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Obesity (Silver Spring). 2009 Jan;17(1):30-9. Epub 2008 Nov 6.
*
Rational design of a combination medication for the treatment of obesity.
Greenway FL, Whitehouse MJ, Guttadauria M, Anderson JW, Atkinson RL,
Fujioka K, Gadde KM, Gupta AK, O'Neil P, Schumacher D, Smith D,
Dunayevich E, Tollefson GD, Weber E, Cowley MA.
1Pennington Biomedical Research Center, Louisiana State University
System, Baton Rouge, Louisiana, USA.

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.

Publication Types:
* Multicenter Study
* Randomized Controlled Trial
* Research Support, N.I.H., Extramural
* Research Support, Non-U.S. Gov't

PMID: 18997675