The Experts below are selected from a list of 1413 Experts worldwide ranked by ideXlab platform
Meir Bialer - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetic analysis and Antiepileptic Activity of two new isomers of n valproyl glycinamide
Biopharmaceutics & Drug Disposition, 1997Co-Authors: Salim Hadad, Meir BialerAbstract:: Valproyl glycinamide (TV 1901-VPGD) is a new Antiepileptic drug, which is currently undergoing clinical trials. The present study explored the pharmacokinetics and pharmacodynamics (anticonvulsant Activity and neurotoxicity) of two new isomers of valproyl glycinamide: valnoctyl glycinamide (VCGD) and diisopropylacetyl (DIGD). Both VCGD and DIGD showed anticonvulsant Activity and a safety margin in mice similar to those of VPGD. Following i.v. administration (556 mg) to six dogs, VCGD had a clearance (Cl) value of 3.8 +/- 1.1 Lh-1 (mean +/- SD), a volume of distribution (Vss) of 15 +/- 2 L, and a half-life (t1/2) of 1.9 +/- 0.3 h. DIGD had Cl, Vss, and t1/2 values of 10 +/- 0.8 Lh-1, 19 +/- 3 L, and 1.6 +/- 0.2 h, respectively. Neither VCGD nor DIGD operated as chemical drug delivery systems (CDDSs) of glycine, valnoctic acid, or diisopropyl acetic acid and both showed Antiepileptic profiles different from that of valproic acid (VPA). Both glycinamides were biotransformed to their glycine analogues with similar fractions metabolized (fm): 59 +/- 5% (VCGD) and 62 +/- 15% (DIGD). The two glycine metabolites, valnoctyl glycine (VCGA) and diisopropylacetyl glycine (DIGA), were also administered to the same dogs in order to calculate the above fm values. Both VCGA and DIGA had higher Cl and lower Vss values than VCGD and DIGD and therefore their mean t1/2 values were 0.43 +/- 0.02 and 0.30 +/- 0.07 h, respectively. VCGA and DIGA were excreted mainly intact in the urine, with fractions excreted unchanged (fe) of 60 +/- 9 and 55 +/- 7%, respectively. The improved pharmacokinetic profile of VCGD and DIGD relative to their glycine analogues may explain the similarity of their anticonvulsant Activity to that of valproyl glycinamide. The current study demonstrates the benefit of the structure-pharmacokinetic-pharmacodynamic relationship (SPPR) approach in developing and selecting a potent Antiepileptic compound in intact animals based not only on its intrinsic pharmacodynamic Activity but also on its improved pharmacokinetic profile.
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Pharmacokinetic analysis and Antiepileptic Activity of two new isomers of N‐valproyl glycinamide
Biopharmaceutics & Drug Disposition, 1997Co-Authors: Salim Hadad, Meir BialerAbstract:: Valproyl glycinamide (TV 1901-VPGD) is a new Antiepileptic drug, which is currently undergoing clinical trials. The present study explored the pharmacokinetics and pharmacodynamics (anticonvulsant Activity and neurotoxicity) of two new isomers of valproyl glycinamide: valnoctyl glycinamide (VCGD) and diisopropylacetyl (DIGD). Both VCGD and DIGD showed anticonvulsant Activity and a safety margin in mice similar to those of VPGD. Following i.v. administration (556 mg) to six dogs, VCGD had a clearance (Cl) value of 3.8 +/- 1.1 Lh-1 (mean +/- SD), a volume of distribution (Vss) of 15 +/- 2 L, and a half-life (t1/2) of 1.9 +/- 0.3 h. DIGD had Cl, Vss, and t1/2 values of 10 +/- 0.8 Lh-1, 19 +/- 3 L, and 1.6 +/- 0.2 h, respectively. Neither VCGD nor DIGD operated as chemical drug delivery systems (CDDSs) of glycine, valnoctic acid, or diisopropyl acetic acid and both showed Antiepileptic profiles different from that of valproic acid (VPA). Both glycinamides were biotransformed to their glycine analogues with similar fractions metabolized (fm): 59 +/- 5% (VCGD) and 62 +/- 15% (DIGD). The two glycine metabolites, valnoctyl glycine (VCGA) and diisopropylacetyl glycine (DIGA), were also administered to the same dogs in order to calculate the above fm values. Both VCGA and DIGA had higher Cl and lower Vss values than VCGD and DIGD and therefore their mean t1/2 values were 0.43 +/- 0.02 and 0.30 +/- 0.07 h, respectively. VCGA and DIGA were excreted mainly intact in the urine, with fractions excreted unchanged (fe) of 60 +/- 9 and 55 +/- 7%, respectively. The improved pharmacokinetic profile of VCGD and DIGD relative to their glycine analogues may explain the similarity of their anticonvulsant Activity to that of valproyl glycinamide. The current study demonstrates the benefit of the structure-pharmacokinetic-pharmacodynamic relationship (SPPR) approach in developing and selecting a potent Antiepileptic compound in intact animals based not only on its intrinsic pharmacodynamic Activity but also on its improved pharmacokinetic profile.
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pharmacokinetics and Antiepileptic Activity of valproyl hydroxamic acid derivatives
Pharmaceutical Research, 1997Co-Authors: Micha Levi, Boris Yagen, Meir BialerAbstract:Purpose. To explore the utilization of seven novel hydroxamic acid derivatives of valproic acid (VPA) as new Antiepileptics.
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pharmacokinetic analysis and Antiepileptic Activity of tetra methylcyclopropane analogues of valpromide
Pharmaceutical Research, 1996Co-Authors: Meir Bialer, Salim Hadad, Bashier Kadry, Ali Abdulhai, Abdulla Hajyehia, Jeff Sterling, Yaacov Herzig, Boris YagenAbstract:Purpose. The described structure pharmacokinetic pharmacodynamic relationships (SPPR) study explored the utilization of tetramethylcyclopropane analogues of valpromide (VPD), or tetra-methylcyclopropane carboxamide derivatives of valproic acid (VPA) as new Antiepileptics.
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pharmacokinetic analysis and Antiepileptic Activity of n valproyl derivatives of gaba and glycine
Pharmaceutical Research, 1995Co-Authors: Salim Hadad, Meir BialerAbstract:Purpose. To explore the possibility of utilizing valproyl derivatives of GABA and glycine as new Antiepileptics by using the structure pharmacokinetic-pharmacodynamic relationship (SPPR) approach.
Weiwei Li - One of the best experts on this subject based on the ideXlab platform.
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abhd6 blockade exerts Antiepileptic Activity in ptz induced seizures and in spontaneous seizures in r6 2 mice
Neuron, 2014Co-Authors: Alipi V Naydenov, Eric A Horne, Christine S Cheah, Katie Swinney, William R Marrs, Jacqueline L Blankman, Sarah Tu, Allison E Cherry, Susan Fung, Weiwei LiAbstract:Summary The serine hydrolase α/β-hydrolase domain 6 (ABHD6) hydrolyzes the most abundant endocannabinoid (eCB) in the brain, 2-arachidonoylglycerol (2-AG), and controls its availability at cannabinoid receptors. We show that ABHD6 inhibition decreases pentylenetetrazole (PTZ)-induced generalized tonic-clonic and myoclonic seizure incidence and severity. This effect is retained in Cnr1 −/− or Cnr2 −/− mice, but blocked by addition of a subconvulsive dose of picrotoxin, suggesting the involvement of GABA A receptors. ABHD6 inhibition also blocked spontaneous seizures in R6/2 mice, a genetic model of juvenile Huntington's disease known to exhibit dysregulated eCB signaling. ABHD6 blockade retained its Antiepileptic Activity over chronic dosing and was not associated with psychomotor or cognitive effects. While the etiology of seizures in R6/2 mice remains unsolved, involvement of the hippocampus is suggested by interictal epileptic discharges, increased expression of vGLUT1 but not vGAT, and reduced Neuropeptide Y (NPY) expression. We conclude that ABHD6 inhibition may represent a novel Antiepileptic strategy.
Salim Hadad - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetic analysis and Antiepileptic Activity of two new isomers of n valproyl glycinamide
Biopharmaceutics & Drug Disposition, 1997Co-Authors: Salim Hadad, Meir BialerAbstract:: Valproyl glycinamide (TV 1901-VPGD) is a new Antiepileptic drug, which is currently undergoing clinical trials. The present study explored the pharmacokinetics and pharmacodynamics (anticonvulsant Activity and neurotoxicity) of two new isomers of valproyl glycinamide: valnoctyl glycinamide (VCGD) and diisopropylacetyl (DIGD). Both VCGD and DIGD showed anticonvulsant Activity and a safety margin in mice similar to those of VPGD. Following i.v. administration (556 mg) to six dogs, VCGD had a clearance (Cl) value of 3.8 +/- 1.1 Lh-1 (mean +/- SD), a volume of distribution (Vss) of 15 +/- 2 L, and a half-life (t1/2) of 1.9 +/- 0.3 h. DIGD had Cl, Vss, and t1/2 values of 10 +/- 0.8 Lh-1, 19 +/- 3 L, and 1.6 +/- 0.2 h, respectively. Neither VCGD nor DIGD operated as chemical drug delivery systems (CDDSs) of glycine, valnoctic acid, or diisopropyl acetic acid and both showed Antiepileptic profiles different from that of valproic acid (VPA). Both glycinamides were biotransformed to their glycine analogues with similar fractions metabolized (fm): 59 +/- 5% (VCGD) and 62 +/- 15% (DIGD). The two glycine metabolites, valnoctyl glycine (VCGA) and diisopropylacetyl glycine (DIGA), were also administered to the same dogs in order to calculate the above fm values. Both VCGA and DIGA had higher Cl and lower Vss values than VCGD and DIGD and therefore their mean t1/2 values were 0.43 +/- 0.02 and 0.30 +/- 0.07 h, respectively. VCGA and DIGA were excreted mainly intact in the urine, with fractions excreted unchanged (fe) of 60 +/- 9 and 55 +/- 7%, respectively. The improved pharmacokinetic profile of VCGD and DIGD relative to their glycine analogues may explain the similarity of their anticonvulsant Activity to that of valproyl glycinamide. The current study demonstrates the benefit of the structure-pharmacokinetic-pharmacodynamic relationship (SPPR) approach in developing and selecting a potent Antiepileptic compound in intact animals based not only on its intrinsic pharmacodynamic Activity but also on its improved pharmacokinetic profile.
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Pharmacokinetic analysis and Antiepileptic Activity of two new isomers of N‐valproyl glycinamide
Biopharmaceutics & Drug Disposition, 1997Co-Authors: Salim Hadad, Meir BialerAbstract:: Valproyl glycinamide (TV 1901-VPGD) is a new Antiepileptic drug, which is currently undergoing clinical trials. The present study explored the pharmacokinetics and pharmacodynamics (anticonvulsant Activity and neurotoxicity) of two new isomers of valproyl glycinamide: valnoctyl glycinamide (VCGD) and diisopropylacetyl (DIGD). Both VCGD and DIGD showed anticonvulsant Activity and a safety margin in mice similar to those of VPGD. Following i.v. administration (556 mg) to six dogs, VCGD had a clearance (Cl) value of 3.8 +/- 1.1 Lh-1 (mean +/- SD), a volume of distribution (Vss) of 15 +/- 2 L, and a half-life (t1/2) of 1.9 +/- 0.3 h. DIGD had Cl, Vss, and t1/2 values of 10 +/- 0.8 Lh-1, 19 +/- 3 L, and 1.6 +/- 0.2 h, respectively. Neither VCGD nor DIGD operated as chemical drug delivery systems (CDDSs) of glycine, valnoctic acid, or diisopropyl acetic acid and both showed Antiepileptic profiles different from that of valproic acid (VPA). Both glycinamides were biotransformed to their glycine analogues with similar fractions metabolized (fm): 59 +/- 5% (VCGD) and 62 +/- 15% (DIGD). The two glycine metabolites, valnoctyl glycine (VCGA) and diisopropylacetyl glycine (DIGA), were also administered to the same dogs in order to calculate the above fm values. Both VCGA and DIGA had higher Cl and lower Vss values than VCGD and DIGD and therefore their mean t1/2 values were 0.43 +/- 0.02 and 0.30 +/- 0.07 h, respectively. VCGA and DIGA were excreted mainly intact in the urine, with fractions excreted unchanged (fe) of 60 +/- 9 and 55 +/- 7%, respectively. The improved pharmacokinetic profile of VCGD and DIGD relative to their glycine analogues may explain the similarity of their anticonvulsant Activity to that of valproyl glycinamide. The current study demonstrates the benefit of the structure-pharmacokinetic-pharmacodynamic relationship (SPPR) approach in developing and selecting a potent Antiepileptic compound in intact animals based not only on its intrinsic pharmacodynamic Activity but also on its improved pharmacokinetic profile.
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pharmacokinetic analysis and Antiepileptic Activity of tetra methylcyclopropane analogues of valpromide
Pharmaceutical Research, 1996Co-Authors: Meir Bialer, Salim Hadad, Bashier Kadry, Ali Abdulhai, Abdulla Hajyehia, Jeff Sterling, Yaacov Herzig, Boris YagenAbstract:Purpose. The described structure pharmacokinetic pharmacodynamic relationships (SPPR) study explored the utilization of tetramethylcyclopropane analogues of valpromide (VPD), or tetra-methylcyclopropane carboxamide derivatives of valproic acid (VPA) as new Antiepileptics.
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pharmacokinetic analysis and Antiepileptic Activity of n valproyl derivatives of gaba and glycine
Pharmaceutical Research, 1995Co-Authors: Salim Hadad, Meir BialerAbstract:Purpose. To explore the possibility of utilizing valproyl derivatives of GABA and glycine as new Antiepileptics by using the structure pharmacokinetic-pharmacodynamic relationship (SPPR) approach.
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Comparative Pharmacokinetic and Pharmacodynamic Analysis of Phthaloyl Glycine Derivatives with Potential Antiepileptic Activity
Pharmaceutical Research, 1994Co-Authors: Omar Abu Salach, Salim Hadad, Abdullah Haj-yehia, Sherbel Sussan, Meir BialerAbstract:Glycine, in addition to GABA, is one of the most important neurotransmitter amino acids. The described structure pharmacokinetic pharmacodynamic relationships (SPPR) study explored the possibility of utilizing phthaloyl derivatives of glycine as new Antiepileptics. This was carried out by investigating the pharmacokinetics and pharmacodynamics (anticonvulsant Activity and neurotoxicity) of the following four phthalimide derivatives: phthaloyl glycine, phthaloyl glycinamide, N,N-diethyl phthaloyl glycinamide and N,N-diisopropyl phthaloyl glycinamide. Phthaloyl glycine did not demonstrate anticonvulsant Activity, possibly because of its poor pharmacokinetics, high clearance, low volume of distribution and short half life. The three glycinamide derivatives showed anticonvulsant Activity and had better pharmacokinetic profiles, longer half life and mean residence time, than phthaloyl glycine. Phthaloyl glycinamide was more potent than one of the major Antiepileptic agents— valproic acid and showed a better margin between Activity and neurotoxicity. The four investigated phthaloyl glycine derivatives did not operate as chemical drug delivery systems (CDDS) of glycine, but acted rather as drugs on their own. Phthaloyl glycine was excreted unchanged in the urine while the urinary metabolites of the glycinamide derivatives were phthaloyl glycine and phthaloyl glycinamide. In this analogous series of phthalimide derivatives, minor chemical changes affected dramatically the compounds’ pharmacokinetics. The current study demonstrates the benefit of the SPPR approach in developing and selecting a potent Antiepileptic compound in intact animals based not only on its intrinsic pharmacodynamic Activity, but also on its better pharmacokinetic profile.
Alipi V Naydenov - One of the best experts on this subject based on the ideXlab platform.
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abhd6 blockade exerts Antiepileptic Activity in ptz induced seizures and in spontaneous seizures in r6 2 mice
Neuron, 2014Co-Authors: Alipi V Naydenov, Eric A Horne, Christine S Cheah, Katie Swinney, William R Marrs, Jacqueline L Blankman, Sarah Tu, Allison E Cherry, Susan Fung, Weiwei LiAbstract:Summary The serine hydrolase α/β-hydrolase domain 6 (ABHD6) hydrolyzes the most abundant endocannabinoid (eCB) in the brain, 2-arachidonoylglycerol (2-AG), and controls its availability at cannabinoid receptors. We show that ABHD6 inhibition decreases pentylenetetrazole (PTZ)-induced generalized tonic-clonic and myoclonic seizure incidence and severity. This effect is retained in Cnr1 −/− or Cnr2 −/− mice, but blocked by addition of a subconvulsive dose of picrotoxin, suggesting the involvement of GABA A receptors. ABHD6 inhibition also blocked spontaneous seizures in R6/2 mice, a genetic model of juvenile Huntington's disease known to exhibit dysregulated eCB signaling. ABHD6 blockade retained its Antiepileptic Activity over chronic dosing and was not associated with psychomotor or cognitive effects. While the etiology of seizures in R6/2 mice remains unsolved, involvement of the hippocampus is suggested by interictal epileptic discharges, increased expression of vGLUT1 but not vGAT, and reduced Neuropeptide Y (NPY) expression. We conclude that ABHD6 inhibition may represent a novel Antiepileptic strategy.
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ABHD6 blockade exerts Antiepileptic Activity in PTZ-induced seizures and in spontaneous seizures in R6/2 mice.
Neuron, 2014Co-Authors: Alipi V Naydenov, Eric A Horne, Christine S Cheah, Katie Swinney, William R Marrs, Jacqueline L Blankman, Sarah Tu, Allison E CherryAbstract:Summary The serine hydrolase α/β-hydrolase domain 6 (ABHD6) hydrolyzes the most abundant endocannabinoid (eCB) in the brain, 2-arachidonoylglycerol (2-AG), and controls its availability at cannabinoid receptors. We show that ABHD6 inhibition decreases pentylenetetrazole (PTZ)-induced generalized tonic-clonic and myoclonic seizure incidence and severity. This effect is retained in Cnr1 −/− or Cnr2 −/− mice, but blocked by addition of a subconvulsive dose of picrotoxin, suggesting the involvement of GABA A receptors. ABHD6 inhibition also blocked spontaneous seizures in R6/2 mice, a genetic model of juvenile Huntington's disease known to exhibit dysregulated eCB signaling. ABHD6 blockade retained its Antiepileptic Activity over chronic dosing and was not associated with psychomotor or cognitive effects. While the etiology of seizures in R6/2 mice remains unsolved, involvement of the hippocampus is suggested by interictal epileptic discharges, increased expression of vGLUT1 but not vGAT, and reduced Neuropeptide Y (NPY) expression. We conclude that ABHD6 inhibition may represent a novel Antiepileptic strategy.
Allison E Cherry - One of the best experts on this subject based on the ideXlab platform.
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abhd6 blockade exerts Antiepileptic Activity in ptz induced seizures and in spontaneous seizures in r6 2 mice
Neuron, 2014Co-Authors: Alipi V Naydenov, Eric A Horne, Christine S Cheah, Katie Swinney, William R Marrs, Jacqueline L Blankman, Sarah Tu, Allison E Cherry, Susan Fung, Weiwei LiAbstract:Summary The serine hydrolase α/β-hydrolase domain 6 (ABHD6) hydrolyzes the most abundant endocannabinoid (eCB) in the brain, 2-arachidonoylglycerol (2-AG), and controls its availability at cannabinoid receptors. We show that ABHD6 inhibition decreases pentylenetetrazole (PTZ)-induced generalized tonic-clonic and myoclonic seizure incidence and severity. This effect is retained in Cnr1 −/− or Cnr2 −/− mice, but blocked by addition of a subconvulsive dose of picrotoxin, suggesting the involvement of GABA A receptors. ABHD6 inhibition also blocked spontaneous seizures in R6/2 mice, a genetic model of juvenile Huntington's disease known to exhibit dysregulated eCB signaling. ABHD6 blockade retained its Antiepileptic Activity over chronic dosing and was not associated with psychomotor or cognitive effects. While the etiology of seizures in R6/2 mice remains unsolved, involvement of the hippocampus is suggested by interictal epileptic discharges, increased expression of vGLUT1 but not vGAT, and reduced Neuropeptide Y (NPY) expression. We conclude that ABHD6 inhibition may represent a novel Antiepileptic strategy.
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ABHD6 blockade exerts Antiepileptic Activity in PTZ-induced seizures and in spontaneous seizures in R6/2 mice.
Neuron, 2014Co-Authors: Alipi V Naydenov, Eric A Horne, Christine S Cheah, Katie Swinney, William R Marrs, Jacqueline L Blankman, Sarah Tu, Allison E CherryAbstract:Summary The serine hydrolase α/β-hydrolase domain 6 (ABHD6) hydrolyzes the most abundant endocannabinoid (eCB) in the brain, 2-arachidonoylglycerol (2-AG), and controls its availability at cannabinoid receptors. We show that ABHD6 inhibition decreases pentylenetetrazole (PTZ)-induced generalized tonic-clonic and myoclonic seizure incidence and severity. This effect is retained in Cnr1 −/− or Cnr2 −/− mice, but blocked by addition of a subconvulsive dose of picrotoxin, suggesting the involvement of GABA A receptors. ABHD6 inhibition also blocked spontaneous seizures in R6/2 mice, a genetic model of juvenile Huntington's disease known to exhibit dysregulated eCB signaling. ABHD6 blockade retained its Antiepileptic Activity over chronic dosing and was not associated with psychomotor or cognitive effects. While the etiology of seizures in R6/2 mice remains unsolved, involvement of the hippocampus is suggested by interictal epileptic discharges, increased expression of vGLUT1 but not vGAT, and reduced Neuropeptide Y (NPY) expression. We conclude that ABHD6 inhibition may represent a novel Antiepileptic strategy.
