Biomedical subjects

Stanisław J Czuczwar

Publications and source records attributed to Stanisław J Czuczwar.

At least 19 recordsLinked to original sources

PubMed2006

Interactions between zonisamide and conventional antiepileptic drugs in the mouse maximal electroshock test model.

Despite the major advances in antiepileptic drug (AED) therapeutics, about one third of patients with epilepsy still do not have adequate seizure control with currently available AEDs when prescribed as monotherapy. Typically, in this setting polytherapy with two or more AEDs is used. Zonisamide (ZNS) is a new AED effective in the treatment of refractory epilepsy and since it is only prescribed in polytherapy regimens, its interactions with other AEDs is of particular importance. The aim of this study was to isobolographically determine interactions between ZNS and four conventional AEDs: carbamazepine (CBZ), phenytoin (PHT), phenobarbital (PB), and valproate (VPA), in the mouse maximal electroshock (MES)-induced seizure model. The total brain concentrations of conventional AEDs and ZNS were measured with immunofluorescence and high-pressure liquid chromatography (HPLC), respectively, in order to determine any pharmacokinetic contribution in any observed interactions. With isobolography, synergistic interactions were observed for the combination of ZNS plus VPA and ZNS plus PHT at the fixed-ratio of 1:1, while additivity was observed for their combinations at the remaining dose ratios of 1:3 and 3:1. In contrast, the interactions between ZNS and PB and between ZNS and CBZ, applied at the fixed-ratios of 1:3, 1:1 and 3:1 proved to be additive. None of these AED combinations were associated with motor and long-term memory impairment. Furthermore, whilst brain AED concentrations were unaffected by ZNS, PHT significantly increased and PB reduced brain ZNS concentrations. Thus, the resultant interactions between ZNS and PHT and between ZNZ and PB were consequent to both pharmacodynamic and pharmacokinetic components. Finally, one can conclude that because of the synergistic pharmacodynamic interaction between ZNS and VPA, this combination might be useful in clinical practice.

Animals↗

PubMed2005

Influence of aminoglutethimide and spironolactone on the efficacy of carbamazepine and diphenylhydantoin against amygdala-kindled seizures in rats.

Antagonists of steroid receptors may interfere with seizure phenomena. The present study deals with effects of aminoglutethimide and spironolactone on the action of carbamazepine and diphenylhydantoin in amygdala-kindled rats of both genders. Co-administration of the antimineralocorticoid with carbamazepine at their ineffective doses (50 and 15 mg/kg, respectively) led to significant reduction of the seizure and afterdischarge durations. No anticonvulsant effect was observed when spironolactone was combined with diphenylhydantoin. The concomitant treatment of aminoglutethimide and carbamazepine (both drugs at their subprotective doses of 5 and 15 mg/kg, respectively) resulted in antiseizure activity in respect of all measured parameters, including the afterdischarge threshold, seizure severity, seizure duration and afterdischarge duration. The similar combination of aminoglutethimide with diphenylhydantoin (2.5 mg/kg) significantly shortened the seizure and afterdischarge durations. The antiseizure effect of tested combinations was not sex-dependent and not reversed by hydrocortisone pretreatment. Pharmacokinetic events may be involved only in the interaction between spironolactone and carbamazepine. Among various chemoconvulsants, bicuculline reversed the action of aminoglutethimide on carbamazepine and diphenylhydantoin. The effect of aminoglutethimide on diphenylhydantoin was also abolished by N-methyl-d-aspartic acid and aminophylline. In conclusion, our results suggest that doses of carbamazepine and diphenylhydantoin should be modified in epileptic patients concomitantly treated with aminoglutethimide or spironolactone.

Aminoglutethimide↗

PubMed2005

[Perspectives of neurosteroid derivative application in antiepileptic therapy].

Both steroid hormones and neurosteroids affect seizure expression and propagation in the central nervous system (CNS). Progesterone and allodeoxycorticosterone exhibit anticonvulsant, while estradiol and cortisol present proconvulsant action. Effect of testosterone on seizure phenomena depends on the metabolic route that this androgen is involved in. Natural (allopregnanolone) or synthetic (alphaxolone, ganaxolone, Co 21068) neuroactive steroids show protective effect against variety of experimental seizures, including electrically-triggered convulsions, like maximal electroshock, electrical kindling, and chemically-evoked, like pilocarpine-, pentetrazole-, picrotoxin-, cocaine-, bicuculline-, kainate-, or NMDA-induced ones. Influence of neurosteroids on seizure processes results from their ability to modulate two basic neurotransmitter systems, glutamatergic (mainly through NMDA receptors) and GABA-ergic (realized by GABAA receptors). Neuroactive steroids devoid of hormonal activity, but they preserve the action on neuronal excitability. The anticonvulsant efficacy of allopregnanolone, one of the natural neurosteroids, is greater than that of its hormonal precursor. However, a therapeutic application of natural neuroactive steroids is significantly limited by their rapid biotransformation. Synthetic derivatives are orally-active and their half-life time is essentially longer. Therefore, neurosteroids are good drug candidates for both monotherapy and add-on treatment of epilepsy. The best examined neurosteroid, ganaksolone, is currently under phase II clinical investigation.

Anticonvulsants↗

PubMed2004

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

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

Animals↗

PubMed2004

Interactions between non-barbiturate injectable anesthetics and conventional antiepileptic drugs in the maximal electroshock test in mice--an isobolographic analysis.

The aim of this study was the isobolographic evaluation of interactions between three non-barbiturate intravenous anesthetics and conventional antiepileptic drugs in the maximal electroshock-induced seizures 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). Plasma levels of antiepileptic drugs were measured by immunofluorescence. Obtained results indicate that ketamine acts synergistically with valproate and carbamazepine. Also the combinations of propofol and valproate or phenobarbital led to synergistic interactions. An antagonism was found between etomidate and carbamazepine or phenobarbital. On the other hand, interactions between diphenylhydantoin and injectable anesthetics proved to be additive. The only exception was the combination of diphenylhydantoin and propofol (1:3). Pharmacokinetic phenomena do not seem to interfere with the observed interactions, since none of anesthetics influenced the free plasma concentrations of antiepileptic drugs. Referring to undesired effects, only propofol impaired long-term memory. Although propofol did not disturbed motor coordination, it enhanced motor impairment caused by carbamazepine and diphenylhydantoin. Results of the present study suggest that etomidate needs to be avoided in epileptic patients due to a possibility of negative interactions with some antiepileptic drugs and seizure precipitation.

Anesthetics↗

PubMed2004

[Neuroprotective activity of antiepileptic drugs].

Clinical and experimental data indicate that epilepsy may lead to neuronal death and lesions placed in diverse brain regions. Also, the anticonvulsant activity of some antiepileptic drugs can be impaired in case of neurodegeneration in the brain. The main aim of this review is making a reader familiar with a patomechanism of neurodegeneration as well as the current data concerning the neuro-protective potential of antiepileptic drugs. It is noteworthy that a great number of papers devoted to this problem concern animal models of neurodegeneration produced by either seizure activity or ischemia. Interestingly, there are apparent differences in the direct central effects of antiepileptic drugs in adult and young animals. Majority of antiepileptics at anticonvulsant doses produce massive apoptosis in brains of young rodents, this effect being not present in adult animals. Only topiramate required higher than anticonvulsant doses to induce apoptotic response. Neuroprotective activity in models of ischemia and epilepsy was evident for benzodiazepines (diazepam), lamotrigine, tiagabine, topiramate, and vigabatrin. Recently, topiramate has been documented to exert potent neuroprotective action in human oligodendrocytes exposed to hypoxic-ischemic damage.

Anticonvulsants↗

PubMed2004

Influence of LY 300164 alone or in combination with carbamazepine or diphenylhydantoin on the body temperature in mice.

This study was aimed at evaluating the body temperature of mice following the injection of LY 300164, an AMPA/kainate receptor antagonist, alone or in combination with carbamazepine or diphenylhydantoin. LY 300164, injected alone at the dose of 2 mg/kg, produced a potent hypothermic effect between 15 and 30 min, or 60 and 90 min, after the drug administration. The combined treatment of LY 300164 (2 mg/kg) with diphenylhydantoin (3.6 mg/kg) resulted in a significant decrease of body temperature at the time period between 0 and 30 min, whilst LY 300164 (2 mg/kg) co-administered with carbamazepine (5 mg/kg) did not affect the animal temperature. Moreover, either diphenylhydantoin (11.8 mg/kg) or carbamazepine (15.8 mg/kg) injected alone exerted the hypothermic effects elicited at times ranging between 0 and 15 min, or 60 and 90 min, after the respective drug dose administration. In conclusion, hypothermia induced by LY 300164 along with its neuroprotective effects, may be useful in various brain conditions related with neuronal loss in which hypothermia offers some profitable effects, prolonging a survival rate of neurons in the central nervous system.

Animals↗

PubMed2003

Effects of etomidate, ketamine or propofol, and their combinations with conventional antiepileptic drugs on amygdala-kindled convulsions in rats.

Ketamine, etomidate and propofol modified behavioral and electrographic correlates of kindled seizures in rats. In detail, ketamine (5 mg/kg) and propofol (15 mg/kg) significantly increased afterdischarge threshold, reduced seizure severity and shortened seizure and afterdischarge durations. Etomidate (7.5 mg/kg) was effective in terms of seizure and afterdischarge durations. Moreover, the combinations of ketamine (2.5 mg/kg) with carbamazepine (15 mg/kg) or valproate (50 mg/kg; all drugs at their subeffective doses), reduced the severity and duration of kindled seizures. The antiseizure potency of the ketamine/carbamazepine combination was comparable to that of carbamazepine alone administered at 20 mg/kg, while the effect of ketamine/valproate was comparable to the efficacy of valproate alone at 100 mg/kg. However, the combinations of ketamine with phenobarbital or diphenylhydantoin did not exert any protective action. Propofol and etomidate entirely failed to interact with conventional antiepileptics. The combinations of ketamine with carbamazepine or valproate did not induce any significant motor impairment in the chimney test or memory deficit in the passive avoidance task. A pharmacokinetic interaction, at least in plasma, can be excluded, because ketamine (2.5 mg/kg) did not affect the free plasma concentrations of carbamazepine or valproate. Results of the present study may suggest that there may be no risk of negative interactions between injectable anesthetics and antiepileptics in cases of partial epilepsy.

Amygdala↗

PubMed2003

Interactions of tiagabine with some antiepileptics in the maximal electroshock in mice.

Tiagabine (TGB), a new potent gamma-aminobutyric acid (GABA) uptake inhibitor, is widely applied in adjunctive treatment of partial seizures in humans. Although, polytherapy is not an initial method of epilepsy treatment, clinicians often combine TGB with other antiepileptics as add-on therapy for assuring the anticonvulsant protection in patients with refractory seizures. To evaluate the character of pharmacological interactions between TGB and some antiepileptics, the isobolographic analysis was used as a suitable method for determining the exact types of interactions. Determination of an influence of TGB on the protective effects of diphenylhydantoin (DPH), carbamazepine (CBZ), valproate (VPA), phenobarbital (PB), lamotrigine (LTG), topiramate (TPM), and felbamate (FBM) in maximal electroshock-induced seizures was essential for this study. To exclude or confirm a pharmacokinetic character of observed interactions, the free plasma and brain concentrations of antiepileptic drugs (AEDs) studied were evaluated by using the immunofluorescence or high-pressure liquid chromatography (HPLC).TGB (up to 2.5 mg/kg) remained ineffective upon the electroconvulsive threshold, whilst the drug in doses of 5 and 10 mg/kg significantly raised the electroconvulsive threshold in mice. According to the isobolography, TGB appears to act synergistically with VPA. The remaining combinations tested exerted additive interactions. A pharmacokinetic character of interaction between TGB and VPA was evidently corroborated either in plasma or brains. Moreover, TGB significantly reduced the plasma and brain concentrations of DPH; however, pharmacokinetic events were not accompanied by any changes in anticonvulsant activity of the latter. Finally, the isobolographic analysis revealed that combinations of TGB with VPA exerted synergistic (supra-additive) interaction resulting from a pharmacokinetic interaction.

Animals↗

PubMed2003

Interaction of astemizole, an H1 receptor antagonist, with conventional antiepileptic drugs in mice.

Histamine is one of the aminergic neurotransmitters, playing an important role in the regulation of a number of physiological processes. There are several subtypes of histamine receptors-H(1), H(2), H(3) and the recently discovered H(4). H(1) receptors exist on mast cells, basophils, enterochromaffin cells and in the central nervous system, being located postsynaptically. H(1) receptor antagonists, including classical antiallergy drugs, occasionally have been expected to induce convulsions in children and epileptics. The aim of this study was to evaluate the effects of astemizole-given intraperitoneally, singly or for 7 days on the anticonvulsant activity of antiepileptic drugs (AEDs) against maximal electroshock (MES)-induced convulsions in mice. The following AEDs were administered intraperitoneally: valproate magnesium, carbamazepine, diphenylhydantoin and phenobarbital. Adverse effects were evaluated in the chimney test (motor performance) and passive avoidance task (long-term memory). Brain and plasma levels of AEDs were measured by immunofluorescence. Astemizole (a single dose and following a 7-day treatment at 2-6 mg/kg) reduced the threshold for electroconvulsions, being without effect upon this parameter at lower doses. Astemizole (1 mg/kg) did not significantly alter the protective effect of AEDs against MES (after acute and 7-day administration). Also, acute astemizole (2 mg/kg) remained ineffective in this respect. Astemizole (2 mg/kg), following chronic administration, significantly reduced the protective efficacy of phenobarbital and diphenylhydantoin, reflected by an increase in their ED(50) values (50% effective dose necessary to protect 50% of animals tested against MES) from 21.1 to 34.0 mg/kg and from 10.4 to 19.2 mg/kg, respectively. Astemizole (2 mg/kg) did not alter the protective activity of the remaining AEDs. Moreover, astemizole (2 mg/kg) did not influence the free plasma levels and brain concentration of the studied AEDs. Also, this H(1) receptor antagonist did not impair long-term memory or motor coordination when given acutely. However, 7-day treatment with astemizole (2 mg/kg) significantly decreased TD(50) (50% toxic dose required to induce motor impairment in 50% of animals) value of phenobarbital, being without effect on carbamazepine, valproate and diphenylhydantoin in this respect. Similarly, phenobarbital and diphenylhydantoin, administered alone at their ED(50)s against MES, or combined with astemizole, disturbed long-term memory in mice. The results of this study indicate that astemizole may need to be used with caution in epileptic patients.

Animals↗

PubMed2003

Influence of sex hormone antagonists on the anticonvulsant action of conventional antiepileptic drugs against amygdala-kindled seizures in male and female rats.

The effects of three gonadal steroid antihormones, tamoxifen (TXF, an estrogen antagonist), cyproterone acetate (CYP, an antiandrogen) and mifepristone (MIF, a progesterone antagonist) alone or combined with conventional antiepileptics were evaluated in amygdala-kindled seizures in male and female rats. None of the three antihormones used in this study affected any seizure parameter. TXF (50 mg/kg) and CYP (50 mg/kg), when combined with carbamazepine, or phenobarbital applied at their subprotective doses of 15 mg/kg, resulted in significant reductions of the seizure and afterdischarge durations, both in male and female rats. Additionally, the combination of carbamazepine and CYP markedly increased the afterdischarge threshold in fully-kindled rats of both genders. The interaction between antihormones and carbamazepine, or phenobarbital, was not reversed by respective sex steroid hormones (estradiol, testosterone). However, the TXF- and CYP-induced anticonvulsant effects in combinations with carbamazepine were attenuated by bicuculline, N-methyl-D-aspartate (NMDA) and aminophylline. Kainic acid and strychnine remained ineffective in this respect. The effect of a combination of TXF with phenobarbital was reversed by bicuculline and NMDA and that of CYP with phenobarbital-by bicuculline and aminophylline. Neither TXF nor CYP altered the free plasma concentrations of carbamazepine or phenobarbital, so a pharmacokinetic interaction is not probable. The combined treatment of the two antihormones with antiepileptic drugs did not affect motor performance, and did not result in significant long-term memory deficits. Our data confirm the hypothesis that sex hormone antagonist-mediated events may play some role in seizure processes in the central nervous system and can modulate the protective activity of some conventional antiepileptic drugs against kindled seizures.

Amygdala↗

PubMed2003

Tiagabine synergistically interacts with gabapentin in the electroconvulsive threshold test in mice.

Polytherapy, based on the rational combining of antiepileptic drugs (AEDs), is required for patients with drug-resistant epilepsy. In such cases, the combinations of AEDs usually offer a significant enhancement of their protective effects against seizures. There has appeared a hypothesis that combining two AEDs, influencing the same neurotransmitter system, results in the potentialization of their anticonvulsant effects. For corroborating this hypothesis, a pharmacological character of interaction between tiagabine (TGB) and gabapentin (GBP)-two novel AEDs affecting the GABA-ergic system, in the maximal electroshock seizure threshold (MEST)-test in mice was evaluated. TGB at the dose of 4 mg/kg and GBP at 75 mg/kg significantly raised the electroconvulsive threshold. Further, using the isobolographic calculations, TGB was coadministered with GBP at three fixed-ratios (1 : 3, 1 : 1, and 3 : 1) of their respective protective drug doses. All examined combinations of TGB with GBP exerted supra-additive (synergistic) interactions against MEST-induced seizures in mice. The interaction index, describing the strength and magnitude of interaction, ranged between 0.25 and 0.50 indicating supra-additivity. Adverse (neurotoxic) effects were evaluated in the chimney (motor performance) and the step-through, light-dark passive avoidance (long-term memory) tests in mice. The examined combinations of TGB with GBP did not affect the motor coordination, except for the fixed-ratio of 1 : 1, at which significant impairment of motor performance was observed. Moreover, all combinations selectively impaired the acquisition of the task in the passive avoidance test, having no impact on consolidation and retrieval in the long-term memory test. The pain threshold test revealed that the observed disturbances in the passive avoidance testing resulted presumably from the antinociceptive activity of these AEDs in combinations. After lengthening the exposing time to the direct current stimulus in the passive avoidance test from 2 to 6 s, the acquisition of the task, in animals receiving the combinations of TGB and GBP was not impaired. Neither the plasma, nor brain concentrations of GBP were affected by TGB application, so pharmacokinetic events that might negatively influence the observed effects are not probable. Results of this study clearly indicate that the activation of the same neurotransmitter system (GABA-ergic) leads to a synergistic interaction. The pain threshold test is a very good paradigm for screening the antinociceptive properties of AEDs, which may disturb the long-term memory testing in animals. Combinations of TGB with GBP (very promising from a preclinical point of view) should be clinically verified for elaborating the most effective treatment regimen in patients with intractable seizures.

Acetates↗

PubMed2002

Interaction of the neurosteroid alphaxalone with conventional antiepileptic drugs in different types of experimental seizures.

A number of neurosteroids exert antiseizure and/or neuroprotective properties. The aim of this study was to evaluate the effect of the neurosteroid alphaxalone on the protective action of conventional antiepileptics in four seizure tests. Alphaxalone (up to 5 mg/kg) did not exert a significant action against amygdala-kindled seizures in rats, or against pentetrazole- or aminophylline-induced convulsions in mice. The neuroactive steroid at the dose of 2.5 mg/kg significantly raised the threshold for electroconvulsions in mice. At 2.5 mg/kg, alphaxalone diminished the protective activity of valproate against maximal electroshock and at 2.5-5 mg/kg against pentetrazole-induced seizures in mice. However, alphaxalone (2.5 mg/kg) did not affect the protective activity of carbamazepine, diphenylhydantoin, phenobarbital or clonazepam against maximal electroshock and at 5 mg/kg did not affect that of phenobarbital, clonazepam and ethosuximide against pentetrazole-induced convulsions. Insignificant results were also obtained in the case of co-administration of alphaxalone with phenobarbital, valproate, clonazepam and carbamazepine against aminophylline-evoked seizures in mice. Also, in the kindling model of epilepsy, combinations of the neuroactive steroid (2.5 mg/kg) with valproate, carbamazepine, phenobarbital, diphenylhydantoin or clonazepam at their subprotective doses did not result in pro- or anticonvulsant activity. Valproate (284 mg/kg; the dose used in combination with alphaxalone) produced significant memory deficits in mice. Alphaxalone (2.5 mg/kg), valproate (at its ED(50) value of 226 mg/kg) and the combination of valproate (284 mg/kg) with alphaxalone (2.5 mg/kg) did not affect long-term memory, evaluated in the passive avoidance task with mice. Alphaxalone administered alone or in combination with valproate caused no motor impairment in experimental animals. Finally, alphaxalone (2.5 and 5 mg/kg) significantly increased the free plasma levels of valproate, strongly indicating that the neuroactive steroid-induced reduction of the protective activity of valproate is not related to pharmacokinetic phenomena. Summing up, alphaxalone does not seem to be a promising candidate for adjunctive treatment of epilepsy.

Aminophylline↗

PubMed2002

Nitric oxide and convulsions in 4-aminopyridine-treated mice.

We studied whether N(G)-nitro-L-arginine (NNA), an inhibitor of nitric oxide (NO) synthase as well as L-arginine and molsidomine, two agents elevating NO, influenced convulsions caused by 4-aminopyridine, a K+ channel blocker in mice. NNA, in a dose known to decrease level of NO (40 mg x kg(-1)), enhanced the seizure susceptibility to intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) 4-aminopyridine. L-arginine (500 mg x kg(-1)) and molsidomine (20 mg x kg(-1)) alone did not influence 4-aminopyridine-induced seizure activity. Surprisingly, the proconvulsant effect of NNA upon clonic and tonic seizures was potentiated by molsidomine (20 mg x kg(-1)). No influence of L-arginine on the proconvulsant effect of NNA was found. Taking into account the proconvulsant effect of NNA, an involvement of NO-mediated events in the mechanism of convulsive activity of 4-aminopyridine might be postulated. However, the ineffectiveness of L-arginine and molsidomine to suppress the convulsive activity of 4-aminopyridine as well as a paradoxical potentiation of the proconvulsant effect of NNA by molsidomine seem to exclude the impact of NO pathway on 4-aminopyridine-induced convulsions in mice. Our data suggest that the proconvulsant effect of NNA in this seizure model is caused by other, not related to NO, mechanisms.

4-Aminopyridine↗

PubMed2002

Polytherapy in epilepsy: the experimental evidence.

Monotherapy is recommended preferentially among newly diagnosed epileptic patients. In monotherapy-resistant patients polytherapy may be necessary. Two antiepileptic drugs may produce antagonistic, additive, and supra-additive (synergistic) anticonvulsant effects. The drug combination providing the supra-additive effect seems of clinical significance. However, when the supra-additive anticonvulsant efficacy is also associated by a distinct increase in toxicity, the protective index may be not affected or even lowered. Synergistic interactions have been shown for the combinations of valproate-phenytoin/ethosuximide, topiramate-carbamazepine/phenobarbital and felbamate-all major conventional antiepileptics. In contrast, the protective action of conventional antiepileptics has not been affected by felbamate at subprotective doses against maximal electroshock in mice. This is indicative that synergism is evident at only some drug ratios. Potential antiepileptic drugs, excitatory amino acid antagonists and calcium channel inhibitors, generally enhanced the protection offered by antiepileptic drugs. The experimental data may be helpful for predicting which drug combinations may prove effective in epileptic patients.

Animals↗

PubMed2002

2-Chloroadenosine, a preferential agonist of adenosine A1 receptors, enhances the anticonvulsant activity of carbamazepine and clonazepam in mice.

2-Chloroadenosine (0.25-1 mg/kg) significantly raised the threshold for electroconvulsions in mice. This preferential adenosine A(1) receptor agonist (at 0.125 mg/kg) significantly potentiated the protective activity of carbamazepine against maximal electroshock-induced seizures in mice. 2-Chloroadenosine (1 mg/kg) showed also anticonvulsive efficacy against pentylenetetrazol-evoked seizures, raising the CD(50) value for pentylenetetrazol from 77.2 to 93.7 mg/kg. The drug (at 0.5 mg/kg) significantly enhanced the protective action of clonazepam in this test, decreasing its ED(50) value from 0.033 to 0.011 mg/kg. Moreover, aminophylline, a non-selective adenosine receptor antagonist (5 mg/kg), and 8-cyclopentyl-1,3-dimethylxanthine (8-CPX), a selective A(1) adenosine receptor antagonist (5 mg/kg) reversed the 2-chloroadenosine (0.125 mg/kg)-induced enhancement of the protective activity of carbamazepine and clonazepam. 2-Chloroadenosine administered alone or combined with antiepileptic drugs, caused neither motor nor long-term memory impairment. Finally, the adenosine A(1) agonist did not change the free plasma concentration of antiepileptics, so a pharmacokinetic factor is not probable. Summing up, 2-chloroadenosine potentiated the protective activity of both carbamazepine and clonazepam, which seems to be associated with the enhancement of purinergic transmission mediated through adenosine A(1) receptors.

2-Chloroadenosine↗

PubMed2002

Influence of agents affecting voltage-dependent calcium channels and dantrolene on the anticonvulsant action of the AMPA/kainate receptor antagonist LY 300164 in mice.

It was previously documented that calcium (Ca(2+)) channel inhibitors intensified the protective effects of conventional antiepileptics against electroconvulsions in mice. The aim of this study was to evaluate the effects of Ca(2+) channel inhibitors (nifedipine, nicardipine and flunarizine) on the anticonvulsant action of the new AMPA/kainate receptor antagonist, 7-acetyl-3-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-1,3-dioxazolo[4,5-h][2,3]-benzodiazepine (LY 300164), against maximal electroshock (MES)-induced seizures in mice. Dantrolene (an inhibitor of Ca(2+)release from intracellular stores) was also included. Nifedipine (30 mg/kg) and flunarizine (15 mg/kg) raised the threshold for electroconvulsions, being ineffective at lower doses. Nicardipine (up to 30 mg/kg) and dantrolene (up to 20 mg/kg) did not affect this parameter. Flunarizine (10 mg/kg), nicardipine (20 mg/kg) and dantrolene (20 mg/kg) potentiated the efficacy of LY 300164 against MES. However, nicardipine (at 20 mg/kg) raised the free plasma concentration of LY 300164. Nifedipine (30 mg/kg), given even in a dose raising the electroconvulsive threshold, did not significantly alter the protective effect of LY 300164 against MES. Furthermore, the Ca(2+) channel agonist-BAY k-8644 (at 5 mg/kg) did not influence the protection offered by LY 300164 against MES. Finally, this Ca(2+) channel activator did not affect the enhanced efficacy of LY 300164 by Ca(2+) channel modulators. The only exception was the combination of LY 300164 with flunarizine. Combined treatment with LY 300164 and dantrolene (20 mg/kg), compared to LY 300164 alone, resulted in an impairment of motor performance in mice. Ca(2+) channel inhibitors were without effect upon this parameter evaluated in the chimney test. As shown in the passive avoidance task, LY 300164 alone (at its ED(50)) or combined with agents affecting neuronal Ca(2+) concentration did not disturb long-term memory. The present results suggest that agents preventing influx of Ca(2+) ions into neurons may enhance the protective action of LY 300164.

Animals↗

PubMed2002

Molsidomine potentiates the protective activity of GYKI 52466, a non-NMDA antagonist, MK-801, a non-competitive NMDA antagonist, and riluzole against electroconvulsions in mice.

The influence of molsidomine, a donor of nitric oxide (NO), L-arginine, a substrate for NO synthesis, and N(G)-nitro-L-arginine (NNA), an inhibitor of NO synthase, on the protective activity of CGP 40116, GYKI 52466, MK-801, and riluzole against electroconvulsions was studied in mice. Molsidomine (100 mg kg(-1); i.p.) potentiated the protective activity of GYKI 52466, MK-801, and riluzole but did not influence the protection offered by CGP 40116. In contrast to molsidomine, L-arginine (500 mg kg(-1); i.p.) did not impair the protective activity of any anticonvulsant. In a dose of 40 mg kg(-1), NNA administered i.p. did not affect the protection offered by any excitatory amino acid antagonists and riluzole. Combinations of molsidomine with either GYKI 52466 or MK-801 as well as riluzole did not cause a memory deficit in the passive avoidance task. However, the combined treatment of molsidomine with these anticonvulsants resulted in a motor impairment quantified by the chimney test. The lack of effect of L-arginine and NNA on the protective activity of excitatory amino acid antagonists suggests that molsidomine-evoked alterations in the protection provided by some excitatory amino acid antagonists against electroconvulsions are independent of the NO pathway.

Animals↗