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      Assessment of single-dose benzodiazepines on insulin secretion, insulin sensitivity and glucose effectiveness in healthy volunteers: a double-blind, placebo-controlled, randomized cross-over trial [ISRCTN08745124]

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          Abstract

          Background

          The present study aimed at investigating in healthy volunteers the effects of diazepam and clonazepam on beta-cell function, insulin sensitivity and glucose effectiveness based on the frequently sampled intravenous (0.5 gkg -1) glucose tolerance test with minimal-model analysis.

          Methods

          The study was designed as a double-blind, placebo-controlled, cross-over clinical trial. Diazepam (10 mg) and clonazepam (1 mg) were infused during 30 min to 15 male subjects with a mean age of 22 years (range: 20–29), after informed consent was given. Benzodiazepines were assayed by capillary gas chromatography with electron capture, insulin by radioimmunoassay and glucose by the enzymatic glucose oxidase method.

          Results

          Both benzodiazepines induced significant psychotropic effects. The acute insulin responses (AIR) were significantly and negatively correlated with the clonazepam plasma concentrations (r = -0.609, P < 0.05, n = 14). However, the mean AIR was not significantly different between the benzodiazepine-treated subjects and the controls. In addition, the parameters of glucose assimilation were significantly decreased as compared with placebo in the subgroup of 7 subjects with plasma clonazepam concentrations higher than 6.0 ng ml -1 (median and lower limit of effective therapeutic concentrations): 1.37 ± 0.3 versus 2.84 ± 0.60 × 10 -2min -1 (P = 0.028) for the coefficient of glucose tolerance (K g), 2.18 ± 0.29 versus 3.71 ± 0.89 × 10 -4μUml -1min -1 (P = 0.018) for insulin sensitivity (S i) and 1.80 ± 0.39 versus 3.59 ± 0.71 × 10 -2min -1 (P = 0.028) for glucose effectiveness at basal insulin (S g). These parameters were not significantly modified when diazepam was administered; plasma levels of this drug however, were below the effective therapeutic concentrations (300 ng ml -1) from min 15 after the end of the perfusion.

          Conclusion

          The present results suggest that a benzodiazepine, in particular clonazepam, may alter insulin secretion and insulin sensitivity after a single administration in healthy volunteers.

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          Most cited references29

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          The Pharmacological Basis of Therapeutics

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            Specific benzodiazepine receptors in rat brain characterized by high-affinity (3H)diazepam binding.

            [3H]Diazepam appears to bind specifically to a single, saturable, binding site located on rat brain membranes, with an affinity constant near 3 nM at pH 7.4. Specific binding constitutes more than 90% of total binding at 0 degrees and less than 10% of total binding at 37 degrees. Arrhenius plots suggest a sharp conformational change in the diazepam receptor near 18 degrees. Mitochondrial fractions from rat kidney, liver, and lung exhibit some [3H]diazepam binding that can be displaced by nonradioactive diazepam and several other benzodiazepines. However, Ro-4864, which is almost inactive in displacing [3H]diazepam from brain membranes, is extremely potent in displacing it from kidney mitochondria. Conversely, clonazepam, the most potent inhibitor of brain binding, is an extremely weak inhibitor of kidney binding. Furthermore, diazepam binding to kidney mitochondria has an affinity constantof 40 nM, about 15 times higher than that in brain. No specific diazepam binding was detected in intestine or skeletal muscle. Thus, specific [3H]diazepam binding to membranes appears to be restricted to brain, where it is unevenly distributed: the density of diazepam receptors is about five times higher in cortex (the highest density) than in pons-meddula (lowest density). Trypsin and chymotrypsin completely abolished specific [3H]diazepambinding in brain and kidney.
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              The Pharmaeological basis of therapeutics

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                Author and article information

                Journal
                BMC Clin Pharmacol
                BMC Clinical Pharmacology
                BioMed Central (London )
                1472-6904
                2004
                4 March 2004
                : 4
                : 3
                Affiliations
                [1 ]Clinical Investigation Center, Saint-Eloi University Hospital, Section of Clinical Pharmacology, Montpellier, France
                [2 ]Center for Pharmacology and Health Biotechnology, CNRS UMR 5160, Montpellier, France
                [3 ]Department of Pharmacokinetics, La Timone University Hospital, Marseille, France
                [4 ]Department of Clinical Physiology, Lapeyronie University Hospital, Montpellier, France
                Article
                1472-6904-4-3
                10.1186/1472-6904-4-3
                387833
                15102335
                e6fc01fe-d9d3-4fb8-be30-eacc6adda54b
                Copyright © 2004 Chevassus et al; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.
                History
                : 3 April 2003
                : 4 March 2004
                Categories
                Research Article

                Pharmacology & Pharmaceutical medicine
                diabetes,clinical investigation,insulin sensitivity,benzodiazepine,insulin secretion,glucose tolerance

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