Selective inhibition of 11beta-hydroxysteroid dehydrogenase type 1 decreases blood glucose concentrations in hyperglycaemic mice.

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 11beta-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 11beta-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 11beta-hydroxysteroid dehydrogenase type 1. The aim of the present study is to test if selective inhibition of 11beta-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 11beta-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 11beta-hydroxysteroid dehydrogenase type 1 can become a new approach for lowering blood glucose concentrations in Type II diabetes.

In vitro alpha-adrenoceptor autoradiography of the urethra and urinary bladder of the female pig, cat, guinea-pig and rat.

OBJECTIVE: The aim of this study was to investigate the distribution of alpha1- and alpha2-adrenoceptors in the urethra and urinary bladder of the female pig, cat, guinea-pig and rat. MATERIALS AND METHODS: The binding distributions of an alpha1-adrenoceptor ligand (3H-prazosin) and an alpha2-adrenoceptor ligand (3H-rauwolscine) were determined using in vitro autoradiography. Autoradiograms were analysed by combining computer-based image analysis and light microscopy. RESULTS: In the pig, guinea-pig and rat urethra 3H-prazosin binding was highest in the muscle layer. In the cat urethra 3H-prazosin binding could not be analysed due to a negative chemography artefact. In the pig, cat and guinea-pig urethra 3H-rauwolscine binding was highest in the urothelium, followed by the sub-mucosa, with low levels in muscle. Little 3H-rauwolscine binding was observed in the rat urethra. In the urinary bladder of all species 3H-prazosin binding was low. In the rat bladder, binding was higher in the trigone than in the dome. In the pig, cat and guinea-pig bladder 3H-rauwolscine binding was highest in the mucosa. with little binding in muscle or lamina propria. In the rat bladder, there was little binding and no regional differences. CONCLUSIONS: Alpha1-adrenoceptors were predominantly located in urethral smooth muscle, indicating their contractile importance in maintaining continence. Alpha2-Adrenoceptors were present in the urethral submucosa and bladder mucosa, but not in muscle, suggesting a role in regulation of blood flow, urethral lubrication and tumescence, but not in contraction.

The effect of phenylpropanolamine on the urethral pressure and heart rate is retained after repeated short-term administration in the unanaesthetized, conscious dog.

The present study was performed to test whether high dose agonist (phenylpropanolamine) administration twice a day causes desensitization of urethral alpha-adrenoceptors in vivo. Urethral pressure was measured on five consecutive days of phenylpropanolamine treatment of the unanaesthetized, conscious dog, and the method is described in detail. Phenylpropanolamine hydrochloride proper (75 mg, 5.1-6.1 mg kg-1), and a sustained-release formulation, both significantly increased urethral pressure and decreased heart rate. Interruption of administration for two to three days did not alter the effect. The present results suggest that the effect of phenylpropanolamine was retained, and that the alpha-adrenoceptors of dog urethra did not desensitize after repeated administration of the alpha-adrenoceptor agonist phenylpropanolamine twice a day.

References used in a drug information centre.

The literature sources used in 461 consecutive problem-oriented questions submitted during 1993 to a Drug Information Centre were reviewed retrospectively. Journals were the most frequently used literature source (36% of all quotations). Commonly used medical and clinical pharmacology journals, together with standard textbooks, provided the necessary information to solve more than 50% of drug information requests. Most questions could be answered by including the complementary use of the question/answer database Drugline. Drug information access is important for the improvement of rational use of drugs. According to the present study, this activity is possible with a fairly limited number of sources.

Use of DRUGLINE--a question-and-answer database.

BACKGROUND: DRUGLINE is a full-text, question-and-answer database offering drug information that has been evaluated as a result of consultations in a drug information center. A problem-oriented database such as DRUGLINE can be an efficient way to meet the increasing need among healthcare professionals for timely and accurate drug information. OBJECTIVE: To investigate how DRUGLINE was used during the years 1988 and 1990 and to identify any changes in needs, expectations, satisfaction, and use that occurred during those two years. DESIGN: This study investigated the use of DRUGLINE during two separate years. Questionnaires relating to DRUGLINE use during 1988 and 1990 were sent on two occasions to all users having access to the database. The anonymous questionnaires contained 17 and 18 questions, respectively. SETTING: The setting included MEDLINE/DRUGLINE use in healthcare institutions, pharmacies, medical libraries, and the pharmaceutical industry. PARTICIPANTS: The questionnaires were sent to all customers of the database host Medical Information Centre at the Karolinska Institute Library and Information Centre having access to DRUGLINE during 1988 and 1990.

Clinical pharmacology and the provision of drug information.

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.

[Medical drug information in the database Drugline]. / Medicinsk läkemedelsinformation i databasen Drugline.

Drugline is a problem-oriented drug information data base. The information available is based on queries submitted by health care professionals, mainly physicians, to the Drug Information Center (DIC), Huddinge University Hospital, Sweden. Clinical pharmacologists and pharmacists evaluate relevant information from medical publications, and queries are answered individually with a referenced review of pertinent literature. Most queries deal with adverse drug reactions or the safety of drug treatment during pregnancy or breast feeding. A joint project, undertaken by Huddinge's DIC and the National Corporation of Swedish Pharmacies (Apoteksbolaget), aims to promote Drugline and the institution of DICs at university hospitals throughout the country.

Subchronic treatment of rats with nicotine: interconversion of nicotinic receptor subtypes in brain.

A significant increase in the number of cortical high-affinity (-)-[3H]nicotine binding sites was measured in rats treated with nicotine (0.45 mg/kg) twice daily for 18 days. Competition experiments with (-)-[3H]nicotine and various concentrations of unlabelled (-)-nicotine revealed that the proportion of high-affinity nicotine binding sites was significantly increased in the nicotine-treated group while the proportion of low-affinity nicotinic binding sites was similarly significantly reduced compared to the controls. In addition there was a significant decrease in the affinity of both subtypes of nicotinic binding sites.

[3H]acetylcholine nicotinic recognition sites in human brain: characterization of agonist binding.

In the presence of a cholinesterase inhibitor to prevent hydrolysis and atropine to block muscarinic cholinergic receptors, [3H]acetylcholine ([3H]ACh) binding to human brain membranes showed highest levels of nicotinic binding sites in the thalamus. [3H]ACh, in the presence of atropine, binds to heterogeneous high-affinity binding sites in human thalamus. Scatchard analysis of the binding gave a Kd of 0.58 nM and a Bmax of 3.3 pmol/g protein for the 'super high-affinity' site and a Kd of 27 nM and a Bmax of 70 pmol/g protein for the 'high-affinity' site. Moreover, in competition studies nicotinic agonists such (-)-nicotine and carbachol displaceable [3H]ACh-specific binding sites consist of both a high- and a low-affinity population of sites. These results indicate that highest levels of [3H]ACh binding in human brain were found in the thalamus. Moreover, the human thalamus was found to have multiple high-affinity nicotinic agonist sites.

Problem-oriented drug information: a clinical pharmacological service.

The experience of a drug information centre run by clinical pharmacologists and pharmacists with expertise in literature retrieval and evaluation shows there is a need for specialised drug information services both within hospital and in outpatient care. Complex clinical situations demand judicious drug use beyond the scope of desk manual guidelines. Clinical pharmacologists can help by reviewing information from medical literature and data bases not readily available to community physicians. Clinical questions are personally answered by referenced reviews after a literature search. The answers are then kept for future use in a data bank ('Drugline').