The ATP-sensitive K+ (KATP) channel is an emerging pathway in the skeletal muscle atrophy which is a comorbidity condition in diabetes. The "in vitro" effects of the sulfonylureas and glinides were evaluated on the protein content/muscle weight, fibers viability, mitochondrial succinic dehydrogenases (SDH) activity, and channel currents in oxidative soleus (SOL), glycolitic/oxidative flexor digitorum brevis (FDB), and glycolitic extensor digitorum longus (EDL) muscle fibers of mice using biochemical and cell-counting Kit-8 assay, image analysis, and patch-clamp techniques. The sulfonylureas were: tolbutamide, glibenclamide, and glimepiride; the glinides were: repaglinide and nateglinide. Food and Drug Administration-Adverse Effects Reporting System (FDA-AERS) database searching of atrophy-related signals associated with the use of these drugs in humans has been performed. The drugs after 24 h of incubation time reduced the protein content/muscle weight and fibers viability more effectively in FDB and SOL than in the EDL. The order of efficacy of the drugs in reducing the protein content in FDB was: repaglinide (EC50 = 5.21 × 10-6) ≥ glibenclamide(EC50 = 8.84 × 10-6) > glimepiride(EC50 = 2.93 × 10-5) > tolbutamide(EC50 = 1.07 × 10-4) > nateglinide(EC50 = 1.61 × 10-4) and it was: repaglinide(7.15 × 10-5) ≥ glibenclamide(EC50 = 9.10 × 10-5) > nateglinide(EC50 = 1.80 × 10-4) ≥ tolbutamide(EC50 = 2.19 × 10-4) > glimepiride(EC50=-) in SOL. The drug-induced atrophy can be explained by the KATP channel block and by the enhancement of the mitochondrial SDH activity. In an 8-month period, muscle atrophy was found in 0.27% of the glibenclamide reports in humans and in 0.022% of the other not sulfonylureas and glinides drugs. No reports of atrophy were found for the other sulfonylureas and glinides in the FDA-AERS. Glibenclamide induces atrophy in animal experiments and in human patients. Glimepiride shows less potential for inducing atrophy. e00028

Database search of spontaneous reports and pharmacological investigations on the sulfonylureas and glinides-induced atrophy in skeletal muscle

Mele, Antonietta;Calzolaro, Sara;Cannone, Gianluigi;Conte, Diana;Tricarico, Domenico;
2014-01-01

Abstract

The ATP-sensitive K+ (KATP) channel is an emerging pathway in the skeletal muscle atrophy which is a comorbidity condition in diabetes. The "in vitro" effects of the sulfonylureas and glinides were evaluated on the protein content/muscle weight, fibers viability, mitochondrial succinic dehydrogenases (SDH) activity, and channel currents in oxidative soleus (SOL), glycolitic/oxidative flexor digitorum brevis (FDB), and glycolitic extensor digitorum longus (EDL) muscle fibers of mice using biochemical and cell-counting Kit-8 assay, image analysis, and patch-clamp techniques. The sulfonylureas were: tolbutamide, glibenclamide, and glimepiride; the glinides were: repaglinide and nateglinide. Food and Drug Administration-Adverse Effects Reporting System (FDA-AERS) database searching of atrophy-related signals associated with the use of these drugs in humans has been performed. The drugs after 24 h of incubation time reduced the protein content/muscle weight and fibers viability more effectively in FDB and SOL than in the EDL. The order of efficacy of the drugs in reducing the protein content in FDB was: repaglinide (EC50 = 5.21 × 10-6) ≥ glibenclamide(EC50 = 8.84 × 10-6) > glimepiride(EC50 = 2.93 × 10-5) > tolbutamide(EC50 = 1.07 × 10-4) > nateglinide(EC50 = 1.61 × 10-4) and it was: repaglinide(7.15 × 10-5) ≥ glibenclamide(EC50 = 9.10 × 10-5) > nateglinide(EC50 = 1.80 × 10-4) ≥ tolbutamide(EC50 = 2.19 × 10-4) > glimepiride(EC50=-) in SOL. The drug-induced atrophy can be explained by the KATP channel block and by the enhancement of the mitochondrial SDH activity. In an 8-month period, muscle atrophy was found in 0.27% of the glibenclamide reports in humans and in 0.022% of the other not sulfonylureas and glinides drugs. No reports of atrophy were found for the other sulfonylureas and glinides in the FDA-AERS. Glibenclamide induces atrophy in animal experiments and in human patients. Glimepiride shows less potential for inducing atrophy. e00028
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11586/203933
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