WO2017181978A1 - Produit de protéine adhésive de moule et son utilisation pour inhiber une inflammation vasculaire - Google Patents

Produit de protéine adhésive de moule et son utilisation pour inhiber une inflammation vasculaire Download PDF

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WO2017181978A1
WO2017181978A1 PCT/CN2017/081308 CN2017081308W WO2017181978A1 WO 2017181978 A1 WO2017181978 A1 WO 2017181978A1 CN 2017081308 W CN2017081308 W CN 2017081308W WO 2017181978 A1 WO2017181978 A1 WO 2017181978A1
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vasculitis
mussel mucin
vascular inflammation
mussel
mucin
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PCT/CN2017/081308
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Chinese (zh)
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高敏
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江阴市本特塞缪森生命科学研究院有限公司
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/06Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/10Dispersions; Emulsions
    • A61K9/12Aerosols; Foams

Definitions

  • the present invention relates generally to the fields of pharmaceuticals, medical products, health care products, and food technology, and more particularly to mussel mucin products and their use in inhibiting vascular inflammation.
  • Blood vessels are a series of tubes through which blood flows. They are divided into arteries, veins, and capillaries according to their structural functions.
  • Vascular inflammation is an infiltration of inflammatory cells around the blood vessel wall and blood vessels, accompanied by vascular damage, including cellulose deposition, collagen fiber degeneration, endothelial cells and myocyte necrosis.
  • the clinical manifestations of vascular inflammation are multiple systemic damage, unexplained fever, pleomorphic skin lesions such as erythema, nodules, cyanosis, wheal, blood blisters, necrosis and ulcers.
  • vascular inflammation can be aimed at the cause and eliminate allergens; it can be the treatment of underlying diseases, such as connective tissue diseases, tumors; vasculitis confined to the skin, often using antihistamines, causing telangiectasia and permeability Increase; systemic vasculitis can be treated with prednisone, by inhibiting the proliferation of connective tissue, reducing the permeability of the capillary wall and cell membrane, reducing inflammatory exudation.
  • vascular inflammation is primarily achieved by increasing permeability to relieve symptoms for therapeutic purposes.
  • Mussel adhesive protein also known as Mytilus edulis foot protein (Mefp)
  • Mefp Mytilus edulis foot protein
  • Mytilus coruscus A special protein secreted by Perna viridis. Mussels are usually attached in groups to the reefs on the coast or to the bottom of the ship, and have the ability to withstand wave impacts in the offshore. In fact, mussels can be attached extremely strongly to the substrate of any material, such as metal, wood, glass, and the like. The main reason for the above characteristics of mussels is that they can form and store this special mucin in the girth of the foot. The mussels release the mucin through the foot silk to a solid surface such as rock to form a water-resistant combination. Fix yourself.
  • Mussel mucin has two structural features: (1) containing lysine, which has a high loading of positive charge; (2) containing 3,4 dihydroxyphenylalanine (DOPA, dopa). The cells and tissues of the human body are negatively charged.
  • Mussel mucin plays a protective and therapeutic role by tightly binding cells and tissues through the electrostatic interaction between its own positive charge and the negative charge of cells and tissues.
  • dopa oxidation produces ortho-dioxins, which can be cross-linked with unoxidized dopa to form a membrane or a network scaffold, which promotes the protein to adhere more closely and firmly to the surface of the human body, thereby protecting.
  • Mussel mucin is a macromolecular protein that is completely degraded in the human body for about 3-10 days. Its ability to attach to cell tissues is excellent, so that mussel mucin can be stabilized locally and continue to function.
  • mussel mucin has the above characteristics, its current application field is very limited.
  • Commercial mussel mucin products are Cell-Tak from BD Biosciences, MAP Trix from Kollodis, Korea, and Hydrogel from Biopolymer, Sweden. These products are either used directly in the mussel mucin solution state, or are stored as lyophilized powder formulations and dissolved prior to use, and their primary application is limited to microscopic cell adhesion and tissue adhesives. Mussel mucin has also been reported for use in the repair of fetal membranes, as a coating against seawater corrosion, and as a drug-loaded stent for the heart.
  • Mussel mucin used herein refers to Mytilus edulis Linnaeus, Mytilus coruscus or Perna viridis from the Mytilidae bivalve mollusc. 11 subclasses of mussel mucin, currently known as purified from marine mussels: mefp1, mefp-2, mefp-3, mefp-4, mefp-5, mefp-6, collagen pre-COL- A mixture of one or more of P, pre-COL-D, pre-COL-NG, foot silk matrix proteins PTMP and DTMP.
  • the mussel mucin used herein may have a pH of 1.0 to 7.0 in an aqueous solution, and particularly may be in the range of pH 3.0 to 6.5 to make the therapeutic effect better.
  • the mussel mucin used herein can be obtained by the following preparation method, for example, a method for separating and purifying mussel mucin using mixed adsorption chromatography in Chinese Patent No. ZL200710179491.0, a kind of carboxy using Chinese Patent No. ZL200710179492.5 Purification by methyl ion exchange chromatography A method of shelling mucin, Chinese Patent No. ZL200910087567.6, a method for separating and purifying mussel mucin using salting out and dialysis.
  • the mussel mucin used herein may be in the form of a solution or a lyophilized powder, in particular, the concentration of mussel mucin in the product may be 0.1-15.0 mg/ml, and when the concentration is too low, the effect of mussel mucin Not large, when the concentration is too high, it can cause cytotoxicity, skin irritation, etc., which is not conducive to the treatment of vascular inflammation.
  • the mussel mucin used herein can also be prepared as a liquid agent by combining it with an excipient.
  • An exemplary mussel mucin liquid preparation is prepared by dissolving or diluting mussel mucin solution mother liquor or lyophilized powder to a certain concentration or pH, and the solution for dissolving or diluting may be water, physiological saline, phosphate solution, vinegar. Acid solution, borate solution, and the like.
  • the pH of mussel mucin in the final product may be pH 1.0-7.0, and in particular, the therapeutic effect may be better in the range of pH 3.0-6.5.
  • the mussel mucin used herein can also be prepared as a gelling agent in combination with an excipient.
  • An exemplary mussel mucin gel is prepared by mixing a mussel mucin solution or a lyophilized powder with a gel matrix material, which may be selected from the group consisting of cellulose derivatives, carbomers, and seaweeds. Acid salt, tragacanth, gelatin, pectin, carrageenan, gellan gum, starch, xanthan gum, cationic guar gum, agar, non-cellulosic polysaccharide, ethylene polymer, acrylic resin, polyvinyl alcohol or poly One of carboxyvinyl or any combination thereof.
  • the mussel mucin used herein can be used as a main raw material to prepare a medicine using a pharmaceutically acceptable carrier.
  • the drug may be a liquid agent or a gel.
  • the drug may be administered by oral, spray, injection, targeted topical sustained release, targeted administration, and may be administered at a low temperature or in a heated manner.
  • the mussel mucin used herein can be used as a main raw material to prepare a medical device.
  • the term medical device as used herein refers to materials that are used directly or indirectly to the human body and other similar or related items.
  • the medical device can be a liquid agent or a gel.
  • the medical device can be used by oral, spray, injection, targeted local sustained release, targeted administration, and can be administered at a low temperature or in a heated manner.
  • the mussel mucin used herein can be used as a main raw material, and a health care product or food can be prepared by using an excipient which is acceptable in the field of health care or food.
  • the health care product or food may be a liquid agent or a gel.
  • the health supplement or food may be administered by oral, spray, injection, targeted topical sustained release, targeted administration, and may be administered at a low temperature or in a heated manner.
  • Another object of the invention is to provide an application of mussel mucin products to inhibit vascular inflammation.
  • mussel mucin can alleviate cellulose deposition, collagen fiber degeneration, endothelial cells and myocyte necrosis caused by various vascular inflammations.
  • Common vascular inflammation includes allergic leukocyte vasculitis, nodular polyarteritis, thrombotic vasculitis, granulomatous vasculitis, lymphocytic vasculitis, abnormal blood vessel vasculitis, and rheumatoid vasculitis. .
  • Allergic leukocyte rupture vasculitis is vascular inflammation caused by infection, drug or immune abnormalities, and clinical manifestations may include irregular fever, myalgia, joint pain and the like. Skin lesions are mostly distributed in the lower limbs, and the lesions are diverse. Purpura is the most common, characteristic, often higher than the leather surface, the pressure does not fade. There may be genital erythema, blistering, blood blister in severe cases. Pustules can also occur when neutrophils ooze out into surrounding tissues. Sometimes there are subcutaneous nodules of varying sizes. If the vascular endothelium is damaged, the stenosis of the lumen may cause local ulceration and necrosis, and occasionally reticular leukoplakia.
  • rash is sometimes accompanied by itching or pain, usually lasting 2-4 weeks, with pigmentation or residual atrophic scar after absorption.
  • Allergic leukocyte vasculitis is usually treated with glucocorticoids, which can inhibit telangiectasia, reduce exudation and edema, inhibit white blood cell infiltration and phagocytosis, thereby reducing inflammation symptoms.
  • glucocorticoids can inhibit telangiectasia, reduce exudation and edema, inhibit white blood cell infiltration and phagocytosis, thereby reducing inflammation symptoms.
  • long-term or large-scale administration can lead to hypercortical hyperplasia, induce or aggravate infection, induce or aggravate ulcers, induce hypertension and arteriosclerosis.
  • Nodular polyarteritis is a kind of necrotizing vasculitis involving the whole layer of small and medium arteries caused by viral infection. It can affect the blood vessels of various tissues and organs of the whole body. The clinical manifestations are diverse and can be limited to the skin and can affect multiple organs. Or system. Usually characterized by skin nodules, arranged along the superficial arteries or irregularly gathered near the blood vessels, pain and tenderness, rose red, bright red or near normal skin color, severe cases can cause death or disability. There are mainly systemic nodular polyarteritis, benign skin type nodular polyarteritis, and infant nodular polyarteritis. The treatment of nodular polyarteritis usually uses corticosteroids, which can cause full moon face, osteoporosis, gastric ulcer, buffalo shoulder, high blood pressure, cataract, hemorrhoids and mold infections.
  • Thrombotic vasculitis mainly involves small and medium arteries and veins, with intravascular thrombosis Characterized and presented with different clinical manifestations. There are mainly thromboangiitis obliterans, thrombophlebitis, malignant atrophic papulosis, reticular leukocytitis, thrombotic thrombocytopenic purpura and so on. Angiogenic vasculitis is often treated with vasodilators, anticoagulants or plasma expanders.
  • Granulomatous vasculitis is a multi-system disease involving large, medium and small blood vessels, characterized by the formation of granuloma inside and outside the vessel wall, and the course of disease is slow. There are mainly Wegener's granulomatosis, allergic granulomatous vasculitis, temporal arteritis, arteritis and the like. Its pathology is characterized by inflammation of the blood vessel wall, mainly invading the upper and lower respiratory tract and the kidney, usually starting with focal granulomatous inflammation of the nasal mucosa and lung tissue, and then progressing to diffuse necrotizing granulomatous inflammation of the blood vessel. . Clinical manifestations of nasal and paranasal sinusitis, lung disease and progressive renal failure. It can also affect joints, eyes, skin, and can also invade the eyes, heart, nervous system and ears. Glucocorticoid vasculitis is often treated with glucocorticoids or immunosuppressive agents.
  • Lymphocytic vasculitis is characterized by infiltration of lymphocytes in the small blood vessels of the skin, the wall of the tube and surrounding tissues, and produces various types of skin lesions, mainly lymphoma-like papules and acute acne-like lichen-like pityriasis.
  • Glucocorticoids and cyclophosphamide are the main drugs for treatment.
  • Blood component abnormal vasculitis is a small vascular inflammatory disease caused by abnormal components in the blood, which is manifested as skin or visceral damage, mainly cryoglobulinemia, cold hyperglobulinemia, macroglobulinemia, etc. .
  • rheumatic vasculitis The typical feature of rheumatic vasculitis is peripheral vascular damage, which often occurs in patients with high rheumatoid factor titer and systemic complications.
  • the clinical manifestations are cutaneous vasculitis damage, localized palpation of purpura, non-specific erythema of the trunk, vascular infarction, large Blisters and ulcers, 20% of patients have finger mites.
  • Capillary vasodilation, infarct papules and nodules occur in nail folds. Treatment with salicylate or antimalarial drugs is generally used, and corticosteroids are available for severe cases.
  • vascular inflammation is often treated with glucocorticoids or corticosteroids, but long-term or large doses can lead to hypercortical hyperplasia, induce or aggravate infections, induce or aggravate ulcers, induce hypertension and arteriosclerosis.
  • the mussel mucin of the present invention can be used for the treatment of allergic leukocyte vasculitis, nodular polyarteritis, thrombotic vasculitis, granulomatous vasculitis, lymphocytic vasculitis, blood components Inflammation such as abnormal vasculitis and rheumatoid vasculitis.
  • the mussel mucin of the present invention can be used for inhibiting allergic leukocyte vasculitis, nodular polyarteritis, thrombotic vasculitis, granulomatous vasculitis, lymphatic Cystic vasculitis, abnormal blood vessel vasculitis, and vascular cancer caused by rheumatoid vasculitis.
  • Fig. 1 shows the repairing effect of the common bone powder and the mussel mucin bone powder according to the present invention on the bone defect site of the test animal, wherein the left image shows the results of using ordinary bone powder, and the right image shows the results of using mussel mucin bone powder.
  • the mussel mucin application according to embodiment 1, wherein the mussel mucin concentration may be from 0.1 to 15.0 mg/ml.
  • Mussel mucin application according to embodiment 1, wherein the mussel mucin in the final product may be in the range of pH 1.0-7.0, in particular in the range of pH 3.0-6.5.
  • vascular inflammation may be selected from the group consisting of: allergic leukocyte vasculitis, nodular polyarteritis, thrombotic vasculitis, Granulomatous vasculitis, lymphocytic vasculitis, abnormal blood component vasculitis, and rheumatic vasculitis.
  • vascular inflammation may be selected from the group consisting of: allergic leukocyte vasculitis, nodular polyarteritis, thrombotic vasculitis, Vascular vasculitis, lymphocytic vasculitis, abnormal blood vessel vasculitis, and vascular cancer caused by rheumatoid vasculitis.
  • composition can be administered by oral, spray, injection, targeted topical sustained release, targeted administration.
  • a medicament for the treatment of vascular inflammation comprising mussel mucin and a pharmaceutically acceptable carrier, wherein the concentration of mussel mucin may be from 0.1 to 15.0 mg/ml.
  • a medical device for treating vascular inflammation comprising a mussel mucin and a carrier acceptable for use in the field of medical devices, wherein the concentration of mussel mucin can be from 0.1 to 15.0 mg/ml.
  • a health care product/food for treating vascular inflammation comprising mussel mucin and a health care product or a carrier acceptable for the food field, wherein the concentration of mussel mucin may be from 0.1 to 15.0 mg/ml.
  • vascular inflammation may be selected from the group consisting of: allergic leukocyte vasculitis, nodular polyarteritis, thrombotic vasculitis, granulation Swollen vasculitis, lymphocytic vasculitis, abnormal blood vessel vasculitis, and rheumatic vasculitis.
  • vascular inflammation may be selected from the group consisting of: allergic leukocyte vasculitis, nodular polyarteritis, thrombotic vasculitis, granulation Tumor vasculitis, lymphocytic vasculitis, abnormal blood vessel vasculitis, and vascular cancer caused by rheumatoid vasculitis.
  • vascular inflammation can be selected from the group consisting of: allergic leukocyte vasculitis, nodular polyarteritis, thrombotic vasculitis, Granulomatous vasculitis, lymphocytic vasculitis, abnormal blood component vasculitis, and rheumatic vasculitis.
  • vascular inflammation can be selected from the group consisting of: allergic leukocyte vasculitis, nodular polyarteritis, thrombotic vasculitis, Vascular vasculitis, lymphocytic vasculitis, abnormal blood vessel vasculitis, and vascular cancer caused by rheumatoid vasculitis.
  • vascular inflammation may be selected from the group consisting of: allergic leukocyte vasculitis, nodular polyarteritis, thrombotic blood vessel Inflammation, granulomatous vasculitis, lymphocytic vasculitis, and abnormal vasculitis of blood components.
  • vascular inflammation may be selected from the group consisting of: allergic leukocyte vasculitis, nodular polyarteritis, thrombotic blood vessel Inflammation, granulomatous vasculitis, lymphocytic vasculitis, abnormal blood vessel vasculitis, and vascular cancer caused by rheumatoid vasculitis.
  • a method of treating vascular inflammation comprising formulating a mussel mucin liquid or gel according to any one of the preceding embodiments 11-13 and administering to a subject in need thereof, wherein mussel mucin
  • the concentration can be from 0.1 to 15.0 mg/ml.
  • vascular inflammation is selected from the group consisting of: allergic leukocyte vasculitis, nodular polyarteritis, thrombotic vasculitis, granulomatous vasculitis, lymphocytic vasculitis , blood component abnormal vasculitis and vascular cancer caused by rheumatoid vasculitis.
  • Example 1 Application of mussel mucin liquid medicine in the treatment of allergic cutaneous vasculitis.
  • the selected patients were randomly divided into the control group and the experimental group, and the control group was treated with 0.1% citric acid solution.
  • the experimental group was treated with the above-mentioned mussel mucin aqueous solution drug.
  • the two groups were used three times a day. After the meal, the affected area was sprayed, and each time it was sprayed 2-3 times, the affected area was completely covered.
  • the pain or itching of the affected area was significantly weakened within 10-30 minutes, from the visual analog VAS score of 5.0-7.0 before treatment to 1.0-3.0, and the analgesic or antipruritic time lasted for 2-7 hours. There was no change in the VAS score of the affected area before and after the control group. As the use time is extended, the duration of pain relief is prolonged. The use interval was extended and did not show any dependence.
  • Example 2 Application of mussel mucin gel medical device in the treatment of skin type nodular polyarteritis.
  • the skin of the patients in the control group was red and swollen, ulceration and exudation were not improved, and the pain was slightly relieved.
  • the skin and sore surface of the legs were regressed, ulceration, exudation, and pain were obvious. Reduced.
  • the redness and swelling of the sore surface of the control group slightly subsided, the ulceration surface was not reduced, and a small amount of exudate was still present; all the patients in the test group had dry sores and scarring. It can be seen that the mussel mucin gel medical device can be used for the treatment of skin type nodular polyarteritis, and the effect is better than the existing drugs prednisone and lamivudine.
  • Example 3 Application of mussel mucin liquid health care products in the treatment of thrombotic vasculitis.
  • the selected patients were orally administered with the above-mentioned mussel mucin liquid health care products, taken once a day, 10 ml each time, and reviewed monthly. After taking it for 2 months, the patient's lower extremity pain symptoms disappeared, intermittent claudication time and distance decreased, and the sputum index returned to 0.9. It can be seen that mussel mucin liquid health care products are beneficial for the treatment of thrombotic vasculitis.
  • Example 4 Application of mussel mucin liquid medicine in the treatment of granulomatous vasculitis.
  • the selected patients were assigned to the control group or the experimental group, and the control group was treated with oral 1.5 mg/kg.d prednisone.
  • the test group received the above mussel mucin liquid medicine twice a day, 1.0 mg each time. After 4 weeks of treatment, the symptoms of the patients in the control group and the test group were all relieved. The control group reduced the dose by 1.0 mg/kg.d, and the test group reduced the dose to 0.5 mg/time. Until 8 weeks, no recurrence or symptom aggravation occurred in the control group and the test group. It can be seen that oral mussel mucin liquid medicine contributes to the treatment of granulomatous vasculitis.
  • Example 5 Application of mussel mucin liquid medical device in the treatment of lymphocytic vasculitis.
  • the selected patients were randomly assigned to the control group or the experimental group.
  • oral prednisone 50 mg/d in the test group, the affected area was sprayed with mussel mucin liquid medical device twice a day.
  • the amount of mussel mucin can evenly cover the affected area.
  • the papules in the control group were significantly reduced and the exudation was reduced.
  • the papules were significantly reduced and the exudation was reduced.
  • the papules in the control group were exacerbated, the redness and swelling were aggravated, and the treatment effect was repeated; the papules in the experimental group subsided. It can be seen that mussel mucin liquid medical devices can be used for the treatment of lymphocytic vasculitis.
  • Example 6 Application of mussel mucin gel drug in the treatment of rheumatic vasculitis.
  • the selected patients were randomly assigned to the control group or the experimental group.
  • the patients in the control group were treated with oral prednisone 50 mg/d.
  • the patients in the experimental group were treated with mussel mucin gel drug, applied twice a day for each dose. In order to evenly cover the affected area. After 1 week of treatment, the exudation of the ulcer in the control group decreased and the area of the ulcer did not change; the exudation of the ulcer in the test group decreased, and the area of the ulcer decreased to varying degrees. After 2 weeks of treatment, the exudation of the ulcer in the control group was reduced, and the average healing rate was 32%. All the ulcers in the experimental group were basically healed, and the symptoms were covered by the neonatal epithelium. It can be seen that mussel mucin gel drugs can be used for the treatment of rheumatoid vasculitis.
  • Example 7 Mussel mucin liquid is used to promote angiogenesis in animal experiments
  • the mussel mucin solution (MAP) was prepared by column chromatography with a protein concentration of 5.0 mg/ml and a purity of 90%. The above mussel mucin solution was taken and diluted with physiological saline to a mussel mucin content of 1.0 mg/ml to obtain a mussel mucin liquid. Each 100 ml mussel mucin product contains mussel mucin 1.0 mg, sodium chloride 0.9 g, and the rest is water for injection.
  • the mussel mucin was prepared into a mussel mucin liquid having a mussel mucin concentration of 1.0 mg/ml.
  • the mussel mucin was mixed with the artificial bone powder to obtain a test group sample.
  • the physiological saline was mixed with the artificial bone powder to obtain a control sample.
  • the left and right legs of the test animals were tested at the same time.
  • the left and right legs were randomly divided into the experimental group and the control group.
  • the experimental group was implanted with mussel mucin mixed bone powder at the bone defect, and the control group was implanted at the bone defect.
  • Postoperative test animals were injected with antibiotics, numbered and returned to the cage for rearing.
  • the animals were sacrificed 8 weeks after surgery, and the bone defect site was taken out.
  • the blood vessels in the bone defect were formed in the test group, but the blood vessels in the bone defect of the control group had not yet grown. It can be seen that mussel mucin can promote the repair of blood vessels at the injury site.

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Abstract

L'invention concerne l'utilisation d'une protéine adhésive de moule ou d'une formulation de cette dernière pour inhiber une inflammation vasculaire. En particulier, l'utilisation de la protéine adhésive de moule ou de sa formulation dans des inflammations telles que la vascularite leucocytoclasique allergique, la périartérite noueuse, la vascularite thrombotique, la granulomatose avec polyangéite, la vascularite lymphocytaire, la vascularite provoquée par une composition sanguine anormale, la vascularite rhumatoïde et similaire ; et l'utilisation de cette dernière dans le cancer vasculaire provoqué par une vascularite. La protéine adhésive de moule permet d'inhiber des symptômes tels que la rougeur, le gonflement, la fièvre, la douleur et similaires provoqués par l'inflammation vasculaire, et présente de larges perspectives d'application dans le domaine de la médecine, des produits médicaux, des produits de soins de santé et des aliments.
PCT/CN2017/081308 2016-04-20 2017-04-20 Produit de protéine adhésive de moule et son utilisation pour inhiber une inflammation vasculaire WO2017181978A1 (fr)

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