DOCSLIB.ORG

The Role of Intercalated Cell Nedd4–2 in BP Regulation, Ion Transport, and Transporter Expression

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Role of Intercalated Cell Nedd4–2 in BP Regulation, Ion Transport, and Transporter Expression BASIC RESEARCH www.jasn.org The Role of Intercalated Cell Nedd4–2 in BP Regulation, Ion Transport, and Transporter Expression Masayoshi Nanami,1 Truyen D. Pham,1 Young Hee Kim,1 Baoli Yang,2 Roy L. Sutliff,3 Olivier Staub,4,5 Janet D. Klein,1 Karen I. Lopez-Cayuqueo,6,7 Regine Chambrey,8 Annie Y. Park,1 Xiaonan Wang,1 Vladimir Pech,1 Jill W. Verlander,9 and Susan M. Wall1,10 Due to the number of contributing authors, the affiliations are listed at the end of this article. ABSTRACT Background Nedd4–2 is an E3 ubiquitin-protein ligase that associates with transport proteins, causing their ubiquitylation, and then internalization and degradation. Previous research has suggested a corre- lation between Nedd4–2 and BP. In this study, we explored the effect of intercalated cell (IC) Nedd4–2 gene ablation on IC transporter abundance and function and on BP. Methods We generated IC Nedd4–2 knockout mice using Cre-lox technology and produced global pen- 2/2 drin/Nedd4–2 null mice by breeding global Nedd4–2 null (Nedd4–2 ) mice with global pendrin null 2/2 (Slc26a4 ) mice. Mice ate a diet with 1%–4% NaCl; BP was measured by tail cuff and radiotelemetry. We 2 measured transepithelial transport of Cl and total CO2 and transepithelial voltage in cortical collecting ducts perfused in vitro. Transporter abundance was detected with immunoblots, immunohistochemistry, and immunogold cytochemistry. 2 2 Results IC Nedd4–2 gene ablation markedly increased electroneutral Cl /HCO3 exchange in the cortical col- lecting duct, although benzamil-, thiazide-, and bafilomycin-sensitive ion flux changed very little. IC Nedd4–2 gene ablation did not increase the abundance of type B IC transporters, such as AE4 (Slc4a9), H+-ATPase, barttin, + 2 2 or the Na -dependent Cl /HCO3 exchanger (Slc4a8). However, IC Nedd4–2 gene ablation increased CIC-5 total protein abundance, apical plasma membrane pendrin abundance, and the ratio of pendrin expression on the apical membrane to the cytoplasm. IC Nedd4–2 gene ablation increased BP by approximately 10 mm Hg. Moreover, pendrin gene ablation eliminated the increase in BP observed in global Nedd4–2 knockout mice. 2 2 Conclusions IC Nedd4–2 regulates Cl /HCO3 exchange in ICs., Nedd4–2 gene ablation increases BP in part through its action in these cells. J Am Soc Nephrol 29: 1706–1719, 2018. doi: https://doi.org/10.1681/ASN.2017080826 In people and rodent models of salt-sensitive hy- through a mechanism that involves the E3 ubiq- pertension, BP elevation requires increased intake uitin-protein ligase neuronal precursor cell 2 of Na+ and Cl .1,2 One commonly used rodent model of human salt-sensitive hypertension is Received August 2, 2017. Accepted March 29, 2018. achieved with the administration of aldosterone J.W.V. and S.M.W. contributed equally to this work. and a high-NaCl diet. This treatment model pro- duces salt-sensitive hypertension partly by stimu- M.N. and T.D.P. contributed equally to this work. + 2 lating renal Na and Cl transporters, such as the Published online ahead of print. Publication date available at epithelial Na+ channel (ENaC),3 the thiazide-sensitive www.jasn.org. 4 5 NaCl cotransporter, and pendrin. Aldosterone Correspondence: Dr. Susan M. Wall, Renal Division, Emory modulates NaCl absorption, at least in some renal University School of Medicine, WMB Room 338, 1639 Pierce cell types, by changing the number of func- Drive, NE, Atlanta, GA 30322. Email: [email protected] tional transporters in the cell membrane partly Copyright © 2018 by the American Society of Nephrology 1706 ISSN : 1046-6673/2906-1706 JAmSocNephrol29: 1706–1719, 2018 www.jasn.org BASIC RESEARCH Significance Statement Nedd4–2 associates with the epithelial Na+ channel (ENaC), resulting in its ubiquitylation and then, internalization and deg- radation. In the absence of Nedd4–2, increased renal Na+ ab- sorption and increased BP are observed. Despite high levels of Nedd4–2 expression in intercalated cells, the role that these cells play in the changes in BP observed with Nedd4–2 gene ablation is unknown. This study is the first to show that Nedd4–2-dependent changes in BP occur in part from Nedd4–2 expressed in in- tercalated cells. Moreover, this study shows that Nedd4–2 gene ablation within intercalated cells stimulates electroneutral apical 2 2 Cl /HCO3 exchange in mouse CCD, in part by upregulating pendrin. In the cortical collecting duct (CCD), Na+ is absorbed primarily 2 by principal cells, whereas Cl is absorbed primarily across 2 2 15 ICs, largely through electroneutral Cl /HCO3 exchange across type B ICs.16 Apical anion exchange occurs through apical + 2 2 Na -independent Cl /HCO3 exchange mediated principally by pendrin (Slc26a4),17,18 which acts in parallel with the + 2 2 Figure 1. Ion transporters in mouse cortical collecting duct. Na -dependent Cl /HCO3 exchanger, NDCBE, encoded by + Mouse cortical collecting duct is made up of principal cells, which Slc4a819. NaCl and net H equivalentsexitacrossthetypeBIC 2 mediate electrogenic Na+ absorption through the benzamil- basolateral plasma membrane through a Cl channel (ClC-K2/ + 20,21 22 sensitive epithelial Na channel (ENaC) on the apical plasma barttin or ClC-Kb), an NaHCO3 cotransporter (AE4), membrane. Na+ exits principal cells across the basolateral plasma and an H+ pump (H+-ATPase)22. This NaCl and H+ exit in- + membrane through the Na,K-ATPase. ENaC-mediated Na ab- creases the electrochemical gradient for apical anion sorption creates a lumen-negative voltage, which provides the 2 2 exchange, thereby increasing Cl absorption and HCO3 driving force for K+ secretion. Type B ICs mediate electroneutral 2 secretion. In contrast to type B ICs, type A ICs mediate net NaCl absorption and HCO3 secretion through an apical plasma 23–26 2 + 2 2 HCl secretion into the luminal fluid in series with Cl membrane Na -independent electroneutral Cl /HCO3 ex- 2 + uptake and HCO3 exit across the basolateral membrane changer (pendrin) that acts in tandem with an Na -dependent 2 2 2 2 2 + + through Cl /HCO3 exchange (AE1), Na -K -2Cl cotrans- Cl /HCO3 exchanger. NaCl exits the cell through a basolateral 2 2 20,21,26,27 plasma membrane Cl channel and an NaHCO3 cotransporter porter 1, and a Cl channel (Figure 1). (AE4). Net H+ equivalents exit across the basolateral plasma Nedd4–2 is expressed in the aldosterone-sensitive region membrane through the H+-ATPase. The type A IC mediates up- of the nephron,10 which includes the connecting tubule 2 take of H+ equivalents and Cl across the basolateral plasma (CNT), the CCD, and the OMCD. Mouse CNT is made 2 2 membrane through Na+-K+-2Cl cotransporter 1 (NKCC1), Cl / 2 2 up of CNT cells and ICs, whereas mouse CCD is composed HCO3 exchange (AE1), and possibly, a Cl channel. This cell 28 – + 2 of principal cells and ICs. Nedd4 2 is highly expressed in type secretes HCl through an apical H -ATPase and an apical Cl 10 2 2 the CCD and the CNT, particularly within type B and channel or Cl /HCO3 exchanger. non-A, non-B ICs; CNT cells; and principal cells, with much lower abundance in type A ICs.10 Although the role expressed developmentally downregulated 4–2 (Nedd4–2).6–9 of Nedd4–2 in principal cells has been well studied, little is When a transporter or a channel associates with Nedd4–2,it known about its function in ICs. Our ability to generate is ubiquitylated, and then, endocytosed and degraded in mice in which Nedd4–2 gene ablation has occurred specif- proteasomes or lysosomes.9,10,11 Conversely, in the absence ically within ICs of the CCD plus our ability to perfuse of Nedd4–2 (i.e.,inNedd4–2 knockout mice), channel in- CCDs in vitro from these mice29 provide a unique oppor- ternalization and degradation fall, which increases plasma tunity by which to explore the physiologic role of IC membrane abundance of channels such as ENaC, thereby Nedd4–2 in native tissue. contributing to the salt-sensitive hypertension observed in Aldosterone’s signal transduction mechanism in type B ICs global Nedd4–2 null mice.8 As such, increased BP is ob- is poorly understood. Because Nedd4–2 participates in aldo- served in mice with embryonic, global Nedd4–2 gene abla- sterone signaling in many cell types and because Nedd4–2 is tion8; mice with inducible, kidney-specific Nedd4–2 gene expressed in ICs, we sought to determine if Nedd4–2 changes ablation12; and people with certain polymorphisms of BP by altering IC function. The purpose of this study was to NEDD4-L, the human homolog of rodent Nedd4–2.13,14 determine if IC Nedd4–2 gene ablation changes CCD ion 2 The Na+ and Cl transporters expressed in principal cells and transport or BP and determine the transporter(s) regulated the various intercalated cell (IC) subtypes are displayed in Figure 1. by Nedd4–2 within ICs. J Am Soc Nephrol 29: 1706–1719, 2018 Intercalated Cell Nedd4–2 1707 BASIC RESEARCH www.jasn.org METHODS Animals IC Nedd4–2 null mice were generated by breeding floxed Nedd4–2 mice8 with transgenic mice expressing Cre recombi- nase driven by the ATP6V1B1 promoter (B1-H+-ATPase Cre),30 asubunitoftheH+-ATPase that is expressed in renal ICs.30 The Cre was carried through the female line. We com- pared IC Nedd4–2 null (Nedd4–2loxloxcre) with Cre(2)sex- matched, wild-type littermates (Nedd4–2loxlox). Unless otherwise stated, IC Nedd4–2 knockout and wild-type littermates will refer to Nedd4–2loxloxcre and Nedd4–2loxlox, respectively. Mice were genotyped by quantitative PCR (Transnetyx) and sometimes, standard PCR.8,30 Global Nedd4–2 null mice were generated as described previously8 by breeding floxed Nedd4–2 mice with mice ex- pressing Cre recombinase globally (EIIa-Cre, Stock 003724; 2 2 2 2 Jackson Labs).8 To generate Nedd4–2 / /Slc26a4 / ; Nedd4–2+/+ 2 2 2 2 /Slc26a4 / , Nedd4–2 / /Slc26a4+/+, and wild-type littermates on a C57Bl/6 background, we first bred global pendrin null 2 2 (Slc26a4 / ) on a 129 SvEv Tac background with wild-type mice on a C57Bl/6 background over ten generations.
Load more

Recommended publications
  • Association of Hypertensive Status and Its Drug Treatment with Lipid and Haemostatic Factors in Middle-Aged Men: the PRIME Study
    Journal of Human Hypertension (2000) 14, 511–518 2000 Macmillan Publishers Ltd All rights reserved 0950-9240/00 $15.00 www.nature.com/jhh ORIGINAL ARTICLE Association of hypertensive status and its drug treatment with lipid and haemostatic factors in middle-aged men: the PRIME Study P Marques-Vidal1, M Montaye2, B Haas3, A Bingham4, A Evans5, I Juhan-Vague6, J Ferrie`res1, G Luc2, P Amouyel2, D Arveiler3, D McMaster5, JB Ruidavets1, J-M Bard2, PY Scarabin4 and P Ducimetie`re4 1INSERM U518, Faculte´ de Me´decine Purpan, Toulouse, France; 2MONICA-Lille, Institut Pasteur de Lille, Lille, France; 3MONICA-Strasbourg, Laboratoire d’Epide´miologie et de Sante´ Publique, Strasbourg, France; 4INSERM U258, Hoˆ pital Broussais, Paris, France; 5Belfast-MONICA, Department of Epidemiology, The Queen’s University of Belfast, UK; 6Laboratory of Haematology, La Timone Hospital, Marseille, France Aims: To assess the association of hypertensive status this effect remained after multivariate adjustment. Cal- and antihypertensive drug treatment with lipid and hae- cium channel blockers decreased total cholesterol and mostatic levels in middle-aged men. apoproteins A-I and B; those differences remained sig- Methods and results: Hypertensive status, antihyperten- nificant after multivariate adjustment. ACE inhibitors sive drug treatment, total and high-density lipoprotein decreased total cholesterol, triglycerides, apoprotein B (HDL) cholesterol, triglyceride, apoproteins A-I and B, and LpE:B; and this effect remained after multivariate lipoparticles LpA-I,
    [Show full text]
  • Comparing the Efficacy of Angiotensin Converting Enzyme In- Hibitors with Calcium Channel Blockers on the Treatment of Di- Abetic Nephropathy: a Meta-Analysis
    Iran J Public Health, Vol. 48, No.2, Feb 2019, pp.189-197 Review Article Comparing the Efficacy of Angiotensin Converting Enzyme In- hibitors with Calcium Channel Blockers on the Treatment of Di- abetic Nephropathy: A Meta-Analysis *Zhaowei ZHANG 1, Chunlin CHEN 2, Shiwen LV 1, Yalan ZHU 1, Tianzi FANG 1 1. Department of Pharmacy, Jin Hua Municipal Central Hospital, Jin Hua 32100, China 2. College of Chemistry and Bio-Engineering, Yi Chun University, Yi Chun 336000, China *Corresponding Author: Email: [email protected] (Received 21 Mar 2018; accepted 11 Jun 2018) Abstract Background: The angiotensin-converting enzyme inhibitors (ACEIs) could improve the symptoms of diabetic nephropathy. Whether the calcium channel blockers (CCBs) could be as effective as ACEIs on treating diabetic nephropathy is controversial. Here, we aimed to compare the efficacy of ACEIs with CCBs on the treatment of diabetic nephropathy by performing a meta-analysis of randomized controlled trials (RCTs). Methods: The Pubmed, Medline, Embase and The Cochrane Database were searched up to July 2017 for eli- gible randomized clinical trials studies. Effect sizes were summarized as mean difference (MD) or standardized mean difference (SMD) with 95% confidence intervals (P-value<0.05). Results: Seven RCTs involving 430 participants comparing ACEIs with CCBs were included. No benefit was seen in comparative group of ACEIs on systolic blood pressure（SBP） (MD=1.05 mmHg; 95% CI: -0.97 to 3.08, P=0.31), diastolic blood pressure (DBP) (MD= -0.34 mmHg; 95% CI: -1.2 to 0.51, P=0.43), urinary al- bumin excretion rates (UAER) (MD=1.91μg/min; 95% CI: -10.3 to 14.12, P=0.76), 24-h urine protein (24-UP) (SMD=-0.26; 95%CI: -0.55 to 0.03, P=0.08), glomerular filtration rate (GFR) (SMD=0.01; 95% CI: -0.38 to 0.41, P=0.95).
    [Show full text]
  • Actual Place of Diuretics in Hypertension Treatment
    Mini Review J Cardiol & Cardiovasc Ther Volume 3 Issue 4 - March 2017 Copyright © All rights are reserved by Farouk Abcha DOI: 10.19080/JOCCT.2017.03.555616 Actual Place of Diuretics in Hypertension Treatment Farouk Abcha, Marouane Boukhris*, Zied Ibn Elhadj, Lobna Laroussi, Faouzi Addad, Afef Ben Halima and Salem Kachboura Cardiology Department of Abderrahmen Mami Hospital, University of Tunis El Manar, Tunisia Submission: February 03, 2017; Published: March 07, 2017 *Corresponding author: Marouane Boukhris, Cardiology Department of Abderrahmen Mami Hospital, Ariana, Faculty of Medicine of Tunis, University of Tunis El Manar, Tunisia, Tel: ; Email: Abstract Diuretics represent a large and heterogeneous class of drugs, differing from each other by structure, site and mechanism of action. Diuretics are widely used, and have several indications in different cardiovascular disorders, particularly in hypertension and heart failure. Despite the large number of available anti-hypertensive drugs, diuretics remained a cornerstone of hypertension treatment. In the current editorial, we assessed the actual place of different diuretics in the hypertension guidelines focusing on the concept of tailored approach in prescribing them for hypertensive patients. Keywords: Diuretics; Hypertension; Hydrochlorothiazide; Indapamide; Guidelines Introduction Diuretics represent a large and heterogeneous class of drugs, differing from each other by structure, site and mechanism of action. Diuretics are widely used, and have several indications in different cardiovascular disorders, particularly in hypertension and heart failure. Despite the large number of available anti-hypertensive drugs, diuretics remained a cornerstone of hypertension treatment [1]. Indeed, they are the second most commonly prescribed class of antihypertensive medication. For instance, 12% of US adults were prescribed a diuretic, and the relative increase in prescriptions from 1999 through 2012 was 1.4 [2].
    [Show full text]
  • The Role of Intercalated Cell Nedd4–2 in BP Regulation, Ion Transport, and Transporter Expression
    BASIC RESEARCH www.jasn.org The Role of Intercalated Cell Nedd4–2 in BP Regulation, Ion Transport, and Transporter Expression Masayoshi Nanami,1 Truyen D. Pham,1 Young Hee Kim,1 Baoli Yang,2 Roy L. Sutliff,3 Olivier Staub,4,5 Janet D. Klein,1 Karen I. Lopez-Cayuqueo,6,7 Regine Chambrey,8 Annie Y. Park,1 Xiaonan Wang,1 Vladimir Pech,1 Jill W. Verlander,9 and Susan M. Wall1,10 Due to the number of contributing authors, the affiliations are listed at the end of this article. ABSTRACT Background Nedd4–2 is an E3 ubiquitin-protein ligase that associates with transport proteins, causing their ubiquitylation, and then internalization and degradation. Previous research has suggested a corre- lation between Nedd4–2 and BP. In this study, we explored the effect of intercalated cell (IC) Nedd4–2 gene ablation on IC transporter abundance and function and on BP. Methods We generated IC Nedd4–2 knockout mice using Cre-lox technology and produced global pen- 2/2 drin/Nedd4–2 null mice by breeding global Nedd4–2 null (Nedd4–2 ) mice with global pendrin null 2/2 (Slc26a4 ) mice. Mice ate a diet with 1%–4% NaCl; BP was measured by tail cuff and radiotelemetry. We 2 measured transepithelial transport of Cl and total CO2 and transepithelial voltage in cortical collecting ducts perfused in vitro. Transporter abundance was detected with immunoblots, immunohistochemistry, and immunogold cytochemistry. 2 2 Results IC Nedd4–2 gene ablation markedly increased electroneutral Cl /HCO3 exchange in the cortical col- lecting duct, although benzamil-, thiazide-, and bafilomycin-sensitive ion flux changed very little.
    [Show full text]
  • Initial Medication Selection for Treatment of Hypertension in an Open-Panel HMO
    J Am Board Fam Pract: first published as 10.3122/jabfm.8.1.1 on 1 January 1995. Downloaded from Initial Medication Selection For Treatment Of Hypertension In An Open-Panel HMO Micky jerome, PharmD, MBA, George C. Xakellis, MD, Greg Angstman, MD, and Wayne Patchin, MBA Background: During the past 25 years recommendations for treating hypertension have evolved from a stepped-care approach to monotherapy or sequential monotherapy as experience has been gained and new antihypertensive agents have been introduced. In an effort to develop a disease management strategy for hypertension, we investigated the prescribing patterns of initial medication therapy for newly treated hypertensive patients. Methods: We examined paid claims data of an open-panel HMO located in the midwest. Charts from 377 patients with newly treated hypertension from a group of 12,242 hypertenSive patients in a health insurance population of 85,066 persons were studied. The type of medication regimen received by patients newly treated for hypertension during an 18-month period was categorized into monotherapy, sequential monotherapy, stepped care, and initial treatment with multiple agents. With monotherapy, the class of medication was also reported. Associations between use of angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers, or (3-blockers and presence of comorbid conditions were reported. Results: Fifty-five percent of patients received monotherapy, 22 percent received stepped care, and 18 percent received sequential monotherapy. Of those 208 patients receiving monotherapy, 30 percent were prescribed a calcium channel blocker, 22 percent an ACE inhibitor, and 14 percent a f3-blocker. No customization of treatment for comorbid conditions was noted.
    [Show full text]
  • Drugs for Primary Prevention of Atherosclerotic Cardiovascular Disease: an Overview of Systematic Reviews
    Supplementary Online Content Karmali KN, Lloyd-Jones DM, Berendsen MA, et al. Drugs for primary prevention of atherosclerotic cardiovascular disease: an overview of systematic reviews. JAMA Cardiol. Published online April 27, 2016. doi:10.1001/jamacardio.2016.0218. eAppendix 1. Search Documentation Details eAppendix 2. Background, Methods, and Results of Systematic Review of Combination Drug Therapy to Evaluate for Potential Interaction of Effects eAppendix 3. PRISMA Flow Charts for Each Drug Class and Detailed Systematic Review Characteristics and Summary of Included Systematic Reviews and Meta-analyses eAppendix 4. List of Excluded Studies and Reasons for Exclusion This supplementary material has been provided by the authors to give readers additional information about their work. © 2016 American Medical Association. All rights reserved. 1 Downloaded From: https://jamanetwork.com/ on 09/28/2021 eAppendix 1. Search Documentation Details. Database Organizing body Purpose Pros Cons Cochrane Cochrane Library in Database of all available -Curated by the Cochrane -Content is limited to Database of the United Kingdom systematic reviews and Collaboration reviews completed Systematic (UK) protocols published by by the Cochrane Reviews the Cochrane -Only systematic reviews Collaboration Collaboration and systematic review protocols Database of National Health Collection of structured -Curated by Centre for -Only provides Abstracts of Services (NHS) abstracts and Reviews and Dissemination structured abstracts Reviews of Centre for Reviews bibliographic
    [Show full text]
  • RESEARCH UPDATES (Cont.)
    RESEARCH UPDATES (cont.) RESEARCH UPDATES Resident Editors: David Bunch, Pharm.D., Ally Kingsbury, Pharm.D., Monika Tawfik, Pharm.D. Faculty Editors: Sarah Schweiss, Pharm.D., BCACP RESEARCH UPDATES Volume 18, Issue 1 – First The HUNT Study: Proton Pump Inhibitors and Fracture Risk1 Quarter 2020 Kaylin Maddy, PharmD Park Nicollet Health Services Research Updates The HUNT Study: Proton Pump Background: Proton pump inhibitors (PPIs) are broadly prescribed for gastrointestinal conditions. These medications have been correlated with an increased risk of fractures Inhibitors and Fracture Risk in multiple previous studies, however a definite causative link is not well understood. A Comparison of Two LDL The FDA requires PPI packaging information to include a warning about increased hip, Cholesterol Targets after Ischemic wrist, or spine fracture risk with long term and high dose PPI use. Many mechanisms for this risk have been proposed including reduced calcium and magnesium absorption, Stroke though these have not been adequately demonstrated in humans. Therapeutic Thoughts Purpose: The Nord-Trøndelag Health Study (HUNT) study aimed to examine a possible Migraine Pharmacotherapy and association between the use of PPIs and risk of fracture in a large group of Norwegian individuals. Novel Agents Study Design: A total of 15,017 women and 13,241 men aged 50 to 85, with a mean age Antihypertensive Treatment of 65 years old were analyzed. Data was retrospectively reviewed from a large Update Norwegian Health Study (HUNT3), the Norwegian Fracture Registry, and the Norwegian Prescription Database. The fracture registry collects information on hip and Who Should Receive PCV13? forearm fractures. History of exposure to PPIs, anti-osteoporotic drugs (AODs), and oral glucocorticoids (GCs) were pulled from the prescription database.
    [Show full text]
  • Pharmacy Précis
    Samford University Global Drug Information Service PHARMACY RÉCIS P Précis: a concise summary of essential points, statements or facts Volume 30 (Issue 1) January 2012 NEW MOLECULAR ENTITIES OF 2011 New molecular entities, biologic agents, and drug formulations/combinations approved during 2011 (including indication, approval date, and comments) are presented in this issue of Pharmacy Précis. An explanation of the FDA classification of the new drugs also is included. If you need any additional information regarding these agents, please call the Samford University Global Drug Information Service at (205) 726-2659. FDA classifications for newly approved drugs are based on chemical classification and are outlined below. FDA CLASSIFICATIONS CHEMICAL CLASSIFICATION THERAPEUTIC CLASSIFICATION 1. New molecular entity - drug S = Standard review - assigned not marketed in U.S. by any to drugs that appear to have manufacturer therapeutic qualities similar to 2. New salt - active moiety is drugs already approved marketed in the U.S., but this P = Priority review - assigned particular salt, ester, or to drugs that appear to have derivative is not therapeutic gain over drugs 3. New formulation - drug currently available marketed in the U.S., but this O = Orphan designation - particular formulation is not Pursuant to Section 526 of the 4. New combination - two or Orphan Drug Act (Public Law more ingredients in 97-414 as amended). combination not marketed in 1. Providing effective therapy the U.S. or diagnosis for a disease 5. New manufacturer - already not adequately treated or marketed by another firm; diagnosed by any marketed duplicated salt, formulation or drug combination 2. Providing improved 6.
    [Show full text]
  • Self-Measured Compared to Office
    Systematic Review for the 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: Supplemental Tables and Figures Part 1: Self-Measured Compared to Office-Based Measurement of Blood Pressure in the Management of Adults With Hypertension Table 1.1 Electronic search terms used for the current meta-analysis (Part 1 – Self-Measured Compared to Office-Based Measurement of Blood Pressure in the Management of Adults With Hypertension). PubMed Search (Blood Pressure Monitoring, Ambulatory [mesh] OR self care [mesh] OR telemedicine [mesh] OR patient participation [tiab] OR ambulatory [tiab] OR kiosk [tiab] OR kiosks [tiab] OR self-monitor* [tiab] OR self-measure* [tiab] OR self-care* [tiab] OR self-report* [tiab] OR telemonitor* [tiab] OR tele-monitor* [tiab] OR home monitor* [tiab] OR telehealth [tiab] OR tele-health [tiab] OR telemonitor* [tiab] OR tele-monitor* [tiab] OR telemedicine [tiab] OR patient-directed [tiab] OR Blood pressure monitoring “patient directed” [tiab] OR HMBP [tiab] OR SMBP [tiab] OR home [tiab] OR white coat [tiab] OR concept + Self Care concept ((patient participation [ot] OR ambulatory [ot] OR kiosk [ot] OR kiosks [ot] OR self-monitor* [ot] OR self-measure* [ot] OR self-care* [ot] OR self-report* [ot] OR telemonitor* [ot] OR tele-monitor* [ot] OR home monitor* [ot] OR telehealth [ot] OR tele-health [ot] OR telemonitor* [ot] OR tele- monitor* [ot] OR telemedicine [ot] OR patient-directed [tiab] OR “patient directed” [tiab]
    [Show full text]
  • Australian Public Assessment Report for Aliskiren, Amlodipine and Hydrochlorothiazide Proprietary Product Name: Rasilamlo HCT
    Australian Public Assessment Report for Aliskiren, Amlodipine and Hydrochlorothiazide Proprietary Product Name: Rasilamlo HCT Sponsor: Novartis Pharmaceuticals Australia Pty Ltd June 2012 Therapeutic Goods Administration About the Therapeutic Goods Administration (TGA) · The Therapeutic Goods Administration (TGA) is a division of the Australian Government Department of Health and Ageing, and is responsible for regulating medicines and medical devices. · TGA administers the Therapeutic Goods Act 1989 (the Act), applying a risk management approach designed to ensure therapeutic goods supplied in Australia meet acceptable standards of quality, safety and efficacy (performance), when necessary. · The work of the TGA is based on applying scientific and clinical expertise to decision- making, to ensure that the benefits to consumers outweigh any risks associated with the use of medicines and medical devices. · The TGA relies on the public, healthcare professionals and industry to report problems with medicines or medical devices. TGA investigates reports received by it to determine any necessary regulatory action. · To report a problem with a medicine or medical device, please see the information on the TGA website. About AusPARs · An Australian Public Assessment Record (AusPAR) provides information about the evaluation of a prescription medicine and the considerations that led the TGA to approve or not approve a prescription medicine submission. · AusPARs are prepared and published by the TGA. · An AusPAR is prepared for submissions that relate to new chemical entities, generic medicines, major variations, and extensions of indications. · An AusPAR is a static document, in that it will provide information that relates to a submission at a particular point in time. · A new AusPAR will be developed to reflect changes to indications and/or major variations to a prescription medicine subject to evaluation by the TGA.
    [Show full text]
  • Systematic Evidence Review from the Blood Pressure Expert Panel, 2013
    Managing Blood Pressure in Adults Systematic Evidence Review From the Blood Pressure Expert Panel, 2013 Contents Foreword ............................................................................................................................................ vi Blood Pressure Expert Panel ..............................................................................................................vii Section 1: Background and Description of the NHLBI Cardiovascular Risk Reduction Project ............ 1 A. Background .............................................................................................................................. 1 Section 2: Process and Methods Overview ......................................................................................... 3 A. Evidence-Based Approach ....................................................................................................... 3 i. Overview of the Evidence-Based Methodology ................................................................. 3 ii. System for Grading the Body of Evidence ......................................................................... 4 iii. Peer-Review Process ....................................................................................................... 5 B. Critical Question–Based Approach ........................................................................................... 5 i. How the Questions Were Selected ................................................................................... 5 ii. Rationale for the Questions
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 6,541,479 B1 Mehanna Et Al
    USOO6541479 B1 (12) United States Patent (10) Patent No.: US 6,541,479 B1 Mehanna et al. (45) Date of Patent: Apr. 1, 2003 (54) CALCIUM CHANNEL BLOCKERS 5,132,106 A 7/1992 Tuloup et al. ................ 424/70 5,134,139 A 7/1992 Kawai et al. ............... 514/211 (75) Inventors: Ahmed S. Mehanna, Sudbury; Jinyung 5,135,936 A 8/1992 Adams et al. .............. 514/305 T. Kim, Boston, both of MA (US) 5,144,029 A 9/1992 Ward et al. ................. 540/610 5,198.433 A 3/1993 Palfreyman et al. ........ 514/212 5,276,026 A 1/1994 Barrish et al. .............. 514/212 (73) ASSignee: Masays sole of Pharmacy, 5,281,592 A 1/1994 Ozeki et al. ............. 514/224.2 s 5,344,830 A 9/1994 Mills et al. .............. 514/235.8 (*) Notice: Subject to any disclaimer, the term of this rig: A : y R t t r 5. patent is extended or adjusted under 35 5,496,815. A 3/1996 Ozeki et al. ............. 514/224.2 U.S.C. 154(b) by 0 days. 5,514,693 A 5/1996 Cozzi et al. ................ 514/341 5,607,939 A 3/1997 Kato et al. .................. 514/278 (21) Appl. No.: 08/982,953 5,623,051. A 4/1997 Catterall et al. ............ 530/324 (22) Filed: Dec. 2, 1997 OTHER PUBLICATIONS (51) Int. Cl." .............................................. A61K31/495 Abstract to Gialdi et al. of CA56:4664g, Mar. 8, 1962.* (52) U.S. Cl. ................................... 514/255.01: 514/310 Fugita, M. et al., "Synthesis and Ca" Antagonistic Activity (58) Field of Search ............................
    [Show full text]