutamatergic agonists and strychnine remained ineffective in this respect. Moreover, the action of TXF or CYP on the activity of antiepileptics was not influenced by strychnine, and reversed to various extents by the remaining convulsants. In contrast to maximal electroshock, none of the three antihormones affected the protective action of antiepileptic drugs against pentylenetetrazol-induced seizures in mice. Neither TXF nor CYP altered the free plasma levels of antiepileptic drugs, so a pharmacokinetic interaction is not probable. The combined treatment of the two antihormones with antiepileptic drugs, providing 50% protection against maximal electroshock, did not affect motor performance in mice, and did not result in significant long-term memory deficits. Our data indicate that steroid receptor-mediated events may be indirectly associated with seizure phenomena in the central nervous system and can modulate the protective activity of some conventional antiepileptic drugs.