11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) has been proposed as a new target for type 2 diabetes drugs. The aim of the present study was to assess the effects of inhibition of 11 beta-HSD1 on blood glucose levels, glucose tolerance, and insulin sensitivity in mouse models of type 2 diabetes. BVT.2733 is an isoform-selective inhibitor of mouse 11 beta-HSD1. Hyperglycemic and hyperinsulinemic ob/ob, db/db, KKAy, and normal C57BL/6J mice were orally administered BVT.2733 (200 mg/kg.d, twice daily). In hyperglycemic, but not in normal mice, BVT.2733 lowered circulating glucose (to 50-88% of control) and insulin (52-65%) levels. In oral glucose tolerance tests in ob/ob and KKAy mice, glucose concentrations were 65-75% of vehicle values after BVT.2733 treatment, and in KKAy mice insulin concentrations were decreased (62-74%). Euglycemic, hyperinsulinemic clamps demonstrated decreased endogenous glucose production (21-61%). Analysis of hepatic mRNA in KKAy mice showed reduced phosphoenolpyruvate carboxykinase mRNA (71%). A slight reduction in food intake was observed in ob/ob and KKAy mice. Cholesterol, triglycerides, and free fatty acid levels were decreased to 81-86% in KKAy mice after a 4-h fast. The results support previous suggestions that selective 11 beta-HSD1 inhibitors lower blood glucose levels and improve insulin sensitivity in different mouse models of type 2 diabetes.

Novel antidiabetic arylsulfonamidothiazoles are presented that exert action through selective inhibition of the 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) enzyme, thereby attenuating hepatic gluconeogenesis. The diethylamide derivative 2a was shown to potently inhibit human 11beta-HSD1 (IC(50) = 52 nM), whereas the N-methylpiperazinamide analogue 2b only inhibited murine 11beta-HSD1 (IC(50) = 96 nM). Both compounds showed >200-fold selectivity over human and murine 11beta-HSD2. 2b was subsequently shown to reduce glucose levels in diabetic KKA(y) mice, substantiating the 11beta-HSD1 enzyme as a target for the treatment of type 2 diabetes.

Information must be collected, evaluated and utilized to support every qualified activity. Medicine, with a written scientific tradition stretching back more than 2,000 years, is no exception. Here, we discuss a number of important items associated with the establishment of a drug information centre run by clinical pharmacologists and information pharmacists, serving a broad demand, mainly among clinical specialists. The working methods include a professional literature search, critical evaluation of the material, writing a structured answer, quality control, feedback to the inquirer and storage in a database which is publicly available. One can foresee even more complex systems wherein a number of active and specialized databases communicate to provide relevant advice and support at the point of care, supplying information on drug recommendations, reimbursement, environmental aspects, antimicrobial resistance, pharmacogenetics and adverse effects, and linked to a list of prescribed drugs for the individual patient. This will be possible in both rich and poor countries through the application of modern and developing information technology. However, research on the best and safest methods of such decision support systems will be needed to ensure that they really do improve the quality of drug prescribing and use.

Aims/hypothesis. Current pharmacological treatments for Type II (non-insulin-dependent) diabetes mellitus have various limitations. New treatments are needed to reduce long-term risks for diabetic complications and mortality. We tested a new principle for lowering blood glucose. It is well known that glucocorticoids in excess cause glucose intolerance and insulin resistance. The enzymes 11β-hydroxysteroid dehydrogenase type 1 and type 2 inter-convert inactive and active glucocorticoids, thereby playing a major role in local modulation of agonist concentration and activation of corticosteroid receptors in target tissues. It has been hypothesized that selective inhibition of 11β-hydroxysteroid dehydrogenase type 1 decreases excessive hepatic glucose production in hyperglycemia and diabetes. BVT.2733 is a new, small molecule, non-steroidal, isoform-selective inhibitor of mouse 11β-hydroxysteroid dehydrogenase type 1. The aim of the present study is to test if selective inhibition of 11β-hydroxysteroid dehydrogenase type 1 lowers blood glucose concentrations in a hyperglycaemic and hyperinsulinaemic mouse model. Methods.BVT.2733 was given to spontaneously hyperglycaemic KKA y mice for 7 days using subcutaneous osmotic mini-pumps. Results. BVT.2733 lowered hepatic PEPCK and glucose-6-phosphatase mRNA, blood glucose and serum insulin concentrations compared with vehicle treated mice. In contrast, hepatic 11β-hydroxysteroid dehydrogenase type 1 mRNA, liver function marker enzyme expression (aspartate aminotransferase, alanine aminotransferase and alkaline phosphatases), daily food intake and body weight were not altered by the treatment. Conclusion/interpretation. These results suggest that a selective inhibitor of human 11β-hydroxysteroid dehydrogenase type 1 can become a new approach for lowering blood glucose concentrations in Type II diabetes. [Diabetologia (2002[Diabetologia ( ) 45:1528[Diabetologia ( -1532

Clinical pharmacologists have a service role in the provision of drug information to individuals both in hospitals and primary health care. We present here a systematic approach in answering questions in a drug information centre (DIC), and describe the working method and the documentation of the work in a question answer (Q/A) data base. Drugline is a full-text data base offering problem-oriented drug evaluation comparable to a clinical consultation. The drug information is produced in a non-commercial drug information centre sponsored by the national health care sector and the National Corporation of Swedish Pharmacies, and run jointly by clinical pharmacologists and pharmacists. A minor part of Drugline is available in English for online searching, in parallel with Medline at the database host, the Medical Information Centre at the Karolinska Institute Library and Information Centre, and the users represent mainly medical libraries, hospital pharmacies, university clinics, and the pharmaceutical industry. A network of DICs has been organized in Swedish university hospitals with access to Drugline for searching and the storage of questions and answers. This network has the potential for expansion throughout Europe. It offers the unique possibility of complementing drug product information with problem-oriented drug information emerging from cases in the real world of prescribing.