EP0318488A1 - Stimulation of angiogenesis and promotion of endothelialisation - Google Patents
Stimulation of angiogenesis and promotion of endothelialisationInfo
- Publication number
- EP0318488A1 EP0318488A1 EP87905152A EP87905152A EP0318488A1 EP 0318488 A1 EP0318488 A1 EP 0318488A1 EP 87905152 A EP87905152 A EP 87905152A EP 87905152 A EP87905152 A EP 87905152A EP 0318488 A1 EP0318488 A1 EP 0318488A1
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- European Patent Office
- Prior art keywords
- inflammatory compound
- angiogenesis
- inflammatory
- proline
- composition
- Prior art date
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/60—Salicylic acid; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Definitions
- This invention relates to the control of angiogenesis, and methods and compositions therefor.
- a method for stimulating angiogenesis in a mammal characterized by the use of an anti-inflammatory agent.
- 3T3-cell derived growth factor McAuslan et al. , 1980
- tumor-derived growth factor Klagsbrun et al.. , 1982
- ECGF endothelial cell growth stimulator
- concentrations of copper ions can induce neovascularisation in the anterior eye chamber or corneal pocket and also migration of endothelial cells in culture (McAuslan, 1979; McAuslan and Gole, 1980; McAuslan and Reilly, 1980).
- an ideal agent for control of angiogenesis should have a direct action, and should itself be anti-inflammatory.
- a further limitation is imposed by the necessity for the agent to penetrate the target organ.
- NB also called hydratropic acids 2— henylpropanoic acids
- a method of stimulating angiogenesis in a mammal comprising the step of administering to that animal an anti-in lammatory compound.
- a method of stimulating endothelialisation in a mammal comprising the step of administering to that mammal an anti-inflammatory compound.
- the anti-inflammatory compound is preferably selected from the group which includes salicylic acid, anthranilic acid, phenyl acetic acid, and thiazole acetic acid, and their angiogenically-active analogues and derivatives.
- the anti-inflammatory compound has a directly-acting angiogenic effect.
- the compound comprises an aromatic carboxylic acid group.
- the compound is administered so as to achieve a diffusion gradient of concentration to which endothelial cells respond.
- Combinations of two or more compounds according to the invention may optionally be used.
- Combinations of one or more compounds according to the invention together with one or more other stimulators of angiogenesis may also optionally be used.
- Said second stimulator is suitably a modulator of collagen synthesis or of collagen fibril assembly.
- the modulator is an inhibitor of the ' activity of the enzyme proline hydroxylase.
- the inhibitory agent is selected from the group which includes cis-4-hyroxy-L-proline, 3, 4-dehydro-L-proline, L-azetidine-2-carboxylic acid, L-proline analogues, and their angiogenically-active analogues and derivatives.
- said second stimulator of angiogenesis is epidermal growth factor or a pharmacologically active analogue, fragment or derivative thereof.
- the compound according to the invention may optionally be administered in a slow-release form or in a biodegradable matrix.
- the corneal pocket assay in rabbits as described by Gimbrone et al. (1974) was used according to the modification of McAuslan and Gole (1981).
- McAuslan et al_. , 9183 it is extremely difficult to distinguish a directly acting angiogenic stimulus from one which is mediated by leukocytes (McAuslan et al_. , 9183).
- endothelial cell migration is a primary event in neovascularisation, and since there is a correlation between the ability of certain metal ions to induce vascularisation and their ability to cause migration of cultured cells, such migration has been suggested (McAuslan 1979) as the basis for a quantitative assay of angiogenic activity. There is comparatively little information on the correlation between this activity and neovascularising activity, and furthermore, a number of unrelated substances will induce migration of cultured endothelial cells and neovascularisation (McAuslan- 1979) Proliferation of endothelial cells is thought to be a response secondary to cell migration during new vessel formation. There are reports of low-molecular-weight neovasculogenic activities that can stimulate proliferation of cultured endothelial cells. However, the proliferative responses have been marginal and the reports are not in accord as to the minimal conditions or cell type necessary.
- Each polymer fragment is impregnated with approximately 0.5 mg of the solid agent to be tested, so that the agent diffuses out of the polymer and sets up a concentration gradient which changes with time.
- the corneal pocket assay of Gimbrone et. a _ (1974) as modified by Gole and McAuslan (1981) was used on New Zealand white rabbits of 2-3kg body weight. Opposite eyes of each animal were used as control and test, respectively. The results were documented photographically and histologically 10 days postoperation.
- Anti-inflammatory agents were tested for angiogenic activity in the subcutaneous implant assay in rabbits as described above. The results are shown in Table 2. Both flufenamic acid and diclofenac showed strong activity in stimulating vascularization. Only one of twelve controls showed any activity, giving a weak response.
- Elvax pellets contained 0.05* mg test'-agent per mm , i.e. equivalent to 2 x 10 -4M.
- Diclofenac 10 "5 M 145 31.31 10 " ⁇ M 111 33.60 10 ⁇ 7 M 76 28.i ⁇
- the present invention is capable of application in a wide variety of clinical fields.
- Stimulation of angiogenesis can be used to enhance the healing of burns and wounds, especially those involving large tissue defects, acceptance of skin or organ grafts, and can also be used in reconstructive and cosmetic surgery, including the use of subdermal implants, and in prosthetic surgery, particularly that involving vascular prostheses.
- Such stimulation may be used in any situation wherein endothelial cell migration and regeneration of endothelium are advantageous, or where an increase in blood flow is desirable, e.g., stroke, heart disease, or foetal blood insufficiency.
- the method according to the invention could be used in the following situations: a) Where development of a capillary network would be advantageous, e.g. Surgical repair, wound healing, b) Where stimulation of endothelialisation would be advantageous, . e.g. Synthetic or natural graft materials. c) Where healing may be enhanced by either angiogenic or anti-inflammatory action, e.g. ImpIantable prosthetic devices.
- This application excludes the use of Diclofenac as an anti-inflammatory agent which might improve the performance of cardiac pacemaker electrodes.
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Abstract
Un procédé, permettant de stimuler l'angiogénèse ou l'endothélialisation chez un mammifère, consiste à administrer audit mammifère un composé anti-inflammatoire. Celui-ci a de préférence un effet angiogène agissant directement; les composés préférés comportent de l'acide salicyclique, de l'acide anthranilique, de l'acide acétique de phényle et de l'acide acétique de thiazole. Un composé anti-inflammatoire peut être administré en même temps qu'un second stimulateur de l'angiogénèse. Des compositions et des articles sont également revendiqués.One method of stimulating angiogenesis or endothelialization in a mammal is to administer to said mammal an anti-inflammatory compound. This preferably has an angiogenic effect acting directly; preferred compounds include salicyclic acid, anthranilic acid, phenyl acetic acid and thiazole acetic acid. An anti-inflammatory compound can be administered at the same time as a second angiogenesis stimulator. Compositions and articles are also claimed.
Description
STIMULATION OF ANGIOGENESIS AND PROMOTION OF ENDOTHELIALISA ION
This invention relates to the control of angiogenesis, and methods and compositions therefor.
According to one aspect of the present invention there is provided a method for stimulating angiogenesis in a mammal, characterized by the use of an anti-inflammatory agent.
Knowledge of factors controlling proliferation of the endothelium is essential for understanding the molecular and cellular basis of the normal process of capillary
formation and of pathological process such as abnormal retinal vasoproliferation leading to blindness, and tumor-induced angiogenesis.
Full identification of the references cited 5 hereinafter will be found at the end of this specification. By studying the migratory and proliferative responses of cultured endothelial cells it should be possible to identify those substances that might be involved in regulation of neovascularisation. A number of polypeptide
10 growth factors has been shown to enhance vascular endothelial cell proliferation in vitro. These include 3T3-cell derived growth factor (McAuslan et al. , 1980), tumor-derived growth factor (Klagsbrun et al.. , 1982) and endothelial cell growth stimulator (ECGF) (Maciag et al. , 1981).
15 The Induction of new blood vessel growth and formation of a .vascular network is elicited in animals by extracts of carcinoma cells (Folkman, 1974) or of normal bovine parotid glands (Fleming, 1959). Partially purified^ fractions of quite low-mdlecular-weight substances (200-300
20 Dalton) from Walker carcinoma (McAuslan and Hoffman, 1979; Weiss et al_ 1979; Fenselau et al_. - 1981), bovine parotid glands, or bovine liver (McAuslan et al. , 1981) have been shown to be angiogenic by ocular implant or chick chorioallantoic membrane assays. It has been shown that low
25. concentrations of copper ions can induce neovascularisation in the anterior eye chamber or corneal pocket and also migration of endothelial cells in culture (McAuslan, 1979; McAuslan and Gole, 1980; McAuslan and Reilly, 1980).
Thus a wide variety of agents has been shown to be
30 capable of inducing angiogenesis in various assay systems. Some of these agents appear to act via a leukocyte-mediated mechanism, since the response is blocked by pretreatment of the test animals with corticosteroids.
It is known that some of the mediators produced in
35 response to an inflammatory stimulus are angiogenic. Because of undesirable side effects of Inflammation, an ideal agent for control of angiogenesis should have a direct action, and
should itself be anti-inflammatory. A further limitation is imposed by the necessity for the agent to penetrate the target organ.
It has previously been suggested that aspirin and indomethacin could affect endothelial cells and that aspirin had some angiogenic activity; however, it was thought that this activity was mediated via leucocytes (McAuslan and Gole, 1980)
I have now found that a number of potent anti-inflammatory compounds are angiogenic as assessed by their ability to stimulate migration of capillary endothelial cells in vitro and to induce angiogenesis in vivo. I have further found that aspirin exerts a directly-acting angiogenic activity. The mechanism of action of these compounds is unclear, but may be"related to inhibition of either glycoprotein or prostaglandin synthesis. Without wishing to be bound by any postulated or hypothetical mechanism for the observed beneficial effects, it is noted that the active compounds possess an aromatic carboxylic acid group.
Classes of anti-inflammatory compounds whose structure includes an aromatic carboxylic acid group are summarized in Table 1.
TABLE 1
CLASSES OF ANTI-INFLAMMATORY COMPOUNDS WHOSE STRUCTURE INCLUDES AN AROMATIC CARBOXYLIC ACID MOIETY
Salicylates Benzene Anthranilic Phenyl Thiazole acetic acid acid acetic acid acetic acid derivatives derivatives derivatives derivatives
N-acetyl Ibuprofen Diclofenac (see Alclofenac Fenclozic salicyclic also phenylacetic acid acid (aspirin) acid derivatives
salicyclic Indoprofen Etofenamate Diclofenac acid
salicylamide etoprofen Flufenamic acid Fenclofenac
Diflunisal Meclofenamic Fenclorac acid
Fendosal Mefenamic acid Ibufenac
NB also called hydratropic acids 2— henylpropanoic acids
According to one aspect of the present invention there is provided a method of stimulating angiogenesis in a mammal, comprising the step of administering to that animal an anti-in lammatory compound.
According to another aspect of the invention there is provided a method of stimulating endothelialisation in a mammal, comprising the step of administering to that mammal an anti-inflammatory compound. The anti-inflammatory compound is preferably selected from the group which includes salicylic acid, anthranilic acid, phenyl acetic acid, and thiazole acetic acid, and their angiogenically-active analogues and derivatives. Preferably the anti-inflammatory compound has a directly-acting angiogenic effect.
Preferably the compound comprises an aromatic carboxylic acid group.
Most preferably the compound is administered so as to achieve a diffusion gradient of concentration to which endothelial cells respond.
Combinations of two or more compounds according to the invention may optionally be used.
Combinations of one or more compounds according to the invention together with one or more other stimulators of angiogenesis may also optionally be used. Said second stimulator is suitably a modulator of collagen synthesis or of collagen fibril assembly.
Preferably the modulator is an inhibitor of the ' activity of the enzyme proline hydroxylase.
More preferably, the inhibitory agent is selected from the group which includes cis-4-hyroxy-L-proline, 3, 4-dehydro-L-proline, L-azetidine-2-carboxylic acid, L-proline analogues, and their angiogenically-active analogues and derivatives. Alternatively, said second stimulator of angiogenesis is epidermal growth factor or a pharmacologically active analogue, fragment or derivative thereof.
The compound according to the invention may optionally be administered in a slow-release form or in a biodegradable matrix.
We have used two principal assay systems to test compounds for their ability to stimulate or inhibit angiogenesis. The corneal pocket assay in rabbits as described by Gimbrone et al. (1974) was used according to the modification of McAuslan and Gole (1981). However, in this system it is extremely difficult to distinguish a directly acting angiogenic stimulus from one which is mediated by leukocytes (McAuslan et al_. , 9183). Since endothelial cell migration is a primary event in neovascularisation, and since there is a correlation between the ability of certain metal ions to induce vascularisation and their ability to cause migration of cultured cells, such migration has been suggested (McAuslan 1979) as the basis for a quantitative assay of angiogenic activity. There is comparatively little information on the correlation between this activity and neovascularising activity, and furthermore, a number of unrelated substances will induce migration of cultured endothelial cells and neovascularisation (McAuslan- 1979) Proliferation of endothelial cells is thought to be a response secondary to cell migration during new vessel formation. There are reports of low-molecular-weight neovasculogenic activities that can stimulate proliferation of cultured endothelial cells. However, the proliferative responses have been marginal and the reports are not in accord as to the minimal conditions or cell type necessary.
I have found that compounds which stimulate endothelial cell migration are always angiogenic. However because of the role of inflammatory mediators In some angiogenic systems, the converse is not necessarily true. Consequently, as a further confirmation of angiogenic activity, I have used an assay system in which an annular ring of silicone containing a matrix of highly purified atelocollagen in which is embedded a 1 mm fragment of slow-release copolymer of polyethylene-vinyl acetate impregnated with the agent to be tested is implanted
subcutaneously (S/C) into .rabbits. This polymer is biocompatible and non-inflammatory, and the assay is highly sensitive.
Materials and Methods Polymer Preparation.
Slow-release polymers of ethylene vinyl acetate (Elvax 60, trade mark of Polysciences Corp.) were prepared by the method of Langer and Folkman (1976). For ocular assays, sterile fragments of approximately 1 mm were used and for the chorioallantois assay, approximately 2 mm .
Rabbit Subcutaneous Implant Assay
An annular ring of silicone containing a matrix of
3 highly purified atelocollagen in which is embedded a 1 mm fragment of slow-release copolymer of polyethylene-vinyl acetate impregnated with the agent to be tested is implanted
» subcutaneously into each rabbit.
Each polymer fragment is impregnated with approximately 0.5 mg of the solid agent to be tested, so that the agent diffuses out of the polymer and sets up a concentration gradient which changes with time.
Corneal Pocket Assay
The corneal pocket assay of Gimbrone et. a _ (1974) as modified by Gole and McAuslan (1981) was used on New Zealand white rabbits of 2-3kg body weight. Opposite eyes of each animal were used as control and test, respectively. The results were documented photographically and histologically 10 days postoperation.
Endothelial Cells
Clonal lines of bovine aortal endothelial cells, whose growth and maintenance was as described by McAuslan e_t al (1982) were used. Similar results were obtained with either type of cell line.
A line of bovine retinal capillary endothelial cells free from mural cells was established essentially by the procedures of Buzney and Massicotte (1979).
-Cell Migration Assays
The procedure for studying induced endothelial cell migration as well as the quantitation of average track lengths has been presented in detail by McAuslan and Reilly (1980). The invention will be illustrated by reference to the following non-limiting examples.
Example 1
Anti-inflammatory agents were tested for angiogenic activity in the subcutaneous implant assay in rabbits as described above. The results are shown in Table 2. Both flufenamic acid and diclofenac showed strong activity in stimulating vascularization. Only one of twelve controls showed any activity, giving a weak response.
TABLE 2
. SUBCUTANEOUS IMPLANT ASSAY
Elvax pellets contained 0.05* mg test'-agent per mm , i.e. equivalent to 2 x 10 -4M.
Inducer Total number of implants and intensity of vascularisa ion
++++ +++ +■-. + ~
Controls 0 0 1 0 11
Flufenamic acid 3 6 2 1 0 Diclofenac 4 4 3 1 0
Intensity score:
++++ Large numbers of distinct blood vessels invading the gel; numerous blood vessels growing toward the silicon tube. Markedly angiogenic.
+++ Fine blood vessels invading the collagen gel; less intense than above; fine blood vessels around the silicon tube; strongly angiogenic.
++ Slight pink around the periphery of the collagen gel due to a few fine capillaries; fine vessels around the silicon tube; weakly angiogenic.
+ Collagen gel unchanged; fine blood vessels growing towards the silicon tube; incipient angiogenesis.
- Collagen gel unchanged; no blood vessels around the silicon tube; non-angiogenic.
Example 2
The same agents were tested for their ability to stimulate migration of bovine capillary endothelial cells by the method of McAuslan and Reilly (1980). Results are shown in Table 3. Aspirin, flufenamic acid, and diclofenac all had strong stimulatory activity, whereas phenylbutazone was negative. It is noted that phenylbutazone does not contain an aromatic carboxylic acid group.
TABLE 3
MIGRATION ASSAYS Bovine capillary endothelial cells
Inducer Cone. % Response Average track area
(xlθ"3/ιm2)
Control. - 0 15. 93
Flufenamic acid 10"5M 80 28 .71
10"6M 140 38. 23 10~7M 130 36. 63
Diclofenac 10"5M 145 31.31 10"δM 111 33.60 10~7M 76 28.iθ
- *
Aspirin 10 DM 63 26.0
Phenylbutazone 10"5M 0 15.8
10~6M 0 15.0
10~7M 0 15.9
Example 3
Anti-inflammatory agents were tested for angiogenic activity in the corneal pocket assay as described above. Results are shown in Table 4. Both flufenamic acid and diclofenac showed strong activity. One of the six controls was positive.
TABLE 4
CORNEAL POCKET ASSAY Elvax pellets (1 mm ) contained approx. 26 ng. agent/mm i.e. equivalent to 10 -4M.
Left Eyes Right Eyes
Controls 1/6
Flufenamic acid - 6/6 Diclofenac - 4/6
Anterior Eye Chamber Assays for Aspirin: see: McAuslan B.R. and Gole G.A. - Trans Ophthal. Soc. U.K.
(1980) 1 £ 354.
Applications of the Invention
The present invention is capable of application in a wide variety of clinical fields.
Stimulation of angiogenesis can be used to enhance the healing of burns and wounds, especially those involving large tissue defects, acceptance of skin or organ grafts, and can also be used in reconstructive and cosmetic surgery, including the use of subdermal implants, and in prosthetic surgery, particularly that involving vascular prostheses. Such stimulation may be used in any situation wherein endothelial cell migration and regeneration of endothelium are advantageous, or where an increase in blood flow is desirable, e.g., stroke, heart disease, or foetal blood insufficiency.
In particular, the method according to the invention could be used in the following situations: a) Where development of a capillary network would be advantageous, e.g. Surgical repair, wound healing, b) Where stimulation of endothelialisation would be advantageous, .
e.g. Synthetic or natural graft materials. c) Where healing may be enhanced by either angiogenic or anti-inflammatory action, e.g. ImpIantable prosthetic devices. This application excludes the use of Diclofenac as an anti-inflammatory agent which might improve the performance of cardiac pacemaker electrodes.
It will be clearly understood that the invention in its general aspects is not limited to the specific details referred to hereinabove.
References cited herein are listed on the following pages-
REFERENCES
Buzney, S.M. and S.J. Massicotte (1970) Invest. Ophthalmol. Visual Sci. _18_ 1191-1195
Fenselau, A., S. Watt, and R.J. Mello (1981) J. Biol. Chem. 256 9605-9611
Fleming, H.S. (1959) J. Dent. Res. _3 374-385
Folkman, J. (1974) Adv. Cancer Res. 19_ 331-358
Gimbrone, M.A., R.S. Cotran, S.B. Leapman and J. Folkman (1974) J. Nat. Cancer Inst. 52_ 413-427
Gullino, P.M. (1981) in Tissue Growth Factors ed. R. Baserga; Springer-Verlag, N.Y. p. 427-449
Klagsbrun M. , R. Sullivan, P. D'Amore, K. Butterfield and J. Folkman (1982) J. Cell Biol. (Abstract 9091) 95 201
Langer, R and J. Folkman (1976) Nature 263 797-799.
McAuslan, B.R. (1979) EMBO Workshop on Specific Growth Factors, Rome, Oct. 9-11.
McAuslan, B.R. and G.A. Gole (1980) Trans. Ophthalmol. Soc. U.K. 100 (3) 354-358
McAuslan, B.R. G.N. Hannan, and W. Reilly (1980) Exptl Cell Res. 1_28 95-101
McAuslan, B.R. and H. Hoffmann (1979) Exptl Cell Res. 199 181-190
McAuslan, B.R. and W. Reilly (1980) Exptl Cell Res. 130 147-157
- McAuslan, B.R. , W. Reilly and G.N. Hannan (1981) in Progress in Microvascular Research (ed. D. Garlick) p.470-501
McAuslan, B.R. W. Reilly, G.N. Hannan, and G.A. Gole (1983) Microvascular Res. 2__ 323-328
Maciag, T., A. Hoover, M.B. Stemmerman, and R. Weinstein (1982) J. Cell Biol. 9_1 420-426
Weiss, J.B., R.A. Brown, S. Kumar, and P. Phillips (1979) Brit. J. Cancer 40 493-496.
Claims
1. A method of stimulating angiogenesis in a mammal, comprising the step of administering to that animal an anti-inflammatory compound.
2. A method of stimulating endothelialisation in a mammal, characterized by the step of administering to that mammal an anti-inflammatory compound.
3. A method according to Claim 1 or Claim 2, wherein the anti-inflammatory compound has a directly-acting angiogenic: effect..
4.. A method, according to any one of claims 1 to 3, wherein the anti-inflammatory compound comprises an aromatic carboxylic acid group.
5. A method according to Claim 1 or Claim 2, wherein the anti-inflammatory compound is selected from the group which includes salicylic acid, anthran-ilic acid, phenyl acetic acid, and thiazole acetic acid, and their angiogenically-active analogues and derivatives.
6". A method according to any' one of Claims 1 to 5, wherein two or more anti-inflammatory compounds are used.
7. A method according to any preceding claim, wherein one or more second stimulators of angiogenesis is additionally used.
8. A method according to Claim 7, wherein the second stimulator of angiogenesis is a modulator of collagen synthesis or of collagen fibre assembly.
9 . A method according to Claim 8, wherein the modulator is an inhibitor of the activity of the enzyme proline hydroxylase.
10. A method according to Claim 9, wherein the inhibitor is selected from the group which includes cis-4-hydroxy-L-proline, 3, 4-dehydro-L-proline, L-azetidine-2-carboxylic acid, L-proline analogues, and their angiogenically-active analogues and derivatives.
11. A method according to Claim 7, wherein the second stimulator of angiogenesis is epidermal growth factor or a pharmacologically-active analogue, fragment or derivative thereof.
12. A method according to any preceding claim, wherein the anti-inflammatory compound is administered so as to achieve a diffusion gradient of concentration to which endothelial cells respond.
13. A method according to any one of Claims 1 to 12, wherein the anti-inflammatory compound is administered in a siσw-release form or in a biodegradable matrix.
14'_ The use of an anti-inflammatory compound for manufacture of a medicament for stimulating angiogenesis or promoting endothelialisation in a mammal.
15. The use of an anti-inflammatory compound according to Claim 14, wherein the anti-inflammatory compound has a directly-acting angiogenic effect.
16. The use of an anti-inflammatory compound according to Claim 14 or Claim 15, wherein the anti-inflammatory compound comprises an aromatic carboxyl group.
17. The use of an anti-inflammatory compound according to any one of Claims 14 to 16, wherein the anti-inflammatory compound is selected from the group which includes salicylic acid, anthranilic acid, phenyl acetic acid, and thiazole acetic acid, and their angiogenically active analogues and derivatives.
1.8.. The use of an anti-inflammatory compound according to any one of Claims 14 to 17, wherein two or more anti-inflammatory compounds are used.
19. The use of an anti-inflammatory compound according to any one of Claims 14 to 18, wherein the medicament additionally comprises one or more second stimulators of angiogenesis.
20. The use of an anti-inflammatory compound according to Claim 19 wherein the second stimulator of angiogenesis is a modulator of collagen synthesis or of collagen fibre assembly.
21. The use of an anti-inflammatory compound according to Claim 20, wherein the modulator is an inhibitor of the activity of the enzyme proline hydroxylase.
22. The use of an anti-inflammatory compound according to Claim 21, wherein the inhibitor is selected from the group which includes cis-4-hydroxy-L-proline, 3, 4-dehydro-L-proline, L-azetidine-2-carboxylic acid, L-proline analogues, and their angiogenically-active analogues and derivatives.
23. The use of an anti-inflammatory compound according to Claim 19, wherein the second stimulator of angiogenesis is epidermal growth factor or a pharmacologically-active analogue, fragment or derivative thereof.
24. The use of an anti-inflammatory compound according to any one of Claims 14 to 23, wherein the medicament is adapted to be administered so as to achieve a diffusion gradient of concentration to which endothelial cells respond.
25. The use of an anti-inflammatory compound according to any one of Claims 14' to 23, wherein the medicament is adapted to be administered in a slow-release form o in a biodegradable matrix.
26. A topically-applicable composition for stimulation of angiogenesis or of endothelialisation comprising an anti-inflammatory compound, together with a pharmaceutically-acceptable diluent or excipient.
27. A composition for stimulation of angiogenesis or of endothelialisation comprising an anti-inflammatory compound and a pharmaceutically-acceptable diluent or excipient, wherein the composition is adapted to release the anti-inflammatorycompound over an extended period after administration.
28. A composition for stimulation of angiogenesis or of endothelialisation comprising an anti-inflammatory compound and a pharmaceutically-acceptable diluent or excipient, wherein the composition is adapted to be administered in a biodegradable matrix.
29. A composition for stimulation of angiogenesis or of endothelialisation comprising an anti-inflammatory compound and a pharmaceutically-acceptable diluent or excipient, wherein the composition is adapted to be administered so as to achieve a diffusion gradient of concentration to which endothelial cells respond.
30. A composition for stimulation of angiogenesis or of endothelialisation comprising an anti-inflammatory compound and one or more second stimulators of angiogenesis, together with, a pharmaceutically-acceptable diluent or excipient.
31^ A composition according to Claim 30, wherein the second stimulator of angiogenesis is a modulator of collagen synthesis or of collagen fibre assembly.
32. A composition according to Claim 31, wherein the modulator is an inhibitor of the activity of the enzyme proline hydroxylase.
33. A composition according to Claim 32, wherein the inhibitor is selected, from the group which includes cis-4-hydroxy-L—proline, 3,4-dehydro-L-proline, L-azetidine-2-carboxylic acid, L-proline analogues, and their angiogenically-active analogues and derivatives.
34. A composition according to Claim 31, wherein the second stimulator of angiogenesis is epidermal growth factor or a pharmacologically-active analogue, fragment or derivative thereof.
35. A composition according to any one of Claims 30 to 34, which Is adapted to be administered so as to achieve a diffusion gradient of concentration to which endothelial cells respond.
36. A composition according to any one of Claims 30 to 34, which is adapted to be administered in a slow-release form or in a biodegradable matrix.
37. A subdermal implant, synthetic or natural graft material, vascular prosthesis or prosthetic device comprising one or more anti-inflammatory compounds as set out In any one of Claims 14 to 33.
38. A subdermal implant, synthetic or natural graft material, vascular prosthesis or prosthetic device comprising one or more anti-inflammatory compounds as set out in any one of Claims 14 to 33 and a second stimulator of angiogenesis as set out in any one of Claims 19 to 23.
39. Methods, compositions and articles substantially as hereinbefore described with reference to the examples.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU7521/86 | 1986-08-18 | ||
| AUPH752186 | 1986-08-18 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP0318488A1 true EP0318488A1 (en) | 1989-06-07 |
| EP0318488A4 EP0318488A4 (en) | 1990-02-26 |
Family
ID=3771766
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP19870905152 Withdrawn EP0318488A4 (en) | 1986-08-18 | 1987-08-10 | Stimulation of angiogenesis and promotion of endothelialisation. |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0318488A4 (en) |
| JP (1) | JPH01503705A (en) |
| WO (1) | WO1988001166A1 (en) |
| ZA (1) | ZA876079B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH03109324A (en) * | 1989-09-22 | 1991-05-09 | Microbial Chem Res Found | Vascularization inhibitor |
| WO1998042329A1 (en) * | 1997-03-21 | 1998-10-01 | Mitsubishi Chemical Corporation | Preventives and/or remedies for diseases caused by abnormal neovascularization |
| US6660283B2 (en) * | 1997-12-19 | 2003-12-09 | Societe L'oreal S.A. | Use of cinnamic acid, or of at least one of its derivatives in a cosmetic composition |
| JP2004262776A (en) * | 2003-02-21 | 2004-09-24 | Teikoku Seiyaku Co Ltd | Angiogenic promoter |
| MXPA06011851A (en) | 2004-04-14 | 2006-12-14 | Genentech Inc | Compositions and methods for modulating vascular development. |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2515189A (en) * | 1948-10-12 | 1950-07-18 | Samson | Preservation of leucocytes in blood |
| BE626119A (en) * | 1961-12-19 | |||
| US3873715A (en) * | 1973-04-06 | 1975-03-25 | Univ Miami | Therapeutic agent for improving cardiovascular function |
| US3928587A (en) * | 1974-08-16 | 1975-12-23 | Philip Nicholas Sawyer | Method of conditioning vascular systems by administering 3,5 dichloroaspirin and method of evaluating pharmaceutical compounds |
| GB1518333A (en) * | 1975-05-30 | 1978-07-19 | Science Union & Cie | Pharmaceutical compositions containing a ypsilon-resorcylic acid derivative |
| JPS5829706A (en) * | 1981-08-14 | 1983-02-22 | Toko Yakuhin Kogyo Kk | Antiphlogistic and analgesic agent for external use |
| CA1229554A (en) * | 1983-04-18 | 1987-11-24 | Warner-Lambert Company | Meclofenamic acid topical pharmaceutical composition |
| MX163953B (en) * | 1984-03-27 | 1992-07-03 | Univ New Jersey Med | PROCEDURE FOR PREPARING A BIODEGRADABLE COLLAGEN MATRIX |
| EP0294380A4 (en) * | 1986-02-18 | 1990-02-20 | Biota Scient Management | Stimulation of angiogenesis. |
-
1987
- 1987-08-10 EP EP19870905152 patent/EP0318488A4/en not_active Withdrawn
- 1987-08-10 JP JP62504759A patent/JPH01503705A/en active Pending
- 1987-08-10 WO PCT/AU1987/000256 patent/WO1988001166A1/en not_active Ceased
- 1987-08-17 ZA ZA876079A patent/ZA876079B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ZA876079B (en) | 1988-06-29 |
| EP0318488A4 (en) | 1990-02-26 |
| WO1988001166A1 (en) | 1988-02-25 |
| JPH01503705A (en) | 1989-12-14 |
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