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WO2025098221A1 - 苯丙酸类似物在治疗或预防代谢紊乱中的用途 - Google Patents

苯丙酸类似物在治疗或预防代谢紊乱中的用途 Download PDF

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Publication number
WO2025098221A1
WO2025098221A1 PCT/CN2024/128595 CN2024128595W WO2025098221A1 WO 2025098221 A1 WO2025098221 A1 WO 2025098221A1 CN 2024128595 W CN2024128595 W CN 2024128595W WO 2025098221 A1 WO2025098221 A1 WO 2025098221A1
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Prior art keywords
jkt
zaltoprofen
uric acid
pharmaceutically acceptable
acceptable salt
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PCT/CN2024/128595
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English (en)
French (fr)
Inventor
王珂
耿燕
王宗贵
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Hefei Jinke Bio-Pharmaceutical Technology Co Ltd
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Hefei Jinke Bio-Pharmaceutical Technology Co Ltd
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Priority claimed from CN202311494324.0A external-priority patent/CN117771238B/zh
Application filed by Hefei Jinke Bio-Pharmaceutical Technology Co Ltd filed Critical Hefei Jinke Bio-Pharmaceutical Technology Co Ltd
Publication of WO2025098221A1 publication Critical patent/WO2025098221A1/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • 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
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

  • the present invention belongs to the field of medicine, and more specifically, the present invention relates to a new use of phenylpropionic acid analogs in treating or preventing metabolic disorders.
  • Metabolic disorder is a state in which the body's digestion, absorption, and excretion of substances are pathological, uncoordinated, and unbalanced, which can be manifested as a disorder of one substance or multiple substances.
  • Disorders in different metabolic states can cause different diseases, such as diabetes caused by sugar metabolism disorders, hyperlipidemia caused by lipid metabolism disorders, and gout caused by uric acid metabolism disorders.
  • Metabolic syndrome significantly increases the risk of type 2 diabetes, cardiovascular disease, and non-alcoholic fatty liver disease (NAFLD). In insulin resistance, elevated hepatic glucose production and lipoprotein secretion contribute to the pathogenesis of hyperglycemia and hyperlipidemia.
  • Obesity is also associated with the accumulation of excess fat in the liver, which is the most typical feature of NAFLD affecting adults and children.
  • NASH non-alcoholic steatohepatitis
  • Zaltoprofen is a phenylpropionic acid nonsteroidal anti-inflammatory drug used to treat chronic rheumatoid arthritis, osteoarthritis, low back pain, periarthritis of the shoulder, cervical shoulder-wrist syndrome, and anti-inflammatory analgesia after surgery, trauma, and tooth extraction.
  • the present invention provides a novel use of zaltoprofen, a phenylpropionic acid analogue, for treating or preventing metabolic disorders, in particular for treating or preventing metabolic disorders associated with uric acid and blood sugar and blood lipids.
  • One aspect of the present invention provides use of zaltoprofen or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and/or preventing metabolic disorders.
  • the zaltoprofen or a pharmaceutically acceptable salt thereof includes at least one of a racemate, an S optical isomer, or an R optical isomer of zaltoprofen or a pharmaceutically acceptable salt thereof.
  • the metabolic disorder comprises at least one of uric acid metabolism disorder, blood glucose metabolism disorder or blood lipid metabolism disorder.
  • the metabolic disorder comprises at least one of hyperuricemia, gout, diabetes, metabolic syndrome, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hyperinsulinemia, lipoprotein aberrations, liver inflammation, adipose tissue inflammation, fatty liver disease, non-alcoholic fatty liver disease, hypercholesterolemia, coronary heart disease, congestive heart failure, stroke, peripheral vascular disease, atherosclerosis, arteriosclerosis, obesity, nephrolithiasis, kidney disease, diabetic retinopathy, insulin resistance, hyperinsulinemia, hypertension, hepatic steatosis, fatty liver, non-alcoholic fatty liver disease, polycystic ovary syndrome, acanthosis nigricans, endocrine abnormalities, neurodegenerative diseases, or Alzheimer's disease.
  • the metabolic disorder includes at least one of acute hyperuricemia, chronic hyperuricemia, gouty arthritis caused by uric acid, glucose and lipid metabolism disorder associated with a chronic hyperuricemia model, or type 2 diabetes.
  • the drug can reduce at least one of blood uric acid, blood sugar, glucose tolerance, cholesterol and triglycerides.
  • Another aspect of the present invention provides use of a racemate or R optical isomer of zaltoprofen or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and/or preventing uric acid metabolism disorders.
  • the uric acid metabolism disorder includes acute hyperuricemia, chronic hyperuricemia, etc.
  • Another aspect of the present invention provides use of a racemic form or an S optical isomer of zaltoprofen or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and/or preventing blood glucose metabolism disorders and/or blood lipid metabolism disorders.
  • the blood glucose metabolism disorder and/or blood lipid metabolism disorder include glucose and lipid metabolism disorder associated with chronic hyperuricemia model, diabetes, etc.
  • the dosage form of the drug includes tablets, capsules, granules, oral solutions, water injections, powder injections, lyophilized powder injections, sprays, suppositories or pills.
  • the administration route of the drug includes oral administration, injection administration, intravenous drip administration, sublingual administration, spray inhalation or rectal administration.
  • Another aspect of the present invention provides a method for reducing uric acid, blood glucose and/or blood lipid levels in a subject, the method comprising administering an effective amount of zaltoprofen or a pharmaceutically acceptable salt thereof to a subject in need thereof.
  • the zaltoprofen or a pharmaceutically acceptable salt thereof includes at least one of a racemate, an S optical isomer, or an R optical isomer of zaltoprofen or a pharmaceutically acceptable salt thereof.
  • the method comprises administering to a subject in need thereof an effective amount of a racemate or R optical isomer of zaltoprofen or a pharmaceutically acceptable salt thereof for reducing uric acid levels in the subject.
  • the method comprises administering to a subject in need thereof an effective amount of a racemate or S optical isomer of zaltoprofen or a pharmaceutically acceptable salt thereof for lowering blood glucose and/or blood lipid levels in the subject.
  • Another aspect of the present invention provides a method for preventing or treating a metabolic disorder, comprising administering an effective amount of zaltoprofen or a pharmaceutically acceptable salt thereof to a subject in need thereof.
  • the zaltoprofen or a pharmaceutically acceptable salt thereof includes at least one of a racemate, an S optical isomer, or an R optical isomer of zaltoprofen or a pharmaceutically acceptable salt thereof.
  • the metabolic disorder comprises at least one of uric acid metabolism disorder, blood glucose metabolism disorder or blood lipid metabolism disorder.
  • the metabolic disorder comprises at least one of hyperuricemia, gout, diabetes, metabolic syndrome, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hyperinsulinemia, lipoprotein aberrations, liver inflammation, adipose tissue inflammation, fatty liver disease, non-alcoholic fatty liver disease, hypercholesterolemia, coronary heart disease, congestive heart failure, stroke, peripheral vascular disease, atherosclerosis, arteriosclerosis, obesity, nephrolithiasis, kidney disease, diabetic retinopathy, insulin resistance, hyperinsulinemia, hypertension, hepatic steatosis, fatty liver, non-alcoholic fatty liver disease, polycystic ovary syndrome, acanthosis nigricans, endocrine abnormalities, neurodegenerative diseases, or Alzheimer's disease.
  • the metabolic disorder includes at least one of acute hyperuricemia, chronic hyperuricemia, gouty arthritis caused by uric acid, glucose and lipid metabolism disorder associated with a chronic hyperuricemia model, or type 2 diabetes.
  • the method comprises administering zaltoprofen or a pharmaceutically acceptable salt thereof at a dose of 0.01-100 mg/kg, preferably 0.1-50 mg/kg, and more preferably 0.5-30 mg/kg to a subject in need thereof.
  • the present invention creatively discovered the uric acid-lowering effect of zaltoprofen on hyperuricemia and the anti-inflammatory effect on gouty arthritis caused by uric acid, and also discovered the hypoglycemic and hypolipidemic effects of zaltoprofen on hyperuricemia-associated glucose and lipid metabolism disorders and type 2 diabetes.
  • the present invention further discovered that different optical isomers of zaltoprofen have different effects on different metabolic disorders, providing important value for its clinical application in the prevention and treatment of metabolic disorder-related diseases such as hyperuricemia, gout, and diabetes.
  • AUC serum uric acid concentration-time curve
  • FIG3 shows the inhibition rate of JKT and its optical isomers on the area under the serum uric acid concentration-time curve (AUC) of hypoxanthine-induced hyperuricemia model in mice (calculated based on the mean value of each group).
  • FIG5 shows the inhibition rate of JKT and its optical isomers on serum uric acid in the chronic hyperuricemia model of mice induced by hypoxanthine+potassium oxonate (calculated based on the mean value of each group).
  • AUC glucose-time curve
  • the term “about” refers to a range of ⁇ 20% of the value that follows. In some embodiments, the term “about” refers to a range of ⁇ 10% of the value that follows. In some embodiments, the term “about” refers to a range of ⁇ 5% of the value that follows.
  • metabolic disorder means metabolic abnormalities caused by diseases in the body or by congenital defects of the body.
  • metabolic disorders include, but are not limited to, uric acid metabolism disorders, sugar metabolism disorders, lipid metabolism disorders, etc.
  • metabolic disorders include hyperuricemia, gout, diabetes, metabolic syndrome, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hyperinsulinemia, lipoprotein aberrations, liver inflammation, adipose tissue inflammation, fatty liver disease, non-alcoholic fatty liver disease, hypercholesterolemia, coronary heart disease, congestive heart failure, stroke, peripheral vascular disease, atherosclerosis, arteriosclerosis, obesity, nephrolithiasis, kidney disease, diabetic retinopathy, insulin resistance, hyperinsulinemia, hypertension, hepatic steatosis, fatty liver, non-alcoholic fatty liver disease, polycystic ovary syndrome, acanthosis nigricans, endocrine abnormalities, neurodegenerative diseases or Alzheimer's disease and other diseases or conditions.
  • Zaltoprofen (10,11-dihydro- ⁇ -methyl-10-oxo-dibenzo[b,f-thiophene-2-acetic acid, Zaltoprofen) has a structure as shown in the following formula (I).
  • Zaltoprofen is a potent nonsteroidal analgesic and anti-inflammatory drug of the phenylpropionic acid class.
  • Zaltoprofen is a racemate containing two optical isomers, the S optical isomer (S-) and the R optical isomer (R-).
  • S- S optical isomer
  • R- the code name of zaltoprofen
  • the code name of zaltoprofen is JKT
  • RS-JKT racemic form
  • S optical isomer S-JKT
  • the R optical isomer is represented by R-JKT.
  • treatment includes actions that occur while a subject has a particular disease, disorder or condition that reduce the severity of, or delay or slow the development of, the disease, disorder or condition ("therapeutic treatment”), as well as actions that occur before a subject develops a particular disease, disorder or condition ("prophylactic treatment").
  • the term "pharmaceutically acceptable” means the carrier, diluent, and/or excipient used for the drug must be compatible with the other ingredients of the formulation and not deleterious to the recipient.
  • the term "pharmaceutically acceptable carrier” refers to any form of non-toxic inert solid, semi-solid, diluent, encapsulating material or formulation adjuvant.
  • materials that can be used as pharmaceutically acceptable carriers are sugars, such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; malt; gelatin and other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate; as well as colorants; release agents; coating agents; sweeteners; flavoring agents and fragrances; preservatives and antioxidants, which can also be used in the drug according to the judgment of the formulationist.
  • subject includes, but is not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and/or non-human animals, e.g., mammals, such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs.
  • the subject is a human.
  • the subject is a non-human animal.
  • the terms "human,” “patient,” and “subject” are used interchangeably herein.
  • the term "effective amount" as used herein refers to an amount sufficient to cause a target biological response.
  • the effective amount of the drug of the present invention may vary depending on factors such as the biological target, the pharmacokinetics of the drug, the disease being treated, the mode of administration, and the age, health, and symptoms of the subject.
  • the effective amount includes a therapeutically effective amount and a prophylactically effective amount.
  • the term "therapeutically effective amount” is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition.
  • a therapeutically effective amount of a drug refers to an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition.
  • the term “therapeutically effective amount” can include an amount that improves overall treatment, reduces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic effect of other therapeutic agents.
  • the effective amount of the drug of the present invention is usually in the range of 0.01 mg to 100 mg drug/kg patient body weight per day, preferably 0.1mg to 50mg drug/kg patient body weight, further preferably 0.5mg to 30mg drug/kg patient body weight in single or multiple administrations.
  • the drug of the present invention can be administered to the patient in need of such treatment in a daily dose range of about 0.1mg/kg to about 50mg/kg per patient, preferably 0.5mg/kg to 30mg/kg.
  • the daily dose per patient can be about 0.1 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 2.5 mg/kg, about 5 mg/kg, about 7.5 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg, about 25 mg/kg, about 26 mg/kg, about 27 mg/kg, about 28 mg/kg, about 29 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg.
  • the drug of the present invention can be administered daily for 5 days, then interrupted for 9 days, and then administered daily for 5 days, then interrupted for 9 days, and so on, indefinitely repeat the cycle or repeat 4-10 times in total.
  • the drug provided herein can also be administered for a long time (“long-term administration").Long-term administration refers to administering the drug for a long time, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or can be continuously administered indefinitely, for
  • prophylactically effective amount is an amount sufficient to prevent a disease, disorder or condition, or an amount sufficient to prevent one or more symptoms associated with a disease, disorder or condition, or an amount to prevent the recurrence of a disease, disorder or condition.
  • a prophylactically effective amount of a drug refers to an amount of a therapeutic agent that provides a prophylactic benefit in the process of preventing a disease, disorder or condition when used alone or in combination with other agents.
  • prophylactically effective amount may include an amount that improves overall prevention, or an amount that enhances the prophylactic effect of other prophylactic agents.
  • an effective amount of the drug provided herein is administered.
  • the amount of the drug actually administered can be determined by a physician according to the relevant circumstances, including the condition being treated, the route of administration selected, the drug actually administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like.
  • the drugs provided herein are administered to a subject at risk of developing the condition, typically based on the advice of a physician and administered under the supervision of a physician, at dosage levels as described above.
  • Subjects at risk of developing a specific condition typically include subjects with a family history of the condition, or those identified by genetic testing or screening as being particularly susceptible to developing the condition.
  • parenteral administration includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intraarticular ... medication, intra-arterial administration, intra-synovial administration, intrasternal administration or infusion techniques, etc.
  • the drug can be administered by push injection, for example, in order to increase the concentration of the drug in the blood to an effective level.
  • the push injection dose depends on the target systemic level of the active component through the body, for example, the intramuscular or subcutaneous push injection dose slowly releases the active component, and the push injection delivered directly to the vein (for example, by IV intravenous drip) can be delivered more quickly, so that the concentration of the active component in the blood is quickly increased to an effective level.
  • the drug can be administered in a continuous infusion form, for example, by IV intravenous drip, so as to provide a steady-state concentration of the active component in the subject's body.
  • the drug of the push injection dose can be given first, and then the continuous infusion.
  • oral medications can be in the form of bulk liquid solutions or suspensions or bulk powders.
  • the drug is provided in a unit dosage form.
  • unit dosage form refers to a physical discrete unit suitable as a unit dose for human patients and other mammals, each unit containing a predetermined amount of active substances and suitable pharmaceutical excipients suitable for producing the desired therapeutic effect.
  • Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid dosage forms, or pills, tablets, capsules, etc. in the case of solid dosage forms.
  • the drug is usually a relatively small component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), and the remainder is various carriers or excipients and processing aids useful for forming the desired dosage form.
  • Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous carriers and buffers, suspending and dispersing agents, colorants, flavoring agents, etc.
  • Solid forms may include, for example, any of the following components, or drugs of similar nature: binders, such as microcrystalline cellulose, tragacanth or gelatin; excipients, such as starch or lactose; disintegrants, such as alginic acid, sodium starch glycolate or corn starch; lubricants, such as magnesium stearate; glidants, such as colloidal silicon dioxide; sweeteners, such as sucrose or saccharin; or flavoring agents, such as mint, methyl salicylate or orange flavoring; stabilizers, such as tartaric acid, aspartic acid, glutamic acid, etc.
  • binders such as microcrystalline cellulose, tragacanth or gelatin
  • excipients such as starch or lactose
  • disintegrants such as alginic acid, sodium starch glyco
  • Injectable dosage forms are typically based on sterile saline or phosphate buffered saline for injection, or other injectable excipients known in the art.
  • active drug is typically a minor component, often about 0.05 to 10% by weight, and the remainder is an injectable excipient, etc.
  • transdermal dosage forms are formulated as topical ointments or creams containing active ingredients.
  • the active ingredient When formulated as an ointment, the active ingredient is typically combined with paraffin or a water-miscible ointment base.
  • the active ingredient can be formulated as an ointment together with, for example, an oil-in-water cream base.
  • Such transdermal formulations are well known in the art and typically include other components for enhancing the stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope provided by the invention.
  • transdermal administration may be achieved using patches of the reservoir or porous membrane type, or a variety of solid matrices.
  • Racemic JKT (RS-JKT), purity: 99.3%; JKT S optical isomer (S-JKT), purity: 99.4%; JKT R optical isomer (R-JKT), purity: 99.1%, all provided by Hefei Jinke Biotechnology Co., Ltd.
  • Rosiglitazone tablets (Aineng): 4mg*7 tablets*2 plates, Chengdu Hengrui Pharmaceutical Co., Ltd.
  • S17061-100g was purchased from Shanghai Yuanye Biotechnology Co., Ltd.
  • Ibuprofen, S31057-5g was purchased from Shanghai Yuanye Biotechnology Co., Ltd.
  • Acetaminophen, H20010394 was purchased from Shanghai Johnson Pharmaceutical Co., Ltd.
  • the tested drugs were ground with 0.3% sodium carboxymethyl cellulose to prepare suspensions of corresponding concentrations for oral administration.
  • mice Male Kunming mice, SPF grade, weighing 18-22 g, were purchased from Henan SCXK Biotechnology Co., Ltd., production license number: SCXK( ⁇ )2020-0005.
  • mice SPF grade, male, 5-6 weeks old, were purchased from the Experimental Animal Management Department of Shanghai Institute of Family Planning Science, license number: SCXK (Su) 2018-0006.
  • mice 48 KM male mice, SPF grade, weighing 18-22 g, were purchased from Henan SCXBest Biotechnology Co., Ltd., production license number: SCXK( ⁇ )2020-0005.
  • mice and male SD rats were housed in the Animal Center of China Pharmaceutical University (Animal Use License No.: SYXK(Su)2021-0011).
  • the temperature of the breeding laboratory was 24 ⁇ 2°C; relative humidity was 40%-70%; air exchange times per hour: 10-15 times/hour; light cycle: 12 (day)/12 (night) hours, no more than 5 rats per cage.
  • the feed was complete pellet feed for mice, purchased from Jiangsu Collaborative Pharmaceutical Bioengineering Co., Ltd., and its quality met the GB14924.1-2010 "General Quality Standard for Experimental Animal Formula Feed".
  • mice were kept in a clean animal room (Animal Use License No.: SYXK (Su) 2021-0011), with a laboratory temperature of 24 ⁇ 2 °C, a relative humidity of 60% to 80%, air exchange times per hour: 10 to 15 times/h, and a light cycle of 12h (day)/12h (night). No more than 5 mice per cage.
  • the feed was a complete basic pellet feed for mice.
  • High-fat diet (80% basal feed, 15% lard, 4% milk powder, 1% cholesterol).
  • Drinking water Drink purified water.
  • Multifunctional ultrapure water system Ruisijie Water Purification Technology Co., Ltd. Unique-R20; multi-purpose high-efficiency centrifuge, BECKMAN COULTER 369003/Avanti J-E; electronic analytical balance, Sartorius Scientific Instrument Co., Ltd. BSA124S-CW; electric constant temperature blast drying oven, Shanghai Yiheng Scientific Instrument Co., Ltd. CIMO DHG-9140A; Varioskan TM LUX multifunctional microplate reader, Thermo Scientific; 4/-20°C low temperature freezer, Hefei Meiling Co., Ltd.
  • Uric acid (UA) test kit colorimetric method
  • Nanjing Jiancheng Bioengineering Institute C012-1
  • glucose (GLU) assay kit glucose oxidase method
  • TG triglyceride assay kit
  • TC total cholesterol
  • mice After the mice were adapted to feeding for 1 week, they were randomly divided into 8 groups according to their body weight, with 8 mice in each group, namely:
  • mice Overnight fasted mice (without water restriction) were given corresponding doses of the test drug by gavage, with the administration volume of 10 mL/kg.
  • the model group was given the same volume of 0.3% sodium carboxymethyl cellulose solution by gavage. After 30 minutes of gavage administration in each group, a single intraperitoneal injection of 1 g/kg hypoxanthine was used to establish an acute hyperuricemia animal model, with an injection volume of 10 mL/kg.
  • Blood was collected from the eye sockets of all mice before hypoxanthine injection and 0.5, 1, 2, and 6 hours after injection. The blood samples were allowed to stand for 1 hour and then centrifuged at 3500 rpm for 15 minutes to separate the serum. The uric acid concentration in the serum of each group was detected using a uric acid kit.
  • the serum uric acid (SUA) levels at different time points in each group were detected using a kit.
  • the uric acid concentration-time curve was drawn according to the time change of the uric acid level, and the area under the curve (AUC) of the uric acid concentration-time curve of each group was calculated.
  • the inhibition rate (%) of each drug on hyperuricemia was calculated based on the mean AUC of each group.
  • the inhibition rate of drug on hyperuricemia (AUC model group - AUC drug group ) / AUC model group ⁇ 100%.
  • mice in each group were similar. After the model group mice were intraperitoneally injected with hypoxanthine, the serum uric acid level increased rapidly, reaching a peak value in 1 hour, and then began to decline. After 6 hours of modeling, it basically dropped to the basal value before modeling. Compared with the model group, each tested drug could inhibit the increase of serum uric acid in mice caused by hypoxanthine to varying degrees, so that the serum uric acid concentration-time curve was depressed.
  • the area under the serum uric acid concentration-time curve (AUC) of each group is shown in Figure 2, and it can be seen that each test drug can significantly reduce the AUC value of the model mice; the results of the AUC inhibition rate of each group are shown in Figure 3, and it can be seen that according to the AUC inhibition rate, the uric acid-lowering effect intensity of the test substances at the same dose is: R-JKT>RS-JKT>S-JKT.
  • mice were purchased and adaptively raised for 1 week.
  • Chronic hyperuricemia animal model was established by oral administration of hypoxanthine 300 mg/kg combined with intraperitoneal injection of potassium oxonate 300 mg/kg.
  • the normal group was treated with oral administration combined with intraperitoneal injection of the corresponding volume of saline as a control.
  • Blood uric acid levels were tested in the normal group and model group two weeks after modeling. Mice with uric acid levels 30% higher than the mean of the normal group were selected from the model group and randomly divided into groups according to uric acid levels.
  • mice with successful modeling of elevated serum uric acid were divided into the following 9 groups, with 8 mice in each group:
  • Each group was given the drug by gavage once a day for 3 consecutive weeks, with a drug volume of 10 mL/kg.
  • the normal group and the model group were given the same volume of 0.3% sodium carboxymethyl cellulose by gavage.
  • mice were fasted overnight (without water deprivation) and blood was collected from their eye sockets before administration on the same day.
  • the blood samples were allowed to stand for 1 hour and then centrifuged at 3500 rpm for 15 minutes to separate the serum.
  • the uric acid concentration in the fasting serum of each group was detected using a uric acid kit.
  • the results are shown in Figure 5. It can be seen that the intensity of the uric acid reduction effect at the same dose is: R-JKT>RS-JKT>S-JKT, which is consistent with the efficacy results of the acute model.
  • Example 3 Effects of JKT and its optical isomers on improving glucose and lipid metabolism disorders associated with chronic hyperuricemia model
  • mice were purchased and adaptively raised for 1 week.
  • Chronic hyperuricemia animal model was established by oral administration of hypoxanthine 300 mg/kg combined with intraperitoneal injection of potassium oxonate 300 mg/kg.
  • the normal group was treated with oral administration combined with intraperitoneal injection of the corresponding volume of saline as a control.
  • Blood uric acid levels were tested in the normal group and model group two weeks after modeling. Mice with uric acid levels 30% higher than the mean of the normal group were selected from the model group and randomly divided into groups according to uric acid levels.
  • mice with elevated serum uric acid levels were divided into the following 10 groups, with 8 mice in each group:
  • Each group was given the drug by gavage once a day for 3 consecutive weeks, with a drug volume of 10 ml/kg.
  • the normal group and the model group were given the same volume of 0.3% sodium carboxymethyl cellulose by gavage.
  • mice fasted overnight were taken for blood sampling from their eye sockets before administration on the same day.
  • the blood samples were allowed to stand for 1 hour and then centrifuged at 3500 rpm for 15 minutes to separate the serum.
  • the uric acid concentration in the fasting serum of each group was detected using a uric acid kit.
  • mice that had been fasted overnight were taken, and blood was collected from the eye sockets before administration on the same day as the basal blood sample (0h); then, each group of mice was intraperitoneally injected with 2.0g/kg of glucose, and blood was collected from the eye sockets at 0.5, 1, and 2h after glucose injection.
  • the blood samples were allowed to stand for 1h and centrifuged at 3500rpm for 15min to separate the serum.
  • the basal blood samples were tested for GLU, TC, and TG levels using a kit, and the remaining 3 time point blood samples were tested for GLU levels.
  • the glucose tolerance curve was drawn based on the blood glucose levels at the 4 time points, and the area under the curve (AUC) was calculated and compared among the groups.
  • the glucose tolerance blood glucose-time curves of each group are shown in Figures 7A-7C, and the area under the glucose tolerance blood glucose-time curve (AUC) is shown in Figure 8.
  • AUC glucose tolerance blood glucose-time curve
  • the fasting blood glucose and the area under the glucose tolerance curve of the hyperuricemia model mice were significantly increased, indicating that the hyperuricemia model also had glucose and lipid metabolism disorders.
  • febuxostat had no significant effect on fasting blood glucose and the area under the glucose tolerance curve
  • rosiglitazone had a significant effect on reducing the fasting blood glucose and the area under the glucose tolerance curve of the model mice.
  • the JKT test groups also showed a significant improvement in the fasting blood glucose and the area under the glucose tolerance curve of the model mice.
  • the volume of rat hind feet was measured by water displacement method. The volume was measured once after sodium urate injection as the basic volume, and then the volume of rat hind feet was measured at 0.5, 1, 2, 4 and 6 hours after inflammation. The peak time and the time of swelling disappearance were observed, and the swelling degree at each time point was calculated to evaluate the anti-inflammatory effect.
  • the calculation formula is as follows:
  • mice Except for the normal control group, the rest of the mice were fed with a high-fat diet. After 3 weeks of feeding, streptozotocin (STZ 40 mg/kg) was injected intraperitoneally. Fasting blood glucose was measured 72 hours after STZ injection, and mice with blood glucose >11mmol/L were selected as type 2 diabetes for testing (mice with blood glucose not reaching the standard were given an additional injection of STZ 40 mg/kg). During the drug treatment, the model mice continued to be fed with a high-fat diet.
  • streptozotocin STZ 40 mg/kg
  • mice with successful hyperglycemia model were divided into the following 8 groups, with 8 mice in each group:
  • mice Eight normal mice were set up as the control group. Each group was intragastrically administered once a day for 4 consecutive weeks, with a dosing volume of 10 ml/kg. The normal group and the model group were intragastrically administered with an equal volume of 0.3% sodium carboxymethyl cellulose.
  • mice Five days before the end of the experiment, the mice were fasted for 12 h but not water, and a glucose (2.0 g/kg) tolerance test was performed. Blood was collected through capillary orbital blood sampling at 3500 rpm and centrifuged for 10 min to separate serum. The blood glucose level of each group of animals before glucose injection and 0.5, 1, and 2 h after the injection was measured using a glucose kit. The glucose tolerance curve was drawn and the area under the curve (AUC) was calculated.
  • AUC area under the curve
  • mice in the normal group were normal during the experiment, and there were no significant changes in feeding, drinking and defecation.
  • the spontaneous activities of mice in the model group decreased during the experiment, and their fur was dirty. Most animals showed symptoms of polydipsia, polyphagia and polyuria. No animals in each group died during the experiment.
  • the results of serum triglyceride levels in each group are shown in Figure 13. Compared with the normal group, the serum triglyceride level in the model group was significantly higher than that in the normal group. The serum triglyceride level of the model mice was significantly increased. The RS-JKT sample intervention for 4 weeks could significantly reduce the serum triglyceride level of the model mice; S-JKT and R-JKT had a tendency to reduce serum triglyceride, but the improvement effect was not significant.
  • JKT and its optical isomers can inhibit the increase of serum uric acid in mice caused by hypoxanthine to varying degrees, so that the serum uric acid concentration-time curve is depressed.
  • This result suggests that JKT and its optical isomers have a potential inhibitory effect on uric acid production, and the uric acid-lowering effect strength of the same dose of the test substance is: febuxostat>R-JKT>RS-JKT>S-JKT.
  • the acute uric acid-lowering effect of febuxostat is significantly stronger than that of JKT and its optical isomers.
  • JKT and its optical isomers can significantly reduce the serum uric acid concentration of the model mice, and the uric acid reduction rate further increases with the prolonged administration time.
  • the uric acid reduction effect strength of the same dose is: febuxostat>R-JKT>RS-JKT>S-JKT.
  • the chronic uric acid-lowering effect of febuxostat is still stronger than that of JKT and its optical isomers, the difference in drug efficacy is significantly narrowed compared with the acute model, especially the uric acid-lowering rate of R-JKT is close to that of febuxostat at the same dose.
  • JKT and its optical isomers significantly improved the fasting blood glucose and area under the glucose tolerance curve of mice, among which RS-JKT had a relatively stronger effect. JKT and its optical isomers reduced the fasting triglyceride level of mice.
  • JKT and its optical isomers significantly inhibited the swelling of gouty arthritis in rats caused by sodium urate, while febuxostat had no effect on joint swelling.
  • the inhibitory effect of each tested drug on sodium urate-induced arthritis was in the order of S-JKT ⁇ RS-JKT>R-JKT.
  • JKT and its optical isomers had no significant effect on the body weight of mice.
  • JKT and its optical isomers can significantly reduce the fasting blood glucose level of mice.
  • RS-JKT and S-JKT can significantly reduce the fasting blood glucose level; R-JKT has a tendency to reduce blood glucose, but the improvement effect is not significant.
  • JKT and its optical isomers JKT and its optical isomers significantly reduced the serum cholesterol level of mice, and RS-JKT significantly reduced the serum cholesterol level of mice; S-JKT and R-JKT had a trend to reduce serum cholesterol, but the improvement was not significant.
  • RS-JKT, S-JKT and R-JKT significantly improved the glucose tolerance curve of diabetic mice, among which RS-JKT had a particularly significant improvement.
  • JKT and its optical isomers have obvious uric acid-lowering effects for acute and chronic hyperuricemia models, and also have obvious anti-inflammatory and detumescent effects for gouty arthritis in rats caused by sodium urate, and have obvious hypoglycemic effects for glucose and lipid metabolism disorders associated with chronic hyperuricemia models, and have obvious hypoglycemic and hypolipidemic effects for type 2 diabetes induced by high-fat diet combined with streptozotocin.
  • Zaltoprofen has been used clinically for many years as a non-steroidal anti-inflammatory analgesic, and the present invention creatively finds that it also has significant use value in the treatment of metabolic disorders such as hyperuricemia, gout, glucose and lipid metabolism disorders, and diabetes.
  • mice KM male mice were housed in a barrier-level room with a 12-hour light-dark cycle and had free access to a standard diet and clean drinking water.
  • the temperature of the animal room was controlled at 25 ⁇ 2°C, and the relative humidity was controlled at 30-70%.
  • the mice were randomly divided into 6 groups according to their weight, with 8 mice in each group, namely the model control group, RS-JKT group, aspirin group, ibuprofen group, diclofenac sodium group, and acetaminophen group, totaling 48 mice.
  • the model group and each drug-treated group were fed with ordinary feed.
  • each group was intraperitoneally injected with hypoxanthine 1g/kg to establish an acute hyperuricemia mouse model, and the injection volume was 10ml/kg.
  • Hypoxanthine and each non-steroidal test drug were suspended and dispersed in 0.5% CMC-Na solution.
  • the dose of each non-steroidal anti-inflammatory drug was converted with reference to the clinical adult dose. Details are shown in Table 1 below.
  • mice were adapted to feeding for 5 days, and fasting blood samples were obtained by capillary orbital blood sampling after fasting blood samples were collected. After the fasting blood samples were collected, each group was gavaged with the corresponding test drugs (RS-JKT-20mg/kg, aspirin-250mg/kg, ibuprofen-150mg/kg, diclofenac sodium-20mg/kg, acetaminophen-250mg/kg), and the model group was gavaged with normal saline, and the gavage volume was 10ml/kg. Each group was intraperitoneally injected with hypoxanthine solution 30min after gavage, and the injection volume was 10ml/kg.
  • test drugs RS-JKT-20mg/kg, aspirin-250mg/kg, ibuprofen-150mg/kg, diclofenac sodium-20mg/kg, acetaminophen-250mg/kg
  • Capillary orbital blood was collected 30, 60, 120, and 360min after the intraperitoneal injection of hypoxanthine solution in each group. After the blood samples were allowed to stand, they were centrifuged at 3500rpm for 15min to obtain serum, and the blood uric acid level was tested according to the instructions of the uric acid kit.
  • the blood uric acid level in the model group peaked at 60 minutes after hypoxanthine injection.
  • the five tested non-steroidal anti-inflammatory drugs showed great differences in their effects on the serum uric acid levels of model mice.
  • RS-JKT can significantly reduce the blood uric acid levels at 1 and 2 hours after modeling (P ⁇ 0.05, P ⁇ 0.01), showing a significant inhibitory effect on uric acid production.
  • Ibuprofen, diclofenac sodium and acetaminophen have an increasing or decreasing effect on blood uric acid levels at different times, but the changes are small and the effect is not obvious.
  • the blood uric acid levels in the aspirin group at each time point after modeling were higher than those in the model group, among which 2 and 6 hours had statistically significant differences (P ⁇ 0.05, P ⁇ 0.01), indicating that aspirin has a clear effect of increasing blood uric acid.
  • RS-JKT has a significant uric acid-lowering effect
  • non-steroidal anti-inflammatory drugs such as ibuprofen, diclofenac sodium, acetaminophen and aspirin have no uric acid-lowering effect.
  • ibuprofen ibuprofen
  • diclofenac sodium ibuprofen
  • acetaminophen acetaminophen
  • aspirin have no uric acid-lowering effect.
  • the uric acid-lowering effect of RS-JKT may not depend on the pharmacological pathway of its non-steroidal anti-inflammatory drugs, but rather on a new pharmacodynamic mechanism.

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Abstract

提供了苯丙酸类似物在治疗和/或预防代谢紊乱中的新用途。

Description

苯丙酸类似物在治疗或预防代谢紊乱中的用途 技术领域
本发明属于医药领域，更具体地，本发明涉及苯丙酸类似物在治疗或预防代谢紊乱中的新用途。
背景技术
代谢紊乱是机体对物质的消化、吸收、排泄出现病理性，不协调的供需不平衡的状态，可以表现为一种物质或多种物质的紊乱。不同代谢状态紊乱会引起不同的疾病，例如糖代谢紊乱引起糖尿病，脂代谢紊乱引起高脂血症，尿酸代谢紊乱引起痛风。代谢综合征显著增加了患2型糖尿病、心血管疾病和非酒精性脂肪肝病(NAFLD)的风险。在胰岛素抵抗中，升高的肝葡萄糖产生和脂蛋白分泌促成高血糖症和高脂血症的发病机理。肥胖症也与过量脂肪在肝脏中的累积相关，过量脂肪在肝脏中的累积是影响成年人和孩子的NAFLD的最典型特征。虽然肝脂肪变性通常作为对肝功能没有明显的不良效应的良性病状出现，但是在20％-30％的患有非酒精性脂肪性肝炎(NASH)的NAFLD患者中观察到进行性肝损伤、炎症和纤维化。NASH正在成为终末期肝病的主要危险因素。因此，开发新的用于治疗代谢紊乱的药物具有非常重要的意义。
扎托布洛芬(Zaltoprofen)是一种苯丙酸类非甾体抗炎药，用于治疗慢性风湿性关节炎、变形性关节炎、腰痛症、肩关节周围炎、颈肩腕综合征以及手术后、外伤后以及拔牙后的抗炎镇痛。
发明内容
本发明提供了苯丙酸类似物扎托布洛芬用于治疗或预防代谢紊乱的新用途，特别是用于治疗或预防尿酸和血糖血脂相关的代谢紊乱。
本发明的一方面提供了扎托布洛芬或其药学上可接受的盐在制备用于治疗和/或预防代谢紊乱的药物中的用途。
在一些实施方式中，所述扎托布洛芬或其药学上可接受的盐包括扎托布洛芬或其药学上可接受的盐的外消旋体、S型光学异构体或R型光学异构体中的至少一种。
在一些实施方式中，所述代谢紊乱包括尿酸代谢紊乱、血糖代谢紊乱或血脂代谢紊乱中的至少一种。
在一些实施方式中，所述代谢紊乱包括高尿酸血症、痛风、糖尿病、代谢综合征、高血糖症、高脂血症、高甘油三酯血症、高胰岛素血症、脂蛋白畸变、肝脏炎症、脂肪组织炎症、脂肪肝疾病、非酒精性脂肪肝疾病、高胆固醇血症、冠心病、充血性心力衰竭、中风、外周血管疾病、动脉粥样硬化、动脉硬化、肥胖症、肾石病、肾脏疾病、糖尿病视网膜病变、胰岛素抵抗、高胰岛素血症、高血压、肝脂肪变性、脂肪肝、非酒精性脂肪性肝病、多囊卵巢综合征、黑棘皮病、内分泌异常、神经退行性疾病或阿尔茨海默氏症中的至少一种。
在一些实施方式中，所述代谢紊乱包括急性高尿酸血症、慢性高尿酸血症、尿酸所致的痛风性关节炎、慢性高尿酸血症模型伴随的糖脂代谢紊乱或2型糖尿病中的至少一种。
在一些实施方式中，所述药物能降低血尿酸、血糖、糖耐量、胆固醇和甘油三脂中的至少一种。
本发明的另一方面提供了扎托布洛芬或其药学上可接受的盐的外消旋体或R型光学异构体在制备用于治疗和/或预防尿酸代谢紊乱的药物中的用途。
在一些实施方式中，所述尿酸代谢紊乱包括急性高尿酸血症、慢性高尿酸血症等。
本发明的又一方面提供了扎托布洛芬或其药学上可接受的盐的外消旋体或S型光学异构体在制备用于治疗和/或预防血糖代谢紊乱和/或血脂代谢紊乱的药物中的用途。
在一些实施方式中，所述血糖代谢紊乱和/或血脂代谢紊乱包括慢性高尿酸血症模型伴随的糖脂代谢紊乱、糖尿病等。
在一些实施方式中，所述药物的剂型包括片剂、胶囊剂、颗粒剂、口服溶液、水针剂、粉针剂、冻干粉针剂、喷雾剂、栓剂或滴丸。
在一些实施方式中，所述药物的给药途径包括口服给药、注射给药、静脉滴注给药、舌下给药、喷雾吸入或直肠给药。
本发明的又一方面提供了降低受试者尿酸、血糖和/或血脂水平的方法，所述方法包括向有需要的受试者施用有效量的扎托布洛芬或其药学上可接受的盐。
在一些实施方式中，所述扎托布洛芬或其药学上可接受的盐包括扎托布洛芬或其药学上可接受的盐的外消旋体、S型光学异构体或R型光学异构体中的至少一种。
在一些实施方式中，所述方法包括向有需要的受试者施用有效量的扎托布洛芬或其药学上可接受的盐的外消旋体或R型光学异构体用于降低受试者的尿酸水平。
在一些实施方式中，所述方法包括向有需要的受试者施用有效量的扎托布洛芬或其药学上可接受的盐的外消旋体或S型光学异构体用于降低受试者的血糖和/或血脂水平。
本发明的又一方面提供了预防或治疗代谢紊乱的方法，所述方法包括向有需要的受试者施用有效量的扎托布洛芬或其药学上可接受的盐。
在一些实施方式中，所述扎托布洛芬或其药学上可接受的盐包括扎托布洛芬或其药学上可接受的盐的外消旋体、S型光学异构体或R型光学异构体中的至少一种。
在一些实施方式中，所述代谢紊乱包括尿酸代谢紊乱、血糖代谢紊乱或血脂代谢紊乱中的至少一种。
在一些实施方式中，所述代谢紊乱包括高尿酸血症、痛风、糖尿病、代谢综合征、高血糖症、高脂血症、高甘油三酯血症、高胰岛素血症、脂蛋白畸变、肝脏炎症、脂肪组织炎症、脂肪肝疾病、非酒精性脂肪肝疾病、高胆固醇血症、冠心病、充血性心力衰竭、中风、外周血管疾病、动脉粥样硬化、动脉硬化、肥胖症、肾石病、肾脏疾病、糖尿病视网膜病变、胰岛素抵抗、高胰岛素血症、高血压、肝脂肪变性、脂肪肝、非酒精性脂肪性肝病、多囊卵巢综合征、黑棘皮病、内分泌异常、神经退行性疾病或阿尔茨海默氏症中的至少一种。
在一些实施方式中，所述代谢紊乱包括急性高尿酸血症、慢性高尿酸血症、尿酸所致的痛风性关节炎、慢性高尿酸血症模型伴随的糖脂代谢紊乱或2型糖尿病中的至少一种。
在一些实施方式中，所述方法包括向有需要的受试者施用0.01-100mg/kg剂量，优选为0.1-50mg/kg剂量，进一步优选为0.5～30mg/kg剂量的扎托布洛芬或其药学上可接受的盐。
本发明创造性地发现了扎托布洛芬对高尿酸血症的降尿酸作用以及对尿酸所致痛风性关节炎的抗炎作用，还发现了扎托布洛芬对高尿酸血症伴随的糖脂代谢紊乱以及2型糖尿病的降血糖和降血脂作用。本发明还进一步发现了扎托布洛芬的不同光学异构体形式对于不同的代谢紊乱的作用有所差异，为其在高尿酸血症、痛风、糖尿病等代谢紊乱相关疾病的预防和治疗的临床应用提供重要价值。
附图说明
图1示出了JKT及其光学异构体对次黄嘌呤诱发小鼠高尿酸模型血清尿酸浓度的影响(N＝8，M±SD)。
图2示出了JKT及其光学异构体对次黄嘌呤诱发小鼠高尿酸模型血清尿酸浓度-时间曲线下面积(AUC)的影响(N＝8，M±SD)；**P<0.01，与模型组相比。
图3示出了JKT及其光学异构体对次黄嘌呤诱发小鼠高尿酸模型血清尿酸浓度-时间曲线下面积(AUC)的抑制率(根据各组均值计算)。
图4示出了JKT及其光学异构体对次黄嘌呤+氧嗪酸钾诱发小鼠慢性高尿酸模型血清尿酸浓度的影响(N＝8，M±SD)，其中A为RS-JKT组，B为R-JKT组，C为S-JKT组；**P<0.01，与正常组相比；#P<0.05，##P<0.01，与模型组相比。
图5示出了JKT及其光学异构体对次黄嘌呤+氧嗪酸钾诱发小鼠慢性高尿酸模型血清尿酸的抑制率(根据各组均值计算)。
图6示出了JKT及其光学异构体对次黄嘌呤+氧嗪酸钾诱发小鼠慢性高尿酸模型血清尿酸浓度的影响(N＝8，M±SD)；**P<0.01，与正常组相比；##P<0.01，与模型组相比。
图7示出了JKT及其光学异构体对次黄嘌呤+氧嗪酸钾诱发小鼠慢性高尿酸模型糖耐量血糖-时间曲线的影响(N＝8，M±SD)，其中A为RS-JKT组，B为R-JKT组，C为S-JKT组；*P<0.05，**P<0.01，与正常组相比；#P<0.05，##P<0.01，与模型组相比。
图8示出了JKT及其光学异构体对次黄嘌呤+氧嗪酸钾诱发小鼠慢性高尿酸模型糖耐量血糖-时间曲线下面积(AUC)的影响(N＝8，M±SD)；**P<0.01，与正常组相比；#P<0.05，##P<0.01，与模型组相比。
图9示出了JKT及其光学异构体对次黄嘌呤+氧嗪酸钾诱发小鼠慢性高尿酸模型血脂水平的影响(N＝8，M±SD)，其中A为甘油三酯(TG)，B为总胆固醇(TC)。
图10示出了JKT及其光学异构体对尿酸钠引起大鼠痛风性关节炎的作用(N＝8，M±SD)，其中A为RS-JKT组，B为R-JKT组，C为S-JKT组；#P<0.05，##P<0.01，与模型组相比。
图11示出了JKT及其光学异构体对体重(g)的影响(N＝8)，其中A为RS-JKT组，B为R-JKT组，C为S-JKT组；*P<0.05，**P<0.01，与正常组相比。
图12示出了对血糖水平(mmol/L)的影响(N＝8)，其中A为RS-JKT组，B为R-JKT组，C为S-JKT组；**P<0.01，与正常组相比；#P<0.05，##P<0.01，与模型组相比。
图13示出了对血清甘油三脂(mmol/L)的影响(N＝8)；**P<0.01，与正常组相比；#P<0.05，##P<0.01，与模型组相比。
图14示出了对血清胆固醇(mmol/L)的影响(N＝8)；*P<0.05，**P<0.01，与正常组相比；#P<0.05，##P<0.01，与模型组相比。
图15示出了JKT及其光学异构体对糖耐量血糖-时间曲线的影响(N＝8，M±SD)，其中A为RS-JKT组，B为R-JKT组，C为S-JKT组；**P<0.01，与正常组相比；#P<0.05，##P<0.01，与模型组相比。
图16示出了JKT及其光学异构体对糖耐量血糖-时间曲线下面积(AUC)的影响(N＝8，M±SD)；**P<0.01，与正常组相比；#P<0.05，##P<0.01，与模型组相比。
图17示出了单次给药后不同时间点血清尿酸含量(mg/L)(N＝8，M±SD)；*P<0.05，**P<0.01，与模型组相比。
具体实施方式
为使本发明的目的、技术方案及优点更加清楚明白，以下结合实施例，对本发明进行进一步的详细说明。此处所描述的具体实施例仅用于解释本发明，并不用于构成对本发明的任何限制。此外，在以下说明中，省略了对公知结构和技术的描述，以避免不必要地混淆本公开的概念。这样的结构和技术在许多出版物中也进行了描述。
定义
除非另有定义，否则本发明使用的所有技术术语和科技术语都具有如在本发明所属领域中通常使用的相同含义。出于解释本说明书的目的，将用途以下定义，并且在适当时，以单数形式使用的术语也将包括复数形式，反之亦然。
除非上下文另有明确说明，否则本文所用的表述“一种”和“一个”包括复数指代。例如，提及“一个细胞”包括多个这样的细胞及本领域技术人员可知晓的等同物等等。
本文所用的术语“约”表示其后的数值的±20％的范围。在一些实施方式中，术语“约”表示其后的数值的±10％的范围。在一些实施方式中，术语“约”表示其后的数值的±5％的范围。
本文所用的术语“代谢紊乱”，意指因体内的疾病或因机体先天的缺陷所造成的代谢异常现象。在本发明中，代谢紊乱包括但不限于，尿酸代谢紊乱，糖代谢紊乱，脂代谢紊乱等。在一些具体实施方式中，代谢紊乱包括高尿酸血症、痛风、糖尿病、代谢综合征、高血糖症、高脂血症、高甘油三酯血症、高胰岛素血症、脂蛋白畸变、肝脏炎症、脂肪组织炎症、脂肪肝疾病、非酒精性脂肪肝疾病、高胆固醇血症、冠心病、充血性心力衰竭、中风、外周血管疾病、动脉粥样硬化、动脉硬化、肥胖症、肾石病、肾脏疾病、糖尿病视网膜病变、胰岛素抵抗、高胰岛素血症、高血压、肝脂肪变性、脂肪肝、非酒精性脂肪性肝病、多囊卵巢综合征、黑棘皮病、内分泌异常、神经退行性疾病或阿尔茨海默氏症等疾病或病况。
扎托布洛芬(10，11-二氢-α-甲基-10-氧代-二苯并[b，f硫卓-2-乙酸，Zaltoprofen)，具有如下式(I)所示的结构。扎托布洛芬是一种强效的苯丙酸类非甾体镇痛抗炎药。扎托布洛芬是外消旋体，含有S型光学异构体(S-)和R型光学异构体(R-)两种光学异构体。本文中，扎托布洛芬的代号为JKT，其外消旋体形式以RS-JKT表示，S型光学异构体以S-JKT 表示，R型光学异构体以R-JKT表示。
本文所用的术语“治疗”包括受试者患有具体疾病、障碍或病症时所发生的作用，它能降低疾病、障碍或病症的严重程度，或延迟或减缓疾病、障碍或病症的发展(“治疗性治疗”)，还包括在受试者开始患有具体疾病、障碍或病症之前发生的作用(“预防性治疗”)。
本文使用的术语“药学上可接受的”是指用于药物的载体、稀释剂、和/或赋形剂必须与制剂的其他组分相容，对接受者无害。
本文使用的术语“药学上可接受的载体”是指任何形式的无毒惰性固体、半固体、稀释剂、包封材料或制剂辅剂。可以作为药学上可接受的载体的材料的一些实施例是糖，如乳糖、葡萄糖和蔗糖；淀粉如玉米淀粉和土豆淀粉；纤维素和它的衍生物如羧甲基纤维素钠、乙基纤维素和醋酸纤维素；麦芽；明胶和其他无毒相容润滑剂如月桂基磺酸钠和硬脂酸镁；以及着色剂；释放剂；涂层剂；甜味剂；调味剂和香料；防腐剂和抗氧化剂，也可以根据制剂师的判断用于药物内。
本文使用的术语“受试者”包括但不限于：人(即，任何年龄组的男性或女性，例如，儿科受试者(例如，婴儿、儿童、青少年)或成人受试者(例如，年轻的成人、中年的成人或年长的成人))和/或非人的动物，例如，哺乳动物，如灵长类(例如，食蟹猴、恒河猴)、牛、猪、马、绵羊、山羊、啮齿动物、猫和/或狗。在一些实施方案中，受试者是人。在一些实施方案中，受试者是非人动物。本文可互换使用术语“人”、“患者”和“受试者”。
本文使用的术语“有效量”是指足以引起目标生物反应的数量。正如本领域普通技术人员所理解的那样，本发明药物的有效量可以根据下列因素而改变：例如，生物学目标、药物的药代动力学、所治疗的疾病、给药模式以及受试者的年龄健康情况和症状。有效量包括治疗有效量和预防有效量。
本文使用的术语“治疗有效量”是在治疗疾病、障碍或病症的过程中足以提供治疗益处的量，或使与疾病、障碍或病症有关的一或多种症状延迟或最小化的量。药物的治疗有效量是指单独使用或与其它疗法联用时，治疗剂的量，它在治疗疾病、障碍或病症的过程中提供治疗益处。术语“治疗有效量”可以包括改善总体治疗、降低或避免疾病或病症的症状或病因、或增强其它治疗剂的治疗效果的量。
本发明药物的有效量通常在平均日剂量为0.01mg至100mg药物/kg患者体重，优选 0.1mg至50mg药物/kg患者体重，进一步优选0.5mg至30mg药物/kg患者体重以单次或多次给药。通常，本发明药物可向该有此治疗需要的患者以每位患者约0.1mg/kg至约50mg/kg的日剂量范围给药，优选0.5mg/kg至30mg/kg。例如，每位患者的日剂量可为约0.1mg/kg、约0.5mg/kg、约1mg/kg、约2.5mg/kg、约5mg/kg、约7.5mg/kg、约10mg/kg、约11mg/kg、约12mg/kg、约13mg/kg、约14mg/kg、约15mg/kg、约16mg/kg、约17mg/kg、约18mg/kg、约19mg/kg、约20mg/kg、约21mg/kg、约22mg/kg、约23mg/kg、约24mg/kg、约25mg/kg、约26mg/kg、约27mg/kg、约28mg/kg、约29mg/kg、约30mg/kg、约35mg/kg、约40mg/kg、约45mg/kg、约50mg/kg的日剂量。可每天、每周(或间隔数天)或以间歇时间表，给药一次或多次。例如，可在每周的基础上(例如每周一)，每天给予所述药物一次或多次，不定地或持续几周，例如4-10周。或者，可每天给药持续几天(例如2-10天)，然后几天(例如1-30天)不给药所述药物，不定地重复该循环或重复给定的次数，例如4-10个循环。例如，本发明药物可每天给药持续5天，然后间断9天，然后再每天给药持续5天，然后间断9天，以此类推，不定地重复该循环或共重复4-10次。还可以长期给予本文所提供的药物(“长期给药”)。长期给药是指在长时间内给予药物，例如，3个月、6个月、1年、2年、3年、5年等等，或者可无限期地持续给药，例如，受试者的余生。在一些实施方案中，长期给药意欲在长时间内在血液中提供所述药物的恒定水平，例如，在治疗窗内。
本文使用的术语“预防有效量”是足以预防疾病、障碍或病症的量，或足以预防与疾病、障碍或病症有关的一或多种症状的量，或防止疾病、障碍或病症复发的量。药物的预防有效量是指单独使用或与其它药剂联用时，治疗剂的量，它在预防疾病、障碍或病症的过程中提供预防益处。术语“预防有效量”可以包括改善总体预防的量，或增强其它预防药剂的预防效果的量。
通常，施用有效量的本文所提供的药物。按照有关情况，包括所治疗的病症、选择的给药途径、实际给予的药物、个体患者的年龄、体重和响应、患者症状的严重程度，等等，可以由医生确定实际上给予的药物的量。
当用于预防本发明所述病症时，给予处于形成所述病症危险之中的受试者本文所提供的药物，典型地基于医生的建议并在医生监督下给药，剂量水平如上所述。处于形成具体病症的危险之中的受试者，通常包括具有所述病症的家族史的受试者，或通过遗传试验或筛选确定尤其对形成所述病症敏感的那些受试者。
本发明提供的药物可以通过许多途径给药，包括但不限于：口服给药、肠胃外给药、吸入给药、局部给药、直肠给药、鼻腔给药、口腔给药、通过植入剂给药或其它给药方式。例如，本文使用的肠胃外给药包括皮下给药、皮内给药、静脉内给药、肌肉内给药、关节内给 药、动脉内给药、滑膜腔内给药、胸骨内给药或输液技术等。
例如，在一些实施方案中，可以推注给药药物，例如，为了使药物在血液中的浓度提高至有效水平。推注剂量取决于通过身体的活性组分的目标全身性水平，例如，肌内或皮下的推注剂量使活性组分缓慢释放，而直接递送至静脉的推注(例如，通过IV静脉滴注)能够更加快速地递送，使得活性组分在血液中的浓度快速升高至有效水平。在其它实施方案中，可以以持续输液形式给予药物，例如，通过IV静脉滴注，从而在受试者身体中提供稳态浓度的活性组分。此外，在其它实施方案中，可以首先给予推注剂量的药物，而后持续输液。
例如，在另一些实施方案中，口服药物可以采用散装液体溶液或混悬剂或散装粉剂形式。然而，更通常，为了便于精确地剂量给药，以单位剂量形式提供所述药物。术语“单位剂型”是指适合作为人类患者及其它哺乳动物的单元剂量的物理离散单位，每个单位包含预定数量的、适于产生所需要的治疗效果的活性物质与合适药学赋形剂。典型的单位剂量形式包括液体剂型的预装填的、预先测量的安瓿或注射器，或者在固体剂型情况下的丸剂、片剂、胶囊剂等。在这种剂型中，所述药物通常为较少的组分(约0.1至约50重量％，或优选约1至约40重量％)，剩余部分为对于形成所需给药形式有用的各种载体或赋形剂以及加工助剂。
适于口服给药的液体形式可包括合适的水性或非水载体以及缓冲剂、悬浮剂和分散剂、着色剂、调味剂，等等。固体形式可包括，例如，任何下列组分，或具有类似性质的药物：粘合剂，例如，微晶纤维素、黄蓍胶或明胶；赋形剂，例如，淀粉或乳糖；崩解剂，例如，褐藻酸、羧甲淀粉钠或玉米淀粉；润滑剂，例如，硬脂酸镁；助流剂，例如，胶体二氧化硅；甜味剂，例如，蔗糖或糖精；或调味剂，例如，薄荷、水杨酸甲酯或橙味调味剂；稳定剂，例如酒石酸、门冬氨酸、谷氨酸等。
可注射的剂型典型地基于可注射用的无菌盐水或磷酸盐缓冲盐水，或本领域中已知的其它可注射的赋形剂。如前所述，在这种剂型中，活性药物典型地为较少的组分，经常为约0.05至10％重量，剩余部分为可注射的赋形剂等。
典型地将透皮剂型配制为含有活性组分的局部软膏剂或乳膏剂。当配制为软膏剂时，活性组分典型地与石蜡或可与水混溶的软膏基质组合。或者，活性组分可与例如水包油型乳膏基质一起配制为乳膏剂。这种透皮制剂是本领域中公知的，且通常包括用于提升活性组分或制剂的稳定的皮肤渗透的其它组分。所有这种已知的透皮制剂和组分包括在本发明提供的范围内。
本发明药物还可通过经皮装置给予。因此，经皮给药可使用贮存器(reservoir)或多孔膜类型、或者多种固体基质的贴剂实现。
下面提供实施例和附图以帮助理解本发明。但应理解，这些实施例和附图仅用于说明本 发明，但不构成任何限制。本发明的实际保护范围在权利要求书中进行阐述。应理解，在不脱离本发明精神的情况下，可以进行任何修改和改变。
实施例
实验材料
1.受试药物
外消旋体JKT(RS-JKT)，纯度：99.3％；JKT S型光学异构体(S-JKT)，纯度99.4％；JKT R型光学异构体(R-JKT)，纯度：99.1％，均由合肥金科生物医药科技有限公司提供。
非布司他片(风定宁)，40mg×14片，杭州朱养心药业有限公司。
罗格列酮片(爱能)：4mg*7片*2板，成都恒瑞制药有限公司。
阿司匹林，S17061-100g，购自上海源叶生物科技有限公司。
布洛芬，S31057-5g，购自上海源叶生物科技有限公司。
双氯芬酸钠，H10960217，购自中国药大制药。
对乙酰氨基酚，H20010394，购自上海强生制药有限公司。
受试药物均采用0.3％羧甲基纤维素钠研磨配置成相应浓度的混悬液，供灌胃用。
2.动物及饲养
(1)种属、来源
雄性昆明小鼠，SPF级，体重为18～22g，购自河南斯克贝斯生物科技股份有限公司，生产许可证号：SCXK(豫)2020-0005。
雄性SD大鼠，SPF级，体重为180～220g，购自杭州医学院实验动物中心，生产许可证号：SCXK(浙)2019-0002。
C57小鼠，SPF级，雄性，5-6周龄，购自上海市计划生育科学研究所实验动物经营部，许可证号：SCXK(苏)2018-0006。
(4)KM雄性小鼠48只，SPF级，体重为18～22g，购自河南斯克贝斯生物科技股份有限公司，生产许可证号：SCXK(豫)2020-0005。
(2)饲养条件
雄性昆明小鼠和雄性SD大鼠饲养于中国药科大学动物中心(动物使用许可证号：SYXK(苏)2021-0011)。饲养实验室温度24±2℃；相对湿度40％～70％；每小时空气交换次数：10-15次/小时；光照周期：12(日)/12(夜)小时，每笼不超过5只。饲料为鼠全价颗粒饲料，购自江苏省协同医药生物工程有限责任公司，其质量符合GB14924.1-2010《实验动物配合饲料通用质量标准》。
C57小鼠均饲养于清洁级动物室中(动物使用许可证号：SYXK(苏)2021-0011)，实验室温度24±2℃，相对湿度60％～80％，每小时空气交换次数：10～15次/h，光照周期：12h(日)/12h(夜)。每笼不超过5只。饲料为鼠全价基础颗粒饲料。
高脂饲料(80％基础饲料，15％猪油，4％奶粉，1％胆固醇)。
饮水：饮用纯化水。
3.主要仪器
多功能超纯水系统，锐思捷水纯化技术有限公司Unique-R20；多用途高效离心机，BECKMAN COULTER 369003/Avanti J-E；电子分析天平，赛多力斯科学仪器有限公司BSA124S-CW；电热恒温鼓风干燥箱，上海一恒科学仪器有限公司CIMO DHG-9140A；Varioskan TM LUX多功能微孔板读数仪，Thermo Scientific；4/-20℃低温冷冻冰箱，合肥美菱股份有限公司BCD-551EPCX；微量台式高速离心机，Thermo Scientific 21R；KD-160型电子秤，东莞百利达健康器材有限公司；3-18k低温离心机，美国SIGMA公司；涡旋仪，Scientific Industries VORTEX-2GENIE。
4.主要试剂
氧嗪酸钾，北京索莱宝科技有限公司(P9770)；次黄嘌呤，上海阿拉丁生化科技股份有限公司(H301755)；尿酸钠(S30775)，上海源叶生物科技有限公司；链脲佐菌素(STZ)，A610130，生工生物工程(上海)股份有限公司；羧甲基纤维素钠，西陇科学股份有限公司。
尿酸(UA)测试盒(比色法)，南京建成生物工程研究所(C012-1)，葡萄糖(GLU)测定试剂盒(葡萄糖氧化酶法)，甘油三酯(TG)检测试剂盒，总胆固醇(TC)检测试剂盒，均购自南京建成生物工程研究所。
实施例1.扎托布洛芬(JKT)及其光学异构体对次黄嘌呤引起小鼠急性高尿酸血症的作用
1.1动物分组
小鼠适应饲养1周后，按体重随机分为8组，每组8只，分别为：
(1)模型组
(2)阳性药非布司他(10mg/kg)
(3)RS-JKT高剂量(20mg/kg)
(4)RS-JKT低剂量(10mg/kg)
(5)R-JKT高剂量(20mg/kg)
(6)R-JKT低剂量(10mg/kg)
(7)S-JKT高剂量(20mg/kg)
(8)S-JKT低剂量(10mg/kg)
1.2模型建立与给药
取过夜禁食小鼠(不禁水)，分别灌胃给予相应剂量的受试药物，给药体积均为10mL/kg，模型组灌胃同体积的0.3％羧甲基纤维素钠溶液。各组灌胃给药30min之后，均采用一次性腹腔注射次黄嘌呤1g/kg建立急性高尿酸动物模型，注射体积10mL/kg。
全部小鼠在次黄嘌呤注射前及注射后0.5、1、2、6h眼眶采血，血样静置1h后并于3500rpm离心15min分离血清，采用尿酸试剂盒检测各组血清中的尿酸浓度。
1.3检测指标
采用试剂盒检测各组不同时间点的血清尿酸(SUA)水平，根据尿酸水平的时间变化情况绘制尿酸浓度-时间曲线并计算各组尿酸浓度-时间曲线的曲线下面积(AUC)。以各组AUC均值计算各个药物对高尿酸血症的抑制率(％)
药物对高尿酸血症的抑制率(％)＝(AUC模型组-AUC药物组)/AUC模型组×100％。
1.4数据处理及统计方法
数据均以平均值±标准差(M±SD)表示，组间比较采用GraphPad Prism 6软件进行ANOVA分析考察显著性，以P＜0.05作为显著性标准。
1.5结果
如图1所示，各组小鼠基础血清尿酸水平接近，模型组小鼠腹腔注射次黄嘌呤后，血清尿酸水平快速升高，1h达到峰值，随后开始下降，造模6h后基本降至造模前基础值。与模型组相比，各受试药物均可不同程度抑制次黄嘌呤引起的小鼠血清尿酸升高，使得血清尿酸浓度时间曲线压低。
各组血清尿酸浓度-时间曲线下面积(AUC)如图2所示，可见各受试药物均能显著降低模型小鼠AUC值；各组AUC抑制率的结果如图3所示，可见按AUC抑制率计，相同剂量受试物降尿酸作用强度依次为：R-JKT>RS-JKT>S-JKT。
实施例2.JKT及其光学异构体对次黄嘌呤+氧嗪酸钾引起小鼠慢性高尿酸血症的作用
2.1模型建立
小鼠购入适应性饲养1周，采用灌胃次黄嘌呤300mg/kg联合腹腔注射氧嗪酸钾300mg/kg建立慢性高尿酸动物模型，正常组采取灌胃联合腹腔注射相应体积生理盐水作为对照。造模两周后对正常组、模型组进行血尿酸水平的检测。从模型组中选取高于正常组尿酸均值30％的小鼠，按照尿酸水平进行随机分组。
2.2分组与给药
取血尿酸升高造模成功小鼠，分为以下9组，每组8只：
(1)正常组
(2)模型组
(3)阳性药非布司他(10mg/kg)
(4)RS-JKT高剂量(10mg/kg)
(5)RS-JKT低剂量(5mg/kg)
(6)R-JKT高剂量(10mg/kg)
(7)R-JKT低剂量(5mg/kg)
(8)S-JKT高剂量(10mg/kg)
(9)S-JKT低剂量(5mg/kg)
各组每日灌胃给药1次，连续给药3周，给药体积10mL/kg，正常组和模型组灌胃等体积0.3％羧甲基纤维素钠。
2.3检测指标
分别于给药的1、2、3周，取过夜禁食小鼠(不禁水)，于当天给药前眼眶采血，血样静置1h后并于3500rpm离心15min分离血清，采用尿酸试剂盒检测各组空腹血清中的尿酸浓度。
2.4数据处理及统计方法
数据均以平均值±标准差(M±SD)表示，组间比较采用GraphPad Prism 6软件进行ANOVA分析考察显著性，以P＜0.05作为显著性标准。
2.5结果
各组血清尿酸浓度结果如图4A-4C所示。在3周给药期间，模型组小鼠血清尿酸水平维持稳定且显著高于正常组(P＜0.01)。给药1周后，各受试药物均可明显降低模型小鼠血清尿酸浓度，且随着给药时间延长降尿酸幅度进一步增加。
根据给药1、2、3周时各组的尿酸浓度分别计算对高尿酸血症的抑制率[＝(模型组尿酸浓度-药物组尿酸浓度)/模型组尿酸浓度×100％]，结果如图5所示，可见相同剂量下降尿酸作用强度依次为：R-JKT>RS-JKT>S-JKT，这与急性模型药效结果保持一致。
实施例3.JKT及其光学异构体对慢性高尿酸血症模型伴随的糖脂代谢紊乱改善作用
3.1模型建立
小鼠购入适应性饲养1周，采用灌胃次黄嘌呤300mg/kg联合腹腔注射氧嗪酸钾300mg/kg建立慢性高尿酸动物模型，正常组采取灌胃联合腹腔注射相应体积生理盐水作为对照。造模两周后对正常组、模型组进行血尿酸水平的检测。从模型组中选取高于正常组尿酸均值30％的小鼠，按照尿酸水平进行随机分组。
3.2分组与给药
取正常及血尿酸升高造模成功小鼠，分为以下10组，每组8只：
(1)正常组
(2)模型组
(3)阳性药非布司他(10mg/kg)
(4)阳性药罗格列酮(10mg/kg)
(5)RS-JKT高剂量(10mg/kg)
(6)RS-JKT低剂量(5mg/kg)
(7)R-JKT高剂量(10mg/kg)
(8)R-JKT低剂量(5mg/kg)
(9)S-JKT高剂量(10mg/kg)
(10)S-JKT低剂量(5mg/kg)
各组每日灌胃给药1次，连续给药3周，给药体积10ml/kg，正常组和模型组灌胃等体积0.3％羧甲基纤维素钠。
3.3检测指标
(1)尿酸检测
分别于给药前及给药3周，取过夜禁食小鼠(不禁水)，于当天给药前眼眶采血，血样静置1h后并于3500rpm离心15min分离血清，采用尿酸试剂盒检测各组空腹血清中的尿酸浓度。
(2)血糖、血脂及糖耐量检测
给药的第3周，取过夜禁食小鼠(不禁水)，于当天给药前眼眶采血作为基础血样(0h)；随后各组小鼠腹腔注射葡萄糖2.0g/kg，分别于葡萄糖注射后0.5、1和2h眼眶采血，血样静置1h后并于3500rpm离心15min分离血清。基础血样采用试剂盒检测GLU、TC和TG水平，余下3个时间点血样检测GLU水平。将4个时间点血糖水平绘制糖耐量曲线，求算曲线下面积(AUC)并进行各组比较。
3.4数据处理及统计方法
数据均以平均值±标准差(M±SD)表示，组间比较采用GraphPad Prism 6软件进行ANOVA分析考察显著性，以P＜0.05作为显著性标准。
3.5结果
(1)对血清尿酸水平的影响
各组血清尿酸水平结果如图6所示。给药3周后，非布司他及JKT各受试物组均可以显著降低模型小鼠血清尿酸浓度，而罗格列酮对模型小鼠血清尿酸浓度未见明显改善作用。
(2)对空腹血糖和糖耐量的影响
各组糖耐量血糖-时间曲线如图7A-7C所示，糖耐量血糖-时间曲线下面积(AUC)如图8所示。与正常小鼠相比，高尿酸血症模型小鼠空腹血糖和糖耐量曲线下面积均明显升高，表明该高尿酸血症模型同时出现了糖脂代谢紊乱。与模型组相比，非布司他对空腹血糖和糖耐量曲线下面积未见明显影响，而罗格列酮对模型小鼠空腹血糖和糖耐量曲线下面积均有明显降低作用。JKT各受试物组对模型小鼠空腹血糖和糖耐量曲线下面积也可见明显改善作用。
(3)对血脂水平的影响
各组血脂甘油三酯(TG)和总胆固醇(TC)水平结果如图9A-9B所示。与正常小鼠相比，高尿酸血症模型小鼠空腹甘油三酯水平(TC)有所升高，总胆固醇(TC)水平未见明显变化。与模型组小鼠相比，各受试药物对模型小鼠甘油三酯水平有所降低，总胆固醇(TC)水平未见明显影响。
实施例4.JKT及其光学异构体对尿酸钠引起大鼠痛风性关节炎的作用
4.1动物分组
SD大鼠购入饲养一周后，按体重随机分为以下8组，每组8只：
(1)模型组
(2)阳性药非布司他(10mg/kg)
(3)RS-JKT高剂量(10mg/kg)
(4)RS-JKT低剂量(5mg/kg)
(5)R-JKT高剂量(10mg/kg)
(6)R-JKT低剂量(5mg/kg)
(7)S-JKT高剂量(10mg/kg)
(8)S-JKT低剂量(5mg/kg)
4.2模型建立
取禁食过夜大鼠，灌胃给予受试药物，给药体积均为20mL/kg，模型组灌胃相同体积的0.3％羧甲基纤维素钠。灌胃受试药物30min后，用碘伏消毒大鼠右后肢踝关节，1mL注射器从右后脚的右踝关节外侧与胫骨呈45度角插入踝关节腔内，每只注射尿酸钠悬液0.2mL(25mg/mL)，拔出注射器，用棉签按压几秒，避免药液漏出。
4.3检测指标
采用排水法测定大鼠后足体积。尿酸钠注入后即测定1次，作为基础体积，随后测定致炎0.5、1、2、4和6h大鼠后足体积，观察肿胀达峰时间和消退时间，求算出各时间点肿胀度，进行抗炎作用评价。计算公式如下：
肿胀度(mL)＝(测定体积-基础体积)
4.4数据处理及统计方法
数据均以平均值±标准差(M±SD)表示，组间比较采用GraphPad Prism 6软件进行ANOVA分析考察显著性，以P＜0.05作为显著性标准。
4.5结果
结果如图10A-10C所示，踝关节注射尿酸钠可引起大鼠后足显著肿胀，在4h左右达到峰值。JKT及其光学异构体对尿酸钠引起大鼠痛风性关节炎的肿胀度具有显著抑制作用，而非布司他对关节肿胀未见影响。相同剂量下，各受试药物对尿酸钠所致关节炎抑制作用强度依次为：S-JKT≈RS-JKT>R-JKT。
实施例5.JKT及其光学异构体对2型糖尿病小鼠模型的改善作用
5.1模型建立
除正常对照组，其余小鼠均采用高脂饲料饲养。饲养3周后，腹腔注射链脲佐菌素(STZ 40mg/kg)，STZ注射72h后测定空腹血糖，选择血糖>11mmol/L的小鼠作为2型糖尿病进行试验(血糖未达标小鼠，追加注射STZ 40mg/kg)。给药治疗期间，模型小鼠继续采用高脂饲料饲养。
5.2分组与给药
取血糖升高造模成功小鼠，分为以下8组，每组8只：
(1)模型组
(2)阳性药罗格列酮(10mg/kg)
(3)RS-JKT高剂量(10mg/kg)
(4)RS-JKT低剂量(5mg/kg)
(5)R-JKT高剂量(10mg/kg)
(6)R-JKT低剂量(5mg/kg)
(7)S-JKT高剂量(10mg/kg)
(8)S-JKT低剂量(5mg/kg)
另设8只正常小鼠作为对照组。各组每日灌胃给药1次，连续给药4周，给药体积10ml/kg，正常组和模型组灌胃等体积0.3％羧甲基纤维素钠。
5.3指标测定
(1)一般状况
观察毛色、神态、精神等，记录动物死亡情况。
(2)体重
每周称1次体重，观察体重变化。
(3)空腹血糖及血脂
给药2、4周后，眼眶采血，分离血清检测血清葡萄糖、总胆固醇、甘油三酯水平。
(4)糖耐量测定
实验结束前5天，小鼠禁食12h，不禁水，注射葡萄糖(2.0g/kg)耐量试验，毛细管眼眶采血，3500转/min，离心10mim分离血清，采用葡萄糖试剂盒测定各组动物注射葡萄糖前及注射后0.5、1、2h血糖值，绘制葡萄糖耐量曲线计算曲线下面积(AUC)。
5.4结果
(1)一般状况
正常组小鼠试验期间外观和行为正常，摄食、饮水以及排便情况未见明显改变。模型组小鼠试验期间自发活动减少，毛色脏乱，多数动物出现多饮、多食、多尿症状。试验期间各组动物无死亡。
(2)体重
各组体重结果如图11A-11C所示。正常组小鼠试验期间体重正常增长，模型组试验期间体重未见增长，符合糖尿病体重下降症状。受试药物各组对模型小鼠体重未见明显影响。
(3)空腹血糖及血脂
各组血糖水平结果如图12A-12C所示。与正常组相比，试验期间模型组空腹血糖水平明显升高，样品RS-JKT、S-JKT干预4周的空腹血糖明显低于模型组；R-JKT有降低血糖趋势，但改善作用不显著。
各组血清甘油三脂水平结果如图13所示。与正常组相比，模型组血清甘油三脂水平明 显升高，样品RS-JKT干预4周可明显降低模型小鼠血清甘油三酯水平；S-JKT和R-JKT有降低血清甘油三酯趋势，但改善作用不显著。
各组血清胆固醇水平结果如图14所示。与正常组相比，模型组餐后血清胆固醇水平明显升高，样品RS-JKT干预4周可明显降低模型小鼠血清胆固醇水平；S-JKT和R-JKT有降低血清胆固醇趋势，但改善作用不显著。
(4)糖耐量测定
各组糖耐量水平的结果如图15A-15C所示，糖耐量血糖-时间曲线下面积(AUC)的结果如图16所示。与正常组相比，糖尿病模型组口服葡萄糖后血糖水平明显升高，糖耐量曲线下面积显著增加，表现为糖耐量受损；样品RS-JKT、S-JKT、R-JKT均能明显改善糖尿病小鼠的糖耐量曲线，其中RS-JKT改善作用尤为明显。
由以上实施例可以发现，在次黄嘌呤诱导的小鼠急性高尿酸血症模型中，JKT及其光学异构体可不同程度抑制次黄嘌呤引起的小鼠血清尿酸升高，使得血清尿酸浓度时间曲线压低。这一结果提示JKT及其光学异构体对于尿酸生成具有潜在的抑制作用，相同剂量受试物降尿酸作用强度依次为：非布司他>R-JKT>RS-JKT>S-JKT。本模型中非布司他的急性降尿酸作用明显强于JKT及其光学异构体。
在次黄嘌呤联合氧嗪酸钾造模的小鼠慢性高尿酸血症模型中，JKT及其光学异构体均可明显降低模型小鼠血清尿酸浓度，且随着给药时间延长降尿酸幅度进一步增加，相同剂量下降尿酸作用强度依次为：非布司他>R-JKT>RS-JKT>S-JKT。本模型中，尽管非布司他的慢性降尿酸作用仍然强于JKT及其光学异构体，但药效强度的差距相较于急性模型明显缩小，尤其是R-JKT降尿酸幅度已经接近相同剂量的非布司他。
在次黄嘌呤联合氧嗪酸钾造模的慢性高尿酸血症模型伴随的糖脂代谢紊乱模型中，JKT及其光学异构体对小鼠空腹血糖和糖耐量曲线下面积均可见明显改善作用，其中RS-JKT作用相对较强。JKT及其光学异构体对小鼠空腹空腹甘油三酯水平有所降低。
JKT及其光学异构体对尿酸钠引起大鼠痛风性关节炎的肿胀度具有显著抑制作用，而非布司他对关节肿胀未见影响。相同剂量下，各受试药物对尿酸钠所致关节炎抑制作用强度依次为：S-JKT≈RS-JKT>R-JKT。
在高脂饲料联合链脲佐菌素诱发的2型糖尿病模型中，JKT及其光学异构体对小鼠体重未见明显影响。JKT及其光学异构体可明显降低小鼠的空腹血糖水平，RS-JKT和S-JKT能够明显降低空腹血糖水平；R-JKT有降低血糖趋势，但改善作用不显著。JKT及其光学异构 体能够降低小鼠的血清甘油三脂水平，RS-JKT可明显降低模型小鼠血清甘油三酯水平；S-JKT和R-JKT有降低血清甘油三酯趋势，但改善作用不显著。JKT及其光学异构体明显降低小鼠的血清胆固醇水平，RS-JKT可明显降低小鼠血清胆固醇水平；S-JKT和R-JKT有降低血清胆固醇趋势，但改善作用不显著。RS-JKT、S-JKT和R-JKT均能明显改善糖尿病小鼠的糖耐量曲线，其中RS-JKT改善作用尤为明显。
综上可见，对于急性和慢性高尿酸血症模型，JKT及其光学异构体均具有明显的降低尿酸作用，对于尿酸钠引起大鼠痛风性关节炎也具有明显的抗炎消肿作用，对于慢性高尿酸血症模型伴随的糖脂代谢紊乱具有明显的降血糖作用，对于高脂饲料联合链脲佐菌素诱发的2型糖尿病具有明显的降血糖降血脂作用。扎托布洛芬作为非甾体抗炎镇痛药已在临床用途多年，本发明创造性地发现其在高尿酸血症、痛风、糖脂代谢紊乱以及糖尿病等代谢紊乱疾病的治疗中也具有显著的用途价值。
实施例6五种非甾体抗炎药抗高尿酸血症的药效学对比
6.1小鼠分组及给药处理
KM雄性小鼠饲养在一个12小时光-暗循环的屏障级别房间里，自由获得标准的饮食和清洁的饮用水。动物房温度控制在25±2℃，相对湿度控制在30～70％。适应后根据小鼠体重进行随机分组，共计6组，每组8只，分别为模型对照组、RS-JKT组、阿司匹林组、布洛芬组、双氯芬酸钠组、对乙酰氨基酚组，共计48只。模型组、各给药组均采用普通饲料喂养。于急性实验当天各组采用腹腔注射次黄嘌呤1g/kg建立急性高尿酸血症小鼠模型，注射体积为10ml/kg。次黄嘌呤及各非甾体受试药均混悬分散于0.5％的CMC-Na溶液中。各非甾体抗炎药剂量参考临床成人用药剂量进行折算详情见下表1。
表1不同非甾体抗炎药剂量设置
6.2急性高尿酸血症下单次给予不同非甾体抗炎药的药效实验
小鼠适应饲养5天，禁食12h后采用毛细管眼眶采血方式获得空腹血样，于空腹血样采集完毕后各组灌胃相应受试药(RS-JKT-20mg/kg、阿司匹林-250mg/kg、布洛芬-150mg/kg、双氯芬酸钠-20mg/kg、对乙酰氨基酚-250mg/kg)，同时模型组灌胃生理盐水，灌胃体积均为10ml/kg。各组于灌胃30min后腹腔注射次黄嘌呤溶液，注射体积为10ml/kg。于各组结束腹腔注射次黄嘌呤溶液后30、60、120、360min进行毛细管眼眶采血。血样静置后，于3500rpm离心15min，得到血清，按尿酸试剂盒说明书进行血尿酸水平检测。
6.3.单次给予不同非甾体抗炎药对急性高尿酸血症小鼠血尿酸水平变化的影响
结果如图17所示，模型组在注射次黄嘌呤后血尿酸水平在60min达峰。5种受试的非甾体抗炎药物，对于模型小鼠血清尿酸水平的影响表现出较大的差异。与模型组相比，RS-JKT可显著降低造模1、2小时血尿酸水平(P<0.05，P<0.01)，表现为明显抑制尿酸生成作用。布洛芬、双氯芬酸钠和对乙酰氨基酚对不同时间血尿酸水平有升高或降低作用，但变化较小，作用不明显。阿司匹林组造模后各时间点血尿酸水平高于模型组，其中2、6小时具有统计学显著差异(P<0.05，P<0.01)，表明阿司匹林具有明确的升高血尿酸作用。
由此可见，虽然同为非甾体抗炎药，具有相近的抗炎镇痛作用机制，但RS-JKT具有明显的降尿酸作用，而布洛芬、双氯芬酸钠、对乙酰氨基酚和阿司匹林等非甾体抗炎药物则未见降尿酸作用。此结果提示，RS-JKT发挥降尿酸的作用可能并不依赖于其非甾体抗炎药的药理途径，而是某种新的药效机制。
本发明的技术方案不限于上述具体实施例的限制，凡是根据本发明的技术方案做出的技术变形，均落入本发明的保护范围之内。

Claims (15)

  1. 扎托布洛芬或其药学上可接受的盐在制备用于治疗和/或预防代谢紊乱的药物中的用途。
  2. 根据权利要求1所述的用途，其特征在于，所述扎托布洛芬或其药学上可接受的盐包括扎托布洛芬或其药学上可接受的盐的外消旋体、S型光学异构体或R型光学异构体中的至少一种。
  3. 根据权利要求1所述的用途，其特征在于，所述代谢紊乱包括尿酸代谢紊乱、血糖代谢紊乱或血脂代谢紊乱中的至少一种。
  4. 根据权利要求1所述的用途，其特征在于，所述代谢紊乱包括高尿酸血症、痛风、糖尿病、代谢综合征、高血糖症、高脂血症、高甘油三酯血症、高胰岛素血症、脂蛋白畸变、肝脏炎症、脂肪组织炎症、脂肪肝疾病、非酒精性脂肪肝疾病、高胆固醇血症、冠心病、充血性心力衰竭、中风、外周血管疾病、动脉粥样硬化、动脉硬化、肥胖症、肾石病、肾脏疾病、糖尿病视网膜病变、胰岛素抵抗、高胰岛素血症、高血压、肝脂肪变性、脂肪肝、非酒精性脂肪性肝病、多囊卵巢综合征、黑棘皮病、内分泌异常、神经退行性疾病或阿尔茨海默氏症中的至少一种；
    优选地，所述代谢紊乱包括急性高尿酸血症、慢性高尿酸血症、尿酸所致的痛风性关节炎、慢性高尿酸血症模型伴随的糖脂代谢紊乱或2型糖尿病中的至少一种。
  5. 根据权利要求1所述的用途，其特征在于，所述药物能降低血尿酸、血糖、糖耐量、胆固醇和甘油三脂中的至少一种。
  6. 扎托布洛芬或其药学上可接受的盐的外消旋体或R型光学异构体在制备用于治疗和/或预防尿酸代谢紊乱的药物中的用途。
  7. 扎托布洛芬或其药学上可接受的盐的外消旋体或S型光学异构体在制备用于治疗和/或预防血糖代谢紊乱和/或血脂代谢紊乱的药物中的用途。
  8. 根据权利要求1-7任一项的用途，其特征在于，所述药物还包括药学上可接受的载体，
    优选地，所述药物的剂型包括片剂、胶囊剂、颗粒剂、口服溶液、水针剂、粉针剂、冻干粉针剂、喷雾剂、栓剂或滴丸。
  9. 根据权利要求1-7任一项的用途，其特征在于，所述药物的给药途径包括口服给药、注射给药、静脉滴注给药、舌下给药、喷雾吸入或直肠给药。
  10. 降低受试者尿酸、血糖和/或血脂水平的方法，所述方法包括向有需要的受试者施用 有效量的扎托布洛芬或其药学上可接受的盐。
  11. 根据权利要求10所述的方法，其特征在于，所述扎托布洛芬或其药学上可接受的盐包括扎托布洛芬或其药学上可接受的盐的外消旋体、S型光学异构体或R型光学异构体中的至少一种，
    优选地，所述方法包括向有需要的受试者施用有效量的扎托布洛芬或其药学上可接受的盐的外消旋体或R型光学异构体用于降低受试者的尿酸水平；
    优选地，所述方法包括向有需要的受试者施用有效量的扎托布洛芬或其药学上可接受的盐的外消旋体或S型光学异构体用于降低受试者的血糖和/或血脂水平。
  12. 预防或治疗代谢紊乱的方法，所述方法包括向有需要的受试者施用有效量的扎托布洛芬或其药学上可接受的盐。
  13. 根据权利要求12所述的方法，其特征在于，所述扎托布洛芬或其药学上可接受的盐包括扎托布洛芬或其药学上可接受的盐的外消旋体、S型光学异构体或R型光学异构体中的至少一种。
  14. 根据权利要求12所述的方法，其特征在于，所述代谢紊乱包括尿酸代谢紊乱、血糖代谢紊乱或血脂代谢紊乱中的至少一种；
    优选地，所述代谢紊乱包括高尿酸血症、痛风、糖尿病、代谢综合征、高血糖症、高脂血症、高甘油三酯血症、高胰岛素血症、脂蛋白畸变、肝脏炎症、脂肪组织炎症、脂肪肝疾病、非酒精性脂肪肝疾病、高胆固醇血症、冠心病、充血性心力衰竭、中风、外周血管疾病、动脉粥样硬化、动脉硬化、肥胖症、肾石病、肾脏疾病、糖尿病视网膜病变、胰岛素抵抗、高胰岛素血症、高血压、肝脂肪变性、脂肪肝、非酒精性脂肪性肝病、多囊卵巢综合征、黑棘皮病、内分泌异常、神经退行性疾病或阿尔茨海默氏症中的至少一种；
    更优选地，所述代谢紊乱包括急性高尿酸血症、慢性高尿酸血症、尿酸所致的痛风性关节炎、慢性高尿酸血症模型伴随的糖脂代谢紊乱或2型糖尿病中的至少一种。
  15. 根据权利要求10-14中任一项所述的方法，其特征在于，所述方法包括向有需要的受试者施用0.01-100mg/kg剂量，优选为0.1-50mg/kg剂量，进一步优选为0.5～30mg/kg剂量的扎托布洛芬或其药学上可接受的盐。
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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002036111A1 (en) * 2000-10-31 2002-05-10 Pabianickie Zaklady Farmaceutyczne Polfa New use of 2-(4-isobutylphenyl)propionic acid
JP2008031164A (ja) * 2006-07-07 2008-02-14 Daiichi Sankyo Healthcare Co Ltd 高尿酸血症又はこれに起因する疾患の予防又は治療のための医薬組成物
JP2008208091A (ja) * 2007-02-27 2008-09-11 Hiroshima Univ 小胞体ストレス関連疾患の治療薬および予防薬
CN101416961A (zh) * 2008-11-21 2009-04-29 合肥金科生物医药科技有限公司 一种苯丙酸类药物光学异构体及其医药用途
US20200093768A1 (en) * 2018-09-23 2020-03-26 Huanggang normal university Method for treating diabetes
CN115916808A (zh) * 2020-05-11 2023-04-04 燃脂医药股份有限公司 用于诱导褐色脂肪生成的方法和组合物
CN117771238A (zh) * 2023-11-08 2024-03-29 合肥金科生物医药科技有限公司 苯丙酸类似物在治疗或预防代谢紊乱中的用途

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002036111A1 (en) * 2000-10-31 2002-05-10 Pabianickie Zaklady Farmaceutyczne Polfa New use of 2-(4-isobutylphenyl)propionic acid
JP2008031164A (ja) * 2006-07-07 2008-02-14 Daiichi Sankyo Healthcare Co Ltd 高尿酸血症又はこれに起因する疾患の予防又は治療のための医薬組成物
JP2008208091A (ja) * 2007-02-27 2008-09-11 Hiroshima Univ 小胞体ストレス関連疾患の治療薬および予防薬
CN101416961A (zh) * 2008-11-21 2009-04-29 合肥金科生物医药科技有限公司 一种苯丙酸类药物光学异构体及其医药用途
US20200093768A1 (en) * 2018-09-23 2020-03-26 Huanggang normal university Method for treating diabetes
CN115916808A (zh) * 2020-05-11 2023-04-04 燃脂医药股份有限公司 用于诱导褐色脂肪生成的方法和组合物
CN117771238A (zh) * 2023-11-08 2024-03-29 合肥金科生物医药科技有限公司 苯丙酸类似物在治疗或预防代谢紊乱中的用途

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHU VAN MEN, KIM KYUNG TAE, KIM SANG HUYCK, LEE WONJAE, LEE KI CHEUL, NGUYEN VAN LONG, HOANG VAN LUONG, LEE YOUNG KEUN, PARK KYUNG: "Chiral pharmacokinetics of zaltoprofen in rats by HPLC with solid-phase extraction", JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, ELSEVIER B.V., AMSTERDAM, NL, vol. 70, 1 November 2012 (2012-11-01), AMSTERDAM, NL , pages 567 - 573, XP093314475, ISSN: 0731-7085, DOI: 10.1016/j.jpba.2012.05.019 *

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