The Search for New Anticonvulsants in a Group of (2,5-Dioxopyrrolidin-1-yl)(phenyl)Acetamides with Hybrid Structure-Synthesis and In Vivo/In Vitro Studies.

Epilepsy belongs to the most common and debilitating neurological disorders with multifactorial pathophysiology and a high level of drug resistance. Therefore, with the aim of searching for new, more effective, and/or safer therapeutics, we discovered a focused series of original hybrid pyrrolidine-2,5-dione derivatives with potent anticonvulsant properties. We applied an optimized coupling reaction yielding several hybrid compounds that showed broad-spectrum activity in widely accepted animal seizure models, namely, the maximal electroshock (MES) test and the psychomotor 6 Hz (32 mA) seizure model in mice. The most potent anticonvulsant activity and favorable safety profile was demonstrated for compound 30 (median effective dose (ED50) MES = 45.6 mg/kg, ED50 6 Hz (32 mA) = 39.5 mg/kg, median toxic dose (TD50) (rotarod test) = 162.4 mg/kg). Anticonvulsant drugs often show activity in pain models, and compound 30 was also proven effective in the formalin test of tonic pain, the capsaicin-induced pain model, and the oxaliplatin (OXPT)-induced neuropathic pain model in mice. Our studies showed that the most plausible mechanism of action of 30 involves inhibition of calcium currents mediated by Cav1.2 (L-type) channels. Importantly, 30 revealed high metabolic stability on human liver microsomes, negligible hepatotoxicity, and relatively weak inhibition of CYP3A4, CYP2D6, and CYP2C9 isoforms of cytochrome P450, compared to reference compounds. The promising in vivo activity profile and drug-like properties of compound 30 make it an interesting candidate for further preclinical development.

Tetramethylpyrazine Reduces Epileptogenesis Progression in Electrical Kindling Models by Modulating Hippocampal Excitatory Neurotransmission.

Antiepileptic drugs (AEDs) are the primary agents prescribed for clinical management of limbic epilepsy. However, high incidence of pharmacoresistance and a limited armory of drugs for inhibiting the pathological progression of epilepsy pose major obstacles to managing epilepsy. Here, we investigated the effect of tetramethylpyrazine (TMP), the main bioactive alkaloid isolated from the oriental medicine Ligusticum chuanxiong Hort., against the epileptogenesis progression of acute hippocampal and corneal (6 Hz) electrical kindling models of TLE. TMP dose-dependently limited the progression of seizures and reduced the after-discharge duration (ADDs) in a hippocampal mouse kindling model. Mice treated with TMP (20, 50 mg/kg, i.p.) remained in stage 1 of epileptic progression for a protracted period, requiring additional stimulation to induce stages 2-5 epileptic phenotypes. TMP (50 mg/kg) also inhibited 6 Hz corneal kindling progression. In contrast, TMP did not reverse the phenotypes induced in a generalized seizures (GS) model, or the maximal electroshock (MES) or pentylenetetrazole (PTZ)-induced models of epilepsy. Furthermore, patch clamp recordings revealed no effect of TMP (10 µM) on CA1 hippocampal neurons' intrinsic properties but suppressed the (i) frequency of spontaneous excitatory post synaptic currents (sEPSCs), (ii) paired pulse ratio (PPR), and (iii) long-term potentiation (LTP) induction in the Schaffer collateral-CA1 pathway. TMP suppressed the activity of calcium, but not sodium, channels. Taken together, these results suggest that TMP has an antiepileptogenic effect, likely through suppression of excitatory synaptic transmission by its effects on inhibition of calcium channels; these traits distinguish TMP from currently available AEDs. As mice administered TMP did not show any neurologic impairment in the object recognition and open field tests, the data support further development of TMP as a promising treatment for epilepsy.

Effects of arachidonyl-2'-chloroethylamide (ACEA) on the protective action of various antiepileptic drugs in the 6-Hz corneal stimulation model in mice.

Accumulating evidence indicates that cannabinoid CB1 receptor ligands play a pivotal role in seizures, not only in preclinical studies on animals, but also in clinical settings. This study was aimed at characterizing the influence of arachidonyl-2'-chloroethylamide (ACEA-a selective cannabinoid CB1 receptor agonist) co-administered with phenylmethylsulfonyl fluoride (PMSF) on the anticonvulsant potency of various antiepileptic drugs (clobazam, lacosamide, levetiracetam, phenobarbital, tiagabine and valproate) in the 6-Hz corneal stimulation model. Psychomotor seizures in male albino Swiss mice were evoked by a current (32 mA, 6 Hz, 3 s stimulus duration) delivered via corneal electrodes. Potential adverse effects produced by the antiepileptic drugs in combination with ACEA+PMSF were assessed using the chimney test (motor performance), passive avoidance task (remembering and acquisition of learning), and grip-strength test (muscular strength). Brain concentrations of antiepileptic drugs were measured by HPLC to exclude any pharmacokinetic contribution to the observed effect. ACEA (5 mg/kg, i.p.) + PMSF (30 mg/kg, i.p.) significantly potentiated the anticonvulsant potency of levetiracetam (P<0.05), but not that of clobazam, lacosamide, phenobarbital, tiagabine or valproate in the 6-Hz corneal stimulation model. Moreover, ACEA+PMSF did not significantly affect total brain concentrations of levetiracetam in mice. No behavioral side effects were observed in animals receiving combinations of the studied antiepileptic drugs with ACEA+PMSF. In conclusion, the combined administration of ACEA+PMSF with levetiracetam is associated with beneficial anticonvulsant pharmacodynamic interaction in the 6-Hz corneal stimulation model. The selective activation of cannabinoid CB1 receptor-mediated neurotransmission in the brain may enhance levetiracetam-related suppression of seizures in epilepsy patients, contributing to the efficacious treatment of epilepsy in future.

Estudio observacional multicéntrico retrospectivo sobre el manejo clínico y terapéutico de los diferentes tipos de estatus epiléptico en la práctica clínica / Retrospective multicentre observational study on clinical management and treatment of different types of status epilepticus in clinical practice

Introducción: El estatus epiléptico es una urgencia neurológica asociada a una mortalidad y morbilidad significativa. Analizamos las características en nuestra población. Métodos: Se recogieron los datos de manera retrospectiva de la historia clínica electrónica de adultos con diagnóstico de estatus epiléptico en 5 centros hospitalarios durante 4 años. Resultados: Se obtuvieron datos de un total de 84 episodios en 77 pacientes, con edad media de 60,3 años. El 52,4% tenían historia previa de epilepsia. Clasificación según el tipo de estatus: 47,6% tónico-clónico; 21,4% parcial complejo; 17,9% parcial motor; 6% parcial simple; 3,6% mioclónico y 3,6% sutil. Si analizamos el momento que finalizó el estatus según las fases definidas para este estudio obtenemos: 13,1% precoz (hasta 30 min); 20,2% establecido (entre 30-120 min); 41,7% refractario (más de 120 min) y 13,1% superrefractario (continúan o recurren después de más de 24 h de anestesia). Diez casos (11,9%) fallecieron sin haberse controlado el estatus. El porcentaje acumulativo de éxito alcanzado con el primer tratamiento fue de 8,3%; segundo 27,3%; tercero 48,7%; cuarto 58,2%; quinto 70,1%; sexto 80,8%; séptimo 83,2% y octavo 84,4%. Conclusiones: En nuestro estudio encontramos que el estatus no se controló en las primeras 2 h en casi la mitad de los casos, y un 11,9% fallecieron sin controlarse, sin haber diferencias significativas entre el tipo de estatus. En casi la mitad se logró el control del estatus con el tercer tratamiento, pero en algún caso se precisó hasta 8. Son necesarios registros amplios que permitan analizar el manejo en los distintos tipos y fases (AU)

Introduction: Status epilepticus (SE) is a neurological emergency associated with significant mortality and morbidity. We analyse characteristics of this entity in our population. Methods: Data from electronic medical records of adults diagnosed with SE were collected retrospectively from 5 hospitals over 4 years. Results: Data reflected 84 episodes of SE in 77 patients with a mean age of 60.3 years. Of this sample, 52.4% had a previous history of epilepsy. Status classification: 47.6% tonic-clonic, 21.4% complex partial, 17.9% partial motor, 6% partial simple, 3.6% myoclonic, and 3.6% subtle SE. Based on the duration of the episode, SE was defined in this study as early stage (up to 30 min) in 13.1%, established (30-120 min) in 20.2%, refractory (more than 120 min) in 41.7%, and super-refractory (episodes continuing or recurring after more than 24h of anaesthesia) in 13.1%. Ten patients (11.9%) died when treatment failed to control SE. The cumulative percentage of success achieved was 8.3% with the first treatment, 27.3% for the second, 48.7% for the third, 58.2% for the fourth, 70.1% for the fifth, 80.8% for the sixth, 83.2% for the seventh, and 84.4% for the eighth. Conclusions: In our study, we found that SE did not respond to treatment within 2h in approximately half the cases and 11.9% of the patients died without achieving seizure control, regardless of the type of status. Half the patients responded by the third treatment but some patients needed as many as 8 treatments to resolve seizures. Using large registers permitting analysis of the different types and stages of SE is warranted (AU)

Recurrent venous thrombosis under rivaroxaban and carbamazepine for symptomatic epilepsy.

BACKGROUND: The direct oral anticoagulant (DOAC) rivaroxaban, an oral Factor Xa inhibitor, is increasingly used as an alternative to vitamin-K-antagonists (VKAs). Absorption and elimination of DOACs are dependent on the permeability glycoprotein (P-gp) efflux transporter protein system, and DOACs are substrates of the hepatic cytochrome P 450 3A4 (CYP3A4) enzymes. Therefore, drug-interactions may occur when DOACs are administered with drugs affecting the activity of P-gp or CYP3A4 systems. Several antiepileptic drugs like carbamazepine are known to affect P-gp and CYP3A4-activity. CASE REPORT: A 55-year-old male was admitted because of pain and swelling of his right leg spontaneously since 2 days. He was under a therapy with 20mg rivaroxaban since 4 months because of an unprovoked venous thrombosis of his right leg. He had a history of poliomyelitis at age 6 months, structural epilepsy due to poly-microgyria with complex partial seizures with secondary generalization since age 6 years, why he was treated with carbamazepine (900mg/d). He reported to be highly adherent to his anticoagulant and antiepileptic medication. Anti-Xa activity was <20ng/ml according to a rivaroxaban calibrated anti-factor Xa assay. Therapy with rivaroxaban was stopped, and low-molecular-weight heparin, followed by phenprocoumon, was started. CONCLUSION: The combination of DOACs with carbamazepine, an inducer of P-gp and CYP3A4-activity, should be avoided since the anticoagulant effect is decreased. There is an urgent need to increase our knowledge and physicians' awareness about the potential of drug-drug interactions of DOACs.

Efficacy of mGlu2 -positive allosteric modulators alone and in combination with levetiracetam in the mouse 6 Hz model of psychomotor seizures.

OBJECTIVE: The metabotropic glutamate receptor subtype 2 (mGlu2 ) possesses both orthosteric and allosteric modulatory sites, are expressed in the frontal cortex and limbic structures, and can affect excitatory synaptic transmission. Therefore, mGlu2 is a potential therapeutic target in the treatment of epilepsy. The present study seeks to evaluate the anticonvulsant potential of mGlu2 -acting compounds. METHODS: The anticonvulsant efficacy of two selective mGlu2 -positive allosteric modulators (PAMs) (JNJ-42153605 and JNJ-40411813/ADX71149) and one mGlu2/3 receptor agonist (LY404039) were evaluated alone and in combination with the antiseizure drug levetiracetam (LEV) in the mouse 6 Hz model. RESULTS: In the 6 Hz (32 mA stimulus intensity) model, median effective dose (ED50 ) values were determined for JNJ-42153605 (3.8 mg/kg), JNJ-40411813 (12.2 mg/kg), and LY404039 (10.9 mg/kg). At the 44 mA stimulus intensity, ED50 values were determined for JNJ-42153605 (5.9 mg/kg), JNJ-40411813 (21.0 mg/kg), LY404039 (14.1 mg/kg), and LEV (345 mg/kg). In addition, subprotective doses of each mGlu2 -acting compound, administered in combination with various doses of LEV, were able to shift the 6 Hz 44 mA ED50 for LEV by >25-fold. When JNJ-42153605 was administered at varying doses in combination with a single dose of LEV (10 mg/kg), the potency of JNJ-42153605 was increased 3.7-fold. Similarly, when a moderately effective dose of LEV (350 mg/kg) was administered in combination with varying doses of JNJ-40411813, the potency of JNJ-40411813 was increased approximately 14-fold. Plasma levels of JNJ-40411813 and LEV were not different when administered alone or in combination, suggesting that increases in potency are not due to pharmacokinetic effects. SIGNIFICANCE: These studies suggest a potential positive pharmacodynamic effect of mGlu2 -acting compounds in combination with LEV. If this effect is translated in a clinical setting, it can support a rational polypharmacy concept in treatment of epilepsy patients.

Treatment of posttraumatic epilepsy with new generation antiepileptic drugs (AEDs) - our experience.

Aim To investigate influence of therapy with new generation antiepileptic drugs (AEDs) in fastening of posttraumatic epilepsy (PTE) remission comparing to therapy with standard AEDs, as well as the time to remission in the presence of psychiatric comorbidities. Methods The study was conducted during the 1988-2008 period and included 113 patients (47 females and 67 males) with PTE and 113 patients (93 females and 20 males) suffering from complex partial seizures (CPS) of temporal lobe origin. In both patient groups, epileptic seizure phenotype, brain magnetic resonance imaging (1.5 T and 3.0 T) and electroencephalogram were analyzed within 24 hours of epileptic seizure and after 5 years of treatment. Psychological testing was administered prior to therapy initiation. Results The patients treated with standard AEDs achieved remission in 82 (73%) cases as compared with 87 (77%) patients administered with a new generation AEDs; in the latter group, remission was achieved faster (1.85 vs. 1.6 months). In both patient groups, psychiatric comorbidity prolonged time to remission by 3.4 months. Conclusion Therapy with new generation AEDs enables achieving faster and complete remission in PTE patients.

Retinal structure and function in vigabatrin-treated adult patients with refractory complex partial seizures.

OBJECTIVE: Evaluate visual-field and retinal-structure changes following adjunctive vigabatrin treatment in vigabatrin-naive adults with refractory complex partial seizures (rCPS). METHODS: Prospective, longitudinal, single-arm, open-label study (NCT01278173). Eligible patients (≥2 seizures/month who failed ≥3 therapies) who could reliably perform perimetry (Humphrey automated static) and retinal-structure assessment (spectral-domain optical coherence tomography) prior to vigabatrin exposure. Following vigabatrin initiation, testing occurred within 1 month (reference) and 3, 6, 9, and 12 months. End points included mean change from reference in mean deviation (dB) and average retinal nerve fiber layer (RNFL) thickness, visual-acuity changes from baseline, and number of patients who met predefined vision-parameter changes at two (confirmed) or three (persistent) consecutive visits. RESULTS: Sixty-five of 91 screened patients received ≥1 vigabatrin dose (all-patients-treated set [APTS]); 55 had valid reference and ≥1 post-reference assessments (full-analysis set [FAS]). Thirty-six APTS patients with valid pre-/post-reference values completed all planned visits (per-protocol set [PPS]). Thirty-eight (59%) APTS patients completed the study; 27 (42%) withdrew (none for visual-field changes); 32% and 15% had abnormally thin RNFL and abnormal visual acuity at baseline, respectively; 20% had abnormal central 30 degree visual fields in the reference period. No significant mean near visual-field changes were observed (PPS); mean change in average RNFL thickness increased significantly (1-year data: Left-eye: 6.37 µm, confidence interval (CI) 4.66-8.09; right-eye: 7.24 µm CI 5.47-9.01; PPS). No confirmed three-line decreases in visual acuity (FAS) were observed; five patients had predefined confirmed/persistent visual-field changes (FAS). All vision-related adverse events were nonserious; the most common was vision blurred (9%). SIGNIFICANCE: Prior to vigabatrin initiation, rCPS patients may already exhibit vision deficits. Up to 1 year of adjunctive vigabatrin treatment did not significantly change population near visual fields. Five patients met predefined visual-field-change criteria. RNFL thickening of unknown clinical significance was observed. Limitations include single-arm, open-label design; patients' inability to perform ophthalmic/visual-field examinations; and limited vigabatrin-exposure duration.

A case of complex partial seizure with reversible MRI abnormalities in the elderly.

A 79-year-old woman was admitted to our hospital because of prolonged impaired consciousness and right hemiparesis. She was treated for acute cerebral infarction because her brain magnetic resonance imaging showed extensive cortical lesions similar to acute infarction in diffusion weighted image, fluid attenuated inversion recovery, and T2 weighted images. On the fifth day, she had a focal seizure on the right side. A new lesion during imaging and electroencephalogram abnormality were observed at that time. After the antiepileptic drug treatment was started, her right hemiparesis considered as ictal paresis, confusion, and the magnetic resonance imaging findings gradually improved. There was also an old, irreversible lesion in the left hippocampus, which was considered as the focus of her complex partial seizure. In the elderly, the post-ictal period of confusion, which occurs with complex partial seizure, may be prolonged. In our case, improvement of hemiparesis and confusion occurred after about 2 weeks.

Which children receive vigabatrin? Characteristics of pediatric patients enrolled in the mandatory FDA registry.

Vigabatrin (Sabril®) is an antiepileptic drug (AED) currently indicated in the US as a monotherapy for patients 1month to 2years of age with infantile spasms (IS) and as adjunctive therapy for patients ≥10years of age with refractory complex partial seizures (rCPS) whose seizures have inadequately responded to several alternative treatments and for whom the potential benefits outweigh the risk of vision loss. The approval required an FDA mandated registry. This article describes 5years of demographic and treatment exposure data from US pediatric patients (<17years). Participation is mandatory for all US Sabril® prescribers and patients. A benefit-risk assessment must be documented for patient progression to maintenance therapy. This includes demographic diagnosis and reports of ophthalmologic assessments (where available). Patient data were grouped by age as proxies for indication (IS: <3years, rCPS: ≥3 to <17years). As of August 26, 2014, 5546/6823 enrolled patients were pediatric/total; 4472 (81%) were vigabatrin-naïve. Seventy-one percent of patients were <3years of age; 29% were ≥3 to <17years of age. Etiologies of IS were identified as cryptogenic (21%), symptomatic tuberous sclerosis (17%), and symptomatic other (42%). The majority of patients with IS (56%) attempted no prior treatments; 16% received adrenocorticotropic hormone prior to vigabatrin. A third of patients with IS were receiving 1 concomitant treatment with vigabatrin. For patients with rCPS, 39% attempted 1-3 prior treatments; 27% were receiving 2 concomitant treatments at enrollment. A total of 1852 (41%) patients did not undergo baseline ophthalmological assessment; 25% of patients with IS and 42% of patients with rCPS were exempted for neurologic disabilities. Kaplan-Meier estimates predict that 71% and 65% of vigabatrin-naïve patients with IS and rCPS, respectively, would remain in the registry at 6months. Most pediatric vigabatrin patients have IS as an underlying diagnosis, especially those <3years of age. A proportion of those with rCPS remain on long-term vigabatrin despite the risk of adverse events.

Population pharmacokinetics of valproic acid in adult Chinese epileptic patients and its application in an individualized dosage regimen.

BACKGROUND: There are several reports describing population pharmacokinetic (PPK) models of valproic acid (VPA). However, little was known in Chinese adult patients with epilepsy. The present study aimed to establish a PPK model for VPA in Chinese adult epileptic patients and to demonstrate its use for dose individualization. METHODS: Data were obtained from a prospective study of 199 adult epileptic patients at 5 hospitals. The trough concentrations at steady state were measured by fluorescence polarization immunoassay. Data were analyzed using the Nonlinear Mixed Effects Model software. The serum trough concentrations at steady state were also measured using samples (n = 20) collected prospectively from a different hospital from those providing the data for deriving the original model. These independent samples served as an evaluation group. RESULTS: The important determinants of apparent VPA clearance were daily dose, body weight, and combination with carbamazepine, phenytoin, or phenobarbital. The final model predicted the individualized doses accurately. A total of 85% of the trough concentrations in the evaluation group were accurately predicted by the final model, whereas the prediction errors of the other patients were all < ± 31%. CONCLUSIONS: A PPK model was developed to estimate the individual clearance for patients taking VPA and could be applied for individualizing doses in the target population.

Vigabatrin pediatric dosing information for refractory complex partial seizures: results from a population dose-response analysis.

We predicted vigabatrin dosages for adjunctive therapy for pediatric patients with refractory complex partial seizures (rCPS) that would produce efficacy comparable to that observed for approved adult dosages. A dose-response model related seizure-count data to vigabatrin dosage to identify dosages for pediatric rCPS patients. Seizure-count data were obtained from three pediatric and two adult rCPS clinical trials. Dosages were predicted for oral solution and tablet formulations. Predicted oral solution dosages to achieve efficacy comparable to that of a 1 g/day adult dosage were 350 and 450 mg/day for patients with body weight ranges 10-15 and >15-20 kg, respectively. Predicted oral solution dosages for efficacy comparable to a 3 g/day adult dosage were 1,050 and 1,300 mg/day for weight ranges 10-15 and >15-20 kg, respectively. Predicted tablet dosage for efficacy comparable to a 1 g/day adult dosage was 500 mg/day for weight ranges 25-60 kg. Predicted tablet dosage for efficacy comparable to a 3 g/day adult dosage was 2,000 mg for weight ranges 25-60 kg. Vigabatrin dosages were identified for pediatric rCPS patients with body weights ≥10 kg.

Age-dependent suppression of hippocampal epileptic afterdischarges by metabotropic glutamate receptor 5 antagonist MTEP.

Action of an antagonist of metabotropic glutamate receptors subtype 5 MTEP was studied in a model of complex partial seizures. Dorsal hippocampus of rat pups 12, 18 and 25 days old was stimulated six times with 10-min intervals. MTEP (20 or 40 mg/kg) was injected after the first afterdischarge and duration of afterdischarges was measured. MTEP exhibited marked anticonvulsant action in 12-day-old-rats, the similar effect in 18-day-old rats was observed only with the second stimulation. No anticonvulsant action was seen in 25-day-old animals. Our results may qualify antagonists of mGluR5 as potential antiepileptic drugs for some types of childhood epilepsies.

Effects of WIN 55,212-2 (a non-selective cannabinoid CB1 and CB 2 receptor agonist) on the protective action of various classical antiepileptic drugs in the mouse 6 Hz psychomotor seizure model.

The aim of this study was to characterize the influence of WIN 55,212-2 (WIN--a non-selective cannabinoid CB1 and CB2 receptor agonist) on the anticonvulsant effects of various classical antiepileptic drugs (clobazam, clonazepam, phenobarbital and valproate) in the mouse 6 Hz-induced psychomotor seizure model. Limbic (psychomotor) seizure activity was evoked in albino Swiss mice by a current (32 mA, 6 Hz, 3 s stimulus duration) delivered via ocular electrodes. Drug-related adverse effects were ascertained by use of the chimney test (evaluating motor performance), step-through passive avoidance task (assessing learning) and grip-strength test (evaluating skeletal muscular strength). Total brain concentrations of antiepileptic drugs were measured by fluorescence polarization immunoassay to ascertain any pharmacokinetic contribution to the observed antiseizure effect. Results indicate that WIN (5 mg/kg, administered intraperitoneally) significantly enhanced the anticonvulsant action of clonazepam (P < 0.001), phenobarbital (P < 0.05) and valproate (P < 0.05), but not that of clobazam in the mouse 6 Hz model. Moreover, WIN (2.5 mg/kg) significantly potentiated the anticonvulsant action of clonazepam (P < 0.01), but not that of clobazam, phenobarbital or valproate in the 6 Hz test in mice. None of the investigated combinations of WIN with antiepileptic drugs was associated with any concurrent adverse effects with regard to motor performance, learning or muscular strength. Pharmacokinetic experiments revealed that WIN had no impact on total brain concentrations of antiepileptic drugs in mice. These preclinical data would suggest that WIN in combination with clonazepam, phenobarbital and valproate is associated with beneficial anticonvulsant pharmacodynamic interactions in the mouse 6 Hz-induced psychomotor seizure test.

Psychosis induced by zonisamide: a case report and review of the literature.

Zonisamide is an anti-seizure medication that is indicated for adjunctive therapy in the treatment of partial seizures. This medication is rarely used in the United States. An infrequent adverse effect of psychosis occurs in about 2% of patients taking zonisamide. This is a case report of a 34-year-old male on phenytoin who presented with psychosis symptoms approximately 10 months after starting adjunctive zonisamide.

Reproducibility of EEG-fMRI results in a patient with fixation-off sensitivity.

Blood oxygenation level-dependent (BOLD) activation associated with interictal epileptiform discharges in a patient with fixation-off sensitivity (FOS) was studied using a combined electroencephalography-functional magnetic resonance imaging (EEG-fMRI) technique. An automatic approach for combined EEG-fMRI analysis and a subject-specific hemodynamic response function was used to improve general linear model analysis of the fMRI data. The EEG showed the typical features of FOS, with continuous epileptiform discharges during elimination of central vision by eye opening and closing and fixation; modification of this pattern was clearly visible and recognizable. During all 3 recording sessions EEG-fMRI activations indicated a BOLD signal decrease related to epileptiform activity in the parietal areas. This study can further our understanding of this EEG phenomenon and can provide some insight into the reliability of the EEG-fMRI technique in localizing the irritative zone.

Psychomotor seizure test, neurotoxicity and in vitro neuroprotection assay of some semicarbazone analogues.

In continuance of our search for anticonvulsant agents, we reported herein the synthesis, characterization and anticonvulsant evaluation of some newer semicarbazone analogues. A few compounds were also screened for neuroprotection assay. Some of the compounds showed significant anticonvulsant activity. Compound 4a showed 25% (1/4, 0.25 h), 75% (3/4, 0.5 & 2.0 h) and 100% (4/4, 1.0 h) protection against 6 Hz psychomotor seizure test at 100 mg/kg devoid of any neurotoxicity. Compound 4d showed neuroprotection activity with 26.3 ± 2.3 percent of total propidium iodide uptake at 100 µM and IC50 of the compound was calculated using dose response curve by probit analysis and was found to be 149 ± 1.22 µM.