Caffeine and Its Interactions with Antiseizure Medications-Is There a Correlation between Preclinical and Clinical Data?

Experimental studies reveal that caffeine (trimethylxanthine) at subconvulsive doses, distinctly reduced the anticonvulsant activity of numerous antiseizure medications (ASMs) in rodents, oxcarbazepine, tiagabine and lamotrigine being the exceptions. Clinical data based on low numbers of patients support the experimental results by showing that caffeine (ingested in high quantities) may sharply increase seizure frequency, considerably reducing the quality of patients' lives. In contrast, this obviously negative activity of caffeine was not found in clinical studies involving much higher numbers of patients. ASMs vulnerable to caffeine in experimental models of seizures encompass carbamazepine, phenobarbital, phenytoin, valproate, gabapentin, levetiracetam, pregabalin and topiramate. An inhibition of R-calcium channels by lamotrigine and oxcarbazepine may account for their resistance to the trimethylxanthine. This assumption, however, is complicated by the fact that topiramate also seems to be a blocker of R-calcium channels. A question arises why large clinical studies failed to confirm the results of experimental and case-report studies. A possibility exists that the proportion of patients taking ASMs resistant to caffeine may be significant and such patients may be sufficiently protected against the negative activity of caffeine.

Association between Polymorphism in the Janus Kinase 2 (JAK2) Gene and Selected Performance Traits in Cattle and Sheep.

The Janus Kinase 2 (JAK2) tyrosine kinase is an essential component of signal transduction of the class II cytokine receptors, including the growth hormone receptor. Therefore, it may play a crucial role in the signaling pathway of the somatotropic axis, which influences growth, development, and reproductive traits in ruminants. For this purpose, for three breeds of cattle (Hereford, Angus, and Limousin; a total of 781 individuals), two polymorphic sites located in exon 16 (rs210148032; p.Ile704Val, within pseudokinase (JH2)) and exon 23 (silent mutation rs211067160, within JH1 kinase domain) were analyzed. For two breeds of sheep (Pomeranian and Suffolk; 333 individuals in total), two polymorphic sites in exon 6 (rs160146162 and rs160146160; encoding the FERM domain) and one polymorphic site in exon 24 of the JAK2 gene (rs160146116; JH1 kinase domain) were genotyped. In our study, the associations examined for cattle were inconclusive. However, Hereford and Limousin cattle with genotypes AA (e16/RsaI) and AA (e23/HaeIII) tended to have the highest body weight and better daily gains (p ≤ 0.05). No clear tendency was observed in the selected reproductive traits. In the case of sheep, regardless of breed, individuals with the AA (e6/EarI), GG (e6/seq), and AA (e24/Hpy188III) genotypes had the highest body weights and daily gains in the study periods (p ≤ 0.01). The same individuals in the Pomeranian breed also had better fertility and lamb survival (p ≤ 0.01). To the best of our knowledge, these are the first association studies for all these polymorphic sites. Single-nucleotide polymorphisms in the JAK2 gene can serve as genetic markers for growth and selected reproductive traits in ruminants given that they are further investigated in subsequent populations and analyzed using haplotype and/or combined genotype systems.

Ultrasound parameters of early pregnancy and Doppler indices of blood vessels in the placenta and umbilical cord throughout the pregnancy period in sheep.

BACKGROUND: Ultrasonography is one of the most important techniques that enable the detection and monitoring of pregnancy. One such study using this technique is the assessment of the hemodynamics of fetal and umbilical blood vessels. However, there is little data on blood flow in the placentomes, which is the basic structural unit of the sheep's placenta. Therefore, the aim of this study was to determine the Doppler parameters in the arterial vessels of the caruncles, cotyledons and the umbilical cord as well as measuring venous flow rates during the entire gestation period of the sheep. Additionally, the usefulness of various other ultrasound parameters in the early diagnosis of pregnancy in sheep was analyzed. RESULTS: Most of the Doppler parameters in umbilical, cotyledonary and caruncular arteries were significantly correlated with the day of pregnancy (p < 0.01). In the early stages of pregnancy, the peak systolic velocity (PSV), regardless of the location of the artery, was significantly lower than that in the later stages of pregnancy (p < 0.01). PSV was also found to be significantly higher in the umbilical artery than in the cotyledonary and caruncular arteries (p < 0.01). Until the 50th day of pregnancy, the end diastolic velocity (EDV) was not found in the umbilical and cotyledonary arteries. EDV was significantly higher in the caruncular arteries than in the cotyledonary and umbilical arteries (p < 0.01). The resistance index (RI) and pulsatility index (PI) in the early stages of pregnancy were found to be significantly higher than that in the later stages of pregnancy (p < 0.01). The RI and PI were significantly lower in the caruncular arteries than in the arteries of the cotyledons and umbilical cord (p < 0.01). In the umbilical vein, all Doppler parameters were observed to be significantly higher than those in the placentomal veins (p < 0.01 or p < 0.05). Using transrectal ultrasound, pregnancy was detected between 20 and 28 days after mating. The ovaries were observed to have corpora lutea, the diameter of which was fairly consistent from the 17th to the 56th day of pregnancy. CONCLUSIONS: It has been demonstrated that both the location of the arterial vessel in the placental-umbilical circulation and the gestational age have a significant impact on hemodynamic parameters. The results also provide new insights about the blood flow in caruncular and cotyledonary arteries, which could contribute to a more holistic understanding of hemodynamic changes in the placentas of sheep. Analyzing haemodynamic parameters in the umbilical and placental veins are preliminary studies in sheep, but it could inspire further research in this field. Furthermore, the research conducted confirms the practicality and convenience of transrectal ultrasonography in the early diagnosis of pregnancy in sheep and also indicates that the identification and imaging of the corpus luteum using B-mode ultrasonography can be a very early and simple method of confirming effective mating in sheep.

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.

Some Candidate Drugs for Pharmacotherapy of Alzheimer's Disease.

Alzheimer's disease (AD; progressive neurodegenerative disorder) is associated with cognitive and functional impairment with accompanying neuropsychiatric symptoms. The available pharmacological treatment is of a symptomatic nature and, as such, it does not modify the cause of AD. The currently used drugs to enhance cognition include an N-methyl-d-aspartate receptor antagonist (memantine) and cholinesterase inhibitors. The PUBMED, Medical Subject Heading and Clinical Trials databases were used for searching relevant data. Novel treatments are focused on already approved drugs for other conditions and also searching for innovative drugs encompassing investigational compounds. Among the approved drugs, we investigated, are intranasal insulin (and other antidiabetic drugs: liraglitude, pioglitazone and metformin), bexarotene (an anti-cancer drug and a retinoid X receptor agonist) or antidepressant drugs (citalopram, escitalopram, sertraline, mirtazapine). The latter, especially when combined with antipsychotics (for instance quetiapine or risperidone), were shown to reduce neuropsychiatric symptoms in AD patients. The former enhanced cognition. Procognitive effects may be also expected with dietary antioxidative and anti-inflammatory supplements-curcumin, myricetin, and resveratrol. Considering a close relationship between brain ischemia and AD, they may also reduce post-brain ischemia neurodegeneration. An investigational compound, CN-105 (a lipoprotein E agonist), has a very good profile in AD preclinical studies, and its clinical trial for postoperative dementia is starting soon.

Health-related quality of life of patients after ischaemic stroke treated in a provincial hospital in Poland.

BACKGROUND: Ischaemic stroke (IS) is a major cause of death and disability and affects the quality of life of patients. Previous studies focused on urban populations. OBJECTIVE: To evaluate the health-related quality of life (QoL) of patients with history of IS and living in a rural area in Poland. PATIENTS: Rural population of 172 patients discharged from a district hospital in Zakopane, Poland with a diagnosis of IS in the period from 01.01.2005 to 31.10.2006. INTERVENTION: QoL was evaluated using the European Quality of Life Scale-5 Dimensions EQ-5D-3 L (EQ-5D) and the Short Form Health Survey - 12 version 2 (SF-12). RESULTS: In the EQ-5D survey, 57.3% of patients had only some problems with mobility, 40.3% with usual activities, 63.2% with pain/discomfort, 59% with anxiety/depression, and 32.2% with self-care. In the SF-12 survey, both summary components (physical and psychological) were reduced compared to the population norm. CONCLUSION: The quality of life in IS survivors is clearly reduced in the majority of domains assessed by the EQ-5D and SF-12 questionnaires. The most important factors affecting QoL were the functional state, depression and anxiety. A significant difference as compared to to urban and mixed populations was observed for a reduced SF-12 mental health component and for the EQ-5D visual analogue scale. We found no effect of gender, age or cognitive disorders on the outcomes of SF-12.

[Serum insulin and glucose concentrations in sheep during late pregnancy in relation to the number and sex of the fetuses]. / Insulin- und Glukosekonzentration im Blutserum hochträchtiger Schafe in Abhängigkeit von Anzahl und Geschlecht der Feten.

OBJECTIVE: The objective of this study was to investigate whether the serum concentration of glucose and insulin in the blood of pregnant sheep depends on the number and the sex of the fetuses. MATERIAL AND METHODS: The presented research was carried out on Pomeranian (n = 42) and Suffolk sheep (n = 42) towards the end of the pregnancy. The following groups were established amongst the Pomeranian sheep: single pregnancies with a female fetuses (n = 19) and male fetuses (n = 10), twin pregnancies with female fetuses (n = 8), male fetuses (n = 8) and fetuses of different sex (n = 7). Similarly, in the Suffolk sheep, the following groups were formed: single pregnancies with female fetuses (n = 9) and male fetuses (n = 12), twin pregnancies with male fetuses (n = 12) and fetuses of different sex (n = 9). RESULTS: In Suffolk sheep, serum insulin concentration was significantly higher than in Pomeranian sheep (p < 0.05). The average insulin concentration in Pomeranian sheep with a single pregnancy was higher than in sheep of the same breed with a twin pregnancy (p < 0.05). In the Pomeranian breed, the highest insulin concentration was recorded in sheep with male fetuses (p < 0.01). Similarly, in Suffolk sheep, the insulin concentration was higher in sheep with male fetuses than female ones (p < 0.05). On the other hand, the concentration of glucose in Pomeranian sheep, with both single and twin pregnancies and with female fetuses, was higher than in sheep with male fetuses or different sex fetuses (p < 0.05 and p < 0.01, respectively). In the Suffolk breed, the glucose concentration was also higher in sheep with female fetuses (p < 0.05). In Suffolk sheep a positive correlation was found between the birth weight of lambs and their mother's glucose concentration (r = 0.56; p < 0.01). CONCLUSION: The differences in the concentration of insulin and glucose in the blood of pregnant sheep demonstrated in this study suggest that sex and the number of fetuses may be further factors affecting the energy metabolism in the late stages of pregnancy. Based in the presented findings these differences may depend on the breed and may be related to the birth weight of lambs.

A viewpoint on rational and irrational fixed-drug combinations.

INTRODUCTION: Considering that there are around 30% of patients with epilepsy resistant to monotherapy, the use of synergistic combinations of antiepileptic drugs is of particular importance. This review shows most beneficial as well as irrational combined treatments both from an experimental and clinical point of view. Areas covered: Preferably, experimental data derived from studies evaluating synergy, additivity, or antagonism by relevant methods, in terms of anticonvulsant or neurotoxic effects and pharmacokinetic data have been considered. Although there have been no randomized clinical trials on this issue, the clinical data have been analyzed from studies on considerable numbers of patients. Case-report studies have been not considered. Expert commentary: The experimental data provide a strong support that co-administration of lamotrigine with carbamazepine is negative, considering the anticonvulsant and neurotoxic effects. Clinical reports do not entirely support this conclusion. Other experimentally documented negative combinations comprise lamotrigine+ oxcarbazepine and oxcarbazepine+ phenytoin. From the experimental and clinical point of view, a combination of lamotrigine+ valproate may deserve recommendation. Other most positive experimental and clinical combinations include carbamazepine+valproate, phenytoin+phenobarbital, carbamazepine+gabapentin, carbamazepine+topiramate, levetiracetam+valproate, levetiracetam+carbamazepine. Certainly, experimental data have some limitations (non-epileptic animals, acute administration of antiepileptic drugs) so all experimental recommendations need a careful clinical evaluation.

The Prophylactic Use of Antiepileptic Drugs in Patients Scheduled for Neurosurgery.

Antiepileptic drugs (AEDs) possess diverse mechanisms of action - enhancement of GABA-mediated events, inhibition of glutamate-mediated excitation, blockade of voltage-dependent sodium or calcium channels being the most frequently shared. They are not only used for the symptomatic management of epilepsy but in the treatment of psychiatric or neurologic disorders (e.g. bipolar disorder, neuropathic pain, prophylaxis of migraine). Generally, this group of drugs is also widely used in neurosurgery patients for the prevention of seizure activity and their effectiveness in this regard has been evaluated in this review. There is no controversy as to whether continue AEDs in patients with epilepsy scheduled for neurosurgery. A question arises on whether AEDs may be recommended to non-epileptic neurosurgical patients for the prevention of post-surgery early or late seizures. There are some positive examples indicating that AEDs may reduce the occurrence of preferably early seizures, some results also being positive in the case of late seizure activity. However, there are also many negative data in this regard. The existence of serious adverse effects and a possibility of pharmacokinetic interactions with the concomitant therapy may further complicate the decision on whether to start the prophylactic use of AEDs. In general, the existing evidence does not support the prophylactic use of AEDs, especially in patients who underwent craniotomy/craniectomy for the inhibition of late seizure activity.

Epilepsy coexisting with depression.

Depression episodes in epilepsy is the most common commorbidity, affecting between 11% and 62% of patients with epilepsy. Although researchers have documented a strong association between epilepsy and psychiatric comorbidities, the nature of this relationship is poorly understood. The manifestation of depression in epilepsy is a complex issue having many interacting neurobiological and psychosocial determinants, including clinical features of epilepsy (seizure frequency, type, foci, or lateralization of foci) and neurochemical or iatrogenic mechanisms. Other risk factors are a family history of psychiatric illness, particularly depression, a lack of control over the seizures and iatrogenic causes (pharmacologic and surgical). In addition, treatment with antiepileptic drugs (AEDs) as well as social coping and adaptation skills have also been recognised as risk factors of depression associated with epilepsy. Epilepsy may foster the development of depression through being exposed to chronic stress. The uncertainty and unpredictability of seizures may instigate sadness, loneliness, despair, low self-esteem, and self-reproach in patients with epilepsy and lead to social isolation, stigmatization, or disability. Often, depression is viewed as a reaction to epilepsy's stigma and the associated poor quality of life. Moreover, patients with epilepsy display a 4-5 higher rate of depression and suicide compared with healthy population.

Pharmacokinetic/pharmacodynamic considerations for epilepsy - depression comorbidities.

INTRODUCTION: Epilepsy may be frequently associated with psychiatric disorders and its co-existence with depression usually results in the reduced quality of life of patients with epilepsy. Also, the efficacy of antiepileptic treatment in depressed patients with epilepsy may be significantly reduced. AREAS COVERED: Results of experimental studies indicate that antidepressants co-administered with antiepileptic drugs may either increase their anticonvulsant activity, remain neutral or decrease the protective action of antiepileptic drugs in models of seizures. Apart from purely pharmacodynamic interactions, pharmacokinetic mechanisms have been proven to contribute to the final outcome. We report on clinical data regarding the pharmacokinetic interactions of enzyme-inducing antiepileptic drugs with various antidepressants, whose plasma concentration may be significantly reduced. On the other hand, antidepressants (especially selective serotonin reuptake inhibitors) may influence the metabolism of antiepileptics, in many cases resulting in the elevation of plasma concentration of antiepileptic drugs. EXPERT OPINION: The preclinical data may provide valuable clues on how to combine these two groups of drugs - antidepressant drugs neutral or potentiating the anticonvulsant action of antiepileptics are recommended in this regard. Avoidance of antidepressants clearly decreasing the convulsive threshold or decreasing the anticonvulsant efficacy of antiepileptic drugs (f.e. bupropion or mianserin) in patients with epilepsy is recommended.

Antiepileptic drugs and adverse skin reactions: An update.

This paper summarizes current views on clinical manifestation, pathogenesis, prognosis and management of antiepileptic drug (AED)-induced adverse skin reactions. Cochrane Central Register of Controlled Trials, MEDLINE (PubMed) and ISI Web of Knowledge were searched. The recent classification, among drug-induced skin injuries, points to Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), acute generalized exanthematous pustulosis and hypersensitivity syndrome (HSS), which may be also recognized as a drug reaction with eosinophilia and systemic symptoms (DRESS) or drug-induced hypersensitivity syndrome (DIHS). The use of aromatic AEDs, e.g. phenytoin, carbamazepine, oxcarbazepine, phenobarbital, primidone, zonisamide, and lamotrigine is more frequently associated with cutaneous eruption and other signs or symptoms of drug hypersensitivity. There is a high degree of cross-reactivity (40-80%) in patients with hypersensitivity or allergic reactions to AEDs. Pharmacogenetic variations in drug biotransformation may also play a role in inducing these undesired effects. It is suggested that avoidance of specific AEDs in populations at special risk, cautious dose titration and careful monitoring of clinical response and, if applicable, laboratory parameters can minimize the serious consequences of idiosyncratic reactions.

The problem of osteoporosis in epileptic patients taking antiepileptic drugs.

INTRODUCTION: Epilepsy is a common neurological disorder associated with recurrent seizures. Therapy with antiepileptic drugs (AEDs) helps achieve seizure remission in approximately 70% of epileptic patients. Treatment with AEDs is frequently lifelong and there are reports suggesting its negative influence on bone health. This is especially important in terms of general occurrence of osteoporosis, affecting over 50 million people worldwide. AREAS COVERED: This study refers to two main groups of AEDs: hepatic enzyme inducers (carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone and topiramate) and non-inducers (clobazam, clonazepam, ethosuximide, gabapentin, lacosamide, lamotrigine, levetiracetam, pregabalin, tiagabine, valproate, vigabatrin and zonisamide). Some reports indicate that enzyme inducers may exert a more negative influence on bone mineral density (BMD) compared to non-inducers. Bone problems may appear in both sexes during AED therapy, although women are additionally burdened with postmenopausal osteoporosis. Supplementation of vitamin D and calcium in patients on AEDs is recommended. EXPERT OPINION: Apart from enzyme inducers, valproate (an even enzyme inhibitor) may also negatively affect BMD. However, the untoward effects of AEDs may depend upon their doses and duration of treatment. Although the problem of supplementation of vitamin D and calcium in epileptic patients on AEDs is controversial, there are recommendations to do so.

Adjunctive brivaracetam in adults with uncontrolled focal epilepsy: results from a double-blind, randomized, placebo-controlled trial.

PURPOSE: Brivaracetam (BRV) is a novel high-affinity synaptic vesicle protein 2A ligand in clinical development for the treatment of epilepsy. This phase III study (N01252; NCT00490035) evaluated the efficacy and safety/tolerability of BRV (20, 50, and 100 mg/day) compared with placebo (PBO) in patients aged 16-70 years with uncontrolled focal seizures with/without secondary generalization, despite treatment with one to two concomitant antiepileptic drugs at a stable and optimal dosage. METHODS: This was a double-blind, randomized, placebo-controlled trial conducted across Europe and India. Eligible patients had two or more focal seizures/month for 3 months prior to screening and eight or more focal seizures during the 8-week prospective baseline. Concomitant use of levetiracetam was limited to 20% of randomized patients. Patients were randomized (1:1:1:1) to BRV 20, 50, 100 mg/day or PBO with no up-titration for 12 weeks, followed by down-titration or entry into a long-term follow-up study. The primary efficacy end point was percent reduction over PBO in baseline-adjusted focal seizure frequency/week over the 12-week treatment period. Comparison of BRV with PBO was sequential to control for multiplicity (50, 100, 20 mg/day), and thus required BRV to demonstrate superiority over PBO at 50 mg/day to meet the primary efficacy end point. Secondary efficacy variables were median percent reduction from baseline in focal seizure frequency/week, ≥50% responder rate, and seizure freedom (all seizure types). Safety assessments included treatment-emergent adverse events (TEAEs). KEY FINDINGS: Of 399 randomized patients, 398 were included in the intent-to-treat (ITT) and safety populations. Overall, 367 (92.2%) of 398 patients completed the study (BRV: 93.9%, 88.9%, and 94.0% for 20, 50, and 100 mg/day, respectively; PBO: 92.0%) and 345 (86.7%) of 398 patients continued into long-term follow-up studies (BRV: 87.9%, 82.8%, and 88.0% for 20, 50, and 100 mg/day, respectively; PBO: 88.0%). The study did not meet its primary efficacy end point based on the predefined sequential testing strategy. Indeed, percent reduction over PBO in baseline-adjusted focal seizure frequency/week (primary efficacy analysis) was 6.8% (p = 0.239), 6.5% (p = 0.261), and 11.7% (p = 0.037) for BRV 20, 50, and 100 mg/day, respectively. Median percent reduction from baseline in focal seizure frequency/week was 30.0% (p = 0.019), 26.8% (p = 0.092), and 32.5% (p = 0.004) for BRV 20, 50, and 100 mg/day, respectively, compared with 17.0% for PBO. Responder rates (≥50%) were 27.3% (p = 0.339), 27.3% (p = 0.372), and 36.0% (p = 0.023) for BRV 20, 50, and 100 mg/day, respectively, compared with 20.0% for PBO. Complete seizure freedom was reported by 2/99, 0/99, and 4/100 patients on BRV 20, 50, and 100 mg/day, respectively, compared with 0/100 on PBO. The incidence of TEAEs was higher for BRV 20 (56/99, 56.6%), 50 (62/99, 62.6%), and 100 mg/day (63/100, 63.0%) than PBO (53/100, 53.0%); most TEAEs were mild or moderate in severity. The most frequently reported TEAEs in the BRV groups were headache, somnolence, dizziness, and fatigue. SIGNIFICANCE: In this study of adjunctive BRV (20-100 mg/day) in adults with uncontrolled focal seizures, the primary efficacy analysis based on the 50 mg/day dose was not statistically significant. However, BRV 100 mg/day reduced baseline-adjusted focal seizure frequency/week by 11.7% over PBO, achieving statistical significance (p = 0.037). Secondary efficacy analyses (percent reduction from baseline in focal seizure frequency/week, ≥50% responder rate) provided supportive evidence for the efficacy of BRV 100 mg/day. BRV 20-100 mg/day was well tolerated without up-titration, with a high completion rate.

The effect of chitosan on the concentration of 17ß-estradiol and free triiodothyronine in mice exposed to polychlorinated biphenyls (PCBs).

The aim of this work was to examine (i) how the applied PCB mixture influences the level of 17ß-estradiol (E2) and free triiodothyronine (FT3) in the blood plasma of mice (C57/BL/6J) and (ii) whether supplementation with chitosan would protect against the observed changes in the examined plasma hormone concentrations. In the study we used a mixture of indicator PCBs (CB no. 28, 52, 101, 118, 138, 153, 180) and our results showed their anti-estrogenic effects. Exposure to the mixture resulted in a significant decrease (P < 0.05) in plasma concentration of E2 relative to the control, and chitosan administration did not prevent the decrease. To the contrary, E2 concentration in the blood plasma of the mice which received both the PCB mixture and chitosan was lower compared to those which did not receive chitosan. Exposure to the PCBs also resulted in a decrease in FT3 concentration in the treatedgroup, although it was not as pronounced as for E2 and was prevented with dietary supplementation with chitosan, with the observed FT3 level in the chitosan-treated group similar to the control. In summary, supplementation with chitosan can only to a certain extent minimize the negative effects of exposure to PCBs.

Novel approaches to anticonvulsant drug discovery.

INTRODUCTION: The history of epilepsy dates back to 2000 BC. Yet, it was not until 1912 that the activity of the first antiepileptic, phenobarbital was discovered by accident. After this discovery, the next antiepileptic drugs to be discovered (phenytoin and primidone) were based on the phenobarbital's structure. Then, in 1960, carbamazepine was developed empirically, while in 1962, valproate demonstrated anticonvulsant activity against experimental seizures. The next antiepileptic drugs synthesized were either modifications of the existing drugs (such as oxcarbazepine and pregabalin) or completely novel chemical structures (lacosamide, perampanel and retigabine). AREAS COVERED: The present paper briefly refers to the history of epilepsy and development of antiepileptic drugs. Further, the paper provides a discussion on the antiepileptogenic effects of antiepileptic drugs in terms of the constant percentage of epileptic patients with refractory seizures. The authors also review the likely factors involved in the false refractoriness (such as through the use of caffeine-containing beverages and smoking). Finally, the authors consider future directions in the search of novel antiepileptic drugs. EXPERT OPINION: In spite of the considerable number of newer antiepileptic drugs, the number of drug-resistant epileptic patients remains unchanged. This may be rather an indication of the suitability of the currently available discovery procedures for effective antiepileptic drugs in the whole population of epileptic patients. The authors, however, believe that it is likely that models of mimic chronic epilepsy will help bridge the gaps and aid in the discovery of novel antiepileptic drugs - ones that can effectively modify the course of the disease.

Single centre 20 year survey of antiepileptic drug-induced hypersensitivity reactions.

BACKGROUND: Epilepsy is a chronic neurological disease which affects about 1% of the human population. There are 50 million patients in the world suffering from this disease and 2 million new cases per year are observed. The necessary treatment with antiepileptic drugs (AEDs) increases the risk of adverse reactions. In case of 15% of people receiving AEDs, cutaneous reactions, like maculopapular or erythematous pruritic rash, may appear within four weeks of initiating therapy with AEDs. METHODS: This study involved 300 epileptic patients in the period between September 1989 and September 2009. A cutaneous adverse reaction was defined as a diffuse rash, which had no other obvious reason than a drug effect, and resulted in contacting a physician. RESULTS: Among 300 epileptic patients of Neurological Practice in Kielce (132 males and 168 females), a skin reaction to at least one AED was found in 30 patients. As much as 95% of the reactions occurred during therapies with carbamazepine, phenytoin, lamotrigine or oxcarbazepine. One of the patients developed Stevens-Johnson syndrome. CONCLUSION: Some hypersensitivity problems of epileptic patients were obviously related to antiepileptic treatment. Among AEDs, gabapentin, topiramate, levetiracetam, vigabatrin, and phenobarbital were not associated with skin lesions, although the number of patients in the case of the latter was small.

[Tiagabine--own experience in the refractory epilepsy treatment]. / Tiagabina--doswiadczenia wlasne w leczeniu padaczki lekoopornej.

Tiagabine belongs to a new generation of antiepileptic drugs with a unique mechanism of action. It is well-absorbable from the gastrointestinal tract, has a linear pharmacokinetics, does not affect cognitive function and it interacts poorly with other antiepileptic drugs. Tiagabine is recommended for adults and children past 12 years of age with epilepsy, suffering from partial seizures, with and without secondary generalization. Following the period of a great enthusiasm as to the use of tiagabine, it was put aside, though unfairly, according to the author's own studies as well as the reports in current literature, it still has its place in the treatment of drug-resistant epilepsy.

Clinical utility of adjunctive retigabine in partial onset seizures in adults.

In ~30% of epileptic patients, full seizure control is not possible, which is why the search for novel antiepileptic drugs continues. Retigabine exhibits a mechanism of action that is not shared by the available antiepileptic drugs. This antiepileptic enhances potassium currents via Kv7.2-7.3 channels, which very likely results from destabilization of a closed conformation or stabilization of the open conformation of the channels. Generally, the pharmacokinetics of retigabine are linear and the drug undergoes glucuronidation and acetylation. Results from clinical trials indicate that, in the form of an add-on therapy, retigabine proves an effective drug in refractory epileptic patients. The major adverse effects of the add-on treatment are dizziness, somnolence, and fatigue. This epileptic drug is also considered for other conditions - neuropathic pain, affective disorders, stroke, or even Alzheimer's disease.

Pregnancy detection in putatively unmated mink (Mustela vison) by serum progesterone level.

The aim of this study was to determine whether blood plasma progesterone is a reliable indicator of pregnancy in mink at an early stage of gestation. We also attempted to establish the threshold value of progesterone as a pregnancy indicator. The analysis was carried out at a production farm on 42 standard female mink aged 1 year, which were grouped both according to the observed success of mating ("mated" and "unmated") and the level of blood serum progesterone measured afterwards ("pregnant" and "nonpregnant"). It was next verified whether a particular female had been assigned to the proper group in the first place. An analysis of accuracy of mating success assessment within the group of unmated females revealed that more than one-third of decisions were wrong, since some females that had been considered unmated ultimately whelped. This suggests that mating supervision by farm workers lacks reliability. A progesterone test for verification of such management decisions should limit the risk of err,or. We suggest that progesterone tests could be carried out using the threshold values 1.9 ng/ml and 20 ng/ml in blood sampled on 25 March and 8 April, respectively, although some level of uncertainty should be taken into account.