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Jasn2512editorial 2679..2687
EDITORIALS www.jasn.org UP FRONT MATTERS Despite their common source of angiotensinogen, circu- Renal Angiotensin-Converting lating and renal Ang II production do not always run in Enzyme Upregulation: A parallel. For instance, in patients with diabetes, plasma reninislow,andyettheir renalplasmaflow response to RAS Prerequisite for Nitric Oxide blockade is greatly enhanced, suggesting an overactive Synthase Inhibition–Induced intrarenal RAS.8 The opposite occurs after treatment with very high doses of a renin inhibitor.9 RAS blockers, by interfering Hypertension? with the negative feedback loop between Ang II and renin release, normally upregulate renin synthesis. Particularly † † Lodi C.W. Roksnoer,* Ewout J. Hoorn, and after high doses this upregulation may be .100-fold.9 Re- A.H. Jan Danser* nin inhibitors selectively accumulate in renal tissue, and, *Division of Pharmacology and Vascular Medicine and †Division of therefore, after stopping treatment,10 renal RAS suppres- Nephrology and Transplantation, Department of Internal Medicine, sion will continue, so that renin release stays high. At the Erasmus MC, Rotterdam, The Netherlands same time the inhibitor starts to disappear from plasma, J Am Soc Nephrol 25: 2679–2681, 2014. and thus insufficient renin inhibitor is around to block all doi: 10.1681/ASN.2014060549 renin molecules that continue to be released. As a conse- quence, plasma renin activity will increase, and extrarenal Ang II and aldosterone levels may even rise to levels above Angiotensin II (Ang II) production at tissue sites is well baseline.9 established. Interference with such local generation, rather The hypertension occurring in animals during inhibition than with Ang II generation in the circulation, is believed to of nitric oxide synthase (NOS) with L-NG-nitroarginine underlie the beneficial cardiovascular and renal effects of methyl ester (L-NAME) is also believed to involve a discrep- renin-angiotensin system (RAS) blockers. -
Tolerance and Resistance to Organic Nitrates in Human Blood Vessels
\ö-\2- Tolerance and Resistance to Organic Nitrates in Human Blood Vessels Peter Radford Sage MBBS, FRACP Thesis submit.ted for the degree of Doctor of Philosuphy Department of Medicine University of Adelaide and Cardiology Unit The Queen Elizabeth Hospital I Table of Gontents Summary vii Declaration x Acknowledgments xi Abbreviations xil Publications xtil. l.INTRODUCTION l.L Historical Perspective I i.2 Chemical Structure and Available Preparations I 1.3 Cellular/biochemical mechanism of action 2 1.3.1 What is the pharmacologically active moiety? 3 1.3.2 How i.s the active moiety formed? i 4 1.3.3 Which enzyme system(s) is involved in nitrate bioconversi<¡n? 5 1.3.4 What is the role of sulphydryl groups in nitrate action? 9 1.3.5 Cellular mechanism of action after release of the active moiety 11 1.4 Pharmacokinetics t2 1.5 Pharmacological Effects r5 1.5.1 Vascular effects 15 l.5.2Platelet Effects t7 1.5.3 Myocardial effects 18 1.6 Clinical Efhcacy 18 1.6.1 Stable angina pectoris 18 1.6.2 Unstable angina pectoris 2t 1.6.3 Acute myocardial infarction 2l 1.6.4 Congestive Heart Failure 23 ll 1.6.5 Other 24 1.7 Relationship with the endothelium and EDRF 24 1.7.1 EDRF and the endothelium 24 1.7.2 Nitrate-endothelium interactions 2l 1.8 Factors limiting nitrate efficacy' Nitrate tolerance 28 1.8.1 Historical notes 28 1.8.2 Clinical evidence for nitrate tolerance 29 1.8.3 True/cellular nitrate tolerance 31 1.8.3.1 Previous studies 31 | .8.3.2 Postulated mechanisms of true/cellular tolerance JJ 1.8.3.2.1 The "sulphydryl depletion" hypothesis JJ 1.8.3.2.2 Desensitization of guanylate cyclase 35 1 8.i.?..3 Impaired nitrate bioconversion 36 1.8.3.2.4'Ihe "superoxide hypothesis" 38 I.8.3.2.5 Other possible mechanisms 42 1.8.4 Pseudotolerance ; 42 1.8.4. -
(12) United States Patent (10) Patent No.: US 7.427.405 B2 Agrawal Et Al
USOO7427405B2 (12) United States Patent (10) Patent No.: US 7.427.405 B2 Agrawal et al. (45) Date of Patent: Sep. 23, 2008 (54) IMMUNOSTIMULATORY Tokunaga et al., “Antitumor Activity of Deoxyribonucleic Acid Frac OLGONUCLEOTDE MULTIMERS tion from Mycobaterium bovis BCG. I. Isolation. Physicochemical Characterization, and Antitumor Activity”. J. Natl. Cancer Inst. 72: (75) Inventors: Sudhir Agrawal, Shrewsbury, MA (US); 955-962(1984). Pisetsky et al., “Stimulation of in vitro proliferation of murine lym Ekambar Kandimala, Southboro, MA phocytes by synthetic oligodeoxynucleotides'. Molecular Biology (US); Dong Yu, Westboro, MA (US) Reports 18:217-221 (1993). Krieg et al., “CpG motifs in bacterial DNA trigger direct B-cell (73) Assignee: Idera Pharmaceuticals, Inc., activation”, Nature 374: 546-549 (1995). Cambridge, MA (US) Sato et al., “Immunostimulatory DNA Sequence Necessary for Effective Intradermal Gene Immunization', Science 273: 352-354 (*) Notice: Subject to any disclaimer, the term of this (1996). patent is extended or adjusted under 35 Krieg et al., “CpG Motifs in Bacterial DNA and their Immune U.S.C. 154(b) by 209 days. Effects”, Annu. Rev. Immunol. 20: 709-760 (2002). Dalpke et al., “Immunopharmacology of CpG DNA'. Biol. Chem. (21) Appl. No.: 11/174,282 383: 1491-1500 (2002). Kandimala et al., “Towards Optimal Design of Second-Generation (22) Filed: Jul. 1, 2005 Immunomodulatory Oligonucleotides'. Curr. Opin. Mol. Ther. 4(2): 122-129 (2002). (65) Prior Publication Data Kandimala et al., “Immunomers-novel 3'-3'-Linked CpG Oligodeoxyribonucleotides as Potent Immunomodulatory Agents'. US 2006/OO19919 A1 Jan. 26, 2006 Nucleic Acids Res. 30: 4460-4469 (2002). Kandimala et al. -
Effect of Aldosterone Breakthrough on Albuminuria During Treatment with a Direct Renin Inhibitor and Combined Effect with a Mineralocorticoid Receptor Antagonist
Hypertension Research (2013) 36, 879–884 & 2013 The Japanese Society of Hypertension All rights reserved 0916-9636/13 www.nature.com/hr ORIGINAL ARTICLE Effect of aldosterone breakthrough on albuminuria during treatment with a direct renin inhibitor and combined effect with a mineralocorticoid receptor antagonist Atsuhisa Sato and Seiichi Fukuda We have reported observing aldosterone breakthrough in the course of relatively long-term treatment with renin–angiotensin (RA) system inhibitors, where the plasma aldosterone concentration (PAC) increased following an initial decrease. Aldosterone breakthrough has the potential to eliminate the organ-protective effects of RA system inhibitors. We therefore conducted a study in essential hypertensive patients to determine whether aldosterone breakthrough occurred during treatment with the direct renin inhibitor (DRI) aliskiren and to ascertain its clinical significance. The study included 40 essential hypertensive patients (18 men and 22 women) who had been treated for 12 months with aliskiren. Aliskiren significantly decreased blood pressure and plasma renin activity (PRA). The PAC was also decreased significantly at 3 and 6 months; however, the significant difference disappeared after 12 months. Aldosterone breakthrough was observed in 22 of the subjects (55%). Urinary albumin excretion differed depending on whether breakthrough occurred. For the subjects in whom aldosterone breakthrough was observed, eplerenone was added. A significant decrease in urinary albumin excretion was observed after 1 month, independent of changes in blood pressure. In conclusion, this study demonstrated that aldosterone breakthrough occurs in some patients undergoing DRI therapy. Aldosterone breakthrough affects the drug’s ability to improve urinary albumin excretion, and combining a mineralocorticoid receptor antagonist with the DRI may be useful for decreasing urinary albumin excretion. -
Guidance on Format of the RMP in the EU in Integrated Format
Splendris Pharmaceuticals GmbH Benazeprilhydrochloride “Splendris” RMP v. 1.0 02 October 2017 VI.2 Elements for a Public Summary VI.2.1 Overview of disease epidemiology Hypertension, is a long term medical condition in which the blood pressure is persistently elevated. Usually it does not cause symptoms, but it is a major risk factor for coronary artery disease, stroke, heart failure, peripheral vascular disease, vision loss, and chronic kidney disease. It is the most important preventable risk factor for premature death worldwide. Hypertension results from a complex interaction of genes and environmental factors like rising age, high salt intake, lack of exercise, obesity, or depression. As mechanisms the most evident are disturbance in the kidneys’ salt and water handling and/or abnormalities of the sympathic nervous system. Approximately one billion adults worldwide are affected. In Europe hypertension occurs in 30-43% of adult people, 1 to 5% of children and adolescents and 0.2 to 3% of newborns. Treatment options include changes in lifestyle, like dietary changes, physical exercise, weight loss, and medications, like ACE-inhibitors or calcium channel blockers. VI.2.2 Summary of treatment benefits The benazepril formulation described is a generic equivalent to the innovator formulation. Clinical studies have been performed with benazepril in hypertensive patients showing that blood pressure is significantly reduced. When given with other blood lowering agents e.g. betablockers, the antihypertensive effect is greater than for benazepril alone. In different studies, it has been shown that benazepril was similar or superior in lowering blood pressure and reducing proteinuria or myocardial ischaemia when compared with hydrochlorthiazide, metoprolol, captopril, nifedipine or nitrendipine. -
A Textbook of Clinical Pharmacology and Therapeutics This Page Intentionally Left Blank a Textbook of Clinical Pharmacology and Therapeutics
A Textbook of Clinical Pharmacology and Therapeutics This page intentionally left blank A Textbook of Clinical Pharmacology and Therapeutics FIFTH EDITION JAMES M RITTER MA DPHIL FRCP FMedSci FBPHARMACOLS Professor of Clinical Pharmacology at King’s College London School of Medicine, Guy’s, King’s and St Thomas’ Hospitals, London, UK LIONEL D LEWIS MA MB BCH MD FRCP Professor of Medicine, Pharmacology and Toxicology at Dartmouth Medical School and the Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA TIMOTHY GK MANT BSC FFPM FRCP Senior Medical Advisor, Quintiles, Guy's Drug Research Unit, and Visiting Professor at King’s College London School of Medicine, Guy’s, King’s and St Thomas’ Hospitals, London, UK ALBERT FERRO PHD FRCP FBPHARMACOLS Reader in Clinical Pharmacology and Honorary Consultant Physician at King’s College London School of Medicine, Guy’s, King’s and St Thomas’ Hospitals, London, UK PART OF HACHETTE LIVRE UK First published in Great Britain in 1981 Second edition 1986 Third edition 1995 Fourth edition 1999 This fifth edition published in Great Britain in 2008 by Hodder Arnold, an imprint of Hodden Education, part of Hachette Livre UK, 338 Euston Road, London NW1 3BH http://www.hoddereducation.com ©2008 James M Ritter, Lionel D Lewis, Timothy GK Mant and Albert Ferro All rights reserved. Apart from any use permitted under UK copyright law, this publication may only be reproduced, stored or transmitted, in any form, or by any means with prior permission in writing of the publishers or in the case of reprographic production in accordance with the terms of licences issued by the Copyright Licensing Agency. -
Journal of Arthroscopy and Joint Surgery 6 (2019) 98E102
Journal of Arthroscopy and Joint Surgery 6 (2019) 98e102 Contents lists available at ScienceDirect Journal of Arthroscopy and Joint Surgery journal homepage: www.elsevier.com/locate/jajs Comparative evaluation of periarticular infiltration of two cocktail regimens for analgesia in post-operative patients of total knee replacement * V.K. Gautam a, Ajeet Kumar a, Munisha Agarwal b, Bushu Harna a, , Rishabh Saini a, Siddharth Sharma a, Dhananjaya Sabat a a Dept. of Orthopaedics, Maulana Azad Medical College, New Delhi, India b Dept. of Anaesthesia, Maulana Azad Medical College, New Delhi, India article info abstract Article history: Purpose: To compare the efficacy of two periarticular cocktail regimens for analgesia in postoperative Received 30 April 2018 patients of total knee replacement. Received in revised form Method: This is a Randomized Control study done over the duration of 1.5 years. Twenty-five knees of 28 October 2018 either gender were selected with inclusion criteria (All osteoarthritis patients planned for TKA) and Accepted 9 November 2018 exclusion criteria (Inflammatory arthritis, patients allergic to local anaesthetic e.g. Ropivacaine, bupi- Available online 19 November 2018 vacaine, known cardiac disorder patient having AV block, arrhythmia) & divided into 2 groups. Group A was given a cocktail of Ropivacaine, adrenaline, clonidine & cefuroxime. Keywords: & Periarticular Group B was given a cocktail of bupivacaine, fentanyl, methylprednisolone cefuroxime. The preoper- Multimodal approach ative pain of the patient was assessed using VAS score. Combined spinal and epidural anaesthesia was Perioperative analgesia given using 0.5% 2 ml of bupivacaine heavy in all patients. After taking bone cuts & before the placement Corticosteroids of the implant, cocktail of the drug was infiltrated using sterile technique into 9 specific sites. -
Apple Health Preferred Drug List (PDL) Updates
Apple Health Preferred Drug List (PDL) Updates The Health Care Authority (HCA) implemented the Apple Health Preferred Drug List (PDL) on January 1, 2018. All managed care plans and the fee-for-service program serving Apple Health clients use this PDL. The PDL now includes over-the-counter medications, vitamins, and many other outpatient drugs. There are now 441 therapeutic drug classes included in the PDL. Updates are ongoing. See which drugs are preferred and whether they require a PA: https://www.hca.wa.gov/billers-providers-partners/programs-and-services/apple-health-preferred- drug-list-pdl. HCA has created policies that document the coverage criteria for drug classes or individual drugs. To view the policies visit: https://www.hca.wa.gov/billers-providers-partners/programs-and- services/apple-health-medicaid-drug-coverage-criteria The drugs within a chosen therapeutic class are evaluated by the HCA Pharmacy and Therapeutic (P&T) Committee/Drug Utilization Review (DUR) Board. The HCA P&T Committee / DUR Board meet at least quarterly. All meetings are open to the public. You can read more about the meetings here: https://www.hca.wa.gov/about-hca/prescription-drug-program/meetings-and-materials Upcoming meeting dates are below: April 21, 2021 June 16, 2021 August 18, 2021 October 20, 2021 December 15, 2021 Current drug classes are listed below: ADHD / ANTI-NARCOLEPSY : DOPAMINE AND NOREPINEPHRINE REUPTAKE INHIBITORS (DNRIS) ADHD / ANTI-NARCOLEPSY : HISTAMINE H3-RECEPTOR ANTAGONIST / INVERSE AGONIST ADHD / ANTI-NARCOLEPSY : NON-STIMULANTS -
Aliskiren: a Novel, Orally Active Renin Inhibitor
Review Article Aliskiren: A Novel, Orally Active Renin Inhibitor Mohamed Saleem TS, Jain A1, Tarani P1, Ravi V1, Gauthaman K1 Department of Pharmacology, Annamacharya College of Pharmacy, Rajampet, AP, 1Himalayan Pharmacy Institute, Majhitar, East Sikkim - 737 136, India ARTICLE INFO ABSTRACT Article history: Renin-angiotensin-aldosterone systems play a major role in the regulation of human homeostasis Received 01 July 2009 mechanism, which are also involved in the development of hypertension and end-organ damage Accepted 07 July 2009 through activation of angiotensin II. Inhibitors of the renin-angiotensin-aldosterone system may Available online 04 February 2010 reduce the development of end-organ damage to a greater extent than other antihypertensive Keywords: agents. Aliskiren is the first member of the new class of orally active direct renin inhibitors Aliskiren recently approved by the US Food and Drug Administration for the treatment of hypertension. Hypertension Aliskiren directly inhibiting the renin and reducing the formation of angiotensin II, which is the Renin-angiotensin-aldosterone system most effective mediator involved in the pathogenesis of cardiovascular diseases. The present Renin inhibitors review mainly focuses on the pharmacodynamics and pharmacokinetics and clinical aspects of aliskiren. In this respect, the review will improve the basic idea to understand the pharmacology of aliskiren, which is useful for the further research in cardiovascular disease. DOI: 10.4103/0975-8453.59518 Introduction inhibit renin have been available for many years but have been limited by low potency, bioavailability and duration of action. Activation of the renin-angiotensin (Ang)-aldosterone system However, a new class of nonpeptide, low molecular weight, orally [5] (RAAS) plays an important role in the development of hypertension active inhibitors has recently been developed. -
Adverse Effects of Xenogenic Scaffolding in the Context of A
Lamas et al. Trials (2019) 20:387 https://doi.org/10.1186/s13063-019-3504-3 RESEARCH Open Access Adverse effects of xenogenic scaffolding in the context of a randomized double-blind placebo-controlled study for repairing full- thickness rotator cuff tears José Ramón Lamas1†, Carlos García-Fernández2, Pilar Tornero-Esteban1, Yaiza Lópiz2, Luis Rodriguez-Rodriguez1, Luis Ortega3, Benjamín Fernández-Gutiérrez1*† and Fernando Marco2† Abstract Purpose: The purpose of the study was to compare the safety and efficacy of autologous mesenchymal stem cells (MSCs) embedded in a xenogenic scaffold for repairing the supraspinatus tendon. Methods: This was a randomized, double-blind and placebo-controlled trial evaluating patients with full-thickness rotator cuff tears (Eudra-CT, 2007–007630-19). Effectiveness was evaluated using the Constant score and a visual analogue pain scale (VAS). Constant score has four domains including pain (15 possible points), activities of daily living (20 possible points), mobility (40 possible points), and strength (25 possible points). Scores range from 0 points (most disability) to 100 points (least disability). The structural integrity of the repaired tendon was assessed by magnetic resonance imaging (MRI) according to Patte and Thomazeau classification criteria. The primary study end point was an improvement in the Constant score by 20 points at one year compared to initial assessment. Results: The trial was stopped due to adverse effects observed in both groups. Only thirteen patients were included and analyzed. The Constant questionnaire showed a significant improvement in the MSC treatment group compared with the preoperative data (p = 0.0073). Secondary outcome measures were similar in both groups. -
New Zealand Regulatory Guidelines for Medicines
New Zealand Regulatory Guidelines for Medicines Part G: Resources Edition 6.13 March 2011 (consolidation of fifth edition and subsequent updates) Table of Contents PART G: RESOURCES Section 1: Description of Dosage Form...............................................................................2 Section 2: Routes of Administration....................................................................................4 Section 3: Shelf Life and Storage Conditions .....................................................................5 Section 4: Abbreviations.......................................................................................................6 Description of Dosage Form The dosage form description for a product should be selected from the following list: Block Granules, oral Capsule Implant, subcutaneous Capsule, combination Implant, intracranial Capsule, liquid filled Implant, intraocular Capsule, modified release Infusion, concentrate Capsule, powder filled Infusion, emulsion Capsule, powder filled, nasal inhalation Infusion, powder for Capsule, soft gelatin Infusion, powder for concentrate Cement, bone, liquid component Infusion, solution Cement, bone, powder component Inhalation, capsule, liquid filled Cement, dental Inhalation, capsule, powder filled Chewing gum Inhalation, powder Chocolate, medicated Inhalation, solution Combination Inhalation, solution, powder for Condom, medicated Inhalation, suspension Condom with spermicide Inhalation, volatile liquid Cream, rectal Inhaler, aerosol, metered Cream, topical Injection -
JMSCR Vol||05||Issue||01||Page 15625-15629||January 2017
JMSCR Vol||05||Issue||01||Page 15625-15629||January 2017 www.jmscr.igmpublication.org Impact Factor 5.84 Index Copernicus Value: 83.27 ISSN (e)-2347-176x ISSN (p) 2455-0450 DOI: https://dx.doi.org/10.18535/jmscr/v5i1.71 Transdermal Patch: A Comprehensive Overview of Newer Drug Delivery System in Modern Medical Science Authors Dr Neelkanth Kote1, Dr. Poornima B2 Department of Physiology and Department of Pharmacology Raja Rajeswari Medical Collegeand Hospital Bangalore, Karnataka– 560074 Corresponding Author Dr Neelkanth Kote Department of Physiology, RRMC Bangalore, Karnataka -560074 Email: [email protected] Abstract Background: Oral route of drug administration has been the most common route of drug administration since the beginning of the therapeuticarea in medical science. However this route of drug administration fails at bypassing the first pass metabolism of the drug in liver with poor bio availability. Oral route of drug administration also fails in uncooperative /unconscious semiconscious / pediatric subjects. Transdermal patch, a new drug delivery system through skin to the parenteral circulation has been the most recently discussed topic in pharmacology and medicine as it is a noninvasive route of drug administration, delivered in a sustained / pre fixed dosage with no / extremely less first pass metabolism and better bio availability. Most importantly it can be used in semiconscious / unconscious & pediatric subjects without affecting their hemodynamics. The transdermal patches have many beneficial factors however they also come with some major drawbacks like varieties of formulation, design and quality of adhesiveness. This articles provides an insight of transdermal patch in terms of its mechanism of action, advantages, disadvantages and future scope of it in the medical science.