吡格列酮激活过的过氧化物酶体增殖物激活受体γ并不能抑制对酒精的渴望，并且与治疗寻求酒精依赖患者的肌病风险相关：一项随机对照的原理验证研究。
PPARγ activation by pioglitazone does not suppress cravings for alcohol, and is associated with a risk of myopathy in treatment seeking alcohol dependent patients: a randomized controlled proof of principle study.
机构信息
Office of the Clinical Director, National Institute on Alcohol Abuse and Alcoholism, 10 Center Drive, CRC 1-5330, Bethesda, MD, 20892, USA.
Center for Drug Evaluation and Research (CDER), United States Food and Drug Administration, Washington, DC, USA.
出版信息
Psychopharmacology (Berl). 2020 Aug;237(8):2367-2380. doi: 10.1007/s00213-020-05540-w. Epub 2020 May 22.
RATIONALE
Proinflammatory processes have been implicated in alcohol addiction, craving, and relapse, while studies in experimental animals have suggested that activation of peroxisome proliferator-activated receptor gamma (PPARγ) inhibits proinflammatory signaling. Accordingly, it is hypothesized that medications with PPARγ activity may have therapeutic potential in alcohol dependence.
OBJECTIVES
We conducted a double-blind, placebo-controlled mechanistic proof of principle study in alcohol-dependent inpatients to investigate the effect of pioglitazone on alcohol craving.
METHODS
Participants were treated for withdrawal, if needed, and then randomized to pioglitazone (target dose 45 mg/day) or placebo. Once at target dose, they completed two experimental manipulations: guided imagery, which used personalized auditory scripts to induce alcohol cravings, and a low-dose challenge with i.v. lipopolysaccharide (LPS; 0.8 ng/kg) or placebo, on two separate sessions, in counterbalanced order. Behavioral and endocrine responses as well as CSF levels of proinflammatory cytokines were evaluated.
RESULTS
The study was prematurely terminated after randomization of 16 subjects, following an independent review that established a high risk of myopathy in the active treatment group. Analysis of those who completed the study indicated that pioglitazone was associated with elevated, rather than suppressed alcohol cravings in response to alcohol-associated stimuli. LPS did not induce cravings for alcohol and thus did not lend itself to evaluating pioglitazone effects; however, pioglitazone increased the neuroendocrine stress response to LPS. CSF levels of IL-6, TNF-α, or MCP-1 were unaffected by pioglitazone treatment.
CONCLUSIONS
Both safety and efficacy biomarker data suggest that pioglitazone lacks potential as a medication for the treatment of alcohol dependence.
CLINICAL TRIAL REGISTRATION
NCT01631630.
背景
炎症过程与酒精成瘾、渴求及复发有关，而实验动物研究表明过氧化物酶体增殖物激活受体γ（PPARγ）的激活可抑制炎症信号。因此，人们推测具有 PPARγ 活性的药物可能具有治疗酒精依赖的潜力。
目的
我们对酒精依赖住院患者进行了一项双盲、安慰剂对照的机制原理验证研究，以探究吡格列酮对酒精渴求的影响。
方法
参与者先接受戒断治疗（如果需要），然后随机分配至吡格列酮（目标剂量 45mg/天）或安慰剂组。一旦达到目标剂量，他们完成了两项实验操作：通过个性化听觉脚本诱导酒精渴求的引导想象，以及两次分开进行的、以安慰剂为对照的低剂量静脉内脂多糖（LPS；0.8ng/kg）挑战。评估行为和内分泌反应以及脑脊液中促炎细胞因子的水平。
结果
在对 16 名受试者进行随机分组后，该研究因独立审查发现活性治疗组存在较高的肌病风险而提前终止。对完成研究的受试者进行分析表明，吡格列酮与酒精相关刺激引起的酒精渴求增加有关，而不是抑制。LPS 并未引起对酒精的渴求，因此无法评估吡格列酮的作用；然而，吡格列酮增加了 LPS 引起的神经内分泌应激反应。CSF 中 IL-6、TNF-α 或 MCP-1 的水平不受吡格列酮治疗的影响。
结论
安全性和疗效生物标志物数据均表明，吡格列酮缺乏成为治疗酒精依赖药物的潜力。
临床试验注册
NCT01631630。
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