Abstract
BackgroundDue to co-occurrence of seizures and cardiovascular disorders, nebivolol, a widely used selective β1-blocker with vasodilatory properties, may be co-administered with antiepileptic drugs. Therefore, we wanted to assess interactions between nebivolol and four conventional antiepileptic drugs: carbamazepine, valproate, phenytoin and phenobarbital in the screening model of tonic–clonic convulsions.MethodsSeizure experiments were conducted in the electroconvulsive threshold and maximal electroshock tests in mice. The chimney test served as a method of assessing motor coordination, whereas long-term memory was evaluated in the computerized step-through passive-avoidance task. To exclude or confirm pharmacokinetic interactions, we measured brain concentrations of antiepileptic drugs using the fluorescence polarization immunoassay.ResultsIt was shown that nebivolol applied at doses 0.5–15 mg/kg did not raise the threshold for electroconvulsions. However, nebivolol at the dose of 15 mg/kg reduced the anti-electroshock properties of carbamazepine. The effect of valproate, phenytoin, and phenobarbital remained unchanged by combination with the β-blocker. Nebivolol significantly decreased the brain concentration of valproate, but did not affect concentrations of remaining antiepileptic drugs. Therefore, contribution of pharmacokinetic interactions to the final effect of the nebivolol/carbamazepine combination seems not probable. Nebivolol alone and in combinations with antiepileptic drugs did not impair motor performance in mice. Nebivolol alone did not affect long-term memory of animals, and did not potentiate memory impairment induced by valproate and carbamazepine.ConclusionsThis study indicates that nebivolol attenuated effectiveness of some antiepileptic drugs. In case the results are confirmed in clinical settings, this β-blocker should be used with caution in epileptic patients.
Highlights
Based on many studies, a bidirectional relationship between cardiac arrhythmias and seizures was established
This β-blocker elevated the seizure threshold and potentiated the action of lamotrigine in the model of increasing current electroshock seizures (ICES) in mice [13]. This encouraged us to evaluate the effect of nebivolol on the anticonvulsant action of conventional antiepileptic drugs in the maximal electroshock test, the leading animal model of tonic–clonic seizures and screening test for potential anticonvulsant agents
Antiepileptic drugs were applied at their ED50s, while nebivolol at its highest dose used in this study (15 mg/kg)
Summary
A bidirectional relationship between cardiac arrhythmias and seizures was established. Because of the potentially beneficial action of β-adrenoceptor antagonists in seizures and relationship between seizures and arrhythmias, antiepileptic drugs and β-blockers may be co-administered in patients suffering of both disorders. Nebivolol and other lipophilic β-blockers are frequently used for the treatment of migraine and essential tremor [12] Such properties make the effect of nebivolol on seizures very probable. There is only one report describing the action of nebivolol on experimental convulsions According to authors, this β-blocker elevated the seizure threshold and potentiated the action of lamotrigine in the model of increasing current electroshock seizures (ICES) in mice [13]. This encouraged us to evaluate the effect of nebivolol on the anticonvulsant action of conventional antiepileptic drugs in the maximal electroshock test, the leading animal model of tonic–clonic seizures and screening test for potential anticonvulsant agents
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