Introduction Methods Results Conclusions

Total Page:16

File Type:pdf, Size:1020Kb

Introduction Methods Results Conclusions 133 Sebelipase Alfa Improves Atherogenic Biomarkers in Adults and Children With Lysosomal Acid Lipase Deficiency Don P Wilson,1 Sachin Marulkar,2 Radhika Tripuraneni,2 and Barbara K Burton3 1Cook Children’s Medical Center, Fort Worth, TX; 2Alexion Pharmaceuticals, Inc, New Haven, CT; 3Northwestern University Feinberg School of Medicine, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL • Management with lipid-lowering medications10: INTRODUCTION RESULTS Table 4. Effect of Sebelipase Alfa on Atherogenic Biomarkers in LAL-D Subjects – HMG CoA reductase inhibitors disrupt synthesis of FC, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors Stratified by Use of Lipid-Lowering Medication (LLM) at 20 Weeks of Treatment • Lysosomal acid lipase deficiency (LAL-D) is a rare, autosomal recessive lysosomal storage disorder (Online Mendelian prevent degradation of LDL receptors, and both types of lipid-lowering medications can markedly increase LDL uptake and increase lysosomal accumulation of LDL (Figure 2)2,10 Subject Characteristics Subjects Using LLM Subjects Not Using LLM Inheritance in Man [OMIM] #278000), historically called Wolman disease in infants and cholesteryl ester storage disease (n=24) (n=37) in older children and adults, that is associated with accumulation of cholesteryl esters and triglycerides in the liver and – Although statin therapy may improve lipid parameters, clinical reports have noted progression of liver disease in • Complete data on atherogenic biomarkers were available from 61 of 66 subjects (N=33 for sebelipase alfa and N=28 for 1 other organs1-3 patients with LAL-D despite long-term treatment with HMG-CoA reductase inhibitors placebo) Mean (SD) Percentage Mean (SD) Percentage Change From Baseline Change From Baseline – Hydroxymethylglutaryl-coenzyme A (HMG CoA) reductase inhibitor (statin) therapy may improve lipid parameters but 2 • Subjects had marked dyslipidemia at baseline (Table 2), and 39% (24/61) were using lipid-lowering medication – LAL maintains cholesterol homeostasis in hepatocytes (Figure 1A) does not improve liver disease associated with LAL-D, and, in some patients, it may be associated with progression of Sebelipase Percentage Sebelipase Percentage LAL catalyzes hydrolysis of low-density lipoprotein cholesterol (LDL-C)–derived cholesteryl esters to free liver disease over time1,4 – Mean LDL-P, LDL-C, and apoB levels were elevated compared with normal ranges; mean apoA1 level was at the low Atherogenic Alfa Placebo Point Alfa Placebo Point cholesterol (FC) and triglycerides to free fatty acids (FFA) end of the normal range Biomarker (n=14) (n=10) Difference P Value (n=19) (n=18) Difference P Value Increased levels of cytosolic FC and FFA downregulate sterol regulatory element–binding protein (SREBP) Figure 2. Lipid-Lowering Medications May Exacerbate the Underlying Mechanism of – Overall, the mean total LDL-P concentration at baseline was 2151 nmol/L (reference value: very high, >2000 nmol/L) LDL-P number, −34.2 (13.6) −1.6 (11.3)a 32.6 0.0002 −21.7 (20.6) 1.9 (20.7) 23.6 0.0017 transcription factors to decrease LDL uptake and production of FC and fatty acids Disease in LAL-Da nmol/L – LAL-D is characterized by lysosomal accumulation of lipids enhanced by increased LDL uptake and upregulation of LDL-C, mg/dL −36.1 (16.4) −10.3 (15.9) 25.8 0.0034 −27.4 (18.8) −4.6 (11.8) 22.8 0.0003 LDL LDL Table 2. Atherogenic Biomarkers and Lipid-Lowering Medication Use at Baseline in lipid production in response to decreased cytosolic FC (Figure 1B)2 ARISE Trial Subjects apoB, mg/dL −29.1 (12.3) −6.5 (10.4) 22.6 0.0005 −26.2 (14.3) −3.2 (7.3) 23.0 <0.0001 a Figure 1. Lipid Metabolism in Normal and LAL-D Hepatocytes Lysosome Sebelipase Alfa Placebo apoA1, mg/dL 10.2 (14.3) −2.5 (10.7) 12.7 0.0224 8.9 (9.2) −2.1 (13.2) 11.0 0.0041 Parameter N=33 N=28 Reference Value LDL-P size, nm −1.0 (2.2)b 0.4 (2.8)a 1.4 0.1927 −0.8 (3.9) 0.1 (2.3) 0.9 0.3302 LDLR A. Normal Hepatocyte B. LAL-D Hepatocyte LAL a b Mean LDL-P number, nmol/L 1942 2414 Very high, >2000 nmol/L apo, apolipoprotein; LAL-D, lysosomal acid lipase deficiency; LDL-C, low-density lipoprotein cholesterol; LDL-P, low-density lipoprotein particle. an=9; bn=13. LDL LDL LDL LDL Mean LDL-C, mg/dL 189.1 233.0 Normal, <130 mg/dL Increased LDLR uptake Mean apoB, mg/dL 148.0a 168.9 ULN, 120 mg/dL Lysosome FA synthesis pathway Lysosome SREBP CONCLUSIONS a LDLR Mean apoA1, mg/dL 102.5 102.1 LLN, 100 mg/dL LAL Nucleus LDLR LAL ACAT TG • Dyslipidemia in LAL-D resembles heterozygous familial hypercholesterolemia (HeFH) and familial combined HMG - Mean LDL-P size, nm 21.6a 21.7b — FC & FFA CoA FC CE hyperlipidemia (FCH) Feedback inhibition FA synthesis pathway Increased LDLR uptake and cellular production LLM use, n (%) 14 (42) 10 (36) – Given their similar lipid profiles, LAL-D should be considered in children and adults thought to have HeFH or FCH SREBP FA synthesis pathway SREBP VLDL Nucleus ACAT FC FC TG Nucleus ABCA1 Statin 14 (42) 8 (29) • Baseline atherogenic markers were elevated in LAL-D patients, often beginning in childhood. This life-long exposure HMG - ACAT TG FC CoA CE HMG - — represents significant atherosclerotic risk in patients with this disease FC CoA CE LCAT Other LLM 5 (15)c 3 (11)d VLDL apoA1 HDL FC FC • Sebelipase alfa treatment resulted in statistically significant decreases in mean LDL-P number, LDL-C level, and apoB ABCA1 FC FC VLDL ABCA1 ABCA1, adenosine triphosphate–binding cassette transporter A1; ACAT, acyl-coenzyme A:cholesterol acyltransferase; apoA1, apolipoprotein A1; CE, cholesteryl esters; Combination therapy 5 (15) 1 (4) level, and a significant increase in mean apoA1 level, representing an improved cardiovascular risk profile for these LCAT apoA1 HDL LCAT FA, fatty acid; FC, free cholesterol; HDL, high-density lipoprotein; HMG-CoA, hydroxymethylglutaryl-coenzyme A; LAL, lysosomal acid lipase; LAL-D, lysosomal acid lipase apo, apolipoprotein; ARISE, Acid Lipase Replacement Investigating Safety and Efficacy; LDL-C, low-density lipoprotein cholesterol; LDL-P, low-density lipoprotein particle; patients compared with placebo recipients apoA1 HDL deficiency; LCAT, lecithin-cholesterol acyltransferase; LDL, low-density lipoprotein; LDLR, LDL receptors; SREBP, sterol regulatory element–binding proteins; TG, triglycerides; LLM, lipid-lowering medication; LLN, lower limit of normal; ULN, upper limit of normal. – These improvements were observed even in LAL-D patients who were receiving concomitant lipid-lowering VLDL very-low-density lipoprotein. aN=34; bN=27; cOther LLM category included ezetimibe (n=3), cholestyramine (n=1), colestilan (n=1), fenofibrate (n=1), and fish oil (n=1); dOther LLM category included ABCA1, adenosine triphosphate–binding cassette transporter A1; ACAT, acyl-coenzyme A:cholesterol acyltransferase; CE, cholesteryl esters; FA, fatty acid; FC, free aAdapted from Reiner et al.2 medication, suggesting that use of lipid-lowering medication alone is not sufficient cholesterol; FFA, free fatty acids; HDL, high-density lipoprotein; HMG-CoA, hydroxymethylglutaryl-coenzyme A; LAL, lysosomal acid lipase; LAL-D, LAL deficiency; LCAT, lecithin- cholestyramine (n=2) and fish oil (n=1). cholesterol acyltransferase; LDL, low-density lipoprotein; LDLR, LDL receptors; SREBP, sterol regulatory element–binding proteins; TG, triglycerides; VLDL, very-low-density • The observed reduction in LDL-C with sebelipase alfa appears to be associated with a reduction in LDL-P number, lipoprotein. • Sebelipase alfa is a recombinant human LAL that catalyzes the hydrolysis of cholesteryl esters to FC and triglycerides to aAdapted from Reiner et al.2 glycerol and FFA; it is indicated for treatment of patients of all ages with a diagnosis of LAL-D11 Efficacy suggesting that cardiovascular disease risk in LAL-D patients may be reduced with sebelipase alfa treatment • Clinical manifestations of LAL-D include severe dyslipidemia and hepatic steatosis, fibrosis, and cirrhosis1,4 • In the Acid Lipase Replacement Investigating Safety and Efficacy (ARISE) study, sebelipase alfa normalized serum • Treatment with sebelipase alfa significantly improved key atherogenic biomarkers from baseline compared with placebo • Treatment with sebelipase alfa improves lipid biochemistry and other atherogenic biomarkers in LAL-D by addressing aminotransferase levels; improved LDL-C, non-high-density lipoprotein cholesterol (HDL-C), triglyceride, and HDL-C levels; the underlying pathogenetic mechanism of disease and is the recommended treatment for LAL-D patients of all ages – The dyslipidemia may cause accelerated atherosclerosis in LAL-D patients, increasing the risk of premature ischemia, (Table 3) 8 myocardial infarction, and stroke1 and decreased hepatic fat content in children and adults with LAL-D – The atherogenic biomarker profile associated with LAL-D is similar to that observed in heterozygous familial Table 3. Effect of Sebelipase Alfa on Atherogenic Biomarkers in LAL-D Subjects at hypercholesterolemia (HeFH) and familial combined hyperlipidemia (FCH, Table 1) REFERENCES METHODS 20 Weeks of Treatment Table 1. Atherogenic Biomarker Profiles in HeFH, FCH, and LAL-D 1. Bernstein DL, et al. J Hepatol. 2013;58:1230-43. 2. Reiner Z, et al. Atherosclerosis. 2014;235:21-30. 3. Lysosomal acid lipase deficiency (#278000). Mean (SD) Percentage OMIM database. 2015. http://omim.org/entry/278000. Accessed April 27, 2016. 4. Grabowski GA, et al. In: Valle D, et al, eds. Metabolic and Molecular LAL-Da Objective Change From Baseline Bases of Inherited Disease. 8th ed. New York, NY: McGraw-Hill; 2012. 5. Kusters DM, et al. JAMA. 2014;312:1055-7. 6. Wiegman A, et al. JAMA. HeFH FCH SA Placebo 2004;292:331-7. 7. Veerkamp MJ, et al. Circulation. 2004;109:2980-5. 8. Burton BK, et al.
Recommended publications
  • Lipid Lowering Drugs and Inflammatory Changes: an Impact on Cardiovascular Outcomes?
    Annals of Medicine ISSN: 0785-3890 (Print) 1365-2060 (Online) Journal homepage: http://www.tandfonline.com/loi/iann20 Lipid Lowering Drugs and Inflammatory Changes: an Impact on Cardiovascular Outcomes? M. Ruscica, N. Ferri, C. Macchi, A. Corsini & C. R. Sirtori To cite this article: M. Ruscica, N. Ferri, C. Macchi, A. Corsini & C. R. Sirtori (2018): Lipid Lowering Drugs and Inflammatory Changes: an Impact on Cardiovascular Outcomes?, Annals of Medicine, DOI: 10.1080/07853890.2018.1498118 To link to this article: https://doi.org/10.1080/07853890.2018.1498118 Accepted author version posted online: 06 Jul 2018. Submit your article to this journal View Crossmark data Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=iann20 LIPID LOWERING DRUGS AND INFLAMMATORY CHANGES: AN IMPACT ON CARDIOVASCULAR OUTCOMES? M. Ruscica1*, N. Ferri2*, C. Macchi1, A. Corsini1 and C. R. Sirtori3 1Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy; 2Dipartimento di Scienze del Farmaco, Università degli Studi di Padova, Padova, Italy; 3Centro Dislipidemie, A.S.S.T. Grande Ospedale Metropolitano Niguarda, Milan, Italy *Both authors contributed equally to this work Corresponding Author: Cesare R. Sirtori [email protected] Abstract Inflammatory changes are responsible for maintenance of the atherosclerotic process and may underlie some of the most feared vascular complications. Among the multiple mechanisms of inflammation, the arterial deposition of lipids and particularly of cholesterol crystals is the one responsible for activation of inflammasome NLRP3, followed by the rise of circulating markers, mainly C-reactive protein (CRP). Elevation of lipoproteins, LDL but also VLDL and remnants, associates with increased inflammatory changes and coronary risk.
    [Show full text]
  • Role of Bile Acids in the Regulation of Food Intake, and Their Dysregulation in Metabolic Disease
    nutrients Review Role of Bile Acids in the Regulation of Food Intake, and Their Dysregulation in Metabolic Disease Cong Xie 1,† , Weikun Huang 1,2,† , Richard L. Young 1,3 , Karen L. Jones 1,4 , Michael Horowitz 1,4, Christopher K. Rayner 1,5 and Tongzhi Wu 1,4,6,* 1 Adelaide Medical School, Center of Research Excellence (CRE) in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide 5005, Australia; [email protected] (C.X.); [email protected] (W.H.); [email protected] (R.L.Y.); [email protected] (K.L.J.); [email protected] (M.H.); [email protected] (C.K.R.) 2 The ARC Center of Excellence for Nanoscale BioPhotonics, Institute for Photonics and Advanced Sensing, School of Physical Sciences, The University of Adelaide, Adelaide 5005, Australia 3 Nutrition, Diabetes & Gut Health, Lifelong Health Theme South Australian Health & Medical Research Institute, Adelaide 5005, Australia 4 Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide 5005, Australia 5 Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide 5005, Australia 6 Institute of Diabetes, School of Medicine, Southeast University, Nanjing 210009, China * Correspondence: [email protected] † These authors contributed equally to this work. Abstract: Bile acids are cholesterol-derived metabolites with a well-established role in the digestion and absorption of dietary fat. More recently, the discovery of bile acids as natural ligands for the nuclear farnesoid X receptor (FXR) and membrane Takeda G-protein-coupled receptor 5 (TGR5), and Citation: Xie, C.; Huang, W.; Young, the recognition of the effects of FXR and TGR5 signaling have led to a paradigm shift in knowledge R.L.; Jones, K.L.; Horowitz, M.; regarding bile acid physiology and metabolic health.
    [Show full text]
  • )&F1y3x PHARMACEUTICAL APPENDIX to THE
    )&f1y3X PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE )&f1y3X PHARMACEUTICAL APPENDIX TO THE TARIFF SCHEDULE 3 Table 1. This table enumerates products described by International Non-proprietary Names (INN) which shall be entered free of duty under general note 13 to the tariff schedule. The Chemical Abstracts Service (CAS) registry numbers also set forth in this table are included to assist in the identification of the products concerned. For purposes of the tariff schedule, any references to a product enumerated in this table includes such product by whatever name known. Product CAS No. Product CAS No. ABAMECTIN 65195-55-3 ACTODIGIN 36983-69-4 ABANOQUIL 90402-40-7 ADAFENOXATE 82168-26-1 ABCIXIMAB 143653-53-6 ADAMEXINE 54785-02-3 ABECARNIL 111841-85-1 ADAPALENE 106685-40-9 ABITESARTAN 137882-98-5 ADAPROLOL 101479-70-3 ABLUKAST 96566-25-5 ADATANSERIN 127266-56-2 ABUNIDAZOLE 91017-58-2 ADEFOVIR 106941-25-7 ACADESINE 2627-69-2 ADELMIDROL 1675-66-7 ACAMPROSATE 77337-76-9 ADEMETIONINE 17176-17-9 ACAPRAZINE 55485-20-6 ADENOSINE PHOSPHATE 61-19-8 ACARBOSE 56180-94-0 ADIBENDAN 100510-33-6 ACEBROCHOL 514-50-1 ADICILLIN 525-94-0 ACEBURIC ACID 26976-72-7 ADIMOLOL 78459-19-5 ACEBUTOLOL 37517-30-9 ADINAZOLAM 37115-32-5 ACECAINIDE 32795-44-1 ADIPHENINE 64-95-9 ACECARBROMAL 77-66-7 ADIPIODONE 606-17-7 ACECLIDINE 827-61-2 ADITEREN 56066-19-4 ACECLOFENAC 89796-99-6 ADITOPRIM 56066-63-8 ACEDAPSONE 77-46-3 ADOSOPINE 88124-26-9 ACEDIASULFONE SODIUM 127-60-6 ADOZELESIN 110314-48-2 ACEDOBEN 556-08-1 ADRAFINIL 63547-13-7 ACEFLURANOL 80595-73-9 ADRENALONE
    [Show full text]
  • PHARMACEUTICAL APPENDIX to the TARIFF SCHEDULE 2 Table 1
    Harmonized Tariff Schedule of the United States (2020) Revision 19 Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE Harmonized Tariff Schedule of the United States (2020) Revision 19 Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE TARIFF SCHEDULE 2 Table 1. This table enumerates products described by International Non-proprietary Names INN which shall be entered free of duty under general note 13 to the tariff schedule. The Chemical Abstracts Service CAS registry numbers also set forth in this table are included to assist in the identification of the products concerned. For purposes of the tariff schedule, any references to a product enumerated in this table includes such product by whatever name known.
    [Show full text]
  • 146 – March 2015 Produced by NHS Tayside Drug and Therapeutics Committee Medicines Advisory Group (MAG)
    TAYSIDE PRESCRIBER Tayside DTC Supplement No 146 – March 2015 Produced by NHS Tayside Drug and Therapeutics Committee Medicines Advisory Group (MAG) Special Points of Interest Drug Safety Updates for Primary Care Please follow link - Drug Safety Update Download - March 2015 Statin Update (page 2) Drug Driving SMC Advice - February: Abiraterone acetate (Zytiga®) The Drug Driving (Specified Limits)(England and Wales) Regulations 2014 came into effect in nd Bosutinib (Bosulif®) England and Wales on 2 March 2015. Similar legislation will be apply in Scotland, but the date on which it comes into effect has still to be set by the Scottish Parliament. It should be noted Colestilan (BindRen®) that patients may travel in England and Wales and be subject to the regulations at present. Follitropin alfa (Bemfola®) These regulations set maximum blood levels for several prescription medicines including Paclitaxel formulated as albumin diazepam, lorazepam, methadone, morphine, ketamine, and temazepam. bound nanoparticles (Abraxane®) ® Umeclidinium / vilanterol(Anoro ) The BNF already specifies the cautionary labels recommended for inclusion with the dispensed medicine. SMC Advice - March: The BNF specifies that patients should be advised if the treatment is likely to affect their ability Apixaban (Eliquis®) to drive (although it is not specified if this is the prescriber or pharmacist). ® Cabozantinib (Cometriq ) Dabrafenib (Tafinlar®) Further information is available using the links below: Fosfomycin (Fomicyt®) Information for Healthcare Professionals:
    [Show full text]
  • Ehealth DSI [Ehdsi V2.2.2-OR] Ehealth DSI – Master Value Set
    MTC eHealth DSI [eHDSI v2.2.2-OR] eHealth DSI – Master Value Set Catalogue Responsible : eHDSI Solution Provider PublishDate : Wed Nov 08 16:16:10 CET 2017 © eHealth DSI eHDSI Solution Provider v2.2.2-OR Wed Nov 08 16:16:10 CET 2017 Page 1 of 490 MTC Table of Contents epSOSActiveIngredient 4 epSOSAdministrativeGender 148 epSOSAdverseEventType 149 epSOSAllergenNoDrugs 150 epSOSBloodGroup 155 epSOSBloodPressure 156 epSOSCodeNoMedication 157 epSOSCodeProb 158 epSOSConfidentiality 159 epSOSCountry 160 epSOSDisplayLabel 167 epSOSDocumentCode 170 epSOSDoseForm 171 epSOSHealthcareProfessionalRoles 184 epSOSIllnessesandDisorders 186 epSOSLanguage 448 epSOSMedicalDevices 458 epSOSNullFavor 461 epSOSPackage 462 © eHealth DSI eHDSI Solution Provider v2.2.2-OR Wed Nov 08 16:16:10 CET 2017 Page 2 of 490 MTC epSOSPersonalRelationship 464 epSOSPregnancyInformation 466 epSOSProcedures 467 epSOSReactionAllergy 470 epSOSResolutionOutcome 472 epSOSRoleClass 473 epSOSRouteofAdministration 474 epSOSSections 477 epSOSSeverity 478 epSOSSocialHistory 479 epSOSStatusCode 480 epSOSSubstitutionCode 481 epSOSTelecomAddress 482 epSOSTimingEvent 483 epSOSUnits 484 epSOSUnknownInformation 487 epSOSVaccine 488 © eHealth DSI eHDSI Solution Provider v2.2.2-OR Wed Nov 08 16:16:10 CET 2017 Page 3 of 490 MTC epSOSActiveIngredient epSOSActiveIngredient Value Set ID 1.3.6.1.4.1.12559.11.10.1.3.1.42.24 TRANSLATIONS Code System ID Code System Version Concept Code Description (FSN) 2.16.840.1.113883.6.73 2017-01 A ALIMENTARY TRACT AND METABOLISM 2.16.840.1.113883.6.73 2017-01
    [Show full text]
  • Annexes of the Annual Report 2011
    1 June 2012 EMA/363033/2012 Office of the Executive Director Annexes of the annual report 2011 The main body of this report is available on the website of the European Medicines Agency (EMA) here. 7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7418 8416 E-mail [email protected] Website www.ema.europa.eu An agency of the European Union © European Medicines Agency, 2012. Reproduction is authorised provided the source is acknowledged. Table of contents Annex 1 – Members of the Management Board ................................................... 3 Annex 2 – Members of the Committee for Medicinal Products for Human Use ......... 5 Annex 3 – Members of the Committee for Medicinal Products for Veterinary Use .... 9 Annex 4 – Members of the Committee for Orphan Medicinal Products.................. 11 Annex 5 – Members of the Committee on Herbal Medicinal Products ................... 13 Annex 6 – Members of the Paediatric Committee .............................................. 16 Annex 7 – Members of the Committee for Advanced Therapies ........................... 18 Annex 8 – National competent authority partners ............................................. 20 Annex 9 – Budget summaries 2010–2011........................................................ 31 Annex 10 – Establishment plan ...................................................................... 32 Annex 11 – CHMP opinions in 2011 on medicinal products for human use ............ 33 Annex 12 – CVMP opinions in 2011
    [Show full text]
  • Publications with Genetically Modified Mouse Models in Pharma * Indicates Collaborative Study with Partners from Industry
    Transgenic mouse models in TNO Pharma March 2020 Publications with genetically modified mouse models in Pharma * indicates collaborative study with partners from industry Reviews on mouse models for atherosclerosis and metabolic disease Zadelaar ASM, Kleemann R, Verschuren L, de Vries-van der Weij J, van der Hoorn J, Princen HM, Kooistra T. Mouse models for atherosclerosis and pharmaceutical modifiers. Arterioscler Thromb Vasc Biol 2007; 27: 1706-1721. Kühnast S, Fiocco M, van der Hoorn JWA, Princen HMG, Jukema JW. Innovative pharmaceutical interventions in cardiovascular disease: focusing on the contribution of non-HDL-C/ LDL-C-lowering versus HDL-C-raising - A systematic review and meta-analysis of relevant preclinical studies and clinical trials. Eur J Pharmacol 2015; 763: 48-63. doi: 10.1016/j.ejphar.2015.03.089 Princen HMG, Pouwer MG, Pieterman EJ. Comment on “Hypercholesterolemia with consumption of PFOA-laced Western diets is dependent on strain and sex of mice” by Rebholz S.L. et al. Toxicol. Rep. 2016 (3) 46–54. Toxicol Rep 2016; 3: 306-309. Morrison MC, Kleemann R. Role of Macrophage Migration Inhibitory Factor in Obesity, Insulin Resistance, Type 2 Diabetes, and Associated Hepatic Co-Morbidities: A Comprehensive Review of Human and Rodent Studies. Front Immunol. 2015; 6: 308. doi: 10.3389/fimmu.2015.00308. Liang W, Menke AL, Driessen A, Koek GH, Lindeman JH, Stoop R, Havekes LM, Kleemann R, van den Hoek AM. Establishment of a general NAFLD scoring system for rodent models and comparison to human liver pathology. PLoS ONE 2014; 9: e115922. doi: 10.1371/journal.pone.0115922. Kleemann R, Zadelaar S, Kooistra T.
    [Show full text]
  • Development of Bile Acid Sequestrants Based on Cationic Hydrogels
    André Alexandre Cruz de Matos Development of Bile Acid Sequestrants based on Cationic Hydrogels Dissertation guided by Jorge F.J. Coelho, PhD, and Arménio C. Serra, PhD, and presented to the Faculty of Sciences and Technology of University of Coimbra to obtain a Master’s degree in Biomedical Engineering September 2016 André Alexandre Cruz de Matos Development of bile acid sequestrants based on cationic hydrogels Dissertation presented to the Faculty of Sciences and Technology of the University of Coimbra to obtain a Master’s degree in Biomedical Engineering Supervisors: Jorge Fernando Jordão Coelho (DEQ-UC) Arménio Coimbra Serra (DEQ-UC) Coimbra, 2016 This work was developed with the colaboration of: Department of Chemical Engineering Faculty of Sciences and Technology University of Coimbra III Esta cópia da tese é fornecida na condição de que quem a consulta reconhece que os direitos de autor são pertença do autor da tese e que nenhuma citação ou informação obtida a partir dela pode ser publicada sem a referência apropriada. This copy of the thesis has been supplied on the condition that anyone who consults it is understood to recognize that its copyright rests with its author and that no quotation from the thesis and no information derived from it may be published without proper citation. V Agradecimentos Esta tese tem como função permitir a obtenção de um grau académico, mas acima de tudo serve para marcar o fim de uma longa caminhada. Pelo que gostaria de agradecer a todos o que me auxiliaram, neste percurso que nem sempre foi fácil. Em primeiro lugar quero agradecer aos meus orientadores, o Professor Doutor Jorge Coelho e a Doutora Patrícia Mendonça, por todo o auxílio prestado no decorrer deste projeto.
    [Show full text]
  • Anatomical Classification Guidelines V2021 EPHMRA ANATOMICAL CLASSIFICATION GUIDELINES 2021
    EPHMRA ANATOMICAL CLASSIFICATION GUIDELINES 2021 Anatomical Classification Guidelines V2021 "The Anatomical Classification of Pharmaceutical Products has been developed and maintained by the European Pharmaceutical Marketing Research Association (EphMRA) and is therefore the intellectual property of this Association. EphMRA's Classification Committee prepares the guidelines for this classification system and takes care for new entries, changes and improvements in consultation with the product's manufacturer. The contents of the Anatomical Classification of Pharmaceutical Products remain the copyright to EphMRA. Permission for use need not be sought and no fee is required. We would appreciate, however, the acknowledgement of EphMRA Copyright in publications etc. Users of this classification system should keep in mind that Pharmaceutical markets can be segmented according to numerous criteria." © EphMRA 2021 Anatomical Classification Guidelines V2021 CONTENTS PAGE INTRODUCTION A ALIMENTARY TRACT AND METABOLISM 1 B BLOOD AND BLOOD FORMING ORGANS 28 C CARDIOVASCULAR SYSTEM 36 D DERMATOLOGICALS 51 G GENITO-URINARY SYSTEM AND SEX HORMONES 58 H SYSTEMIC HORMONAL PREPARATIONS (EXCLUDING SEX HORMONES) 68 J GENERAL ANTI-INFECTIVES SYSTEMIC 72 K HOSPITAL SOLUTIONS 88 L ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS 96 M MUSCULO-SKELETAL SYSTEM 106 N NERVOUS SYSTEM 111 P PARASITOLOGY 122 R RESPIRATORY SYSTEM 124 S SENSORY ORGANS 136 T DIAGNOSTIC AGENTS 143 V VARIOUS 145 Anatomical Classification Guidelines V2021 INTRODUCTION The Anatomical Classification was initiated in 1971 by EphMRA. It has been developed jointly by Intellus/PBIRG and EphMRA. It is a subjective method of grouping certain pharmaceutical products and does not represent any particular market, as would be the case with any other classification system.
    [Show full text]
  • 2 12/ 35 74Al
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 22 March 2012 (22.03.2012) 2 12/ 35 74 Al (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 9/16 (2006.01) A61K 9/51 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 9/14 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, (21) International Application Number: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/EP201 1/065959 HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (22) International Filing Date: KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, 14 September 201 1 (14.09.201 1) ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, (25) Filing Language: English RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, (26) Publication Language: English TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 61/382,653 14 September 2010 (14.09.2010) US (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicant (for all designated States except US): GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, NANOLOGICA AB [SE/SE]; P.O Box 8182, S-104 20 ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, Stockholm (SE).
    [Show full text]
  • Update of Comparative Effectiveness of Lipid-Modifying Agents
    Evidence-based Practice Center Systematic Review Protocol Project Title: Update of Comparative Effectiveness of Lipid-Modifying Agents I. Background and Objectives for the Systematic Review Epidemiology and Practice Guidelines Cardiovascular disease (CVD) affects 83.6 million Americans.1 CVD includes a variety of conditions such as myocardial infarction, stroke, heart failure, arrhythmia, heart valve disease, and hypertension. In 2009, CVD contributed to 32.3 percent of U.S. deaths and is a leading cause of disability.1 Atherosclerosis plays a major role in the development of certain cardiovascular diseases—coronary heart disease (CHD) including myocardial infarction, angina, and heart failure and cerebrovascular accident. These atherosclerotic diseases affect 15.4 million Americans.1 Elevated blood lipids are a major risk factor for atherosclerotic CVD. Abnormal lipoprotein metabolism predisposes individuals to atherosclerosis, especially increased concentrations of apolipoprotein B (apo B)-100–containing low-density lipoprotein (LDL-c). Oxidized LDL is atherogenic, causing endothelial damage, alteration of vascular tone, and recruitment of monocytes and macrophages. Many studies have underscored the importance of LDL-c in development of atherosclerotic CVD.2,3 Due to the consistent and robust association of higher LDL-c levels with atherosclerotic CVD across experimental and epidemiologic studies, therapeutic strategies to decrease risk have focused on LDL-c reduction as the primary goal. The trial results are most compelling regarding the reduction of CHD by lowering LDL-c. 4,5 Based on this evidence, the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) report established three CHD risk strata together with guidelines regarding the initiation of treatment and therapeutic targets based on LDL-c cutoffs.
    [Show full text]