Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Web – sheet or filament bases; compositions of bandages; or...
Patent
1994-08-24
1996-05-28
Page, Thurman K.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Web, sheet or filament bases; compositions of bandages; or...
424422, 424444, 424445, 424446, 424447, 424448, 424449, 514 23, A61K 970
Patent
active
055209262
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to the use of certain known compounds for the novel purpose of healing wounds and treating certain other conditions associated with the accumulation of extracellular matrix In tissue.
2. Description of the Related Art
It is a problem that although wounds in humans and other mammals usually heal reasonably quickly, unsightly scar tissue is often formed. It is known that growth factors are implicated in fibrotic disorders. Various proposals have been made to ameliorate the effects of fibrotic disorders by administering either the growth factor or antibodies thereto. See, for example W. A. Border et al., Nature 346 371-374 (1990), who showed that extracellular matrix production in acute mesangial proliferative glomerulonephritis (inflammation of the kidney believed caused by immunological injury to cells) is associated with increased production of transformlng growth factor (TGF)-.beta.1 and suppressed by administering anti-TGF-.beta.1. E. Kovacs, Immunology Today 12 (1) 17-23 (1991) concludes that blocking the effects of certain cytokines (such as TNF-.alpha.) with antibodies has diminished fibrosis in animal models of tissue injury. PCT Application Publication No. WO91/04748 (La Jolla Cancer Research Foundation) proposes to treat pathologies associated with accumulation of extracellular matrix in tissue with platelet derived growth factor (PGDF) or with antibodies to TGF-.beta.1. The diseases treated are in general fibrotic diseases and include glomerulonephritis, adult respiratory distress syndrome, cirrhosis of the liver, fibrocytic disease, fibrosis, fibrotic cancers, fibroids, fibroadenomas and fibrosarcomas. Other fibrotic conditions are mentioned. Also, the method can be used to treat or prevent excessive scarring such as keloid scars (hard, irregular scar tissue in the skin which forms when a wound is under tension) and/or is produced in genetically pre-disposed people. H. Shah, D. H. Foreman and M. W. J. Ferguson, The Lancet 339, 213-214 (Jan 25, 1992), describe the control of scarring in wounds by administering antibody which neutralises TGF-.beta.1 and -.beta.2.
The biological mechanisms by which the growth factors operate is not well understood, see C. C. Bascom et. al., Molecular and Cellular Biology 9, 5508-5515 (1989).
It is known that TGF-.beta.1 is synthesised as a pre-pro-protein of 390 amino acids which is converted to mature protein by cleavage between aa residues 278 and 279. However, TGF-.beta.1 isolated in vivo is found predominantly as a high molecular weight latent complex (LTGF .beta.1) in which the pro-region is still associated with the mature molecule, despite the cleavage of the peptide bond. TGF-.beta.2 and .beta.-3 also have latent forms. All have been shown to bind to a plasma membrane receptor called the cation-independent mannose-6-phosphate/insulin-like growth factor II receptor. Binding occurs through mannose-6-phosphate residues attached at glycosylation sites within the pro-region and, in the case of TGF-.beta.1 and TGF-.beta.2, has been shown to be inhibited by antibodies to the receptor. In the case of TGF-.beta.1, binding is inhibited by mannose-6-phosphate itself. See P. A. Dennis and D. B. Rifkin, Proc. Natl. Acad. Sci. USA, 88, 580-584 (1991), M. N. Lioubin, H. Marquardt, R. Roth, K. S. Kovacina and A. F. Purchio, Journal of Cellular Biochemistry 45, 112-121 (1991) and K. Miyazano et al., Annals of the New York Academy of Sciences 593, 51-58 (1990). It has not been clear whether it is desirable to prevent the generation in vivo of the mature active forms of TGFs or whether mannose-6-phosphate receptor binding is the only means of activating the mature protein. It has been suggested in the literature that TGF-.beta.1 becomes activated under various pH conditions: see "The Transforming Growth Factor .beta.s" in "Peptide Growth Factors and Their Receptors 1" (eds. M. B. Sporn and A. B. Roberts), Springer Verlag 1990, pages 419-472, at page 432, and references cited therein. See also K. Miya
REFERENCES:
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Owaku et al., Chemical Abstracts, vol. 106, #89993 (1985).
P A Dennis and D B Rifkind, "Cellular activation of latent transforming growth factor .beta.. . . ", Proc. Natl. Acad. Sci. USA 88, 580-584 (1991).
M N Lioubin et al., "Characterization of Latent Recombinant TGF-.beta.2 Produced by Chinese Hamster Ovary Cells" Journal of Cellular Biochemistry 45, 112-121 (1991).
K Miyazono et al. "Latent Forms of TGF-.beta. : Structure and Biology", Annals N.Y. Acad. Sci. 593, 51-58 (1990).
K Miyazono and C-H. Heldin, "Latent Forms of TGF-.beta. : molecular structure and mechanisms of activation", Ciba Foundation Symposium 157, 81-92 (1991).
E J Kovacs, "Fibrogenic cytokines : the role of immune mediators in the development of scar tissue", Immunology Today 12 (1), 17-23 (1991).
K Miyazono et al., "Role for carbohydrate structures in TGF-.beta.1 latency" Nature 338, 158-160 (1989).
L Storckenfeldt et al., "Stimulatory effects of insulin like growth factor II on DNA synthesis in the human embryonic cornea", Cell Biology International Reports 15 (12) 1217-1233 (1991).
Scars and Stripes, The Newsletter of the Wound Healing Society (The Wound Healing Center, Richmond Va. 23298-0117), vol. 2 No. 3 Spring 1992 (Mailed Feb. 7, 1992), pp. 4-6.
D. M. Foreman et al., "The effect of mannose-6-phosphate on healing adult rodent dermal wounds", European Tissue Repair Society, Second Annual Meeting, Aug. 26-28 1992, Malmo, Sweden, Abstract 15, p. 26.
M. W. J. Ferguson, "Control of Scarring in Adult Wounds", American College of Surgeons, 78th Annual Clinical Congress, Oct. 11-16 1992, New Orleans, No. 22, pp. 36 & 37.
M. W. J. Ferguson, "Fetal Wound Healing: Clinical Implications", American College of Surgeons, 78th Annual Clinical Congress, Oct. 11-16, 1992, New Orleans, No. 13, pp. 47 & 48.
Letter of Aug. 7, 1992 from Prof. M. W. J. Ferguson to Dr. D. B. Rifkin and reply dated Aug. 19, 1992 from Dr. D. B. Rifkin to Prof. M. W. J. Ferguson.
Letter of Sep. 9, 1992 from Prof. M. W. J. Ferguson to Dr. C-H. Heldin and reply dated Sep. 16, 1992 from Dr. C-H. Heldin to Prof. M. W. J. Ferguson.
British Technology Group Limited
Page Thurman K.
Webber Pamela S.
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