Isobolographic characterization of interactions of retigabine with carbamazepine, lamotrigine, and valproate in the mouse maximal electroshock-induced seizure model

The aim of this study was to characterize the pharmacodynamic, pharmacokinetic, and adverse-effect profiles of retigabine (RTG) in combination with carbamazepine (CBZ), lamotrigine (LTG), and valproate (VPA). The isobolographic analysis for parallel and nonparallel dose–response effects was used in the mouse maximal electroshock seizure (MES) model for evaluation of pharmacodynamic interaction. Potential adverse-effect profiles of interactions of RTG with CBZ, LTG, and VPA at the fixed ratio of 1:1 in the MES test were evaluated in the chimney (motor performance), passive avoidance (long-term memory), and grip strength (muscular strength) tests. Free plasma and total brain concentrations of CBZ, LTG, and VPA were determined by immunofluorescence and chromatography to assess pharmacokinetic interaction. In the MES model, RTG administered singly had its dose–response relationship curve (DRRC) parallel to that for VPA and nonparallel to that for CBZ and LTG. With isobolography for parallel DRRCs, the combination of RTG with VPA at fixed ratios of 1:3, 1:1, and 3:1 exerted supraadditive (synergistic) interaction. Isobolography for nonparallel DRRCs revealed that the combinations of RTG with CBZ and LTG at the fixed ratio of 1:1 produced additive interaction. In all combinations, neither motor coordination, long-term memory, nor muscular strength were affected. Only the combination of RTG with VPA at the fixed ratio of 3:1 was complicated by a pharmacokinetic increase in both free plasma and total brain VPA concentrations. All remaining combinations of RTG with VPA, CBZ, and LTG were pharmacodynamic in nature. RTG synergistically interacted with VPA and exerted additive interaction with CBZ and LTG in the mouse MES model.     

Interactions of MRZ 2/576 with felbamate, lamotrigine, oxcarbazepine and topiramate in the mouse maximal electroshock-induced seizure model

This study focused on the evaluation of interactions between MRZ 2/576 (8-chloro-4-hydroxy-1-oxo-1,2-dihydropyridazino(4,5-b)quinoline-5-oxide choline salt), an N-methyl-D-aspartate (NMDA) receptor antagonist acting at the NMDA receptor/glycine(B) site and four newer antiepileptic drugs (felbamate, lamotrigine, oxcarbazepine, and topiramate) in the mouse maximal electroshock seizure model. Results indicate that MRZ 2/576 administered intraperitoneally, 5 min before the test, exerted a clear-cut anticonvulsant effect in the maximal electroshock seizure test in mice and its ED(50) value was 13.71 (11.95-15.73) mg/kg. In the subthreshold method, MRZ 2/576 (administered intraperitoneally, at a subthreshold dose of 5 mg/kg) significantly enhanced the anticonvulsant action of felbamate, oxcarbazepine and topiramate, by reducing their ED(50) values from 73.0 to 53.8 mg/kg (p < 0.05) for felbamate, from 10.77 to 7.48 mg/kg (p < 0.05) for oxcarbazepine, and from 49.3 to 28.7 mg/kg (p < 0.01) for topiramate. In contrast, MRZ 2/576 (5 mg/kg, i.p.) did not significantly affect the antiseizure effects of lamotrigine in the maximal electroshock seizure test in mice. Isobolographic transformation of data revealed that MRZ 2/576 (5 mg/kg, i.p.) exerted barely additive interactions with all investigated antiepileptic drugs in the maximal electroshock seizure test. In conclusion, the isobolographic analysis revealed that MRZ 2/576 additively cooperates with newer antiepileptic drugs in terms of suppression of maximal electroshock-induced seizures in mice.     

2-Chloro-N6-cyclopentyladenosine enhances the anticonvulsant action of carbamazepine in the mouse maximal electroshock-induced seizure model

This study examines the anticonvulsant profile of interactions between 2-chloro-N6-cyclopentyladenosine (CCPA, a selective adenosine A1 receptor agonist) and four conventional antiepileptic drugs (AEDs: carbamazepine--CBZ, phenobarbital, phenytoin and valproate) in the mouse maximal electroshock seizure (MES) model. Acute adverse effects produced by AEDs in combination with CCPA were determined in the chimney test (motor performance) and passive avoidance task (long-term memory). Results indicate that CCPA administered alone at 0.25 and 0.5 mg/kg significantly elevated the electroconvulsive threshold in mice. Additionally, the agent at a sub-threshold dose of 0.125 mg/kg potentiated the anticonvulsant activity of CBZ by reducing its ED50 in the MES test from 11.2 to 7.7 mg/kg (p < 0.01). In contrast, 8-cyclopentyl-1,3-dimethylxanthine (DPCPX, a selective adenosine A1 receptor antagonist at 5 mg/kg) abolished the enhanced anticonvulsant effects offered by the combination of CBZ with CCPA (0.125 mg/kg). Moreover, CCPA (0.125 mg/kg) co-administered with other tested AEDs had no significant impact on their antiseizure properties in the MES test in mice. Neither CCPA (0.125 mg/kg) administered singly, nor in combinations with conventional AEDs (at their ED50s) affected motor performance in the chimney test and long-term memory in the passive avoidance task. No pharmacokinetic alterations in brain CBZ concentrations were observed after administration of CCPA at 0.125 mg/kg. It may be concluded that CCPA, acting selectively on adenosine A1 receptors, enhances pharmacodynamically the antiseizure effect of CBZ in the MES test.     

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

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

Pharmacokinetic and pharmacodynamic interactions of aminophylline and topiramate in the mouse maximal electroshock-induced seizure model

The aim of this study was to determine the influence of acute (single) and chronic (twice daily for 14 consecutive days) treatments with aminophylline (theophylline(2).ethylenediamine) on the anticonvulsant potential of topiramate (a broad-spectrum antiepileptic drug) in the mouse maximal electroshock-induced seizure model. Additionally, the effects of acute and chronic administration of aminophylline on the adverse effect potential of topiramate were assessed in the chimney test (motor performance). To evaluate pharmacokinetic characteristics of interaction between topiramate and aminophylline, total brain concentrations of topiramate and theophylline were estimated with fluorescence polarization immunoassay technique. Results indicate that aminophylline in non-convulsive doses of 50 and 100 mg/kg (i.p.), both in acute and chronic experiments, markedly attenuated the anticonvulsant potential of topiramate by raising its ED(50) value against maximal electroconvulsions. Aminophylline at a lower dose of 25 mg/kg did not affect significantly the ED(50) value of topiramate in the acute experiment, but the drug markedly increased the ED(50) value of topiramate during the chronic treatment in mice. Only, aminophylline at 12.5 mg/kg, in both acute and chronic experiments, did not affect the antielectroshock action of topiramate in mice. Moreover, aminophylline at a dose of 100 mg/kg had no impact on the adverse effect potential of topiramate in the chimney test. Pharmacokinetic evaluation of total brain concentrations of topiramate and theophylline revealed that topiramate significantly increased total brain theophylline concentrations following both acute and chronic applications of aminophylline. Conversely, aminophylline did not alter total brain concentrations of topiramate in mice. Based on this preclinical study, one can conclude that aminophylline attenuated the antiseizure action of topiramate in the mouse maximal electroshock-induced seizure model and the observed interaction between drugs was both pharmacokinetic and pharmacodynamic in nature.     

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

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

7-Nitroindazole, but not NG-nitro-L-arginine, enhances the anticonvulsant activity of pregabalin in the mouse maximal electroshock-induced seizure model

The objective of this study was to determine the effects of 7-nitroindazole (7NI--a preferential neuronal nitric oxide synthase (NOS) inhibitor) and NG-nitro-L-arginine (NNA--a non-selective NOS inhibitor) on the anticonvulsant action of pregabalin (PGB--a third-generation antiepileptic drug) in the maximal electroshock (MES)-induced seizure model in mice. Electroconvulsions were produced in mice by means of an alternating current (50 Hz, 500 V, 25 mA, ear-clip electrodes, 0.2 s stimulus duration, tonic hindlimb extension taken as the endpoint). The anticonvulsant action of PGB in the MES test was expressed as median effective doses (ED50 values) of the drug, protecting 50% of animals tested against MES-induced seizures. The acute adverse-effect potentials of PGB in combination with 7NI and NNA were evaluated in the chimney test (motor coordination), step-through passive avoidance task (long-term memory) and grip-strength test (skeletal muscular strength) in mice. 7NI (50 mg/kg, ip) significantly enhanced the anticonvulsant action of PGB by reducing the ED50 value of PGB from 145.0 mg/kg to 74.4 mg/kg (p<0.01). Similarly, 7NI at the lower dose of 25 mg/kg also potentiated the anticonvulsant action of PGB by lowering the ED50 value of PGB from 145.0 mg/kg to 117.9 mg/kg, although the results did not attain statistical significance. In contrast, NNA (40 mg/kg, ip) had no impact on the anticonvulsant effects of PGB. Moreover, none of the examined combinations of PGB with 7NI and NNA affected motor coordination, long-term memory and skeletal muscular strength in mice. Based on this preclinical study, one can conclude that 7NI significantly enhanced and NNA had no effect on the anticonvulsant activity of PGB against MES-induced seizures in mice.     

Arachidonyl-2'-chloroethylamide, a highly selective cannabinoid CB1 receptor agonist, enhances the anticonvulsant action of valproate in the mouse maximal electroshock-induced seizure model

Endogenous cannabinoid ligands and cannabinoid CB(1) receptor agonists have been shown to exert potent anticonvulsant effects in various experimental models of epilepsy. The purpose of this study was to determine the effects of arachidonyl-2'-chloroethylamide (ACEA; N-(2-chloroethyl)-5Z,8Z,11Z,14Z-eicosatetraenamide, a highly selective cannabinoid CB(1) receptor agonist) on the threshold for electroconvulsions and the anticonvulsant activity of valproate in the maximal electroshock-induced seizures in mice. To inhibit the rapid metabolic degradation of ACEA by the fatty-acid amide hydrolase, phenylmethylsulfonyl fluoride (PMSF) was used at a constant ineffective dose of 30 mg/kg (i.p.). Moreover, the effects of ACEA and PMSF on the acute adverse-effect profile of valproate were determined in the chimney test. Additionally, the adverse-effect potentials of combination of ACEA, PMSF with valproate were examined in the step-through passive avoidance task (long-term memory) and grip-strength test (neuromuscular strength). To ascertain any pharmacokinetic contribution of ACEA and PMSF to the observed interaction between tested drugs, both free (non-protein bound) plasma and total brain concentrations of valproate were estimated. Results indicated that ACEA (5 and 7.5 mg/kg; i.p.) combined with PMSF increased significantly (P<0.001) the electroconvulsive threshold in mice. ACEA at low doses of 1.25 and 2.5 mg/kg, i.p., with PMSF had no impact on threshold for electroconvulsions. Similarly, neither PMSF (30 mg/kg) nor ACEA (15 mg/kg) administered alone affected the electroconvulsive threshold in mice. Moreover, ACEA (at a subthreshold dose of 2.5 mg/kg; i.p.) co-administered with PMSF potentiated significantly the antielectroshock activity of valproate by reducing its ED(50) from 258.3 to 195.1 mg/kg (P<0.01). Isobolographic transformation of data revealed that the interactions between valproate and ACEA (at 1.25 and 2.5 mg/kg) combined with PMSF were additive. In the chimney test, the combination of ACEA (2.5 mg/kg) and PMSF (30 mg/kg) had no effect on acute adverse effect of valproate and its TD(50) (356.4 mg/kg) did not differ significantly from that for valproate administered alone (TD(50)=404.4 mg/kg). Moreover, none of the examined drugs administered either alone or in combinations produced long-term memory deficits in the step-through passive avoidance task and impaired neuromuscular strength in the grip-strength test in mice. In contrast, ACEA (2.5 mg/kg; i.p.) combined with PMSF (30 mg/kg; i.p.) considerably increased both, the free plasma (by 42%; P<0.01) and total brain (by 49%; P<0.001) concentrations of valproate (administered at 195 mg/kg; i.p.) in mice. Hence, the observed interaction between valproate and ACEA with PMSF in the maximal electroshock test was pharmacokinetic in nature. Finally, based on this preclinical study, one can conclude that ACEA--a cannabinoid CB(1) receptor agonist co-administered with PMSF pharmacokinetically interacted with valproate and thus, providing the enhancement of the antielectroshock activity of valproate in mice, although, the isobolographically determined interaction between drugs was additive. To elucidate the protective role of cannabinoids in the brain during seizures, more advanced neurochemical studies are required.     

7-Nitroindazole enhances dose-dependently the anticonvulsant activities of conventional antiepileptic drugs in the mouse maximal electroshock-induced seizure model

7-Nitroindazole (7NI, a nitric oxide synthase [NOS] inhibitor) administered intraperitoneally (ip), 30 min before the test, at doses ranging between 50-200 mg/kg, raised the threshold for electroconvulsions in mice. Linear regression analysis revealed that the doses increasing the threshold by 50% (TID50) and 100% (TID100) over the control value for 7NI were 115.2 and 173.4 mg/kg, respectively. Moreover, 7NI dose-dependently potentiated the anticonvulsant effects of four conventional antiepileptic drugs (AEDs: carbamazepine - CBZ, phenobarbital - PB, phenytoin - PHT, and valproate - VPA) in the mouse maximal electroshock-induced seizure (MES) model. 7NI at 50 mg/kg enhanced only the anticonvulsant effect of PB, whereas the drug at 75 and 100 mg/kg potentiated the antiseizure effects of PB, PHT and VPA, but not those of CBZ against MES-induced seizures. Only 7NI at 150 mg/kg enhanced considerably the antielectroshock action of all studied AEDs in the MES test. Pharmacokinetic evaluation of interactions between 7NI and the investigated AEDs revealed that 7NI (150 mg/kg; ip) did not alter total brain concentrations of conventional AEDs in mice. L-arginine (L-Arg - a natural precursor of NO; administered ip, 500 mg/kg, 60 min before electroconvulsions) did not reverse the activity of 7NI (150 mg/kg), but in contrast, it significantly potentiated the anticonvulsant action of conventional AEDs combined with 7NI (150 mg/kg). Pharmacokinetic increase in total brain AED concentrations was observed for the combinations of L-Arg (500 mg/kg) with 7NI (150 mg/kg) and PHT (by 32%; p<0.01) or VPA (by 22%; p<0.05). Neither total brain CBZ nor PB concentrations were altered following the co-administration of L-Arg (500 mg/kg) with 7NI (150 mg/kg). 7NI at doses of 100-200 mg/kg significantly impaired spontaneous ambulatory activity in mice subjected to the Y-maze task. The NOS inhibitor at doses of 50 and 75 mg/kg had no significant effect on locomotor activity of animals, although the number of arm entries within the 5 min of observational time was reduced. Finally, it can be concluded that the enhancement of anticonvulsive efficacy of CBZ, PB, PHT and VPA by 7NI alone or in combination with L-Arg in the MES test, deserves more attention and further neurochemical studies are required to elucidate the exact role of NO in the brain.     

Effect of amlodipine upon the protective activity of antiepileptic drugs against maximal electroshock-induced seizures in mice.

Amlodipine, a calcium channel antagonist of the dihydropyridine class, up to 10 mg kg(-1)(i.p.) did not significantly affect the threshold for electroconvulsions. However, this calcium channel antagonist (10 mg kg(-1)) enhanced the anticonvulsive activity of carbamazepine, valproate and phenobarbital against maximal electroshock-induced seizures in mice. Furthermore, amlodipine (5 mg kg(-1)) intensified the protection offered by carbamazepine. This effect was associated with the increased free plasma level of carbamazepine in the presence of amlodipine. Amlodipine did not influence the free or total plasma level of phenobarbital and valproate, so a pharmacokinetic interaction is not probable for valproate and phenobarbital. The anticonvulsive action and free plasma level of diphenylhydantoin was not modified by amlodipine. The combined treatment of the calcium channel antagonist and antiepileptics caused motor impairment (evaluated in the chimney test). Long-term memory (assessed in the passive avoidance test) in case of combinations of amlodipine with carbamazepine or diphenylhydantoin was not affected. The combination of amlodipine with valproate or phenobarbital significantly influenced the retention in this test. A possible usefulness of amlodipine as add-on therapy in epileptic patients may be limited by its considerable adverse effect revealed by behavioural tests. The pharmacokinetic interaction between carbamazepine and amlodipine might have some clinical importance for patients treated with these drugs.     

Effects of N-(morpholinomethyl)- p-isopropoxyphenylsuccinimide on the protective action of different classical antiepileptic drugs against maximal electroshock-induced tonic seizures in mice

BackgroundThe aim of this study was to determine the effects of N-(morpholinomethyl)-p-isopropoxy-phenylsuccinimide (MMIPPS) on the protective action of four classical antiepileptic drugs (AEDs: carbamazepine [CBZ], phenobarbital [PB], phenytoin [PHT] and valproate [VPA]) against maximal electroshock (MES)-induced seizures in mice.MethodsTonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (sine-wave, 25 mA, 500 V, 50 Hz, 0.2 s stimulus duration) delivered via auricular electrodes. Total brain concentrations of AEDs were measured to determine the characteristics of interaction between MMIPPS and classical AEDs in the mouse MES model.ResultsMMIPPS administered intraperitoneally (ip) at 100 mg/kg significantly elevated the threshold for electroconvulsions in mice (p < 0.01). MMIPPS at doses of 25 and 50 mg/kg had no impact on the threshold for electroconvulsions in mice. Moreover, MMIPPS (50 mg/kg) significantly enhanced the anticonvulsant activity of PB and VPA(p < 0.05), but not that of CBZ or PHT, in the MES test in mice. Pharmacokinetic studies revealed that MMIPPS (50 mg/kg) did not alter total brain concentrations of PB, but significantly elevated total brain concentrations of VPA in mice (p < 0.05).ConclusionsThe enhanced anticonvulsant action of PB byMMIPPS in themouseMESmodel and lack of any pharmacokinetic interaction between drugs make the combination of MMIPPS with PB of pivotal importance for further experimental and clinical studies. Pharmacokinetic increase in total brain VPAconcentration seems to be responsible for the enhanced anticonvulsant action of VPAby MMIPPS in the mouse MES model. The combinations of MMIPPS with CBZ and PHT are neutral from a preclinical viewpoint.     

Biphasic characteristic of interactions between stiripentol and carbamazepine in the mouse maximal electroshock-induced seizure model: a three-dimensional isobolographic analysis

The anticonvulsant effects produced by stiripentol (STP), carbamazepine (CBZ), and their combination in the maximal electroshock (MES)-induced seizures in mice were investigated using three-dimensional (3D) isobolographic analysis. With 3D isobolography, the combinations of both drugs at the fixed-ratios of 1:3, 1:1, and 3:1 for 16%, 50% and 84% antiseizure effects, respectively, were examined in order to evaluate the preclinical characteristics of the interactions between STP and CBZ. Additionally, to characterize precisely the types of interactions observed in the MES test, free plasma and total brain CBZ concentrations were estimated for all fixed-ratios tested. The 3D isobolographic analysis showed that STP and CBZ combined at the fixed-ratio of 1:3 produced supra-additive (synergistic) interactions in the MES test for the anticonvulsant effects ranging between 16% and 84%. In contrast, the combination of STP with CBZ at the fixed-ratio of 3:1 exerted sub-additive (antagonistic) interactions in 3D isobolography for all antiseizure effects examined in the MES test. Only the combination of STP and CBZ at the fixed-ratio of 1:1 was additive for the investigated effects (16%, 50% and 84%) in 3D isobolography. Pharmacokinetic evaluation of CBZ concentrations revealed that STP increased both free plasma and total brain CBZ concentrations for all fixed-ratio combinations tested (1:3, 1:1 and 3:1). In conclusion, the 3D isobolographic findings suggest that the combination of STP with CBZ exerted biphasic characteristics of interactions in the MES test, despite the pharmacokinetic increase in CBZ content in plasma and brains of experimental animals.     

Anticonvulsant effects of four linear furanocoumarins, bergapten, imperatorin, oxypeucedanin, and xanthotoxin, in the mouse maximal electroshock-induced seizure model: a comparative study

The aim of this study was to determine and compare the anticonvulsant activities of four natural furanocoumarins [bergapten (5-methoxypsoralen), imperatorin (8-isopentenyloxypsoralen), oxypeucedanin (5-epoxy-isopentenyloxypsoralen) and xanthotoxin (8-methoxypsoralen)] in the maximal electroshock-induced seizure test in mice. The anticonvulsant effects of bergapten, imperatorin, oxypeucedanin, and xanthotoxin were evaluated at 15, 30, 60 and 120 min after their systemic (intraperitoneal) administration. Tonic hind limb extension (seizure activity) was evoked in adult albino Swiss mice by a current (sine-wave, 25 mA, 500 V, 50 Hz, 0.2 s stimulus duration) delivered via auricular electrodes. The time courses of protection by bergapten, imperatorin, oxypeucedanin and xanthotoxin against maximal electroshock-induced seizures revealed that 300 mg/kg imperatorin and xanthotoxin (C-8 substituted derivatives of psoralen) exerted strong anticonvulsant activity, whereas 300 mg/kg bergapten and oxypeucedanin (C-5 substituted derivatives of psoralen) did not produce any anticonvulsant activity in this model. In conclusion, imperatorin and xanthotoxin protected the animals against maximal electroshock-induced seizures, whereas bergapten and oxypeucedanin, despite their chemical and structural similarities to xanthotoxin and imperatorin, exerted no anticonvulsant activity in this seizure test.     

Effects of the calcium antagonists verapamil and nitrendipine on carbamazepine withdrawal

This study was aimed at examining the effects of two frequently used Ca2+ antagonists, nitrendipine and verapamil, on withdrawal after cessation of long-term treatment with the anticonvulsant drug carbamazepine in rats. The 48-h interruption of long-term (21 days) carbamazepine treatment led to the appearance of withdrawal characterized by increases in seizure intensity, the percentage of rats with tonic seizures and mortality. Oral treatment with the two calcium antagonists in combination with carbamazepine abolished the signs of carbamazepine withdrawal. Seizure intensity, the percentage of rats with tonic seizures and mortality in the groups treated with the combinations of carbamazepine + verapamil and carbamazepine + nitrendipine were significantly lower than those of the group of rats treated with carbamazepine alone. In conclusion, some Ca2+ antagonists could attenuate the manifestations of anticonvulsant withdrawal and thus could be used as adjuvants in long-term anticonvulsant therapy.     

Inhibition of hepatic microsomal drug metabolism by the calcium channel blockers diltiazem and verapamil

Diltiazem and verapamil were found to be inhibitors of the cytochrome P-450-dependent biotransformation of drugs. Diltiazem and verapamil competitively inhibited the N-demethylation of aminopyrine in hepatic microsomes with Ki values of 100 and 140 microM respectively. Both diltiazem and verapamil were N-demethylated themselves by hepatic microsomes with Km values of 62 and 145 microM respectively. Both drugs also interacted directly with cytochrome P-450 as measured by difference spectra. Diltiazem caused a type I spectral change and verapamil caused a reverse type I spectral change. No metabolic intermediate complexes could be demonstrated for either drug. Inhibition also occurred in vivo as both drugs could prolong pentobarbital-induced sleeping times in mice at doses comparable to those used in man. These results suggest that diltiazem and verapamil may have the potential to cause drug interactions involving inhibition of drug biotransformation.     

Effects of long-acting calcium channel antagonists on neurohumoral factors: comparison of nifedipine coat-core with amlodipine

Calcium channel antagonists can induce sympathetic hyperactivity, leading to a poor prognosis for hypertensive patients. Nifedipine formulations that allow once-daily administration are now available for use in clinical practice. To compare the effects of nifedipine with those of amlodipine, we studied 36 essential hypertensive patients. Those who had been administered nifedipine sustained-release were treated with amlodipine in place of nifedipine sustained-release, and those who had been administered amlodipine were treated with nifedipine coat-core in place of amlodipine. Substitution of nifedipine sustained-release by amlodipine had no significant effect on hypertensive symptoms. However, the plasma levels of norepinephrine, renin, and aldosterone were significantly lower (p < 0.001-0.05) in patients taking amlodipine in place of nifedipine sustained-release. Substitution of amlodipine by nifedipine coat-core again had no significant effect on hypertensive symptoms. However, the plasma levels of norepinephrine, renin, and aldosterone did not change significantly after the substitution. These findings indicate that, at the effective anti-hypertensive concentrations of nifedipine coat-core and amlodipine, nifedipine coat-core may not increase sympathetic nerve activity as is observed with amlodipine. The results also suggest that the duration of action of nifedipine formulations is an important determinant for nifedipine-induced hyperactivity in the reflex sympathetic nerve and the renin-angiotensin systems.     

Effects of the calcium antagonists diltiazem, verapamil and nitrendipine on the contractile responses of guinea-pig isolated ileum to electrical stimulation or carbachol.

The effects of the organic Ca2+ antagonists nitrendipine, verapamil and diltiazem on the cholinergic contractile responses induced by field electrical stimulation or carbachol (0.1 microM) and on contractions evoked by high concentration KCl (30 mM) were studied in isolated preparations from the guinea-pig ileum. The three Ca2+ antagonists dose-dependently suppressed the contractile responses showing the same order of potency (nitrendipine greater than verapamil greater than diltiazem) with the three different types of stimulation. Comparison of the IC50 values of the Ca2+ antagonists for carbachol-, KCl- and electrically-evoked contractions demonstrated that the carbachol-evoked contractions were most sensitive to the inhibitory action of the antagonists tested. The presynaptic inhibitory effect of (Met)enkephalin (10 nM) on the electrically-evoked cholinergic contractions was only slightly potentiated by high concentrations (1 or 10 microM) of nitrendipine and diltiazem and remained unchanged by verapamil. The results suggest that the Ca2+ antagonists tested block mainly the carbachol-activated L-type Ca2+ channels on the smooth muscle cells, while the effects on the N-type Ca2+ channels are insignificant, except for the high concentrations of nitrendipine and diltiazem.     

Effects of some convulsant agents on the protective activity of topiramate against maximal electroshock-induced seizures in mice

The anticonvulsant activity of topiramate combined with some convulsant agents (bicuculline--BIC, N-methyl-D-aspartate--NMDA, and kainic acid--KA), given at subconvulsive doses, was evaluated in the maximal electroshock (MES)-test in mice. BIC (1.5 mg/kg), KA (10 mg/kg) and NMDA (50 mg/kg) significantly decreased the anticonvulsant activity of topiramate raising its ED(50) from 76.2 mg/kg to 135, 102, and 107 mg/kg, respectively. BIC (0.75 mg/kg) and KA (5 mg/kg) did not alter the protective activity of topiramate in the MES-test. Moreover, topiramate injected alone (up to 135 mg/kg) did not affect motor performance and long-term memory of animals tested in the chimney and passive avoidance tests, respectively. In contrast, combinations of topiramate with BIC (1.5 mg/kg), NMDA (50 mg/kg) or KA (10 mg/kg) considerably disturbed long-term memory in mice. Additionally, co-administration of topiramate with KA (10 mg/kg) or BIC (1.5 mg/kg) significantly impaired motor performance, whereas topiramate co-administered with NMDA (50 mg/kg) had no impact on motor coordination in mice. None of the studied convulsants affected the free plasma concentration of topiramate assayed with immunofluorescence method. The results of this study seem to indicate the expression of the anticonvulsant activity of topiramate is dependent on all ionotropic glutamate and GABAA receptor-mediated events.