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Summary: Purpose: Valproate (VPA) is an extensively used drug in the therapy of epilepsies. One of the most frequently reported side effects of VPA is hemorrhagic diathesis. Some authors emphasized the decreased platelet count as the basis of VPA-induced hemorrhagic diathesis, but some reports suggested that a significant proportion of patients with normal platelet count may still have an altered platelet function. The mechanism of the VPA-induced platelet dysfunction has not yet been elucidated. A determining element of platelet functions is the arachidonate cascade. Present ex vivo experiments were designed to determine whether a relation exists between the incidence of hemostasis caused by VPA and the effect of this drug on the arachidonate cascade of platelets. Methods: Platelets were isolated from patients receiving long-term VPA treatment (serum level, 36.04 ± 16.12 μg/ml; n = 10) or carbamazepine (CBZ) treatment (serum level, 5.24 ± 2.67 μg/ml; n = 10) and were labeled with [14C]arachidonic acid. (CBZ-treated patients were chosen as a control group, because CBZ causes blood dyscrasias similar to those elicited by VPA, but there has been no report that CBZ induces a platelet dysfunction.) The 14C-eicosanoids were separated by means of overpressure thin-layer chromatography and determined quantitatively by liquid scintillation. Results: Even when the mean plasma concentration of the drug was low, VPA treatment reduced the activity of the arachidonate cascade in platelets. VPA effectively inhibited the cyclooxygenase pathway and the synthesis of the strong platelet aggregator thromboxane A2. Conclusions: Inhibition of the platelet arachidonate cascade may contribute to the platelet-function alterations caused by VPA.

Epilepsy is not a singular disease, but a variety of disorders. It affects up to 0.5% of the population. Over the past decade, researchers have made great advances in the field of epilepsy. These have been accompanied by the licensing of a great number of antiepileptic drugs. However, despite these efforts, up to 15-20% of patients have refractory epilepsy. The novel antiepileptic drugs must suit several requirements: higher efficacy, especially in resistant cases, better tolerability, and improved pharmacokinetic properties. Recently, three new drugs have been introduced to the market. Retigabine is a carbamic derivate, and its anticonvulsive properties are largely due to its ability to prolong the opening of neuronal voltage-gated potassium Kv7.2 and Kv7.3 channels. Lacosamide is a functionalized amino acid, and selectively enhances voltage-gated sodium channel slow inactivation. Eslicarbazepine acetate is a new member of the dibenzazepine family, and blocks the fast inactivated voltage-gated sodium channel. All three of them differ from the foregoing agents in several important ways, including new mechanism of action (retigabine, lacosamide), or pharmacokinetics (eslicarbazepine acetate). These novel anticonvulsants appear to be a safe and effective addition to the armamentarium for the treatment of patients with refractory epilepsy. However, it will take the consideration of new concepts in shaping the new therapeutic algorithm.

It is well known that alterations in sexual functions occur more frequently in men with epilepsy than in general population. The results of the epidemiological studies are considerably diverge from one another (3-61%), so the exact value of the incidence is not known. The most common form of sexual dysfunctions is the hyposexuality, determined as a overall reduction in sexual interest, awareness, and activity. Sexual dysfunction, as a disorder is often multifactorial, but the role of medical factors can be the most important in the development. The endocrinological disturbances occurring in epilepsy are mainly caused by the pharmacokinetic interactions among the antiepileptic medication. The enzyme inductor drugs decrease the level of free testosterone, dihydrotestosterone, follicle stimulating hormone, and luteinizing hormone, and increase the sex-hormone-binding globulin and estradiol levels. In valproate treated men significantly lower follicle stimulating hormone and luteinizing hormone concentrations, and free/total carnitine ratio, and higher dehydroepiandrosterone concentration can be detected. The enzyme inductor antiepileptic drugs can decrease the biologically active testosterone level by stimulating the aromatase and the hepatic cytochrome P450 enzymes, which can result in the development of sexual dysfunctions. Hormonal changes resulting in the alteration of the androgen synthesis and gonadotropin levels may contribute to the sexual dysfunction observed in valproate treated epileptic patients. If the role of the antiepileptic medication can be proven in the development of the sexual dysfunctions, changing in the antiepileptic drug therapy is recommended. According to evidences, the usage of oxcarbazepine and lamotrigine is not associated with changes in hormonal levels, and does not lead to alterations in sexual functions. In case of sexual dysfunctions switching from carbamazepine to oxcarbazepine, levetiracetam, or gabapentin is recommended in patients with partial epilepsy, and from valproate to lamotrigine or levetiracetam in patients with idiopathic generalized epilepsy. Enforcement of the primary prevention in the treatment of men with epilepsy is an important task of the future.

Summary: Purpose: The functional significance of gap-junction (GJ) channels in seizure susceptibility and induction and maintenance of seizures in the developing rat brain was investigated on the 4-aminopyridine (4-AP) in vivo epilepsy model. Methods: In electrophysiological experiments, GJs were manipulated with a blocker or opener before induction or at the active epileptic foci between postnatal days 9 and 28 (P9–28). Semiquantitative reverse transcriptase–polymerase chain reaction (RT-PCR) amplification was used to measure the levels of connexin (Cx) 26, 32, 36, and 43 mRNAs at the untreated cortex or epileptic foci. Results: The basic electrocorticogram (ECoG) and Cx messenger RNA (mRNA) expression patterns exhibited characteristic maturation; the 4-AP–induced epileptiform activity correlated well with these changes. Cx mRNA expressions were significantly upregulated around P16 (except for Cx26). The Cx26, 36, and 43 gene inducibility was highest around P16 and then declined significantly. In the youngest animals, the GJ opener induced rhythmic synchronous cortical activity. On maturation, the seizures became focalized and periodic; the discharges accelerated their amplitude and frequency increase. A transient decrease (P13–14) and then increase (P15–16) in seizure susceptibility were followed by a tendency to periodicity and focalization. Conclusions: The study suggests that GJ communication is involved in rhythm genesis and synchronization of cortical activity and may enhance the epileptogenicity of the developing brain.

Summary: Purpose: The selective contribution of neuronal gap junction (GJ) communication via connexin 36 (Cx36) channels to epileptogenesis and to the maintenance and propagation of seizures was investigated in both the primary focus and the mirror focus by using pharmacologic approaches with the 4aminopyridine in vivo epilepsy model. Methods: ECoG recording was performed on anesthetized adult rats, in which either quinine, a selective blocker of Cx36, or the broad-spectrum GJ blockers carbenoxolone and octanol were applied locally, before the induction or at already active epileptic foci. Results: The blockade of Cx36 channels by quinine before the induction of epileptiform activity slightly reduced the epileptogenesis. When quinine was applied after 25‐30 repetitions of seizures, a new discharge pattern appeared with frequencies >15 Hz at the initiation of seizures. In spite of the increased number of seizures, the summated ictal activity decreased, because of the significant reduction in the duration of the seizures. The amplitudes of the seizure discharges of all the patterns decreased, with the exception of those with frequencies of 11‐12 Hz. The blockade of Cx36 channels and the global blockade of the GJ channels resulted in qualitatively different modifications in ictogenesis. Conclusions: The blockade of Cx36 channels at the already active epileptic focus has an anticonvulsive effect and modifies the manifestation of the 1- to 18-Hz seizure discharges. Our findings indicate that the GJ communication via Cx36 channels is differently involved in the synchronization of the activities of the networks generating seizure discharges with different frequencies. Additionally, we conclude that both neuronal and glial GJ communication contribute to the manifestation and propagation of seizures in the adult rat neocortex. Ke yW ords: Gap junctions—Cx36—4-AP‐induced seizure—Epileptogenesis— Ictogenesis—In vivo—Quinine—Carbenoxolone. Epilepsy is one of the most prevalent neurologic disorders worldwide, but pharmacologic therapy remains the best remedy for its treatment. One reason for the incomplete effectiveness of the currently available anticonvulsants is that they were identified by using the same classic epilepsy models, which mainly involve the same actions, without a consideration of the variations in the pathophysiologic mechanisms that result in epilepsy. Growing evidence indicates that, besides the chemical synapses, direct coupling via gap junction (GJ) channels provides a second major pathway, contributing to normal and abnormal physiologic rhythms both during development and in the adult brain (1‐3). GJ channels mediating electrical signaling are involved in the physiologic synchronizing mechanism in the brain (3‐5) and contribute to pathologic hypersynchrony in various in vitro (6‐9) and in vivo (10‐13) epilepsy models.

Antiepileptic drug treatment is essential and provides excellent therapeutic effects in more than the two-third of the epileptic patients. The antiepileptic drugs influence the chronic hyperexcitability of the brain developed during the epileptogenesis. As an effect, it decreases the excitability and/or increases the inhibition of the pathological cells, which prevents the precipitation of the epileptic seizure (anticonvulsive effect). The anticonvulsive effect comes into operation by the influence of the transport of one ore more ion-channels. The anticonvulsive effect is only symptomatic and it doesn't cure the disorder. The drug selection is based on the knowledge of the therapeutic markers and the effectiveness of the drug to be used. This can occur on the basis of the action of the drug or in syndrome-specific way. The pharmacokinetic properties of the drugs determine how they can be used in the practice. The drug interactions can take place in several levels. Among them, the change of the metabolism is the most important. Acute dose-dependent side effects, organ-specific chronic interactions and idiosyncratic reactions must be taken into consideration during the use of antiepileptic drugs. The patient's individual aspects must be considerably taken into account during the treatment. There are other medical areas that can benefit from the antiepileptic drugs. Among them, the most important diseases are: restless legs syndrome, neuropathic pain, trigeminal neuralgia, essential tremor, bulimia and bipolar disorders. There are other pharmacological (adrenocorticotropic hormone, immunoglobulins, neurosteroids) and dietary methods, which may be effective at certain epileptic syndromes. The principles of the pharmacotherapy have been changing continuously during the past decades and since. New drugs have been introduced into the marketing and new expectations are coming into the limelight concerning the treatment. As a consequence this will bring on the modification of antiepileptic drug therapeutic habits.

In the present electrophysiological study the effect of aminooxyacetic acid (AOAA) on the cortical epileptogenicity, and on the basic electro-cortical activity was investigated in anesthetized rats. AOAA did not induce spontaneous epileptiform discharges but modified the somato-sensory evoked responses and the cortical epileptogenicity (induced by 4-aminopyridine) in the same manner depending on its concentration. AOAA at low concentrations increased the amplitude of evoked responses and the ipsilateral manifestation of epileptiform activity, however, at high concentrations significantly suppressed both the evoked responses and the induction and expression of seizures discharges. The anticonvulsive effect of AOAA was time-dependent (reached its maximum after 2h AOAA pre-treatment) and reversible. AOAA at low concentrations probably increases the efficacy of the NMDA excitatory system and decreases GABA-synthesis, resulting neuronal hyperexcitation. However, AOAA at high concentrations can lead to an effective cortical inhibition through intra- and extracellular accumulation of GABA. The gradual GABA accumulation - up to a certain level - at the synapses could also explain the time-dependency of the anticonvulsive effect of AOAA.