Novel drug development opportunities for heparin

Nature Reviews Drug Discovery

Volumn 1, Issue 2, 2002, Pages 140-148

  Lever, Rebecca ^a   Page, Clive P ^a  

^a KING'S COLLEGE LONDON   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ANTICOAGULANT AGENT; ANTITHROMBIN; BETA2 INTEGRIN; CATHEPSIN; CD31 ANTIGEN; CYTOKINE; CYTOTOXIC FACTOR; ELASTASE; EOTAXIN; FIBROBLAST GROWTH FACTOR 2; GROWTH FACTOR; HEPARAN SULFATE; HEPARANASE; HEPARIN; HEPARIN DERIVATIVE; HEPARIN PLATELET FACTOR 4 ANTIBODY; INTERLEUKIN 8; L SELECTIN; LOW MOLECULAR WEIGHT HEPARIN; N ACETYL BETA GLUCOSAMINIDASE; OLIGOSACCHARIDE; PADGEM PROTEIN; PENTOSAN POLYSULFATE; PLATELET DERIVED GROWTH FACTOR; POLYSACCHARIDE; RANTES; SERINE PROTEINASE; THROMBOCYTE FACTOR 4; UNINDEXED DRUG; VASCULOTROPIN; BETA GLUCURONIDASE; CELL ADHESION MOLECULE;

ANTICOAGULANT THERAPY; ANTICOAGULATION; ASTHMA; CANCER; CLINICAL TRIAL; DRUG ABSORPTION; DRUG EFFECT; DRUG PROTEIN BINDING; DRUG RELEASE; DRUG STRUCTURE; DRUG SYNTHESIS; EXTRAVASATION; HUMAN; INFLAMMATION; NONHUMAN; PRIORITY JOURNAL; REVIEW; THROMBOCYTOPENIA; THROMBOSIS; VENOUS THROMBOEMBOLISM; ANIMAL; ARTICLE; DRUG DESIGN; METABOLISM; NEOPLASM; PHYSIOLOGY;

ANIMALS; ANTICOAGULANTS; CELL ADHESION MOLECULES; DRUG DESIGN; GLUCURONIDASE; HEPARIN; HUMANS; INFLAMMATION; NEOPLASMS;

EID: 0036463453     PISSN: 14741776     EISSN: 14741784     Source Type: Journal    
DOI: 10.1038/nrd724     Document Type: Review

References (117)

1. Tumbull, J., Powell, A. & Guimond, S. Heparan sulfate: decoding a dynamic multifunctional cell regulator. Trends Cell Biol. 11, 75-82(2001). An excellent review on the role of heparan sulphate as a regulatory molecule, with reference to specific structural features and their relevance in protein binding.
2. Vlodavsky, I. & Friedmann, Y. Molecular properties and involvement of heparanase in cancer metastasis and angiogenesis. J. Clin. Invest. 108, 341-347(2001).
3. Tyrrell, D. J. et al. Heparin in inflammation: potential therapeutic applications beyond anticoagulation. Adv. Pharmacol. 46, 151-208(1999). A comprehensive review of the literature concerning the non-anticoagulant effects of heparin with an emphasis on its anti-inflammatory actions.
4. McLean, J. The thromboplastic action of cephalin. Am. J. Physiol. 41, 250(1916).
5. Rosenberg, J. S., McKenna, P. W. & Rosenberg, R. D. Inhibition of human factor IXa by human antithrombin. J. Biol. Chem. 250, 8883-8888(1975).
6. Davie, E. W. Biochemical and molecular aspects of the coagulation cascade. Thromb. Haemost. 71, 1-6(1995).
7. Broze, G. J. Jr. Tissue factor pathway inhibitor and the revised theory of coagulation. Annu. Rev. Med. 46, 103-112 (1995).
8. Luchtm an-Jones, L. & Broze, G. J. Jr. The current status of coagulation. Ann. Med. 27, 47-52(1995).
9. Rosenberg, R. D. & Damus, P. S. The purification and mechanism of action of human antithrombin-heparin cofactor. J. Biol. Chem. 248, 6490-6505(1973).
10. Choay, J. et al. Structure activity relationship in heparin: a synthetic pentasaccharide with high affinity for antithrombin III and eliciting high anti-Xa activity. Biochem. Biophys. Res. Commun. 116, 492(1983).
11. Lindahl, U., Backstrom, G., Thunberg, L. & Leder, I. G. Evidence for a 3-O-sulfated D-glucosamine residue in the antithrombin-binding sequence of heparin. Proc. Natl Acad. Sci. USA 77, 6551-6555(1980).
12. Lindahl, U. et al. Extension and structural variability of the antithrombin-binding sequence in heparin. J. Biol. Chem. 259, 12368-12376(1984).
13. Thunberg, L., Bäckström, G. & Lindahl, U. Further characterisation of the antithrombin-binding sequence in heparin. Carbohydr. Res. 100, 393-410(1982).
14. McCrae, K. R., Bussel, J. B., Mannucci, P. M., Remuzzi, G. & Cines, D. B. Platelets: an update on diagnosis and management of thrombocytopenic disorders. Hematology (Am. Soc. Hematol. Educ. Prog.) 282-305(2001).
15. Petitou, M. et al. Synthesis of thrombin-inhibiting heparin mimetics without side effects. Nature 398, 417-422(1999). This study describes the rationale for structural modification of heparin for the production of anticoagulant drugs with reduced immunogenicity and potential for side effects.
16. Buijsman, R. C. et al. Design and synthesis of a novel synthetic NAPAP-pentasaccharide conjugate displaying a dual antithrombotic action. Bioorg. Med. Chem. Lett. 9, 2013-2018(1999).
17. Baughman, R. A et al. Oral delivery of anticoagulant doses of heparin. Circulation 98, 1610-1615(1998).
18. Mulloy, B., Crane, D. T., Drake, A. F. & Davies, D. B. The interaction between heparin and polylysine: a circular dichroism and molecular modelling study. Braz. J. Med. Biol. Res. 29, 721-729(1996).
19. 2-agonists. Lancet 337, 717-720(1991).
20. Damus, P. S., Hicks, M. & Rosenberg, R. D. Anticoagulant action of heparin. Nature 246, 355-357(1973).
21. Klein, N.J., Shennan, G. I., Heyderman, R. S. & Levin, M. Alteration in glycosaminoglycan metabolism and surface charge on human umbilical vein endothelial cells induced by cytokines, endotoxin and neutrophils. J. Cell Sci. 102, 821-832(1992).
22. Hiebert, L. M. & Jacques, L. B. The observation of heparin on endothelium after injection. Thromb. Res. 8, 195-204 (1976).
23. Kraemer, P. M. Heparin releases heparan sulfate from the cell surface. Biochem. Biophys. Res. Commun. 78, 1334-1340(1977).
24. Lever, R., Hoult, J. R. S. & Page, C. P. The effects of heparin and related molecules upon the adhesion of human polymorphonuclear leukocytes to vascular endothelium in vitro. Br. J. Pharmacol. 129, 533-540(2000).
25. Parsons, C. L., Stauffer, C. & Schmidt, J. D. Bladder-surface glycosaminoglycans: an efficient mechanism of environmental adaptation. Science 208, 605-607(1980). This study describes the importance of an endogenous GAG layer in preventing non-specific adhesion to an epithelial surface and how administration of exogenous GAGs can restore this function to a disrupted epithelium.
26. Koenig, A., Norgard-Sumnicht, K., Unhardt, R. & Varki, A. Differential interactions of heparin and heparan sulfate glycosaminoglycans with the selectins. J. Clin. Invest. 101, 877-889(1998).
27. Giufirè, L. et al. Monocyte adhesion to activated aortic endothelium: role of L-selectin and heparan sulfate proteoglycans. J. Cell Biol. 136, 945-956(1997).
28. Diamond, M. S., Alon, R., Parkos, C. A., Quinn, M. T. & Springer, T. A. Heparin is an adhesive ligand for the leukocyte integrin MAC-1 (CD11b/CD18). J. Cell Biol. 130, 1473-1482(1995).
29. Salas, A.et al. Heparin attenuates TNF-α induced inflammatory response through a CD11b dependent mechanism. Gut 47, 88-96(2000).
30. Skinner, M. P., Lucas, C. M., Burns, G. F., Chesterman, C. N. & Berndt, M. C. GMP-140 binding to neutrophils is inhibited by sulfated glycans. J. Biol. Chem. 266, 5371-5374(1991).
31. + hematopoietic precursor cells with early myeloid and B-lymphoid cell phenotypes. Blood 82, 2649-2663(1993).
32. Silvestro, L. et al. Effects of heparin and its desulfated derivatives on leukocyte-endothelial adhesion. Semin. Thromb. Hemost. 20, 254-258(1994).
33. Smailbegovic, A., Lever, R. & Page, C. P. The effects of heparin on the adhesion of human peripheral blood mononuclear cells to human stimulated umbilical van endothelial cells. Br. J. Pharmacol. 134, 827-836 (2001).
34. Xie, X., Thoriacius, 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. Br. J. Pharmacol. 122, 906-910 (1997).
35. Ley, K., Cerrito, M. & Arfors, K.-E. Sulfated polysaccharides inhibit leukocyte rolling in rabbit mesentery venules. Am. J. Physiol. 260, H1667-H1673(1991).
36. Tangelder, G. J. & Arfors, K.-E. Inhibition of leukocyte rolling in venules by protamine and sulfated polysaccharides. Blood 7, 1565-1571(1991).
37. Seeds, E. A. M., Hanss, J. & Page, C. P. The effect of heparin and related proteoglycans on allergen and PAF-induced eosinophil infiltration. J. Lipid Mediat. 7, 269-278(1993).
38. Seeds, E. A. M., Home, A. P., Tyrrell, D. J. & Page, C. P. The effect of inhaled heparin and related glycosaminoglycans on allergen-induced eosinophil infiltration in guinea-pigs. Pulm. Pharmacol. 8, 97-105 (1995).
39. Seeds, E. A. M. & Page, C. P. Heparin inhibits allergen-induced eosinophil infiltration into guinea-pig lung via a mechanism unrelated to its anticoagulant activity. Pulm. Pharmacol. Ther. 14, 111-119(2001).
40. Sasaki, M., Herd, C. M. & Page, C. P. Effect of heparin and a low-molecular weight heparinoid on PAF-induced airway responses in neonatally immunized rabbits. Br. J. Pharmacol. 110, 107-112(1993).
41. Teixeira, M. M. & Hellewell, P. G. Suppression by intradermal administration of heparin of eosinophil accumulation but not oedema formation in inflammatory reactions in guinea-pig skin. Br. J. Pharmacol. 110, 1496-1500(1993).
42. Sy, M. S. et al. Inhibition of delayed-type hypersensitivity by heparin depleted of anticoagulant activity. Cell. Immunol. 82, 23-32(1983).
43. Yanaka, K., Nose, T. & Hindman, B. J. Heparin ameliorates brain injury by inhibiting leukocyte accumulation. Stroke 27, 2146-2147(1996).
44. Ahmed, T. et al. Heparin prevents antigen-induced airway hyperresponsiveness: interference with IP3-mediated mast cell degranulation? J. Appl. Physiol. 76, 893-901(1994).
45. Ahmed, T. 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. Am. J. Respir. Crit. Care Med 155, 1848-1855(1997).
46. Preuss, J. M. H. & Page, C. P. Effect of heparin on antigen-induced airway responses and pulmonary leukocyte accumulation in neonatally immunized rabbits. Br. J. Pharmacol. 129, 1585-1596(2000).
47. Dolowitz, D. A. & Dougherty, T. F. The use of heparin as an anti-inflammatory agent. Laryngoscope 70, 873-874 (1960).
48. Dolowitz, D. A. & Dougherty, T. F. The use of heparin in the control of allergies. Ann. Allergy 23, 309-313(1965).
49. Diamant, Z. et al. Effect of inhaled heparin on allergen-induced early and late asthmatic responses in patients with atopic asthma. Am. J. Respir. Crit. Care Med. 153, 1790-1795(1996).
50. Ahmed, T., Garrigo, J. & Danta, I. Preventing bronchoconstriction in exercise-induced asthma with inhaled heparin. N. Engl. J. Med. 329, 90-95(1993).
51. Antczak, M. & Kuna, P. Heparin inhibits allergen induced airway response in asthmatics. Results of a double blind placebo-controlled, crossover study. J. Allergy Clin. Immunol. 95, 386(1995).
52. Bowler, S. D., Smith, S. M. & Laverombe, P. S. Heparin inhibits the immediate response to antigen in the skin and lungs of allergic subjects. Am. Rev. Respir. Dis. 147, 160-163(1993).
53. 99mTc-heparin in healthy volunteers. Am. J. Respir. Crit. Care Med. 160, 1653-1658(1999). Many studies, carried out in vivo, of the non-anticoagulant effects of heparin have found clotting parameters to be unaffected, in particular when heparin is administered topically. This study describes a pharmacokinetic study that follows the fate of heparin and its effects on clotting parameters when it is administered by inhalation in humans.
54. Gaffney, A. & Gaffney, P. Rheumatoid arthritis and heparin. Br. J. Rheumatol. 35, 808(1996).
55. Gaffney, P. R. et al. Response to heparin in patients with ulcerative colitis. Lancet 337, 238-239(1991).
56. Gaffney, P. R. et al. Paradoxical response to heparin in 10 patients with ulcerative colitis. Am. J. Gastroenterol. 90, 220-223(1995).
57. Evans, R. C., Wong, V. S., Morris, A. I. & Rhodes, J. M. Treatment of corticosteroid-resistant ulcerative colitis with heparin - a report of 16 cases. Aliment. Pharmacol. Ther. 11, 1037-1040(1997).
58. Vancheri, C. et al. Intranasal heparin reduces eosinophil recruitment after nasal allergen challenge in patients with allergic rhinitis. J. Allergy Clin. Immunol. 108, 703-708 (2001).
59. Fryer, A. et al. Selective O-desulphation produces nonanticoagulant heparin that retains pharmacologic activity in the lung. J. Pharmacol. Exp. Ther. 282, 209-219(1997). Many of the non-anticoagulant actions of heparin are likely to be separable from this property, which would be considered an undesirable effect in indications aside of thrombosis. This study describes chemical modification of the unfractionated heparin molecule to yield a species that lacks the anticoagulant activity, but retains the anti-inflammatory characteristics of the parent drug.
60. Alonso, D. F. et al. Antimetastatic effects associated with anticoagulant properties of heparin and chemically modified heparin species in a mouse mammary tumor model. Oncology Reports 3, 219-222(1996).
61. Sciumbata, T. et al. Treatment with modified heparins inhibits experimental metastasis formation and leads, in some animals, to long-term survival. Invasion Metastasis 16, 132-143(1996).
62. Nakajima, M., Irimura, T. & Nicolson, G. L. Heparanases and tumor metastasis. J. Cell. Biochem. 36, 157-167(1988).
63. Parish, C. R., Freeman, C. & Hulett, M. D. Heparanase: a key enzyme involved in cell invasion. Biochim. Biophys. Acta 1471, M99-M108(2001). An excellent review on heparanase, with particular reference to tumour growth and metastasis. Current opinion on the structure of the heparanase enzyme is discussed.
64. Zacharski, L. R., Ornstein, D. L. & Mamourian, A. C. Low-molecular-weight heparin and cancer. Semin. Thromb. Hemostas. 26, 69-77(2000).
65. Hettiarachchi, R. J. K. et al. Do heparins do more than just treat thrombosis? The influence of heparins on cancer spread. Thromb. Haemostas. 82, 947-952(1999).
66. Zacharski, L. R. & Omstein, D. L. Heparin and cancer. Thromb. Haemostas, 80, 10-23(1988).
67. Engelberg, H. Actions of heparin that may affect the malignant process. Cancer 85, 257-272(1999).
68. Hulett, M. D. et al. Cloning of mammalian heparanase: an essential enzyme involved in tumor invasion and metastasis. Nature Med. 5, 803-809(1999). This paper, and references 82 and 83, were the first reports on cloning and sequencing of the heparanase gene, which was found to be expressed in metastatic tumour cells and leukocytes.
69. Bar-Ner, M. et al. Inhibition of heparanase-mediated degradation of extracellular matrix heparan sulfate by non-anticoagulant heparin. Blood 70, 551-557(1987).
70. Bartlett, M. R., Underwood, P. A. & Parish, C. R. Comparative analysis of the ability of leukocytes, endothelial cells and platelets to degrade the subendothelial basement membrane: evidence for cytokine dependence and detection of a novel sulfatase. Immunol. Cell Biol. 73, 113-124(1995).
71. Gorski, A. et al. New strategies of heparin treatment used to prolong allograft survival. Transplant. Proc. 23, 2251-2252 (1991).
72. Lider, O. et al. Suppression of experimental autoimmune diseases and prolongation of allograft survival by treatment of animals with low doses of heparin. J. Clin. Invest. 83, 752-756(1989).
73. Sy, M. S. et al. Inhibition of delayed-type hypersensitivity by heparin depleted of anticoagulant activity. Cell. Immunol. 82, 23-32(1983).
74. Lider, O. et al. Inhibition of T-lymphocyte heparanase by heparin prevents T cell migration and T cell mediated immunity. Eur. J. Immunol. 20, 493-499(1990).
75. Willenborg, D. O. & Parish, C. R. Inhibition of allergic encephalomyelitis in rats by treatment with sulphated polysaccharides. J. Immunol. 140, 3401-3405(1988).
76. Vlodavsky, I. et al. Expression of heparanase by platelets and circulating cells of the immune system: possible involvement in diapedesis and extravasation. Invasion Metastasis 12, 112-127(1992).
77. Borsig, L. et al. Heparin and cancer revisited: mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis. Proc. Natl Acad. Sci. USA 98, 3352-3357(2001). This study highlights the important roles of P-selectin and tumour cell-surface mucins in metastasis and shows a mechanism for the antimetastatic activity of heparin, through interference with P-selectin ligand binding.
78. Forsberg, E. et al. Abnormal mast cells in mice deficient in a heparin-synthesising enzyme. Nature 400, 773-776(1999).
79. Humphries, D. E. et al. Heparin is essential for the storage of specific granule proteases in mast cells. Nature 400, 769-772(1999).
80. Bullock, S. L. et al. Renal agenesis in mice homozygous for a gene trap mutation in the gene encoding heparan sulfate 2-sulfotransferase. Genes Dev. 12, 1894-1906 (1998).
81. Ringvall, M. et al. Defective heparan sulfate biosynthesis and neonatal lethality in mice lacking N-deacetylase/N-sulfotransferase-1. J. Biol. Chem. 275, 25926-25930 (2000).
82. Vlodavsky, I. et al. Cloning of mammalian heparanase, an important enzyme in tumor invasion and metastasis. Nature Med. 5, 793-802(1999).
83. Kussie, P. H. et al. Cloning and functional expression of a human heparanase gene. Biochem. Biophys. Res. Commun. 261, 183-187(1999).
84. Fairbanks, M. B. et al. Processing of the human heparanase prescursor and evidence that the active enzyme is a heterodimer. J. Biol. Chem. 274, 29587-29590(1999).
85. Hulett, M. D. et al. Identification of active-site residues of the pro-metastatic endoglycosidase heparanase. Biochemistry 39, 15659-15667(2000).
86. McKenzie, E. et al. Cloning and expression profiling of HPA2, a novel mammalian heparanase family member. Biochem. Biophys. Res. Commun. 276, 1170-1177(2000). This study describes the cloning of a heparanase gene that is related to that described in references 68, 82 and 83, but encoding a protein with an unknown substrate. Marked differences between the two enzymes were found with respect to tissue expression.
87. Murch, S. H. et al. Disruption of sulphated glycosaminoglycans in intestinal inflammation. Lancet 341, 711-714(1993). In this histological study, breakdown of endogenous GAGs is found to correlate with sites of active inflammation in human disease.
88. Shute, J. K., Parmar, J., Holgate, S. T. & Howart, P. H. Urinary glycosaminoglycan levels are increased in acute severe asthma - a role for eosinophil-derived gelatinase B? Int. Arch. Allergy Immunol. 113, 366-367(1997).
89. Lam, L. H., Silbert, J. E. & Rosenberg, R. D. The separation of active and inactive forms of heparin. Biochem. Biophys. Res. Commun. 69, 570-577 (1976).
90. Bretthauer, R. K., Kaczorowski, G. J. & Weise, M. J. Characterization of a phosphorylated pentasaccharide isolated from Hansenula holstii NRRL Y-2448 phosphomannan. Biochemistry 12, 1251-1256(1973).
91. Pikas, D. S. et al. Substrate specificity of heparanases from human hepatoma and platelets. J. Biol. Chem. 273, 18770-18777(1998).
92. Parish, C. et al. Identification of sulphated oligosaccharide-based inhibitors of tumor growth and metastasis using novel in vitro assays for angiogenesis and heparanase activity. Cancer Res. 59, 3433-3441(1999).
93. Gotkin, B., Mendoza-Ayala, R., Campo, C., Zhou, M. & Ahmed, T. Effect of heparin tetrasaccharide on late phase responses in ovine and murine models of asthma: comparison with budesonide. Am. J. Respir. Crit. Care Med. 159, A874(1999).
94. 2+ signalling. Proc. Natl Acad. Sci. USA 96, 14499-14504(1999).
95. Jaques, L. B., Hiebert, L. M. & Wice, S. M. Evidence from endothelium of gastric absorption of heparin and of dextran sulphates 8000. J. Lab. Clin. Med. 117, 122-130(1991).
96. Hiebert, L. M., Wice, S. M. & Jaques, L. B. Antithrombotic activity of oral unfractionated heparin. J. Cardiovasc. Pharmacol. 28, 26-29(1996).
97. Costantini, V., Deveglia, R., Stabile, A. & Nenci, G. G. Absorption and antithrombotic activity of unfractionated heparin after intraduodenal administration in rats. Blood Coag. Fibriolysis 11, 7-13(2000).
98. 14C-labeled porcine intestinal mucosal heparin following administration to rats by the oral route. Can. J. Physiol. Pharmacol. 78, 307-320(2000).
99. Hiebert, L. M., Wice, S. M., Ping, T., Herr, D. & Laux, V. Antithrombotic efficacy in a rat model of the low molecular weight heparin, reviparin sodium, administered by the oral route. Thromb. Haemostas. 85, 114-118(2001).
100. Chander, C. L. et al. The effects of heparin and cortisone on an experimental model of pannus. Int. J. Tissue React. 11, 113-116(1989).
101. Li, Y., Shin, V. Y., Cheuk, C. Y., Liu, E. S. L. & Cho, C. H. A 3.0-kDa low molecular weight heparin promotes gastric ulcer healing in rats. Aliment. Pharmacol. Ther. 15, 2009-2017(2001).
102. Doutremepuich, C., Toulemonde, F. & Lormeau, J. C. Oral administration of low molecular weight heparin fractions in rabbits. Semin. Thromb. Hemost. 11, 323-325(1985).
103. Dryjski, M., Schneider, D. E., Mojaverian, P., Kuo, B. S. & Bjornsson, T. D. Investigations on plasma activity of low molecular weight heparin after intravenous and oral administrations. Br. J. Clin. Pharmacol. 28, 188-192(1989).
104. Silvestro, L. et al. Human pharmacokinetics of glycosaminoglycans using deuterium-labeled and unlabeled substances: evidence for oral absorption. Semin. Thromb. Hemost. 20, 281-292(1994).
105. Thanou, M., Verhoef, J. C. & Junginger, H. E. Oral drug absorption enhancement by chitosan and its derivatives. Adv. Drug Deliv. Rev. 52, 117-126(2001).
106. Lee, Y.-K, Nam, J. H., Shin, H.-C. & Byun, Y. Conjugation of low-molecular-weight heparin and deoxycholic acid for the development of a new oral anticoagulant agent. Circulation 104, 3116-3120(2001).
107. Money, S. R. & York, J. W. Development of oral heparin for prophylaxis and treatment of deep vein thrombosis. Cardiovasc. Surg. 9, 211-218 (2001).
108. Revelle, B. M., Scott, D. & Beck, P. J. Single amino acid residues in the E- and P-selectin epidermal growth factor domains can determine carbohydrate binding specificity. J. Biol. Chem. 271, 16160-16170(1996).
109. Tabeur, G. et al. Oligosaccharides corresponding to the regular sequence of heparin: chemical synthesis and interaction with FGF-2. Bioorg. Med. Chem. 7, 2003-2012 (1999).
110. Lundin, L. et al. Selectively desulphated heparin inhibits fibroblast growth factor-induced mitogenicity and angiogenesis. J. Biol. Chem. 275, 24653-24660(2000).
111. Fath, M. A. et al. Interaction of secretory leukocyte protease inhibitor with heparin inhibits proteases involved in asthma. J. Biol. Chem. 273, 13563-13569(1998).
112. Parsons, C. L. Epithelial coating techniques in the treatment of interstitial cystitis. Urology 49, 100-104(1997).
113. Kennedy, T. P. Use of heparin to inhibit interleukin-8. International patent WO94/18989(1994).
114. Innes, J., Barr, A, Sharif, M. & Dieppe, P. A. A one year double blind placebo controlled trial of oral pentosan polysulphate as a treatment for naturally occuring osteoarthritis of the stifle (knee) in dogs. Osteoarth. Cartilage 5, 49(1997).
115. McLeskey, S.W. et al. Effects of AGM-1470 and pentosan polysulphate on tumorigenicity and metastasis of FGF-transfected MCF-7 cells. Br. J. Cancer 73, 1053-1062 (1996).
116. Turpie, A. G. G., Gallus, A. S. & Hoek, J. A. A synthetic pentasaccharide for the prevention of deep-vein thrombosis after total hip replacement. N. Engl. J. Med. 344, 619-625 (2001).
117. Tsukida, T. et al. Studies on selectin blockers. 7. Structure-activity relationships of sialyl Lewis X mimetics based on modified Ser-Glu dipeptides. J. Med. Chem. 41, 4279-4287 (1998).