Compositions comprising 15-HEPE for treating or preventing hematologic disorders, and / or related diseases

Abstract

To provide methods for treating or preventing hematologic disorders and / or related diseases.SOLUTION: Provided is a method of treating and / or preventing a hematologic disorder in a subject in need thereof, the method comprising administering to the subject 15- hydroxyeicosapentaenoic acid (15-HEPE) or a composition comprising 15-HEPE.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This application relates generally to compositions containing 15-HEPE and methods of using the same.

[0002] Sequence Listing This disclosure includes a Sequence Listing submitted in ASCII format via EFS Web, the entirety of which is hereby incorporated by reference. ASCII copy created April 1, 2020. This is a sequence listing named 124318-8014.US00_ST25.txt. , and is 3 kilobytes in size. [Background technology]

[0003] Blood disorders include red blood cell disorders and thrombosis tendency. It affects the production, lifespan, and shape of red blood cells (RBCs) and their oxygen-carrying molecule, hemoglobin. These diseases interfere with the transport of oxygen from the lungs to the rest of the body. Thrombophilia is a disorder that increases a subject's risk of developing blood clots in veins and arteries. These clots can break free from blood vessels, travel through the bloodstream to organs, and This can impair blood flow to the organ and cause ischemia. and / or cause an increased risk of pulmonary embolism. Summary of the Invention

[0004] The present application relates to a composition comprising 15-hydroxyeicosapentaenoic acid (15-HEPE), and methods of using such compositions in the treatment of various diseases and disorders.

[0005] In some aspects, the present disclosure provides a method for treating and / or preventing a blood disorder in a subject in need of such treatment. The present invention provides a method for treating and / or preventing a blood disorder using 15-HEPE or The method includes administering to a subject a composition comprising 15-HEPE.

[0006] In some aspects, the present disclosure provides a method for treating and / or preventing a blood disorder in a subject in need of such treatment. and a method for treating and / or preventing a blood disorder using up to about 8 g of 15 15-HEPE, wherein the total amount of 15-HEPE in the composition is 15-HEPE. It represents at least about 90% by weight of all lipids.

[0007] In yet another aspect, the present disclosure provides a method for treating and / or preventing a blood disorder in a subject in need thereof. and a method for treating and / or preventing a blood disorder, the method comprising administering up to about 8 g of 15- The method includes administering to a subject a composition containing 15-HEPE, wherein all of the 15-HEPE in the composition is and the subject has (a) an increase in red blood cell count, (b) a decrease in red blood cell mass, and and / or (c) a decrease in reticulocyte count.

[0008] In various embodiments, the blood disorder is hereditary hemolytic anemia, acquired hemolytic anemia, Fanconi hemolytic anemia, or From the group consisting of anemia, iron deficiency anemia, folate deficiency, B12 deficiency, and myelodysplastic syndrome be selected.

[0009] In some aspects, the present disclosure relates to a method for treating and / or preventing hemoglobin disorders.

[0013] Provided is a method for treating and / or preventing hemoglobin disorders in a subject, the method comprising: The method includes administering 15-HEPE or a composition containing 15-HEPE to a subject.

[0010] In another aspect, the present disclosure provides a method for treating and / or preventing a red blood cell disorder in a subject in need of treatment and / or prevention. A method for treating and / or preventing red blood cell disorders is provided, the method comprising administering 15-HEPE or The method includes administering to a subject a composition comprising 15-HEPE.

[0011] In another aspect, the present disclosure provides a method for treating and / or preventing hemoglobin disorders and / or red blood cell disorders. Treating hemoglobin abnormalities and / or red blood cell disorders in a subject in need thereof; and / or The present invention provides a method for preventing or treating a pulmonary embolism, the method comprising administering to a subject a composition comprising up to about 8 g of 15-HEPE. and administering 15-HEPE in an amount of at least about 90% by weight of all lipids in the composition. Equivalent to %.

[0012] In yet another aspect, the present disclosure provides a method for treating and / or treating hemoglobin disorders and / or red blood cell disorders. treating hemoglobin abnormalities and / or red blood cell disorders in a subject in need of prevention; and The present invention provides a method for preventing and / or treating a pulmonary embolism, the method comprising administering to a subject a composition comprising up to about 8 g of 15-HEPE. and administering to an elephant, wherein 15-HEPE accounts for at least about 90% of all lipids in the composition. % and subjects have (a) an increased red blood cell count, (b) a decreased red blood cell distribution width, and / or c) Decreased reticulocyte count.

[0013] In various embodiments, the blood disorder, hemoglobin disorder and / or red blood cell disorder is a genetic lytic disorder. Hemolytic anemia, acquired hemolytic anemia, Fanconi anemia, iron deficiency anemia, folic acid deficiency, B12 deficiency and myelodysplastic syndrome.

[0014] In yet another aspect, the present disclosure provides a method for treating and / or preventing hemolytic anemia in a subject in need of such treatment and / or prevention. and a method for treating and / or preventing hemolytic anemia using up to about 8 g of 1 The method comprises administering to a subject a composition comprising 5-HEPE, wherein 15-HEPE is It represents at least about 90% by weight of all lipids.

[0015] In some embodiments, the hemolytic anemia is hereditary hemolytic anemia or acquired hemolytic anemia. In another embodiment, the acquired hemolytic anemia occurs secondary to an infection, from drug treatment, From hematological malignancies, autoimmune diseases, hypersplenism, mechanical heart valve placement, blood transfusions, In yet another embodiment, sickle cell anemia and sickle Sickle cell anemia can be caused by sickle cell crisis, vaso-occlusive crisis, splenic sequestration, or any of these It relates to the combination of

[0016] In some embodiments, the subject has an increased red blood cell count, a decreased red blood cell distribution width, and reticulitis. In some aspects, the present disclosure provides a method for treating and / or administering to a subject a thrombophilic disorder. Methods for treating and / or preventing thrombophilic disorders in a subject in need thereof The method comprises administering 15-HEPE or a composition comprising 15-HEPE to a subject. Includes:

[0017] In another aspect, the present disclosure provides a method for treating and / or preventing thrombophilia in a subject in need thereof. and a method for treating and / or preventing thrombophilia, the method comprising administering up to about 8 g of 1 The method comprises administering to a subject a composition comprising 5-HEPE, wherein 15-HEPE is It represents at least about 90% by weight of all lipids.

[0018] In another aspect, the present disclosure provides a method for treating and / or preventing thrombophilia in a subject in need thereof. and a method for treating and / or preventing thrombophilia, the method comprising administering up to about 8 g of 1 The method comprises administering to a subject a composition comprising 5-HEPE, wherein 15-HEPE is representing at least about 90% of all lipids, and the subject has (a) a prolonged prothrombin time; (b) prolongation of activated partial thromboplastin time, and / or (c) fibrinogen concentration The present invention shows one or more of the following decreases:

[0019] In yet another aspect, the present disclosure provides a method for treating and / or preventing venous thromboembolism in a subject in need of the treatment and / or prevention of venous thromboembolism. The present invention provides a method for treating and / or preventing venous thromboembolism in a subject, the method comprising administering to a subject a dose of up to about The method comprises administering to a subject a composition comprising 8 g of 15-HEPE, wherein the 15-HEPE is It represents at least about 90% by weight of all lipids in the composition.

[0020] In one aspect, the present disclosure provides a method for the treatment and / or prevention of arterial thrombosis in a subject in need thereof. The present invention provides a method for treating and / or preventing vein thrombosis, the method comprising administering up to about 8 g of 15-H The method includes administering to a subject a composition containing 15-HEPE, wherein 15-HEPE is present in all of the composition. It represents at least about 90% by weight of the lipids.

[0021] In another aspect, the present disclosure provides a method for preventing embolism in a subject in need thereof. The method includes administering to a subject a composition comprising up to about 8 g of 15-HEPE. and 15-HEPE represents at least about 90% by weight of all lipids in the composition.

[0022] In some embodiments, the subject has a prolonged prothrombin time, activated partial thromboplastin time, or The results show an increase in the lastin time and a decrease in fibrinogen concentration.

[0023] In another embodiment, the 15-HEPE is in the free acid form, an esterified form, or a salt form. In yet another embodiment, the esterified form is an alkyl ester form or a triglyceride. In some embodiments, 15-HEPE is in the form of 15(S)-HEPE, 1 5(R)-HEPE, or a combination thereof.

[0024] In some embodiments, 15-HEPE is the ethyl ester (15-HEPE EE ), or 15-HEPE is in the form of an optically active ester (15(S)-HEPE EE) form.

[0025] In some embodiments, the composition comprises about 10 mg to about 10,000 mg of 15-HEP In another embodiment, the composition comprises about 1 g to about 2 g of 15-HEPE. In an embodiment, the composition comprises about 2 g or more of 15-HEPE. The composition may be administered at a dose of about 5 mg per kilogram of body weight (mg / kg), about 50 mg / kg, or about 250 mg / kg, or approximately 500 mg / kg of 15-HEPE. In various embodiments, 15-HEPE accounts for at least 1% of all fatty acids present in the composition. This corresponds to approximately 90% by weight.

[0026] In some embodiments, 15-HEPE is administered orally. The composition is administered in 1 to 8 capsules per day. [Brief explanation of the drawings]

[0027] [Figure 1] FIG. 1 is a schematic diagram of the study and its duration described in Example 1.

[0028] [Figure 2]1 shows the changes in animal weight from the study described in Example 1.

[0029] [Figure 3] 1 shows the body weights of the animals on the day of sacrifice according to the study described in Example 1.

[0030] [Figure 4A] 1 shows the kidney weights of animals on the day of sacrifice from the study described in Example 1. [Figure 4B] 1 shows the kidney weight to body weight ratio of animals on the day of sacrifice from the study described in Example 1. [Figure 4C] 1 shows the kidney weights of animals on the day of sacrifice from the study described in Example 1. [Figure 4D] 1 shows the kidney weight to body weight ratio of animals on the day of sacrifice from the study described in Example 1.

[0031] [Figure 5] 1 shows the kidney hydroxyproline content of animals from the study described in Example 1.

[0032] [Figure 6A] 1 shows Sirius Red staining of animals from the study described in Example 1. [Figure 6B] 1 shows Sirius Red staining of animals from the study described in Example 1. [Figure 6C] 1 shows Sirius Red staining of animals from the study described in Example 1. [Figure 6D] 1 shows Sirius Red staining of animals from the study described in Example 1. [Figure 6E] 1 shows Sirius Red staining of animals from the study described in Example 1. [Figure 6F] 1 shows Sirius Red staining of animals from the study described in Example 1. [Figure 6G] 1 shows Sirius Red staining of animals from the study described in Example 1.

[0033] [Figure 7]1 shows a plot showing the % Sirius Red positive area of ​​animals from the study described in Example 1.

[0034] [Figure 8A] 1 shows gene expression analysis for α-SMA in animals from the study described in Example 1. [Figure 8B] 1 shows gene expression analysis for TIMP-1 in animals from the study described in Example 1. [Figure 8C] 1 shows gene expression analysis for TGF-β in animals from the study described in Example 1. [Figure 8D] 1 shows gene expression analysis for type 1 collagen in animals from the study described in Example 1.

[0035] [Figure 9] FIG. 1 is a schematic diagram of the study and its duration described in Example 2.

[0036] [Figure 10] 1 shows the changes in animal weight from the study described in Example 2.

[0037] [Figure 11] 1 shows the body weights of the animals on the day of sacrifice according to the study described in Example 2.

[0038] [Figure 12A] 1 shows the liver weights of the animals on the day of sacrifice according to the study described in Example 2. [Figure 12B] 1 shows the liver weight to body weight ratios of the animals on the day of sacrifice from the study described in Example 2, respectively.

[0039] [Figure 13] 1 shows the changes in serum ALT levels in animals from the study described in Example 2.

[0040] [Figure 14] 1 shows the change in serum total bilirubin levels in animals from the study described in Example 2.

[0041] [Figure 15A] 1 shows Sirius red staining and areas of fibrosis in animals from the study described in Example 2. [Figure 15B] 1 shows Sirius red staining and areas of fibrosis in animals from the study described in Example 2. [Figure 15C] 1 shows Sirius red staining and areas of fibrosis in animals from the study described in Example 2. [Figure 15D] 1 shows Sirius red staining and areas of fibrosis in animals from the study described in Example 2. [Figure 15E] 1 shows Sirius red staining and areas of fibrosis in animals from the study described in Example 2.

[0042] [Figure 16] 1 shows a plot showing the % Sirius Red positive area of ​​animals from the study described in Example 2.

[0043] [Figure 17A] 1A-1C show gene expression analysis for α-SMA in animals from the study described in Example 2, respectively. [Figure 17B] 1 shows gene expression analysis for TIMP-1 in animals from the study described in Example 2, respectively. [Figure 17C] 1A-1C show gene expression analysis for TGF-β in animals from the study described in Example 2, respectively. [Figure 17D] 1A and 1B show gene expression analysis for type 1 collagen in animals from the study described in Example 2, respectively.

[0044] [Figure 18A] 1 shows that DS102 (15-HEPE) induced inhibition of TGF-β, according to the study described in Example 3. [Figure 18B] 1 shows that DS102 (15-HEPE) induced inhibition of TGF-β, according to the study described in Example 3.

[0045] [Figure 18C]1 shows the effect of DS102 on membrane trafficking and degradation of TGF-β type I receptor, TGF-β type II receptor, TGF-β type III receptor, EGFR, and caveolin-1 from the study described in Example 3. [Figure 18D] 1 shows the effect of DS102 on membrane trafficking and degradation of TGF-β type I receptor, TGF-β type II receptor, TGF-β type III receptor, EGFR, and caveolin-1 from the study described in Example 3. [Figure 18E] 1 shows the effect of DS102 on membrane trafficking and degradation of TGF-β type I receptor, TGF-β type II receptor, TGF-β type III receptor, EGFR, and caveolin-1 from the study described in Example 3. [Figure 18F] 1 shows the effect of DS102 on membrane trafficking and degradation of TGF-β type I receptor, TGF-β type II receptor, TGF-β type III receptor, EGFR, and caveolin-1 from the study described in Example 3. [Figure 18G] 1 shows the effect of DS102 on membrane trafficking and degradation of TGF-β type I receptor, TGF-β type II receptor, TGF-β type III receptor, EGFR, and caveolin-1 from the study described in Example 3.

[0046] [Figure 19] FIG. 1 is a schematic diagram of the study and its duration described in Example 4.

[0047] [Figure 20] 1 shows the baseline lipidomic profile of patients from the study described in Example 4.

[0048] [Figure 21A] 1 is a plot showing the change in insulin levels in patients receiving epeleuton (15-HEPE) and placebo, respectively. [Figure 21B] 1 is a plot showing the change in glucose levels in patients administered epeleuton (15-HEPE) and placebo, respectively. [Figure 21C]1 is a plot showing the change in free fatty acid levels in patients administered epeleuton (15-HEPE) and placebo, respectively.

[0049] [Figure 22A] 1 is a plot showing the change in HOMA-IR levels in patients administered epeleuton and placebo, respectively. [Figure 22B] 1 is a plot showing the change in apido-IR levels in patients receiving epeleuton and placebo, respectively.

[0050] [Figure 23A] 1 is a plot showing the change in mean HbA1C levels in patients, respectively. [Figure 23B] 1A and 1B are plots showing the proportion of patients with HbA1C levels ≧6.5% at 16 weeks, respectively.

[0051] [Figure 24A] 1A-1C are plots showing the mean change in lipid profile in patients receiving epeleuton and placebo, respectively. [Figure 24B] 1 is a plot showing the median % change in lipid profile in patients receiving epeleuton and placebo, respectively.

[0052] [Figure 25A] 1 is a plot showing the change in cholesterol levels in patients receiving Epeleuton and placebo, respectively. [Figure 25B] 1A-1C are plots showing the change in triglyceride levels in patients receiving Epeleuton and placebo, respectively. [Figure 25C] 1A-1C are plots showing the change in VLDL-C levels in patients receiving Epeleuton and placebo, respectively.

[0053] [Figure 26]1 is a chart showing changes in hepatotoxic lipid profiles in patients receiving DS102.

[0054] [Figure 27] 1 is a plot demonstrating that administration of DS102 resolves NASH using the OWL Liver Care trial.

[0055] [Figure 28] 1 is a plot showing the change in liver fat content by CAP in patients receiving DS102 and placebo.

[0056] [Figure 29A] 1 is a chart showing changes in levels of inflammatory and profibrotic proteins in patients receiving DS102 and placebo. [Figure 29B] 1 is a chart showing changes in levels of inflammatory and profibrotic proteins in patients receiving DS102 and placebo. [Figure 29C] 1 is a chart showing changes in levels of inflammatory and profibrotic proteins in patients receiving DS102 and placebo.

[0057] [Figure 30] 1 is a plot showing changes in expression of proteins, including NASH development targets, in patients receiving DS102 and placebo.

[0058] [Figure 31] 1 is a volcano plot showing reductions in inflammatory and profibrotic proteins in patients receiving DS102 and placebo.

[0059] [Figure 32] 1 is a plot showing changes in vascular adhesion molecules in patients receiving DS102 and placebo.

[0060] [Figure 33]1 is a plot showing changes in cardiovascular risk proteins in patients receiving DS102 and placebo.

[0061] [Figure 34] 1 is a plot showing changes in chemokines in patients receiving DS102 and placebo.

[0062] [Figure 35] 1 is a plot showing changes in tumor necrosis factor receptor superfamily members in patients receiving DS102 and placebo.

[0063] [Figure 36A] 1 is a plot showing the reduction in ALP levels in patients receiving DS102 and placebo. [Figure 36B] 1 is a plot showing the reduction in ALP levels in patients receiving DS102 and placebo.

[0064] [Figure 37] FIG. 1 is a box plot of 15-HEPE ethyl ester trough plasma relative concentrations.

[0065] [Figure 38A] 1 is a bar graph showing the mean change and standard deviation of red blood cell counts in rats administered 15(S)-HEPE EE and placebo, respectively. [Figure 38B] 1 is a bar graph showing the mean change and standard deviation of red blood cell distribution width in rats administered 15(S)-HEPE EE and placebo, respectively. [Figure 38C] 1 is a bar graph showing the mean change and standard deviation of reticulocyte counts in rats administered 15(S)-HEPE EE and placebo, respectively.

[0066] [Figure 39A] 1 is a bar graph showing the mean change and standard deviation of prothrombin time in rats administered 15(S)-HEPE EE and placebo, respectively. [Figure 39B] 1 is a bar graph showing the mean change and standard deviation of activated partial thromboplastin time in rats administered 15(S)-HEPE EE and placebo, respectively. [Figure 39C] 1 is a bar graph showing the mean change and standard deviation of fibrinogen concentration in rats administered 15(S)-HEPE EE and placebo, respectively. DETAILED DESCRIPTION OF THE INVENTION

[0067] While the present invention may be embodied in many different forms, the following description of some embodiments is provided to illustrate, but not to limit the scope of the present invention. It is understood that the disclosure should be considered as an exemplification of the invention and that the invention may be practiced in accordance with the specific embodiments described. It is understood that the present invention is not intended to be limiting to the embodiments. It is provided for convenience only and should not be construed as limiting the invention in any way. No embodiment shown under any heading may be combined with any embodiment shown under any other heading. can be combined.

[0068] The use of numerical values ​​for various quantitative values ​​specified in this application is intended to be indicative of the intended use unless expressly stated otherwise. Unless otherwise specified, both the minimum and maximum values ​​within a stated range are preceded by the word "about." In this way, slight variations from the stated values ​​can be used. can be used to achieve substantially the same results as the values ​​recited. A continuous range including every value between the minimum and maximum values ​​recited, and It is also intended that any range that can be formed herein be used to compare any recited value with any other range. Any and all ratios (and any or all of the Accordingly, one of ordinary skill in the art will be able to easily identify and interpret many such ratios, ranges, and ratio subranges. Ranges can be clearly derived from the numerical values ​​presented herein, and in all cases, such It will be understood that the ratios, ranges, and ratio ranges represent various embodiments of the present invention.

[0069] Unless otherwise defined, all technical and scientific terms used herein are defined by the principles of the present disclosure. It has the same meaning as commonly understood by one of ordinary skill in the art to which it pertains. Methods and materials similar or equivalent to those described herein can be used. However, suitable methods and materials are described below. All publications, patent applications and other references cited herein are incorporated by reference. All patents, patents, and other references are expressly incorporated by reference in their entirety. In the event that the present specification, including definitions, prevails, the materials, methods, and The examples are illustrative only and are not intended to be limiting.

[0070] definition As used herein, "15-HEPE" refers to 15-hydroxy-eicosa-5Z ,8Z,11Z,13E,17Z-pentaenoic acid. 15-HEPE is 15-OH Eicosapentaenoic acid, also known as EPA, an omega-3 fatty acid, can be prepared according to methods known in the art. Pentaenoic acid (EPA, eicosa-5,8,11,14,17-pentaenoic acid or 2 0:5n-3). For example, 15-HEPE can be synthesized by catalyzing EPA with the enzyme 15-lipoic acid. As used herein, the term "protein" refers to a protein that can be synthesized by exposure to xygenase. The term "15-HEPE" refers to 15-HEPE in its free acid form (e.g., 15-hepa). hydroxy-eicosa-5Z,8Z,11Z,13E,17Z-pentaenoic acid) and / or a pharmaceutically acceptable ester, conjugate or salt thereof, or a mixture of any of the foregoing; Alternatively, derivatives of 15-HEPE may be used, including 15-HE It does not include any derivative compounds that lack the hydroxy group of PE. 5-HEPE is used in its free acid form. Alternatively, in this disclosure, 15-HEPE A pharmaceutically acceptable ester or salt is used. In some embodiments, 15-HE PE is a methyl ester, an ethyl ester, or a combination of a methyl ester and an ethyl ester. Combination C 1~4 In yet another embodiment, 15-HE is in the form of an alkyl ester. PE is in the form of a glyceride (e.g., a diglyceride or a triglyceride). In embodiments, the 15-HEPE is in the form of an ethyl ester (referred to herein as E-15 15-HEPE, also known as 15-HEPEEE, or ethyl-15-HEPE).

[0071] 15-HEPE is a chiral molecule and exists in either the (S)- or (R)-enantiomeric form. As used herein, "15-HEPE" may be used as a racemic mixture. In another embodiment, 15 includes all such forms without limitation as to stereospecificity. -HEPE is in the (S) form: 15(S)-hydroxy-(5Z, 8Z, 11Z, 13E, 17Z)-Eicosapentaenoic acid or (R) form ((R)from): 15(R)-Hydroxy It also contains hydroxy-(5Z,8Z,11Z,13E,17Z)-eicosapentaenoic acid. In another embodiment, 15-HEPE EE is in the (S) form: 15(S)-HEPE EE Includes.

[0072] As used herein, "DS102" refers to 15-HEPE, 15-HEPE EE , a composition containing 15-HEPE, a composition containing 15-HEPE EE, or 15-HEP E and 15-HEPE EE.

[0073] As used herein, "Epeleuton" refers to 15-HEPE, 15-HEP E EE, a composition containing 15-HEPE, a composition containing 15-HEPE EE, or 15 This refers to a composition containing 15-HEPE and 15-HEPE EE.

[0074] As used herein, the term "treating" or "curing" a disease, disorder, or condition refers to "Treatment" means, at least in part, (1) a treatment for a disease, disorder, or condition ( inhibiting a disease, disorder, or condition, i.e., (2) halting or reducing the progression of a disease (di alleviating a disease, disorder, or condition, i.e., a disease, This includes causing the regression of a disorder or condition or its clinical symptoms. The term "prevention" in relation to a given disease or disorder means preventing disease progression if nothing occurs. to prevent the onset of a disorder or disease, and to prevent the onset of a disorder or disease in individuals who may be predisposed to the disorder or disease but who are still young or have the disorder. or to prevent a disease or disorder from occurring in a subject who has not been diagnosed with the disease. and / or if already suffering from a disease or disorder, to prevent further progression of the disease / disorder. It means to do.

[0075] As used herein, an "effective amount" is the amount required to confer a therapeutic effect on a subject. As used herein, a "therapeutically effective amount" refers to the amount of active compound that is effective in treating the disease being treated. relieve to some extent one or more of the symptoms of a disease, disorder, or condition In some embodiments, the result is , reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other adverse effect on a biological system. For example, in some embodiments, an "effective amount" for therapeutic use is is required to provide a clinically significant reduction in disease symptoms without undue adverse side effects. In some embodiments, the amount of a composition comprising a compound disclosed herein is An appropriate "effective amount" in any individual case may be determined using techniques, such as a dose escalation study. The term "therapeutically effective amount" includes, for example, a prophylactically effective amount. In another embodiment, An "effective amount" of a compound disclosed herein, such as a compound of formula (A) or formula (I), does not include an excessively effective amount. an amount effective to achieve the desired pharmacological effect or therapeutic improvement without adverse side effects. In another embodiment, an "effective amount" or "therapeutically effective amount" is determined based on the subject's metabolism, age, weight, and overall the underlying condition, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician It is understood that variability will vary from subject to subject. The term "to be" refers to the substance in question that is unacceptably toxic to the subject or to other components of the composition. This means that it does not produce any interaction with the substance.

[0076] Other features and advantages of the present disclosure will become apparent from the following detailed description.

[0077] composition In one embodiment, the compositions of the present disclosure comprise 15-HEPE as an active ingredient. The term "pharmaceutically acceptable" in this context means that the substance in question is not unacceptable to the subject. This means that it does not produce toxicity or interact with other components of the composition.

[0078] In one embodiment, the 15-HEPE is in the form of an ester (referred to herein as E-15 (Also referred to as ethyl-15-HEPE, ethyl-15-HEPE, or 15-HEPE EE). In some forms, 15-HEPE includes C1-C5 alkyl esters of 15-HEPE. In embodiments, 15-HEPE is 15-HEPE methyl ester, 15-HEPE pro In yet another embodiment, the 15-HEPE may be a butyl ester or a butyl ester of 15-HEPE. -HEPE is an optically active 15(S)-hydroxy-(5Z, 8Z, 11Z, 13E, 17 Z)-eicosapentaenoic acid. This isomer may be used in any of the forms described above. do.

[0079] In another embodiment, the 15-HEPE is lithium 15-HEPE, mono-, di-, or is the triglyceride 15-HEPE, or any other ester or salt of 15-HEPE , or the free acid form of 15-HEPE.

[0080] In various embodiments, the present disclosure provides pharmaceutical compositions, e.g., orally deliverable compositions, comprising 15- In one embodiment, the composition comprises a therapeutically effective amount of 15-HEPE. In embodiments, the pharmaceutical composition comprises from about 0.1% to about 99% by weight, from about 1% to about 95% by weight , and contains about 5% to about 90% by weight of 15-HEPE. The phrases "composition" and "pharmaceutical composition" are used interchangeably.

[0081] In one embodiment, the pharmaceutical composition comprises at least about 70% by weight, at least about 80% by weight, or at least about 90% by weight of 15-HEPE. In one embodiment, the pharmaceutical composition comprises: At least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least The composition also contains about 80% by weight, or at least about 90% by weight, of 15-HEPE.

[0082] In another embodiment, 15-HEPE is from about 1 mg to about 10,000 mg, from about 25 mg to about 10,000 mg, Approx. 7500mg, approx. 25mg to approx. 5000mg, approx. 50mg to approx. 5000mg, approx. 50m g to about 3000 mg, about 75 mg to about 2500 mg, or about 100 mg to about 1000 mg , for example, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, Approximately 8 mg, approximately 9 mg, approximately 10 mg, approximately 11 mg, approximately 12 mg, approximately 13 mg, approximately 14 mg, Approximately 15mg, approximately 16mg, approximately 17mg, approximately 18mg, approximately 19mg, approximately 20mg, approximately 21m g, approx. 22 mg, approx. 23 mg, approx. 24 mg, approx. 25 mg, approx. 50 mg, approx. 75 mg, approx. 1 00mg, about 125mg, about 150mg, about 175mg, about 200mg, about 225mg, Approx. 250mg, approx. 275mg, approx. 300mg, approx. 325mg, approx. 350mg, approx. 375m g, approx. 400mg, approx. 425mg, approx. 450mg, approx. 475mg, approx. 500mg, approx. 52 5mg, approximately 550mg, approximately 575mg, approximately 600mg, approximately 625mg, approximately 650mg, approximately 675mg, about 700mg, about 725mg, about 750mg, about 775mg, about 800mg , about 825mg, about 850mg, about 875mg, about 900mg, about 925mg, about 950 mg, approx. 975mg, approx. 1000mg, approx. 1025mg, approx. 1050mg, approx. 1075m g, about 1100mg, about 1025mg, about 1050mg, about 1075mg, about 1200m g, about 1225mg, about 1250mg, about 1275mg, about 1300mg, about 1325mg g, about 1350mg, about 1375mg, about 1400mg, about 1425mg, about 1450mg g, about 1475mg, about 1500mg, about 1525mg, about 1550mg, about 1575mg g, about 1600mg, about 1625mg, about 1650mg, about 1675mg, about 1700m g, about 1725mg, about 1750mg, about 1775mg, about 1800mg, about 1825mg g, about 1850mg, about 1875mg, about 1900mg, about 1925mg, about 1950mg g, about 1975mg, about 2000mg, about 2025mg, about 2050mg, about 2075mg g, about 2100mg, about 2125mg, about 2150mg, about 2175mg, about 2200m g, about 2225mg, about 2250mg, about 2275mg, about 2300mg, about 2325mg g, about 2350mg, about 2375mg, about 2400mg, about 2425mg, about 2450mg g, about 2475mg, about 2500mg, 2525mg, about 2550mg, about 2575mg , about 2600mg, about 2625mg, about 2650mg, about 2675mg, about 2700mg , about 2725mg, about 2750mg, about 2775mg, about 2800mg, about 2825mg , about 2850mg, about 2875mg, about 2900mg, about 2925mg, about 2950mg , about 2975mg, about 3000mg, about 3025mg, about 3050mg, about 3075mg , about 3100mg, about 3125mg, about 3150mg, about 3175mg, about 3200mg , about 3225mg, about 3250mg, about 3275mg, about 3300mg, about 3325mg , about 3350mg, about 3375mg, about 3400mg, about 3425mg, about 3450mg , about 3475mg, about 3500mg, about 3525mg, about 3550mg, about 3575mg , about 3600mg, about 3625mg, about 3650mg, about 3675mg, about 3700mg , about 3725mg, about 3750mg, about 3775mg, about 3800mg, about 3825mg , about 3850mg, about 3875mg, about 3900mg, about 3925mg, about 3950mg , about 3975mg, about 4000mg, about 4025mg, about 4050mg, about 4075mg , about 4100mg, about 4125mg, about 4150mg, about 4175mg, about 4200mg , about 4225mg, about 4250mg, about 4275mg, about 4300mg, about 4325mg , about 4350mg, about 4375mg, about 4400mg, about 4425mg, about 4450mg , about 4475mg, about 4500mg, about 4525mg, about 4550mg, about 4575mg , about 4600mg, about 4625mg, about 4650mg, about 4675mg, about 4700mg , about 4725mg, about 4750mg, about 4775mg, about 4800mg, about 4825mg , about 4850mg, about 4875mg, about 4900mg, about 4925mg, about 4950mg , about 4975mg, about 5000mg, about 5025mg, about 5050mg, about 5075mg , about 5100mg, about 5125mg, about 5150mg, about 5175mg, about 5200mg , about 5225mg, about 5250mg, about 5275mg, about 5300mg, about 5325mg , about 5350mg, about 5375mg, about 5400mg, about 5425mg, about 5450mg , about 5475mg, about 5500mg, about 5525mg, about 5550mg, about 5575mg , about 5600mg, about 5625mg, about 5650mg, about 5675mg, about 5700mg , about 5725mg, about 5750mg, about 5775mg, about 5800mg, about 5825mg , about 5850mg, about 5875mg, about 5900mg, about 5925mg, about 5950mg , about 5975mg, about 6000mg, about 6025mg, about 6050mg, about 6075mg , about 6100mg, about 6125mg, about 6150mg, about 6175mg, about 6200mg , about 6225mg, about 6250mg, about 6275mg, about 6300mg, about 6325mg , about 6350mg, about 6375mg, about 6400mg, about 6425mg, about 6450mg , about 6475mg, about 6500mg, about 6525mg, about 6550mg, about 6575mg , about 6600mg, about 6625mg, about 6650mg, about 6675mg, about 6700mg , about 6725mg, about 6750mg, about 6775mg, about 6800mg, about 6825mg , about 6850mg, about 6875mg, about 6900mg, about 6925mg, about 6950mg , about 6975mg, about 7000mg, about 7025mg, about 7050mg, about 7075mg , about 7100mg, about 7125mg, about 7150mg, about 7175mg, about 7200mg , about 7225mg, about 7250mg, about 7275mg, about 7300mg, about 7325mg , about 7350mg, about 7375mg, about 7400mg, about 7425mg, about 7450mg , about 7475mg, about 7500mg, about 7525mg, about 7550mg, about 7575mg , about 7600mg, about 7625mg, about 7650mg, about 7675mg, about 7700mg , about 7725mg, about 7750mg, about 7775mg, about 7800mg, about 7825mg , about 7850mg, about 7875mg, about 7900mg, about 7925mg, about 7950mg , about 7975mg, about 8000mg, about 8025mg, about 8050mg, about 8075mg , about 8100mg, about 8125mg, about 8150mg, about 8175mg, about 8200mg , about 8225mg, about 8250mg, about 8275mg, about 8300mg, about 8325mg , approximately 8350mg, approximately 8375mg, approximately 8400mg, approximately 8425mg, approximately 8450mg , about 8475mg, about 8500mg, about 8525mg, about 8550mg, about 8575mg , about 8600mg, about 8625mg, about 8650mg, about 8675mg, about 8700mg , about 8725mg, about 8750mg, about 8775mg, about 8800mg, about 8825mg , about 8850mg, about 8875mg, about 8900mg, about 8925mg, about 8950mg , about 8975mg, about 9000mg, about 9025mg, about 9050mg, about 9075mg , about 9100mg, about 9125mg, about 9150mg, about 9175mg, about 9200mg , about 9225mg, about 9250mg, about 9275mg, about 9300mg, about 9325mg , about 9350mg, about 9375mg, about 9400mg, about 9425mg, about 9450mg , about 9475mg, about 9500mg, about 9525mg, about 9550mg, about 9575mg , about 9600mg, about 9625mg, about 9650mg, about 9675mg, about 9700mg , about 9725mg, about 9750mg, about 9775mg, about 9800mg, about 9825mg , about 9850mg, about 9875mg, about 9900mg, about 9925mg, about 9950mg , about 9975 mg, or about 10,000 mg.

[0083] In one embodiment, the 15-HEPE present in the composition of the present disclosure is at least about 90 times % by weight of 15-HEPE (the term "15-HEPE" is defined and exemplified herein). The 15-HEPE composition may further comprise 15-HEPE of higher purity, e.g., at least It may contain about 95% by weight of 15-HEPE, or at least about 97% by weight of 15-HEPE. , 15-HEPE is any form of 15-HEPE described herein. The purity of PE may be further defined by any of the descriptions of 15-HEPE provided herein. It is possible to obtain a profile (e.g., impurity profile).

[0084] The above discusses the amount of 15-HEPE in the pharmaceutical composition and its purity. The properties and their synthesis indicate that 15-HEPE compounds play a key role in the essential fatty acid metabolic cascade. Such fatty acids may contain moieties from other essential fatty acids.

[0085] In one embodiment, the compositions of the present invention contain up to about 10% by weight, up to about 9% by weight, up to about 8% by weight Below about 7% by weight, below about 6% by weight, below about 5% by weight, below about 4% by weight, about 3% by weight about 2% by weight or less, about 1% by weight or less, or about 0.5% by weight or less of alpha-linolenic acid, stearyl alcohol, Other omega-3 fatty acids such as aridonic acid, docosahexaenoic acid (DHA), or their derivatives In other embodiments, such other omega-3 fatty acids are substantially absent or does not exist.

[0086] In another embodiment, 15-HEPE represents a minority of all fatty acids present in the compositions of the present disclosure. at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least About 90% by weight, at least about 95% by weight, at least about 97% by weight, at least about 98% by weight %, at least about 99% by weight, or 100% by weight.

[0087] In one embodiment, the salt form of 15-HEPE present in the composition of the present invention is at least Contains 90% by weight of a salt form of 15-HEPE. Composition containing a salt form of 15-HEPE may have a higher purity, for example, at least 91% by weight, at least 92% by weight, at least 93% by weight, at least 94% by weight, at least 95% by weight, at least 96% by weight, or may contain at least 97% by weight of the salt form of 15-HEPE.

[0088] Some residual eicosapentaenoic acid from the synthesis of 15-HEPE may be present. About 10% by weight or less, about 9% by weight or less, about 8% by weight or less, about 7% by weight or less, about 6% by weight or less, about 5% or less, about 4% or less, about 3% or less, about 2% or less, about 1% or less, or about 0.5 times % or less of EPA may be present, or may not be modified to the hydroxyl form. Substantially no or no EPA in its pure form.

[0089] In one embodiment, the present disclosure provides 15-HEPE or a derivative thereof encapsulated in a capsule shell. In one embodiment, the composition is administered in an amount of up to about 1 g, about 2 g, about 3 g, about 4 g, about 5 g, about 6 g, about 7 g, about 8 g, about 9 g, or about 10 g In one embodiment, the subject is administered an amount sufficient to provide HEPEE or a derivative thereof. The composition may be administered in an amount of about 4 g to about 8 g, about 1 g to about 2 g, about 2 g to about 4 g, or about 3 g to about 4 g per day. about 8 g, about 4 g to about 6 g of 15-HEPE or its derivatives. In one embodiment, about 500 mg to about 1 g of 15-HEPE or a derivative thereof is administered. is enclosed in a capsule shell.

[0090] In one embodiment, the capsule shell is made of gelatin (e.g., a gelatin having a lower molecular weight). In another embodiment, the capsule shell comprises gelatin (RXL or lime bone gelatin). by proteolytic enzymes to cleave the pattern and effectively reduce its molecular weight. In another embodiment, the pharmaceutical composition comprises processed gelatin RXL. and 15-HEPE ester of 1,4-sorbitan. The gel contains (a) gelatin and (b) one of D-sorbitol and 1,4-sorbitan. and a plasticizer selected from one or more of the gelatin disclosed in U.S. Pat. and gelatin as described in US Pat. No. 4,855,323, the entire contents of which are incorporated herein by reference. be incorporated into the book.

[0091] In one embodiment, the plasticizer is present in an amount of about 20% to about 30%, for example, about 24% to about 28%, %, or 28% (on a dry basis) of 1,4-sorbitan, and about 30% to about 50%, For example, it contains about 35% to about 45% (on a dry basis) D-sorbitol.

[0092] In some embodiments, the capsule is a hard gelatin capsule. The capsules are soft gelatin capsules.

[0093] In some embodiments, the capsule shell is made of modified starch, carrageenan (e.g., red algae extract), disodium phosphate, glycerol, and / or sorbitol. In some embodiments, the capsule shell further comprises water. The capsule shell is stable up to a temperature of about 65°C and / or a pH of about 12.

[0094] In some embodiments, the capsule shell is odorless and neutral in color (e.g., colorless, white). , or transparent).

[0095] In some embodiments, the capsule shell comprises glycerol, purified water, titanium dioxide, It also contains medium chain triglycerides and lecithin.

[0096] Additional activators In one embodiment, the pharmaceutical composition further comprises one or more additional active agents. In some cases, the pharmaceutical composition may contain an additional amount of the active agent that is less than the generally recognized therapeutically effective amount. In one embodiment, the pharmaceutical composition comprises a commonly recognized therapeutic agent for the active agent. The additional active agent, if used, may be in an amount greater than or equal to an effective amount of 15-HEPE. may be formulated together as a single dosage unit, or may be administered in concert, in combination, or It may be formulated as two or more dosage units for simultaneous administration.

[0097] EPA itself has beneficial properties for the treatment of fatty liver disease and / or cardiovascular disease, making it an alternative In an embodiment, 15-HEPE can be combined with EPA.

[0098] In one embodiment, 15-HEPE and one or more active agents are present in the composition of the present disclosure. or about 1:1000 to about 1000:1, about 1:500 to about 500:1, or about 1:10 0 to approx. 100:1, approx. 1:50 to approx. 50:1, approx. 1:25 to approx. 25:1, approx. 1:10 to approx. 10:1, approx. 1:5 to approx. 5:1, approx. 1:4 to approx. 4:1, approx. 1:3 to approx. 3:1, approx. 1:2 or more The co-administration is at a weight ratio of about 2:1, or about 1:1, of 15-HEPE:additional active agent.

[0099] Dosage form Compositions for use in accordance with the present disclosure may be formulated as one or more dosage units. As used herein, the terms "dose unit" and "administration unit" refer to a single dose of a compound to provide a therapeutic effect. Such a dosage unit refers to a portion of a composition containing an amount of a therapeutic agent suitable for a single administration of 1 One to multiple times per day (e.g., 1 to about 10 times, 1 to 8 times, 1 to 6 times, 1 to 4 times, or 1 2 times), or as many times as needed to elicit a therapeutic response.

[0100] In some embodiments, the compositions of the present disclosure are in the form of orally deliverable dosage forms or dosage units. Non-limiting examples of suitable dosage forms include tablets (e.g., suspension tablets, bite suspension tablets, fast-dispersing tablets, chewable tablets, etc.), caplets, capsules (e.g., soft or hard gelatin capsules or HPMC capsules), lozenges, sachets, cachets, troches, pens a drop, suspension, elixir, syrup, or any other solid reasonably adapted for oral administration As used herein, the terms "oral delivery" and "oral administration" refer to oral administration. Any agent or composition placed in the mouth of a subject being treated, whether or not embedded in the mouth. This therefore includes buccal and sublingual administration as well as esophageal administration. nothing.

[0101] Alternatively, the compositions of the present disclosure can also be administered rectally, topically, or parenterally (e.g., subcutaneously, intramuscularly, It can be formulated for delivery (intravenous and intradermal or infusion).

[0102] When considering the amount of 15-HEPE in the compositions of the present disclosure, it is important to consider the amount of 15-HEPE divided into several dosage forms. There is a limit to the size for oral administration. If EPE is administered, this can be up to four capsules, each weighing approximately 1g, 15- Provide HEPE.

[0103] The compositions of the present disclosure may be in the form of a liquid dosage form or a dosage unit for direct absorption, or can be mixed with food or beverages prior to ingestion. Non-limiting examples of suitable liquid dosage forms include: Examples include solutions, suspensions, elixirs, syrups, liquid aerosol formulations, and the like.

[0104] In another embodiment, the compositions of the present disclosure comprise one or more pharmaceutically acceptable excipients. The term "pharmaceutically acceptable excipient" as used herein refers to a substance that is not itself a therapeutic agent. or as a carrier or vehicle for delivering a therapeutic agent to a subject. Added to the composition to improve handling or storage characteristics, or for use in a unit of the composition added to the composition to enable or facilitate the formation of a large amount and which has unacceptable toxicity or It means any substance that does not produce interactions with other components in the composition. The pharmaceutical compositions according to the present disclosure may contain additives such as antioxidants, surfactants, preservatives, flavoring agents, co-solvents, viscosity enhancers, and the like. It may include one or more of an auxiliary agent, a suspending aid, and a lipophilic phase.

[0105] In one embodiment, the pharmaceutical composition comprises ascorbic acid, palmitic acid, ascorbic acid palmitate, Irubilic acid, α-tocopherol, idebenone, ubiquinone, ferulic acid, coenzyme Q10, Copene, green tea, catechin, epigallocatechin 3-gallate (EGCG), green tea polypheno GTP, silymarin, coffee berry, resveratrol, grape seed, pomegranate Contains one or more antioxidants such as extracts, genisten, pycnogenol, and niacinamide. In one embodiment, the pharmaceutical composition contains from about 0.01% to about 2% by weight of an antioxidant, e.g. , about 0.01% by weight, about 0.02% by weight, about 0.03% by weight, about 0.04% by weight, about 0. 05% by weight, approximately 0.06% by weight, approximately 0.07% by weight, approximately 0.08% by weight, approximately 0.09% by weight %, about 0.1% by weight, about 0.11% by weight, about 0.12% by weight, about 0.13% by weight, about 0. 14% by weight, approximately 0.15% by weight, approximately 0.16% by weight, approximately 0.17% by weight, approximately 0.18% by weight %, approximately 0.19% by weight, approximately 0.2% by weight, approximately 0.21% by weight, approximately 0.22% by weight, approximately 0. 23% by weight, approximately 0.24% by weight, approximately 0.25% by weight, approximately 0.26% by weight, approximately 0.27% by weight %, about 0.28% by weight, about 0.29% by weight, about 0.3% by weight, about 0.31% by weight, about 0. 32% by weight, approximately 0.33% by weight, approximately 0.34% by weight, approximately 0.35% by weight, approximately 0.36% by weight %, approximately 0.37% by weight, approximately 0.38% by weight, approximately 0.39% by weight, approximately 0.4% by weight, approximately 0. 41% by weight, approximately 0.42% by weight, approximately 0.43% by weight, approximately 0.44% by weight, approximately 0.45% by weight %, approx. 0.46 wt%, approx. 0.47 wt%, approx. 0.48 wt%, approx. 0.49 wt%, approx. 0 .5% by weight, approximately 0.51% by weight, approximately 0.52% by weight, approximately 0.53% by weight, approximately 0.54% by weight %, approx. 0.55 wt%, approx. 0.56 wt%, approx. 0.57 wt%, approx. 0.58 wt%, approx. 0 .59% by weight, approximately 0.6% by weight, approximately 0.61% by weight, approximately 0.62% by weight, approximately 0.63% by weight %, approx. 0.64 wt%, approx. 0.65 wt%, approx. 0.66 wt%, approx. 0.67 wt%, approx. 0 .68% by weight, approximately 0.69% by weight, approximately 0.7% by weight, approximately 0.71% by weight, approximately 0.72% by weight %, approx. 0.73 wt%, approx. 0.74 wt%, approx. 0.75 wt%, approx. 0.76 wt%, approx. 0 .77% by weight, approximately 0.78% by weight, approximately 0.79% by weight, approximately 0.8% by weight, approximately 0.81% by weight %, approx. 0.82 wt%, approx. 0.83 wt%, approx. 0.84 wt%, approx. 0.85 wt%, approx. 0 .86% by weight, approximately 0.87% by weight, approximately 0.88% by weight, approximately 0.89% by weight, approximately 0.9% by weight %, approx. 0.91 wt%, approx. 0.92 wt%, approx. 0.93 wt%, approx. 0.94 wt%, approx. 0 .95% by weight, approximately 0.96% by weight, approximately 0.97% by weight, approximately 0.98% by weight, approximately 0.99% by weight Amount%, approximately 1% by weight, approximately 1.1% by weight, approximately 1.2% by weight, approximately 1.3% by weight, approximately 1.4% by weight , about 1.5% by weight, about 1.6% by weight, about 1.7% by weight, about 1.8% by weight, about 1.9% by weight , or about 2% by weight of one or more antioxidants.

[0106] Treatment method The compositions and formulations disclosed herein are useful for treating and / or preventing blood disorders. In some embodiments, the compounds may be used to treat and / or prevent blood disorders in elephants. Fluid disorders include hemoglobin abnormalities, red blood cell disorders, hemolytic anemia, thrombosis tendency disorders, and venous thrombosis. In some embodiments, the cause of the thrombosis is a thrombosis, an arterial thrombosis, an embolism, or a combination thereof. The method involves administering 15-hydroxyeicosapentaenoic acid (15-HEPE) or 15-hydroxyeicosapentaenoic acid (15-HEPE) to a subject. The method includes administering a composition containing 15-hydroxyeicosapentaenoic acid (15-HEPE).

[0107] The compositions and formulations disclosed herein are useful for treating blood disorders, hemoglobin disorders, and / or red blood It can be used to treat and / or prevent hematologic disorders. Hematologic disorders affect the blood and blood-forming organs. Hemoglobin disorders and red blood cell disorders are similar to blood disorders. However, both hemoglobin disorders and red blood cell disorders define narrower classifications of diseases. Generally, hemoglobinopathy refers to a defect in hemoglobin, the oxygen-carrying protein in red blood cells. Red blood cell disorders refer to defects in the red blood cells themselves. Blood disorders, hemoglobin abnormalities, and red blood cell Non-limiting examples of risk factors for the disorder include low red blood cell count, increased red blood cell distribution width, and Increased reticulocyte count. Unlimited blood disorders, hemoglobin abnormalities, and red blood cell disorders. Typical examples include anemia (nutritional and non-nutritional anemia, sickle cell disease, sickle cell anemia) Hereditary hemolytic anemias such as beta-thalassemia and hereditary spherocytosis, infections, drug treatments, Occurs in association with hematologic malignancies, autoimmune diseases, hypersplenism, mechanical heart valves, and blood transfusions Acquired hemolytic anemia, Fanconi anemia, iron deficiency anemia), blood cancers (lymphoma, leukemia) and myeloma), coagulation disorders (thrombophilia, hemophilia, von Willebrand disease, and hemoglobinuria) thrombocytopenia), folate deficiency, B12 deficiency, and myelodysplastic syndrome. In some embodiments, sickle cell disease and sickle cell anemia are characterized by sickle cell crisis, vaso-occlusion, associated with idiopathic crisis and / or splenic sequestration.

[0108] In some embodiments, the subject is at least 10% below the standard, at least 10% above the standard, 15% below standard, at least 20% below standard, at least 25% below standard , or have a red blood cell count at least 30% below normal.

[0109] In some embodiments, the subject has an increased red blood cell distribution width, with red blood cells having a size of about 15-20%, approximately 20-25%, approximately 25-30%, approximately 30-35%, or approximately 35-40% It fluctuates.

[0110] In another embodiment, the subject has at least about 5% of the total red blood cell mass, at least about 5% of the total red blood cell mass, at least about 10%, at least about 15%, or at least about 2% of the total amount of red blood cells 0% with an increased reticulocyte count.

[0111] In some embodiments, the subject has a blood glucose level of between about 135 mg / dL and about 2000 mg / dL, e.g., For example, about 135 mg / dL to about 500 mg / dL, about 150 mg / dL to about 500 mg / dL L, approx. 200mg / dL ~ approx. 499mg / dL, approx. 200mg / dL ~ <500mg / d L, approx. 300mg / dL ~ approx. 1800mg / dL, approx. 500mg / dL ~ approx. 1500mg / dL, about 500mg / dL to about <2000mg / dL, or about 500mg / dL to about 2 000 mg / dL. In embodiments, the subject has a blood cholesterol level of about 50 mg / dL to about 2000 mg / dL, e.g., about 50 mg / dL ~ approx. 1500mg / dL, approx. 80mg / dL ~ approx. 1500mg / dL, approx. 50mg / dL ~ approx. 190mg / dL, approx. 80mg / dL ~ approx. 190mg / dL, approx. 190mg / dL ~ approx. 250mg / dL, approx. 250mg / dL ~ approx. 1400mg / dL, approx. 500mg / dL ~ approx. 1200mg / dL, approx. 500mg / dL ~ approx. 1500mg / dL, approx. 500 mg / dL to approximately <2000 mg / dL, or approximately 500 mg / dL to approximately 2000 mg / dL In one embodiment, the subject has a fasting baseline triglyceride level of about Fasting baseline triglyceride levels of 80 mg / dL to approximately 1400 mg / dL In some embodiments, the subject or group of subjects has a blood glucose level of about 50 mg / dL, about 55 mg / dL, about 60mg / dL, about 65mg / dL, about 70mg / dL, about 75mg / dL, Approx. 80mg / dL, approx. 85mg / dL, approx. 90mg / dL, approx. 95mg / dL, approx. 100 mg / dL, about 105 mg / dL, about 110 mg / dL, about 115 mg / dL, about 120 mg / dL, about 125 mg / dL, about 130 mg / dL, about 135 mg / dL, about 140 mg / dL, about 145 mg / dL, about 150 mg / dL, about 155 mg / dL, about 160 mg / dL, about 165 mg / dL, about 170 mg / dL, about 175 mg / dL, about 180 mg / dL, about 185 mg / dL, about 190 mg / dL, about 195 mg / dL, about 200 mg / dL, about 205 mg / dL, about 210 mg / dL, about 215 mg / dL, about 220 mg / dL, about 225 mg / dL, about 230 mg / dL, about 235 mg / dL, about 240 mg / dL, about 245 mg / dL, about 250 mg / dL, about 255 mg / dL, about 260 mg / dL, about 265 mg / dL, about 270 mg / dL, about 275 mg / dL, about 280 mg / dL, about 285 mg / dL, about 290 mg / dL, about 295 mg / dL, about 300 mg / dL, about 305 mg / dL, about 310 mg / dL, about 315 mg / dL, about 320 mg / dL, about 325 mg / dL, about 330 mg / dL, about 335 mg / dL, about 340 mg / dL, about 345 mg / dL, about 350 mg / dL, about 355 mg / dL, about 360 mg / dL, about 365 mg / dL, about 370 mg / dL, about 375 mg / dL, about 380 mg / dL, about 385 mg / dL, about 390 mg / dL, about 395 mg / dL, about 400 mg / dL, about 405 mg / dL, about 410 mg / dL, about 415 mg / dL, about 420 mg / dL, about 425 mg / dL, about 430 mg / dL, about 435 mg / dL, about 440 mg / dL, about 445 mg / dL, about 450 mg / dL, about 455 mg / dL, about 460 mg / dL, approx. 465 mg / dL, approx. 470 mg / dL, approx. 475 mg / dL, approx. 480 mg / dL, approx. 485 mg / dL, approx. 490 mg / dL, approx. 495 mg / dL, approx. 500 mg / dL, approx. 1000mg / dL, approx. 1100mg / dL, approx. 1200mg / dL, approx. 1300mg / dL, approx. 1400mg / dL, approx. 1500mg / dL, approx. 2000mg / dL, approx. 2500mg / dL, approx. 3000mg / dL, approx. 3500mg / dL, approx. 400 0 mg / dL, about 4500 mg / dL, about 5000 mg / dL, or about 5000 mg / dL Fed or fasting baseline triglyceride levels (or baseline triglycerides in the control group) of >1 L In some embodiments, the subject has a median baseline triglyceride level. Or the control group is 80 mg / dL or more, approximately 100 mg / dL or more, approximately 120 mg / dL or more , about 150 mg / dL or more, about 175 mg / dL or more, about 250 mg / dL or more, about 50 0 mg / dL or more, for example, about 190 mg / dL to about 250 mg / dL, about 80 mg / dL L ~ approx. 190mg / dL, approx. 250mg / dL ~ approx. 1400mg / dL, approx. 200mg / dL ~ approx. 500mg / dL, approx. 300mg / dL ~ approx. 1800mg / dL, approx. 500mg / dL ~ approx. 1500mg / dL, approx. 80mg / dL ~ approx. 1500mg / dL, approx. 80mg / dL to less than approximately 2000mg / dL, approximately 80mg / dL to approximately 2000mg / dL, approximately 50 0 mg / dL to less than about 2000 mg / dL, or about 500 mg / dL to about 2000 mg / Baseline fed or fasting triglyceride levels in dL (or baseline triglyceride levels in the control group) have median baseline triglyceride levels.

[0112] In another embodiment, the subject has a blood pressure of at least about 100 mmHg, at least about 115 mmHg g, at least about 120 mmHg, at least about 125 mmHg, at least about 130 m mHg, at least about 135 mmHg, at least about 140 mmHg, at least about 14 5mmHg, at least about 150mmHg, at least about 155mmHg, at least about an increase of 160 mmHg, at least about 165 mmHg, or at least about 170 mmHg Have a consistent baseline blood pressure.

[0113] In some embodiments, the subject has a blood glucose level of at least about 100 mg / dL, at least about 11 5 mg / dL, at least about 120 mg / dL, at least about 125 mg / dL, or less at least about 130 mg / dL, at least about 135 mg / dL, and at least about 140 mg / dL L, at least about 145 mg / dL, at least about 150 mg / dL, at least about 15 5 mg / dL, at least about 160 mg / dL, at least about 165 mg / dL, or less Have an elevated baseline fasting blood glucose level of at least about 170 mg / dL.

[0114] In some embodiments, the subject has a blood glucose level of less than about 60 mg / dL, less than about 55 mg / dL, less than about Less than 50 mg / dL, less than about 45 mg / dL, less than about 40 mg / dL, about 35 mg / dL Less than about 30 mg / dL, less than about 25 mg / dL, less than about 20 mg / dL, less than about 15 m Decreased baseline Hg < about 10 mg / dL, < about 5 mg / dL Has DL-C level.

[0115] In some aspects, the present disclosure provides a method for treating and / or preventing a hematological disorder in a subject. In another embodiment, a method is provided for administering 15-HEPE to a subject. The method includes administering up to about 8 g of 15-HEPE to the subject. In some embodiments, 15-HEPE represents at least about 90% by weight of all fatty acids in the composition. do.

[0116] In some aspects, the present disclosure provides a method for treating and / or preventing a hematological disorder in a subject. The method comprises administering 15-HEPE or a composition comprising 15-HEPE to a subject. In another embodiment, the method includes adding up to about 8 g of 15-HEPE or 15-H In yet another embodiment, the method comprises administering to a subject a composition comprising 15-HEP. E represents at least about 90% by weight of all fatty acids in the composition.

[0117] In some embodiments, the present disclosure provides a method for treating and / or preventing a blood disorder in a subject in need of such treatment. The present invention provides a method for treating and / or preventing a blood disorder in a patient, the method comprising administering a 15-hydrogen stearate to a patient. For hydroxyeicosapentaenoic acid (15-HEPE) or compositions containing 15-HEPE In another embodiment, the method includes administering up to about 8 g of a composition comprising 15-HEPE. In another embodiment, the 15-HEPE is administered to a subject. It represents at least about 90% by weight of all fatty acids.

[0118] In some aspects, the present disclosure provides a method for treating and / or preventing a hematological disorder in a subject. The method comprises administering 15-HEPE or a composition comprising 15-HEPE to a subject. In some embodiments, the method comprises: and determining that the subject has at least one risk factor for a blood disorder prior to administration of a composition comprising: In some embodiments, the method further comprises, prior to administration of 15-HEPE: Measuring the subject's baseline red blood cell count, red blood cell distribution width, and / or reticulocyte count In one embodiment, the subject further comprises an increased red blood cell count, a decreased red blood cell distribution width, and / or In another embodiment, the method comprises administering up to about 8 g of 15-HEPE or administering to a subject a composition comprising 15-HEPE. 15-HEPE represents at least about 90% by weight of all fatty acids in the composition.

[0119] In some embodiments, the present disclosure provides a method for treating and / or preventing a blood disorder in a subject in need of such treatment. The present invention provides a method for treating and / or preventing a blood disorder in a patient, the method comprising administering a 15-hydrogen stearate to a patient. For hydroxyeicosapentaenoic acid (15-HEPE) or compositions containing 15-HEPE In some embodiments, the method comprises administering 15-HEPE or 15-HE Prior to administration of the composition comprising PE, the subject is determined to have at least one risk factor for a blood disorder. In some embodiments, the method further comprises determining whether or not the patient has a high risk of developing 15-HEPE before administration of the 15-HEPE. Measure the subject's baseline red blood cell count, red blood cell distribution width, and / or reticulocyte count. In one embodiment, the subject further comprises: an increased red blood cell count, a decreased red blood cell distribution width, and In another embodiment, the method comprises administering up to about 8 g of 15-HE. In another embodiment, the method comprises administering to a subject a composition comprising 15-HEPE. Represents at least about 90% by weight of all fatty acids in the composition.

[0120] In some embodiments, the present disclosure provides a method for treating and / or preventing hemoglobin disorders. The present invention provides a method for treating and / or preventing hemoglobin abnormalities in a subject, contains 15-hydroxyeicosapentaenoic acid (15-HEPE) or 15-HEPE. In another embodiment, the method includes administering to a subject up to about 8 g of a composition comprising 15- In another embodiment, the method comprises administering to a subject a composition comprising 15-HEPE. represents at least about 90% by weight of all fatty acids in the composition.

[0121] In some embodiments, the present disclosure provides a method for treating and / or preventing hemoglobin disorders. The present invention provides a method for treating and / or preventing hemoglobin abnormalities in a subject, contains 15-hydroxyeicosapentaenoic acid (15-HEPE) or 15-HEPE. In some embodiments, the method includes administering to a subject a composition containing 15-HEP. and (b) administering to the subject a composition comprising 15-HEPE or 15-HEPE, the ... In some embodiments, the method further comprises determining that the individual has one or more risk factors. Prior to administration of 15-HEPE, subjects' baseline red blood cell count, red blood cell distribution width, and / or In one embodiment, the subject is diagnosed with an elevated red blood cell count, In another embodiment, the method comprises: In another embodiment, the method comprises administering to a subject a composition comprising up to about 8 g of 15-HEPE. In this case, 15-HEPE represents at least about 90% by weight of all fatty acids in the composition. .

[0122] In some embodiments, the present disclosure provides a method for treating and / or preventing a red blood cell disorder.

[0010] A method for treating and / or preventing red blood cell disorders in elephants is provided, the method comprising administering 15-H In another embodiment, the method comprises administering to a subject a composition comprising EPE or 15-HEPE. The method includes administering to a subject a composition comprising up to about 8 g of 15-HEPE. In embodiments, 15-HEPE comprises at least about 90% by weight of all fatty acids in the composition. Equivalent.

[0123] In some embodiments, the present disclosure provides a method for treating and / or preventing a red blood cell disorder.

[0010] A method for treating and / or preventing red blood cell disorders in elephants is provided, the method comprising administering 15-H The method includes administering to a subject a composition comprising EPE or 15-HEPE. In one embodiment, the method comprises administering 15-HEPE or a composition comprising 15-HEPE to a subject, the subject being treated with red blood cells. and determining that the individual has at least one risk factor for a blood cell disorder. In an embodiment of the method, the subject's baseline red blood cell count, prior to administration of 15-HEPE, In one embodiment, the method further comprises measuring the red blood cell distribution width and / or reticulocyte count. Patients will have an increased red blood cell count, a decreased red blood cell distribution width, and / or a decreased reticulocyte count. In this embodiment, the method comprises administering to the subject a composition comprising up to about 8 g of 15-HEPE. In another embodiment, 15-HEPE comprises at least one of all fatty acids in the composition. This corresponds to approximately 90% by weight.

[0124] In some embodiments, the present disclosure provides a method for treating blood disorders, hemoglobin abnormalities, and / or blood redness. In a subject in need of treatment and / or prevention of a blood cell disorder, a blood disorder, a hemoglobin disorder, and / or a method for treating and / or preventing blood red blood cell disorders, the method comprising: In another embodiment, the method comprises administering to a subject a composition comprising 15-HEPE or 15-HEPE. In the method, the method includes administering to the subject a composition comprising up to about 8 g of 15-HEPE. In another embodiment, 15-HEPE accounts for at least about 90% by weight of all fatty acids in the composition. Equivalent to %.

[0125] In some embodiments, the present disclosure provides a method for treating blood disorders, hemoglobin abnormalities, and / or blood redness. In a subject in need of treatment and / or prevention of a blood cell disorder, a blood disorder, a hemoglobin disorder, and / or a method for treating and / or preventing blood red blood cell disorders, the method comprising: Some embodiments involve administering to a subject a composition containing 15-HEPE or 15-HEPE. In embodiments, the method includes administering 15-HEPE or a composition comprising 15-HEPE to a subject. have at least one risk factor for blood disorders, hemoglobin disorders, and / or red blood cell disorders In some embodiments, determining that at least one link has children. Risk factors are a low red blood cell count, an increased red blood cell distribution width, and / or an increased reticulocyte count. In some embodiments, the subject has an increased red blood cell count, a decreased red blood cell distribution width, and / or indicates one or more of the following: a decreased reticulocyte count.

[0126] In some embodiments, the present disclosure provides a method for treating blood disorders, hemoglobin abnormalities, and / or blood redness. In a subject in need of treatment and / or prevention of a blood cell disorder, a blood disorder, a hemoglobin disorder, and / or a method for treating and / or preventing blood red blood cell disorders, the method comprising: In another embodiment, the method comprises administering to a subject a composition comprising 15-HEPE or 15-HEPE. In the method, the method includes administering to the subject a composition comprising up to about 8 g of 15-HEPE. In another embodiment, 15-HEPE accounts for at least about 90% by weight of all fatty acids in the composition. In another embodiment, the blood disorder, hemoglobin disorder and / or red blood cell disorder corresponds to , hereditary hemolytic anemia, acquired hemolytic anemia, Fanconi anemia, iron deficiency anemia, folate deficiency, In some embodiments, the present invention is directed to a method for treating or preventing the onset of inflammatory bowel disease, including the treatment of inflammatory bowel disease, including the treatment of or with ... The method includes administering 15-HEPE or a composition comprising 15-HEPE to a subject, the subject being diagnosed with a genetic disorder. Hemolytic anemia, acquired hemolytic anemia, Fanconi anemia, iron deficiency anemia, folic acid deficiency, B12 deficiency determining that the patient has at least one risk factor for myelodysplastic syndrome and / or myelodysplastic syndrome; In some embodiments, the method further comprises administering 15-HEPE to the subject. measuring the red blood cell count, red blood cell distribution width, and / or reticulocyte count of the patient. In one embodiment, the subject has an elevated red blood cell count, a decreased red blood cell distribution width, and / or reticulitis. Indicates a decrease in pitch count.

[0127] In some embodiments, the present disclosure provides a method for treating and / or preventing hemolytic anemia in a subject in need of such treatment. A method for treating and / or preventing hemolytic anemia in elephants is provided, the method comprising administering 15-H In another embodiment, the method comprises administering to a subject a composition comprising EPE or 15-HEPE. The method includes administering to a subject a composition comprising up to about 8 g of 15-HEPE. In embodiments, 15-HEPE comprises at least about 90% by weight of all fatty acids in the composition. Equivalent.

[0128] In some embodiments, the present disclosure provides a method for treating and / or preventing hemolytic anemia in a subject in need of such treatment. A method for treating and / or preventing hemolytic anemia in elephants is provided, the method comprising administering 15-H The method includes administering to a subject a composition comprising EPE or 15-HEPE. In some embodiments, the method includes administering 15-HEPE or a composition comprising 15-HEPE to a subject. and determining that the individual has at least one risk factor for hemolytic anemia. In embodiments, the at least one risk factor is a low red blood cell count, an increased red blood cell distribution width, In some embodiments, the subject has an increased red blood cell count, and / or an increased reticulocyte count. increased red blood cell count, decreased red blood cell distribution width, and / or decreased reticulocyte count.

[0129] In some embodiments, the present disclosure provides a method for treating and / or preventing hemolytic anemia in a subject in need of such treatment. and / or a method for treating and / or preventing hemolytic anemia in an elephant, the method comprising administering to the elephant a dose of up to about 8 mg / kg of hemolytic anemia. g of 15-HEPE to the subject. 15-HEPE represents at least about 90% by weight of all fatty acids in the composition. In some embodiments, the hemolytic anemia is hereditary hemolytic anemia or acquired hemolytic anemia. In another embodiment, the hereditary hemolytic anemia is sickle cell disease, sickle cell anemia, β-thalassemia In yet another embodiment, the erythrocyte segregation syndrome is selected from the group consisting of: acquired erythrocyte segregation syndrome, and hereditary spherocytosis. Hemolytic anemia can be caused by infections, drug treatments, hematologic malignancies, autoimmune diseases, hypersplenism, and mechanical heart disease. In various embodiments, the present invention is selected from the group consisting of: liver flap, pulmonary vein ... Sickle cell disease and sickle cell anemia can lead to sickle cell crisis, vaso-occlusive crisis, and In some embodiments, the subject has a red blood cell count after administration of Increased red blood cell count, decreased red blood cell distribution width, and decreased reticulocyte count.

[0130] In some embodiments, the present disclosure provides a method for treating and / or preventing hemolytic anemia in a subject in need of such treatment. and / or a method for treating and / or preventing hemolytic anemia in an elephant, the method comprising administering to the elephant a dose of up to about 8 mg / kg of hemolytic anemia. g of 15-HEPE to the subject. 15-HEPE represents at least about 90% by weight of all fatty acids in the composition. In some embodiments, the hemolytic anemia is hereditary hemolytic anemia or acquired hemolytic anemia. In another embodiment, the hereditary hemolytic anemia is sickle cell disease, sickle cell anemia, β-thalassemia In some embodiments, the method is selected from the group consisting of: a) atopic dermatitis; and b) hereditary spherocytosis. The present invention relates to a method for treating a subject suffering from hereditary hemolytic anemia, the method comprising administering 15-HEPE or a composition containing 15-HEPE to the subject. determining that the subject has at least one risk factor for hemolytic anemia or acquired hemolytic anemia; In yet another embodiment, the acquired hemolytic anemia is caused by an infection, a drug treatment, a hematologic malignancy, A group consisting of those occurring in association with autoimmune diseases, hypersplenism, mechanical heart valves, and blood transfusions In various embodiments, sickle cell disease and sickle cell anemia are selected from the group consisting of: In some embodiments, the condition is associated with splenic hemoglobin accumulation, vaso-occlusive crisis, and / or splenic hemoglobin accumulation. In this embodiment, the method includes measuring the subject's baseline red blood cell count, red blood cell fraction, and blood glucose level prior to administration of 15-HEPE. In one embodiment, the subject further comprises measuring the fabric width and / or reticulocyte count. Shows elevated blood cell counts, decreased red blood cell distribution width, and / or decreased reticulocyte count.

[0131] The compositions and formulations disclosed herein are further useful in the treatment and / or prevention of thrombophilic disorders. Thrombophilic disorders are characterized by abnormal blood clotting that increases the risk of thrombosis. Non-limiting examples of risk factors for thrombophilia disorders include prothrombin time, Decreased thrombin time, decreased activated partial thromboplastin time, and fibrinogen Increased concentrations of ethanol are one of the reasons for this.

[0132] In some embodiments, the subject is at least 10% below the standard, at least 10% above the standard, 15% below standard, at least 20% below standard, at least 25% below standard or have a reduced prothrombin time that is at least 30% below normal.

[0133] In some embodiments, the subject is at least 10% below the standard, at least 10% above the standard, 15% below standard, at least 20% below standard, at least 25% below standard or have a reduced activated partial thromboplastin time that is at least 30% below the standard do.

[0134] In some embodiments, the subject is at least 10% below the standard, at least 10% above the standard, 15% below standard, at least 20% below standard, at least 25% below standard , or have an increased fibrinogen concentration that is at least 30% below the standard.

[0135] In some embodiments, the present disclosure provides a method for treating and / or preventing a thrombophilic disorder. The present invention provides a method for treating and / or preventing a thrombophilic disorder in a subject, contains 15-hydroxyeicosapentaenoic acid (15-HEPE) or 15-HEPE. In another embodiment, the method includes administering to a subject up to about 8 g of a composition comprising 15- In another embodiment, the method comprises administering to a subject a composition comprising 15-HEPE. represents at least about 90% by weight of all fatty acids in the composition.

[0136] In some embodiments, the present disclosure provides a method for treating and / or preventing a thrombophilic disorder. The present invention provides a method for treating and / or preventing a thrombophilic disorder in a subject, The method involves administering 15-HEPE or a composition containing 15-HEPE to a subject. In some embodiments, the method includes administering 15-HEPE or a composition comprising 15-HEPE prior to administration. determining that the subject has at least one risk factor for a thrombophilic disorder; In some embodiments, the at least one risk factor is prothrombin time. reduction in activated partial thromboplastin time, and / or fibrinogen concentration In some embodiments, the subject is taking 15-HEPE or a 15-HEPE-containing After administration of a composition containing the compound, prolongation of prothrombin time, activated partial thromboplastin time, prolongation of the pulmonary circulation, and / or a decrease in fibrinogen concentration.

[0137] In some embodiments, the present disclosure provides a method for treating and / or preventing venous thromboembolism in a subject in need of such treatment. The present invention provides a method for treating and / or preventing venous thromboembolism in a subject, the method comprising: 15-hydroxyeicosapentaenoic acid (15-HEPE) or a composition containing 15-HEPE In another embodiment, the method includes administering up to about 8 g of 15-HE to a subject. In another embodiment, the method comprises administering to a subject a composition comprising 15-HEPE. Represents at least about 90% by weight of all fatty acids in the composition.

[0138] In some embodiments, the present disclosure provides a method for treating and / or preventing venous thromboembolism in a subject in need of such treatment. The present invention provides a method for treating and / or preventing venous thromboembolism in a subject, the method comprising: The method includes administering 15-HEPE or a composition containing 15-HEPE to a subject. In one embodiment of the method, prior to administration of 15-HEPE or a composition comprising 15-HEPE, determining that the subject has at least one risk factor for venous thromboembolism. In some embodiments, at least one risk factor is a decreased prothrombin time. , a decrease in activated partial thromboplastin time, and / or an increase in fibrinogen concentration. In some embodiments, the subject has a prolonged prothrombin time, activated partial thrombin time, or The patient exhibits one or more of the following symptoms: prolonged plastin time, and / or decreased fibrinogen concentration.

[0139] In some embodiments, the present disclosure provides a method for treating and / or preventing arterial thrombosis in a patient in need of such treatment. The present invention provides a method for treating and / or preventing arterial thrombosis in an elephant, the method comprising administering 15-hydroxytryptamine to an elephant. hydroxyeicosapentaenoic acid (15-HEPE) or a composition containing 15-HEPE In another embodiment, the method comprises administering to an elephant up to about 8 g of 15-HEPE. In another embodiment, the 15-HEPE is administered to a subject in a composition containing the compound. represents at least about 90% by weight of all fatty acids of the

[0140] In some embodiments, the present disclosure provides a method for treating and / or preventing arterial thrombosis in a patient in need of such treatment.

[0010] A method for treating and / or preventing arterial thrombosis in elephants is provided, the method comprising administering 15-H The method includes administering to a subject a composition comprising EPE or 15-HEPE. In one embodiment, the method comprises administering 15-HEPE or a composition comprising 15-HEPE to a subject. and determining that the subject has at least one risk factor for vascular thrombosis. In an embodiment, the at least one risk factor is a reduced prothrombin time, an activated portion The primary causes of thromboplastin time reduction and / or increased fibrinogen concentration are: In some embodiments, the subject is diagnosed with prolonged prothrombin time, activated partial thromboplastin The results show one or more of: an increase in the time to complete the treatment and / or a decrease in the fibrinogen concentration.

[0141] In some embodiments, the present disclosure provides a method for preventing embolism in a subject in need thereof. The present invention provides a method for preventing the development of 15-hydroxyeicosapentaenoic acid (15-HEP In another embodiment, the method comprises administering to a subject a composition comprising 15-HEPE or 15-HEPE. The method includes administering to the subject a composition comprising up to about 8 g of 15-HEPE. In embodiments, 15-HEPE represents at least about 90% by weight of all fatty acids in the composition. Correct.

[0142] In some embodiments, the present disclosure provides a method for preventing embolism in a subject in need thereof. The present invention provides a method for preventing 15-HEPE or a composition comprising 15-HEPE. In some embodiments, the method comprises administering 15-HEPE or 15-H Prior to administration of a composition comprising EPE, the subject is diagnosed with at least one risk factor for developing an embolism. In some embodiments, the method further comprises determining that the at least one list The factors involved in the reduction of prothrombin time, the reduction of activated partial thromboplastin time, and In some embodiments, the subject has an increased level of prothrombin. Prolonged thromboplastin time, prolonged activated partial thromboplastin time, and / or fibrinogen The concentration of the α-glucan is 0.01 to 0.15.

[0143] In some aspects, the present disclosure provides a method for treating and / or preventing endothelial dysfunction in a subject. The present invention provides a method for preventing inflammatory bowel disease, the method comprising administering 15-HEPE to a subject. In some embodiments, the method includes administering up to about 8 g of 15-HEPE to the subject. In embodiments, 15-HEPE represents at least about 90% by weight of all fatty acids in the composition. Correct.

[0144] In some aspects, the present disclosure provides a method for treating and / or preventing endothelial dysfunction in a subject. The present invention provides a method for preventing 15-HEPE or a composition comprising 15-HEPE. In another embodiment, the method includes administering up to about 8 g of 15-HEPE or 15 In yet another embodiment, the method comprises administering to a subject a composition comprising 15-H-HEPE. The EPE represents at least about 90% by weight of all fatty acids in the composition.

[0145] In some aspects, the present disclosure provides methods for treating, preventing, and treating cell stress apoptosis. The present invention provides a method for reducing and / or inhibiting the production of 15-HEPE or a composition comprising 15-HEPE. In some embodiments, the subject is administered a composition comprising: Li-derived proteins, activated fragments of caspases, and / or cleaved PAR It shows a reduction in markers associated with apoptosis such as P-1.

[0146] In some embodiments, the present disclosure provides a method for treating, preventing, and / or reducing inflammation. The method comprises administering 15-HEPE or a composition comprising 15-HEPE to a subject. In some embodiments, the subject is treated with T cell activation, B cell activation, and / or exhibit reduced chemotaxis.

[0147] The compositions and formulations disclosed herein can be used to treat or prevent cardiovascular disease or disorders. In one embodiment, the cardiovascular disease or disorder is dyslipidemia, hyperlipidemia, hypertension, Cholesterolemia, hypertriglyceridemia, primary hypercholesterolemia, primary hyperlipidemia Hyperlipidemia, common primary hyperlipidemia, common hypercholesterolemia, familial hyperlipidemia, family Primary hyperlipidemia, familial hypercholesterolemia, familial hypertriglyceridemia, familial Combined hyperlipidemia, familial defective apolipoprotein b-100, secondary hyperlipidemia, mixed hyperlipidemia Prediction of blood glucose levels, cardiovascular disease, residual cardiovascular risk, and atherosclerotic plaque formation / progression Prevention of microvascular disease, macrovascular disease, atherosclerosis, coronary atherosclerosis Sclerosis, diastolic dysfunction, cardiovascular risk reduction, prevention of major coronary events, major adverse Prevention of cardiovascular events, prevention of ischemic events, secondary / primary prevention of cardiovascular events, prevention of cardiovascular death Prevention, myocardial infarction, stroke, angina, restoration of normal endothelial function, diabetes, diabetes mellitus, Induction of insulin resistance, hyperinsulinemia, hyperglycemia, dysglycemia, glycemic control, impaired glucose tolerance, and impaired fasting glucose. Non-limiting examples of microvascular diseases include retinopathy, nephropathy, Non-limiting examples of macrovascular disease include stroke, peripheral vascular disease, and neuropathy. In some embodiments, the subject is a non-alcoholic Patients with liver disease, cholestatic liver disease, kidney disease, or metabolic syndrome. Any of the aforementioned examples of diseases may be referred to as non-limiting examples of cardiometabolic diseases.

[0148] In some aspects, the present disclosure provides a method for treating and / or preventing cardiovascular disease in a subject. The present invention provides a method for treating a cancer of the present invention, the method comprising administering 15-HEPE to a subject.

[0149] In some aspects, the present disclosure provides a method for treating and / or preventing cardiovascular disease in a subject. The present invention provides a method for administering 15-HEPE or a composition containing 15-HEPE to a subject. This includes giving.

[0150] In another embodiment, the present disclosure provides a method for treating diabetes in a subject with diabetes (e.g., type I or type II). The present invention provides a method for preventing a blood disorder by administering 15-HEPE to a subject. In some embodiments, the method comprises determining that the subject has diabetes prior to administration of 15-HEPE. In another embodiment, the method further comprises determining that the subject has a blood glucose level of about 100 mg / kg / day. mg (mg / kg), about 50 mg / kg, about 250 mg / kg, or about 500 mg / kg In yet another embodiment, the 15-HEPE is administered to a subject. represents at least about 90% by weight of all fatty acids in the composition.

[0151] In another embodiment, the present disclosure provides a method for treating diabetes in a subject with diabetes (e.g., type I or type II). The present invention provides a method for preventing blood disorders using 15-HEPE or a compound containing 15-HEPE. In some embodiments, the method comprises administering the composition to a subject. and determining that the subject has diabetes prior to administration of a composition containing E or 15-HEPE. In another embodiment, the method further comprises administering about 10 mg per kg of body weight of the subject (mg / kg), about 50 mg / kg, about 250 mg / kg, or about 500 mg / kg of 15-HEPE; In yet another embodiment, the method comprises administering to a subject a composition comprising 15-HEPE. -HEPE represents at least about 90% by weight of all fatty acids in the composition.

[0152] In another aspect, the present disclosure provides a method for treating a blood disorder in a subject with cardiovascular disease, and and / or a method for preventing the same, comprising administering 15-HEPE to a subject. In some embodiments, the method includes determining that the subject has cardiovascular disease prior to administration of 15-HEPE. In another embodiment, the method further comprises administering a dose of about 10 mg (m g / kg), about 50 mg / kg, about 250 mg / kg, or about 500 mg / kg of 15- In yet another embodiment, 15-HEPE is administered to a subject. It represents at least about 90% by weight of all fatty acids in the product.

[0153] In another aspect, the present disclosure provides a method for treating a blood disorder in a subject with cardiovascular disease, and and / or a method for preventing the same, the method comprising: In some embodiments, the method comprises administering to a subject 15-HEPE or The method further includes determining that the subject has cardiovascular disease prior to administering the composition comprising 15-HEPE. In another embodiment, the method provides a method for administering a dose of about 10 mg / kg of the subject's body weight, about 50 mg / kg of the subject's body weight, or about 10 mg / kg of the subject's body weight. mg / kg, about 250 mg / kg, or about 500 mg / kg of 15-HEPE or 15- In yet another embodiment, the method comprises administering to a subject a composition comprising 15-HEPE. The PE represents at least about 90% by weight of all fatty acids in the composition.

[0154] In another aspect, the present disclosure provides a method for treating a blood disorder in a subject with hypertension, and / or provides a method of preventing the disease, the method comprising administering 15-HEPE to a subject. In some embodiments, the method includes determining that the subject has hypertension prior to administration of 15-HEPE. In some embodiments, the subject has a blood pressure of at least about 130 mmHg, At least about 135 mmHg, at least about 140 mmHg, at least about 145 mmHg g, at least about 150 mmHg, at least about 155 mmHg, at least about 160 m have high blood pressure of at least about 165 mmHg, or at least about 170 mmHg In another embodiment, the method comprises administering a dose of about 10 mg, about 50 mg / kg, about 250 mg / kg, or administering about 500 mg / kg of 15-HEPE to the subject. In some embodiments, 15-HEPE represents at least about 90% by weight of all fatty acids in the composition. do.

[0155] In another aspect, the present disclosure provides a method for treating a blood disorder in a subject with hypertension, and / or The present invention provides a method for preventing 15-HEPE, the method comprising administering 15-HEPE or a composition containing 15-HEPE to a subject. In some embodiments, the method comprises administering 15-HEPE or 15- The method further includes determining that the subject has hypertension prior to administering the composition comprising HEPE. In some embodiments, the subject has a blood pressure of at least about 130 mmHg, at least about 135 mmHg, Hg, at least about 140 mmHg, at least about 145 mmHg, at least about 150 mmHg, at least about 155 mmHg, at least about 160 mmHg, at least about 1 In another embodiment, the patient has high blood pressure of at least about 65 mmHg, or at least about 170 mmHg. The method includes administering about 10 mg, about 50 mg / kg, about 250 mg / kg, or about 500 mg / kg The method further comprises administering 15-HEPE or a composition containing 15-HEPE to a subject. In this embodiment, 15-HEPE is at least about 90% by weight of all fatty acids in the composition. is equivalent to

[0156] The compositions and formulations disclosed herein may also be used to treat patients with cardiovascular and / or hematological disorders. It can be used to reduce cytokines and / or chemokines in a subject. The cytokines and / or chemokines that are of interest include α-smooth muscle actin (α-SMA), metastasis factor (TF), and mitochondrial cytokines (MTC). TNF-α, thrombin-inhibitor-1 (TIMP-1), transforming growth factor beta-β (TGF-β), and type 1 collagen.

[0157] In another embodiment, treatment with a composition of the present invention results in a subject or group of subjects experiencing one of the following outcomes: Indicates one or more of the following.

[0158] (a) Serum amino acids at baseline, in placebo-controlled, and / or untreated patients transferase (ALT) and / or aspartate aminotransferase (AS No increase or decrease in the levels of T

[0159] (b) Bilirubin ( No increase or decrease in BUN (blood urea nitrogen) levels,

[0160] (c) Area of ​​fibrosis compared to baseline, placebo control, and / or untreated patients No increase or decrease,

[0161] (d) baseline, placebo-controlled, and / or treatment-naive patients, fasting blood glucose levels No increase or decrease in

[0162] (e) For baseline, placebo-controlled, and / or treatment-naïve patients, insulin levels were No increase or decrease in bell

[0163] (f) Alkaline lysates were administered to baseline, placebo-controlled, and / or untreated patients. No increase or reduction in phosphate (ALP) levels,

[0164] (g) Hemoglobin for baseline, placebo-controlled, and / or untreated patients No increase or decrease in A1C (HbA1C) levels,

[0165] (h) baseline, placebo-controlled, and / or treatment-naive patients, and insulin resistance No increase or decrease in homeostasis model assessment of resistance (HOMA-IR),

[0166] (i) Adipose tissue index at baseline, placebo-controlled, and / or untreated patients No increase or reduction in insulin resistance (adipo-IR) levels,

[0167] (j) Total cholesterol for baseline, placebo-controlled, and / or untreated patients No increase or decrease in serum levels,

[0168] (k) Triglycerides for baseline, placebo-controlled, and / or untreated patients No increase or reduction in oxidative stress levels

[0169] (l) Diglycerides for baseline, placebo-controlled, and / or untreated patients No increase or decrease in levels,

[0170] (m) Baseline, placebo-controlled, and / or treatment-naïve patients were treated with very low-density lipopolysaccharide (ULLZ). No increase or reduction in protein cholesterol (VLDL-C) levels,

[0171] (n) Remnant-like versus baseline, placebo-controlled, and / or treatment-naive patients No increase or reduction in RLP-C levels,

[0172] (o) Non-dense lipoproteins were used at baseline, placebo control, and / or for untreated patients. No increase or reduction in protein cholesterol (non-HDL-C) levels,

[0173] (p) Baseline, placebo-controlled, and / or treatment-naïve patients were treated with high-density lipoproteins. No reduction or increase in HDL-C levels,

[0174] (q) Low-density lipoprotein (LDL) was used for baseline, placebo-controlled, and / or treatment-naïve patients. No increase or reduction in low-protein cholesterol (LDL-C) levels

[0175] (r) Renal hydroxylase activity at baseline, placebo-controlled, and / or treatment-naïve patients No increase or decrease in cyproline levels,

[0176] (s) Baseline, placebo-controlled, and / or treatment-naïve patients were treated with interleukin-1 (IL-1) no increase or decrease in interleukin-33 (IL-33) levels,

[0177] (t) Baseline, placebo-controlled, and / or treatment-naïve patients were treated with interleukin-1 (IL-1) or IL-1. no increase or decrease in interleukin-17 (IL-17) levels,

[0178] (u) Baseline, placebo-controlled, and / or treatment-naïve patients were randomly assigned to aryl carbonitrides. No increase or reduction in levels of hydrogen receptor (AhR),

[0179] (v) baseline, placebo-controlled, and / or treatment-naïve patients, and No increase or decrease in TransL1A (TL1A) levels,

[0180] (w) baseline, placebo-controlled, and / or treatment-naïve patients, tumor necrosis factor No increase or reduction in (TNF-α) levels,

[0181] (x) baseline, placebo-controlled, and / or treatment-naïve patients were treated with interleukin-1 (IL-1) no increase or decrease in interleukin-13 (IL-13) levels,

[0182] (y) baseline, placebo-controlled, and / or treatment-naïve patients were treated with interleukin-1 (IL-1) no increase or decrease in interleukin-6 (IL-6) levels,

[0183] (z) Baseline, placebo-controlled, and / or treatment-naïve patients were treated with interleukin-1 (IL-1) or IL-1. No increase or decrease in interleukin 1 beta-β (IL-1β) levels,

[0184] (aa) Baseline, placebo-controlled, and / or treatment-naïve patients with type 1 cholesterol No increase or decrease in gen levels,

[0185] (bb) Baseline, placebo-controlled, and / or treatment-naïve patients were treated with transferrin. No increase or reduction in transforming growth factor beta (TGF-β) levels,

[0186] (cc) α-smooth muscle for baseline, placebo-controlled, and / or treatment-naive patients No increase or decrease in α-SMA levels

[0187] (dd) Tumor necrosis factors for baseline, placebo-controlled, and / or treatment-naïve patients No increase in the levels of the child ligand superfamily member 11A (TNRSF11A), or reduction,

[0188] (ee) Serine protease inhibitors were administered at baseline, in placebo-controlled, and / or untreated patients. no increase or decrease in PRSS2 levels,

[0189] (ff) Baseline, placebo-controlled, and / or treatment-naïve patients were treated with amine oxidase no increase or reduction in AOC3 levels,

[0190] (gg) Leukocyte immunoglobulin levels were measured at baseline, in placebo-controlled, and / or untreated patients. no increase or decrease in globulin-like receptor B1 (LILBR1) levels;

[0191] (hh) Baseline, placebo-controlled, and / or treatment-naïve patients were compared for transfer no increase or decrease in thyroid receptor protein 1 (TR) levels,

[0192] (ii) elafin for baseline, placebo-controlled, and / or treatment-naive patients No increase or decrease in (PI3) levels,

[0193] (jj) Serum amyloid levels at baseline, in placebo-controlled, and / or treatment-naïve patients No increase or decrease in serum adenosine triphosphate (SAA4) levels,

[0194] (kk) Monocyte chemotaxis versus baseline, placebo control, and / or untreated patients no increase or decrease in MCP-1 levels,

[0195] (ll) Chemokine-based treatments for baseline, placebo-controlled, and / or untreated patients No increase or reduction in (CC motif) ligand 16 (CCL16) levels,

[0196] (mm) Tre-like versus baseline, placebo-controlled, and / or treatment-naive patients no increase or decrease in TLT2 levels;

[0197] (nn) Dipeptidyl peptidase-1 (DPP-1) was administered at baseline, placebo control, and / or for untreated patients. No increase or decrease in dipeptidase 4 (DPP4) levels, and

[0198] (oo) Baseline, placebo-controlled, and / or treatment-naïve patients were treated with metalloprotease inhibitors. no increase or decrease in TIMP-1 levels,

[0199] (pp) Baseline, placebo-controlled, and / or untreated patients were treated with plasminogen activator. No increase or decrease in protein activator inhibitor-1 (PAI-1) levels,

[0200] (qq) Baseline, placebo-controlled, and / or treatment-naive patients with NAFLD No increase or decrease in score (NFS), and

[0201] (rr) Fibrosis-4 vs. baseline, placebo-controlled, and / or treatment-naive patients (FIB-4) No increase or decrease in levels,

[0202] (ss) Liver stiffness levels for baseline, placebo-controlled, and / or untreated patients No increase or decrease in

[0203] (tt) Liver fat content for baseline, placebo-controlled, and / or untreated patients No increase or decrease in abundance,

[0204] (uu) Glycerol for baseline, placebo-controlled, and / or untreated patients No reduction or increase in lipid levels,

[0205] (vv) Increase in blood pressure relative to baseline, placebo control, and / or untreated patients None or reduced

[0206] (ww) Enhanced liver fibrosis compared to baseline, placebo control, and / or untreated patients No increase or decrease in ELF score,

[0207] (xx) For baseline, placebo-controlled, and / or treatment-naïve patients, pulmonary and / or No increase or decrease in collagen production in skin fibroblasts,

[0208] (yy) For baseline, placebo-controlled, and / or untreated patients, glucose No reduction or increase in uptake,

[0209] (zz) baseline, placebo-controlled, and / or treatment-naïve patients with pulmonary and / or Increased survival rate of skin fibroblasts,

[0210] (ab) Baseline, placebo-controlled, and / or treatment-naive patients were compared with interrogated No change or reduction in IL-8 (IL-8) levels,

[0211] (ac) Baseline, placebo-controlled, and / or treatment-naive patients were compared with the interrogated No change or reduction in IL-23 (IL-23) levels,

[0212] (ad) Baseline, placebo-controlled, and / or treatment-naive patients were interviewed. No change or a decrease in interleukin-11 (IL-11) levels, and / or

[0213] (ae) Baseline, placebo-controlled, and / or treatment-naïve patients at intervention No change or reduction in interferon gamma (IFNγ) levels,

[0214] (af) For baseline, placebo-controlled, and / or treatment-naive patients, T and / or No change or reduction in B cell activation,

[0215] (ag) Changes in chemotaxis versus baseline, placebo control, and / or untreated patients No or reduced

[0216] (ah) Phosphorylated B for baseline, placebo control, and / or untreated patients unchanged or reduced Bcl-2 family members,

[0217] (ai) Caspase activity at baseline, placebo control, and / or treatment-naïve patients no change or reduction in the level of activated fragments of

[0218] (aj) Baseline, placebo-controlled, and / or untreated patients were amputated No change or low levels of poly(ADP-ribose) polymerase-1 (PARP-1) decrease,

[0219] (ak) Change in waist circumference compared to baseline, placebo-controlled, and / or untreated patients None or reduced

[0220] (a) AST vs. blood for baseline, placebo-controlled, and / or untreated patients No change or decrease in platelet distribution index (APRI),

[0221] (am) Liver inflammation at baseline, in placebo-controlled, and / or untreated patients and no change or reduction in fibrosis (LIF) score,

[0222] (an) Lok score for baseline, placebo-controlled, and / or treatment-naive patients No change or reduction in

[0223] (ao) Fibrosis scores for baseline, placebo-controlled, and / or untreated patients No change or reduction in

[0224] (ap) Baseline, placebo-controlled, and / or treatment-naïve patients, Kingsco No change or reduction in

[0225] (aq) Baseline, placebo-controlled, and / or treatment-naive patients, Bonacini No change or decrease in score,

[0226] (ar) Transient error versus baseline, placebo-controlled, and / or untreated patients No change or decrease in endoscopic endography (TE) score.

[0227] (as) baseline, placebo-controlled, and / or untreated patients, No increase or decrease in children,

[0228] (at) baseline, placebo-controlled, and / or treatment-naïve patients, cardiovascular risk No increase or decrease in lactic acid protein

[0229] (au) Chemokine-based treatments for baseline, placebo-controlled, and / or untreated patients No increase or decrease in

[0230] (av) Tumor necrosis factors for baseline, placebo-controlled, and / or treatment-naïve patients No increase or decrease in members of the chromosome receptor superfamily,

[0231] (aw) Changes in red blood cell counts compared to baseline, placebo control, and / or untreated patients No or increased

[0232] (ax) Changes in white blood cell counts compared to baseline, placebo control, and / or untreated patients No or increased

[0233] (ay) Change in platelet counts relative to baseline, placebo control, and / or untreated patients No or increased

[0234] (az) Prothrombin time at baseline, placebo control, and / or for untreated patients No change or increase in time

[0235] (ba) Baseline, placebo-controlled, and / or activated partial tonoplast for treatment-naive patients No change or increase in thromboplastin time,

[0236] (bc) Hemoglobin for baseline, placebo-controlled, and / or untreated patients No change or increase in production,

[0237] (bd) Hemoglobin for baseline, placebo-controlled, and / or untreated patients No change or increase in the synthesis of tetrameric beta-globin chains,

[0238] (be) baseline, placebo-controlled, and / or treatment-naive patients' red blood cell hemolysis No change or decrease,

[0239] (bf) Change in shortness of breath relative to baseline, placebo control, and / or treatment-naive patients None or reduced

[0240] (bg) Heart rate change relative to baseline, placebo control, and / or untreated patients None or reduced

[0241] (bh) Spleen size for baseline, placebo-controlled, and / or untreated patients No change or decrease,

[0242] (bi) liver size at baseline, placebo control, and / or for untreated patients No change or decrease,

[0243] (bj) Change in dactylitis compared to baseline, placebo-controlled, and / or untreated patients or reduce,

[0244] (bk) Change in pain attacks relative to baseline, placebo control, and / or treatment-naive patients No or reduced

[0245] (bl) Abnormal clots for baseline, placebo-controlled, and / or untreated patients No change or reduction in occurrence,

[0246] (bm) Red blood cell distribution width for baseline, placebo-controlled, and / or untreated patients No change or reduction in

[0247] (bn) Reticulemia for baseline, placebo-controlled, and / or treatment-naive patients No change or reduction in pitch count, and / or

[0248] (bo) Fibrinogen for baseline, placebo control, and / or treatment-naive patients No change or reduction in concentration.

[0249] In one embodiment, the method of the present invention comprises the steps of: (a) administering to a subject or group of subjects the method comprising ... measuring the baseline levels of one or more markers or parameters listed in In another embodiment, the method comprises: After measuring the baseline level of the parameter, the subject is administered a composition disclosed herein. followed by taking additional measurements of the one or more markers.

[0250] In another embodiment, for example, about 1 to about 12 weeks, about 1 to about 8 weeks, or about 1 to about 4 weeks. Upon treatment with the compositions of the present invention for a period of time, the subject or group of subjects will experience the transitions described immediately above. Any of (a) to (bo) 5 or more, any of (a) to (bo) 10 or more, any of (a) to (bo) 15 or more Above, any 20 or more, any 25 or more, any 30 or more, any 35 or more Above, any 40 or more, any 45 or more, any 50 or more, any 55 or more Above, any 60 or more, any 65 or more, any 70 or more, any 75 or more Above, any 80 or more, any 85 or more, any 90 or more, or all 91 show.

[0251] In another embodiment, treatment with a composition of the present invention results in a subject or group of subjects experiencing one of the following outcomes: Indicates one or more of the following.

[0252] (a) Serum ALT and no increase in the levels of AST, or at least about 5%, at least about 10%, or at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least at least about 75%, at least about 80%, at least about 85%, at least about 90%, or or at least about 95% reduction,

[0253] (b) BUN levels for baseline, placebo-controlled, and / or untreated patients No increase, or at least about 5%, at least about 10%, at least about 15%, or less At least about 20%, at least about 25%, at least about 30%, at least about 35%, or less At least about 40%, at least about 45%, at least about 50%, at least about 55%, or less At least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, at least about 85%, at least about 90%, or at least about 95% reduction of

[0254] (c) Area of ​​fibrosis compared to baseline, placebo control, and / or untreated patients No increase, or at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least at least about 80%, at least about 85%, at least about 90%, or at least about 95% reduction,

[0255] (d) baseline, placebo-controlled, and / or treatment-naive patients, fasting blood glucose levels No increase, or at least about 5%, at least about 10%, at least about 15%, or less At least about 20%, at least about 25%, at least about 30%, at least about 35%, or less At least about 40%, at least about 45%, at least about 50%, at least about 55%, or less At least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, at least about 85%, at least about 90%, or at least about 95% reduction of

[0256] (e) baseline, placebo-controlled, and / or treatment-naive patients, insulin No increase, or at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least at least about 80%, at least about 85%, at least about 90%, or at least about 95% reduction,

[0257] (f) ALP levels for baseline, placebo-controlled, and / or untreated patients No increase, or at least about 5%, at least about 10%, at least about 15%, or less At least about 20%, at least about 25%, at least about 30%, at least about 35%, or less At least about 40%, at least about 45%, at least about 50%, at least about 55%, or less At least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, at least about 85%, at least about 90%, or at least about 95% reduction of

[0258] (g) HB1Ac levels for baseline, placebo-controlled, and / or treatment-naïve patients No increase in the level, or at least about 5%, at least about 10%, at least about 15%, or a small increase at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 9 5% reduction,

[0259] (h) HOMA-I for baseline, placebo-controlled, and / or treatment-naive patients No increase in R levels, or at least about 5%, at least about 10%, or at least about 15% , at least about 20%, at least about 25%, at least about 30%, at least about 35% , at least about 40%, at least about 45%, at least about 50%, at least about 55% , at least about 60%, at least about 65%, at least about 70%, at least about 75% , at least about 80%, at least about 85%, at least about 90%, or at least Approximately 95% reduction,

[0260] (i) Baseline, placebo-controlled, and / or treatment-naïve patients were treated with adipo- No increase in IR levels, or at least about 5%, at least about 10%, at least about 15% %, at least about 20%, at least about 25%, at least about 30%, at least about 35 %, at least about 40%, at least about 45%, at least about 50%, at least about 55 %, at least about 60%, at least about 65%, at least about 70%, at least about 75 %, at least about 80%, at least about 85%, at least about 90%, or at least Approximately 95% reduction

[0261] (j) Total cholesterol for baseline, placebo-controlled, and / or untreated patients No increase in serum levels, or at least about 5%, at least about 10%, at least about 15% %, at least about 20%, at least about 25%, at least about 30%, at least about 35 %, at least about 40%, at least about 45%, at least about 50%, at least about 55 %, at least about 60%, at least about 65%, at least about 70%, at least about 75 %, at least about 80%, at least about 85%, at least about 90%, or at least Approximately 95% reduction

[0262] (k) Triglycerides for baseline, placebo-controlled, and / or untreated patients No increase in blood glucose levels, or at least about 5%, at least about 10%, or at least about 15% , at least about 20%, at least about 25%, at least about 30%, at least about 35% , at least about 40%, at least about 45%, at least about 50%, at least about 55% , at least about 60%, at least about 65%, at least about 70%, at least about 75% , at least about 80%, at least about 85%, at least about 90%, or at least Approximately 95% reduction,

[0263] (l) Diglycerides for baseline, placebo-controlled, and / or untreated patients no increase in levels, or at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, At least about 60%, at least about 65%, at least about 70%, at least about 75%, At least about 80%, at least about 85%, at least about 90%, or at least about 95% reduction,

[0264] (m) VLDL-C for baseline, placebo-controlled, and / or treatment-naive patients no increase in levels, or at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, At least about 60%, at least about 65%, at least about 70%, at least about 75%, At least about 80%, at least about 85%, at least about 90%, or at least about 95% reduction,

[0265] (n) RLP-C levels for baseline, placebo-controlled, and / or treatment-naive patients No increase in the level, or at least about 5%, at least about 10%, at least about 15%, or a small increase at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 9 5% reduction,

[0266] (o) Non-HDL-C for baseline, placebo-controlled, and / or untreated patients no increase in levels, or at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, At least about 60%, at least about 65%, at least about 70%, at least about 75%, At least about 80%, at least about 85%, at least about 90%, or at least about 95% reduction,

[0267] (p) HDL-C levels for baseline, placebo-controlled, and / or untreated patients No reduction in signal level, or at least about 5%, at least about 10%, at least about 15%, or a small reduction in signal level at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 9 5% increase,

[0268] (q) LDL-C levels for baseline, placebo-controlled, and / or untreated patients No increase in the level, or at least about 5%, at least about 10%, at least about 15%, or a small increase at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 9 5% reduction,

[0269] (r) Renal hydroxylase activity at baseline, placebo-controlled, and / or treatment-naïve patients No increase in cyproline levels, or at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least About 55%, at least about 60%, at least about 65%, at least about 70%, at least About 75%, at least about 80%, at least about 85%, at least about 90%, or less At least about 95% reduction,

[0270] (s) IL-33 levels at baseline, placebo control, and / or treatment-naïve patients No increase in the level, or at least about 5%, at least about 10%, at least about 15%, or a small increase at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 9 5% reduction,

[0271] (t) IL-17 levels at baseline, placebo control, and / or treatment-naïve patients No increase in the level, or at least about 5%, at least about 10%, at least about 15%, or a small increase at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 9 5% reduction,

[0272] (u) AhR levels for baseline, placebo-controlled, and / or untreated patients No increase, or at least about 5%, at least about 10%, at least about 15%, or less At least about 20%, at least about 25%, at least about 30%, at least about 35%, or less At least about 40%, at least about 45%, at least about 50%, at least about 55%, or less At least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, at least about 85%, at least about 90%, or at least about 95% reduction of

[0273] (v) TL1A levels at baseline, placebo control, and / or treatment-naïve patients No increase in the level, or at least about 5%, at least about 10%, at least about 15%, or less at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least at least about 80%, at least about 85%, at least about 90%, or at least about 95% % reduction,

[0274] (w) TNF-α levels at baseline, placebo control, and / or for untreated patients No increase in the level, or at least about 5%, at least about 10%, at least about 15%, or a small increase at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 9 5% reduction,

[0275] (x) IL-13 levels at baseline, placebo control, and / or treatment-naïve patients No increase in the level, or at least about 5%, at least about 10%, at least about 15%, or a small increase at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 9 5% reduction,

[0276] (y) IL-6 levels at baseline, placebo control, and / or for untreated patients No increase in the level, or at least about 5%, at least about 10%, at least about 15%, or less at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least at least about 80%, at least about 85%, at least about 90%, or at least about 95% % reduction,

[0277] (z) IL-1β levels at baseline, in placebo-controlled, and / or untreated patients No increase in the level, or at least about 5%, at least about 10%, at least about 15%, or a small increase at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 9 5% reduction,

[0278] (aa) Baseline, placebo-controlled, and / or treatment-naïve patients with type 1 cholesterol No increase in gen levels, or at least about 5%, at least about 10%, at least about 15% %, at least about 20%, at least about 25%, at least about 30%, at least about 35 %, at least about 40%, at least about 45%, at least about 50%, at least about 55 %, at least about 60%, at least about 65%, at least about 70%, at least about 75 %, at least about 80%, at least about 85%, at least about 90%, or at least Approximately 95% reduction

[0279] (bb) TGF-β for baseline, placebo-controlled, and / or treatment-naïve patients no increase in levels, or at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, At least about 60%, at least about 65%, at least about 70%, at least about 75%, At least about 80%, at least about 85%, at least about 90%, or at least about 95% reduction,

[0280] (cc) α-SMA for baseline, placebo-controlled, and / or treatment-naive patients No increase, or at least about 5%, at least about 10%, at least about 15%, or less At least about 20%, at least about 25%, at least about 30%, at least about 35%, or less At least about 40%, at least about 45%, at least about 50%, at least about 55%, or less At least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, at least about 85%, at least about 90%, or at least about 95% reduction of

[0281] (dd) TNRSF for baseline, placebo-controlled, and / or treatment-naive patients no increase in 11A, or at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, At least about 60%, at least about 65%, at least about 70%, at least about 75%, At least about 80%, at least about 85%, at least about 90%, or at least about 95% reduction,

[0282] (ee) PRSS2 for baseline, placebo-controlled, and / or treatment-naive patients no increase in levels, or at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, At least about 60%, at least about 65%, at least about 70%, at least about 75%, At least about 80%, at least about 85%, at least about 90%, or at least about 95% reduction.

[0283] (ff) AOC3 levels for baseline, placebo-controlled, and / or treatment-naïve patients No increase in the level, or at least about 5%, at least about 10%, at least about 15%, or a small increase at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 9 5% reduction,

[0284] (gg) For baseline, placebo-controlled, and / or treatment-naïve patients, LILBR No increase in 1 level, or at least about 5%, at least about 10%, or at least about 15% , at least about 20%, at least about 25%, at least about 30%, at least about 35% , at least about 40%, at least about 45%, at least about 50%, at least about 55% , at least about 60%, at least about 65%, at least about 70%, at least about 75% , at least about 80%, at least about 85%, at least about 90%, or at least Approximately 95% reduction,

[0285] (hh) TR levels for baseline, placebo-controlled, and / or treatment-naive patients No increase, or at least about 5%, at least about 10%, at least about 15%, or less At least about 20%, at least about 25%, at least about 30%, at least about 35%, or less At least about 40%, at least about 45%, at least about 50%, at least about 55%, or less At least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, at least about 85%, at least about 90%, or at least about 95% reduction of

[0286] (ii) Increase in PI3 versus baseline, placebo control, and / or treatment-naïve patients No addition, or at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least About 40%, at least about 45%, at least about 50%, at least about 55%, at least About 60%, at least about 65%, at least about 70%, at least about 75%, at least About 80%, at least about 85%, at least about 90%, or at least about 95% lower decrease,

[0287] (jj) SAA4 levels for baseline, placebo-controlled, and / or treatment-naïve patients No increase in the level, or at least about 5%, at least about 10%, at least about 15%, or a small increase at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 9 5% reduction,

[0288] (kk) MCP-1 for baseline, placebo-controlled, and / or treatment-naive patients no increase in levels, or at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, At least about 60%, at least about 65%, at least about 70%, at least about 75%, At least about 80%, at least about 85%, at least about 90%, or at least about 95% reduction,

[0289] (ll) CCL16 for baseline, placebo-controlled, and / or treatment-naïve patients no increase in levels, or at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, At least about 60%, at least about 65%, at least about 70%, at least about 75%, At least about 80%, at least about 85%, at least about 90%, or at least about 95% reduction,

[0290] (mm) TLT2 levels for baseline, placebo control, and / or untreated patients No increase in the level, or at least about 5%, at least about 10%, at least about 15%, or a small increase at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 9 5% reduction,

[0291] (nn) DPP4 levels at baseline, placebo control, and / or for treatment-naïve patients No increase in the level, or at least about 5%, at least about 10%, at least about 15%, or a small increase at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 9 5% reduction,

[0292] (oo) For baseline, placebo-controlled, and / or treatment-naive patients, TIMP- No increase in 1 level, or at least about 5%, at least about 10%, or at least about 15% , at least about 20%, at least about 25%, at least about 30%, at least about 35% , at least about 40%, at least about 45%, at least about 50%, at least about 55% , at least about 60%, at least about 65%, at least about 70%, at least about 75% , at least about 80%, at least about 85%, at least about 90%, or at least Approximately 95% reduction,

[0293] (pp) PAI-1 for baseline, placebo-controlled, and / or treatment-naive patients no increase in levels, or at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, At least about 60%, at least about 65%, at least about 70%, at least about 75%, At least about 80%, at least about 85%, at least about 90%, or at least about 95% reduction,

[0294] (qq) Increase in NFS versus baseline, placebo control, and / or treatment-naive patients No addition, or at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least About 40%, at least about 45%, at least about 50%, at least about 55%, at least About 60%, at least about 65%, at least about 70%, at least about 75%, at least About 80%, at least about 85%, at least about 90%, or at least about 95% lower decrease,

[0295] (rr) FIB-4 for baseline, placebo-controlled, and / or treatment-naive patients no increase in levels, or at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, At least about 60%, at least about 65%, at least about 70%, at least about 75%, At least about 80%, at least about 85%, at least about 90%, or at least about 95% reduction,

[0296] (ss) Increase in liver stiffness versus baseline, placebo control, and / or untreated patients No addition, or at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least About 40%, at least about 45%, at least about 50%, at least about 55%, at least About 60%, at least about 65%, at least about 70%, at least about 75%, at least About 80%, at least about 85%, at least about 90%, or at least about 95% lower decrease,

[0297] (tt) Liver fat content for baseline, placebo-controlled, and / or untreated patients No increase in the amount, or at least about 5%, at least about 10%, at least about 15%, or a small increase at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 9 5% reduction,

[0298] (uu) Glycerol for baseline, placebo-controlled, and / or untreated patients No reduction in lipid levels, or at least about 5%, at least about 10%, at least about 1 5%, at least about 20%, at least about 25%, at least about 30%, at least about 3 5%, at least about 40%, at least about 45%, at least about 50%, at least about 5 5%, at least about 60%, at least about 65%, at least about 70%, at least about 7 5%, at least about 80%, at least about 85%, at least about 90%, or less Both increased by approximately 95%.

[0299] (vv) Increase in blood pressure relative to baseline, placebo control, and / or untreated patients None, or at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% reduction ,

[0300] (ww) ELF scores for baseline, placebo-controlled, and / or treatment-naive patients No increase in serum, or at least about 5%, at least about 10%, at least about 15%, or less at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least at least about 80%, at least about 85%, at least about 90%, or at least about 95% % reduction,

[0301] (zz) For baseline, placebo-controlled, and / or treatment-naïve patients, pulmonary and / or There was no increase in collagen production score in dermal fibroblasts, or at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, At least about 70%, at least about 75%, at least about 80%, at least about 85%, a reduction of at least about 90%, or at least about 95%,

[0302] (yy) For baseline, placebo-controlled, and / or untreated patients, glucose No reduction in uptake, or at least about 5%, at least about 10%, at least about 15% , at least about 20%, at least about 25%, at least about 30%, at least about 35% , at least about 40%, at least about 45%, at least about 50%, at least about 55% , at least about 60%, at least about 65%, at least about 70%, at least about 75% , at least about 80%, at least about 85%, at least about 90%, or at least An increase of approximately 95%

[0303] (zz) For baseline, placebo-controlled, and / or treatment-naïve patients, pulmonary and / or reduces the viability of skin fibroblasts by at least about 5%, at least about 10%, at least about 15% %, at least about 20%, at least about 25%, at least about 30%, at least about 35 %, at least about 40%, at least about 45%, at least about 50%, at least about 55 %, at least about 60%, at least about 65%, at least about 70%, at least about 75 %, at least about 80%, at least about 85%, at least about 90%, or at least about 95% increase,

[0304] (ab) IL-8 levels at baseline, placebo control, and / or treatment-naïve patients No change in Bell score, or at least about 5%, at least about 10%, at least about 15% %, at least about 20%, at least about 25%, at least about 30%, at least about 35 %, at least about 40%, at least about 45%, at least about 50%, at least about 55 %, at least about 60%, at least about 65%, at least about 70%, at least about 75 %, at least about 80%, at least about 85%, at least about 90%, or at least Approximately 95% reduction

[0305] (ac) IL-23 versus baseline, placebo control, and / or treatment-naïve patients No change in level, or at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, At least about 60%, at least about 65%, at least about 70%, at least about 75%, At least about 80%, at least about 85%, at least about 90%, or at least about 95% reduction, and / or

[0306] (ad) IL-11 at baseline, placebo control, and / or treatment-naïve patients No change in level score, or at least about 5%, at least about 10%, at least about 1 5%, at least about 20%, at least about 25%, at least about 30%, at least about 3 5%, at least about 40%, at least about 45%, at least about 50%, at least about 5 5%, at least about 60%, at least about 65%, at least about 70%, at least about 7 5%, at least about 80%, at least about 85%, at least about 90%, or less Both are reduced by approximately 95%.

[0307] (ae) IFNγ levels at baseline, placebo control, and / or for untreated patients No change in the level, or at least about 5%, at least about 10%, at least about 15%, or a small change at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 9 5% reduction,

[0308] (af) For baseline, placebo-controlled, and / or treatment-naive patients, T and / or no change in B cell activation, or at least about 5%, at least about 10%, at least about 15%, about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least About 55%, at least about 60%, at least about 65%, at least about 70%, at least About 75%, at least about 80%, at least about 85%, at least about 90%, or less At least about 95% reduction,

[0309] (ag) Changes in chemotaxis versus baseline, placebo control, and / or untreated patients No, or at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least About 40%, at least about 45%, at least about 50%, at least about 55%, at least About 60%, at least about 65%, at least about 70%, at least about 75%, at least About 80%, at least about 85%, at least about 90%, or at least about 95% lower decrease,

[0310] (ah) Bcl-2 vs. baseline, placebo control, and / or treatment-naive patients No change in family members, or at least about 5%, at least about 10%, or at least at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least at least about 75%, at least about 80%, at least about 85%, at least about 90%, or a reduction of at least about 95%;

[0311] (ai) Caspase activity at baseline, placebo control, and / or treatment-naïve patients no change in the level of activated fragments, or at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, At least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about a 95% reduction;

[0312] (aj) Baseline, placebo-controlled, and / or untreated patients were amputated No change in PARP-1 levels, or at least about 5%, at least about 10%, or at least at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least at least about 75%, at least about 80%, at least about 85%, at least about 90%, or a reduction of at least about 95%;

[0313] (ak) Change in waist circumference compared to baseline, placebo-controlled, and / or untreated patients None, or at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% reduction ,

[0314] (al) Baseline, placebo-controlled, and / or treatment-naïve patients, and No change, or at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least at least about 80%, at least about 85%, at least about 90%, or at least about 95% reduction,

[0315] (am) LIF scores for baseline, placebo-controlled, and / or treatment-naïve patients No change in the amount of α, or at least about 5%, at least about 10%, at least about 15%, or less at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least at least about 80%, at least about 85%, at least about 90%, or at least about 95% % reduction,

[0316] (an) Lok score for baseline, placebo-controlled, and / or treatment-naive patients No change in the amount of α, or at least about 5%, at least about 10%, at least about 15%, or less at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least at least about 80%, at least about 85%, at least about 90%, or at least about 95% % reduction,

[0317] (ao) Fibrosis scores for baseline, placebo-controlled, and / or untreated patients No change in the amount of α, or at least about 5%, at least about 10%, at least about 15%, or less at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least at least about 80%, at least about 85%, at least about 90%, or at least about 95% % reduction,

[0318] (ap) Baseline, placebo-controlled, and / or treatment-naïve patients, Kingsco No change in the amount of α, or at least about 5%, at least about 10%, at least about 15%, or less at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least at least about 80%, at least about 85%, at least about 90%, or at least about 95% % reduction,

[0319] (aq) Baseline, placebo-controlled, and / or treatment-naive patients, Bonacini No change in score, or at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, At least about 60%, at least about 65%, at least about 70%, at least about 75%, At least about 80%, at least about 85%, at least about 90%, or at least about 95% reduction, and / or

[0320] (ar) TE score for baseline, placebo-controlled, and / or treatment-naive patients No change, or at least about 5%, at least about 10%, at least about 15%, or less At least about 20%, at least about 25%, at least about 30%, at least about 35%, or less At least about 40%, at least about 45%, at least about 50%, at least about 55%, or less At least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, at least about 85%, at least about 90%, or at least about 95% Reduction of.

[0321] (as) baseline, placebo-controlled, and / or untreated patients, At least about 5%, at least about 10%, at least about 15%, at least about 20% of the children , at least about 25%, at least about 30%, at least about 35%, at least about 40% , at least about 45%, at least about 50%, at least about 55%, at least about 60% , at least about 65%, at least about 70%, at least about 75%, at least about 80% , an increase of at least about 85%, at least about 90%, or at least about 95%;

[0322] (at) baseline, placebo-controlled, and / or treatment-naïve patients, cardiovascular risk At least about 5%, at least about 10%, at least about 15%, at least about 16%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least at least about 80%, at least about 85%, at least about 90%, or at least about 95% increase,

[0323] (au) Chemokine-based treatments for baseline, placebo-controlled, and / or untreated patients at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, an increase of at least about 85%, at least about 90%, or at least about 95%;

[0324] (av) Tumor necrosis factors for baseline, placebo-controlled, and / or treatment-naïve patients At least about 5%, at least about 10%, or at least about 10% of the receptor superfamily members At least about 15%, at least about 20%, at least about 25%, at least about 30%, At least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least At least about 55%, at least about 60%, at least about 65%, at least about 70%, or at least At least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least At least an increase of about 95%.

[0325] (aw) baseline, placebo-controlled, and / or untreated patients, red blood cell count No change, or at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least at least about 80%, at least about 85%, at least about 90%, or at least about 95% increase,

[0326] (ax) baseline, placebo-controlled, and / or treatment-naïve patients, and white blood cell counts No change, or at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least at least about 80%, at least about 85%, at least about 90%, or at least about 95% increase,

[0327] (ay) Platelet counts for baseline, placebo-controlled, and / or untreated patients No change, or at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least at least about 80%, at least about 85%, at least about 90%, or at least about 95% increase,

[0328] (az) Prothrombin time points were measured at baseline, placebo control, and / or for untreated patients. No change in bin time, or at least about 5%, at least about 10%, at least about 1 5%, at least about 20%, at least about 25%, at least about 30%, at least about 3 5%, at least about 40%, at least about 45%, at least about 50%, at least about 5 5%, at least about 60%, at least about 65%, at least about 70%, at least about 7 5%, at least about 80%, at least about 85%, at least about 90%, or less Both increased by approximately 95%.

[0329] (ba) baseline, placebo-controlled, and / or treatment-naive patients, No change in thromboplastin time, or at least about 5%, at least about 10%, or a small change at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least at least about 75%, at least about 80%, at least about 85%, at least about 90%, or or at least about a 95% increase,

[0330] (bc) baseline, placebo-controlled, and / or treatment-naïve patients, and hemoglobin levels were no change in steroid production, or at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, At least about 60%, at least about 65%, at least about 70%, at least about 75%, At least about 80%, at least about 85%, at least about 90%, or at least about 95% increase,

[0331] (bd) Baseline, placebo-controlled, and / or treatment-naïve patients were randomly assigned to hemoglobin-dependently. No change, or at least about 5%, or at least about 10% in the synthesis of tetrameric beta-globin chains , at least about 15%, at least about 20%, at least about 25%, at least about 30% , at least about 35%, at least about 40%, at least about 45%, at least about 50% , at least about 55%, at least about 60%, at least about 65%, at least about 70% , at least about 75%, at least about 80%, at least about 85%, at least about 90% or an increase of at least about 95%;

[0332] (be) Red blood cell hemolysis for baseline, placebo-controlled, and / or treatment-naive patients No change, or at least about 5%, at least about 10%, at least about 15%, or less At least about 20%, at least about 25%, at least about 30%, at least about 35%, or less At least about 40%, at least about 45%, at least about 50%, at least about 55%, or less At least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, at least about 85%, at least about 90%, or at least about 95% reduction of

[0333] (bf) Change in shortness of breath compared to baseline, placebo-controlled, and / or untreated patients No, or at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least About 40%, at least about 45%, at least about 50%, at least about 55%, at least About 60%, at least about 65%, at least about 70%, at least about 75%, at least About 80%, at least about 85%, at least about 90%, or at least about 95% lower decrease,

[0334] (bg) Heart rate changes compared to baseline, placebo-controlled, and / or untreated patients No, or at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least About 40%, at least about 45%, at least about 50%, at least about 55%, at least About 60%, at least about 65%, at least about 70%, at least about 75%, at least About 80%, at least about 85%, at least about 90%, or at least about 95% lower decrease,

[0335] (bh) Spleen size at baseline, in placebo-controlled, and / or untreated patients No change, or at least about 5%, at least about 10%, at least about 15%, or less At least about 20%, at least about 25%, at least about 30%, at least about 35%, or less At least about 40%, at least about 45%, at least about 50%, at least about 55%, or less At least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, at least about 85%, at least about 90%, or at least about 95% reduction of

[0336] (bi) liver size at baseline, placebo control, and / or for untreated patients No change, or at least about 5%, at least about 10%, at least about 15%, or less At least about 20%, at least about 25%, at least about 30%, at least about 35%, or less At least about 40%, at least about 45%, at least about 50%, at least about 55%, or less At least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, at least about 85%, at least about 90%, or at least about 95% reduction of

[0337] (bj) Change in dactylitis compared to baseline, placebo-controlled, and / or untreated patients None, or at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% reduction ,

[0338] (bk) Baseline, placebo-controlled, and / or treatment-naive patients: No change, or at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least at least about 80%, at least about 85%, at least about 90%, or at least about 95% reduction,

[0339] (bl) Abnormal clots compared to baseline, placebo control, and / or untreated patients No change in the occurrence of, or at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, At least about 60%, at least about 65%, at least about 70%, at least about 75%, At least about 80%, at least about 85%, at least about 90%, or at least about 95% reduction,

[0340] (bm) Red blood cell distribution for baseline, placebo-controlled, and / or untreated patients No change, or at least about 5%, at least about 10%, at least about 15%, or less At least about 20%, at least about 25%, at least about 30%, at least about 35%, or less At least about 40%, at least about 45%, at least about 50%, at least about 55%, or less At least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, at least about 85%, at least about 90%, or at least about 95% reduction of

[0341] (bn) Reticulocyte counts for baseline, placebo-controlled, and / or untreated patients No change in number, or at least about 5%, at least about 10%, at least about 15%, or a small change at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least at least about 80%, at least about 85%, at least about 90%, or at least about 95% % reduction, and / or

[0342] (bo) Fibrinolysis for baseline, placebo-controlled, and / or untreated patients No change in gen concentration, or at least about 5%, at least about 10%, or at least about 15% , at least about 20%, at least about 25%, at least about 30%, at least about 35% , at least about 40%, at least about 45%, at least about 50%, at least about 55% , at least about 60%, at least about 65%, at least about 70%, at least about 75% , at least about 80%, at least about 85%, at least about 90%, or at least Approximately 95% reduction.

[0343] Without further explanation, one skilled in the art can, using the preceding description and the following illustrative examples, It is believed that the indicated agents can be made and utilized to practice the claimed methods. The following examples are provided to facilitate the practice of the present disclosure and in no way constitute a limitation on the present disclosure. The remainder should not be construed as limiting. [Example]

[0344] Example 1: Unilateral ureteral obstruction-induced renal interstitial fibrosis The purpose of this study was to investigate the effect of DS109 (15-HETr) on UUO-induced renal interstitial fibrosis. E) and DS102 (15-HEPE).

[0345] Figure 1 shows the study design from surgery and treatment through day 14 of the study.

[0346] 1.1 Materials and Methods Test substances: The test substances in this study were DS109 (15-HETrE) and DS102 ( To prepare the dosing solution for each substance, DS109 was first weighed. and then in a vehicle of 0.5% hydroxypropyl methylcellulose (HPMC). and DS102 was diluted in a vehicle of 0.5% HPMC.

[0347] UUO surgery: On day 0 of the study, mice were anesthetized with sodium pentobarbital for UUO surgery. Surgery was performed. First, the mouse's hair was shaved, and then an abdominal incision was made to expose the left ureter of the mouse. The ureter was ligated at two points with 4-0 nylon sutures. The skin was closed with sutures and the mice were transferred to clean cages until they recovered from anesthesia. In mice, the left ureter was exposed but not ligated.

[0348] Drug administration: DS109 and DS109 in a volume of 10 milliliters (mL) / kilogram (Kg). DS102 was orally administered to mice.

[0349] Therapeutic Dose: DS109 is available in three doses: 5, 50, and 250 milligrams (mg) / kg. DS102 was administered once daily at dose levels of 50 and 500 mg / kg on days 0 through 13 of the study. The two dose levels were administered once daily from days 0 to 13 of the study.

[0350] Animals: Seven-week-old female C57BL / 6 mice (i.e., animals) were purchased from Japan SLC, The mice were obtained from Inc. (Japan), raised under controlled conditions, and fed a normal diet (CE-2, CLEA The animals were kept in a controlled environment, with temperature (e.g., 23±2°C), humidity (e.g., 100°F), and humidity (e.g., 100°F). For example, 45±10%), lighting (for example, a 12-hour artificial light-dark cycle, 8:00–2:00 The mice were reared in a specific pathogen-free (SPF) facility under controlled lighting conditions (lights on at 0:00) and ventilation. Hyperbaric pressure was maintained in the laboratory to prevent contamination of the facility. Animals were housed in cages with a maximum of four mice. The mice were kept in TPX cages (CLEA Japan) containing sterile paper cling films. The bedding was made of soft plastic (Japan SLC) and was changed once a week. Sterile solid normal food was provided ad libitum in a lid. Pure water was also provided ad libitum from a water bottle, which was changed once a week, washed, and sterilized in an autoclave. Mice were identified by ear punch and each cage was given a specific identification code. .

[0351] Measurement of renal biochemistry: To quantify renal hydroxyproline content, frozen left kidneys were used. The kidney samples were treated with alkaline acid hydrolysis as follows: the kidney samples were heated at 65°C for 2 h. Dissolve in normal (N) sodium hydroxide (NaOH) and autoclave at 121°C for 20 minutes. The dissolved sample (400 μL) was treated with 400 μL of 6N hydrochloric acid (HCl). The mixture was acid hydrolyzed at 121°C for 20 minutes and then added to 400 μL of 10 mg / mL activated carbon. Neutralized with 4N NaOH. AC buffer (e.g., 2.2M acetic acid / 0.48M citric acid) Acid (400 μL) was added to the sample, followed by centrifugation and collection of the supernatant. The phosphorus standard curve was trans-4-hydroxy-L-proline starting at 16 μg / mL. The samples and standards were prepared by serial dilution of 100mg of PEG-400 (Sigma-Aldrich, USA). The quasi-solution (e.g., 400 μL each) was mixed with 400 μL of chloramine T solution (Wako Pure Chemical Industries, Japan) and incubated at room temperature for 25 minutes. The sample was then mixed with Ehrlich's solution (e.g., 400 μL) and incubated for 6 h. Color was developed by heating at 5°C for 20 minutes. Samples were cooled on ice and centrifuged to remove precipitate. Afterwards, the optical density of each supernatant was measured at 560 nanometers (nm). The protein concentrations of kidney samples were calculated from a hydroxyproline standard curve. Cinchoninic Acid (BCA) Protein Assay Kit (Thermo Fisher Scientific Hydroxyproline values ​​were measured and calculated using a chromatographic method (Centific, USA). Kidney hydroxyproline content was calculated as micrograms per mg of protein. The values ​​were expressed as log (μg).

[0352] Histopathological analysis: To visualize collagen deposition, kidney sections were visualized using picrosirius. Staining was performed using thread solution (Waldeck, Germany). Interstitial fibrosis areas For quantification of the area, bright-field images of the corticomedullary region were taken with a digital camera (e.g., D FC295, Leica Microsystems, Germany) The positive areas in five fields / sections were captured at 10x magnification and analyzed using ImageJ software. Using the National Institute of Health, USA and measured.

[0353] Quantitative RT-PCR: RNAiso (Takara Bio, Japan) was used. Total ribonucleic acid (RNA) was extracted from kidney samples according to the manufacturer's instructions. 1 μg of RNA 4.4 micromolar (mM) magnesium chloride (Mg Cl2)(F.Hoffmann-La Roche,Switzerland), 40 0.5 mM RNase inhibitor (Toyobo, Japan), 0.5 mM dNTP (Prom ega, USA), 6.28 μM random hexamer (Promega), 5x1 strand buffer (Promega), 10 mM dithiothreitol (Invitrogen) gen, USA), and 200 U of MMLV-RT (Invitrogen). The reaction was performed at 37°C for 1 hour, followed by 99°C for 5 minutes. Real-time PCR was performed using DICE and TB Green™ Premix E. x Real-time PCR was performed using Taq™ II (Takara Bio) To calculate the relative expression levels of microRNAs (mRNAs), we used the For example, the expression of α-SMA, TIMP-1, TGF-β, and type 1 collagen is Normalized to the expression of gene 36B4 (gene symbol: Rplp0). Information about the assay set and plate layout is provided in Tables 1 and 2.

[0354] [Table 1]

[0355] [Table 2]

[0356] Sample collection: For serum samples, anticoagulant-free serum separation was performed by direct cardiac puncture. Non-fasting blood was collected into a tube and centrifuged at 3,500 x g for 4 minutes at 4°C. The supernatant was collected and stored at -80°C for transport. For kidney samples, the left kidney was collected. The upper part of the left kidney was fixed in Bouin's solution and then embedded in paraffin. The paraffin blocks were stored at room temperature for histological analysis. The anterior part of the left kidney was snap-frozen in liquid nitrogen and used for gene expression assays. The posterior portion of the left kidney was snap-frozen in liquid nitrogen and stored at -80°C for renal biochemistry. Stored at -80°C.

[0357] Statistical tests: Statistical analyses were performed using GraphPad Prism 6 (GraphPad Software The Bonferroni multiple comparison test was performed using the software (ftware Inc., USA). A P value of <0.05 was considered statistically significant. A one-tailed t-test returned a P value <0.1. When a trend or tendency was observed, it was assumed that there was a trend. Results are presented as mean ± SD It was expressed as:

[0358] 1.2 Experimental design and treatments The research design included the following study arms: Group 1 (sham control): Eight sham-operated mice remained without any treatment until sacrifice. Group 2 (vehicle): Eight UUO mice received 10 mg of vehicle [0.5% HPMC]. The drug was orally administered once daily at a volume of mL / kg from day 0 to day 13. Group 3 (DS109 low): Eight UUO mice received 5 doses of vehicle supplemented with DS109. The drug was orally administered at a dose of mg / kg once daily from day 0 to day 13. Group 4 (in DS109): 8 UUO mice received 5 doses of vehicle supplemented with DS109. The drug was orally administered once daily at a dose of 0 mg / kg from day 0 to day 13. Group 5 (DS109 high): Eight UUO mice received 2 doses of vehicle supplemented with DS109. The drug was orally administered once daily at a dose of 50 mg / kg from day 0 to day 13. Group 6 (DS102 low): Eight UUO mice received 5 doses of vehicle supplemented with DS102. The drug was orally administered once daily at a dose of 0 mg / kg from day 0 to day 13. Group 7 (DS102 high): Eight UUO mice received 5 doses of vehicle supplemented with DS102. The test was orally administered once daily at a dose of 000 mg / kg from day 0 to day 13.

[0359] Table 3 summarizes the treatment schedule for each of the study groups 1–7. .

[0360] [Table 3]

[0361] Animal monitoring and sacrifice: Mice were monitored daily for survival, clinical signs, and behavior. , and daily during the treatment period. Approximately 60 minutes after each administration, toxicity, moribundity, and death were assessed. Mice were observed for significant clinical signs. Animals were anesthetized with isoflurane (Pf The animals were sacrificed by exsanguination via direct cardiac puncture under a microscope (Microscope Inc.).

[0362] 1.3 Results Weight Change and General Considerations: Figure 2 shows the weight change of all animals. In the control group, body weight decreased after surgery and gradually recovered during the treatment period. The mean body weight of the vehicle group was On days 2-5 and 10-11, the mean body weights of the rats were significantly lower than those of the sham control group. There was no significant difference in mean body weight between the vehicle and treatment groups on any day during the treatment period. No animals died in any of the groups during the treatment period. None of the animals showed any deterioration in their general condition.

[0363] Body weight and kidney weight on the day of sacrifice: Figure 3 and Table 4 show the body weight of the animals on the day of sacrifice. There was no significant difference in mean body weight on the day of sacrifice between the vehicle group and the treatment group. There was no significant difference in mean body weight on the day of slaughter between the groups.

[0364] [Table 4]

[0365] Figures 4A-4D and Table 4 show the kidney weights and kidney weight to body weight ratios of the animals on the day of sacrifice. The vehicle group showed a significant increase in mean right kidney weight compared to the sham control group. There was no significant difference in mean right kidney weight between the vehicle and treatment groups. The mean right kidney weight to body weight ratio was significantly increased compared to the sham control group. There was no significant difference in mean right kidney weight to body weight ratio between the vehicle and sham treatment groups. There was a significant increase in mean left kidney weight compared to the control group. There was no significant difference in mean left kidney weight. Finally, the vehicle group had a significantly lower mean left kidney weight compared to the sham control group. There was a significant increase in the mean left kidney weight to body weight ratio, but no significant difference in mean left kidney weight between the vehicle and treatment groups. There was no significant difference in kidney weight-to-body weight ratio.

[0366] Kidney Chemistry: Figure 5 and Table 5 show the kidney hydroxyproline content of the animals. The DS1 group showed a significant increase in renal hydroxyproline content compared to the sham control group. The DS109 low, DS109 high, DS102 low, and DS102 high groups had significantly higher renal function compared to the vehicle group. The results showed a significant decrease in liver hydroxyproline content between the vehicle group and the DS109 medium group. There was no significant difference in renal hydroxyproline content.

[0367] [Table 5]

[0368] Histological analysis: Figures 6A-6G and Table 6 show Sirius Red staining, and Figure 7 shows the histological analysis of the animals. Figure 6A shows a representative photomicrograph of a kidney section stained with Sirius Red, showing areas of fibrosis. The vehicle group showed a significant decrease in fibrotic area (Sirius Red positive area) compared to the sham control group. The Bonferroni multiple comparison showed a significant increase in the proportion of The fibrotic area was found to be reduced compared to the vehicle group. There were no significant differences in fibrosis area between the RA group and other treatment groups. Notable outliers exist. A Mann-Whitney U test was conducted to determine the correlation coefficients for DS109 low, DS109 medium, DS109 high, The fibrotic area in the DS102 low and DS102 high groups tended to be reduced compared to the vehicle group. It was revealed that (p<0.1).

[0369] [Table 6]

[0370] Gene expression analysis: α-SMA, TIMP-1, TGF-β, and type 1 collagen Gene expression analysis is shown in Figures 8A-8D and Table 7.

[0371] [Table 7]

[0372] α-SMA: The vehicle group showed significant improvement in α-SMA mRNA expression levels compared to the sham control group. There was a significant increase in the mRNA expression level of α-SMA between the vehicle and treatment groups. There was no significant difference.

[0373] TIMP-1: The vehicle group showed significantly lower TIMP-1 mRNA expression levels compared to the sham control group. There was a significant increase in TIMP-1 mRNA expression levels between the vehicle and treatment groups. There was no significant difference in bell.

[0374] TGF-β: The vehicle group showed a significant decrease in TGF-β mRNA expression levels compared to the sham control group. There was a significant increase in the mRNA expression level of TGF-β between the vehicle and treatment groups. There was no significant difference.

[0375] Type 1 collagen: The vehicle group showed significantly lower mRNA expression levels of type 1 collagen compared to the sham control group. There was a significant increase in the level of type 1 collagen mRNA between the vehicle and treatment groups. There was no significant difference in expression levels.

[0376] 1.4 Summary Renal glands, as indicated by Sirius Red staining and kidney hydroxyproline content Fibrosis was established in the vehicle group of the study.

[0377] DS109: Treatment with low doses of DS109 significantly reduced renal hydroxylation compared to the vehicle group. There was a significant decrease in lorin content (p<0.05) and a tendency toward a decrease in fibrotic area (p<0.1). Treatment with medium dose DS109 tended to reduce the fibrosis area compared to the vehicle group ( Finally, treatment with high doses of DS109 significantly reduced the risk of rheumatoid arthritis compared to the vehicle group. Significant reduction in renal hydroxyproline content (p<0.05) and a trend towards reduced fibrotic area (p<0.1) was shown.

[0378] DS102: Treatment with low doses of DS102 significantly reduced renal hydroxylation compared to the vehicle group. Significant reduction in lorin content (p<0.05) and a tendency towards reduction in fibrotic area (p<0.1) Treatment with high doses of DS102 significantly reduced renal hydroxyproline compared to the vehicle group. The results showed a significant reduction in the fibrosis area (p<0.1) and a tendency toward a reduction in the fibrosis area (p<0.05). did.

[0379] In conclusion, the results from this study suggest that DS109 and DS102 have an important role in renal fibrosis. It has inhibitory effects against fibrosis and has the potential to be a therapeutic agent for chronic kidney disease that progresses to fibrosis. This suggests that:

[0380] Example 2: Cholestatic Liver Disease and / or Liver Fibrosis Bile Duct Ligation (BDL) Study The purpose of this study was to evaluate the effect of DS012 on BDL-induced cholestasis. It was to investigate.

[0381] Figure 9 shows the study design from surgery and treatment through day 14 of the study.

[0382] 1.1 Materials and Methods Test Substance: The test substance for this study was DS102. Dosing solutions for each substance were prepared. To achieve this, DS102 was mixed with 0.5% hydroxypropyl methylcellulose (HPMC) Diluted in vehicle.

[0383] BDL surgery: On day 0 of the study, pentobarbital (Kyoritsu Seiyak BDL surgery was performed under anesthesia (U, Japan). First, the mouse hair was shaved and the abdominal cavity was incised. The common bile duct was opened and ligated twice with 7-0 surgical silk. The peritoneum and skin of the mouse were sutured. The catheter was closed and the mouse was transferred to a clean cage (e.g., a resting cage) until it recovered from anesthesia. In sham-operated mice, the common bile duct was exposed but not ligated.

[0384] Drug administration: 10 milliliters (mL) / kilogram (Kg) via DS102 It was administered orally.

[0385] Therapeutic Doses: DS102 is available in three doses: 50, 250, and 500 milligrams (mg) / Kg. The dose levels were administered once daily from days 0 to 13 of the study.

[0386] Animals: Pathogen-free, 6-week-old male C57BL / 6J mice were obtained from Japan SLC, The animals were obtained from the University of Tokyo, Inc. (Japan). The animals were kept under controlled temperature (e.g., 23±2°C), humidity (e.g., For example, 45±10%), lighting (for example, a 12-hour artificial light-dark cycle, 8:00–2:00 The mice were reared in a specific pathogen-free (SPF) facility under controlled lighting conditions (lights on at 0:00) and ventilation. Hyperbaric pressure was maintained in the laboratory to prevent contamination of the facility. Animals were housed in cages with a maximum of four mice. The mice were kept in TPX cages (CLEA Japan) containing sterile paper cling films. The bedding was made of soft plastic (Japan SLC) and was changed once a week. Sterile solid normal food was provided ad libitum in a lid. Pure water was also provided ad libitum from a water bottle, which was changed once a week, washed, and sterilized in an autoclave. Mice were identified by ear punch and each cage was given a specific identification code. .

[0387] Serum biochemistry measurements: Bouin's fixed liver sections were used to visualize collagen deposition. , staining was performed using picrosirius red solution (Waldeck, Germany). For quantification of fibrotic areas, bright-field images of Sirius Red stained sections were digitally captured. The images were captured at 100x magnification using a Leica camera (DFC295, Leica, Germany). The positive areas in five fields / sections were analyzed using ImageJ software (Nati Measurements were performed using the National Institutes of Health (USA).

[0388] Histological analysis: To visualize collagen deposition, kidney sections were visualized using a picrosirius filter. The interstitial fibrosis areas were stained using a fibrotic solution (Waldeck, Germany). For quantification, bright-field images in the corticomedullary region were captured using a digital camera (e.g., DFC). 295, Leica Microsystems, Germany) at 200x magnification. The positive areas in five fields / sections were captured at a magnification of 100x and analyzed using ImageJ software. (National Institute of Health, USA) It was determined.

[0389] Quantitative RT-PCR: RNAiso (Takara Bio, Japan) was used. Total ribonucleic acid (RNA) was extracted from liver samples according to the manufacturer's instructions. 1 μg of RNA 4.4 mM magnesium chloride (MgCl) (F. Hof) in a final volume of 20 μL fmann-La Roche, Switzerland), 40 U of RNase inhibitor (Toyobo, Japan), 0.5 mM dNTP (Promega, USA), 6 0.28 μM random hexamers (Promega), 5x first strand buffer ( Promega), 10 mM dithiothreitol (Invitrogen, USA), and 200 U of MMLV-RT (Invitrogen) were used. The reaction was carried out at 37°C for 1 hour, followed by 99°C for 5 minutes. PCR DICE and TB Green™ Premix Ex Taq™ I Real-time PCR was performed using I (Takara Bio). To calculate the expression level of each gene (e.g., α-SMA, TIMP-1, TG Reference gene 36B4 (gene symbol: Rplp0) for expression of F-β and type 1 collagen PCR primer sets and plate layout The information is set out in Tables 8 and 9.

[0390] [Table 8]

[0391] [Table 9]

[0392] Sample collection: For serum samples, anticoagulant-free serum separation was performed by direct cardiac puncture. Non-fasting blood was collected into a tube and centrifuged at 3,500 x g for 4 minutes at 4°C. The supernatant was collected and stored at -80°C for biochemistry (30 μL) and transport (all remaining). For liver samples, the left lateral lobe was harvested and cut into six pieces. Two pieces of the left lateral lobe were fixed in Bouin's solution. The tissue was then immobilized in paraffin and stored at room temperature for histological analysis. The other two pieces of the left lateral lobe were embedded in OCT compound and flash frozen in liquid nitrogen. The remaining part of the left lobe was snap frozen in liquid nitrogen and stored at 4°C for gene expression analysis. The right middle lobe, left middle lobe, right lobe, and caudate lobe were quickly frozen in liquid nitrogen and transported. The mixture was stored at -80°C for further analysis.

[0393] Statistical tests: Statistical analyses were performed using GraphPad Prism 6 (GraphPad Software The Bonferroni multiple comparison test was performed using the software (ftware Inc., USA). A P value of <0.05 was considered statistically significant. A one-tailed t-test returned a P value <0.1. When the data were collected, it was assumed that there was a trend or tendency. , expressed as mean ± SD.

[0394] 1.2 Experimental design and treatments The research design included the following study arms: Group 1 (sham control): Eight sham-operated mice remained without any treatment until sacrifice. Group 2 (vehicle): 15 mice that underwent BDL surgery were treated with vehicle [0.5% H PMC] was orally administered once daily at a volume of 10 mL / kg from day 0 to day 13. Group 3 (DS102 low): 15 mice undergoing BDL surgery were supplemented with DS102. The vehicle was orally administered at a dose of 50 mg / kg once a day from day 0 to day 13. Group 4 (DS102): 15 mice undergoing BDL surgery were supplemented with DS102. The vehicle was orally administered at a dose of 250 mg / kg once a day from day 0 to day 13. Group 5 (DS102 high): 15 mice undergoing BDL surgery were supplemented with DS102. The vehicle was orally administered at a dose of 500 mg / kg once a day from day 0 to day 13.

[0395] Table 10 summarizes the treatment schedule for each of the study arms 1–5. do.

[0396] [Table 10]

[0397] Animal monitoring and sacrifice: Mice were monitored daily for survival, clinical signs, and behavior. , and daily during the treatment period. Approximately 60 minutes after each administration, toxicity, moribundity, and death were assessed. Mice were observed for significant clinical signs. Animals were treated with isoflurane on day 14 after BDL surgery. The animals were sacrificed by exsanguination via direct cardiac puncture under acetaminophen anesthesia (Pfizer Inc.).

[0398] 1.3 Results Weight Change and General Considerations: Figure 10 shows the weight change of all animals. In all groups except for the vehicle group, mean body weight gradually decreased over the course of the study. The mean body weight of the vehicle group was significantly lower than that of the sham control group on days 2 to 14. There were no significant changes in mean body weight between the S102 treatment groups on any day during the study period. There wasn't.

[0399] During the treatment period, the following mice were confirmed dead before the 14th day: In the vehicle group, 3 out of 15 mice died, and DS102 Seven of 15 mice died in the low, DS102 medium, and DS102 high groups. This model simply predicted the proportion of disease-induced deaths and not the observed deaths. The mortality rates are consistent with historical data.

[0400] Body weight and liver weight on the day of sacrifice: Figure 11 and Table 11 show the body weight of the animals on the day of sacrifice. The DS group showed a significant reduction in mean body weight on the day of sacrifice compared to the sham control group. There were no significant differences in mean body weight on the day of sacrifice between the 102 treatment groups.

[0401] [Table 11]

[0402] 12A and 12B and Table 11 show the liver weights and liver weight to body weight ratios of the animals on the day of sacrifice. The vehicle group showed a significant increase in mean liver weight compared to the sham control group. The mean liver weight of the O2-high group tended to be lower than that of the vehicle group. There were no significant differences in mean liver weights between the other treatment groups. The vehicle group was significantly different from the sham control group. The mean liver weight to body weight ratio of the DS102 high group was significantly increased compared to the mean liver weight to body weight ratio of the DS102 high group. The body weight ratio tended to decrease compared to the vehicle group. There was no significant difference in the mean liver weight-to-body weight ratio.

[0403] Biochemistry: Figure 13 and Table 12 show serum aminotransferases (ALT) of animals The vehicle group showed a significant increase in serum ALT levels compared to the sham control group. There was no significant difference in serum ALT levels between the DS102-treated and DS102-treated groups. However, previous data from this model showed that ALT levels decreased by day 14 without treatment. Therefore, this may affect the ability to detect differences between groups. do.

[0404] [Table 12]

[0405] Figure 14 and Table 12 show the serum total bilirubin of the animals. The vehicle group was compared to the sham control group. The serum total bilirubin level was significantly increased in the vehicle group compared with the DS102-treated group. There was no significant difference in serum total bilirubin levels between the groups.

[0406] Histological analysis: Figures 15A-14E and Table 13 show Sirius Red staining, and Figure 16 The graph shows the fibrotic areas of the animals. Figure 14A shows a representative image of a liver section stained with Sirius Red. The liver sections from the vehicle group showed significantly increased portal vein function in the hepatic lobule compared to the sham control group. showed increased collagen deposition in the PV-CV or PV-PV bridging fibrosis. The vehicle group showed a significant increase in fibrotic area (Sirius Red positive area) compared to the sham control group. The DS102 medium group showed a significant reduction in the fibrosis area compared to the vehicle group. The fibrotic area in the DS102 high group tended to be reduced compared to the vehicle group. There was no significant difference in the fibrosis area between the DS102 low and DS102 low groups.

[0407] [Table 13]

[0408] Gene expression analysis: α-SMA, TIMP-1, TGF-β, and type 1 collagen All gene expression analyses are shown in Figures 17A to 17D and Table 14.

[0409] [Table 14]

[0410] α-SMA: The vehicle group showed significant improvement in α-SMA mRNA expression levels compared to the sham control group. The mRNA expression level of α-SMA in the DS102 high group was significantly higher than that in the vehicle group. There was a tendency for the α-SMA to decrease compared to the vehicle group. There was no significant difference in the mRNA expression levels.

[0411] TIMP-1: The vehicle group showed significantly lower TIMP-1 mRNA expression levels compared to the sham control group. The mRNA expression level of TIMP-1 in the DS102 high group was significantly higher than that in the vehicle group. There was a tendency for TI to be reduced compared to the DS102-treated group. There was no significant difference in the mRNA expression level of MP-1.

[0412] TGF-β: The vehicle group showed a significant decrease in TGF-β mRNA expression levels compared to the sham control group. The DS102 high group showed a significant increase in TGF-β mRNA expression compared to the vehicle group. There was a significant decrease in the levels of TGF-β between the vehicle and DS102 treatment groups. There was no significant difference in mRNA expression levels.

[0413] Type 1 collagen: The vehicle group showed significantly lower mRNA expression levels of type 1 collagen compared to the sham control group. The mRNA expression level of type 1 collagen in the DS102 high group was significantly increased. The difference between the vehicle group and the DS102-treated group was However, there was no significant difference in the mRNA expression level of type 1 collagen.

[0414] 1.4 Summary In this study, the biochemical parameters (e.g., ALT and total bilirubin) of the vehicle group were ), histological collagen deposition (e.g., areas of fibrosis), and gene expression levels (e.g., , α-SMA, TIMP-1, TGF-β, and type 1 collagen) were significantly increased compared to the sham control group. These results suggest that cholestasis and liver fibrosis were established in the vehicle group. suggested.

[0415] Treatment with medium dose DS102 resulted in a significant reduction in fibrosis area compared to the vehicle group (p<0.05). Treatment with high doses of DS102 significantly increased TGF-β expression compared to the vehicle group. There was a significant decrease in the mRNA expression level (p<0.05), as well as in the fibrosis area, liver weight, and liver Liver weight-to-body weight ratio, mRNA expression levels of α-SMA, TIMP-1, and type 1 collagen These results suggest that DS102 significantly reduces the amount of erythropoietin in the liver. It inhibits the production of multiple pro-fibrotic cytokines in liver and has the effect of suppressing liver fibrosis. , showing potential as a therapeutic agent for cholestatic liver disease.

[0416] Example 3: TGF-β receptors, signaling, and D for inducible fibrotic proteins Effects of S102 The purpose of this study is to clarify the role of TGF-β receptors, TGF-β-induced intracellular signaling, and fibroblast growth factor receptors (FGFs). 15-HEPE and 15-HEPE on the expression of profibrotic epithelial-mesenchymal transition proteins The purpose of this study was to investigate the effects of EE.

[0417] 1.1 Materials and Methods Cytotoxicity test: The cytotoxicity of 15-HEPE free acid and ethyl ester was evaluated in various liver (liver The compound was tested in a number of different cell lines (e.g., 100-1500 cells / cell carcinoma) to understand the concentration range in the test system.

[0418] Transcriptional activity: Promoter (luciferase) assay was performed to assess the activity of 15-HEPE. TGFβ-induced transcriptional activation was measured after administration of β-lactams.

[0419] Sucrose-induced TGF-β Receptor Transfection Using Sucrose Gradient Ultracentrifugation and Confocal Microscopy 15-HEPE-induced microdomain migration was identified. Sucrose density of TGF-β receptor The gradient analysis consisted of 100 μM 15-HEPE and an equal volume of DMSO (dimethyl sulfoxide). Mv1Lu cells (mink lung epithelial cells) treated with 1000kJ / mL IgG4 (B1) for 0, 1, 4, and 24 hours at 37°C. ) plasma membranes, and cell lysates from these treated cells were analyzed on a sucrose density gradient. The sucrose gradient fraction was then subjected to ultracentrifugation. anti-TβR-II (type II TGF-β receptor), anti-TβR-III (type III TGF-β receptor) -β receptor, betaglycan), anti-EGFR (epidermal growth factor receptor), and anti-caveolin The cells were analyzed by Western blot using the 15-HE antibody. TβR-I, TβR-II, and TβR-III in the plasma membrane of cells treated with PE Lipid raft / caveolae and non-lipid raft microdomains of EGFR and caveolin-1 To assess the localization of TGF-β receptors, 15-H was used to assess the membrane microdomain localization of TGF-β receptors. The effect of EPE was determined.

[0420] 1.2 Results The effects of 15-HEPE on TGF-β-induced signaling and cellular responses were determined. To test the effect of 15-HEPE on TGF-β-induced signaling, TG We tested the activity of 15-HEPE in regulating F-β-stimulated Smad2 phosphorylation and nuclear translocation. Both of these are important signaling events that lead to TGF-β-induced cellular responses. One of the important biological activities of TGF-β is its role in causing epithelial-mesenchymal transition (EMT). transcriptional activation of genes, which are important in wound healing, tissue fibrosis, and cancer progression TGFβ-induced epithelial-mesenchymal transition-related proteins in HepG2 and LXR cells 15-H on the expression of proteins (fibronectin, PAI-1, N-cadherin, etc.) The effect of EPE was evaluated. HepG2 cells (human liver cancer cell line) were cultured in 0.1% FBS. Treatment with increasing doses of 15-HEPE Stage II in DMEM containing 1% DMSO for 1 hour followed by The cells were stimulated with or without 200 picomolar (pM) TGF-β for 48 hours.

[0421] 15-HEPE directly inhibits TGF-β signaling as shown in Figures 18A and 18B. Specifically, Figure 18A shows that 15-HEPE inhibited the degradation of type II TGF-β receptor. induces TGF-β-induced epithelial-mesenchymal transition (EMT) (i.e., profibrotic). HepG2 cells (human liver cancer cell line) were used to investigate the effect of ATP on the production of ATP-dependent protein. Increasing doses of 15-HEPE stage II were cultured in DMEM containing 0.1% FBS for 1 h. followed by 48 hours with or without 200 picomolar (pM) TGF-β. The two panels shown in Figure 18A are from two separate experiments performed under the same experimental conditions. The results from these separate experiments indicated that 15-HEPE was induced by TGF-β. The study blocked the production of EMT proteins involved in TGF-β activation and induced the degradation of type II TGF-β receptors. Figure 18A shows that TGF-β-induced tumors are associated with increased cardiovascular risk. 15-H against the protein plasminogen activator inhibitor-1 (PA-1) The effect of EPE is also shown. Figure 18B shows that 15-HEPE inhibits TGF-β-stimulated hepatic stellate cells. It is shown to inhibit intracellular signaling (e.g., phosphorylation of SMAD2 / 3). For the experiments performed in 8B, LX2 cells (human hepatic stellate cells) were increased in concentration from 0 μM to 100 μM. This included 24-hour pretreatment with DS102 at various concentrations followed by 30-minute TGF-β stimulation. The results of the experiment showed that 15-HEPE inhibited TGF-β stimulation.

[0422] 15-HEPE sucrose density gradient analysis of TGF-β receptors was performed using 100 μM 15-HEPE. E and an equal volume of dimethyl sulfoxide (DMSO) at 37°C for 0, 1, 4, and 24 h. The plasma membranes of mink lung epithelial cells (Mv1Lu) treated with 2-HT2F were analyzed. The cell lysate from the purified cells was subjected to sucrose density gradient ultracentrifugation. The fractions were then purified using the following antibodies: anti-TβR-I (type I TGF-β receptor - Figure 18C), anti-TβR-II (type II T GF-β receptor - Figure 18D), anti-TβR-III (type III TGF-β receptor, beta-tag anti-EGFR (epidermal growth factor receptor - Figure 18F), and anti-caveolin Fractions 4 and 5 were analyzed by Western blot using the IgG-1 antibody (Figure 18G). contained lipid rafts / caveolae, whereas fractions 7–10 were non-lipid raft fractions. Treatment with 15-HEPE did not affect the abundance of TβR-I protein. However, 24-hour treatment induced the translocation of TβR-I to lipid rafts (Figure 18C). *) indicates that 15-HEPE was present in the fractions compared to the control and shorter treatment periods. The results show that 15-HEP increased the abundance of TβR-I (24 hours) (Fig. 18C). E induced translocation of TβR-II within 1–4 h and further degradation within 24 h of treatment. (Figure 18D). Triangles (▼) indicate the shift of TβR-II in the fraction compared to control cells. In Figures 18E, 18F, and 18G, the 1 5-HEPE alters the localization and abundance of TβR-III, EGFR, and caveolin-1. It did not become.

[0423] 1.3 Summary Therefore, taken together, these results indicate that both the free acid and ethyl ester forms 15-HEPE in this state induces the translocation and degradation of type II TGF-β receptors, and inhibits TGF-β induction. Blocks the production of TGF-β-induced profibrotic proteins and inhibits TGF-β-induced intracellular signaling in hepatic stellate cells. Therefore, 15-HEPE and 1 5-HEPE EE can directly inhibit TGF-β signaling, which is a non- Alcoholic steatohepatitis (NASH), other fibrotic diseases, cardiometabolic diseases, and 15-HEPE and 15-HEP in the treatment of multiple fibrotic disorders, including multiple manifestations of cancer These results support the potential for treatment of EEE.

[0424] Example 4: Efficacy of orally administered DS102 in patients with NAFLD The purpose of this study is to evaluate the treatment of adult patients with nonalcoholic fatty liver disease (NAFLD). To evaluate the efficacy of orally administered DS102 capsules versus placebo in the treatment of That was the case.

[0425] 1.1 Study endpoints Primary Endpoint: The primary endpoint of this study was the efficacy and safety of DS102 administration. Safety was included. Efficacy was assessed by serum alanine aminotransferase (ALT) levels from baseline to week 16. Changes in ALT and transient elastography from baseline to week 16 were assessed. Safety was assessed based on changes in liver stiffness measured at baseline. The number of TEAEs was assessed in each treatment group.

[0426] Secondary Endpoints: The secondary endpoints of this study included any one of the following: Changes in serum ALT from baseline to weeks 2, 4, 8, and 12 were included. Aspartate aminotransferases at baseline to weeks 2, 4, 8, 12, and 16 AST, AST:ALT ratio from baseline to weeks 2, 4, 8, 12, and 16, Fibrosis-4 (FIB-4) index from baseline to week 16, N from baseline to week 16 AFLD fibrosis score (NFS), controlled decay parameters from baseline to week 16 ( Changes in liver fat measured by CAP, enhanced liver fibrosis ( ELF) scores and homeostatic model scores from baseline to weeks 2, 4, 8, 12, and 16 Assessment of insulin resistance (HOMA-IR) and adipose tissue insulin resistance (adipo- IR).

[0427] Exploratory analyses: Exploratory analyses included total cholesterol, triglycerides, and very low-density lipoproteins. Very low density lipoprotein cholesterol (VLDL-C), low density lipoprotein cholesterol (LDL -C), high-density lipoprotein cholesterol (HDL-C), non-high-density lipoprotein Cholesterol (non-HDL-C), remnant-like particle cholesterol (RLP-C), empty Abdominal blood glucose, insulin, free fatty acids, and lipids such as hemoglobin A1C (HbA1C) Additional exploratory analyses included high-throughput lipid analysis and metabolic parameter analysis. These included genomics and proteomics.

[0428] 1.2 Research Plan This was a randomized, placebo-controlled, double-blind, parallel-group, multicenter exploratory phase IIa study. Safety of orally administered DS102 capsules in patients aged 18 to 75 years with NAFLD The efficacy and dose-response relationship between the two doses of DS102 and placebo were investigated. The study investigated three parallel groups of patients with confirmed NAFLD and included a 16-week treatment period. The study compared placebo with two different doses of DS102 over a period of time. Planned to include 96 evaluable patients with 32 randomized patients per treatment group was done.

[0429] The study consisted of a 28-day screening period, a 16-week treatment period, and a 4-week follow-up period. At the screening visit, patients were assessed using a screening test. Patients who met the inclusion criteria and no exclusion criteria were enrolled.

[0430] A schematic diagram of the overall timeframe of the study is provided in Figure 19. Once patients are enrolled in the study, NA The use of any other treatment for FLD was restricted. Any medication that, in the opinion of the investigator, will not interfere with the evaluation of safety and efficacy (e.g., prescription and over-the-counter (OTC) medications) or therapeutic interventions, if they are included in the "concomitant use" section below. Patients were allowed to continue taking these medications as long as they were not included in the list of "medications for which they are prescribed."

[0431] Before starting the comparison treatment period, patients returned to the center for a baseline evaluation of their disease. Eligible patients were randomized 1:1:1 to one of three parallel-arm treatment regimens. was assigned for Treatment Group A: Two 500 mg placebo capsules twice daily (four capsules daily) , administered orally for 16 weeks. Treatment Group B: One 500 mg capsule of DS102 and one 500 mg capsule of placebo One cell was administered orally twice daily (four capsules per day) for 16 weeks. Treatment Group C: Two 500 mg capsules of DS102 twice daily (four capsules daily) ), administered orally for 16 weeks.

[0432] To maintain double-blind conditions, the DS102 capsules and placebo capsules were visually inspected. were identical.

[0433] 1.3 Patients and Screening To participate in this study, patients must meet all of the following inclusion criteria: The inclusion and exclusion criteria were Tested at the cleaning visit (Visit 1) and at the start of treatment / baseline visit (Visit 2). Ta.

[0434] The inclusion criteria for this study were: NAFLD diagnosed by the presence of hepatic steatosis on imaging or histology in the absence of secondary causes Patients. ALT ≥ 1.5ULN and < 5ULN on two occasions at least 7 days apart during screening Patients with: NASH and / or fibrosis ≥ F1 or NF within 3 months of screening S is ≥ -1.455, or Fib-4 is ≥ 1.3, or Fibroscan is ≥ Patients with a previous liver biopsy showing 8 kPa. Patients with a body mass index (BMI) of 25.0 to 40.0 kg / m2. Patients with a history of obesity or controlled diabetes were allowed into the study. In the opinion of the investigator, pre-study clinical laboratory findings did not preclude participation in the study patient. Patients aged 18-75 years. Female patients and male patients with female partners of childbearing potential must use appropriate contraception during the study. Women had to use contraception or have their partners sterilized. Systemic hormonal contraceptives, intrauterine devices combined with spermicides, or barrier method of contraception or their preferred usual method for the entire duration of the risk associated with the study treatment. Agree to sexual abstinence, defined as the patient abstaining from heterosexual intercourse in accordance with the IFST format. Hormonal contraceptives must be on a stable dose for at least 1 month prior to baseline. There was a need. Communicate well with the investigator, understand and follow the requirements of the study, and complete the Patients who were able to understand and sign informed consent.

[0435] The exclusion criteria for this study were: Patients with unstable metabolic status, such as weight change of >5% in the 3 months prior to enrollment person. - History of gastric bypass surgery, orthotopic liver transplant (OLT), or Patients enrolled in LT. Uncontrolled type 2 diabetes, i.e., HbA1c ≥ 9% (75%) at screening Patients with ≥100 mmol / mol. Patients with decompensated or severe liver disease as evidenced by one or more of the following: cirrhosis If liver cirrhosis is confirmed or suspected, esophageal varices, ascites, portal hypertension, or Hospitalization for liver disease within 60 days of lean body mass index (BMI) > 2xULN, or ALT > 0.05. or AST ≥ 5 × ULN. Patients with Gilbert syndrome should be monitored for conjugated bilirubin. Bins were eligible if ≦1.5×ULN. Patients with active or medically treated inflammatory bowel disease. Autoimmune diseases such as systemic lupus erythematosus (SLE) and / or rheumatoid arthritis (RA) Patients diagnosed with or suspected of having the disease. Non-hepatic malignancies other than curatively treated skin cancer (basal cell carcinoma or squamous cell carcinoma) Patients with a history of or active tumor. Coronary artery disease, cerebrovascular disease, pulmonary disease, renal failure, serious mental illness, respiratory or hypertensive disease and any diabetes that, in the opinion of the investigator, precluded the patient from participating in and completing the study. Patients with serious systemic or critical illnesses other than liver disease, including diabetes, arthritis, etc. - Patients who require antidiabetic treatment (including insulin sensitizers) and / or lipid-lowering treatment and who have a history of stroke Patients who had not been on a stable dose for at least 3 months before lean were excluded. If the patient is insulin dependent, this treatment must have been discontinued for at least 3 months prior to screening. should have been initiated, but dose modifications were permitted. Patients with known hypersensitivity to any component of the investigational treatment. At screening, human immunodeficiency virus (HIV) antibodies, hepatitis B surface antigen, or are patients who test positive for hepatitis C antibodies. Drug-induced, autoimmune hepatitis, primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), hemochromatosis, alpha-1 antitrypsin (A1AT) deficiency, Wilson disease Patients with liver disease of other etiologies, such as liver cirrhosis. Patients with a significant medical history of drug / solvent abuse in the opinion of the investigator. -Have a history of alcohol abuse in the opinion of the investigator or consume 21 units (or more) of alcohol per week Patients who drink more than 10ml or 8ml of alcohol per week (men) or 14 units per week (women) g of pure alcohol). Use of dietary supplements rich in omega-3 or omega-6 fatty acids 4 weeks prior to baseline Patients who did. Participation in any other clinical study using an investigational drug within 3 months prior to the first day of study treatment Patients who did. - Pregnant, planning pregnancy, breastfeeding, and / or using adequate contraception during the study Patients who did not want to use Patients who, in the opinion of the investigator, were unsuitable for participation in the study.

[0436] 1.4 Conducting the Research During the study, 10 clinic visits were scheduled after the screening visit. Once at the start / baseline of the comparative treatment period (Day 0 / Visit 2) and eight times during the comparative treatment period (Week 2 / Visit 3, Week 4 / Visit 4, Week 6 / Visit 5, Week 8 / Visit 6, Week 10 / Visit Week 7, Week 12 / Visit 8, Week 14 / Visit 9, Week 16 / Visit 10). The follow-up visit (Visit 11) was 4 weeks after Visit 10 or if the patient did not complete the study. The study was conducted 2 weeks after the last visit attended. Table 17 describes the clinical visits of the study. It is something.

[0437] [Table 15] TIFF2025131596000016.tif74170

[0438] Screening Visit (Visit 1): The following screening visits:

[0439] Screening Visit (Visit 1): Once informed consent is obtained, patients are A screening number was assigned. Ideally, the patient was fasting. A screening assessment / sampling was performed, i.e., verification of inclusion / exclusion criteria, demographic data data, medical history, physical examination, 12-lead electrocardiogram (ECG), vital signs (blood pressure, heart rate, and and body temperature), samples for clinical laboratory safety tests (hematology, serum biochemistry, and coagulation tests), Pregnancy testing (for female patients with potential pregnancy), ALT and AST tests (screening) The unscheduled visits were for the assessment of adverse events (ALT) and concomitant medications. Adverse events (AEs), difficulty in adhering to study protocol requirements, or significant changes in disease status This occurred when a patient needed to visit between scheduled visit dates due to a medically necessary condition. If eligible, before leaving the clinic, patients were asked to have no further morning They were instructed not to eat and were given a minimum fasting period of 8 hours.

[0440] Treatment Period: After successful completion of the screening visit, patients will enter the comparative treatment period (16 weeks At the start of the comparison treatment period, after confirmation of continued eligibility, patients were assigned to one of three treatments. Patients were randomly assigned to one of two regimens: DS102 capsules or prothrombin time. Placebo capsules of the assigned investigational medicinal product (IMP) were administered twice daily during the comparative treatment period. Each self-administration of IMP was recorded on the patient's diary card. Patients were asked to take the dose in the morning and evening. Patients were instructed to take DS102 during or after meals (if patients had taken DS1 before the visit). Patients were instructed to refrain from taking DS102 and take DS102 as soon as possible after their clinic visit. (Excluding the mornings of clinic visits 3, 4, 6, 8, and 10). At the start of baseline (visit 2), Week 2 (Visit 3), Week 4 (Visit 4), Week 8 (Visit 6), Week 12 (Visit 8), Week 16 At week 1 (Visit 10), and week 20 (Visit 11), patients were asked to fast for at least 8 hours before the visit. If not fasting, the duration of the fasting period was documented and the patient was asked if they had fasted. Patients were then instructed again regarding the timing of the meal period. Juice and toast were provided at baseline (Visit 2), week 8 (Visit 8) ), and at week 16 (visit 10), blood sampling assessments were performed before patients had a light breakfast. Unscheduled visits may occur due to adverse events (AEs), difficulty in adhering to study protocol requirements, or other reasons. occurs when a patient needs to visit between scheduled visit dates due to a significant change in disease status. All medically necessary procedures were followed. Patients who discontinued the study early were excluded from all study Schedule visit 10 as soon as possible after patient withdrawal so that relevant information can be recorded. At the investigator's discretion, urinary DO was measured at any time during the study. A and alcohol breath tests were administered.

[0441] Baseline (Visit 2): Patients attended the study site at Visit 2. Blood samples were taken at the earliest possible time point. After blood sampling, the following evaluations were performed: verification of inclusion / exclusion criteria; , medical history, physical examination, 12-lead ECG, pharmacokinetic sampling, vital signs (blood pressure, cardiac and temperature), samples for clinical laboratory safety tests (hematology, serum biochemistry, and coagulation tests) , lipid profile, urine test, pregnancy test (for female patients of childbearing potential), AL T, AST test, HOMA-IR / Adipo-IR, ELF, liver stiffness and CAP, FI B-4, NFS (including BMI), biomarker blood samples, exploratory blood samples, patient Randomization, administration of study drug / placebo, AE evaluation, and evaluation of concomitant medications. If the criteria are met, the investigator will randomize the patient and administer one of the patient treatment packs. Patients were given their designated IMP or placebo. All baseline assessments were completed. Once the first dose of IMP or placebo was administered at the facility, patients received the second dose on the evening of Day 0. The patients received either a placebo or a dose of IMP. Participants received either IMP or placebo on the morning of their return visit to the facility (Visit 3). , patients were instructed not to eat breakfast at all before their next visit and to complete a minimum 8-hour fasting period. was given.

[0442] Week 2 (Visit 3): Patients returned to the study site at Visit 3. Patients were administered IMP or No placebo was administered. The following assessments were performed: physical examination, pharmacokinetic samples, and Ring, vital signs (e.g., blood pressure, heart rate, and temperature), ALT, AST test, H OMA-IR / Adipo-IR, AE evaluation, and evaluation of concomitant medications. The patient was given either IMP or placebo after the initial visit. Upon completion, patients received the next dose of IMP or placebo. Upon completion of this visit, patients were to return to the study site within 2 weeks for Visit 4. Patients were informed that they would need to take IMP or placebo on the morning of their return visit to the facility. Before leaving the clinic, patients were advised not to eat breakfast at all before their next visit. They were instructed to fast for at least 8 hours.

[0443] Week 4 (Visit 4): Patients returned to the study site at Visit 4. Patients were administered IMP or No placebo was administered. The following assessments were performed: physical examination, pharmacokinetic samples, and Ring, vital signs (blood pressure, heart rate, and temperature), clinical laboratory safety tests (hematology, blood Samples for serum biochemistry and coagulation tests, pregnancy tests (for female patients of childbearing potential) , ALT, AST test, HOMA-IR / Adipo-IR, AE evaluation, and evaluation of concomitant medications The IMP or placebo was returned, and the patient was given another dose of IMP or placebo. Patients received their next dose of IMP or placebo as soon as all visit assessments were completed. Patients continued to receive capsules twice daily. At the completion of this visit, patients were assessed for the steroid drug agonist ... Patients were informed that they would need to return to the study site within two weeks. did not receive IMP or placebo (Visit 5).

[0444] Week 6 (Visit 5): Patients returned to the study site at Visit 5. AE assessment and concomitant medication assessment were performed. The IMP or placebo was returned, and the patient was given another dose of IMP or placebo. As soon as the visit assessment was completed, patients received the next dose of IMP or placebo. The patients received capsules twice daily. At the completion of this visit, patients were scheduled to receive a follow-up of 10 mg / kg of steroids within 2 weeks at Visit 6. Patients were informed that they would need to return to the study site. Patients were asked to complete the IMP or No placebo was taken (Visit 6). Before leaving the clinic, patients were asked to refrain from taking any medication before their next visit. They were instructed not to eat breakfast and were given a minimum fasting period of 8 hours.

[0445] Week 8 (Visit 6): Patients returned to the study site at Visit 6. Patients were administered IMP or No placebo was administered. Blood sampling was the first evaluation performed. After blood sampling, the following evaluations were performed: The following were performed: physical examination, pharmacokinetic sampling, vital signs (blood pressure, heart rate, and body temperature), samples for clinical laboratory safety tests (hematology, serum biochemistry, and coagulation tests), lipids Quality profile, pregnancy test (for female patients of childbearing potential), ALT, AST tests Experiments, HOMA-IR / Adipo-IR, biomarker blood samples, AE assessment, and combination The IMP or placebo was returned, and the patient was given either the IMP or placebo. Participants received their next dose of IMP or placebo as soon as all visit assessments were completed. Patients continued to receive capsules twice daily. At the completion of this visit, patients received 2 capsules at Visit 7. Patients were informed that they would need to return to the study site within a week. They received IMP or placebo (Visit 7).

[0446] Week 10 (Visit 7): Patients returned to the study site at Visit 7 for AE assessment and concomitant medication assessment. The IMP or placebo was returned, and more IMP or placebo was provided to the patient. Participants received their next dose of IMP or placebo as soon as all visit assessments were completed. Patients continued to receive capsules twice daily. At the completion of this visit, patients received 2 capsules at Visit 8. Patients were informed that they would need to return to the study site within a week. No IMP or placebo was taken (Visit 8). Before leaving the clinic, patients were asked to They were instructed not to eat any breakfast before the interview and were given a minimum fasting period of 8 hours.

[0447] Week 12 (Visit 8): Patients returned to the study site at Visit 8. Patients were given IMP or The subjects did not receive placebo. The following assessments were performed: physical examination, pharmacokinetics sample, and Ploudping, vital signs (blood pressure, heart rate, and temperature), clinical laboratory safety tests (hematology, serum biochemistry and coagulation tests), pregnancy tests (for female patients of childbearing potential) ), ALT, AST test, HOMA-IR / Adipo-IR, AE evaluation, and concomitant medications The IMP or placebo was returned, and further IMP or placebo was provided to the patient. Patients will receive their next dose of IMP or placebo as soon as all visit assessments are completed. Patients continued to receive capsules twice daily. At the completion of this visit, patients were admitted to Visit 9. Patients were informed that they would need to return to the study site within 2 weeks. No IMP or placebo was taken in the morning (Visit 9).

[0448] Week 14 (Visit 9): Patients returned to the study site at Visit 9. AE assessment and concomitant medication assessment were performed. The IMP or placebo was returned, and more IMP or placebo was provided to the patient. Participants received their next dose of IMP or placebo as soon as all visit assessments were completed. Patients continued to receive capsules twice daily. At the completion of this visit, patients were assessed for steroids at Visit 10. Patients were informed that they would need to return to the study site within two weeks. Before leaving the clinic, patients should not take IMP or placebo (Visit 10). They were instructed not to eat breakfast at all before their next visit, and a minimum fasting period of 8 hours was allowed. .

[0449] Week 16 (Visit 10) or Early Withdrawal: Patients returned to the study site at Visit 10. No IMP or placebo was taken on the morning of the 10th. Blood sampling was the first evaluation performed. After blood tests, the following evaluations were performed: physical examination, 12-lead ECG, pharmacokinetic samples, and Ring, vital signs (blood pressure, heart rate, and temperature), clinical laboratory safety tests (hematology, blood Samples for serum biochemistry and coagulation tests, urinalysis, lipid profile, pregnancy test (to check for the possibility of pregnancy) (for female patients with recurrence), ALT, AST test, HOMA-IR / Adipo-IR , ELF, liver stiffness and CAP, FIB-4, NFS [including BMI], biomarker blood fluid samples, exploratory blood samples, AE assessment, and concomitant medication assessment. No further IMP or placebo blister packs or patient diary cards were issued. After completion of the study assessments at this visit, study restrictions followed. At the completion of this visit, patients Patients were to return to the study site within 4 weeks at Visit 11 to assess any AEs since this visit. Before leaving the clinic, patients were informed that safety and efficacy evaluations would need to be performed. The subjects were instructed not to eat breakfast at all before their next visit and were given a minimum 8-hour fasting period. It was.

[0450] Follow-up visit (week 20 / visit 11): 4 weeks after visit 10 (or 2 weeks after the early withdrawal visit) After 24 hours, patients returned to the study site. The following evaluations were performed: physical examination, pharmacokinetics, Sampling, vital signs (blood pressure, heart rate, and temperature), clinical laboratory safety tests (blood samples for blood chemistry, serum biochemistry, and coagulation tests; pregnancy tests (for female patients of childbearing potential); ALT, AST test, HOMA-IR / Adipo-IR, biomarkers, A E rating and evaluation of concomitant medications.

[0451] 1.5 Rating Efficacy was evaluated using ALT, AST, ALT:AST ratio, and HOMA-IR / Adipo-I. These included R, ELF, liver stiffness and CAP, FIB-4 index, and NFS. A detailed description is provided below.

[0452] Increased levels of ALT, AST, and ALT:AST ratios indicate liver damage. markers at Visit 1 / Screening (2 visits during screening, at least 7 days apart) , Visit 2 / Baseline, Visit 3 / Week 2, Visit 4 / Week 4, Visit 6 / Week 8, Visit 8 / Assessments were conducted at week 12, visits 10 / 16 weeks, and follow-up visits 11 / 20 weeks.

[0453] HOMA-IR / Adipo-IR: HOMA-IR / Adipo-IR levels were HOMA-IR is a method to measure fasting plasma insulin resistance (FP). I) multiplied by fasting plasma glucose (FPG) and divided by a constant of 405 Adipo-IR is a stimulant for the fasting nonesterified fatty acids (NEFA) and fasting insulin. Blood samples were taken at Visit 2 / Baseline, Visit 3 / Baseline, and Visit 4 / Baseline. Visit 3 / 2 weeks, Visit 4 / 4 weeks, Visit 6 / 8 weeks, Visit 8 / 12 weeks, Visit 10 / 16 weeks HOMA-IR and Adipo-IR were assessed at the follow-up visits of weeks 11 and 20. All subjects were required to have fasted for at least 8 hours before blood collection. If not, the duration of the fasting period was recorded and the subject was advised to fast appropriately for the next clinical visit. I was urged to do so.

[0454] ELF:ELF score is a measure of tissue inhibitor of metalloproteinase 1 (TIMP-1), II The amino-terminal propeptide of type I procollagen (PIIINP) and hyaluronic acid (H A) is a set of extracellular matrix markers consisting of baseline (Visit 2) and 1 Blood samples were taken at week 6 (visit 10) for this assessment.

[0455] Liver stiffness and CAP: Liver stiffness and CAP can be measured by transient elastography (e.g., Fibre The evaluation was performed using an oScan® 502Touch model or equivalent. If so, patients should fast for baseline (week 0) and visit 10 (week 16). , and scanned at the same time on the same day. For this evaluation, the following conditions were met: the patient , in a position similar to that used for liver biopsy (LB), with the right arm maximally abducted behind the head The patient lay in the supine position with the tip of the transducer resting on the skin between the ribs over the right lobe of the liver. Placed (physicians performed measurements with a probe placed in the intercostal space); FibroScan ( During a test, the selection of an M+ or XL+ probe is performed using the Automatic Probe The APS tool was used to select the XL+ Use "Switch" continuously between "M+ Probe" and "XL+ Probe" or "M+ Probe" and "XL+ Probe" Only XL+ probes were used; the operator was advised to use ultrasound. With the help of the time movie, the area of ​​the liver free of large vascular structures was identified (depth of measurement). The length ranged from 35 to 75 mm for the XL+ probe and from 25 to 65 mm for the M+ probe. The volume to be explored is 3cm 3 For each patient, the operator must use an XL+ probe or At least 10 valid measurements or a maximum of 20 trials at the same location using the M+ probe The entire test lasted no more than 10-15 minutes. CAP values ​​were recorded as the median of available measurements.

[0456] FIB-4 index: The FIB-4 index is a function of age, platelet count, ALT level, and AST level. The study was based on a randomized controlled trial and assessed at baseline (Visit 2) and week 16 (Visit 10). The FIB-4 score is determined as follows:

number

[0457] NFS: NFS is a function of age, hyperglycemia, BMI, platelet count, albumin level, and AST. Based on the ratio of ALT to NAFLD, NAFLD fibrosis score = -1.675 + 0.037 × age (years) + 0.094 × BMI (kg / m2) + 1.13 × IFG / diabetes (yes = 1, no = 2) No = 0) + 0.99 × AST / ALT ratio - 0.013 × platelets (× 109 / l) - 0. 66 × albumin (g / dl). NFS was measured at baseline (Visit 2) and at Week 16 (Visit 10) was evaluated.

[0458] Safety assessments included: medical history, physical examination, ECG, vital signs, Clinical laboratory safety studies (e.g., hematology, serum chemistry, coagulation, lipid profile, and urinalysis) smear), virology, pregnancy testing, blood sampling, pharmacokinetic sampling, exploratory blood sampling, biomarkers - Blood collection, urine DOA and alcohol breath testing, adverse event assessment, concomitant medications, bioanalysis, specimens, storage piping, handling, and transportation, and restrictions. A detailed description of each is provided below. .

[0459] Medical History: A thorough review of the patient's medical history will ensure that exclusion criteria have not been met. To do so, investigators or were conducted by designees, whether or not considered relevant to the research. All intercurrent illnesses were reported by the investigator, regardless of the cause. If possible, the date of diagnosis or The duration of the disease was recorded.

[0460] Physical Examination: Physical examination (including height and weight) will be performed according to the study flow chart in Table 19. , Visit 1 / Screening, Visit 2 / Baseline, Visit 3 / 2 by the investigator Week, Visit 4 / Week 4, Visit 6 / Week 8, Visit 8 / Week 12, Visit 10 / Week 16, and This test was performed at the follow-up visit of weeks 11 / 20. This test was fully completed at baseline and The rest was symptom-based (i.e., a standard panel of body systems was not evaluated unless indicated by the patient). For example, if a patient reports the presence of a "rash" to the investigator, the skin It was not necessary to evaluate additional body systems unless clinically justified. Any abnormal findings were recorded. Changes in physical examination findings compared to baseline examination were considered AEs. and recorded it.

[0461] ECG: 12-lead ECG with 10-second lead II rhythm strips 10mm / 1mv, 2 The ECG was recorded at 5 mm / sec at each time point. The patient was allowed to rest quietly in a completely supine position for 5 minutes before the ECG was taken. Records were kept at Visit 1 / Screening, Visit 2 / Baseline, and Visit 10 / Week 16. The study was conducted on the dates indicated in the study flow chart in Table 19.

[0462] Vital signs: Vital signs were measured at each visit according to the study flow chart in Table 19. Question 1 / Screening, Visit 2 / Baseline, Visit 3 / Week 2, Visit 4 / Week 4, Visit Weeks 6 / 8, visits 8 / 12, visits 10 / 16, and follow-up visits 11 / 20 Vital signs were measured before any blood samples were taken. If findings arise after signing, all new findings or findings considered clinically significant should be included. Any change in the previous findings was recorded as an AE. Systolic and diastolic blood pressure (mmHg) of the performed blood pressure (e.g., after at least 5 minutes of rest) ), heart rate measured at rest in beats per minute (bpm), and temperature measured according to clinical practice. Included.

[0463] Clinical Laboratory Safety Testing: Hematology, serum biochemistry, coagulation, lipid profile, and urinalysis Safety studies were performed on the 100mg / kg body weight. Blood and urine samples were collected for routine hematology, serum chemistry, coagulation, and urinary For analysis, lipid profiles were collected according to the study flow chart in Table 19. All samples were analyzed at a central laboratory. All subjects had fasted for at least 8 hours before blood collection. If the subject did not fast for at least 8 hours, the duration of the fasting period was recorded and the subject was then admitted to the next clinical visit. I was urged to fast properly for this. Hematology: Red blood cell count, hemoglobin, hematocrit, white blood cell count, differential white blood cell count, microcirculation Complete blood count including platelet count and reticulocytes. Serum biochemistry: urea (blood urea nitrogen; BUN), creatinine, uric acid, total bilirubin, Indirect and direct bilirubin, sodium, potassium bicarbonate, phosphorus, calcium chloride, alkali ALP, aspartate aminotransferase (AST), Lanin aminotransferase (ALT), ALT / AST ratio, lactate dehydrogenase (LDH), creatine phosphokinase (CPK), albumin, total protein, cholesterol terols, triglycerides, glucose, and C-reactive protein (CRP). Coagulation: Prothrombin time (PT), International Normalized Ratio (INR), and activated partial prothrombin APTT. Lipid profile: LDL, HDL, and VLDL-C. Urinalysis: pH, protein, glucose, blood, ketones, white blood cells, white blood cell esters Ze, bilirubin, specific gravity, urobilinogen, and nitrates. Blood, protein, leukocytes terase, or nitrate / nitrite if present.

[0464] Virology: HIV, HepC, and Blood samples were taken for virology testing, including HepB.

[0465] Pregnancy testing: For female patients of childbearing potential, follow the study flow chart in Table 19. Visit 1 / Screening, Visit 2 / Baseline, Visit 4 / Week 4, Visit 6 / Week 8 Pregnancy tests were performed at visits 8 / 12 weeks, 10 / 16 weeks, and 11 / 20 weeks. Ta.

[0466] Blood Collection: Blood samples were obtained and administered clinically by each investigator following sample analysis and validation. Test results were reviewed for clinically significant values. Additional blood samples were required to repeat safety laboratory tests. may be necessary.

[0467] Pharmacokinetic (PK) Sampling: Blood samples for PK analysis were collected according to the study flow chart in Table 19. Visit 2 / Baseline, Visit 3 / Week 2, Visit 4 / Week 4, Visit 6 / Week 8 according to the , Visit 8 / 12 weeks, Visit 10 / 16 weeks, and Follow-up Visit 11 / 20 weeks Blood samples were collected by puncture. 1 mL of blood was collected at each time point. After centrifugation, plasma samples were collected. The samples were split into two and the reserve sample was stored at a central laboratory until the bioanalytical assays were completed.

[0468] Exploratory Blood Sampling: Baseline (Week 0) and Visits 1-4 according to the study flow chart in Table 19 Blood samples will be taken at weeks 10 / 16 for potential gene array analysis or additional exploratory testing at a later date. Saved to.

[0469] Biomarker Blood Collection: Baseline (Week 0) according to the study flow chart in Table 19 Blood samples were taken at visits 6 / 8 weeks, 10 / 16 weeks, and follow-up visits 11 / 20 weeks. The data were stored for potential biomarker analysis.

[0470] Urine DOA and alcohol breath testing: Alcohol will be administered at the investigator's discretion as clinically appropriate. A Cole breath test was administered and a urine sample was collected from the patient at any time during the study. Ethamines, barbiturates, benzodiazepines, cocaine, cannabinoids, and opioids Tests were performed to detect ethates.

[0471] Concomitant medications: Patients must be taking any concomitant medications at stable doses for at least 3 months prior to screening. Patients had to be taking medication and their dose had to remain stable throughout the study period. If the patient is insulin dependent, this treatment should be initiated at least 3 months prior to screening. should have been, but dose modifications were permitted.

[0472] Restrictions: The study included restrictions on food, alcohol, caffeine, and physical activity. Patients were required to consume omega-3 or omega-6 fatty acids both during the study and in the 4 weeks prior to baseline. Avoid taking dietary supplements rich in vitamins (e.g., cod liver oil capsules). Patients were found to consume more than 21 units of alcohol per week (men) or 14 units per week (women). Alcohol consumption was avoided (1 unit consists of 10 mL or 8 mg of pure alcohol). There were no caffeine restrictions during the study or any of the studies. Avoid exercise and strenuous physical activity for at least 3-4 hours before laboratory tests (e.g., biochemistry). It was necessary to

[0473] 1.6 Investigational Drugs DS102 capsules contain 5% w / w colloidal silicon dioxide as a viscosity modifier. Both contain 500 mg of 15-HEPE ethyl ester (EE) in a white, opaque, hard shell. It was a wel capsule (size 0).

[0474] The placebo (paraffin oil) for DS102 contained 1% w / w of coagulant as a viscosity modifier. White, opaque, rigid, containing liquid paraffin with an equal fill weight of silica. It was a shell capsule (size 0).

[0475] DS102 and placebo capsules should be stored in a secure location (e.g., The drug was stored at 2-8°C in a locked cabinet or drug storage room. Blinding was performed and randomization numbers were included.

[0476] Dosage and Administration: This study consisted of DS102 administered orally twice daily for a total period of 16 weeks. Comparison with placebo was included. Last study drug administration was at the Week 16 visit / Early Termination (ET). The patient was required to take the capsules with or after a meal. Medications for other illnesses permitted in the study were taken as usual. The dispensed blister pack contains 4 capsules for 7 days, at the end of which the patient receives the assigned The patients took the prescribed medication for 16 consecutive weeks.

[0477] 1.7 Adverse Events and Serious Adverse Events Adverse events (AEs) and serious adverse events (SAEs) in this study were defined as follows:

[0478] Adverse Event (AE): Any adverse event that occurs during treatment, whether or not considered related to the investigational IMP. Any untoward experience that occurs in a patient who receives the first dose of an investigational drug. AEs include IMPs and The relationship between the severity and the severity of the symptoms was recorded in a case report form.

[0479] Serious Adverse Event (SAE): Patient experienced a serious adverse event after the first dose of study drug If the event was fatal, life-threatening, or involved in the patient's requiring hospitalization or extension of existing hospitalization, or having a persistent or significant disability / incapacity characterized as any adverse medical occurrence at any dose, including any of the following: The term "life-threatening" refers to an event in which the patient was at risk of death at the time of the event. It does not refer to an event that, if more severe, could hypothetically cause death. Examples of non-life-threatening events include intensive care in an emergency room, allergic reactions, Bronchospasm, blood disorders or convulsions that did not result in hospitalization, or drug dependence or abuse Onset was cited.

[0480] Unexpected adverse events (UAE): similar to the investigator's brochure or summary of product characteristics (SPC) An experience not previously reported in the product information sheet.

[0481] The intensity of an AE is an estimate of the relative severity of the event, determined by the investigator based on clinical experience. The following definitions were used to assess the severity of AEs: Mild: Adverse events were transient and easily tolerated. Moderate: The adverse event caused discomfort to the patient and interfered with the patient's usual activities. Severe: The adverse event significantly interferes with the patient's usual activities and is potentially incapacitating or could be life-threatening.

[0482] Consideration of the patient's medical history, recent physical examination findings, and concomitant medications may lead to the selection of experimental treatments. The causal relationship of the AE to the AE was also established. The following definitions were used to determine the causal relationship of the AE: did. Unrelated: The temporal relationship of the onset of the AE to the experimental treatment is not reasonable, or Other causes could explain the occurrence of AEs. Relevant: The temporal relationship of the onset of AEs to the experimental treatment is reasonable and relevant to the treatment. The results followed known response patterns and were unlikely to have alternative causes.

[0483] All AEs were reported throughout the study period up to and including the follow-up period. Ta.

[0484] 1.8 Drug-induced liver injury Severe Drug-Induced Liver Injury (DILI): Severe DILI, regardless of recognized cause If the drug was not the cause of liver damage, the drug was discontinued until the symptoms were deemed to have resolved. If the cause was determined to be a contributing factor, the patient was not re-challenged with the drug. DILI, as indicated by total bilirubin >2 x ULN or INR >1.5 Evidence of liver damage is required.

[0485] Patients with abnormal baseline liver biochemistry: In determining abnormal baseline liver biochemistry, U Instead of using LN, the fold increase was calculated relative to the baseline level. Double baseline ALT or AST (or >200 IU / L) levels followed by 72 hours Repeat testing within 24 hours to confirm / determine whether biochemical changes have improved or worsened AE information was collected along with a thorough physical examination. Liver etiology screening and / or or other appropriate tests were performed. If liver dysfunction occurred, the patient was classified as severe DILI. If any of the criteria for severe DILI occur, temporary discontinuation of medication is recommended. Suspension was considered.

[0486] 1.9 Serious and Unexpected Adverse Reactions Adverse Reaction: Any untoward and unintended response to a medicinal product related to any dose. The phrase "response to a drug" refers to a causal relationship between a drug and an AE. The relationship is at least a reasonable possibility (i.e., the relationship cannot be ruled out). In the case of over-the-counter medicines, an adverse reaction means any harmful, unintended, and / or life-threatening event that does not prevent or prevent a disease. occurring in doses normally used by humans for the diagnosis, treatment, or modification of physiological function. This is a response to the drug.

[0487] Unexpected adverse reaction: An adverse reaction whose nature or severity was not consistent with the applicable product information. Response.

[0488] Suspected Unexpected Serious Adverse Reaction (SUSAR): Any reaction that may be related to an IMP as defined above. Any unexpected serious adverse reaction.

[0489] 1.10 Statistical Methodology and Data Management This clinical trial employed a randomized, double-blind, placebo-controlled, parallel-group design. Randomization minimizes allocation bias and accounts for known and unknown patient attributes (e.g., demographic kinetic characteristics) were used to increase the likelihood that the treatment groups were equally balanced. Blinding reduces potential bias during data collection and evaluation of safety and efficacy. The use of a placebo as a comparator was due to the short duration of the study and the in patients based on the absence of any potential long-term irreversible damage that may be the result of treatment It was justified as a rational design for evaluating safety and efficacy.

[0490] Sample size estimate: 20% delta response rate between active drug and placebo groups, 25% Assuming a standard deviation of and a 20% dropout rate, the statistical significance level is 5% and the power is 80%. The study required 32 patients per group. Sample size was determined based on recommendations from unblinded investigators. The primary endpoint achieved 80% conditional power. To achieve this, the sample size could be increased to a total of up to 150 patients.

[0491] Blinding and decoding instructions: All study site personnel and anyone involved in overseeing or conducting the study The investigators were blinded to the treatment allocation of individual patients. Details of randomization are available It was kept strictly secret and was accessible only to authorized personnel in emergency situations until the time of formal unblinding. The blinding code for the study was recorded and verified, and the database was locked. It was only deciphered after

[0492] Interim analysis and data monitoring: When at least 50% of patients have completed the 16-week visit An interim safety analysis was performed to estimate the conditional output. Based on data collected on the primary efficacy endpoint and secondary endpoints, and use it to estimate conditional outputs to achieve the primary research objectives and Potentially re-estimated size and potentially excluded less effective treatment arms.

[0493] Clinically meaningful response: A higher mean or mean ALT or liver stiffness compared to placebo At least a 20% median reduction in both ALT and liver stiffness compared to placebo Higher average or at least 10% median reduction

[0494] The analysis sets were the registration set, the complete analysis set (FAS), and the protocol compliance set (PP The analysis sets included a safety analysis set (S), a safety analysis set (SAS), and a pharmacokinetic (PK) set. A detailed description of the method is provided below.

[0495] Enrollment set: Patients who signed the informed consent form. Screening failures were , patients from the enrolled population who did not meet the eligibility requirements and who withdrew from the study before randomization It was.

[0496] FAS: Patients who have received at least one dose of study treatment and have at least one post-baseline measurement Patients were randomized once. Patients were assigned the treatment assigned at randomization regardless of the treatment they actually received. Patients were analyzed according to the treatment they received.

[0497] PPS: A subset of the FAS consisting of patients from the FAS who did not have a major protocol violation. All protocol deviations are individually evaluated and documented prior to database lock. Significant deviations may have a serious impact on efficacy results, leading to the exclusion of affected patients from the PPS. was considered to have an impact.

[0498] SAS: Patients who received at least one dose of study treatment. Patients were followed for the treatment they actually received. It was analyzed as follows.

[0499] PK Set: Patients with SAS who had at least one DS102 PK concentration. They were analysed according to the treatment actually received.

[0500] Safety Analysis: Demographic, medical history, and physical examination data will be listed and descriptively compiled for each patient. All AEs recorded during the study were summarized in the Medical Dictionary for or Regulatory Activities (MedDRA) AEs were classified by treatment, relationship to treatment, severity, and Clinical laboratory values ​​(e.g., hematology, biochemistry, and urinalysis) were tabulated and summarized by severity. Laboratory values ​​outside the normal range were considered clinically significant. The phenotypes are listed separately with comments on gender and highlighting potentially clinically significant abnormalities. , summarized by treatment. Laboratory values ​​obtained before dosing were defined as baseline values. The results of the alcohol breath test and DOA test were listed for each patient. Individual values ​​were listed and summarized descriptively by treatment and day. 12-lead ECG assessments were performed with relevant The results were listed by patient, along with any comments made, and summarised by treatment and day. World Health Organization Concomitant medications (present) classified by drug classes and subclasses according to the latest version of the Drug Dictionary of the In general, appropriate descriptive statistics depending on the nature of the variables were used. Categorical variables were presented using numbers and percentages, and continuous variables were presented using means and standard deviations. The data were presented using median, minimum, maximum, coefficient of variation, and number of patients.

[0501] Pharmacokinetic Analysis: Plasma concentrations of 15(S)-HEPE were tabulated and summarized descriptively. The individual and mean plasma concentration-time profiles of S)-HEPE are shown graphically.

[0502] Primary Variable: The primary efficacy variable was serum ALT from baseline to Week 16 (Visit 10). The corresponding baseline values ​​were calculated using an analysis of covariance (ANCOVA) model. The active treatment group was compared against placebo, with α = 0.05 as a covariate. The test was performed according to Dunnett's multiple test procedure. For the missing week 16 value, The last possible value was filled (LOCF). A similar method was applied to liver stiffness. In this case, longitudinal modeling was additionally considered.

[0503] Secondary variables: Secondary efficacy variables and their changes from baseline to Week 16 (Visit 10) Descriptive statistics were summarized by treatment group and visit. These included AST, AST:ALT ratio, CA Liver fat measured by P, liver stiffness measured by transient elastography, FIB-4 , NFS, ELF, and HOMA-IR / Adipo-IR. Changes from baseline were compared to placebo using an ANOVA model including a center effect term. A significance level of 5% was used for all treatment comparisons.

[0504] Exploratory analyses: Exploratory analyses included total cholesterol, triglycerides, and very low-density lipoproteins. Very low density lipoprotein cholesterol (VLDL-C), low density lipoprotein cholesterol (LDL -C), high-density lipoprotein cholesterol (HDL-C), non-high-density lipoprotein Cholesterol (non-HDL-C), remnant-like particle cholesterol (RLP-C), empty Abdominal blood glucose, insulin, free fatty acids, and lipids such as hemoglobin A1C (HbA1C) Additional exploratory analyses included high-throughput lipid analysis and metabolic parameter analysis. These included genomics and proteomics.

[0505] 1.11 Results The study involved patients diagnosed with NAFLD who were administered DS102 at doses of 1g or 2g per day. Patients receiving the drug experienced a statistically significant reduction in markers of metabolic overload, as well as an increase in insulin sensitivity. and demonstrated improved glycemic control.

[0506] Figure 20 shows that the three treatment groups were well balanced at baseline and the lipidomic profiles The patient's baseline and metabolomic profiles are similar. Characteristics are shown in Table 18. 10–13% of patients were receiving statin therapy at baseline. .

[0507] [Table 16]

[0508] Figures 21A-21C show the effect of either 1 g or 2 g of D per day compared to placebo. Insulin, glucose, and serotonin levels from baseline to 16 weeks in patients receiving S102 Shows changes in free fatty acid levels. Metabolic groups including glucose, carbohydrates, and free fatty acids Since quality of blood promotes the pathogenesis of NASH, the administration of DS102 may decrease insulin, glucose, and and reduction in free fatty acid levels is clinically significant.

[0509] Figures 22A and 22B show the effect of either 1 g or 2 g per day of steroids compared to placebo. HOMA-IR and adip from baseline to week 16 in patients receiving DS102 The changes in the level of o-IR are shown. Patients were observed in patients who received 2 g of DS102. Both interventions were effective at week 16, with significant improvements in observed protocol adherence scores (PPS). Improvement in phosphorus resistance indices (e.g., reduction in HOMA-IR and adipo-IR levels) showed.

[0510] Figures 23A and 23B show the effect of either 1 g or 2 g per day of steroids compared to placebo. Glycated hemoglobin (e.g., Specifically, Figure 23A shows the change in HbA1c levels. However, Figure 23B shows high HbA1c levels at baseline, but normal levels at 16 weeks. The change in HbA1c levels in the proportion of patients who reached the threshold. It is a measure of the amount of glucose attached to blood cells and is a surrogate for long-term blood sugar control. These results demonstrate that administration of DS102 resulted in clinically significant improvements and a dose-dependent increase in blood pressure. Shown to normalize glucose control.

[0511] Figures 24A and 24B show lipid profiles of patients at week 16 in the Safety Analysis Set (SAS). The mean and median (%) changes in the profiles are shown. These results are shown in Figures 25A-25C. 5C further shows that administration of DS102 reduces total cholesterol, VLDL, and -C, non-HDL-C, remnant-like particle (RLP) cholesterol, and triglycerides significantly improved the lipid profile of patients by either maintaining or reducing the levels of Importantly, the reduction did not plateau at 16 weeks, suggesting that longer-term administration of DS102 This suggests that there is a possibility that even greater changes may be induced in the interim study.

[0512] As shown in Figure 26, administration of DS102 reversed the hepatotoxic lipid signature of NASH. and improve multiple lipid classes that are altered in patients diagnosed with NASH. reported that a 2g dose of DS102 significantly reduced levels of several hepatotoxic diglycerides. Patients with NASH had significantly increased levels of several glycerophospholipid classes in the liver and This finding is important because the levels of glycerophospholipids in the blood and plasma are low.

[0513] Figure 27 shows that administration of DS102 improves survival in patients with NASH using the OWL Liver Care non-invasive diagnostic test. OWL Liver Care is a company that provides comprehensive, cost-effective, and cost-effective treatment for NASH. , a test developed based on plasma lipidomics in patients with biopsy-confirmed NASH. OWL Liver Care differentiates between patients with NAFLD and those with normal liver. The area under the curve (AUC) of 0.88 for distinguishing between NAFLD without steatohepatitis and NAFLD without steatohepatitis The AUC for distinguishing between patients with NASH and those without was 0.79. There was a significant dose-dependent improvement in NASH diagnosed by OWL Liver Care compared with placebo at week 1 Table 19 shows the baseline study diagnoses by treatment group. Most patients were classified as NASH or NAFLD at baseline and received 2g of DS102. This indicates a low proportion of patients.

[0514] [Table 17]

[0515] As shown in Figure 28, administration of DS102 significantly reduced CA in patients diagnosed with NAFLD. DS102 also reduced liver fat content as assessed by P. Furthermore, DS102 In studies, greater changes in liver content were observed when assessed by more sensitive methods. It is thought that this is expected to induce

[0516] As shown in Table 20, administration of DS102 also reduced triglyceride levels in patients. Therefore, DS102 may also be effective in reducing cardiovascular risk.

[0517] [Table 18]

[0518] Figures 29A-29C show that administration of DS102 reduces inflammatory and profibrotic proteins. For this evaluation, blood samples were collected before and after treatment with DS102 at 350°C. A panel of over 100 different protein biomarkers was analyzed. The treatment targets over 150 markers associated with inflammation, fibrosis, lipid metabolism, apoptosis, and chemotaxis. After treatment with DS102, the expression of CAR was significantly downregulated. A resolution of metabolic overload and lipotoxicity, which prevents fibrosis, was observed. Reduction of toxic proteins may allow DS102 to reverse NASH and prevent fibrosis This suggests that:

[0519] As shown in Figure 30, administration of DS102 also reduces the expression of multiple NASH development targets. In particular, administration of 2g of DS102 inhibited CCR2 / 5 signaling (cenicriviroc -Allergan), galectin 3 (GR-MD-02-Galectin), and AOC3 (Boehringer Ingelheim) It was reduced.

[0520] Volcano plot of Figure 31 (data of Bonferroni and Benjamini-Hochberg tests) The study found that administration of 2g of DS102 significantly reduced inflammation and fibrosis based on changes in protein expression. Table 21 shows that the stimulatory proteins were reduced. The most significant reduction in inflammatory and profibrotic proteins is shown.

[0521] [Table 19]

[0522] Administration of 1 g of DS102 also showed a significant reduction in TR. Table 22 shows the linear model Based on the assay used, the most significant reductions in inflammatory and profibrotic proteins are shown.

[0523] [Table 20]

[0524] This analysis also showed that 1 protein in the 1g DS107 group and 1 in the placebo group 0 proteins exceed the first threshold based on the Benjamini-Hochberg test This shows that

[0525] As shown in Figure 32, administration of DS102 also reduced the expression of multiple vascular adhesion molecules. Vascular adhesion molecules are involved in atherosclerosis, and their circulating levels are associated with cardiovascular disease. associated with vascular risk

[0526] As shown in Figure 33, administration of DS102 also inhibited several anti-cancer drugs associated with increased cardiovascular risk. The expression of the protein was reduced.

[0527] As shown in Figure 34, administration of DS102 also reduced the expression of several circulating chemokines. Chemokines are important drivers of chronic inflammation in atherosclerosis.

[0528] As shown in Figure 35, administration of DS102 also inhibited the expression of multiple tumor necrosis factor receptor superfamily members. Reduced expression of family members. Members of the tumor necrosis factor receptor superfamily is involved in inflammation and atherosclerosis.

[0529] DS102 also demonstrated no observed differences in safety or tolerability compared to placebo. It was proven to be safe and well tolerated. There were no drug-related serious adverse events (SAEs). The incidence of adverse events (AEs) was low and consistent across all treatment groups. All AEs were mild to moderate and transient, and patients who experienced AEs leading to treatment discontinuation The safety profile across treatment groups is shown in Table 23.

[0530] [Table 21]

[0531] DS102 also has been shown to be effective in treating a related indication, primary biliary tract infection, as shown in Figures 36A and 36B. Potential efficacy in improving primary sclerosing cholangitis (PBC) and primary sclerosing cholangitis (PSC) Importantly, a 2g dose of DS102 significantly reduced the risk of developing an alkaline phosphate ( DS102 reduces ALP and multiple markers of liver fibrosis, demonstrating its potential for the treatment of PBC and PSC This suggests that it may also be effective in treating

[0532] Figure 37 shows a box plot of the relative trough plasma concentrations of 15-HEPE ethyl ester (EE). As expected, there was a higher systematic exposure in the DS102-treated group at weeks 8 and 16. Indicates that there was.

[0533] 1.12 Summary Overall, these results demonstrate that DS102 significantly reduces metabolic load and improves insulin sensitivity. This demonstrates that the drug targets multiple stages of NASH pathology by improving efficacy. Administration of S102 also reverses the levels of lipid accumulation associated with NASH, Improved the lipid profile of patients. Specifically, those receiving DS102 total cholesterol, non-HDL cholesterol, RLP cholesterol, triglycerides reducing the accumulation of hepatotoxic lipid levels, including glycerides, diglycerides, and VLDL-C; and Patients diagnosed with NASH showed increased levels of total cholesterol and glycerophospholipids. High levels of cholesterol, triglycerides, diglycerides, and VLDL-C, and glycerophospholipids These effects are due to the fact that it is characterized by low levels of lipids and omega-3 PUFAs. Furthermore, changes in multiple lipids have been shown to reduce cardiovascular risk and improve metabolic health. It is expected to bring about improvements in multiple aspects of the program.

[0534] Results also showed that 2g or more of DS1 was associated with a large and statistically significant improvement compared to placebo. These results suggest that there is a dose-dependent effect supporting the administration of O2.

[0535] In conclusion, DS102 is a potential monotherapy or combination therapy for the treatment of NASH. It is highly suitable for either NASH or metabolic syndrome. It is believed to reduce cardiovascular risk in patients diagnosed with metabolic disease.

[0536] Example 5: 15(S)-HE by oral gavage in rats with a 4-week recovery period 26-week toxicity study of PEEE The objectives of this study were to (1) examine the liver function of rats given by oral gavage for 26 weeks; 15(S)-HEPEEE, an omega-3 fatty acid used to treat lung and pulmonary diseases To determine the potential toxicity of the drug and to assess the potential reversibility of any findings, (2 The objective of this study was to determine the toxicokinetic properties of 15(S)-HEPEEE.

[0537] 1.1 Research design Test and control articles were administered by oral gavage once daily, 7 days a week, for a minimum of 26 weeks. The dose was administered to the appropriate animal as soon as possible. The dose per animal was based on the most recent body weight measurement. The administration was given using a syringe equipped with a gavage cannula. The first day of administration was designated as day 1. The dosing formulations were removed from the refrigerator and stirred for at least 30 minutes before administration. The dosage formulation was continuously stirred during administration.

[0538] The onset of clinical signs such as hunched posture, ruffled fur and abnormal gait, as well as weight loss, Treatment of animals 3206M, 3515F, and 3703F was discontinued on day 45, and the remaining groups Dosing of animals with 3 was discontinued from day 48. Dosing of animals with lower doses was discontinued from day 64. The following table shows the levels used in the study: Treatments (Table 23) and animal groups (Table 24) are shown.

[0539] [Table 22] a The onset of clinical signs, such as hunched posture, ruffled fur and abnormal gait, and weight loss, Dosing of animals was discontinued from day 48. Dosing of animals was discontinued from day 64 onwards. The initial dose will be at a dose level (3000 mg / kg / day). b Adjusted concentrations of batches 2540M-1801 and 2540M-1802. c Adjusted concentrations of batches 2540M / 1901 and 2540M / 1902.

[0540] [Table 23] The spare animals are numbered 4001M, 4002M, and 4501F, 4502F. This will be the case.

[0541] Recovery Period: Upon completion of the dosing period, designated recovery animals will undergo a minimum 4-week recovery period. It was held as such.

[0542] Route Justification and Dose Level: Because this is the intended route of human administration, The oral route of administration was chosen for the study. Oral toxicity of showed no adverse effects at the highest dose tested (1 mg / kg / day). . Warren, H(2017).A 26 Week Study of 15(S) -HEPE EE by Oral(Gavage)in Rats with a 4 Week Recovery Period.Charles River Stud See Pharmacology No. 529123. No dose-limiting toxicity was observed in this study. Given this, an additional 28-day dose-ranging study was conducted to determine the oral maximum tolerated dose (MTD) of 6 g / kg / day. ) was determined. Murie, E (ongoing). A Pilot 28-Day S study of DS102 by Oral Gavage in Rats.Cha See Rivers River Study No. 506611. The study evaluated the chronic toxicity potential of 15(S)-HEPE EE (DS102) at this MTD. The evaluation was carried out to comply with ICH M3(R2). ripartite Guideline M3(R2).Nonclinical S afety Studies for the Conduct of Human C Clinical Trials and Marketing Authorisati on for Pharmaceuticals.

[0543] 1.2 Antemortem Procedures, Observations, and Measurements Antemortem procedures, observations, and measurements were performed on all main study animals and recovery animals. Biokinetics Animals were weighed and clinical observations were recorded at the same time points as the main study animals.

[0544] Mortality / moribund checks were performed daily. Animals were observed for general health / mortality and moribundity. Animals were not removed from their cages during observations unless necessary to identify or confirm potential findings. It never happened.

[0545] Clinical Observations:

[0546] Cageside observations were performed daily, unless to identify or confirm potential findings. No animals were removed from their cages during observation.

[0547] Detailed clinical observations were made weekly. Animals were removed from their cages for examination.

[0548] Post-dose observations were performed periodically throughout the day. All animals were monitored for response to treatment. The onset, intensity, and duration of these symptoms were recorded. paid special attention to the animals.

[0549] Body weight was measured twice during the pretreatment period, once daily during the treatment period, and twice weekly during the recovery period. Animals were weighed individually. Weights were recorded on the first day of scheduled necropsy (main and recovery animals only). Recorded.

[0550] Food intake was quantitatively measured weekly beginning at week 1 and throughout the dosing and recovery period.

[0551] Water consumption was measured periodically throughout the study by visual inspection of water bottles.

[0552] Ophthalmic examination was performed using an indirect ophthalmoscope after application of a mydriatic (1% tropicamide, Mydriacy). All main study animals and recovery animals were examined during the pre-treatment period. Week 13 The main study animals (control and high dose) were examined during weeks 1 and 26. At week 30, all The animals were examined.

[0553] 1.3 Laboratory Evaluation: clinical pathology

[0554] Sample collection: Blood was collected from the orbital venous plexus under irreversible isoflurane anesthesia immediately prior to necropsy. Blood was collected from the tail vein unless otherwise specified. Samples were not collected prior to necropsy in accordance with the euthanasia protocol. Animals were bled in ascending order as far as possible. If the permitted sampling frequency and blood volume were not exceeded, Additional blood samples were obtained (e.g., for clotting of non-serum samples). After collection, the samples were submitted to the appropriate laboratory The samples were taken according to the following table:

[0555] [Table 24] X = sample to be collected, - = not applicable.

[0556] Hematology: A 0.5 mL blood sample was taken using the anticoagulant K2EDTA. were labeled, stained and stored. Blood smears were analyzed according to the following parameters:

[0557] [Table 25]

[0558] Coagulation: Anticoagulant 3.8% (w / v) trisodium citrate was added to process the plasma. A 0.5 mL blood sample was taken using a 0.5 mL syringe. To assess coagulation, the following coagulation parameters were measured: The rotor was measured.

[0559] [Table 26]

[0560] Clinical Chemistry: 0.7 mL was processed to plasma using anticoagulant lithium heparin. Blood samples were taken. To assess clinical chemistry, the following parameters were measured:

[0561] [Table 27] a If total bilirubin is >8.55 μmol / L, indirect and direct bilirubin The bottles will also be measured.

[0562] Urine test: In the absence of food and the presence of moisture, over a period of 6 hours (+ / - 30 minutes) Urine was collected from the animals at once. After collection, the samples were transported to the appropriate laboratory for processing. To evaluate the test, the following parameters were measured:

[0563] [Table 28]

[0564] Bone marrow smear analysis: Bone marrow was collected from all animals and preserved in 10% neutral buffered formalin. Ta.

[0565] Bioanalysis and toxicokinetic evaluation

[0566] Bioanalytical sample collection: Using a sterile needle and disposable syringe, insert a syringe into the jugular vein (or jugular vein access). via the vein (or tail vein if the vein is not accessible) using 0.5 mL of anticoagulant K2EDTA. Blood samples were collected. Upon completion of the blood sampling schedule, the toxicokinetic animals were euthanized. were discarded without testing. Samples were taken according to the table below.

[0567] [Table 29] X = Sample to be collected. - = Not applicable. aSamples are taken prior to administration b Day 1 samples were collected for animal 3702F, but on day 44, this animal was withdrawn for humane reasons. Additional samples were collected at week 26 from animals 3707F (collected at time 0) and 3707F. A sample was taken from 04F (4-hour collection) to replenish the missing time point for animal 3702F.

[0568] Bioanalytical sample processing: Samples were gently mixed and pulverized until centrifuged within 60 minutes of collection. The samples were centrifuged at 1500 g for 10 minutes at 4°C and kept on crushed wet ice. The resulting plasma was separated and transferred to a uniquely labeled clear polypropylene tube and dried. The samples were frozen as quickly as possible on ice or set to maintain a temperature of -20°C. It was frozen in the freezer.

[0569] Bioanalytical sample analysis: Non-esterified HEPE and total HEPE using validated analytical procedures Plasma samples were analyzed for concentrations of: a) Non-esterified (occurs in plasma as free fatty acids or bound to plasma albumin) HEPE). b) Total (non-esterified and esterified HEPE (e.g., Quantify blood glucose (e.g., triglycerides, cholesterol esters) concentrations.

[0570] For this study, non-esterified HE was used in accordance with the appropriate standard operating procedures of the bioanalytical laboratory. A real sample reanalysis (ISR) was performed for PE. Measurement of total HEPE in rat plasma samples The ISR for determination was conducted using the analytical procedures referenced above in Laboratory Study No. 5279. 43 was successfully performed in this study and does not need to be repeated.

[0571] All residue / retention bioanalytical samples were stored for a minimum of 6 months after publication of the draft and then destroyed. or a six-month holding period if the release of the final report occurs before the end of the six-month holding period. The remaining / carrying samples were discarded before the end of the study period. These early discards of remaining / carrying samples also May be requested and approved by the responsible party.

[0572] Toxicokinetic evaluation: Toxicokinetic parameters were evaluated using Phoenix pharmacokinetic software. The parameters were estimated using a non-compartmental approach consistent with the oral route of administration. All parameters were measured using plasma 15% CO2 at day 1 and week 26, where practical. The concentrations of total free acid and unbound free acid in the (S)-HEPEEE composition were calculated as follows: parameters were estimated.

[0573] [Table 30]

[0574] Partial AUC (for any given sample time) was derived and reported to aid interpretation. Use Phoenix to generate descriptive statistics ( Cmax and AUC(0-t) (standard error) were generated. TK tables and graphs were also generated.

[0575] 1.4 Exit Procedures The table below summarizes the end-of-life procedures used in the study.

[0576] [Table 31] X =Steps to be taken:-=Not applicable a For a list of tissues, see the Tissue Collection and Preservation Table. b Target tissues were liver (males and females), thyroid gland (males and females), kidney (females only), sternal bone marrow ( (Males only).

[0577] Unscheduled Death: If a primary study animal or recovery animal dies during the study, a necropsy should be performed to identify the Tissues were preserved. When necessary, animals were refrigerated to minimize autolysis. Animals were humanely euthanized according to the SOP of the testing facility. Body weights were recorded. When possible, samples were obtained for evaluation of clinical pathology parameters. When necessary, animals were refrigerated to minimize autolysis. Toxicokinetic animals that died during the study or were euthanized for humane reasons were subjected to limited necropsy examination. The examination consisted of an evaluation of the organs and tissues within the thoracic, abdominal, and pelvic cavities, with tissues preserved. During the limited autopsy examination, particular attention was paid to evidence of potential gavage trauma. Body weights were recorded and samples were taken for toxicokinetic evaluation.

[0578] Planned euthanasia: Main study animals and recovery animals that survived to scheduled euthanasia were Animals were euthanized by exposure to rising carbon dioxide. Terminal body weights were recorded. When possible, a similar number of animals from each group, including controls, were necropsied throughout the day. Animals were euthanized sequentially across dose groups to ensure consistent euthanasia. Animals were fasted prior to scheduled necropsy. Toxicokinetic animals that survived until scheduled euthanasia were euthanized using an approved method. No autopsies were performed and no tissues were collected.

[0579] Necropsy: Main study animals and recovery animals were subjected to a complete necropsy. all external surfaces and orifices; the cranial cavity and the external surface of the brain; and the thoracic, abdominal, and pelvic cavities. The necropsy procedure included an examination of animal anatomy and gross pathology. carried out by qualified personnel with appropriate training and experience in the field;

[0580] Organ Weights: Organs identified for weighing in the Tissue Collection and Preservation Table should be weighed at all planned times. Euthanized animals were weighed at necropsy (unless otherwise specified). Animals found dead: Or, for animals that are euthanized due to insufficient or imminent death, organ weights shall be recorded. Paired organs were weighed together. In the case of gross abnormalities, each of the paired organs was weighed in addition to the total weight. Organs were weighed and entered as tissue comments. Body and brain weights at the end were used for organ weight analysis. Used.

[0581] Tissue collection and storage: Tissues collected according to the table below were stored in 10% neutral buffered formalin. Saved to.

[0582] [Table 32] TIFF2025131596000035.tif225143X=Procedure to be performed. -=Not applicable. (1)=Unilateral. (2)=Bilateral. Gross abnormalities in the listed organs and other organs were sampled at necropsy and processed for histological analysis. and inspected under a microscope. a Two bone marrow smears were taken from the femur at scheduled and unscheduled autopsies (for possible testing). Smears are taken from animals found dead or moribund and euthanized. The bone marrow smears were air-dried and fixed in formalin. do not have. bEyes and optic nerves are preserved in Davidson's fixative. Testes and epididymides are Store in Tongue in modified fixative. c From the small intestine: Peyer's patches or isolated lymphoid nodules. d Weighed after fixation

[0583] 1.5 Dose Formulation and Analysis Control Article: The control article for this study was 0.5% HPMC in Milli-Q water. Control articles were prepared as needed and set to maintain 4°C when not in use. The prepared control articles were removed from the refrigerator and stored for at least 30 minutes before administration. The control article was continuously stirred during administration.

[0584] Test Article: The test article in this study was DS102 or 15(S)-HEPEEE Dosage formulations of test articles should be prepared in the test laboratory at appropriate concentrations to meet dosage level requirements. The dosage form was prepared weekly and kept at 4°C. The dosage formulation was taken out of the refrigerator and was kept at least 10 minutes before administration. The dosage formulation was also stirred for 30 minutes. The dosage formulation was continuously stirred during administration.

[0585] Sampling and analysis

[0586] The analyzed samples were submitted within the specified stability period. All analyzed samples were stored at ambient temperature. All residue / retention analytical samples were transferred to the analytical laboratory at the test facility within a minimum of 6 days after publication of the draft. or the publication of the final report was before the end of the six-month retention period. If this occurs, the residual / retained samples were discarded before the 6-month period. Premature destruction of samples may also be approved by the Investigator after consultation with the Sponsor. Formulation samples were taken for analysis as shown in the table below. Additional samples were taken at the discretion of the investigator. can be collected and analyzed.

[0587] [Table 33] N / A=Not Applicable. a The homogeneity results from the top, middle, and bottom of the preparations in Groups 2-3 were averaged, and the concentration results were Use it as a fruit.

[0588] Analysis method

[0589] The analyses described below were performed by UPLC with UV detection using a validated analytical procedure. provided.

[0590] Concentration analysis: Analytical samples: two each of the upper, middle, and lower samples (two middle samples for the control) When only concentration was to be evaluated, two central samples were collected. Reserve samples: Three samples each of the upper, middle, and lower parts (three middle samples for the control) were tested. Reserve samples may be analyzed at the discretion of the principal investigator. If so, collect three central samples only. Collection vessel: A suitable sized volumetric flask. Sample volume: Group 1: 0.5 mL in a 50 mL volumetric flask. Group 2: 0.25 mL in a 50 mL volumetric flask. Group 3: 0.25 mL in a 50 mL volumetric flask. The weight of all samples was recorded. Storage conditions: Stored in a refrigerator set to maintain 4°C. Pass / fail criteria: The pass / fail criteria was an average sample concentration within ±10% of the theoretical concentration. In this case, the pass / fail criterion was a relative standard deviation (RSD) of concentrations of ≤10% per group.

[0591] Stability Studies: Stability studies previously performed in conjunction with laboratory study number 439414 The test article was prepared and stored under the same conditions at multiple concentrations, including those used in this study. It was demonstrated to be stable in the vehicle. Rogers, E (2018). Vali dation of an Ultra High-Performance Liquor id Chromatographic Method for the Determining ination of 15(S)HEPE EE in oral(Gavage)D osing Formulations.Charles River Study N See lab study no. 439414. Stability data are available from the same laboratory study no. Retained in research records.

[0592] 1.6 Test System Animals: Studies were carried out by Charles River UK Limited, Margate, Kelowna. Male and female Sprague-Dawley rats purchased from the UK were used. The target age at the time of administration was 7-8 weeks. The target weight at the time of the first administration was 175-300 g (males Each animal weighed 120-250 g (females) and 120-250 g (females). The patient was identified using a "Trovan" electronic microchip.

[0593] 1.7 Breeding Housing: Animals were housed in the Rodent Toxicology Department of the testing facility for a period of up to 3 weeks prior to the start of dosing. Animals were allowed to acclimate to the facility. They were randomly assigned to groups. Males and females were randomized separately. Animals in poor health were not assigned to groups. The animals were placed in a cage with a stainless steel grid on top and a stainless steel grid on the bottom. Solid, appropriately sized, suspended polycarbonate / polypropylene Cages were housed with 2 or 3 animals per sex. Sterile white wood chips were used as bedding. was used as the material.

[0594] Environmental conditions: The target conditions for the animal room environment were as follows: temperature 19-23°C; humidity Temperature 40-70%; minimum 10 air changes per hour; 12 hours light and 12 hours dark Light cycle. Light, temperature, and humidity control are automatically controlled and continuously monitored and recorded. It was.

[0595] Bait: SDS Rat and Mouse (Modified) No.1 Diet SQC Expanded was provided freely. Water from the public water supply was provided freely from water bottles. The water used in the test facility was tested for dissolved solids, heavy metals, pesticide residues, pH, nitrates, and The samples were analyzed for nitrite and nitrite at regular intervals. Microbiological screening was also performed.

[0596] Animal Enrichment: Animals are socialized for mental / environmental enrichment. Concealment devices and equipment except when kept in captivity and interrupted by research procedures / activities Objects to chew on and other items were provided.

[0597] Veterinary Care: Veterinary care is provided throughout the course of the study and animals are monitored for any clinical signs or As required by other changes, all veterinary staff have been inspected. Diagnostic tests and recommended treatments, if any, were documented in the study records.

[0598] 1.8 Histology and Histopathology Histology: Tissues identified in the Tissue Collection and Preservation Table were embedded in paraffin, sectioned, and sliced. The sections were mounted on slides and stained with hematoxylin and eosin.

[0599] Histopathology: Histopathological evaluation should be performed by a qualified veterinary pathologist or a person trained in laboratory animal pathology. Microscopic examination was performed by a trained and experienced veterinary pathologist. High-dose animals, unscheduled deaths and gross lesions (including the main study low-dose group and recovery animals) If a treatment effect was present in the high-dose pivotal study group, a treatment effect was observed in the low-dose pivotal study group. Microscopic examination of target tissues from groups and recovered animals was performed in accordance with the clinical trial agreement between the sponsor and the investigator. This was carried out after agreement was reached on a revised implementation plan.

[0600] 1.9 Computerized Systems Computerized Systems: The computerized systems in the table below are available for use in the study. was available.

[0601] [Table 34]

[0602] 1.10 Statistical analysis Data collected during the pre-treatment period were tabulated, summarized, and statistically analyzed. All statistical analyses were performed at each study stage, unless otherwise specified. The data (excluding data from toxicokinetic animals) were summarised and presented below according to sex and occasion. The results were statistically analyzed as follows.

[0603] Constituent variables: Body weight change was calculated between scheduled intervals. Organ weights versus body weight were calculated between scheduled intervals. Organ weights were calculated relative to the body weight at the end of each interval. I calculated it.

[0604] Descriptive statistical analysis: Mean, standard deviation (or % coefficient of variation or standard error, if deemed appropriate) Difference), percentages, numbers, and / or incidence rates were reported for each dataset as appropriate.

[0605] Inferential statistical analysis: All statistical analyses were performed at a significance level of 5%. All pairwise comparisons were two-sided. The results were performed using the 1% and 5% test and reported at the 1% and 5% levels unless otherwise stated. The pairwise comparisons are listed below. ·Group 2 vs. Group 1 ·Group 3 vs. Group 1

[0606] Analysis was performed according to the following matrix where possible, except for cases with fewer than three observations. All groups with this condition were excluded.

[0607] [Table 35]

[0608] Parametric / Non-parametric: Use Levene's test to assess homogeneity of group variances The Levene test was not significant, or the Kruskal-Wallis test was not significant. In cases where there was no significant difference, groups were compared using the general one-way ANOVA F-test. are used when the Kruskal-Wallis test is found to be significant, respectively, by Dunnett's test or Pairwise comparisons were performed using Tan's test.

[0609] 1.11 Results Changes in red blood cell count, red blood cell distribution width, and reticulocyte count: Figures 38A to 38C show the changes in red blood cell count, red blood cell distribution width, and reticulocyte count over 15 (s Red blood cell count (RBC) and red blood cell distribution in rats administered )-HEPE EE or placebo The changes in red blood cell width (RDW) and reticulocyte count (RETIC) are shown. E and placebo were administered once daily by oral gavage, 7 days a week for a minimum of 26 weeks. The volume of each animal was based on the most recent body weight measurement. The highest dose was not well tolerated and was replaced with a lower dose of 3 g / kg / day. .

[0610] [Table 36]

[0611] RBC Changes: Figure 38A and Table 38 show that administration of the 3 g / kg / day dose resulted in a significant reduction in RBC compared to the control. This shows that it resulted in a significant increase in BC.

[0612] Changes in RDW: Figure 38B and Table 38 show the changes in RDW for both the 2 g / kg / day and 3 g / kg / day doses. 1 shows that treatment resulted in a significant reduction in RDW compared to the control.

[0613] Changes in RETIC: Figure 38C and Table 38 show the effect of both 2g / kg / day and 3g / kg / day The results show that administration of the dose resulted in a significant reduction in RETIC compared to the control.

[0614] These results suggest that 15-HEPE may be effective in treating a number of diseases that affect hemoglobin and red blood cells. These findings suggest that the drug may have therapeutic potential for the treatment of this disease.

[0615] Prothrombin time, activated partial thromboplastin time, and fibrinogen concentration Changes: Figures 39A-39C show the changes in the 15(s)-HEPE EE and placebo-treated rats. Prothrombin time (PT), activated partial thromboplastin time (APTT), The changes in 15(S)-HEPEEE and fibrinogen (FIB) concentrations are shown. Each animal was administered 100 mg of ... Volumes were based on the most recent body weight measurement. As shown in Table 39, a maximum dose of 6 g / kg / day was administered. The dose was not well tolerated and was replaced with a lower dose of 3 g / kg / day.

[0616] [Table 37]

[0617] Changes in PT: Figure 39A and Table 39 show the changes in PT after administration of both the 2 g / kg / day and 3 g / kg / day doses. 10 shows that administration of 100 mg / kg of sucrose resulted in a significant reduction in PT compared to the control.

[0618] Change in APTT: Figure 39B and Table 39 show the change in APTT for both the 2 g / kg / day and 3 g / kg / day doses. 10 shows that administration of 100 mg ...

[0619] Changes in FIB concentration: Figure 39C and Table 39 show the changes in FIB concentration after both 2 g / kg / day and 3 g / kg / day administration. 1 shows that administration of the dose resulted in a significant reduction in FIB concentration compared to the control.

[0620] These results suggest that 15-HEPE has anticoagulant and antithrombotic effects. do.

[0621] Various embodiments of the present disclosure are described herein below.

[0622] Section A. Metabolic Syndrome Treatment and / or Prevention in Subjects in Need of Treatment and / or Prevention A method for treating and / or preventing atherosclerotic syndrome, the method comprising administering to a subject 5-HEPE, 15-HETrE, or containing 15-HEPE and / or HETrE The method comprising administering the composition.

[0623] Section B. Cardiometabolic Disease Treatment and / or Prevention in Subjects in Need of Treatment and / or Prevention of Cardiometabolic Disease A method for treating and / or preventing a disease, the method comprising administering to a subject 15-HEPE, 1 Administering 5-HETrE or a composition containing 15-HEPE and / or HETrE A method comprising:

[0624] Section C. Treatment and / or prevention of metabolic syndrome and / or cardiometabolic disorders Treating metabolic syndrome and / or cardiometabolic disease in a subject in need thereof and / or preventing the development of rheumatoid arthritis, the method comprising administering to a subject up to about 8 g of 15-HEPE and and / or 15-HETrE, 15-HETrE represents at least about 90% by weight of all fatty acids in the composition; method.

[0625] Section D. Treatment and / or prevention of metabolic syndrome and / or cardiometabolic disorders Treating metabolic syndrome and / or cardiometabolic disease in a subject in need thereof and / or preventing the development of rheumatoid arthritis, wherein the method comprises administering to a subject up to about 8 g of 15-HEPE. and administering a composition comprising 15-HEPE to a subject, wherein 15-HEPE is at least one of all fatty acids in the composition. The target is diglycerides, glycerophospholipids, liver fat, blood pressure, Reduction in waist circumference and / or free fatty acid levels and / or glycerophospholipid levels The method exhibits one or more of an increase in

[0626] Section E. The first stage of nonalcoholic steatohepatitis (NASH) in a subject is NASH A method for preventing progression to a second stage, the method comprising administering to a subject up to about 8 g of 15-H A method comprising administering a composition comprising EPE.

[0627] Section F. The first stage is metabolic overload, increased liver fat content and lipotoxicity, and cellular stress. The method according to paragraph E, wherein the remodeling is apoptosis, inflammation, and / or fibrogenic remodeling.

[0628] Section G. The second stage is the increase in liver fat content and lipotoxicity, cell stress and apoptosis. , inflammation, and / or fibrogenic remodeling.

[0629] Section H. Non-alcoholic fatty liver disease (NFA) requiring treatment and / or prevention of cardiovascular disease Subjects with NAFLD, metabolic syndrome, and / or cardiometabolic disease 1. A method for treating and / or preventing cardiovascular disease in a subject, the method comprising administering to the subject 15- HEPE, 15-HETrE, or a composition containing 15-HEPE and / or HETrE A method comprising administering an

[0630] Section I. Non-alcoholic fatty liver disease ( Subjects with NAFLD, metabolic syndrome, and / or cardiometabolic disease 1. A method for treating and / or preventing cardiovascular disease in a subject, the method comprising administering to the subject up to about 8 g of 15-HEPE, wherein the 15-HEPE is The method of claim 1, wherein the fatty acids of the fatty acid mixture of the present invention correspond to at least about 90% by weight of all fatty acids of the fatty acid mixture of the present invention.

[0631] Section J. Subject to alpha-smooth muscle action (α-SMA), metallopeptidase inhibitors Transient Injurious Agent-1 (TIMP-1), Transforming Growth Factor Beta-β (TGF-β), and / or any of paragraphs A-I showing a decrease in one or more of the levels of type 1 collagen. 10. The method according to claim 1.

[0632] Section K. Subjects are evaluated for diglycerides, liver fat, blood pressure, abdominal circumference, and / or free fatty acid levels. Items A to C or items E to J showing a decrease in blood glucose level and / or an increase in glycerophospholipid level 10. The method according to any one of the preceding claims.

[0633] Item L. The subject is taking any of items A-K that exhibits reduced alkaline phosphate (ALP) levels. 1. The method according to claim 1.

[0634] Section M. Subjects are those with serum alanine aminotransferase (ALT), aspartate aminotransferase (ASA), Reduction of AST and / or BUN levels The method according to any one of items A to L,

[0635] Item N. The method of any one of items A-M, wherein the subject exhibits a reduced area of ​​fibrosis.

[0636] Section O. The subject is a homeostatic model of hemoglobin A1C (HbA1C) and insulin resistance. Assessment of insulin resistance (HOMA-IR) and / or adipose tissue insulin resistance (adipo-IR) The method of any one of paragraphs A to N, wherein the method exhibits a reduced level of

[0637] Item P.NAFLD is nonalcoholic steatohepatitis (NASH), any of items H to O The method according to any one of claims 1 to 5.

[0638] Section Q. Cardiovascular metabolic or cardiovascular diseases include dyslipidemia, hyperlipidemia, and hypercholesterolemia. Hyperlipidemia, hypertriglyceridemia, primary hypercholesterolemia, primary hyperlipidemia, general Primary hyperlipidemia, general hypercholesterolemia, familial hyperlipidemia, familial primary hyperlipidemia disease, familial hypercholesterolemia, familial hypertriglyceridemia, familial combined hyperlipidemia, Familial defective apolipoprotein b-100, secondary hyperlipidemia, mixed hyperlipidemia, cardiovascular disease Prevention of atherosclerotic plaque formation / progression, microvascular disease, residual cardiovascular risk Disease, large vessel disease, atherosclerosis, coronary atherosclerosis, dilatation impairment, cardiovascular risk reduction, prevention of major coronary events, major adverse cardiovascular events Prevention, prevention of ischemic events, secondary / primary prevention of cardiovascular events, prevention of cardiovascular death, myocardial infarction , stroke, angina, restoration of normal endothelial function, diabetes, diabetes mellitus, insulin resistance, Hyperinsulinemia, hyperglycemia, dysglycemia, induction of glycemic control, impaired glucose tolerance, and fasting blood glucose The method according to any one of paragraphs B to D or F to P, wherein the abnormality is one or more of the following:

[0639] Item R. The microvascular disease is retinopathy, nephropathy, neuropathy, or a combination thereof. The method described in Q.

[0640] Section S. Macrovascular disease includes stroke, peripheral vascular disease, limb ischemia, heart disease, or a combination thereof. The method described in item Q.

[0641] Section T. Subjects are assessed for very low density lipoprotein cholesterol (VLDL-C), non-high density lipoprotein cholesterol (NDL-C), Polyprotein cholesterol (non-HDL-C) and / or remnant-like particle cholesterol of RLP-C, and / or high-density lipoprotein cholesterol (HDL-C) The method of any one of paragraphs AS, which exhibits a reduced level of

[0642] Section U. Subjects were assessed for liver stiffness, fibrosis-4 (FIB-4), enhanced liver fibrosis (ELF) score, and / or a reduction in NAFLD score (NFS) according to any one of items A to T. method.

[0643] Section V. Subject to Plasminogen Activator Inhibitor-1 (PAI-1), Metallopharyngoprotein A (MPA) TNF-α, t ... rem-like transcript 2 (TLT2), chemokine (CC motif) ligand 16 (CCL1 6), monocyte chemotactic protein-1 (MCP-1), serum amyloid A4 (SAA4), Phosphoinositide 3 (PI3), thioredoxin reductase (TR), leukocyte immunoglobulin -like receptor B1 (LILBR1), amine oxidase, copper-containing 3 (AOC3), serine protease protease 2 (PRSS2) and tumor necrosis factor ligand superfamily member 1 Inflammatory and profibrotic proteins selected from the group consisting of 1A (TNRSF11A) and 2A (TNRSF21A). The method of any one of paragraphs A to U, which exhibits a reduction in

[0644] Section W. A method of treating or preventing cholestatic liver disease in a subject, comprising: subjects were administered 15-HEPE, 15-HETrE, or 15-HEPE and / or 15 - A method comprising administering a composition comprising HETrE.

[0645] Section X. Cholestatic liver disease includes primary biliary cholangitis (PBC), primary sclerosing cholangitis ( PSC), progressive familial intrahepatic cholestasis, or a combination thereof, as described in section W method.

[0646] Section Y. Cholestatic liver disease is a condition caused by drug-induced liver injury, total parenteral nutrition (TPN), viral infections, and Chronic and alcoholic hepatitis, cholestasis secondary to systemic disease, graft dysfunction , post-liver transplant cholestasis, pancreatitis, common bile duct stones, Mirizzi syndrome, genetic disorders, malignant tumors, or a combination thereof.

[0647] Section Z. The malignant tumor is hepatocellular carcinoma, bile duct tumor, pancreatic cancer, or a combination thereof. , the method described in item Y.

[0648] Section AA. The subject is α-smooth muscle activity (α-SMA), metallopeptidase inhibitor-1 (T IMP-1), transforming growth factor beta-β (TGF-β), and type 1 collagen and a reduction in the levels of cytokines and / or chemokines selected from the group consisting of: The method according to any one of items W to Z.

[0649] Paragraph BB. A method of treating or preventing kidney disease in a subject, the method comprising administering to the subject 15-HEPE and / or 15-HETrE, or 15-HEPE and / or 1 administering a composition comprising 5-HETrE to a subject, the subject having at least one renal disease. having risk factors.

[0650] Section CC. Kidney Disease includes renal fibrosis, tubulointerstitial fibrosis, chronic kidney disease, and severe interstitial fibrosis. The method according to paragraph BB, wherein the condition is selected from the group consisting of renal interstitial fibrosis, renal interstitial fibrosis, and end-stage renal disease.

[0651] Item DD. Kidney disease leads to fibrosis, the method according to item CC.

[0652] Section EE. At least one risk factor for kidney disease is diabetes, hypertension, cardiovascular disease, glomerular nephritis, and polycystic kidney disease, as described in any one of paragraphs BB to DD. How to post.

[0653] Item FF. The subject is any of items BB-EE, which exhibits reduced renal hydroxyproline levels. 1. The method according to claim 1.

[0654] Section GG. The subject is a patient with α-SMA, TIMP-1, TGF-β, and / or type 1 collagen. The method of any one of paragraphs BB to FF, wherein the method does not exhibit a reduction in the level of

[0655] Section HH. The subject is a patient with α-SMA, TIMP-1, TGF-β, and / or type 1 collagen. The method of any one of paragraphs BB-GG, wherein the method exhibits a reduced level of

[0656] Section II. Subjects exhibit reduced pro-fibrotic cytokines in the liver, Sections AA-HH 10. The method according to any one of the preceding claims.

[0657] Section JJ. Profibrotic cytokines include α-SMA, TIMP-1, TGF-β, and type 1 Collagen, interleukin 1β (IL-1β), interleukin-6 (IL-6) , interleukin-6 (IL-8), interleukin-13 (IL-13), tumor lysis Death factor (TNF-α), TNF-like ligand 1A (TL1A), aryl hydrocarbon receptor ( AhR), interleukin-17 (IL-17), interleukin-23 (IL-2 3), interleukin-11 (IL-11), and / or interleukin-33 (I L-33).

[0658] Paragraph KK. The subject is a vascular adhesion molecule and / or a chemokine and / or a tumor necrosis factor receptor serogroup. The method of any one of paragraphs A-JJ, wherein the method exhibits a reduction in a gene family member.

[0659] Section LL.15-HEPE, 15-HETrE, or 15-HEPE and / or 15 - The method according to any one of paragraphs A to KK, wherein the composition containing HETrE is administered orally.

[0660] Section MM.15-HEPE and / or 15-HETrE may be in the free acid form, in the esterified form or a salt form.

[0661] Item NN. The esterified form is an alkyl ester form or a triglyceride form. The method described in MM.

[0662] Section OO.15-HEPE refers to 15(S)-HEPE, 15(R)-HEPE, or and / or 15-HETrE includes 15(S)-HETrE, 15(R)-HETrE, or any combination thereof, ...

Claims

1. A method for treating and / or preventing a blood disorder in a subject in need thereof, said method comprising administering to said subject 15-hydroxyeicosapentaenoic acid (15-HEPE) or a composition comprising 15-HEPE.

2. A method for treating and / or preventing hemoglobin disorders in a subject in need thereof, said method comprising administering 15-HEPE or a composition comprising 15-HEPE to said subject.

3. A method for treating and / or preventing an red blood cell disorder in a subject in need thereof, said method comprising administering 15-HEPE or a composition comprising 15-HEPE to said subject.

4. A method for treating and / or preventing hemolytic anemia in a subject in need thereof, the method comprising administering to the subject a composition comprising up to about 8 g of 15-HEPE.

5. 10. The method of claim 1, wherein the blood disorder is selected from the group consisting of anemia, blood cancer, and coagulation disorder.

6. 6. The method of claim 5, wherein the anemia is nutritional anemia, non-nutritional anemia, or a combination thereof.

7. 6. The method of claim 5, wherein the hematological cancer is selected from the group consisting of lymphoma, leukemia, and myeloma.

8. 6. The method of claim 5, wherein the coagulation disorder is selected from the group consisting of thrombophilia, hemophilia, von Willebrand's disease, and thrombocytopenia.

9. 9. The method of any one of claims 1 to 8, wherein the subject has an increased red blood cell count, a decreased red blood cell distribution width, and / or a decreased reticulocyte count compared to a control subject not administered the 15-HEPE or the composition.

10. 10. The method of any one of claims 1 to 9, wherein the subject has an increase in red blood cell count of at least 10%, at least 15%, at least 20%, at least 25%, or at least 30% compared to a control subject not administered the 15-HEPE or the composition.

11. 11. The method of any one of claims 1 to 10, wherein the subject has a reduction in red blood cell distribution width of about 15% to about 20%, about 20% to about 25%, about 25% to about 30%, about 30% to about 35%, or about 35% to about 40% compared to a control subject not administered the 15-HEPE or the composition.

12. The method of any one of claims 9 to 11, wherein the control subject has a red blood cell distribution width of greater than 15%.

13. 13. The method of any one of claims 1 to 12, wherein the subject has a reduction in reticulocyte count of at least about 5%, at least about 10%, at least about 15%, or at least about 20% compared to a control subject not administered the 15-HEPE or the composition.

14. The method of any one of claims 9 to 13, wherein the control subject has a reticulocyte count of greater than 5% of the total red blood cell count.

15. 15. The method of any one of claims 2 to 14, wherein the hemoglobin abnormality and / or the red blood cell disorder is selected from the group consisting of hereditary hemolytic anemia, acquired hemolytic anemia, Fanconi anemia, iron deficiency anemia, folate deficiency, B12 deficiency, and myelodysplastic syndrome.

16. 16. The method of claim 15, wherein the hereditary hemolytic anemia is selected from the group consisting of sickle cell disease, sickle cell anemia, β-thalassemia, and hereditary spherocytosis.

17. 16. The method of claim 15, wherein the acquired hemolytic anemia results from a disorder or disease selected from the group consisting of primary infection, drug treatment, hematologic malignancy, autoimmune disease, hypersplenism, placement of a mechanical heart valve, and a disease occurring concomitantly with blood transfusion.

18. 17. The method of claim 16, wherein the sickle cell disease and sickle cell anemia are associated with sickle cell crisis, vaso-occlusive crisis, and / or splenic blood cell retention.

19. A method for treating and / or preventing a thrombophilic disorder in a subject in need thereof, said method comprising administering 15-HEPE or a composition comprising 15-HEPE to said subject.

20. 1. A method for treating and / or preventing thrombophilia in a subject in need thereof, the method comprising administering to the subject 15-HEPE or a composition comprising up to about 8 g of 15-HEPE.

21. 1. A method for treating and / or preventing venous thromboembolism in a subject in need thereof, the method comprising administering to the subject 15-HEPE or a composition comprising up to about 8 g of 15-HEPE.

22. 1. A method for treating and / or preventing arterial thrombosis in a subject in need thereof, said method comprising administering to said subject 15-HEPE or a composition comprising up to about 8 g of 15-HEPE.

23. A method of preventing embolism in a subject in need thereof, said method comprising administering to said subject 15-HEPE or a composition comprising up to about 8 g of 15-HEPE.

24. 24. The method of any one of claims 19 to 23, wherein the subject has an increased prothrombin time, an increased activated partial thromboplastin time, and / or a decreased fibrinogen concentration compared to a control subject not administered the composition.

25. 25. The method of any one of claims 1 to 24, wherein the 15-HEPE is in a free acid form, an esterified form, a conjugate form, or a salt form.

26. 26. The method of any one of claims 1 to 25, wherein the 15-HEPE represents at least about 90% by weight of all fatty acids in the composition.

27. 27. The method of any one of claims 1 to 26, wherein the composition comprises up to about 2 g of 15-HEPE.

28. 28. The method of any one of claims 1 to 27, wherein the composition is administered in 1 to 8 capsules per day.

29. The method of any one of claims 1 to 28, wherein the composition comprises at least 2 g of 15-HEPE.

30. 30. The method of any one of claims 1 to 29, wherein the composition is formulated to provide the subject with about 5 mg 15-HEPE per kg body weight (mg / kg), about 50 mg / kg, about 250 mg / kg, or about 500 mg / kg.

31. The method of any one of claims 1 to 30, wherein the 15-HEPE or the composition comprising 15-HEPE is administered orally.

32. 32. The method of any one of claims 1 to 31, wherein the 15-HEPE is in a free acid form, an esterified form, a conjugated form, or a salt form.

33. 33. The method of any one of claims 1 to 32, wherein the esterified form of 15-HEPE is a methyl ester, an ethyl ester, or a combination thereof.

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