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WO2022080846A1 - Composition pour la prévention ou le traitement de la fibrose, comprenant une flavone - Google Patents

Composition pour la prévention ou le traitement de la fibrose, comprenant une flavone Download PDF

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Publication number
WO2022080846A1
WO2022080846A1 PCT/KR2021/014084 KR2021014084W WO2022080846A1 WO 2022080846 A1 WO2022080846 A1 WO 2022080846A1 KR 2021014084 W KR2021014084 W KR 2021014084W WO 2022080846 A1 WO2022080846 A1 WO 2022080846A1
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WIPO (PCT)
Prior art keywords
fibrosis
dimethoxyflavone
composition
food composition
present
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/KR2021/014084
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English (en)
Korean (ko)
Inventor
이은주
김효수
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Seoul National University Hospital
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Seoul National University Hospital
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Filing date
Publication date
Priority claimed from KR1020210135177A external-priority patent/KR102751651B1/ko
Application filed by Seoul National University Hospital filed Critical Seoul National University Hospital
Publication of WO2022080846A1 publication Critical patent/WO2022080846A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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

Definitions

  • the present invention relates to a composition for preventing or treating fibrosis comprising a flavone as an active ingredient, and the like.
  • Fibrotic disease that is, fibrosis (fibrosis) is a general term for a disease in which excessive fibrous connective tissue is formed due to abnormal accumulation of collagen matrix in the process of regeneration or reaction, and its form is that of normal fibrous tissue. This is in stark contrast to formation.
  • Representative tissues in which fibrosis occurs include heart, kidney, liver, fat, lung, bone, bone marrow, and skin.
  • Cardiac fibrosis is a phenomenon common to many heart diseases, and includes replacement (scarring) fibrosis and interstitial (reactive) fibrosis.
  • Scleroderma is a chronic disease characterized by excessive deposition of collagen in the skin or other organs, and is known to affect blood vessels and internal organs in severe cases.
  • Skeletal muscle fibrosis is a phenomenon primarily induced in damaged muscles and is characterized by an overgrowth of fibrous tissue, primarily resulting from the body's attempts to recover from the injury.
  • pulmonary fibrosis is caused by polyhexamethylene guanidine (PHMG) and ethoxyethyl guanidine chloride (Oligo(2-)ethoxy ethoxyethyl guanidine chloride; PGH) included in humidifier disinfectants.
  • PGH ethoxyethyl guanidine chloride
  • fibrosis is a disease that is caused by repetitive action as well as various factors and pathways, and the mechanism itself is not clearly known, so the development of effective drugs for treatment is insufficient.
  • anti-inflammatory agents known to be partially helpful in the treatment of fibrosis include prednisone, glucocorticoid, etc., but their therapeutic effect or safety has not been verified, and stem cells with high proliferative capacity are used.
  • stem cells with high proliferative capacity are used.
  • stem cells with high proliferative capacity are used.
  • differentiated cells instead of tissue transplantation, but it is difficult to apply them to direct treatment yet because of low cell viability in vivo or risks that may cause immune rejection (Korea Patent Application Publication No. 10-2019-0003422).
  • methods such as inhibition of fibrosis factor activity and decomposition of extracellular matrix are known for the treatment of fibrosis, but since the fibrosis process is chronic, there is no perfect treatment method yet.
  • the present invention has been devised to solve the problems in the prior art as described above, and contains 3,7-dimethoxyflavone, which can treat fibrosis by inhibiting the expression of ⁇ -SMA protein and simultaneously reducing the fibrotic matrix, as an active ingredient.
  • An object of the present invention is to provide a composition for preventing or treating fibrosis.
  • the present invention provides a pharmaceutical composition for preventing or treating a fibrotic disease comprising 3,7-dimethoxyflavone or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the 3,7-dimethoxyflavone may include a derivative thereof.
  • the derivative is not limited as long as it is a compound obtained by chemically changing a part of 3,7-dimethoxyflavone.
  • the present invention provides a food composition for the improvement or prevention of fibrotic diseases comprising 3,7-dimethoxyflavone or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the food composition may be a health functional food composition.
  • the 3,7-dimethoxyflavone is preferably represented by the following formula (1).
  • the 3,7-dimethoxyflavone suppresses the expression of ⁇ -smooth muscle actin ( ⁇ -SMA), thereby inhibiting the progression of fibrosis and significantly inhibiting the proliferation of hepatic stellate cells, By reducing the fibrotic matrix at the same time, it is possible to protect the tissue and treat fibrosis.
  • ⁇ -SMA smooth muscle actin
  • the fibrotic disease is preferably liver fibrosis, renal fibrosis, lung fibrosis, pancreatic fibrosis, systemic scleroderma, macular degeneration, cardiac fibrosis, cystic fibrosis of the pancreas and lungs, rosacea rosacea, Endocardial myocardial fibrosis, systemic idiopathic fibrosis, idiopathic pulmonary fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive mass fibrosis, nephrogenic systemic fibrosis, nodular subepithelial fibrosis, breast fibrosis, lymph node fibrosis, scarring, scleroderma, Skin fibrosis, bladder fibrosis, myofibrosis, arterial fibrosis, chronic obstructive pulmonary disease, thyroid fibrosis, articular fibrosis,
  • the present invention also provides a method for preventing or treating fibrotic diseases, comprising administering a composition comprising 3,7-dimethoxyflavone as an active ingredient to a subject.
  • the present invention provides a preventive or therapeutic use of a composition comprising 3,7-dimethoxyflavone as an active ingredient for fibrotic disease.
  • the present invention provides the use of 3,7-dimethoxyflavone for producing a drug used for fibrotic diseases.
  • 3,7-dimethoxyflavone or a derivative thereof according to the present invention significantly inhibits ⁇ -SMA expression, thereby inhibiting the activation of hepatic stellate cells, as well as significantly inhibiting the proliferation of hepatic stellate cells, resulting in fibrosis It is expected that it can be used as a stable and effective therapeutic agent for the treatment of various fibrotic diseases because it can effectively restore tissue function by downregulating the fibrosis index by inhibiting fibrosis.
  • FIG. 1 is a diagram schematically illustrating an experimental method for screening a substance exhibiting an anti-fibrotic effect according to an embodiment of the present invention.
  • FIG. 2 is a view showing the results of confirming the anti-fibrotic effect of the compound according to an embodiment of the present invention by ⁇ -SMA strength.
  • FIG. 3 is a view showing the result of confirming the anti-fibrotic effect of the compound according to an embodiment of the present invention as an elongation factor.
  • FIG. 4 is a view showing the results of confirming the liver function recovery effect of the compound according to an embodiment of the present invention.
  • 5 is a view showing the results of confirming the anti-fibrotic effect of the compound according to an embodiment of the present invention by picrosirius red staining.
  • FIG. 6 is a view showing the results of quantifying picrosirius red staining results according to an embodiment of the present invention.
  • FIG. 7 is a view showing the results of confirming the anti-fibrotic effect of the compound according to an embodiment of the present invention by Western blotting.
  • FIG. 8 is a view showing the results of confirming the liver function recovery effect of the compound according to an embodiment of the present invention.
  • FIG. 9 is a view showing the results of confirming the anti-fibrotic effect of the compound according to an embodiment of the present invention by picrosirius red staining.
  • FIG. 10 is a view showing the results of quantifying the picrosirius red staining results according to an embodiment of the present invention.
  • 3,7-dimethoxyflavone or a derivative thereof of the present invention is expected to be effectively used in the treatment of various fibrotic diseases by effectively inhibiting the expression of ⁇ -SMA.
  • fibrosis refers to all symptoms in which abnormal accumulation of collagen matrix or excessive formation of fibrous connective tissue in tissue occurs, and fibrosis disease (fibrosis) may occur due to such fibrosis, There is no restriction on the location of occurrence.
  • prevention refers to a broad concept that blocks the occurrence of fibrosis, preferably primary prevention to prevent it before occurrence, and secondary prevention to detect and timely treatment Including, but not limited to, prophylaxis, as long as it is a process and/or activity to combat the occurrence of fibrosis.
  • treatment refers to a broad concept of coping with the occurrence of fibrosis, and there is no limitation as long as it is a process and/or activity for treating, curing, alleviating, reducing, etc., fibrosis.
  • composition of the present invention can be administered, and the subject is not limited.
  • the term "pharmaceutical composition” may be characterized in the form of capsules, tablets, granules, injections, ointments, powders, or beverages, and the pharmaceutical composition is intended for humans.
  • the pharmaceutical composition is not limited thereto, but may be formulated in the form of oral dosage forms such as powders, granules, capsules, tablets, aqueous suspensions, external preparations, suppositories, and sterile injection solutions, respectively, according to conventional methods.
  • the pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers may include binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, dyes, fragrances, etc. for oral administration, and in the case of injections, buffers, preservatives, pain-free agents
  • a topical agent, solubilizer, isotonic agent, stabilizer, etc. can be mixed and used, and in the case of topical administration, a base, excipient, lubricant, preservative, etc. can be used.
  • the dosage form of the pharmaceutical composition of the present invention can be prepared in various ways by mixing with a pharmaceutically acceptable carrier as described above.
  • oral administration in the case of oral administration, it can be prepared in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc., and in the case of injections, it can be prepared in the form of unit dose ampoules or multiple doses. there is.
  • it can be formulated as a solution, suspension, tablet, capsule, sustained release formulation, and the like.
  • suitable carriers, excipients and diluents for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil may be used.
  • it may further include a filler, an anti-agglomeration agent, a lubricant, a wetting agent, a flavoring agent, an emulsifier, a preservative, and the like.
  • the route of administration of the pharmaceutical composition according to the present invention is not limited thereto, but oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical , sublingual or rectal. Oral or parenteral administration is preferred.
  • parenteral includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrabursar, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • the pharmaceutical composition of the present invention may also be administered in the form of a suppository for rectal administration.
  • the pharmaceutical composition of the present invention depends on several factors including the activity of the specific compound used, age, weight, general health, sex, formula, administration time, administration route, excretion rate, drug formulation, and the severity of the specific disease to be prevented or treated.
  • the dosage of the pharmaceutical composition may vary depending on the patient's condition, body weight, degree of disease, drug form, administration route and period, but may be appropriately selected by those skilled in the art, and 0.0001 to 500 mg per day It can be administered at /kg or 0.001 to 500 mg/kg. Administration may be administered once a day, or may be administered in several divided doses. The above dosage does not limit the scope of the present invention in any way.
  • pharmaceutically acceptable salt or food acceptable salt refers to a concentration having a relatively non-toxic and harmless effective action, and the side effects due to this salt are of the compounds of the present invention.
  • any organic or inorganic addition salt of the compounds of the present invention which does not diminish the beneficial efficacy.
  • inorganic acids and organic acids can be used as free acids, and hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, perchloric acid, phosphoric acid, etc. can be used as inorganic acids, and citric acid, acetic acid, lactic acid, and maleic acid can be used as organic acids.
  • these salts may include alkali metal salts (sodium salt, potassium salt, etc.) and alkaline earth metal salt (calcium salt, magnesium salt, etc.) and the like.
  • acid addition salts include acetate, aspartate, benzate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, Gluceptate, gluconate, glucuronate, hexafluorophosphate, hebenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, maleate, malate ate, malonate, mesylate, methylsulfate, naphthylate, 2-naphsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate Late, stearate, succinate, tartrate, tosylate, trifluoroacetate
  • “food composition” may be used in various foods, for example, beverages, gum, tea, vitamin complexes, health supplements, etc., and may be used in pills, powders, granules, needles, tablets, capsules, or It can be used in the form of drinks.
  • the food composition includes a health functional food composition.
  • the amount of 3,7-dimethoxyflavone or a derivative thereof of the present invention in food or beverage is generally 0.01 to 30% by weight of the total food weight in the case of the food composition of the present invention, and in the case of a health drink composition, 100mL It can be added in a ratio of 0.02 to 10 g, preferably 0.3 to 1 g, based on the amount.
  • the food composition of the present invention is an essential ingredient, and there is no particular limitation on ingredients added other than 3,7-dimethoxyflavone or a derivative thereof of the present invention, and conventional food additives used in the art, for example, natural carbohydrates, flavoring agents, flavors It may contain agents, colorants, fillers, stabilizers, various nutrients, vitamins, minerals (electrolytes), and the like.
  • Examples of the natural carbohydrate include monosaccharides such as glucose, fructose, and the like; disaccharides such as maltose, sucrose and the like; polysaccharides such as dextrins, cyclodextrins; Conventional sugars and sugar alcohols such as xylitol, sorbitol, and erythritol can be used.
  • Examples of the flavoring agent include natural flavoring agents (taumatine, stevia extract (eg, rebaudioside A, glycyrrhizin, etc.)) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. .
  • the flavoring agent examples include honey, D-mannitol, maltitol liquid, krill concentrate, and the like.
  • it may contain pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like.
  • pectic acid and its salts alginic acid and its salts
  • organic acids protective colloidal thickeners
  • pH adjusters stabilizers
  • preservatives glycerin
  • alcohols carbonation agents used in carbonated beverages, and the like.
  • carbonation agents used in carbonated beverages and the like.
  • the proportion of these additives is not critical, but is generally selected in the range of 0 to about 20 parts by weight per 100 parts by weight of the composition of the present invention.
  • the LX2-based anti-fibrotic substance screening experiment was performed with the compound library provided by Pasteur Korea Research Institute.
  • the LX2 cell line a human hepatic stellate cell line (HSC)
  • HSC human hepatic stellate cell line
  • CTRL naive
  • T+H negative control group treated with 10 ng/mL of TGF- ⁇ daily for 3 days
  • T+T the experimental group treated with 10 ng/mL of TGF- ⁇ daily for 2 days.
  • 10 ng/mL of TGF- ⁇ and 5 ⁇ M of the compound to be tested were divided into groups (T+C) treated with each treatment, and after additional incubation for 2 days, the cells were fixed and stained. .
  • the result of analyzing the elongation factor using the obtained fluorescence image is shown in FIG. 3 .
  • the elongation factor was increased due to the induction of cell fibrosis, but in the case of the sample treated with 3,7-dimethoxyflavone, the positive control It was confirmed that the elongation factor was reduced similarly to the group treated with HGF.
  • TAA thioacetamide
  • IACUC Animal Experimental Ethics Committee
  • mice were anesthetized, blood was obtained from the heart, and liver tissue was obtained.
  • a serum assay was performed using the obtained blood.
  • blood was centrifuged at 3,000 rpm for 15 minutes to obtain serum, and using an automatic chemistry analyzer (HITACHI 7070) according to the manufacturer's instructions, aspartate aminotransferase (AST; aspartate aminotransferase) and alanine aminotransferase (ALT; alanine aminotransferase) activity was measured to confirm liver function.
  • HITACHI 7070 automatic chemistry analyzer
  • liver tissue immunohistochemistry (Immunohistochemistry) analysis was performed. More specifically, the liver was perfused with cold PBS, fixed using a 10% neutral formalin solution and paraffin, and cut to a thickness of 4-5 ⁇ m. And the cut paraffin sections were stained with hematoxin and eosin, or picrosirius red according to a standard protocol. Collagen was confirmed through Picrosirius red staining and connective tissue was visualized. After staining, it was observed using a Leica optical microscope (Leica). The results are shown in FIG. 5 . And for each image, the fibrous liver area was quantified by quantifying the area stained with picrosirius red using ImageJ software (National Institutes of Health). The results are shown in FIG. 6 .
  • liver tissue was analyzed using protein lysis buffer (50 mM Tris-HCl, 150 mM NaCl, 0.5% deoxycholate, 1% NP40 and 0.1% sodium dodecyl sulfate (SDS) containing protease inhibitor cocktail (Roche)). After dissolving and heating the whole protein extract (25-30 ⁇ g) at 95 °C for 5 minutes, SDS-PAGE was performed to separate the protein, and the separated protein was transferred to polyvinylidene fluoride membranes (Millipore) using a BioRad transfer unit.
  • protein lysis buffer 50 mM Tris-HCl, 150 mM NaCl, 0.5% deoxycholate, 1% NP40 and 0.1% sodium dodecyl sulfate (SDS) containing protease inhibitor cocktail (Roche)
  • liver fibrosis was induced by TAA treatment, which resulted in an increase in the expression of ⁇ -SMA protein, but it was confirmed that the expression of ⁇ -SMA protein was significantly reduced in the experimental group injected with 3,7-dimethoxyflavone. .
  • mice 16-week-old C57BL/6 male mice were intraperitoneally injected with TAA at a concentration of 0.1 mg/g on the first day. And on days 4, 7, 10, 13, 16, 19, and 22, TAA was injected intraperitoneally at a concentration of 0.2 mg/g. From the 9th to the 22nd, 3,7-dimethoxyflavone was added to 0.5% carboxymethyl cellulose (CMC) and administered orally daily at a concentration of 10 mg/kg. And on the 23rd day, the mice were anesthetized, blood was obtained from the heart, and liver tissue was obtained. Thereafter, serum analysis was performed in the same manner as in Example 2.1 to confirm liver function. The results are shown in FIG. 8 .
  • CMC carboxymethyl cellulose
  • liver tissue immunohistochemical analysis was performed in the same manner as in Example 2.1. The results are shown in FIG. 9 . And for each image, the area stained with picrosirius red was quantified using ImageJ software, and the fibrotic liver area was quantified. The results are shown in FIG. 10 .
  • 3,7-dimethoxyflavone of the present invention has an anti-fibrotic effect, so when fibrosis is induced, it can reduce the expression level of ⁇ -SMA protein and effectively restore tissue function by down-regulating the fibrosis index. confirmed that there is. In addition, it was confirmed that the same effect was exhibited in various administration methods. Therefore, it was confirmed that the 3,7-dimethoxyflavone of the present invention can be used as a drug in various forms as a therapeutic agent for various fibrosis.
  • 3,7-dimethoxyflavone or a derivative thereof according to the present invention has the effect of significantly inhibiting the expression of ⁇ -SMA, thereby downregulating the fibrosis index to effectively restore the tissue function, so it is an effective therapeutic agent for the treatment of various fibrotic diseases can be used as

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Abstract

La présente invention concerne une composition pour le traitement de maladies fibrotiques, comprenant de la 3,7-diméthoxyflavone ou un dérivé de celle-ci, et plus spécifiquement, une composition qui peut être appliquée à diverses maladies fibrotiques par inhibition de l'expression de l'α-SMA.
PCT/KR2021/014084 2020-10-13 2021-10-13 Composition pour la prévention ou le traitement de la fibrose, comprenant une flavone Ceased WO2022080846A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR10-2020-0131527 2020-10-13
KR20200131527 2020-10-13
KR1020210135177A KR102751651B1 (ko) 2020-10-13 2021-10-12 플라본을 포함하는 섬유증의 예방 또는 치료용 조성물
KR10-2021-0135177 2021-10-12

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WO2022080846A1 true WO2022080846A1 (fr) 2022-04-21

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20040013919A (ko) * 2002-08-09 2004-02-14 대한민국(서울대학교 총장) 간 섬유화 또는 간 경화의 예방 또는 치료용 의약 조성물
CN1519236A (zh) * 2003-09-01 2004-08-11 ƽ 黄酮类化合物及含该类化合物提取物的用途和剂型
WO2005020881A2 (fr) * 2003-09-01 2005-03-10 Shanghai Comman Pharmaceutical Co. Compositions de flavonoides et d'extraits qui contiennent des flavonoides, et traitement de maladies
KR20140020966A (ko) * 2011-03-22 2014-02-19 재단법인 공업기술연구원 간 질환 치료용 약학 조성물
US20190134140A1 (en) * 2017-11-03 2019-05-09 Lauranell Harrison BURCH Orally administered composition for treating cystic fibrosis, copd, asthma and other inflammatory conditions

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20040013919A (ko) * 2002-08-09 2004-02-14 대한민국(서울대학교 총장) 간 섬유화 또는 간 경화의 예방 또는 치료용 의약 조성물
CN1519236A (zh) * 2003-09-01 2004-08-11 ƽ 黄酮类化合物及含该类化合物提取物的用途和剂型
WO2005020881A2 (fr) * 2003-09-01 2005-03-10 Shanghai Comman Pharmaceutical Co. Compositions de flavonoides et d'extraits qui contiennent des flavonoides, et traitement de maladies
KR20140020966A (ko) * 2011-03-22 2014-02-19 재단법인 공업기술연구원 간 질환 치료용 약학 조성물
US20190134140A1 (en) * 2017-11-03 2019-05-09 Lauranell Harrison BURCH Orally administered composition for treating cystic fibrosis, copd, asthma and other inflammatory conditions

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