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WO1993016717A1 - Procede et agents favorisant la cicatrisation des blessures - Google Patents

Procede et agents favorisant la cicatrisation des blessures Download PDF

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Publication number
WO1993016717A1
WO1993016717A1 PCT/US1993/001677 US9301677W WO9316717A1 WO 1993016717 A1 WO1993016717 A1 WO 1993016717A1 US 9301677 W US9301677 W US 9301677W WO 9316717 A1 WO9316717 A1 WO 9316717A1
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WO
WIPO (PCT)
Prior art keywords
agent
group
mixtures
wound healing
advanced glycosylation
Prior art date
Application number
PCT/US1993/001677
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English (en)
Inventor
Michael A. Yamin
Veronica M. Ruszala-Mallon
Anthony Cerami
Original Assignee
The Rockefeller University
Alteon Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The Rockefeller University, Alteon Inc. filed Critical The Rockefeller University
Publication of WO1993016717A1 publication Critical patent/WO1993016717A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/39—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/38—Albumins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/76—Albumins
    • C07K14/765—Serum albumin, e.g. HSA
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/78—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin or cold insoluble globulin [CIG]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/16—Hydrolases (3) acting on ester bonds (3.1)
    • C12N9/22—Ribonucleases [RNase]; Deoxyribonucleases [DNase]
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/66—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood sugars, e.g. galactose

Definitions

  • the present invention generally relates to the repair of damaged tissues in animals and particularly humans, and, more particularly, to the modulation of the healing of wounds in such tissue.
  • tissue wounds occurs from an endless variety • of pathological and non-pathological causes.
  • a variety of cells have been determined to cooperate to repair the damaged tissue and heal the wound.
  • Cells resident in the local tissue participate, as do circulating blood cells specifically recruited into the wound itself and the area nearby.
  • Dramatic changes in cellular function are required by both the resident and recruited cells in order to initiate, coordinate, and sustain the complex process of wound healing. Damaged cells and disrupted tissue matrix must be removed, new cells must be formed, and must grow and mature to replace those lost.
  • the tissue matrix must be resynthesized and remodeled, and even the microvasculature may need to be rebuilt to supply the new tissue.
  • AGEs advanced glycosylation endproducts
  • reducing sugars e.g., glucose
  • protein amino groups react non-enzymatically with protein amino groups to form a diverse series of protein bound moieties with fluorescent and crosslinking properties.
  • These compounds have been implicated in structural and functional alteration of proteins during aging and in certain diseases that are considered degradative and undesirable, e.g., the embrittlement of structural proteins observed in long-term diabetes.
  • AGEs have been identified on the basis of de novo synthesis and tissue isolation procedures.
  • diagnostic and therapeutic protocols are proposed that are predicated in part on the discovery that advanced glycosylation endproducts (AGEs) and other agents previously described for the promotion of the vivo recognition and removal of AGEs, possess a definitive modulating effect upon the progression of tissue reconstruction and wound healing in mammals, and are capable of stimulating and promoting both activities.
  • AGEs advanced glycosylation endproducts
  • the present invention relates in its broadest aspect to the treatment of wounds as well as various wound healing dysfunctions by the administration of a wound healing modulator comprising a material selected from the group consisting of agents capable of modulating wound healing, binding partners thereto, and the muteins and fragments thereof, wherein the agents are selected from advanced glycosylation endproducts (AGEs), compositions and complexes containing advanced glycosylation endproducts alone or bound to a carrier, derivatives thereof, and mixtures thereof.
  • the carrier may include a material selected from carbohydrates, proteins, synthetic polypeptides, lipids, bio- compatible natural and synthetic resins, antigens, and mixtures thereof.
  • the agent could include other advanced glycosylation endproducts that may be prepared synthetically or from the reaction between sugars and other macromolecules, and monokines which stimulate phagocytic cells to increase their activity toward advanced glycosylation endproducts.
  • the agent may comprise the compounds FFI or AFGP bound to a protein such as albumin.
  • the agent may comprise a synthetically derived advanced glycosylation endproduct which is prepared, for example, by the reaction of glucose or glucose-6-phosphate with albumin. This reaction product can be used alone or with a carrier in the same fashion as the FF1- albumin complex.
  • a monokine that functions as an agent comprises the protein known as Tumor Necrosis Factor (TNF) and its variant discovered and isolated by one of the inventors herein and named "cachectin". This material may be administered alone or in conjunction with other agents.
  • TNF Tumor Necrosis Factor
  • the agents of the present invention may be administered in conjunction with materials identified hereinafter as "co-stimulatory" agents.
  • co-stimulatory agents include monokines such as lnterleukin-1 (IL-1 ) and gamma-interferon.
  • AGEs useful in accordance herewith may be introduced to particular tissues by injection to stimulate and promote cellular growth or regrowth, in some instances, that will result in the structural and functional enhancement of the treated tissues.
  • the growth stimulating effect of the modulators of the invention finds a further application in the promotion of tissue acceptance and the corresponding limitation or inhibition of tissue rejection in tissue transplantation and reconstruction.
  • fibers implanted to promote tissue regrowth, transplanted organs or synthetic organs prepared in some instances, at least in part from structural proteinaceous material such as collagen may have applied to them one or more of the present wound healing modulators before implantation, to promote acceptance of the exogenous material and incorporation into the target tissue.
  • the modulators in this instance may be bound to the protein or may be otherwise adherently applied as a coating by known techniques. Accordingly, the invention extends to the corresponding prosthetic materials having the modulators applied as a coating thereto, or chemically linked by known methods such as for example, coupling thereto a synthetic AGE such as FFI-BSA or the like.
  • modulators of the present invention derives from the observations presented below, that the application of the wound healing modulator to skin stimulates hair growth. It is apparent from this that the stimulation of hair growth may be achieved by the topical or intradermal application of the present modulators, and the present invention accordingly extends to a method of stimulating hair growth thereby.
  • This method may comprise the local application of the modulator to the dermal area, with the formulation of the modulator dosage contemplating both topical applications and if appropriate, dermal implants or injections.
  • the AGEs that may serve as agents may comprise the reaction product of a sugar selected from the group consisting of glucose, glucose-6-phosphate, fructose and ribose; and a protein selected from the group consisting of collagen, albumin, ribonuclease, avidin, and mixtures thereof.
  • the agent may comprise an advanced glycosylation endproduct selected from the group consisting of the chromophores 2-(2-furoyl)-4(5)-(2-furanyl)-1 H_-imidazole (FFI), 1 -alkyl-2-formyl-3,4-diglycosyl-pyrrole (AFGP), alone and coupled to carriers such as BSA, HSA, and avidin.
  • Suitable agents also include materials capable of promoting agent production and/or activity, and materials capable of mimicking agent activity, such as homologous agents derived synthetically or from other cellular sources or from other species.
  • the agent binding partners contemplated by the invention include anti-agent antibodies, receptors for the agents, materials not antibodies that antagonize the production and/or wound healing modulating activity of the agents, binding partners thereto, and other binding partners thereof.
  • the present wound healing modulators may comprise materials that are capable of acting in vivo, and in a further embodiment, may be promoters of wound healing.
  • the invention accordingly includes a method for promoting wound healing comprising administering an effective amount of one of the above wound healing modulators individually, or in mixture with each other or formulated as a pharmaceutical composition.
  • the modulators contemplated for use in this method comprise those agents and binding partners that act as promoters of wound healing, and extend for example, to homologous agents derived from other cellular sources or from other species, materials capable of promoting agent production and/or activity, and materials capable of mimicking agent activity.
  • compositions may be prepared in accordance with the invention and comprise therapeutically effective amounts of the present wound healing modulators, either alone or in admixture with each other, and a pharmaceutically acceptable diluent or carrier.
  • the modulators may preferably be present in amounts effective to deliver at least 100 ng/cm 2 and preferably from about 1 ⁇ gfcm 2 to about 10 g/cm 2 thereof.
  • the therapeutic methods of the present invention apply generally to mammals and contemplate veterinary use as well as application to humans.
  • the particular therapeutic protocols will vary accordingly upon the subject of treatment.
  • the present invention contemplates a method for measuring the activity of the wound healing modulators of the present invention.
  • the method comprises retrieving a sample of wound fluid which such disorder is suspected, and incubating the sample with a quantity of a wound healing modulator of the present invention bearing an appropriate detectable label.
  • the sample may thereafter be examined to determine whether such aberrant cellular activity is due to a deficiency in wound healing factor presence or activity, and to thereby attempt to isolate and identify the cause of such disorder.
  • the present invention may also extend to appropriate new drug assays and test kits including the wound healing modulators of the present invention. Accordingly, it is a principal object of the present invention to provide a method for treating wound healing dysfunctions in mammals.
  • compositions for use in therapeutic methods for treating wound healing dysfunctions and/or promoting wound healing which comprise or are based upon certain wound healing modulators including agents and their binding partner(s).
  • wound healing modulator refers to protein material having the profile of activities set forth herein and in the Claims.
  • AGE and “AGEs” are used as appropriate to refer to advanced glycosylation endproducts which are in the form of stable compounds and intermediates which are produced synthetically, ]n vivo, and ]n vitro by the reaction of reducing sugars with protein amino groups. AGEs therefore encompass intermediates as well as stable endproducts that are implicated in the structural and functional alteration of proteins seen during aging. For example, AGEs are recognized to react with free polypeptide amino groups, which leads to protein crosslinking. Additionally, such AGES are observed in elevated levels in circulation and in tissues in certain diseases, e.g. diabetes mellitus.
  • AGE-RNAse refers to the advanced glycosylation endproducts which are formed upon chemical reaction of the substrates RNAse, Hb, BSA, HSA, albumin, collagen and LDL, respectively with a reducing sugar.
  • AGE-RNAse refers to the advanced glycosylation endproducts of the reaction between bovine ribonuclease and a reducing sugar.
  • Albumin when recited generically, refers to any species from which it was obtained, e.g., human, bovine, etc.
  • BSA refers to bovine serum albumin.
  • HSA refers to human serum albumin.
  • RNAse refers to ribonuclease generally, and where appropriate, to bovine pancreatic ribonuclease in particular.
  • Collagen is used in the conventional sense to refer to any type of collagen and derived from any appropriate source. When a specific type of collagen was used, such as in the example, the particular type is noted. However, it is recognized that alternative collagen types can also be used.
  • FFI-BSA refers to a model AGE-protein produced by mixing 2-(2-furoyl)-4(5)J2-furanyl)-1 H_-imidazole hexanoic acid with bovine serum albumin and coupling the reactive compounds with dicyclohexylcarbodiimide.
  • proteins displaying substantially equivalent or altered activity are likewise contemplated. These modifications may be deliberate, for example, such as modifications obtained through site-directed mutagenesis, or may be accidental, such as those obtained through mutations in hosts that are producers of these materials. Also, the terms "wound healing modulator” and “agent” are intended where appropriate, to include within their scope proteins specifically recited herein as well as all substantially homologous analogs and allelic variations.
  • an “antibody” is any immunoglobulin, including antibodies and fragments thereof, that binds a specific epitope.
  • the term encompasses, inter alia, polyclonal, monoclonal, and chimeric antibodies, the last mentioned described in further detail in U.S. Patent Nos. 4,81 6,397 and 4,816,567.
  • phrases “pharmaceutically acceptable” refers to molecular entities and compositions that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastric upset, dizziness and the like, when administered to a human.
  • terapéuticaally effective amount is used herein in the qualitative sense to mean an amount sufficient to promote the healing of a non-healing wound. Quantitatively, this phrase means an amount sufficient to promote, and preferably accelerate by at least about 10 percent, more preferably by at least 20 percent, a clinically significant change in the rate or extent of wound healing as a result of the administration of the wound healing modulator of the present invention.
  • the present invention concerns methods of diagnosing and treating wound healing dysfunction by resort to the identification and administration of certain modulators of wound healing, including certain agents represented in part by a class of compounds known as advanced glycosylation endproducts (AGEs) that are believed to take part in the promotion of wound healing.
  • AGEs advanced glycosylation endproducts
  • the present invention includes therapeutic methods employing the wound healing modulators identified herein and compositions containing the same for use in such methods.
  • the wound healing modulators of the present invention comprising the agents, their homologs, similarly active drugs, their receptors, their binding partner(s) or other ligands or agents exhibiting either mimicry or antagonism to the agents or control over their production, may be prepared in pharmaceutical compositions, with a suitable carrier and at a strength effective for administration by various means to a patient having a tissue wound or a wound healing disorder or dysfunction, for the treatment thereof.
  • compositions may be administered by parenteral techniques such as subcutaneous, intravenous and intraperitoneal injections, including delivery in an irrigation fluid used to wash body wound areas, catheterizations and the like.
  • parenteral techniques such as subcutaneous, intravenous and intraperitoneal injections, including delivery in an irrigation fluid used to wash body wound areas, catheterizations and the like.
  • Average quantities of the wound healing modulator may vary and in particular should be based upon the recommendations and prescription of a qualified physician or veterinarian.
  • concentrations of the wound healing modulator may range from at least about 100 ng/cm 2 , and preferably from about 1 /g/cm 2 to about 10 ⁇ g/cm 2 may be used.
  • concentrations of the wound healing modulator administered may vary and should be based upon the recommendations and prescription of a qualified physician or veterinarian.
  • the materials that function as modulators of wound healing extend to the binding partners of the agents defined herein, and particularly include the antibodies, receptors, materials not antibodies to the agents that antagonize the production and/or wound healing modulating activity of the agents and other binding partners thereto.
  • certain agents such as AGE-RNAse
  • specific antibodies that would antagonize the modulating effect that they exert on wound healing could be identified.
  • Antibodies including both polyclonal and monoclonal antibodies, and drugs may also be raised to the agent and may be utilized where appropriate for the purpose of modulating wound healing by a mammalian host.
  • the agent may be used to produce antibodies to itself in a variety of animals, by known techniques such as the hybridoma technique utilizing, for example, fused mouse spleen lymphocytes and myeloma cells.
  • the resulting antibodies could then be prepared in a suitable pharmaceutical composition and administered to the intended host.
  • the exact quantities, intervals of administration and administrative techniques respecting such pharmaceutical compositions may vary in accordance with those known in the medical arts, and upon the specific instruction of a qualified physician or veterinarian.
  • the agents may bind to particular naturally occurring binding activities including cell associated and soluble receptors to facilitate intracellular transmission of messages relating to wound healing activity, and these binding activities or receptor molecules may be identified as they form complexes with the agents, and thereafter may be isolated and prepared in sufficient quantities to be used in the same fashion as the agents themselves, to modulate wound healing activity.
  • binding activities or receptor molecules may be identified as they form complexes with the agents, and thereafter may be isolated and prepared in sufficient quantities to be used in the same fashion as the agents themselves, to modulate wound healing activity.
  • a variety of diverse receptor systems are known, such as the tyrosine kinases and G-protein receptors are already known and operate to transmit messages to the genetic material of the cell to cause corresponding changes in protein synthesis, and the present invention contemplates that these molecules and other functionally similar molecules, may participate in wound healing modulation in accordance herewith.
  • the present invention also relates to a variety of diagnostic applications, including methods for detecting or investigating disorders or dysfunctions in wound healing by reference to the ability of the present wound healing modulators of the present invention comprising the agents and their binding partners to promote or inhibit wound healing activity.
  • the agents or their binding partners could be appropriately labeled and placed in contact with a sample of wound inflammatory fluid, tissue or blood from a mammal in which the disorder is suspected. Thereafter, the sample could be examined to determine the location and status of the labeled material as well as the general activity of the sample, i.e. whether wound healing activity has increased or decreased.
  • Solutions of purified AGE-collagen and collagen alone were prepared in vehicle from concentrated stocks (below) to the desired final concentrations. A 50 ⁇ drop of AGE-collagen- or collagen-vehicle or vehicle alone was applied to each wound, and spread over the wound with the tip of a sterile pipette.
  • Wounds were individually sealed with a semipermeable dressing: Benzoin was applied as an adhesive to a zone of intact skin surrounding the perimeter of each wound and the wound was sealed with a patch of Opsite applied to cover the wound and extend over and adhere to the zone of Benzoin-treated intact skin surrounding each wound. Ops ⁇ te-sealed wounds were then covered with a bulky dressing.
  • Biopsies of healing wounds were initially taken on days 3, 4 and 5 after wounding. Preliminary analysis of control wounds revealed that day 4 wounds were best suited to display differences in the rate or degree of healing, and day 4 biopsies were obtained from subsequent tests. Control wounds on day 4 typically show mild residual inflammation and fibroblast activity with persisting ulceration in the sense that epidermal regrowth is still incomplete and portions of the dermis remain exposed. Where epidermis is reforming from the margins of the wound and focally from the hair follicles spared by wounding, there is good granular layer formation with areas of overlying cornified epithelium and little parakeratosis. At this incompletely healed stage, then, a variety of histological characteristics of wound healing are intermediate.
  • Acceleration or retardation of wound healing is manifest to a trained dermatopathologist by light microscopic comparison of histological sections prepared from biopsies of the healing wounds. Histological sections from wounds in which healing has been accelerated by treatment can be expected to have less remaining ulceration or even complete recoverage by epidermis with good granular layer formation and a more complete overlying cornified layer, and little or no residual fibroblast proliferation or parakeratosis. These histological criteria for completeness of healing can be expected to vary in the other direction if wound healing is retarded by treatment.
  • test pigs were anesthetized as at wounding, wound dressings were removed, and the wounds photographed for gross characterization of healing. When fully anesthetized, test pigs were then overdosed with SleepAway euthanasia solution. Elliptical biopsy samples through the full skin thickness (into the layer of subcutaneous fat) and extending across the full width of the wound and into intact skin on either side were then cut from each wound by hand using a scalpel. Biopsy samples were individually fixed by immersion in 10% buffered formalin in coded containers which did not reveal what treatment the parent wound had received.
  • Coded samples were then routinely processed for light microscopic histological analysis by sectioning at 5 ⁇ m, mounting on slides, and staining with hematoxyiin and eosin.
  • the biopsies were cut into histological sections in a plane normal (perpendicular) to the surface of the skin, so as to include both the full extent of the wound and a small margin of non-wounded skin at each end of the section.
  • the degree of wound healing was assessed by measuring the linear extent of re- epithelialization across the full width of the histological sections from the wound biopsy; that is, from the boundary of non-wounded skin on one side of the section to the boundary of non-wounded skin at the other side of the wound.
  • Measurements were taken microscopically, by using a calibrated ocular reticule to measure the linear extent of the total wound, and the linear extent of re- epithelial ⁇ zed wound.
  • the linear extent of re-epithel ⁇ alized wound was then expressed as a percentage of the linear extent of the total wound, and this percentage was taken as a measurement of the degree of wound healing.
  • the sections taken 3 days after healing show a marked difference between tissue treated with AGE-collagen and that treated with unmodified collagen.
  • the treated tissue shows completely healed epidermis, with full epithelialization overlying a slightly cellular dermis.
  • the epidermis shows focally a good granular layer, and only minimal parakeratosis.
  • the control tissue while fully epithelialized, still contains many fibroblasts within the dermis, and there is only poor granular layer formation. This suggests a much less advanced healing wound. Similar changes are seen in tissue taken 4 and 5 days post wounding.
  • the tissue treated with AGE-coilagen consistently shows more mature appearing epidermis, with full granular and minimal overlying parakeratosis.
  • the control sections, while almost completely epithelialized still show poor granular layer formation and extensive overlying parakeratosis.
  • mice Male Lewis rats (350-450 g) were made diabetic by intravenous injection of streptozotocin (65 mg/kg). One week later, they were bled, and their plasma tested for glucose levels. Rats with glucose levels greater than 400 mg/dl were considered diabetic. Diabetic and non-diabetic rats were then divided into groups:
  • the rats were anesthetized using a mixture of Xylazine and Ketamine (1 :9), given intramuscularly at a level of .001 mg/g body weight.
  • the backs of the rats were shaved, washed with soap and water, sprayed with alcohol, and swabbed with Provadine.
  • An incision of approximately 5 cm was made in the skin along the midline of the back.
  • a subcutaneous continuous stitch was used to close the incision, using the appropriate suture lot.
  • the incision sites were visually inspected on a daily basis to monitor healing.
  • the animals were sacrificed at 14 days using C0 2 .
  • the skin from their backs was removed, and evaluated visually as to how they have healed in comparison with the control groups.
  • the extent of wound closure was evaluated, blinded to group, by three individuals and graded on a scale of 1 + to 3+ with 1 + being the least healed and 3 + being the best closure with little or no scar.
  • the degree of vascularization was evaluated by examination of the underlying skin using a light box. This enabled the investigator to visualize by transmitted light the amount of blood vessels formed along the suture line.
  • Vascularity was evaluated on a 1 + to 4+ scale with 1 + being little vascularity around the incision site and 4 + being the greatest degree of vascularity. All animals were coded so that the final evaluations were done blinded as to the treatment group.
  • Rat # F had some pus oozing from incision TABLE C
  • mice 25 non-diabetic male C 3 H/Hej mice (25-30g) were anesthetized as described above. Their backs were shaved, washed with soap and water, sprayed with alcohol, and swabbed with Provadine. An incision of approximately 2-2.5 cm was made in the skin along the midline of the back. A cutaneous interrupted stitch was used to close the incision, using either control silk sutures or AGE-silk sutures (incubated with ribose as described in Example 2). The animals were sacrificed 7 days later and the skin removed as described above. The closure could not be evaluated adequately in mice due to the thin nature of the skin and the dark color of the strain being tested. Therefore, only the degree of vascularity was assessed as described above. One obvious but unexpected occurrence in this study was related to the degree of new hair growth in mice whose wounds were closed using AGE sutures. These results are included in Table D, below. TABLE D
  • the agents herein may be formulated for the treatment of a variety of mammals, including domestic and farm animals, as well as humans, to control the wound healing process, and where desired, to assist in its promotion and the promotion of tissue growth and reconstruction as described and as evidenced hereinabove.

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Abstract

L'invention concerne l'administration d'un ou plusieurs modulateurs de cicatrisation de blessures afin de favoriser le retournement des tissus. Le modulateur de cicatrisation de blessures peut être choisi parmi des agents appropriés de cicatrisation des blessures et des partenaires de liaison, et en particulier des agents qui améliorent la cicatrisation des blessures. L'agent peut comprendre des produits de fin de glycosylation avancée, des compositions et des complexes contenant des produits de fin de glycosylation avancée, leurs dérivés et leurs mélanges. Les agents constituant les produits de fin de glycosylation avancée peuvent comprendre en particulier le produit de réaction d'un sucre sélectionné dans le groupe comprenant le glucose, le glucose-6-phosphate, le fructose et le ribose; et une protéine sélectionnée dans le groupe comprenant le collagène, l'albumine, une ribonucléase, l'avidine, et des mélanges de ceux-ci. Des applications diagnostiques et thérapeutiques sont proposées, ces dernières comprenant le traitement du dysfonctionnement de cicatrisation de blessures, ces agents améliorant la tolérance de tissus transplantés et favorisant également la croissance capillaire. Des compositions pharmaceutiques et des matériaux protétiques sont également l'objet de l'invention.
PCT/US1993/001677 1992-02-25 1993-02-25 Procede et agents favorisant la cicatrisation des blessures WO1993016717A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
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US5854221A (en) * 1996-12-12 1998-12-29 The Children's Medical Center Corporation Endothelial cell proliferation inhibitor and method of use
US5945403A (en) * 1997-05-30 1999-08-31 The Children's Medical Center Corporation Angiostatin fragments and method of use
US6024688A (en) * 1996-03-08 2000-02-15 The Children's Medical Center Corporation Angiostatin fragments and method of use
WO2001091773A3 (fr) * 2000-05-31 2002-05-02 Encelle Inc Methode permettant de stimuler la croissance des cheveux
EP1319392A3 (fr) * 2001-12-12 2003-08-27 Beiersdorf AG Teinture pour cheveux favorisant la mélanogénèse
WO2010063678A3 (fr) * 2008-12-01 2011-12-29 Henkel Ag & Co. Kgaa Nouveaux déodorants et anti-transpirants permettant d'inhiber la croissance pileuse

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0157359A2 (fr) * 1984-04-02 1985-10-09 National Jewish Hospital and Research Center Matrice de collagène pour la régénération de tissus
EP0259893A2 (fr) * 1986-09-12 1988-03-16 The Rockefeller University Agents pour éliminer les produits terminaux de la glycosylation avancée
WO1990000060A1 (fr) * 1988-06-30 1990-01-11 Collagen Corporation Matrices collagenes de cicatrisation de blessures et leur procede de production
WO1993004086A1 (fr) * 1991-08-23 1993-03-04 The Rockefeller University Recepteurs de produits finaux de glycosylation avancee et leurs utilisations

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0157359A2 (fr) * 1984-04-02 1985-10-09 National Jewish Hospital and Research Center Matrice de collagène pour la régénération de tissus
EP0259893A2 (fr) * 1986-09-12 1988-03-16 The Rockefeller University Agents pour éliminer les produits terminaux de la glycosylation avancée
WO1990000060A1 (fr) * 1988-06-30 1990-01-11 Collagen Corporation Matrices collagenes de cicatrisation de blessures et leur procede de production
WO1993004086A1 (fr) * 1991-08-23 1993-03-04 The Rockefeller University Recepteurs de produits finaux de glycosylation avancee et leurs utilisations

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6024688A (en) * 1996-03-08 2000-02-15 The Children's Medical Center Corporation Angiostatin fragments and method of use
US6521439B2 (en) 1996-03-08 2003-02-18 The Children's Medical Center Corporation Nucleic acids encoding plasminogen fragments
US5854221A (en) * 1996-12-12 1998-12-29 The Children's Medical Center Corporation Endothelial cell proliferation inhibitor and method of use
US5945403A (en) * 1997-05-30 1999-08-31 The Children's Medical Center Corporation Angiostatin fragments and method of use
WO2001091773A3 (fr) * 2000-05-31 2002-05-02 Encelle Inc Methode permettant de stimuler la croissance des cheveux
US6992062B2 (en) 2000-05-31 2006-01-31 Encelle, Inc. Method of stimulation hair growth
US7700660B2 (en) 2000-05-31 2010-04-20 Encelle, Inc. Method of treating chronic ulcers
EP1319392A3 (fr) * 2001-12-12 2003-08-27 Beiersdorf AG Teinture pour cheveux favorisant la mélanogénèse
WO2010063678A3 (fr) * 2008-12-01 2011-12-29 Henkel Ag & Co. Kgaa Nouveaux déodorants et anti-transpirants permettant d'inhiber la croissance pileuse

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