Interactions between tiagabine and conventional antiepileptic drugs in the rat model of complex partial seizures.

This study evaluated the interactions between tiagabine (TGB) and three conventional antiepileptic drugs (AEDs): valproate (VPA), carbamazepine (CBZ), and phenobarbital (PB) in amygdala-kindled rats, a reliable model of complex partial seizures in humans. Isobolographic analysis of interactions revealed that TGB interacted additively with all tested conventional AEDs for the fixed-ratio combinations of 1:3, 1:1, and 3:1. Evaluation of pharmacokinetic interactions between AEDs revealed that the observed additivity was pharmacodynamic in nature. TGB did not affect the plasma and brain concentrations of VPA, CBZ and PB. Similarly, none of the studied conventional AEDs changed the plasma or brain levels of TGB. Also, TGB, VPA, CBZ, and PB administered alone (at their median effective doses) and in combinations at the fixed-ratio of 1:1 did not impair motor performance evaluated in the chimney test. In conclusion, additivity between TGB and conventional AEDs in amygdala-kindled rats and lack of bidirectional pharmacokinetic interactions suggest that TGB appears to be a valuable drug for an add-on therapy of refractory complex partial seizures in humans.

Aminoglutethimide but not spironolactone enhances the anticonvulsant effect of some antiepileptics against amygdala-kindled seizures in rats.

Aminoglutethimide (AGLD, an inhibitor of adrenal steroid synthesis) up to 5 mg/kg and spironolactone (SPIR, a mineralocorticosteroid antagonist and a weak antiandrogen) up to 50 mg/kg did not affect any seizure parameter in amygdala-kindled rats. AGLD (10 mg/kg) significantly reduced seizure activity in rats of both gender. The combination of AGLD (5 mg/kg) with phenobarbital (PB, applied at its subeffective dose of 15 mg/kg) significantly shortened motor seizure and afterdischarge duration in amygdala-kindled seizures. The combined treatment of AGLD (5 mg/kg) and clonazepam (CLO) at its subeffective dose of 0.01 mg/kg caused significant reduction of the seizure severity, seizure duration and afterdischarge duration. Finally, AGLD (5 mg/kg) proved ineffective upon the action of valproate (VPA) in this model of epilepsy. In contrast to AGLD, SPIR (50 mg/kg) did not affect the action of PB, CLO or VPA against kindled seizures in rats. AGLD did not alter the free plasma levels and brain concentration of PB or CLO, so a pharmacokinetic interaction does not seem probable. Among a variety of chemoconvulsants, bicuculline and N-methyl-D-aspartic acid reversed the effects of AGLD/PB and AGLD/CLO combinations. Aminophylline, kainic acid, strychnine and the glucocorticosteroid (hydrocortisone) were ineffective in this respect. Our data confirm the hypothesis that AGLD-mediated events may play a role in seizure activity and can affect the anticonvulsant activity of some conventional antiepileptic drugs against kindled seizures. Moreover, extrapolation of obtained results to clinical practice may indicate that patients with complex partial seizures may be safely co-medicated with AGLD or SPIR without the risk of worsening of seizure control.

Neuroprotective role of testosterone in the nervous system.

Testosterone -- the gonadal sex steroid hormone plays an important role in the central nervous system (CNS) development. One of the less known testosterone actions is neuroprotection. There are some evidences supporting the hypothesis that testosterone may act protectively in neurodegenerative disorders, e.g. Alzheimer's disease (AD), mild cognitive impairment (MCI) or depression. Androgens alter also the morphology, survival and axonal regeneration of motor neurons. These hormones accelerate the regeneration of hamster facial nerve and anterior tibialis sciatic nerve in rabbits following crush axotomy. Androgens exert trophic action in laryngeal motor nucleus of Xenopus laevis. Testosterone is linked to an increase in neuron somal size, neuritic growth, plasticity and synaptogenesis in both motoneurons of the spinal nucleus of the bulbocavernosus and several populations of pelvic autonomic neurons. The hormone reduced the extent of spinal cord damage in vitro. There are also evidences against the neuroprotective action of testosterone. Testosterone does not protect against methamphetamine-induced neurotoxicity of the dopaminergic system in mice and does not provide significant neuroprotection against glutamate-induced neurotoxicity. Androgens do not prevent striatal dopamine depletion induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice. Although the role of testosterone in the CNS is still poorly understood, accumulating evidence suggests that testosterone may create a future treatment for MCI and related cognitive diseases, including dementia and may influence motor neuron regeneration in adulthood. Androgen replacement therapy in selected male populations may hold therapeutic promise for the prevention and/or treatment of age-related disorders associated with neuronal injury.

Effect of MPEP, a selective mGluR5 antagonist, on the antielectroshock activity of conventional antiepileptic drugs.

MPEP, a selective non-competitive antagonist of group I metabotropic glutamate receptor subtype 5 (mGluR5), administered at doses ranging from 0.75 to 1 mg/kg, failed to influence the electroconvulsive threshold in mice. However, when administered at higher doses (1.25 and 1.5 mg/kg), it significantly increased the threshold. Moreover, MPEP (applied at its highest subprotective dose of 1 mg/kg) did not affect the protective action of valproate, carbamazepine, diphenylhydantoin and phenobarbital against maximal electroshock-induced seizures in mice. The presented results indicate that mGluR5 antagonists should not be considered as good candidates for add-on therapy of generalized seizures.

Interactions between riluzole and conventional antiepileptic drugs -- a comparison of results obtained in the subthreshold method and isobolographic analysis.

The exact types of pharmacodynamic interactions between riluzole and conventional antiepileptic drugs were evaluated in two available ways, the subthreshold and isobolographic analysis. Maximal electroshock test in mice was used as an animal model for generalized tonic-clonic convulsions. In the first method, riluzole (1.25-2.5 mg/kg) significantly raised the electroconvulsive threshold in mice. The drug administered at its subprotective dose of 0.3125 mg/kg enhanced the antiseizure activity of carbamazepine and phenobarbital, while, when applied at the higher dose of 0.625 mg/kg, it potentiated also the action of valproate and diphenylhydantoin. Riluzole (0.625) alone and in combinations with antiepileptic drugs did not produced any motor or log-term memory deficit. Results obtained from isobolographic analysis determined pure additive interaction between riluzole and all used conventional antiepileptic drugs. Since riluzole did not change plasma concentrations of co-administered antiepileptics, pharmacokinetic interactions, at least in terms of their free plasma levels, do not seem probable. The results of the present study confirm significant antiseizure properties of riluzole in the model of generalized tonic-clonic epileptic attacks. Moreover, comparison of effects obtained from both methods evaluating drug interactions strongly indicates a crucial role of the isobolographic analysis in verification and supplementation data achieved from the subthreshold method.

Influence of the combined treatment of LY 300164 (an AMPA/kainate receptor antagonist) with adenosine receptor agonists on the electroconvulsive threshold in mice.

7-Acetyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-1,3-dioxolo-4,5H-2,3-benzodiazepine hydrochloride (LY 300164; a selective noncompetitive AMPA/kainate antagonist; 2 mg/kg) and N(6)-2-(4-aminophenyl)ethyl-adenosine (APNEA; a nonselective adenosine A(1)/A(3) receptor agonist; 2 and 3 mg/kg) significantly raised the threshold for electroconvulsions in mice. In contrast, 5'-N-ethylcarboxamidoadenosine (NECA; a nonselective adenosine A(1)/A(2) receptor agonist; up to 1 mg/kg) did not affect the electroconvulsive threshold. The combined treatment of LY 300164 with NECA or APNEA was superior to single-drug medication as regards their protective action in this seizure model. Moreover, the combinations of LY 300164 with either NECA or APNEA were devoid of motor impairment, although they produced a significant long-term memory deficit. Measurement of the plasma levels of LY 300164 alone and in combination with APNEA or NECA did not suggest pharmacokinetic phenomena as an explanation for the interaction between these drugs. APNEA did not influence the plasma concentration of LY 300164. Moreover, NECA even significantly decreased the plasma levels of the AMPA/kainate antagonist. The present study clearly indicates a strong positive interaction in terms of anticonvulsant activity between LY 300164 and the drugs acting via adenosine receptors.

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.

Interaction of loreclezole with conventional antiepileptic drugs in amygdala-kindled rats.

Loreclezole (5 mg/kg) exerted a significant protective action against amygdala-kindled rats, reducing both seizure and afterdischarge (AD) durations. Subsequently, the effect of combinations of loreclezole (at non-effective doses) with some conventional antiepileptics (at their subtherapeutic doses) was evaluated. The co-administration of loreclezole (2.5 mg/kg) with phenobarbital (15 mg/kg) or diphenylhydantoin (2.5 mg/kg) did not influence any seizure correlates. However, the combined treatment of loreclezole (2.5 mg/kg) with valproate (50 mg/kg) significantly reduced the afterdischarge duration. Its combination with carbamazepine (15 mg/kg) reduced the seizure severity (SSv) and both seizure and afterdischarge durations. Also, the concomitant treatment of loreclezole (2.5 mg/kg) with clonazepam (0.05 mg/kg) resulted in a significant decrease of seizure and afterdischarge durations. Loreclezole did not affect the free plasma concentrations of valproate or clonazepam, so a pharmacokinetic interaction is not probable. Although, loreclezole significantly increased the free plasma concentration of carbamazepine. The results point to the potential therapeutic effects of combinations of loreclezole with valproate or clonazepam.

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.

Influence of several convulsants on the protective activity of a non-competitive AMPA/kainate antagonist, LY 300164, and lamotrigine against maximal electroshock in mice.

Aminophylline (50-100 mg/kg) and strychnine (0.125-0.5 mg/kg) significantly raised the ED50 values of LY 300164 against maximal electroshock in mice, from 4 to 8 mg/kg (aminophylline 100 mg/kg) and from 3.6 to 11.5 mg/kg (strychnine 0.5 mg/kg). Also, aminophylline (25-50 mg/kg) and strychnine (0.125-0.25 mg/kg) increased the ED50 value of lamotrigine in this test, for instance from 5.5 to 8.0 mg/kg (aminophylline 50 mg/kg) and from 5.2 to 8.9 mg/kg (strychnine 0.25 mg/kg). Moreover, the ED50S values of aminophylline and strychnine for the reduction of the anticonvulsant effect of LY 300164 (7 mg/kg, the dose equal to its ED97 value against maximal electroshock) were 79.9 and 0.2 mg/kg, respectively. The respective ED50 values for the inhibition of the antiseizure action of lamotrigine were 40.9 and 0.2 mg/kg. Neither bicuculline nor picrotoxin affected the protective action of LY 300164 or lamotrigine. Strychnine significantly lowered the plasma concentrations of LY 300164 and this my point to a pharmacokinetic mechanism of the observed interaction. Aminophylline did not affect the plasma concentrations of the studied anticonvulsant drugs and strychnine - that of lamotrigine, so a pharmacokinetic interaction does not seem probable. The present results indicate that the potential of aminophylline and strychnine to attenuate the anticonvulsant activity of conventional antiepileptics is extended to LY 300164 and lamotrigine.

Adrenal ganglioneuroblastoma in pregnant woman: diagnosis with three-dimensional ultrasound.

The diagnostic approach for evaluation of adrenal tumour in pregnant women is a problem. This article presents the multifactorial diagnosis of rare, incidentally detected massive adrenal tumour with 2D and 3D US. Grey-scale 2D and 3D US with tissue harmonic imaging showed inhomogeneous, encapsulated, solid tumour of the right adrenal region. Three-dimensional colour Doppler and power Doppler studies showed ample neovascularization in the tumour and the adrenal vein draining to the inferior vena cava similarly to angiographic studies performed in the past.

Glutamate receptor antagonists differentially affect the protective activity of conventional antiepileptics against amygdala-kindled seizures in rats.

LY 300164 (5 mg/kg), a selective non-competitive antagonist of AMPA/kainate receptors, exerted a significant anticonvulsant effect in amygdala-kindled rats, being ineffective at 2 mg/kg. LY 235959 (1--5 mg/kg), a selective competitive antagonist of NMDA receptors, failed to modify behavioral and electrographic correlates of kindled seizures. Amygdala-kindled seizures were inhibited by conventional antiepileptics, their lowest effective doses were: 20 mg/kg for carbamazepine and phenobarbital, 50 mg/kg for diphenylhydantoin, and 100 mg/kg for valproate magnesium. The combined treatment of the AMPA/kainate antagonist (2 mg/kg) with valproate at sub-effective doses (25--75 mg/kg) resulted in the reduced severity and duration of kindled seizures. Also, a clear-cut protective effect was observed when LY 235959 was co-administered with diphenylhydantoin (40 mg/kg). Any interaction at the pharmacokinetic level can be excluded because neither LY 300164 nor LY 235959 interfered with the free plasma levels of valproate or diphenylhydantoin, respectively. The combination of the AMPA/kainate receptor antagonist (2 mg/kg) with valproate (75 mg/kg) did not impair performance of rats in the rotorod test (motor co-ordination) or passive-avoidance task (long-term memory). Conversely, the NMDA receptor antagonist alone or in combination with diphenylhydantoin, produced significant mnemonic deficits. The results indicate that AMPA/kainate receptor antagonists might be of importance as adjuvant antiepileptic drugs in patients treated with valproate. A possible use of NMDA receptor antagonists may be questionable.

Interaction of GYKI 52466, a selective non-competitive antagonist of AMPA/kainate receptors, with conventional antiepileptic drugs in amygdala-kindled seizures in rats.

GYKI 52466 [1,4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine], a non-competitive AMPA/kainate receptor antagonist, administered i.p. at the dose of 5 mg/kg, exerted a significant anticonvulsant effect, as it decreased seizure and afterdischarge durations, being ineffective at 2 mg/kg. Subsequently, GYKI 52466 (2 mg/kg) was combined with antiepileptic drugs at doses ineffective in fully kindled rats. Co-administration of GYKI 52466 with clonazepam (0.003 mg/kg i.p.) resulted in a significant reduction of seizure severity (by 20%), seizure duration (by 31%) and afterdischarge duration (by 24%). Co-injection of GYKI 52466 with valproate (75 mg/kg i.p.) also resulted in the respective 8%, 16%, and 17% reductions of the three studied seizure parameters. No protection was observed when GYKI 52466 was co-administered with carbamazepine (20 mg/kg i.p.), phenobarbital (20 mg/kg i.p.), or diphenylhydantoin (40 mg/kg i.p.). Combinations of GYKI 524662 with antiepileptic drugs did not cause any significant motor (rotarod test) or long-term memory deficits (passive avoidance task). Only GYKI 52466 administered alone at 5 mg/kg, caused a significant impairment of retention in amygdala-kindled rats. The interaction at a pharmacokinetic level, at least in case of the combination of GYKI 52466 with valproate, can be excluded because GYKI 52466 did not interfere with the free plasma level of valproate. These results give further support to the idea of a potential clinical benefits of the combined treatment of AMPA/kainate receptor antagonists with some antiepileptic drugs.

Effect of antihormones in amygdala-kindled seizures in rats.

Tamoxifen (TXF; an antiestrogen), cyproterone acetate (CYP; an antiandrogen) and mifepristone (MIF; an antigestagen) did not affect kindling parameters (afterdischarge threshold, seizure severity, seizure duration and afterdischarge duration) in fully-kindled rats. TXF (50 mg/kg) and CYP (50 mg/kg), when combined with carbamazepine, or phenobarbital, both antiepileptics administered at their highest subprotective doses of 15 mg/kg, resulted in significant reduction of the seizure and afterdischarge durations, both in male and female rats. Additionally, the combination of carbamazepine and cyproterone markedly increased the afterdischarge threshold in fully-kindled rats of both genders. The interaction between antihormones and carbamazepine, or phenobarbital, was not reversed by the respective gonadal hormones (estradiol, progesterone, and testosterone), kainic acid, or strychnine. However, the TXF-, and CYP-induced effect on the action of carbamazepine was abolished by bicuculline, N-methyl-D-aspartic acid and aminophylline. The effect of TXF on the protective activity of phenobarbital was reversed by bicuculline and N-methyl-D-aspartic acid. Finally, the CYP-mediated effect on phenobarbital action was abolished by bicuculline and aminophylline. Neither TXF nor CYP altered free plasma levels and brain levels of carbamazepine or phenobarbital, so a pharmacokinetic interaction between antihormones and antiepileptic drugs is not probable. In view of the present data, it may be suggested that the protective activity of the antiestrogen and antiandrogen are mostly associated with the enhancement of GABA-ergic and purinergic transmission in the central nervous system. Also the augmentation of glutamatergic transmission, realized through NMDA receptors, may be involved in the mechanism of antiseizure action of TXF and CYP.

7-Nitroindazole, a nitric oxide synthase inhibitor, enhances the anticonvulsive action of ethosuximide and clonazepam against pentylenetetrazol-induced convulsions.

The interaction of 7-nitroindazole (7-NI), a nitric oxide synthase (NOS) inhibitor, with the protective activity of conventional antiepileptics against pentylenetetrazol (PTZ)-induced seizures was tested in mice. Alone, 7-nitroindazole (up to 50mg/kg) was ineffective in this model of experimental epilepsy. However, it potentiated the anticonvulsive activity of ethosuximide and clonazepam, significantly reducing their ED50S against PTZ-induced convulsions (from 144 to 76 mg/kg, and from 0.05 to 0.016 mg/kg, respectively). Conversely, the protective actions of valproate and phenobarbital were not affected by the NOS inhibitor. Since the nitric oxide precursor, L-arginine, did not reverse the action of 7-NI on ethosuximide or clonazepam, an involvement of central NO does not seem probable. Neither ethosuximide nor clonazepam, administered at their ED50S (144 and 0.05 mg/kg, respectively), produced significant adverse effects as regards motor coordination (chimney test) and long-term memory (passive avoidance task). Also 7-NI (50 mg/kg) and its combinations with ethosuximide and clonazepam (providing a 50% protection against PTZ-evoked seizures) did not disturb motor and mnemonic performance in mice. The interaction at the pharmacokinetic level does not seem probable, at least in the case of ethosuximide, because the NOS inhibitor did not interfere with its plasma or brain concentrations.

7-nitroindazole differentially affects the anticonvulsant activity of antiepileptic drugs against amygdala-kindled seizures in rats.

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.

Low propensity of conventional antiepileptic drugs for interaction with felbamate against maximal electroshock-induced seizures in mice.

The objective of this study was to evaluate an interaction of the novel antiepileptic drug felbamate (2-phenyl-1,3-propanediol dicarbamate) with conventional antiepileptic drugs against maximal electroshock-induced convulsions in mice. Electroconvulsions were produced by means of an alternating current (ear-clip electrodes, 0.2-s stimulus duration, tonic hindlimb extension taken as the endpoint). Adverse effects were evaluated in the chimney test (motor performance) and passive avoidance task (long-term memory). Brain and plasma levels of antiepileptic drugs were measured by immunofluorescence. Felbamate (7.5-30 mg/kg) significantly increased the electroconvulsive threshold. Felbamate at the subprotective dose of 5 mg/kg did not affect the anticonvulsive action of antiepileptics studied. On the other hand, this drug used at the lowest protective dose of 7.5mg/kg remained without effect upon the activity of valproate, carbamazepine or phenobarbital, but significantly potentiated the protective potential of diphenylhydantoin. No adverse effects were observed with combinations of felbamate with these antiepileptics. Neither brain nor free plasma levels of antiepileptic drugs were changed by felbamate. The results indicate that the combination of felbamate with conventional antiepileptic drugs is not promising from the experimental point of view.

The AMPA/kainate receptor antagonist, LY 300164, increases the anticonvulsant effects of diazepam.

The aim of this study was to evaluate the influence of 7-acetyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-1,3-dioxolo(4,5 H)-2,3-benzodiazepine (LY 300164), a selective non-competitive antagonist at alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate receptors, on the protection provided by diazepam against electrically- and chemically-evoked seizures in rodents. LY 300164 (2 mg/kg) was devoid of any significant action upon each seizure parameter in kindled rats (seizure severity, seizure duration, after-discharge duration). LY 300164 (5 mg/kg) exerted a significant anticonvulsive effect as regards seizure and after-discharge durations. Combined treatment with LY 300164 (2 mg/kg) and diazepam (0.3125-1.25 mg/kg) resulted in the clear-cut anticonvulsive activity. It is noteworthy that the antiseizure potency of the combined treatment (diazepam 1.25 mg/kg plus LY 300164 2 mg/kg) was comparable to that of diazepam (10-20 mg/kg) alone. The combination of diazepam (1.25 mg/kg) with LY 300164 (2 mg/kg) did not induce any significant motor impairment in the rotorod test or memory deficit in the passive-avoidance task. In contrast, diazepam alone (10-20 mg/kg) had pronounced adverse effects in kindled animals. LY 300164 (up to 2 mg/kg) did not influence the threshold for electro- and pentylenetetrazol-induced convulsions but potentiated the anticonvulsive action of diazepam in the maximal electroshock and pentylenetetrazol test in mice, the ED50s of the benzodiazepine being reduced from 13 to 8.7 and from 0.29 to 0.049 mg/kg, respectively. As shown in the passive-avoidance task, combination of LY 300164 (2 mg/kg) with diazepam (8.7 mg/ kg) produced significant motor and long-term memory impairment. Diazepam alone (at the dose equal to its ED50 against maximal electroshock) also caused motor and memory deficits in mice. Interaction at the pharmacokinetic level, at least in plasma, can be excluded, because LY 300164 (2 mg/kg) did not affect the free plasma diazepam concentration. In conclusion, LY 300164 potentiates the protective action of diazepam in some animal models of seizures. This profitable interaction may create a new approach for the treatment of drug resistant epilepsy or status epilepticus.

N(6)-2-(4-aminophenyl)ethyl-adenosine enhances the anticonvulsive action of conventional antiepileptic drugs in the kindling model of epilepsy in rats.

APNEA [(N(6)-2-(4-aminophenyl)ethyl-adenosine; a non-selective adenosine A(3) receptor agonist; 2-4 mgkg(-1)] had no significant effect on seizure parameters (seizure severity, seizure duration and afterdischarge duration) in amygdala-kindled rats. Subsequently, APNEA was combined with antiepileptic drugs administered at doses ineffective in fully kindled rats. Co-administration of APNEA (0.5-2 mg kg(-1)) with carbamazepine (2.5-20 mg kg(-1)) resulted in the significant reduction of all studied seizure parameters. Moreover, 8-cyclopentyl-1,3-dimethylxanthine 8-CPX (a selective adenosine A(1) receptor antagonist; 5 mg kg(-1)) partially reduced the anticonvulsive activity of a combination of APNEA (2 mg kg(-1)) with carbamazepine (20 mg kg(-1)), but not that of carbamazepine (20 mgkg(-1))+APNEA (0.5 mg kg(-1)). When APNEA (2 mg kg(-1)) was combined with phenobarbital (20 mg kg(-1)), valproate (75 mg kg(-1)) or clonazepam (0.003 mg kg(-1)), seizure and afterdischarge durations were significantly shortened. 8-CPX (5 mg kg(-1)) totally reversed the APNEA (2 mg kg(-1))-induced enhancement of the anticonvulsive action of valproate. However, when the non-selective adenosine A(3) receptor agonist was administered together with diphenylhydantoin, no protection was observed in the kindling model of epilepsy. The interaction at the pharmacokinetic level can be excluded because APNEA did not interfere with the free plasma level of antiepileptics used in this study. It may be concluded that the interaction of APNEA with carbamazepine involves A(3) adenosine receptor-dependent events.

Two essential amino acids, L-lysine and L-histidine, in five types of experimental seizures.

L-Lysine (250-2,000 mg/kg) and L-histidine (1,000-2,000 mg/kg) significantly raised the electroconvulsive threshold. D-Histidine (1,000 mg/kg) was completely ineffective in this regard. Both amino acids were generally inactive in pentetrazole-, picrotoxin- and aminophylline-induced seizures, though L-histidine (2,500 mg/kg) significantly reduced the number of mice with clonic convulsions in the pentetrazole test. Also, L-lysine (2,500 and 3,000 mg/kg) significantly diminished mortality rate in aminophylline-induced seizures. In addition, L-lysine (2,500-3,000 mg/kg) and L-histidine (2,000-2,500 mg/kg) delayed the onset of aminophylline- and picrotoxin-evoked convulsions. L-Lysine and L-histidine (both up to 1,000 mg/kg) did not affect amygdala-kindled seizures in rats. The results indicate that some of indispensable amino acids may play a role in the inhibitory transmission in the central nervous system. A possibility arises that appropriate diet may be an important supportive factor in the treatment of some epileptic patients, probably suffering from generalized tonic-clonic seizures.