WO2018108161A1 - 一种预防和治疗肥胖症的方法和药物 - Google Patents
一种预防和治疗肥胖症的方法和药物 Download PDFInfo
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- WO2018108161A1 WO2018108161A1 PCT/CN2017/116562 CN2017116562W WO2018108161A1 WO 2018108161 A1 WO2018108161 A1 WO 2018108161A1 CN 2017116562 W CN2017116562 W CN 2017116562W WO 2018108161 A1 WO2018108161 A1 WO 2018108161A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/482—Serine endopeptidases (3.4.21)
- A61K38/484—Plasmin (3.4.21.7)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
- C12Y304/21—Serine endopeptidases (3.4.21)
- C12Y304/21007—Plasmin (3.4.21.7), i.e. fibrinolysin
Definitions
- the present invention relates to a method and medicament for preventing and/or treating obesity and related disorders.
- Obesity refers to excessive accumulation and/or abnormal distribution of fat in the body. According to the definition of the World Health Organization, overweight and obesity refer to excessive and/or abnormal accumulation of body fat that may damage health. As early as 1948, WHO defined obesity as a disease and increased it into the International Classification of Disease (ICD). In June 2013, the American Medical Association (AMA) officially declared obesity as a disease for the first time in its history and required medical interventions to prevent and treat it [1] .
- ICD International Classification of Disease
- Overweight and obesity are also risk factors for a variety of diseases, including cardiovascular and cerebrovascular diseases (heart disease, hypertension, dyslipidemia, stroke), type 2 diabetes, musculoskeletal diseases (osteoarthritis, etc.), digestive diseases (galling Disease), sleep apnea or respiratory disorders and certain cancers (endometrial cancer, breast cancer, colon cancer), etc. [2] .
- cardiovascular and cerebrovascular diseases heart disease, hypertension, dyslipidemia, stroke
- type 2 diabetes musculoskeletal diseases (osteoarthritis, etc.)
- digestive diseases galling Disease
- sleep apnea or respiratory disorders endometrial cancer, breast cancer, colon cancer
- cancers endometrial cancer, breast cancer, colon cancer
- BMI body mass index
- WC waist circumference
- the treatment of obesity is mainly divided into lifestyle intervention, drug treatment and surgical treatment.
- evidence-based medical evidence recommends lifestyle intervention as a first-line treatment.
- the Chinese Adult Overweight and Obesity Prevention and Control Guide (Trial) states that when lifestyle interventions are ineffective, ie, weight loss is not reduced by 5%, and the BMI is still greater than 28, it is recommended for medical treatment.
- Patients who are overweight and have a complication (cardiovascular disease, hypertension, type 2 diabetes, etc.) are also recommended for medical treatment if they are not effective in life intervention.
- Weight-loss drugs can be divided into: central appetite suppressant drugs, appetite-suppressing gastrointestinal hormones, drugs that interfere with nutrient absorption in peripheral areas and increase nutrient metabolism.
- Two of the three long-acting weight-loss drugs for centrally suppressive appetite drugs have been discontinued: rimonabant and sibutramine were added to the risk of mental and cardiovascular disease in October 2008, respectively. And in January 2010, it was requested by EMEA to stop [5-6] , and its widespread application made it a blank in the market for diet pills.
- the role of gastrointestinal hormones in regulating appetite and controlling blood sugar has become a hot topic.
- Drugs acting on the periphery target two targets 1. In the gastrointestinal tract, reduce fat-absorbing lipase inhibitors and sodium-glucose co-transporter 2 (SGLT2) inhibitors; 2. Act on adipose tissue to reduce fat synthesis, promote Fat hydrolysis: mainly enzymes on the lipid metabolism pathway. Lipase inhibitors reduce the absorption of fat in the diet by inhibiting lipases in the gastrointestinal tract and pancreas. Orlistat is effective for weight loss and has fewer side effects, but 13 patients in the United States reported severe liver damage. Recently, the FDA decided to urge its manufacturers to update the product manual [7] .
- SGLT2 sodium-glucose co-transporter 2
- the effectiveness and safety of the drug should be assessed at least monthly for the first 3 months of drug treatment, and should be assessed once every 3 months [8] .
- the safety of weight-loss drugs is the main reason for limiting their widespread use, and the efficacy of drugs for weight loss is limited. Therefore, drug therapy is still an adjunct to the treatment of obesity, and improving lifestyles with the help of medical professionals is the preferred method for treating overweight and obesity.
- Obesity is a chronic disease. No medicine can produce permanent weight loss. Only long-term medication can maintain weight. In the face of a growing number of overweight and obese patients, it is an urgent desire to find safer and more effective weight-loss drugs.
- the invention relates to the following items:
- WHAT IS CLAIMED IS 1. A method of preventing or treating obesity in a subject comprising administering to the subject an effective amount of plasminogen.
- a method of preventing or treating obesity in a subject comprising administering to the subject an effective amount of plasminogen, wherein the obesity is secondary to an endocrine disorder disease, a glucose metabolism disease, a liver disease, a kidney disease , cardiovascular disease, intestinal disease, thyroid disease, gallbladder or biliary tract disease, excessive drinking, drug effects.
- a method for preventing and/or treating obesity complicated by a disease in a subject comprising administering to the subject an effective amount of plasminogen, wherein the obesity complicated by the disease comprises obesity, a metabolic disease complicated by an endocrine disease Concurrent obesity, obesity complicated by cardiovascular disease, obesity complicated by digestive diseases, and obesity complicated by degenerative diseases.
- the obesity comprises obesity complicated by diabetes, obesity complicated by hypertension, obesity complicated by atherosclerosis, obesity complicated by liver disease, and obesity complicated by osteoporosis.
- a method of preventing or treating complications caused by obesity comprising administering to a subject a therapeutically effective amount of plasminogen, wherein the complications of obesity include cardiovascular and cerebrovascular diseases, metabolic diseases, musculoskeletal diseases , digestive diseases, sleep apnea, respiratory disorders.
- a method of reducing the risk of developing atherosclerosis in a subject comprising administering to the subject an effective amount of plasminogen.
- a method of reducing the risk of obesity in a subject comprising administering to the subject an effective amount of plasmin originally reduces abnormal or excessive deposition of fat in or around the tissue, subcutaneous or abdominal cavity.
- a method of lowering blood lipids in a subject comprising administering to the subject an effective amount of plasminogen.
- a method of reducing the risk of atherosclerosis or heart disease in a subject comprising administering to the subject an effective amount of plasminogen to alleviate abnormal or excessive deposition of lipids in the vessel wall.
- a method of treating obesity in a subject comprising administering to the subject an effective amount of plasminogen to promote clearance of deposited fat by the liver.
- a method of treating obesity in a subject comprising administering to the subject an effective amount of plasminogen, wherein the plasminogen attenuates body fat by one or more selected from the group consisting of: :
- the one or more other drugs include a therapeutic drug for hypertension, a drug for treating diabetes, a drug for treating atherosclerosis, a drug for treating chronic glomerulonephritis, a drug for treating chronic pyelonephritis, Drugs for the treatment of nephrotic syndrome, drugs for the treatment of renal insufficiency, drugs for the treatment of uremia, drugs for the treatment of kidney transplantation, drugs for the treatment of fatty liver, drugs for the treatment of liver cirrhosis, drugs for the treatment of obesity.
- the other drug comprises: a hypolipidemic drug, an antiplatelet drug, a blood pressure lowering drug, a dilated vascular drug, a hypoglycemic drug, an anticoagulant drug, a thrombolytic drug, a hepatoprotective drug, an anti-heart rhythm Abnormal drugs, cardiotonic drugs, diuretic drugs, anti-infective drugs, antiviral drugs, immunomodulatory drugs, inflammatory regulatory drugs, anti-tumor drugs, hormone drugs, thyroxine.
- the medicament comprises a hypolipidemic drug: a statin; a fibrate; a niacin; a cholestyramine; clofibrate; an unsaturated fatty acid such as Yishouning, Xuezhiping and Xinmai; Sodium diester; antiplatelet drugs: aspirin; dipyridamole; clopidogrel; cilostazol; dilated vascular drugs: hydralazine; nitroglycerin and heartache; sodium nitroprusside; alpha nitrate receptor blockers such as prazosin ; alpha receptor blockers such as phentolamine; beta pull receptor stimulants such as salbutamol; captopril, enalapril; heart pain, thiazolone; lysine, long pressure , prostaglandins, atrial natriuretic peptide; thrombolytic drugs: urokinase and streptokin
- plasminogen is a protein comprising a plasminogen active fragment and still having plasminogen activity.
- plasminogen is selected from the group consisting of Glu-plasminogen, Lys-plasminogen, small plasminogen, microplasminogen, and delta-fibrinolysis Proenzymes or their variants that retain plasminogen activity.
- plasminogen is a natural or synthetic human plasminogen, or a variant or fragment thereof that still retains plasminogen activity.
- plasminogen is a human plasminogen ortholog from a primate or a rodent or a variant thereof that still retains plasminogen activity Or a fragment.
- a plasminogen for use in the method of any of items 1-39.
- a pharmaceutical composition comprising a pharmaceutically acceptable carrier and plasminogen for use in the method of any of items 1-39.
- a prophylactic or therapeutic kit comprising: (i) plasminogen for use in the method of any of items 1-39 and (ii) for delivery of said plasminogen to The subject of the subject.
- kit of item 42 wherein the member is a syringe or vial.
- kit of item 42 or 43 further comprising a label or instructions for use, the label or instructions for use instructing administration of the plasminogen to the subject to perform any of items 1-39 method.
- a pharmaceutical composition comprising (i) plasminogen or a plasminogen-containing composition for use in the method of any one of clauses 1 to 39, wherein the label indicates administration of the plasminogen or composition
- the subject is the method of any of items 1-39.
- kit of claim 42 or the article of item 45 further comprising one or more additional members or containers containing other drugs.
- kits or article of item 46 wherein the other drug is selected from the group consisting of a hypolipidemic drug, an antiplatelet drug, a blood pressure lowering drug, a dilated vascular drug, a hypoglycemic drug, an anticoagulant drug, a thrombolytic drug, and a drug.
- a hypolipidemic drug an antiplatelet drug, a blood pressure lowering drug, a dilated vascular drug, a hypoglycemic drug, an anticoagulant drug, a thrombolytic drug, and a drug.
- the invention further relates to the use of plasminogen in the manufacture of a medicament, a pharmaceutical composition, an article, a kit for use in the above method.
- the invention relates to a method of preventing and/or treating obesity and a related disorder thereof in a subject, comprising administering to the subject a prophylactically and/or therapeutically effective amount of plasminogen.
- the invention also relates to the use of plasminogen for the prevention and/or treatment of obesity and related disorders in a subject.
- the invention further relates to the use of plasminogen for the preparation of a medicament, pharmaceutical composition, preparation, kit for the prevention and/or treatment of obesity and related disorders in a subject.
- the present invention relates to plasminogen for preventing and/or treating obesity and related disorders in a subject.
- the invention also relates to a plasminogen-containing drug, pharmaceutical composition, article, kit for use in preventing and/or treating obesity and related disorders in a subject.
- the obesity is obesity caused by excessive diet.
- the obesity is secondary obesity, such as secondary to a fatty metabolic disorder, such as an endocrine disorder, a glucose metabolism disease, a liver disease, a kidney disease, a cardiovascular disease, an intestinal disease, a thyroid gland Disease, gallbladder or biliary tract disease, alcohol consumption, drug treatment caused or accompanied by disorders of fat metabolism.
- a fatty metabolic disorder such as an endocrine disorder, a glucose metabolism disease, a liver disease, a kidney disease, a cardiovascular disease, an intestinal disease, a thyroid gland Disease, gallbladder or biliary tract disease, alcohol consumption, drug treatment caused or accompanied by disorders of fat metabolism.
- the disorder of fat metabolism is hypertension, diabetes, chronic hepatitis, cirrhosis, kidney damage, chronic glomerulonephritis, chronic pyelonephritis, nephrotic syndrome, renal insufficiency, kidney transplantation, uremia, A disorder of fat metabolism caused by or associated with hypothyroidism, obstructive cholecystitis, obstructive cholangitis, drug or hormonal therapy.
- the disorder of fat metabolism is hyperlipidemia, hyperlipoproteinemia, fatty liver, atherosclerosis, obesity, organ fat deposition.
- the present invention relates to a method of preventing and/or reducing abnormal or excessive deposition of fat in a body tissue of a subject, comprising administering to the subject an effective amount of plasminogen.
- the invention also relates to And the use of plasminogen for preventing and/or reducing abnormal or excessive deposition of fat in a body tissue of a subject.
- the invention further relates to the use of plasminogen for the preparation of a medicament, pharmaceutical composition, article, kit for preventing and/or reducing abnormal or excessive deposition of fat in a subject.
- the present invention relates to plasminogen for preventing and/or reducing abnormal or excessive deposition of fat in a body tissue of a subject.
- the present invention also relates to a medicament, a pharmaceutical composition, an article, a kit comprising plasminogen for preventing and/or reducing abnormal or excessive deposition of fat in a body tissue of a subject.
- the present invention relates to a method of preventing and/or treating a condition caused by abnormal or excessive deposition of fat in a body tissue of a subject, comprising administering to the subject an effective amount of plasminogen.
- the invention further relates to the use of plasminogen for preventing and/or treating a condition caused by abnormal or excessive deposition of fat in a body tissue of a subject.
- the invention further relates to the use of plasminogen for the manufacture of a medicament, pharmaceutical composition, preparation, kit for the prevention and/or treatment of a condition in which a subject's fat is abnormal or excessively deposited in body tissues and organs.
- the present invention relates to a plasminogen-containing drug, pharmaceutical composition, preparation, kit for preventing and/or treating a condition caused by abnormal or excessive deposition of fat in a body tissue of a subject.
- abnormal or excessive deposition of the fat in the body tissue refers to abnormal or excessive deposition of fat in the blood, subcutaneous tissue, blood vessel walls, internal organs.
- the disorders caused by abnormal or excessive deposition of fat in body tissues include obesity, hyperlipidemia, hyperlipoproteinemia, fatty liver, atherosclerosis, lipid heart damage, lipids Qualitary renal damage, lipid islet damage.
- the present invention relates to a method of preventing and/or treating obesity caused by a disorder of fat metabolism in a subject, comprising administering to the subject an effective amount of plasminogen.
- the invention further relates to the use of plasminogen for the prevention and/or treatment of obesity caused by a disorder of fat metabolism in a subject.
- the present invention also relates to the use of plasminogen for the preparation of a medicament, a pharmaceutical composition, an article, a kit for preventing and/or treating obesity caused by a disorder of fat metabolism in a subject.
- the present invention relates to plasminogen for preventing and/or treating obesity caused by a disorder of fat metabolism in a subject.
- the present invention also relates to a plasminogen-containing drug, pharmaceutical composition, preparation, kit for preventing and/or treating obesity caused by a disorder of fat metabolism in a subject.
- the condition comprises obesity, hyperlipidemia, hyperlipoproteinemia, fatty liver, atherosclerosis, lipid heart tissue damage, lipid renal injury.
- the invention relates to a method of treating a disease in a subject by reducing fat abnormalities or excessive deposition comprising administering to the subject an effective amount of plasminogen.
- the invention also relates to the use of plasminogen for treating diseases in a subject by reducing fat abnormalities or excessive deposition.
- the invention further relates to the use of plasminogen for the preparation of a medicament, pharmaceutical composition, article, kit for treating a disease in a subject by reducing fat abnormalities or excessive deposition.
- the present invention also relates to plasminogen for treating a disease in a subject by reducing fat abnormality or excessive deposition.
- the present invention also relates to a plasminogen-containing drug, pharmaceutical composition, preparation, kit for treating a disease of a subject by reducing fat abnormality or excessive deposition.
- the disease comprises atherosclerosis, coronary heart disease, angina pectoris, myocardial infarction, arrhythmia, fatty liver, cirrhosis, cerebral ischemia, cerebral infarction, renal insufficiency, nephrotic syndrome, renal insufficiency Obesity.
- the present invention relates to a method of preventing and/or treating lipid damage in a tissue of a subject comprising administering to the subject an effective amount of plasminogen.
- the invention further relates to the use of plasminogen for the prevention and/or treatment of lipid damage in tissues and organs of a subject.
- the invention further relates to the use of plasminogen for the preparation of a medicament, pharmaceutical composition, preparation, kit for the prevention and/or treatment of lipid damage in tissues and organs of a subject.
- the present invention relates to plasminogen for preventing and/or treating lipid damage in tissues and organs of a subject.
- the present invention also relates to a plasminogen-containing drug, pharmaceutical composition, preparation, kit for preventing and/or treating lipid damage in tissues and organs of a subject.
- the tissue organ comprises an arterial wall, a heart, a liver, a kidney, a pancreas.
- the invention relates to a method of improving hyperlipidemia in a subject comprising administering to the subject an effective amount of plasminogen.
- the invention also relates to the use of plasminogen for improving hyperlipidemia in a subject.
- the invention further relates to the use of plasminogen for the preparation of a medicament, a pharmaceutical composition, an article, a kit for improving hyperlipidemia in a subject.
- the present invention also relates to plasminogen for improving hyperlipidemia in a subject.
- the present invention also relates to a medicament, a pharmaceutical composition, an article, a kit comprising plasminogen for improving hyperlipidemia in a subject.
- the hyperlipidemia is selected from one or more of the group consisting of hypercholesterolemia, hypertriglyceridemia, mixed hyperlipidemia, and low high density lipoproteinemia.
- the invention relates to a method of reducing the risk of atherosclerosis in a subject comprising administering to the subject an effective amount of plasminogen.
- the invention also relates to the use of plasminogen for reducing the risk of atherosclerosis in a subject.
- the invention further relates to the use of plasminogen in the manufacture of a medicament, pharmaceutical composition, article, kit for reducing the risk of atherosclerosis in a subject.
- the present invention also relates to plasminogen for reducing the risk of atherosclerosis in a subject.
- the invention also relates to a medicament, pharmaceutical composition, preparation, kit comprising plasminogen for reducing the risk of atherosclerosis in a subject.
- the subject has hypertension, obesity, diabetes, chronic hepatitis, cirrhosis, kidney injury, chronic glomerulonephritis, chronic pyelonephritis, nephrotic syndrome, renal insufficiency, kidney transplantation , uremia, hypothyroidism, obstructive cholecystitis or obstructive cholangitis, or the subject taking a drug or hormone that affects fat metabolism.
- the plasminogen reduces the risk of atherosclerosis in a subject by one or more of the following: lowering total cholesterol levels in the blood, triglyceride levels, low density lipoprotein levels, Increase blood HDL levels.
- the invention relates to a method of treating a disease by ameliorating hyperlipidemia in a subject comprising administering to the subject an effective amount of plasminogen.
- the invention also relates to the use of plasminogen for the treatment of diseases by improving hyperlipidemia in a subject.
- the invention further relates to the use of plasminogen for the preparation of a medicament, pharmaceutical composition, preparation, kit for the treatment of a disease by improving hyperlipidemia in a subject.
- the present invention also relates to plasminogen for treating diseases by improving hyperlipidemia in a subject.
- the present invention also relates to a medicament, a pharmaceutical composition, an article, a kit comprising plasminogen for treating a disease by improving hyperlipidemia in a subject.
- the condition comprises diabetes, hypertension, atherosclerosis, coronary heart disease, angina pectoris, myocardial infarction, arrhythmia, chronic hepatitis, fatty liver, cirrhosis, cerebral insufficiency, cerebral ischemia, cerebral infarction Chronic nephritis, chronic pyelonephritis, renal insufficiency, nephrotic syndrome, uremia, obesity.
- the present invention relates to a method of preventing and/or treating a hyperlipidemia-related disorder in a subject comprising administering to the subject an effective amount of plasminogen.
- the invention also relates to the use of plasminogen for the prevention and/or treatment of a hyperlipidemia-related disorder in a subject.
- the invention further relates to the use of plasminogen for the preparation of a medicament, pharmaceutical composition, preparation, kit for the prevention and/or treatment of a hyperlipidemic disorder in a subject.
- the present invention relates to a method for preventing and/or treating a hyperlipidemia phase in a subject The plasminogen of the condition.
- the present invention also relates to a plasminogen-containing drug, pharmaceutical composition, preparation, kit for use in preventing and/or treating a hyperlipidemia-related disorder in a subject.
- the condition comprises diabetes, hypertension, atherosclerosis, coronary heart disease, angina pectoris, myocardial infarction, arrhythmia, chronic hepatitis, fatty liver, cirrhosis, cerebral insufficiency, cerebral ischemia, cerebral infarction Chronic nephritis, chronic pyelonephritis, renal insufficiency, nephrotic syndrome, uremia, obesity.
- the plasminogen can be administered in combination with one or more other drugs or methods of treatment.
- the one or more other drugs include a therapeutic drug for hypertension, a drug for treating diabetes, a drug for treating atherosclerosis, a drug for treating chronic glomerulonephritis, a drug for treating chronic pyelonephritis, and a combination of nephropathy Drugs for treatment, drugs for treatment of renal insufficiency, drugs for uremia treatment, drugs for kidney transplantation, drugs for treatment of fatty liver, drugs for treatment of liver cirrhosis, drugs for treatment of obesity.
- the other drug comprises: a hypolipidemic drug, an antiplatelet drug, a blood pressure lowering drug, a dilated vascular drug, a hypoglycemic drug, an anticoagulant drug, a thrombolytic drug, a hepatoprotective drug, an antiarrhythmic drug, Cardiotonic drugs, diuretic drugs, anti-infective drugs, antiviral drugs, immunomodulatory drugs, inflammatory regulating drugs, anti-tumor drugs, hormone drugs, thyroxine.
- the medicament comprises a hypolipidemic drug: a statin; a fibrate; a niacin; a cholestyramine; clofibrate; an unsaturated fatty acid such as erosin, a blood lipid, and a heart pulse; alginic acid Sodium diester; antiplatelet drugs: aspirin; dipyridamole; clopidogrel; cilostazol; dilated vascular drugs: hydralazine; nitroglycerin and heartache; sodium nitroprusside; alpha nitrate receptor blockers such as prazosin ; alpha receptor blockers such as phentolamine; beta pull receptor stimulants such as salbutamol; captopril, enalapril; heart pain, thiazolone; lysine, long pressure , prostaglandins, atrial natriuretic peptide; thrombolytic drugs: urokinase and strept
- the plasminogen may have at least 75%, 80%, 85%, 90%, 95%, 96%, 97 with sequence 2, 6, 8, 10 or 12. %, 98% or 99% sequence identity and still have plasminogen activity.
- the plasminogen is added, deleted, and/or substituted on the basis of sequence 2, 6, 8, 10, or 12, 1-100, 1-90, 1-80, 1-70 , 1-60, 1-50, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1- 10, 1-5, 1-4, 1-3, 1-2, 1 amino acid, and still have plasminogen activity protein.
- the plasminogen is a protein comprising a plasminogen active fragment and still having plasminogen activity.
- the plasminogen is selected from the group consisting of Glu-plasminogen, Lys-plasminogen, small plasminogen, microplasminogen, delta-plasminogen, or their retention A variant of plasminogen activity.
- the plasminogen is a native or synthetic human plasminogen, or a variant or fragment thereof that still retains plasminogen activity.
- the plasminogen is a human plasminogen ortholog from a primate or a rodent or a variant or fragment thereof that still retains plasminogen activity.
- the amino acid of plasminogen is as shown in sequence 2, 6, 8, 10 or 12.
- the plasminogen is human natural plasminogen.
- the subject is a human. In some embodiments, the subject lacks or lacks plasminogen. In some embodiments, the deficiency or deficiency is innate, secondary, and/or local.
- the pharmaceutical composition comprises a pharmaceutically acceptable carrier and plasminogen for use in the foregoing methods.
- the kit can be a prophylactic or therapeutic kit comprising: (i) plasminogen for use in the foregoing methods and (ii) for delivery of the plasminogen to The subject of the subject.
- the member is a syringe or vial.
- the kit further comprises a label or instructions for use, the label or instructions for use indicating administration of the plasminogen to the subject to perform any of the methods described above.
- the article of manufacture comprises: a container comprising a label; and a pharmaceutical composition comprising (i) plasminogen or a plasminogen for use in the foregoing method, wherein the label indicates that the fiber is to be The lysogen or composition is administered to the subject to perform any of the methods described above.
- the kit or article further comprises an additional one or more components or containers containing other drugs.
- the other drug is selected from the group consisting of a hypolipidemic drug, an antiplatelet drug, a blood pressure lowering drug, a dilated vascular drug, a hypoglycemic drug, an anticoagulant drug, a thrombolytic drug, a hepatoprotective drug, and an anti-heart rhythm Abnormal drugs, cardiotonic drugs, diuretic drugs, anti-infective drugs, antiviral drugs, immunomodulatory drugs, inflammatory regulatory drugs, anti-tumor drugs, hormone drugs, thyroxine.
- the plasminogen is administered systemically or locally, preferably by the following route: intravenous, intramuscular, subcutaneous administration of plasminogen for treatment.
- the plasminogen is administered in combination with a suitable polypeptide carrier or stabilizer.
- the plasminogen is 0.0001-2000 mg/kg, 0.001-800 mg/kg, 0.01-600 mg/kg, 0.1-400 mg/kg, 1-200 mg/kg, 1-100 mg per day.
- the present invention expressly covers all combinations of the technical features between the embodiments of the present invention, and these combined technical solutions are explicitly disclosed in the present application, just as the above technical solutions have been separately and explicitly disclosed.
- the present invention also explicitly covers combinations between various embodiments and elements thereof, and the combined technical solutions are explicitly disclosed herein.
- fat metabolism disorder is also called “abnormal fat metabolism” and "fat metabolism disorder”, and is a general term for clinical or pathological manifestations caused by abnormal, disorder or disorder of fat metabolism.
- fat metabolism disorder “abnormal fat metabolism”, and “fat metabolic disorder” are used interchangeably.
- fat metabolism “lipid metabolism”, and “lipid metabolism” are used interchangeably.
- Fat metabolism disorder-related disorders is a general term for disorders associated with disorders of fat metabolism.
- the correlation may be related to etiology, pathogenesis, pathological relevance, clinical symptom correlation, and/or treatment principles.
- “Blood fat” is a general term for triglycerides, cholesterol and phospholipids.
- Lipoprotein is a spherical macromolecular complex composed of apolipoprotein and blood lipid. Because lipoproteins contain different components of cholesterol and triglycerides, and the density is different. Divided into five categories: chylomicrons (CM) very low density lipoprotein (VLDL) medium density lipoprotein (IDL) low density lipoprotein (LDL) high density lipoprotein (HDL).
- CM chylomicrons
- VLDL very low density lipoprotein
- IDL medium density lipoprotein
- LDL low density lipoprotein
- HDL high density lipoprotein
- dyslipidemia Following Symptoms of dyslipidemia are found in diabetes, hypothyroidism, nephrotic syndrome, kidney transplantation, severe liver disease, obstructive biliary tract disease, obesity, alcohol consumption, medication, such as estrogen therapy, etc. If secondary dyslipidemia can be ruled out Primary dyslipidemia.
- “Hyperlipidemia” refers to a pathological condition in which blood lipids such as cholesterol, triglyceride, phospholipids, and non-lipidated fatty acids are increased in plasma.
- “Hyperlipid-related disorder” refers to a condition associated with high blood lipids, etiology, pathogenesis, pathological manifestations, clinical symptoms, and/or treatment principles.
- the condition includes, but is not limited to, diabetes, hypertension, atherosclerosis, coronary heart disease, angina pectoris, myocardial infarction, arrhythmia, chronic hepatitis, fatty liver, cirrhosis, cerebral insufficiency, cerebral ischemia, cerebral infarction, chronic Nephritis, chronic pyelonephritis, renal insufficiency, nephrotic syndrome, uremia, obesity.
- hypolipidemia One or several lipid abnormalities in plasma are referred to as “hyperlipidemia”, “hyperlipemia” or “dyslipidemia” due to fat metabolism or abnormal function.
- lipids are insoluble or slightly soluble in water, they must bind to proteins to form lipoproteins to function in the blood circulation. Therefore, hyperlipidemia is often a reflection of "high-lipoproteinemia.”
- hyperlipidemia-related disorder of the present invention may also be referred to as “hyperlipidemic-related disorder” and “hyperlipoproteinemia-related disorder”.
- Obsity or “obesity” refers to excessive accumulation and/or abnormal distribution of fat in the body.
- Commonly used indicators of obesity or obesity are body mass index (BMI) and waist circumference (WC).
- BMI body mass index
- WC waist circumference
- BMI ⁇ 25kg ⁇ m 2 for overweight
- BMI ⁇ 30kg ⁇ m 2 for obesity
- this index varies slightly depending on the country, region and ethnicity.
- Trial “Chinese adults overweight and obesity prevention and control guidelines (Trial)” made in China BMI ⁇ 24kg ⁇ m 2 is overweight boundaries, BMI ⁇ 28kg ⁇ m 2 to limit obesity. From the above classification of "obesity” and “overweight”, overweight and obesity reflect the degree of difference.
- Obesity or obesity as referred to in the claims and the description of the present invention encompasses the meaning of "overweight”.
- the "obesity”, “obesity” and “overweight” according to the present invention may be for various reasons such as an excessive increase in body weight caused by eating alone.
- the experiment of the invention proves that plasminogen can improve the abnormal or excessive deposition of fat in organs, organs around the body, abdominal cavity and the like, and therefore can be used as a slimming drug to treat obesity or overweight and reduce fat. Reduce weight.
- the present invention relates to plasminogen for use as a slimming drug or a pharmaceutical composition, kit or article comprising plasminogen.
- the plasminogen of the present invention can be used as a food additive in foods or drinks, in addition to being used as a medicine.
- the plasminogen of the present invention can also be used in beauty slimming products for weight loss.
- the plasminogen of the present invention can be administered to a subject in need of weight loss or weight loss in various convenient forms.
- Plasmin is a key component of the plasminogen activation system (PA system). It is a broad-spectrum protease that hydrolyzes several components of the extracellular matrix (ECM), including fibrin, gelatin, fibronectin, laminin, and proteoglycans [9] . In addition, plasmin activates some metalloproteinase precursors (pro-MMPs) to form active metalloproteinases (MMPs). Therefore, plasmin is considered to be an important upstream regulator of extracellular proteolysis [10,11] .
- ECM extracellular matrix
- MMPs active metalloproteinases
- Plasmin is formed by proteolytic plasminogen by two physiological PAs: tissue plasminogen activator (tPA) or urokinase-type plasminogen activator (uPA). Due to the relatively high levels of plasminogen in plasma and other body fluids, it has been traditionally believed that the regulation of the PA system is primarily achieved by the synthesis and activity levels of PAs. The synthesis of components of the PA system is tightly regulated by various factors such as hormones, growth factors and cytokines. In addition, specific physiological inhibitors of plasmin and PAs are also present. The main inhibitor of plasmin is ⁇ 2-antiplasmin.
- PAI-1 plasminogen activator inhibitor-1
- PAI-2 lysogen activator inhibitor-2
- Certain cell surface activity of uPA direct hydrolysis specific cell surface receptor (uPAR) [12,13].
- Plasminogen is a single-chain glycoprotein consisting of 791 amino acids with a molecular weight of approximately 92 kDa [14,15] . Plasminogen is mainly synthesized in the liver and is abundantly present in the extracellular fluid. The plasma plasminogen content is approximately 2 ⁇ M. Therefore, plasminogen is a huge potential source of proteolytic activity in tissues and body fluids [16,17] . Plasminogen exists in two molecular forms: glutamate-plasminogen and Lys-plasminogen. The naturally secreted and uncleaved forms of plasminogen have an amino terminal (N-terminal) glutamate and are therefore referred to as glutamate-plasminogen.
- plasminogen glutamate-plasminogen is hydrolyzed to Lys-Lysinogen at Lys76-Lys77.
- lysine-plasminogen has a higher affinity for fibrin and can be activated by PAs at a higher rate.
- the Arg560-Val561 peptide bond of these two forms of plasminogen can be cleaved by uPA or tPA, resulting in the formation of a disulfide-linked double-chain protease plasmin [18] .
- the amino terminal portion of plasminogen contains five homotrimeric rings, the so-called kringles, which contain a protease domain.
- Some kringles contain a lysine binding site that mediates the specific interaction of plasminogen with fibrin and its inhibitor alpha2-AP.
- the main substrate for plasmin is fibrin, which is the key to preventing pathological thrombosis [19] .
- Plasmin also has substrate specificity for several components of ECM, including laminin, fibronectin, proteoglycans and gelatin, suggesting that plasmin also plays an important role in ECM reconstruction [ 15, 20, 21] .
- plasmin can also degrade other components of ECM, including MMP-1, MMP-2, MMP-3 and MMP-9, by converting certain protease precursors into active proteases. Therefore, it has been suggested that plasmin may be an important upstream regulator of extracellular proteolysis [22] .
- plasmin has the ability to activate certain potential forms of growth factors [23-25] . In vitro, plasmin also hydrolyzes components of the complement system and releases chemotactic complement fragments.
- Plasmid is a very important enzyme found in the blood that hydrolyzes fibrin clots into fibrin degradation products and D-dimers.
- Plasinogen is a zymogen form of plasmin, which is composed of 810 amino acids, based on the sequence in swiss prot, based on the native human plasminogen amino acid sequence (sequence 4) containing the signal peptide. 90 kD, a glycoprotein synthesized mainly in the liver and capable of circulating in the blood, and the cDNA sequence encoding the amino acid sequence is shown in SEQ ID NO:3.
- Full-length plasminogen contains seven domains: a serine protease domain at the C-terminus, a Pan Apple (PAp) domain at the N-terminus, and five Kringle domains (Kringle 1-5).
- the signal peptide includes the residue Met1-Gly19
- PAp includes the residue Glu20-Val98
- Kringle1 includes the residue Cys103-Cys181
- Kringle2 includes the residue Glu184-Cys262
- Kringle3 includes the residue Cys275-Cys352
- Kringle4 Including the residue Cys377-Cys454
- Kringle5 includes the residue Cys481-Cys560.
- the serine protease domain includes the residues Val581-Arg804.
- Glu-plasminogen is a natural full-length plasminogen consisting of 791 amino acids (not containing a 19 amino acid signal peptide), and the cDNA sequence encoding the sequence is shown in SEQ ID NO: 1, and its amino acid sequence is sequence 2. Shown. In vivo, there is also a Lys-plasminogen which is hydrolyzed from amino acids 76-77 of Glu-plasminogen, and as shown in SEQ ID NO: 6, the cDNA sequence encoding the amino acid sequence is as shown in SEQ ID NO: 5 Shown.
- Delta-plasminogen is a fragment of full-length plasminogen deleted from the Kringle2-Kringle5 structure and contains only the Kringle1 and serine protease domains [26,27] .
- the delta-plasminogen has been reported in the literature.
- the amino acid sequence (SEQ ID NO: 8) [27] the cDNA sequence encoding the amino acid sequence is shown in Sequence 7.
- Mini-plasminogen consists of Kringle5 and a serine protease domain, which has been reported in the literature to include the residue Val443-Asn791 (starting amino acid with a Glu residue of Glu-plasminogen sequence not containing a signal peptide) [28] , the amino acid sequence thereof is shown in SEQ ID NO: 10, and the cDNA sequence encoding the amino acid sequence is shown in SEQ ID NO: 9.
- Micro-plasminogen contains only the serine protease domain, and its amino acid sequence has been reported to include the residue Ala543-Asn791 (from the Glu residue of the Glu-plasminogen sequence containing no signal peptide).
- Plasin of the present invention is used interchangeably with “fibrinolytic enzyme” and “fibrinolytic enzyme”, and has the same meaning; “plasminogen” and “plasminogen”, “fibrinogenase” "Interchangeable use, meaning the same.
- the meaning or activity of the "deficiency" of plasminogen is such that the level of plasminogen in the subject is lower than that of a normal person, which is low enough to affect the normal physiological function of the subject;
- the meaning or activity of plasminogen "deletion” is that the level of plasminogen in the subject is significantly lower than that of normal people, and even the activity or expression is minimal, and only by external supply can maintain normal physiological function.
- plasminogen adopts a closed inactive conformation, but when bound to the surface of a thrombus or cell, it is converted to openness mediated by plasminogen activator (PA).
- PA plasminogen activator
- Conformational active plasmin The active plasmin further hydrolyzes the fibrin clot into a fibrin degradation product and a D-dimer, thereby dissolving the thrombus.
- the PAp domain of plasminogen contains an important determinant that maintains plasminogen in an inactive blocking conformation, while the KR domain is capable of binding to lysine residues present on the receptor and substrate.
- Enzymes that act as plasminogen activators include: tissue plasminogen activator (tPA), urokinase plasminogen activator (uPA), kallikrein, and factor XII (Hagman factor) .
- a "plasminogen active fragment” refers to an active fragment that binds to a target sequence in a substrate and exerts a proteolytic function in a plasminogen protein.
- the technical solution of the present invention relating to plasminogen covers the technical solution of replacing plasminogen with a plasminogen active fragment.
- the plasminogen active fragment of the present invention is a protein comprising a serine protease domain of plasminogen.
- the plasminogen active fragment of the present invention comprises the sequence 14, and the sequence 14 has at least 80%, 90.
- the plasminogen of the present invention comprises a protein comprising the plasminogen active fragment and still retaining the plasminogen activity.
- blood plasminogen and its activity assays include: detection of tissue plasminogen activator activity (t-PAA), detection of plasma tissue plasminogen activator antigen (t-PAAg), Detection of plasma tissue plasminogen activity (plgA), detection of plasma tissue plasminogen antigen (plgAg), detection of plasma tissue plasminogen activator inhibitor activity, inhibition of plasma tissue plasminogen activator Detection of antigens, plasma plasmin-anti-plasmin complex assay (PAP).
- t-PAA tissue plasminogen activator activity
- t-PAAg detection of plasma tissue plasminogen activator antigen
- plgA Detection of plasma tissue plasminogen activity
- plgAg detection of plasma tissue plasminogen antigen
- PAP plasma plasmin-anti-plasmin complex assay
- the most commonly used detection method is the chromogenic substrate method: adding streptokinase (SK) and chromogenic substrate to the plasma to be tested, and the PLG in the tested plasma is converted into PLM under the action of SK, and the latter acts on The chromogenic substrate is then measured spectrophotometrically and the increase in absorbance is directly proportional to the plasminogen activity.
- plasminogen activity in blood can also be measured by immunochemical method, gel electrophoresis, immunoturbidimetry, or radioimmunoassay.
- ortholog or ortholog refers to homologs between different species, including both protein homologs and DNA homologs, also known as orthologs, orthologs. It specifically refers to a protein or gene that has evolved from the same ancestral gene in different species.
- the plasminogen of the present invention includes human natural plasminogen, and also includes plasminogen orthologs or orthologs of plasminogen activity derived from different species.
- Constant substitution variant refers to a change in one of the given amino acid residues without altering the overall conformation and function of the protein or enzyme, including but not limited to similar properties (eg, acidic, basic, hydrophobic, etc.)
- the amino acid replaces the amino acid in the amino acid sequence of the parent protein.
- Amino acids having similar properties are well known. For example, arginine, histidine, and lysine are hydrophilic basic amino acids and are interchangeable.
- isoleucine is a hydrophobic amino acid that can be bright ammonia Replace with acid, methionine or valine. Therefore, the similarity of two protein or amino acid sequences of similar function may be different.
- Constant substitution variants also includes determining polypeptides or enzymes having more than 60% amino acid identity by BLAST or FASTA algorithm. If it is more than 75%, preferably more than 85%, or even more than 90%. Optimal and have the same or substantially similar properties or functions as the native or parent protein or enzyme.
- Isolated plasminogen refers to a plasminogen protein that is isolated and/or recovered from its natural environment.
- the plasminogen will purify (1) to a purity greater than 90%, greater than 95%, or greater than 98% by weight, as determined by the Lowry method, eg, over 99% (by weight), (2) to a degree sufficient to obtain at least 15 residues of the N-terminal or internal amino acid sequence by using a rotating cup sequence analyzer, or (3) to homogeneity, which is by use Coomassie blue or silver staining was determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) under reducing or non-reducing conditions.
- Isolated plasminogen also includes plasminogen prepared from recombinant cells by bioengineering techniques and isolated by at least one purification step.
- polypeptide peptide
- protein protein
- fusion proteins including, but not limited to, fusion proteins having a heterologous amino acid sequence, fusions having heterologous and homologous leader sequences (with or without an N-terminal methionine residue);
- percent amino acid sequence identity with respect to a reference polypeptide sequence is defined as the introduction of a gap as necessary to achieve maximum percent sequence identity, and without any conservative substitution being considered as part of sequence identity, in the candidate sequence The percentage of amino acid residues that are identical in amino acid residues in the reference polypeptide sequence. Comparisons for the purpose of determining percent amino acid sequence identity can be achieved in a variety of ways within the skill of the art, for example using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art will be able to determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximum contrast over the full length of the sequences being compared. However, for the purposes of the present invention, amino acid sequence identity percent values are generated using the sequence comparison computer program ALIGN-2.
- amino acid sequence identity of a given amino acid sequence A relative to a given amino acid sequence B (or may be expressed as having or comprising relative to, and, or for a given amino acid sequence)
- a given amino acid sequence A of a certain % amino acid sequence identity of B is calculated as follows:
- X is the number of amino acid residues scored by the sequence alignment program ALIGN-2 in the A and B alignments of the program, and wherein Y is the total number of amino acid residues in B. It will be appreciated that where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % amino acid sequence identity of A relative to B will not be equal to the % amino acid sequence identity of B relative to A. All % amino acid sequence identity values used herein are obtained using the ALIGN-2 computer program as described in the previous paragraph, unless explicitly stated otherwise.
- the terms “treating” and “treating” refer to obtaining a desired pharmacological and/or physiological effect.
- the effect may be to completely or partially prevent the disease or its symptoms, and/or to partially or completely cure the disease and/or its symptoms, and includes: (a) preventing the disease from occurring in the subject, the subject may have The cause of the disease, but not yet diagnosed as having a disease; (b) inhibiting the disease, ie, retarding its formation; and (c) reducing the disease and/or its symptoms, ie causing the disease and/or its symptoms to subside.
- the terms "individual”, “subject” and “patient” are used interchangeably herein to refer to a mammal, including but not limited to a mouse (rat, mouse), a non-human primate, a human, a dog, a cat. Hoofed animals (such as horses, cattle, sheep, pigs, goats).
- “Therapeutically effective amount” or “effective amount” refers to an amount of plasminogen sufficient to effect such prevention and/or treatment of a disease when administered to a mammal or other subject to treat the disease.
- the “therapeutically effective amount” will vary depending on the plasminogen used, the severity of the disease and/or its symptoms of the subject to be treated, and the age, weight, and the like.
- Plasminogen can be isolated and purified from nature for further therapeutic use, or it can be synthesized by standard chemical peptide synthesis techniques. When the polypeptide is chemically synthesized, it can be synthesized in a liquid phase or a solid phase.
- Solid phase polypeptide synthesis SPPS
- Fmoc and Boc Various forms of SPPS, such as Fmoc and Boc, can be used to synthesize plasminogen.
- small insoluble porous beads are treated with functional units on which the peptide chains are constructed.
- the attached solid phase free N-terminal amine is coupled to a single N-protected amino acid unit. This unit is then deprotected to reveal a new N-terminal amine that can be attached to other amino acids.
- the peptide remains immobilized on the solid phase and then cut off.
- the plasminogen of the present invention can be produced using standard recombinant methods.
- a nucleic acid encoding plasminogen is inserted into an expression vector operably linked to a regulatory sequence in an expression vector.
- Expression control sequences include, but are not limited to, promoters (eg, naturally associated or heterologous promoters), signal sequences, enhancer elements, and transcription termination sequences.
- Expression regulation can be a eukaryotic promoter system in a vector that is capable of transforming or transfecting eukaryotic host cells (eg, COS or CHO cells). Once the vector is incorporated into a suitable host, the host is maintained under conditions suitable for high level expression of the nucleotide sequence and collection and purification of plasminogen.
- Suitable expression vectors are typically replicated as an episome in the host organism or as an integral part of the host chromosomal DNA.
- expression vectors typically contain a selection marker (eg, ampicillin resistance, hygromycin resistance, tetracycline resistance, kanamycin resistance, or neomycin resistance) to facilitate transformation of the desired DNA sequence with foreign sources. Those cells are tested.
- a selection marker eg, ampicillin resistance, hygromycin resistance, tetracycline resistance, kanamycin resistance, or neomycin resistance
- Escherichia coli is an example of a prokaryotic host cell that can be used to clone a subject antibody-encoding polynucleotide.
- Other microbial hosts suitable for use include bacilli, such as Bacillus subtilis and other enterobacteriaceae, such as Salmonella, Serratia, and various Pseudomonas species. Genus (Pseudomonas) species.
- expression vectors can also be generated which will typically contain expression control sequences (e.g., origins of replication) that are compatible with the host cell.
- promoters such as the lactose promoter system, the tryptophan (trp) promoter system, the beta-lactamase promoter system, or the promoter system from phage lambda. Promoters typically control expression, optionally in the context of manipulating a gene sequence, and have a ribosome binding site sequence, etc., to initiate and complete transcription and translation.
- yeast can also be used for expression.
- Yeast e.g., S. cerevisiae
- Pichia are examples of suitable yeast host cells in which a suitable vector has expression control sequences (e.g., a promoter), an origin of replication, a termination sequence, and the like, as desired.
- a typical promoter comprises 3-phosphoglycerate kinase and other saccharolytic enzymes.
- Inducible yeast is initiated by a promoter specifically comprising an alcohol dehydrogenase, an isocytochrome C, and an enzyme responsible for the utilization of maltose and galactose.
- mammalian cells e.g., mammalian cells cultured in in vitro cell culture
- an anti-Tau antibody of the invention e.g., a polynucleotide encoding a subject anti-Tau antibody.
- Suitable mammalian host cells include CHO cell lines, various Cos cell lines, HeLa cells, myeloma cell lines, and transformed B cells or hybridomas. Expression vectors for these cells may contain expression control sequences such as origins of replication, promoters and enhancers (Queen et al, Immunol. Rev.
- RNA splice sites sites that are ribosome binding.
- RNA splice sites sites that are ribosome binding.
- polyadenylation sites sites that are ribosome binding sites.
- transcription terminator sequences sites that are ribosome binding sites.
- suitable expression control sequences are promoters derived from the white immunoglobulin gene, SV40, adenovirus, bovine papilloma virus, cytomegalovirus, and the like. See Co et al, J. Immunol. 148: 1149 (1992).
- the invention may be purified according to standard procedures in the art, including ammonium sulfate precipitation, affinity column, column chromatography, high performance liquid chromatography (HPLC), gel electrophoresis, and the like.
- Plasminogen is substantially pure, such as at least about 80% to 85% pure, at least about 85% to 90% pure, at least about 90% to 95% pure, or 98% to 99% pure. Or more pure, for example, free of contaminants, such as cellular debris, macromolecules other than the subject antibody, and the like.
- a lyophilized formulation can be formed by mixing plasminogen of the desired purity with an optional pharmaceutical carrier, excipient, or stabilizer (Remington's Pharmaceutical Sciences, 16 Edition, Osol, A. ed. (1980)) Or aqueous solutions for the preparation of therapeutic formulations.
- Acceptable carriers, excipients, and stabilizers are non-toxic to the recipient at the dosages and concentrations employed, and include buffers such as phosphates, citrates and other organic acids; antioxidants including ascorbic acid and methionine; preservatives such as Octadecyldimethylbenzylammonium chloride; chlorinated hexane diamine; benzalkonium chloride, benzethon chloride Ammonium; phenol, butanol or benzyl alcohol; alkyl p-hydroxybenzoate such as methyl or propyl p-hydroxybenzoate; catechol; resorcinol; cyclohexanol; 3-pentanol; M-cresol); low molecular weight polypeptide (less than about 10 residues); proteins such as serum albumin, gelatin or immunoglobulin; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine , hist
- the formulations of the invention may also contain more than one active compound as required for the particular condition being treated, preferably those having complementary activities and no side effects to each other.
- active compound for example, antihypertensive drugs, antiarrhythmic drugs, drugs for treating diabetes, and the like.
- the plasminogen of the present invention may be encapsulated in microcapsules prepared by, for example, coacervation techniques or interfacial polymerization, for example, may be placed in a glial drug delivery system (eg, liposomes, albumin microspheres, microemulsions, Nanoparticles and nanocapsules are placed in hydroxymethylcellulose or gel-microcapsules and poly-(methyl methacrylate) microcapsules in a macroemulsion.
- glial drug delivery system eg, liposomes, albumin microspheres, microemulsions, Nanoparticles and nanocapsules are placed in hydroxymethylcellulose or gel-microcapsules and poly-(methyl methacrylate) microcapsules in a macroemulsion.
- the plasminogen of the invention for in vivo administration must be sterile. This can be easily achieved by filtration through a sterile filter before or after lyophilization and reconstitution.
- the plasminogen of the present invention can prepare a sustained release preparation.
- sustained release formulations include solid hydrophobic polymeric semi-permeable matrices having a shape and containing glycoproteins, such as films or microcapsules.
- sustained release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate) (Langer et al, J. Biomed. Mater.
- Polymers such as ethylene - Vinyl acetate and lactic acid-glycolic acid can release molecules for more than 100 days, while some hydrogels release proteins for a short time. It is reasonable to design the protein according to the relevant mechanism.
- Strategy For example, if the mechanism of aggregation is found to be an intermolecular SS bond by thiodisulfide bond exchange, it can be modified by modifying the thiol residue, lyophilizing from an acidic solution, controlling humidity, using suitable additives, and developing specific The polymer matrix composition is used to achieve stability.
- compositions of this invention may be effected intramuscularly in different ways, such as by intravenous, intraperitoneal, subcutaneous, intracranial, intrathecal, intraarterial (e.g., via the carotid artery).
- Preparations for parenteral administration include sterile aqueous or nonaqueous solutions, suspensions and emulsions.
- non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
- Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffering media.
- Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, or fixed oils.
- Intravenous vehicles contain liquid and nutritional supplements, electrolyte supplements, and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, antioxidants, chelating agents, and inert gases, and the like.
- the medical staff will determine the dosage regimen based on various clinical factors. As is well known in the medical arts, the dosage of any patient depends on a variety of factors, including the patient's size, body surface area, age, specific compound to be administered, sex, number and route of administration, overall health, and other medications administered simultaneously. .
- the pharmaceutical composition of the present invention comprising plasminogen may be, for example, in the range of about 0.0001 to 2000 mg/kg per day, or about 0.001 to 500 mg/kg (e.g., 0.02 mg/kg, 0.25 mg/kg, 0.5 mg/kg, 0.75 mg/kg, 10 mg/kg, 50 mg/kg, etc.) Subject weight.
- the dose can be 1 mg/kg body weight or 50 mg/kg body weight or in the range of 1-50 mg/kg, or at least 1 mg/kg. Dosages above or below this exemplary range are also contemplated, particularly in view of the above factors. Intermediate doses in the above ranges are also included in the scope of the present invention.
- the subject can administer such doses daily, every other day, every week, or according to any other schedule determined by empirical analysis.
- An exemplary dosage schedule includes 1-10 mg/kg for several days. The therapeutic effect and safety need to be evaluated in real time during the administration of the drug of the present invention.
- One embodiment of the invention relates to an article or kit comprising a plasminogen or plasmin of the invention useful for treating obesity and a related condition thereof.
- the article preferably includes a container , label or package insert. Suitable containers are bottles, vials, syringes, and the like.
- the container can be made of various materials such as glass or plastic.
- the container contains a composition that is effective to treat a disease or condition of the invention and has a sterile access port (eg, the container can be an intravenous solution or vial containing a stopper that can be penetrated by a hypodermic needle) of).
- At least one active agent in the composition is plasminogen/plasmin.
- the label on or attached to the container indicates that the composition is used to treat the diabetes-induced obesity and related conditions of the present invention.
- the article of manufacture may further comprise a second container comprising a pharmaceutically acceptable buffer, such as phosphate buffered saline, Ringer's solution, and dextrose solution. It may further comprise other materials required from a commercial and user standpoint, including other buffers, diluents, filters, needles and syringes.
- the article comprises a package insert with instructions for use, including, for example, a user instructing the composition to administer the plasminogen composition and other drugs to treat the accompanying disease.
- Figure 1 shows the results of weight gain calculation in obese model mice induced by plasminogen for 28 days high calorie feed. The results are shown as the value of body weight minus day 1 body weight on day 29. The results showed that the weight change of the blank control group was not obvious, and the weight loss of the vehicle control group was significantly lower than that of the plasminogen group, and the statistical difference was significant (*P ⁇ 0.05). This indicates that plasminogen can promote the weight loss of obese model mice.
- Figure 2 shows the results of body mass index of obese model mice induced by plasminogen for 28 days high calorie feed.
- the results showed that the body mass index of the plasminogen group was significantly lower than that of the vehicle control group, and the statistical difference was significant (*P ⁇ 0.05, **P ⁇ 0.01), and compared with the vehicle PBS control group.
- the body mass index of the mice given plasminogen group was closer to the blank control group. This indicates that plasminogen can significantly reduce the body mass index and reduce obesity in obese model mice.
- Figure 3 shows the results of Lee's index of obese model mice induced by plasminogen for 28 days high calorie feed.
- the results showed that the Lee's index of the plasminogen group was significantly lower than that of the vehicle control group, and the statistical difference was significant (*P ⁇ 0.05), and it was smaller than the vehicle PBS control group.
- the mouse's Lee's index is closer to the blank control group. This indicates that plasminogen can significantly reduce the Lee's index of obese model mice and reduce obesity.
- FIG. 4 Results of blood lipid testing in obese model mice induced by high-calorie feed.
- A is total cholesterol
- B is low density lipoprotein
- C is high density lipoprotein.
- the results showed that the plasminogen group and the vehicle PBS were given. There were no significant differences in total cholesterol, low-density lipoprotein, and high-density lipoprotein concentrations between the control group and the blank control group. This indicates that there is no significant change in blood lipids in the high-energy feed-induced obese model mice in this experiment.
- Figure 7 shows the results of intraperitoneal fat coefficient in obese model mice induced by plasminogen for 28 days high calorie feed.
- the results showed that the intraperitoneal fat coefficient of the plasminogen group was significantly lower than that of the control vehicle PBS control group, and the statistical difference was significant (*P ⁇ 0.05), and the peritoneal cavity of the plasminogen group was compared with the control vehicle PBS control group. The fat content was closer to the blank control group. This indicates that plasminogen can significantly reduce the deposition of abdominal fat in obese model mice.
- Figure 8 shows the results of peritoneal fat HE staining of fat vacuole area in obese model mice induced by plasminogen for 28 days high calorie diet.
- A is a blank control group
- B is a vehicle control group
- C is a plasminogen group
- D is a quantitative analysis result.
- the results showed that the area of the average fat vacuoles in the plasminogen group was significantly smaller than that in the control vehicle PBS control group, and the statistical difference was extremely significant (** indicates P ⁇ 0.01), and the plasminogen was given compared with the vehicle PBS control group.
- the group of fat vacuoles was closer to the blank control mice. This indicates that plasminogen can significantly reduce the size of fat cells in obese model mice and reduce abdominal fat deposition.
- Figure 9 shows the results of serum leptin detection in mice with plasminogen for 28 days and 14-15 weeks old diabetic mice.
- the results showed that the serum leptin concentration in the plasminogen group was significantly lower than that in the vehicle control group, and the statistical difference was extremely significant (**P ⁇ 0.01), and the plasmin was given compared with the vehicle PBS control group.
- the serum leptin levels in the original group were closer to normal mice. This indicates that plasminogen can reduce serum leptin levels in early type 2 diabetic mice.
- Figure 10 shows the results of serum leptin detection of plasminogen 28 days 23-25 weeks old diabetic mice. The results showed that the serum leptin concentration in the plasminogen group was significantly lower than that in the vehicle control group. The difference was extremely significant (** is P ⁇ 0.01). This indicates that plasminogen can reduce serum leptin levels in late type 2 diabetic mice.
- Figure 11 shows the results of liver oil red O staining after administration of plasminogen for 30 days in a 16-week hyperlipidemia model mouse.
- A is the control vehicle PBS control group
- B is the plasminogen group
- C is the quantitative analysis result.
- the results showed that the liver fat deposition in the plasminogen group was significantly less than that in the vehicle control group, and the statistical analysis was statistically significant (* indicates P ⁇ 0.05). This indicates that plasminogen can improve the deposition of fat in the liver of hyperlipidemia model mice.
- Figure 12 Results of aortic sinus oil red O staining after administration of plasminogen for 30 weeks in a 16-week hyperlipidemia model mouse.
- a and C are the control group for the vehicle PBS
- B and D are for the plasminogen group
- E is the quantitative analysis result.
- the results showed that the aortic sinus fat deposition in the plasminogen group was significantly less than that in the vehicle control group, and the statistical difference was significant (* indicates P ⁇ 0.05). This indicates that plasminogen can improve the deposition of fat in the aortic sinus of hyperlipidemia model mice.
- Figure 13 shows the results of observation of renal oil red O in mice with hyperlipidemia induced by 3% cholesterol feed after 30 days of plasminogen administration.
- A is a blank control group
- B is a vehicle control group
- C is a plasminogen group
- D is a quantitative analysis result.
- the results showed that the renal fat deposition (arrow mark) in the plasminogen group was significantly less than that in the vehicle control group, and the quantitative analysis was statistically significant.
- the lipid deposition level in the plasminogen group was compared with the blank control group. The mice are similar. This indicates that plasminogen can reduce the deposition of fat in the kidney of hyperlipidemia model mice, thereby reducing kidney damage caused by fat deposition.
- FIG 14 3% cholesterol feed induced hyperlipidemia in mice.
- Serum low-density lipoprotein cholesterol was measured 20 days after administration of plasminogen. The results showed that the serum low density lipoprotein cholesterol concentration in the plasminogen group was significantly lower than that in the vehicle PBS control group, and the statistical difference was significant (* indicates P ⁇ 0.05). This indicates that plasminogen can reduce the content of low-density lipoprotein cholesterol in the serum of hyperlipidemia model mice and has the function of improving hyperlipemia.
- FIG. 15 3% cholesterol feed induced hyperlipidemia model mice 20 days after administration of plasminogen serum atherosclerosis index test results.
- the results showed that the atherosclerosis index of the plasminogen group was significantly lower than that of the vehicle PBS control group, and the statistical difference was extremely significant (** means P ⁇ 0.01). This indicates that plasminogen can effectively reduce the risk of atherosclerosis in mice with hyperlipidemia.
- Figure 16 shows the results of serum total cholesterol test after 30 days of administration of plasminogen in ApoE atherosclerotic model mice. The results showed that the total cholesterol concentration in the plasminogen group was significantly lower than that in the vehicle PBS control group, and the statistical difference was significant (* indicates P ⁇ 0.05). Explain that plasminogen can be reduced The total cholesterol level in the serum of ApoE atherosclerotic model mice improves dyslipidemia in atherosclerotic model mice.
- Figure 17 shows the results of serum triglyceride test after 30 days of administration of plasminogen in ApoE atherosclerotic model mice.
- the results showed that the concentration of triglyceride in the plasminogen group was significantly lower than that in the vehicle PBS control group, and the statistical difference was significant (* indicates P ⁇ 0.05). This indicates that plasminogen can reduce the serum triglyceride content of ApoE atherosclerosis model mice and improve dyslipidemia in atherosclerotic model mice.
- Figure 18 shows the results of serum low density lipoprotein cholesterol assay after 30 days of plasminogen administration in ApoE atherosclerotic model mice.
- the results showed that the serum low density lipoprotein cholesterol concentration in the plasminogen group was significantly lower than that in the vehicle PBS control group, and the statistical difference was significant (* indicates P ⁇ 0.05). This indicates that plasminogen can reduce the content of low-density lipoprotein cholesterol in serum of ApoE atherosclerotic model mice and improve dyslipidemia in atherosclerotic model mice.
- Figure 19 shows the results of immunohistochemical staining of hypothalamic leptin receptor in obese model mice after administration of plasminogen.
- a and D were blank control groups
- B and E were the vehicle control group
- C and F were the plasminogen group
- G was the quantitative analysis result.
- the results showed that the expression of hypothalamic leptin receptor in the PBS control group was significantly higher than that in the blank control group.
- mice Fourteen C57 male mice, 8 weeks old, were randomly divided into two groups according to body weight, 4 in the blank control group and 10 in the model group.
- the blank control mice were fed normal maintenance diet; the model group mice were fed a fat-heat 45% high-fat diet model (TP23000, Nantong Trophy Feed Technology Co., Ltd.) for 12 weeks to establish an obese model [30] .
- 45% of high fat diet is called high calorie feed.
- the model group mice were weighed and randomly divided into two groups according to body weight, and given to the plasminogen group and the vehicle PBS control group, 5 in each group. Human plasminogen was dissolved in PBS.
- the plasminogen group was injected with human plasminogen 1 mg/0.1 mL/day/day into the tail vein, and the same volume of PBS was injected into the tail of the vehicle PBS control group.
- the blank control group was not treated.
- the above experimental animals were continuously administered for 28 days (starting the administration as the first day), and on the 29th day, the following treatment and detection were carried out.
- Body mass index body weight (kg) / body length 2 (m).
- Body mass index is a standard commonly used in the world to measure the fatness and health of the human body.
- the body mass index can also be used as an indicator of obesity model animal fatness and thinness [43,44] .
- the results showed that the body mass index of the plasminogen group was significantly lower than that of the vehicle control group, and the statistical difference was significant (*P ⁇ 0.05), and it was smaller than the vehicle PBS control group.
- the body mass index of the rats was closer to the blank control group (Fig. 2). This indicates that plasminogen can significantly reduce the body mass index and reduce obesity in obese model mice.
- mice were weighed on the 29th day, the body length of the mice was measured, and the Lee's index was calculated.
- Lee's index is an effective index for the degree of obesity [31-32] .
- the results showed that the Lee's index of the plasminogen group was significantly lower than that of the vehicle control group, and the statistical difference was significant (*P ⁇ 0.05), and it was smaller than the vehicle PBS control group.
- the mouse's Lee's index is closer to the blank control group ( Figure 3). This indicates that plasminogen can significantly reduce the Lee's index of obese model mice and reduce obesity.
- the model mice took the eyeballs and took the blood.
- the supernatant was taken by centrifugation, and the serum total cholesterol, low-density lipoprotein and high-density lipoprotein detection kits were used (Nanjing Institute of Bioengineering, article number A111-1, A113-1, A112-1), serum total cholesterol, low density lipoprotein and high density lipoprotein concentrations were measured according to the method described in the corresponding kit.
- the serum leptin test kit (Nanjing Institute of Bioengineering, item number H174) was used, and the serum leptin levels were measured according to the method described in the kit.
- Leptin is a hormone secreted by adipose tissue. It has been widely believed that after entering the blood circulation, it will participate in the regulation of sugar, fat and energy metabolism, prompting the body to reduce food intake, increase energy release, inhibit the synthesis of fat cells, and thus reduce weight. But some obese individuals there is the phenomenon of leptin resistance, elevated blood levels of leptin [34]. Related studies have shown that leptin resistance is present in db/db mice, and serum leptin levels are significantly elevated [35-36] .
- a serum insulin test kit (Nanjing Institute of Bioengineering, item number H174) was used, and the insulin levels in the above serum were measured according to the method described in the kit.
- mice were sacrificed on the 29th day, and their abdominal fat was fixed in 4% paraformaldehyde for 24-48 hours.
- the fixed tissue samples were dehydrated by alcohol gradient and transparent to xylene for paraffin embedding. The thickness of the tissue section was 4 ⁇ m.
- the sections were dewaxed and rehydrated and stained with hematoxylin and eosin (HE staining). After 1% hydrochloric acid alcohol was differentiated, the ammonia water was returned to the blue and dehydrated with an alcohol gradient. The sections were observed under a 200-fold optical microscope. Analyze the area of fat vacuoles using Image-pro plus image processing software.
- mice There were 12 male db/db mice and 3 db/m mice aged 14-15 weeks. After weighing, db/db mice were randomly divided into two groups according to their body weight. The plasminogen group and the vehicle PBS control group were given. , each group of 6 each. The first dose was started on the first day, the first day was given plasminogen or PBS, and the plasminogen group was injected with human plasminogen 2 mg/0.2 ml/day/day to the plasminogen group. The same volume of PBS was injected into the tail vein for 28 consecutive days. The db/m mice were used as normal control mice and were not administered. On day 28, the mice were fasted for 16 hours.
- the serum leptin test kit (Nanjing Institute of Bioengineering, item number H174) was used, and the serum leptin levels were measured according to the method described in the kit.
- mice Thirteen male db/db mice aged 23-25 weeks were randomly divided into two groups according to their body weight, 7 rats in the plasminogen group and 6 rats in the vehicle control group.
- plasminogen or PBS was administered to the plasminogen group for injection of human plasminogen 2 mg/0.2 ml/day/day, and the same volume of PBS was injected into the tail of the vehicle PBS control group.
- mice fasted On the 29th day blood was taken from the eyeball on the 29th day, and the supernatant was centrifuged to measure the serum leptin concentration.
- the serum leptin test kit (Nanjing Institute of Bioengineering, item number H174) was used, and the serum leptin levels were measured according to the method described in the kit.
- Example 4 Degradation of plasminogen in the liver of a 16-week hyperlipidemia model mouse
- mice Nine-year-old male C57 mice were fed a high-fat, high-cholesterol diet (Nantong Trophy, item TP2031) for 16 weeks to induce a hyperlipidemia model [37-38] . This model was designated as 16-week hyperlipidemia. model. Mice after modeling continue to feed high cholesterol feed. 50 ⁇ l of blood was taken from each of the three days before administration to detect the total cholesterol (T-CHO) content, and was randomly divided into two groups according to the T-CHO content, 6 in the vehicle PBS control group, and 5 in the plasminogen group. .
- the start of administration was recorded as the first day, and the plasminogen group was injected with human plasminogen 1 mg/0.1 ml/day/day into the tail vein, and the same volume of PBS was injected into the tail of the vehicle PBS control group.
- the mice were sacrificed for 30 days, and the mice were sacrificed on the 31st day.
- the liver was fixed in 4% paraformaldehyde for 24-48 hours, respectively, in a 15%, 30% sucrose solution at 4 ° C overnight, embedded in OCT, and frozen section thickness. 8 ⁇ m, oil red O staining for 15min, 75% alcohol differentiation for 5 seconds, hematoxylin staining for 30 seconds, glycerin gelatin seal. Sections were observed under a 400x optical microscope.
- Example 5 Plasminogen reduces lipid deposition in aortic sinus of a 16-week hyperlipidemia model mouse
- mice Nine-year-old male C57 mice were fed a high-fat, high-cholesterol diet (Nantong Trophy, item TP2031) for 16 weeks to induce a hyperlipidemia model [37-38] . This model was designated as 16-week hyperlipidemia. model. Mice after modeling continue to feed high cholesterol feed. 50 ⁇ l of blood was taken from each of the three days before administration to detect the total cholesterol (T-CHO) content, and was randomly divided into two groups according to the T-CHO content, 6 in the vehicle PBS control group, and 5 in the plasminogen group. .
- the start of administration was recorded as the first day, and the plasminogen group was injected with human plasminogen 1 mg/0.1 ml/day/day into the tail vein, and the same volume of PBS was injected into the tail of the vehicle PBS control group.
- the mice were sacrificed for 30 days, and the mice were sacrificed on the 31st day.
- the heart tissue was fixed in 4% paraformaldehyde for 24-48 hours, respectively, in a 15%, 30% sucrose overnight at 4 ° C, OCT embedding, aorta
- the sinus frozen section thickness was 8 ⁇ m, oil red O staining for 15 min, 75% alcohol differentiation for 5 seconds, hematoxylin staining for 30 seconds, and glycerin gelatin for sealing.
- the sections were observed under a 40-fold (Fig. 11A, 11B), 200-fold (Fig. 11C, 11D) magnification optical microscope.
- Example 6 Plasminogen Reduces Renal Fat Deposition in Mice with Hyperlipidemia Induced by 3% Cholesterol Feed
- mice Sixteen-week-old male C57 mice were fed with 3% cholesterol and high-fat diet (Nantong Trofe) for 4 weeks to induce hyperlipidemia [37-38] .
- This model was classified as a 3% cholesterol hyperlipidemia model.
- the modeled mice continued to be fed a 3% cholesterol high fat diet.
- Another 5 male C57 mice of the same age were used as a blank control group, and normal maintenance feed was fed during the experiment.
- Three days before the administration 50 ⁇ L of blood was taken from each mouse to measure total cholesterol.
- the model mice were randomly divided into two groups according to the total cholesterol concentration and body weight, and given to the plasminogen group and the vehicle PBS control group, each group was 8 only. The first dose was recorded as the first day.
- the plasminogen group was injected with human plasminogen 1 mg/0.1 ml/day/day into the tail vein, and the same volume of PBS was injected into the tail of the vehicle PBS control group. 30 days. On the 31st day, the mice were sacrificed and the kidneys were fixed in 4% paraformaldehyde for 24-48 hours. They were sedimented in 15% and 30% sucrose at 4 °C overnight, embedded in OCT, frozen sections were 8 ⁇ m thick, and oil red O stained for 15 min. 75% alcohol differentiation for 5 seconds, hematoxylin staining for 30 seconds, glycerin gelatin seal. Sections were observed under a 400x optical microscope.
- kidney fat deposition (arrow mark) was significantly less in the plasminogen group (Fig. 13C) than in the vehicle PBS control group (Fig. 13B), and the quantitative analysis was statistically significant (Fig. 13D); Lipid deposition levels in the lysogen group were similar to those in the blank control group (Fig. 13A). This indicates that plasminogen can reduce the deposition of fat in the kidney of 3% cholesterol hyperlipidemia model mice, thereby reducing the damage of kidney caused by fat deposition.
- Example 7 Plasminogen Reduces Serum Low Density Lipoprotein Cholesterol Level in Mice with Hyperlipidemia Induced by 3% Cholesterol Feed
- mice 9 16 week old male C57 mice fed high fat cholesterol diet 3% (Nangtong Te Luofei) 4 weeks induced hyperlipidemia [37-38], this model is set at 3% cholesterol in hyperlipidemic.
- the modeled mice continued to be fed a 3% cholesterol high fat diet.
- 50 ⁇ l of blood was taken from each mouse three days before administration, total cholesterol was measured, and two groups were randomly divided into two groups according to the total cholesterol concentration and body weight. The first dose was recorded as the first day.
- the plasminogen group was injected with human plasminogen 1 mg/0.1 ml/day/day into the tail vein, and the same volume of PBS was injected into the tail of the vehicle PBS control group. 20 days. On the 20th day, the mice were fasted for 16 hours.
- LDL-C Low density lipoprotein cholesterol
- Example 8 Plasminogen Reduces Risk of Atherosclerosis in Mice with Hyperlipidemia Induced by 3% Cholesterol Feed
- mice Sixteen-week-old male C57 mice were fed with 3% cholesterol and high-fat diet (Nantong Trofe) for 4 weeks to induce hyperlipidemia [37-38] .
- This model was designated as a model of 3% cholesterol hyperlipidemia.
- the modeled mice continued to be fed a 3% cholesterol high fat diet.
- 50 ⁇ l of blood was taken from each mouse three days before administration, total cholesterol (T-CHO) was detected, and two groups were randomly divided into two groups according to the total cholesterol concentration and body weight.
- the start of administration was recorded as the first day, and the plasminogen group mice were injected with human plasminogen 1 mg/0.1 ml/day/day into the tail vein, and the same volume of PBS was injected into the tail of the vehicle PBS control group.
- mice After the 20th day of administration, the mice began to fast, fasted for 16 hours, and on the 21st day, 50 ⁇ L of blood was taken from the iliac venous plexus, and the supernatant was obtained by centrifugation.
- the total cholesterol content was determined by the total cholesterol test kit (Nanjing Jianshe Bioengineering Research Institute). , Item No. A111-1) was tested; high-density lipoprotein cholesterol (HDL-C) content was detected using a high-density lipoprotein cholesterol test kit (Nanjing Institute of Bioengineering, item number A112-1).
- the atherosclerosis index is a comprehensive indicator of clinical prediction of atherosclerosis. It is considered to be clinically more meaningful than the individual cholesterol, triglyceride, high-density lipoprotein and low-density lipids in estimating the degree of risk of coronary heart disease.
- the protein is larger [40] .
- Atherosclerosis index (T-CHO-HDL-C) / HDL-C.
- Example 9 plasminogen reduces serum total cholesterol in ApoE atherosclerotic mice
- mice at 6 weeks of age were fed a high-fat, high-cholesterol diet (Nantong Trofe, TP2031) for 16 weeks to induce an atherosclerosis model [41-42] .
- Mice after modeling continue to feed high-fat, high-cholesterol feed.
- 50 ⁇ l of blood was taken from each of the three days before administration to detect the total cholesterol (T-CHO) content, and was randomly divided into two groups according to the T-CHO content, 7 rats in the vehicle PBS control group, and 6 cells in the plasminogen group. .
- the first dose was started on the first day.
- the plasminogen group was injected with human plasminogen 1 mg/0.1 ml/day/day into the tail vein, and the same volume of PBS was injected into the tail of the vehicle PBS control group. 30 days. On the 30th day, the mice were fasted for 16 hours. On the 31st day, the eyeballs were removed and blood was taken. The supernatant was centrifuged to obtain a total cholesterol test using a total cholesterol test kit (Nanjing Institute of Bioengineering, item number A111-1).
- mice at 6 weeks of age were fed a high-fat, high-cholesterol diet (Nantong Trofe, TP2031) for 16 weeks to induce an atherosclerosis model [41-42] .
- Mice after modeling continue to feed high-fat, high-cholesterol feed.
- 50 ⁇ l of blood was taken from each of the three days before administration to detect the total cholesterol (T-CHO) content, and was randomly divided into two groups according to the T-CHO content, 7 rats in the vehicle PBS control group, and 6 cells in the plasminogen group. .
- the first dose was recorded as the first day.
- the plasminogen group was injected with human plasminogen 1 mg/0.1 ml/day/day into the tail vein, and the same volume of PBS was injected into the tail of the vehicle PBS control group. 30 days. On the 30th day, the mice were fasted for 16 hours. On the 31st day, the eyeballs were taken for blood collection, and the supernatant was centrifuged to obtain a triglyceride detection kit (Nanjing Institute of Bioengineering, article number A110-1) for triglyceride detection.
- mice at 6 weeks of age were fed a high-fat, high-cholesterol diet (Nantong Trofe, TP2031) for 16 weeks to induce an atherosclerosis model [41-42] .
- Mice after modeling continue to feed high-fat, high-cholesterol feed.
- 50 ⁇ l of blood was taken from each of the three days before administration to detect the total cholesterol (T-CHO) content, and was randomly divided into two groups according to the T-CHO content, 7 rats in the vehicle PBS control group, and 6 cells in the plasminogen group. .
- the first dose was recorded as the first day.
- the plasminogen group was injected with human plasminogen 1 mg/0.1 ml/day/day into the tail vein, and the same volume of PBS was injected into the tail of the vehicle PBS control group. 30 days. On the 30th day, the mice were fasted for 16 hours. On the 31st day, the eyeballs were taken for blood collection, and the supernatant was centrifuged to obtain a low-density lipoprotein cholesterol (LDL-C) test kit (Nanjing Institute of Bioengineering, item number A113-1). LDL-C detection.
- LDL-C low-density lipoprotein cholesterol
- mice Fourteen C57 male mice, 8 weeks old, were randomly divided into two groups according to body weight, 4 in the blank control group and 10 in the model group.
- the blank control mice were fed normal maintenance feed; the model group mice were fed a fat-heat 45% high-fat diet (TP23000, Nantong Trophy Feed Technology Co., Ltd.) for 12 weeks to establish an obese model [1] .
- the model group mice were weighed and randomly divided into two groups according to body weight, and given to the plasminogen group and the vehicle PBS control group, 5 in each group.
- the plasminogen group was injected with human plasminogen 1 mg/0.1 ml/day/day in the tail vein, and the same volume of PBS was injected into the tail of the vehicle PBS control group.
- the blank control group was not injected with any liquid, and the drug was administered continuously for 28 days. During the administration, the mice continued to feed the model feed. On day 29, the mice were sacrificed and the hypothalamus was fixed in 4% paraformaldehyde for 24-48 hours. The fixed tissue was paraffin-embedded after dehydration by alcohol gradient and transparency of xylene. The thickness of the tissue section was 4 ⁇ m, and the sections were dewaxed and rehydrated and washed once with water. The citric acid was repaired for 30 minutes, and after cooling at room temperature for 10 minutes, the water was gently rinsed. Incubate for 15 minutes in 3% hydrogen peroxide and circle the tissue with a PAP pen.
- leptin receptor The main physiological function of the leptin receptor is to bind to leptin, which is a physiological function that regulates energy balance, fat storage, reproductive activity, and is involved in the autocrine regulation of leptin.
- leptin a physiological function that regulates energy balance, fat storage, reproductive activity, and is involved in the autocrine regulation of leptin.
- Different types of leptin receptors are selectively expressed in central and peripheral tissues [45-47] .
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Abstract
Description
Claims (48)
- 一种预防或治疗受试者肥胖症的方法,包括给药受试者有效量的纤溶酶原。
- 权利要求1的方法,其中所述纤溶酶原通过减少脂质在组织器官、组织器官周围和/或腹腔的异常或过度沉积治疗肥胖症。
- 权利要求2的方法,其中所述纤溶酶原减少脂质在皮下、心脏、肝脏、肺脏、肾脏、血管、肠系膜、腹膜、体腔、器官周围的异常或过度沉积。
- 权利要求1的方法,其中所述纤溶酶原降低受试者血脂,尤其是甘油三酯和低密度脂蛋白的水平治疗肥胖症。
- 权利要求1-4任一项的方法,其中所述肥胖症为单纯性肥胖或继发于其它疾病导致的肥胖。
- 一种预防或治疗受试者肥胖症的方法,包括给药受试者有效量的纤溶酶原,其中所述肥胖症继发于内分泌紊乱疾病、糖代谢疾病、肝脏疾病、肾脏疾病、心血管疾病、肠道疾病、甲状腺疾病、胆囊或胆道疾病、过量饮酒、药物作用。
- 一种预防和/或治疗受试者疾病并发的肥胖的方法,包括给药受试者有效量的纤溶酶原,其中所述疾病并发的肥胖包括内分泌疾病并发的肥胖、代谢性疾病并发的肥胖、心血管疾病并发的肥胖、消化系统疾病并发的肥胖、退行性疾病并发的肥胖。
- 权利要求7的方法,其中所述肥胖包括糖尿病并发的肥胖、高血压并发的肥胖、动脉粥样硬化并发的肥胖、肝脏疾病并发的肥胖、骨质疏松并发的肥胖。
- 一种预防或治疗肥胖导致的并发症的方法,包括给药受试者治疗有效量的纤溶酶原,其中所述肥胖的并发症包括心脑血管疾病、代谢性疾病、肌肉骨骼疾病、消化系统疾病、睡眠呼吸暂停、呼吸障碍。
- 权利要求9的方法,其中所述并发症为高血压、糖尿病、冠心病、心绞痛、心肌梗死、心律失常、动脉粥样硬化、脑血栓、脑出血、骨关节炎、骨质增生、胆囊炎、脂肪肝、肝硬化。
- 一种降低受试者动脉粥样硬化发病风险的方法,包括给药受试者有效量的纤溶酶原。
- 权利要求11的方法,其中所述纤溶酶原通过治疗肥胖症降低受试者动脉粥样硬化发病风险。
- 一种降低受试者肥胖症发病风险的方法,包括给药受试者有效量的纤溶酶原来减少脂肪在组织器官或其周围、皮下或腹腔中的异常或过度沉积。
- 纤溶酶原在制备预防或治疗受试者肥胖症的药物中的用途。
- [根据细则26改正28.02.2018]
权利要求14的用途,其中所述纤溶酶原通过选自如下的一项或多项消减受试者体内异常或过度沉积的脂肪:1)减少脂质在选自如下一处或多处部位的沉积:皮下、心脏、肝脏、肺脏、肾脏、血管、肠系膜、腹膜、体腔、器官周围的异常或过度沉积,2)促进肝脏脂肪的清除,和3)促进血中脂质的清除以降低受试者心脏病发病风险。 - 一种降低受试者血脂的方法,包括给药受试者有效量的纤溶酶原。
- [根据细则26改正28.02.2018]
权利要求16的方法,其中所述纤溶酶原降低血清甘油三酯水平、低密度脂蛋白水平。 - 一种降低受试者动脉粥样硬化或心脏病发病风险的方法,包括给药受试者有效量的纤溶酶原减轻脂质在血管壁的异常或过度沉积。
- 一种治疗受试者肥胖症的方法,包括给药受试者有效量的纤溶酶原促进肝脏对沉积脂肪的清除。
- 一种治疗受试者肥胖症的方法,包括给药受试者有效量的纤溶酶原,其中所述纤溶酶原通过选自如下的一项或多项消减受试者体内脂肪:1)减少脂质在选自如下一处或多处部位的沉积:皮下、心脏、肝脏、肺脏、肾脏、血管、肠系膜、腹膜、体腔、器官周围的异常或过度沉积,2)促进肝脏脂肪的清除,和3)促进血中脂质的清除。
- [根据细则26改正28.02.2018]
权利要求20的方法,其中所述肥胖症为单纯性肥胖症或继发于其它疾病导致的肥胖症。 - [根据细则26改正28.02.2018]
权利要求21的方法,其中所述肥胖症继发于内分泌紊乱疾病、糖代谢疾病、肝脏疾病、肾脏疾病、心血管疾病、肠道疾病、甲状腺疾病、胆囊或胆道疾病、过量饮酒、药物作用。 - [根据细则26改正28.02.2018]
根据权利要求1-22任一项的方法,其中所述纤溶酶原可与一种或多种其它药物或治疗手段联合施用。 - [根据细则26改正28.02.2018]
权利要求23的方法,其中所述一种或多种其它药物包括高血压治疗药物、糖尿病治疗用药物、动脉粥样硬化治疗用药物、慢性肾小球肾炎治疗药物、慢性肾盂肾炎治疗药物、肾病综合征治疗用药物、肾功能不全治疗用药物、尿毒症治疗用药物、肾移植治疗用药物、脂肪肝治疗用药物、肝硬化治疗用药物、肥胖症治疗用药物。 - [根据细则26改正28.02.2018]
根据权利要求24的方法,其中所述其它药物包括:降血脂药物、抗血小板药物、降血压药物、扩张血管药物、降血糖药物、抗凝血药物、溶血栓药物,保肝药物,抗心律失常药物,强心药物,利尿药物,抗感染药物、抗病毒药物、免疫调节药物、炎症调节类药物、抗肿瘤药物、激素类药物、甲状腺素。 - [根据细则26改正28.02.2018]
权利要求25的方法,其中所述药物包括降血脂药物:他汀类;贝特类;烟酸;消胆胺;安妥明;不饱和脂肪酸如益寿宁、血脂平及心脉乐;藻酸双酯钠;抗血小板药物:阿司匹林;潘生丁;氯吡格雷;西洛他;扩张血管药物:肼苯哒嗪;硝酸甘油和消心痛;硝普钠;α硝受体阻断剂如哌唑嗪;α受体阻断剂如酚妥拉明;β拉受体兴奋剂如舒喘灵;卡托普利、依那普利;心痛定、硫氮卓酮;柳丁氨酸、长压定、前列腺素、心钠素;溶血栓药物:尿激酶和链激酶;组织型纤溶酶原激活剂;单链尿激酶型纤溶酶原激活剂;TNK-组织型纤溶酶原激活剂;抗凝血药物:肝素;依诺肝素;那曲肝素;比伐卢定。 - [根据细则26改正28.02.2018]
权利要求1-26任一项的方法,其中所述纤溶酶原与序列2、6、8、10或12具有至少75%、80%、85%、90%、95%、96%、97%、98%或99%的序列同一性,并且仍然具有纤溶酶原活性。 - [根据细则26改正28.02.2018]
权利要求1-27任一项的方法,所述纤溶酶原是在序列2、6、8、10或12的基础上,添加、删除和/或取代1-100、1-90、1-80、1-70、1-60、1-50、1-45、1-40、1-35、1-30、1-25、1-20、1-15、1-10、1-5、1-4、1-3、1-2、1个氨基酸,并且仍然具有纤溶酶原活性的蛋白质。 - [根据细则26改正28.02.2018]
权利要求1-28任一项的方法,所述纤溶酶原是包含纤溶酶原活性片段、并且仍然具有纤溶酶原活性的蛋白质。 - [根据细则26改正28.02.2018]
权利要求1-29任一项的方法,所述纤溶酶原选自Glu-纤溶酶原、Lys-纤溶酶原、小纤溶酶原、微纤溶酶原、delta-纤溶酶原或它们的保留纤溶酶原活性的变体。 - [根据细则26改正28.02.2018]
权利要求1-30任一项的方法,所述纤溶酶原为天然或合成的人纤溶酶原、或其仍然保留纤溶酶原活性的变体或片段。 - [根据细则26改正28.02.2018]
权利要求1-31任一项的方法,所述纤溶酶原为来自灵长类动物或啮齿类动物的人纤溶酶原直向同系物或其仍然保留纤溶酶原活性的变体或片段。 - [根据细则26改正28.02.2018]
权利要求1-32任一项的方法,所述纤溶酶原的氨基酸如序列2、6、8、10或12所示。 - [根据细则26改正28.02.2018]
权利要求1-33任一项的方法,其中所述纤溶酶原是人天然纤溶酶原。 - [根据细则26改正28.02.2018]
权利要求1-34任一项的方法,其中所述受试者是人。 - [根据细则26改正28.02.2018]
权利要求1-35任一项的方法,其中所述受试者缺乏或缺失纤溶酶原。 - [根据细则26改正28.02.2018]
权利要求36的方法,其中所述缺乏或缺失是先天的、继发的和/或局部的。 - [根据细则26改正28.02.2018]
一种用于权利要求1-37任一项的方法的纤溶酶原。 - 一种药物组合物,其包含药学上可接受的载剂和用于权利要求1-39中任一项所述方法的纤溶酶原。
- [根据细则26改正28.02.2018]
一种预防性或治疗性试剂盒,其包含:(i)用于权利要求1-37中任一项所述方法的纤溶酶原和(ii)用于递送所述纤溶酶原至所述受试者的构件(means)。 - [根据细则26改正28.02.2018]
根据权利要求420所述的试剂盒,其中所述构件为注射器或小瓶。 - [根据细则26改正28.02.2018]
权利要求40或41的试剂盒,其还包含标签或使用说明书,该标签或使用说明书指示将所述纤溶酶原投予所述受试者以实施权利要求1-37中任一项所述方法。 - [根据细则26改正28.02.2018]
一种制品,其包含:含有标签的容器;和包含(i)用于权利要求1-37中任一项所述方法的纤溶酶原或包含纤溶酶原的药物组合物,其中所述标签指示将所述纤溶酶原或组合物投予所述受试者以实施权利要求1-37中任一项所述方法。 - [根据细则26改正28.02.2018]
权利要求40-42中任一项的试剂盒或权利要求43的制品,还包含另外的一个或多个构件或容器,该构件或容器中含有其他药物。 - [根据细则26改正28.02.2018]
权利要求44的试剂盒或制品,其中所述其他药物选自下组:降血脂药物、抗血小板药物、降血压药物、扩张血管药物、降血糖药物、抗凝血药物、溶血栓药物,保肝药物,抗心律失常药物,强心药物,利尿药物,抗感染药物、抗病毒药物、免疫调节药物、炎症调节类药物、抗肿瘤药物、激素类药物、甲状腺素。 - 包含纤溶酶原的减肥药。
- 包含纤溶酶原的减肥产品。
- 纤溶酶原用于减低体重的用途。
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US11207387B2 (en) | 2021-12-28 |
EP3556379A1 (en) | 2019-10-23 |
TW201829448A (zh) | 2018-08-16 |
EP3556379A4 (en) | 2020-08-19 |
CA3047181A1 (en) | 2018-06-21 |
JP2020502153A (ja) | 2020-01-23 |
CN110114079A (zh) | 2019-08-09 |
JP7168990B2 (ja) | 2022-11-10 |
US20190328849A1 (en) | 2019-10-31 |
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