Study of anticonvulsant properties of 1,2,4-triazole derivatives and prospects for their use in pharmacy

Summary:Behavior and cognition in patients with epilepsy may be affected by multiple factors including seizure etiology, type, frequency, duration, and severity; cerebral lesions acquired before seizure onset; age at seizure onset; intraictal and interictal physiological dysfunction due to the seizures; structural cerebral damage due to repetitive or prolonged seizures; hereditary factors; psychosocial factors; sequelae of epilepsy surgery; and untoward effects of antiepileptic drugs (AEDs). Although the behavioral and cognitive effects of AEDs are less than the total of other factors in epilepsy, AEDs are of special concern because they are the major therapeutic modality for seizures. The risk of AED cognitive side effects is increased with polypharmacy and at higher dosages and higher AED blood levels. In general, the cognitive effects of AEDs are modest when used in monotherapy with AED blood levels within the standard therapeutic ranges. Further, the cognitive effects of AEDs are offset in part by reduced seizures. However, the cognitive effects of AEDs may be clinically significant. The most common AED cognitive effects include psychomotor slowing, reduced vigilance, and impairments in memory. Phenobarbital (PB) and benzodiazepines (BZDs) possess the most marked adverse cognitive effects. Regarding the other major older AEDs, carbamazepine (CBZ), phenytoin (PHT), and valproate (VPA) have cognitive effects that are similar to each other. In contrast, some of the newer AEDs appear to produce fewer adverse cognitive effects. Gabapentin (GBP) and lamotrigine (LTG) have demonstrated fewer cognitive effects than CBZ and minimal effects compared with placebo. Tiagabine (TGB) and vigabatrin (VGB) also have shown few cognitive effects compared with placebo. Of the new AEDs, topiramate (TPM) appears to have the greatest cognitive side effects, but slow titration during drug initiation reduces these effects. Additional studies are needed to delineate fully the relative effects of all the new AEDs to each other and to the older AEDs. The elderly have increased susceptibility to the cognitive effects of AEDs for both pharmacodynamic and pharmacokinetic reasons. However, only a few studies have examined the cognitive effects of AEDs in the elderly. Although incomplete, the available data reflect a pattern of relative effects similar to those seen in younger adults. Children also may have increased susceptibility because the relatively modest effects of AEDs could be additive over the course of neurodevelopment. Again in children, the cognitive effects of CBZ, PHT, and VPA are comparable, whereas the effects of PB are worse. Unfortunately, there are no studies on the cognitive effects of the new AEDs in children. The effects of AEDs on cognition may have even greater consequences for the children of mothers with epilepsy, who are exposed to AEDs in utero. Animal studies have demonstrated that in utero AED exposure can impair behavioral neurodevelopment at dosages below those required to produce somatic malformations and at clinically relevant blood levels. However, the magnitude and differential effects of in utero AED exposure on neurodevelopment in humans remain uncertain. AEDs may produce positive or negative behavioral alterations (e.g., mood stabilization, irritability/agitation, depression, psychosis). CBZ, GBP, LTG, and VPA have demonstrated positive psychotropic effects. Patients with epilepsy are at increased risk for behavioral disorders, and these AEDs may be particularly useful in such patients. The most severe negative behavioral effects of AEDs occur in a small percentage of patients. However, more subtle adverse behavioral effects are much more common. A patient's perception of his or her quality of life is correlated more with neurotoxicity symptoms and mood than with seizure frequency in the absence of seizure freedom. Even subtle behavioral effects can reduce the patient's quality of life. Thus, the behavioral effects of AEDs should be considered in the choice of AED along with other side effects and efficacy for seizure control.

Sexual dysfunction in women with epilepsy

Modern drug therapy of epilepsy is complicated by the inability of drugs to control seizures in some patients and side effects that range in severity from minimal impairment of the central nervous system to death from aplastic anemia or hepatic failure. Medicinal plants used in traditional medicine for the treatment of epilepsy have been scientifically shown to possess promising anticonvulsant activities in animal models for screening for anticonvulsant activity and can be a source of newer anticonvulsants. The aim of this study was to investigate the preliminary phytochemical properties, anticonvulsant and anxiolytic activities of Melanthera scandens aqueous and ethanolic extracts. Phytochemicals from the aqueous and ethanolic extracts were screened by standard methods. Anticonvulsant activity was evaluated against pentylenetetrazol (PTZ)-induced seizure model in rats. The effect of the extract at oral dose levels of 250, 500 and 1000 mg/kg was evaluated in an experimental rat model, using diazepam (5 mg/kg) as positive control. Anxiolytic activity was performed using elevated plus maze method. Phytochemical screening revealed that M. scandens extracts contain carbohydrates, flavonoids, saponins, glycosides, tannins, terpenoids, phenols and phytosterols. The aqueous extract at a dose of 500 mg/kg significantly increased seizure latency (P=0.0023), while the ethanolic extract did not have a significant effect on seizure latency. Both extracts significantly reduced the seizure severity (P= 0.0155), and provided up to 100% protection against PTZ induced death at 1000 mg/kg. Both extracts had no significant effect on the duration of PTZ induced seizures. Both extracts were found to increase the number of entries and the time spent in the open arms of the maze at a dose of 250 mg/kg, indicating anxiolytic activity, which was not seen at higher doses (500 and 1000 mg/kg). The total numbers of entries into the closed arm were significantly reduced at 500 and 1000 mg/kg oral doses of both extracts, indicating a reduction in locomotor activity of the rats. The results obtained in this study suggest that both the aqueous and ethanolic extracts of M. scandens possess anticonvulsant and anxiolytic activities in a rat model.

On the basis of strong evidence, treatment is highly dependent on the seizure semiology results, electroencephalography (EEG) findings, and origin. • On the basis of moderate evidence and consensus, vigorous use of video EEG recordings and home video cameras should be used to delineate the epileptic syndromes. • On the basis of strong evidence, pediatric epilepsy syndromes have common comorbidities. As a consensus, some pediatric epilepsy centers consider referral to a neuropsychologist to be first-line care in these patients. • On the basis of strong evidence and consensus, antiepileptic drug therapy has its own complications and should be discontinued after an appropriate treatment course. • On the basis of moderate evidence and consensus, uncontrolled seizures put patients at risk for significant morbidity and mortality.

Epilepsy is frequently associated with cognitive dysfunction. However, the reasons for this correlation are unclear. Possible influential factors include patient age; duration, frequency, etiology, and type of seizures; hereditary factors; psychosocial issues; and antiepileptic drug (AED) therapy. Whereas many of these factors are beyond the physician's control, AED therapy is one element that can be addressed in treatment decisions by recognizing the potential cognitive effects of particular AEDs. For example, phenobarbital impairs memory and concentration; phenytoin affects attention, problem solving ability, and performance of visuomotor tasks. In contrast, carbamazepine may affect concentration, while valproate would appear to have minimal effects on cognition. Moreover, cognitive effects of AEDs are amplified with coadministration of multiple anticonvulsants (polytherapy). A review of studies on the cognitive effects of monotherapy with AEDs, as opposed to those of polytherapy, provides evidence that drug-related cognitive dysfunction can be reversed if patients are switched to a simpler therapeutic regimen. Future research should be directed toward developing reliable measures for assessing and monitoring cognition, and understanding the particular cognitive side effects of each AED. Physicians also need to revise their opinions about which side effects are "tolerable" for epileptic patients.

To survey the characteristics of epilepsy in patients with juvenile neuronal ceroid lipofuscinosis (JNCL) and determine the antiepileptic drug (AED) treatment most suitable for these patients. The study included 60 patients with JNCL; their mean age was 16.5 years (range 5-33). The age at onset of epilepsy, type of seizures, effect of the first AED on seizures, and the current seizure frequency and AED therapy were studied. The side effects of the AEDs were also clarified. Fifty of the 60 patients had epilepsy. Patients' first epileptic seizure occurred at a mean age of 10.0 years (range 5-16), the most common type being generalized seizures. As the first AED tried, valproate (VPA) and lamotrigine (LTG) appeared equally effective, with 80% of the patients responding to these AEDs. During the study year, the median seizure frequency was four seizures a year (range 0-120), and 72% of the patients had good or satisfactory seizure control (0-6 seizures a year). In the different AED therapy groups, the proportion of patients with good or satisfactory seizure control ranged from 25% to 100%. LTG in monotherapy or in combination with clonazepam (CZP) was superior to other AEDs or combinations, but VPA also seemed effective. Adverse effects leading to the discontinuation of an AED were observed in 25% of the patients, most frequently in patients receiving phenobarbital (PB). No patient receiving LTG had to discontinue the drug due to adverse effects. Epilepsy in JNCL can usually be successfully treated with the current AEDs. In Finnish patients with JNCL, treatment is based on LTG, or, secondarily, VPA. In combination therapy, CZP seems a valuable add-on AED.

A variety of observations suggest that decreasing glycolysis and increasing levels of reduced glutathione, generated by metabolism of glucose through the pentose phosphate pathway, would have an anticonvulsant effect. Because fructose-1,6-bisphosphate (F1,6BP) shifts the metabolism of glucose from glycolysis to the pentose phosphate pathway, it was hypothesized to have anticonvulsant activity. The anticonvulsant activity of F1,6BP was determined in rat models of acute seizures induced by pilocarpine, kainic acid, or pentylenetetrazole. The efficacy of F1,6BP was compared with that of 2-deoxyglucose (2-DG; an inhibitor of glucose uptake and glycolysis), valproic acid (VPA), and the ketogenic diet. One hour before each convulsant, Sprague Dawley rats received either saline (as seizure controls), F1,6BP (0.25, 0.5 or 1 g/kg), 2-DG (0.25 or 0.5 g/kg), or VPA (0.3 g/kg). Additional animals received the ketogenic diet (starting at 20 or 60 d old). Time to seizure onset, seizure duration, and seizure score were measured in each group. F1,6BP had dose-dependent anticonvulsant activity in all three models, whereas VPA had partial efficacy. 2-DG was only effective in the pilocarpine model. The ketogenic diet had no effect in these models. F1,6BP was also partially effective when given at the first behavioral seizure after pilocarpine. Administration of sodium lactate, which bypasses the block in the glycolytic pathway, abolished the anticonvulsant activity of 2-DG in the pilocarpine model, but only decreased the efficacy of F1,6BP. These data demonstrate that F1,6BP has significant anticonvulsant efficacy.

Seventeen 7-alkyl-7H-tetrazolo[1,5-g]purine derivatives were synthesized, and their anticonvulsant and antidepressant activities were evaluated in a mouse model. The anticonvulsant effect and neurotoxicity of the compounds were evaluated with a maximal electroshock test and a rotated test in mice, respectively. Most of the compounds had anticonvulsant activity; among the compounds studied, 7-(3-chlorobenzyl)-7H-tetrazolo[1,5-g]purine (3h) was found to be the most potent compound with a median effective dose (ED50) value of 28.9 mg/kg and a protective index value of 15.8, possessing better anticonvulsant activity and higher safety than the marketed drug carbamazepine. To explain the possible mechanism of anticonvulsant activity, compound 3h was tested in pentylenetetrazole-induced seizures tests, and the results suggest that compound 3h exerts anticonvulsant activity through a GABA-mediated mechanism. Forced swimming test showed that at a dose of 40 mg/kg, five compounds have significant antidepressant activity, the most active compound was 7-(2-chlorobenzyl)-7H-tetrazolo[1,5-g]purine (3g), which decreased immobility time by 56 %.

Context: Currently available antiepileptic drugs have debilitating adverse effects. Natural products and plants already used in traditional medicine can be a good place to start in the search for safer and more effective options. Aims: To investigate the anticonvulsant potential of Achillea nobilis and Momordica charantia extracts in maximal electroshock (MES), as well as pentylenetetrazole (PTZ)- and strychnine nitrate (STN)- induced seizure models in rats. Methods: For each model, eight groups of 21-day-old male Albino rats were used. The 1st group was kept as control, 2nd as standard (diazepam, 7.5 mg/kg); 3rd - 5th treated with A. nobilis (100, 200 and 300 mg/kg); and 6th - 8th administered M. charantia (100, 200 and 300 mg/kg). After 30 min, rats were exposed to a shock of 150 mA by a convulsiometer, via ear electrodes for 2 s (in MES test) or sc injection of PTZ (85 mg/kg) or STN (2.5 mg/kg). Results: A. nobilis and M. charantia extracts (200 and 300 mg/kg) demonstrated dose-dependent anticonvulsant effect against MES-induced seizures. In the PTZ induced convulsion, A. nobilis and M. charantia (200 and 300 mg/kg) significantly slowed the commencement of convulsions and minimized the duration of seizures. A. nobilis (300 mg/kg) showed 60% protection in rats against STN induced seizures. In contrast, A. nobilis (100 and 200 mg/kg) and M. charantia (100, 200 and 300 mg/kg) showed no significant protection against STN-induced seizures in rats. Conclusions: The results of the present study suggest that both extracts exhibited marked anticonvulsant activities.

To investigate the tolerability and efficacy of carbamazepine treatment in patients with partial-onset seizures and the association with polymorphisms in the sodium channel α-subunit type 1 (SCN1A), and gamma-aminobutyric acid (GABA) receptor genes among the Chinese Han population. 448 patients were genotyped for single nucleotide polymorphisms selected of the SCN1A and GABA-receptor genes. Monotherapy with carbamazepine (CBZ) was administered to the patients. The effectiveness of CBZ treatment was evaluated with regard to efficacy by the decrease in seizures and tolerability by retention rates. SCN1A rs3812718 A/G with CBZ tolerability (P= 0.038) throughout 24 months of clinical follow-up and the GABRA1 rs2290732 A/G were significantly associated with CBZ tolerability (P= 0.001). The maintenance dose and serum level of CBZ in AA genotype carriers of rs3812718 A/G were significantly higher than those of GG genotype carriers between 3 and 12 months of follow-up. The proportion of AA genotype carriers of rs2298771 A/G with seizure free was significantly higher than that of AG+GG genotype carriers from 3 months to 15 months of follow-up (P < 0.05). rs3812718 A/G and rs2290732 A/G polymorphisms affected the tolerability of CBZ. rs2298771 A/G was associated with efficacy of CBZ treatment.

The search for new antiepileptic drugs that would have greater margins of safety and fewer adverse effects is relevant. Thiazolidinone are a promising class for the development of new anticonvulsants. Aim. To conduct a screening study of new thiazolidinone derivatives for anticonvulsant activity on a seizure model induced by pentylenetetrazole and maximal electroshock; to analyze the structure – activity relationship; to reveal a lead-compound and investigate its dose-dependent manner. Materials and methods. Basic screening seizure models of pentylenetetrazol and maximal electroshock test were used in mice. The test original 9 thiazolidinone derivatives (100 mg/kg) and the reference drugs of sodium valproate (300 mg/kg), carbamazepine (40 mg/kg) were administered intragastrically 30 minutes before subcutaneous administration of pentylenetetrazol (90 mg/kg) or induction with maximal electroshock by giving a current with strength of 50 mA and frequency of 50 Hz for 0.2 s. In order to study the dose-dependent manner, the lead-compound was administered intragastrically in doses ranging from 25 mg/kg to 150 mg/kg. Results. A total of 9 compounds were studied, of which 3 did not affect experimental convulsions, 2 showed proconvulsive activity, and 4 had an anticonvulsant effect. The lead-compound 5-[( Z )-(4-nitrobenzylidene)]-2-(thiazol-2-ylimino)-4-thiazolidinone was determined under laboratory code Les-6222, which exhibited the highest anticonvulsant properties. The “structure–anticonvulsant activity” relationship in a series of thiazolidinone derivatives was analyzed. The dose-dependent manner of 5-[( Z )-(4-nitrobenzylidene)]-2-(thiazol-2-ylimino)-4-thiazolidinone anticonvulsant effect was studied using 2 seizure models, and the most effective dose of 100 mg / kg was identified. Conclusions. 5-[( Z )-(4-nitrobenzylidene)]-2-(thiazol-2-ylamino)-4-thiazolidinone is a promising compound for in-depth studies on anticonvulsant and related pharmacological activities in order to develop new original anticonvulsants.

Increase in antiepileptic efficacy during prolonged treatment with valproic acid: Role of inhibition of histone deacetylases?

What should we ask patients with epilepsy on telemedicine during the COVID-19 crisis? A checklist for clinicians

Review on phytotherapy in epilepsy

To evaluate the effects of adjunctive pregabalin 300 mg/day versus placebo on polysomnographic (PSG) variables in patients with well controlled partial seizures and subjectively reported sleep disturbance. An exploratory, 4-week, double-blind, randomized study in patients with well controlled partial seizures on AED monotherapy and subjective sleep disturbance over the previous 6 months. Mean changes from baseline to endpoint in PSG and subjective sleep variables (MOS Sleep Scale, Groningen Sleep Questionnaire) in patients on adjunctive pregabalin 300 mg/day (n=8) were compared with patients on placebo (n=7). Baseline PSGs showed sleep fragmentation. Mean sleep efficiency improved significantly in both treatment groups in the mean baseline to endpoint change; there was no significant between-group difference. Pregabalin treatment was associated with a significant reduction in number of awakenings (p = 0.02), and improvement in wake time after sleep onset approached significance (p = 0.055), suggesting improvement in sleep continuity that was not observed in the placebo group. Pregabalin was also associated with significant improvements in the MOS sleep disturbance and sleep quantity subscales compared with placebo (p < or =0.03). There were no changes in self-reported seizure control. This exploratory pilot study suggests that pregabalin may improve sleep continuity in patients with clinically relevant sleep disturbance. The effect on disturbed sleep appears independent of seizure control. The effects of pregabalin on disturbed sleep and seizures and their interrelationships warrant further study.