DOCSLIB.ORG

Combined Effects of Probucol and Bezafibrate on Lipoprotein Metabolism and Liver Cholesteryl Ester Transfer Protein Mrna in Chol

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Combined Effects of Probucol and Bezafibrate on Lipoprotein Metabolism and Liver Cholesteryl Ester Transfer Protein Mrna in Chol EXPERIMENTAL STUDIES Jpn Circ J 1999; 63: 471–477 Combined Effects of Probucol and Bezafibrate on Lipoprotein Metabolism and Liver Cholesteryl Ester Transfer Protein mRNA in Cholesterol-Fed Rabbits Jiafu Ou, MD; Keijiro Saku, MD; Shiro Jimi, PhD*; Yuan-Lan Liao, MD; Takao Ohta, MD**; Bo Zhang, PhD; Kikuo Arakawa, MD Probucol decreases and bezafibrate increases plasma high density lipoprotein-cholesterol (HDL-C) levels in humans. This study was performed to determine whether the HDL-C-lowering effects of probucol could be reversed by treatment with bezafibrate in hypercholesterolemic rabbits. Forty-nine normolipidemic Japanese White rabbits were divided into 5 groups [group 1: normal chow; group 2: 0.2% cholesterol (Ch) diet; group 3: 0.2% Ch and 1% probucol diet; group 4: 0.2% Ch and 1% bezafibrate diet; group 5: 0.2% Ch and 1% probucol plus 1% bezafibrate diet] and treated for 8 weeks. Plasma lipids, cholesteryl ester transfer protein (CETP) activ- ity in the lipoprotein-deficient plasma fraction, CETP mRNA in liver tissue and plasma drug concentrations were investigated. Serum total cholesterol (TC) increased after the rabbits in groups 2, 3, 4 and 5 were fed Ch, but overall, no significant differences were observed in serum TC and triglyceride (TG) among these groups. Serum HDL-C levels increased (p<0.01) in the bezafibrate-treated group, but a significant (p<0.05) reduction in HDL-C was observed in both the Ch + probucol (group 3) and Ch + probucol plus bezafibrate (group 5) groups; no significant difference was observed between groups 3 and 5. Significant correlation (p<0.01) was found between serum low density lipoprotein cholesterol (LDL-C) levels and plasma probucol concentrations in groups 3 and 5, but no correlation was found between plasma concentrations of probucol/bezafibrate and serum HDL-C levels. CETP activity in the lipoprotein-deficient plasma fraction increased in the Ch-, Ch + probucol-, and Ch + probu- col and bezafibrate-fed groups (groups 2, 3 and 5, respectively), whereas a significant reduction in this activity was observed in the Ch + bezafibrate-fed group (group 4). An analysis of covariance showed that the CETP activity responded more sensitively to drug treatment than did the serum HDL-C level. CETP mRNA in liver tissue was assessed by Northern blotting at 8 weeks, but no changes were observed among the 5 groups. Probucol decreased and bezafibrate increased serum HDL-C levels, through CETP activity without affecting liver CETP mRNA levels, and the decrease in HDL-C levels produced by probucol could not be reversed by bezafibrate. (Jpn Circ J 1999; 63: 471–477) Key Words: Bezafibrate; Cholesteryl ester transfer protein; Hypercholesterolemia; Lipids; Lipoproteins; mRNA; Probucol robucol is a potent hypolipidemic agent that has been HDL-C levels in patients with various types of dyslipopro- reported to have antioxidant effects that may retard teinemia.9–11 The large-scale, 5-year Bezafibrate Coronary P the progression or accelerate the regression of Atherosclerosis Intervention Trial (BECAIT) demonstrated atherosclerosis.1,2 Probucol is known to lower high-density that bezafibrate slowed the progression of coronary athero- lipoprotein-cholesterol (HDL-C) levels and this reduction sclerosis, and reduced coronary events in young survivors of HDL-C has been shown to be associated with increased of myocardial infarction;12,13 bezafibrate effectively cholesteryl ester transfer protein (CETP) activity3 and lowered the serum very low density lipoprotein (VLDL)- mass.4 Yamamoto et al showed that a reduction in achilles TG, VLDL-C, and fibrinogen levels, but no change was tendon xanthoma was related to a decrease in HDL-C levels observed in low density lipoprotein-cholesterol (LDL-C). after probucol treatment.5 Recent studies have shown that it Therefore, some factor (s) other than LDL-C may play reduces the rate of restenosis after balloon coronary angio- important roles in the progression/regression of coronary plasty.6,7 However, a clinical study found that probucol had lesions.12,13 Generally, direct evidence of the antiatheroscle- no effect on the regression of femoral atherosclerosis.8 rotic effects of fibrates in animal studies is rare.14 An excep- Bezafibrate is a homologue of clofibrate that has been tion is fenofibrate,15 another homologue of clofibrate, which shown to reduce plasma triglyceride (TG) and increase has been shown to inhibit an early event in the atherogene- sis of rabbits fed a cholesterol diet; however, this action has (Received November 2, 1998; revised manuscript received December been also shown to be independent of the hypolipidemic 28, 1998; accepted February 5, 1999) effects of fenofibrate.15 Departments of Internal Medicine and *Pathology, Fukuoka Univer- Combination therapy with drugs that use different mech- sity School of Medicine, Fukuoka and **Department of Pediatrics, anisms has been evaluated in several studies of hyper- Faculty of Medicine, University of the Ryukyus, Okinawa, Japan lipoproteinemia;16–20 however, it is unclear whether probu- Mailing address: Keijiro Saku, MD, PhD, FACP, Department of Internal Medicine, Fukuoka University School of Medicine, 45-1-7 col-reduced HDL levels should be treated by drugs, and if Nanakuma Jonanku, Fukuoka 814-0180, Japan. E-mail: hh035399@ so, whether the addition of bezafibrate could possibly msat.fukuoka-u.ac.jp reverse probucol-reduced HDL levels. In addition, the Japanese Circulation Journal Vol.63, June 1999 472 OU J et al. combination of probucol and fibrates quite often induces an ing [3H]-cholesterol oleate ([3H]-DBP) were prepared. To extreme reduction in HDL-C,16,20,21 and the mechanism of remove total lipoproteins from the rabbit plasma sample, this phenomenon is unclear. the plasma density was adjusted to d=1.21g/ml by KBr, In the present study, we investigated the effects of and then ultracentrifuged in a Beckman TL-100 Tabletop probucol, bezafibrate and their combination on lipoprotein Ultracentrifuge (Beckman Instruments, USA) for 3.5h at metabolism in hypercholesterolemic rabbits. We used 165,000 × g. The bottom fraction was collected and cholesterol-fed rabbits because in a previous HDL-apo A-I dialyzed against 10mmol/L Tris-HCl, 150mmol/L NaCl kinetic study we found that probucol had a greater effect in (pH7.4) for 24 h with 2 changes of dialysate buffer. The the hypercholesterolemic state, and that treatment with a total CET activity in lipoprotein-deficient (d>1.21 g/ml) similar dose of gemfibrozil, another homologue of clofi- plasma was determined in terms of the percentage of [3H]- brate, increased the rate of apolipoprotein (apo) A-I synthe- cholesterol oleate transferred from discoidal bilayer parti- sis in Watanabe heritable hyperlipidemic (WHHL) cles to human LDL.26 The reaction mixture containing 110 rabbits.14 The combined effects of probucol and bezafibrate μl of [3H]-DBP (1,587.3 Bq (42.9 nCi)) as a donor of on CETP gene expression in vivo were also examined, cholesterol ester and 130μg of LDL protein as an acceptor because there has been no previous report on the effects of was incubated with 10μl of lipoprotein-deficient (d>1.21 their interaction. The underlying mechanism of the HDL g/ml) plasma for 60 min at 37°C in the presence of 1.4 deficiency was also investigated. To the best of our knowl- mmol/L 2,2'-dithio-bis-(5'-nitropyridine), an inhibitor of edge, this is the first report to demonstrate the effect of lecithin-cholesterol acyltransferase (LCAT). After incuba- probucol/bezafibrate on plasma CETP activity and liver tion, 30μl of 0.1% dextran sulphate and 30μl of 60mmol/L CETP mRNA levels in hypercholesterolemic rabbits. magnesium chloride were added to the reaction mixture. The mixture was kept on ice for 20min and centrifuged at 10,500 × g for 10 min. The supernatant was collected and Methods the pellets (LDL) were dissolved in 0.1 mol/L NaOH. Rabbits Radioactivities in both the supernatant and pellets were Male Japanese White normolipidemic rabbits (ages counted using a Beckman liquid scintillation counter. The approximately 4 months and weighing 2.1–2.6kg) were result of the assay without a sample was used as nonspe- obtained from Kyudo Co, Ltd (Fukuoka, Japan). All of the cific CETP activity. CETP activity was expressed as total animals were housed individually under a 12-h light/dark CETP activity minus nonspecific CETP activity. cycle. The project was assessed and approved by the Ethics Committee of Fukuoka University. Northern Blot Analysis The rabbits were anesthetized with sodium phenobarbi- Study Groups tal. The liver tissue was excised, immediately frozen in Rabbits were divided into 5 groups: group 1 (N), normal liquid N2, and then stored at –80°C until use. Total cellular chow diet for 8 weeks (n=10); group 2 (Ch), 0.2% choles- RNA was extracted from the liver tissue with RNAzol B terol diet for 8 weeks (n=10); group 3 (Ch+P), 1% probucol (Biotecx Laboratories, Inc). Twenty micrograms of total with 0.2% cholesterol diet for 8 weeks (n=10); group 4 RNA was fractionated on 1% agarose formaldehyde gel (Ch+B), 1% bezafibrate with 0.2% cholesterol diet for 8 and blotted onto a positively charged nylon membrane weeks (n=10); and group 5 (Ch+P+B), 1% probucol plus (Amersham). A cDNA probe (479-base fragment, 1% bezafibrate with 0.2% cholesterol diet for 8 weeks nucleotides 437–915) for rabbit CETP27 was generated by (n=9). Each dietary treatment was started on the same day. reverse transcription-polymerase chain reaction (RT-PCR) using a GeneAmp RNA PCR Kit (Perkin Elmer), and then Preparation of Probucol and Bezafibrate Diets labeled with [32P]-deoxy-cytidinetriphosphate (dCTP) Pure probucol and bezafibrate powders (supplied by using a rediprime random labeling kit (Amersham). The Daiichi Pharmaceutical Co, Tokyo, and Kissei Co, Ltd, primers used for RT-PCR of rabbit CETP were (sense) 5'- Matsumoto, respectively) were added to the basal animal CTTTCCATAAACTGCTCCTG-3', and (antisense) 5'- chow (RC-4 or RC-4 with 0.2% cholesterol, Oriental Yeast, CTGGTTGGTGTCGAAACCCT-3'.
Load more

Recommended publications
  • Deliverable 5.A Interim Report on the Study Results APPENDIX 2
    Deliverable 5.a Interim report on the study results APPENDIX 2: Algorithms used to identify study variables for service contract EMA/2011/38/CN ‐ PIOGLITAZONE November 28th 2012 D5.a Interim report on the study results (Appendix 2) for Service Contract EMA/2011/38/CN PIOGLITAZONE Author(s): Vera Ehrenstein (AUH‐AS) APPENDIX 2. ALGORITHMS USED TO IDENTIFY STUDY VARIABLES Algorithms for AU Database DISEASE/CONDITION ICD-8 CODE (1977-1993) ICD-10 CODE (1994-) Diabetes type 2 250.00; 250.06; 250.07; 250.09 E11.0; E11.1; E11.9 Cancer of bladder 188 C67 Haematuria N/A R31 Haematuria, unspecified B18, K70.0–K70.3, K70.9, K71, K73, Mild hepatic impairment 571, 573.01, 573.04 K74, K76.0 Moderate to severe hepatic 070.00, 070.02, 070.04, 070.06, B15.0, B16.0, B16.2, B19.0, K70.4, impairment 070.08, 573.00, 456.00–456.09 K72, K76.6, I85 Acute myocardial infarction 410 I21-I23 Acute coronary syndrome 410, 413 I20-I24 Ischemic heart disease 410-414 I20-I25 427.09, 427.10, 427.11, 427.19, Congestive heart failure I50, I11.0, I13.0,I13.2 428.99, 782.49; Acute renal failure N/A N17 Diabetic coma N/A E10.0, E11.0, E12.0,E13.0, E14.0 Diabetic acidosis N/A E10.1, E11.1, E12.1,E13.1, E14.1 F10.1-F10.9, G31.2, G62.1, G72.1, Alcoholism 291, 303, 577.10, 571.09, 571.10 I42.6, K29.2, K86.0, Z72.1 Obesity 277.99 E65-E66 D5.a Interim report on the study results (Appendix 2) for Service Contract EMA/2011/38/CN PIOGLITAZONE Author(s): Vera Ehrenstein (AUH‐AS) Algorithms for defining acute events in Denmark, ICD-10 code Event ICD-10 code I21.x, I23.x http://apps.who.int/classifications/icd10/browse/2010/en#/I21
    [Show full text]
  • Partial Agreement in the Social and Public Health Field
    COUNCIL OF EUROPE COMMITTEE OF MINISTERS (PARTIAL AGREEMENT IN THE SOCIAL AND PUBLIC HEALTH FIELD) RESOLUTION AP (88) 2 ON THE CLASSIFICATION OF MEDICINES WHICH ARE OBTAINABLE ONLY ON MEDICAL PRESCRIPTION (Adopted by the Committee of Ministers on 22 September 1988 at the 419th meeting of the Ministers' Deputies, and superseding Resolution AP (82) 2) AND APPENDIX I Alphabetical list of medicines adopted by the Public Health Committee (Partial Agreement) updated to 1 July 1988 APPENDIX II Pharmaco-therapeutic classification of medicines appearing in the alphabetical list in Appendix I updated to 1 July 1988 RESOLUTION AP (88) 2 ON THE CLASSIFICATION OF MEDICINES WHICH ARE OBTAINABLE ONLY ON MEDICAL PRESCRIPTION (superseding Resolution AP (82) 2) (Adopted by the Committee of Ministers on 22 September 1988 at the 419th meeting of the Ministers' Deputies) The Representatives on the Committee of Ministers of Belgium, France, the Federal Republic of Germany, Italy, Luxembourg, the Netherlands and the United Kingdom of Great Britain and Northern Ireland, these states being parties to the Partial Agreement in the social and public health field, and the Representatives of Austria, Denmark, Ireland, Spain and Switzerland, states which have participated in the public health activities carried out within the above-mentioned Partial Agreement since 1 October 1974, 2 April 1968, 23 September 1969, 21 April 1988 and 5 May 1964, respectively, Considering that the aim of the Council of Europe is to achieve greater unity between its members and that this
    [Show full text]
  • Consumer Medicine Information
    NEW ZEALAND DATA SHEET PRAVASTATIN MYLAN 1. Product Name Pravastatin Mylan, 10 mg, 20 mg and 40 mg, tablets 2. Qualitative and Quantitative Composition Each tablet contains either 10 mg, 20 mg or 40 mg of pravastatin sodium. Excipient with known effect: lactose. For the full list of excipients, see section 6.1. 3. Pharmaceutical Form Tablet. 10 mg: Yellow coloured, rounded, rectangular shaped, biconvex uncoated tablet debossed with ‘PDT’ on one side and ‘10’ on the other side. 20 mg: Yellow coloured, rounded, rectangular shaped, biconvex uncoated tablet debossed with ‘PDT’ on one side and ‘20’ on the other side. 40 mg: Yellow coloured, rounded, rectangular shaped, biconvex uncoated tablet debossed with ‘PDT’ on one side and ‘40’ on the other side. 4. Clinical Particulars 4.1 Therapeutic indications • In hypercholesterolaemic patients without clinically evident coronary heart disease, Pravastatin Mylan is indicated as an adjunct to diet to reduce the risk of fatal and non-fatal myocardial infarction, need for myocardial revascularisation procedures, and to improve survival by reducing cardiovascular deaths. • Pravastatin Mylan is indicated for the reduction of elevated total and LDL-cholesterol levels in patients with primary hypercholesterolaemia when the response to diet and other non- pharmacological measures alone have been inadequate. • Pravastatin Mylan is indicated as an adjunct to diet to slow the progressive course of atherosclerosis and reduce the incidence of clinical cardiovascular events in hypercholesterolaemic men under 75 years of age with coronary artery disease. • Coronary Artery Disease: In patients with a history of either a myocardial infarction or unstable angina pectoris, Pravastatin Mylan is indicated to reduce the risk for total mortality, CHD death, recurrent coronary event (including myocardial infarction), need for myocardial revascularisation procedures, and need for hospitalisation.
    [Show full text]
  • Clofibrate Causes an Upregulation of PPAR- Target Genes but Does Not
    tapraid4/zh6-areg/zh6-areg/zh600707/zh65828d07a xppws S� 1 4/20/07 9: 48 MS: R-00603-2006 Ini: 07/rgh/dh A " #h!si$l %egul Integr &$ ' #h!si$l 2%&' R000 (R000) 200!$ 3. Originalarbeiten *irst publis#ed "arc# + 5) 200! doi' + 0$ + + 52,a-pregu$ 0060&$ 2006$ Clofibrate causes an upregulation of PPAR-� target genes but does not alter AQ: 1 expression of SREBP target genes in liver and adipose tissue of pigs Sebastian Luci, Beatrice Giemsa, Holger Kluge, and Klaus Eder Institut fu¨r Agrar- und Erna¨hrungswissenschaften, Martin-Luther-Universita¨t Halle-Wittenberg, Halle (Saale), Ger an! Submitted 25 August 2006 accepted in final form ! "arc# 200! AQ: 2 Luci S, Giemsa B, Kluge H, Eder K. Clofibrate causes an usuall0 increased 3#en baseline concentrations are lo3 1?62$ upregulation of PPAR-� target genes but does not alter expression of Effects of PPAR-� activation #ave been mostl0 studied in SREBP target genes in liver and adipose tissue of pigs$ A " #h!si$l rodents) 3#ic# ex#ibit a strong expression of PPAR-� in liver %egul Integr &$ ' #h!si$l 2%&' R000 (R000) 200!$ *irst publis#ed and s#o3 peroxisome proliferation in t#e liver in response to "arc# + 5) 200! doi' + 0$ + + 52,a-pregu$ 0060&$ 2006$ ./#is stud0 inves- PPAR-� activation 1&62$ Expression of PPAR-� and sensitivit0 tigated t#e effect of clofibrate treatment on expression of target genes of peroxisome proliferator-activated receptor 1PPAR2-� and various to peroxisomal induction b0 PPAR-� agonists) #o3ever) var0 genes of t#e lipid metabolism in liver and adipose tissue of pigs$ An greatl0
    [Show full text]
  • PCSK9 Inhibition in Familial Hypercholesterolemia: a Revolution in Treatment
    PCSK9 inhibition in familial hypercholesterolemia: A revolution in treatment Frederick Raal FCP(SA), FRCP, FCRPC, Cert Endo, MMED, PHD Head, Division of Endocrinology & Metabolism Director, Carbohydrate and Lipid Metabolism Research Unit Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa A case of severe hypercholesterolemia Mrs. TDK 50 year old female. Well. Non smoker and no other risk factors for cardiovascular disease. Serum cholesterol measured because of positive family history of coronary artery disease, her father having undergone coronary bypass surgery at age 52. On examination she had arcus cornealis as well as marked thickening of her tendo-Achilles. Mrs TDK, a case of severe hypercholesterolemia Fasting lipid profile Total cholesterol: 15.6 mmol/L Triglycerides: 1.34 mmol/L HDL-cholesterol: 1.8 mmol/L LDL-cholesterol 13.2 mmol/L Heterozygous vs Homozygous FH Heterozygous FH Homozygous FH Prevalence 1:200- 500 Prevalence 1:300 000 -1000 000 LDL-cholesterol LDL-cholesterol 5.0-12 mmol/L 12-20 mmol/L (190-500mg/dL) (500–1000 mg/dL) CHD onset usually age 30-60 yrs CHD onset in early childhood Most patients respond to drug therapy, but individual response Poorly responsive to quite variable lipid-lowering drug therapy Nordestgaard B.G. et al. Eur Heart J 2013;34:3478-3490 Diagnostic definition of homozygous familial hypercholesterolemia . Genetic confirmation of 2 mutant alleles at the LDL receptor, APOB, PCSK9, or ARH adaptor protein gene locus OR . An untreated LDL cholesterol of 13 mmol/L (>500 mg/dL) or treated LDL cholesterol 7.8 mmol/L (≥300 mg/dL) or treated non-HDL cholesterol 8.5 mmol/L (≥330 mg/dL) together with either: - Cutaneous or tendonous xanthoma before age 10 years OR - Elevated LDL cholesterol levels before lipid-lowering therapy consistent with heterozygous FH in both parents* * Except in the case of ARH Raal FJ, Santos RD.
    [Show full text]
  • Pharmaceuticals Appendix
    )&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 ADAPALENE 106685-40-9 ABANOQUIL 90402-40-7 ADAPROLOL 101479-70-3 ABECARNIL 111841-85-1 ADEMETIONINE 17176-17-9 ABLUKAST 96566-25-5 ADENOSINE PHOSPHATE 61-19-8 ABUNIDAZOLE 91017-58-2 ADIBENDAN 100510-33-6 ACADESINE 2627-69-2 ADICILLIN 525-94-0 ACAMPROSATE 77337-76-9 ADIMOLOL 78459-19-5 ACAPRAZINE 55485-20-6 ADINAZOLAM 37115-32-5 ACARBOSE 56180-94-0 ADIPHENINE 64-95-9 ACEBROCHOL 514-50-1 ADIPIODONE 606-17-7 ACEBURIC ACID 26976-72-7 ADITEREN 56066-19-4 ACEBUTOLOL 37517-30-9 ADITOPRIME 56066-63-8 ACECAINIDE 32795-44-1 ADOSOPINE 88124-26-9 ACECARBROMAL 77-66-7 ADOZELESIN 110314-48-2 ACECLIDINE 827-61-2 ADRAFINIL 63547-13-7 ACECLOFENAC 89796-99-6 ADRENALONE 99-45-6 ACEDAPSONE 77-46-3 AFALANINE 2901-75-9 ACEDIASULFONE SODIUM 127-60-6 AFLOQUALONE 56287-74-2 ACEDOBEN 556-08-1 AFUROLOL 65776-67-2 ACEFLURANOL 80595-73-9 AGANODINE 86696-87-9 ACEFURTIAMINE 10072-48-7 AKLOMIDE 3011-89-0 ACEFYLLINE CLOFIBROL 70788-27-1
    [Show full text]
  • Quasi-Experimental Health Policy Research: Evaluation of Universal Health Insurance and Methods for Comparative Effectiveness Research
    Quasi-Experimental Health Policy Research: Evaluation of Universal Health Insurance and Methods for Comparative Effectiveness Research The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Garabedian, Laura Faden. 2013. Quasi-Experimental Health Policy Research: Evaluation of Universal Health Insurance and Methods for Comparative Effectiveness Research. Doctoral dissertation, Harvard University. Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:11156786 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA Quasi-Experimental Health Policy Research: Evaluation of Universal Health Insurance and Methods for Comparative Effectiveness Research A dissertation presented by Laura Faden Garabedian to The Committee on Higher Degrees in Health Policy in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the subject of Health Policy Harvard University Cambridge, Massachusetts March 2013 © 2013 – Laura Faden Garabedian All rights reserved. Professor Stephen Soumerai Laura Faden Garabedian Quasi-Experimental Health Policy Research: Evaluation of Universal Health Insurance and Methods for Comparative Effectiveness Research Abstract This dissertation consists of two empirical papers and one methods paper. The first two papers use quasi-experimental methods to evaluate the impact of universal health insurance reform in Massachusetts (MA) and Thailand and the third paper evaluates the validity of a quasi- experimental method used in comparative effectiveness research (CER). My first paper uses interrupted time series with data from IMS Health to evaluate the impact of Thailand’s universal health insurance and physician payment reform on utilization of medicines for three non-communicable diseases: cancer, cardiovascular disease and diabetes.
    [Show full text]
  • Colesevelam Hydrochloride (Cholestagel) a New, Potent Bile Acid Sequestrant Associated with a Low Incidence of Gastrointestinal Side Effects
    ORIGINAL INVESTIGATION Colesevelam Hydrochloride (Cholestagel) A New, Potent Bile Acid Sequestrant Associated With a Low Incidence of Gastrointestinal Side Effects Michael H. Davidson, MD; Maureen A. Dillon; Bruce Gordon, MD; Peter Jones, MD; Julie Samuels, MD; Stuart Weiss, MD; Jonathon Isaacsohn, MD; Phillip Toth, MD; Steven K. Burke, MD Objectives: To compare colesevelam hydrochloride mg/dL) (19.1%) in the 3.75-g/d colesevelam treatment (Cholestagel), a nonabsorbed hydrogel with bile acid– group. Low-density lipoprotein cholesterol concentra- sequestering properties, with placebo for its lipid- tions at the end of treatment were significantly reduced lowering efficacy, its effects on laboratory and clinical from baseline levels in the 3.0- and 3.75-g/d colesevelam safety parameters, and the incidence of adverse events. treatment groups (P = .01 and P,.001, respectively). To- tal cholesterol levels demonstrated a similar response to Methods: Following diet and placebo lead-in periods, colesevelam treatment, with an 8.1% decrease from base- placebo or colesevelam was administered at 4 dosages (1.5, line in the 3.75-g/d treatment group (P<.001). High- 2.25, 3.0, or 3.75 g/d) for 6 weeks with morning and density lipoprotein cholesterol levels rose significantly evening meals to men and women with hypercholester- in the 3.0- and 3.75-g/d colesevelam treatment groups, olemia (low-density lipoprotein cholesterol level .4.14 by 11.2% (P = .006) and 8.1% (P = .02), respectively. mmol/L [.160 mg/dL]). Patients returned to the clinic Median triglyceride levels did not change from baseline, every 2 weeks throughout the treatment period for lipid nor were there any significant differences between parameter measurements and adverse event assess- treatment groups.
    [Show full text]
  • 06. Barter Evolving Concepots PACE.Pdf
    Evolving concepts in management of patients at increased CV risk Philip Barter, MD Sydney, Australia Evolving concepts in management of patients at increased CV risk? Philip Barter School of Medical Sciences University of New South Wales Sydney, Australia Disclosures Received honorariums for participating as a consultant or as a member of advisory boards for AMGEN, AstraZeneca, CSL-Behring, Lilly, Merck, Novartis, Pfizer and Sanofi and for giving lectures for AMGEN, AstraZeneca, Merck and Pfizer. Major risk factors for Atherosclerotic Cardiovascular Disease (ASCVD) • Age • Gender • Smoking • Elevated LDL-C • Elevated triglyceride-rich lipoproteins • Reduced HDL-C • Elevated blood pressure • Diabetes • Abdominal obesity Modifiable risk factors for ASCVD • Smoking • Elevated LDL-C • Elevated triglyceride-rich lipoproteins • Reduced HDL-C • Elevated blood pressure • Diabetes • Abdominal obesity Modifiable risk factors for ASCVD • Smoking • Elevated LDL-C • Elevated triglyceride-rich lipoproteins • Reduced HDL-C • Elevated blood pressure • Diabetes • Abdominal obesity Treatment with statins has been shown in many trials to reduce the risk of having an atherosclerotic cardiovascular event In these statin trials, the more the LDL-C is reduced, the greater is the reduction in risk of having an event. Relationship of CVD events to LDL-C reduction achieved in statin clinical trials CTT Collaboration. Lancet 2005; 366:1267-78; Lancet 2010;376:1670-81. And the lower the achieved level of LDL-C, the lower the risk of having an event Secondary Prevention
    [Show full text]
  • Download Product Insert (PDF)
    PRODUCT INFORMATION Etofibrate Item No. 21022 CAS Registry No.: 31637-97-5 Formal Name: ​3-pyridinecarboxylic acid, Cl 2-[2-(4-chlorophenoxy)-2-methyl- O 1-oxopropoxy]ethyl ester O Synonym: Nicotinic Acid O O N MF: C18H18ClNO5 O FW: 363.8 Purity: ≥98% UV/Vis.: λmax: 222, 263 nm Supplied as: A crystalline solid Storage: -20°C Stability: ≥2 years Information represents the product specifications. Batch specific analytical results are provided on each certificate of analysis. Laboratory Procedures Etofibrate is supplied as a crystalline solid. A stock solution may be made by dissolving the etofibrate in the solvent of choice. Etofibrate is soluble in organic solvents such as ethanol, DMSO, and dimethyl formamide (DMF), which should be purged with an inert gas. The solubility of etofibrate in ethanol and DMSO is approximately 80 mg/ml and approximately 50 mg/ml in DMF. Etofibrate is sparingly soluble in aqueous buffers. For maximum solubility in aqueous buffers, etofibrate should first be dissolved in ethanol and then diluted with the aqueous buffer of choice. Etofibrate has a solubility of approximately 0.1 mg/ml in a 1:5 solution of ethanol:PBS (pH 7.2) using this method. We do not recommend storing the aqueous solution for more than one day. Description Etofibrate is a combination of niacin and clofibrate (Item No. 10956) that acts as a hypolipidemic agent.1 In vivo, etofibrate decreases plasma cholesterol and triglyceride concentrations and increases bile cholesterol content in rats.1,2 It also decreases thromboxane formation, platelet aggregation, and plasma viscosity and inhibits neointima formation in a carotid artery balloon injury rat model.3 Formulations containing etofibrate have been used to treat hyperlipidemia.
    [Show full text]
  • Rosuvastatin
    Rosuvastatin Rosuvastatin Systematic (IUPAC) name (3R,5S,6E)-7-[4-(4-fluorophenyl)-2-(N-methylmethanesulfonamido)-6-(propan- 2-yl)pyrimidin-5-yl]-3,5-dihydroxyhept-6-enoic acid Clinical data Trade names Crestor AHFS/Drugs.com monograph MedlinePlus a603033 Pregnancy AU: D category US: X (Contraindicated) Legal status AU: Prescription Only (S4) UK: Prescription-only (POM) US: ℞-only Routes of oral administration Pharmacokinetic data Bioavailability 20%[1] Protein binding 88%[1] Metabolism Liver (CYP2C9(major) andCYP2C19-mediated; only minimally (~10%) metabolised)[1] Biological half-life 19 hours[1] Excretion Faeces (90%)[1] Identifiers CAS Registry 287714-41-4 Number ATC code C10AA07 PubChem CID: 446157 IUPHAR/BPS 2954 DrugBank DB01098 UNII 413KH5ZJ73 KEGG D01915 ChEBI CHEBI:38545 ChEMBL CHEMBL1496 PDB ligand ID FBI (PDBe, RCSB PDB) Chemical data Formula C22H28FN3O6S Molecular mass 481.539 SMILES[show] InChI[show] (what is this?) (verify) Rosuvastatin (marketed by AstraZenecaas Crestor) 10 mg tablets Rosuvastatin, marketed as Crestor, is a member of the drug class of statins, used in combination with exercise, diet, and weight-loss to treat high cholesterol and related conditions, and to prevent cardiovascular disease. It was developed by Shionogi. Crestor is the fourth- highest selling drug in the United States, accounting for approx. $5.2 billion in sales in 2013.[2] Contents [hide] 1Medical uses 2Side effects and contraindications 3Drug interactions 4Structure 5Mechanism of action 6Pharmacokinetics 7Indications and regulation
    [Show full text]
  • Pharmacological Targeting of the Atherogenic Dyslipidemia Complex: the Next Frontier in CVD Prevention Beyond Lowering LDL Cholesterol
    Diabetes Volume 65, July 2016 1767 Changting Xiao,1 Satya Dash,1 Cecilia Morgantini,1 Robert A. Hegele,2 and Gary F. Lewis1 Pharmacological Targeting of the Atherogenic Dyslipidemia Complex: The Next Frontier in CVD Prevention Beyond Lowering LDL Cholesterol Diabetes 2016;65:1767–1778 | DOI: 10.2337/db16-0046 Notwithstanding the effectiveness of lowering LDL cho- has been the primary goal of dyslipidemia management, lesterol, residual CVD risk remains in high-risk popula- with statins as the treatment of choice for CVD prevention. tions, including patients with diabetes, likely contributed Large-scale, randomized, clinical trials of LDL-lowering PERSPECTIVES IN DIABETES to by non-LDL lipid abnormalities. In this Perspectives therapies have demonstrated significant reduction in CVD in Diabetes article, we emphasize that changing demo- events over a wide range of baseline LDL-C levels (2,3). graphics and lifestyles over the past few decades have However, even with LDL-C levels lowered substantially or “ resulted in an epidemic of the atherogenic dyslipidemia at treatment goals with statin therapy, CVD risks are not ” complex, the main features of which include hypertrigly- eliminated and there remains significant “residual risk.” In- ceridemia, low HDL cholesterol levels, qualitative changes tensifying statin therapy may provide additional benefits in LDL particles, accumulation of remnant lipoproteins, (4,5); this approach, however, has limited potential, owing and postprandial hyperlipidemia. We brieflyreviewthe to tolerability, side effects, and finite efficacy. Further LDL-C underlying pathophysiology of this form of dyslipidemia, lowering may also be achieved with the use of nonstatin in particular its association with insulin resistance, obe- sity, and type 2 diabetes, and the marked atherogenicity agents, such as cholesterol absorption inhibitors and PCSK9 of this condition.
    [Show full text]