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Stimulatory Action of Telmisartan, an Antagonist of Angiotensin II Receptor, on Voltage-Gated Na+ Current: Experimental and Theoretical Studies
Chinese Journal of Physiology 61(1): 1-13, 2018 1 DOI: 10.4077/CJP.2018.BAG516 Stimulatory Action of Telmisartan, an Antagonist of Angiotensin II Receptor, on Voltage-Gated Na+ Current: Experimental and Theoretical Studies Tzu-Tung Chang, Chia-Jung Yang, Yu-Chi Lee, and Sheng-Nan Wu Department of Physiology, National Cheng Kung University Medical College, Tainan 70101, Taiwan, Republic of China Abstract Telmisartan (Tel) is recognized as a non-peptide blocker of AT1R. Whether this agent has any direct effects on ion currents remains unexplored. In whole-cell current recordings, addition of Tel + increased the peak amplitude of voltage-gated Na (NaV) current (INa) accompanied by the increased time constant of INa inactivation in differentiated NSC-34 motor neuron-like cells. Tel-stimulated INa in these cells is unlinked to either blockade of AT1R or activation of peroxisome proliferator-activated receptor gamma (PPAR-γ). In order to explore how this compound affects the amplitude and kinetics of INa in neurons, a Hodgkin-Huxley-based (HH-based) model designed to mimic effect of Tel on the functional activities of neurons was computationally created in this study. In this framework, the parameter for h inactivation gating variable, which was changed in a stepwise fashion, was implemented + + to predict changes in membrane potentials (V) as a function of maximal Na (GNa), K conductance (GK), or both. As inactivation time course of INa was increased, the bifurcation point of V versus GNa became lower, and the range between subcritical and supercritical values at the bifurcation of V versus GK correspondingly became larger. -
REVIEW Peroxisome Proliferator-Activated Receptors In
199 REVIEW Peroxisome proliferator-activated receptors in reproductive tissues: from gametogenesis to parturition P Froment, F Gizard1, D Defever2, B Staels1, J Dupont3 and P Monget3 INSERM U.418, UMR Communications Cellulaire et Différenciation, Hôpital Debrousse, 29 rue Soeur Bouvier, 69322 Lyon, France 1INSERM U.545, Institut Pasteur de Lille et Faculté de Pharmacie Université de Lille 2, 1 rue du Pr Calmette, 59019 Lille, France 2LMCB, Department of Molecular Biomedical Research, V.I.B., Technologiepark 927, B-9052 Ghent (Zwijnaarde), Belgium 3Physiologie de la reproduction et des comportements, UMR 6175 INRA-CNRS-Université F. Rabelais de Tours-Haras Nationaux, 37380 Nouzilly, France (Requests for offprints should be addressed to P Froment; [email protected]) Abstract Peroxisome proliferator-activated receptors (PPAR, granulosa cell proliferation and steroidogenesis in vitro. All PPAR/ and PPAR) are a family of nuclear receptors these recent data raise new questions about the biologic that are activated by binding of natural ligands, such as actions of PPARs in reproduction and their use in polyunsaturated fatty acids or by synthetic ligands. Syn- therapeutic treatments of fertility troubles such as PCOS thetic molecules of the glitazone family, which bind to or endometriosis. In this review, we first describe the roles PPAR, are currently used to treat type II diabetes and of PPARs in different compartments of the reproductive also to attenuate the secondary clinical symptoms fre- axis (from male and female gametogenesis to parturition), quently associated with insulin resistance, including poly- with a focus on PPAR. Secondly, we discuss the possible cystic ovary syndrome (PCOS). PPARs are expressed molecular mechanisms underlying the effect of glitazones in different compartments of the reproductive system on PCOS. -
Endocrine Drugs
PharmacologyPharmacologyPharmacology DrugsDrugs thatthat AffectAffect thethe EndocrineEndocrine SystemSystem TopicsTopicsTopics •• Pituitary Pituitary DrugsDrugs •• Parathyroid/Thyroid Parathyroid/Thyroid DrugsDrugs •• Adrenal Adrenal DrugsDrugs •• Pancreatic Pancreatic DrugsDrugs •• Reproductive Reproductive DrugsDrugs •• Sexual Sexual BehaviorBehavior DrugsDrugs FunctionsFunctionsFunctions •• Regulation Regulation •• Control Control GlandsGlandsGlands ExocrineExocrine EndocrineEndocrine •• Secrete Secrete enzymesenzymes •• Secrete Secrete hormoneshormones •• Close Close toto organsorgans •• Transport Transport viavia bloodstreambloodstream •• Require Require receptorsreceptors NervousNervous EndocrineEndocrine WiredWired WirelessWireless NeurotransmittersNeurotransmitters HormonesHormones ShortShort DistanceDistance LongLong Distance Distance ClosenessCloseness ReceptorReceptor Specificity Specificity RapidRapid OnsetOnset DelayedDelayed Onset Onset ShortShort DurationDuration ProlongedProlonged Duration Duration RapidRapid ResponseResponse RegulationRegulation MechanismMechanismMechanism ofofof ActionActionAction HypothalamusHypothalamusHypothalamus HypothalamicHypothalamicHypothalamic ControlControlControl PituitaryPituitaryPituitary PosteriorPosteriorPosterior PituitaryPituitaryPituitary Target Actions Oxytocin Uterus ↑ Contraction Mammary ↑ Milk let-down ADH Kidneys ↑ Water reabsorption AnteriorAnteriorAnterior PituitaryPituitaryPituitary Target Action GH Most tissue ↑ Growth TSH Thyroid ↑ TH secretion ACTH Adrenal ↑ Cortisol Cortex -
Effect of Chronic Treatment with Rosiglitazone on Leydig Cell Steroidogenesis in Rats
Couto et al. Reproductive Biology and Endocrinology 2010, 8:13 http://www.rbej.com/content/8/1/13 RESEARCH Open Access Effect of chronic treatment with Rosiglitazone on Leydig cell steroidogenesis in rats: In vivo and ex vivo studies Janaína A Couto1, Karina LA Saraiva2, Cleiton D Barros3, Daniel P Udrisar4, Christina A Peixoto2, Juliany SB César Vieira4, Maria C Lima3, Suely L Galdino3, Ivan R Pitta3, Maria I Wanderley4* Abstract Background: The present study was designed to examine the effect of chronic treatment with rosiglitazone - thiazolidinedione used in the treatment of type 2 diabetes mellitus for its insulin sensitizing effects - on the Leydig cell steroidogenic capacity and expression of the steroidogenic acute regulatory protein (StAR) and cholesterol side-chain cleavage enzyme (P450scc) in normal adult rats. Methods: Twelve adult male Wistar rats were treated with rosiglitazone (5 mg/kg) administered by gavage for 15 days. Twelve control animals were treated with the vehicle. The ability of rosiglitazone to directly affect the production of testosterone by Leydig cells ex vivo was evaluated using isolated Leydig cells from rosiglitazone- treated rats. Testosterone production was induced either by activators of the cAMP/PKA pathway (hCG and dbcAMP) or substrates of steroidogenesis [22(R)-hydroxy-cholesterol (22(R)-OH-C), which is a substrate for the P450scc enzyme, and pregnenolone, which is the product of the P450scc-catalyzed step]. Testosterone in plasma and in incubation medium was measured by radioimmunoassay. The StAR and P450scc expression was detected by immunocytochemistry. Results: The levels of total circulating testosterone were not altered by rosiglitazone treatment. A decrease in basal or induced testosterone production occurred in the Leydig cells of rosiglitazone-treated rats. -
PHARMACEUTICAL APPENDIX to the TARIFF SCHEDULE 2 Table 1
Harmonized Tariff Schedule of the United States (2020) Revision 19 Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE Harmonized Tariff Schedule of the United States (2020) Revision 19 Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE TARIFF SCHEDULE 2 Table 1. This table enumerates products described by International Non-proprietary Names INN which shall be entered free of duty under general note 13 to the tariff schedule. The Chemical Abstracts Service CAS registry numbers also set forth in this table are included to assist in the identification of the products concerned. For purposes of the tariff schedule, any references to a product enumerated in this table includes such product by whatever name known. -
AVANDIA® (Rosiglitazone Maleate) Tablets
PRESCRIBING INFORMATION AVANDIA® (rosiglitazone maleate) Tablets WARNING: CONGESTIVE HEART FAILURE ● Thiazolidinediones, including rosiglitazone, cause or exacerbate congestive heart failure in some patients (see WARNINGS). After initiation of AVANDIA, and after dose increases, observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain, dyspnea, and/or edema). If these signs and symptoms develop, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction of AVANDIA must be considered. ● AVANDIA is not recommended in patients with symptomatic heart failure. Initiation of AVANDIA in patients with established NYHA Class III or IV heart failure is contraindicated. (See CONTRAINDICATIONS and WARNINGS.) DESCRIPTION AVANDIA (rosiglitazone maleate) is an oral antidiabetic agent which acts primarily by increasing insulin sensitivity. AVANDIA is used in the management of type 2 diabetes mellitus (also known as non-insulin-dependent diabetes mellitus [NIDDM] or adult-onset diabetes). AVANDIA improves glycemic control while reducing circulating insulin levels. Pharmacological studies in animal models indicate that rosiglitazone improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic gluconeogenesis. Rosiglitazone maleate is not chemically or functionally related to the sulfonylureas, the biguanides, or the alpha-glucosidase inhibitors. Chemically, rosiglitazone maleate is (±)-5-[[4-[2-(methyl-2- pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione, (Z)-2-butenedioate (1:1) with a molecular weight of 473.52 (357.44 free base). The molecule has a single chiral center and is present as a racemate. Due to rapid interconversion, the enantiomers are functionally indistinguishable. The structural formula of rosiglitazone maleate is: The molecular formula is C18H19N3O3S•C4H4O4. -
Inhibition of Mitochondrial Fatty Acid Oxidation in Drug-Induced Hepatic Steatosis*
Liver Research 3 (2019) 157e169 Contents lists available at ScienceDirect Liver Research journal homepage: http://www.keaipublishing.com/en/journals/liver-research Review Article Inhibition of mitochondrial fatty acid oxidation in drug-induced hepatic steatosis* Bernard Fromenty INSERM, UMR 1241, Universite de Rennes 1, Rennes, France article info abstract Article history: Mitochondrial fatty acid oxidation (mtFAO) is a key metabolic pathway required for energy production in Received 17 April 2019 the liver, in particular during periods of fasting. One major consequence of drug-induced impairment of Received in revised form mtFAO is hepatic steatosis, which is characterized by an accumulation of triglycerides and other lipid 16 May 2019 species, such as acyl-carnitines. Actually, the severity of this liver lesion is dependent on the residual Accepted 14 June 2019 mitochondrial b-oxidation flux. Indeed, a severe inhibition of mtFAO leads to microvesicular steatosis, hypoglycemia and liver failure. In contrast, moderate impairment of mtFAO can cause macrovacuolar Keywords: steatosis, which is a benign lesion in the short term. Because some drugs can induce both microvesicular Drug-induced liver injury (DILI) Steatosis and macrovacuolar steatosis, it is surmised that severe mitochondrial dysfunction could be favored in Mitochondria some patients by non-genetic factors (e.g., high doses and polymedication), or genetic predispositions b-Oxidation involving genes that encode proteins playing directly or indirectly a role in the mtFAO pathway. Example Acetaminophen (APAP) of drugs inducing steatosis include acetaminophen (APAP), amiodarone, ibuprofen, linezolid, nucleoside Troglitazone reverse transcriptase inhibitors, such as stavudine and didanosine, perhexiline, tamoxifen, tetracyclines, troglitazone and valproic acid. Because several previous articles reviewed in depth the mechanism(s) whereby most of these drugs are able to inhibit mtFAO and induce steatosis, the present review is rather focused on APAP, linezolid and troglitazone. -
Conjugated Estrogens Sustained Release Tablets) 0.3 Mg, 0.625 Mg, and 1.25 Mg
PRODUCT MONOGRAPH PrPREMARIN® (conjugated estrogens sustained release tablets) 0.3 mg, 0.625 mg, and 1.25 mg ESTROGENIC HORMONES ® Wyeth Canada Date of Revision: Pfizer Canada Inc., Licensee December 1, 2014 17,300 Trans-Canada Highway Kirkland, Quebec H9J 2M5 Submission Control No: 177429 PREMARIN (conjugated estrogens sustained release tablets) Page 1 of 46 Table of Contents PART I: HEALTH PROFESSIONAL INFORMATION .........................................................3 SUMMARY PRODUCT INFORMATION ...........................................................................3 INDICATIONS AND CLINICAL USE ................................................................................3 CONTRAINDICATIONS ......................................................................................................4 WARNINGS AND PRECAUTIONS ....................................................................................4 ADVERSE REACTIONS ....................................................................................................14 DRUG INTERACTIONS ....................................................................................................20 DOSAGE AND ADMINISTRATION ................................................................................23 OVERDOSAGE ...................................................................................................................25 ACTION AND CLINICAL PHARMACOLOGY ...............................................................25 STORAGE AND STABILITY ............................................................................................28 -
Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation, Final, July 2009
Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) July 2009 Drug Safety Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation Additional copies are available from: Office of Communications, Division of Drug Information Center for Drug Evaluation and Research Food and Drug Administration 10903 New Hampshire Ave., Bldg. 51, rm. 2201 Silver Spring, MD 20993-0002 Tel: 301-796-3400; Fax: 301-847-8714; E-mail: [email protected] http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm or Office of Communication, Outreach, and Development, HFM-40 Center for Biologics Evaluation and Research Food and Drug Administration 1401 Rockville Pike, Rockville, MD 20852-1448 Tel: 800-835-4709 or 301-827-1800 http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) July 2009 Drug Safety TABLE OF CONTENTS I. INTRODUCTION............................................................................................................. 1 II. BACKGROUND: DILI ................................................................................................... 2 III. SIGNALS OF DILI AND HY’S -
Hepatobiliary Disposition of Troglitazone and Metabolites in Rat
0022-3565/10/3321-26–34$20.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 332, No. 1 Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics 156653/3540910 JPET 332:26–34, 2010 Printed in U.S.A. Hepatobiliary Disposition of Troglitazone and Metabolites in Rat and Human Sandwich-Cultured Hepatocytes: Use of Monte Carlo Simulations to Assess the Impact of Changes in Biliary Excretion on Troglitazone Sulfate Accumulation Jin Kyung Lee, Tracy L. Marion, Koji Abe, Changwon Lim, Gary M. Pollock, and Kim L. R. Brouwer Division of Pharmacotherapy and Experimental Therapeutics, The University of North Carolina at Chapel Hill Eshelman School of Pharmacy, Chapel Hill, North Carolina (J.K.L., K.A., G.M.P., K.L.R.B.); Curriculum in Toxicology, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (T.L.M., G.M.P., K.L.R.B.); and Department of Statistics and Operations Research, College of Arts and Sciences, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (C.L.) Received May 25, 2009; accepted October 1, 2009 ABSTRACT This study examined the hepatobiliary disposition of troglita- TS and TGZ concentrations ranged from 136 to 160 M and zone (TGZ) and metabolites [TGZ sulfate (TS), TGZ glucuronide from 49.4 to 84.7 M, respectively. Pharmacokinetic modeling (TG), and TGZ quinone (TQ)] over time in rat and human sand- and Monte Carlo simulations were used to evaluate the impact wich-cultured hepatocytes (SCH). Cells were incubated with of modulating the biliary excretion rate constant (Kbile) for TS on TGZ; samples were analyzed for TGZ and metabolites by liquid TS accumulation in hepatocytes and medium. -
Pharmaceuticals Appendix
)&f1y3X PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE )&f1y3X PHARMACEUTICAL APPENDIX TO THE TARIFF SCHEDULE 3 Table 1. This table enumerates products described by International Non-proprietary Names (INN) which shall be entered free of duty under general note 13 to the tariff schedule. The Chemical Abstracts Service (CAS) registry numbers also set forth in this table are included to assist in the identification of the products concerned. For purposes of the tariff schedule, any references to a product enumerated in this table includes such product by whatever name known. Product CAS No. Product CAS No. ABAMECTIN 65195-55-3 ADAPALENE 106685-40-9 ABANOQUIL 90402-40-7 ADAPROLOL 101479-70-3 ABECARNIL 111841-85-1 ADEMETIONINE 17176-17-9 ABLUKAST 96566-25-5 ADENOSINE PHOSPHATE 61-19-8 ABUNIDAZOLE 91017-58-2 ADIBENDAN 100510-33-6 ACADESINE 2627-69-2 ADICILLIN 525-94-0 ACAMPROSATE 77337-76-9 ADIMOLOL 78459-19-5 ACAPRAZINE 55485-20-6 ADINAZOLAM 37115-32-5 ACARBOSE 56180-94-0 ADIPHENINE 64-95-9 ACEBROCHOL 514-50-1 ADIPIODONE 606-17-7 ACEBURIC ACID 26976-72-7 ADITEREN 56066-19-4 ACEBUTOLOL 37517-30-9 ADITOPRIME 56066-63-8 ACECAINIDE 32795-44-1 ADOSOPINE 88124-26-9 ACECARBROMAL 77-66-7 ADOZELESIN 110314-48-2 ACECLIDINE 827-61-2 ADRAFINIL 63547-13-7 ACECLOFENAC 89796-99-6 ADRENALONE 99-45-6 ACEDAPSONE 77-46-3 AFALANINE 2901-75-9 ACEDIASULFONE SODIUM 127-60-6 AFLOQUALONE 56287-74-2 ACEDOBEN 556-08-1 AFUROLOL 65776-67-2 ACEFLURANOL 80595-73-9 AGANODINE 86696-87-9 ACEFURTIAMINE 10072-48-7 AKLOMIDE 3011-89-0 ACEFYLLINE CLOFIBROL 70788-27-1 -
New Mechanism-Based Anticancer Drugs That Act As Orphan
NEW MECHANISM-BASED ANTICANCER DRUGS THAT ACT AS ORPHAN NUCLEAR RECEPTOR AGONISTS A Dissertation by SUDHAKAR REDDY CHINTHARLAPALLI Submitted to the Office of Graduate Studies of Texas A&M University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY May 2006 Major Subject: Biochemistry NEW MECHANISM-BASED ANTICANCER DRUGS THAT ACT AS ORPHAN NUCLEAR RECEPTOR AGONISTS A Dissertation by SUDHAKAR REDDY CHINTHARLAPALLI Submitted to the Office of Graduate Studies of Texas A&M University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Approved by: Chair of Committee, Stephen Safe Committee Members, David Peterson James Sacchettini Robert Burghardt Head of Department, Gregory Reinhart May 2006 Major Subject: Biochemistry iii ABSTRACT New Mechanism-Based Anticancer Drugs That Act as Orphan Nuclear Receptor Agonists. (May 2006) Sudhakar Reddy Chintharlapalli, B.V.M., College of Veterinary Science, Acharya N.G.Ranga Agricultural University, India; M.S., Texas A&M University-Kingsville Chair of Advisory Committee: Dr. Stephen Safe 1,1-Bis(3'-indolyl)-1-(p-substitutedphenyl)methanes containing p- trifluoromethyl (DIM-C-pPhCF3), p-t-butyl (DIM-C-pPhtBu), and phenyl (DIM-C- pPhC6H5) substituents have been identified as a new class of peroxisome proliferator- activated receptor γ (PPARγ) agonists that exhibit antitumorigenic activity. In this study, the PPARγ-active compounds decreased HT-29, HCT-15, RKO, HCT116 and SW480 colon cancer cell survival and KU7 and 253JB-V33 bladder cancer cell survival. In HT- 29, HCT-15, SW480 and KU7 cells, the PPARγ agonists induced caveolin-1 expression and this induction was significantly downregulated after cotreatment with the PPARγ antagonist GW9662.