Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1998-05-14
2000-05-09
Kunz, Gary L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
514 8, 514 56, 536118, 5361231, 530350, 530395, A61K 31715, A61K 3816, A61K 31725, C07K 900
Patent
active
060604603
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB96/01841, filed Jul. 31, 1996.
The present invention concerns pharmaceutical compositions for promoting the healing of wounds or fibrotic disorders, in particular for promoting the healing of wounds or fibrotic disorders with reduced scarring.
By "wounds or fibrotic disorders" is meant any condition which may result in the formation of scar tissue. In particular, this includes the healing of skin wounds, the repair of tendon damage, the healing of crush injuries, the healing of eye wounds, including wounds to the cornea, the healing of central nervous system (CNS) injuries, conditions which result in the formation of scar tissue in the CNS, scar tissue formation resulting from strokes, and tissue adhesion, for example, as a result of injury or surgery (this may apply to e.g. tendon healing and abdominal strictures and adhesions). Examples of fibrotic disorders include pulmonary fibrosis, glomerulonephritis, cirrhosis of the liver, and proliferative vitreoretinopathy.
By "reduced scarring" is meant reduced level of scarring relative to an untreated wound or fibrotic disorder.
In particular, there is a lack of compositions for promoting the healing of wounds or fibrotic disorders with reduced scarring. Scar tissue formation, although providing mechanical strength to a healed wound, can be unsightly and may impair the function of the tissue.
This is particularly the case in wounds which result in scar tissue formation in the CNS, the scar tissue inhibiting the reconnection of severed or re-growing nerve ends, so significantly affecting their function.
There is also a lack of compositions for treating and promoting the healing of chronic wounds, for example venous ulcers, diabetic ulcers and bed sores (decubitus ulcers), especially in the elderly and wheel chair bound patients. Such compositions may be extremely useful in patients where wound healing is either slow or in whom the wound healing process has not yet started. Such compositions may be used to "kick-start" wound healing and may then be used in combination with compositions for promoting healing with reduced scarring. Hence not only may a chronic wound be healed, but it may be healed with reduced scarring.
Betaglycan (BG), otherwise known as TGF.beta. (Transforming Growth Factor-.beta.) receptor III (RIII), is a widely distributed membrane proteoglycan comprising a 100 kDa core protein with heparan- and chondroitin-sulphate side chains attached to it (see Lopez-Casillas et al., 1991, Cell, 67: 785-795). TGF-.beta. binds to the BG core protein, not requiring the glycosaminoglycan (GAG) side chains for this interaction, whilst FGF-2 binds to BG through the heparan-sulphate side-chains (Cheifetz, S. et al., 1988, J. Biol. Chem., 263: 16984-16991).
The BG core protein comprises:
Cells are able to release the extracellular domain via a cleavage site near the transmembrane domain, and this appears to occur in vivo, soluble BG (solBG) being found in the serum (Andres, J. L. et al., 1989, J. Biol. Chem., 109: 3137-3145).
TGF-.beta. binds to various membrane proteins (see Massague, J. et al., 1994, Trends in Cell Biol., 4: 172-178 for a review), two of which, TGF-.beta. receptors I and II (RI and RII) form a signalling receptor complex. RI appears to require the presence of RII to bind ligand and RIl appears to require the presence of RI for signalling, but not for ligand binding (see Wrana, J. L. et al., 1992, Cell, 71: 1003-1014). TGF.beta. receptor isoforn specificity may be conferred by the three different receptor types since RI and RII bind TGF.beta..sub.1 and TGF.beta..sub.3 with much greater affinity than TGF.beta..sub.2, this difference being most pronounced in cells which lack BG. Expression of BG correlates with elevated binding of all TGF.beta.s to RII and this correlation is particularly evident in the case of TGF.beta..sub.2, an isoforrn which has a low affinity for RI and RII in the absence of BG (see Lopez-Casillas, F. et al., 1993, Cell, 73: 1435-1444). An important function of membrane-anchored BG is the pr
REFERENCES:
patent: 5453492 (1995-09-01), Butzow et al.
The Journal of Cell Biology, vol. 124, No. 4, Feb. 1994, pp. 557-568, Lopez-Casillas et al, "Betaglycan Can Act as a Dual Modulator of TFG-Beta Access to Signaling Receptors: Mapping of Ligand Binding and GAG Attachment Sites".
Journal of Cell Science, vol. 108, Mar. 1995, pp. 985-1002, Shah et al, Neutralisation of TGF-Beta1 and TGF-Beta2 or Exogenous Addition of TGF-Beta3 to Cutaneous Rat Wounds Reduces Scarring.
Journal of Cell Science, vol. 107, 1994, pp. 1137-1157, Shah et al, "Neutralising Antibody to TGF-Beta1,2 Reduces Cutaneous Scarring in Adult Rodents".
Border, Wayne A., M.D. et al., "Transforming Growth Factor .beta. in Tissue Fibrosis", The New England Journal of Medicine, vol. 331, No. 19, Nov. 10, 1994, pp. 1286-1292.
Kunz Gary L.
The Victoria University of Manchester
White Everett
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