Effects of a novel weight-loss combination product containing orlistat and acarbose on obesity: A randomized, placebo-controlled trial.

OBJECTIVE: The aim of this study was to evaluate the effect of a novel, oral, modified-release formulation of the lipase inhibitor orlistat and the glucosidase/amylase inhibitor acarbose (denoted EMP16) on relative body weight after 26 weeks compared with placebo. METHODS: The randomized, double-blind, placebo-controlled trial had a 26-week treatment period, with dose escalation up to 6 weeks. Participants, adults between ages 18 and 75 years, with BMI ≥30 kg/m2 or ≥28 kg/m2 with risk factors, were randomly assigned to EMP16 120-mg orlistat/40-mg acarbose (EMP16-120/40), EMP16-150/50, or placebo. The primary end point was relative weight loss from baseline to week 26 assessed in participants with at least one post-baseline weight measurement. RESULTS: Of 156 randomized participants, 149 constituted the intention-to-treat population. The mean (95% CI) estimated treatment difference to placebo in relative weight loss after 26 weeks in the intention-to-treat population was -4.70% (-6.16% to -3.24%; p < 0.0001) with EMP16-120/40 and -5.42% (-6.60% to -4.24%; p < 0.0001) with EMP16-150/50. CONCLUSIONS: This trial indicates that orlistat and acarbose can be successfully combined in a modified-release formulation to provide efficacious weight loss with no unexpected safety issues. EMP16 may be a promising candidate among other medications for improved weight management.

Safety of a Novel Weight Loss Combination Product Containing Orlistat and Acarbose.

The safety of a novel modified-release oral capsule with orlistat and acarbose (MR-OA) was investigated in 67 obese middle-aged White men with a body mass index of 32 to 40 kg/m2 or 30 to 32 kg/m2 plus waist circumference >102 cm. The purpose of this investigation was to compare MR-OA with the existing conventional orlistat regarding systemic safety defined as plasma orlistat concentration at the end of the treatment period of 14 days. Participants took the MR-OA fixed-dose combination formulation 3 times a day together with a major meal. Three different doses of MR-OA were evaluated-60/20, 90/30, and 120/40 (mg orlistat/mg acarbose)-as well as 1 reference group who received the conventional orlistat, Xenical, with 120 mg of orlistat. Blood plasma was sampled on days 1 and 14. The orlistat plasma concentrations of the MR-OA dose showed a delayed absorption and were lower compared with conventional orlistat at the end of the study. All doses were safe and well tolerated without any unexpected adverse events and no serious adverse events. The delay in the rise of orlistat plasma concentration indicates that the modified-release properties of the MR-OA formulation are effective. The systemic exposure of orlistat resulting from MR-OA was similar, albeit a bit lower than the conventional orlistat with 120 mg of orlistat. We can therefore assume that the safety profile regarding the orlistat moiety of MR-OA is comparable to the conventional orlistat and a promising approach for weight control in obese patients. Further clinical evaluation is underway.

Effects of a novel combination of orlistat and acarbose on tolerability, appetite, and glucose metabolism in persons with obesity.

OBJECTIVE: There is an unmet medical need for a safe and effective weight loss product with minimal systemic side-effects. In this study, the effect of a novel modified-release fixed-dose combination of orlistat and acarbose (MR-OA) was compared with conventional orlistat (CO) regarding tolerability, appetite and glucose metabolism. METHODS: Sixty-seven men with obesity, aged 24 to 60 years with body mass indexes (BMIs) 33 to 40 kg m-2 or BMIs 30 to 32 kg m-2 and waist circumference above 102 cm were included. They were randomized to either three different doses of the test formulation MR-OA (60 mg orlistat/20 mg acarbose, 90/30 and 120/40) or CO (Xenical, 120 mg orlistat) for a 2-week study of daily treatment. The participants spent days 1 and 14 at the clinical research centre where they received standardized meals, had blood sampling and filled in questionnaires regarding tolerability and appetite after meals. In days 2 to 13, the participants were at home and continued to fill in the questionnaires daily. RESULTS: In the MR-OA groups, reports of liquid and oily stools as well as faecal incontinence were fewer, whereas reports of gastric distension and flatulence were higher, compared with the CO group. More participants reported decreased hunger in the 90/30 and 120/40 MR-OA, and postprandial plasma glucose concentration was reduced in all MR-OA groups compared with CO. CONCLUSIONS: This study shows that by using a modified-release dosage form, orlistat and acarbose can be combined without compromising tolerability. Furthermore, MR-OA shows promising effects regarding reduction of appetite and reduces postprandial glucose. Tolerability is coupled to compliance and thereby efficacy of a treatment; therefore, this novel combination MR-OA could be an effective approach for weight loss treatment. A follow-up study in a more diverse population and for a longer duration with weight loss as primary outcome variable is planned.

Differential but competitive binding of Nogo protein and class i major histocompatibility complex (MHCI) to the PIR-B ectodomain provides an inhibition of cells.

Binding of class I MHC molecules (MHCI) to an inhibitory receptor, PIR-B, expressed on B cells and myeloid cells provides constitutive cellular inhibition, thus ensuring peripheral tolerance. Recent unexpected findings pointed to a novel inhibitory role of PIR-B in neurite regeneration through binding to three axonal outgrowth inhibitors of myelin, including Nogo. Thus, it becomes interesting to determine whether the actions of the inhibitory myelin proteins and MHCI could coexist independently or be mutually exclusive as to the PIR-B-mediated immune and neural cell inhibition. Here, we present data supporting the competition of Nogo- and MHCI-mediated inhibition where they coexist. Kinetic analyses of Nogo and MHCI binding to the whole or a part of the recombinant PIR-B ectodomain revealed that PIR-B binds with higher affinity to Nogo than MHCI and that the MHCI binding only occurred with the N-terminal domains of PIR-B, whereas Nogo binding occurred with either the N- or C-terminal ectodomains. Importantly, kinetic tests indicated that the binding to PIR-B of Nogo and MHCI was competitive. Both endogenous and exogenous Nogo intensified the PIR-B-mediated suppression of interleukin-6 release from lipopolysaccharide-stimulated wild-type, but not PIR-B-deficient, cultured mast cells, indicating that PIR-B mediates Nogo-induced inhibition. Thus, we propose a novel mechanism by which PIR-B-mediated regulation is achieved differentially but competitively via MHCI and Nogo in cells of the immune system.