The Experts below are selected from a list of 105 Experts worldwide ranked by ideXlab platform
Anat Biegon - One of the best experts on this subject based on the ideXlab platform.
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Dexanabinol hu 211 in the treatment of severe closed head injury a randomized placebo controlled phase ii clinical trial
Critical Care Medicine, 2002Co-Authors: Nachshon Knoller, Leon Levi, Igal Shoshan, Eli Reichenthal, Nissim Razon, Z H Rappaport, Anat BiegonAbstract:Objective To establish the safety of intravenous Dexanabinol in severe head injury.Design Prospective, randomized, double-blind, placebo- (vehicle) controlled, multicenter, escalating dose study of a single administration of drug (48 or 150 mg) or vehicle (1 or 3 mL).Setting All Israeli neurosurgica
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Dexanabinol hu 211 effect on experimental autoimmune encephalomyelitis implications for the treatment of acute relapses of multiple sclerosis
Journal of Neuroimmunology, 2000Co-Authors: Anat Achiron, Shmuel Miron, V Lavie, Raanan Margalit, Anat BiegonAbstract:Dexanabinol (HU-211) is a synthetic non-psychotropic cannabinoid which suppresses TNF-alpha production in the brain and peripheral blood. The effects of Dexanabinol in rat experimental autoimmune encephalomyelitis (EAE) were studied using different doses, modes of administration and time regimes. Dexanabinol, 5 mg/kg i.v. given once after disease onset (day 10), significantly reduced maximal EAE score. Increasing the dose or treatment duration resulted in further suppression of EAE. Drug administration at earlier phases during disease induction was not effective. Histological studies supported the clinical findings demonstrating reduction in the inflammatory response in the brain and spinal cord in animals treated with Dexanabinol. The results suggest that Dexanabinol may provide an alternative mode of treatment for acute exacerbations of multiple sclerosis (MS).
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in vitro and in vivo study of water soluble prodrugs of Dexanabinol
Journal of Pharmaceutical Sciences, 1999Co-Authors: Emil Pop, Anat Biegon, Stanislaw Rachwal, Jirina Vlasak, Alevtina D Zharikova, Laszlo ProkaiAbstract:Trialkylammonium acetoxymethyl esters of Dexanabinol were synthesized and evaluated as water-soluble prodrugs. Syntheses were performed by conventional methods; solubility in water and stability in buffers and human plasma were determined by HPLC, and in vivo tissue distribution studies were performed in a rat model. Most of the new derivatives were soluble in water (∼50 mg/mL). They were relatively stable in water, while rapidly hydrolyzed in human plasma. Distribution studies indicated that peak concentrations of drug both in blood (30 μg/mL) and brain (2 μg/mL) were rapidly (5 min) achieved after iv administration of a selected prodrug to rats. The blood concentration decreased faster than brain levels which were detectable even after 24 h. Some of the examined esters could be further developed as water soluble prodrugs of Dexanabinol.
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interaction of Dexanabinol hu 211 a novel nmda receptor antagonist with the dopaminergic system
European Journal of Pharmacology, 1997Co-Authors: Sarina Striem, Avi Barjoseph, Yafit Berkovitch, Anat BiegonAbstract:The interaction of 7-hydroxy-delta6-tetrahydrocannabinol 1,1-dimethylheptyl (Dexanabinol: HU-211), a novel NMDA receptor antagonist, with the dopaminergic system was examined using in vitro and in vivo systems. HU-211 (50 or 100 microM) inhibited the binding of [3H]R(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepi n-7-ol hydrochloride ([3H]SCH-23390), a dopamine D1 receptor antagonist, by 29.7 +/- 1.8% and 52.7 +/- 6.3%, respectively. HU-211 10 microM, like the dopamine D1 receptor agonist R(+)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride (SKF-38393), enhanced the conversion of [3H]adenine to cyclic AMP (cAMP) (51.8 +/- 29.7% and 35.6 +/- 21.5% over control, respectively). The HU-211-induced increase was not inhibited by SCH-23390. HU-211 together with the dopamine D1 receptor agonist caused a synergistic elevation (314.7 +/- 14.3%). HU-211 reduced the catalepsy induced by dopamine receptor antagonists. At 10 mg/kg, HU-211 significantly (P < 0.001) reduced the catalepsy time induced by D1, D2 and non-selective dopamine receptor antagonists. Overall, the results of the present study demonstrate that HU-211 interacts with the dopaminergic system and enhances activity at the dopamine D1 receptor level. This activity may have implications in diseases involving the dopaminergic system, such as Parkinson's disease.
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protection against septic shock and suppression of tumor necrosis factor alpha and nitric oxide production by Dexanabinol hu 211 a nonpsychotropic cannabinoid
Journal of Pharmacology and Experimental Therapeutics, 1997Co-Authors: Ruth Gallily, Haim Ovadia, Anat Biegon, Raphael Mechoulam, Aviva Yamin, Yaakov Waksmann, Joseph Weidenfeld, Avi Barjoseph, Esther ShohamiAbstract:Dexanabinol, HU-211, a synthetic cannabinoid devoid of psychotropic effects, improves neurological outcome in models of brain trauma, ischemia and meningitis. Recently, HU-211 was found to inhibit brain tumor necrosis factor (TNFalpha) production after head injury. In the present study, we demonstrate the ability of HU-211 to suppress TNFalpha production and to rescue mice and rats from endotoxic shock after LPS (Escherichia coli 055:B5) inoculation. In BALB/c mice, a dose of 10 mg/kg LPS, injected i.p., caused 57% and 100% mortality, at 24 and 48 hr, respectively. HU-211, administered i.p. 30 min before lipopolysaccharide (LPS), reduced lethality to 9 and 67% at these time points (P 90%) by both murine peritoneal macrophages and rat alveolar macrophage cell line exposed to LPS. HU-211 may, therefore, have therapeutic implications in the treatment of TNFalpha-mediated pathologies.
Esther Shohami - One of the best experts on this subject based on the ideXlab platform.
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long term cerebroprotective effects of Dexanabinol in a model of focal cerebral ischemia
Brain Research, 2001Co-Authors: Gil Lavie, Haim Ovadia, Esther Shohami, Angella Teichner, Ronen R LekerAbstract:In order to test the long-term cerebroprotective effects of Dexanabinol, a synthetic non-competitive NMDA antagonist that also has anti-TNFalpha effects, spontaneously hypertensive rats underwent permanent middle cerebral artery occlusion (PMCAO). Rats were given vehicle or Dexanabinol (4.5 mg/kg) 1, 3 or 6 h after PMCAO. The research consisted of 2 stages. In the short-term set of experiments animals (n=5/group), were tested with a motor disability scale 24 h post PMCAO, then sacrificed and the infarct volume was measured using 2,3,5-Triphenyltetrazolium chloride (TTC) staining. In the long-term set of experiments the rats (n=7/group) were examined daily with a motor disability scale up to 30 days after PMCAO and then sacrificed and infarct volumes were determined using TTC staining. Motor scores were significantly improved in the Dexanabinol treated rats (P<0.05 for all groups) at all the time points examined. Infarct volumes were significantly reduced 24 h after PMCAO in the groups treated 1 or 3 h, but not 6 h after PMCAO compared with vehicle (Mean+/-S.D., 11.5+/-2.02, 12+/-3.2 and 14.4+/-2.4% vs. 20.8+/-1.3% hemispheric volume respectively). The lesions remained significantly smaller in the Dexanabinol groups 30 days after PMCAO (Mean+/-S.D., 24.49+/-1.9% vs. 8.1+/-0.6, 11.1+/-2.3 and 13.8+/-2.5% hemispheric volume in animals treated with vehicle vs. Dexanabinol 1, 3 or 6 h after PMCAO respectively; P<0.05 for all). In conclusion, the extended therapeutic window and the multi-mechanistic durable neuroprotective effects of Dexanabinol make it a promising candidate for future stroke therapy.
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Dexanabinol hu 211 a nonpsychotropic cannabinoid with neuroprotective properties
Drug Development Research, 2000Co-Authors: Esther Shohami, Raphael MechoulamAbstract:The synthetic cannabinoid (+)-(6aS,10aS)-11-hydroxy-Δ-8-tetrahydrocannabinol 1′,1′-dimethylheptyl (Dexanabinol, HU-211) is inactive as a cannabimimetic, but exhibits pharmacological properties characteristic of an N-methyl-D-aspartate (NMDA)-receptor antagonist. It blocks NMDA-receptors stereospecifically by interacting with a site close to, but distinct from, that of uncompetitive NMDA-receptor antagonists and from the recognition sites of glutamate, glycine, and polyamines. HU-211 inhibits the synthesis of tumor necrosis factor alpha (TNFα) and possesses antioxidant properties. HU-211 blocked NMDA-induced 45Ca uptake by primary neuronal cultures of rat forebrain and protected the same neuronal cultures against NMDA and glutamate neurotoxicity. Moreover, HU-211 effectively scavenged peroxy radicals in vitro and protected cultured neurons from the toxic effects of reactive oxygen species (ROS). In addition, HU-211 markedly suppressed in vitro TNFα production and nitric oxide (NO) generation (by >90%) by both murine peritoneal macrophages and rat alveolar macrophage cell line exposed to lipopolysaccharide (LPS). Since glutamate, ROS and TNFα are implicated in the pathophysiology of various acute conditions, the promising results showing neuroprotection by HU-211, acting via multiple mechanisms, led to a series of studies in which the drug was given to experimental animals. In the present review we discuss results from experiments describing the potential use of HU-211 as a neuroprotective agent in models of traumatic brain injury, stroke, optic nerve injury, pneumacocal meningitis, sepsis, and soman toxicity. In addition, HU-211 was introduced into clinical trials for traumatic brain injury and the successful results of two phases of clinical trials in head injured patients are also shown. Drug Dev. Res. 50:211–215, 2000. © 2000 Wiley-Liss, Inc.
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Dexanabinol a novel neuroprotective drug in experimental focal cerebral ischemia
Journal of the Neurological Sciences, 1999Co-Authors: Ronen R Leker, Esther Shohami, Oded Abramsky, Haim OvadiaAbstract:The permanent middle cerebral artery occlusion (PMCAO) model was used to investigate the cerebroprotective effects of the synthetic cannabinoid, Dexanabinol (HU-211). Dexanabinol is a noncompetitive N-methyl-d-aspartate antagonist, with antioxidant and anti-TNFα properties. Twenty hypertensive rats were subjected to PMCAO. Eight were given 4 mg/kg Dexanabinol, i.v., 1 h after PMCAO, eight received vehicle and four were not injected. Five rats underwent sham surgery. Infarct volumes were assessed, as well as TNFα concentrations and NOS activity in brain homogenates. Dexanabinol significantly decreased infarct volumes. It also significantly lowered TNFα levels in the ipsilateral hemisphere although not to the level of sham operated rats. No effect could be demonstrated on NOS activity. In conclusion, Dexanabinol may be a pluripotent cerebroprotective agent.
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protection against septic shock and suppression of tumor necrosis factor alpha and nitric oxide production by Dexanabinol hu 211 a nonpsychotropic cannabinoid
Journal of Pharmacology and Experimental Therapeutics, 1997Co-Authors: Ruth Gallily, Haim Ovadia, Anat Biegon, Raphael Mechoulam, Aviva Yamin, Yaakov Waksmann, Joseph Weidenfeld, Avi Barjoseph, Esther ShohamiAbstract:Dexanabinol, HU-211, a synthetic cannabinoid devoid of psychotropic effects, improves neurological outcome in models of brain trauma, ischemia and meningitis. Recently, HU-211 was found to inhibit brain tumor necrosis factor (TNFalpha) production after head injury. In the present study, we demonstrate the ability of HU-211 to suppress TNFalpha production and to rescue mice and rats from endotoxic shock after LPS (Escherichia coli 055:B5) inoculation. In BALB/c mice, a dose of 10 mg/kg LPS, injected i.p., caused 57% and 100% mortality, at 24 and 48 hr, respectively. HU-211, administered i.p. 30 min before lipopolysaccharide (LPS), reduced lethality to 9 and 67% at these time points (P 90%) by both murine peritoneal macrophages and rat alveolar macrophage cell line exposed to LPS. HU-211 may, therefore, have therapeutic implications in the treatment of TNFalpha-mediated pathologies.
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cytokine production in the brain following closed head injury Dexanabinol hu 211 is a novel tnf α inhibitor and an effective neuroprotectant
Journal of Neuroimmunology, 1997Co-Authors: Esther Shohami, Raphael Mechoulam, Ruth Gallily, Roman Bass, T BenhurAbstract:Traumatic brain injury triggers a cascade of events resulting in delayed edema, necrosis and impaired function. Harmful mediators are accumulating in the brain after injury and recently, the role of cytokines in the pathophysiology of brain injury has been suggested. We have developed an experimental model for closed head injury (CHI), in which edema, blood–brain-barrier disruption, motor and memory dysfunctions have been demonstrated. In this study, spatial and temporal induction of IL-1, IL-6 and TNF-α gene mRNA transcription and of TNF-α and IL-6 activity in rat brain after CHI are shown. Dexanabinol, HU-211, is a synthetic cannabinoid devoid of cannabimimetic effects; it exhibits pharmacological properties of N-methyl-d-aspartate (NMDA)-receptor antagonist and is an effective cerebroprotecant. We report here that HU-211 is a novel inhibitor of TNF-α production at a post-transcriptional stage. HU-211, pentoxyfilline and TNF-binding protein improved the outcome of CHI. We suggest that TNF-α is a primary mediator of neurotoxicity after CHI, as inhibition of TNF-α is associated with better clinical recovery. TNF-α modulating agents, if given within the early time window post-injury, may improve the final neurological outcome in victims of brain trauma.
Raphael Mechoulam - One of the best experts on this subject based on the ideXlab platform.
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Dexanabinol hu 211 a nonpsychotropic cannabinoid with neuroprotective properties
Drug Development Research, 2000Co-Authors: Esther Shohami, Raphael MechoulamAbstract:The synthetic cannabinoid (+)-(6aS,10aS)-11-hydroxy-Δ-8-tetrahydrocannabinol 1′,1′-dimethylheptyl (Dexanabinol, HU-211) is inactive as a cannabimimetic, but exhibits pharmacological properties characteristic of an N-methyl-D-aspartate (NMDA)-receptor antagonist. It blocks NMDA-receptors stereospecifically by interacting with a site close to, but distinct from, that of uncompetitive NMDA-receptor antagonists and from the recognition sites of glutamate, glycine, and polyamines. HU-211 inhibits the synthesis of tumor necrosis factor alpha (TNFα) and possesses antioxidant properties. HU-211 blocked NMDA-induced 45Ca uptake by primary neuronal cultures of rat forebrain and protected the same neuronal cultures against NMDA and glutamate neurotoxicity. Moreover, HU-211 effectively scavenged peroxy radicals in vitro and protected cultured neurons from the toxic effects of reactive oxygen species (ROS). In addition, HU-211 markedly suppressed in vitro TNFα production and nitric oxide (NO) generation (by >90%) by both murine peritoneal macrophages and rat alveolar macrophage cell line exposed to lipopolysaccharide (LPS). Since glutamate, ROS and TNFα are implicated in the pathophysiology of various acute conditions, the promising results showing neuroprotection by HU-211, acting via multiple mechanisms, led to a series of studies in which the drug was given to experimental animals. In the present review we discuss results from experiments describing the potential use of HU-211 as a neuroprotective agent in models of traumatic brain injury, stroke, optic nerve injury, pneumacocal meningitis, sepsis, and soman toxicity. In addition, HU-211 was introduced into clinical trials for traumatic brain injury and the successful results of two phases of clinical trials in head injured patients are also shown. Drug Dev. Res. 50:211–215, 2000. © 2000 Wiley-Liss, Inc.
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protection against septic shock and suppression of tumor necrosis factor alpha and nitric oxide production by Dexanabinol hu 211 a nonpsychotropic cannabinoid
Journal of Pharmacology and Experimental Therapeutics, 1997Co-Authors: Ruth Gallily, Haim Ovadia, Anat Biegon, Raphael Mechoulam, Aviva Yamin, Yaakov Waksmann, Joseph Weidenfeld, Avi Barjoseph, Esther ShohamiAbstract:Dexanabinol, HU-211, a synthetic cannabinoid devoid of psychotropic effects, improves neurological outcome in models of brain trauma, ischemia and meningitis. Recently, HU-211 was found to inhibit brain tumor necrosis factor (TNFalpha) production after head injury. In the present study, we demonstrate the ability of HU-211 to suppress TNFalpha production and to rescue mice and rats from endotoxic shock after LPS (Escherichia coli 055:B5) inoculation. In BALB/c mice, a dose of 10 mg/kg LPS, injected i.p., caused 57% and 100% mortality, at 24 and 48 hr, respectively. HU-211, administered i.p. 30 min before lipopolysaccharide (LPS), reduced lethality to 9 and 67% at these time points (P 90%) by both murine peritoneal macrophages and rat alveolar macrophage cell line exposed to LPS. HU-211 may, therefore, have therapeutic implications in the treatment of TNFalpha-mediated pathologies.
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cytokine production in the brain following closed head injury Dexanabinol hu 211 is a novel tnf α inhibitor and an effective neuroprotectant
Journal of Neuroimmunology, 1997Co-Authors: Esther Shohami, Raphael Mechoulam, Ruth Gallily, Roman Bass, T BenhurAbstract:Traumatic brain injury triggers a cascade of events resulting in delayed edema, necrosis and impaired function. Harmful mediators are accumulating in the brain after injury and recently, the role of cytokines in the pathophysiology of brain injury has been suggested. We have developed an experimental model for closed head injury (CHI), in which edema, blood–brain-barrier disruption, motor and memory dysfunctions have been demonstrated. In this study, spatial and temporal induction of IL-1, IL-6 and TNF-α gene mRNA transcription and of TNF-α and IL-6 activity in rat brain after CHI are shown. Dexanabinol, HU-211, is a synthetic cannabinoid devoid of cannabimimetic effects; it exhibits pharmacological properties of N-methyl-d-aspartate (NMDA)-receptor antagonist and is an effective cerebroprotecant. We report here that HU-211 is a novel inhibitor of TNF-α production at a post-transcriptional stage. HU-211, pentoxyfilline and TNF-binding protein improved the outcome of CHI. We suggest that TNF-α is a primary mediator of neurotoxicity after CHI, as inhibition of TNF-α is associated with better clinical recovery. TNF-α modulating agents, if given within the early time window post-injury, may improve the final neurological outcome in victims of brain trauma.
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derivatives of Dexanabinol ii salts of amino acid esters containing tertiary and quaternary heterocyclic nitrogen with increased water solubility
Pharmaceutical Research, 1996Co-Authors: Emil Pop, Marcus E Brewster, Ferenc Soti, Yechezkel Barenholz, Veronica Korablyov, Raphael Mechoulam, Varda Nadler, Anat BiegonAbstract:Purpose. Amino acid esters containing tertiary or quaternary nitrogen heterocycles were synthesized for Dexanabinol (1) and evaluated as water-soluble prodrugs or congeners.
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Derivatives of Dexanabinol. I. Water-soluble salts of glycinate esters.
Pharmaceutical research, 1996Co-Authors: Emil Pop, Marcus E Brewster, Yechezkel Barenholz, Veronica Korablyov, Raphael Mechoulam, Varda Nadler, Zong Zheng Liu, Anat BiegonAbstract:Purpose. Glycinate ester-type water soluble derivatives of Dexanabinol (HU-211) (1) a non-psychotropic cannabinoid with potential use in the treatment of brain damage were synthesized and evaluated as prodrugs or congeners.
Emil Pop - One of the best experts on this subject based on the ideXlab platform.
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in vitro and in vivo study of water soluble prodrugs of Dexanabinol
Journal of Pharmaceutical Sciences, 1999Co-Authors: Emil Pop, Anat Biegon, Stanislaw Rachwal, Jirina Vlasak, Alevtina D Zharikova, Laszlo ProkaiAbstract:Trialkylammonium acetoxymethyl esters of Dexanabinol were synthesized and evaluated as water-soluble prodrugs. Syntheses were performed by conventional methods; solubility in water and stability in buffers and human plasma were determined by HPLC, and in vivo tissue distribution studies were performed in a rat model. Most of the new derivatives were soluble in water (∼50 mg/mL). They were relatively stable in water, while rapidly hydrolyzed in human plasma. Distribution studies indicated that peak concentrations of drug both in blood (30 μg/mL) and brain (2 μg/mL) were rapidly (5 min) achieved after iv administration of a selected prodrug to rats. The blood concentration decreased faster than brain levels which were detectable even after 24 h. Some of the examined esters could be further developed as water soluble prodrugs of Dexanabinol.
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synthesis of deuterated Dexanabinol a nonpsychotropic cannabinoid with neuroprotective properties
Journal of Labelled Compounds and Radiopharmaceuticals, 1998Co-Authors: Emil Pop, Marcus E Brewster, Stanislaw Rachwal, Jirina Vlasak, Bogumila Rachwal, Laszlo ProkaiAbstract:The deuterium labeled form of Dexanabinol, a potential neuroprotective agent, was synthesized by coupling the deuterated 5-(1,1-dimethylheptyl)resorcinol, obtained in a 5-step procedure, with 4-hydroxymyrtenyl pivalate, followed by deprotection.Copyright © 1998 John Wiley & Sons, Ltd.
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clinical pharmacokinetics of escalating i v doses of Dexanabinol hu 211 a neuroprotectant agent in normal volunteers
International Journal of Clinical Pharmacology and Therapeutics, 1997Co-Authors: Marcus E Brewster, Emil Pop, R L Foltz, S Reuschel, W Griffith, S Amselem, Anat BiegonAbstract:The pharmacokinetics of Dexanabinol (HU-211), a synthetic, nonpsychotropic cannabinoid with neuroprotectant action, was evaluated in a phase I clinical trial. The compound was administered at doses of 48 mg, 100 mg, and 200 mg as short i.v. infusions in a Cremophor-ethanol vehicle diluted with saline. All administrations were well-tolerated and no compound-related side-effects were observed. Plasma concentrations of Dexanabinol were quantitated using a GC/MS/MS technique which provided a limit of quantitation of 100 pg/ml. The elimination of Dexanabinol was best fitted to a 3-compartment model with a rapid distribution half-life (< 5 min), an intermediate phase half-life of approximately 90 min, and a slow terminal elimination half-life (approximately 9 h). The pharmacokinetics were linear over the evaluated dose range. The plasma clearance of the drug was high (1,700 ml/min) and the volume of distribution approximately 15 l/kg. These data are similar to those reported for naturally occurring cannabinoids such as delta 9-tetrahydrocannabinol and cannabidiol.
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dimerization of Dexanabinol by hydrogen bonding accounts for its hydrophobic character
International Journal of Quantum Chemistry, 1997Co-Authors: Emil Pop, Marcus E BrewsterAbstract:Dexanabinol, a dihydroxylated synthetic cannabinoid, is a member of . the nonpsychotropic q 3S, 4S enantiomeric series. Experimental evidence suggests that . Dexanabinol might form aggregates e.g., dimers in which the two OH a phenol and an . allylic alcohol groups are involved in hydrogen bonding. The extremely low solubility of Dexanabinol in water implies that this interaction may not involve solvent molecules. A theoretical study of this phenomenon in the framework of the PM3 molecular approximation is described. Simple molecular models phenol and 6-cyclohexene-1- . methanol were initially examined followed by extension of the calculations to Dexanabinol. The results indicate that dimers of Dexanabinol resulting from hydrogen bonding are more stable than the isolated molecules with the differences attributed to hydrogen bonding energies. It is suggested that the phenolic hydroxy group of one molecule forms a hydrogen bond with the allylic OH group of the second molecule and vice versa, resulting in dimers which contain two hydrogen bonds. The hydrogen bonds . are more stable 6.14 kcalrmol and the complex formed is more favored energetically when the phenol groups act as hydrogen bond donors and the allylic OH groups as acceptors. These interactions are also energetically more favored than those between . Dexanabinol and water 3.70 kcalrmol . The Dexanabinol dimer manifested a lower . dipole moment as compared to the monomer 1.211 vs. 2.221 debye as well as a much . larger log P 11.16 vs. 5.90 , indicating strong hydrophobic character. The optimized structure shows that the OH groups involved in hydrogen bonds are oriented to the interior of the dimers, while the lipophilic side chains are oriented toward the exterior. These properties of the dimer may explain the low water solubility of Dexanabinol.
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derivatives of Dexanabinol ii salts of amino acid esters containing tertiary and quaternary heterocyclic nitrogen with increased water solubility
Pharmaceutical Research, 1996Co-Authors: Emil Pop, Marcus E Brewster, Ferenc Soti, Yechezkel Barenholz, Veronica Korablyov, Raphael Mechoulam, Varda Nadler, Anat BiegonAbstract:Purpose. Amino acid esters containing tertiary or quaternary nitrogen heterocycles were synthesized for Dexanabinol (1) and evaluated as water-soluble prodrugs or congeners.
Haim Ovadia - One of the best experts on this subject based on the ideXlab platform.
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Combination of Dexanabinol and tempol in focal cerebral ischemia: is there a ceiling effect?
Experimental neurology, 2003Co-Authors: Angella Teichner, Haim Ovadia, G. Lavie, Ronen R LekerAbstract:Because ischemic neuronal death is triggered by several parallel mechanisms, a combination of drugs active against individual death-promoting mechanisms may have synergistic effects. Dexanabinol is a noncompetitive NMDA antagonist with anti-inflammatory effects and tempol is a nitroxide antioxidant. Therefore, we explored whether their combined use results in smaller infarct volumes as compared with their individual administration. Rats underwent permanent middle cerebral artery occlusion (PMCAO) and were given vehicle, Dexanabinol alone, tempol alone, or a combination of Dexanabinol and tempol (n = 13 per group) 1 h later. Five animals in each group were evaluated with a motor rating scale 24 h after PMCAO and the infarct volumes were then measured. The remaining animals were examined with motor and behavioral scales up to 30 days after PMCAO and their infarct volumes were then determined. Motor disability and water maze latencies at all time points examined and infarct volumes at days 1 and 30 were significantly reduced in all active treatment groups when compared with vehicle. However, no significant differences were observed between the active treatment groups. In conclusions, combination therapy with Dexanabinol and tempol does not appear to have additional neuroprotective effects compared to those conferred by each agent alone even when administered at optimal timing and dosing. Therefore, a ceiling neuroprotective effect that is impossible to overcome may exist.
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long term cerebroprotective effects of Dexanabinol in a model of focal cerebral ischemia
Brain Research, 2001Co-Authors: Gil Lavie, Haim Ovadia, Esther Shohami, Angella Teichner, Ronen R LekerAbstract:In order to test the long-term cerebroprotective effects of Dexanabinol, a synthetic non-competitive NMDA antagonist that also has anti-TNFalpha effects, spontaneously hypertensive rats underwent permanent middle cerebral artery occlusion (PMCAO). Rats were given vehicle or Dexanabinol (4.5 mg/kg) 1, 3 or 6 h after PMCAO. The research consisted of 2 stages. In the short-term set of experiments animals (n=5/group), were tested with a motor disability scale 24 h post PMCAO, then sacrificed and the infarct volume was measured using 2,3,5-Triphenyltetrazolium chloride (TTC) staining. In the long-term set of experiments the rats (n=7/group) were examined daily with a motor disability scale up to 30 days after PMCAO and then sacrificed and infarct volumes were determined using TTC staining. Motor scores were significantly improved in the Dexanabinol treated rats (P<0.05 for all groups) at all the time points examined. Infarct volumes were significantly reduced 24 h after PMCAO in the groups treated 1 or 3 h, but not 6 h after PMCAO compared with vehicle (Mean+/-S.D., 11.5+/-2.02, 12+/-3.2 and 14.4+/-2.4% vs. 20.8+/-1.3% hemispheric volume respectively). The lesions remained significantly smaller in the Dexanabinol groups 30 days after PMCAO (Mean+/-S.D., 24.49+/-1.9% vs. 8.1+/-0.6, 11.1+/-2.3 and 13.8+/-2.5% hemispheric volume in animals treated with vehicle vs. Dexanabinol 1, 3 or 6 h after PMCAO respectively; P<0.05 for all). In conclusion, the extended therapeutic window and the multi-mechanistic durable neuroprotective effects of Dexanabinol make it a promising candidate for future stroke therapy.
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Dexanabinol a novel neuroprotective drug in experimental focal cerebral ischemia
Journal of the Neurological Sciences, 1999Co-Authors: Ronen R Leker, Esther Shohami, Oded Abramsky, Haim OvadiaAbstract:The permanent middle cerebral artery occlusion (PMCAO) model was used to investigate the cerebroprotective effects of the synthetic cannabinoid, Dexanabinol (HU-211). Dexanabinol is a noncompetitive N-methyl-d-aspartate antagonist, with antioxidant and anti-TNFα properties. Twenty hypertensive rats were subjected to PMCAO. Eight were given 4 mg/kg Dexanabinol, i.v., 1 h after PMCAO, eight received vehicle and four were not injected. Five rats underwent sham surgery. Infarct volumes were assessed, as well as TNFα concentrations and NOS activity in brain homogenates. Dexanabinol significantly decreased infarct volumes. It also significantly lowered TNFα levels in the ipsilateral hemisphere although not to the level of sham operated rats. No effect could be demonstrated on NOS activity. In conclusion, Dexanabinol may be a pluripotent cerebroprotective agent.
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protection against septic shock and suppression of tumor necrosis factor alpha and nitric oxide production by Dexanabinol hu 211 a nonpsychotropic cannabinoid
Journal of Pharmacology and Experimental Therapeutics, 1997Co-Authors: Ruth Gallily, Haim Ovadia, Anat Biegon, Raphael Mechoulam, Aviva Yamin, Yaakov Waksmann, Joseph Weidenfeld, Avi Barjoseph, Esther ShohamiAbstract:Dexanabinol, HU-211, a synthetic cannabinoid devoid of psychotropic effects, improves neurological outcome in models of brain trauma, ischemia and meningitis. Recently, HU-211 was found to inhibit brain tumor necrosis factor (TNFalpha) production after head injury. In the present study, we demonstrate the ability of HU-211 to suppress TNFalpha production and to rescue mice and rats from endotoxic shock after LPS (Escherichia coli 055:B5) inoculation. In BALB/c mice, a dose of 10 mg/kg LPS, injected i.p., caused 57% and 100% mortality, at 24 and 48 hr, respectively. HU-211, administered i.p. 30 min before lipopolysaccharide (LPS), reduced lethality to 9 and 67% at these time points (P 90%) by both murine peritoneal macrophages and rat alveolar macrophage cell line exposed to LPS. HU-211 may, therefore, have therapeutic implications in the treatment of TNFalpha-mediated pathologies.