WO2022117004A1 - 间质性肺炎的治疗方法 - Google Patents
间质性肺炎的治疗方法 Download PDFInfo
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- WO2022117004A1 WO2022117004A1 PCT/CN2021/134828 CN2021134828W WO2022117004A1 WO 2022117004 A1 WO2022117004 A1 WO 2022117004A1 CN 2021134828 W CN2021134828 W CN 2021134828W WO 2022117004 A1 WO2022117004 A1 WO 2022117004A1
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- medicament
- hydroxyprogesterone caproate
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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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
Definitions
- the present application provides methods for treating interstitial pneumonia with hydroxyprogesterone caproate alone or in combination with other drugs, as well as corresponding pharmaceutical uses, pharmaceutical compositions, and the like.
- Interstitial lung disease refers to a group of heterogeneous diseases characterized by the disorder of cells in the alveolar structure and the matrix in the connective tissue.
- the main clinical symptoms include dyspnea, hypoxia, carbon monoxide.
- the amount of dispersion (DLCO) decreased, etc.
- ILD in a broad sense includes almost all diseases that occur in the pulmonary interstitium with different etiologies, pathogenesis and lesions. At present, there are nearly 200 known causes of ILD, including dust, infection, drugs, inhalation of special gases, etc., but there are still No specific etiology can be identified in more than 70% of ILD cases.
- Idiopathic interstitial pneumonia is a group of unexplained ILDs characterized by diffuse alveolitis and alveolar structural disorders that eventually lead to pulmonary fibrosis. According to the classification of the American Thoracic Society (ATS) and the European Respiratory Society (ERS) in 2002, IIP mainly includes the following seven subtypes: idiopathic pulmonary fibrosis (IPF), nonspecific interstitial pneumonia (NSIP), Organizing pneumonia of origin (COP), acute interstitial pneumonia (AIP), respiratory bronchiolitis with interstitial lung disease (RBILD), desquamative interstitial pneumonia (DIP) and lymphocytic interstitial Sexual Pneumonia (LIP).
- IPF idiopathic pulmonary fibrosis
- NSIP nonspecific interstitial pneumonia
- COP Organizing pneumonia of origin
- AIP acute interstitial pneumonia
- RILD respiratory bronchiolitis with interstitial lung disease
- DIP desquamative interstitial pneumonia
- LIP lympho
- IPF is the most common and most representative disease in IIP, and it has been reported that it accounts for more than 60% of the incidence of IIP. After the patient's disease, the pulmonary interstitium will continue to produce fibrosis, which will lead to the thickening of the lung tissue, resulting in an irreversible loss of the ability of the lung tissue to exchange oxygen. IPF is a fatal respiratory disease, and the average patient's survival time after diagnosis is only 2-3 years.
- the pathogenesis and pathogenesis of IIP and IPF are not fully elucidated.
- the persistence or recurrence of lung tissue damage will lead to dysregulation of cytokines, chemical factors and growth factors, abnormal angiogenesis, damage to the fibrinolytic system, reduction of extracellular matrix degradation and enhanced oxidative stress, etc.
- the microenvironment changes, thereby suppressing the host inflammatory response.
- changes in the alveolar microenvironment may also lead to dysregulation of repair and abnormal tissue remodeling, failure of re-epithelialization of alveolar epithelial cells, recruitment and activation of fibroblasts or myofibroblasts, and ultimately progressive fibrosis. Due to the unclear etiology, the current treatment methods for IIP are very limited.
- glucocorticoids and immunosuppressive drugs have been proved to be effective, and the therapeutic effect also depends on different IIP subtypes. Compared with other interstitial pneumonias, inflammation is mild in the pathogenesis of IPF, while fibrosis is dominant. Therefore, the therapeutic effects of glucocorticoids and immunosuppressive agents are very limited. In recent years, studies on abnormal fibroblast proliferation and function, abnormal alveolar epithelial cell apoptosis and TGF- ⁇ signaling pathway in the process of pulmonary fibrosis have also shown that high-dose glucocorticoids are not recommended for the treatment of IPF. Really effective treatment.
- Non-IPF IIP treatment strategies are different, such as COP, DIP and RBILD have a better response to glucocorticoids, and the prognosis is also different from IPF.
- LIP needs to be supplemented with certain immunosuppressants or even cytotoxic drugs to achieve better therapeutic effects. Therefore, the subtypes of glucocorticoid therapy for IIP should also be identified and treated differently.
- glucocorticoid drugs In addition to the unsatisfactory treatment effect of IIP, especially IFP, glucocorticoid drugs also have the following problems: 1) Drug resistance. Glucocorticoid resistance or insensitivity is a difficult-to-control problem in glucocorticoid-treated disease, manifested primarily by unresponsiveness to adequate doses of corticosteroids, or requiring very high doses of treatment, or response to corticosteroids There is an initial response, but the disease recurs rapidly when the drug is discontinued or the dose is tapered.
- glucocorticoid resistance Molecular mechanisms of glucocorticoid resistance include decreased glucocorticoid receptor expression, defective and translocation of glucocorticoid receptor binding, genetic susceptibility, activation of inflammatory signaling pathways, etc. Patients may therefore not be able to obtain effective glucocorticoid therapy. 2) Side effects. Due to the extensive pharmacological activities of glucocorticoids, long-term administration of large doses will inevitably cause side effects and complications, and even lead to death of patients in severe cases.
- Common clinical side effects include secondary infection, gastrointestinal symptoms such as gastric ulcer, cardiovascular system-related symptoms such as hypertension, edema, elevated blood sugar, Cushing-like syndrome such as central obesity, full moon face, neuropsychiatric symptoms such as Emotional changes such as excitement, insomnia, irritability, bone and joint complications such as osteoporosis, and eye diseases such as glaucoma and cataracts. Therefore, clinically, how to increase the sensitivity of glucocorticoid drugs, reduce the dosage of glucocorticoids and reduce their side effects is also an urgent problem to be solved.
- the present application provides the use of hydroxyprogesterone caproate in the preparation of a medicament for the treatment of interstitial pneumonia.
- hydroxyprogesterone caproate is the only active ingredient in the medicine.
- the present application provides the use of hydroxyprogesterone caproate and glucocorticoid in the preparation of a medicament for treating interstitial pneumonia.
- glucocorticoid is dexamethasone
- the pharmaceutical dosage form is an injection, an oral preparation or an external preparation; preferably an injection, an oral preparation; particularly preferably an injection.
- injections include injections and powders
- oral preparations include tablets, capsules, oral liquids, throat or nasal sprays
- external preparations include ointments, sprays, and patches.
- interstitial pneumonia includes reducing lung inflammation and fibrosis symptoms.
- said treating interstitial pneumonia comprises reducing pulmonary collagen deposition.
- the treatment of interstitial pneumonia comprises reducing the count of inflammatory cells in bronchoalveolar lavage fluid.
- said treating interstitial pneumonia comprises reducing the level of hydroxyproline in lung tissue.
- the treatment of interstitial pneumonia includes reducing the levels of various inflammatory factors in bronchoalveolar lavage fluid and plasma; preferably, the inflammatory factors include TNF- ⁇ , IL-1 ⁇ , IFN- ⁇ , IL-6, TGF- ⁇ 1, IL-4, MCP-1/CCL2.
- the inflammatory factors include TNF- ⁇ , IL-1 ⁇ , IFN- ⁇ , IL-6, TGF- ⁇ 1, IL-4, MCP-1/CCL2.
- the treatment of interstitial pneumonia comprises reducing the levels of various pro-fibrotic factors and inflammatory cytokines and type I collagen in bronchoalveolar lavage fluid and/or plasma, and/or increasing the level of anti-fibrotic factors; preferably
- the pro-fibrotic factors and inflammatory cytokines are TNF- ⁇ , IL-1 ⁇ , IL-6, MCP-1, PDGF, SMAD3, SMAD2, MMP9, MMP2, CXCL-12 and/or TGF- ⁇ 1
- the anti-fibrotic factor is IFN- ⁇ and/or IL-4; more preferably, the pro-fibrotic factor is TNF- ⁇ , IL-1 ⁇ , IL-6, PDGF, SMAD3, SMAD2, MMP2 and/or or TGF- ⁇ 1.
- abnormal lipid metabolism comprises increased levels of triglycerides and total cholesterol and/or decreased levels of leptin.
- the present application provides a method of treating interstitial pneumonia, characterized in that the method comprises administering hydroxyprogesterone caproate to a patient with interstitial pneumonia.
- the method does not include the step of administering a glucocorticoid.
- the method comprises the step of administering a glucocorticoid.
- glucocorticoid is dexamethasone
- the dosage form of hydroxyprogesterone caproate is injection, oral preparation or external preparation; preferably injection, oral preparation; particularly preferably injection.
- injections include injections and powders
- oral preparations include tablets, capsules, oral liquids, throat or nasal sprays
- external preparations include ointments, sprays, and patches.
- hydroxyprogesterone caproate is 30-100 mg/day, or 250-750 mg/week.
- hydroxyprogesterone caproate is 20-80 mg/kg; preferably 40-80 mg/kg; more preferably 40 or 80 mg/kg.
- hydroxyprogesterone caproate administration regimen is administered 1-7 times per week, preferably 1-4 times, more preferably 1-2 times.
- interstitial pneumonia includes reducing lung inflammation and fibrosis symptoms.
- said treating interstitial pneumonia comprises reducing pulmonary collagen deposition.
- the treatment of interstitial pneumonia comprises reducing the count of inflammatory cells in bronchoalveolar lavage fluid.
- said treating interstitial pneumonia comprises reducing the level of hydroxyproline in lung tissue.
- the treatment of interstitial pneumonia includes reducing the levels of various inflammatory factors in bronchoalveolar lavage fluid and plasma; preferably, the inflammatory factors include TNF- ⁇ , IL-1 ⁇ , IFN- ⁇ , IL-6, TGF- ⁇ 1, IL-4, MCP-1/CCL2.
- the inflammatory factors include TNF- ⁇ , IL-1 ⁇ , IFN- ⁇ , IL-6, TGF- ⁇ 1, IL-4, MCP-1/CCL2.
- the treatment of interstitial pneumonia comprises reducing the levels of various pro-fibrotic factors and inflammatory cytokines and type I collagen in bronchoalveolar lavage fluid and/or plasma, and/or increasing the level of anti-fibrotic factors; preferably
- the pro-fibrotic factors and inflammatory cytokines are TNF- ⁇ , IL-1 ⁇ , IL-6, MCP-1, PDGF, SMAD3, SMAD2, MMP9, MMP2, CXCL-12 and/or TGF- ⁇ 1
- the anti-fibrotic factor is IFN- ⁇ and/or IL-4; more preferably, the pro-fibrotic factor is TNF- ⁇ , IL-1 ⁇ , IL-6, PDGF, SMAD3, SMAD2, MMP2 and/or or TGF- ⁇ 1.
- abnormal lipid metabolism comprises increased levels of triglycerides and total cholesterol and/or decreased levels of leptin.
- the present application provides a medicament for treating interstitial pneumonia, characterized in that the medicament comprises hydroxyprogesterone caproate.
- hydroxyprogesterone caproate is the only active ingredient in the medicine.
- the medicament further comprises glucocorticoid.
- glucocorticoid is dexamethasone
- the pharmaceutical dosage form is an injection, an oral preparation or an external preparation; preferably an injection, an oral preparation; particularly preferably an injection.
- injections include injections and powders
- oral preparations include tablets, capsules, oral liquids, throat or nasal sprays
- external preparations include ointments, sprays, and patches.
- the medicament is used to reduce the symptoms of pulmonary inflammation and fibrosis.
- the medicament is used to reduce pulmonary collagen deposition.
- the drug is used to reduce the inflammatory cell count in bronchoalveolar lavage fluid.
- the medicament is used to reduce the level of hydroxyproline in lung tissue.
- the medicine is used to reduce the levels of various inflammatory factors in bronchoalveolar lavage fluid and plasma; preferably, the inflammatory factors include TNF- ⁇ , IL-1 ⁇ , IFN- ⁇ , IL-6, TGF- ⁇ 1 , IL-4, MCP-1/CCL2.
- the inflammatory factors include TNF- ⁇ , IL-1 ⁇ , IFN- ⁇ , IL-6, TGF- ⁇ 1 , IL-4, MCP-1/CCL2.
- the drug is used to reduce the levels of various pro-fibrotic factors and inflammatory cytokines and type I collagen in bronchoalveolar lavage fluid and/or plasma, and/or increase the level of anti-fibrotic factors;
- the Said pro-fibrotic factor and inflammatory cytokine are TNF- ⁇ , IL-1 ⁇ , IL-6, MCP-1, PDGF, SMAD3, SMAD2, MMP9, MMP2, CXCL-12 and/or TGF- ⁇ 1, said
- the anti-fibrotic factor is IFN- ⁇ and/or IL-4; more preferably, the pro-fibrotic factor is TNF- ⁇ , IL-1 ⁇ , IL-6, PDGF, SMAD3, SMAD2, MMP2 and/or TGF- ⁇ 1.
- abnormal lipid metabolism comprises increased levels of triglycerides and total cholesterol and/or decreased levels of leptin.
- the dosage of the drug hydroxyprogesterone caproate is 30-100 mg/day, or 250-750 mg/week, and/or the administration scheme of hydroxyprogesterone caproate is 1-7 times a week, preferably 1- 4 times, more preferably 1-2 times.
- the daily dose of the drug hydroxyprogesterone caproate is 20-80 mg/kg; preferably 40-80 mg/kg; more preferably 40 or 80 mg/kg.
- the present application provides the use of hydroxyprogesterone caproate in the preparation of a medicament for treating pulmonary fibrosis.
- hydroxyprogesterone caproate is the only active ingredient in the medicine.
- the present application provides the use of hydroxyprogesterone caproate and glucocorticoid in the preparation of a medicament for treating pulmonary fibrosis.
- glucocorticoid is dexamethasone
- the pharmaceutical dosage form is an injection, an oral preparation or an external preparation; preferably an injection, an oral preparation; particularly preferably an injection.
- injections include injections and powders
- oral preparations include tablets, capsules, oral liquids, throat or nasal sprays
- external preparations include ointments, sprays, and patches.
- treating pulmonary fibrosis comprises reducing pulmonary inflammation and fibrosis symptoms.
- said treating pulmonary fibrosis comprises reducing pulmonary collagen deposition.
- said treating pulmonary fibrosis comprises reducing inflammatory cell count in bronchoalveolar lavage fluid.
- said treating pulmonary fibrosis comprises reducing the level of hydroxyproline in lung tissue.
- the treatment of pulmonary fibrosis includes reducing the levels of various inflammatory factors in bronchoalveolar lavage fluid and plasma; preferably, the inflammatory factors include TNF- ⁇ , IL-1 ⁇ , IFN- ⁇ , IL-6, TGF - ⁇ 1, IL-4, MCP-1/CCL2.
- the inflammatory factors include TNF- ⁇ , IL-1 ⁇ , IFN- ⁇ , IL-6, TGF - ⁇ 1, IL-4, MCP-1/CCL2.
- the treatment of pulmonary fibrosis comprises reducing the levels of various pro-fibrotic factors and inflammatory cytokines and type I collagen in bronchoalveolar lavage fluid and/or plasma, and/or increasing the level of anti-fibrotic factors; preferably , the pro-fibrotic factor and inflammatory cytokine are TNF- ⁇ , IL-1 ⁇ , IL-6, MCP-1, PDGF, SMAD3, SMAD2, MMP9, MMP2, CXCL-12 and/or TGF- ⁇ 1,
- the anti-fibrotic factor is IFN- ⁇ and/or IL-4; more preferably, the pro-fibrotic factor is TNF- ⁇ , IL-1 ⁇ , IL-6, PDGF, SMAD3, SMAD2, MMP2 and/or TGF- ⁇ 1.
- abnormal lipid metabolism comprises increased levels of triglycerides and total cholesterol and/or decreased levels of leptin.
- the present application provides a method of treating pulmonary fibrosis, characterized in that the method comprises administering hydroxyprogesterone caproate to a patient with pulmonary fibrosis.
- the method does not include the step of administering a glucocorticoid.
- the method comprises the step of administering a glucocorticoid.
- glucocorticoid is dexamethasone
- the dosage form of hydroxyprogesterone caproate is injection, oral preparation or external preparation; preferably injection, oral preparation; particularly preferably injection.
- injections include injections and powders
- oral preparations include tablets, capsules, oral liquids, throat or nasal sprays
- external preparations include ointments, sprays, and patches.
- hydroxyprogesterone caproate is 30-100 mg/day, or 250-750 mg/week.
- hydroxyprogesterone caproate is 20-80 mg/kg; preferably 40-80 mg/kg; more preferably 40 or 80 mg/kg.
- hydroxyprogesterone caproate administration regimen is administered 1-7 times per week, preferably 1-4 times, more preferably 1-2 times.
- treating pulmonary fibrosis comprises reducing pulmonary inflammation and fibrosis symptoms.
- said treating pulmonary fibrosis comprises reducing pulmonary collagen deposition.
- said treating pulmonary fibrosis comprises reducing inflammatory cell count in bronchoalveolar lavage fluid.
- said treating pulmonary fibrosis comprises reducing the level of hydroxyproline in lung tissue.
- the treatment of pulmonary fibrosis includes reducing the levels of various inflammatory factors in bronchoalveolar lavage fluid and plasma; preferably, the inflammatory factors include TNF- ⁇ , IL-1 ⁇ , IFN- ⁇ , IL-6, TGF - ⁇ 1, IL-4, MCP-1/CCL2.
- the inflammatory factors include TNF- ⁇ , IL-1 ⁇ , IFN- ⁇ , IL-6, TGF - ⁇ 1, IL-4, MCP-1/CCL2.
- the treatment of pulmonary fibrosis comprises reducing the levels of various pro-fibrotic factors and inflammatory cytokines and type I collagen in bronchoalveolar lavage fluid and/or plasma, and/or increasing the level of anti-fibrotic factors; preferably , the pro-fibrotic factor and inflammatory cytokine are TNF- ⁇ , IL-1 ⁇ , IL-6, MCP-1, PDGF, SMAD3, SMAD2, MMP9, MMP2, CXCL-12 and/or TGF- ⁇ 1,
- the anti-fibrotic factor is IFN- ⁇ and/or IL-4; more preferably, the pro-fibrotic factor is TNF- ⁇ , IL-1 ⁇ , IL-6, PDGF, SMAD3, SMAD2, MMP2 and/or TGF- ⁇ 1.
- abnormal lipid metabolism comprises increased levels of triglycerides and total cholesterol and/or decreased levels of leptin.
- the present application provides a medicament for treating pulmonary fibrosis, characterized in that the medicament comprises hydroxyprogesterone caproate.
- hydroxyprogesterone caproate is the only active ingredient in the medicine.
- the medicament further comprises glucocorticoid.
- glucocorticoid is dexamethasone
- the pharmaceutical dosage form is an injection, an oral preparation or an external preparation; preferably an injection, an oral preparation; particularly preferably an injection.
- injections include injections and powders
- oral preparations include tablets, capsules, oral liquids, throat or nasal sprays
- external preparations include ointments, sprays, and patches.
- the medicament is used to reduce the symptoms of pulmonary inflammation and fibrosis.
- the medicament is used to reduce pulmonary collagen deposition.
- the drug is used to reduce the inflammatory cell count in bronchoalveolar lavage fluid.
- the medicament is used to reduce the level of hydroxyproline in lung tissue.
- the medicine is used to reduce the levels of various inflammatory factors in bronchoalveolar lavage fluid and plasma; preferably, the inflammatory factors include TNF- ⁇ , IL-1 ⁇ , IFN- ⁇ , IL-6, TGF- ⁇ 1 , IL-4, MCP-1/CCL2.
- the inflammatory factors include TNF- ⁇ , IL-1 ⁇ , IFN- ⁇ , IL-6, TGF- ⁇ 1 , IL-4, MCP-1/CCL2.
- the drug is used to reduce the levels of various pro-fibrotic factors and inflammatory cytokines and type I collagen in bronchoalveolar lavage fluid and/or plasma, and/or increase the level of anti-fibrotic factors;
- the Said pro-fibrotic factor and inflammatory cytokine are TNF- ⁇ , IL-1 ⁇ , IL-6, MCP-1, PDGF, SMAD3, SMAD2, MMP9, MMP2, CXCL-12 and/or TGF- ⁇ 1, said
- the anti-fibrotic factor is IFN- ⁇ and/or IL-4; more preferably, the pro-fibrotic factor is TNF- ⁇ , IL-1 ⁇ , IL-6, PDGF, SMAD3, SMAD2, MMP2 and/or TGF- ⁇ 1.
- abnormal lipid metabolism comprises increased levels of triglycerides and total cholesterol and/or decreased levels of leptin.
- the dosage of the drug hydroxyprogesterone caproate is 30-100 mg/day, or 250-750 mg/week, and/or the administration scheme of hydroxyprogesterone caproate is 1-7 times a week, preferably 1- 4 times, more preferably 1-2 times.
- the daily dose of the drug hydroxyprogesterone caproate is 20-80 mg/kg; preferably 40-80 mg/kg; more preferably 40 or 80 mg/kg.
- the application provides hydroxyprogesterone caproate, or a combination of hydroxyprogesterone caproate and a glucocorticoid in the preparation of inhibiting profibrotic and inflammatory cytokines, and/or collagen type I; and/or increasing Use in a medicament for anti-fibrotic factor levels; or as an inhibitor of pro-fibrotic factors and inflammatory cytokines, and/or as an inhibitor of type I collagen, and/or as an anti-fibrotic factor Application of accelerators.
- glucocorticoid is dexamethasone
- the inflammatory factors are TNF- ⁇ , IL-1 ⁇ , IFN- ⁇ , IL-6, TGF- ⁇ 1, IL-4 and/or MCP-1/CCL2.
- the pro-fibrotic factors and inflammatory cytokines are TNF- ⁇ , IL-1 ⁇ , IL-6, MCP-1, PDGF, SMAD3, SMAD2, MMP9, MMP2, CXCL-12 and/or TGF - ⁇ 1
- the anti-fibrotic factor is IFN- ⁇ and/or IL-4; more preferably, the pro-fibrotic factor is TNF- ⁇ , IL-1 ⁇ , IL-6, PDGF, SMAD3, SMAD2, MMP2 and/or TGF- ⁇ 1.
- the pharmaceutical dosage form is an injection, an oral preparation or an external preparation; preferably an injection, an oral preparation; particularly preferably an injection.
- injections include injections and powders
- oral preparations include tablets, capsules, oral liquids, throat or nasal sprays
- external preparations include ointments, sprays, and patches.
- the present application provides methods of inhibiting pro-fibrotic and inflammatory cytokines, and/or collagen type I; and/or increasing levels of anti-fibrotic factors, the methods comprising administering hydroxyprogesterone caproate.
- the method does not include the step of administering a glucocorticoid.
- the method comprises the step of administering a glucocorticoid.
- glucocorticoid is dexamethasone
- the inflammatory factors are TNF- ⁇ , IL-1 ⁇ , IFN- ⁇ , IL-6, TGF- ⁇ 1, IL-4 and/or MCP-1/CCL2.
- the pro-fibrotic factors and inflammatory cytokines are TNF- ⁇ , IL-1 ⁇ , IL-6, MCP-1, PDGF, SMAD3, SMAD2, MMP9, MMP2, CXCL-12 and/or TGF - ⁇ 1
- the anti-fibrotic factor is IFN- ⁇ and/or IL-4; more preferably, the pro-fibrotic factor is TNF- ⁇ , IL-1 ⁇ , IL-6, PDGF, SMAD3, SMAD2, MMP2 and/or TGF- ⁇ 1.
- the dosage form of hydroxyprogesterone caproate is injection, oral preparation or external preparation; preferably injection, oral preparation; particularly preferably injection.
- injections include injections and powders
- oral preparations include tablets, capsules, oral liquids, throat or nasal sprays
- external preparations include ointments, sprays, and patches.
- hydroxyprogesterone caproate is 30-100 mg/day, or 250-750 mg/week.
- hydroxyprogesterone caproate is 20-80 mg/kg; preferably 40-80 mg/kg; more preferably 40 or 80 mg/kg.
- hydroxyprogesterone caproate administration regimen is administered 1-7 times per week, preferably 1-4 times, more preferably 1-2 times.
- the present application provides a medicament for inhibiting pro-fibrotic factors and inflammatory cytokines, and/or collagen type I; and/or increasing the level of anti-fibrotic factors, characterized in that the medicament comprises caproic acid Hydroxyprogesterone.
- hydroxyprogesterone caproate is the only active ingredient in the medicine.
- the medicament further comprises glucocorticoid.
- glucocorticoid is dexamethasone
- the inflammatory factors are TNF- ⁇ , IL-1 ⁇ , IFN- ⁇ , IL-6, TGF- ⁇ 1, IL-4 and/or MCP-1/CCL2.
- the pro-fibrotic factors and inflammatory cytokines are TNF- ⁇ , IL-1 ⁇ , IL-6, MCP-1, PDGF, SMAD3, SMAD2, MMP9, MMP2, CXCL-12 and/or TGF - ⁇ 1
- the anti-fibrotic factor is IFN- ⁇ and/or IL-4; more preferably, the pro-fibrotic factor is TNF- ⁇ , IL-1 ⁇ , IL-6, PDGF, SMAD3, SMAD2, MMP2 and/or TGF- ⁇ 1.
- the pharmaceutical dosage form is an injection, an oral preparation or an external preparation; preferably an injection, an oral preparation; particularly preferably an injection.
- injections include injections and powders
- oral preparations include tablets, capsules, oral liquids, throat or nasal sprays
- external preparations include ointments, sprays, and patches.
- the dosage of the drug hydroxyprogesterone caproate is 30-100 mg/day, or 250-750 mg/week, and/or the administration scheme of hydroxyprogesterone caproate is 1-7 times a week, preferably 1- 4 times, more preferably 1-2 times.
- hydroxyprogesterone caproate is 20-80 mg/kg; preferably 40-80 mg/kg; more preferably 40 or 80 mg/kg.
- the medicine also includes pharmaceutically acceptable adjuvants, which include but are not limited to solvents, cosolvents, stabilizers, dispersants, viscosity modifiers, antioxidants, sweeteners, Adhesive, gas generating agent.
- pharmaceutically acceptable adjuvants include but are not limited to solvents, cosolvents, stabilizers, dispersants, viscosity modifiers, antioxidants, sweeteners, Adhesive, gas generating agent.
- hydroxyprogesterone caproate is the only active ingredient in the method or the medicine; or in the method, other active ingredients are also included in the method or the medicine also includes other active ingredients; the described Other active ingredients include but are not limited to glucocorticoids, other anti-inflammatory drugs other than glucocorticoids, anti-fibrotic drugs such as pirfenidone, nintedanib, antacids, drugs that increase blood oxygen levels or device.
- the present application provides the use of hydroxyprogesterone caproate in the preparation of a medicament for reducing abnormal lipid metabolism caused by glucocorticoids.
- glucocorticoid is dexamethasone
- abnormal lipid metabolism comprises increased levels of triglycerides and total cholesterol and/or decreased levels of leptin.
- the present application provides a method for reducing glucocorticoid-induced dyslipidemia, comprising administering hydroxyprogesterone caproate.
- glucocorticoid is dexamethasone
- abnormal lipid metabolism comprises increased levels of triglycerides and total cholesterol and/or decreased levels of leptin.
- the daily dose of hydroxyprogesterone caproate is 20-80 mg/kg; preferably 40-80 mg/kg; more preferably 40 or 80 mg/kg; and/or the dexamethasone dose is 1-2 mg/kg, preferably 1 mg /kg or 2mg/kg; when hydroxyprogesterone caproate and dexamethasone are administered in combination, the preferred administration regimen is: hydroxyprogesterone caproate 40mg/kg+dexamethasone 2mg/kg, preferably hydroxyprogesterone caproate 40mg/kg+ Dexamethasone 1mg/kg.
- hydroxyprogesterone caproate is also referred to as 17-alpha hydroxyprogesterone caproate, 17-HPC, 17-hydroxyprogesterone caproate, 17-hydroxyprogesterone caproate, CAS number 630-56-8, in The codename PR2005 is used in the experimental part.
- Interstitial pneumonias described in this application include, but are not limited to, idiopathic interstitial pneumonia (IIP), including various subtypes of idiopathic interstitial pneumonia, including but not limited to idiopathic pulmonary Fibrosis (IPF), nonspecific interstitial pneumonia (NSIP), cryptogenic organizing pneumonia (COP), acute interstitial pneumonia (AIP), respiratory bronchiolitis with interstitial lung disease (RBILD) , desquamative interstitial pneumonia (DIP) and lymphocytic interstitial pneumonia (LIP); idiopathic pulmonary fibrosis (IPF) is preferred.
- IIP idiopathic interstitial pneumonia
- IPF idiopathic pulmonary Fibrosis
- NIP nonspecific interstitial pneumonia
- COP cryptogenic organizing pneumonia
- AIP acute interstitial pneumonia
- RILD respiratory bronchiolitis with interstitial lung disease
- DIP desquamative interstitial pneumonia
- LIP lymphocytic interstitial pneumonia
- Pulmonary fibrosis as described in this application includes pulmonary fibrosis caused by various causes, including but not limited to idiopathic pulmonary fibrosis, primary pulmonary fibrosis, secondary non-fibrotic, interstitial pulmonary fibrosis et al; idiopathic pulmonary fibrosis is preferred.
- the drugs of the present application can be used alone or in combination with drugs and therapies known in the art for treating interstitial pneumonia or alleviating symptoms associated with interstitial pneumonia, including but not limited to glucocorticoids, glucocorticoids
- anti-fibrotic drugs such as pirfenidone, nintedanib, antacids, drugs or devices that increase blood oxygen levels.
- the available dosage forms of this application include but are not limited to injections such as injections, powder injections, etc., oral preparations such as tablets, capsules, oral liquids, etc., throat or nasal sprays, external preparations such as ointments, sprays, patches, etc.; Injections and oral preparations are preferred; oral preparations are particularly preferred.
- the different drugs in the pharmaceutical combination may be prepared in the same formulation; may also be provided in the same package in the same or different dosage forms; or in separate packages in the same or different dosage forms.
- excipients for the drugs involved in this application according to the general knowledge in the pharmaceutical field.
- the types of excipients that can be used include but are not limited to solvents, cosolvents, stabilizers, dispersants, viscosity modifiers, antioxidants, sweeteners Flavoring agents, adhesives, gas generating agents, etc.
- hydroxyprogesterone caproate can significantly improve the changes of various inflammatory cytokines in the blood of rats, and the comprehensive effect is better than the positive control drug pirfenidone; caproic acid Hydroxyprogesterone has obvious inhibitory effects on various pro-fibrotic proteins and collagen type I COLI in rat lung tissue; hydroxyprogesterone caproate combined with dexamethasone can improve the lipid induced by dexamethasone alone. Metabolic abnormalities.
- the above results provide new drug types and development directions for the treatment of interstitial pneumonia.
- Hydroxyprogesterone Caproate (Hydroxyprogesterone Caproate): purchased from Symbiotec Company;
- Bleomycin hydrochloride purchased from Hanhui Pharmaceutical Co., Ltd.; (15mg of bleomycin was added with 3ml of physiological saline to obtain a solution with a concentration of 5mg/ml);
- Dexamethasone Hydrochloride Tablets purchased from Shanghai Jinbuhuan Lanco Pharmaceutical Co., Ltd.;
- Pirfenidone capsules purchased from Beijing Kangdini Pharmaceutical Co., Ltd.
- SD rats (weight 240-280 g) were purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd. (animal license number: SCXK (Beijing) 2016-0006; animal certificate number: NO.110011201110788686).
- the quarantine and acclimation period was 1 week, after which they were divided into control group and interstitial pneumonia model group according to body weight.
- rats in the model group were given a single dose of 5 mg/kg bleomycin by a single intratracheal injection of bleomycin.
- the rats in the control group were given a single instillation of normal saline.
- the animals were placed upright and rotated to facilitate even distribution of the drug in the lungs. Lie down in a warm environment and wake up naturally. Animals ate and drank freely after they were awake.
- Weight physical signs, coat status, behavioral activities, presence or absence of nervous reactions such as tremors and spasms, presence or absence of abnormal breath sounds and abnormal gait movements, response to sound shock, stool shape and color, etc.
- rats in each group were fasted for 12 hours, and then anesthetized by intraperitoneal injection of 100 mg/L chloral hydrate (3.5 mL/kg), the muscles were separated, the trachea was exposed, a T-shaped mouth was cut on the trachea, and a tracheal syringe was inserted. 2ml of PBS was injected into the lung tissue, gently aspirated, centrifuged at 2500 r/min for 10 min, and the supernatant was aspirated to detect the content of cytokines, and the cell pellet was collected at the same time to detect the number of inflammatory cells.
- the rats in each group were fasted for 12 hours, and then anesthetized by intraperitoneal injection of 100 mg/L chloral hydrate (3.5 mL/kg).
- the cytokines TNF- ⁇ , IL-1 ⁇ , IFN- ⁇ , IL-6, TGF- ⁇ 1, IL-4, MCP-1/CCL2 in bronchoalveolar lavage fluid and serum were detected by ELISA, and HYP, MMP2, MMP9 in lung tissue were detected , ⁇ 6, VEGF content, the steps are the same as the standard flow of the kit.
- TGs blood sugar
- TC total cholesterol
- FFA free fatty acids
- high-density lipoprotein high-density lipoprotein cholesterol, HDL- c
- low-density lipoprotein low-density lipoprotein cholesterol, LDL-c
- corticosterone corticosterone
- insulin insulin
- leptin leptin
- 5-HT 5-hydroxytryptamine
- 5-HT no
- bleomycin induces a variety of Increased levels of profibrotic factors including PDGF, SMAD3, SMAD2, MMP9, MMP2, CXCL-12, TGF- ⁇ 1, and type I collagen COL I protein levels were reduced by hydroxyprogesterone caproate treatment, among which PDGF , SMAD3, SMAD2, MMP2, TGF- ⁇ 1 changes were statistically significant.
- profibrotic factors including PDGF, SMAD3, SMAD2, MMP9, MMP2, CXCL-12, TGF- ⁇ 1, and type I collagen COL I protein levels were reduced by hydroxyprogesterone caproate treatment, among which PDGF , SMAD3, SMAD2, MMP2, TGF- ⁇ 1 changes were statistically significant.
- hydroxyprogesterone caproate can significantly improve the changes of various inflammatory cytokines in the blood of rats, and the comprehensive effect is better than the positive control drug pyridoxine.
- Fenidone; hydroxyprogesterone caproate showed significant inhibitory effects on various pro-fibrotic proteins and collagen type I COLI in rat lung tissue; hydroxyprogesterone caproate combined with dexamethasone can improve dexamethasone single treatment caused by abnormal lipid metabolism.
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Abstract
以单独的或者与其他药物联合的己酸羟孕酮治疗间质性肺炎的方法,以及相应制药用途,药物组合物。己酸羟孕酮可以减轻肺部炎症和纤维化症状、减少肺部胶原沉积、减少肺泡灌洗液和血浆中多种炎症因子水平。己酸羟孕酮与地塞米松联用时可以改善地塞米松单独治疗所引起的脂质代谢异常等。
Description
交叉引用
本申请要求在2020年12月1日提交中国专利局、申请号为202011388458.0、发明名称为“间质性肺炎的治疗方法”的中国专利申请的优先权,其全部内容通过引用结合在本申请中;本申请还要求在2021年11月29日提交中国专利局、申请号为202111428491.6、发明名称为“己酸羟孕酮在制备治疗间质性肺炎的药物中的用途”的中国专利申请的优先权,其全部内容通过引用结合在本申请中。
本申请提供了以单独的或者与其他药物联合的己酸羟孕酮治疗间质性肺炎的方法,以及相应制药用途,药物组合物等。
间质性肺病(interstitial lung disease,ILD)是指以肺泡结构内的细胞以及结缔组织内的基质发生紊乱为特征的一组异质性疾病,主要临床症状包括呼吸困难,低血氧症,一氧化碳弥散量(DLCO)降低等。广义的ILD几乎包括所有发生于肺间质的病因、发病和病变各不相同的疾病,目前已知可引起ILD的病因近200种,包括粉尘、感染、药物、吸入特殊气体等,但仍有70%以上的ILD病例无法确定具体病因。特发性间质性肺炎(idiopathic interstitial pneumonia,IIP),是一组以弥漫性肺泡炎和肺泡结构紊乱最终导致肺纤维化为特征的、原因不明的ILD。根据2002年美国胸科学会(ATS)和欧洲呼吸学会(ERS)的分类,IIP主要包括以下7种亚型:特发性肺纤维化(IPF),非特异性间质性肺炎(NSIP),隐源性机化性肺炎(COP),急性间质性肺炎(AIP),呼吸性细支气管炎伴间质性肺疾病(RBILD),脱屑性间质性肺炎(DIP)和淋巴细胞性间质性肺炎(LIP)。其中,IPF是IIP中最常见和最具有代表性的疾病,有报道称其占IIP发病的60%以上。患者患病后肺间质会不断产生纤维化,进而导致肺组织增厚,造成不可逆转地丧失肺组织氧气交换的能力。IPF是一种致命的呼吸系统疾病,一般患者确诊后的存活时间只有2-3年。
目前IIP和IPF的致病原因和发病过程均未完全阐明。一般情况下,肺部组织损伤的 持续存在或者复发会导致细胞因子、化学因子和生长因子等失调,血管再生异常,纤溶系统受损,细胞外基质降解减少和氧化应激增强等,使肺泡微环境发生变化,从而抑制宿主炎症反应。但是肺泡微环境改变也可能导致修复失调和组织重构异常,使肺泡上皮细胞重新上皮化失败,成纤维细胞或肌成纤维细胞募集、活化,最终导致进行性纤维化。由于病因不明确,目前针对IIP的治疗手段非常有限,除对症治疗外,仅有糖皮质激素类药物和免疫抑制剂类药物被证明有效,且治疗效果亦取决于不同的IIP亚型。IPF发病过程中炎症相对于其它间质性肺炎较轻,而纤维化则占主导地位,因此,糖皮质激素和免疫抑制剂的治疗效果都非常有限。近年来对于肺纤维化过程中成纤维细胞增殖和功能异常、肺泡上皮细胞凋亡异常以及TGF-β信号通路的研究也表明对IPF的治疗已经不推荐大剂量使用糖皮质激素,但目前仍然没有真正有效的治疗手段。非IPF的IIP治疗策略则不同,如COP,DIP和RBILD对糖皮质激素有较好的反应,预后和IPF亦不相同。而LIP则还需要辅助一定的免疫抑制剂甚至细胞毒类药物才可以达到较好的治疗效果。因此,对于IIP的糖皮质激素类药物治疗也要明确亚型,区别对待。
除了对IIP尤其是IFP的治疗效果不够理想之外,糖皮质激素类药物亦存在以下问题:1)耐药性。糖皮质激素耐药性或不敏感性是用糖皮质激素治疗的疾病中很难控制的问题,主要表现为对足够剂量的皮质类固醇无反应,或者需要非常高剂量的治疗,亦或者对皮质类固醇最初有反应,但当停药或药量逐渐减少后疾病迅速复发。糖皮质激素耐药性的分子机制包括糖皮质激素受体表达减少,与糖皮质激素受体结合的缺陷和易位,遗传易感性,炎症信号通路的活化等,据报道有20-40%的患者可能因此而无法获得有效的糖皮质激素治疗效果。2)副作用。由于糖皮质激素广泛的药理学活性,长期大剂量的给药不可避免地会引起机体副作用和并发症,严重者甚至可导致病人死亡。其临床常见的副作用包括继发性感染,消化道症状如胃溃疡,心血管系统相关症状如高血压、水肿、血糖升高,类柯兴综合征如向心性肥胖、满月脸,神经精神症状如兴奋、失眠、暴躁易怒等情绪改变,骨关节并发症如骨质疏松,眼病如青光眼和白内障等。因此,在临床上如何增加糖皮质激素类药物的敏感性,减少糖皮质激素的用量并减弱其副作用亦是亟待解决的问题。
鉴于目前临床上对IIP尤其是IFP缺乏有效的治疗手段,以及现有糖皮质激素治疗的耐药性和副作用问题,在本领域中存在对用于治疗该疾病药物的极大需要。
发明内容
一方面,本申请提供了己酸羟孕酮在制备治疗间质性肺炎的药物中的应用。
进一步地,其中己酸羟孕酮为所述药物中的唯一有效成分。
另一方面,本申请提供了己酸羟孕酮和糖皮质激素在制备治疗间质性肺炎的药物中的应用。
进一步地,其中所述糖皮质激素为地塞米松。
进一步地,其中药物剂型为注射剂,口服制剂或外用制剂;优选注射剂,口服制剂;特别优选注射剂。
进一步地,其中所述注射剂包括注射液、粉针剂;口服制剂包括片剂、胶囊剂、口服液、咽喉或鼻喷剂,外用制剂包括软膏剂、喷剂、贴剂。
进一步地,其中所述治疗间质性肺炎包括减轻肺部炎症和纤维化症状。
进一步地,其中所述治疗间质性肺炎包括减少肺部胶原沉积。
进一步地,其中所述治疗间质性肺炎包括减少支气管肺泡灌洗液中炎症细胞计数。
进一步地,其中所述治疗间质性肺炎包括减少肺部组织中羟基脯氨酸水平。
进一步地,其中所述治疗间质性肺炎包括减少肺泡灌洗液和血浆中多种炎症因子水平;优选的,所述炎症因子包括TNF-α,IL-1β,IFN-γ,IL-6,TGF-β1,IL-4,MCP-1/CCL2。
进一步地,其中所述治疗间质性肺炎包括减少肺泡灌洗液和/或血浆中多种促纤维化因子和炎性细胞因子以及I型胶原水平,和/或增加抗纤维化因子水平;优选的,所述促纤维化因子和和炎性细胞因子为TNF-α、IL-1β、IL-6、MCP-1、PDGF,SMAD3,SMAD2,MMP9,MMP2,CXCL-12和/或TGF-β1,所述抗纤维化因子为IFN-γ和/或IL-4;更优选的,所述促纤维化因子为TNF-α、IL-1β、IL-6、PDGF、SMAD3、SMAD2、MMP2和/或TGF-β1。
进一步地,其中所述治疗间质性肺炎过程中的脂代谢异常被降低。
进一步地,其中所述脂代谢异常包括甘油三酯和总胆固醇的水平升高和/或瘦素水平降低。
另一方面,本申请提供了治疗间质性肺炎的方法,其特征在于,所述方法包括向间质性肺炎患者施用己酸羟孕酮。
进一步地,其中所述方法中不包含施用糖皮质激素的步骤。
进一步地,其中所述方法中包含施用糖皮质激素的步骤。
进一步地,其中所述糖皮质激素为地塞米松。
进一步地,其中己酸羟孕酮的剂型为注射剂,口服制剂或外用制剂;优选注射剂,口服制剂;特别优选注射剂。
进一步地,其中注射剂包括注射液、粉针剂;口服制剂包括片剂、胶囊剂、口服液、 咽喉或鼻喷剂,外用制剂包括软膏剂、喷剂、贴剂。
进一步地,其中己酸羟孕酮剂量为30-100mg/日,或250-750mg/周。
进一步地,其中己酸羟孕酮每日剂量为20-80mg/kg;优选40-80mg/kg;更优选40或80mg/kg。
进一步地,其中己酸羟孕酮施用方案每周给药1-7次,优选1-4次,更优选1-2次。
进一步地,其中所述治疗间质性肺炎包括减轻肺部炎症和纤维化症状。
进一步地,其中所述治疗间质性肺炎包括减少肺部胶原沉积。
进一步地,其中所述治疗间质性肺炎包括减少支气管肺泡灌洗液中炎症细胞计数。
进一步地,其中所述治疗间质性肺炎包括减少肺部组织中羟基脯氨酸水平。
进一步地,其中所述治疗间质性肺炎包括减少肺泡灌洗液和血浆中多种炎症因子水平;优选的,所述炎症因子包括TNF-α,IL-1β,IFN-γ,IL-6,TGF-β1,IL-4,MCP-1/CCL2。
进一步地,其中所述治疗间质性肺炎包括减少肺泡灌洗液和/或血浆中多种促纤维化因子和炎性细胞因子以及I型胶原水平,和/或增加抗纤维化因子水平;优选的,所述促纤维化因子和和炎性细胞因子为TNF-α、IL-1β、IL-6、MCP-1、PDGF,SMAD3,SMAD2,MMP9,MMP2,CXCL-12和/或TGF-β1,所述抗纤维化因子为IFN-γ和/或IL-4;更优选的,所述促纤维化因子为TNF-α、IL-1β、IL-6、PDGF、SMAD3、SMAD2、MMP2和/或TGF-β1。
进一步地,其中所述治疗间质性肺炎过程中的脂代谢异常被降低。
进一步地,其中所述脂代谢异常包括甘油三酯和总胆固醇的水平升高和/或瘦素水平降低。
另一方面,本申请提供了用于治疗间质性肺炎的药物,其特征在于,所述药物包含己酸羟孕酮。
进一步地,其中所述药物中己酸羟孕酮为唯一有效成分。
进一步地,其中所述药物中还包含糖皮质激素。
进一步地,其中所述糖皮质激素为地塞米松。
进一步地,其中所述药物剂型为注射剂,口服制剂或外用制剂;优选注射剂,口服制剂;特别优选注射剂。
进一步地,其中注射剂包括注射液、粉针剂;口服制剂包括片剂、胶囊剂、口服液、咽喉或鼻喷剂,外用制剂包括软膏剂、喷剂、贴剂。
进一步地,其中所述药物用于减轻肺部炎症和纤维化症状。
进一步地,其中所述药物用于减少肺部胶原沉积。
进一步地,其中所述药物用于减少支气管肺泡灌洗液中炎症细胞计数。
进一步地,其中所述药物用于减少肺部组织中羟基脯氨酸水平。
进一步地,其中所述药物用于减少肺泡灌洗液和血浆中多种炎症因子水平;优选的,所述炎症因子包括TNF-α,IL-1β,IFN-γ,IL-6,TGF-β1,IL-4,MCP-1/CCL2。
进一步地,其中所述药物用于减少肺泡灌洗液和/或血浆中多种促纤维化因子和炎性细胞因子以及I型胶原水平,和/或增加抗纤维化因子水平;优选的,所述促纤维化因子和和炎性细胞因子为TNF-α、IL-1β、IL-6、MCP-1、PDGF,SMAD3,SMAD2,MMP9,MMP2,CXCL-12和/或TGF-β1,所述抗纤维化因子为IFN-γ和/或IL-4;更优选的,所述促纤维化因子为TNF-α、IL-1β、IL-6、PDGF、SMAD3、SMAD2、MMP2和/或TGF-β1。
进一步地,其中所述药物治疗间质性肺炎过程中的脂代谢异常被降低。
进一步地,其中所述脂代谢异常包括甘油三酯和总胆固醇的水平升高和/或瘦素水平降低。
进一步地,其中所述药物己酸羟孕酮剂量为30-100mg/日,或250-750mg/周,和/或己酸羟孕酮施用方案为每周给药1-7次,优选1-4次,更优选1-2次。
进一步地,其中所述药物己酸羟孕酮每日剂量为20-80mg/kg;优选40-80mg/kg;更优选40或80mg/kg。
另一方面,本申请提供了己酸羟孕酮在制备治疗肺纤维化的药物中的应用。
进一步地,其中己酸羟孕酮为所述药物中的唯一有效成分。
另一方面,本申请提供了己酸羟孕酮和糖皮质激素在制备治疗肺纤维化的药物中的应用。
进一步地,其中所述糖皮质激素为地塞米松。
进一步地,其中药物剂型为注射剂,口服制剂或外用制剂;优选注射剂,口服制剂;特别优选注射剂。
进一步地,其中所述注射剂包括注射液、粉针剂;口服制剂包括片剂、胶囊剂、口服液、咽喉或鼻喷剂,外用制剂包括软膏剂、喷剂、贴剂。
进一步地,其中所述治疗肺纤维化包括减轻肺部炎症和纤维化症状。
进一步地,其中所述治疗肺纤维化包括减少肺部胶原沉积。
进一步地,其中所述治疗肺纤维化包括减少支气管肺泡灌洗液中炎症细胞计数。
进一步地,其中所述治疗肺纤维化包括减少肺部组织中羟基脯氨酸水平。
进一步地,其中所述治疗肺纤维化包括减少肺泡灌洗液和血浆中多种炎症因子水平;优选的,所述炎症因子包括TNF-α,IL-1β,IFN-γ,IL-6,TGF-β1,IL-4,MCP-1/CCL2。
进一步地,其中所述治疗肺纤维化包括减少肺泡灌洗液和/或血浆中多种促纤维化因子和炎性细胞因子以及I型胶原水平,和/或增加抗纤维化因子水平;优选的,所述促纤维化因子和和炎性细胞因子为TNF-α、IL-1β、IL-6、MCP-1、PDGF,SMAD3,SMAD2,MMP9,MMP2,CXCL-12和/或TGF-β1,所述抗纤维化因子为IFN-γ和/或IL-4;更优选的,所述促纤维化因子为TNF-α、IL-1β、IL-6、PDGF、SMAD3、SMAD2、MMP2和/或TGF-β1。
进一步地,其中所述治疗肺纤维化过程中的脂代谢异常被降低。
进一步地,其中所述脂代谢异常包括甘油三酯和总胆固醇的水平升高和/或瘦素水平降低。
另一方面,本申请提供了治疗肺纤维化的方法,其特征在于,所述方法包括向肺纤维化患者施用己酸羟孕酮。
进一步地,其中所述方法中不包含施用糖皮质激素的步骤。
进一步地,其中所述方法中包含施用糖皮质激素的步骤。
进一步地,其中所述糖皮质激素为地塞米松。
进一步地,其中己酸羟孕酮的剂型为注射剂,口服制剂或外用制剂;优选注射剂,口服制剂;特别优选注射剂。
进一步地,其中注射剂包括注射液、粉针剂;口服制剂包括片剂、胶囊剂、口服液、咽喉或鼻喷剂,外用制剂包括软膏剂、喷剂、贴剂。
进一步地,其中己酸羟孕酮剂量为30-100mg/日,或250-750mg/周。
进一步地,其中己酸羟孕酮每日剂量为20-80mg/kg;优选40-80mg/kg;更优选40或80mg/kg。
进一步地,其中己酸羟孕酮施用方案每周给药1-7次,优选1-4次,更优选1-2次。
进一步地,其中所述治疗肺纤维化包括减轻肺部炎症和纤维化症状。
进一步地,其中所述治疗肺纤维化包括减少肺部胶原沉积。
进一步地,其中所述治疗肺纤维化包括减少支气管肺泡灌洗液中炎症细胞计数。
进一步地,其中所述治疗肺纤维化包括减少肺部组织中羟基脯氨酸水平。
进一步地,其中所述治疗肺纤维化包括减少肺泡灌洗液和血浆中多种炎症因子水平;优选的,所述炎症因子包括TNF-α,IL-1β,IFN-γ,IL-6,TGF-β1,IL-4,MCP-1/CCL2。
进一步地,其中所述治疗肺纤维化包括减少肺泡灌洗液和/或血浆中多种促纤维化因子和炎性细胞因子以及I型胶原水平,和/或增加抗纤维化因子水平;优选的,所述促纤维化因子和和炎性细胞因子为TNF-α、IL-1β、IL-6、MCP-1、PDGF,SMAD3,SMAD2,MMP9, MMP2,CXCL-12和/或TGF-β1,所述抗纤维化因子为IFN-γ和/或IL-4;更优选的,所述促纤维化因子为TNF-α、IL-1β、IL-6、PDGF、SMAD3、SMAD2、MMP2和/或TGF-β1。
进一步地,其中所述治疗肺纤维化过程中的脂代谢异常被降低。
进一步地,其中所述脂代谢异常包括甘油三酯和总胆固醇的水平升高和/或瘦素水平降低。
另一方面,本申请提供了用于治疗肺纤维化的药物,其特征在于,所述药物包含己酸羟孕酮。
进一步地,其中所述药物中己酸羟孕酮为唯一有效成分。
进一步地,其中所述药物中还包含糖皮质激素。
进一步地,其中所述糖皮质激素为地塞米松。
进一步地,其中所述药物剂型为注射剂,口服制剂或外用制剂;优选注射剂,口服制剂;特别优选注射剂。
进一步地,其中注射剂包括注射液、粉针剂;口服制剂包括片剂、胶囊剂、口服液、咽喉或鼻喷剂,外用制剂包括软膏剂、喷剂、贴剂。
进一步地,其中所述药物用于减轻肺部炎症和纤维化症状。
进一步地,其中所述药物用于减少肺部胶原沉积。
进一步地,其中所述药物用于减少支气管肺泡灌洗液中炎症细胞计数。
进一步地,其中所述药物用于减少肺部组织中羟基脯氨酸水平。
进一步地,其中所述药物用于减少肺泡灌洗液和血浆中多种炎症因子水平;优选的,所述炎症因子包括TNF-α,IL-1β,IFN-γ,IL-6,TGF-β1,IL-4,MCP-1/CCL2。
进一步地,其中所述药物用于减少肺泡灌洗液和/或血浆中多种促纤维化因子和炎性细胞因子以及I型胶原水平,和/或增加抗纤维化因子水平;优选的,所述促纤维化因子和和炎性细胞因子为TNF-α、IL-1β、IL-6、MCP-1、PDGF,SMAD3,SMAD2,MMP9,MMP2,CXCL-12和/或TGF-β1,所述抗纤维化因子为IFN-γ和/或IL-4;更优选的,所述促纤维化因子为TNF-α、IL-1β、IL-6、PDGF、SMAD3、SMAD2、MMP2和/或TGF-β1。
进一步地,其中所述脂代谢异常包括甘油三酯和总胆固醇的水平升高和/或瘦素水平降低。
进一步地,其中所述药物己酸羟孕酮剂量为30-100mg/日,或250-750mg/周,和/或己酸羟孕酮施用方案为每周给药1-7次,优选1-4次,更优选1-2次。
进一步地,其中所述药物己酸羟孕酮每日剂量为20-80mg/kg;优选40-80mg/kg;更 优选40或80mg/kg。
另一方面,本申请提供了己酸羟孕酮,或者己酸羟孕酮与糖皮质激素的组合在制备抑制促纤维化因子和炎性细胞因子,和/或I型胶原;和/或增加抗纤维化因子水平的药物中的应用;或者作为促纤维化因子和炎性细胞因子的抑制剂的应用,和/或作为I型胶原的抑制剂的应用,和/或作为抗纤维化因子的促进剂的应用。
进一步地,其中所述糖皮质激素为地塞米松。
进一步地,其中所述炎症因子为TNF-α,IL-1β,IFN-γ,IL-6,TGF-β1,IL-4和/或MCP-1/CCL2。
进一步地,其中所述促纤维化因子和和炎性细胞因子为TNF-α、IL-1β、IL-6、MCP-1、PDGF,SMAD3,SMAD2,MMP9,MMP2,CXCL-12和/或TGF-β1,所述抗纤维化因子为IFN-γ和/或IL-4;更优选的,所述促纤维化因子为TNF-α、IL-1β、IL-6、PDGF、SMAD3、SMAD2、MMP2和/或TGF-β1。
进一步地,其中所述药物剂型为注射剂,口服制剂或外用制剂;优选注射剂,口服制剂;特别优选注射剂。
进一步地,其中注射剂包括注射液、粉针剂;口服制剂包括片剂、胶囊剂、口服液、咽喉或鼻喷剂,外用制剂包括软膏剂、喷剂、贴剂。
另一方面,本申请提供了抑制促纤维化因子和炎性细胞因子,和/或I型胶原;和/或增加抗纤维化因子水平的方法,所述方法包括施用己酸羟孕酮。
进一步地,其中所述方法中不包含施用糖皮质激素的步骤。
进一步地,其中所述方法中包含施用糖皮质激素的步骤。
进一步地,其中所述糖皮质激素为地塞米松。
进一步地,其中所述炎症因子为TNF-α,IL-1β,IFN-γ,IL-6,TGF-β1,IL-4和/或MCP-1/CCL2。
进一步地,其中所述促纤维化因子和和炎性细胞因子为TNF-α、IL-1β、IL-6、MCP-1、PDGF,SMAD3,SMAD2,MMP9,MMP2,CXCL-12和/或TGF-β1,所述抗纤维化因子为IFN-γ和/或IL-4;更优选的,所述促纤维化因子为TNF-α、IL-1β、IL-6、PDGF、SMAD3、SMAD2、MMP2和/或TGF-β1。
进一步地,其中己酸羟孕酮的剂型为注射剂,口服制剂或外用制剂;优选注射剂,口服制剂;特别优选注射剂。
进一步地,其中注射剂包括注射液、粉针剂;口服制剂包括片剂、胶囊剂、口服液、 咽喉或鼻喷剂,外用制剂包括软膏剂、喷剂、贴剂。
进一步地,其中己酸羟孕酮剂量为30-100mg/日,或250-750mg/周。
进一步地,其中己酸羟孕酮每日剂量为20-80mg/kg;优选40-80mg/kg;更优选40或80mg/kg。
进一步地,其中己酸羟孕酮施用方案每周给药1-7次,优选1-4次,更优选1-2次。
另一方面,本申请提供了用于抑制促纤维化因子和炎性细胞因子,和/或I型胶原;和/或增加抗纤维化因子水平的药物,其特征在于,所述药物包含己酸羟孕酮。
进一步地,其中所述药物中己酸羟孕酮为唯一有效成分。
进一步地,其中所述药物中还包含糖皮质激素。
进一步地,其中所述糖皮质激素为地塞米松。
进一步地,其中所述炎症因子为TNF-α,IL-1β,IFN-γ,IL-6,TGF-β1,IL-4和/或MCP-1/CCL2。
进一步地,其中所述促纤维化因子和和炎性细胞因子为TNF-α、IL-1β、IL-6、MCP-1、PDGF,SMAD3,SMAD2,MMP9,MMP2,CXCL-12和/或TGF-β1,所述抗纤维化因子为IFN-γ和/或IL-4;更优选的,所述促纤维化因子为TNF-α、IL-1β、IL-6、PDGF、SMAD3、SMAD2、MMP2和/或TGF-β1。
进一步地,其中所述药物剂型为注射剂,口服制剂或外用制剂;优选注射剂,口服制剂;特别优选注射剂。
进一步地,其中注射剂包括注射液、粉针剂;口服制剂包括片剂、胶囊剂、口服液、咽喉或鼻喷剂,外用制剂包括软膏剂、喷剂、贴剂。
进一步地,其中所述药物己酸羟孕酮剂量为30-100mg/日,或250-750mg/周,和/或己酸羟孕酮施用方案为每周给药1-7次,优选1-4次,更优选1-2次。
进一步地,其中己酸羟孕酮每日剂量为20-80mg/kg;优选40-80mg/kg;更优选40或80mg/kg。
进一步地,所述的药物还包括药学上可接受的辅料,所述药学上可接受的辅料包括但不限于溶剂、助溶剂、稳定剂、分散剂、粘度调节剂、抗氧化剂、甜味剂、粘合剂、气体发生剂。
进一步地,所述的方法或所述的药物中,己酸羟孕酮为方法或药物中的唯一有效成分;或者在方法中还包括施用其他有效成分或药物中还包含其他有效成分;所述其他有效成分包括但不限于糖皮质激素类药物,糖皮质激素类之外的其他抗炎药物,抗纤维化药物如吡 非尼酮,尼达尼布,抗酸药物,提高血氧水平的药物或装置。
另一方面,本申请提供了己酸羟孕酮制备减少糖皮质激素引起的脂代谢异常的药物中的应用。
进一步地,其中所述糖皮质激素为地塞米松。
进一步地,其中所述脂代谢异常包括甘油三酯和总胆固醇的水平升高和/或瘦素水平降低。
另一方面,本申请提供了减少糖皮质激素引起的脂代谢异常的方法,其特征在于,包括施用己酸羟孕酮。
进一步地,其中所述糖皮质激素为地塞米松。
进一步地,其中所述脂代谢异常包括甘油三酯和总胆固醇的水平升高和/或瘦素水平降低。
本申请中,己酸羟孕酮每日剂量为20-80mg/kg;优选40-80mg/kg;更优选40或80mg/kg;和/或地塞米松剂量为1-2mg/kg,优选1mg/kg或2mg/kg;其中己酸羟孕酮与地塞米松联合施用时,优选施用方案为:己酸羟孕酮40mg/kg+地塞米松2mg/kg,优选己酸羟孕酮40mg/kg+地塞米松1mg/kg。
本申请中己酸羟孕酮也被称为17-α己酸羟孕酮、17-HPC、17-己酸羟孕酮、17-羟己孕酮,CAS编号为630-56-8,在实验部分中使用PR2005的代号。
本申请中所述的间质性肺炎包括但不限于特发性间质性肺炎(idiopathic interstitial pneumonia,IIP),包括特发性间质性肺炎的各个亚型,包括但不限于特发性肺纤维化(IPF),非特异性间质性肺炎(NSIP),隐源性机化性肺炎(COP),急性间质性肺炎(AIP),呼吸性细支气管炎伴间质性肺疾病(RBILD),脱屑性间质性肺炎(DIP)和淋巴细胞性间质性肺炎(LIP);优选特发性肺纤维化(IPF)。
本申请中所述的肺纤维化包括各种原因导致的肺纤维化,包括但不限于特发性肺纤维化、原发性肺纤维化、继发性非纤维化、间质性肺纤维化等;优选特发性肺纤维化。
本申请的药物可以单独使用或者与本领域已知的治疗间质性肺炎或者缓解间质性肺炎相关症状的药物和疗法联用,这些药物包括但不限于糖皮质激素类药物,糖皮质激素类之外的其他抗炎药物,抗纤维化药物如吡非尼酮,尼达尼布,抗酸药物,提高血氧水平的药物或装置。
本申请的可用剂型包括但不限于注射剂如注射液、粉针剂等,口服制剂如片剂、胶囊剂、口服液等,咽喉或鼻喷剂,外用制剂如软膏剂、喷剂、贴剂等;优选注射剂,口服制 剂;特别优选口服制剂。药物组合中的不同药物可以被制备入同一制剂中;也可以以相同或不同的剂型在同一包装中提供;或者以相同或不同的剂型在各自单独的包装中提供。
本领域技术人员可以根据药学领域一般知识为为本申请所涉及的药物选择适合的辅料,可用的辅料种类包括但不限于溶剂、助溶剂、稳定剂、分散剂、粘度调节剂、抗氧化剂、甜味剂、粘合剂、气体发生剂等。
实验表明,在博来霉素诱导的疾病模型中,己酸羟孕酮可以显著改善大鼠血液中多种炎性细胞因子的变化,且综合效果优于阳性对照药物吡非尼酮;己酸羟孕酮对大鼠肺组织中多种促纤维化蛋白以及I型胶原COL I显示出明显抑制作用;己酸羟孕酮与地塞米松联用时可以改善地塞米松单独治疗所引起的脂质代谢异常。以上结果为治疗间质性肺炎提供了新的药物种类和发展方向。
图1为17-α羟孕酮可以显著改善博来霉素诱导的大鼠血液中多种炎性细胞因子的变化(数据为平均值±标准误,N=6-10,与模型组相比*p<0.05,**p<0.01,***p<0.001);
图2为17-α羟孕酮可以显著改善博来霉素诱导的大鼠肺组织中多种促纤维化蛋白以及I型胶原蛋白的变化(数据为平均值±标准误,N=3,与模型组相比*p<0.05,**p<0.01,***p<0.001);
图3为在博来霉素诱导的大鼠肺纤维化模型中,17-α羟孕酮对地塞米松治疗引起的脂质代谢异常的影响(数据为平均值±标准误,N=6-10)。
主要药物和试剂:
己酸羟孕酮(Hydroxyprogesterone Caproate):购自Symbiotec公司;
盐酸博来霉素(BLM):购于瀚晖制药有限公司;(博来霉素15mg加入3ml生理盐水,得浓度为5mg/ml溶液);
盐酸地塞米松片(DEX):购自上海金不换兰考制药有限公司;
吡非尼酮胶囊(PFD):购自北京康蒂尼药业有限公司。
实施例1大鼠模型的建立
SD大鼠(重240-280g)购自北京市维通利华实验动物技术有限公司(动物许可证号: SCXK(京)2016-0006;动物合格证编号:NO.110011201110788686)。
检疫与驯化期为1周,之后按体重蛇行分组到对照组和间质性肺炎模型组。在研究的第0日,通过一次性气管内注射博来霉素的方法,向模型组的大鼠单次给药5mg/kg博来霉素。对照组的大鼠则给予生理盐水单次滴注。完毕后立即将动物直立、旋转,以利药物在肺中分布均匀。卧置于温暖环境中,自然苏醒。动物清醒后随意进食、饮水。
实施例2实验分组
实施例3检测的指标
一般观察和检查:
体重、外观体征、被毛状态、行为活动,有无震颤、痉挛等神经反应,有无呼吸音异常及步态行动异常,对声音惊吓的反应,粪便形状及颜色等。给药时观察动物下腹部、肛门处有无污物及排泄物,捉拿时的反应性,眼、鼻、口周围的状态,皮肤的状态(有无颜色变化及外伤、肿瘤等)。
肺泡灌洗液采集
末次给药后,各组大鼠禁食不禁水12h,经腹腔注射100mg/L水合氯醛(3.5mL/kg)麻醉,分离肌肉,暴露气管,在气管上剪一个T形口,插入气管注射器注入2ml的PBS至肺部组织中,轻柔后吸出,2500r/min离心10min,吸取上清,用于检测细胞因子含量,同时收集细胞沉淀,检测炎性细胞数目。
肺泡灌洗液炎性细胞分类计数
取肺泡灌洗液中细胞沉淀,滴加到玻片上,晾干,添加瑞氏-吉姆萨染液A,室温中固定2min后,添加瑞氏-吉姆萨染液B平衡10min后,双蒸水洗涤2次,晾干,对白细胞数量、中性粒细胞数量、嗜酸性粒细胞数量、淋巴细胞数量、巨噬细胞数量进行分类计数。
细胞因子检测
末次给药后,各组大鼠禁食不禁水12h,经腹腔注射100mg/L水合氯醛(3.5mL/kg)麻醉,腹主动脉取血,3500rpm离心15min分离血清。ELISA法检测肺泡灌洗液及血清中细胞因子TNF-α、IL-1β、IFN-γ、IL-6、TGF-β1、IL-4、MCP-1/CCL2,检测肺组织HYP、MMP2、MMP9、ανβ6、VEGF含量,步骤同试剂盒标准流程。
地塞米松副作用指标检测
检测血清中血钾、血糖、甘油三酯酸(triglycerides,TGs)、总胆固醇(total cholesterol,TC)、游离脂肪酸(free fatty acid,FFA)、高密度脂蛋白(high-density lipoprotein cholesterol,HDL-c)、低密度脂蛋白(low-density lipoprotein cholesterol,LDL-c)、皮质酮(corticosterone,CORT)、胰岛素(insulin)、瘦素(leptin)、5-羟色胺(5-hydroxy tryptamine,5-HT)、去甲肾上腺素(norepinephrine,NE)含量。
实施例4实验结果
1)在博来霉素诱导的大鼠肺纤维化模型中(图1),血液样本分析显示,与正常对照大鼠相比,博来霉素会诱导血液中炎性因子和促纤维化因子包括TNF-α,IL-1β,IL-6,MCP-1和TGF-β1的显著增加,己酸羟孕酮治疗则可以显著降低这些因子的水平,且具有统计学意义。此外,与正常对照大鼠相比,博来霉素会降低血液中IFN-γ和IL-4的水平, 17-α羟孕酮治疗则可以显著增加这两个因子的水平,且具有统计学意义。己酸羟孕酮对血液中炎性因子和促纤维化因子的综合改善效果要明显优于阳性对照药物吡非尼酮。
2)在博来霉素诱导的大鼠肺纤维化模型中,对大鼠肺组织的进一步分析表明(图2),与正常对照大鼠相比,博来霉素会诱导肺组织中多种促纤维化因子包括PDGF,SMAD3,SMAD2,MMP9,MMP2,CXCL-12,TGF-β1以及I型胶原COL I蛋白水平的增加,己酸羟孕酮治疗则可以降低这些蛋白的水平,其中对PDGF,SMAD3,SMAD2,MMP2,TGF-β1的改变具有统计学意义。
3)在博来霉素诱导的大鼠肺纤维化模型中,对大鼠血液中与脂质代谢有关指标的分析显示(图3),地塞米松治疗会引起血液中甘油三酯和总胆固醇的升高,其中甘油三酯的升高更为明显。与地塞米松治疗组相比,己酸羟孕酮和地塞米松联用则可以减少血液中甘油三酯和总胆固醇的水平。此外在该疾病模型中,和正常对照大鼠相比,模型组、己酸羟孕酮组以及地塞米松组血液中瘦素水平均明显减少,而己酸羟孕酮和地塞米松联用时则表现出增加血液中瘦素水平的趋势。
综上所述,在博来霉素诱导的大鼠肺纤维化模型中,己酸羟孕酮可以显著改善大鼠血液中多种炎性细胞因子的变化,且综合效果优于阳性对照药物吡非尼酮;己酸羟孕酮对大鼠肺组织中多种促纤维化蛋白以及I型胶原COLI显示出明显抑制作用;己酸羟孕酮与地塞米松联用时可以改善地塞米松单独治疗所引起的脂质代谢异常。
此外,在博来霉素诱导的大鼠肺纤维化模型中体现有炎症和肺纤维化两个发病特征。而这两个特征也是特发性间质性肺炎的主要表现。从上述己酸羟孕酮或己酸羟孕酮与地塞米松的组合在博来霉素诱导的大鼠肺纤维化模型中的效果完全可以预期其对特发性间质性肺炎也有疗效。
Claims (130)
- 己酸羟孕酮在制备治疗间质性肺炎的药物中的应用。
- 根据权利要求1所述的应用,其中己酸羟孕酮为所述药物中的唯一有效成分。
- 己酸羟孕酮和糖皮质激素在制备治疗间质性肺炎的药物中的应用。
- 根据权利要求3所述的应用,其中所述糖皮质激素为地塞米松。
- 根据权利要求1-4任一项所述的应用,其中药物剂型为注射剂,口服制剂或外用制剂;优选注射剂,口服制剂;特别优选注射剂。
- 根据权利要求5所述的应用,其中所述注射剂包括注射液、粉针剂;口服制剂包括片剂、胶囊剂、口服液、咽喉或鼻喷剂,外用制剂包括软膏剂、喷剂、贴剂。
- 根据权利要求1-6任一项所述的应用,其中所述治疗间质性肺炎包括减轻肺部炎症和纤维化症状。
- 根据权利要求1-6任一项所述的应用,其中所述治疗间质性肺炎包括减少肺部胶原沉积。
- 根据权利要求1-6任一项所述的应用,其中所述治疗间质性肺炎包括减少支气管肺泡灌洗液中炎症细胞计数。
- 根据权利要求1-6任一项所述的应用,其中所述治疗间质性肺炎包括减少肺部组织中羟基脯氨酸水平。
- 根据权利要求1-6任一项所述的应用,其中所述治疗间质性肺炎包括减少肺泡灌洗液和血浆中多种炎症因子水平;优选的,所述炎症因子包括TNF-α,IL-1β,IFN-γ,IL-6,TGF-β1,IL-4,MCP-1/CCL2。
- 根据权利要求1-6任一项所述的应用,其中所述治疗间质性肺炎包括减少肺泡灌洗液和/或血浆中多种促纤维化因子和炎性细胞因子以及I型胶原水平,和/或增加抗纤维化因子水平;优选的,所述促纤维化因子和和炎性细胞因子为TNF-α、IL-1β、IL-6、MCP-1、PDGF,SMAD3,SMAD2,MMP9,MMP2,CXCL-12和/或TGF-β1,所述抗纤维化因子为IFN-γ和/或IL-4;更优选的,所述促纤维化因子为TNF-α、IL-1β、IL-6、PDGF、SMAD3、SMAD2、MMP2和/或TGF-β1。
- 根据权利要求3-12任一项所述的应用,其中所述治疗间质性肺炎过程中的脂代谢异常被降低。
- 根据权利要求13的所述的应用,其中所述脂代谢异常包括甘油三酯和总胆固醇的水平升高和/或瘦素水平降低。
- 治疗间质性肺炎的方法,其特征在于,所述方法包括向间质性肺炎患者施用己酸羟孕酮。
- 根据权利要求15所述的方法,其中所述方法中不包含施用糖皮质激素的步骤。
- 根据权利要求15所述的方法,其中所述方法中包含施用糖皮质激素的步骤。
- 根据权利要求17所述的方法,其中所述糖皮质激素为地塞米松。
- 根据权利要求15-18任一项所述的方法,其中己酸羟孕酮的剂型为注射剂,口服制剂或外用制剂;优选注射剂,口服制剂;特别优选注射剂。
- 根据权利要求19所述的方法,其中注射剂包括注射液、粉针剂;口服制剂包括片剂、胶囊剂、口服液、咽喉或鼻喷剂,外用制剂包括软膏剂、喷剂、贴剂。
- 根据权利要求15-20任一项所述的方法,其中,己酸羟孕酮剂量为30-100mg/日,或250-750mg/周。
- 根据权利要求15-20任一项所述的方法,其中,己酸羟孕酮每日剂量为20-80mg/kg;优选40-80mg/kg;更优选40或80mg/kg。
- 根据权利要求15-22任一项所述的方法,其中己酸羟孕酮施用方案每周给药1-7次,优选1-4次,更优选1-2次。
- 根据权利要求15-23任一项所述的方法,其中所述治疗间质性肺炎包括减轻肺部炎症和纤维化症状。
- 根据权利要求15-23任一项所述的方法,其中所述治疗间质性肺炎包括减少肺部胶原沉积。
- 根据权利要求15-23任一项所述的方法,其中所述治疗间质性肺炎包括减少支气管肺泡灌洗液中炎症细胞计数。
- 根据权利要求15-23任一项所述的方法,其中所述治疗间质性肺炎包括减少肺部组织中羟基脯氨酸水平。
- 根据权利要求15-23任一项所述的方法,其中所述治疗间质性肺炎包括减少肺泡灌洗液和血浆中多种炎症因子水平;优选的,所述炎症因子包括TNF-α,IL-1β,IFN-γ,IL-6,TGF-β1,IL-4,MCP-1/CCL2。
- 根据权利要求15-23任一项所述的方法,其中所述治疗间质性肺炎包括减少肺泡灌洗液和/或血浆中多种促纤维化因子和炎性细胞因子以及I型胶原水平,和/或增加抗纤维化因子水平;优选的,所述促纤维化因子和和炎性细胞因子为TNF-α、IL-1β、IL-6、MCP-1、PDGF,SMAD3,SMAD2,MMP9,MMP2,CXCL-12和/或TGF-β1,所述抗纤维化因子为IFN-γ 和/或IL-4;更优选的,所述促纤维化因子为TNF-α、IL-1β、IL-6、PDGF、SMAD3、SMAD2、MMP2和/或TGF-β1。
- 根据权利要求17-29任一项所述的方法,其中所述治疗间质性肺炎过程中的脂代谢异常被降低。
- 根据权利要求30的所述的方法,其中所述脂代谢异常包括甘油三酯和总胆固醇的水平升高和/或瘦素水平降低。
- 用于治疗间质性肺炎的药物,其特征在于,所述药物包含己酸羟孕酮。
- 根据权利要求32所述的药物,其中所述药物中己酸羟孕酮为唯一有效成分。
- 根据权利要求32所述的药物,其中所述药物中还包含糖皮质激素。
- 根据权利要求34所述的药物,其中所述糖皮质激素为地塞米松。
- 根据权利要求32-35任一项所述的药物,其中所述药物剂型为注射剂,口服制剂或外用制剂;优选注射剂,口服制剂;特别优选注射剂。
- 根据权利要求36所述的药物,其中注射剂包括注射液、粉针剂;口服制剂包括片剂、胶囊剂、口服液、咽喉或鼻喷剂,外用制剂包括软膏剂、喷剂、贴剂。
- 根据权利要求32-37任一项所述的药物,其中所述药物用于减轻肺部炎症和纤维化症状。
- 根据权利要求32-37任一项所述的药物,其中所述药物用于减少肺部胶原沉积。
- 根据权利要求32-37任一项所述的药物,其中所述药物用于减少支气管肺泡灌洗液中炎症细胞计数。
- 根据权利要求32-37任一项所述的药物,其中所述药物用于减少肺部组织中羟基脯氨酸水平。
- 根据权利要求32-37任一项所述的药物,其中所述药物用于减少肺泡灌洗液和血浆中多种炎症因子水平;优选的,所述炎症因子包括TNF-α,IL-1β,IFN-γ,IL-6,TGF-β1,IL-4,MCP-1/CCL2。
- 根据权利要求32-37任一项所述的药物,其中所述药物用于减少肺泡灌洗液和/或血浆中多种促纤维化因子和炎性细胞因子以及I型胶原水平,和/或增加抗纤维化因子水平;优选的,所述促纤维化因子和和炎性细胞因子为TNF-α、IL-1β、IL-6、MCP-1、PDGF,SMAD3,SMAD2,MMP9,MMP2,CXCL-12和/或TGF-β1,所述抗纤维化因子为IFN-γ和/或IL-4;更优选的,所述促纤维化因子为TNF-α、IL-1β、IL-6、PDGF、SMAD3、SMAD2、MMP2和/或TGF-β1。
- 根据权利要求34-43任一项所述的药物,其中所述药物治疗间质性肺炎过程中的脂代谢异常被降低.
- 根据权利要求44所述的药物,其中所述脂代谢异常包括甘油三酯和总胆固醇的水平升高和/或瘦素水平降低。
- 根据权利要求32-45任一项所述的药物,其中所述药物包括说明书,说明书中记载己酸羟孕酮剂量为30-100mg/日,或250-750mg/周,和/或己酸羟孕酮施用方案为每周给药1-7次,优选1-4次,更优选1-2次。
- 根据权利要求32-46任一项所述的药物,其中所述药物包括说明书,说明书中记载己酸羟孕酮每日剂量为20-80mg/kg;优选40-80mg/kg;更优选40或80mg/kg。
- 己酸羟孕酮在制备治疗肺纤维化的药物中的应用。
- 根据权利要求48所述的应用,其中己酸羟孕酮为所述药物中的唯一有效成分。
- 己酸羟孕酮和糖皮质激素在制备治疗肺纤维化的药物中的应用。
- 根据权利要求50所述的应用,其中所述糖皮质激素为地塞米松。
- 根据权利要求48-51任一项所述的应用,其中药物剂型为注射剂,口服制剂或外用制剂;优选注射剂,口服制剂;特别优选注射剂。
- 根据权利要求52所述的应用,其中所述注射剂包括注射液、粉针剂;口服制剂包括片剂、胶囊剂、口服液、咽喉或鼻喷剂,外用制剂包括软膏剂、喷剂、贴剂。
- 根据权利要求48-53任一项所述的应用,其中所述治疗肺纤维化包括减轻肺部炎症和纤维化症状。
- 根据权利要求48-53任一项所述的应用,其中所述治疗肺纤维化包括减少肺部胶原沉积。
- 根据权利要求48-53任一项所述的应用,其中所述治疗肺纤维化包括减少支气管肺泡灌洗液中炎症细胞计数。
- 根据权利要求48-53任一项所述的应用,其中所述治疗肺纤维化包括减少肺部组织中羟基脯氨酸水平。
- 根据权利要求48-53任一项所述的应用,其中所述治疗肺纤维化包括减少减少肺泡灌洗液和血浆中多种炎症因子水平;优选的,所述炎症因子包括TNF-α,IL-1β,IFN-γ,IL-6,TGF-β1,IL-4,MCP-1/CCL2。
- 根据权利要求48-53任一项所述的应用,其中所述治疗肺纤维化包括减少肺泡灌洗液和/或血浆中多种促纤维化因子和炎性细胞因子以及I型胶原水平,和/或增加抗纤维化因 子水平;优选的,所述促纤维化因子和和炎性细胞因子为TNF-α、IL-1β、IL-6、MCP-1、PDGF,SMAD3,SMAD2,MMP9,MMP2,CXCL-12和/或TGF-β1,所述抗纤维化因子为IFN-γ和/或IL-4;更优选的,所述促纤维化因子为TNF-α、IL-1β、IL-6、PDGF、SMAD3、SMAD2、MMP2和/或TGF-β1。
- 根据权利要求50-59任一项所述的应用,其中所述治疗肺纤维化过程中的脂代谢异常被降低。
- 根据权利要求60的所述的应用,其中所述脂代谢异常包括甘油三酯和总胆固醇的水平升高和/或瘦素水平降低。
- 治疗肺纤维化的方法,其特征在于,所述方法包括向肺纤维化患者施用己酸羟孕酮。
- 根据权利要求62所述的方法,其中所述方法中不包含施用糖皮质激素的步骤。
- 根据权利要求62所述的方法,其中所述方法中包含施用糖皮质激素的步骤。
- 根据权利要求64所述的方法,其中所述糖皮质激素为地塞米松。
- 根据权利要求62-65任一项所述的方法,其中己酸羟孕酮的剂型为注射剂,口服制剂或外用制剂;优选注射剂,口服制剂;特别优选注射剂。
- 根据权利要求66所述的方法,其中注射剂包括注射液、粉针剂;口服制剂包括片剂、胶囊剂、口服液、咽喉或鼻喷剂,外用制剂包括软膏剂、喷剂、贴剂。
- 根据权利要求62-67任一项所述的方法,其中,己酸羟孕酮剂量为30-100mg/日,或250-750mg/周。
- 根据权利要求62-67任一项所述的方法,其中己酸羟孕酮施用方案每周给药1-7次,优选1-4次,更优选1-2次。
- 根据权利要求62-67任一项所述的方法,其中所述治疗肺纤维化包括减轻肺部炎症和纤维化症状。
- 根据权利要求62-67任一项所述的方法,其中所述治疗肺纤维化包括减少肺部胶原沉积。
- 根据权利要求62-67任一项所述的方法,其中所述治疗肺纤维化包括减少支气管肺泡灌洗液中炎症细胞计数。
- 根据权利要求62-67任一项所述的方法,其中所述治疗肺纤维化包括减少肺部组织中羟基脯氨酸水平。
- 根据权利要求62-67任一项所述的方法,其中所述治疗肺纤维化包括减少肺泡灌洗液和血浆中多种炎症因子水平;优选的,所述炎症因子包括TNF-α,IL-1β,IFN-γ,IL-6, TGF-β1,IL-4,MCP-1/CCL2。
- 根据权利要求62-67任一项所述的方法,其中所述治疗肺纤维化包括减少肺泡灌洗液和/或血浆中多种促纤维化因子和炎性细胞因子以及I型胶原水平,和/或增加抗纤维化因子水平;优选的,所述促纤维化因子和和炎性细胞因子为TNF-α、IL-1β、IL-6、MCP-1、PDGF,SMAD3,SMAD2,MMP9,MMP2,CXCL-12和/或TGF-β1,所述抗纤维化因子为IFN-γ和/或IL-4;更优选的,所述促纤维化因子为TNF-α、IL-1β、IL-6、PDGF、SMAD3、SMAD2、MMP2和/或TGF-β1。
- 根据权利要求64-75任一项所述的方法,其中所述治疗肺纤维化过程中的脂代谢异常被降低。
- 根据权利要求76的所述的方法,其中所述脂代谢异常包括甘油三酯和总胆固醇的水平升高和/或瘦素水平降低。
- 用于治疗肺纤维化的药物,其特征在于,所述药物包含己酸羟孕酮。
- 根据权利要求78所述的药物,其中所述药物中己酸羟孕酮为唯一有效成分。
- 根据权利要求78所述的药物,其中所述药物中还包含糖皮质激素。
- 根据权利要求80所述的药物,其中所述糖皮质激素为地塞米松。
- 根据权利要求78-81任一项所述的药物,其中所述药物剂型为注射剂,口服制剂或外用制剂;优选注射剂,口服制剂;特别优选注射剂。
- 根据权利要求82所述的药物,其中注射剂包括注射液、粉针剂;口服制剂包括片剂、胶囊剂、口服液、咽喉或鼻喷剂,外用制剂包括软膏剂、喷剂、贴剂。
- 根据权利要求78-83任一项所述的药物,其中所述药物用于减轻肺部炎症和纤维化症状。
- 根据权利要求78-83任一项所述的药物,其中所述药物用于减少肺部胶原沉积。
- 根据权利要求78-83任一项所述的药物,其中所述药物用于减少支气管肺泡灌洗液中炎症细胞计数。
- 根据权利要求78-83任一项所述的药物,其中所述药物用于减少肺部组织中羟基脯氨酸水平。
- 根据权利要求78-83任一项所述的药物,其中所述药物用于减少肺泡灌洗液和血浆中多种炎症因子水平;优选的,所述炎症因子包括TNF-α,IL-1β,IFN-γ,IL-6,TGF-β1,IL-4,MCP-1/CCL2。
- 根据权利要求78-83任一项所述的药物,其中所述药物用于减少肺泡灌洗液和/或血 浆中多种促纤维化因子和炎性细胞因子以及I型胶原水平,和/或增加抗纤维化因子水平;优选的,所述促纤维化因子和和炎性细胞因子为TNF-α、IL-1β、IL-6、MCP-1、PDGF,SMAD3,SMAD2,MMP9,MMP2,CXCL-12和/或TGF-β1,所述抗纤维化因子为IFN-γ和/或IL-4;更优选的,所述促纤维化因子为TNF-α、IL-1β、IL-6、PDGF、SMAD3、SMAD2、MMP2和/或TGF-β1。
- 根据权利要求80-89任一项所述的药物,其中所述药物治疗肺纤维化过程中的脂代谢异常被降低.
- 根据权利要求90所述的药物,其中所述脂代谢异常包括甘油三酯和总胆固醇的水平升高和/或瘦素水平降低。
- 根据权利要求78-91任一项所述的药物,其中所述药物包括说明书,说明书中记载己酸羟孕酮剂量为30-100mg/日,或250-750mg/周,和/或己酸羟孕酮施用方案为每周给药1-7次,优选1-4次,更优选1-2次。
- 根据权利要求78-92任一项所述的药物,其中所述药物包括说明书,说明书中记载己酸羟孕酮每日剂量为20-80mg/kg;优选40-80mg/kg;更优选40或80mg/kg。
- 己酸羟孕酮,或者己酸羟孕酮与糖皮质激素的组合在制备抑制促纤维化因子和炎性细胞因子,和/或I型胶原;和/或增加抗纤维化因子水平的药物中的应用;或者作为促纤维化因子和炎性细胞因子的抑制剂的应用,和/或作为I型胶原的抑制剂的应用,和/或作为抗纤维化因子的促进剂的应用。
- 根据权利要求94所述的应用,其中所述糖皮质激素为地塞米松。
- 根据权利要求94或95的应用,其中所述炎症因子为TNF-α,IL-1β,IFN-γ,IL-6,TGF-β1,IL-4和/或MCP-1/CCL2。
- 根据权利要求94或95的应用,其中所述促纤维化因子和和炎性细胞因子为TNF-α、IL-1β、IL-6、MCP-1、PDGF,SMAD3,SMAD2,MMP9,MMP2,CXCL-12和/或TGF-β1,所述抗纤维化因子为IFN-γ和/或IL-4;更优选的,所述促纤维化因子为TNF-α、IL-1β、IL-6、PDGF、SMAD3、SMAD2、MMP2和/或TGF-β1。
- 根据权利要求94-97任一项所述的用途,其中所述药物剂型为注射剂,口服制剂或外用制剂;优选注射剂,口服制剂;特别优选注射剂。
- 根据权利要求98所述的用途,其中注射剂包括注射液、粉针剂;口服制剂包括片剂、胶囊剂、口服液、咽喉或鼻喷剂,外用制剂包括软膏剂、喷剂、贴剂。
- 抑制促纤维化因子和炎性细胞因子,和/或I型胶原;和/或增加抗纤维化因子水平的 方法,所述方法包括施用己酸羟孕酮。
- 根据权利要求100所述的方法,其中所述方法中不包含施用糖皮质激素的步骤。
- 根据权利要求100所述的方法,其中所述方法中包含施用糖皮质激素的步骤。
- 根据权利要求102所述的方法,其中所述糖皮质激素为地塞米松。
- 根据权利要求100-103任一项所述的方法,其中所述炎症因子为TNF-α,IL-1β,IFN-γ,IL-6,TGF-β1,IL-4和/或MCP-1/CCL2。
- 根据权利要求100-103任一项所述的方法,其中所述促纤维化因子和和炎性细胞因子为TNF-α、IL-1β、IL-6、MCP-1、PDGF,SMAD3,SMAD2,MMP9,MMP2,CXCL-12和/或TGF-β1,所述抗纤维化因子为IFN-γ和/或IL-4;更优选的,所述促纤维化因子为TNF-α、IL-1β、IL-6、PDGF、SMAD3、SMAD2、MMP2和/或TGF-β1。
- 根据权利要求100-105任一项所述的方法,其中己酸羟孕酮的剂型为注射剂,口服制剂或外用制剂;优选注射剂,口服制剂;特别优选注射剂。
- 根据权利要求106所述的方法,其中注射剂包括注射液、粉针剂;口服制剂包括片剂、胶囊剂、口服液、咽喉或鼻喷剂,外用制剂包括软膏剂、喷剂、贴剂。
- 根据权利要求100-107任一项所述的方法,其中,己酸羟孕酮剂量为30-100mg/日,或250-750mg/周。
- 根据权利要求100-107任一项所述的方法,其中,己酸羟孕酮每日剂量为为20-80mg/kg;优选40-80mg/kg;更优选40或80mg/kg。
- 根据权利要求100-109任一项所述的方法,其中己酸羟孕酮施用方案每周给药1-7次,优选1-4次,更优选1-2次。
- 用于抑制促纤维化因子和炎性细胞因子,和/或I型胶原;和/或增加抗纤维化因子水平的药物,其特征在于,所述药物包含己酸羟孕酮。
- 根据权利要求99所述的药物,其中所述药物中己酸羟孕酮为唯一有效成分。
- 根据权利要求99所述的药物,其中所述药物中还包含糖皮质激素。
- 根据权利要求101所述的药物,其中所述糖皮质激素为地塞米松。
- 据权利要求111-114任一项所述的药物,其中所述炎症因子为TNF-α,IL-1β,IFN-γ,IL-6,TGF-β1,IL-4和/或MCP-1/CCL2。
- 根据权利要求111-114任一项所述的药物,其中所述促纤维化因子和和炎性细胞因子为TNF-α、IL-1β、IL-6、MCP-1、PDGF,SMAD3,SMAD2,MMP9,MMP2,CXCL-12和/或TGF-β1,所述抗纤维化因子为IFN-γ和/或IL-4;更优选的,所述促纤维化因子为TNF-α、 IL-1β、IL-6、PDGF、SMAD3、SMAD2、MMP2和/或TGF-β1。
- 根据权利要求111-116任一项所述的药物,其中所述药物剂型为注射剂,口服制剂或外用制剂;优选注射剂,口服制剂;特别优选注射剂。
- 根据权利要求117所述的药物,其中注射剂包括注射液、粉针剂;口服制剂包括片剂、胶囊剂、口服液、咽喉或鼻喷剂,外用制剂包括软膏剂、喷剂、贴剂。
- 根据权利要求111-118任一项所述的药物,其中所述药物包括说明书,说明书中记载己酸羟孕酮剂量为30-100mg/日,或250-750mg/周,和/或己酸羟孕酮施用方案为每周给药1-7次,优选1-4次,更优选1-2次。
- 根据权利要求111-119任一项所述的药物,其中所述药物包括说明书,说明书中记载己酸羟孕酮每日剂量为20-80mg/kg;优选40-80mg/kg;更优选40或80mg/kg。
- 根据权利要求1-120任一项所述的药物,方法或应用,其中药物还包括药学上可接受的辅料,所述药学上可接受的辅料包括但不限于溶剂、助溶剂、稳定剂、分散剂、粘度调节剂、抗氧化剂、甜味剂、粘合剂、气体发生剂。
- 根据权利要求1-121任一项所述的药物,方法或应用,其中己酸羟孕酮为方法或药物中的唯一有效成分;或者在方法中还包括施用其他有效成分或药物中还包含其他有效成分;所述其他有效成分包括但不限于糖皮质激素类药物,糖皮质激素类之外的其他抗炎药物,抗纤维化药物如吡非尼酮,尼达尼布,抗酸药物,提高血氧水平的药物或装置。
- 己酸羟孕酮制备减少糖皮质激素引起的脂代谢异常的药物中的应用。
- 根据权利要求123所述的应用,其中所述糖皮质激素为地塞米松。
- 根据权利要求123或124所述的应用,其中所述脂代谢异常包括甘油三酯和总胆固醇的水平升高和/或瘦素水平降低。
- 减少糖皮质激素引起的脂代谢异常的方法,其特征在于,包括施用己酸羟孕酮。
- 根据权利要求126所述的方法,其中所述糖皮质激素为地塞米松。
- 根据权利要求126或127所述的方法,其中所述脂代谢异常包括甘油三酯和总胆固醇的水平升高和/或瘦素水平降低。
- 根据上述任一权利要求所述的应用或者方法或药物,其中,己酸羟孕酮每日剂量为20-80mg/kg;优选40-80mg/kg;更优选40或80mg/kg;和/或地塞米松剂量为1-2mg/kg,优选1mg/kg或2mg/kg;其中己酸羟孕酮与地塞米松联合施用时,优选施用方案为:己酸羟孕酮40mg/kg+地塞米松2mg/kg,优选己酸羟孕酮40mg/kg+地塞米松1mg/kg。
- 根据上述任一权利要求所述的应用或者方法或药物,所述的间质性肺炎包括但不限 于特发性间质性肺炎,以及特发性间质性肺炎的各个亚型,包括但不限于特发性肺纤维化,非特异性间质性肺炎,隐源性机化性肺炎,急性间质性肺炎,呼吸性细支气管炎伴间质性肺疾病,脱屑性间质性肺炎和淋巴细胞性间质性肺炎;优选特发性肺纤维化;所述的肺纤维化包括各种原因导致的肺纤维化,包括但不限于特发性肺纤维化、原发性肺纤维化、继发性非纤维化、间质性肺纤维化等;优选特发性肺纤维化。
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