Drugs online research references
J Pharmacol Exp Ther. 2000 May;293(2):444-52.
Pancreatic beta-cell K(ATP) channel activity and membrane-binding studies with nateglinide: A comparison with sulfonylureas and repaglinide.
Hu S, Wang S, Fanelli B, Bell PA, Dunning BE, Geisse S, Schmitz R, Boettcher BR.
Metabolic and Cardiovascular Disease Department, Novartis Institute for Biomedical Research, Summit, New Jersey 07901, USA.
Nateglinide (A-4166) is an amino acid derivative with insulinotrophic action in clinical development for treatment of type 2 diabetes. The aim of this study was to determine whether nateglinide's interaction at the K(ATP) channel/sulfonylurea receptor underlies its more rapid onset and shorter duration of action in animal models. Binding studies were carried out with membranes prepared from RIN-m5F cells and HEK-293 cells expressing recombinant human sulfonylurea receptor 1 (SUR1). The relative order for displacement of [(3)H]glibenclamide in competitive binding experiments with RIN-m5F cell membranes was glibenclamide > glimepiride > repaglinide > glipizide > nateglinide > L-nateglinide > tolbutamide. The results with HEK-293/recombinant human SUR1 cells were similar with the exception that glipizide was more potent than repaglinide. Neither nateglinide nor repaglinide had any effect on the dissociation kinetics for [(3)H]glibenclamide, consistent with both compounds competitively binding to the glibenclamide-binding site on SUR1. Finally, the inability to measure [(3)H]nateglinide binding suggests that nateglinide dissociates rapidly from SUR1. Direct interaction of nateglinide with K(ATP) channels in rat pancreatic beta-cells was investigated with the patch-clamp method. The relative potency for inhibition of the K(ATP) channel was repaglinide > glibenclamide > nateglinide. Kinetics of the inhibitory effect on K(ATP) current showed that the onset of inhibition by nateglinide was comparable to glibenclamide but more rapid than that of repaglinide. The time for reversal of channel inhibition by nateglinide was also faster than with glibenclamide and repaglinide. These results suggest that the unique characteristics of nateglinide are largely the result of its interaction at the K(ATP) channel.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10773014&dopt=Abstract
Metabolism. 1983 Apr;32(4):398-402.
Extrapancreatic action of sulfonylureas: hypoglycemic effects are not dependent on altered insulin binding or inhibition of transglutaminase.
Nowak SM, McCaleb ML, Lockwood DH.
It has been proposed by others that sulfonylureas exert their extrapancreatic hypoglycemic effects by increasing insulin binding through inhibition of receptor-mediated hormone internalization. In this study, we examined the possibility that the drugs act by inhibiting transglutaminase, an enzyme thought important in the internalization process. For ten days, male rats were fed pulverized chow containing either no drug, glipizide (5 mg/kg initial body wt/d), or tolazamide (75 mg/kg initial body wt/d). Prior to sacrifice, the six-hour fasting level of serum glucose was significantly reduced from 96 mg/100 ml in the control rats to 81 and 42 mg/100 ml in the glipizide- and tolazamide-treated rats, respectively. In contrast, the serum level of insulin was similar for all groups. The activity of transglutaminase in the postnuclear fraction of liver homogenate also was the same for all experimental groups. The specific binding of labeled insulin to purified liver plasma membranes was examined over a broad range of insulin concentrations; once again, there was no difference between experimental groups. Thus, the hypoglycemia caused by sulfonylurea administration could not be attributed to increases in insulin binding, inhibition of transglutaminase activity, or enhanced insulin levels. These data support our previous suggestion, based on in vitro studies, that sulfonylureas act predominately on processes beyond the binding portion of the insulin receptor.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6137754&dopt=Abstract
Res Commun Chem Pathol Pharmacol. 1984 Dec;46(3):331-49.
Inhibition of transglutaminase by hypoglycaemic sulphonylureas in pancreatic islets and its possible relevance to insulin release.
Gomis R, Mathias PC, Lebrun P, Malaisse-Lagae F, Sener A, Malaisse WJ.
Pancreatic islet homogenates display calcium-sensitive transglutaminase activity, but the role of this enzyme in the process of insulin release remains to be elucidated. Tolbutamide, gliclazide, glisoxepide, glipizide and glibenclamide inhibited transglutaminase activity in islet homogenates. When the cationic response of islet cells to hypoglycaemic sulphonylureas was suppressed by exposing intact islets to quinine, tolbutamide, gliclazide and glibenclamide caused a rapid, sustained, reversible and dose-related inhibition of insulin release. The relative efficiency of distinct hypoglycaemic sulphonylureas as inhibitor of transglutaminase activity was in mirror image of their relative potency as insulin secretagogue. However, the dose-action relationship for the inhibitory action of these agents upon insulin release from quinine-treated islets was similar in response to either tolbutamide, gliclazide or glibenclamide. These results indicate that hypoglycaemic sulphonylureas may exert an inhibitory action upon insulin release, but suggest that such an effect is not tightly related to inhibition of transglutaminase.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6151221&dopt=Abstract
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