Meir Bialer's research while affiliated with Hebrew University of Jerusalem and other places

Publications (290)

Article
Background: CYP2C9 is a member of the cytochrome P450 (CYP) superfamily responsible for the metabolism of 16% of drugs that undergo oxidative metabolism. The activity of CYP2C9 exhibits marked inter-individual variability, which translates into prominent differences in the pharmacokinetics of CYP2C9 substrates, some of which are characterized by a...
Article
Lorcaserin, a selective serotonin 5-HT2C receptor agonist, was developed as an appetite suppressant with the rationale of minimizing the risk of cardiovascular toxicity associated with non-selective serotoninergic agents such as fenfluramine. Eight years after FDA approval, however, it was withdrawn from the market, when a large safety study sugges...
Article
In 2020, racemic-fenfluramine was approved in the U.S. and Europe for the treatment of seizures associated with Dravet syndrome, through a restricted/controlled access program aimed at minimizing safety risks. Fenfluramine had been used extensively in the past as an appetite suppressant, but it was withdrawn from the market in 1997 when it was foun...
Article
Full-text available
We recently reported a new class of carbamate derivatives as anticonvulsants. Among these, 3-methylpentyl(4-sulfamoylphenyl)carbamate (MSPC) stood out as the most potent compound with ED50 values of 13 mg/kg (i.p.) and 28 mg/kg (p.o.) in the rat maximal electroshock test (MES). 3-Methylpropyl(4-sulfamoylphenyl)carbamate (MBPC), reported and charact...
Article
The safety of switching between generic products of antiseizure medications (ASMs) continues to be a hot topic in epilepsy management. The main reason for concern relates to the uncertainty on whether, and when, two generics found to be bioequivalent to the same brand (reference) product are bioequivalent to each other, and the risk of a switch bet...
Article
The therapeutic potential of cannabidiol (CBD) in seizure disorders has been known for many years, but it is only in the last decade that major progress has been made in characterizing its preclinical and clinical properties as an antiseizure medication. The mechanisms responsible for protection against seizures are not fully understood, but they a...
Article
The Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV) was held as a fully virtual conference from July 27 to July 30, 2020 for the sessions on drugs, and on August 3, 2020 for the sessions on devices. A total of 534 delegates from 63 countries attended lectures and interactive discussions, representing a broad range of di...
Article
Since 1992, the Eilat Conferences have provided a forum for all stakeholders in the epilepsy community to appraise the latest data on new antiepileptic drugs and emergency seizure treatments, including, in recent years, updates on progress with the development of novel monitoring and therapeutic devices. Because of the COVID‐19 pandemic, the Fiftee...
Article
For highly lipophilic drugs, passage into the intestinal lymphatic system rather than the portal vein following oral administration may represent a major alternative route of delivery into the general circulation. Increasing intestinal lymphatic transport provides an effective strategy to improve oral bioavailability when hepatic first-pass metabol...
Article
The success rate from first time in man to regulatory approval of central nervous system (CNS) drugs is lower than the overall success rate across all therapeutic indications (eg, cardiovascular, infectious diseases). To understand the reasons for drug‐candidate failure and to capture trends in antiseizure drug (ASD) design, we have analyzed the ph...
Article
This article provides a critical appraisal of the available evidence concerning clinical exposure to orally administered cannabidiol (CBD), with special reference to factors affecting gastrointestinal absorption, presystemic elimination, and susceptibility to metabolic drug interactions. Although detailed studies have not been published, the availa...
Article
Four pivotal randomized placebo‐controlled trials have demonstrated that adjunctive therapy with cannabidiol (CBD) improves seizure control in patients with Dravet syndrome (DS) and Lennox‐Gastaut syndrome (LGS). Between 47% and 68% of patients allocated to CBD treatment in these trials were receiving clobazam (CLB), which shows complex interaction...
Article
Objectives: To advance the development of (2S,3S)-sec-butylpropylacetamide (SPD) as a new treatment for acute repetitive seizures (ARS), by studying its pharmacokinetics (PK) in pigs and its PK-pharmacodynamic (PK-PD) correlation in rats. Methods: Two (2S,3S)-SPD intramuscular formulations (FA and FB ) were administered to pigs and rats and bloo...
Article
Full-text available
3-Methylpentyl(4-sulphamoylphenyl)carbamate (MSPC) came as the most potent compound out of a new series of carbamates composed of phenyl-ethanol or branched aliphatic alcohols, and 4-benzenesulphonamide-carbamic acid. In this study, the anticonvulsant activity and pharmacokinetics (PKs) of MSPC-two individual enantiomers were comparatively analysed...
Article
This paper contains five contributions which were presented as part of the novel therapies section of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures. These illustrate recent advances being made in the management and therapy of status epilepticus. The five contributions concern: genetic variations in Na + channel genes...
Article
The Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV) took place in Madrid, Spain from May 13th to 16th 2018. Again, presentations on new medical devices and neuromodulation and discussions on device-related regulatory aspects were included in the programme. The virtual special issue on "neuromodulation" summarises the...
Article
Full-text available
Objectives Children and adults are likely to be among the casualties in a civilian nerve agent exposure. This study evaluated the efficacy of valnoctamide (racemic‐VCD), sec‐butylpropylacetamide (racemic‐SPD), and phenobarbital for stopping nerve agent seizures in both immature and adult rats. Methods Female and male postnatal day (PND) 21, 28, an...
Article
Objectives: The anticonvulsant valproic acid (VPA) has a known teratogenic effect capable of inducing major congenital malformations and developmental disorders. A comparative teratogenicity study of VPA and its analog valnoctamide (VCD), which is a new generation candidate antiepileptic drug, was carried out using Swiss Vancouver (SWV) mice. Metho...
Article
The Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV) took place in Madrid, Spain, on May 13‐16, 2018 and was attended by 168 delegates from 28 countries. The conference provided a forum for professionals involved in basic science, clinical research, regulatory affairs, and clinical care to meet and discuss the latest a...
Article
The Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV) took place in Madrid, Spain, on May 13‐16, 2018 and was attended by 168 delegates from 28 countries. The conference provided a forum for professionals involved in basic science, clinical research, regulatory affairs, and clinical care to meet and discuss the latest a...
Article
Full-text available
The liver toxicity of valproic acid (VPA) is an established side effect of this widely used antiepileptic drug, which is extremely problematic for patients with metabolic epilepsy and particularly epilepsy due to mitochondrial dysfunction. In the present report, we investigated the reason for liver mitochondrial toxicity of VPA and several acid and...
Article
Full-text available
Epilepsy is one of the most common neurological diseases, with between 34 and 76 per 100,000 people developing epilepsy annually. Epilepsy therapy for the past 100(+) years is based on the use of antiepileptic drugs (AEDs). Despite the availability of more than twenty old and new AEDs, approximately 30% of patients with epilepsy are not seizure-fre...
Article
Full-text available
Objectives: Mood stabilizers administered for bipolar disorder during pregnancy, such as valproic acid, can increase the risk of congenital anomalies in offspring. Valnoctamide is a valproic acid derivative associated with a decreased risk for congenital abnormalities in animals. The present study evaluated the efficacy and safety of valnoctamide...
Article
The Thirteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIII) took place in Madrid, Spain, on June 26-29, 2016, and was attended by >200 delegates from 31 countries. The present Progress Report provides an update on experimental and clinical results for drugs presented at the Conference. Compounds for which summary data are pr...
Article
The Thirteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIII) took place in Madrid, Spain from June 26th to 29th 2016. For the first time, the last day of the conference focused solely on new medical devices and neuromodulation. The current article summarises the presentations of that day, focusing first on EEG- and ECG based...
Article
Background Genetic polymorphisms in CYP2C9 account for 10–20% of the variability in warfarin dose requirement. As such CYP2C9 genetic polymorphisms are commonly included in algorithms aimed to optimize warfarin therapy as a way to account for variability in warfarin responsiveness that is due to altered pharmacokinetics. However, most of the curren...
Article
Chronic pain is a multifactorial disease comprised of both inflammatory and neuropathic components that affect ∼20% of the world’s population. sec-Butylpropylacetamide (SPD) is a novel amide analogue of valproic acid (VPA) previously shown to possess a broad spectrum of anticonvulsant activity. In this study we defined the pharmacokinetic parameter...
Article
A novel series of carbamoyl derivatives of alkylimidazole has been designed and their anticonvulsant activity was comparatively evaluated in the mice- and rats-maximal-electroshock (MES), subcutaneous-metrazol (scMet) seizure tests and the mice-6 Hz psychomotor (6 Hz) models. The ten new designed molecules contain in their chemical structure imidaz...
Article
sec-Butylpropylacetamide (SPD) is a valproic acid (VPA) corresponding amide derivative. SPD possess a broad-spectrum antiseizure profile superior to that of VPA and blocks behavioral- and electrographic-status epilepticus (SE) induced by pilocarpine and the organophosphate soman. SPD activity on SE is superior to that of benzodiazepines (BZD) in te...
Article
Full-text available
Background: Though migraine is disabling and affects 12%-15% of the population, there are few drugs that have been developed specifically for migraine prevention. Valproic acid (VPA) is a broad-spectrum antiepileptic drug (AED) that is also used for migraine prophylaxis, but its clinical use is limited by its side effect profile. sec-Butylpropylac...
Chapter
Eslicarbazepine acetate (ESL) is a voltage-gated sodium and calcium channel blocker that was identified as a promising candidate for clinical development in epilepsy through a drug discovery programme initiated in the mid-1990s by BIAL. This chapter reviews the preclinical pharmacology and the clinical pharmacokinetics, efficacy and safety data of...
Article
Based on the recent findings from animal studies, it has been proposed that the therapeutic use of valnoctamide, an anxiolytic drug developed in the early 1960s, be extended to treat other neurological disorders such as epilepsy and bipolar disease. Given the scarcity of adequate data on its prenatal toxicity, a comparative teratogenicity study of...
Article
Epilepsy is both a disease of the brain and the mind. Here, we present the first of two papers with extended summaries of selected presentations of the Third International Congress on Epilepsy, Brain and Mind (April 3-5, 2014; Brno, Czech Republic). Epilepsy in history and the arts and its relationships with religion were discussed, as were overvie...
Article
sec-Butylpropylacetamide (SPD) is a one-carbon homologue of valnoctamide (VCD), a chiral constitutional isomer of valproic acid's (VPA) corresponding amide — valpromide. Racemic-SPD and racemic-VCD possess a unique and broad-spectrum antiseizure profile superior to that of VPA. In addition, SPD blocks behavioral and electrographic status epilepticu...
Article
Objective Organophosphates (OPs) are commonly used insecticides for agriculture and domestic purposes, but may also serve as nerve agents. Exposure to OPs result in overstimulation of the cholinergic system and lead to status epilepticus (SE), a life-threatening condition that is often resistant to treatment. SE is associated with significant neuro...
Article
Objective: 2-Ethyl-3-methylbutyl-carbamate (EMC) and 2-isopropylpentyl-carbamate (IPC) are among the most potent anticonvulsant carbamate derivatives of valproic acid. EMC and IPC are chiral compounds. Consequently, the aim of the current study was to comparatively evaluate the pharmacokinetic (PK) and pharmacodynamic (PD anticonvulsant activity)...
Patent
Novel acyl-urea containing compounds, processes of preparing same, compositions containing same and uses thereof in the treatment of neurological diseases and disorders such as epilepsy, neuropathic pain, bipolar disorder, status epilepticus, chemically-induced convulsions and/or seizure disorders, febrile convulsions conditions, metabolic disturba...
Patent
Full-text available
Amide derivatives of valproic acid are provided along their use in the treatment of epilepsy.
Article
Valnoctamide (VCD), a central nervous system (CNS)-active chiral constitutional isomer of valpromide, the corresponding amide of valproic acid (VPA), is currently undergoing phase IIb clinical trials in acute mania. VCD exhibits stereoselective pharmacokinetics (PK) in animals and humans. The current study comparatively evaluated the pharmacodynami...
Article
Generic products of antiepileptic drugs (AEDs) are currently a controversial topic as neurologists and patients are reluctant to switch from brand products to generics and to switch between generics. The aim of this study was to provide enlightenment on issues of bioequivalence (BE) and interchangeability of AED products. Monte Carlo simulations of...
Article
sec-Butyl-propylacetamide (SPD) is a one-carbon homolog of valnoctamide (VCD), a chiral constitutional isomer of valproic acid's (VPA) corresponding amide valpromide. VCD has potential as a therapy in epilepsy including status epilepticus (SE) and neuropathic pain, and is currently being developed for the treatment of bipolar disorder. Both VCD and...
Patent
Full-text available
Novel Alpha-halo- and Alpha-alkyl-cyclopropylcarboxy compounds, and uses of these and related compounds in the treatment of a variety of neurological diseases and disorders, and particularly epilepsy, are provided.
Article
Generics are usually considered to exhibit comparable in vivo properties in terms of efficacy and safety and for this reason are intended to be interchangeable with the reference product. The aim of this study is to provide a quantitative picture of the switchability problem between two generics and to introduce the concept of conditional probabili...
Article
Valproic acid (VPA), widely used to treat epilepsy, bipolar disorders, and migraine prophylaxis, is known to cause neural tube and skeletal defects in humans and animals. Aminobenzensulfonamide derivatives of VPA with branched aliphatic carboxylic acids, namely 2-methyl-N-(4-sulfamoyl-phenyl)-pentanamide (MSP), 2-ethyl-N-(4-sulfamoyl-phenyl)-butyra...
Article
sec-Butyl-propylacetamide (racemic-SPD) is a chiral CNS-active amide derivative of valproic acid (VPA). This study describes synthesis and stereospecific comparative pharmacodynamics (PD; anticonvulsant activity and teratogenicity) and pharmacokinetic (PK) analysis of SPD four individual stereoisomers. SPD stereoisomers' anticonvulsant activity was...
Article
To determine the cytotoxicity of valproic acid (VPA) and its derivatives in human hepatoblastoma cells (HepG2), and to study the possible toxicity of these compounds in human lymphocytes from patients with known hypersensitivity syndrome reactions (HSR) to other medication. Cells were exposed to physiological doses of VPA, valnoctamide (VCD) and it...
Article
Propylisopropyl acetamide (PID) and valnoctamide (VCD) are two CNS-active constitutional isomers of valproic acid (VPA) corresponding amide (and prodrug) valpromide. VPA is a major antiepileptic drug (AED) used also in children. Consequently, the purpose of the current study was to see if PID, VCD and two of VCD stereoisomers are active also in juv...
Article
PurposeInvestigate the pharmacokinetics of once-daily (QD; 900 mg) and twice-daily (BID; 450 mg) regimens of eslicarbazepine acetate (ESL) and BID (450 mg) regimen of oxcarbazepine (OXC) at steady state in healthy volunteers.Methods Single-center, open-label, randomized, three-way (n = 12) crossover studies in healthy volunteers.Key FindingsMean es...
Article
Purpose: Compare the pharmacokinetic (PK) profiles of immediate- and extended-release formulations of topiramate (TPM) in healthy subjects following multiple dosing, and evaluate maintenance of topiramate exposures after switching formulations. Methods: A randomized, open-label, single-center, two-way crossover, multiple-dose study comparing the...
Patent
Full-text available
The invention relates to the use of valnoctamide (VCD) for the treatment of bipolar disorder and in particular for the treatment of the manic phase of the bipolar disorder.
Article
Antiepileptic drugs (AEDs) are used to treat various nonepileptic central nervous system (CNS) disorders, both in neurology and psychiatry. Most AEDs have multiple mechanisms of action (MOAs), which include modulation of γ-aminobutyric acid (GABA)ergic and glutamatergic neurotransmission, and alteration of voltage-gated ion channels or intracellula...
Article
Phenobarbital has been in clinical use as an antiepileptic drug (AED) since 1912. The initial clinical success of phenobarbital and other barbiturates affected the design of subsequent AEDs (e.g., phenytoin, primidone, ethosuximide), developed between 1938 and 1962, the chemical structures of which resemble that of phenobarbital. However, the empir...
Article
Better treatment of status epilepticus (SE), which typically becomes refractory after about 30 min, will require new pharmacotherapies. The effect of sec-butyl-propylacetamide (SPD), an amide derivative of valproic acid (VPA), on electrographic status epilepticus (ESE) was compared quantitatively to other standard-of-care compounds. Cortical electr...
Article
Eslicarbazepine acetate (ESL) is a novel once-daily antiepileptic drug (AED) approved in Europe since 2009 that was found to be efficacious and well tolerated in a phase III clinical program in adult patients with partial onset seizures previously not controlled with treatment with one to three AEDs, including carbamazepine (CBZ). ESL shares with C...
Article
The cytochrome P450 (CYP) 4F2 isozyme has been reported to metabolize vitamin K(1) in vitro, and the V433M polymorphism in the CYP4F2 gene has been associated with reduced vitamin K(1) metabolism and the need for a higher maintenance dosage in patients receiving warfarin. The purpose of the present study was to evaluate the effects of V433M polymor...
Article
A novel class of 19 carbamates was synthesized, and their anticonvulsant activity was comparatively evaluated in the rat maximal electroshock (MES) and subcutaneous metrazol (scMet) seizure tests and pilocarpine-induced status epilepticus (SE) model. In spite of the alkyl-carbamates' close structural features, only compounds 34, 38, and 40 were act...
Article
sec-Butyl-propylacetamide (SPD) is a one-carbon homolog of valnoctamide (VCD), a central nervous system (CNS)-active amide derivative of valproic acid (VPA) currently in phase II clinical trials. The study reported herein evaluated the anticonvulsant activity of SPD in a battery of rodent seizure and epilepsy models and assessed its efficacy in rat...
Article
Between 1990 and 2011 the following fifteen new antiepileptic drugs (AEDs) were approved: eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, retigabine, rufinamide, stiripentol, tiagabine, topiramate, vigabatrin, and zonisamide. These AEDs (except felbamate) offer appreciable advantage...
Article
Valproic acid (VPA) is a major antiepileptic drug (AED) that is less potent than other AEDs. 2,2,3,3-Tetramethylcyclopropanecarboxylic acid (TMCA) is an inactive cyclopropyl analogue of VPA that serves as a starting material for the synthesis of CNS-active compounds. New conjugation products between N,N'-dimethylethanolamine to VPA and TMCA to form...
Article
A series of glycinamide conjugates and N-methoxy amide derivatives of valproic acid (VPA) analogs and constitutional isomers were synthesized and evaluated for anticonvulsant activity. Of all compounds synthesized and tested, only N-methoxy-valnoctamide (N-methoxy-VCD) possessed better activity than VPA in the following anticonvulsant tests: maxima...
Article
Full-text available
Valproic acid (VPA) is the most widely prescribed epilepsy treatment worldwide, but its mechanism of action remains unclear. Our previous work identified a previously unknown effect of VPA in reducing phosphoinositide production in the simple model Dictyostelium followed by the transfer of data to a mammalian synaptic release model. In our current...
Article
To compare the pharmacokinetics of USL255, a once-daily extended-release (ER) formulation of topiramate (TPM), with Topamax (immediate-release TPM) in healthy subjects after oral dosing and evaluate the effect of food on USL255 bioavailability and pharmacokinetics. This randomized, single-center, open-label, cross-over design study had three dosing...
Article
Aromatic amides comprising branched aliphatic carboxylic acids and 4-aminobenzenesulfonamide were evaluated for their inhibition of carbonic anhydrase (CA) isoforms. Of the most anticonvulsant-active compounds (2, 4, 13, 16, and 17), only 13, 16, and 17 were potent inhibitors of CAs VII and XIV. Compounds 9, 14, and 19 inhibited CA II, while 10 and...
Article
The Twelfth Eilat Conference on New Antiepileptic Drugs (AEDs) - EILAT XII, took place in Madrid, Spain from August 31st to September 3rd 2014. About 130 basic scientists, clinical pharmacologists and neurologists from 22 countries attended the conference, whose main themes included "Conquering pharmacoresistant epilepsy", "Innovative emergency tre...
Article
α-Fluoro-2,2,3,3-tetramethylcyclopropanecarboxamide (α-F-TMCD) and α-Cl-TMCD, are α-halo derivatives of TMCD, the corresponding amide of a cyclopropane analog of valproic acid (VPA). This study aimed to comparatively evaluate the pharmacodynamics and pharmacokinetics of α-F-TMCD and α-Cl-TMCD in rodent models of epilepsy and for antiepileptic drug...
Article
Despite the availability of 14 new antiepileptic drugs (AEDs), about 30% of epileptic patients are not seizure-free. Consequently there is substantial need to develop new effective AEDs. A novel class of aromatic amides composed of phenylacetic acid or branched aliphatic carboxylic acids, with five to nine carbons in their carboxylic moiety, and am...
Article
Most antiepileptic drugs (AEDs) are currently available as generic products, yet neurologists and patients are reluctant to switch to generics. Generic AEDs are regarded as bioequivalent to brand AEDs after meeting the average bioequivalence criteria; consequently, they are considered to be interchangeable with their respective brands without loss...
Article
The purpose of this study was to evaluate the stereoselective pain relieving (antiallodynic) activity, antiallodynic-anticonvulsant correlation, teratogenicity and pharmacokinetic profile of two stereoisomers of valnoctamide (VCD), a CNS-active amide derivative of a chiral isomer of valproic acid (VPA). The individual stereoisomers (diastereomers),...
Article
Since the early 1990s, many new antiepileptic drugs (AEDs) that offer appreciable advantages in terms of their favourable pharmacokinetics, improved tolerability and lower potential for drug-drug interactions have entered the market. However, despite the therapeutic arsenal of old and new AEDs, approximately 30% of patients with epilepsy still suff...
Article
Valproic acid (VPA, 1) is a major broad spectrum antiepileptic and central nervous system drug widely used to treat epilepsy, bipolar disorder, and migraine. VPA's clinical use is limited by two severe and life-threatening side effects, teratogenicity and hepatotoxicity. A number of VPA analogues and their amide, N-methylamide and urea derivatives,...
Article
Valproic acid (VPA) is used to treat epilepsy and bipolar disorders, as well as for migraine prophylaxis. However, its clinical use is limited by two life-threatening side effects: hepatotoxicity and teratogenicity. To develop a more potent and safer second-generation VPA drug, the urea derivatives of four VPA analogs (2-ethyl-3-methylpentanoyl ure...
Article
The purpose of this study was to evaluate the stereoselective anticonvulsant activity, neurotoxicity, pharmacokinetics, and teratogenic potential of two stereoisomers of valnoctylurea (VCU), a central nervous system (CNS)-active urea derivative of valnoctic acid, which is a constitutional isomer of valproic acid (VPA). VCU stereoisomers (2S,3S)-VCU...