Effects of calcium channel inhibitors upon the efficacy of common antiepileptic drugs

Czuczwar, Stanisław J.; Chodkowska, A; Kleinrok, Z; Malek, Urszula; Jagiełło-Wójtowicz, E

doi:10.1016/0014-2999(90)90134-r

Cited by 54 publications

(18 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our previous studies also provided support for the beneficial effects of combined treatment of some calcium channel inhibitors and antiepileptic drugs against both pentylenetetrazol-induced seizures (Czuczwar et al, 1990b) and electroconvulsions (Czuczwar et al, 1990a(Czuczwar et al, , 1992 which are a well recognized model of generalized tonic-clonic epilepsy in man. However, nimodipine may be of lesser value because of the clearcut motor impairment which was also observed by Czuczwar et al (1992).…”

Section: Discussionmentioning

confidence: 55%

“…Taking above mentioned data into consideration it is not surprising why some calcium channel inhibitors possess anticonvulsant activity. They were demonstrated to reduce the incidence of seizures in many experimental models of epilepsy: pentylenetetrazol-induced seizures (Czuczwar et al, 1990b;Dolin et al, 1988;Jagietq'o-Wdjtowicz et al, 1991) and electroconvulsions (Czuczwar et al, 1990a(Czuczwar et al, , 1992Desmedt et al, 1976). Moreover, De Sarro et al (1988) described anticonvulsant properties of flunarizine (diphenylmethylpiperazine) and dihydropyridine derivatives in audiogenic seizures in DBA/2 mice, while Palmer et al (1993) reported on a similar activity of calcium channel inhibitors against N-methyl-D,L-aspartic acidinduced convulsions.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Influence of nicardipine, nimodipine and flunarizine on the anticonvulsant efficacy of antiepileptics against pentylenetetrazol in mice

Gąsior

Kamiński

Brudniak

et al. 1996

J. Neural Transmission

View full text Add to dashboard Cite

Among three calcium channel inhibitors, only nicardipine (10-40 mg/kg) significantly inhibited clonic seizures induced by pentylenetetrazol administered at its CD97 (convulsive dose 97%) of 81 mg/kg, subcutaneously. Nimodipine and flunarizine (both up to 80 mg/kg) did not suppress pentylenetetrazol-induced clonic seizures per se. Co-administration of nicardipine (5 mg/kg) resulted in a significant enhancement of the protective potency of either ethosuximide (50 mg/kg) or valproate (100 mg/kg) against clonic seizures in this test. Similar effects were noted in case of combined treatment of nimodipine (20-40 mg/kg) with these antiepileptics. On the contrary, flunarizine (up to 20 mg/kg) did not modify the anticonvulsive action of these antiepileptic drugs. Moreover, none of the studied calcium channel inhibitors influenced the protective activity of clonazepam (0.01 mg/kg). The antiepileptic drugs, administered alone in above doses, were ineffective against pentylenetetrazol-induced clonic convulsions. In case of ethosuximide and valproate, the motor performance in the chimney test was worsened by co-administration of nimodipine (40 mg/kg). We found no pharmacokinetic interactions (at least in relation to the plasma levels of ethosuximide and valproate) that could explain the observed results. Thus, we conclude that a combination of some calcium channel inhibitors and antiepileptic drugs may provide more efficient protection against experimental seizures which may bear a potential clinical significance.

show abstract

Section: Discussionmentioning

confidence: 55%

Section: Introductionmentioning

confidence: 99%

Influence of nicardipine, nimodipine and flunarizine on the anticonvulsant efficacy of antiepileptics against pentylenetetrazol in mice

Gąsior

Kamiński

Brudniak

et al. 1996

J. Neural Transmission

View full text Add to dashboard Cite

show abstract

“…This, however, could have been expected for verapamil, since voltage-operated Ca 2ϩ channels have been suggested as a pharmacotherapeutic drug target to correct the aberrant pathophysiology of epileptogenesis via a phenomenon known as "intrinsic burst firing" driven by an inward Ca 2ϩ current (Kulak et al, 2004). Several Ca 2ϩ channel antagonists were shown to possess anticonvulsant potential in experimental and clinical studies (De Sarro et al, 1988;Czuczwar et al, 1990;Larkin et al, 1992;Speckmann et al, 1993;Gasior et al, 1995Gasior et al, , 1996Swiader et al, 2002). However, systemic isradipine and verapamil administration per se or in combination with AEDs failed to display any anticonvulsant activity (Czuczwar et al, 1990;Borowicz et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

“…Several Ca 2ϩ channel antagonists were shown to possess anticonvulsant potential in experimental and clinical studies (De Sarro et al, 1988;Czuczwar et al, 1990;Larkin et al, 1992;Speckmann et al, 1993;Gasior et al, 1995Gasior et al, , 1996Swiader et al, 2002). However, systemic isradipine and verapamil administration per se or in combination with AEDs failed to display any anticonvulsant activity (Czuczwar et al, 1990;Borowicz et al, 1997). Moreover, verapamil was shown to lack anticonvulsant effects after intracerebroventricular administration in DBA/2 mice, a strain genetically susceptible to sound-induced seizures (De Sarro et al, 1988).…”

Section: Discussionmentioning

confidence: 99%

Quantitative in Vivo Microdialysis Study on the Influence of Multidrug Transporters on the Blood-Brain Barrier Passage of Oxcarbazepine: Concomitant Use of Hippocampal Monoamines as Pharmacodynamic Markers for the Anticonvulsant Activity

Clinckers¹,

Smolders²,

Meurs³

et al. 2005

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Various antiepileptic drugs were shown to be substrates for multidrug transporters at the level of the blood-brain barrier. These ATP-dependent efflux pumps actively limit brain accumulation of xenobiotics and drugs. Intrahippocampal oxcarbazepine perfusion in rat was previously shown to exert anticonvulsant effects associated with increases in extracellular dopamine and serotonin levels. In contrast, preliminary studies in our laboratory revealed that no anticonvulsant or monoaminergic effects could be obtained after systemic oxcarbazepine administration. The present in vivo microdialysis study was conducted to investigate the impact of the transport kinetics of oxcarbazepine across the blood-brain barrier on the observed treatment refractoriness. More precisely, the influence of intrahippocampal perfusion of verapamil, a P-glycoprotein inhibitor, and probenecid, a multidrug resistance protein inhibitor, on the blood-brain barrier passage and anticonvulsant properties of oxcarbazepine were investigated in the focal pilocarpine model for limbic seizures. Simultaneously, the effects on hippocampal monoamines were studied as pharmacodynamic markers for the anticonvulsant activity. Although systemic oxcarbazepine administration alone failed in preventing the animals from developing seizures, coadministration with verapamil or probenecid offered complete protection. Concomitantly, significant increases in extracellular hippocampal dopamine and serotonin levels were observed within our previously defined anticonvulsant monoamine range. The present data indicate that oxcarbazepine is a substrate for multidrug transporters at the bloodbrain barrier. Coadministration with multidrug transporter inhibitors significantly potentiates the anticonvulsant activity of oxcarbazepine and offers opportunities for treatment of pharmacoresistant epilepsy.Oxcarbazepine (OXC) is the 10,11-keto analog of carbamazepine (CBZ). Like CBZ, it is considered to exert its antiepileptic effects by stabilization of the Na ϩ channels in a voltage-, frequency-, and time-dependent manner. OXC can also block high-threshold Ca 2ϩ currents and increase K ϩ channel conductance (McLean et al., 1994). Previously, we showed that increases in hippocampal dopamine (DA) and serotonin (5-HT) levels can have important anticonvulsant effects in the focal pilocarpine model for limbic psychomotor seizures (Clinckers et al., 2004a). These anticonvulsant effects were restricted to a well defined anticonvulsant concentration range and were proven to be mediated by D 2 and 5-HT 1A receptor stimulation. Anticonvulsant activity against pilocarpine-induced seizures can also be achieved by intrahippocampal perfusion of OXC (unpublished data). From the anticonvulsant threshold concentration (i.e., 100 M) onward, significant increases in extracellular (EC) hippocampal DA and 5-HT levels were observed, within the previously determined anticonvulsant monoamine ranges. These monoaminergic neurotransmitter increases were again shown to importantly contribute to the ant...

show abstract

“…It has been shown that this drug displays antiepileptic activity in pentylenetetrazol (PTZ)-induced epilepsy (25,36), maximal electroshock (MES)-evoked seizures in a dose dependent manner (19), hippocampalkindled seizures (46) and picrotoxin-induced seizures (44). Contrary to expectations, nifedipine did not influence aminophylline-induced seizures (12), seizures elicited by MES (36) and the protective action of diazepam against PTZ-induced seizures (13). Further, nifedipine decreased topiramate activity in WAG/Rij rats but paradoxically enhanced it in lh/lh mice (41) and increased epileptiform activity in spontaneous seizures in the isolated mouse hippocampus (16).…”

Section: Yilmaz I Et Al: Nifedipine and Hippocampal Neuron Numbermentioning

confidence: 87%

Effect of nifedipine on hippocampal neuron number in penicillin-induced epileptic rats

Yılmaz

Akdogan²,

Kaya³

et al. 2013

Turkish Neurosurgery

View full text Add to dashboard Cite

AIm: Epileptic seizures lead to neuronal loss in the hippocampus. Experimental epilepsy can be induced by direct application of various chemicals to cerebral cortex. Nifedipine is an L-type voltage-dependent calcium channel blocker. In spite of several studies that show the seizure-suppressing effects of nifedipine, it has been shown that nifedipine does not suppress but conversely increases epileptic seizures. Similarly, contradictory effects of nifedipine have been reported, such as neuroprotection, failed neuroprotection and neurotoxicity. We therefore aimed to investigate the effect of nifedipine on hippocampal neuronal loss in penicillin induced epileptic rats in this study. mATeRIAL and meTHods:The effect of nifedipine on total hippocampal neuron number was estimated by using the optical fractionator method (an unbiased stereological method) in penicillin-G induced epileptic rats. ResuLTs:The total number of hippocampal neurons in the control group was 183687 ± 3184. In the penicillin-induced group, the total neuron number significantly decreased to 146318 ± 3042 compared to the control group. In the nifedipine group, the neuron number significantly decreased to 128873 ± 1157 compared to both control and penicillin-induced groups.CoNCLusIoN: Nifedipine increased neuronal loss and did not suppress epileptic seizures in penicillin-induced epileptic rats. Nifedipine could not protect against hippocampal neuronal loss in penicillin-induced epileptic rats.KeywoRds: Penicillin epilepsy model, Nifedipine, Hippocampus, Neuron number, The optical fractionator method, Rat, Epilepsy, Seizure ÖZ AmAÇ: Epileptik nöbetler hipokampusta nöron kaybına yol açmaktadır. Çeşitli kimyasalların beyin korteksine direkt olarak uygulanmasıyla deneysel epilepsi oluşturulabilir. Nifedipin, L-tipi voltaj bağımlı kalsiyum kanal blokörüdür. Nifedipinin nöbet baskılayıcı etkilerini gösteren çeşitli çalışmalar bulunduğu gibi, epileptik nöbetleri baskılamadığı tam tersine arttırdığı da gösterilmiştir. Benzer şekilde, nifedipinin çelişkili etkileri bildirilmiştir; olumlu -olumsuz nöroprotektif (nöron koruyucu) ve nörotoksisite gibi. Bu nedenle, bu çalışmada, penisilin ile deneysel epilepsi oluşturulan sıçanlarda nifedipinin hipokampal nöron kaybı üzerine etkisini araştırmayı amaçladık. yÖNTem ve GeReÇLeR: Nifedipinin penisilin G ile deneysel epilepsi oluşturulan sıçanlarda toplam hipokampal nöron sayısına etkisi tarafsız (objektif ) bir stereolojik metot olan optik parçalama yöntemi ile değerlendirildi.BuLGuLAR: Kontrol grubunun toplam hipokampal nöron sayısı 183687 ± 3184 idi. Penisilin grubunun toplam nöron sayısı kontrol grubuna göre anlamlı olarak düşüktü (146318 ± 3042). Penisilin+nifedipin grubunun toplam nöron sayısı (128873 ± 1157) hem kontrol hem de penisilin grubuna göre istatistiksel olarak anlamlı olarak azalmış bulundu. soNuÇ: Nifedipinin epileptik sıçanlarda nöron kaybını arttırdığı ve epileptik nöbetleri baskılamadığı ortaya kondu. Nifedipin, penisilin ile deneysel epilepsi oluşturulan sıçanlarda ortaya çıkan nöron ka...

show abstract

Effects of calcium channel inhibitors upon the efficacy of common antiepileptic drugs

Cited by 54 publications

References 36 publications

Influence of nicardipine, nimodipine and flunarizine on the anticonvulsant efficacy of antiepileptics against pentylenetetrazol in mice

Influence of nicardipine, nimodipine and flunarizine on the anticonvulsant efficacy of antiepileptics against pentylenetetrazol in mice

Quantitative in Vivo Microdialysis Study on the Influence of Multidrug Transporters on the Blood-Brain Barrier Passage of Oxcarbazepine: Concomitant Use of Hippocampal Monoamines as Pharmacodynamic Markers for the Anticonvulsant Activity

Effect of nifedipine on hippocampal neuron number in penicillin-induced epileptic rats

Contact Info

Product

Resources

About