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Drugs Affecting Thrombosis and Atherosclerosis

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Drugs Affecting Lipid Metabolism

Part of the book series: Medical Science Symposia Series ((MSSS,volume 2))

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Abstract

The effect of drugs affecting lipid metabolism on atherosclerosis development/progression may be linked to their activity on the clotting system, i.e. at the platelet, fibrinogen or Fibrinolysis levels. Both resins and HMG CoA reductase inhibitors reduce, over prolonged treatments, platelet sensitivity to major aggregants. This effect seems to occur best with non-liver selective agents (e.g. simvastatin) although recent data cast doubts on the constancy of the effect. A comparative evaluation of different reductase inhibitors has never been carried out. These drugs also reduce the circulating levels of the tissue factor pathway inhibitor (TFPI) carried by LDL, this being a potentially negative effect.

Fibric acids belong to a multifaceted series of “fraudolent” fatty acids, known to interact with a liver nuclear receptor, thus activating fatty acid catabolism. A similar activity may be exerted by n-3 fatty acids, MEDICA 16, thia-fatty acids etc. Among fibric acids, all but gemfibrozil can reduce fibrinogen levels; this last compound can, however, apparently activate Fibrinolysis. Bezafibrate, as well as n-3 fatty acids, also exerts a significant platelet antiaggregatory activity. Anti-oxidants may possibly play a role in controlling platelet activation. Probucol was recently shown to reduce the excretion of thromboxane metabolites in patients with homocystinuria. The complex effect of this molecule may, however, also suggest other mechanisms.

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References

  1. Ross, — (1988) The pathogenesis of atherosclerosis, in E. Braunwald (ed), Heart Disease, WB Saunders Co, Philadelphia, pp 1135–1152.

    Google Scholar 

  2. Fuster V., Badimon L., Cohen, M, Ambrose, J.A., Badimon, J.J. and Chesebro, J.H. (1988) Insights into the pathogenesis of acute ischemic syndromes, Circulation 77, 1213–1220.

    Article  PubMed  CAS  Google Scholar 

  3. Meade, T.W., Brozovic M., Chakrabarti, R.R., Haines, A.P., Jameson, J.D., Mellowes S., Miller, G.J., North, W.R.S., Stirling, Y. and Thompson, S.G. (1986) Haemostatic function and ischemic heart disease: principal results of the Northwich Park heart study, Lancet II, 533–537.

    Article  Google Scholar 

  4. Tremoli E., Maderna P., Sirtori, M. and Sirtori, C.R. (1979) Platelet aggregation and malondialdehyde function in type IIa hypercholesterolemic patients, Haemostasis 8, 47–53.

    PubMed  CAS  Google Scholar 

  5. Tremoli E., Maderna P., Colli S., Morazzoni G., Sirtori, M. and Sirtori C.R. (1984) Increased platelet sensitivity and thromboxane B2 formation in type-ll hyperlipoproteinaemic patients, Eur. J. Clin. Invest. 14, 329–333.

    Article  PubMed  CAS  Google Scholar 

  6. Tremoli E., Folco, G.C., Agradi, E. and Galli, C. (1979) Platelet thromboxane and serum cholesterol, Lancet I, 106–107.

    Google Scholar 

  7. Oliva, D.W., Maderna P., Accomazzo, M.R., Nicosia, S. and Tremoli, E. (1989) IIoprost binding and inhibition of aggregation in platelet rich plasma. Differences between normal and type IIa hypercholesterolemic subjects, Biochem. Pharmacol. 38, 39–45.

    Article  PubMed  CAS  Google Scholar 

  8. Löbel P., Steinhagen-Thiessen, E. and Schrör, K. (1988) Cholestyramine treatment of type IIa hypercholesterolemia normalizes platelet reactivity against prostacyclin, Eur. J. Clin. Invest. 18, 256–260.

    Article  PubMed  Google Scholar 

  9. Briones, E.R., Steiger D., Palumbo, P.J. and Kottke, B.A. (1984) Primary hypercholesterolemia: effect of treatment on serum lipids, lipoprotein fractions, cholesterol absorption, sterol balance and platelet aggregation, Mayo Clin. Proc. 59, 251–257.

    Article  PubMed  CAS  Google Scholar 

  10. Zucker, M.L., Trowbridge C., Krehbiel P., Jackson B., Chernoff, S.B. and Dujovne, C.A. (1986) Platelet function in hypercholesterolaemics before and after hypolipidemic drug therapy, Haemostasis 16, 57–64.

    PubMed  CAS  Google Scholar 

  11. Schrör, K., Löbel, P. and Steinhagen-Thiessen, E. (1989) Simvastatin reduces platelet-thromboxane formation and restores normal platelet sensitivity against prostacyclin in type IIa hypercholesterolemia, Eicosanoids 2, 39–45.

    PubMed  Google Scholar 

  12. Davì, G., Averna M., Novo S., Barbagallo, C.M., Mogavero A., Notarbartolo, A. and Strano, A. (1989) Effects of synvinolin on platelet aggregation and thromboxane B2 synthesis in type IIa hypercholesterolemic patients, Atherosclerosis 79, 79–83.

    Article  PubMed  Google Scholar 

  13. Crepaldi G., Baggio G., Arca M., Avellone G., Avogaro P., Bittolo Bon G., Bompiani, G.D., Capurso A., Cattin L., D’Alò, G., Descovich, G.C., Feruglio, F.S., Gaddi A., Gnasso A., Liberatore S., Lupattelli G., Mancini M., Miccoli R., Muggeo M., Muntoni S., Navalesi R., Patrizi, G.F., Pintus F., Querena M., Resta F., Ricci G., Segato T., Sirtori, C.R., Sirtori, M. and Ventura, A. (1991) Pravastatin vs gemfibrozil in the treatment of primary hypercholesterolemia, Arch. Int. Med. 151, 146–152.

    Article  CAS  Google Scholar 

  14. Sirtori, C.R. (1990) Pharmacology and mechanism of action of the new HMG-CoA reductase inhibitors, Pharmacol. Res., 22, 555–563.

    Article  PubMed  CAS  Google Scholar 

  15. Davì, G., Averna M., Catalano I., Barbagallo, C, Ganci A., Notarbartolo A., Ciabattoni, G. and Patrono, C. (1992) Increased thromboxane biosynthesis in type IIa hypercholesterolemia, Circulation 85, 1792–1798.

    Article  PubMed  Google Scholar 

  16. Schick, B.P. and Schick, P.K. (1985) The effect of hypercholesterolemia on guinea pig platelets, erythrocytes and megakaryocytes, Biochim. Biophys. Acta 833, 291–302.

    Article  PubMed  CAS  Google Scholar 

  17. Nordfang O., Bjorn, S.E., Valentin S., Nielsen, L.S., Wildgoose P., Beck, T.C. and Hedner, U. (1991) The C-terminus of tissue factor pathway inhibitor is essential to its anticoagulant activity, Biochemistry 30, 10371–10376.

    Article  PubMed  CAS  Google Scholar 

  18. Broze, G.J. Jr, Warren, L.A., Novotny, W.F., Higuchi, D.A., Girard, J.J. and Miletich, J.P. (1988) The lipoprotein-associated coagulation inhibitor that inhibits factor VII-tissue factor complex also inhibits Xa: insight into its possible mechanism of action, Blood 71, 335–343.

    PubMed  CAS  Google Scholar 

  19. Rapaport, S. (1991) The extrinsic pathway inhibitor: — regulator of tissue factor-dependent blood coagulation, Thromb. Haemost. 66, 6–15.

    PubMed  CAS  Google Scholar 

  20. Sandset, P.M., Lund H., Norseth, J. Abildgaard, U. and Ose, L. (1991) Treatment with hydroxymethylglutaryl-coenzyme — reductase inhibitors in hypercholesterolemia induces changes in the components of the extrinsic coagulation system, Arteriosclerosis and Thrombosis 11, 138–145.

    Article  PubMed  CAS  Google Scholar 

  21. Hertz R., Bar-Tana J., Sujatta M., Pill J., Schmidt, E.H. and Fahimi, H.D. (1988) The induction of liver peroxisomal proliferation by β, β’-methyl-substituted hexadecanedioic acid (MEDICA 16), Biochem. Pharmacol. 37, 3571–3577.

    Article  PubMed  CAS  Google Scholar 

  22. lssemann, I. and Green S. (1990) Activation of — member of the steroid hormone receptor superfamily by peroxisome proliferators, Nature 347, 645–649.

    Article  Google Scholar 

  23. Aoyama T., Hardwick, J.P., Imaoka S., Funae Y., Gelboin H.V. and Gonzalez, F.J. (1990) Clofibrate-inducible rat hepatic P450s IVA1 and IVA3 catalyze the ω-and (ω-1)-hydroxylation of fatty acids and the ω-hydroxylation of prostaglandins E1 and F2α, J. Lipid Res. 31, 1477, 1482.

    PubMed  CAS  Google Scholar 

  24. Sirtori, C.R. and Franceschini, G. (1988) Effects of fibrates on serum lipids and atherosclerosis, Pharmacol. Ther. 37, 167–191.

    Article  PubMed  CAS  Google Scholar 

  25. Patsch, J.R., Prasad S., Gotto, A.M. Jr and Bengtsson-Olivecrona, G. (1984) Postprandial lipemia. — key for the conversion of high density lipoprotein — into high density lipoprotein — by hepatic lipase, J. Clin. Invest. 74, 2017–2023.

    Article  PubMed  CAS  Google Scholar 

  26. Franceschini G., Calabresi, L, Maderna P., Galli C., Gianfranceschi, G. and Sirtori, C.R. (1991) ω-3 fatty acids selectively raise high-density lipoprotein — levels in healthy volunteers, Metabolism 40, 1283–1286.

    Article  PubMed  CAS  Google Scholar 

  27. Phillips, D.R., Charo, I.F., Parise, L.V. and Fitzgerald, L.A. (1988) The platelet membrane glycoprotein IIb-IIIa complex, Blood 71, 831–843.

    PubMed  CAS  Google Scholar 

  28. Cook, N.S. and Ubben, D. (1990) Fibrinogen as — major risk factor in cardiovascular disease, TIPS 11, 444–451.

    PubMed  Google Scholar 

  29. Leschke, M. (1992) Fibrinogen-pathogenetical and therapeutical implications in atherosclerosis XI Int. Symposium on “Drugs Affecting Lipid Metabolism”, Florence, Italy May 13-16, pp. 4

    Google Scholar 

  30. Andersen P., Smith P., Seljeflot, I, Brataker, S. and Arnesen, H. (1990) Effects of gemfibrozil on lipids and haemostasis after myocardial infarction, Thromb. Haemost. 63, 174–177.

    PubMed  CAS  Google Scholar 

  31. Niort G., Bulgarelli A., Cassader, M. and Pagano, G. (1988) Effect of short term treatment with bezafibrate on plasma fibrinogen, fibrinopeptide. — platelet activation and blood filterability in atherosclerotic hyperfibrinogenemic patients, Atherosclerosis 71, 113–119.

    Article  PubMed  CAS  Google Scholar 

  32. Pazzucconi F., Mannucci, L, Mussoni L., Gianfranceschi G., Maderna P., Franceschini G., Sirtori, C.R. and Tremoli, E. (1992) Bezafibrate lowers plasma lipids, fibrinogen and platelet aggregability in hypertriglyceridemic patients, Eur. J. Clin. Pharmacol. in press.

    Google Scholar 

  33. Okazaki M., Suzuki, M. and Oguchi, K. (1990) Changes in coagulative and fibrinolytic activities in Triton WR-1339 induced hyperlipidemia in rats, Japan J. Pharmacol. 52, 353–361.

    Article  CAS  Google Scholar 

  34. Ernst E., Saradeth, T. and Achhammer, G., (1991) N-3 fatty acids and acute-phase proteins, Eur. J. Clin. Invest. 21, 77–82.

    Article  PubMed  CAS  Google Scholar 

  35. De Carvalho, A.C., Colman, R.W. and Lees, R.S. (1974) Clofibrate reversal of platelet hypersensitivity in hyperbetalipoproteinemia, Circulation 50, 570–574.

    Article  PubMed  CAS  Google Scholar 

  36. von Schacky, C, Fischer, S. and Weber, P.C. (1985) Long-term effects of dietary marine ω-3 fatty acids upon plasma and cellular lipids, platelet function, and eicosanoid formation in humans, J. Clin. Invest. 76, 1626–1631.

    Article  Google Scholar 

  37. Sirtori, C.R., Franceschini G., Gianfranceschi G., Sirtori M., Montanari G., Tremoli E., Maderna P., Colli, S. and Zoppi, F. (1987) Effects of gemfibrozil on plasma lipoprotein-apolipoprotein distribution and platelet-reactivity in patients with hypertriglyceridemia, J. Lab. Clin. Med. 110, 279–286.

    PubMed  CAS  Google Scholar 

  38. Mehta J., Mehta P., Lawson, D. and Saldeen, T. (1987) Plasma tissue plasminogen activator inhibitor levels in coronary artery disease: correlation with age and serum triglyceride concentrations, J. Am. Coll. Cardiol. 9, 263–268.

    Article  PubMed  CAS  Google Scholar 

  39. Juhan-Vague I., Vague P., Alessi, M.C., Badier, C, Valadier J., Aillaud, M.F. and Atlan, C. (1987) Relationships between plasma insulin, triglyceride, body mass index and plasminogen activator inhibitor 1, Diabete Metab. 13, 331–336.

    PubMed  CAS  Google Scholar 

  40. Reaven, G.M. (1988) Role of insulin resistance in human disease, Diabetes 37, 1595–1607.

    Article  PubMed  CAS  Google Scholar 

  41. Fumeron F., Brigant L., Ollivier V., de Prost D., Driss F., Darcet P., Bard, J.M., Parra, H.J., Fruchart, J.C. and Apfelbaum, M. (1991) N-3 polyunsaturated fatty acids raise low-density lipoproteins, high-density lipoprotein 2, and plasminogen-activator inhibitor in healthy young men, Am. J. Clin. Nutr. 54, 118–122.

    PubMed  CAS  Google Scholar 

  42. Satoshi, F. and Burton, E.S. (1992) Direct effects of gemfibrozil on the fibrinolytic system: diminution of synthesis of plasminogen activator inhibitor type I, Circulation 85, 1888–1893.

    Article  Google Scholar 

  43. Montanari G., Bondioli A., Rizzato G., Puttini M., Tremoli E., Mussoni, L, Mannucci L., Pazzucconi, F. and Sirtori, C.R. (1992) Treatment with low dose metformin in patients with peripheral vascular disease, Pharmacol. Res. 25, 63–73.

    Article  PubMed  CAS  Google Scholar 

  44. Vague P., Juhan-Vague I., Alessi, M.C., Badier, C. and Valadier, J. (1987) Metformin decreases the high plasminogen inhibition capacity, plasma insulin and triglyceride levels in non-diabetic obese subjects, Thromb. Haemost 57, 326–328.

    PubMed  CAS  Google Scholar 

  45. Buckley, M.M.T., Goa, K.L., Price, A.H. and Brogden, R.N. (1989) Probucol, — reappraisal of its pharmacological properties and therapeutic use in hypercholesterolemia, Drugs 37, 761–800.

    Article  PubMed  CAS  Google Scholar 

  46. Carew, T.E., Schwenke, D.C. and Steinberg, D. (1987) Antiatherogenic effect of probucol unrelated to its hypocholesterolemic effect: evidence that antioxidants in vivo can selectively inhibit low density lipoprotein degradation in macrophage rich fatty streaks slowing the progression of atherosclerosis in the WHHL rabbit, Proc. Natl. Acad. Sci. USA 84, 7725–7729.

    Article  PubMed  CAS  Google Scholar 

  47. Franceschini G., Chiesa, G. and Sirtori, C.R. (1991) Probucol increases cholesteryl ester transfer protein activity in hypercholesterolaemic patients, Eur. J. Clin. Invest. 21, 384–388.

    Article  PubMed  CAS  Google Scholar 

  48. Parthasarathy S., Young, S.G., Witztum, J.L., Pittman, R.C. and Steinberg, D. (1986) Probucol inhibits oxidative modification of low density lipoprotein, J. Clin. Invest. 77, 641–644.

    Article  PubMed  CAS  Google Scholar 

  49. Mao, S.J.T., Yates, M.T., Parker, R.A., Chi, E.M. and Jackson, R.L (1991) Attenuation of atherosclerosis in — modified strain of hypercholesterolemic Watanabe rabbits with use of — probucol analogue (MDL 29, 311) that does not lower serum cholesterol, Arteriosclerosis and Thrombosis 11, 1266–1275.

    Article  PubMed  CAS  Google Scholar 

  50. Mori Y., Wada H., Nagano, Y, Deguchi K., Kita, T. and Shirakawa, S. (1989) Hypercoagulable state in the Watanabe heritable hyperlipidemic rabbit, an animal model for the progression of atherosclerosis-Effect of probucol on coagulation, Thromb. Haemostas. 61, 140–143.

    CAS  Google Scholar 

  51. Di Minno G., Davì, G., Margaglione M., Cirillo F., Ciabattoni G., and Patrono, C. (1992) Enhanced thromboxane biosynthesis in homozygous cystathionine β-synthase deficiency, Clin. Res. 40, 202a.

    Google Scholar 

  52. Vesterqvist, O. and Green, K. (1984) Urinary excretion of 2,3-dinor-thromboxane B2 in man under normal conditions, following drugs and during some pathological conditions, Prostaglandins 27, 627–644.

    PubMed  CAS  Google Scholar 

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Authors
  1. S. Colli
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  2. C. R. Sirtori
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Editors and Affiliations

  1. Istituto di Scienze Farmacologiche, Università di Milano, Via Balzaretti 9, I-20133, Milano, Italy

    A. L. Catapano  & Rodolfo Paoletti (Direttore) &  (Direttore)

  2. Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA

    A. M. Gotto Jr. (Chairman) (Chairman)

  3. Department of Medicine, The Methodist Hospital, 6565 Fannin M.S. A601, Houston, TX, 77030-2797, USA

    Louis C. Smith (Professor of Experimental Medicine) (Professor of Experimental Medicine)

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Colli, S., Sirtori, C.R. (1993). Drugs Affecting Thrombosis and Atherosclerosis. In: Catapano, A.L., Gotto, A.M., Smith, L.C., Paoletti, R. (eds) Drugs Affecting Lipid Metabolism. Medical Science Symposia Series, vol 2. Springer, Dordrecht. https://doi.org/10.1007/978-94-011-1703-6_28

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  • DOI: https://doi.org/10.1007/978-94-011-1703-6_28

  • Publisher Name: Springer, Dordrecht

  • Print ISBN: 978-94-010-4746-3

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