DOCSLIB.ORG

(12) United States Patent (10) Patent No.: US 6,365,186 B1 Huval Et Al

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

USOO63651.86B1 (12) United States Patent (10) Patent No.: US 6,365,186 B1 Huval et al. (45) Date of Patent: *Apr. 2, 2002 (54) COMBINATION THERAPY FOR TREATING EP 326386 8/1989 HYPERCHOLESTEROLEMIA EP 329 124 8/1989 EP 36932.3 5/1990 (75) Inventors: Chad Cori Huval, Somerville; Stephen EP O 375 350 A2 6/1990 Randall Holmes-Farley, Arlington; EP 380392 B1 8/1990 John S. Petersen, Acton; Pradeep K. E. 3. B1 3.1991/1991 Dhal, Westford, all of MA (US) EP 464.845 B1 1/1992 EP O 580 O78 A1 1/1994 (73) ASSignee: GelTex Pharmaceuticals, Inc., EP O 580 O79 A1 1/1994 Waltham, MA (US) EP O 665 245 A1 8/1995 GB 86O303 2/1961 (*) Notice: Subject to any disclaimer, the term of this GB 2 O90 605 A 7/1982 patent is extended or adjusted under 35 GB 227.0312 3/1994 U.S.C. 154(b) by 0 days. GB 2329 334 3/1999 JP 56-51992 5/1981 This patent is Subject to a terminal dis- E. 3.E. claimer. WO WO 90/OO897 2/1990 WO WO 98/291.07 7/1998 (21) Appl. No.: 09/311,103 WO WO 98/40375 9/1998 (22) Filed: May 13, 1999 OTHER PUBLICATIONS Related U.S. Application Data McCarthy, P.A., “New Approaches to Atherosclerosis: An Overview,” Medicinal Research Reviews, 13(2):139-159 (63) Continuation-in-part of application No. 08/964,536, filed on (1993). Nov. 5, 1997, now Pat. No. 6,083,497. Heming, A.E. and Flanagan, T.L., “Considerations in the (51) Int. Cl." ........................ A61K 9/10; A61K 31/787; Selection of Cation Exchange Resins for Therapeutic Use,” A61P 9/10 In Annals of the New York Academy of Sciences, 57:239-251 (52) U.S. Cl. ........................................ 424/486; 514/824 (1954). (58) Field of Search ................................. 424/400, 486, Harada, Susumu and Kunio Arai, “The Cyclo-copolymer 424/78.35, 78.14, 78.15; 514/824 ization of Diallyl Compounds and Sulfur Dioxide, II. Dial lyldimethylammonium Chloride and Sulfur Dioxide,” Die (56) References Cited Makromolekulare Chemie 107:64-77 (1967). U.S. PATENT DOCUMENTS (List continued on next page.) 2.926,161 A 2/1960 Butler et al. ............... 260/89.7 3.262,850 A 7/1966 Jones et al. ................... 167/65 Primary Examiner Edward J. Webman 3.288,770 A 11/1966 Butler .......... ... 260/88.3 (74) Attorney, Agent, or Firm-Hamilton, Brook, Smith & 3,369,025 A 2/1968 Bolhofer et al. .. ... 260/295 Reynolds, P.C. 3,494.957 A 2/1970 Nakanishi et al. .......... 260/473 3,607.909 A 9/1971 Boulogne et al. ....... 260/477 R (57) ABSTRACT 3,674,836 A 7/1972 Creger ................... 260/473 G 3,700,623 A 10/1972 Keim .................... 260/80.3 R The invention relates to methods for treating hypercholes 3,716,583 A 2/1973 Nakamura et al. .......... 260/520 terolemia and atherosclerosis, and reducing Serum choles 3,723,446 A 3/1973 Scherm et al. ........ 260/295.5 R terol in a mammal. The methods of the invention comprise 3,781,328 A 12/1973 Witte et al. ............. 260/471 R administering to a mammal a first amount of a bile acid 3,833,531 A 9/1974 Keim ........ ... 260/29.6 CM Sequestrant compound which is an unsubstituted polydial 3,840,504. A 10/1974 Keim .................... 260/79.3 A lylamine polymer and a Second amount of a cholesterol 3,948,973 A 4/1976 Phillips ..... ... 260/473 lowering agent. The first and Second amounts together 3.966,694 A 6/1976 Espy et al. ... ... 526/11.2 3,971,798. A 7/1976 Humbert et al. ............ 2600s comprise a therapeutically effective amount. (List continued on next page.) The invention further relates to pharmaceutical composi tions useful for the treatment of hypercholesterolemia and FOREIGN PATENT DOCUMENTS atherOSclerosis, and for reducing Serum cholesterol. The CA 2007641 8/1990 pharmaceutical compositions comprise a combination of a CA 20164.67 12/1990 first amount of an unsubstituted polydiallylamine polymer DE 2038835 2/1971 compound and a Second amount of a cholesterol-lowering DE 214907O 4/1973 agent. The first and Second amounts comprise a therapeuti DE 2250327 4/1973 cally effective amount. The pharmaceutical compositions of DE 312.2499 12/1981 the present invention may optionally contain a pharmaceu EP 22478 B1 1/1981 tically acceptable carrier. EP 33538 B1 8/1981 EP 244364 11/1987 EP 245003 11/1987 EP 321090 6/1989 30 Claims, No Drawings US 6,365,186 B1 Page 2 U.S. PATENT DOCUMENTS Falck, J.R. and Yang, Y-L., “Total Synthesis of (+)-Dihy 3,983,140 A 9/1976 Endo et al. .............. 260/343.5 dromevinolin.” Tetrahedron Lett., 25(33), 3563-66 (1984). 3,984,413 A 10/1976 Metz et al. ................. 260/254 Beck, G., et al., “Synthesis and Biological Activity of New 3.990,958 A 11/1976 Sasse ........ ... 204/159.22 4,049,813 A 9/1977 Nadelson .................... 424/263 HMG-CoA Reductase Inhibitors. 1. Lactones of Pyridine 4,058,552 A 11/1977 Mieville ...................... 560/52 and Pyrimidine-Substituted 3,5-Dihydroxy-6-heptenoic 4,121.986 A 10/1978 Battaerd ................ 204/159.22 (-heptanoic) Acids,” J. Med. Chem., 33(1), 52-60 (1990). 4,230,626 A 10/1980 Chorvat ................... 260/397.2 4231938 A 11/1980 Monaghan et al. ...... 260/343.5 Jendralla, H., et al., “Synthesis and Biological Activity of 4,298.715 A 11/1981 Van Eenam ......... ... 525/340 New HMG-CoA Reductase Inhibitors. 3. Lactones of 4,346.227 A 8/1982 Terahara et al. .. ... 560/119 6-Phenoxy-3,5-dihydroxyhexanoic Acids,” J. Med. Chem., 4,444,784. A 4/1984 Hoffman et al. ............ 424/279 34(10) 2962–83 (1991). 4,450,171 A 5/1984 Hoffman et al. ............ 424/279 4,452.957 A 6/1984 Neigel ......................... 526/71 Chiang, Y-C.P., et al., “Total Synthesis of L-659,699, a 4.483,999 A 11/1984 Thiele et al. ................. 560/57 Novel Inhibitor of Cholesterol Biosynthesis,” J. Org. Chem., 4,739,073. A 4/1988 Kathawala .... ... 548/406 4,759,923 A 7/1988 Buntin et al. .. ... 424/440 54(24), 5708–12 (1989). 4,812,540 A 3/1989 Kageno et al. ... 526/218.1 Ogawa, H., et al., "Pannorin, A New 4.937,259 A 6/1990 Lee .................. ... 514/460 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase 5,134,155 A 7/1992 Connolly et al. ... 514/403 5,200,482 A 4f1993 Gartner ............ ... 526/295 Inhibitor Produced by Chrysosporium pannorum,” J. Anti 5,273.995 A 12/1993 Roth ................ ... 514/422 biot., 44(7), 762–7 (1991). 5,274,155 A 12/1993 Thottathi et al. ... 556/405 Carte, B.K., et al., “Rawsonol, An Inhibitor of HMG-CoA 5,316,765 A 5/1994 Folkers et al. .... ... 424/94.1 5,428,112 A 6/1995 Ahlers et al. ..... ... 525/326.7 Reductase from the Tropical Green Alga Avrain villea Raw 5,430,110 A 7/1995 Ahlers et al. ..... ... 525/328.2 Soni,” Phytochemistry, 28(11), 2917–19 (1989). 5,462,730 A 10/1995 McTaggart et al. ...... 424/78.35 5,607,669 A 3/1997 Mandeville, III Baumann, K.L., et al., “The Convergent Synthesis of et al. ....................... 424/78.12 CI-981, an Optically Active, Highly Potent, Tissue selective 5,618,530 A 4/1997 Mandeville, III Inhibitor of HMG-CoA Reductase.” Tetrahedron Lett., et al. ....................... 424/78.12 33(17), 2283–4 (1992). 5,624.963 A 4/1997 Mandeville, III et al. ... 514/789 5,679,717 A 10/1997 Mandeville, III et al. ... 514/742 Larsen, S.D., et al., “Design and Synthesis of Seco-oxys 5,693,675 A 12/1997 Mandeville, III et al. ... 514/742 terol Analogs S Potential Inhibitors of 5,703,188 A 12/1997 Mandeville, III et al. ... 526/290 3-Hydroxy-3-methylglutaryl-Coenzyme A (HMG-CoA) 6,083,497 A * 7/2000 Huval et al. Reductase Gene Transcription,” J. Med. Chem., 37(15), OTHER PUBLICATIONS 2343–51 (1994). Negi, Youji et al., “Cyclopolymerization of Diallylamine Kumar, N., et al., “Separation of Derivatives in Dimethyl Sulfoxide,” Journal of Polymer 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibi Science: Part A-1, 5:1951–1965 (1967). tor drug Substance diastereomers, and their analogues on Kuron, G.W. et al., “The Bile Acid Binding and Hypocho B-cyclodextrin Stationary phase,” J. Chromatrogr: A, lesterolemic Action of Two Water-soluble Polymers,” Ath 678(2): 259-63 (1994). erosclerosis 37:353–360 (1980). Stokker, G.E., “Synthesis of L-669,262, a Potent HMG Hodgkin, J.H. et al., “Use of 'C-NMR in the Study of CoA Reductase Inhibitor,” J. Org. Chem., 59(20), 5983-6 Reactions on Crosslinked Resins,” Journal of Polymer Sci (1994). ence 19(5):1239–1249 (1981). United States Serial No. 08/777,408, filed on Dec. 30, 1996, Kramer, W., et al., “Bile Acid Derived HMG-CoA Reduc “Poly(diallylamine)-Based Bile Acid Sequestrant” by tase Inhibitors,” Biochimica et Biophysica Acta, 1227(3), Stephen Randall Holmes-Farley, Pradeep K. Dhal and John 137-54 (1994). S. PeterSen. Huang, Y. and Hall, I.H., “Hypolipidemic Effects of C, B, Takano, S., et al., “Enantioconvergent Synthesis of a Prom and Y-Alkylaminophenone Analogs in Rodents, Eur: J. ising HMG Co-A Reductase Inhibitor NK-104 from Both Enantiomers of Epichlorohydrin.” Tetrahedron ASSymetry, Med. Chem., 31(4), 281–90 (1996). 4(2), 201–4 (1993). Huang, Y. and Hall, I.H., “Hypolipidemic Activity of Sood, A., et al., “Boron analogues of amino acids VI.
Recommended publications
  • Triggering of Erythrocyte Death by Triparanol

    Triggering of Erythrocyte Death by Triparanol

    Toxins 2015, 7, 3359-3371; doi:10.3390/toxins7083359 OPEN ACCESS toxins ISSN 2072-6651 www.mdpi.com/journal/toxins Article Triggering of Erythrocyte Death by Triparanol Arbace Officioso 1,2, Caterina Manna 2, Kousi Alzoubi 1 and Florian Lang 1,* 1 Department of Physiology, University of Tübingen, Gmelinstr. 5, 72076 Tuebingen, Germany; E-Mails: [email protected] (A.O.); [email protected] (K.A.) 2 Department of Biochemistry, Biophysics and General Pathology, School of Medicine and Surgery, Second University of Naples, Via L. De Crecchio 7, 80138 Naples, Italy; E-Mail: [email protected] * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +49-7071-29-72194; Fax: +49-7071-29-5618. Academic Editor: Azzam Maghazachi Received: 22 July 2015 / Accepted: 12 August 2015 / Published: 24 August 2015 Abstract: The cholesterol synthesis inhibitor Triparanol has been shown to trigger apoptosis in several malignancies. Similar to the apoptosis of nucleated cells, erythrocytes may enter eryptosis, the suicidal death characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Triggers of eryptosis include oxidative stress which may activate erythrocytic Ca2+ permeable unselective cation 2+ 2+ 2+ channels with subsequent Ca entry and increase of cytosolic Ca activity ([Ca ]i). The present study explored whether and how Triparanol induces eryptosis. To this end, phosphatidylserine exposure at the cell surface was estimated from annexin-V-binding, cell 2+ volume from forward scatter, hemolysis from hemoglobin release, [Ca ]i from Fluo3-fluorescence, and ROS formation from 2’,7’-dichlorodihydrofluorescein diacetate (DCFDA) dependent fluorescence.
  • (12) Patent Application Publication (10) Pub. No.: US 2004/0224012 A1 Suvanprakorn Et Al

    (12) Patent Application Publication (10) Pub. No.: US 2004/0224012 A1 Suvanprakorn Et Al

    US 2004O224012A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0224012 A1 Suvanprakorn et al. (43) Pub. Date: Nov. 11, 2004 (54) TOPICAL APPLICATION AND METHODS Related U.S. Application Data FOR ADMINISTRATION OF ACTIVE AGENTS USING LIPOSOME MACRO-BEADS (63) Continuation-in-part of application No. 10/264,205, filed on Oct. 3, 2002. (76) Inventors: Pichit Suvanprakorn, Bangkok (TH); (60) Provisional application No. 60/327,643, filed on Oct. Tanusin Ploysangam, Bangkok (TH); 5, 2001. Lerson Tanasugarn, Bangkok (TH); Suwalee Chandrkrachang, Bangkok Publication Classification (TH); Nardo Zaias, Miami Beach, FL (US) (51) Int. CI.7. A61K 9/127; A61K 9/14 (52) U.S. Cl. ............................................ 424/450; 424/489 Correspondence Address: (57) ABSTRACT Eric G. Masamori 6520 Ridgewood Drive A topical application and methods for administration of Castro Valley, CA 94.552 (US) active agents encapsulated within non-permeable macro beads to enable a wider range of delivery vehicles, to provide longer product shelf-life, to allow multiple active (21) Appl. No.: 10/864,149 agents within the composition, to allow the controlled use of the active agents, to provide protected and designable release features and to provide visual inspection for damage (22) Filed: Jun. 9, 2004 and inconsistency. US 2004/0224012 A1 Nov. 11, 2004 TOPCAL APPLICATION AND METHODS FOR 0006 Various limitations on the shelf-life and use of ADMINISTRATION OF ACTIVE AGENTS USING liposome compounds exist due to the relatively fragile LPOSOME MACRO-BEADS nature of liposomes. Major problems encountered during liposome drug Storage in vesicular Suspension are the chemi CROSS REFERENCE TO OTHER cal alterations of the lipoSome compounds, Such as phos APPLICATIONS pholipids, cholesterols, ceramides, leading to potentially toxic degradation of the products, leakage of the drug from 0001) This application claims the benefit of U.S.
  • Clinical and Laboratory Responses to Niceritrol in the Treatment of Hypercholesterolaemia

    Clinical and Laboratory Responses to Niceritrol in the Treatment of Hypercholesterolaemia

    Postgrad Med J: first published as 10.1136/pgmj.64.755.672 on 1 September 1988. Downloaded from Postgraduate Medical Journal (1988) 64, 672-675 Clinical and laboratory responses to niceritrol in the treatment of hypercholesterolaemia L.D. Curtis,' J.P.D. Reckless,2 A.F. Winder3 and D.J. Betteridge1 1Department of Medicine, University College and Middlesex School of Medicine, University College London, 2Royal United Hospital, Bath and 3Leicester Royal Infirmary, Leicester, UK. Summary: Twenty-five hypercholesterolaemic patients from three centres in the UK were investigated in an open study of the efficacy and side effects of niceritrol. Five patients dropped out of the study at an early stage and had insufficient data for analysis. There were 13 males and 7 females (mean age 49.2 years, range 18-69). Fourteen patients had heterozygous familial hyperchol- esterolaemia, and six polygenic hypercholesterolaemia. Niceritrol was started at a dose of 750mg/ day and this was increased at weekly intervals over 4 weeks to the maximum tolerated dosage up to 3 g/day. This was then maintained for a further 8 weeks. There were statistically significant decreases in total plasma cholesterol, total triglyceride, LDL cholesterol and VLDL triglyceride; HDL cholesterol remained unchanged after 12 weeks of treatment (Wilcoxon matched pairs, signed ranks test). The 14 patients with familial hypercholesterolaemia showed a 13.9% fall in total cholesterol and a 19.8% fall in LDL cholesterol. All patients reported flushing and some had Protected by copyright. gastrointestinal symptoms but 19 would have been prepared to continue with the therapy at doses up to 3g/day.
  • HMG-Coa Reductase (HMGCR)

    HMG-Coa Reductase (HMGCR)

    HMG-CoA Reductase (HMGCR) HMG-CoA Reductase (HMGCR) is the rate-limiting enzyme for cholesterol synthesis in the conversion of HMG-CoA to mevalonate. HMGCR is found in eukaryotes and prokaryotes. The phylogenetic analysis has revealed two classes of HMG-CoA reductase, the Class I enzymes of eukaryotes and some archaea and the Class II enzymes of eubacteria and certain other archaea. Both in eukaryotes and in archaebacteria the enzyme HMGCR is known to catalyze an early reaction unique to isoprenoid biosynthesis. In humans, the HMG-CoA reductase reaction is rate-limiting for the biosynthesis of cholesterol and therefore constitutes a prime target of drugs that reduce serum cholesterol levels. www.MedChemExpress.com 1 HMG-CoA Reductase (HMGCR) Inhibitors (3R,5R)-Rosuvastatin (3R,5S)-Fluvastatin Cat. No.: HY-17504C ((3R,5S)-XU 62-320 free acid) Cat. No.: HY-14664B (3R,5R)-Rosuvastatin is the (3R,5R)-enantiomer of (3R,5S)-Fluvastatin is the Rosuvastatin. Rosuvastatin is a competitive 3R,5S-isomer Fluvastatin. Fluvastatin (XU HMG-CoA reductase inhibitor with an IC50 of 11 62-320 free acid) is a first fully synthetic, nM. Rosuvastatin potently blocks human competitive HMG-CoA reductase inhibitor with ether-a-go-go related gene (hERG) current with an an IC50 of 8 nM. IC50 of 195 nM. Purity: >98% Purity: >98% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 1 mg, 5 mg Size: 1 mg, 5 mg (3S,5R)-Fluvastatin D6 sodium (3S,5R)-Fluvastatin sodium ((3S,5R)-XU 62-320 D6) Cat. No.: HY-14664CS ((3S,5R)-XU 62-320) Cat.
  • FIELD Study Revealed Fenofibrate Reduced Need for Laser Treatment for Diabetic Retinopathy by Anthony C

    FIELD Study Revealed Fenofibrate Reduced Need for Laser Treatment for Diabetic Retinopathy by Anthony C

    Supplement to Supported by an unrestricted educational grant from Abbott Laboratories March/April 2008 FIELD Study Revealed Fenofibrate Reduced Need for Laser Treatment for Diabetic Retinopathy By Anthony C. Keech, MBBS, Msc Epid, FRANZCS, FRACP; and Paul Mitchell, MBBS(Hons), MD, PhD, FRANZCO, FRACS, FRCOphth, FAFPHM This agent’s mechanism of benefit in diabetic retinopathy appears to go beyond its effects on lipid concentration or blood pressure, and this potential mechanism of action operates even when glycemic control and blood pressure levels are within goal. ABSTRACT icant relative reduction was seen of almost one-third in PURPOSE the rate of first laser application for retinopathy after The FIELD (Fenofibrate Intervention and Event an average treatment duration of 5 years with fenofi- Lowering in Diabetes) study sought to investigate brate 200 mg/day. whether long-term lipid-lowering therapy with fenofi- In this report, we detail the effects of fenofibrate brate would reduce macro- and microvascular compli- administration on ophthalmic microvascular compli- cations among patients with type 2 diabetes. We previ- cations and attempt to clarify some of the underlying ously reported that in type 2 diabetes patients with pathologies being addressed among patients undergo- adequate glycemic and blood pressure control, a signif- ing laser treatment. Jointly sponsored by The Dulaney Foundation and Retina Today MARCH/APRIL 2008 I SUPPLEMENT TO RETINA TODAY I 1 FIELD Study Revealed Fenofibrate Reduced Need for Laser Treatment for Diabetic Retinopathy Jointly sponsored by The Dulaney Foundation and Retina Today. Release date: April 2008. Expiration date: April 2009. This continuing medical education activity is supported by an unrestricted educational grant from Abbott Laboratories.
  • PHARMACEUTICAL APPENDIX to the TARIFF SCHEDULE 2 Table 1

    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.
  • Profile Profile Uses and Administration Adverse Effects And

    Profile Profile Uses and Administration Adverse Effects And

    Etacrynic Acid/Ezetimibe 1379 unchanged and partly in the form of metabolites. It is Efortil; Etilefril; Chile: Elfortilt; Fin.: Elfortil; Fr.: Effortil; Ger.: over 10 years, may be given ezetimibe for the same indica­ extensively bound to plasma proteins. Bioflutin; Effortil; Etil; Pholdyston; Thomasin; Gr.: Effortil; tions and at the same doses as in adults (see above). ' Efortil; Ita/. : Elfortil; Jpn: Effortil; Mex.: Effortil; Quimtatil; Pol.: Effortil; Port.: Effortil; S.Afr.: Effortilt; Spain: Efortil; Swed.: Hyperlipidaemias. Ezetimibe inhibits the absorption of �:.�!?.�.��.!��-��--·········································································· Effortil; Switz. : Effortil; Thai.: Buracard; Circula; Circuman; dietary cholesterol' and, although there is a compensatory Proprietary Preparations (details are given in Volume B) Venez. : Elfortilt; Effrine; Efxine; Hyposia; Hyprosiat; Effontil. increase in cholesterol synthesis in the liver.' overall Single-ingredient Preparations. Austral.: Edecrin; Canad.: Multi-ingredient Preparations. Austria: Agilan; Amphodynt; plasma LDL-cholesterol concentrations are reduced.2 Ezeti­ Edecrin; Hung.: Uregyt; Ita!. : Reomax; Rus.: Uregyt (Ypei"HT); Effortil camp; Hypodynt; Influbenet; Ger.: Dibydergot plus; mibe may be used alone' in the management of hyperlipi­ Ukr.: Uregyt (YperHT); USA: Edecrin. Effortil plust; Switz.: Dibydergot plust; Elfortil plust. daentias (p. 1248.1) but use with lipid regulating drugs Phannacopoeial Preparations that act by reducing cholesterol synthesis may
  • Inhibition of Cholesterol Biosynthesis in Hypercholesterolemia

    Inhibition of Cholesterol Biosynthesis in Hypercholesterolemia

    J Med Biochem 2013; 32 (1) DOI: 10.2478/v10011-012-0020-3 UDK 577.1 : 61 ISSN 1452-8258 J Med Biochem 32: 16–19, 2013 Review article Pregledni ~lanak INHIBITION OF CHOLESTEROL BIOSYNTHESIS IN HYPERCHOLESTEROLEMIA – IS IT THE RIGHT CHOICE? INHIBICIJA BIOSINTEZE HOLESTEROLA U HIPERHOLESTEROLEMIJI – DA LI JE PRAVI IZBOR? Abdurrahman Coskun, Mustafa Serteser, Ibrahim Unsal Acibadem University, School of Medicine, Department of Biochemistry, Istanbul, Turkey Summary: Cholesterol biosynthesis is a complex pathway Kratak sadr`aj: Biosinteza holesterola je kompleksan me - comprising more than 20 biochemical reactions. Although ta boli~ki put koji obuhvata vi{e od 20 biohemijskih reakcija. the final product created in the pathway is cholesterol, the Iako je kona~an proizvod koji nastaje holesterol, interme- intermediate products, such as ubiquinone and dolichol, also dijerni proizvodi, kao {to su ubihinon i dolihol, tako|e obez- provide vital metabolic functions. Statins are HGM-CoA be |u ju vitalne metaboli~ke funkcije. Statini su inhibitori reductase inhibitors that stop the production of cholesterol HMG-KoA reduktaze koji zaustavljaju produkciju holestero- by directly inhibiting the mevalonate production. Mevalonate la di rektnom inhibicijom produkcije mevalonata. Mevalonat is a precursor of two additional vital molecules, squalene and je prekursor dva dodatna vitalna molekula, skvalena i ubihi - ubiquinone (coenzyme Q10). We hypothesized that inhibit- no na (koenzim Q10). Postavili smo hipotezu da produ`eno ing the cholesterol biosynthesis with statins for an extended trajanje inhibicije biosinteze holesterola statinima mo`e da duration may potentiate the oxidative stress, neurodegener- po tencira oksidativni stres, neurodegenerativne bolesti i ative disease and cancer. Our recommendation was to meas- kan cer.
  • The Effectiveness of Statins for Primary Prevention: a Rapid Review

    The Effectiveness of Statins for Primary Prevention: a Rapid Review

    The Effectiveness of Statins for Primary Prevention: A Rapid Review A Schaink February 2013 Effectiveness of Statins for Primary Prevention: A Rapid Review. February 2013; pp. 1–23. Suggested Citation This report should be cited as follows: Schaink A. The effectiveness of statins for primary prevention: a rapid review. Toronto, ON: Health Quality Ontario; 2013 Feb. 23 p. Available from: http://www.hqontario.ca/evidence/publications-and-ohtac- recommendations/rapid-reviews. Conflict of Interest Statement All reports prepared by the Division of Evidence Development and Standards at Health Quality Ontario are impartial. There are no competing interests or conflicts of interest to declare. Rapid Review Methodology Clinical questions are developed by the Division of Evidence Development and Standards at Health Quality Ontario in consultation with experts, end-users, and/or applicants in the topic area. A systematic literature search is then conducted to identify relevant systematic reviews, health technology assessments, and meta-analyses; if none are located, the search is expanded to include randomized controlled trials (RCTs), and guidelines. Systematic reviews are evaluated using a rating scale developed for this purpose. If the systematic review has evaluated the included primary studies using the GRADE Working Group criteria (http://www.gradeworkinggroup.org/index.htm), the results are reported and the rapid review process is complete. If the systematic review has not evaluated the primary studies using GRADE, the primary studies included in the systematic review are retrieved and a maximum of two outcomes are graded. If no well-conducted systematic reviews are available, RCTs and/or guidelines are evaluated. Because rapid reviews are completed in very short timeframes, other publication types are not included.
  • Cardiovascular Disease Dyslipidemia | Non-Pharmacologic Treatment |

    Cardiovascular Disease Dyslipidemia | Non-Pharmacologic Treatment |

    Cardiovascular Disease Dyslipidemia: Non-Pharmacologic Treatment Mark C. Houston, M.D., M.S. ABAARM, FACP, FACN, FAHA, FASH INTRODUCTION Cardiovascular disease (CVD) is the number one cause of morbidity and mortality in the United States,1 coronary heart disease (CHD) and myocardial infarction being the leading causes of death.1 The five major risk factors for CHD – hypertension, dyslipidemia, diabetes mellitus, smoking, and obesity – account for 80% of the risk for CHD.1,2 Interventions, both pharmacologic and nonpharmacologic, can improve all of these risk factors and decrease the incidence of CVD and its consequences, such as 3-6 myocardial infarction, angina, congestive heart failure and stroke. Recent guidelines by the National Cholesterol Education Program (NCEP) recommend more aggressive control of serum lipids to reduce the incidence of CHD.7 Nutritional and dietary therapy, weight loss, exercise, and scientifically-proven nutritional supplementation should be used initially in appropriately selected patients to manage dyslipidemia. Hypertriglyceridemia, which is frequently due to obesity, insulin resistance, metabolic syndrome and diabetes mellitus, deserves special attention.7 Pharmacologic therapy should be administered in those cases that are at high or very high-risk for CHD and those who do not respond to non-drug therapy. Many patients prefer non-drug therapies for many reasons including adverse effects of anti-lipid drugs, contraindications or allergic reactions to drugs, perceptions of adverse effects of drugs, or personal preference for natural or alternative therapies. A more aggressive integrative approach to the management of dyslipidemia is recommended to improve CHD outcomes, minimize adverse effects, and reduce health-care costs. NUTRITION AND EXERCISE Optimal nutrition and proper aerobic and resistance exercise form the cornerstone for the management of dyslipidemia.
  • Information to Users

    Information to Users

    INFORMATION TO USERS This manuscript has been reproduced from the microfilm master. UMI films the text directly from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter face, while others may be from any type of computer printer. The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleedthrough, substandard margins, and improper alignment can adversely affect reproduction. In the unlikely event that the author did not send UMI a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note will indicate the deletion. Oversize materials (e.g., maps, drawings, charts) are reproduced by sectioning the original, beginning at the upper left-hand corner and continuing from left to right in equal sections with small overlaps. Each original is also photographed in one exposure and is included in reduced form at the back of the book. Photographs included in the original manuscript have been reproduced xerographically in this copy. Higher quality 6" x 9" black and white photographic prints are available for any photographs or illustrations appearing in this copy for an additional charge. Contact UMI directly to order. University Microfilms International A Bell & Howell Information Company 300 North Zeeb Road, Ann Arbor, Ml 48106-1346 USA 313/761-4700 800/521-0600 Order Number 0211150 The role of fatty acids and related analogs in mediating peroxisome proliferation in primary cultures of rat hepatocytes Intrasuksri, Urusa, Ph.D.
  • Joint Assessment Report Was Discussed by the Phvwp at Its Meeting in July 2007 and Finalised in September 2007

    Joint Assessment Report Was Discussed by the Phvwp at Its Meeting in July 2007 and Finalised in September 2007

    ASSESSMENT REPORT on the benefit:risk of fibrates EXECUTIVE SUMMARY 1. BACKGROUND In the light of the established role of statins in the primary and secondary prevention of cardiovascular disease (CVD) and safety concerns arising from the use of fibrates, the CHMP Pharmacovigilance Working Party (PhVWP) agreed to undertake a benefit:risk assessment of this class of medicines. The objective was to establish the current place of fibrates in the treatment of cardiovascular and dyslipidaemic diseases, and in diabetes mellitus; also to provide recommendations regarding amendments of the Summary of Product Characteristics (SPC), as necessary. Fibrates exert their effects mainly by activating the peroxisome proliferator-activated receptor-alpha (PPAR-alpha). Unique in this class, bezafibrate is an agonist for all three PPAR isoforms alpha, gamma, and delta. Fibrates have been shown to reduce plasma triglycerides by 30% to 50% and raise the level of high density lipoprotein cholesterol (HDL- C) by 2% to 20%. Their effect on low density lipoprotein cholesterol (LDL-C) is variable, ranging from no effect to a small decrease of the order of 10%. Today there are four licensed fibrates: bezafibrate, fenofibrate, gemfibrozil and ciprofibrate. Their currently approved indications are quite broad and in many cases still use the old Fredrickson classification for dyslipidaemias. 2. METHODOLOGY In February 2006 a List of Questions was agreed by the PhVWP for the Marketing Authorisation Holders (MAHs) of medicinal products containing one of the four currently licensed fibrates (Annex 1). Other clofibrate-containing medicinal products (e.g. etofibrate, etofyllinclofibrate) were excluded from this class review, since these are available only in a few member states via national marketing authorizations.