Pharmacological differentiation of opioid receptor antagonists by molecular and functional imaging of target occupancy and food reward-related brain activation in humans.

Opioid neurotransmission has a key role in mediating reward-related behaviours. Opioid receptor (OR) antagonists, such as naltrexone (NTX), can attenuate the behaviour-reinforcing effects of primary (food) and secondary rewards. GSK1521498 is a novel OR ligand, which behaves as an inverse agonist at the µ-OR sub-type. In a sample of healthy volunteers, we used [(11)C]-carfentanil positron emission tomography to measure the OR occupancy and functional magnetic resonance imaging (fMRI) to measure activation of brain reward centres by palatable food stimuli before and after single oral doses of GSK1521498 (range, 0.4-100 mg) or NTX (range, 2-50 mg). GSK1521498 had high affinity for human brain ORs (GSK1521498 effective concentration 50 = 7.10 ng ml(-1)) and there was a direct relationship between receptor occupancy (RO) and plasma concentrations of GSK1521498. However, for both NTX and its principal active metabolite in humans, 6-ß-NTX, this relationship was indirect. GSK1521498, but not NTX, significantly attenuated the fMRI activation of the amygdala by a palatable food stimulus. We thus have shown how the pharmacological properties of OR antagonists can be characterised directly in humans by a novel integration of molecular and functional neuroimaging techniques. GSK1521498 was differentiated from NTX in terms of its pharmacokinetics, target affinity, plasma concentration-RO relationships and pharmacodynamic effects on food reward processing in the brain. Pharmacological differentiation of these molecules suggests that they may have different therapeutic profiles for treatment of overeating and other disorders of compulsive consumption.

Pragmatic study of orlistat 60 mg on abdominal obesity.

BACKGROUND/OBJECTIVES: It is well established that combining a reduced calorie, low-fat diet with the lipase inhibitor orlistat results in significantly greater weight loss than placebo plus diet. This weight loss is accompanied by changes in adipose tissue (AT) distribution. As 60 mg orlistat is now available as an over-the-counter medication, the primary objective of this study was to determine whether 60 mg orlistat is effective as a weight loss option in a free-living community population with minimal professional input. METHODS: AT and ectopic lipid content were measured using magnetic resonance imaging and (1)H MR spectroscopy, respectively, in 27 subjects following 3 months treatment with orlistat 60 mg and a reduced calorie, low-fat diet. RESULTS: Significant reductions in intra-abdominal AT (-10.6%, P=0.023), subcutaneous (-11.7% P<0.0001) and pericardial fat (-9.8%, P=0.034) volumes and intrahepatocellular lipids (-43.3%, P=0.0003) were observed. These changes in body fat content and distribution were accompanied by improvements in plasma lipids and decreases in blood pressure and heart rate. CONCLUSION: These findings suggest that over-the-counter 60 mg orlistat, in combination with the type of advice a subject could expect to be given when obtaining 60 mg orlistat in a community setting, does indeed result in potentially clinically beneficial changes in body composition and risk factors for metabolic diseases.