Sulfonylureas are widely used as an antidiabetic drug. In the present study, the effects of sulfonylurea administered supraspinally on immobilization stress-induced blood glucose level were studied in ICR mice. Mice were once enforced into immobilization stress for 30 min and returned to the cage. The blood glucose level was measured 30, 60, and 120 min after immobilization stress initiation. We found that intracerebroventricular (i.c.v.) injection with 30 microg of glyburide, glipizide, glimepiride or tolazamide attenuated the increased blood glucose level induced by immobilization stress. Immobilization stress causes an elevation of the blood corticosterone and insulin levels. Sulfonylureas pretreated i.c.v. caused a further elevation of the blood corticosterone level when mice were forced into the stress. In addition, sulfonylureas pretreated i.c.v. alone caused an elevation of the plasma insulin level. Furthermore, immobilization stress-induced insulin level was reduced by i.c.v. pretreated sulfonylureas. Our results suggest that lowering effect of sulfonylureas administered supraspinally against immobilization stress-induced increase of the blood glucose level appears to be primarily mediated via elevation of the plasma insulin level.
Animals ; Blood Glucose* ; Brain ; Corticosterone ; Glipizide ; Glyburide ; Immobilization* ; Insulin ; Mice ; Mice, Inbred ICR ; Plasma ; Tolazamide

Glutamate Is the predominant excitatory neurotransmitter in the mammalian CNS. To elucidate the influence of glutamate on the noradrenergic neurotransmission in rat cortex, we examined the effects of agents that act in several steps of neurotransmission on [3H]norepinephrine ([3H])NE) release evoked by glutamate. Glutamate (1 mM) evoked significant release of [3H]NE from rat cortex slices in the absence of Mg2+in the incubation media. This effect was attenuated by cromakalime (10 nM) and lemakalime (10 nM), and the inhibitory effect of cromakalime was abolished by glipizide. Inhibitory effect of muscimol (30 uM) and baclofen (3 uM, 30 uM) was antagonized by biccuculine (3 uM), respectively. Nipecotic acid(10 uM), DABA(300 uM), and beta-alanine(100 uM) attenuated the glutamate-induced release of [3H]NE. Dihydrokinate (300 uM) PDC (100 nM) increased the glutamate-induced release of [3H]NE. Ifenprodile (10 nM) and arcaine (1 uN), blockers of polyamine site, attenuated the release of ("H)NE. The stimulatory effect of spermine was abolished by arcaine. CPA(100 nM) and CPCA(100 nM), EHNA(30 uN) and NBTI(1 uN) attenuated the release of ("H)NE. Verapamil(S uN), nitredipine(10 uN), u- conotoxin (100 nM) and flunarizine (5 uM) attenuated the release of (3H)NE. Dantrolene(30 uM), KT-362(3 uM), and ryanodine(10 nM), attenuated the glutamate-induced release of [3H]NE. Glycine (10 uM) increased the release of [3H]NE. DCQX (30 uN) attenuated the release of [3H]NE. These results suggest that glutamate-evoked release of norepinephrine can be modulated by GABAergic, adenosinergic neurotransmitters, and by various drugs which modulate ion channel activities in rat cortex.
Animals ; Baclofen ; Cerebral Cortex ; Conotoxins ; Cromakalim ; Flunarizine ; Glipizide ; Glutamic Acid ; Glycine ; Ion Channels ; Muscimol ; Neurotransmitter Agents ; Norepinephrine* ; Rats* ; Spermine ; Synaptic Transmission

BACKGROUND: Sulfonylurea primarily stimulates insulin secretion by binding to its receptor on the pancreatic beta-cells. Recent studies have suggested that sulfonylureas induce insulin sensitivity through peroxisome proliferator-activated receptor gamma (PPARgamma), one of the nuclear receptors. In this study, we investigated the effects of sulfonylurea on PPARgamma transcriptional activity and on the glucose uptake via PPARgamma. METHODS: Transcription reporter assays using Cos7 cells were performed to determine if specific sulfonylureas stimulate PPARgamma transactivation. Glimepiride, gliquidone, and glipizide (1 to 500 microM) were used as treatment, and rosiglitazone at 1 and 10 microM was used as a control. The effects of sulfonylurea and rosiglitazone treatments on the transcriptional activity of endogenous PPARgamma were observed. In addition, 3T3-L1 adipocytes were treated with rosiglitazone (10 microM), glimepiride (100 microM) or both to verify the effect of glimepiride on rosiglitazone-induced glucose uptake. RESULTS: Sulfonylureas, including glimepiride, gliquidone and glipizide, increased PPARgamma transcriptional activity, gliquidone being the most potent PPARgamma agonist. However, no additive effects were observed in the presence of rosiglitazone. When rosiglitazone was co-treated with glimepiride, PPARgamma transcriptional activity and glucose uptake were reduced compared to those after treatment with rosiglitazone alone. This competitive effect of glimepiride was observed only at high concentrations that are not achieved with clinical doses. CONCLUSION: Sulfonylureas like glimepiride, gliquidone and glipizide increased the transcriptional activity of PPARgamma. Also, glimepiride was able to reduce the effect of rosiglitazone on PPARgamma agonistic activity and glucose uptake. However, the competitive effect does not seem to occur at clinically feasible concentrations.
Adipocytes ; Diabetes Mellitus, Type 2 ; Glipizide ; Glucose ; Insulin ; Insulin Resistance ; Peroxisome Proliferator-Activated Receptors ; Peroxisomes ; PPAR gamma ; Receptors, Cytoplasmic and Nuclear ; Sulfonylurea Compounds ; Thiazolidinediones ; Transcriptional Activation

BACKGROUND: Sulfonylurea drugs have been used for many decades as one of the main families of drugs for the treatment of type 2 diabetes mellitus. Even though there are many opportunities to medicate sulfonylurea drugs concomitantly with many other drugs, and furthermore there have been several case reports on drug interactions with sulfonylurea drugs, there has been no clear demonstration revealing the mechanisms that cause these interactions. We therefore evaluated inhibitory potential of sulfonylurea drugs, including glibenclamide, glipizide and gliclazide, on the cytochrome P450 (CYP)-catalyzing enzymes using human liver microsomes. METHODS: The inhibitory effects of glibenclamide, glipizide and gliclazide, on the CYP-catalyzing reaction, were evaluated for CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 using human liver microsomes, and probe drugs for each. RESULTS: Glibenclamide showed relative potent inhibitory effects on the CYP2C9- and CYP3A4-catallyzed reaction (IC50; 11.3 ( microM and 59.0 ( microM). The other CYP isoforms tested showed only weak inhibitory effects by due to glibenclamide (IC50 > 112 ( microM). Glipizide showed potent inhibitory effect on CYP3A4-catalyzed reaction only (IC50; 11.2 ( microM), and weak, or no, inhibitory effects on each on the other CYP isoforms tested (IC50 > 276 ( microM). CONCLUSION: The sulfonylurea drugs showed inhibitory potential on the CYP-catalyzing reaction in human liver microsomes. The results obtained in the present study provide insights into the potential of the drug interaction to ward drugs co-administered with sulfonylureas. It will be necessary to take into consideration the control of blood glucose, as well as therapeutic drug monitoring, to reduced toxicities when sulfonylurea drugs are co-administered with drugs of a narrow therapeutic range, or with severe dose-dependent toxicities.
Blood Glucose ; Cytochrome P-450 CYP1A2 ; Cytochrome P-450 CYP2D6 ; Cytochrome P-450 Enzyme System ; Cytochromes* ; Diabetes Mellitus, Type 2 ; Drug Interactions ; Drug Monitoring ; Gliclazide ; Glipizide ; Glyburide ; Humans* ; Liver* ; Microsomes, Liver* ; Protein Isoforms

To develop a sensitive and rapid liquid chromatographic-tandem mass spectrometric (LC-MS/MS) method for simultaneous quantitation of metformin and glipizide in human plasma, metformin, glipizide and internal standard diphenhydramine were separated from plasma by protein precipitation with acetonitrile (containing 0.3% formic acid), then chromatographed by using a Zorbax Extend C18 column. The mobile phase consisted of acetonitrile-water-formic acid (70:30: 0.3, v/v/v), at a flow rate of 0.50 mL x min(-1). A tandem mass spectrometer equipped with atmospheric pressure chemical ionization source was used as detector and operated in the positive ion mode. Selected reaction monitoring (SRM) using the precursor/production combinations of m/z 130-->m/z 60, m/z 446-->m/z 321 and m/z 256-->m/z 167 were used to quantify metformin, glipizide and diphenhydramine, respectively. The linear concentration ranges of the calibration curves for metformin and glipizide were 2.00 - 2000 ng x mL(-1) and 1.00 - 1000 ng x mL(-1), respectively. The lower limits of quantitation of metformin and glipizide were 2.00 ng x mL(-1) and 1.00 ng x mL(-1), respectively. The method proved to be sensitive, simple and rapid, and suitable for clinical investigation of compound preparation containing metformin and glipizide.
Administration, Oral ; Chromatography, Liquid ; methods ; Glipizide ; administration & dosage ; blood ; pharmacokinetics ; Humans ; Hypoglycemic Agents ; administration & dosage ; blood ; pharmacokinetics ; Male ; Metformin ; administration & dosage ; blood ; pharmacokinetics ; Sensitivity and Specificity ; Tandem Mass Spectrometry ; methods ; Young Adult

Converting two poorly water-soluble crystalline drugs to co-amorphous drug systems by ball milling, quench-cooling, or cryo-milling method can improve stability of the drug, enhance dissolution rates, and reduce adverse reactions of the single drug. Co-amorphous system has been used to solve problems of co-administration of medicines. Formation and intermolecular interactions of co-amorphous drug systems may be verified by differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), Raman spectroscopy (RS) and Fourier transform infrared spectroscopy (FT-IR). Stability of co-amorphous drug systems is influenced by their glass transition temperature (Tg) and intermolecular interactions. The theoretical Tg values and the interaction parameter x are calculated by Gordon-Taylor equation and the Flory-Huggins equation, respectively. Thus, co-amorphous drug systems are analyzed theoretically at molecular level. Co-amorphous drug systems provide a new sight for the co-administration of medicines.
Calorimetry, Differential Scanning ; Chemistry, Pharmaceutical ; methods ; Cimetidine ; chemistry ; Drug Combinations ; Drug Compounding ; Drug Stability ; Glipizide ; chemistry ; Indomethacin ; chemistry ; Naproxen ; chemistry ; Ranitidine ; chemistry ; Simvastatin ; chemistry ; Solubility ; Spectroscopy, Fourier Transform Infrared ; Spectrum Analysis, Raman ; Technology, Pharmaceutical ; methods ; Temperature ; X-Ray Diffraction

To explore the underlying mechanism of acetylcholine (ACh)-evoked membrane hyperpolarizing response in isolated rat vas deferens smooth muscle cells (SMCs), intracellular microelectrode recording technique and intracellular microelectrophoresis fluorescent staining technique were used to study ACh-evoked membrane hyperpolarizing response in SMCs freshly isolated from Wistar rat vas deferens. By using microelectrodes containing fluorescent dye 0.1% propidium iodide (PI), 37 and 17 cells were identified as SMCs in outer longitudinal and inner circular muscular layers, respectively. The resting membrane potentials of SMCs were (-53.56+/-3.88) mV and (-51.62+/-4.27) mV, respectively. The membrane input resistances were (2245.60+/-372.50) MOmega and (2101.50+/-513.50) MOmega, respectively. ACh evoked membrane hyperpolarizing response in a concentration-dependent manner with an EC(50) of 36 micromol/L. This action of ACh was abolished by both a non-sepcific muscarinic (M) receptor antagonist atropine (1 mumol/L) and a selective M(3 ) receptor antagonist diphenylacetoxy-N-methylpiperidine-methiodide (DAMP, 100 nmol/L). ACh-evoked membrane hyperpolarization was also abolished by a nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME, 300 micromol/L) and suppressed by an ATP-sensitive potassium (K(ATP)) channel blocker glipizide (5 micromol/L) and an inward rectifier potassium (K(ir)) channel inhibitor bariumion (50 micromol/L). A combination of glipizide and bariumion abolished ACh-evoked membrane hyperpolarizing response. The results suggest that ACh-evoked membrane hyperpolarization in rat vas deferens SMCs is mediated by M(3) receptor followed with activation of K(ATP) channels, K(ir) channels, and NO release.
Acetylcholine ; pharmacology ; Animals ; Glipizide ; pharmacology ; In Vitro Techniques ; Male ; Membrane Potentials ; drug effects ; Myocytes, Smooth Muscle ; physiology ; Nitric Oxide ; physiology ; Potassium Channels ; physiology ; Potassium Channels, Inwardly Rectifying ; Rats ; Rats, Wistar ; Vas Deferens ; drug effects ; physiology

BACKGROUND: Previous studies have noted that the simultaneous use of sulfonylureas and antimicrobials, which is common, could increase the risk of hypoglycemia. In particular, an age of 65 years or older is a known risk factor for sulfonylurea-related hypoglycemia in hospitalized patients. Therefore, we performed this study to determine the potential risk of hypoglycemia from the concurrent use of antimicrobials and sulfonylureas. METHODS: We performed a cross-sectional study on the National Health Insurance Service-National Sample Cohort from 2013. The eligibility criteria included patients of 65 years of age or older taking a sulfonylurea with 25 different antimicrobials. Different risk ratings of severity in drug-drug interactions (potential DDIs), level X, D, or C in Lexi-Interact™online, and contraindicated, major, or moderate severity level in Micromedex® were included. SAS version 9.4 was used for data analysis. RESULTS: A total of 6,006 elderly patients with 25,613 prescriptions were included. The largest age group was 70 to 74 (32.7%), and 39.7% of patients were men. The mean number of prescriptions was 4.3 per patient. The most frequently used antimicrobials were levofloxacin (6,583, 25.7%), ofloxacin (6,549, 25.6%), fluconazole (4,678, 18.0%), and ciprofloxacin (2,551, 9.8%). Among sulfonylureas, glimepiride was prescribed most frequently, followed by gliclazide, glibenclamide, and glipizide. CONCLUSION: Of the antimicrobials with a high potential of hypoglycemia, levofloxacin, ofloxacin, fluconazole, and ciprofloxacin were used frequently. Thus, the monitoring of clinically relevant interactions is required for patients concurrently administered sulfonylureas and antimicrobials.
Aged* ; Anti-Infective Agents ; Ciprofloxacin ; Cohort Studies ; Cross-Sectional Studies ; Drug Interactions ; Fluconazole ; Gliclazide ; Glipizide ; Glyburide ; Humans ; Hypoglycemia* ; Korea* ; Levofloxacin ; Male ; National Health Programs ; Ofloxacin ; Prescriptions ; Risk Factors ; Statistics as Topic ; Sulfonylurea Compounds

The purpose of present study is to investigate the influence of a spinal gamma-aminobutyric acid B(GABA|B) receptor on a central regulation of blood pressure (BP) and heart rate (HR), and to define its mechanism in the spinal cord. In urethane-anesthetized, d-tubocurarine-paralyzed and artificially ventilated male Sprague-Dawley rats, intrathecal administration of drugs were carried out using injection cannula (33-gauge stainless steel) through the guide cannula (PE 10) which was inserted intrathecally at lower thoracic level through the puncture of a atlantooccipital membrane. Intrathecal injection of an GABA|B receptor agonist, baclofen (30, 60, 100 nmol) decreased both BP and HR dose-dependently. Pretreatment with 8-bromo-cAMP (50 nmol), a cAMP analog, or glipizide (50 nmol), a ATP-sensitive K+ channel blocker, attenuated the depressor and bradycardic effects of baclofen (100 nmol), but not with 8-bromo-cGMP (50 nmol), a cGMP analog. These results suggest that the GABA|B receptor in the spinal cord plays an inhibitory role in central cardiovascular regulation and that this depressor and bradycardic actions are mediated by the decrease of cAMP via the inhibition of adenylate cyclase and the opening of K+ channel.
8-Bromo Cyclic Adenosine Monophosphate ; Adenylyl Cyclases ; Animals ; Baclofen* ; Blood Pressure ; Catheters ; gamma-Aminobutyric Acid ; Glipizide* ; Heart Rate ; Humans ; Injections, Spinal ; Male ; Membranes ; Nucleotides, Cyclic* ; Punctures ; Rats* ; Rats, Sprague-Dawley ; Spinal Cord

The purpose of this study is to investigate the applicability of a natural swelling matrix derived from boat-fruited sterculia seed (SMS) as the propellant of osmotic pump tablets. The sugar components, static swelling, water uptake and viscosity of SMS were determined and compared with that of polythylene oxide (WSR-N10 and WSR-303). Both ribavirin and glipizide were used as water-soluble and water-insoluble model drugs. Then, the monolayer osmotic pump tablets of ribavirin and the bilayer osmotic pump tablets of glipizide were prepared using SMS as the osmotically active substance and propellant. SMS was mainly composed of rhamnose, arabinose, xylose and galactose and exhibited relatively high swelling ability. The area of the disintegrated matrix tablet was 20.1 times as that at initial after swelling for 600 s. SMS swelled rapidly and was fully swelled (0.5%) in aqueous solution with relative low viscosity (3.66 +/- 0.03) mPa x s at 25 degrees C. The monolayer osmotic pump tablets of ribavirin and the bilayer osmotic pump tablets of glipizide using SMS as propellant exhibited typical drug release features of osmotic pumps. In conclusion, the swelling matrix derived from boat-fruited sterculia seed, with low viscosity and high swelling, is a potential propellant in the application of osmotic pump tablets.
Arabinose ; chemistry ; isolation & purification ; Chemistry, Pharmaceutical ; Delayed-Action Preparations ; Drug Carriers ; Galactose ; chemistry ; isolation & purification ; Glipizide ; administration & dosage ; chemistry ; Osmosis ; Plants, Medicinal ; chemistry ; Rhamnose ; chemistry ; isolation & purification ; Ribavirin ; administration & dosage ; chemistry ; Seeds ; chemistry ; Solubility ; Sterculiaceae ; chemistry ; Tablets ; Technology, Pharmaceutical ; methods ; Viscosity ; Water ; Xylose ; chemistry ; isolation & purification