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

中文翻译：

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吡格列酮激活 PPARγ 不会抑制对酒精的渴望，并且与寻求酒精依赖患者治疗的肌病风险相关：一项随机对照原理研究证明。

 基本原理

促炎过程与酒精成瘾、渴望和复发有关，而实验动物研究表明，过氧化物酶体增殖物激活受体γ (PPAR γ ) 的激活会抑制促炎信号传导。因此，推测具有 PPAR γ活性的药物可能具有治疗酒精依赖的潜力。

 目标

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证明研究，以研究吡格列酮对酒精渴望的影响。

 方法

如果需要，参与者接受戒断治疗，然后随机接受吡格列酮（目标剂量 45 毫克/天）或安慰剂。一旦达到目标剂量，他们就完成了两项实验操作：引导意象，使用个性化的听觉脚本来诱导对酒精的渴望，以及在两个单独的疗程中用静脉注射脂多糖（LPS；0.8 ng/kg）或安慰剂进行低剂量挑战。平衡秩序。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

该研究在对 16 名受试者进行随机分组后提前终止，此前一项独立审查确定积极治疗组存在肌病高风险。对完成这项研究的人的分析表明，吡格列酮与酒精相关刺激引起的酒精渴望升高有关，而不是抑制。 LPS 不会引起对酒精的渴望，因此不适合评估吡格列酮的效果；然而，吡格列酮增加了对脂多糖的神经内分泌应激反应。脑脊液中 IL-6、TNF-α 或 MCP-1 的水平不受吡格列酮治疗的影响。

 结论

安全性和有效性生物标志物数据表明，吡格列酮缺乏作为治疗酒精依赖药物的潜力。

临床试验注册

NCT01631630