Greenway Frank L, Whitehouse M J, Guttadauria Maria, Anderson James W, Atkinson Richard L, Fujioka Ken, Gadde Kishore M, Gupta Alok K, O'Neil Patrick, Schumacher Donald, Smith Diane, Dunayevich Eduardo, Tollefson Gary D, Weber Eckard, Cowley Michael A
1Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, USA.
Obesity (Silver Spring). 2009 Jan;17(1):30-9. doi: 10.1038/oby.2008.461. Epub 2008 Nov 6.
Existing obesity therapies are limited by safety concerns and modest efficacy reflecting a weight loss plateau. Here, we explore combination therapy with bupropion (BUP), a putative stimulator of melanocortin pathways, and an opioid antagonist, naltrexone (NAL), to antagonize an inhibitory feedback loop that limits sustained weight reduction. In vitro electrophysiologic experiments were conducted to determine the extent to which BUP+NAL stimulated hypothalamic pro-opiomelanocortin (POMC) neurons in mouse brain. A subsequent study further characterized the effect of combination BUP+NAL treatment on food intake in lean and obese mice. Finally, a randomized, blinded, placebo-controlled trial in obese adult subjects was conducted. Randomization included: BUP (300 mg) + NAL (50 mg), BUP (300 mg) + placebo (P), NAL (50 mg) + P or P+P for up to 24 weeks. BUP+NAL stimulated murine POMC neurons in vitro and caused a greater reduction in acute food intake than either monotherapy, an effect consistent with synergism. Combined BUP+NAL provided sustained weight loss without evidence of an efficacy plateau through 24 weeks of treatment. BUP+NAL completers diverged from NAL+P (P < 0.01) and P+P (P < 0.001) at week 16 and from BUP+P by week 24 (P < 0.05). The combination was also well tolerated. Translational studies indicated that BUP+NAL therapy produced synergistic weight loss which exceeded either BUP or NAL alone. These results supported the hypothesis that NAL, through blockade of beta-endorphin mediated POMC autoinhibition, prevents the classic weight loss plateau observed with monotherapies such as BUP. This novel treatment approach (BUP+NAL) holds promise for the treatment of obesity.\
现有的肥胖症治疗方法受到安全性问题和减肥效果有限的限制，减肥效果会达到平台期。在此，我们探索了安非他酮（BUP，一种假定的黑皮质素途径刺激剂）与阿片类拮抗剂纳曲酮（NAL）的联合疗法，以对抗限制持续体重减轻的抑制性反馈回路。进行了体外电生理实验，以确定BUP+NAL刺激小鼠下丘脑促阿片黑素细胞皮质素（POMC）神经元的程度。随后的一项研究进一步表征了BUP+NAL联合治疗对瘦小鼠和肥胖小鼠食物摄入量的影响。最后，在肥胖成年受试者中进行了一项随机、双盲、安慰剂对照试验。随机分组包括：BUP（300毫克）+NAL（50毫克）、BUP（300毫克）+安慰剂（P）、NAL（50毫克）+P或P+P，治疗长达24周。BUP+NAL在体外刺激了小鼠POMC神经元，并且比单一疗法导致急性食物摄入量有更大幅度的减少，这一效果与协同作用一致。联合使用BUP+NAL可实现持续体重减轻，在24周的治疗期间没有出现疗效平台期的迹象。在第16周时，BUP+NAL治疗组与NAL+P组（P<0.01）和P+P组（P<0.001）出现差异，到第24周时与BUP+P组出现差异（P<0.05）。该联合疗法的耐受性也良好。转化研究表明，BUP+NAL疗法产生的协同减肥效果超过单独使用BUP或NAL。这些结果支持了以下假设，即NAL通过阻断β-内啡肽介导的POMC自身抑制作用，防止了如BUP等单一疗法中常见的体重减轻平台期。这种新的治疗方法（BUP+NAL）有望用于肥胖症的治疗。
