XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Identification of the active-site serine in human pancreatic lipase by chemical modification with tetrahydrolipstatin. [Study of the month. Long-term (1-2 years) clinical trials with orlistat, a new drug for the treatment of obesity] Rx drugs

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Diabetes Care. 2004 Jan;27(1):155-61.
XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients.

Torgerson JS, Hauptman J, Boldrin MN, Sjostrom L.

Department of Body Composition and Metabolism, Sahlgrenska University Hospital, Goteborg, Sweden.

OBJECTIVE: It is well established that the risk of developing type 2 diabetes is closely linked to the presence and duration of overweight and obesity. A reduction in the incidence of type 2 diabetes with lifestyle changes has previously been demonstrated. We hypothesized that adding a weight-reducing agent to lifestyle changes may lead to an even greater decrease in body weight, and thus the incidence of type 2 diabetes, in obese patients. RESEARCH DESIGN AND METHODS: In a 4-year, double-blind, prospective study, we randomized 3,305 patients to lifestyle changes plus either orlistat 120 mg or placebo, three times daily. Participants had a BMI >/=30 kg/m2 and normal (79%) or impaired (21%) glucose tolerance (IGT). Primary endpoints were time to onset of type 2 diabetes and change in body weight. Analyses were by intention to treat. RESULTS: Of orlistat-treated patients, 52% completed treatment compared with 34% of placebo recipients (P < 0.0001). After 4 years' treatment, the cumulative incidence of diabetes was 9.0% with placebo and 6.2% with orlistat, corresponding to a risk reduction of 37.3% (P = 0.0032). Exploratory analyses indicated that the preventive effect was explained by the difference in subjects with IGT. Mean weight loss after 4 years was significantly greater with orlistat (5.8 vs. 3.0 kg with placebo; P < 0.001) and similar between orlistat recipients with impaired (5.7 kg) or normal glucose tolerance (NGT) (5.8 kg) at baseline. A second analysis in which the baseline weights of subjects who dropped out of the study was carried forward also demonstrated greater weight loss in the orlistat group (3.6 vs. 1.4 kg; P < 0.001). CONCLUSIONS: Compared with lifestyle changes alone, orlistat plus lifestyle changes resulted in a greater reduction in the incidence of type 2 diabetes over 4 years and produced greater weight loss in a clinically representative obese population. Difference in diabetes incidence was detectable only in the IGT subgroup; weight loss was similar in subjects with IGT and or NGT.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14693982&dopt=Abstract [PubMed - in process]

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FEBS Lett. 1992 Mar 24;299(1):111-5.
Identification of the active-site serine in human pancreatic lipase by chemical modification with tetrahydrolipstatin.

Luthi-Peng Q, Marki HP, Hadvary P.

Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd., Basel, Switzerland.

A chemical modification approach was used in this study to identify the active site serine residue of human pancreatic lipase. Purified human pancreatic lipase was covalently modified by incubation with [3H], [14C] tetrahydrolipstatin (THL), a potent inhibitor of pancreatic lipase. The radiolabeled lipase was digested with thermolysin, and the peptides were separated by HPLC. A single THL-peptide-adduct was obtained which was identical to that obtained earlier from porcine pancreatic lipase. This pentapeptide with the sequence VIGHS is covalently bound to a THL molecule via the side chain hydroxyl group of the serine unit corresponding to Ser-152 of the lipase. The selective cleavage of the THL-serine bond by mild acid treatment resulted in the formation of the delta-lactone Ro 40-4441 in high yield and clearly proves that THL is attached via an ester bond and with retention of stereochemistry at all chiral centers to the side chain hydroxyl group of Ser-152 of the lipase. The results obtained for human pancreatic lipase corroborate the inhibition mechanism of THL found on the porcine enzyme, and are in full agreement with the identification of the Ser-152 ... His-263 ... Asp-176 catalytic triad in the X-ray structure of human pancreatic lipase.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1544468&dopt=Abstract

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Rev Med Liege. 1999 Aug;54(8):707-9.
[Study of the month. Long-term (1-2 years) clinical trials with orlistat, a new drug for the treatment of obesity]

[Article in French]

Scheen AJ.

Departement de Medecine, Universite de Liege.

Orlistat (Xenical), whose original mechanism of action consists of the selective inhibition of gastrointestinal lipases, has been recently commercialized for the treatment of obesity. Despite its recent launch and when compared to common anorectic agents, it has been much better evaluated in long-term trials carried out according to the rules of Good Clinical Practice. We will summarize the four recently published randomized, placebo-controlled, double-blind clinical trials lasting up to 1 to 2 years and evaluating the effects of orlistat 3 x 120 mg/day in obese patients (BMI > or = 28 kg/m2).

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10548902&dopt=Abstract

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