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Meir Bialer - One of the best experts on this subject based on the ideXlab platform.
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teratogenicity of valproic acid and its constitutional isomer amide derivative Valnoctamide in mice
Birth defects research, 2019Co-Authors: Ying Linda Lin, Meir Bialer, Robert M Cabrera, Richard H Finnell, Bogdan J WlodarczykAbstract: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. METHODS Pregnant SWV dams were treated with either a single intraperitoneal injection of VPA (1.8 and 2.7 mmol/kg), VCD (1.8 and 2.7 mmol/kg), or vehicle on E8:12 (gestational day:hour). The numbers of implantation and resorption, viable and dead fetuses, and the presence of gross fetal visceral and skeletal abnormalities were determined (E18). Real-time Polymerase chain reaction (RT-PCR) arrays were used to analyze the expression of 84 genes related to the processes of neurogenesis and neural stem cell differentiation. RESULTS Significant decreases in pregnancy weight gain and the number of live fetuses were observed when VPA was administered at the high dose, whereas the percentage of exencephalic fetuses was significantly increased in VPA treated compared with an equivalent VCD dosage group. There was a dose-related increase in visceral defects in the VPA-exposed fetuses. Missing skull bones and fused vertebrae in fetuses occurred at the high dose of VPA. Three genes (Mtap2, Bmp8b, and Stat3) were significantly upregulated and one (Heyl) was downregulated in samples from VPA-treated dams. CONCLUSIONS The study demonstrates that the teratogenicity of VPA was significantly greater than that of an equimolar dose of VCD. Four genes (Mtap2, Bmp8b, Stat3, and Heyl) represent candidate target genes for the underlying teratogenic mechanism responsible for VPA-induced malformations.
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comparative efficacy of Valnoctamide and sec butylpropylacetamide spd in terminating nerve agent induced seizures in pediatric rats
Epilepsia, 2019Co-Authors: Kari M Haines, John H Mcdonough, Liana M Matson, Emily N Dunn, Cherish E Ardinger, Robyn B Leestubbs, David Bibi, Meir BialerAbstract: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, and 70 (adult) rats, previously implanted with electroencephalography (EEG) electrodes were exposed to seizure-inducing doses of the nerve agents sarin or VX and EEG was recorded continuously. Five minutes after seizure onset, animals were treated with SPD, VCD, or phenobarbital. The up-down method was used over successive animals to determine the anticonvulsant median effective dose (ED50 ) of the drugs. Results SPD-ED50 values in the VX model were the following: PND21, 53 mg/kg (male) and 48 mg/kg (female); PND28, 108 mg/kg (male) and 43 mg/kg (female); and PND70, 101 mg/kg (male) and 40 mg/kg (female). SPD-ED50 values in the sarin model were the following: PND21, 44 mg/kg (male) and 28 mg/kg (female); PND28, 79 mg/kg (male) and 34 mg/kg (female); and PND70, 53 mg/kg (male) and 53 mg/kg (female). VCD-ED50 values in the VX model were the following: PND21, 34 mg/kg (male) and 43 mg/kg (female); PND28, 165 mg/kg (male) and 59 mg/kg (female); and PND70, 87 mg/kg (male) and 91 mg/kg (female). VCD-ED50 values in the sarin model were the following: PND21, 45 mg/kg (male), 48 mg/kg (female); PND28, 152 mg/kg (male) 79 mg/kg (female); and PND70, 97 mg/kg (male) 79 mg/kg (female). Phenobarbital-ED50 values in the VX model were the following: PND21, 43 mg/kg (male) and 18 mg/kg (female); PND28, 48 mg/kg (male) and 97 mg/kg (female). Phenobarbital-ED50 values in the sarin model were the following: PND21, 32 mg/kg (male) and 32 mg/kg (female); PND28, 58 mg/kg (male) and 97 mg/kg (female); and PND70, 65 mg/kg (female). Significance SPD and VCD demonstrated anticonvulsant activity in both immature and adult rats in the sarin- and VX-induced status epilepticus models. Phenobarbital was effective in immature rats, whereas in adult rats, higher doses were required that were accompanied by toxicity. Overall, significantly less drug was required to stop seizures in PND21 animals than in the older animals, and overall, males required higher amounts of drug than females.
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a randomized double blind placebo and risperidone controlled study on Valnoctamide for acute mania
Bipolar Disorders, 2017Co-Authors: Meir Bialer, Tawfeeq Shekhahmad, Mark Weiser, Linda Levi, Stephen Z Levine, Valentin Petre Matei, Alexandru Tiugan, Diana Cirjaliu, Cristinel SavaAbstract: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 monotherapy, compared to placebo, in the treatment of patients in an acute manic episode. Methods A 3-week, double-blind, randomized, placebo- and risperidone-controlled, parallel group trial was conducted on 173 patients in an acute manic episode. Patients were randomized to receive Valnoctamide 1500 mg/d (n=71), risperidone 6 mg/d (n=32), or matching placebo (n=70). The primary outcome measure was the change in Young Mania Rating Scale (YMRS) scores. Results Valnoctamide did not differ significantly from placebo on any of the study endpoints (YMRS, Positive and Negative Syndrome Scale, and the Clinical Global Impression Scale for Bipolar Disorder [CGI-BP] scales; all P>.60). Mixed models for repeated measures showed that risperidone produced significantly more improvement than placebo in the overall bipolar disorder CGI-BP severity scale (P=.036), and the CGI-BP severity scale for mania (P=.021). The Kaplan-Meier survival curve revealed higher all-cause discontinuation rates (mainly due to lack of efficacy) in the Valnoctamide group compared to the other study groups (P=.026). Patients with higher Valnoctamide plasma levels had a numerically higher YMRS response, but this was not statistically significant. Conclusions Valnoctamide was well tolerated at 1500 mg/d but lacked efficacy in the treatment of symptoms in patients with acute mania. Possible differences between the biological mechanisms of action of valproic acid and Valnoctamide are discussed.
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Mitochondrial Liver Toxicity of Valproic Acid and Its Acid Derivatives Is Related to Inhibition of α-Lipoamide Dehydrogenase
MDPI AG, 2017Co-Authors: Alexei P. Kudin, Meir Bialer, Hafiz Mawasi, Arik Eisenkraft, Christian E. Elger, Wolfram S. KunzAbstract: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 amide VPA analogues. While the pyruvate and 2-oxoglutarate oxidation rates of rat brain mitochondria were nearly unaffected by VPA, rat liver mitochondrial pyruvate and 2-oxoglutarate oxidation was severely impaired by VPA concentrations above 100 µM. Among the reactions involved in pyruvate oxidation, pyruvate transport and dehydrogenation steps were not affected by VPA, while α-lipoamide dehydrogenase was strongly inhibited. Strong inhibition of α-lipoamide dehydrogenase was also noted for the VPA one-carbon homolog sec-butylpropylacetic acid (SPA) and to a lesser extent for the VPA constitutional isomer valnoctic acid (VCA), while the corresponding amides of the above three acids valpromide (VPD), sec-butylpropylacetamide (SPD) and Valnoctamide (VCD) showed only small effects. We conclude that the active inhibitors of pyruvate and 2-oxoglutarate oxidation are the CoA conjugates of VPA and its acid analogues affecting selectively α-lipoamide dehydrogenase in liver. Amide analogues of VPA, like VCD, show low inhibitory effects on mitochondrial oxidative phosphorylation in the liver, which might be relevant for treatment of patients with mitochondrial epilepsy
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comparative teratogenicity analysis of Valnoctamide risperidone and olanzapine in mice
Bipolar Disorders, 2015Co-Authors: Bogdan J Wlodarczyk, Meir Bialer, Krystal Ogle, Richard H FinnellAbstract:Objectives 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 Valnoctamide and two of the most commonly used drugs to treat bipolar disorder, risperidone and olanzapine, was carried out in a mouse model system.
Boris Yagen - One of the best experts on this subject based on the ideXlab platform.
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the potential of sec butylpropylacetamide spd and Valnoctamide and their individual stereoisomers in status epilepticus
Epilepsy & Behavior, 2015Co-Authors: Tawfeeq Shekhahmad, Hafiz Mawasi, Boris Yagen, John H Mcdonough, Meir BialerAbstract: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 epilepticus (SE) induced by pilocarpine and the organophosphates soman and paraoxon. Valnoctamide has similar activity as SPD in the soman-induced SE model. The activity of SPD and VCD against SE is superior to that of diazepam and midazolam in terms of rapid onset, potency, and ability to block SE when given 20 to 60 min after seizure onset. sec-Butylpropylacetamide and VCD possess two stereogenic carbons in their chemical structure and, thus, exist as a racemic mixture of four individual stereoisomers. The anticonvulsant activity of the individual stereoisomers of SPD and VCD was comparatively evaluated in several anticonvulsant rodent models including the benzodiazepine-resistant SE model. sec-Butylpropylacetamide has stereoselective pharmacokinetics (PK) and pharmacodynamics (PD). The higher clearance of (2R,3S)-SPD and (2S,3R)-SPD led to a 50% lower plasma exposure and, consequently, to a lower anticonvulsant activity compared to racemic-SPD and its two other stereoisomers. Racemic-SPD, (2S,3S)-SPD, and (2R,3R)-SPD have similar anticonvulsant activities and PK profiles that are better than those of (2R,3S)-SPD and (2S,3R)-SPD. Valnoctamide has a stereoselective PK with (2S,3S)-VCD exhibiting the lowest clearance and, consequently, a twice-higher plasma exposure than all other stereoisomers. Nevertheless, there was less stereoselectivity in VCD anticonvulsant activity, and each stereoisomer had similar ED50 values in most models. sec-Butylpropylacetamide and VCD stereoisomers did not cause teratogenicity (i.e., neural tube defect) in mice at doses 3-12 times higher than their anticonvulsant-ED50 values. This article is part of a Special Issue entitled "Status Epilepticus".
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Antiepileptic Drugs and neuropathic pain: Comparative analysis of CNS-active derivatives of valproic acid in the (rat) spinal nerve ligation model
2015Co-Authors: Ilan Winkler, Boris Yagen, Marshall Devor, Meir BialerAbstract:Antiepileptic drugs (AEDs) are widely utilized in the management of neuropathic pain. The AED valproic acid (VPA) holds out particular promise as it is engaging a variety of different anticonvulsant mechanisms simultaneously. However, the clinical use of VPA is limited by two rare but potentially life-threatening side effects: teratogenicity and hepatotoxicity. We synthesized VPA’s corresponding amide: valpromide (VPD), two of VPA’s isomers and their corresponding amides; valnoctic acid (VCA), Valnoctamide (VCD), diisopropyl acetic acid (DIA), diisopropylacetamide (DID) and VPD”s congener N-methyl-VPD (MVPD). VCD, DID and VPD are non-teratogenic, potentially non-hepatotoxic, and exhibit better anticonvuslant potency than VPA. In addition, we have synthesized several tetramethylcyclopropyl analogues of VPA amides that are non-teratogenic, and non-hepatotoxic, that exhibit good antiepileptic efficacy. In this study we have assessed the antiallodynic activity of these compounds in comparison to VPA and gabapentin (GBP) using the rat spinal nerve ligation (SNL) model of neuropathic pain. VCA and MVPD were inactive. However, VPD (20-100 mg/kg), VCD (20-100 mg/kg) and DID (20-90 mg/kg), produced dose-related reversal of tactile allodynia with ED50 values of 61, 52 and 58 mg/kg, respectively. All the amides were more potent than VPA (ED50=269 mg/kg). Th
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stereoselective anticonvulsant and pharmacokinetic analysis of Valnoctamide a cns active derivative of valproic acid with low teratogenic potential
Epilepsia, 2014Co-Authors: Tawfeeq Shekhahmad, Richard H Finnell, Bogdan J Wlodarczyk, Naama Hen, Boris Yagen, John H Mcdonough, Meir BialerAbstract:Summary Objective 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 pharmacodynamics (PD; anticonvulsant activity and teratogenicity) and PK of the four individual stereoisomers of VCD. Methods The anticonvulsant activity of VCD individual stereoisomers was evaluated in several rodent anticonvulsant models including maximal electroshock, 6 Hz psychomotor, subcutaneous metrazol, and the pilocarpine-induced and soman-induced status epilepticus (SE). The PK-PD (anticonvulsant activity) relationship of VCD stereoisomers was evaluated following intraperitoneal administration (70 mg/kg) to rats. Induction of neural tube defects (NTDs) by VCD stereoisomers was evaluated in a mouse strain that was highly susceptible to teratogen-induced NTDs. Results VCD had a stereoselective PK, with (2S,3S)-VCD exhibiting the lowest clearance, and consequently a twice-higher plasma exposure than all other stereoisomers. Nervertheless, there was less stereoselectivity in VCD anticonvulsant activity and each stereoisomer had similar median effective dose (ED)50 values in most models. VCD stereoisomers (258 or 389 mg/kg) did not cause NTDs. These doses are 3–12 times higher than VCD anticonvulsant ED50 values. Significance VCD displayed stereoselective PK that did not lead to significant stereoselective activity in various anticonvulsant rodent models. If VCD exerted its broad-spectrum anticonvulsant activity using a single mechanism of action (MOA), it is likely that it would exhibit a stereoselective PD. The fact that there was no significant difference between racemic VCD and its individual stereoisomers suggests that VCD's anticonvulsant activity is due to multiple MOAs.
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Valnoctamide and sec butyl propylacetamide spd for acute seizures and status epilepticus
Epilepsia, 2013Co-Authors: Tawfeeq Shekhahmad, Naama Hen, Boris Yagen, John H Mcdonough, Meir BialerAbstract:Summary 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 SPD possess two stereogenic carbons in their chemical structure. SPD possesses a unique and broad-spectrum antiseizure profile superior to that of valproic acid (VPA) and better than that of VCD. In addition SPD blocked behavioral- and electrographic-SE induced by pilocarpine and soman (organophosphate nerve gas) and afforded in vivo neuroprotection that was associated with cognitive sparing. VCD has activity similar to that of SPD in pilocarpine-induced status epilepticus (SE), although at higher doses. The activity of SPD and VCD against SE is superior to that of diazepam in terms of rapid onset, potency, and ability to block SE when given 20–60 min after seizure onset. When administered 20 and 40 min after SE onset, SPD (100–174 mg/kg) produced long-lasting efficacy (e.g., 4–8 h) against soman-induced convulsive and electrographic SE in both rats and guinea pigs. SPD activity in the pilocarpine and soman-induced SE models when administered 20–60 min after seizure onset, differentiates SPD from benzodiazepines and all other antiepileptic drugs .
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a new derivative of valproic acid amide possesses a broad spectrum antiseizure profile and unique activity against status epilepticus and organophosphate neuronal damage
Epilepsia, 2012Co-Authors: Steve H White, Tawfeeq Shekhahmad, Naama Hen, John H Mcdonough, Anitha Alex, Amanda Pollock, Karen S Wilcox, James P Stables, Dan Kaufmann, Boris YagenAbstract:Purpose sec-Butyl-propylacetamide (SPD) is a one-carbon homologue of Valnoctamide (VCD), a CNS-active amide derivative of valproic acid (VPA) currently in phase II clinical trials. The current study evaluated the anticonvulsant activity of SPD in a battery of rodent seizure and epilepsy models and assessed its efficacy in rat and guinea pig models of status epilepticus (SE) and neuroprotection in an organotypic hippocampal slice model of excitotoxic cell death.
Tawfeeq Shekhahmad - One of the best experts on this subject based on the ideXlab platform.
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a randomized double blind placebo and risperidone controlled study on Valnoctamide for acute mania
Bipolar Disorders, 2017Co-Authors: Meir Bialer, Tawfeeq Shekhahmad, Mark Weiser, Linda Levi, Stephen Z Levine, Valentin Petre Matei, Alexandru Tiugan, Diana Cirjaliu, Cristinel SavaAbstract: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 monotherapy, compared to placebo, in the treatment of patients in an acute manic episode. Methods A 3-week, double-blind, randomized, placebo- and risperidone-controlled, parallel group trial was conducted on 173 patients in an acute manic episode. Patients were randomized to receive Valnoctamide 1500 mg/d (n=71), risperidone 6 mg/d (n=32), or matching placebo (n=70). The primary outcome measure was the change in Young Mania Rating Scale (YMRS) scores. Results Valnoctamide did not differ significantly from placebo on any of the study endpoints (YMRS, Positive and Negative Syndrome Scale, and the Clinical Global Impression Scale for Bipolar Disorder [CGI-BP] scales; all P>.60). Mixed models for repeated measures showed that risperidone produced significantly more improvement than placebo in the overall bipolar disorder CGI-BP severity scale (P=.036), and the CGI-BP severity scale for mania (P=.021). The Kaplan-Meier survival curve revealed higher all-cause discontinuation rates (mainly due to lack of efficacy) in the Valnoctamide group compared to the other study groups (P=.026). Patients with higher Valnoctamide plasma levels had a numerically higher YMRS response, but this was not statistically significant. Conclusions Valnoctamide was well tolerated at 1500 mg/d but lacked efficacy in the treatment of symptoms in patients with acute mania. Possible differences between the biological mechanisms of action of valproic acid and Valnoctamide are discussed.
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the potential of sec butylpropylacetamide spd and Valnoctamide and their individual stereoisomers in status epilepticus
Epilepsy & Behavior, 2015Co-Authors: Tawfeeq Shekhahmad, Hafiz Mawasi, Boris Yagen, John H Mcdonough, Meir BialerAbstract: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 epilepticus (SE) induced by pilocarpine and the organophosphates soman and paraoxon. Valnoctamide has similar activity as SPD in the soman-induced SE model. The activity of SPD and VCD against SE is superior to that of diazepam and midazolam in terms of rapid onset, potency, and ability to block SE when given 20 to 60 min after seizure onset. sec-Butylpropylacetamide and VCD possess two stereogenic carbons in their chemical structure and, thus, exist as a racemic mixture of four individual stereoisomers. The anticonvulsant activity of the individual stereoisomers of SPD and VCD was comparatively evaluated in several anticonvulsant rodent models including the benzodiazepine-resistant SE model. sec-Butylpropylacetamide has stereoselective pharmacokinetics (PK) and pharmacodynamics (PD). The higher clearance of (2R,3S)-SPD and (2S,3R)-SPD led to a 50% lower plasma exposure and, consequently, to a lower anticonvulsant activity compared to racemic-SPD and its two other stereoisomers. Racemic-SPD, (2S,3S)-SPD, and (2R,3R)-SPD have similar anticonvulsant activities and PK profiles that are better than those of (2R,3S)-SPD and (2S,3R)-SPD. Valnoctamide has a stereoselective PK with (2S,3S)-VCD exhibiting the lowest clearance and, consequently, a twice-higher plasma exposure than all other stereoisomers. Nevertheless, there was less stereoselectivity in VCD anticonvulsant activity, and each stereoisomer had similar ED50 values in most models. sec-Butylpropylacetamide and VCD stereoisomers did not cause teratogenicity (i.e., neural tube defect) in mice at doses 3-12 times higher than their anticonvulsant-ED50 values. This article is part of a Special Issue entitled "Status Epilepticus".
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pharmacodynamic and pharmacokinetic analysis of cns active constitutional isomers of Valnoctamide and sec butylpropylacetamide amide derivatives of valproic acid
Epilepsy & Behavior, 2015Co-Authors: Hafiz Mawasi, Bogdan J Wlodarczyk, Richard H Finnell, Tawfeeq Shekhahmad, Meir BialerAbstract:article i nfo Valnoctamide (VCD) and sec-butylpropylacetamide (SPD) are CNS-active closely related amide derivatives of valproic acid with unique anticonvulsant activity. This study evaluated how small chemical changes affect the pharmacodynamics (PD; anticonvulsant activity and teratogenicity) and pharmacokinetics (PK) of three consti- tutional isomers of SPD (sec-butylisopropylacetamide (SID) and tert-butylisopropylacetamide (TID)) and of VCD (tert-butylethylacetamide (TED)). The anticonvulsant activity of SID, TID, and TED was comparatively evaluated in several rodent anticonvulsant models. The PK-PD relationship of SID, TID, and TED was evaluated in rats, and their teratogenicity was evaluated in a mouse strain highly susceptible to teratogen-induced neural tube de- fects (NTDs).sec-Butylisopropylacetamide andTID have a similarPK profileto SPD which may contribute totheir similar anticonvulsant activity. tert-Butylethylacetamide had a better PK profile than VCD (and SPD); however, this did not lead to a superior anticonvulsant activity. sec-Butylisopropylacetamide and TED did not cause NTDs at doses 4-7 times higher than their anticonvulsant ED50 values. In rats, SID, TID (ip), and TED exhibited a broad spectrum of anticonvulsant activity. However, combined anticonvulsant analysis in mice and rats shows SID as the most potent compound with similar activity to that of SPD, demonstrating that substitution of the isobutyl moiety in the SPD or VCD molecule by tert-butyl as well as a propyl-to-isopropyl replacement in the SPD molecule did not majorly affect the anticonvulsant activity.
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sec butyl propylacetamide spd and two of its stereoisomers rapidly terminate paraoxon induced status epilepticus in rats
Epilepsia, 2014Co-Authors: Guy Barklein, Arik Eisenkraft, Tawfeeq Shekhahmad, Evyatar Swissa, Lyn Kamintsky, Rotem Saarashkenazy, Yechiel Hubary, Shai Shrot, Liran StetlanderAbstract:Summary 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 neuronal damage, neurocognitive dysfunction, and the development of lifelong epilepsy. Therefore, rapid termination of SE and prevention of brain damage is of high interest. Here we tested the efficacy of sec-butyl-propylacetamide (SPD) and two of its individual stereoisomers, (2S,3S)-SPD and (2R,3R)-SPD, in discontinuing OP-induced seizures. SPD is a one carbon homolog of Valnoctamide, a central nervous system (CNS)–active constitutional isomer of valproic acid (VPA) corresponding amide valpromide. Methods Rats were implanted with epidural telemetric electrodes to allow electrocorticography (ECoG) recording 24 h prior, during and 24 h after poisoning with the OP paraoxon (at a dose equivalent to 1.4 LD50 Median lethal dose). All rats were provided with antidotal treatment of atropine and toxogonin. Epileptic activity was measured using a novel automated system to evaluate the different effects of midazolam, SPD, and its individual stereoisomers in comparison to nontreated controls. Results Treatment with SPD or its individual stereoisomer (2S,3S)-SPD significantly shorten paraoxon-induced SE and reduced the duration of recorded pathologic activity after SE was terminated. (2S,3S)-SPD was superior to racemic-SPD in diminishing delayed pathologic epileptiform activity within the first 8 h after SE. Significance These results suggest SPD as an efficient drug for the rapid termination of SE and pathological epileptiform activity following OP poisoning, a strategy to reduce neuronal dysfunction and the risk for lifelong epilepsy.
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stereoselective anticonvulsant and pharmacokinetic analysis of Valnoctamide a cns active derivative of valproic acid with low teratogenic potential
Epilepsia, 2014Co-Authors: Tawfeeq Shekhahmad, Richard H Finnell, Bogdan J Wlodarczyk, Naama Hen, Boris Yagen, John H Mcdonough, Meir BialerAbstract:Summary Objective 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 pharmacodynamics (PD; anticonvulsant activity and teratogenicity) and PK of the four individual stereoisomers of VCD. Methods The anticonvulsant activity of VCD individual stereoisomers was evaluated in several rodent anticonvulsant models including maximal electroshock, 6 Hz psychomotor, subcutaneous metrazol, and the pilocarpine-induced and soman-induced status epilepticus (SE). The PK-PD (anticonvulsant activity) relationship of VCD stereoisomers was evaluated following intraperitoneal administration (70 mg/kg) to rats. Induction of neural tube defects (NTDs) by VCD stereoisomers was evaluated in a mouse strain that was highly susceptible to teratogen-induced NTDs. Results VCD had a stereoselective PK, with (2S,3S)-VCD exhibiting the lowest clearance, and consequently a twice-higher plasma exposure than all other stereoisomers. Nervertheless, there was less stereoselectivity in VCD anticonvulsant activity and each stereoisomer had similar median effective dose (ED)50 values in most models. VCD stereoisomers (258 or 389 mg/kg) did not cause NTDs. These doses are 3–12 times higher than VCD anticonvulsant ED50 values. Significance VCD displayed stereoselective PK that did not lead to significant stereoselective activity in various anticonvulsant rodent models. If VCD exerted its broad-spectrum anticonvulsant activity using a single mechanism of action (MOA), it is likely that it would exhibit a stereoselective PD. The fact that there was no significant difference between racemic VCD and its individual stereoisomers suggests that VCD's anticonvulsant activity is due to multiple MOAs.
Emilio Perucca - One of the best experts on this subject based on the ideXlab platform.
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Progress report on new antiepileptic drugs: A summary of the Eleventh Eilat Conference (EILAT XI)
2013Co-Authors: Meir Bialer, Emilio Perucca, Svein I. Johannessen, René H. Levy, Torbjörn Tomson, Steve H WhiteAbstract:The Eleventh Eilat Conference on New Antiepileptic Drugs (AEDs)-EILAT XI, took place in Eilat, Israel from the 6th to 10th of May 2012. About 100 basic scientists, clinical pharmacologists and neurologists from 20 countries attended the conference, whose main themes included "Indications overlapping with epilepsy" and "Securing the successful development of an investigational antiepileptic drug in the current environment". Consistent with previous formats of this conference, a large part of the program was devoted to a review of AEDs in development, as well as updates on AEDs introduced since 1994. Like the EILAT X report, the current manuscript focuses only on the preclinical and clinical pharmacology of AEDs that are currently in development. These include brivaracetam, 2-deoxy-glucose, ganaxolone, ICA-105665, imepitoin, NAX 801-2, perampanel and other AMPA receptor antagonists, tonabersat, Valnoctamide and its homologue sec-propylbutylacetamide (SPD), VX-765 and YK3089. Since the previous Eilat conference, retigabine (ezogabine) has been marketed and four newer AEDs in development (NAX 810-2, SPD, tonabersat and VX-765) are included in this manuscript. (c) 2012 Elsevier B.V. All rights reserved
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Progress report on new antiepileptic drugs: a summary of the Tenth Eilat Conference (EILAT X).
Epilepsy Research, 2010Co-Authors: Meir Bialer, Emilio Perucca, Svein I. Johannessen, René H. Levy, Torbjörn Tomson, H. Steve WhiteAbstract:The Tenth Eilat Conference on New Antiepileptic Drugs (AEDs)-EILAT X, took place in Eilat, Israel from the 25th to 29th of April 2010. About 200 basic scientists, clinical pharmacologists and neurologists from 25 countries attended the conference, whose main themes included learning from the past: Lessons learnt after 18 years of Eilat Conferences and Detecting assessing and preventing adverse effects of AEDs. Consistent with previous formats of this conference, a large part of the program was devoted to a review of AEDs in development, as well as updates on AEDs introduced since 1994. Like the previous EILAT (EILAT IX) manuscript, the current (EILAT X) manuscript focuses only on the preclinical and clinical pharmacology of AEDs that are currently in development. These include brivaracetam, carisbamate, 2-deoxy-glucose, ganaxolone, huperizine A, ICA-105665, NAX-5055, retigabine, perampanel, T-2007, Valnoctamide and YK3089. Since the previous Eilat Conference (EILAT IX-2008) two new AEDs; eslicarbazepine acetate and lacosamide have been marketed and three new AEDs in development not included in the EILAT IX manuscript were added: ICA-105665, perampanel and Valnoctamide. The CNS efficacy of these compounds in anticonvulsant animal models as well as other disease model systems are presented in Tables 1 and 2 and their proposed mechanism of action at summarized in Table 3.
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stereoselective pharmacokinetic analysis of Valnoctamide in healthy subjects and in patients with epilepsy
Clinical Pharmacology & Therapeutics, 1997Co-Authors: Shimon Barel, Boris Yagen, Volker Schurig, Stephan Soback, Francesco Pisani, Emilio Perucca, Meir BialerAbstract:Objective To investigate the pharmacokinetics of the four stereoisomers of Valnoctamide, a mild tranquilizer endowed with anticonvulsant properties. Methods Racemic Valnoctamide, 400 mg, was administered orally to seven healthy subjects and to six patients with epilepsy stabilized with long-term carbamazepie therapy. In the patients with epilepsy, Valnoctamide kinetics was also reassessed after 8-day oral dosing at a dosage of 600 mg daily. Plasma samples were assayed by gas chromatography-mass spectrometry with use of a capillary column coated with chiral stationary phase that enabled baseline resolution of the four stereoisomers, designated hereafter as A, B, C, and D (where A and C, together with B and D, represent enantiomeric pairs). Results In healthy subjects, steroisomers A, C, and D showed similar kinetics, with an apparent oral clearance (CL/F) of about 4½ L/hr, a half-life (t½) of about 10 hours, and an apparent volume of distribution (VSS/F) of about 65 L. However, stereoisomer B showed a much higher clearance (8.7 ± 0.9 L/hr) and a shorter t½ (5.8 hours). For all stereoisomers, CL/F values in patients with epilepsy were about tenfold higher than those found in healthy subjects. Compared with healthy subjects, patients with epilepsy also showed shorter t½ values and higher VSS/F values for each of the stereoisomers. After 7-day dosing, CL/F values at steady state were lower than those determined in the same patients after a single dose. Conclusions Valnoctamide exhibits enantioselectivity and diastereoselectivity, an observation that may have important practical implications if pharmacodynamic differences between stereoisomers are also found. The observed pharmacokinetic differences between healthy subjects and patients with epilepsy are likely to be related to induction of metabolism of Valnoctamide stereoisomers by carbamazepine. Clinical Pharmacology & Therapeutics (1997) 61, 442–449; doi:
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Stereoselective pharmacokinetic analysis of Valnoctamide in healthy subjects and in patients with epilepsy.
1997Co-Authors: Shimon Barel, Boris Yagen, Volker Schurig, Stephan Soback, Francesco Pisani, Emilio Perucca, Meir BialerAbstract:OBJECTIVE: To investigate the pharmacokinetics of the four stereoisomers of Valnoctamide, a mild tranquilizer endowed with anticonvulsant properties. METHODS: Racemic Valnoctamide, 400 mg, was administered orally to seven healthy subjects and to six patients with epilepsy stabilized with long-term carbamazepine therapy. In the patients with epilepsy, Valnoctamide kinetics was also reassessed after 8-day oral dosing at a dosage of 600 mg daily. Plasma samples were assayed by gas chromatography-mass spectrometry with use of a capillary column coated with chiral stationary phase that enabled baseline resolution of the four stereoisomers, designated hereafter as A, B, C, and D (where A and C, together with B and D, represent enantiomeric pairs). RESULTS: In healthy subjects, stereoisomers A, C, and D showed similar kinetics, with an apparent oral clearance (CL/F) of about 4 1/2 L/hr, a half-life (t1/2) of about 10 hours, and an apparent volume of distribution (VSS/F) of about 65 L. However, stereoisomer B showed a much higher clearance (8.7 +/- 0.9 L/hr) and a shorter t1/2 (5.8 hours). For all stereoisomers, CL/F values in patients with epilepsy were about tenfold higher than those found in healthy subjects. Compared with healthy subjects, patients with epilepsy also showed shorter t1/2 values and higher VSS/F values for each of the stereoisomers. After 7-day dosing, CL/F values at steady state were lower than those determined in the same patients after a single dose. CONCLUSIONS: Valnoctamide exhibits enantioselectivity and diastereoselectivity, an observation that may have important practical implications if pharmacodynamic differences between stereoisomers are also found. The observed pharmacokinetic differences between healthy subjects and patients with epilepsy are likely to be related to induction of metabolism of Valnoctamide stereoisomers by carbamazepine
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carbamazepine Valnoctamide interaction in epileptic patients in vitro in vivo correlation
Epilepsia, 1993Co-Authors: F Pisani, Emilio Perucca, A Fazio, C Artesi, G Oteri, A Hajyehia, Deanna L Kroetz, R H Levy, M DialerAbstract:Six patients stabilized with carbamazepine (CBZ) therapy received an 8-day "add-on" supplement of Valnoctamide (VCD), a tranquilizer available over the counter (OTC) in several European countries that exhibits promising anticonvulsant activity in animal models. During VCD intake, serum levels of the active CBZ metabolite, carbamazepine-10,11-epoxide (CBZ-E), increased fivefold from 1.5 +/- 0.7 micrograms/ml at baseline to 7.4 +/- 4.4 micrograms/ml after 4 days of VCD therapy and 7.7 +/- 3.1 micrograms/ml after 7 days of VCD therapy (means +/- SD, p < 0.01). In 4 patients, the increase in serum CBZ-E levels was associated with clinical signs of CBZ intoxication. CBZ-E levels returned to baseline after VCD therapy was discontinued. Serum CBZ levels remained stable throughout the study. The interaction observed in this study is similar to that described in patients treated with CBZ and valpromide (VPD, an isomer of VCD). In a mechanistic study, therapeutic concentrations of VCD inhibited hydrolysis of styrene oxide in human liver microsome preparations. Thus, VCD is a potent inhibitor of microsomal epoxide hydrolase (IC50 15 microM). There was a striking similarity between in vitro and in vivo inhibition potencies. In this study, VCD clearance was higher in epileptic patients (treated with CBZ) than in healthy subjects.
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comparative efficacy of Valnoctamide and sec butylpropylacetamide spd in terminating nerve agent induced seizures in pediatric rats
Epilepsia, 2019Co-Authors: Kari M Haines, John H Mcdonough, Liana M Matson, Emily N Dunn, Cherish E Ardinger, Robyn B Leestubbs, David Bibi, Meir BialerAbstract: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, and 70 (adult) rats, previously implanted with electroencephalography (EEG) electrodes were exposed to seizure-inducing doses of the nerve agents sarin or VX and EEG was recorded continuously. Five minutes after seizure onset, animals were treated with SPD, VCD, or phenobarbital. The up-down method was used over successive animals to determine the anticonvulsant median effective dose (ED50 ) of the drugs. Results SPD-ED50 values in the VX model were the following: PND21, 53 mg/kg (male) and 48 mg/kg (female); PND28, 108 mg/kg (male) and 43 mg/kg (female); and PND70, 101 mg/kg (male) and 40 mg/kg (female). SPD-ED50 values in the sarin model were the following: PND21, 44 mg/kg (male) and 28 mg/kg (female); PND28, 79 mg/kg (male) and 34 mg/kg (female); and PND70, 53 mg/kg (male) and 53 mg/kg (female). VCD-ED50 values in the VX model were the following: PND21, 34 mg/kg (male) and 43 mg/kg (female); PND28, 165 mg/kg (male) and 59 mg/kg (female); and PND70, 87 mg/kg (male) and 91 mg/kg (female). VCD-ED50 values in the sarin model were the following: PND21, 45 mg/kg (male), 48 mg/kg (female); PND28, 152 mg/kg (male) 79 mg/kg (female); and PND70, 97 mg/kg (male) 79 mg/kg (female). Phenobarbital-ED50 values in the VX model were the following: PND21, 43 mg/kg (male) and 18 mg/kg (female); PND28, 48 mg/kg (male) and 97 mg/kg (female). Phenobarbital-ED50 values in the sarin model were the following: PND21, 32 mg/kg (male) and 32 mg/kg (female); PND28, 58 mg/kg (male) and 97 mg/kg (female); and PND70, 65 mg/kg (female). Significance SPD and VCD demonstrated anticonvulsant activity in both immature and adult rats in the sarin- and VX-induced status epilepticus models. Phenobarbital was effective in immature rats, whereas in adult rats, higher doses were required that were accompanied by toxicity. Overall, significantly less drug was required to stop seizures in PND21 animals than in the older animals, and overall, males required higher amounts of drug than females.
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the potential of sec butylpropylacetamide spd and Valnoctamide and their individual stereoisomers in status epilepticus
Epilepsy & Behavior, 2015Co-Authors: Tawfeeq Shekhahmad, Hafiz Mawasi, Boris Yagen, John H Mcdonough, Meir BialerAbstract: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 epilepticus (SE) induced by pilocarpine and the organophosphates soman and paraoxon. Valnoctamide has similar activity as SPD in the soman-induced SE model. The activity of SPD and VCD against SE is superior to that of diazepam and midazolam in terms of rapid onset, potency, and ability to block SE when given 20 to 60 min after seizure onset. sec-Butylpropylacetamide and VCD possess two stereogenic carbons in their chemical structure and, thus, exist as a racemic mixture of four individual stereoisomers. The anticonvulsant activity of the individual stereoisomers of SPD and VCD was comparatively evaluated in several anticonvulsant rodent models including the benzodiazepine-resistant SE model. sec-Butylpropylacetamide has stereoselective pharmacokinetics (PK) and pharmacodynamics (PD). The higher clearance of (2R,3S)-SPD and (2S,3R)-SPD led to a 50% lower plasma exposure and, consequently, to a lower anticonvulsant activity compared to racemic-SPD and its two other stereoisomers. Racemic-SPD, (2S,3S)-SPD, and (2R,3R)-SPD have similar anticonvulsant activities and PK profiles that are better than those of (2R,3S)-SPD and (2S,3R)-SPD. Valnoctamide has a stereoselective PK with (2S,3S)-VCD exhibiting the lowest clearance and, consequently, a twice-higher plasma exposure than all other stereoisomers. Nevertheless, there was less stereoselectivity in VCD anticonvulsant activity, and each stereoisomer had similar ED50 values in most models. sec-Butylpropylacetamide and VCD stereoisomers did not cause teratogenicity (i.e., neural tube defect) in mice at doses 3-12 times higher than their anticonvulsant-ED50 values. This article is part of a Special Issue entitled "Status Epilepticus".
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stereoselective anticonvulsant and pharmacokinetic analysis of Valnoctamide a cns active derivative of valproic acid with low teratogenic potential
Epilepsia, 2014Co-Authors: Tawfeeq Shekhahmad, Richard H Finnell, Bogdan J Wlodarczyk, Naama Hen, Boris Yagen, John H Mcdonough, Meir BialerAbstract:Summary Objective 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 pharmacodynamics (PD; anticonvulsant activity and teratogenicity) and PK of the four individual stereoisomers of VCD. Methods The anticonvulsant activity of VCD individual stereoisomers was evaluated in several rodent anticonvulsant models including maximal electroshock, 6 Hz psychomotor, subcutaneous metrazol, and the pilocarpine-induced and soman-induced status epilepticus (SE). The PK-PD (anticonvulsant activity) relationship of VCD stereoisomers was evaluated following intraperitoneal administration (70 mg/kg) to rats. Induction of neural tube defects (NTDs) by VCD stereoisomers was evaluated in a mouse strain that was highly susceptible to teratogen-induced NTDs. Results VCD had a stereoselective PK, with (2S,3S)-VCD exhibiting the lowest clearance, and consequently a twice-higher plasma exposure than all other stereoisomers. Nervertheless, there was less stereoselectivity in VCD anticonvulsant activity and each stereoisomer had similar median effective dose (ED)50 values in most models. VCD stereoisomers (258 or 389 mg/kg) did not cause NTDs. These doses are 3–12 times higher than VCD anticonvulsant ED50 values. Significance VCD displayed stereoselective PK that did not lead to significant stereoselective activity in various anticonvulsant rodent models. If VCD exerted its broad-spectrum anticonvulsant activity using a single mechanism of action (MOA), it is likely that it would exhibit a stereoselective PD. The fact that there was no significant difference between racemic VCD and its individual stereoisomers suggests that VCD's anticonvulsant activity is due to multiple MOAs.
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Valnoctamide and sec butyl propylacetamide spd for acute seizures and status epilepticus
Epilepsia, 2013Co-Authors: Tawfeeq Shekhahmad, Naama Hen, Boris Yagen, John H Mcdonough, Meir BialerAbstract:Summary 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 SPD possess two stereogenic carbons in their chemical structure. SPD possesses a unique and broad-spectrum antiseizure profile superior to that of valproic acid (VPA) and better than that of VCD. In addition SPD blocked behavioral- and electrographic-SE induced by pilocarpine and soman (organophosphate nerve gas) and afforded in vivo neuroprotection that was associated with cognitive sparing. VCD has activity similar to that of SPD in pilocarpine-induced status epilepticus (SE), although at higher doses. The activity of SPD and VCD against SE is superior to that of diazepam in terms of rapid onset, potency, and ability to block SE when given 20–60 min after seizure onset. When administered 20 and 40 min after SE onset, SPD (100–174 mg/kg) produced long-lasting efficacy (e.g., 4–8 h) against soman-induced convulsive and electrographic SE in both rats and guinea pigs. SPD activity in the pilocarpine and soman-induced SE models when administered 20–60 min after seizure onset, differentiates SPD from benzodiazepines and all other antiepileptic drugs .
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a new derivative of valproic acid amide possesses a broad spectrum antiseizure profile and unique activity against status epilepticus and organophosphate neuronal damage
Epilepsia, 2012Co-Authors: Steve H White, Tawfeeq Shekhahmad, Naama Hen, John H Mcdonough, Anitha Alex, Amanda Pollock, Karen S Wilcox, James P Stables, Dan Kaufmann, Boris YagenAbstract:Purpose sec-Butyl-propylacetamide (SPD) is a one-carbon homologue of Valnoctamide (VCD), a CNS-active amide derivative of valproic acid (VPA) currently in phase II clinical trials. The current study evaluated the anticonvulsant activity of SPD in a battery of rodent seizure and epilepsy models and assessed its efficacy in rat and guinea pig models of status epilepticus (SE) and neuroprotection in an organotypic hippocampal slice model of excitotoxic cell death.
