Inflammatory activation following interruption of long-term cardiac resynchronization therapy.

Previous observations suggest that cardiac resynchronization therapy (CRT) may exert an anti-inflammatory effect. The objective of this study was to evaluate the effect of temporary interruption of long-term CRT on plasma concentrations of proinflammatory cytokines and brain natriuretic peptide (BNP). The study group consisted of 54 patients (32 male and 22 female, mean age 64 years) with chronic heart failure (HF) treated with CRT. BNP, high-sensitivity C-reactive protein (hs-CRP), interleukin 6 (IL-6), and neopterin were measured three times: after 26-28 weeks of continuous CRT (CRT-on), 48 h after its cessation (CRT-off), and 48 h after switching the CRT-on again. CRT interruption resulted in a significant worsening of left ventricular systolic function: reduction of cardiac output (CO), dP/dt, and left ventricular ejection fraction (LVEF), as well as deterioration of mitral regurgitation in the CRT responder group. A significant increase in serum concentrations of hs-CRP, neopterin, IL-6, and BNP was noted in this subpopulation. In CRT nonresponders, no significant changes were observed. In responders the changes in serum concentrations of hs-CRP, IL-6, neopterin, and BNP, following CRT interruption, significantly correlated with the respective changes in thoracic fluid content (TFC) and inversely correlated with LVEF changes. Even short (48 h) interruption of long-term CRT led to a significant increase of proinflammatory cytokines and BNP concentrations in responders. The changes in hs-CRP, IL-6, neopterin, and BNP concentrations correlated with the change in TFC-marker of pulmonary congestion and inversely correlated with the change in LVEF.

Effects of three calcium channel antagonists (amlodipine, diltiazem and verapamil) on the protective action of lamotrigine in the mouse maximal electroshock-induced seizure model.

The aim of this study was to assess the effect of three calcium channel antagonists (amlodipine, diltiazem and verapamil) on the anticonvulsant action of lamotrigine (a second generation antiepileptic drug) against maximal electroshock-induced seizures in mice. Results indicated that all three calcium channel antagonists when administered alone [amlodipine (up to 20 mg/kg, ip), diltiazem (up to 10 mg/kg, ip) and verapamil (up to 20 mg/kg, ip)], did not significantly affect the threshold for maximal electroconvulsions in mice. However, amlodipine at a non-protective dose of 20 mg/kg, ip significantly enhanced the anticonvulsant activity of lamotrigine in the maximal electroshock-induced seizure test in mice by reducing its ED(50) value from 6.33 to 2.87 mg/kg (p < 0.05). In contrast, amlodipine at lower doses of 5 and 10 mg/kg, ip, diltiazem (at doses up to 10 mg/kg, ip) and verapamil (at doses up to 20 mg/kg, ip) had no significant impact on the antiseizure action of lamotrigine in the maximal electroshock-induced seizure test in mice. In conclusion, one can ascertain that the favorable combination of lamotrigine with amlodipine deserves more attention from a clinical viewpoint because of the enhanced antiseizure action of lamotrigine.

Endogenous neuroprotective factors: neurosteroids.

Neurosteroids are a group of steroid hormones synthesized by the brain in the presence of steroidogenic enzymes. Specific neurosteroids modulate function of several receptors, and also regulate growth of neurons, myelinization and synaptogenesis in the central nervous system. Some neurosteroids have been shown to display neuroprotective properties, which may have important implications for their potential use in the treatment of various neuropathologies such as: age-dependent dementia, stroke, epilepsy, spinal cord injury, Alzheimer's disease (AD), Parkinson's disease (PD) and Niemann-Pick type C disease (NP-C). This paper focuses on neuroprotection afforded by neurosteroids.

Stiripentol. A novel antiepileptic drug.

Epilepsy is one of the most widespread pathologies of human brain, affecting approximately 1% of world population. Despite the development of new methods of seizure control, chronic administration of antiepileptic drugs (AEDs) remains the treatment of choice. Nevertheless, pharmacotherapy is not always effective. In the case of single drug treatment, the number of non-responding patients is as high as 30%. Moreover, chronic medication with currently available AEDs may result in severe side-effects and undesired drug interactions. That is why in recent years intensive research has been carried out aiming at the development of new therapeutic strategies in epilepsy. The goal of this review is to assemble current literature data on stiripentol (STP), a novel anticonvulsant unrelated to any other AEDs. STP potentiates central gamma-aminobutyric acid (GABA) transmission and is characterized by nonlinear pharmacokinetics and inhibition of liver microsomal enzymes. STP has proved its anticonvulsant potency in different types of animal seizures, as well as in clinical trials. The drug seems a good candidate for adjunctive therapy in intractable epilepsy.

Interactions of stiripentol with clobazam and valproate in the mouse maximal electroshock-induced seizure model.

The aim of this study was to characterize the anticonvulsant effects of stiripentol (STP) in combination with clobazam [CLB], and valproate [VPA]) in the mouse maximal electroshock (MES)-induced seizure model using the type I isobolographic analysis for parallel and non-parallel dose-response relationship curves (DRRCs). Potential adverse-effect profiles of interactions of STP with CLB and VPA at the fixed-ratio of 1:1 in the MES test with respect to motor performance, long-term memory and skeletal muscular strength were measured along with total brain antiepileptic drug concentrations. In the mouse MES model, STP administered singly had its DRRC non-parallel to that for CLB and, simultaneously, parallel to that for VPA. With type I isobolography for parallel DRRCs, the combinations of STP with VPA at three fixed-ratios of 1:3, 1:1 and 3:1 exerted sub-additive (antagonistic) interaction. Isobolography for non-parallel DRRCs revealed that the combination of STP with CLB at the fixed-ratio of 1:1 produced additive interaction. For all combinations, neither motor coordination, long-term memory nor muscular strength was affected. Total brain antiepileptic drug concentrations revealed bi-direction changes with the most profound being an 18.6-fold increase in CLB by STP and a 2.3-fold increase in STP by VPA. In conclusion, the additive interaction between STP and CLB was associated with a concurrent pharmacokinetic interaction and these data may explain the clinical efficacy seen with this combination. In contrast, the antagonism between STP and VPA was surprising since synergism is observed clinically.

Stiripentol - characteristic of a new antiepileptic drug.

BACKGROUND: As 20 - 30% of patients are refractory to the presently available antiepileptic drugs, there is a strong need for the development of newer antiepileptics. OBJECTIVE: A question arises whether stiripentol fulfills the criteria for a promising newer antiepileptic drug. METHODS: A literature search, including experimental and clinical studies, with no time limit was performed. RESULTS/CONCLUSION: Stiripentol represents a group of drugs indirectly enhancing GABA-ergic neurotransmission and it exerts a protective activity in some experimental seizure models, including maximal electroshock (MES)-, pentylenetetrazol-, bicuculline-, strychnine-, and cocaine-induced convulsions. The drug potently inhibits metabolism of other antiepileptic drugs, significantly elevating their plasma and brain concentrations. This requires dosage adjustments of the concomitant antiepileptic drugs used in combination. In the form of an add-on therapy, stiripentol has proved to be effective in partial and atypical absence epilepsies. Considering its particular efficacy against severe myoclonic seizures in infancy (Dravet's syndrome), stiripentol has been awarded an orphan drug status for an adjunctive therapy of this difficult-to-treat condition.

Effects of amlodipine, diltiazem, and verapamil on the anticonvulsant action of topiramate against maximal electroshock-induced seizures in mice.

To assess the effect of 3 calcium channel antagonists (amlodipine, diltiazem, and verapamil) on the anticonvulsant action of topiramate (a new generation antiepileptic drug) in the mouse maximal electroshock seizure (MES) model. Amlodipine (20 mg/kg) significantly enhanced the anticonvulsant activity of topiramate in the MES test in mice, reducing its ED50 value from 54.83 to 33.10 mg/kg (p < 0.05). Similarly, diltiazem (5 and 10 mg/kg) markedly potentiated the antiseizure action of topiramate against MES, lowering its ED50 value from 54.83 to 32.48 mg/kg (p < 0.05) and 28.68 mg/kg (p < 0.01), respectively. In contrast, lower doses of amlodipine (5 and 10 mg/kg) and diltiazem (2.5 mg/kg) and all doses of verapamil (5, 10, and 20 mg/kg) had no significant impact on the antiseizure action of topiramate. Pharmacokinetic verification of the interaction of topiramate with amlodipine and diltiazem revealed that neither amlodipine nor diltiazem affected total brain topiramate concentration in experimental animals, and thus, the observed interactions were concluded to be pharmacodynamic in nature. The favorable combinations of topiramate with amlodipine or diltiazem deserve more attention from a clinical viewpoint because the enhanced antiseizure action of topiramate was not associated with any pharmacokinetic changes in total brain topiramate concentration.

New generation of valproic acid.

Valproic acid (VPA) is one of four first-line antiepileptic drugs (AEDs) currently established in the long-term treatment of epilepsy. Despite VPA's wide spectrum of action, in some cases its use is limited due to specific pharmacokinetics and dangerous adverse effects. These include hepatotoxicity and teratogenecity. Such limitations account for intensive research that has been carried out in order to develop new analogues or derivatives of VPA. In our review, we focus on three out of a number of substances that have been lately under investigation: NPS 1776, valrocemide and DP-VPA. These potential AEDs present both good anticonvulsive and safety profiles and seem to be more potent than the original VPA. Clinical trials, which are now ongoing, will answer the question whether or not they could become second generation of VPA.

Neuroprotective effects of antiepileptic drugs.

Experimental and clinical data indicate that epilepsy and seizures lead to neuronal cell loss and irreversible brain damage. This neurodegeneration results not only in the central nervous system dysfunction but may also be responsible for the decreased efficacy of some antiepileptic drugs (AEDs). The aim of this review was to assemble current literature data on neuroprotective properties of AEDs. The list of hypothetical neuroprotectants is long and consists of substances which act via different mechanisms. We focus on AEDs since this heterogeneous group of pharmaceuticals, as far as mechanisms of their action and mechanisms of neuronal death are concerned, should provide protection in addition to antiseizure effect itself. Most studies on neuroprotection are based on animal experimental models of neuronal degeneration. Electrically and pharmacologically evoked seizures as well as different models of ischemia are frequently used. Although our knowledge about properties of AEDs is still not complete and discrepancies occasionally occur, the group seems to be promising in terms of neuroprotection. Some of the drugs, though, turn out to be neutral or even have adverse effects on the central nervous system, especially on immature brain tissue (barbiturates and benzodiazepines). Unfortunatelly, we cannot fully extrapolate animal data to humans, therefore further well designed clinical trials are necessary to determine neuroprotective properties of AEDs in humans. However, there is a hope that AEDs will have a potential to serve as neuroprotectants not only in seizures, but perhaps, in other neurodegenerative conditions in humans as well. The novel AEDs (especially lamotrigine, tiagabine, and topiramate) seem particularly promising.