A Novel Compound for Alcoholism Treatment: a Translational Strategy

治疗酗酒的新型化合物：转化策略

• 批准号: 8689206
• 负责人: Fatemeh Akhlaghi
• 金额: $ 53.94万
• 依托单位: UNIVERSITY OF RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-18 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8689206
• 关键词: Adverse event; Affect; Agonist; Alcohol consumption; Alcohol dependence; Alcohols; Amino Acids; Animal Model; Animals; Behavior; Behavioral; Bioavailable; Biological Markers; Blood; Blood - brain barrier anatomy; Blood alcohol level measurement; Brain; Cerebrospinal Fluid; Clinical Data; Clinical Research; Cues; Data; Dose; Double-Blind Method; Drug Kinetics; Drug usage; Eating; Equilibrium; Ethanol; Evaluation; Food; Functional Magnetic Resonance Imaging; Future; Genetic Crossing Over; Goals; Human; Image; Incentives; Individual; Industry; Infusion procedures; Intervention; Intramural Research Program; Intravenous; Investigation; Laboratory Study; Lead; Ligands; Liquid Chromatography; Measures; Mediating; Modeling; Morbidity - disease rate; Motor Activity; Mus; National Institute on Alcohol Abuse and Alcoholism; Neurobiology; Oral; Outcome; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Phase; Phosphorylation; Placebo Control; Placebos; Plasma; Play; Population; Pre-Clinical Model; Procedures; Process; Property; Randomized Clinical Trials; Regimen; Relapse; Research; Rewards; Rhode Island; Role; Safety; Schedule; Self Administration; Series; Signal Transduction; Smoking; Staging; System; Testing; Time; Tissues; Translational Research; United States National Institutes of Health; Universities; Ventral Striatum; Ventral Tegmental Area; addiction; alcohol craving; alcohol cue; alcohol reward; alcohol seeking behavior; alcohol sensitivity; alcoholism therapy; blood oxygenation level dependent response; cholinergic; cue reactivity; design; drinking; drug efficacy; effective therapy; feeding; ghrelin; ghrelin receptor; growth hormone secretagogue receptor; improved; increased appetite; intravenous administration; mortality; neuromechanism; novel; pre-clinical; preclinical study; problem drinker; programs; psychologic; psychosocial; public health priorities; research study; reward processing; sedative; social; tandem mass spectrometry

Alcohol dependence (AD) afflicts ~10% of the US population and causes serious morbidity and mortality. Ghrelin is a 28-aminoacid peptide that stimulates appetite and food intake. It is an endogenous ligand for the growth hormone secretagogue receptor (GHSR1a). Preclinical studies suggest that ghrelin also modulates alcohol reward processing. Central ghrelin administration to mice significantly increased alcohol intake, and this increase was even more robust when ghrelin was administered bilaterally into specific brain reward nodes, e.g. the ventral tegmental area. Similarly, in alcoholic individuals, higher plasma ghrelin concentrations are associated with higher alcohol craving and consumption. Collectively, these studies provide evidence that manipulations of the ghrelin system affect alcohol craving and consumption. Therefore, an orally bioavailable, ghrelin receptor antagonist, that can pass through the blood brain barrier holds particular promise as an AD treatment. This proposal will allow us to generate preliminary evidence on the safety and efficacy of such pharmacological agent via three projects, i.e.: (P1) a set of experiments testing the effect of this drug in well-validated animal models of alcohol-seeking behavior; (P2) a drug/alcohol interaction study to establish safety in humans (Phase 1b); and (P3) a human laboratory study to assess the efficacy of this drug on alcohol-seeking behavior via a set of well- validated procedures (alcohol cue-reactivity, alcohol self-administration, intravenous alcohol progressive ratio infusion) as well as characterization of the drug effect on reward processing neurocircuitry in the context of alcohol using fMRI (Phase 2a). These projects will be conducted in the NIAAA Intramural Program (PI: Leggio). Furthermore, all three projects will include pharmacokinetics (PK) and pharmacodynamic (PD) investigations conducted at University of Rhode Island (URI; PI: Akhlaghi). The PK/PD component will include (i) measuring total, unbound or tissue concentrations of the drug using liquid chromatography tandem mass spectrometry (LC- MS/MS) and evaluation of biomarkers of effect and (ii) estimation of PK and PD parameters in both animal and human studies by the use of conventional and semimechanistic modeling approaches to assist in identifying an optimal dosing regimen of the drug in AD. In summary, this research will investigate the tolerability, efficacy and mechanism of this novel pharmacological approach for AD thus leading to the potential identification of a new treatment for AD.

酒精依赖（AD）困扰着约10%的美国人口，并导致严重的发病率和死亡率