Epilepsy in Pregnancy—Management Principles and Focus on Valproate

An estimated 60 million people worldwide suffer from epilepsy, half of whom are women. About one-third of women with epilepsy are of childbearing age. The childbirth rate in women with epilepsy is about 20–40% lower compared to that of the general population, which may be partly due to a lower number of these women being in relationships. Lower fertility in women with epilepsy may be linked to the disease itself, but it is mainly a result of the treatment provided. Valproate, as an antiepileptic drug inhibiting histone deacetylases, may affect the expression of genes associated with cell cycle control and cellular differentiation. Evidently, this drug is associated with the risk of malformations although other antiepileptic drugs (AEDs) may also trigger birth defects, however, to a lower degree. Valproate (and to a certain degree other AEDs) may induce autism spectrum disorders and attention deficit hyperactivity disorder. The main mechanism responsible for all negative effects of prenatal exposure to valproate seems inhibition of histone deacetylases. Animal studies show a reduction in the expression of genes involved in social behavior and an increase in hippocampal cytokines. Valproate-induced oxidative stress may also contribute to neural tube defects. Interestingly, paternal exposure to this AED in mice may trigger neurodevelopmental disorders as well although a population-based cohort study does not confirm this effect. To lower the risk of congenital malformations and neurodevelopmental disorders, a single AED at the optimal dose and supplementation with folic acid is recommended. VPA should be avoided in women of childbearing age and especially during pregnancy

Additive interactions between retigabine and oxcarbazepine in the chimney test and the model of generalized tonic-clonic seizures in mice

Introduction. Patients with pharmacoresistant epilepsy are usually treated with two or more antiepileptic drugs (AEDs). The search for therapeutically efficacious AED combinations is still a challenging issue for clinicians and epileptologists throughout the world

Interactions of retigabine with topiramate in the mouse tonic-clonic seizure model and chimney test - an isobolographic analysis

Introduction and objectives. Nowadays, one of the treatment options for patients with refractory epilepsy is polytherapy with two or more antiepileptic drugs (AEDs). Retigabine (RTG) is a novel third-generation AED with unique molecular mechanisms of action that has recently been approved as an add-on drug for the treatment of tonic-clonic seizures. To characterize types of interactions between RTG and topiramate (TPM – a second-generation AED), the maximal electroshock- induced seizure model (MES) and chimney test in mice were used. Materials and method. In the MES model, the anticonvulsant effects of the drugs in terms of suppression of tonic-clonic seizures in male albino Swiss mice were assessed. In the chimney test, the acute neurotoxic effects of the drugs with respect to impairment of motor coordination were determined. Type I isobolographic analysis for the combination of RTG and TPM was applied to assess the anticonvulsant and neurotoxic effects in both the MES and chimney tests. Total brain concentrations of RTG and TPM were measured to exclude any pharmacokinetic interaction between drugs. Results. The type I isobolographic analysis of interaction revealed that the combination of RTG with TPM produced additive interaction in the MES test and additivity, with a slight tendency towards antagonism in terms of acute neurotoxic effects in the chimney test. Neither RTG nor TPM mutually affected total brain concentrations in the experimental animals. Conclusions. The isobolographically analyzed combination of RTG with TPM is favourable and may be recommended to some patients with refractory epilepsy