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EP-4119139-B1 - ICARITIN FOR USE IN THE TREATMENT OF A BLEEDING DISORDER CAUSED BY PLATELET DYSFUNCTION

EP4119139B1EP 4119139 B1EP4119139 B1EP 4119139B1EP-4119139-B1

Inventors

  • ZHANG, Guimin
  • YAO, Jingchun
  • SUN, Chenghong
  • LI, BIN
  • PAN, Sina

Dates

Publication Date
20260513
Application Date
20210309

Claims (8)

  1. Icaritin for use in preventing or treating a bleeding disorder caused by platelet dysfunction, wherein the bleeding disorder caused by the platelet dysfunction is hemorrhagic transformation after cerebral infarction, gastrointestinal bleeding caused by a thrombolytic or antithrombotic drug for cerebral infarction, or a bleeding complication of a thrombolytic or antithrombotic drug for myocardial infarction.
  2. Icaritin for use according to claim 1, wherein the hemorrhagic transformation after cerebral infarction is secondary, primary or asymptomatic hemorrhagic transformation after ischemic cerebral infarction; preferably, the secondary hemorrhagic transformation is caused by using one or more treatment methods of a thrombolytic drug, an antithrombotic drug and endovascular therapy; further preferably, the thrombolytic drug is selected from the group consisting of urokinase, streptokinase, reteplase, alteplase, tenecteplase and lanoteplase; further preferably, the antithrombotic drug is one or more of an anticoagulant drug and an antiplatelet drug; further preferably, the anticoagulant drug is selected from the group consisting of heparin or a pharmaceutically acceptable salt thereof, low-molecular-weight heparin or a pharmaceutically acceptable salt thereof, and recombinant hirudin; further preferably, the antiplatelet drug is selected from the group consisting of aspirin, clopidogrel and ticlopidine; and preferably, the primary hemorrhagic transformation is spontaneous hemorrhagic transformation after acute cerebral infarction.
  3. Icaritin for use according to claim 1, wherein in the bleeding complication of a thrombolytic or antithrombotic drug for myocardial infarction, the thrombolytic drug is selected from the group consisting of urokinase, streptokinase, reteplase, alteplase, tenecteplase and lanoteplase; the antithrombotic drug is used for antithrombotic treatment in an onset stage, and primary and secondary prevention stages of myocardial infarction; or the antithrombotic drug is one or more of an anticoagulant drug or an antiplatelet drug; preferably, the antiplatelet drug is selected from the group consisting of aspirin, clopidogrel and ticlopidine; and the anticoagulant drug is selected from the group consisting of heparin or a pharmaceutically acceptable salt thereof, low-molecular-weight heparin or a pharmaceutically acceptable salt thereof, and recombinant hirudin; and preferably, the bleeding complication is one or more of subcutaneous bleeding, intracranial bleeding, upper gastrointestinal bleeding or gingival bleeding.
  4. Icaritin for use according to claim 1, wherein in the gastrointestinal bleeding caused by a thrombolytic or antithrombotic drug for cerebral infarction, the thrombolytic drug is one or more of urokinase, streptokinase, reteplase, alteplase, tenecteplase or lanoteplase; and the antithrombotic drug is one or more of an anticoagulant drug or an antiplatelet drug; and preferably, the antiplatelet drug is selected from the group consisting of aspirin, clopidogrel and ticlopidine; and the anticoagulant drug is selected from the group consisting of heparin or a pharmaceutically acceptable salt thereof, low-molecular-weight heparin or a pharmaceutically acceptable salt thereof, and recombinant hirudin.
  5. Icaritin for use according to claim 1, wherein the platelet dysfunction is platelet activation or aggregation dysfunction; preferably, the platelet dysfunction is congenital platelet defect or acquired platelet defect; preferably, the congenital platelet defect is hereditary giant platelet syndrome, hereditary Glanzmann thrombasthenia or congenital connective tissue disease; and the acquired platelet defect is caused by a drug or a disease; and further preferably, the drug is one or more of an antimicrobial drug, an anti-tumor drug or heparin, and the disease is one or more of uremia, diabetes, nephrotic syndrome, coronary heart disease or leukemia.
  6. Icaritin for use according to any one of claims 1-5, wherein icaritin is in a form of pharmaceutical formulation, the pharmaceutical formulation is an injection, powder for injection, a capsule, a tablet, a microemulsion, a dropping pill or an enteric soft capsule.
  7. Icaritin for use according to any one of claims 1-5, wherein icaritin is administrated at a dose of 0.01 mg/kg-100 mg/kg.
  8. Icaritin for use according to claim 7, wherein icaritin is administrated at a dose of 0.1 mg/kg-10 mg/kg.

Description

FIELD OF TECHNOLOGY The present disclosure belongs to the field of medicine, and relates to medical use of icaritin, in particular to the use in preparing a drug for preventing or treating a bleeding disorder. BACKGROUND When a human blood vessel is injured, blood can flow out or seep out of the blood vessel. At this time, the body will stop bleeding through a series of physiological reactions and the process is called hemostasis. The hemostasis involves a variety of factors and a series of complex physiological and biochemical reactions. Bleeding disorders are characterized by spontaneous bleeding or continuous bleeding after vascular injury due to defective hemostatic functions. The bleeding disorders can be classified into the following main types according to etiology and pathogenesis. (I) Caused by platelet dysfunction. The bleeding disorders comprise hemorrhagic transformation after cerebral infarction, gastrointestinal bleeding caused by thrombolytic or antithrombotic drugs for cerebral infarction, or bleeding complications of thrombolytic or antithrombotic drugs for myocardial infarction. The hemorrhagic transformation after cerebral infarction is secondary, primary or asymptomatic hemorrhagic transformation after ischemic cerebral infarction. A thrombolytic drug or anticoagulant drug treatment is effective for treating acute ischemic infarction at present, but can also cause various serious complications such as hemorrhagic transformation and the like while dissolving thrombus, and therefore, the clinical application of the treatment is seriously limited. At present, western medicine only prevents and treats various complications after the thrombolytic drug or anticoagulant drug treatment from each single link or single factor, and does not obtain a satisfactory curative effect. Therefore, it is very important to fully exert advantages of traditional Chinese medicines in integral regulation and multi-link comprehensive treatment and find an effective treatment method and a prescription capable of relieving or eliminating various bleeding transformation risks while dissolving thrombus to improve short-term and long-term curative effects of thrombolytic treatment of infarction diseases. (II) Caused by vessel wall abnormalities. The vessel wall abnormalities are congenital or genetic and acquired. The congenital vessel wall abnormalities comprise hereditary hemorrhagic telangiectasia; familial purpura simplex and congenital connective tissue disease. (III) Caused by coagulation abnormalities. The coagulation abnormalities are congenital or genetic and acquired. The congenital coagulation abnormalities refer to hemophilia A and B and hereditary FXI deficiency, hereditary prothrombin, FV, FVII and FX deficiencies, hereditary fibrinogen deficiency and hypofibrinogenemia, hereditary FXII deficiency and hypofunction. The hereditary coagulation abnormalities refer to coagulation disorders in liver disease, vitamin K deficiency, formation of anti-factor VIII and IX antibodies, coagulation disorders in uremia, etc. (IV) Caused by anticoagulation and fibrinolysis abnormalities. The bleeding disorders are mainly acquired and caused by factors including but not limited to heparin overuse, coumarin overdose, increased immune-related anticoagulants or overdose of thrombolytic drugs. Herba epimedii is dry stems and leaves of Epimedium brevicornum Maxim., Epimedium sagittatum Maxim., Epimedium pubescens Maxim. or Epimedium koreanum Nakai. The herba epimedii is mainly used for treating kidney-yang deficiency, impotence, frequent micturition and infertility, rheumatism pain, numbness and contracture of limbs, flaccidity of muscles and bones, difficulty in walking, dyspnea with cough and shortness of breath clinically. Icaritin (IT) is a polyhydroxy flavonoid monomer component in Epimedium brevicornu belonging to Epimedium of Berberidaceae. Pharmacological researches show that the icaritin has a stronger osteoporosis resisting effect than other flavonoid glycoside compounds in herba epimedii and has effects on promoting osteoblast activity and inhibiting osteoclast activity in vitro. Icariin and icaritin, as important active ingredients in herba epimedii, are receiving more attention from medical workers in recent years. For example, patent application CN101637467A discloses use of icaritin in preparing a drug for treating osteoporosis. Patent US6399579 discloses use of icaritin in treating sexual dysfunction. CN104546823A discloses the use of icaritin for the treatment of thrombocytopenia. SUMMARY During a study, the applicant finds that icaritin can relieve platelet dysfunction, shorten thromboplastin time, and promote blood coagulation, and can be used for preventing and treating platelet dysfunction and a bleeding disorder caused thereby. The invention is set out in the appended set of claims. The bleeding disorder caused by the platelet dysfunction is selected from the group consisting of hemorrhagic transformatio