Agmatine is not a good candidate as endogenous ligand for imidazoline sites of pancreatic B cells and vascular bed.

In order to determine whether agmatine could be a putative endogenous ligand for imidazoline receptors mediating insulin secretion and vasoconstriction, we compared its effects with those of the imidazoline, efaroxan. Agmatine exhibited a much lower potency and efficacy than efaroxan on insulin secretion from rat pancreas perfused with 8.3 mM glucose. On the other hand, in contrast to efaroxan (100 microM), agmatine (3 mM) did not increase arginine-induced insulin release. In addition, agmatine failed to reproduce the vasoconstrictor effect of efaroxan on pancreatic vessels. These results show that agmatine does not behave like efaroxan, an agonist for the imidazoline receptors mediating insulin secretion or vasoconstriction in the pancreas.

Effects of imidazolines and derivatives on insulin secretion and vascular resistance in perfused rat pancreas.

The effects of imidazolines and derivatives were studied on insulin secretion and vascular resistance in the isolated perfused rat pancreas. On insulin secretion, two imidazoline alpha 2-adrenoceptor antagonists, efaroxan (1-100 microM) and RX821002 (10 microM), had a stimulating response; however, idazoxan, like the non-imidazoline alpha 2-adrenoceptor antagonist yohimbine, was ineffective at 10 microM. The oxazoline rilmenidine with alpha 2-adrenergic activity at 10 microM), an imidazoline devoid of alpha 2-adrenergic activity, also had an insulin-releasing effect. On pancreatic vessels, all imidazolines tested (efaroxan, RX821002, antazoline and idazoxan), in contrast to yohimbine, induced vasoconstriction. Rilmenidine did not have a vasoconstrictor effect after blockade of alpha 2-adrenoceptors. Furthermore, the efaroxan-induced insulin release or vasoconstriction was not affected by the blockade of alpha 2- and alpha 1-adrenoceptors. This study shows that imidazolines and derivatives are able to stimulate insulin release and induce vasoconstriction in the rat pancreas. These effects cannot be ascribed to an interaction with alpha-adrenoceptors but may involve different types of imidazoline sites.

Effects of a peripheral-type benzodiazepine on glucose-induced insulin secretion.

Benzodiazepines, besides interacting with central-type receptors which mediate their well-known pharmacological actions, bind to peripheral-type receptors that are distributed in a variety of peripheral tissues including numerous endocrine organs. The present work was designed to investigate the effects of a selective peripheral-type benzodiazepine, 4'-chlordiazepam (Ro 5-4864), on glucose-induced insulin secretion in vitro. In the rat isolated pancreas perfused with a Krebs-bicarbonate buffer containing 8.3 mM glucose, the drug (10(-6) and 10(-5) M) induced a progressive and significant decrease in insulin release. Concomitantly, it induced a vasodilator response of the pancreatic vascular bed. In rat isolated islets incubated for 1 h in the presence of 15 mM glucose, 4'-chlordiazepam (10(-5) and 10(-4) M) induced a significant and dose-dependent inhibition of insulin release. In contrast, the selective central-type benzodiazepine, clonazepam (10(-6) - 10(-4) M), did not significantly modify glucose-induced insulin secretion. In addition, experiments were performed to test the effect of 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline-carboxamid e (PK 11195), a peripheral non-benzodiazepine ligand proposed as a putative antagonist. This substance did not counteract the inhibitory effect of 4'-chlordiazepam but itself (10(-6) and 10(-5) M) elicited a potent inhibitory effect on insulin secretion. These results show that drugs such as 4'-chlordiazepam and PK 11195 which have a high affinity for peripheral-type benzodiazepine receptors, in contrast to a central-type benzodiazepine agonist, inhibit glucose-induced insulin secretion in vitro.

Antazoline increases insulin secretion and improves glucose tolerance in rats and dogs.

In vivo effects of an imidazoline devoid of alpha2-adrenoceptor antagonistic properties, antazoline, on insulin secretion and glycemia were investigated both in fasted rats and dogs. In both species, antazoline (1.5 mg/kg i.v.) transiently increased insulinemia without affecting basal plasma glucose levels. In contrast, during an i.v. glucose tolerance test, antazoline markedly potentiated insulin release and thus increased the glucose disappearance rate. In rats, during an oral glucose tolerance test, the intragastric administration of antazoline (1.5 mg/kg) clearly enhanced insulin secretion and reduced hyperglycemia. In dogs provided with a venous pancreatico-duodenal bypass, antazoline (0.5 mg/kg i.v.) induced an immediate and transient increase in insulin and somatostatin but not in glucagon pancreatico-duodenal outputs. In conclusion, intravenously and orally administered, the imidazoline antazoline is able to stimulate insulin secretion in vivo and improve glucose tolerance. The imidazoline compounds could therefore have a potential therapeutic relevance as new antihyperglycemic insulinotropic agents.

Evidence for two different imidazoline sites on pancreatic B cells and vascular bed in rat.

The relative potencies of imidazoline compounds to induce insulin secretion and vascular resistance were compared in the isolated perfused rat pancreas. On insulin secretion, only the two imidazolines, antazoline and efaroxan, induced a concentration-dependent response, antazoline being 10 times more potent than efaroxan. In contrast, idazoxan, a blocker of imidazoline I1 sites, at concentrations up to 30 microM, antagonized the insulin response to 10 microM efaroxan (IC50 approximately equal to 14 +/- 2 microM) without affecting that to 3 microM tolbutamide. On pancreatic vessels, not only antazoline and efaroxan but also idazoxan induced a concentration-dependent vasoconstriction; the rank order of agonist potency was antazoline > efaroxan > idazoxan. In addition, cimetidine, an imidazole known to bind imidazoline I1 sites, ineffective per se, partially reversed the insulin stimulatory effect of efaroxan without affecting its vasoconstrictor effect. This study demonstrates that the insulin secretory and vasoconstrictor actions of imidazolines involve different imidazoline sites in rat pancreas. The results provide evidence for an I1 type mediating insulin secretion on B cells and an I2 type mediating vasoconstriction in vessels.

[Clinical trials in the elderly: ethical and methodologic considerations]. / Essais thérapeutiques chez le sujet âgé: particularités éthiques et méthodologiques.

INTRODUCTION: Based on a literature review, main ethical and methodological issues raised by the implementation of randomized clinical trials involving elderly patients are discussed. CURRENT KNOWLEDGE AND KEY POINTS: Despite their rapidly growing number and the subsequent significant increase in consumption of health care services and its cost, elderly patients have seldom been involved in clinical trials. FUTURE PROSPECTS AND PROJECTS: However, the need for accurate scientific information on which relevant therapeutic decisions regarding this vulnerable population may be based has introduced marked changes in attitudes towards either clinical trials conducted in the elderly or requirements of various licensing authorities in regard to assessment of new drugs in elderly patients. Although difficulties pertaining to controlled clinical trials involving elderly patients may hamper both planning and carrying out of studies, completion of such trials may be achieved.

Ethical assessment of clinical research publications.

The ethical quality of research could be improved in four ways: increasing the expertise of research committees, encouraging the popularization of research in ethics, delivering medical training in ethics, and improving the a posteriori control of editorial committees. With regard to the last point, we propose ethical guidelines that may be used as a screening device for publication. Scientific publications have a duty to contribute to the diffusion and application of ethical principles. But too often pieces of research published in these journals do not adequately demonstrate their ethical reflections and chosen ethical procedures. Only scientific procedures are extensively discussed. We think it is essential to develop an assessment of the ethical value of research that is featured in journals, in the same way that the methodological value is assessed. This paper reports what motivated our group to create an ethical scheme, how we developed this scheme and what was our process of validation. In the same way that today a study can be refused publication for methodological inadequacies, in the future publication could more likely be refused for ethical shortcomings.

Cost-effectiveness analysis of treatments for phimosis: a comparison of surgical and medicinal approaches and their economic effect.

OBJECTIVE: To compare the cost-effectiveness of surgery and topical steroids as treatments for phimosis (defined as a clinically verifiable, pathological, cicatricial stenosis of the prepuce) and to evaluate the financial basis of these treatments. METHODS: Data on treatment using topical steroids was obtained from published reports and those for circumcision from claims by private hospitals for children < 13 years old registered at the health insurance department of our facility. The estimate of the French national financial cost of the treatments for 1998 was calculated from public and private institutional information. RESULTS: Treatment with topical steroids for 4-8 weeks was successful in approximately 85% of patients (mean age 5 years) and had no side-effects; the remaining 15% were treated by circumcision. Topical steroid therapy costs (in French francs) F 360 per patient. For those primarily treated by circumcision (81 boys, mean age 4.3 years) and diagnosed as having phimosis, the cost was F 3330 per patient in the private sector. The total number of circumcisions performed in France, regardless of sector (public or private) for 1998 was estimated to be 51 080, which represents an annual cost of F 195.7 million. CONCLUSION: As topical pharmacological treatment avoids the disadvantages, trauma and potential complications of penile surgery, including anaesthesia-related risks, the use of topical steroids as a primary treatment appears to be justified in boys with clinically verifiable phimosis. This treatment could reduce costs by 75%, which represents a potential annual saving of approximately F 150 million.