Heparin and related drugs: beyond anticoagulant activity

Clive Page, Clive Page

Abstract

Heparin has been widely used as an anticoagulant for more than 80 years. However, there is now considerable evidence that heparin also possesses anti-inflammatory activity, both experimentally and clinically. Importantly in many instances, the anti-inflammatory actions of heparin are independent of anticoagulant activity raising the possibility of developing novel drugs based on heparin that retain the anti-inflammatory activity. Heparin exhibits anti-inflammatory activities via a variety of mechanisms including neutralization of cationic mediators, inhibition of adhesion molecules, and the inhibition of heparanase, all involved in leukocyte recruitment into tissues. It is anticipated that furthering our understanding of the anti-inflammatory actions of heparin will lead to the development of novel anti-inflammatory drugs for a variety of clinical indications.

Figures

Figure 1
Figure 1
Generic disaccharide backbone structure of glycosaminoglycans with (a) 1–4 linkage, common to heparin and heparan sulphate and (b) 1–3 linkage, common to chondroitin and dermatan sulphates. Numbers on the rings relate to the carbon position, hydroxyl, and amine groups can be sulphated and alternatively orientated.

References

    1. Mulloy B, Gray E, Barrowcliffe TW. Characterization of unfractionated heparin: comparison of materials from the last 50 years. Thrombosis and Haemostasis. 2000;84(6):1052–1056.
    1. Lever R, Page CP. Non-anticoagulant effects of heparin: an overview. In: Lever R, Mulloy B, Page CP, editors. Heparin—A Century of Progress. Vol. 207. Berlin, Germany: Springer; 2012. pp. 281–305. (Handbook of Experimental Pharmacology).
    1. Page CP. One explanation of the asthma paradox: inhibition of natural anti-inflammatory mechanism by β2-agonists. Lancet. 1991;337(8743):717–720.
    1. Humphries DE, Wong GW, Friend DS, et al. Heparin is essential for the storage of specific granule proteases in mast cells. Nature. 1999;400(6746):769–772.
    1. Green WF, Konnaris K, Woolcock AJ. Effect of salbutamol, fenoterol, and sodium cromoglycate on the release of heparin from sensitized human lung fragments challenged with Dermatophagoides pteronyssinus allergen. American Journal of Respiratory Cell and Molecular Biology. 1993;8(5):518–521.
    1. Guyton JR, Rosenberg RD, Clowes AW, Karnovsky MJ. Inhibition of rat arterial smooth muscle cell proliferation by heparin. in vivo studies with anticoagulant and nonanticoagulant heparin. Circulation Research. 1980;46(5):625–634.
    1. Lasser EC, Simon RA, Lyon SG, Hamblin AE, Stein R. Heparin-like anticoagulants in asthma. Allergy. 1987;42(8):619–625.
    1. Diamant Z, Timmers MC, Van Der Veen H, Page CP, Van Der Meer FJ, Sterk PJ. Effect of inhaled heparin on allergen-induced early and late asthmatic responses in patients with atopic asthma. American Journal of Respiratory and Critical Care Medicine. 1996;153(6 I):1790–1795.
    1. Bendstrup KE, Chambers CB, Jensen JI, Newhouse MT. Lung deposition and clearance of inhaled 99mTc-heparin in healthy volunteers. American Journal of Respiratory and Critical Care Medicine. 1999;160(5 I):1653–1658.
    1. Sy MS, Schneeberger E, McCluskey R, Greene MI, Rosenberg RD, Benacerraf B. Inhibition of delayed-type hypersensitivity by heparin depleted of anticoagulant activity. Cellular Immunology. 1983;82(1):23–32.
    1. Seeds EAM, Page CP. Heparin inhibits allergen-induced eosinophil infiltration into guinea-pig lung via a mechanism unrelated to its anticoagulant activity. Pulmonary Pharmacology & Therapeutics. 2001;14(2):111–119.
    1. Fryer A, Huang YC, Rao G, et al. Selective O-desulfation produces nonanticoagulant heparin that retains pharmacological activity in the lung. Journal of Pharmacology and Experimental Therapeutics. 1997;282(1):208–219.
    1. Lever R, Smailbegovic A, Page CP. Locally available heparin modulates inflammatory cell recruitment in a manner independent of anticoagulant activity. European Journal of Pharmacology. 2010;630(1-3):137–144.
    1. Ahmed T, Garrigo J, Danta I. Preventing bronchoconstriction in exercise-induced asthma with inhaled heparin. The New England Journal of Medicine. 1993;329(2):90–95.
    1. Ahmed T, Syriste T, Mendelssohn R, et al. Heparin prevents antigen-induced airway hyperresponsiveness: interference with IP3-mediated mast cell degranulation? Journal of Applied Physiology. 1994;76(2):893–901.
    1. Ahmed T, Campo C, Abraham MK, et al. Inhibition of antigen-induced acute bronchoconstriction, airway hyperresponsiveness, and mast cell degranulation by a nonanticoagulant heparin: comparison with a low molecular weight heparin. American Journal of Respiratory and Critical Care Medicine. 1997;155(6):1848–1855.
    1. Bazzoni G, Nuñez AB, Mascellani G, Bianchini P, Dejana E, Del Maschio A. Effect of heparin, dermatan sulfate, and related oligo-derivatives on human polymorphonuclear leukocyte functions. Journal of Laboratory and Clinical Medicine. 1993;121(2):268–275.
    1. Brown RA, Lever R, Jones NA, Page CP. Effects of heparin and related molecules upon neutrophil aggregation and elastase release in vitro . British Journal of Pharmacology. 2003;139(4):845–853.
    1. Evangelista V, Piccardoni P, Maugeri N, De Gaetano G, Cerletti C. Inhibition by heparin of platelet activation induced by neutrophil-derived cathepsin G. European Journal of Pharmacology. 1992;216(3):401–405.
    1. Inase N, Schreck RE, Lazarus SC. Heparin inhibits histamine release from canine mast cells. American Journal of Physiology. 1993;264(4):L387–L390.
    1. Lever R, Lo WT, Faraidoun M, et al. Size-fractionated heparins have differential effects on human neutrophil function in vitro . British Journal of Pharmacology. 2007;151(6):837–843.
    1. Piccardoni P, Evangelista V, Piccoli A, De Gaetano G, Walz A, Cerletti C. Thrombin-activated human platelets release two NAP-2 variants that stimulate polymorphonuclear leukocytes. Thrombosis and Haemostasis. 1996;76(5):780–785.
    1. Rohrer MJ, Kestin AS, Ellis PA, et al. High-dose heparin suppresses platelet alpha granule secretion. Journal of Vascular Surgery. 1992;15(6):1000–1009.
    1. Slungaard A, Vercellotti GM, Walker G, Nelson RD, Jacob HS. Tumor necrosis factor α/cachectin stimulates eosinophil oxidant production and toxicity towards human endothelium. Journal of Experimental Medicine. 1990;171(6):2025–2041.
    1. Teixeira MM, Rossi AG, Hellewell PG. Adhesion mechanisms involved in C5a-induced eosinophil homotypic aggregation. Journal of Leukocyte Biology. 1996;59(3):389–396.
    1. Redini F, Tixier JM, Petitou M, Choay J, Robert L, Hornebeck W. Inhibition of leucocyte elastase by heparin and its derivatives. Biochemical Journal. 1988;252(2):515–519.
    1. Walsh RL, Dillon TJ, Scicchitano R, McLennan G. Heparin and heparan sulphate are inhibitors of human leucocyte elastase. Clinical Science. 1991;81(3):341–346.
    1. Pégorier S, Wagner LA, Gleich GJ, Pretolani M. Eosinophil-derived cationic proteins activate the synthesis of remodeling factors by airway epithelial cells. The Journal of Immunology. 2006;177:4861–4869.
    1. Fredens K, Dahl R, Venge P. In vitro studies of the interaction between heparin and eosinophil cationic protein. Allergy. 1991;46(1):27–29.
    1. Swaminathan GJ, Myszka DG, Katsamba PS, Ohnuki LE, Gleich GJ, Acharya KR. Eosinophil-granule major basic protein, a C-type lectin, binds heparin. Biochemistry. 2005;44(43):14152–14158.
    1. Muramatsu T, Muramatsu H. Glycosaminoglycan-binding cytokines as tumor markers. Proteomics. 2008;8(16):3350–3359.
    1. Shute J. Glycosaminoglycan and chemokine/growth factor interactions. In: Lever R, Mulloy B, Page CP, editors. Heparin—A Century of Progress. Vol. 207. Heidelberg, Germany: Springer; 2011. pp. 307–324. (Handbook of Experimental Pharmacology).
    1. Bono F, Rigon P, Lamarche I, Savi P, Salel V, Herbert JM. Heparin inhibits the binding of basic fibroblast growth factor to cultured human aortic smooth-muscle cells. Biochemical Journal. 1997;326(part 3):661–668.
    1. McCaffrey TA, Falcone DJ, Brayton CF, Agarwal LA, Welt FG, Weksler BB. Transforming growth factor-b activity is potentiated by heparin via dislocation of the transforming growth factor-b/a2-macroglobulin inactive complex. The Journal of Cell Biology. 1989;109(1):441–448.
    1. Okona-Mensah KB, Shittu E, Page C, Costello J, Kilfeather SA. Inhibition of serum and transforming growth factor beta (TGF-β1)-induced DNA synthesis in confluent airway smooth muscle by heparin. British Journal of Pharmacology. 1998;125(4):599–606.
    1. Clowes AW, Karnowsky MJ. Suppression by heparin of smooth muscle cell proliferation in injured arteries. Nature. 1977;265(5595):625–626.
    1. Kanabar V, Hirst SJ, O’Connor BJ, Page CP. Some structural determinants of the antiproliferative effect of heparin-like molecules on human airway smooth muscle. British Journal of Pharmacology. 2005;146(3):370–377.
    1. Kilfeather SA, Tagoe S, Perez AC, Okona-Mensa K, Matin R, Page CP. Inhibition of serum-induced proliferation of bovine tracheal smooth muscle cells in culture by heparin and related glycosaminoglycans. British Journal of Pharmacology. 1995;114(7):1442–1446.
    1. Dragstedt CA, Wells JA, Rocha E, Silva M. Inhibitory effect of heparin upon histamine release by trypsin, antigen, and protease. Proceedings of the Society for Experimental Biology and Medicine. 1942;51:191–192.
    1. Ghosh TK, Eis PS, Mullaney JM, Ebert CL, Gill DL. Competitive, reversible, and potent antagonism of inositol 1,4,5-trisphosphate-activated calcium release by heparin. Journal of Biological Chemistry. 1988;263(23):11075–11079.
    1. Matzner Y, Marx G, Drexler R, Eldor A. The Inhibitory effect of heparin and related glycosaminoglycans on neutrophil chemotaxis. Thrombosis and Haemostasis. 1984;52:134–137.
    1. Li S, Zheng Z, Li X, Xiochun M. Unfractionated heparin inhibits lipopolysaccharide-induced response through blocking p38 MAPK and NF-KB activation on endothgelial cells. Cytokine. 2012;60(1):114–121.
    1. Leculier C, Benzerara O, Couprie N, et al. Specific binding between human neutrophils and heparin. British Journal of Haematology. 1992;81(1):81–85.
    1. Freischlag JA, Colburn MD, Quiñones-Baldrich WJ, Moore WS. Heparin, urokinase, and ancrod alter neutrophil function. Journal of Vascular Surgery. 1992;16(4):565–574.
    1. Pasini FL, Pasqui AL, Ceccatelli L. Heparin inhibition of polymorphonuclear leukocyte activation in vitro. A possible pharmacological approach to granulocyte-mediated vascular damage. Thrombosis Research. 1984;35(5):527–537.
    1. Silvestro L, Viano I, Macario M, et al. Effects of heparin and its desulfated derivatives on leukocyte-endothelial adhesion. Seminars in Thrombosis and Hemostasis. 1994;20(3):254–258.
    1. Smailbegovic A, Lever R, Page CP. The effects of heparin on the adhesion of human peripheral blood mononuclear cells to human stimulated umbilical vein endothelial cells. British Journal of Pharmacology. 2001;134(4):827–836.
    1. Johnson Z, Kosco-Vilbois MH, Herren S, et al. Interference with heparin binding and oligomerization creates a novel anti-inflammatory strategy targeting the chemokine system. Journal of Immunology. 2004;173(9):5776–5785.
    1. Ley K, Cerrito M, Arfors KE. Sulfated polysaccharides inhibit leukocyte rolling in rabbit mesentery venules. American Journal of Physiology. 1991;260(5):H1667–H1673.
    1. Nelson RM, Cecconi O, Roberts WG, Aruffo A, Linhardt RJ, Bevilacqua MP. Heparin oligosaccharides bind L- and P-selectin and inhibit acute inflammation. Blood. 1993;82(11):3253–3258.
    1. Salas A, Sans M, Soriano A, et al. Heparin attenuates TNF-alpha induced inflammatory response through a CD11b dependent mechanism. Gut. 2000;47(1):88–96.
    1. Tangelder GJ, Arfors KE. Inhibition of leukocyte rolling in venules by protamine and sulfated polysaccharides. Blood. 1991;77(7):1565–1571.
    1. Xie X, Thorlacius H, Raud J, Hedqvist P, Lindbom L. Inhibitory effect of locally administered heparin on leukocyte rolling and chemoattractant-induced firm adhesion in rat mesenteric venules in vivo. British Journal of Pharmacology. 1997;122(5):906–910.
    1. Sasaki M, Herd CM, Page CP. Effect of heparin and low-molecular weight heparinoid on PAF-induced airway responses in neonatally immunized rabbits. British Journal of Pharmacology. 1993;110(1):107–112.
    1. Seeds EAM, Horne AP, Tyrrell DJ, Page CP. The effect of inhaled heparin and related glycosaminoglycans on allergen-induced eosinophil infiltration in guinea-pigs. Pulmonary Pharmacology. 1995;8(2-3):97–105.
    1. Vancheri C, Mastruzzo C, Armato F, et al. Intranasal heparin reduces eosinophil recruitment after nasal allergen challenge in patients with allergic rhinitis. Journal of Allergy and Clinical Immunology. 2001;108(5):703–708.
    1. Teixeira MM, Hellewell PG. Suppression by intradermal administration of heparin of eosinophil accumulation but not oedema formation in inflammatory reactions in guinea-pig skin. British Journal of Pharmacology. 1993;110(4):1496–1500.
    1. Yanaka K, Nose T, Hindman BJ. Heparin ameliorates brain injury by inhibiting leukocyte accumulation. Stroke. 1996;27(11):2146–2147.
    1. Fritzsche J, Alban S, Ludwig RJ, et al. The influence of various structural parameters of semisynthetic sulfated polysaccharides on the P-selectin inhibitory capacity. Biochemical Pharmacology. 2006;72(4):474–485.
    1. Koenig A, Norgard-Sumnicht K, Linhardt R, Varki A. Differential interactions of heparin and heparan sulfate glycosaminoglycans with the selectins: implications for the use of unfractionated and low molecular weight heparins as therapeutic agents. Journal of Clinical Investigation. 1998;101(4):877–889.
    1. Giuffrè L, Cordey AS, Monai N, Tardy Y, Schapira M, Spertini O. Monocyte adhesion to activated aortic endothelium: role of L-selectin and heparan sulfate proteoglycans. Journal of Cell Biology. 1997;136(4):945–956.
    1. Diamond MS, Alon R, Parkos CA, Quinn MT, Springer TA. Heparin is an adhesive ligand for the leukocyte integrin Mac-1 (CD11b/CD18) Journal of Cell Biology. 1995;130(6):1473–1482.
    1. Peter K, Schwarz M, Conradt C, et al. Heparin inhibits ligand binding to the leukocyte integrin Mac-1 (CD11b/CD18) Circulation. 1999;100(14):1533–1539.
    1. Skinner MP, Lucas CM, Burns GF, Chesterman CN, Berndt MC. GMP-140 binding to neutrophils is inhibited by sulfated glycans. Journal of Biological Chemistry. 1991;266(9):5371–5374.
    1. Stevenson JL, Choi SH, Varki A. Differential metastasis inhibition by clinically relevant levels of heparins—correlation with selectin inhibition, not antithrombotic activity. Clinical Cancer Research. 2005;11(19):7003–7011.
    1. Stevenson JL, Varki A, Borsig L. Heparin attenuates metastasis mainly due to inhibition of P- and L-selectin, but non-anticoagulant heparins can have additional effects. Thrombosis Research. 2007;120(2):S107–S111.
    1. Lawrence MB, Springer TA. Leukocytes roll on a selectin at physiologic flow rates: distinction from and prerequisite for adhesion through integrins. Cell. 1991;65(5):859–873.
    1. Revelle BM, Scott D, Beck PJ. Single amino acid residues in the E-and P-selectin epidermal growth factor domains can determine carbohydrate binding specificity. The Journal of Biological Chemistry. 1996;271:16160–16170.
    1. Watt SM, Williamson J, Genevier H, et al. The heparin binding PECAM-1 adhesion molecule is expressed by CD34+ hematopoietic precursor cells with early myeloid and B-lymphoid cell phenotypes. Blood. 1993;82(9):2649–2663.
    1. DeLisser HM, Yan HC, Newman PJ, Muller WA, Buck CA, Albelda SM. Platelet/endothelial cell adhesion molecule-1 (CD31)-mediated cellular aggregation involves cell surface glycosaminoglycans. Journal of Biological Chemistry. 1993;268(21):16037–16046.
    1. Cole GJ, Loewy A, Glaser L. Neuronal cell-cell adhesion depends on interactions of N-CAM with heparin-like molecules. Nature. 1986;320(6061):445–447.
    1. Kiselyov VV, Berezin V, Maar TE, et al. The first immunoglobulin-like neural cell adhesion molecule (NCAM) domain is involved in double-reciprocal interaction with the second immunoglobulin-like NCAM domain and in heparin binding. Journal of Biological Chemistry. 1997;272(15):10125–10134.
    1. Kallapur SG, Akeson RA. The neural cell adhesion molecule (NCAM) heparin binding domain binds to cell surface heparan sulfate proteoglycans. Journal of Neuroscience Research. 1992;33(4):538–548.
    1. Powell AK, Yates EA, Fernig DG, Turnbull JE. Interactions of heparin/heparan sulfate with proteins: appraisal of structural factors and experimental approaches. Glycobiology. 2004;14(4):17R–30R.
    1. Turnbull J, Powell A, Guimond S. Heparan sulfate: decoding a dynamic multifunctional cell regulator. Trends in Cell Biology. 2001;11(2):75–82.
    1. Fairbanks MB, Mildner AM, Leone JW, et al. Processing of the human heparanase precursor and evidence that the active enzyme is a heterodimer. Journal of Biological Chemistry. 1999;274(42):29587–29590.
    1. Hulett MD, Freeman C, Hamdorf BJ, Baker RT, Harris MJ, Parish CR. Cloning of mammalian heparanase, an important enzyme in tumor invasion and metastasis. Nature Medicine. 1999;5(7):803–809.
    1. Kussie PH, Hulmes JD, Ludwig DL, et al. Cloning and functional expression of a human heparanase gene. Biochemical and Biophysical Research Communications. 1999;261(1):183–187.
    1. Vlodavsky I, Friedmann Y, Elkin M, et al. Mammalian heparanase: gene cloning, expression and function in tumor progression and metastasis. Nature Medicine. 1999;5(7):793–802.
    1. Parish CR, Freeman C, Hulett MD. Heparanase: a key enzyme involved in cell invasion. Biochimica et Biophysica Acta. 2001;1471(3):M99–M108.
    1. Hulett MD, Hornby JR, Ohms SJ, et al. Identification of active-site residues of the pro-metastatic endoglycosidase heparanase. Biochemistry. 2000;39(51):15659–15667.
    1. McKenzie EA. Heparanase: a target for drug discovery in cancer and inflammation. British Journal of Pharmacology. 2007;151(1):1–14.
    1. McKenzie E, Tyson K, Stamps A, et al. Cloning and expression profiling of Hpa2, a novel mammalian heparanase family member. Biochemical and Biophysical Research Communications. 2000;276(3):1170–1177.
    1. Murch SH, MacDonald TT, Walker-Smith JA, Levin M, Lionetti P, Klein NJ. Disruption of sulphated glycosaminoglycans in intestinal inflammation. Lancet. 1993;341(8847):711–714.
    1. Shute JK, Parmar J, Holgate ST, Howarth PH. Urinary glycosaminoglycan levels are increased in acute severe asthma—a role for eosinophil-derived gelatinase B? International Archives of Allergy and Immunology. 1997;113(1-3):366–367.
    1. Bar-Ner M, Eldor A, Wasserman L, et al. Inhibition of heparanase-mediated degradation of extracellular matrix heparan sulfate by non-anticoagulant heparin species. Blood. 1987;70(2):551–557.
    1. Lider O, Mekori YA, Miller T, et al. Inhibition of T lymphocyte heparanase by heparin prevents T cell migration and T cell-mediated immunity. European Journal of Immunology. 1990;20(3):493–499.
    1. Matzner Y, Vlodavsky I, Bar-Ner M, Ishai-Michaeli R, Tauber AI. Subcellular localization of heparanase in human neutrophils. Journal of Leukocyte Biology. 1992;51(6):519–524.
    1. Lider O, Baharav E, Mekori YA, et al. Suppression of experimental autoimmune diseases and prolongation of allograft survival by treatment of animals with low doses of heparins. Journal of Clinical Investigation. 1989;83(3):752–756.
    1. Willenborg DO, Parish CR. Inhibition of allergic encephalomyelitis in rats by treatment with sulfated polysaccharides. Journal of Immunology. 1988;140(10):3401– 3405.
    1. Gorski A, Lao M, Gradowska L, Nowaczyk M, Wasik M, Lagodzinski Z. New strategies of heparin treatment used to prolong allograft survival. Transplantation Proceedings. 1991;23(4):2251–2252.
    1. Naparstek E, Slavin S, Weiss L, et al. Low-dose heparin inhibits acute graft versus host disease in mice. Bone Marrow Transplantation. 1993;12(3):185–189.
    1. Chen G, Wang D, Vikramadithyan R, et al. Inflammatory cytokines and fatty acids regulate endothelial cell heparanase expression. Biochemistry. 2004;43(17):4971–4977.
    1. Edovitsky E, Lerner I, Zcharia E, Peretz T, Vlodavsky I, Elkin M. Role of endothelial heparanase in delayed-type hypersensitivity. Blood. 2006;107(9):3609–3616.
    1. Seeds EAM, Hanss J, Page CP. The effect of heparin and related proteoglycans on allergen and PAF-induced eosinophil infiltration. Journal of Lipid Mediators. 1993;7(3):269–278.
    1. Carr J. The anti-inflammatory action of heparin: heparin as an antagonist to histamine, bradykinin and prostaglandin E1 . Thrombosis Research. 1979;16(3-4):507–516.
    1. Jones H, Paul W, Page CP. The effects of heparin and related molecules on vascular permeability and neutrophil accumulation in rabbit skin. British Journal of Pharmacology. 2002;135(2):469–479.
    1. Maarsingh H, De Boer J, Kauffman HF, Zaagsma J, Meurs H. Heparin normalizes allergen-induced nitric oxide deficiency and airway hyperresponsiveness. British Journal of Pharmacology. 2004;142(8):1293–1299.
    1. Becker M, Menger MD, Lehr HA. Heparin-released superoxide dismutase inhibits postischemic leukocyte adhesion to venular endothelium. American Journal of Physiology. 1994;267(3):H925–H930.
    1. Kilgore KS, Tanhehco EJ, Naylor KB, Lucchesi BR. Ex vivo reversal of heparin-mediated cardioprotection by heparinase after ischemia and reperfusion. Journal of Pharmacology and Experimental Therapeutics. 1999;290(3):1041–1047.
    1. Simard JM, Schreibman D, Aldrich EF, et al. Unfractionated heparin: multitargeted therapy for delayed neurological deficits induced by subarachnoid hemorrhage. Neurocritical Care. 2010;13(3):439–449.
    1. Tekkök IH, Tekkök S, Ozcan OE, Erbengi T, Erbengi A. Preventive effect of intracisternal heparin for proliferative angiopathy after experimental subarachnoid haemorrhage in rats. Acta Neurochirurgica. 1994;127(1-2):112–117.
    1. Dolowitz DA, Dougherty TF. The use of heparin as an anti-inflammatory agent. Laryngo­Scope. 1960;70:873–874.
    1. Dolowitz DA, Dougherty TF. The use of heparin in the control of allergies. Annals of Allergy. 1965;23:309–313.
    1. Antczak M, Kuna P. Heparin inhibits allergen induced airway response in asthmatics. Results of a double blind placebo-controlled, crossover study. Journal of Allergy and Clinical Immunology. 1995;95:p. 386.
    1. Bowler SD, Smith SM, Laverombe PS. Heparin inhibits the immediate response to antigen in the skin and lungs of allergic subjects. The American Review of Respiratory Disease. 1993;147(1):160–163.
    1. Venge P, Pedersen B, Håkansson L, Hällgren R, Lindblad G, Dahl R. Subcutaneous administration of hyaluronan reduces the number of infectious exacerbations in patients with chronic bronchitis. American Journal of Respiratory and Critical Care Medicine. 1996;153(1):312–316.
    1. 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. Pulmonary Pharmacology and Therapeutics. 2006;19(6):419–424.
    1. Evans RC, Wong VS, Morris AI, Rhodes JM. Treatment of corticosteroid-resistant ulcerative colitis with heparin—a report of 16 cases. Alimentary Pharmacology & Therapeutics. 1997;11(6):1037–1040.
    1. Gaffney PR, O’Leary JJ, Doyle CT, et al. Response to heparin in patients with ulcerative colitis. Lancet. 1991;337(8735):238–239.
    1. Gaffney PR, Doyle CT, Gaffney A, Hogan J, Hayes DP, Annis P. Paradoxical response to heparin in 10 patients with ulcerative colitis. American Journal of Gastroenterology. 1995;90(2):220–223.
    1. Michell NP, Lalor P, Langman MJ. Heparin therapy for ulcerative colitis? Effects and mechanisms. European Journal of Gastroenterology & Hepatology. 2001;13:449–456.
    1. Chande N, McDonald JW, Macdonald JK. Unfractionated or low-molecular weight heparin for induction of remission in ulcerative colitis. Cochrane Database of Systematic Reviews. 2008;(2)CD006774
    1. Shen J, Ran ZH, Tong JL, Xiao SD. Meta-analysis: the utility and safety of heparin in the treatment of active ulcerative colitis. Alimentary Pharmacology & Therapeutics. 2007;26(5):653–663.
    1. Borsig L. Antimetastatic activities of heparins and modified heparins. Experimental evidence. Thrombosis Research. 2010;125:S66–71.
    1. Engelberg H. Actions of heparin that may affect the malignant process. Cancer. 1999;85:257–272.
    1. Hettiarachchi RJK, Smorenburg SM, Ginsberg J, Levine M, Prins MH, Buller HR. Do heparins do more than just treat thrombosis? The influence of heparins on cancer spread. Thrombosis and Haemostasis. 1999;82(2):947–952.
    1. Mousa SA. Heparin and low-molecular weight heparins in thrombosis and beyond. Methods in Molecular Biology. 2010;663:109–132.
    1. Niers TMH, Klerk CPW, DiNisio M, et al. Mechanisms of heparin induced anti-cancer activity in experimental cancer models. Critical Reviews in Oncology/Hematology. 2007;61(3):195–207.
    1. Smorenburg SM, Van Noorden CJF. The complex effects of heparins on cancer progression and metastasis in experimental studies. Pharmacological Reviews. 2001;53(1):93–105.
    1. Zacharski LR, Ornstein DL. Heparin and cancer. Thrombosis and Haemostasis. 1988;80(1):10–23.
    1. Zacharski LR, Ornstein DL, Mamourian AC. Low-molecular-weight heparin and cancer. Seminars in Thrombosis and Hemostasis. 2000;26(3):69–77.
    1. Akl EA, van Doormaal FF, Barba M, et al. Parenteral anticoagulation for prolonging survival in patients with cancer who have no other indication for anticoagulation. Cochrane Database of Systematic Reviews. 2007;(3)CD006652
    1. Kuderer NM, Khorana AA, Lyman GH, Francis CW. A meta-analysis and systematic review of the efficacy and safety of anticoagulants as cancer treatment: impact on survival and bleeding complications. Cancer. 2007;110(5):1149–1161.
    1. Vlodavsky I, Friedmann Y. Molecular properties and involvement of heparanase in cancer metastasis and angiogenesis. Journal of Clinical Investigation. 2001;108(3):341–347.
    1. Borsig L, Wong R, Feramisco J, Nadeau DR, Varki NM, Varki A. Heparin and cancer revisited: mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis. Proceedings of the National Academy of Sciences of the United States of America. 2001;98(6):3352–3357.
    1. Pitchford SC, Yano H, Lever R, et al. Platelets are essential for leukocyte recruitment in allergic inflammation. Journal of Allergy and Clinical Immunology. 2003;112(1):109–118.
    1. Alonso DF, Bertolesi GE, Farias EF, Eijan AM, Joffe EBD, De Cidre LL. Antimetastatic effects associated with anticoagulant properties of heparin and chemically modified heparin species in a mouse mammary tumor model. Oncology Reports. 1996;3(1):219–222.
    1. Mousa SA, Linhardt R, Francis JL, Amirkhosravi A. Anti-metastatic effect of a non-anticoagulant low-molecular-weight heparin versus the standard low-molecular-weight heparin, enoxaparin. Thrombosis and Haemostasis. 2006;96(6):816–821.
    1. Nakajima M, Irimura T, Nicolson GL. Heparanases and tumor metastasis. Journal of Cellular Biochemistry. 1988;36(2):157–167.
    1. Sciumbata T, Caretto P, Pirovano P, et al. Treatment with modified heparins inhibits experimental metastasis formation and leads, in some animals, to long-term survival. Invasion and Metastasis. 1996;16(3):132–143.
    1. Amirkhosravi A, Meyer T, Amaya M, et al. The role of tissue factor pathway inhibitor in tumor growth and metastasis. Seminars in Thrombosis and Hemostasis. 2007;33(7):643–652.
    1. Vlodavsky I, Eldor A, Haimovitz-Friedman A, et al. Expression of heparanase by platelets and circulating cells of the immune system: possible involvement in diapedesis and extravasation. Invasion and Metastasis. 1992;12(2):112–127.
    1. 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. British Journal of Pharmacology. 2005;146(3):333–343.
    1. Khorana AA, Sahni A, Altland OD, Francis CW. Heparin inhibition of endothelial cell proliferation and organization is dependent on molecular weight. Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:2110–2115.
    1. Marchetti M, Vignoli A, Russo L, et al. Endothelial capillary tube formation and cell proliferation induced by tumor cells are affected by low molecular weight heparins and unfractionated heparin. Thrombosis Research. 2008;121(5):637–645.
    1. Mehrad B, Keane MP, Strieter RM. Chemokines as mediators of angiogenesis. Thrombosis and Haemostasis. 2007;97(5):755–762.
    1. Cancio LC. Airway management and smoke inhalation injury in the burn patient. Clinics in Plastic Surgery. 2009;36(4):555–567.
    1. Toon MH, Maybauer MO, Greenwood JE, Maybauer DM, Fraser JF. Management of acute smoke inhalation injury. Critical Care and Resuscitation. 2010;12(1):53–61.
    1. Miller AC, Rivero A, Ziad S, Smith DJ, Elamin EM. Influence of nebulized unfractionated heparin and N-acetylcysteine in acute lung injury after smoke inhalation injury. Journal of Burn Care and Research. 2009;30(2):249–256.
    1. Oremus M, Hanson MD, Whitlock R, et al. A systematic review of heparin to treat burn injury. Journal of Burn Care and Research. 2007;28(6):794–804.
    1. Chacon JMF, De Andrea MLM, Blanes L, Ferreira LM. Effects of topical application of 10,000 IU heparin on patients with perineal dermatitis and second-degree burns treated in a public pediatric hospital. Journal of Tissue Viability. 2010;19(4):150–158.
    1. Cribbs RK, Harding PA, Luquette MH, Besner GE. Endogenous production of heparin-binding EGF-like growth factor during murine partial-thickness burn wound healing. Journal of Burn Care and Rehabilitation. 2002;23(2):116–125.
    1. Cribbs RK, Luquette MH, Besner GE. Acceleration of partial-thickness burn wound healing with topical application of heparin-binding EGF-like growth factor (HB-EGF) Journal of Burn Care and Rehabilitation. 1998;19(2):95–101.
    1. Radulescu A, Zhang HY, Chen CL, et al. Heparin-binding egf-like growth factor promotes intestinal anastomotic healing. Journal of Surgical Research. 2010;171(2):540–550.
    1. Prince RN, Schreiter ER, Zou P, et al. The heparin-binding domain of HB-EGF mediates localization to sites of cell-cell contact and prevents HB-EGF proteolytic release. Journal of Cell Science. 2010;123(13):2308–2318.
    1. Sen S, Meteoglu I, Ogurlu M, Sen S, Derinceoz OO, Barutca S. Topical heparin: a promising agent for the prevention of tracheal stenosis in airway surgery. Journal of Surgical Research. 2009;157(1):e23–e29.
    1. Lilly JD, Parsons CL. Bladder surface glycosaminoglycans is a human epithelial permeability barrier. Surgery, Gynecology & Obstetrics. 1990;171(6):493–496.
    1. Hellgren M, Andersson E, Bystrom B, et al. Dalteparin shortens human labour. Journal of Thrombosis and Haemostasis. 2007;5(Supplement 2)
    1. Osman I, Young A, Ledingham MA, et al. Leukocyte density and pro-inflammatory cytokine expression in human fetal membranes, decidua, cervix and myometrium before and during labour at term. Molecular Human Reproduction. 2003;9(1):41–45.
    1. Ekman-Ordeberg G, Hellgren M, Kerud A, et al. Low molecular weight heparin stimulates myometrial contractility and cervical remodeling in vitro . Acta Obstetricia et Gynecologica Scandinavica. 2009;88(9):984–989.
    1. Serisier DJ, Shute JK, Hockey PM, Higgins B, Conway J, Carroll MP. Inhaled heparin in cystic fibrosis. European Respiratory Journal. 2006;27(2):354–358.
    1. King M, Rubin BK. Pharmacological approaches to discovery and development of new mucolytic agents. Advanced Drug Delivery Reviews. 2002;54(11):1475–1490.
    1. Hiebert LM. Oral heparins. Clinical Laboratory. 2002;48:111–116.
    1. Hiebert LM, Ping T, Wice SM. Enhanced antithrombotic effects of unfractionated heparin in rats after repeated oral doses and its relationship to endothelial heparin concentration. British Journal of Pharmacology. 2008;153(6):1177–1184.
    1. Pinel C, Wice SM, Hiebert LM. Orally administered heparins prevent arterial thrombosis in a rat model. Thrombosis and Haemostasis. 2004;91(5):919–926.
    1. Baughman RA, Kapoor SC, Agarwal RK, Kisicki J, Catella-Lawson F, FitzGerald GA. Oral delivery of anticoagulant doses of heparin. A randomized, double- blind, controlled study in humans. Circulation. 1998;98(16):1610–1615.
    1. Berkowitz SD, Marder VJ, Kosutic G, Baughman RA. Oral heparin administration with a novel drug delivery agent (SNAC) in healthy volunteers and patients undergoing elective total hip arthroplasty. Journal of Thrombosis and Haemostasis. 2003;1(9):1914–1919.
    1. Gonze MD, Salartash K, Sternbergh WC, Baughman RA, Leone-Bay A, Money SR. Orally administered unfractionated heparin with carrier agent is therapeutic for deep venous thrombosis. Circulation. 2000;101(22):2658–2661.
    1. Pineo GF, Hull RD, Marder VJ. Orally active heparin and low-molecular-weight heparin. Current Opinion in Pulmonary Medicine. 2001;7(5):344–348.
    1. Bai S, Ahsan F. Synthesis and evaluation of pegylated dendrimeric nanocarrier for pulmonary delivery of low molecular weight heparin. Pharmaceutical Research. 2009;26(3):539–548.
    1. Bai S, Ahsan F. Inhalable liposomes of low molecular weight heparin for the treatment of venous thromboembolism. Journal of Pharmaceutical Sciences. 2010;99(11):4554–4564.
    1. Bai S, Gupta V, Ahsan F. Inhalable lactose-based dry powder formulations of low molecular weight heparin. Journal of Aerosol Medicine and Pulmonary Drug Delivery. 2010;23(2):97–104.
    1. Qi Y, Zhao G, Liu D, et al. Delivery of therapeutic levels of heparin and low-molecular-weight heparin through a pulmonary route. Proceedings of the National Academy of Sciences of the United States of America. 2004;101(26):9867–9872.
    1. Rawat A, Yang T, Hussain A, Ahsan F. Complexation of a poly-L-arginine with low molecular weight heparin enhances pulmonary absorption of the drug. Pharmaceutical Research. 2008;25(4):936–948.
    1. Yang T, Mustafa F, Ahsan F. Alkanoylsucroses in nasal delivery of low molecular weight heparins: in vivo absorption and reversibility studies in rats. Journal of Pharmacy and Pharmacology. 2004;56(1):53–60.
    1. Yang T, Mustafa F, Bai S, Ahsan F. Pulmonary delivery of low molecular weight heparins. Pharmaceutical Research. 2004;21(11):2009–2016.
    1. Mustafa F, Yang T, Khan MA, Ahsan F. Chain length-dependent effects of alkylmaltosides on nasal absorption of enoxaparin. Journal of Pharmaceutical Sciences. 2004;93(3):675–683.
    1. Yang T, Hussain A, Paulson J, Abbruscato TJ, Ahsan F. Cyclodextrins in nasal delivery of low-molecular-weight heparins: in vivo and in vitro studies. Pharmaceutical Research. 2004;21(7):1127–1136.
    1. Yang T, Hussain A, Bai S, Khalil IA, Harashima H, Ahsan F. Positively charged polyethylenimines enhance nasal absorption of the negatively charged drug, low molecular weight heparin. Journal of Controlled Release. 2006;115(3):289–297.
    1. Baer CL, Bennett WM, Folwick DA, Erickson RS. Effectiveness of a jet injection system in administering morphine and heparin to healthy adults. American Journal of Critical Care. 1996;5:42–48.
    1. Wagner S, Dues G, Sawitzky D, Frey P, Christ B. Assessment of the biological performance of the needle-free injector INJEX using the isolated porcine forelimb. British Journal of Dermatology. 2004;150(3):455–461.
    1. Hollingsworth SJ, Hoque K, Linnard D, Corry DG, Barker SG. Delivery of low molecular weight heparin for prophylaxis against deep vein thrombosis using a novel, needle-less injection device (J-Tip) Annals of the Royal College of Surgeons of England. 2000;82(6):428–431.
    1. Casu B, Vlodavsky I, Sanderson RD. Non-anticoagulant heparins and inhibition of cancer. Pathophysiology of Haemostasis and Thrombosis. 2008;36(3-4):195–203.
    1. Mousa SA. Heparin, low molecular weight heparin, and derivatives in thrombosis, angiogenesis, and inflammation: emerging links. Seminars in Thrombosis and Hemostasis. 2007;33(5):524–533.
    1. Baba M, Snoeck R, Pauwels R, De Clercq E. Sulfated polysaccharides are potent and selective inhibitors of various enveloped viruses, including herpes simplex virus, cytomegalovirus, vesicular stomatitis virus, and human immunodeficiency virus. Antimicrobial Agents and Chemotherapy. 1988;32(11):1742–1745.
    1. Sezer AD, Hatipoğlu F, Cevher E, Oğurtan Z, Baş AL, Akbuğa J. Chitosan film containing fucoidan as a wound dressing for dermal burn healing: preparation and in vitro/in vivo evaluation. AAPS PharmSciTech. 2007;8(2, article no. 39)
    1. Ahmed T, Smith G, Vlahov I, Abraham WM. Inhibition of allergic airway responses by heparin derived oligosaccharides: identification of a tetrasaccharide sequence. Respiratory Research. 2012;13(article 6)
    1. Severin IC, Soares A, Hantson J, et al. Glycosaminoglycan analogues as a novel anti-inflammatory strategy. Frontiers in Immunology. 2012;293:1–12.
    1. Colliec-Jouault S, Bavington C, Delbarre-Lodrat C. Heparin-like entities from marine organisms. In: Lever R, Mulloy B, Page CP, editors. Heparin—A Century of Progress. Vol. 207. Berlin, Germany: Springer; 2012. pp. 423–429. (Handbook of Experimetnal Pharmacology).

Source: PubMed

スポンサーと協力者

医学的状態

薬物療法

3
購読する