title: Rational design of a combination medication for the treatment of obesity.
abstract: 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.\
authors.affiliation: 1Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, USA.
authors.forename: Frank L
authors.initials: FL
authors.lastname: Greenway
authors.forename: M J
authors.initials: MJ
authors.lastname: Whitehouse
authors.forename: Maria
authors.initials: M
authors.lastname: Guttadauria
authors.forename: James W
authors.initials: JW
authors.lastname: Anderson
authors.forename: Richard L
authors.initials: RL
authors.lastname: Atkinson
authors.forename: Ken
authors.initials: K
authors.lastname: Fujioka
authors.forename: Kishore M
authors.initials: KM
authors.lastname: Gadde
authors.forename: Alok K
authors.initials: AK
authors.lastname: Gupta
authors.forename: Patrick
authors.initials: P
authors.lastname: O'Neil
authors.forename: Donald
authors.initials: D
authors.lastname: Schumacher
authors.forename: Diane
authors.initials: D
authors.lastname: Smith
authors.forename: Eduardo
authors.initials: E
authors.lastname: Dunayevich
authors.forename: Gary D
authors.initials: GD
authors.lastname: Tollefson
authors.forename: Eckard
authors.initials: E
authors.lastname: Weber
authors.forename: Michael A
authors.initials: MA
authors.lastname: Cowley
mesh_terms: D000328:Adult; D000821:Animal Feed; D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use; D016642:Bupropion / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005215:Fasting; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008820:Mice, Obese; D009271:Naltrexone / Q000627:therapeutic use*; D009292:Narcotic Antagonists / Q000627:therapeutic use; D009765:Obesity / Q000188:drug therapy* / Q000453:epidemiology; D050177:Overweight / Q000453:epidemiology; D014481:United States / Q000453:epidemiology; D015431:Weight Loss
chemical_list: D000928:Antidepressive Agents; D009292:Narcotic Antagonists; D016642:Bupropion; D009271:Naltrexone