Enoxaparin is a low-molecular-weight heparin with a complex chemical structure and various non-anticoagulant properties


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The paper discusses the non-anticoagulant properties of unfractionated heparin and enoxaparin and their relation to their chemical structures. It is emphasized that enoxaparin has multiple, often interrelated, non-anticoagulant effects that can complement its antithrombotic activity and enhance the efficiency of therapy in patients receiving the drug for various indications. The realization of these effects requires the complex structure with the standard distribution of molecular weight (Mw) (average Mw, about 4500 Da, as well as Mw of less than 2000 Da (<20%), 2000 to 8000 Da (>68%), and more than 8000 Da (<18%), and with the standard content of 1.6-anhidro rings (15—25%), which is determined by the source of raw materials and by the production technology of the original drug and cannot be fully reproduced when designing its bioanalogues.

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S K Zyryanov

E A Ushkalova

References

  1. Paschoa AF. Heparin: 100 years of pleiotropic effects. J Thromb Thrombolysis. 2016;41(4):636-643. doi: 10.1007/s11239-015-1261-z
  2. Page C. Heparin and Related Drugs: Beyond Anticoagulant Activity. ISRN Pharmacol. 2013;2013:910743. doi: 10.1155/2013/910743
  3. Mulloy B, Hogwood J, Gray E, Lever R, Page CP. Pharmacology of Heparin and Related Drugs. Pharmacol Rev. 2016;68(1):76-141. doi: 10.1124/pr.115.011247
  4. Walenga JM, Jackson CM, Kessler CM. Low molecular weight heparins differ substantially: impact on developing biosimilar drugs. Semin Thromb Hemost. 2011;37(3):322-327. doi: 10.1055/s-0031-1274515
  5. Brown RA, Allegra L, Matera MG, Page CP, Cazzola M. Additional clinical benefit of enoxaparin in COPD patients receiving salmeterol and fluticasone propionate in combination. Pulm Pharmacol Ther. 2006;19:419-424. doi: 10.1016/j.pupt.2006.04.004
  6. Shastri MD, Peterson GM, Stewart N, Sohal SS, Patel RP. Non-anticoagulant derivatives of heparin for the management of asthma: distant dream or close reality? Expert Opin Investig Drugs. 2014;23(3):357-373. doi: 10.1517/13543784.2014.866092
  7. Sohal SS, Patel RP, Lean QY, Gueven N, Eri RD. Heparins in ulcerative colitis: proposed mechanisms of action and potential reasons for inconsistent clinical outcomes. Expert Rev Clin Pharmacol. 2015;8(6):795-811. doi: 10.1586/17512433.2015.1082425
  8. Iraji F, Asilian A, Saeidi A, Hassanzadeh A, Iraji F, Asilian A. Comparison of therapeutic effect of low-dose low-molecular-weight heparin (enoxaparin) vs. oral prednisone in treatment of patients with lichen planus; A clinical trial. Adv Biomed Res. 2013;2:76. doi: 10.4103/2277-9175.115798
  9. Moreira DM, da Silva RL, Vieira JL, Fattah T, Lueneberg ME, Gottschall CA. Role of vascular inflammation in coronary artery disease: potential of anti-inflammatory drugs in the prevention of atherothrombosis. Inflammation and anti-inflammatory drugs in coronary artery disease. Am J Cardiovasc Drugs. 2015;15(1):1-11. doi: 10.1007/s40256-014-0094-z
  10. James S. Coagulation, inflammation and myocardial dysfunction in unstable coronary artery disease and the influence of glycoprotein IIb/IIIa inhibition and low molecular weight heparin. Ups J Med Sci. 2004;109(2):71-122. doi: 10.3109/2000-1967-101
  11. Khorana AA, Sahni A, Altland OD, Francis CW. Heparin inhibition of endothelial cell proliferation and organization is dependent on molecular weight. Arterioscler Thromb Vasc Biol. 2003;23:2110-2115. doi: 10.1111/j.1538-7836.2003.tb04659.x
  12. Heinzelmann M, Miller M, Platz A, Gordon LE, Herzig DO, Polk HC Jr. Heparin and enoxaparin enhance endotoxin-induced tumor necrosis factor-alpha production in human monocytes. Ann Surg. 1999;229(4):542-550. doi: 10.1097/00000658-199904000-00014
  13. Ejiri M, Fujita M, Miwa K, Yamanishi K, Sakai O, Ishizaka S, Sasayama S. Effects of heparin treatment on collateral development and regional myocardial function in acute myocardial infarction. Am Heart J. 1990;119(2 Pt 1):248-253. doi: 10.1016/s0002-8703(05)80012-2
  14. Collino M, Pini A, Mastroianni R, Benetti E, Lanzi C, Bani D, Manoni M, Fantozzi R, Masini E. The non-anticoagulant heparin-like K5 polysaccharide derivative K5-N,OSepi attenuates myocardial ischaemia/reperfusion injury. J Cell Mol Med. 2012;16(9):2196-2207. doi: 10.1111/j.1582-4934.2012.01530.x
  15. Barry WH, Kennedy TP. Heparins with reduced anti-coagulant activity reduce myocardial reperfusion injury. Recent Pat Cardiovasc Drug Discov. 2011;6(2):148-157. doi: 10.2174/157489011795933855
  16. He W, Lu N. Emergent triglyceride-lowering therapy for hypertriglyceridemic pancreatitis. Hepatogastroenterology. 2015;62(138): 429-434. doi: 10.1097/mcg.0000000000000552
  17. Gerber U, Hoß SG, Shteingauz A, Jüngel E, Jakubzig B, Ilan N, Blaheta R, Schlesinger M, Vlodavsky I, Bendas G. Latent heparanase facilitates VLA-4-mediated melanoma cell binding and emerges as a relevant target of heparin in the interference with metastatic progression. Semin Thromb Hemost. 2015;41(2):244-254. doi: 10.1055/s-0035-1544229
  18. Akl EA, Gunukula S, Barba M, Yosuico VE, van Doormaal FF, Kuipers S, Middeldorp S, Dickinson HO, Bryant A, Schünemann H. Parenteral anticoagulation in patients with cancer who have no therapeutic or prophylactic indication for anticoagulation. Cochrane Database Syst Rev. 2011;(4):CD006652. doi: 10.1002/14651858.CD006652.pub3
  19. Kamath G, Kim SY, Kuipers S, Middeldorp S, Yosuico V, Dickinson HO, Schünemann HJ. Parenteral anticoagulation for prolonging survival in patients with cancer who have no other indication for anticoagulation. Cochrane Database Syst Rev. 2007;(3):CD006652. doi: 10.1002/14651858.cd006652
  20. Engelberg H. Actions of heparin that may affect the malignant process. Cancer 1999;85:257-272. doi: 10.1002/(sici)1097-0142(19990115)
  21. Borsig L, Wong R, Feramisco J, Nadeau DR, Varki NM, Varki A. Heparin and cancer revisited: mechanistic connections involving platelets, P-selectin, carcinomamucins, and tumor metastasis. Proc Natl Acad Sci USA 2001;98:3352-3357. doi: 10.1073/pnas.061615598
  22. Amirkhosravi A, Meyer T, Amaya M, Davila M, Mousa SA, Robson T, Francis JL. The role of tissue factor pathway inhibitor in tumor growth and metastasis. Semin Thromb Hemost 2007;33:643-652. doi: 10.1055/s-2007-991531
  23. Mousa SA, Fareed J, Iqbal O, Kaiser B. Tissue factor pathway inhibitor in thrombosis and beyond. Methods Mol Med. 2004;93: 133-155. doi: 10.1385/1-59259-658-4:133
  24. Takahashi H, Ebihara S, Okazaki T, Asada M, Sasaki H, Yamaya M. A comparison of the effects of unfractionated heparin, dalteparin and danaparoid on vascular endothelial growth factor-induced tumour angiogenesis and heparanase activity. Br J Pharmacol. 2005;146(3):333-343. doi: 10.1038/sj.bjp.0706344
  25. Marchetti M, Vignoli A, Russo L, Balducci D, Pagnoncelli M, Barbui T, and Falanga A. Endothelial capillary tube formation and cell proliferation induced by tumor cells are affected by low molecular weight heparins and unfractionated heparin. Thromb Res. 2008;121:637-645. doi: 10.1016/j.thromres.2007.06.015
  26. Mehrad B, Keane MP, Strieter RM. Chemokines as mediators of angiogenesis. ThrombHaemost 2007; 97:755-762. doi: 10.1160/th07-01-0040
  27. Макацария А.Д., Бицадзе В.О., Акиньшина С.В. Применение низкомолекулярного гепарина в акушерской, гинеколо-гической и онкологической практике. Consilium medicum 2005;7:556-565. http://old.consilium-medicum.com/media/consilium/05_07/556.shtml
  28. Ekman-Ordeberg G, Hellgren M, Akerud A Andersson E, Dubicke A, Sennstrom M, Byström B, Tzortzatos G, Gomez MF, Edlund M, Lindahl U, Malmström A. Low molecular weight heparin stimulates myometrial contractility and cervical remodeling in vitro. 2009;88(9):984-989. doi: 10.1080/00016340903176818
  29. Veenstra DL, Prabulos AM, Vandvik PO; American College of Chest Physicians. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e691S-736S. doi: 10.1378/chest.11-2300
  30. Konstantinides SV, Torbicki A, Agnelli G, Danchin N, Fitzmaurice D, Galiè N, Gibbs J, Huisman MV, Humbert M, Kucher N, Lang I, Lankeit M, Lekakis J, Maack C, Mayer E, Meneveau N, Perrier A, Pruszczyk P, Rasmussen LH, Schindler TH, Svitil P, Vonk Noordegraaf A, Zamorano JL, Zompatori M; Authors/Task Force Members. 2014 ESC Guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 201;36(39):2642. doi: 10.1093/eurheartj/ehu479
  31. Casu B. Structure and active domains of heparin In: Garg HG, Linhardt RJ, Hales CA, editors. Chemistry and biology of heparin and heparan sulfate. Oxfordshire: Elsevier; 2005:1-28. doi: 10.1016/b978-008044859-6/50002-2
  32. Linhardt R. Heparin: an important drug enters its seventh decade. Chem Ind. 1991;1:45-50.
  33. Shastri MD, Stewart N, Eapen M, Peterson GM, Zaidi ST, Gueven N, Sohal SS, Patel RP. Opposing effects of low molecular weight heparins on the release of inflammatory cytokines from peripheral blood mononuclear cells of asthmatics. PLoS One. 2015;10(3):e0118798. doi: 10.1371/journal.pone.0118798
  34. Faham S, Hileman RE, Fromm JR, Linhardt RJ, Rees DC. Heparin structure and interactions with basic fibroblast growth factor. Science 1996;271:1116—1120. doi: 10.1126/science.271.5252.1116
  35. Chiu LY, Hung KW, Tjong SC, Chiang YW, Sue SC. NMR characterization of the electrostatic interaction of the basic residues in HDGF and FGF2 during heparin binding. Biochim Biophys Acta. 2014;1844(10):1851-1859. doi: 10.1016/j.bbapap.2014.08.002
  36. Kanabar V, Page CP, Simcock DE, Karner C, Mahn K, O’Connor BJ, Hirst SJ. Heparin and structurally related polymers attenuate eotaxin-1 (CCL11) release from human airway smooth muscle. Br J Pharmacol. 2008;154(4):833-842. doi: 10.1038/bjp.2008
  37. Shastri MD, Stewart N, Horne J, Zaidi ST, Sohal SS, Peterson GM, Korner H, Gueven N, Patel RP. Non-Anticoagulant Fractions of Enoxaparin Suppress Inflammatory Cytokine Release from Peripheral Blood Mononuclear Cells of Allergic Asthmatic Individuals. PLoS One. 2015;10(6):e0128803. doi: 10.1371/journal.pone.0128803
  38. Castelli R, Porro F, Tarsia P. The heparins and cancer: review of clinical trials and biological properties. Vasc Med 2004;9(3):205-213. doi: 10.1191/1358863x04vm566ra
  39. Adiguzel C, Jeske WP, Hoppensteadt D, et al. Structural and functional characterization of low-molecular-weight heparins: impact on the development of guidelines for generic products. Clin Appl Thromb Hemost. 2009;15(2):137-144. doi: 10.1191/1358863x04vm566ra
  40. Hirsh J, Raschke R. Heparin and low-molecular-weight heparin. Chest. 2004;126:188S-203S. doi: 10.1378/chest.126.3_suppl.188s
  41. Joseph PA, Garg HG, Thompson BT, et al. Influence of molecular weight, protein core and charge of native heparin fractions on pulmonary artery smooth muscle cell proliferation. Biochem Biophys Res Commun. 1997;241(1):18-23. doi: 10.1006/bbrc.1997.7687
  42. Garg HG, Cindhuchao N, Quinn DA, et al. Heparin oligosaccharide sequence and size essential for inhibition of pulmonary artery smooth muscle cell proliferation. Carbohydr Res. 2002;337(21-23):2359-2364. doi: 10.1016/s0008-6215(02)00190-8
  43. Aquino RS, Pereira MS, Vairo BC, Cinelli LP, Santos GR, Fonseca RJ, Mourão PA. Heparins from porcine and bovine intestinal mucosa: Are they similar drugs? Thromb Haemost 2010;103:1005-1015. doi: 10.1160/th09-11-0761
  44. Tovar AM, Teixeira LA, Rembold SM, Leite M Jr, Lugon JR, Mourão PA. Bovine and porcine heparins: different drugs with similar effects on human haemodialysis. BMC Res Notes. 2013;6:230. doi: 10.1186/1756-0500-6-230
  45. Santos GR, Tovar AM, Capillé NV, Pereira MS, Pomin VH, Mourão PA. Structural and functional analyses of bovine and porcine intestinal heparins confirm they are different drugs. Drug Discov Today. 2014;19(11):1801-1807. doi: 10.1016/j.drudis.2014.07.004
  46. Iqbal Z, Cohen M. Enoxaparin: a pharmacologic and clinical review. ExpertOpinPharmacother. 2011;12(7):1157-1170. doi: 10.1517/14656566.2011.570261
  47. Новое показание к применению препарата Клексан (эноксапарин натрия). http://www.rlsnet.ru/news_683.htm
  48. Manduteanu I, Voinea M, Capraru M, Dragomir E, Simionescu M. A novel attribute of enoxaparin: inhibition of monocyte adhesion to endothelial cells by a mechanism involving cell adhesion molecules. Pharmacology. 2002;65(1):32-37. doi: 10.1159/000056183
  49. Shastri MD, Stewart N, Horne J, Peterson GM, Gueven N, Sohal SS, Patel RP. In-vitro suppression of IL-6 and IL-8 release from human pulmonary epithelial cells by non-anticoagulant fraction of enoxaparin. PLoS One. 2015;10(5):e0126763. doi: 10.1371/journal.pone.0126763
  50. Tasatargil A, Ogutman C, Golbasi I, Karasu E, Dalaklioglu S. Comparison of the vasodilatory effect of nadroparin, enoxaparin, dalteparin, and unfractioned heparin in human internal mammary artery. J Cardiovasc Pharmacol 2005;45(6):550-554. doi: 10.1097/01.fjc.0000159878.66325.fc
  51. Rudolph TK, Rudolph V, Witte A, Klinke A, Szoecs K, Lau D, Heitzer T, Meinertz T, Baldus S. Liberation of vessel adherent myeloperoxidase by enoxaparin improves endothelial function. Int J Cardiol. 2010;140(1):42-47. doi: 10.1016/j.ijcard.2008.10.035
  52. Currier JW, Pow TK, Haudenschild CC, Minihan AC, Faxon DP. Low molecular weight heparin (enoxaparin) reduced restenosis following angioplasty in the hypercholesterolemic rabbit. J Am Coll Cardiol 1991;17:118-25B. doi: 10.1016/0735-1097(91)90947-8
  53. Kiesz RS, Buszman P, Martin JL, Deutsch E, Rozek MM, Gaszewska E, Rewicki M, Seweryniak P, Kosmider M, Tendera M. Local delivery of enoxaparin to decrease restenosis after stenting: results of initial multicenter trial: Polish-American Local Lovenox NIR Assessment study (The POLONIA study). Circulation. 2001;103(1):26-31. doi: 10.1161/01.cir.103.1.26
  54. Manduteanu I, Dragomir E, Voinea M, Capraru M, Simionescu M. Enoxaparin reduces H2O2-induced activation of human endothelial cells by a mechanism involving cell adhesion molecules and nuclear transcription factors. Pharmacology. 2007;79(3):154-162. doi: 10.1159/000098952
  55. Manduteanu I, Voinea M, Antohe F, Dragomir E, Capraru M, Radulescu L, Simionescu M. Effect of enoxaparin on high glucose-induced activation of endothelial cells. Eur J Pharmacol. 2003;477(3):269-276. doi: 10.1016/j.ejphar.2003.08.016
  56. Grosskopf I, Shaish A, Ray A, Harats D, Kamari Y. Low molecular weight heparin-induced increase in chylomicron-remnants clearance, is associated with decreased plasma TNF-α level and increased hepatic lipase activity. Thromb Res. 2014;133(4):688-692. doi: 10.1016/j.thromres.2014.01.019
  57. European Pharmacopoeia 5.3 01/2006: 1097.
  58. Jeske WP, Walenga JM, Hoppensteadt DA, Vandenberg C, Brubaker A, Adiguzel C, Bakhos M, Fareed J. Differentiating low-molecular-weight heparins based on chemical, biological, and pharmacologic properties: implications for the development of generic versions of low-molecular weight heparins. Semin Thromb Hemost 2008;34(1):74-85. doi: 10.1055/s-2008-1066026
  59. Walenga JM, Adiguzel C, Iqbal O, Hoppensteadt D, Cunanan J, Bakhos M. Fibrin clot formation differs in the presence of branded and generic enoxaparins. J Thromb Haemost 2009;7(Suppl 2):Abstract PP-WE-387. doi: 10.1055/s-0028-1086091
  60. Adiguzel C, Litinas E, Cunanan J, Hoppensteadt D, Walenga JM, Fareed J. Differential thrombin generation inhibition by branded and generic low molecular weight heparins (LMWHs) as studied by using fluorescence substrate based kinetic method. J Thromb Haemost 2009;7(Suppl 2):Abstract PP-MO-139. doi: 10.1055/s-2008-1066026
  61. Walenga JM, Hoppensteadt D, Cunanan J,. Adiguzel C, Iqbal O, Jeske WP, Preche M, Bakhos M. Immunogenicity of low molecular weight heparins and biosimilars. J Thromb Haemost 2009;7(Suppl 2):Abstract PP-MO-399.
  62. McCamish, M.; Woollett, G. Worldwide experience with biosimilar development. MAbs 2011;3:209-217. doi: 10.4161/mabs.3.2.15005
  63. Lean QY, Patel RP, Stewart N, Sohal SS, Gueven N. Identification of pro- and anti-proliferative oligosaccharides of heparins. Integr Biol (Camb). 2014;6(1):90-99. doi: 10.1039/c3ib40206a
  64. Guideline on non-clinical and clinical development of similar biological medicinal products containing low molecular weight heparins. London, 19 March 2009. EMEA/CHMP/BMWP /118264/2007

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