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Effects of classical and new antiepileptic drugs on bupropion-induced convulsions in mice
Second Conference on Progress in epilepsy and antiepileptic drugs
to treat erectile dysfunctions in epileptic patients [Harden, Epilepsy Behav, 2002; Smaldone et al., Seizure, 2004], although proconvulsant activity of sildenafil was recently reported in men [Gilad et al., BMJ, 2002] and mice [Riazi et al., Br J Pharmacol, 2006; Akula et al., Eur J Pharmacol, 2008]. The ability of sildenafil to cross the blood-brain barrier and the presence of PDE5 in different brain areas suggests that this drug may exert some central actions. It was reported that sildenafil may enhance neurogenesis, memory and learning processes. In addition, antinociceptive, anxiogenic, abusive and aggressive potential of sildenafil was reported [Uthayathas et al., Pharmacol Rep, 2007]. We examined the effect of sildenafil on the threshold for electroconvulsions and its effect on the anticonvulsant activity of some classical (valproate [VPA], carbamazepine [CBZ], phenytoin [PHT], phenobarbital [PB]) and second-generation antiepileptic drugs (AEDs) (lamotrigine [LTG], topiramate [TPM]) in the maximal electroshock seizure (MES) test in mice. Moreover, the effect of sildenafil on some neurotoxic effects of AEDs was determined in the chimney test (motor coordination), passive avoidance task (long-term memory) and grip-strength test (muscular strength) in mice. To exclude pharmacokinetic interactions, free plasma and total brain concentrations of AEDs were determined in mice treated with AEDs alone or in combination with sildenafil. We showed that sildenafil at doses of 15 and 20 mg/kg significantly increased the threshold for tonic hindlimb
extension in the maximal electroshock seizure threshold (MEST) test in mice. Sildenafil at lower doses of 5, 7.5 and 10 mg/kg was ineffective in this respect. Sildenafil at a dose of 15 mg/kg enhanced the anticonvulsant activity of VPA, CBZ and TPM, but remained without effect on the activity of PB, PHT and LTG in the MES test. Sildenafil given alone in a dosedependent manner increased muscular strength as assessed by the grip-strength test. In contrast, coapplication of sildenafil with the studied AEDs did not affect muscular strength in mice. No significant changes in the long-term memory and motor coordination were noted after administration of sildenafil alone or in co-administration with the studied AEDs. Sildenafil (15 mg/kg) significantly increased free plasma and total brain concentrations of CBZ and total brain VPA concentration in mice. However, sildenafil did not affect concentrations of the other AEDs. Our results suggest that sildenafil may influence the generation and propagation of seizure activity in the CNS. Sildenafil combined with certain AEDs, such as CBZ and VPA, may lead to pharmacokinetic interactions. We showed that interactions between sildenafil and CBZ and VPA are pharmacokinetic in nature while the interaction between sildenafil and TPM seems to be purely pharmacodynamic. Only combination of sildenafil with TPM seems to be safe and effective. The present results cannot be directly extrapolated into clinical practice, but they may be a valuable direction which suggests caution in using sildenafil in epileptic patients.
Effects of classical and new antiepileptic drugs on bupropion-induced convulsions in mice Tomasz Mróz, Katarzyna Mróz, Marian Wielosz, Piotr Tutka Department of Experimental and Clinical Pharmacology, Medical University of Lublin, Jaczewskiego 8, PL 20-090 Lublin, Poland
Bupropion is an antidepressant and a widely-used smoking-cessation aid [Dhillon et al., CNS Drugs, 2008; Paterson, Eur J Pharmacol, 2009]. Clinical reports indicate that bupropion produces seizures not only in overdose but also in the doses considered to be therapeutic [Ross and Williams, Expert Opin Drug Saf, 2005]. Experimental background for the efficacy
and safety of antiepileptic drugs in the protection against bupropion-induced convulsions has not been established yet. The aim of the study was to evaluate the effectiveness of 13 antiepileptic drugs [diazepam, ethosuximide, felbamate, phenobarbital sodium, phenytoin, gabapentin, carbamazepine, clonazepam, lamotrigine, tiagabine, topiramate, valproate sodium and Pharmacological Reports, 2009, 61, 573–588
587
vigabatrin given intraperitoneally (ip)] in convulsions induced by a single ip injection of bupropion in a dose of 139.5 mg/kg in mice. Moreover, motor impairment evoked by the antiepileptic drugs was investigated with a rotarod test, and protective index (PI) for each antiepileptic drug was calculated. To conclude: 1. A single administration of bupropion produces clonic seizures in a dose-dependent manner. 2. Among the examined antiepileptic drugs, clonazepam was the most potent drug to antagonize convulsant activity of bupropion. Clonazepam antagonizes
588
Pharmacological Reports, 2009, 61, 573–588
convulsant activity of bupropion in the doses which do not produce significant motor impairment. 3. The efficacy of the drugs modifying GABA-ergic transmission (diazepam, felbamate, phenobarbital sodium, gabapentin, clonazepam, topiramate, valproate sodium and vigabatrin) suggests the role of GABAergic system in the pathogenesis of these convulsions. 4. The results encourage further preclinical and clinical testing of clonazepam against bupropion-induced seizures.
to treat erectile dysfunctions in epileptic patients [Harden, Epilepsy Behav, 2002; Smaldone et al., Seizure, 2004], although proconvulsant activity of sildenafil was recently reported in men [Gilad et al., BMJ, 2002] and mice [Riazi et al., Br J Pharmacol, 2006; Akula et al., Eur J Pharmacol, 2008]. The ability of sildenafil to cross the blood-brain barrier and the presence of PDE5 in different brain areas suggests that this drug may exert some central actions. It was reported that sildenafil may enhance neurogenesis, memory and learning processes. In addition, antinociceptive, anxiogenic, abusive and aggressive potential of sildenafil was reported [Uthayathas et al., Pharmacol Rep, 2007]. We examined the effect of sildenafil on the threshold for electroconvulsions and its effect on the anticonvulsant activity of some classical (valproate [VPA], carbamazepine [CBZ], phenytoin [PHT], phenobarbital [PB]) and second-generation antiepileptic drugs (AEDs) (lamotrigine [LTG], topiramate [TPM]) in the maximal electroshock seizure (MES) test in mice. Moreover, the effect of sildenafil on some neurotoxic effects of AEDs was determined in the chimney test (motor coordination), passive avoidance task (long-term memory) and grip-strength test (muscular strength) in mice. To exclude pharmacokinetic interactions, free plasma and total brain concentrations of AEDs were determined in mice treated with AEDs alone or in combination with sildenafil. We showed that sildenafil at doses of 15 and 20 mg/kg significantly increased the threshold for tonic hindlimb
extension in the maximal electroshock seizure threshold (MEST) test in mice. Sildenafil at lower doses of 5, 7.5 and 10 mg/kg was ineffective in this respect. Sildenafil at a dose of 15 mg/kg enhanced the anticonvulsant activity of VPA, CBZ and TPM, but remained without effect on the activity of PB, PHT and LTG in the MES test. Sildenafil given alone in a dosedependent manner increased muscular strength as assessed by the grip-strength test. In contrast, coapplication of sildenafil with the studied AEDs did not affect muscular strength in mice. No significant changes in the long-term memory and motor coordination were noted after administration of sildenafil alone or in co-administration with the studied AEDs. Sildenafil (15 mg/kg) significantly increased free plasma and total brain concentrations of CBZ and total brain VPA concentration in mice. However, sildenafil did not affect concentrations of the other AEDs. Our results suggest that sildenafil may influence the generation and propagation of seizure activity in the CNS. Sildenafil combined with certain AEDs, such as CBZ and VPA, may lead to pharmacokinetic interactions. We showed that interactions between sildenafil and CBZ and VPA are pharmacokinetic in nature while the interaction between sildenafil and TPM seems to be purely pharmacodynamic. Only combination of sildenafil with TPM seems to be safe and effective. The present results cannot be directly extrapolated into clinical practice, but they may be a valuable direction which suggests caution in using sildenafil in epileptic patients.
Effects of classical and new antiepileptic drugs on bupropion-induced convulsions in mice Tomasz Mróz, Katarzyna Mróz, Marian Wielosz, Piotr Tutka Department of Experimental and Clinical Pharmacology, Medical University of Lublin, Jaczewskiego 8, PL 20-090 Lublin, Poland
Bupropion is an antidepressant and a widely-used smoking-cessation aid [Dhillon et al., CNS Drugs, 2008; Paterson, Eur J Pharmacol, 2009]. Clinical reports indicate that bupropion produces seizures not only in overdose but also in the doses considered to be therapeutic [Ross and Williams, Expert Opin Drug Saf, 2005]. Experimental background for the efficacy
and safety of antiepileptic drugs in the protection against bupropion-induced convulsions has not been established yet. The aim of the study was to evaluate the effectiveness of 13 antiepileptic drugs [diazepam, ethosuximide, felbamate, phenobarbital sodium, phenytoin, gabapentin, carbamazepine, clonazepam, lamotrigine, tiagabine, topiramate, valproate sodium and Pharmacological Reports, 2009, 61, 573–588
587
vigabatrin given intraperitoneally (ip)] in convulsions induced by a single ip injection of bupropion in a dose of 139.5 mg/kg in mice. Moreover, motor impairment evoked by the antiepileptic drugs was investigated with a rotarod test, and protective index (PI) for each antiepileptic drug was calculated. To conclude: 1. A single administration of bupropion produces clonic seizures in a dose-dependent manner. 2. Among the examined antiepileptic drugs, clonazepam was the most potent drug to antagonize convulsant activity of bupropion. Clonazepam antagonizes
588
Pharmacological Reports, 2009, 61, 573–588
convulsant activity of bupropion in the doses which do not produce significant motor impairment. 3. The efficacy of the drugs modifying GABA-ergic transmission (diazepam, felbamate, phenobarbital sodium, gabapentin, clonazepam, topiramate, valproate sodium and vigabatrin) suggests the role of GABAergic system in the pathogenesis of these convulsions. 4. The results encourage further preclinical and clinical testing of clonazepam against bupropion-induced seizures.