Long-term pharmacotherapy for obesity.

Klein S.

Division of Geriatrics and Nutritional Sciences, Center for Human Nutrition, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8031, St. Louis, MO 63110, USA. sklein im.wustl.edu

Obese patients unable to achieve significant weight loss with lifestyle changes alone may require drug therapy, and such therapy may be needed long term lest weight lost be regained. In the United States, only sibutramine and orlistat are available for the long-term treatment of obesity. Clinical trials have shown that both drugs can induce and maintain weight loss, even in patients with comorbid conditions such as hypertension or type 2 diabetes. Their use must be combined with behavior modification and a structured meal plan, however, for patients to reap the full benefits of such treatment.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15687412&dopt=Abstract orlistat Xenical online refs
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Preventing type 2 diabetes mellitus.

Curtis J, Wilson C.

Phoenix Indian Medical Center, Indian Health Service, Phoenix, Arizona.

Type 2 diabetes is a serious, costly, and increasingly common disease. Several conditions commonly seen in family medicine settings confer increased risk of developing diabetes. Among these conditions are impaired glucose tolerance, impaired fasting glucose, obesity, gestational diabetes, hypertension, hyperlipidemia, and menopause. We here present the results of a systematic review of the literature examining the evidence for different strategies aimed at preventing type 2 diabetes in patients with these conditions. The strongest evidence supports an intensive lifestyle intervention designed to induce modest weight loss. The greatest degree of prevention, based on lesser quality evidence, may be imparted by bariatric surgery. Metformin and troglitazone have appreciable evidence in specific populations, and orlistat and acarbose have slightly less evidence among obese patients, for preventing diabetes. Ramipril, captopril, losartan, pravastatin, and estrogens show some very preliminary promise for preventing diabetes in patients treated for hypertension, hyperlipidemia, and menopause, but each needs a more rigorous evaluation. Although more questions remain to be answered, family physicians now have tools available to help our patients lead lives free of diabetes.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15709062&dopt=Abstract orlistat Xenical online refs
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Improvement of glycaemic control with rebound following orlistat initiation and cessation associated with minimal weight change.

Gonzalez S, Kilpatrick ES, Atkin SL.

Department of Medicine, University of Hull, Hull, UK.

Abstract A 57-year-old Caucasian woman with Type 2 diabetes treated for seven years with diet and oral combination hypoglycaemic therapy was referred because of the progressive deterioration of glycaemic control. She was obese (77 kg, BMI = 39.9), hypertensive, hypercholesterolaemic with marked osmotic symptoms (HbA(1c) 12.2%), therefore she was started on insulin (Human Mixtard 30 b.d.) with metformin therapy. Dietary counselling, recommendations to increase physical activity, and supervised self-injection technique with titration of her insulin were also provided. She was routinely followed-up to assess her progress. Two years later, her glycaemic control remained suboptimal. Average HbA(1c) was 10.4% despite an increasingly high dose of insulin (94 units/day) although it improved when metformin was increased to 1 g t.d.s. (HbA(1c) = 9.3%). Her BMI progressively rose from 39.9 to 42.1 (77 to 82.5 kg) despite dietary advice. A trial of orlistat (three months) was commenced, after intensive dietary counselling, that reduced her body weight by 1.5 kg (2% reduction, BMI 41.3). However, her HbA(1c) improved by 0.5% (from 9.3 to 8.8%). Six months after orlistat was stopped her HbA(1c) rose to 10.5% and weight increased to 81.8 kg (BMI 41.8). Despite the orlistat treatment broaching NICE guidelines should it have been continued? Diabet. Med. 22, 344 -345 (2005).

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15717886&dopt=Abstract orlistat Xenical online refs
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Effective oral treatment of unconjugated hyperbilirubinemia in Gunn rats.

Hafkamp AM, Havinga R, Sinaasappel M, Verkade HJ.

Division of Pediatric Gastroenterology, Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, Groningen, The Netherlands.

We sought to develop an oral treatment for unconjugated hyperbilirubinemia. In the Gunn rat model of unconjugated hyperbilirubinemia, dietary supplementation with the lipase inhibitor orlistat (Orl) or with calcium phosphate (CaP) decreases plasma unconjugated bilirubin (UCB) levels. We determined whether Orl, CaP, or their combination is superior to phototherapy, the conventional treatment, and whether the effects of Orl and CaP are influenced by dietary fat content. Gunn rats were treated with Orl (200 mg/kg chow), CaP (20 g/kg chow), Orl + CaP, or continuous phototherapy (19 muW/cm(2)/nm) during a low-fat (LF) diet (13 energy%) or high-fat (HF) diet (35 energy%). Plasma UCB and fecal fat excretion were measured before, during, and/or at the end of treatment. Orl treatment for 2 weeks (HF diet) reduced plasma UCB concentrations similar to phototherapy (-34% and -28%, respectively); the combination of both was more effective than either treatment alone (-48%; P < .001). After 3 weeks of a HF diet, plasma UCB was 46% lower compared with the LF diet (P < .001). Plasma UCB concentrations were negatively correlated with fecal fat excretion (r = -0.96; P < .001). Irrespective of dietary fat content, 3 weeks of combined treatment (Orl + CaP) decreased plasma UCB by approximately 50% (P < .01) and was more effective than phototherapy (P < .05) at the intensity provided. In conclusion, plasma UCB concentrations in Gunn rats are negatively related to fecal fat excretion and dietary fat content. Orlistat is equally effective as phototherapy for the treatment of unconjugated hyperbilirubinemia in Gunn rats, and combined oral treatment with Orl + CaP is more effective than phototherapy. The present results support the feasibility of an efficient oral treatment of unconjugated hyperbilirubinemia. (HEPATOLOGY 2005;41:526-534.).

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15726662&dopt=Abstract orlistat Xenical online refs
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Quantitative determination of Orlistat (tetrahydrolipostatin, Ro 18-0647) in human plasma by high-performance liquid chromatography coupled with ion spray tandem mass spectrometry.

Bennett PK, Li YT, Edom R, Henion J.

Advanced BioAnalytical Services, Ithaca, New York 14850, USA.

A rapid, sensitive and specific analytical method was developed and validated to quantify tetrahydrolipostatin (Orlistat, Ro 18-0647) in human plasma in order to provide pharmacokinetic data from clinical trials. This method employs a preliminary plasma protein precipitation step followed by a simple, one-step liquid-liquid extraction procedure to isolate Ro 18-0647 and its pentadeuterated internal standard, Ro 18-0647-d5, from the biological matrix. Reconstituted extracts were analyzed by liquid chromatography/ion spray tandem mass spectrometry (LC/MS/MS) in the selected reaction monitoring (SRM) mode. Chromatography was carried out using a 2 mm i.d. x 50 mm Deltabond Phenyl column. The eluent was acetonitrile-2 mM ammonium acetate (90:10). The retention time of the analyte was 1.2 min and chromatographic run times were less than 1.5 min. No interferences from anticoagulants, collection devices or endogenous constituents of the plasma were observed. The assay has a lower limit of quantitation (LLQ) of 0.20 ng ml-1 in plasma and a lower limit of detection (LLD) of 0.10 ng ml-1 plasma, based on 1 ml aliquots. The capability to detect 0.025 ng ml-1 in plasma has also been demonstrated. The calibration graphs were linear from 0.20 to 10 ng ml-1. The assay was initially validated with a linear range of 0.20-1.0 ng ml-1. This range was later extended and validated to an upper level of quantitation of 10 ng ml-1. Intra- and inter-assay precision studies showed a mean variability of less than 10%. The recovery, inter-assay precision and accuracy of the method were within acceptable bioanalytical standards. The assay has been shown to reliably provide automated, unattended sample analysis for approximately 150 samples per day. In an additional series of tests, Ro 18-0467 was shown to be stable under conditions that might be encountered during the analysis of samples from clinical trials. This LC/MS/MS assay procedure for Ro 18-0647 in human plasma has proven to be robust, sensitive, specific, accurate and reproducible. This method has been used to analyze over 5000 study samples.

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