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Purpose: When monotherapy with antiepileptic drugs (AEDs) fails, combination therapy is tried in an attempt to improve effectiveness by improving efficacy, tolerability, or both. We reviewed the available studies (both animal and human) on AED polytherapy to determine whether AEDs can be selected for combination therapy based on their mechanisms of action, and if so, which combinations are associated with increased effectiveness. Because various designs and methods of analysis were used in these studies, it was also necessary to evaluate the appropriateness of these approaches., Methods: Published papers reporting on AED polytherapy in animals or humans were identified by Medline search and by checking references cited in these papers., Results: Thirty-nine papers were identified reporting on two-drug AED combinations. Several combinations were reported to offer improved effectiveness, but no uniform approach was used in either animal or human studies for the evaluation of pharmacodynamic drug interactions; efficacy was often the only end point., Conclusions: There is evidence that AED polytherapy based on mechanisms of action may enhance effectiveness. In particular, combining a sodium channel blocker with a drug enhancing GABAergic inhibition appears to be advantageous. Combining two GABA mimetic drugs or combining an AMPA antagonist with an NMDA antagonist may enhance efficacy, but tolerability is sometimes reduced. Combining two sodium channel blockers seems less promising. However, given the incomplete knowledge of the pathophysiology of seizures and indeed of the exact mechanisms of action of AEDs, an empirical but rational approach for evaluating AED combinations is of fundamental importance. This would involve appropriate testing of all possible combinations in animal models and subsequent evaluation of advantageous combinations in clinical trials. Testing procedures in animals should include the isobologram method, and the concept of drug load should be the basis of studies in patients with epilepsy.

Purpose: The objective of this study was to evaluate the interaction of the preferential brain nitric oxide synthase (NOS) inhibitor, 7-nitroindazole (7-NI), with conventional antiepileptic drugs (AEDs) against amygdala-kindled seizures in rats., Methods: Experiments were performed on fully kindled rats. Adverse effects were evaluated with the rotorod test, which assesses motor coordination, and the passive-avoidance task, which assesses memory. Plasma levels of AEDs were measured by immunofluorescence., Results: 7-NI (up to 100 mg/kg) failed to modify seizure parameters. However, it reduced the severity and duration of kindled seizures when coadministered with otherwise ineffective doses of carbamazepine (CBZ) (10-20 mg/kg) or phenobarbital (PB) (20 mg/kg). Combinations of 7-NI with valproate (VPA), diphenylhydantoin (DPH), or clonazepam (CLO) were not protective. L-Arginine (500 mg/kg) did not reverse the seizure-suppressing interactions between 7-NI and the conventional AEDs. The combinations of 7-NI and CBZ or PB did not impair performance in the rotorod test. Coadministration of 7-NI with CBZ did not affect long-term memory, and 7-NI given with PB didn't affect the mnemonic effect of PB. Finally, 7-NI did not affect the free plasma levels of CBZ or PB., Conclusions: Pharmacokinetic interactions do not seem to account for the anticonvulsant effects of 7-NI combined with CBZ or PB. Central nitric oxide (NO) is possibly not involved in the synergism between 7-NI and these AEDs.

Purpose: The aim of this study was to evaluate the efficacy of conventional antiepileptic drugs (AEDs) against the generalized tonic-clonic seizures in mice subjected to the subconvulsive doses of N-methyl-D-aspartate (NMDA) or kainate., Methods: Mice were given NMDA and kainate in the doses of 50.0 and 9.0 mg/kg i.p., respectively [i.e., equal to 75% of their CD16 values (convulsive dose in 16% of the animals studied)]. Subsequently the anticonvulsive potential of conventional AEDs against the maximal electroshock-induced seizures was estimated. Where necessary, the plasma levels of AEDs were assessed., Results: NMDA or kainate application did not affect the electroconvulsive threshold. NMDA, but not kainate, diminished the antiepileptic activity of diazepam (DZP) and carbamazepine (CBZ), increasing their 50% effective doses (ED50s) from 14.1 and 8.6 to 19.0 and 12.1 mg/kg i.p., respectively. Neither NMDA nor kainate affected the ED50 for valproate (VPA), phenobarbital (PB), or diphenylhydantoin (DPH) against electroconvulsions. NMDA-evoked effects were reversed with the use of the NMDA antagonist, D-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 40116) and were not accompanied by the alterations in the free plasma levels of AEDs., Conclusions: The NMDA-mediated events, but not kainate-related ones, seem to be involved in the protective action of DZP and CBZ against maximal electroshock-induced seizures. Moreover, it might be concluded that when subthreshold activation of NMDA receptors adds to other epileptogenic factors, DZP and CBZ are less efficacious. Presented data indicate that in such situations, adding the NMDA receptor antagonist (at very low doses) to the AED may yield beneficial therapeutic effects.

Purpose: D-Cycloserine (DCS) is a high-efficacy partial agonist at the strychnine-insensitive glycine modulatory site within the N-methyl-D-aspartate (NMDA)-receptor/ionophore complex. Previous studies demonstrated that DCS exhibits anticonvulsant activity in a variety of experimental epilepsy models. In this study, we determined the influence of DCS in subprotective doses on the anticonvulsant action of phenytoin (PHT) and carbamazepine (CBZ) in mice., Methods: Two electroconvulsive tests were used, i.e., determination of seizure threshold and maximal electroshock seizures. Antiepileptic drug-induced motor and long-term memory deficits were quantified by using the chimney test and the passive-avoidance test, respectively. In addition, plasma levels of PHT and CBZ were measured by fluorescence polarization immunoassay to exclude any pharmacokinetic interactions., Results: DCS, when used alone in doses of 80 and 160 mg/kg, significantly increased the threshold for electroconvulsive seizures. DCS in a wide range of doses (1.25-40 mg/kg) was combined with either PHT or CBZ and tested in electroconvulsive tests. DCS, at doses of 2.5 and 10 mg/kg, was the most effective in potentiating the threshold-increasing action of PHT; higher doses of DCS (20 and 40 mg/kg) were required to achieve a similar effect of CBZ. In maximal electroshock-induced seizures, DCS (10 mg/kg) augmented the protective action of PHT, but was ineffective at a dose of 40 mg/kg with CBZ. DCS did not potentiate the neurotoxicity produced by PHT and CBZ in the chimney test. Both PHT and CBZ induced impairments of long-term memory; PHT-induced memory adverse effects were counteracted by DCS (10 mg/kg). There was no such effect on CBZ-induced memory impairment, and a worsening influence was observed. Any pharmacokinetic interactions were excluded by measuring total and free plasma levels of both antiepileptic drugs., Conclusion: Our results suggest that combining DCS with PHT and CBZ may be beneficial in treating epileptic seizures.

Purpose: The objective of this study was to evaluate an interaction of two competitive N-methyl-D-aspartate (NMDA)-receptor antagonists, LY 235959 l(-)-3R,4aS,6R,8aR-6-(phosphonomethyl)-decahydroiso-qu inoline-3-carboxylic acid; < or = 0.5 mg/kg] or LY 233053 cis-(+/-)-4-[(2H-tetrazol-5-yl) methyl]piperidine-2-carboxylic acid; < or = 5 mg/kg] with carbamazepine, diphenylhydantoin, phenobarbital, or valproate magnesium against maximal electroshock-induced convulsions in mice., Methods: Electroconvulsions were produced by means of an alternating current (ear-clip electrodes, 0.2-s stimulus duration, tonic hindlimb extension taken as the end point) delivered by a Hugo-Sachs stimulator (Type 221, reiburg, FRG). Adverse effects were evaluated in the chimney test (motor performance) and passive-avoidance ask (long-term memory). Plasma levels of antiepileptic rugs were measured by immunofluorescence., Results: Both LY 235959 and LY 233053 ( < or = 0.5 and 5 mg/kg, respectively) did not influence the electroconvulsive threshold but potentiated the anticonvulsant action of all antiepileptics studied. The combined treatment of LY 233053 (5 mg/kg) with carbamazepine, diphenylhydantoin, or phenobarbital (providing a 50% protection against maximal electroshock) resulted in the impairment of long-term memory. No adverse effects were observed with combinations of LY 235959 with these antiepileptics. The combined treatment of valproate with either LY 235959 or LY 233053 was superior to valproate alone, as regards motor impairment, but not the impairment of long-term memory. Neither NMDA-receptor antagonist elevated the total plasma levels of antiepileptic drugs studied., Conclusions: It may be concluded that NMDA-receptor blockade leads to the enhanced anticonvulsive action of conventional antiepileptics against maximal electroshock-induced seizures. A pharmacokinetic interaction does not seem probable.

We evaluated the protective activity (expressed as ED50 values in mg/kg of phenobarbital (PB, 120 min before testing) and valproate (30 min) alone or combined with caffeine in male mice with seizures induced by maximal electroshock (MES). Both antiepileptic drugs (AEDs) were administered by intraperitoneal (i.p.) injection in a single dose to mice receiving intraperitoneal caffeine either in a single dose 30 min before the test or as pretreatment every 12 h for 3 and 14 days. In addition, we determined the ED50 values of the AEDs 24 and 72 h after 14-day treatment with caffeine. Finally, we studied the influence of a challenge dose of caffeine, injected in mice 24 and 72 h after 14 days of treatment with caffeine, on the protective activity of PB or VPA. Caffeine in a single dose of 23.1 mg/kg reduced the anticonvulsant effect of PB. Its protective activity was further impaired after 3 and 14 days of caffeine treatment. The ED50 for VPA was significantly increased both by the single dose of caffeine and by chronic treatment. The anticonvulsant activity of PB and VPA measured 24 and 72 h after 14-day treatment with caffeine did not differ from control values, but a challenge dose of caffeine injected 24 or 72 h after daily injections for 14 days resulted in a significant reduction in the protective activity of both AEDs. Measurement of the total plasma levels of caffeine, VPA, and PB did not suggest pharmacokinetic interactions as an explanation for our results. Our results indicate that chronic caffeine exposure may progressively reduce the antiepileptic potency of VPA and PB.

The protective efficacy of phenobarbital (PB, 120 min before testing) and valproate (VPA, 30 min before testing) alone or combined with aminophylline (a single dose of 50 mg/kg, 3-day or 14-day administration twice daily 50 mg/kg at 8.00 a.m. and 8.00 p.m.) was evaluated against maximal electroshock-induced seizures (MES) in male mice. All drugs were given intraperitoneally (i.p.), and the protection provided by PB and VPA was evaluated as the respective ED50 value (in mg/kg). Aminophylline in a single dose of 50 mg/kg (30 min before electroconvulsions) distinctly reduced the protective efficacy of both PB and VPA, reflected by the increase in the respective ED50 values from 22 to 31 mg/kg (p < 0.001) for PB and from 247 to 281 mg/kg (p < 0.001) for VPA. After administration of aminophylline for 3 days (electroshock was performed 30 min after the last aminophylline injection), the respective ED50 values for PB and VPA were 29.5 (p < 0.01) and 269 mg/kg (p < 0.01 vs. saline-treated animals). Chronic treatment with aminophylline (14 days) resulted in further impairment of the protective activity of PB and VPA. Specifically, the ED50 value of PB was 39 mg/kg (p < 0.05 vs. PB+single injection of aminophylline) and that of VPA was 318 mg/kg (p < 0.01 vs VPA+single injection of aminophylline). Plasma levels of both PB and VPA were not affected by chronic aminophylline; moreover, the plasma level of theophylline was even lower after chronic aminophylline as compared with single aminophylline administration.(ABSTRACT TRUNCATED AT 250 WORDS)

The protective activity of carbamazepine (CBZ, 60 min before testing), phenobarbital (PB, 120 min), phenytoin (PHT, 120 min), and valproate (VPA, 30 min) alone or concurrent with methylxanthine derivatives was evaluated against maximal electroshock-induced seizures (MES) in male mice. All drugs were administered intraperitoneally (i.p.), and the protection offered by antiepileptic drugs (AEDs) was expressed as ED50 in mg/kg. Caffeine sodium benzoate in doses of 0.0595-0.476 mmol/kg (11.55-92.4 mg/kg) distinctly reduced the anticonvulsant efficacy of PB, in the highest dose tested with an increase in ED50 value from 19.5 to 38 mg/kg. This methylxanthine derivative in the dose range of 0.119-0.476 mmol/kg (23.1-92.4 mg/kg) also efficiently inhibited the protective action of PHT. When combined with caffeine (0.238 and 0.476 mmol/kg), the ED50 of PHT was raised from 12 to 17 and 24 mg/kg, respectively. In doses of 0.238 and 0.476 mmol/kg, caffeine also diminished the efficacy of CBZ and VPA, and at the highest dose tested the methylxanthine elevated the respective ED50s from 13 to 20.5 mg/kg and from 270 to 420 mg/kg. Generally caffeine sodium benzoate (up to 0.476 mmol/kg) did not affect the plasma levels of studied AEDs, and only at 0.476 mmol/kg did it significantly decrease the level of PHT. Among the other methylxanthines, pentoxifylline (0.238-0.476 mmol/kg; 66.3-132.5 mg/kg) and diprophylline (0.952 mmol/kg; 242.1 mg/kg) inhibited the protective potential of PHT and the respective ED50s were raised from 12 to 16.5, 15.5, and 14 mg/kg. No significant alterations in PHT plasma levels were observed.(ABSTRACT TRUNCATED AT 250 WORDS)

The anticonvulsant potency of phenobarbital (PB) (120 min before the test), phenytoin (PHT) (120 min), carbamazepine (CBZ) (60 min), valproate (VPA) (30 min), and acetazolamide (60 min) alone or in combination with either aminophylline (50 mg/kg, 30 min) or enprofylline (46.2 mg/kg, 30 min) was measured against maximal electroshock-induced convulsions in mice. All drugs were administered intraperitoneally (i.p.), and the protective efficacy of each drug was expressed as ED50 in milligrams per kilogram. Aminophylline decreased anticonvulsant activity of PB, PHT, CBZ, and VPA, increasing the respective ED50 values from 16 to 28 mg/kg, 7.4 to 14 mg/kg, 18 to 26 mg/kg, and 260 to 335 mg/kg. On the contrary, enprofylline in the equimolar dose did not exert such effect. Furthermore, neither aminophylline nor enprofylline affected anticonvulsant action of acetazolamide. The present data favor enprofylline as a preferable drug for treatment of obstructive lung diseases in epilepsy patients. However, accurate pharmacokinetic data in mice and men for both xanthines are necessary if one attempts to compare their cerebral and pulmonary actions.

The increasing amount of data tends to suggest that adenosine-mediated inhibition may play a role in the anticonvulsant activity of a number of antiepileptic drugs. Consequently, we tried to reverse the protective action of acetazolamide [(40 and 80 mg/kg) i.p.; 60 min before the test]; carbamazepine (20 and 30 mg/kg i.p., 60 min); diazepam (5 and 10 mg/kg i.p., 60 min); diphenylhydantoin (8 and 12 mg/kg i.p., 120 min), phenobarbital (20 and 30 mg/kg i.p., 120 min) and valproate (200 and 300 mg/kg i.p., 30 min) with aminophylline (50 and 100 mg/kg i.p., 30 min) against electroconvulsions in mice. Aminophylline markedly decreased the anticonvulsant efficacy of almost all drugs studied, acetazolamide (40 and 80 mg/kg) and carbamazepine (30 mg/kg) being the only exceptions. The ethylenediamine component of aminophylline did not modify the anticonvulsant activity at all. These results seem to support the suggestion that aminophylline-induced blockade of adenosine receptors might be involved in the reversal of the protective action of at least some drugs studied. Regardless of the nature of the aminophylline-induced impairment in the anticonvulsant efficacy of a number of antiepileptic drugs, the use of methylxanthines in epileptic patients for the treatment of obstructive lung diseases should be avoided.

Mice were injected with intracerebroventricular (i.c.v.) kainic acid (KA; 0.1 micrograms per animal) and the pentetrazol test was carried out on the fifth day after the administration of the amino acid. The following antiepileptic drugs were tested for anticonvulsant activity in mice lesioned with KA: diazepam (0.4 mg/kg), phenobarbital (12.5 and 25 mg/kg), trimethadione (200 and 400 mg/kg), depakine (200 and 400 mg/kg), carbamazepine (10 and 20 mg/kg), lefadol (bromophenylsuccinimide; 20 mg/kg), and acetazolamide (320 mg/kg). All drugs were given intraperitoneally, except for carbamazepine, which was also given orally in doses of 100 and 200 mg/kg. Pentetrazol was administered subcutaneously in a dose of 110 mg/kg, and the animals were subsequently observed for the occurrence of clonic and tonic convulsions within 30 min. The protective effects of diazepam and phenobarbital were significantly reduced in the KA-lesioned animals, while the actions of the remaining anticonvulsants were unaltered. Moreover, a substantial loss of pyramidal cells in the CA 3 field of the hippocampus was noted after i.c.v. injection of KA. It may therefore be concluded that the mechanism of the action of diazepam and phenobarbital are partially dependent on the intact functions of the hippocampal formation.

Spontaneous clonic-tonic seizures were occasionally observed in inbred AE mice of both sexes. Determination of seizure thresholds in this strain showed that both female and male AE mice had electroconvulsive thresholds that were markedly lower than those of other strains of mice, whereas susceptibility to seizures induced by pentylenetetrazol was not increased. The antiepileptic drug phenobarbital was much less effective in blocking electroconvulsions in AE mice than in other strains. Similarly, valproic acid was less effective in protecting against pentylenetetrazol-induced seizures. These differences in anticonvulsant efficacy could be explained only partly by differences in pharmacokinetics, thus indicating a lower responsiveness of AE mice to antiepileptic drugs. Determination of the GABA-synthesizing enzyme glutamic decarboxylase in different brain regions showed no significant difference between AE mice and normal NMRI mice except for a lower GAD activity in corpus striatum of male AE mice. The data indicate that AE mice may be an interesting new genetic model of epilepsy.

In the electroshock test--taking hind-limb tonic extension as the end point--apomorphine (10 mg/kg) exerted no effect on the anticonvulsant action of phenobarbital (PB; 20 mg/kg) or diphenylhydantoin (DPH; 8 mg/kg); amantadine (25 and 100 mg/kg) decreased that of DPH, while L-DOPA (500 mg/kg) and d,l-amphetamine (10 mg/kg) potentiated the action of both anticonvulsants. Fluphenazine (4 mg/kg) had no influence on the effects of the two anticonvulsants, but haloperidol lessened that of DPH. All GABA-ergic stimulants used, i.e., gamma-hydroxybutyric acid (GHBA/250 mg/kg), baclofen (2.5 and 10 mg/kg) and aminooxoacetic acid (AOAA; 15 and 20 mg/kg) potentiated the action of PB; the action of DHP was unaffected by these drugs except for AOAA (20 mg/kg). The combined treatment with dopaminergic and GABA-ergic stimulants, being ineffective in terms of anticonvulsant activity, resulted in a marked potentiation of the action of the anticonvulsants tested in this study. The most distinct potentiation was noted in the case of PB, baclofen (1 mg/kg), and amantadine (25 mg/kg).

The electroshock test-taking hind limb tonic extension as the end point-was carried out on the fifth day after the intracerebroventricular injections of kainic acid (KA; 0.2 microgram per mouse). The following antiepileptics were tested for the anticonvulsant effects both in naive and KA-lesioned mice: phenobarbital (20 mg/kg), diazepam (8 mg/kg), carbamazepine (15 mg/kg) and diphenylhydantoin (10 mg/kg), all drugs being injected intraperitoneally 60 min before electroconvulsions. It was found that the protective effects of phenobarbital and diazepam were distinctly reduced in KA-lesioned animals when compared to naive mice. However, both carbamazepine and diphenylhydantoin protected KA-injected and control animals to a similar degree. Further, intracerebroventricular injections of KA resulted in the substantial loss of pyramidal cells in the whole CA3 field of the hippocampus. It is suggested that the intact hippocampus is necessary for the development of the full anticonvulsant effects of phenobarbital and diazepam, whilst the site of action of carbamazepine and diphenylhydantoin is independent of the hippocampus.

Aminophylline (50 and 100 mg/kg) and CGS 8216 (20 and 40 mg/kg) decreased the anticonvulsant potency of diazepam (5 and 10 mg/kg) against electroshock-induced seizures. It should be emphasized that aminophylline moderately affected the protective action of the benzodiazepine at a dose of 5 mg/kg, whereas it was equipotent with CGS 8216 with regard to diazepam at a dose of 10 mg/kg. Consequently, participation of a purinergic component in the anticonvulsant action of diazepam is suggested. On the other hand, the use of aminophylline in epileptic patients suffering from asthma seems unjustified.