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 β‐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.

Prolactinoma-associated obesity treated with bupropion and methylphenidate

“…Animal models show that the expression of POMC-mRNA is regulated by dopamine, especially the activation of D2-receptors of the ARH [Tong and Pelletier, 1992]. Bupropion appears to increase the activity of hypothalamic POMCproducing cells [Greenway et al 2008[Greenway et al , 2009. Previous studies have shown that methylphenidate can amplify dopaminergic signalling within the mesolimbic circuitry when humans are exposed to food stimuli [Volkow et al 2002].…”

Progressos recentes e novas perspectivas em farmacoterapia da obesidade

“…Em contrapartida, foi demonstrado que a β-endorfina, um opioide endóge-no, é responsável por um mecanismo de autoinibição da via da POMC, resultando em um aumento da ingestão alimentar em roedores. Ao inibir os receptores opioides, a naltrexona libera os neurônios da POMC da inibição pela β-endorfina e, portanto, potencializa os efeitos ativadores dessa via pela bupropiona (26,27). Adicionalmente, alguns estudos em ratos demonstraram que a ingestão de alimentos palatáveis (por exemplo, doces) leva a aumento dos níveis de β-endorfina no hipotálamo.…”

Medical Therapy for Obesity

“…Naltrexone blocks β-endorphin and increases the release of α-MSH, which can continue to inhibit feeding. 42 In a 24-week dose-ranging study, 419 subjects were randomized but only 244 (64%) completed the trial. Among the completers, weight loss was 1.2 kg in the placebo group, 3.1 kg in the bupropion-treated group, but only 1.6 kg with the highest (48 mg/day) dose of naltrexone.…”