DOCSLIB.ORG

中国科技论文在线 Original Article 87

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
中国科技论文在线 Original Article 87 中国科技论文在线 http://www.paper.edu.cn Original article 87 Telmisartan ameliorates lipopolysaccharide-induced innate immune response through peroxisome proliferator-activated receptor-g activation in human monocytes Tao Pang, Julius Benicky, Juan Wang, Martina Orecna, Enrique Sanchez-Lemus and Juan M. Saavedra Objective Angiotensin II type 1 receptor (AT1) blockers anti-inflammatory effects of telmisartan were prevented by (ARBs) reduce the bacterial endotoxin lipopolysaccharide both PPARg antagonism and PPARg gene silencing. Anti- (LPS)-induced innate immune response in human inflammatory effects of ARBs correlated with their PPARg circulating monocytes expressing few AT1. To clarify the agonist potency. mechanisms of anti-inflammatory effects of ARBs with Conclusion Our observations demonstrate that in human different peroxisome proliferator-activated receptor-g monocytes, ARBs inhibit the LPS-induced pro-inflammatory (PPARg)-activating potencies, we focused our study on response to a major extent through the PPARg activation telmisartan, an ARB with the highest PPARg-stimulating pathway and may be beneficial for the treatment of activity. cardiovascular and metabolic disorders in which Methods Human circulating monocytes and monocytic inflammation plays a major role. J Hypertens 30:87–96 Q THP-1 (human acute monocytic leukemia cell line) cells 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins. were exposed to 50 ng/ml LPS with or without pre- incubation with telmisartan. AT1 mRNA and protein Journal of Hypertension 2012, 30:87–96 expressions were determined by real-time PCR and membrane receptor binding assay, respectively. The Keywords: angiotensin receptor blockers, cytokines, inflammation, expression of pro-inflammatory factors was determined by peroxisome proliferator-activated receptor-g, transcription factors real-time PCR, western blot analysis and ELISA. PPARg Abbreviations: ABCG1, ATP-binding cassette subfamily G member 1; Ang activation was measured by electrophoretic mobility shift II, angiotensin II; ARB, Ang II receptor blocker; AT1, Ang II type 1 receptor; CD36, cluster of differentiation 36; COX-2, cyclooxygenase-2; EMSA, assay and its role was determined by pharmacological electrophoretic mobility shift assay; ERK1/2, extracellular signal-regulated inhibition and PPARg gene silencing. kinases 1/2; ICAM-1, intercellular adhesion molecule 1; IL, interleukin; IkB- a, inhibitor of kB-a; LPS, lipopolysaccharide; MAPK, mitogen-activated Results In human monocytes, telmisartan significantly protein kinase; MCP-1, monocyte chemotactic protein-1; NF-kB, nuclear factor-kB; PGE2, prostaglandin E2; PPARg, peroxisome proliferator- attenuated the LPS-induced expression of pro- activated receptor-g; ROS, reactive oxygen species; THP-1, human acute inflammatory factors, the release of pro-inflammatory monocytic leukemia cell line; TNFa, tumor necrosis factor-a cytokines and prostaglandin E2, nuclear factor-kB Section on Pharmacology, Division of Intramural Research Programs, Department activation and reactive oxygen species formation. In THP-1 of Health and Human Services, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, USA cells, telmisartan significantly reduced LPS-induced tumor necrosis factor-a, inhibitor of kB-a, monocyte chemotactic Correspondence to Tao Pang, PhD, Section on Pharmacology, Department of Health and Human Services, National Institute of Mental Health, National protein-1 (MCP-1) and lectin-like oxidized low-density Institutes of Health, 10 Center Drive, Building 10, Room #2D-57, Bethesda, MD lipoprotein receptor-1 gene expression and MCP-1-directed 20892, USA Tel: +1 301 451 8379; fax: +1 301 402 0337; e-mail: [email protected] migration. Telmisartan also stimulated the expression of the PPARg target genes cluster of differentiation 36 and ATP- Received 7 July 2011 Revised 15 September 2011 binding cassette subfamily G member 1 in monocytes. The Accepted 5 October 2011 Introduction Most of the ARBs are biphenyl-tetrazole derivatives with Excessive angiotensin II (Ang II) type 1 receptor (AT1) similar but not identical pharmacological profiles [5]. The stimulation is associated with hypertension, and AT1 biphenyl-nontetrazole telmisartan is structurally unique blockers (ARBs) were developed for the treatment of and, in addition to its AT1 blocking properties, functions as high blood pressure to antagonize increased Ang II- a partial agonist of the peroxisome proliferator-activated dependent vasoconstriction [1]. ARBs protect end organs receptor-g (PPARg) [6], an intracellular nuclear hormone not only because they ameliorate hypertension, but also receptor regulating multiple pathways involved in carbo- as a consequence of beneficial effects on associated hydrate and lipid metabolism [7] and the control of expres- inflammatory and metabolic alterations beyond their sion of pro-inflammatory genes [8,9]. Full PPARg agonists effect on blood pressure control [2,3]. The protective reduce inflammation and metabolic alterations associated effect of ARBs is enhanced with increasing doses beyond with cardiovascular disease [10]. However, their associated full AT1 blockade [4], suggesting beneficial mechanisms toxicity limits their therapeutic value [11], and the identi- additional to AT1 blockade. fication of telmisartan as a well tolerated bifunctional 0263-6352 ß 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI:10.1097/HJH.0b013e32834dde5f 转载 中国科技论文在线 http://www.paper.edu.cn 88 Journal of Hypertension 2012, Vol 30 No 1 molecule to treat both hemodynamic and metabolic altera- All experiments were performed on nondifferentiated tions generated a high degree of enthusiasm [6]. It was later THP-1 cells. recognized that other ARBs, such as candesartan, activate PPARg in vitro and in vivo [12,13]. Angiotensin II receptor binding assay Untreated THP-1 cells (10 million) or human monocytes Anti-inflammatory effects of ARBs, first established in the (150 million) were harvested and homogenized in ice-cold peripheral vasculature [14] were later demonstrated in the buffer containing 50 mmol/l Tris-HCl pH 7.5, 1 mmol/l cerebral vasculature [15] and in stress-induced gastric ethylene glycol tetraacetic acid and 5 mmol/l MgCl2.A ulcerations [16]. These observations suggest that ARBs piece of fresh rat kidney cortex (100 mg) to be used as a may exert general anti-inflammatory effects beyond those positive control was homogenized in the same buffer. associated with cardiovascular and metabolic disease. Evi- Crude membrane fraction was pelleted by centrifugation dence in support of this hypothesis was obtained in at 20 000g for 20 min at 48C and the pellets were resus- normotensive rodents in which candesartan reduced the pended in 200 ml of the same buffer. Protein content was peripheral and brain acute inflammation following assessed by the Bradford reagent. The binding assay was systemic administration of the bacterial endotoxin lipopo- performed as previously described [23], with 0.25 nmol/l lysaccharide (LPS) [17–19]. Anti-inflammatory effects of [125I]Sar1-Ile8-Ang II as a receptor ligand. candesartan were also demonstrated in cultured circulating human monocytes expressing few AT1 [20]. Real-time PCR We hypothesized that, in human circulating monocytes Human monocytes or THP-1 cells were pre-incubated for 2 h with ARBs or vehicle (dimethylsulfoxide) followed with poor AT1 expression, the anti-inflammatory effects of ARBs may be associated with PPARg activation. We by exposure to 50 ng/ml LPS or physiological saline, compared ARBs with different PPARg-activating poten- composed of 0.9% w/v sodium chloride, for additional cies and focused on the effect of telmisartan, an ARB with 2 h, and reverse transcriptase-PCR measurements were the highest PPARg-stimulating activity. We studied LPS- performed as described [20] (see Supplemental Materials induced inflammation in monocytes as a relevant model, and Methods, http://links.lww.com/HJH/A136). because these cells are critical in the development of Western blot analysis insulin resistance, diabetes and arteriosclerosis; plasma Human monocytes were pre-incubated for 2 h with tel- LPS is elevated in obesity and diabetes [21]; and low- misartan or vehicle followed by addition of 50 ng/ml LPS grade chronic inflammation with increased expression of or physiological saline, composed of 0.9% w/v sodium monocyte-derived inflammatory factors is an established chloride, for different times, as indicated in the figures. component of vascular inflammatory disease in hyperten- Nuclear and whole-cell protein extracts were subjected to sion [14]. the separation by SDS-PAGE and analyzed as described Materials and methods in Supplemental Materials and Methods (http:// links.lww.com/HJH/A136). Detailed methods can be found in Supplemental Materials and Methods sections (http://links.lww.com/ Measurement of prostaglandin E2 production HJH/A136). Human monocytes were incubated for 24 h with 50 ng/ml LPS alone or in a combination with different concen- Human peripheral blood monocytes trations of telmisartan. The cell supernatants were col- Human peripheral blood mononuclear cells were isolated lected at the end of incubation for prostaglandin E2 by density gradient centrifugation of heparinized blood, (PGE2) measurement by PGE2 enzyme immunoassay collected by leukaphoresis of healthy volunteers at the (EIA) kit (Cayman Chemical, Ann Arbor, Michigan, Department of Transfusion Medicine, National Insti- USA) according to the manufacturer’s instructions. tutes of Health
Load more

Recommended publications
  • 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.
    [Show full text]
  • 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
    [Show full text]
  • 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.
    [Show full text]
  • 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.
    [Show full text]
  • 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.
    [Show full text]
  • 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
    [Show full text]
  • 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
    [Show full text]
  • 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.
    [Show full text]
  • TWYNSTA (Telmisartan/Amlodipine) Tablets Are Indicated for the Treatment of Hypertension, Alone Or with Other Antihypertensive Agents
    HIGHLIGHTS OF PRESCRIBING INFORMATION ---------------------DOSAGE FORMS AND STRENGTHS---------------------- These highlights do not include all the information needed to use • Tablets: 40/5 mg, 40/10 mg, 80/5 mg, 80/10 mg (3) TWYNSTA safely and effectively. See full prescribing information for TWYNSTA. -------------------------------CONTRAINDICATIONS------------------------------ • None TWYNSTA® (telmisartan/amlodipine) Tablets Initial U.S. Approval: 2009 -----------------------WARNINGS AND PRECAUTIONS------------------------ • Avoid fetal or neonatal exposure (5.1) WARNING: AVOID USE IN PREGNANCY • Hypotension: Correct any volume or salt depletion before initiating See full prescribing information for complete boxed warning. therapy. Observe for signs and symptoms of hypotension. (5.2) When pregnancy is detected, discontinue TWYNSTA as soon as possible. • Titrate slowly in patients with hepatic (5.4) or severe renal impairment Drugs that act directly on the renin-angiotensin system can cause injury (5.5) and even death to the developing fetus (5.1) • Heart failure: Monitor for worsening (5.8) • Avoid concomitant use of an ACE inhibitor and angiotensin receptor ----------------------------INDICATIONS AND USAGE--------------------------- blocker (5.6) • TWYNSTA is an angiotensin II receptor blocker (ARB) and a • Myocardial infarction: Uncommonly, initiating a CCB in patients with dihydropyridine calcium channel blocker (DHP-CCB) combination severe obstructive coronary artery disease may precipitate myocardial product indicated for the treatment
    [Show full text]
  • Jp Xvii the Japanese Pharmacopoeia
    JP XVII THE JAPANESE PHARMACOPOEIA SEVENTEENTH EDITION Official from April 1, 2016 English Version THE MINISTRY OF HEALTH, LABOUR AND WELFARE Notice: This English Version of the Japanese Pharmacopoeia is published for the convenience of users unfamiliar with the Japanese language. When and if any discrepancy arises between the Japanese original and its English translation, the former is authentic. The Ministry of Health, Labour and Welfare Ministerial Notification No. 64 Pursuant to Paragraph 1, Article 41 of the Law on Securing Quality, Efficacy and Safety of Products including Pharmaceuticals and Medical Devices (Law No. 145, 1960), the Japanese Pharmacopoeia (Ministerial Notification No. 65, 2011), which has been established as follows*, shall be applied on April 1, 2016. However, in the case of drugs which are listed in the Pharmacopoeia (hereinafter referred to as ``previ- ous Pharmacopoeia'') [limited to those listed in the Japanese Pharmacopoeia whose standards are changed in accordance with this notification (hereinafter referred to as ``new Pharmacopoeia'')] and have been approved as of April 1, 2016 as prescribed under Paragraph 1, Article 14 of the same law [including drugs the Minister of Health, Labour and Welfare specifies (the Ministry of Health and Welfare Ministerial Notification No. 104, 1994) as of March 31, 2016 as those exempted from marketing approval pursuant to Paragraph 1, Article 14 of the Same Law (hereinafter referred to as ``drugs exempted from approval'')], the Name and Standards established in the previous Pharmacopoeia (limited to part of the Name and Standards for the drugs concerned) may be accepted to conform to the Name and Standards established in the new Pharmacopoeia before and on September 30, 2017.
    [Show full text]
  • Importance of Hepatic Transporters, Including Basolateral Efflux Proteins, in Drug Disposition: Impact of Phospholipidosis and Non-Alcoholic Steatohepatitis
    IMPORTANCE OF HEPATIC TRANSPORTERS, INCLUDING BASOLATERAL EFFLUX PROTEINS, IN DRUG DISPOSITION: IMPACT OF PHOSPHOLIPIDOSIS AND NON-ALCOHOLIC STEATOHEPATITIS Brian C. Ferslew A dissertation submitted to the faculty of the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Pharmaceutical Sciences in the UNC Eshelman School of Pharmacy Chapel Hill 2014 Approved by: Dhiren Thakker Mary F. Paine A. Sidney Barritt Kim L.R. Brouwer Jo Ellen Rodgers Wei Jia ©2014 Brian C. Ferslew ALL RIGHTS RESERVED ii ABSTRACT Brian C. Ferslew: Importance of Hepatic Transporters, Including Basolateral Efflux Proteins, in Drug Disposition: Impact of Phospholipidosis and Non-Alcoholic Steatohepatitis (Under the direction of Kim L.R. Brouwer) The objective of this dissertation project was to develop preclinical and clinical tools to assess the impact of liver pathology on transporter-mediated systemic and hepatic exposure to medications. A translational approach utilizing established pre-clinical hepatic transport systems, mathematical modeling, and a pivotal in vivo human study was employed. A novel application of rat sandwich-cultured hepatocytes (SCH) was developed to evaluate the impact of drug-induced phospholipidosis on the vectorial transport of probe substrates for hepatic basolateral and canalicular transport proteins. Results indicated that rat SCH treated with prototypical hepatic phospholipidosis inducers are a sensitive and selective model for drug-induced phospholipidosis; both organic anion transporting polypeptide-mediated uptake and bile salt export pump-mediated biliary excretion were reduced after the onset of phospholipidosis. Enalapril currently is being investigated for its anti-fibrotic effects in the treatment of patients with non-alcoholic steatohepatitis (NASH).
    [Show full text]
  • Open Full Page
    1288 Vol. 8, 1288–1294, May 2002 Clinical Cancer Research Nuclear Receptor Agonists As Potential Differentiation Therapy Agents for Human Osteosarcoma1 Rex C. Haydon,2 Lan Zhou,2 Tao Feng, Conclusions: Our findings suggest that PPAR␥ and/or Benjamin Breyer, Hongwei Cheng, Wei Jiang, RXR ligands may be used as efficacious adjuvant therapeu- tic agents for primary osteosarcoma, as well as potential Akira Ishikawa, Terrance Peabody, chemopreventive agents for preventing the recurrence and Anthony Montag, Michael A. Simon, and metastasis of osteosarcoma after the surgical removal of the Tong-Chuan He3 primary tumors. Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois 60637 INTRODUCTION Osteosarcoma is the most common primary malignant tu- mor of bone, encompassing a class of osteoid-producing neo- ABSTRACT plasms that range in clinical behavior and responsiveness to Purpose: This study was designed to investigate therapeutic regimens (1, 2). Best known of these lesions, the whether nuclear receptor agonists can be used as potential classic high-grade osteosarcoma primarily afflicts individuals in differentiation therapy agents for human osteosarcoma. the second decade of life and is distinguished by its locally Experimental Design: Four osteosarcoma cell lines aggressive character and early metastatic potential. Metastatic (143B, MNNG/HOS, MG-63, and TE-85) were treated with disease is often not apparent at diagnosis and causes the over- proliferator-activated receptor (PPAR)␥ agonists, troglita- whelming majority of deaths among patients with this disease. zone and ciglitazone, and a retinoid X receptor (RXR) li- Recurrent or metastatic tumors are significantly less sensitive, if gand, 9-cis retinoic acid.
    [Show full text]