Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-02-14
2002-09-03
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S015800, C530S316000, C530S327000, C530S328000
Reexamination Certificate
active
06444646
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates generally to the fields of biochemistry and medicine. More particularly, the present invention relates to methods and substances for use in accelerating the growth or healing of tissue.
Wounds (i.e., lacerations or openings) in mammalian tissue result in tissue disruption and coagulation of the microvasculature at the wound face. Repair of such tissue represents an orderly, controlled cellular response to injury. All soft tissue wounds, regardless of size, heal in a similar manner. Tissue growth and repair are biologic systems wherein cellular proliferation and angiogenesis occur in the presence of an oxygen gradient. The sequential morphological and structural changes which occur during tissue repair have been characterized in great detail and have in some instances been quantified [Hunt, T. K. et al., “Coagulation and macrophage stimulation of angiogenesis and wound healing,” in
The surgical wound
, pp. 1-18, ed. F. Dineen & G. Hildrick-Smith (Lea & Febiger, Philadelphia: 1981)].
The cellular morphology consists of three distinct zones. The central avascular wound space is oxygen deficient, acidotic and hypercarbic, and has high lactate levels. Adjacent to the wound space is a gradient zone of local anemia (ischemia) which is populated by dividing fibroblasts. Behind the leading zone is an area of active collagen synthesis characterized by mature fibroblasts and numerous newly-formed capillaries (i.e., neovascularization). While this new blood vessel growth (angiogenesis) is necessary for the healing of wound tissue, angiogenic agents are in general unable to fulfill the long-felt need of providing the additional biosynthetic effects of tissue repair. Despite the need for more rapid healing of wounds (i.e., severe burns, surgical incisions, lacerations and other trauma), to date there has been only limited success in accelerating wound healing with pharmacological agents.
U.S. Pat. No. 5,015,629 to DiZerega (the entire disclosure of which is hereby incorporated by reference) describes a method for increasing the rate of healing of wound tissue, comprising the application to such tissue of angiotensin II (AII) in an amount which is sufficient for said increase. The application of angiotensin II to wound tissue significantly increases the rate of wound healing, leading to a more rapid re-epithelialization and tissue repair. The term angiotensin II refers to an octapeptide present in humans and other species having the sequence Asp-Arg-Val-Tyr-Ile-His-Pro-Phe [SEQ ID NO:1]. Angiotensin II is a known pressor agent and is commercially available.
Despite the utility of angiotensin II in accelerating wound healing, there remains a need for additional agents which are useful in promoting wound healing. Moreover, it would be highly advantageous to employ an agent which is less potent than angiotensin II at inducing hypertension.
PCT Patent Applications PCT/US94/10502 and PCT/US94/10503 disclose the use in wound repair of compositions comprising angiotensin II analogs and angiotensin III and analogs thereof, respectively. While these compositions have clear utility in wound treatment, there remains a need for compositions and methods with which fewer undesired side-effects may be associated.
A peptide agonist selective for the AT2 receptor (the peptide has 1000× higher affinity for AT2 than AT1) has been identified. This peptide is p-aminophenylalanine6-AII [“(p-NH
2
-Phe)6-All”], Asp-Arg-Val-Tyr-Ile-Xaa-Pro-Phe [SEQ ID NO:2] wherein Xaa is p-NH
2
-Phe [Speth, R C and K H Kim. 1990. Discrimination of two angiotensin II receptor subtypes with a selective agonist analogue of angiotensin II, p-aminophenylalanine6 angiotensin II. Biochem Biophys Res Commun 169:997-1006]. This peptide gave binding characteristics comparable to the AT2 antagonists in the experimental models tested [Catalioto et al. 1994. Angiotensins induce the release of prostacyclin from rabbit vas deferens: evidence for receptor heterogeneity. Eur J Pharmacol 256:93-97; Bryson, S E et al. 1992. Induction of the angiotensin At2 receptor subtype expression by differentiation of the neuroblastoma x glioma hybrid, NG-108-15. Eur J Pharmacol 225:119-127].
It is an object of the present invention to provide compositions and methods which do not suffer from all of the drawbacks of the heretofore-known compositions.
SUMMARY OF THE INVENTION
The present invention relates to the use of angiotensin II Type 2 receptor agonists (“AT2 agonist”) in wound healing. These compounds form the basis of compositions useful for accelerating wound healing, the compositions comprising at least one AT2 agonist in an amount effective to accelerate wound healing. Agonists of the AT2 receptor subtype are of benefit in wound repair but do not exhibit many of the side effects of angiotensin II, such as increases in blood pressure and thirst. Preferably, the compositions are in the form of matrical or micellar solutions.
REFERENCES:
patent: 5015629 (1991-05-01), diZerega
patent: 5834432 (1998-11-01), Rodgers et al.
patent: 5955430 (1999-09-01), Rodgers et al.
patent: 6096709 (2000-08-01), Rodgers et al.
patent: WO 95/08565 (1995-03-01), None
Speth et al., Biochemical and Biophysical Research Communications, vol. 169, No. 3.(1990), 997-1006.*
Timmermans et al., “Angiotnsin II Receptor Subtypes”,Am. J. Hypertens5 (6 Part 1), 1992, 406-410, (abstract).
Hunt et al., Coagulation and macrophage stimulation of angiogenesis and wound healing, inThe surgical wound, pp. 1-18, ed. F. Dineen & G. Hildrick-Smith (Lea & Febiger, Philadelphia: 1981).
Speth, RC and KH Kim. 1990. Discrimination of two angiotensin II receptor subtypes with a selective agonist analogue of angiotensin II, p-aminophenylalanine6 angiotensin II. Biochem Biophys Res Commun 169:997-1006.
Catalioto et al. 1994. Angiotensins induce the release of prostacyclin from rabbit vas deferens: evidence for receptor heterogeneity. Eur J Pharmacol 256:93-97.
Bryson, SE et al. 1992. Induction of the angiotensin At2 receptor subtype expression by differentiation of the neuroblastoma x glioma hybrid, NG-108-15. Eur J Pharmacol 225:119-127.
Dzau V.E. et al. (1989) Molecular mechanism of angiotensin in the regulation of vascular and cardiac growth. J Mol Cell Cardiol 21 (Supple III):S7.
Berk, BC et al. (1989) Angiotensin II stimulated protein synthesis in cultured vascular smooth muscle cells. Hypertension 13:305-14.
Kawahara, Y, et al. (1988) Angiotensin II induces expression of the c-fos gene through protein kinase C activ ation and calcium iron mobilization in cultured vascular smooth muscle cells. BBRC 150:52-9.
Naftilan, AJ et al. (1989) Induction of platelet-derived growth factor A-chain and c-myc gene expressions by angiotensin II in cultured rat vascular smooth muscle cells. J Clin Invest 83:1419-24.
Taubman, MB et al. (1989) Angiotensin II induces c-fos mRNA in aortic smooth muscle. Role of Ca2+mobilization and protein kinase C activation. J Biol Chem 264:526-530.
Nakahara, K et al. (1992) Identification of three types of PDGF-A chain gene transcripts in rabbit vascular smooth muscle and their regulated expression during development and by angiotensin II. BBRC 184:811-8.
Stouffer GA and GK Owens. (1992) Angiotensin II induced mitogenesis of spontaneously hypertensive rat derived cultured smooth muscle cells is dependent on autocrine production of transforming growth factor-&bgr;. Circ Res 70:820.
Wolf, G et al. (1992) Angiotensin II stimulates the proliferation and biosynthesis of type I collagen in cultured murine mesangial cells. Am J Pathol 140:95-107.
Bell, L and JA Madri (1990) Influence of the angiotensin system on endothelial and smooth muscle cell migration. Am J Pathol 137:7-12.
Ferndandez, LA et al. (1985) Neovascularization produced by angiotensin II. J Lab Clin Med 105:141.
LeNoble, FAC et al. (1991) Angiotensin II stimulates angiogenesis in the chorio-allantoic membrane of the chick embryo. Eur J Pharmacol 195:305-6.
Grotendorst, GR et al. (1985) Stimulation of gran
Dizerega Gere Stodder
Rodgers Kathleen Elizabeth
Delacroix-Muirheid C.
Harper David S.
Jones Dwayne C.
McDonnell & Boehnen Hulbert & Berghoff
University of Southern California
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