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Pharmaceutical Industry Roundtable Abstracts
338
Conference Abstracts / Alcohol 42 (2008) 303-341
PHARMACEUTICAL INDUSTRY ROUNDTABLE
R119 Gamma-hydroxybutyrate reduces both withdrawal syndrome and hypercortisolim in severe abstinent alcoholics: an open randomized study vs. diazepam Felice Nava, Ezio Manzato, Alfio Lucchini, Italian Society of addiction Medicine (FeDerSerD), Department of Addiction Medicine, Hospital of Castelfranco Veneto, Italy Gamma-hydroxybutyrate (GHB), a naturally occurring short-chain fatty acid related to gamma-aminobutyric acid (GABA) (Wong et al., 2004, Trends Pharmacol Sci, 25, 29-34) has been shown as effective in reducing alcohol withdrawal syndrome, ethanol use and craving at the dose range of 50-150 mg/kg body weight/day (Poldrugo, Addolorato, 1999, Alcohol Alcohol , 34, 15-24). Since a large body of evidence suggests that the severity of alcohol withdrawal syndrome may be strictly correlated to hypercortisolism (Adinoff et al., 1998, Alcohol Health Res World, 22, 67-72; Gallant, Pena, Alcohol Clin Exp Res, 56, 81-95) we would expect that GHB would be more effective than diazepam at reducing both withdrawal syndrome and hypercortisolism in alcoholics. As a proof-of-concept test of this hypothesis, we did an open randomized study to compare the effects of GHB and diazepam at reducing withdrawal syndrome and hypercortisolism in individuals who are in severe alcohol abstinence. In 42 alcoholic inpatients diazepam (0.5 mg/kg bodyweight, q.i.d.) and GHB (50 mg/kg bodyweight, q.i.d.) were orally administered for three weeks. During alll study period, GHB was more able than diazepam in reducing both withdrawal syndrome and hypercortisolism. These effects were evident during the first week of treatment and persited throught the study period. The results confirm a strict correlation between high levels of plasma cortisol and alcohol withdrawal symptoms and they show a slight superiority of GHB over diazepam in the suppression of both ethanol withdrawal and hypercortisolism. Taken together, our data suggest that GHB may act as potent anti-withdrawal agent in severe abstinent alcoholics.
R121 The role of dopamine D3 receptors as a potential pharmacotherapy for ethanol dependence Maria Pilla, Michela Tessari, Michela Andreoli, and Mauro Corsi, Biology Department, Psychiatry Centre of Excellence for Drug Discovery, GlaxoSmithKline Medicines Research Centre, Verona, Italy Alcohol dependence is characterised by compulsive alcohol-seeking, excessive alcohol intake and vulnerability to relapse. Pharmacological agents have also shown limited efficacy in the treatment of alcoholism. The development of new medications with improved long-term efficacy and tolerability is therefore urgent. A number of neurochemical pathways have been implicated in alcoholism. A growing body of evidence has shown that among the five dopamine receptors the D3 receptor (D3R) is significantly involved in mechanisms of drug dependence and abuse. The D3R is primarily localised in brain areas associated with the mesolimbic DA system and the rewarding properties of drugs of abuse. D3R antagonists have been repeatedly shown to significantly attenuate drug seeking behaviour in laboratory animals, and long-term alcohol consumption produced an up-regulation of striatal D3R mRNA in rats (Vengeliene et al., FASEB J. 20: 2223, 2006). In the present work we will review other evidence of the involvement of D3R in alcohol dependence and show that pre-treatment with the selective dopamine D3 receptor antagonist SB-277011-A produced a reduction of drinking in the alcohol deprivation effect model in long-term alcohol drinking Wistar rats, as well as a decrease in cue-induced ethanol seeking behaviour. These results are in agreement with other studies showing that acute administration of SB-277011-A (10, 30 mg/kg i.p.) produced a significant decrease in ethanol intake and preference in alcohol-preferring rats using the two-bottle free choice paradigm (Thanos et al., Pharmacol. Biochem. Behav. 81: 190 2005). Taken together, these results suggest that selective antagonists of the dopamine D3 receptor may therefore provide a specific treatment approach to reduce alcohol craving and relapse behaviour.
R122 R120 Triple uptake inhibitors: Potential medications for the treatment of alcohol abuse, alcoholism, and comorbid depression Phil Skolnick, Anthony S. Basile, and Harry L. June, DOV Pharmaceutical, Inc., Somerset, NJ, USA Triple uptake inhibitors, molecules that increase synaptic concentrations of dopamine, serotonin, and norepinephrine, are currently in clinical trials for the treatment of depression. The prevalence of comorbid depression and alcoholism, together with evidence of serotonergic and dopaminergic dysregulation in both disorders prompted studies to examine the efficacy of DOV 102,677 in: 1) reducing volitional consumption of ethanol by Myers' high ethanol-preferring rats and 2) reducing alcohol-motivated behaviors in the alcohol-preferring (P) rat. DOV 102,677 is a balanced inhibitor of monoamine uptake in recombinant human transporters. Microdialysis studies indicate that DOV 102,677 inhibits all three transporters at doses active in behavioral despair procedures predictive of antidepressant activity (Popik, et al., 2006). DOV 102,677 dose-dependently decreased the volitional consumption of ethanol by as much as 71.2% (20 mg/kg i.p., b.i.d.) over 3 days of administration. Similarly, the proportion of ethanol to total fluids consumed declined by 66.2%, while food consumption and body weight were unaltered. Moreover, in P rats, DOV 102,677 (6.25-50 mg/kg, PO) suppressed alcohol-maintained responding without remarkable effect on sucrose-maintained responding. Preliminary results also indicate that DOV 102,677 significantly reduces rates of responding maintained by binge alcohol drinking in P rats. DOV 102,677 was safe and well tolerated in a Ph IA (single dose escalating) study in normal volunteers. Thus, DOV 102,677 may represent the prototype of a molecule effective in treating alcoholism with comorbid depression.
MTIP: a novel brain penetrant, orally available corticotropinreleasing hormone receptor 1 (CRH-R1) antagonist for treatment of alcoholism D.R. Gehlert1, A. Cippitelli, A. Thorsell, A.D. Lê, P.A. Hipskind, C. Hamdouchi, J. Lu, E.J. Hembre, J. Cramer, M. Song, D. McKinzie, M. Morin, R. Ciccocioppo, M. Heilig, Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, Laboratory of Clinical and Translational Studies, NIAAA/NIH, Bethesda, MD, Centre for Addiction & Mental Health, University of Toronto, Toronto, Canada, Dept Exp. Med & Public Health, University of Camerino, Camerino, Italy We describe a novel CRH-R1 antagonist with advantageous properties for clinical development, and its in vivo activity in preclinical alcoholism models. 3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)2,6-dimethyl-imidazo[1,2-b]pyridazine (MTIP) inhibited 125I-sauvagine binding to rat pituitary membranes and cloned hCRH-R1 with subnanomolar affinities, with no detectable activity at the CRH-R2 receptor or other common drug targets. Following oral administration to rats, MTIP inhibited 125I-sauvagine binding to rat cerebellar membranes ex vivo with an ED50 of app. 1.3mg/kg and an oral bioavailability of 91.1%. Compared to R121919 and CP154,526, MTIP had a markedly reduced volume of distribution and clearance. Neither open field activity nor baseline exploration of an elevated plus-maze was affected by MTIP (110mg/kg). In contrast, MTIP dose-dependently reversed anxiogenic effects of withdrawal from a 3g/kg alcohol dose. Similarly, MTIP blocked excessive alcohol self-administration in Wistar rats with a history of dependence, and in a genetic model of high alcohol preference, the msP rat, at doses that had no effect in non-dependent Wistar rats. Also, MTIP blocked reinstatement of stress-induced alcohol seeking both in post-dependent, and in genetically selected msP animals, again at doses that were ineffective in non-dependent Wistar rats. Based on these findings, MTIP is a promising candidate for treatment of alcohol dependence.
Conference Abstracts / Alcohol 42 (2008) 303-341
PHARMACEUTICAL INDUSTRY ROUNDTABLE
R119 Gamma-hydroxybutyrate reduces both withdrawal syndrome and hypercortisolim in severe abstinent alcoholics: an open randomized study vs. diazepam Felice Nava, Ezio Manzato, Alfio Lucchini, Italian Society of addiction Medicine (FeDerSerD), Department of Addiction Medicine, Hospital of Castelfranco Veneto, Italy Gamma-hydroxybutyrate (GHB), a naturally occurring short-chain fatty acid related to gamma-aminobutyric acid (GABA) (Wong et al., 2004, Trends Pharmacol Sci, 25, 29-34) has been shown as effective in reducing alcohol withdrawal syndrome, ethanol use and craving at the dose range of 50-150 mg/kg body weight/day (Poldrugo, Addolorato, 1999, Alcohol Alcohol , 34, 15-24). Since a large body of evidence suggests that the severity of alcohol withdrawal syndrome may be strictly correlated to hypercortisolism (Adinoff et al., 1998, Alcohol Health Res World, 22, 67-72; Gallant, Pena, Alcohol Clin Exp Res, 56, 81-95) we would expect that GHB would be more effective than diazepam at reducing both withdrawal syndrome and hypercortisolism in alcoholics. As a proof-of-concept test of this hypothesis, we did an open randomized study to compare the effects of GHB and diazepam at reducing withdrawal syndrome and hypercortisolism in individuals who are in severe alcohol abstinence. In 42 alcoholic inpatients diazepam (0.5 mg/kg bodyweight, q.i.d.) and GHB (50 mg/kg bodyweight, q.i.d.) were orally administered for three weeks. During alll study period, GHB was more able than diazepam in reducing both withdrawal syndrome and hypercortisolism. These effects were evident during the first week of treatment and persited throught the study period. The results confirm a strict correlation between high levels of plasma cortisol and alcohol withdrawal symptoms and they show a slight superiority of GHB over diazepam in the suppression of both ethanol withdrawal and hypercortisolism. Taken together, our data suggest that GHB may act as potent anti-withdrawal agent in severe abstinent alcoholics.
R121 The role of dopamine D3 receptors as a potential pharmacotherapy for ethanol dependence Maria Pilla, Michela Tessari, Michela Andreoli, and Mauro Corsi, Biology Department, Psychiatry Centre of Excellence for Drug Discovery, GlaxoSmithKline Medicines Research Centre, Verona, Italy Alcohol dependence is characterised by compulsive alcohol-seeking, excessive alcohol intake and vulnerability to relapse. Pharmacological agents have also shown limited efficacy in the treatment of alcoholism. The development of new medications with improved long-term efficacy and tolerability is therefore urgent. A number of neurochemical pathways have been implicated in alcoholism. A growing body of evidence has shown that among the five dopamine receptors the D3 receptor (D3R) is significantly involved in mechanisms of drug dependence and abuse. The D3R is primarily localised in brain areas associated with the mesolimbic DA system and the rewarding properties of drugs of abuse. D3R antagonists have been repeatedly shown to significantly attenuate drug seeking behaviour in laboratory animals, and long-term alcohol consumption produced an up-regulation of striatal D3R mRNA in rats (Vengeliene et al., FASEB J. 20: 2223, 2006). In the present work we will review other evidence of the involvement of D3R in alcohol dependence and show that pre-treatment with the selective dopamine D3 receptor antagonist SB-277011-A produced a reduction of drinking in the alcohol deprivation effect model in long-term alcohol drinking Wistar rats, as well as a decrease in cue-induced ethanol seeking behaviour. These results are in agreement with other studies showing that acute administration of SB-277011-A (10, 30 mg/kg i.p.) produced a significant decrease in ethanol intake and preference in alcohol-preferring rats using the two-bottle free choice paradigm (Thanos et al., Pharmacol. Biochem. Behav. 81: 190 2005). Taken together, these results suggest that selective antagonists of the dopamine D3 receptor may therefore provide a specific treatment approach to reduce alcohol craving and relapse behaviour.
R122 R120 Triple uptake inhibitors: Potential medications for the treatment of alcohol abuse, alcoholism, and comorbid depression Phil Skolnick, Anthony S. Basile, and Harry L. June, DOV Pharmaceutical, Inc., Somerset, NJ, USA Triple uptake inhibitors, molecules that increase synaptic concentrations of dopamine, serotonin, and norepinephrine, are currently in clinical trials for the treatment of depression. The prevalence of comorbid depression and alcoholism, together with evidence of serotonergic and dopaminergic dysregulation in both disorders prompted studies to examine the efficacy of DOV 102,677 in: 1) reducing volitional consumption of ethanol by Myers' high ethanol-preferring rats and 2) reducing alcohol-motivated behaviors in the alcohol-preferring (P) rat. DOV 102,677 is a balanced inhibitor of monoamine uptake in recombinant human transporters. Microdialysis studies indicate that DOV 102,677 inhibits all three transporters at doses active in behavioral despair procedures predictive of antidepressant activity (Popik, et al., 2006). DOV 102,677 dose-dependently decreased the volitional consumption of ethanol by as much as 71.2% (20 mg/kg i.p., b.i.d.) over 3 days of administration. Similarly, the proportion of ethanol to total fluids consumed declined by 66.2%, while food consumption and body weight were unaltered. Moreover, in P rats, DOV 102,677 (6.25-50 mg/kg, PO) suppressed alcohol-maintained responding without remarkable effect on sucrose-maintained responding. Preliminary results also indicate that DOV 102,677 significantly reduces rates of responding maintained by binge alcohol drinking in P rats. DOV 102,677 was safe and well tolerated in a Ph IA (single dose escalating) study in normal volunteers. Thus, DOV 102,677 may represent the prototype of a molecule effective in treating alcoholism with comorbid depression.
MTIP: a novel brain penetrant, orally available corticotropinreleasing hormone receptor 1 (CRH-R1) antagonist for treatment of alcoholism D.R. Gehlert1, A. Cippitelli, A. Thorsell, A.D. Lê, P.A. Hipskind, C. Hamdouchi, J. Lu, E.J. Hembre, J. Cramer, M. Song, D. McKinzie, M. Morin, R. Ciccocioppo, M. Heilig, Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, Laboratory of Clinical and Translational Studies, NIAAA/NIH, Bethesda, MD, Centre for Addiction & Mental Health, University of Toronto, Toronto, Canada, Dept Exp. Med & Public Health, University of Camerino, Camerino, Italy We describe a novel CRH-R1 antagonist with advantageous properties for clinical development, and its in vivo activity in preclinical alcoholism models. 3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)2,6-dimethyl-imidazo[1,2-b]pyridazine (MTIP) inhibited 125I-sauvagine binding to rat pituitary membranes and cloned hCRH-R1 with subnanomolar affinities, with no detectable activity at the CRH-R2 receptor or other common drug targets. Following oral administration to rats, MTIP inhibited 125I-sauvagine binding to rat cerebellar membranes ex vivo with an ED50 of app. 1.3mg/kg and an oral bioavailability of 91.1%. Compared to R121919 and CP154,526, MTIP had a markedly reduced volume of distribution and clearance. Neither open field activity nor baseline exploration of an elevated plus-maze was affected by MTIP (110mg/kg). In contrast, MTIP dose-dependently reversed anxiogenic effects of withdrawal from a 3g/kg alcohol dose. Similarly, MTIP blocked excessive alcohol self-administration in Wistar rats with a history of dependence, and in a genetic model of high alcohol preference, the msP rat, at doses that had no effect in non-dependent Wistar rats. Also, MTIP blocked reinstatement of stress-induced alcohol seeking both in post-dependent, and in genetically selected msP animals, again at doses that were ineffective in non-dependent Wistar rats. Based on these findings, MTIP is a promising candidate for treatment of alcohol dependence.