A randomized, double-blind, placebo-controlled study of a GHSR blocker in people with alcohol use disorder.

IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Monica L Faulkner, Mehdi Farokhnia, Mary R Lee, Lisa Farinelli, Brittney D Browning, Kelly Abshire, Allison M Daurio, Vikas Munjal, Sara L Deschaine, Selim R Boukabara, Christopher Fortney, Garrick Sherman, Melanie Schwandt, Fatemeh Akhlaghi, Reza Momenan, Thomas J Ross, Susan Persky, Lorenzo Leggio
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Abstract

BACKGROUNDStudies have demonstrated the role of ghrelin in alcohol-related behaviors and consumption. Blockade of the growth hormone secretagogue receptor (GHSR), which is the ghrelin receptor, has been shown to decrease alcohol drinking and reward-related behaviors across several animal models. We previously conducted a human study testing a GHSR inverse agonist/competitive antagonist, PF-5190457, in individuals who are heavy drinkers and showed its safety when coadministered with alcohol. Here, we conducted a phase IIa experimental medicine study in patients with alcohol use disorder (AUD) to investigate the effects of PF-5190457 on alcohol- and food-related outcomes.METHODSForty-two individuals with AUD (n = 29 completers) participated in a randomized, double-blind, placebo-controlled study where they received PF-5190457 100mg b.i.d. (or placebo) in 2 counterbalanced, within-subject stages. Participants completed an alcohol cue-reactivity (CR) experiment in a bar-like laboratory and a virtual food choice experiment in a cafeteria-like virtual reality (VR) environment. A subset of participants (n = 12) performed a CR task during a brain functional MRI (fMRI) experiment.RESULTSPF-5190457 did not reduce cue-elicited alcohol craving. PF-5190457 reduced virtual calories selected (P = 0.04) in the VR environment. PF-5190457 did not influence neural activation during CR task in the fMRI experiment.CONCLUSIONThis study provides human evidence of the role of GHSR blockade in behaviors related to food selection and highlights the need for future investigations into targeting the ghrelin system in AUD.TRIAL REGISTRATIONClinicalTrials.gov (accession no. NCT02707055).FUNDINGNIDA and NIAAA ZIA-DA000635; National Center for Advancing Translational Sciences UH2/UH3-TR000963.

酒精使用障碍患者GHSR阻滞剂的随机、双盲、安慰剂对照研究。
研究已经证明了胃饥饿素在酒精相关行为和消费中的作用。阻断生长激素促分泌受体(GHSR),即胃饥饿素受体,已经在几个动物模型中被证明可以减少饮酒和奖励相关行为。我们之前进行了一项人类研究,在重度饮酒者中测试了GHSR逆激动剂/竞争拮抗剂PF-5190457,并显示其与酒精合用的安全性。在这里,我们在酒精使用障碍(AUD)患者中进行了一项IIa期实验医学研究,以调查PF-5190457对酒精和食物相关结局的影响。方法42名AUD患者(n = 29名完成者)参加了一项随机、双盲、安慰剂对照研究,他们在2个平衡的受试者内阶段接受PF-5190457 100mg b.i.d(或安慰剂)治疗。参与者在类似酒吧的实验室中完成了酒精线索反应(CR)实验,在类似自助餐厅的虚拟现实(VR)环境中完成了虚拟食物选择实验。一部分参与者(n = 12)在脑功能磁共振成像(fMRI)实验中执行了CR任务。结果spf -5190457不能减少线索引起的酒精渴望。PF-5190457在虚拟现实环境中减少了虚拟卡路里的选择(P = 0.04)。在fMRI实验中,PF-5190457对CR任务时的神经激活没有影响。结论本研究为GHSR阻断在食物选择相关行为中的作用提供了人类证据,并强调了未来针对AUD中ghrelin系统的研究的必要性。临床试验注册号:clinicaltrials .govNCT02707055)。基金资助:nida和NIAAA ZIA-DA000635;国家转化科学推进中心UH2/UH3-TR000963。
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来源期刊
JCI insight
JCI insight Medicine-General Medicine
CiteScore
13.70
自引率
1.20%
发文量
543
审稿时长
6 weeks
期刊介绍: JCI Insight is a Gold Open Access journal with a 2022 Impact Factor of 8.0. It publishes high-quality studies in various biomedical specialties, such as autoimmunity, gastroenterology, immunology, metabolism, nephrology, neuroscience, oncology, pulmonology, and vascular biology. The journal focuses on clinically relevant basic and translational research that contributes to the understanding of disease biology and treatment. JCI Insight is self-published by the American Society for Clinical Investigation (ASCI), a nonprofit honor organization of physician-scientists founded in 1908, and it helps fulfill the ASCI's mission to advance medical science through the publication of clinically relevant research reports.
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