Pharmacologic Interven"On in Hypertension: 2015

Total Page:16

File Type:pdf, Size:1020Kb

Pharmacologic Interven 4/25/15 Pharmacologic Interven1on in Hypertension: 2015 Larry Warmoth, M.D. Nephrologist Chief of Staff, Covenant Medical Center Associate Professor of Nephrology, Texas Tech School of Medicine Life1me Risk of Developing Hypertension Beginning at Age 65 100 Men Women 80 60 40 20 0 Risk of hypertension (%) 0 2 4 6 8 10 12 14 16 18 20 Years Residual lifetime risk of developing hypertension among people with blood pressure <140/90 mmHg Vasan RS, et al. JAMA. 2002; 287:1003-1010. www.hypertensiononline.or Copyright 2002, American Medical g Association. 1 4/25/15 Frequency Distribu1on of Untreated HTN by Age Hypertension – Why a Nephrologist???? Isolated Systolic HTN Systolic Diastolic HTN Isolated Diastolic HTN Accurate BP measurement History • Who checks your paents BP? • Angina/MI Stroke: Complicaons of HTN, Angina may improve with • You or Staff b-blockers • IF Staff – Do they know what to listen for or do they use automated eQuipment • Seated properly and Quietly for 5 minutes • Asthma, COPD: Preclude the use of b-blockers • Appropriate size cuff • Inflate 20-30 mmHg above loss of radial pulse • Heart failure: ACE inhibitors indicaon • Deflate at 2mmHg per second • DM: ACE preferred • 1st sound SBP ; Disappearance of Korotkoff sound (phase 5) is DBP • Confirm Elevated blood pressure within 2 weeks • Polyuria and nocturia: Suggest renal impairment • Caffeine, exercise, and smoking should be avoided for at least 30 minutes before BP measurement. • The auscultatory method should be used. • 24 hour ambulatory BP monitoring History-contd. Iden1fiable Causes of HTN • Claudicaon: May be aggravated by b-blockers, atheromatous RAS • Sleep apnea may be present • Drug-induced or related causes • Gout: May be aggravated by diureIcs • Chronic kidney disease • Use of NSAIDs: May cause or aggravate HTN • Primary aldosteronism • Family history of HTN: Important risk factor • Renovascular disease • Family history of premature death: May have been due to HTN • Chronic steroid therapy and Cushing’s syndrome • Pheochromocytoma • Coarctaon of the aorta • Thyroid or parathyroid disease 2 4/25/15 Cardiovascular Risk factors History-contd. • Hypertension • Family history of DM : Paent may also be DiabeIc • Cigarece smoking • CigareLe smoker: Aggravate HTN, independently a risk factor for CAD • Obesity (body mass index ≥30 kg/m2) and stroke • Physical inacIvity • High alcohol: A cause of HTN • Dyslipidemia • High salt intake: Advice low salt intake • Diabetes mellitus • Albuminuria or esImated GFR <60 mL/min • Age (older than 55 for men, 65 for women) • Family history of premature cardiovascular disease (men under age 55 or women under age 65) Examina1on Examina1on-contd. • Appropriate measurement of BP in both arms • Thorough examinaon of the heart and lungs • Opc fundi • Abdomen for enlarged kidneys, masses, and abnormal aorIc • Calculaon of BMI ( waist circumference also may be useful) pulsaon • Auscultaon for caroId, abdominal, and femoral bruits • Lower extremiIes for edema and pulses • Palpaon of the thyroid gland. • Neurological assessment Development of JNC-8 Rou1ne Labs • Commissioned by the NHLBI in 2008 • Panel members appointed • EKG. • Developed focused critical questions relevant to practice • Urinalysis W/ albumin/creanine and protein/creanine raos. • Conducted a systematic search of pertinent literature • Limited to randomized controlled trials (RCTs) published between • Blood glucose and hematocrit; serum potassium, BUN, creanine 1966 and 2009 (eGFR), and calcium. • Included patients age 18 or older with hypertension • HDL cholesterol, LDL cholesterol, and triglycerides. • Sample size of 100 patients or more • Results must have included “hard” outcomes • Subsequent search of studies from 2009 to 2013 required samples of 2000 or more patients James PA et al. JAMA 2014;311:507-20. 3 4/25/15 Development of JNC-8 Development of JNC-8 • 3 critical questions for adults with hypertension • Does initiating antihypertensive pharmacologic therapy at • In 2013, the NHLBI decides that it will no specific blood pressure thresholds improve health outcomes? longer publish clinical guidelines [When to start therapy?] • Proposes to work collaboratively with other organizations • Does treatment with antihypertensive pharmacologic therapy to a specified blood pressure goal lead to improvements in • The appointed panel members for JNC-8 decided to health outcomes? [How low should I go?] publish their findings independently • Do various antihypertensive drugs or drug classes differ in • Published online in JAMA in December 2013 comparative benefits and harms on specific health outcomes? • Received no endorsements from other organizations [What drug do I use?] James PA et al. JAMA 2014;311:507-20. James PA et al. JAMA 2014;311:507-20. But Wait…There’s More JNC-8 Recommendations • A multitude of other hypertension guidelines were also • In patients >60 years of age, start medications at blood published in 2013: pressure of >150/90mm Hg and treat to goal of • AHA/ACC/CDC advisory algorithm <150/90mm Hg • American Society of Hypertension/International Society of Hypertension (ASH/ISH) • European Society of Hypertension and European Society of • In patients >60 years of age, treatment does not need to Cardiology (ESH/ESC) be adjusted if achieved blood pressure is lower than • Canadian Hypertension Education Program (CHEP) goal and well-tolerated James PA et al. JAMA 2014;311:507-20. JNC-8 Recommendations JNC-8 Recommendations • In patients <60 years of age, start medications at blood • For the non-black population (including diabetes), pressure of >140/90mm Hg and treat to goal of initial antihypertensive treatment may include a <140/90mm Hg thiazide, ACEI, ARB, or CCB • For the black population (including diabetes), initial • In all adult patients with diabetes or chronic kidney antihypertensive treatment should include a thiazide or disease, start medications at blood pressure of CCB >140/90mm Hg and treat to goal of <140/90mm Hg • For all patients with CKD, initial (or add-on) therapy for hypertension should include an ACEI or ARB James PA et al. JAMA 2014;311:507-20. James PA et al. JAMA 2014;311:507-20. 4 4/25/15 Initial Drug Selection for HTN JNC-8 Recommendations • What happened to the beta-blockers (BB)? • Initiate therapy according to recommendations • Most evidence for BB is from atenolol • If BP is not at goal in one month, increase dose or add a • Does not meet current FDA criteria for a once-daily drug • Losartan Intervention for Endpoint reduction (LIFE) study second agent from recommended classes • Compared losartan vs. atenolol in pts. with HTN & LVH • If patient is still not at goal, add a third drug from • Primary outcome of CV death, MI, or stroke recommended classes • Overall 13% RRR with losartan vs. atenolol (p=0.021) • Do not use an ACEI and ARB together • Driven mainly by 25% reduction in risk of stroke (p=0.001) • Drugs from other classes may be used if additional BP • BB still recommended for many patients with comorbid lowering is needed or if contraindications exist conditions (CHF, CAD, etc.) • Refer to HTN specialist whenever necessary James PA et al. JAMA 2014;311:507-20. Dahloff B et al. Lancet 2002;359:995-1003. Comparisons to Other Guidelines BP Goal JNC-7 JNC-8 ASH/ISH ESC/ESH CHEP Age < 60 <140/90 <140/90 <140/90 <140/90 <140/90 Age 60-79 <140/90 <150/90 <140/90 <140/90 <140/90 Age 80+ <140/90 <150/90 <150/90 <150/90 <150/90 Diabetes <130/80 <140/90 <140/90 <140/85 <130/80 CKD <130/80 <140/90 <140/90 <130/90 <140/90 Adapted from Salvo M et al. Ann Pharmacother 2014;48:1242-8. Comparisons to Other Guidelines JNC-7 JNC-8 ASH/ISH ESC/ESH CHEP Non-black Thiazide Thiazide, <60:ACEI, Thiazide, Thiazide, (no DM or ACEI, ARB, ARB ACEI, ARB, ACEI, ARB CKD) CCB >60:CCB, CCB, BB (BB if <60) thiazide Black (no Thiazide Thiazide, Thiazide, Thiazide, Thiazide, DM or CCB CCB ACEI, ARB, ARB (BB if CKD) CCB, BB <60) Diabetes ACEI, ARB, CCB, ACEI, ARB, ACEI, ARB ACEI, ARB, CCB, BB, thiazide CCB, CCB, thiazide thiazide thiazide CKD ACEI, ARB ACEI, ARB ACEI, ARB ACEI, ARB ACEI, ARB Adapted from Salvo M et al. Ann Pharmacother 2014;48:1242-8. 5 4/25/15 Hypertension: Pharmacologic Treatment Pharmacologic Treatment of Hypertension • SelecIon of IniIal Therapy Treatment OpIons • Demographics • Diure&cs • Concomitant Diseases and Therapies • ACE inhibitors • Quality of Life • Angiotensin II receptor blockers • Cost • Calcium channel blockers • Drug InteracIons • Beta blockers • Alpha blockers • Centrally acIng alpha agonists • Direct vasodilators • Peripheral adrenergic blockers Arch Inter Med 1997 Hypertension Hypertension Carbonic anhydrase inhibitors • TherapeuIc OpIons: DiureIcs • Promote sodium and water excreIon at various sites of the nephron • Loop diurecs Thiazide diuretics • Thiazide/Thiazide-like diureIcs diureIcs • Potassium-sparing diureIcs • Carbonic Anhydrase Inhibitors Potassium-sparing diuretics Loop diuretics 6 4/25/15 Hypertension Hypertension • DiureIcs: Pharmacodynamics • DiureIcs: Compelling Indicaons* • Decreased intravascular (blood) fluid volume • Isolated Systolic Hypertension • Decreased extravascular (edema) fluid volume • CongesIve Heart Failure • Decreased blood pressure • DiureIcs: Possible Favorable Effects • Osteoporosis (thiazides) • DiureIcs: Possible Unfavorable Effects • Diabetes • Gout • Renal Insufficiency Hypertension Hypertension • DiureIcs: PotenIal Adverse Effects • DiureIcs: Consideraons • Electrolyte disturbances • Useful for paents with ISH, African Americans, CHF • potassium, magnesium, sodium, calcium • Different
Recommended publications
  • Acrolein As a Novel Therapeutic Target for Motor and Sensory Deficits in Spinal Cord Injury
    [Downloaded free from http://www.nrronline.org on Wednesday, September 11, 2019, IP: 128.210.106.129] NEURAL REGENERATION RESEARCH April 2014,Volume 9,Issue 7 www.nrronline.org SPECIAL ISSUE Acrolein as a novel therapeutic target for motor and sensory deficits in spinal cord injury Jonghyuck Park1, 2, Breanne Muratori2, Riyi Shi1, 2 1 Department of Basic Medical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN, USA 2 Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, USA Abstract Corresponding author: In the hours to weeks following traumatic spinal cord injuries (SCI), biochemical processes are Riyi Shi, M.D., Ph.D., initiated that further damage the tissue within and surrounding the initial injury site: a process Department of Basic Medical Sciences, termed secondary injury. Acrolein, a highly reactive unsaturated aldehyde, has been shown to play College of Veterinary Medicine, Purdue a major role in the secondary injury by contributing significantly to both motor and sensory defi- University, West Lafayette, IN 47907, cits. In particular, efforts have been made to elucidate the mechanisms of acrolein-mediated dam- USA, [email protected]. age at the cellular level and the resulting paralysis and neuropathic pain. In this review, we will highlight the recent developments in the understanding of the mechanisms of acrolein in motor doi:10.4103/1673-5374.131564 and sensory dysfunction in animal models of SCI. We will also discuss the therapeutic benefits of http://www.nrronline.org/ using acrolein scavengers to attenuate acrolein-mediated neuronal damage following SCI. Accepted: 2014-04-08 Key Words: oxidative stress; spinal cord injury; 3-hydrxypropyl mercapturic acid; acrolein-lysine ad- duct; hydralazine Park J, Muratori B, Shi RY.
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 6,784,177 B2 Cohn Et Al
    USOO6784177B2 (12) United States Patent (10) Patent No.: US 6,784,177 B2 Cohn et al. (45) Date of Patent: Aug. 31, 2004 (54) METHODS USING HYDRALAZINE Massie et al., The American Journal of Cardiology, COMPOUNDS AND SOSORBIDE 40:794-801 (1977). DINTRATE OR ISOSORBIDE Kaplan et al., Annals of Internal Medicine, 84:639-645 MONONTRATE (1976). Bauer et al., Circulation, 84(1):35-39 (1991). (75) Inventors: Jay N. Cohn, Minneapolis, MN (US); The SOLVD Investigators, The New England Journal of Medicine, 327(10):685–691 (1992). Peter Carson, Chevy Chase, MD (US) Ziesche et al., Circulation, 87(6):VI56-VI64 (1993). Rector et al., Circulation, 87(6):VI71-VI77 (1993). (73) Assignee: Nitro Med, Inc., Bedford, MA (US) Carson et al., Journal of Cardiac Failure, 5(3):178-187 (Sep. 10, 1999). (*) Notice: Subject to any disclaimer, the term of this Dries et al, The New England Journal of Medicine, patent is extended or adjusted under 35 340(8):609-616 (Feb. 25, 1999). U.S.C. 154(b) by 18 days. Freedman et al, Drugs, 54 (Supplement 3):41-50 (1997). Sherman et al., Cardiologia, 42(2):177-187 (1997). (21) Appl. No.: 10/210,113 Biegelson et al., Coronary Artery Disease, 10:241-256 (1999). (22) Filed: Aug. 2, 2002 Rudd et al, Am. J. Physiol., 277(46):H732–H739 (1999). (65) Prior Publication Data Hammerman et al, Am. J. Physiol., 277(46):H1579–1592 (1999). US 2004/0023967 A1 Feb. 5, 2004 LoScalzo et al., Transactions of the American and Climato logical ASS., 111:158-163 (2000).
    [Show full text]
  • Pharmaceutical Appendix to the Tariff Schedule 2
    Harmonized Tariff Schedule of the United States (2007) (Rev. 2) Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE Harmonized Tariff Schedule of the United States (2007) (Rev. 2) 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. ABACAVIR 136470-78-5 ACIDUM LIDADRONICUM 63132-38-7 ABAFUNGIN 129639-79-8 ACIDUM SALCAPROZICUM 183990-46-7 ABAMECTIN 65195-55-3 ACIDUM SALCLOBUZICUM 387825-03-8 ABANOQUIL 90402-40-7 ACIFRAN 72420-38-3 ABAPERIDONUM 183849-43-6 ACIPIMOX 51037-30-0 ABARELIX 183552-38-7 ACITAZANOLAST 114607-46-4 ABATACEPTUM 332348-12-6 ACITEMATE 101197-99-3 ABCIXIMAB 143653-53-6 ACITRETIN 55079-83-9 ABECARNIL 111841-85-1 ACIVICIN 42228-92-2 ABETIMUSUM 167362-48-3 ACLANTATE 39633-62-0 ABIRATERONE 154229-19-3 ACLARUBICIN 57576-44-0 ABITESARTAN 137882-98-5 ACLATONIUM NAPADISILATE 55077-30-0 ABLUKAST 96566-25-5 ACODAZOLE 79152-85-5 ABRINEURINUM 178535-93-8 ACOLBIFENUM 182167-02-8 ABUNIDAZOLE 91017-58-2 ACONIAZIDE 13410-86-1 ACADESINE 2627-69-2 ACOTIAMIDUM 185106-16-5 ACAMPROSATE 77337-76-9
    [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]
  • Hydralazine 25Mg and 50Mg Tablets
    Package leaflet: Information for the patient Hydralazine 25mg and 50mg tablets Read all of this leaflet carefully • have angina pectoris, which causes pain in the chest before you start taking this with exercise medicine because it contains • have cerebrovascular disease (narrowing of the blood vessels in the brain) important information for you. • have been told you are a slow acetylator (this means • Keep this leaflet. You may need to that your body handles some medicines more slowly read it again. than other people) • If you have any further questions, • suffer from any serious liver or kidney problems. ask your doctor or pharmacist. Tests • This medicine has been prescribed If you are taking long-term Hydralazine treatment, for you only. Do not pass it on to your doctor may want to carry out blood and urine others. It may harm them, even if tests every 6 months. their signs of illness are the same as yours. Other medicines and Hydralazine tablets • If you get any side effects, talk to Tell your doctor or pharmacist if you are taking, have your doctor or pharmacist. This recently taken or might take any other medicines. includes any possible side effects It is especially important to tell your doctor if you are not listed in this leaflet. See section taking: 4. • medicines for high blood pressure, such as vasodilators (e.g. minoxidil diazoxide) What is in this leaflet • ACE inhibitors (e.g. enalapril, lisinopril, captopril) • Beta-blockers (e.g. propranolol) 1 What Hydralazine tablets are • calcium antagonists (e.g. nifedipine or diltiazem) and what they are used for • medicines for water retention (e.g.
    [Show full text]
  • Estonian Statistics on Medicines 2013 1/44
    Estonian Statistics on Medicines 2013 DDD/1000/ ATC code ATC group / INN (rout of admin.) Quantity sold Unit DDD Unit day A ALIMENTARY TRACT AND METABOLISM 146,8152 A01 STOMATOLOGICAL PREPARATIONS 0,0760 A01A STOMATOLOGICAL PREPARATIONS 0,0760 A01AB Antiinfectives and antiseptics for local oral treatment 0,0760 A01AB09 Miconazole(O) 7139,2 g 0,2 g 0,0760 A01AB12 Hexetidine(O) 1541120 ml A01AB81 Neomycin+Benzocaine(C) 23900 pieces A01AC Corticosteroids for local oral treatment A01AC81 Dexamethasone+Thymol(dental) 2639 ml A01AD Other agents for local oral treatment A01AD80 Lidocaine+Cetylpyridinium chloride(gingival) 179340 g A01AD81 Lidocaine+Cetrimide(O) 23565 g A01AD82 Choline salicylate(O) 824240 pieces A01AD83 Lidocaine+Chamomille extract(O) 317140 g A01AD86 Lidocaine+Eugenol(gingival) 1128 g A02 DRUGS FOR ACID RELATED DISORDERS 35,6598 A02A ANTACIDS 0,9596 Combinations and complexes of aluminium, calcium and A02AD 0,9596 magnesium compounds A02AD81 Aluminium hydroxide+Magnesium hydroxide(O) 591680 pieces 10 pieces 0,1261 A02AD81 Aluminium hydroxide+Magnesium hydroxide(O) 1998558 ml 50 ml 0,0852 A02AD82 Aluminium aminoacetate+Magnesium oxide(O) 463540 pieces 10 pieces 0,0988 A02AD83 Calcium carbonate+Magnesium carbonate(O) 3049560 pieces 10 pieces 0,6497 A02AF Antacids with antiflatulents Aluminium hydroxide+Magnesium A02AF80 1000790 ml hydroxide+Simeticone(O) DRUGS FOR PEPTIC ULCER AND GASTRO- A02B 34,7001 OESOPHAGEAL REFLUX DISEASE (GORD) A02BA H2-receptor antagonists 3,5364 A02BA02 Ranitidine(O) 494352,3 g 0,3 g 3,5106 A02BA02 Ranitidine(P)
    [Show full text]
  • Stembook 2018.Pdf
    The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances FORMER DOCUMENT NUMBER: WHO/PHARM S/NOM 15 WHO/EMP/RHT/TSN/2018.1 © World Health Organization 2018 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances. Geneva: World Health Organization; 2018 (WHO/EMP/RHT/TSN/2018.1). Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data.
    [Show full text]
  • Essential Hypertension J.J.M.L
    Br. J. clin. Pharmac. (1983), 16, 39-44 EFFECTS OF INTRAVENOUS ENDRALAZINE IN ESSENTIAL HYPERTENSION J.J.M.L. HOFFMANNI"*, TH. THIEN2 & A. VAN 'T LAAR2 'Department of Experimental and Chemical Endocrinology and 2Division of General Internal Medicine, Department of Medicine, St Radboud Hospital, Nijmegen, The Netherlands 1 The effects of endralazine, administered intravenously, on blood pressure, heart rate, forearm blood flow, plasma renin activity, aldosterone, adrenaline and noradrenaline were studied in five patients with essential hypertension. 2 Endralazine reduced peripheral vascular resistance, resulting in decrease in mean arterial pressure from 141 to 116 mm Hg and increase in heart rate from 67 to 92 beats/min. 3 Plasma renin activity, adrenaline and noradrenaline increased significantly after endralazine infusion. 4 All effects observed are consistent with endralazine acting as a peripheral vasodilating drug. Introduction Endralazine (BQ 22-708) is a new antilhypertensive Another important difference between both drugs drug, which chemically and pharrniacologically is their major route of metabolism. After oral resembles hydralazine; endralazine is a substituted administration to fast acetylators, hydralazine is hydrazinopyridazine and hydralazine is;a hydrazino- mainly converted by acetylation of its hydrazino- derivative of phtalazine (Figure 1). Both drugs act as moiety, while in slow acetylators hydralazine-pyruvic peripheral vasodilators by direct relaxatioIn of vascular acid hydrazone is the major metabolite (Reece et al., smooth muscle, especially of the resistaince vessels. 1980). So, the patient's acetylator phenotype causes Besides the close relationship, the drugs (display some appreciable inter-individual variation in metabolic differences. On equal weight-basis enidralazine is half-life. Since the major pathway of endralazine about five times more potent than hydrzalazine, thus metabolism is accounted for by hydrazone formation allowing lower dosages.
    [Show full text]
  • Sum 164 New Template WEB Ready
    Recommendation from the Scientific Committee on Occupational Exposure Limits for hydrazine SCOEL/SUM/164 August 2010 European Commission Employment, Social Affairs and Inclusion Recommendation from the Scientific Committee on Occupational Exposure Limits for hydrazine Table of Contents 1. Occurrence/use and occupational exposure .......................................................................... 4 2. Health significance......................................................................................................................... 4 2.1 Toxicokinetics............................................................................................................................. 4 2.1.1 Human data ....................................................................................................................... 4 2.1.2 Animal data ........................................................................................................................ 4 2.1.3 Biological monitoring......................................................................................................... 5 2.2 Acute toxicity ............................................................................................................................ 5 2.2.1 Human data ....................................................................................................................... 5 2.2.2 Animal data ........................................................................................................................ 6 2.3 Irritation and
    [Show full text]
  • Towards Predicting Drug-Induced Liver Injury (DILI): Parallel
    DMD Fast Forward. Published on March 3, 2015 as DOI: 10.1124/dmd.114.062539 This article has not been copyedited and formatted. The final version may differ from this version. DMD # 62539 Towards Predicting Drug-Induced Liver Injury (DILI): Parallel Computational Approaches to Identify MRP4 and BSEP Inhibitors Matthew A. Welch, Kathleen Köck, Thomas J. Urban, Kim L. R. Brouwer, and Peter W. Swaan Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland (M.A.W., Downloaded from P.W.S.); Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (K.K., T.J.U., K.L.R.B.); Center for Human Genome Variation, Duke University Medical Center, Durham, North dmd.aspetjournals.org Carolina (T.J.U.) at ASPET Journals on October 1, 2021 1 DMD Fast Forward. Published on March 3, 2015 as DOI: 10.1124/dmd.114.062539 This article has not been copyedited and formatted. The final version may differ from this version. DMD # 62539 Running Title: Computational Modeling of MRP4 and BSEP to Predict DILI Corresponding author: Peter W. Swaan, Ph.D., Department of Pharmaceutical Sciences, University of Maryland, Baltimore MD 21201. Tel. 410-706-0103. Email [email protected] Number of text pages: 34 Downloaded from Figures: 9 Tables: 2 dmd.aspetjournals.org Number of References: 26 Number of Words in at ASPET Journals on October 1, 2021 Abstract: 249 Introduction: 693 Discussion: 1,356 Abbreviations: BSEP, bile salt export pump; DILI, drug-induced liver injury; PFIC, progressive familial intrahepatic cholestasis; MRP, multidrug resistance protein 2 DMD Fast Forward.
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 9,682,043 B2 Goldman (45) Date of Patent: Jun
    USOO9682043B2 (12) United States Patent (10) Patent No.: US 9,682,043 B2 Goldman (45) Date of Patent: Jun. 20, 2017 (54) METHOD OF PREPARATION OF MIXED FOREIGN PATENT DOCUMENTS PHASE CO-CRYSTALS WITH ACTIVE AGENTS JP 63-240936 A 10, 1988 JP 2003-522097 A 8, 1999 JP 20O2506876 A 3, 2002 (75) Inventor: David Goldman, Portland, CT (US) JP 2002356419 A 12/2002 WO WO99/47543 A2 9, 1999 (73) Assignee: MedCrystallForms, LLC, Hunt Valley, WO WO O2/O55,059 A2 T 2002 MD (US) WO WO O3/101392 A2 12/2003 WO WO 2004/043358 5, 2004 (*) Notice: Subject to any disclaimer, the term of this WO WO 2004/078161 A1 9, 2004 patent is extended or adjusted under 35 WO WO 2004/082666 9, 2004 U.S.C. 154(b) by 537 days. OTHER PUBLICATIONS (21) Appl. No.: 11/008,034 Lide CRC Handbook of Chemistry and Physics 2003 p. 3-246 and 3-480. (22) Filed: Dec. 9, 2004 Meyerson et al. “Crystals, Crystal Growth, and Nucleation' Hand book of Industrial Crystallization Ed. Meyerson. Woburn: But (65) Prior Publication Data terworth-Heinemann 2002 p. 33, and 38-39.* US 2005/0181041 A1 Aug. 18, 2005 Payne et al. International Journal of Pharmaceutics 1999 177:231 245-k Zhang et al. Journal of Pharmaceutical Sciences 2007 96(5):990 Related U.S. Application Data 995.* (60) Provisional application No. 60/528.232, filed on Dec. Reutzel-Edens et al. Solid-state pharmaceutical development: 9, 2003, provisional application No. 60/559,862, filed Ensuring stability through salt and polymorph screening.
    [Show full text]
  • Supplementary File
    Supplementary File Study design In order to illustrate the case period (the 16 time states in relation to unemployment around the time of drug purchase) and the three control periods, we made a figure illustrating a case (S‐Figure 1). We estimated the risk (odds ratio) of being exposed to unemployment around the date of having a first purchase of a psychotropic drug (here: antidepressant). Dichotomous variables indicating each person’s time‐state according to unemployment and psychotropic drug purchase were generated, making it possible to analyse the data with a conditional logistic fixed‐effects estimator (within person), eliminating time‐invariant confounding. In the analyses we compared the odds of exposure of unemployment within each individual’s case and control periods. S‐Figure 1 Case‐crossover study design indicating the time of the event (drug purchase) and the exposure states of unemployment 1‐6 months before the date of unemployment, the 1,2,3, 4 or more months during unemployment and 1‐6 months after end of unemployment. 1 Medication list S‐Table 1 Medications included in each outcome‐group; N05A Antipsychotics, N05B Anxiolytics, N05C Hypnotics and sedatives, N06A Antidepressants. Daily defined doses (DDD) per 1000 inhabitants per day in the Norwegian population 2006‐2010. See the report “Drug consumption in Norway 2006‐2010” published by the Norwegian Institute of Public Health (2011:1) for details of consumption on each specific drug. ATC ATC level name DDDs/1000 inhabitants/day 2005 2006 2007 2008 2009 2010 N05A Antipsychotics 8.4 8.7 8.9 8.9 9.0 9.1 N05B Anxiolytics 19.6 19.2 19.1 19.3 18.9 18.0 N05C Hypnotics and sedatives 39.5 41.2 43.1 44.2 44.6 44.3 N06A Antidepressants 48.4 49.0 51.0 51.7 51.6 52.8 A08A Anti‐obesity preparations, excl.
    [Show full text]