Monika Dudra-Jastrzębska

Basic mechanisms of antiepileptic drugs and their pharmacokinetic/pharmacodynamic interactions: an update.

This article aims to summarize the current views of AED action and the promising new targets for the pharmacotherapy of epilepsy. In the first section of this paper, a neurobiological basis of epilepsy treatment and brief pharmacological characteristics of classical and new AEDs will be presented. In the second part, the results of experimental studies that have combined AEDs with similar or different mechanisms of action will be discussed.

Pharmacodynamic and pharmacokinetic interaction profiles of levetiracetam in combination with gabapentin, tiagabine and vigabatrin in the mouse pentylenetetrazole-induced seizure model: An isobolographic analysis

To characterize the interactions between levetiracetam and the antiepileptic drugs gabapentin, tiagabine, and vigabatrin in suppressing pentylenetetrazole-induced clonic seizures in mice, type II isobolographic analysis was used. Clonic seizures were evoked in Albino Swiss mice by subcutaneous injection of pentylenetetrazole at its CD(97)(98 mg/kg). Adverse-effect profiles with respect to motor performance, long-term memory and skeletal muscular strength were measured along with total brain antiepileptic drug concentrations. The combination of gabapentin with levetiracetam at the fixed-ratios of 2:1, 1:1, 1:2, and 1:4 were supra-additive (synergistic) in terms of seizure suppression whilst the combination at the fixed-ratio of 4:1 was additive. Tiagabine with levetiracetam and vigabatrin with levetiracetam at the fixed-ratios of 1:25, 1:50, 1:100, 1:200, and 1:400 and at 2:1, 3:1, 4:1, 6:1, 8:1, and 16:1 were additive, respectively. No acute adverse effects were observed. Measurement of total brain antiepileptic drug concentrations revealed that levetiracetam in combination with gabapentin at the fixed-ratio of 1:4 significantly elevated (21%) total brain gabapentin concentrations. In contrast, levetiracetam was without affect on tiagabine or vigabatrin concentrations and co-administration with gabapentin, tiagabine or vigabatrin had no effect on levetiracetam brain concentrations, indicating the pharmacodynamic nature of interaction between these antiepileptic drugs in the mouse pentylenetetrazole model. The combination of gabapentin with levetiracetam at the fixed-ratios of 2:1, 1:1, 1:2, and 1:4 appears to be particularly favorable combination exerting supra-additive interaction in suppressing pentylenetetrazole-induced seizures, although there is a pharmacokinetic contribution to the interaction between levetiracetam and gabapentin at the fixed-ratio of 1:4. Levetiracetam in combination with tiagabine and vigabatrin appear to be neutral combinations producing only additivity in the mouse pentylenetetrazole model.

Prenyloxyphenylpropanoids as a novel class of anticonvulsive agents.

In this study, we synthesized some natural and semi-synthetic prenyloxyphenylpropanoids (e.g., acetophenones, benzoic and cinnamic acids, chalcones, and coumarins), and we assessed their in vivo neuroprotective activity, using the mouse maximal electroshock-induced seizure model (MES test). 7-Isopentenyloxycoumarin and (2E)-3-{4-[(3-methylbut-2-enyl)oxy]phenyl}prop-2-enoic acid, administered ip at a dose of 300 mg/kg, suppressed MES-induced seizures in mice in a time- and dose-dependent manner.

Isobolographic characterization of the anticonvulsant interaction profiles of levetiracetam in combination with clonazepam, ethosuximide, phenobarbital and valproate in the mouse pentylenetetrazole-induced seizure model

This study was designed so as to characterize the interactions between levetiracetam (LEV) and the conventional antiepileptic drugs (AEDs) clonazepam (CZP), ethosuximide (ETS), phenobarbital (PB), and valproate (VPA) in suppressing pentylenetetrazole (PTZ)-induced clonic seizures in mice by use of type II isobolographic analysis. Adverse-effect profiles of the drugs in combination were determined and brain AED concentrations were measured. The combinations of VPA and ETS with LEV at the fixed-ratio of 1:2, CZP with LEV (1:20,000), and PB with LEV (1:20) were supra-additive (synergistic) in suppressing seizures. In contrast, VPA and ETS with LEV (1:1, 2:1, and 4:1), CZP with LEV (1:1000, 1:5000, and 1:10,000), and PB with LEV (1:1, 1:5, and 1:10) were additive. No adverse effects were observed. ETS significantly reduced brain LEV concentrations but no other pharmacokinetic changes were observed. The combinations of CZP with LEV (1:20,000); VPA and ETS with LEV (1:2); and PB with LEV (1:20) appear to be favorable combinations exerting supra-additive interactions in suppressing PTZ-induced seizures.

A Long-Term Treatment with Arachidonyl-2′-Chloroethylamide Combined with Valproate Increases Neurogenesis in a Mouse Pilocarpine Model of Epilepsy

Rational polytherapy in the treatment of refractory epilepsy has been the main therapeutic modality for several years. In treatment with two or more antiepileptic drugs (AEDs), it is of particular importance that AEDs be selected based on their high anticonvulsant properties, minimal side effects, and impact on the formation of new neurons. The aim of the study was to conduct an in vivo evaluation of the relationship between treatments with synthetic cannabinoid arachidonyl-2′-chloroethylamide (ACEA) alone or in combination with valproic acid (VPA) and hippocampal neurogenesis in a mouse pilocarpine model of epilepsy. All studies were performed on adolescent male CB57/BL mice with using the following drugs: VPA (10 mg/kg), ACEA (10 mg/kg), phenylmethylsulfonyl fluoride (PMSF—a substance protecting ACEA against degradation by fatty acid hydrolase, 30 mg/kg), pilocarpine (PILO, a single dose of 290 mg/kg) and methylscopolamine (30 min before PILO to stop peripheral cholinergic effects of pilocarpine, 1 mg/kg). We evaluated the process of neurogenesis after a 10-day treatment with ACEA and VPA, alone and in combination. We observed a decrease of neurogenesis in the PILO control group as compared to the healthy control mice. Furthermore, ACEA + PMSF alone and in combination with VPA significantly increased neurogenesis compared to the PILO control group. In contrast, VPA 10-day treatment had no impact on the level of neurons in comparison to the PILO control group. The combination of ACEA, PMSF and VPA considerably stimulated the process of creating new cells, particularly neurons, while chronic administration of VPA itself had no influence on neurogenesis in the mouse pilocarpine model of epilepsy. The obtained results enabled an in vivo evaluation of neurogenesis after treatment with antiepileptic drugs in an experimental model of epilepsy.

Seizure susceptibility to electroconvulsions or pentylenetetrazol after complete cerebral ischemia in rats due to cardiac arrest

BACKGROUND Experimental data provide evidence on the induction of a susceptibility to audiogenic seizures in rats surviving cardiac arrest and subsequent global brain ischemia. The aim of this study was to find out whether cardiac arrest in rats could affect seizure susceptibility in the long-term period of one and two months, following this event. Seizure susceptibility was evaluated against electroconvulsions and pentylenetetrazol-induced seizures. METHODS Experiments were conducted on 34 rats surviving cardiac arrest and 34 sham-operated animals which also had surgery but their hearts were not stopped. The threshold for electroconvulsions and pentylenetetrazol was calculated in 3 groups of 5-6 rats. The endpoint for electroconvulsions was the tonic hindlimb extension and for pentylenetetrazol-generalized clonic seizure. RESULTS The results indicate that cardiac arrest did not modify the threshold for electroconvulsions either one or two months, following the surgery. On the other hand, a significant reduction in the seizure threshold for pentylenetetrazol was noted one month after cardiac arrest. The median convulsive dose of pentylenetetrazol was decreased from 52.47 mg/kg (sham-operated rats) to 34.03 mg/kg of the convulsant for the induction of clonic seizure activity. This effect was not observed at two months after cardiac arrest. CONCLUSIONS It is evident that global brain ischemia is associated with a transient reduction in the convulsive threshold for pentylenetetrazol whilst the threshold for electroconvulsions remains unchanged.

Evaluation of clinical effectiveness of Aloe vera – a review

Naturally occurring products have gained popularity in recent decades, especially due to their less adverse effects on human health. Various Aloe species are widespread all over the world. Aloe vera is one of the plants exhibiting multiple benefits and has gained considerable importance in clinical research. Historically, it has been used for a variety of medicinal purposes. It has attracted the attention of many researchers because of its different properties. More than 200 different biologically active substances were found in this plant that contributed to the fact it has been used to treat various types of diseases. The healthy effect of Aloe vera is primarily attributed to the polysaccharides contained in the gel of the leaves. It has been traditionally used to treat various conditions, including psoriasis, sunburn or radiation-related dermatitis, mucositis, oesophagitis or lichen planus. Aloe vera has also found application in wound healing, treatment of burns, protection against skin damage caused by X-ray, intestinal problems, reduction of plaque and gingivitis, regulating the levels of plasma lipoproteins, reduction of blood sugar levels and improving the immune system. Other biological activities of aloe, such as antifungal, antibacterial, antiviral, anti-inflammatory, anticancer and immunomodulatory have also been documented in numerous studies. This review examines the possible applications of Aloe vera in clinical trials.

Combination therapy of basal-cell carcinoma in 31-year-old patient with nevoid basal cell carcinoma syndrome – Case study

Nevoid basal cell carcinoma syndrome (NBCCS) is a rare genetic disease that is manifested in a number of disorders concerning the skin, skeleton, cardiovascular and nervous systems. Various defects which can be observed at first contact with a patient visiting a dermatologist or dentist may help to diagnose this syndrome. Frequent problems with odontogenic cysts and metastatic basal-cell carcinomas result in patients being under the constant care of a specialist. This short study presents the case of 31-year-old patient with Gorlin-Goltz syndrome treated with combination therapy using CO2 laser and photodynamic therapy.

A review of selected natural phytochemicals in preventing and treating malignant skin neoplasms

Malignant skin neoplasms are one of the most common human malignancies. The incidence of nonmelanoma skin cancers and malignant melanoma is constantly increasing. The current therapies, especially for malignant melanoma, have relatively low success rates. Therefore, there is an urgent need to develop new remedies that are both safe and effective. Natural substances have always been an important source for the discovery of new therapies. In turn, a number of studies have indicated that some phytocheicals could have an anti-tumour effect. In vitro and in vivo testing of malignant skin neoplasm models revealed different anti-tumour actions, including antioxidation, carcinogen inactivation, anti-proliferation, cell cycle arrest, induction of apoptosis, inhibition of angiogenesis, or a combination of them. The aim of this paper is to describe anti-tumour compounds derived from natural sources that might be used in the therapy of malignant skin neoplasm. The phytochemicals discussed below include carotenoids, terpenoids and flavonoids.

Molecular and environmental aspects of skin cancers

Skin cancers are one of the most common cancers in the Caucasian population. A constantly increasing number of nonmelanoma skin cancers and malignant melanomas is observed. The incidence of skin cancers is associated mainly with exposure to sunlight. Therefore, agricultural workers who work in open spaces are a particularly vulnerable group. Currently, studies on the pathogenesis of skin cancer focus on the molecular basis associated with ultraviolet radiation. This study is an attempt to summarize the current state of knowledge on this issue. There have been demonstrated mutations in different classes of genes associated with carcinogenesis, including protooncogenes, tumour suppressor genes, genes that control apoptosis, genes encoding transcription factors and DNA repair genes in patients with skin cancers. Mutations in the latter result in reducing the effectiveness of DNA repair and fixation of mutations. All changes at the gene level lead to structural changes, quantitative and dysfunction of proteins encoded by these genes. All these factors contribute to the process of carcinogenesis. Due to increasing number of skin cancers, it seems important to increase knowledge of the molecular basis of skin cancers. This knowledge could be crucial for predicting the course of the disease, and for the development of new therapeutic strategies.