Administration of Fenugreek Seed Extract Produces Better Effects in Glibenclamide-Induced Inhibition in Hepatic Lipid Peroxidation: An in vitro Study.

OBJECTIVE: To evaluate the comparative effects of fenugreek (Trigonella foenum graecum) seed extract (FSE) alone and in combination with an antidiabetic conventional medicine, glibenclamide (GLB), on the inhibition of in vitro lipid peroxidation (LPO) in liver, the major target organ of a drug. METHODS: LPO was induced by ferrous sulphate (FeSo4), hydrogen peroxide (H2O2) and carbon tetrachloride (CCl4) and the effects of test seed extract and/or GLB were evaluated. RESULTS: While FeSo4, H2O2 and CCl4 markedly enhanced the hepatic LPO, simultaneous administration of FSE reduced it in a concentration dependent manner. However, when both FSE and GLB were added to the incubation mixture, chemically induced hepatic LPO was further inhibited. The test extract also exhibited high antioxidative activity in 1,1-diphenyl-2-picrylhydrazyl radical and in 2,2'-azinobis, 3-ethylbenzothiazoline-6-sulphonic acid radical scavenging assays. CONCLUSION: FSE therapy in moderate concentration along with a hypoglycemic drug may prove to be advantageous in ameliorating diabetes mellitus and other diseases that are LPO mediated.

Severe hypoglycemia associated with an illegal sexual enhancement product adulterated with glibenclamide: MR imaging findings.

PURPOSE: To describe the magnetic resonance (MR) imaging findings associated with severe hypoglycemia after consumption of an illegal sexual enhancement product (Power 1 Walnut) adulterated with glibenclamide, an oral hypoglycemic agent used to treat diabetes mellitus. MATERIALS AND METHODS: Institutional review board approval was obtained for this retrospective study. Records in eight male patients with severe hypoglycemia of unknown cause, without prior treatment for diabetes, and with positive blood toxicology results for glibenclamide were reviewed. MR imaging included diffusion-weighted imaging and, in some patients, MR angiography, dynamic contrast material-enhanced perfusion MR imaging, and MR spectroscopy. RESULTS: In seven patients, there were hyperintense abnormalities on diffusion-weighted and T2-weighted images in the hippocampus and cerebral cortex, sparing the subcortical white matter and cerebellum. Three patients had abnormalities of the splenium of the corpus callosum, and one had widespread involvement, including the caudate nucleus, basal ganglia, and internal capsule bilaterally. In three patients, unilateral cortical involvement, which did not conform to the typical cerebral arterial territories, was noted. In one patient, perfusion MR imaging showed slightly increased relative cerebral blood volume, and MR spectroscopy revealed no evidence of abnormal lactate in the affected cerebral cortex. CONCLUSION: Diffusion-weighted MR imaging findings in patients with severe hypoglycemia showed typical lesions in the hippocampus and cerebral cortex, but the caudate nucleus and basal ganglia were involved in only the most severely affected patient. The splenium of the corpus callosum and internal capsule were also abnormal in three patients, and unilateral cortical lesions could be distinguished from acute ischemic stroke by the pattern of involvement and MR angiographic, perfusion, and spectroscopic findings.

Glibenclamide interferes with mitochondrial bioenergetics by inducing changes on membrane ion permeability.

The interference of glibenclamide, an antidiabetic sulfonylurea, with mitochondrial bioenergetics was assessed on mitochondrial ion fluxes (H+, K+, and Cl-) by passive osmotic swelling of rat liver mitochondria in K-acetate, KNO3, and KCl media, by O2 consumption, and by mitochondrial transmembrane potential (Deltapsi). Glibenclamide did not permeabilize the inner mitochondrial membrane to H+, but induced permeabilization to Cl- by opening the inner mitochondrial anion channel (IMAC). Cl- influx induced by glibenclamide facilitates K+ entry into mitochondria, thus promoting a net Cl-/K+ cotransport, Deltapsi dissipation, and stimulation of state 4 respiration rate. It was concluded that glibenclamide interferes with mitochondrial bioenergetics of rat liver by permeabilizing the inner mitochondrial membrane to Cl- and promoting a net Cl-/K+ cotransport inside mitochondria, without significant changes on membrane permeabilization to H+.

Electro-acupuncture preconditioning abrogates the elevation of c-Fos and c-Jun expression in neonatal hypoxic-ischemic rat brains induced by glibenclamide, an ATP-sensitive potassium channel blocker.

This study aimed to clarify the neuroprotective mechanism of electro-acupuncture (EA) preconditioning on hypoxic-ischemic brain injury (HIBI). Using Western blot, the expression of c-fos protein (c-Fos) and c-jun protein (c-Jun) induced by glibenclamide, an ATP-sensitive potassium (K(ATP)) channel blocker was examined from cerebral cortical and hippocampal samples in neonatal hypoxic-ischemic rats, with or without EA preconditioning. EA was performed on Hegu (LI4), a well-known acupoint commonly used in Oriental medicine for the treatment of neuronal injury resulting from hypoxia-ischemia (HI). Preconditioned rats were treated with either diazoxide, a K(ATP) channel opener, glibenclamide, or sterile saline injected into the left lateral ventricle (i.c.v.), with or without EA administration before HI insult. Interestingly, low c-Fos and c-Jun expressions were found both in diazoxide and EA groups, 24 h after HI. Furthermore, significant differences in relative optical density (ROD) were found between glibenclamide and HI control groups (P< or =0.05), as well as between the group administered glibenclamide after EA and the HI control group (P< or =0.05). However, the level of c-Fos and c-Jun expression in the group administered glibenclamide after EA was significantly lower than in the glibenclamide group (P< or =0.05). The present findings indicate that the effectiveness of EA preconditioning against HIBI may be mediated via the opening of K(ATP) channels.

Evaluation of hepatotoxic potential of drugs by inhibition of bile-acid transport in cultured primary human hepatocytes and intact rats.

Inhibition of canalicular bile acid efflux by medications is associated with clinical liver toxicity, sometimes in the absence of major liver effects in experimental species. To predict the hepatotoxic potential of compounds in vitro and in vivo, we investigated the effect of clinical cholestatic agents on [3H]taurocholic acid transport in regular and collagen-sandwich cultured human hepatocytes. Hepatocytes established a well-developed canalicular network with bile acid accumulating in the canalicular lumen within 15 min of addition to cells. Removing Ca2+ and Mg2+ from the incubation buffer destroyed canalicular junctions, resulting in bile acid efflux into the incubation buffer. Canalicular transport was calculated based on the difference between the amount of bile acid effluxed into the Ca/Mg2+-free and regular buffers with linear efflux up to 10 min. Hepatocytes cultured in the nonsandwich configuration also transported taurocholic acid, but at 50% the rate in sandwiched cultures. Cyclosporin A, bosentan, CI-1034, glyburide, erythromycin estolate, and troleandomycin inhibited efflux in a concentration-dependent manner. In contrast, new generation macrolide antibiotics with lower incidence of clinical hepatotoxicity were much less potent inhibitors of efflux. An in vivo study was conducted whereby glyburide or CI-1034, administered iv to male rats, produced a 2.4-fold increase in rat total serum bile acids. A synergistic 6.8-fold increase in serum total bile acids was found when both drugs were delivered together. These results provide methods to evaluate inhibitory effects of potentially cholestatic compounds on bile-acid transport, and to rank compounds according to their hepatotoxic potential.