WO2023066162A1 - 莰醇在制备治疗缺血性脑卒中的药物中的用途 - Google Patents

莰醇在制备治疗缺血性脑卒中的药物中的用途 Download PDF

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WO2023066162A1
WO2023066162A1 PCT/CN2022/125421 CN2022125421W WO2023066162A1 WO 2023066162 A1 WO2023066162 A1 WO 2023066162A1 CN 2022125421 W CN2022125421 W CN 2022125421W WO 2023066162 A1 WO2023066162 A1 WO 2023066162A1
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ischemic stroke
stroke
treatment
drug
patients
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PCT/CN2022/125421
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French (fr)
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鱼刚
江传亮
曹宇
邓世平
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苏州沪云新药研发股份有限公司
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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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • 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

Definitions

  • the present application relates to the field of biomedicine, in particular to the use of borneol in the preparation of medicines for treating ischemic stroke.
  • Stroke is the second leading cause of human death and the leading cause of death in my country. It is also listed as the third leading cause of death along with ischemic heart disease and malignant tumors.
  • the current number of stroke patients aged 40 and above in my country It has reached 12.42 million, and it is showing an increasing trend year by year. On average, one person has a stroke every 7 seconds, and one person dies of a stroke every 21 seconds.
  • the mortality rate of hospitalized stroke patients in my country is 2.3% to 3.2% within 1 month after onset, 9% to 9.6% in 3 months, 34.5% to 37.1% in 3 months, and 14.4% in 1 year ⁇ 15.4%, 1-year death/disability rate 33.4% ⁇ 33.8%.
  • Ischemic stroke has the characteristics of high morbidity, high disability and high mortality. It is one of the main causes of death for adults in my country. It is also the disease with the highest disability rate of a single disease, which brings heavy burdens to society and families (Stroke-1989. Recommendations on stroke prevention, diagnosis, and therapy. Report of the WHO Task Force on Stroke and other Cerebrovascular Disorders [J]. Stroke, 1989, 20(10): 1407-1431; Acute ischemia in China Guidelines for Diagnosis and Treatment of Acute Stroke 2018; China Cardiovascular Disease Report 2018).
  • Stroke includes ischemic stroke and hemorrhagic stroke.
  • Cerebral ischemic stroke is the localized ischemic necrosis or softening of brain tissue caused by cerebral blood circulation disorder and ischemia and hypoxia. The main causes include: large artery atherosclerosis, small artery sclerosis and occlusion due to factors such as high blood pressure, blood-derived embolism, increased blood viscosity, and vasospasm.
  • Acute ischemic stroke generally refers to stroke within two weeks of onset, accounting for 69.6%-70.8% of all strokes. In my country, there are more than 2 million new patients with acute ischemic stroke each year (Wang W, Jiang B, Sun H , et al.
  • thrombolysis In addition to effective secondary prevention and stroke rehabilitation for ischemic stroke, there are currently very limited treatment options in the acute phase, mainly including thrombolysis, endovascular interventional therapy, and neuroprotection. Due to the limited treatment time window ( ⁇ 4.5h) and many contraindications, only a small number of patients ( ⁇ 3%) benefited from thrombolysis.
  • 3Animal model The animals used in preclinical tests are generally young and healthy male animals with uniform body weight and age, a single model of cerebral ischemia, and generally no other concurrent diseases; There is no significant difference, and generally accompanied by a variety of chronic diseases (such as arteriosclerosis, hypertension, diabetes and previous stroke history, etc.), these concomitant diseases will not only affect the functional recovery of patients, but also affect the efficacy, metabolism and safety of drugs .
  • chronic diseases such as arteriosclerosis, hypertension, diabetes and previous stroke history, etc.
  • 4Drug treatment time window Preclinical animal experiments can carry out drug treatment or prevention at any time point after ischemia, and the method and route of administration can also be determined and adjusted according to requirements; however, when cerebral ischemia occurs in clinical patients is unpredictable It is estimated that medication in advance is not feasible at all, and it will take some time from the occurrence of cerebral ischemia to the treatment of the doctor. In clinical practice, the possibility of drug treatment within 2 hours after the occurrence of cerebral ischemia is very small. The treatment time window for most patients is 6 hours or longer after stroke. 5Other factors (Chin J Clin Pharmacol2013, 29(11), 869-871).
  • Huang Ruxun a famous neurology expert in my country, proposed the principle of individualized treatment based on classification and staging.
  • NIHSS National Institutes of Health Stroke Scale
  • the NIHSS score has a total of 42 points and 11 items. It has been widely used in international multi-center randomized controlled studies. It is a recognized scoring system for stratifying the severity of stroke patients.
  • the scoring items and scoring standards are as follows:
  • the NIHSS score can characterize the severity of ischemic stroke, prompt the etiology, affect the doctor's diagnosis, and affect the choice of treatment. It can also be used as a category of ischemic stroke in terms of drug application , basis for different indications or contraindications.
  • the stroke severity of patients can be distinguished by NIHSS score.
  • the NIHSS score is a scale for evaluating the severity of neurological deficits. The score ranges from 0 to 42 points. When the neurological deficit is more severe, the score increases accordingly, which also indicates the large size of cerebral infarction, severe damage to the blood-brain barrier, and bleeding. The risk of transformation further increases (“Study on risk factors for hemorrhagic transformation and prognosis in patients with acute cerebral infarction treated with intravenous thrombolysis”, Duan Yanlong et al., Journal of Stroke and Neurological Diseases, 2021). It can be seen that the NIHSS score can reflect the state of stroke.
  • NIHSS score will suggest etiology.
  • An NIHSS score ⁇ 9 within 3 hours of onset or ⁇ 7 within 6 hours of onset indicates the presence of large vessel occlusion (“Endovascular Therapy for Acute Ischemic Stroke (Chinese Guidelines 2018)”).
  • the NIHSS score can affect a doctor's diagnosis. According to the "Guiding Principles for the Construction and Management of Hospital Stroke Centers (Trial)", the hospital first needs to carry out “medical history collection, physical examination, neurological deficit score (NIHSS), vital signs assessment, and head imaging Examination, blood biochemical and other auxiliary examination” step, and then carry out the treatment step. It is generally believed that "ischemic stroke with NIHSS score ⁇ 5 points” is “mild ischemic stroke", and "ischemic stroke with 6 ⁇ NIHSS score ⁇ 15 points” is “moderate ischemic stroke”.
  • ischemic stroke with 15 ⁇ NIHSS score ⁇ 20 points as “moderate-severe ischemic stroke” or “severe ischemic stroke”
  • ischemic stroke with NIHSS score > 20 Stroke is "very critical ischemic stroke”.
  • NIHSS score will affect the choice of treatment. For example, "Chinese Guidelines for the Diagnosis and Treatment of Acute Ischemic Stroke 2014" listed NIHSS score ⁇ 25 as a relative contraindication for intravenous thrombolytic therapy; It is one of the criteria for judging whether to carry out endovascular treatment. As another example, for mild stroke patients (NIHSS score ⁇ 3) who have not received intravenous thrombolytic therapy, dual antiplatelet therapy (aspirin and clopidogrel) should be started as soon as possible within 24 hours of onset and maintained for 21 days (refer to "Chinese Acute Thrombotic Disorders”) Antithrombotic Therapy Consensus”). The industry often considers NIHSS scores when studying stroke treatment methods.
  • thrombectomy vs medical management in low NIHSS acute anterior circulation stroke "Neurology 2020;95:e3364-e3372.
  • thrombectomy vs medical management in low NIHSS acute anterior circulation stroke
  • AIS-LVO anterior circulation acute large vessel occlusive ischemic stroke
  • NIHSS score has the above-mentioned important medical significance, it has been included in the division of indications and contraindications of some marketed drugs.
  • the China Food and Drug Administration (CFDA) stipulated in the "Chemical Drugs and Therapeutic Biological Products Specification Specifications” (2006) that "[Indications] should be based on the use of the drug, using an accurate expression, clearly for the Prevention, treatment, diagnosis, alleviation or auxiliary treatment of certain diseases (states) or symptoms”, “[Contraindications] The population or disease conditions for which the drug is prohibited should be listed”. That is, the target disease or state and the target population are considerations for differentiating the indications of a drug.
  • the contraindications include "severe stroke assessed clinically (NIHSS>25) and/or imaging examination".
  • NIHSS acute ischemic stroke
  • the FDA approved the antiplatelet drug ticagrelor for stroke risk in patients with acute ischemic stroke (NIHSS score ⁇ 5) or high-risk transient ischemic attack.
  • NIHSS score has been reflected in the drug description and is used to characterize the indication range of the drug.
  • the NIHSS score can be used to classify the disease type of ischemic stroke, and form a corresponding relationship with the application of drugs.
  • NIHSS score covers the assessment of the patient's level of consciousness, gaze, visual field, upper and lower extremity movements, etc. It is designed for humans and cannot be implemented through animal experiments or in vitro experiments.
  • (+)-2-camphor is usually used as a drug adjuvant for the treatment of stroke and other diseases, such as in combination with active ingredients such as edaravone for the treatment of stroke, but there is no (+) - A report of 2-borneol alone as an active ingredient in the treatment of patients with ischemic stroke.
  • single-component (+)-2-camphorol has a high degree of selectivity to the ischemic stroke patient population, and has an excellent effect in the treatment of stroke patients with NIHSS score ⁇ 6 points.
  • the effect of treatment is relatively poor or not effective in stroke patients with NIHSS score ⁇ 5 points.
  • the drug group showed significantly higher The difference in absolute effect (patients returning to mRS 0-1 at day 90 representing recovery to full recovery or no disability) was significant.
  • (+)-2-borneol has good human safety, and (+)-2-borneol alone as an active ingredient in the treatment of stroke can effectively avoid the use of other active ingredients in ischemic stroke prevention and/or Or adverse reactions during treatment (such as combined use of edaravone, because the addition of edaravone will cause serious liver and kidney toxicity).
  • (+)-2-camphor alone can improve the dosage of (+)-2-camphor as an active ingredient in human body (such as combined use with edaravone is limited by edaravone toxicity, (+)- The single dose of 2-camphorol is limited to 7.5mg), so as to improve the prevention and/or treatment effect of ischemic stroke.
  • (+)-2-camphorol as the only active ingredient in the preparation of a medicament for treating patients with specific ischemic stroke subtypes or types.
  • Another object of the present invention is to provide a method for treating specific ischemic stroke, comprising administering (+)-2-borneol, a pharmaceutically acceptable salt or ester thereof, to a subject in need thereof, One or a combination of its prodrug, its metabolite, and its solvate.
  • the present application provides the use of (+)-2-camphor in the preparation of a medicament for preventing and/or treating ischemic stroke, wherein the NIHSS score of said ischemic stroke is ⁇ 6 points.
  • the present application provides the use of (+)-2-camphor in the preparation of a drug for improving the prevention and/or treatment effect of ischemic stroke, wherein the NIHSS score of said ischemic stroke is ⁇ 6 point.
  • the preventive and/or therapeutic effects are selected from any one or combination of alleviating symptoms, improving prognosis, reducing the degree of neurological deficit, and improving the daily activity of patients.
  • the effect of (+)-2-camphor is selected from the group consisting of regulating energy metabolism and redox metabolism, improving the survival rate of ischemic injured neurons, and reducing the size of cerebral infarction caused by ischemic stroke , improving any one or combination of neurobehavioral features of ischemic stroke.
  • the application provides the use of (+)-2-camphorol in the preparation of drugs for reducing or avoiding adverse reactions in the prevention and/or treatment of ischemic stroke, wherein the ischemic stroke
  • the NIHSS score of stroke is ⁇ 6 points.
  • the way of reducing or avoiding the adverse reactions in the prevention and treatment of ischemic stroke is selected from: replacing other drugs, reducing the type and/or dosage of other drugs used by patients, and improving the brain function of patients. Provide any one or combination of continuous and stable treatments throughout the stroke prevention and treatment.
  • the ischemic stroke is selected from ischemic stroke with 6 ⁇ NIHSS score ⁇ 20 points.
  • the present application provides the use of (+)-2-camphor in the preparation of a medicament for the prevention and/or treatment of ischemic stroke, wherein the ischemic stroke is selected from moderate, moderate-severe Or any of the patients with severe ischemic stroke.
  • the medicament comprises (+)-2-borneol as the active ingredient only.
  • the (+)-2-camphor also includes pharmaceutically acceptable salts or esters thereof, metabolites thereof, prodrugs thereof, or solvates thereof.
  • the present application provides a method for preventing and/or treating specific ischemic stroke, comprising administering only an effective amount of a drug whose active ingredient is selected from (+)- One or a combination of 2-camphor, its pharmaceutically acceptable salt or ester, its metabolite, its prodrug, and its solvate, and the NIHSS score of the ischemic stroke is ⁇ 6 points.
  • the present application provides a method for improving the effect of preventing and/or treating ischemic stroke, comprising administering only an effective amount of a drug to a subject in need, the active ingredient of which is selected from (+) - One or a combination of 2-camphor, its pharmaceutically acceptable salt or ester, its prodrug, its metabolite, and its solvate, and the NIHSS score of the ischemic stroke is ⁇ 6 points .
  • the preventive and/or therapeutic effects are selected from any one or combination of alleviating symptoms, improving prognosis, reducing the degree of neurological deficit, and improving the daily activity of patients.
  • the effect of the active ingredient is selected from the group consisting of regulating energy metabolism and redox metabolism, increasing the survival rate of neurons injured by ischemia, reducing the size of cerebral infarction caused by ischemic stroke, and improving ischemic cerebral infarction. Any one or combination of neurobehavioral features of stroke.
  • the present application provides a method for reducing or avoiding adverse reactions during the prevention and/or treatment of ischemic stroke, comprising administering only an effective amount of a drug to a subject in need, the drug's
  • the active ingredient is selected from one or a combination of (+)-2-camphor, its pharmaceutically acceptable salt or ester, its prodrug, its metabolite, and its solvate, and the ischemic brain NIHSS score ⁇ 6 points for stroke.
  • the way of reducing or avoiding adverse reactions in the prevention and treatment of ischemic stroke is selected from: replacing other drugs, reducing the type and/or dosage of other drugs used by patients, providing patients with Provide any one or combination of continuous and stable treatments throughout the stroke prevention and treatment.
  • stroke is well known in the art.
  • a stroke can be occlusive (due to a closed blood vessel) or hemorrhagic (due to bleeding from a blood vessel).
  • ischemia refers to the lack of blood supply and oxygen that occurs when autoregulatory dilation of resistive blood vessels fails to compensate for reduced perfusion pressure distal to abnormal narrowing (coarctation) of blood vessels.
  • strokes of either type can occur at any age for a variety of reasons, These causes include heart disease, trauma, infection, tumors, blood dyscrasias, vascular malformations, immune disorders, and exogenous toxins.
  • stroke generally refers to ischemic stroke, usually due to decreased blood flow to the brain or parts thereof, which results in insufficient oxygen supply to brain cells.
  • a stroke causes irreversible tissue damage due to the death of brain cells.
  • the symptoms of stroke are well known in the art. For example, stroke symptoms include sudden numbness or weakness in the face, arm, or leg (especially on one side of the body), sudden confusion, trouble speaking or understanding, sudden loss of vision in one or both eyes, and sudden trouble walking , dizziness, loss of balance or coordination.
  • Ischemic stroke may result from atherothrombosis or cerebral aortic embolism, from coagulopathy or nonneoplastic vascular disease, or from cardiac ischemia that results in a decrease in total blood flow. Examples include atherothrombotic stroke, cardioembolic stroke, and lacunar stroke. Atrial fibrillation can also cause cardioembolic stroke (also commonly called embolic or thromboembolic stroke).
  • (+)-2-borneol also known as d-borneol or ((+)-borneol)
  • (+)-2-borneol is the main component of natural borneol (the 2015 edition of Chinese Pharmacopoeia stipulates that the content of d-borneol in natural borneol should not be less than 96%) .
  • Dextamphalol is a bicyclic monoterpenoid compound, which exists in the volatile oil of many Chinese herbal medicines, and exhibits various biological activities, such as anti-inflammatory, anti-oxidation and enhancing GABA receptor function, etc. (Euro J Pharma 2017,811:1 -11).
  • the structural formula of D-borneol is as follows:
  • the term "pharmaceutically acceptable salt” generally means suitable for use in contact with the tissues of the subject without undue toxicity, irritation, allergic reaction, etc. within the scope of sound medical judgment, and with Take those with a reasonable benefit/risk ratio with a grain of salt.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19.
  • prodrug generally refers to a compound that is readily converted in vivo (eg, by enzymes in the blood) by enzymatic hydrolysis to yield the parent compound.
  • a comprehensive discussion is provided in T. Higuchi and V. Stella in the A.C.S. Proceedings series, Prodrugs as Novel Delivery Systems, Volume 14, and in Bioreversible Carriers in Drug Design, edited by Edward B. Roche, American Pharmaceutical Association and Permagon Press, 1987 , both of which are incorporated herein by reference.
  • the term "metabolite” generally refers to a derivative of any formula that is produced in an individual following administration of a parent compound (eg, (+)-2-borneol).
  • parent compound eg, (+)-2-borneol
  • These derivatives can be produced from the parent compound by various biochemical transformations in the body of an individual such as oxidation, reduction, hydrolysis or conjugation, and include, for example, oxide and demethylated derivatives.
  • Metabolites of the compounds of the invention can be identified using routine techniques known in the art. See, eg, Bertolini, G. et al., J. Med. Chem. 40: 2011-2016 (1997); Shan, D. et al., J. Pharm. Sci. 86(7): 765-767; Bagshawe K. , Drug Dev. Res.
  • solvate is used in a conventional sense, generally referring to a complex of a solute (eg, an active compound, a salt of an active compound) and a solvent. If the solvent is water, the solvate may conveniently be referred to as a hydrate.
  • prevention and/or treatment includes not only preventing and/or treating a disease, but also generally preventing the onset of a disease, slowing or reversing the progression of a disease, preventing or slowing down one or more symptoms associated with a disease onset, reduction and/or alleviation of one or more symptoms associated with the disease, reduction of the severity and/or duration of the disease and/or any symptoms associated therewith and/or prevention of the disease and/or any symptoms associated therewith prevent, reduce or reverse any physiological impairment caused by the disease, and generally any pharmacological effect that is beneficial to the patient being treated.
  • disease or “condition” are used interchangeably and generally refer to any deviation from the normal state of a subject, such as any change in the state of the body or certain organs that prevents or disrupts the performance of function , and/or cause symptoms such as malaise, dysfunction, suffering or even death in those who are sick or come into contact with it.
  • a disease or condition may also be called a disorder, ailing, ailment, malady, disorder, sickness, illness, complaint, inderdisposion or affectation.
  • the term "administration" generally refers to introducing the pharmaceutical formulation of the present application into the body of a subject by any route of introduction or delivery. Any method known to those skilled in the art for contacting cells, organs or tissues with the drug may be used. Such administration may include, without limitation, intravenous, intraarterial, intranasal, intraperitoneal, intramuscular, subcutaneous transdermal or oral.
  • the daily dose may be divided into one, two or more doses of suitable form to be administered at one, two or more times during a certain period of time.
  • the term “effective amount” or “effective dose” generally refers to an amount sufficient to achieve, or at least partially achieve, the desired effect.
  • a “therapeutically effective amount” or “therapeutically effective dose” of a drug or therapeutic agent is typically one that, when used alone or in combination with another therapeutic agent, promotes regression of disease (by reducing the severity of disease symptoms, frequency of asymptomatic periods of disease), any amount of drug that is evidenced by an increase in the degree and duration of the disease, or by the prevention of impairment or disability due to the presence of a disease.
  • a “prophylactically effective amount” or “prophylactically effective dose” of a drug generally refers to the amount of the drug that, alone or in combination with another therapeutic agent, inhibits the development or recurrence of the disease when administered to a subject at risk of disease development or disease recurrence .
  • the ability of a therapeutic or prophylactic agent to promote disease regression or inhibit disease progression or recurrence can be assessed using a variety of methods known to those skilled in the art, such as in human subjects during clinical trials, in animal model systems Efficacy in humans is predicted, or by assaying the activity of the agent in an in vitro assay.
  • the term "subject” generally refers to a human or non-human animal (including mammals), such as a human, a non-human primate (ape, or , gibbons, gorillas, chimpanzees, orangutans, macaques), domestic animals (dogs and cats), farm animals (poultry such as chickens and ducks, horses, cows, goats, sheep, pigs) and laboratory animals (mice, rats, rabbits , guinea pig).
  • Human subjects include fetal, neonatal, infant, adolescent and adult subjects.
  • Subjects include animal disease models.
  • the term “about” generally means approximately, in the vicinity of, roughly, or around.
  • a cut-off or a specific value is used to indicate that the stated value may vary by as much as 10% from the recited value.
  • the term “about” may be used to encompass a variation of ⁇ 10% or less, ⁇ 5% or less, ⁇ 1% or less, ⁇ 0.5% or less, or ⁇ 0.5% or less from the specified value. 0.1% or less variation.
  • stroke has the same meaning as "stroke” for the name of the disease.
  • ischemic stroke usually refers to "ischemic stroke with NIHSS score ⁇ 5 points”
  • moderate ischemic stroke usually refers to "6 ⁇ NIHSS score ⁇ 15
  • Score ischemic stroke "severe ischemic stroke” or “moderate-severe ischemic stroke” usually refers to "ischemic stroke with 15 ⁇ NIHSS score ⁇ 20 points”
  • critically ill ischemic stroke Hemorrhagic stroke
  • the present application provides the use of (+)-2-camphor in the preparation of a medicament for preventing and/or treating ischemic stroke, wherein the NIHSS score of said ischemic stroke is ⁇ 6 points.
  • the ischemic stroke can be selected from ischemic stroke with 6 ⁇ NIHSS score ⁇ 20 points.
  • the ischemic stroke can be selected from ischemic stroke with NIHSS score>20.
  • the ischemic stroke score may be 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or higher.
  • the medicament comprises only one of (+)-2-borneol, a pharmaceutically acceptable salt or ester thereof, a metabolite thereof, a prodrug thereof, and a solvate thereof, or Combination as active ingredient.
  • the medicament contains only (+)-2-borneol as active ingredient.
  • the present application provides the use of (+)-2-camphor in the preparation of a drug for improving the prevention and/or treatment effect of ischemic stroke, wherein the NIHSS score of said ischemic stroke is ⁇ 6 points.
  • the preventive and/or therapeutic effects are selected from any one or combination of alleviating symptoms, improving prognosis, reducing the degree of neurological deficit, and improving the daily activity of patients.
  • the effect of (+)-2-camphor is selected from the group consisting of regulating energy metabolism and redox metabolism, improving the survival rate of ischemic injured neurons, and reducing the size of cerebral infarction caused by ischemic stroke , improving any one or combination of neurobehavioral features of ischemic stroke.
  • the medicament comprises only one of (+)-2-borneol, a pharmaceutically acceptable salt or ester thereof, a metabolite thereof, a prodrug thereof, and a solvate thereof, or Combination as active ingredient.
  • the present application provides the use of (+)-2-camphorol in the preparation of medicines for reducing or avoiding adverse reactions in the prevention and/or treatment of ischemic stroke, wherein the ischemic stroke
  • the NIHSS score of acute stroke is ⁇ 6 points.
  • the way of reducing or avoiding the adverse reactions in the prevention and treatment of ischemic stroke is selected from: replacing other drugs, reducing the type and/or dosage of other drugs used by patients, and improving the brain function of patients. Provide any one or combination of continuous and stable treatments throughout the stroke prevention and treatment.
  • the other drugs are selected from any one of intravenous thrombolytic drugs, antiplatelet drugs, anticoagulant drugs, defibrosis drugs, volume expansion drugs, microcirculation improving drugs, neuroprotective agents, or a combination thereof use.
  • the medicament comprises only one of (+)-2-borneol, a pharmaceutically acceptable salt or ester thereof, a metabolite thereof, a prodrug thereof, and a solvate thereof, or Combination as active ingredient.
  • the medicament contains only (+)-2-borneol as active ingredient.
  • the present application provides a method for preventing and/or treating ischemic stroke, comprising administering to a subject in need only an effective amount of a drug, the active ingredient of which is selected from (+)-2 - one or a combination of camphenol, its pharmaceutically acceptable salt or ester, its metabolite, its prodrug, and its solvate, and the NIHSS score of said ischemic stroke is ⁇ 6 points.
  • the ischemic stroke can be selected from ischemic stroke with 6 ⁇ NIHSS score ⁇ 20 points. In other embodiments, the ischemic stroke can be selected from ischemic stroke with NIHSS score>20.
  • the ischemic stroke score can be 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or higher.
  • the medicament comprises (+)-2-borneol as the active ingredient only.
  • it also includes combining the drug with any one or a combination of intravenous thrombolytic drugs, antiplatelet drugs, anticoagulant drugs, defibrosis drugs, volume expansion drugs, microcirculation improving drugs, neuroprotective agents Combined use.
  • the preventive and/or therapeutic effects are selected from any one or combination of alleviating symptoms, improving prognosis, reducing the degree of neurological deficit, and improving the daily activity of patients.
  • the effect of the active ingredient is selected from the group consisting of regulating energy metabolism and redox metabolism, increasing the survival rate of neurons injured by ischemia, reducing the size of cerebral infarction caused by ischemic stroke, and improving ischemic cerebral infarction. Any one or combination of neurobehavioral features of stroke.
  • the present application provides a method for reducing or avoiding adverse reactions during the prevention and/or treatment of ischemic stroke, comprising administering only an effective amount of a drug to a subject in need, the drug's
  • the active ingredient is selected from one or a combination of (+)-2-camphor, its pharmaceutically acceptable salt or ester, its prodrug, its metabolite, and its solvate, and the ischemic brain NIHSS score ⁇ 6 points for stroke.
  • the way of reducing or avoiding adverse reactions in the prevention and treatment of ischemic stroke is selected from: replacing other drugs, reducing the type and/or dosage of other drugs used by patients, providing patients with Provide any one or combination of continuous and stable treatments throughout the stroke prevention and treatment.
  • the other drugs are selected from any one or combination of intravenous thrombolytic drugs, antiplatelet drugs, anticoagulant drugs, defibrosis drugs, volume expansion drugs, microcirculation improving drugs, and neuroprotective agents Combined use.
  • (+)-2-camphor in the preparation of a medicament for preventing and/or treating ischemic stroke, wherein the NIHSS score of the ischemic stroke is ⁇ 6 points.
  • (+)-2-camphor in the preparation of a medicament for improving the effect of ischemic stroke prevention and/or treatment, wherein the NIHSS score of the ischemic stroke is ⁇ 6 points.
  • Embodiment 3 The use according to Embodiment 2, wherein the preventive and/or therapeutic effect is selected from any one or combination of alleviating symptoms, improving prognosis, reducing the degree of neurological deficit, and improving the patient's ability to perform daily activities.
  • the effect of the (+)-2-camphor is selected from: regulating energy metabolism and redox metabolism, improving the survival rate of ischemic damaged neurons, reducing the risk of ischemic stroke Any one or combination of causing cerebral infarction size and improving the neurobehavioral characteristics of ischemic stroke.
  • (+)-2-camphor in the preparation of medicines for reducing or avoiding the adverse reactions produced during the prevention and/or treatment of ischemic stroke, wherein the NIHSS score of said ischemic stroke ⁇ 6 points.
  • the way of reducing or avoiding adverse reactions in the prevention and treatment of ischemic stroke is selected from: replacing other drugs, reducing the type and/or dosage of other drugs used by patients, Provide any one or combination of continuous and stable treatments for patients throughout the stroke prevention and treatment.
  • the other drugs are selected from any of intravenous thrombolytic drugs, antiplatelet drugs, anticoagulant drugs, defibrosis drugs, volume expansion drugs, microcirculation improving drugs, and neuroprotective agents or a combination thereof.
  • ischemic stroke is selected from ischemic stroke with 6 ⁇ NIHSS score ⁇ 20 points.
  • (+)-2-camphor in the preparation of a medicament for the prevention and/or treatment of ischemic stroke, wherein the ischemic stroke is selected from moderate, moderate-severe or severe ischemia Any type of stroke patient.
  • the content of (+)-2-borneol in the medicament is about 5 mg to about 40 mg.
  • the content of (+)-2-borneol in the medicine is about 5 mg, or about 10 mg, or about 20 mg, or about 30 mg, or about 40 mg .
  • the (+)-2-borneol also includes its pharmaceutically acceptable salt or ester, its metabolite, its prodrug, or its solvent compound.
  • a method for preventing and/or treating ischemic stroke comprising administering to a subject in need only an effective amount of a drug whose active ingredient is selected from (+)-2-borneol, its One or a combination of pharmaceutically acceptable salts or esters, metabolites, prodrugs, and solvates thereof, and the NIHSS score of the ischemic stroke is ⁇ 6 points.
  • a method for improving the effect of preventing and/or treating ischemic stroke comprising administering only an effective amount of a drug whose active ingredient is selected from (+)-2-borneol to a subject in need , a pharmaceutically acceptable salt or ester thereof, a prodrug thereof, a metabolite thereof, and a solvate thereof, or one or a combination thereof, and the NIHSS score of the ischemic stroke is ⁇ 6 points.
  • preventive and/or therapeutic effect is selected from any one or a combination of alleviating symptoms, improving prognosis, reducing the degree of neurological deficit, and improving the patient's ability to perform daily activities.
  • the effect of the active ingredient is selected from: regulating energy metabolism and redox metabolism, improving the survival rate of ischemic damaged neurons, reducing the size of cerebral infarction caused by ischemic stroke, improving Any one or combination of neurobehavioral features of ischemic stroke.
  • a method for reducing or avoiding adverse reactions during the prevention and/or treatment of ischemic stroke comprising administering only an effective amount of a drug to a subject in need, the active ingredient of which is selected from ( +)-2-camphor, its pharmaceutically acceptable salt or ester, its prodrug, its metabolite, and its solvate in one or its combination, the NIHSS score of said ischemic stroke ⁇ 6 points.
  • Embodiment 1 (+)-2-camphorol anti-acute cerebral ischemia dose and effect relationship
  • This experiment adopts rat focal cerebral ischemia model (MCAO), chooses 120 SD rats, male, is divided into 12 groups randomly, is respectively solvent control group (60% 1,2-propanediol, intravenous injection, 5mL/kg), positive control group (nimodipine injection, tail vein injection, 25, 50, 100, 500, 1000 ⁇ g/kg) and (+)-2-camphor injection dosage groups (doses were 0.5, 1, 2, 4, 6, 8 mg/kg, intravenous injection), 10 SD rats in each group, all male.
  • the SD rats in the solvent control group, positive control group and (+)-2-camphor injection group were administered once after MCAO cerebral ischemia according to the above dose design.
  • the area of cerebral infarction after administration and the neurological behavior score 24 hours after cerebral infarction were observed.
  • Simultaneously positive control drug nimodipine 5 dosage group results show that the maximum effect of positive control drug appears at 1000 ⁇ g/kg, increase dose again, cerebral infarction area will not significantly reduce, and at this dose, rat cerebral infarction area is 25.3%, compared with the solvent control group, the maximum effect of reducing cerebral infarct size was 36.2%, and the behavioral scores of all treatment groups were also significantly lower than the solvent control group.
  • (+)-2-borneol Comparing (+)-2-borneol with the positive control drug, it was found that the drug potency of (+)-2-borneol against acute cerebral ischemia in rats was slightly lower than that of nimodipine injection, but the maximum effect was obvious Superior to nimodipine injection.
  • (+)-2-borneol group 0.5mg/kg 2.1 ⁇ 0.88 33.8 ⁇ 4.4** 15.0 (+)-2-borneol group 1mg/kg 2.1 ⁇ 0.57 30.2 ⁇ 2.3*** 24.0 (+)-2-borneol group 2mg/kg 2.0 ⁇ 0.82* 26.2 ⁇ 2.0*** 33.9 (+)-2-borneol group 4mg/kg 1.9 ⁇ 0.57* 21.8 ⁇ 2.0*** 45.2 (+)-2-borneol group 6mg/kg 1.8 ⁇ 0.79* 20.3 ⁇ 2.2*** 48.9 (+)-2-borneol group 8mg/kg 1.7 ⁇ 0.48** 20.3 ⁇ 2.5*** 48.9 positive control group 25 ⁇ g/kg 2.2 ⁇ 0.63 34.0 ⁇ 5.7* 14.3 positive control group 50 ⁇ g/kg 1.9 ⁇ 0.57* 32.2 ⁇ 4.5** 19.0 positive control group 100 ⁇ g/kg 1.8 ⁇ 0.42** 27.3 ⁇ 4.1*** 31.3 positive control group 500 ⁇ g/kg 1.4 ⁇ 0.52*** 26.2 ⁇ 3.2*** 33.9 positive control group 1000 ⁇ g/kg 1.5 ⁇ 0.53*** 25.3
  • Example 2 The protective effect of (+)-2-camphor on focal ischemia-reperfusion brain injury
  • the cerebral ischemia-reperfusion model of rats was prepared by internal carotid artery suture method, and the drug was administered once by tail vein injection 2 hours after ischemia-reperfusion.
  • (+)-2-camphor has 4 dosage groups, which are respectively 0.25, 0.5, 1.0, and 2.0mg/kg; Edaravone also has 4 dosage groups, which are respectively 0.75, 1.5, 3.0, 6.0 mg/kg.
  • the effects of the tested drugs on neurological deficit symptoms, cerebral infarct size and mortality of cerebral ischemia rats were observed. The results showed (see Table 2-1 to Table 2-3), edaravone reduced cerebral ischemia-reperfusion injury in a dose-dependent manner.
  • Clinical trial design multicenter, randomized, double-blind, placebo-controlled, parallel trial design.
  • Subject population 18 years old (minimum age) to 85 years old (maximum age), both male and female; patients diagnosed with acute ischemic stroke according to the "Guidelines for the Diagnosis and Treatment of Acute Ischemic Stroke in China 2018"; "Normal time” to the start of study drug treatment ⁇ 24 hours, for stroke after waking up or when the symptom onset time cannot be accurately obtained due to aphasia, disturbance of consciousness and other reasons, the time when the patient's last normal performance should prevail; Patients with good recovery (mRS score 0-1 points) relapse (relapse); 5 points ⁇ NIHSS score ⁇ 20 points at the time of consultation, and the sum of NIHSS fifth upper limb and sixth lower limb score ⁇ 2 points; understanding And abide by the research process, participate voluntarily, and sign the informed consent (the informed consent is voluntarily signed by the person or legal representative).
  • Test drug group (+)-2-camphor, low dose 10 mg (single administration dose) and high dose 20 mg (single administration dose).
  • Placebo group the difference from the test drug group is that it does not contain the active ingredient (+)-2-camphor.
  • Dosing frequency and interval 2 times a day, with an interval of 12 hours each time.
  • Treatment cycle continuous administration for 7 days
  • the main efficacy endpoint index mRS 0-1 ratio at day 90 ⁇ 7.
  • mRS modified Rankin scale
  • the mRS score also known as the modified Rankin scale (Table 3), is a scale used to evaluate the neurological recovery status of stroke patients and is divided into seven levels.
  • symptom score completely asymptomatic 0
  • Ability to perform all daily duties and activities without significant functional impairment despite symptoms 1 Mildly disabled, unable to perform all premorbid activities, but able to look after self without assistance 2 Moderately disabled, requires some assistance, but walks without assistance 3 Severely disabled, unable to walk independently, unable to meet their own needs without help from others 4 Severely disabled, unable to walk independently, unable to meet their own needs without help from others 5 die 6
  • Day 90 ⁇ 7 mRS 0-1 ratio means that stroke patients recover to mRS score 90 ⁇ 7 days after treatment from baseline mRS score ⁇ 2 (i.e. mild disability or moderate disability or severe disability or severe disability) after treatment On a scale of 0-1 (i.e. completely asymptomatic or no apparent dysfunction), usually expressed as a percentage.
  • NIHSS score The severity of stroke is usually defined by NIHSS score, which affects the evaluation of efficacy.
  • N represents the number of samples
  • n represents the number of patients with an mRS score of 0-1 on the 90th ⁇ 7th day of treatment
  • % represents the proportion of patients with an mRS score of 0-1 on the 90th ⁇ 7th day of treatment.
  • (+)-2-camphor has selective efficacy in patients with different NIHSS scores.
  • NIHSS the more severe the stroke
  • this treatment effect means that stroke patients with NIHSS score Score ⁇ 2 (i.e. mild disability or moderate disability or severe disability or severe disability) recovered to an mRS score of 0-1 (i.e.
  • the absolute effect difference between the experimental drug group and the placebo group ranges from 3.3% to 16.0%, which has significant clinical value and significantly reduces the occurrence of disability in patients.
  • (+)-2-borneol alone as the active ingredient in the treatment of stroke can effectively avoid the serious adverse reactions (such as combined use of ida
  • the use of lavone is caused by the liver and kidney toxicity caused by the ingredients of edaravone).
  • (+)-2-camphor alone can improve the dosage of (+)-2-camphor as an active ingredient in human body (such as combined use with edaravone is limited by edaravone toxicity
  • (+)- The single dose of 2-camphorol is limited to 7.5 mg), such as a single 10 mg or a single 20 mg, so as to improve the prevention and/or treatment effect of ischemic stroke.

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Abstract

本申请涉及(+)-2-莰醇在制备治疗缺血性脑卒中药物中的应用，其中所述缺血性脑卒中选自NIHSS评分≥6分的脑卒中。所述药物能够有效的降低或避免缺血性脑卒中预防和/或治疗过程中产生的严重不良反应，以及提高缺血性脑卒中预防和/或治疗效果。

Description

莰醇在制备治疗缺血性脑卒中的药物中的用途 技术领域
本申请涉及生物医药领域，具体的涉及莰醇在制备治疗缺血性脑卒的药物中的用途。
背景技术
脑卒中是导致人类死亡的第二位原因，在我国是第一大死亡原因，且与缺血性心脏病、恶性肿瘤并列为三大致死性疾病，我国40岁及以上人群脑卒中现患人数达1242万，且呈现逐年上升趋势，平均每7秒就有1人发生卒中，每21秒就有1人死于卒中。我国住院脑卒中患者发病后1个月内死亡率2.3％～3.2％，3个月死亡率9％～9.6％，3个月致死/致残率34.5％～37.1％，1年死亡率14.4％～15.4％，1年致死/致残率33.4％～33.8％。缺血性脑卒中具有高发病率、高致残率和高死亡率的特点，是我国成年人主要死亡原因之一，同时也是单病种致残率最高的疾病，给社会和家庭带来沉重的负担(Stroke-1989.Recommendations on stroke prevention,diagnosis,and therapy.Report of the WHO Task Force on Stroke and other Cerebrovascular Disorders[J].Stroke，1989，20(10):1407-1431；中国急性缺血性脑卒中诊治指南2018；中国心血管病报告2018)。
脑卒中包括缺血性卒中和出血性卒中。缺血性脑卒中(cerebral ischemic stroke)为脑部血液循环障碍、缺血缺氧所致的局限性脑组织缺血性坏死或软化。其主要病因包括：大动脉粥样硬化，因高血压等因素导致小动脉硬化闭塞、血源性栓塞、血液黏度增高和血管痉挛等。急性缺血性脑卒中一般指发病两周内的脑卒中，约占全部卒中的69.6％-70.8％，我国每年新发急性缺血性脑卒中患者超过200万(Wang W，Jiang B，Sun H，et al.Prevalence，Incidence，and Mortality of Stroke in China:Results from a Nationwide Population-Based Survey of 480687Adults[J].Circulation，2017，135(8):759-771；中国急性缺血性脑卒中诊治指南2018)。
缺血性脑卒中除有效的二级预防和卒中康复治疗外，急性期的治疗手段目前非常有限，主要有溶栓、血管内介入治疗和神经保护。溶栓因其治疗时间窗的限制(≤4.5h)和诸多禁忌症等原因，仅少数患者(＜3％)受益，尽管目前临床上存在超窗溶栓趋势(至9h)，但受益患者仍然有限；血管内治疗(机械取栓)目前可将时间窗延长至24h，但血管内介入治疗禁忌症较多、手术实施难度较高、价格昂贵；神经保护剂理论上可抢救缺血半暗带，扩大治疗时间窗(理论上可达72h)，使临床患者明显获益，目前市场上神经保护剂品种众多，但尚无具有循证医学证据、疗效确切的神经保护剂(中国心血管病报告2018；中国急性缺血性脑卒中诊治指南2018；急性缺血性卒中血管内治疗中国指南2018；Thrombolysis Guided by  Perfusion Imaging up to 9 Hours after Onset of Stroke[J].N Engl J Med.2019,380(19):1795-1803)。
当前有超过1000个神经保护剂在动物实验中有效，超过100种药物进行了临床试验，然而所有以随机、双盲、安慰剂对照进行严格临床研究的神经保护剂在临床全部失败(O'Collins VE，Macleod MR，Donnan GA，et al.1，026experimental treatments in acute stroke[J].Ann Neurol,2006；59:467-477)。故以临床前动物药效或体外药效的数据，难以推测临床的有效性。
总结神经保护剂类药物从基础研究(临床前研究)转化至临床研究普遍失败，主要原因可能是：①种属差异：目前临床前试验应用最多的动物是鼠类，少数会用到灵长类动物，这两类动物的脑组织结构和人脑结构不管在解剖学上和组织学上都存在较大差异；临床前研究的实验动物卒中模型都是同质的，而人类卒中则是异质的、千差万别的，存在多种的其他影响因素(如年龄、发作次数、发作部位、伴随疾病、严重程度、并发症、联合用药等)差别，所以临床前动物试验有效的药物对人类不一定有效。②评价标准：在大多数临床前试验中，神经保护剂的有效性是通过观察组织学上梗死体积的变化，或者是否能够挽救梗死半暗带来评价；而在临床试验中，药物的有效性是通过减少死亡率及残障率、改善生活质量(功能)的目的来评价。事实上梗死体积与功能缺失并无直接、必然的联系。③动物模型：现今在临床前试验的动物一般为年轻健康的雄性动物，体重年龄较均一，脑缺血造模方式单一，且一般无其他并发疾病；而临床上脑卒中患者多年老年人，性别亦无明显差异，且一般伴有多种慢性病(如动脉硬化、高血压、糖尿病和既往卒中史等)，这些伴发疾病既会影响患者机能恢复，又影响药物的药效、代谢和安全性。④药物治疗时间窗：临床前动物实验可以在缺血后任意时间点进行药物治疗或预防，给药的方法和途径也可以根据要求确定和调整；而临床患者何时发生脑缺血是不可预估的，提前用药根本不可行，而从发生脑缺血到就诊用药也需要一段时间，临床上在脑缺血发生后2h内进行药物治疗的可能性都很小，大部分患者的治疗时间窗为卒中发生后6h或更长。⑤其他因素(Chin J Clin Pharmacol2013，29(11)，869-871)。
我国著名神经内科专家黄如训在1998年就提出以分型、分期为核心治疗个体化原则。经过长期临床实践的反复思考而形成的一个重要理念：脑卒中是一大类疾病的总称，基于多病因、不同发病机制、多种病理和临床类型，各有相应的治疗方法和治疗效果。临床上有轻、中、重、极危重等的病情分型(如广泛使用的NIHSS评分)；有以临床征象为据，基本反映病变部位及范围OCSP分型；以临床病因为据的TOAST分型(大动脉粥样硬化、心源性、小血管、其他原因、原因不明)；以临床结构影像进行分型，如大、中、小、腔隙、多发等分型。1992年提出重视脑卒中的个体化治疗，其后分型研究，多方面论述，形成“以分型、分期为核心治疗的个体化原则”理念。治疗个体化原则的基本内含是针对性强的方案和有效 措施，同近年兴起的精准医疗有异曲同工之处(Chin J Clin Neurosci 2017,25(1),119～124)。
国际上，缺血性脑卒中患者的严重程度广泛采用美国国立卫生研究院卒中量表(NIH Stroke Scale，NIHSS)进行量化，根据NIHSS总分对卒中患者严重程度进行判断，分值越大，代表病情越严重。NIHSS评分共42分11项，在国际多中心随机对照研究中被广泛应用，是公认的对卒中患者严重程度分层的评分体系，各评分项目和评分标准如下：
Figure PCTCN2022125421-appb-000001
Figure PCTCN2022125421-appb-000002
Figure PCTCN2022125421-appb-000003
Figure PCTCN2022125421-appb-000004
NIHSS评分能够表征缺血性脑卒中的严重程度，提示病因、影响医生的诊断结果、影响治疗手段的选择，其还可以在药品适用方面，作为划分缺血性脑卒中这一大类疾病项下，不同适应症或禁忌症的依据。
通过NIHSS评分可以区分患者的卒中严重程度。NIHSS评分是评估神经缺损功能严重程度的量表，分值范围为0-42分，当神经功能缺损越重，评分也相应增高，也提示脑梗死面积之大、血脑屏障破坏之严重，出血转化风险进一步增加(“急性脑梗死静脉溶栓患者出血转化及预后的危险因素研究”，段延龙等，中风与神经疾病杂志，2021年)。可见，NIHSS 评分能够反映出卒中的状态。
NIHSS评分会提示病因。研究表明，在急诊医师确定患者为缺血性卒中后，预测大血管闭塞的最有效工具为NIHSS评分。发病3h内NIHSS评分≥9分或发病6h内NIHSS评分≥7分时，提示存在大血管闭塞(“急性缺血性卒中血管内治疗(中国指南2018)”)。
NIHSS评分会影响医生的诊断结果。根据《医院卒中中心建设与管理指导原则(试行)》的规定，医院在接诊阶段，首先需要进行“病史采集、体格检查、神经功能缺损评分(NIHSS)、生命体征评估，实施头部影像学检查、血生化等辅助检查”步骤，然后再开展治疗步骤。一般认为，“NIHSS评分≤5分的缺血性脑卒中”为“轻度缺血性脑卒中”，“6≤NIHSS评分≤15分的缺血性脑卒中”为“中度缺血性脑卒中”，“15≤NIHSS评分≤20分的缺血性脑卒中”为“中-重度缺血性脑卒中”或“重度缺血性脑卒中”，“NIHSS评分＞20分的缺血性脑卒中”为“极危重缺血性脑卒中”。
NIHSS评分会影响治疗手段的选择。例如，《中国急性缺血性脑卒中诊治指南2014》将NIHSS评分≥25分列为静脉溶栓治疗的相对禁忌证；《急性缺血性卒中血管内治疗(中国指南2018)》中，NIHSS评分是判断是否开展血管内治疗的标准之一。再如，对于未接受静脉溶栓治疗的轻型卒中患者(NIHSS评分＜3分)，在发病24h内应尽早启动双重抗血小板治疗(阿司匹林和氯吡格雷)并维持21d(参考“中国急性血栓性疾病抗栓治疗共识”)。业内在研究卒中治疗手段时，也经常会考虑NIHSS评分，例如当NIHSS评分≤6分合并大血管闭塞的患者，应当取栓还是药物治疗的研究(“Thrombectomy vs medical management in low NIHSS acute anterior circulation stroke”Neurology 2020；95：e3364-e3372.)。《急性大血管闭塞性缺血性卒中血管内治疗中国专家共识(2019年修订版)》中指出，对于NIHSS评分≥6分的前循环急性大血管闭塞性缺血性卒中(AIS-LVO)患者行血管内治疗获益明确，但对于NIHSS评分＜6分的患者行血管内治疗可能是合理的。对于NIHSS评分＜6分的患者是否获益仍有待于进一步评价，可能获益，也可能不获益，甚至更差。
由于NIHSS评分具有上述重要的医学意义，其已经纳入到部分上市药品的适应症与禁忌症的划分中。中国国家食品药品监督管理总局(CFDA)在《化学药品和治疗用生物制品说明书规范细则》(2006年)中规定“【适应症】应当根据该药品的用途，采用准确的表述方式，明确用于预防、治疗、诊断、缓解或者辅助治疗某种疾病(状态)或者症状”、“【禁忌】应当列出禁止应用该药品的人群或者疾病情况”。即，目标疾病或状态和目标人群是区分药品适应症的考虑因素。例如，注射用阿替普酶，禁忌包括“经临床(NIHSS>25)和/或影像学检查评定为严重脑卒中”。FDA批准抗血小板药物替格瑞洛用于急性缺血性脑卒中(NIHSS 评分≤5)或高危短暂性脑缺血发作患者的中风风险。目前，NIHSS评分已经体现在药品说明中，用于表征药品的适应症范围。使用NIHSS评分可以对缺血性脑卒中这一疾病类型进行分型划分，并与药品的适用形成对应关系。
“以分型、分期为核心治疗的原则”理念已形成广泛共识，有利于在治疗时选择对症药物，获得药物的真实有效人群，提高药物的疗效，避免无效患者选择错误的药物进行治疗而延误病情、增加安全性风险并带来经济损失。然而，对缺血性脑卒中治疗，目前缺少针对以NIHSS评分分型适应症进行精准化治疗的药物，而且，现有的以动物模型或体外实验作为效果表征的药物无法形成与之对应的药效关联，原因在于，NIHSS评分涵盖了对患者意识水平、凝视、视野、上下肢运动等项目的评估，其是针对人类设计的，无法通过动物实验或体外实验实施。
发明内容
现有技术中通常将(+)-2-莰醇作为药物佐剂用于治疗脑卒中等疾病，如与依达拉奉等活性成分联用用于治疗脑卒中，但是尚无将(+)-2-莰醇单独作为活性成分用于治疗缺血性脑卒中患者的报道。
此外，申请人令人惊讶的发现单一组分的(+)-2-莰醇对缺血性脑卒中患者人群具有高度的选择性，在NIHSS评分≥6分的脑卒中患者治疗中有优异的治疗效果，而在NIHSS评分≤5分的脑卒中患者中效果相对较差或者没有效果。在我国超过千万缺血性脑卒中现存患者及每年超过200万新发卒中患者中，在严重缺乏有效的药物治疗措施的背景下，药物组比安慰剂组(不用药的情况下)显示出的绝对效应差值(第90天恢复至mRS 0-1分的患者代表恢复至完全康复或无残疾状态)意义重大。
并且，(+)-2-莰醇具有良好的人体安全性，(+)-2-莰醇单独作为活性成分治疗脑卒中能够有效的避免联用其他活性成分在缺血性脑卒中预防和/或治疗过程中产生的不良反应(如联用依达拉奉使用，因依达拉奉成分的加入带来严重的肝肾毒性)。此外，(+)-2-莰醇单独作为活性成分可提高(+)-2-莰醇的人体用药剂量(如与依达拉奉联用受依达拉奉毒性的限制，(+)-2-莰醇单次使用剂量限制在7.5mg)，进而提高缺血性脑卒中预防和/或治疗效果。
本申请的目的之一是提供(+)-2-莰醇作为唯一的活性成分在制备治疗特定的缺血性脑卒中亚型或分型患者药物中的应用。
本发明的另一个目的在于提供一种治疗特定的缺血性脑卒中的方法，包括向由此需要的受试者施用(+)-2-莰醇、其药学上可接受的盐或酯、其前药、其代谢物、和其溶剂合物中的一种或其组合。
一方面，本申请提供了(+)-2-莰醇在制备用于预防和/或治疗缺血性脑卒中药物中的用途，其中所述缺血性脑卒中的NIHSS评分≥6分。
一方面，本申请提供了(+)-2-莰醇在制备用于提高缺血性脑卒中预防和/或治疗效果的药物中的用途，其中所述缺血性脑卒中的NIHSS评分≥6分。
在某些实施方式中，其中所述预防和/或治疗效果选自缓解症状、改善预后、减轻神经功能缺损程度、提高患者日常活动能力的任一种或其组合。
在某些实施方式中，所述(+)-2-莰醇的效果选自：调节能量代谢与氧化还原代谢，提高缺血损伤神经元存活率，降低缺血性脑卒中所致脑梗死面积，改善缺血性脑卒中神经行为学特征的任一种或其组合。
一方面，本申请提供了(+)-2-莰醇在制备用于降低或避免缺血性脑卒中预防和/或治疗过程中产生的不良反应的药物中的用途，其中所述缺血性脑卒中的NIHSS评分≥6分。
在某些实施方式中，所述的降低或避免缺血性脑卒中防治过程中的不良反应的方式选自：替代其他药物、减少患者使用其他药物的种类和/或使用剂量、为患者在脑卒中防治全程中提供持续稳定治疗的任一种或其组合。
在某些实施方式中，所述缺血性脑卒中选自6≤NIHSS评分≤20分的缺血性脑卒中。
一方面，本申请提供了(+)-2-莰醇在制备用于预防和/或治疗缺血性脑卒中药物中的用途，其中所述缺血性脑卒中选自中度、中-重度或重度型缺血性脑卒中患者的任一种。
在某些实施方式中，所述药物仅包含(+)-2-莰醇作为活性成分。
在某些实施方式中，所述(+)-2-莰醇还包括其药学上可接受的盐或酯，其代谢物，其前药，或其溶剂合物。
另一方面，本申请提供一种预防和/或治疗特定缺血性脑卒中的方法，包括向有需要的受试者仅施用有效量的药物，所述药物的活性成分选自(+)-2-莰醇、其药学上可接受的盐或酯、其代谢物、其前药、和其溶剂合物中的一种或其组合，所述缺血性脑卒中的NIHSS评分≥6分。
另一方面，本申请提供一种提高缺血性脑卒中预防和/或治疗效果的方法，包括向有需要的受试者仅施用有效量的药物，所述药物的活性成分选自(+)-2-莰醇、其药学上可接受的盐或酯、其前药、其代谢物、和其溶剂合物中的一种或其组合，所述缺血性脑卒中的NIHSS评分≥6分。
在某些实施方式中，其中所述预防和/或治疗效果选自缓解症状、改善预后、减轻神经功能缺损程度、提高患者日常活动能力的任一种或其组合。
在某些实施方式中，所述活性成分的效果选自：调节能量代谢与氧化还原代谢，提高缺血损伤神经元存活率，降低缺血性脑卒中所致脑梗死面积，改善缺血性脑卒中神经行为学特征的任一种或其组合。
另一方面，本申请提供一种降低或避免缺血性脑卒中预防和/或治疗过程中产生的不良反应的方法，包括向有需要的受试者仅施用有效量的药物，所述药物的活性成分选自(+)-2-莰醇、其药学上可接受的盐或酯、其前药、其代谢物、和其溶剂合物中的一种或其组合，所述缺血性脑卒中的NIHSS评分≥6分。
在某些实施方式中，其中所述的降低或避免缺血性脑卒中防治过程中的不良反应的方式选自：替代其他药物、减少患者使用其他药物的种类和/或使用剂量、为患者在脑卒中防治全程中提供持续稳定治疗的任一种或其组合。
本领域技术人员能够从下文的详细描述中容易地洞察到本申请的其它方面和优势。下文的详细描述中仅显示和描述了本申请的示例性实施方式。如本领域技术人员将认识到的，本申请的内容使得本领域技术人员能够对所公开的具体实施方式进行改动而不脱离本申请所涉及发明的精神和范围。相应地，本申请的说明书中的描述仅仅是示例性的，而非为限制性的。
具体实施方式
以下由特定的具体实施例说明本申请发明的实施方式，熟悉此技术的人士可由本说明书所公开的内容容易地了解本申请发明的其他优点及效果。
术语定义
术语“脑卒中”在本领域是众所周知的。脑卒中可以是闭塞性的(由于血管闭合)或出血性的(由于血管出血)。本文所用的术语“缺血”是指当阻力血管的自动调整性扩张不能代偿血管异常狭窄(缩窄)的远端减少的灌注压而发生的血液供给和氧的缺乏。虽然大部分闭塞性脑卒中是由动脉粥样硬化和血栓形成引起，以及大部分出血性脑卒中与高血压或动脉瘤相关，任一类型的脑卒中可能在任何年龄由于多种原因而发生，这些原因包括心脏病、外伤、感染、肿瘤、血液恶液质、血管畸形、免疫失调、以及外源毒素。
除非另有说明，在本申请中，术语“脑卒中”一般指缺血性脑卒中，通常是由于流向大脑或其部分的血流量减少所致，该血流量减少导致脑细胞供氧不足。特别地，由于脑细胞死亡，脑卒中会导致不可逆转的组织损伤。脑卒中的症状在本领域是众所周知的。例如，脑卒中症状包括面部、手臂或腿部突然麻木或无力(特别是在身体的一侧)、突然意识混乱、说话或理解困难、一只或两只眼睛突然看不到，以及突然行走困难、头晕、失去平衡或协调。缺 血性脑卒中可能是由动脉粥样硬化血栓形成或大脑主动脉栓塞、由凝血障碍或非肿瘤性血管疾病、或由导致总血流量减少的心脏缺血引起的。例如，动脉粥样硬化性血栓性脑卒中、心源性脑卒中和腔隙性脑卒中，心房颤动也可引起心源性脑卒中(通常也称为栓塞性或血栓栓塞性脑卒中)。
在本申请中，术语“莰醇”，又名片脑、龙脑香、冰片脑、梅冰等，可以由菊科艾纳香茎叶或樟科植物龙脑樟枝叶经水蒸汽蒸馏并重结晶而得。(+)-2-莰醇，又称右旋莰醇或((+)-borneol)，是天然冰片的主要成分(2015版中国药典规定天然冰片中右旋莰醇含量不低于96％)。右旋莰醇是一种双环单萜类化合物，存在于许多中草药的挥发油中，表现出多种生物活性，如抗炎、抗氧化以及增强GABA受体功能等(Euro J Pharma 2017,811:1-11)。右旋莰醇的结构式如下：
Figure PCTCN2022125421-appb-000005
右旋莰醇(分子式C 10H 18O；分子量154.25)
在本申请中，术语“药学上可接受的盐”通常是指在合理的医学判断的范围内适合用于与受试者的组织接触而没有不适当的毒性，刺激，过敏反应等，并且与合理的利益/风险比相称的那些盐。药学上可接受的盐是本领域公知的。例如，Berge等人在J.Pharmaceutical Sciences(1977)66:1–19详细描述了药学上可接受的盐。
在本申请中，术语“前药”通常是指易于在体内(例如通过血液中的酶)通过酶促水解转化产生母体化合物的化合物。在A.C.S.论文集系列的T.Higuchi和V.Stella，Prodrugs as Novel Delivery Systems，第14卷和Edward B.Roche编辑的Bioreversible Carriers in Drug Design，American Pharmaceutical Associtation and Permagon Press，1987中提供了全面的讨论，这两个文献通过引用结合到本文中。
在本申请中，术语“代谢物”通常是指在施用母体化合物(如(+)-2-莰醇)后在个体体内产生的任何结构式的衍生物。这些衍生物可以通过个体体内的各种生物化学转化例如氧化、还原、水解或结合由母体化合物产生，并且包括例如氧化物和去甲基衍生物。可以用现有技术中已知的常规技术鉴定本发明化合物的代谢物。参见例如，Bertolini，G.等人，J.Med.Chem.40：2011-2016(1997)；Shan，D.等人，J.Pharm.Sci.86(7)：765-767；Bagshawe K.，Drug Dev.Res.34：220-230(1995)；Bodor，N.，Advances in Drug Res.13：224-331(1984)；Bundgaard，H.，Design  of Prodrugs(Elsevier Press1985)；和Larsen，I.K.，Design and Application of Prodrugs，Drug Design and Development(Krogsgaard-Larsen等人，编辑，Harwood Academic Publishers，1991)。
在本申请中，术语“溶剂化物”按照常规意义使用，通常是指溶质(例如，活性化合物，活性化合物的盐)和溶剂的配合物。如果溶剂是水，则溶剂化物可以方便地称为水合物。
在本申请中，术语“预防和/或治疗”不仅包括预防和/或治疗疾病，还通常包括预防疾病的发作，减缓或逆转疾病的进展，预防或减缓与疾病相关的一种或多种症状的发作，减少和/或减轻与疾病相关的一种或多种症状，降低疾病和/或与其相关的任何症状的严重程度和/或持续时间和/或预防疾病和/或与其相关的任何症状的严重程度的进一步增加，预防、减少或逆转由疾病引起的任何生理损伤，以及通常对正在治疗的患者有益的任何药理学作用。
在本申请中，术语“疾病”或“病症”可以互换使用，通常是指受试者与正常状态的任意偏离，例如身体或某些器官的状态的任何变化，妨碍或扰乱了功能的履行，和/或在患病或与其接触的人中引起症状例如不适、机能障碍、痛苦或甚至死亡。疾病或病症还可以称为失调(distemper)、不适(ailing)、小病(ailment)、疾病(malady)、紊乱(disorder)、疾病(sickness)、生病(illness)、身体不适(complaint)、inderdisposion或affectation。
本申请中，术语“施用”通常是指通过任意引入或递送途径将本申请药物制剂引入受试者的身体中。可以采用本领域技术人员已知的用于使细胞、器官或组织与所述药物接触的任何方法。所述施用可以包括而不限于静脉内、动脉内、鼻内、腹内、肌内、皮下透皮或口服。每日剂量可以划分成一个、两个或更多个合适形式的剂量以在某个时间段期间的一个、两个或更多个时间施用。
在本申请中，术语“有效量”或“有效剂量”通常是指足以实现或至少部分实现所需效果的量。药物或治疗剂的“治疗有效量”或“治疗有效剂量”通常是当单独使用或与另一种治疗剂组合使用时促进疾病消退(这通过疾病症状严重程度的降低、疾病无症状期的频度和持续时间的增加、或者由于罹患疾病而引起的损害或残疾的预防来证明)的任何药物量。药物的“预防有效量”或“预防有效剂量”通常是指当单独或与另一种治疗剂组合给有疾病发展或疾病复发的风险的受试者施用时抑制疾病的发展或复发的药物量。可以使用本领域技术人员已知的多种方法对治疗剂或预防剂促进疾病消退或抑制疾病发展或复发的能力进行评估，比如在处于临床试验期间的人类受试者中、在动物模型系统中预测对人类的功效、或者通过在体外测定中测定药剂的活性。
在本申请中，术语“受试者”通常是指需要诊断、预后、改善、预防和/或治疗疾病的人或非人动物(包括哺乳动物)，诸如人、非人灵长类动物(猿、长臂猿、大猩猩、黑猩猩、猩 猩、猕猴)、家畜(狗和猫)、农场动物(家禽如鸡和鸭、马、牛、山羊、绵羊、猪)和实验动物(小鼠、大鼠、兔、豚鼠)。人受试者包括胎儿、新生儿、婴儿、青少年和成人受试者。受试者包括动物疾病模型。
在本申请中，术语“包括”、“包含”、“具有”、“可以”、“含有”及其变体通常旨在是开放式过渡性短语、术语或词语，其不排除额外行为或结构的可能性。术语“由……组成”通常表示不能存在别的组分(或同样地，特征、整数、步骤、等)。除非上下文另有明确规定，单数形式如英文的“a”，“an”，“the”，中文的“一个”、“一种”和“所述/该”一般包括所指代事物的复数形式。
在本申请中，术语“约”通常意指大约(approximately)、在......的附近(intheregionof)、粗略地(roughly)、或左右(around)。当术语“约”当用于指涉数值范围时，截值或特定数值用于指示所载明的数值可与该列举数值有多达10％的差异。因此，术语“约”可用于涵盖自特定值±10％或更少的变异、±5％或更少的变异、±1％或更少的变异、±0.5％或更少的变异、或±0.1％或更少的变异。
应理解，数字或一系列数字之前的术语“至少”包括与该术语“至少”相邻的数字，及逻辑上包括在内的所有后续数字或整数，如从上下文中明确的。当“至少”出现在一系列数字或范围之前时，应理解“至少”可修饰该系列或范围中每一个数字。
在本申请中，对于疾病分型或亚型，术语“型”与“性”的含义相同，或者省略“型”或“性”后意义等同。
在本申请中，对于疾病的称呼，术语“脑卒中”与“卒中”的含义相同。
在本申请中，“轻度缺血性脑卒中”通常是指“NIHSS评分≤5分的缺血性脑卒中”，“中度缺血性脑卒中”通常是指“6≤NIHSS评分≤15分的缺血性脑卒中”，“重度缺血性脑卒中”或“中-重度缺血脑卒中”通常是指“15≤NIHSS评分≤20分的缺血性脑卒中”，“极危重缺血性脑卒中”通常是指“NIHSS评分＞20分的缺血性脑卒中”。
发明详述
用途
一方面，本申请提供了(+)-2-莰醇在制备用于预防和/或治疗缺血性脑卒中药物中的用途，其中所述缺血性脑卒中的NIHSS评分≥6分。
在某些实施方式中，所述缺血性脑卒中可以选自6≤NIHSS评分≤20分的缺血性脑卒中。
在另一些实施方式中，所述缺血性脑卒中可以选自NIHSS评分＞20分的缺血性脑卒中。
例如所述缺血性脑卒中的评分可以为6、7、8、9、10、11、12、13、14、15、16、17、 18、19、20或更高。
在某些实施方式中，所述药物仅包含(+)-2-莰醇、其药学上可接受的盐或酯，其代谢物，其前药，和其溶剂合物中的一种或其组合作为活性成分。
例如，所述药物仅包含(+)-2-莰醇作为活性成分。
另一方面，本申请提供了(+)-2-莰醇在制备用于提高缺血性脑卒中预防和/或治疗效果的药物中的用途，其中所述缺血性脑卒中的NIHSS评分≥6分。
在某些实施方式中，其中所述预防和/或治疗效果选自缓解症状、改善预后、减轻神经功能缺损程度、提高患者日常活动能力的任一种或其组合。
在某些实施方式中，所述(+)-2-莰醇的效果选自：调节能量代谢与氧化还原代谢，提高缺血损伤神经元存活率，降低缺血性脑卒中所致脑梗死面积，改善缺血性脑卒中神经行为学特征的任一种或其组合。
在某些实施方式中，所述药物仅包含(+)-2-莰醇、其药学上可接受的盐或酯，其代谢物，其前药，和其溶剂合物中的一种或其组合作为活性成分。
另一方面，本申请提供了(+)-2-莰醇在制备用于降低或避免缺血性脑卒中预防和/或治疗过程中产生的不良反应的药物中的用途，其中所述缺血性脑卒中的NIHSS评分≥6分。
在某些实施方式中，所述的降低或避免缺血性脑卒中防治过程中的不良反应的方式选自：替代其他药物、减少患者使用其他药物的种类和/或使用剂量、为患者在脑卒中防治全程中提供持续稳定治疗的任一种或其组合。
在某些实施方式中，所述的其他药物选自静脉溶栓药、抗血小板药、抗凝药、降纤药、扩容药、改善微循环药、神经保护剂的任一种或其组合联合使用。
在某些实施方式中，所述药物仅包含(+)-2-莰醇、其药学上可接受的盐或酯，其代谢物，其前药，和其溶剂合物中的一种或其组合作为活性成分。
例如，所述药物仅包含(+)-2-莰醇作为活性成分。
治疗方法
另一方面，本申请提供一种预防和/或治疗缺血性脑卒中的方法，包括向有需要的受试者仅施用有效量的药物，所述药物的活性成分选自(+)-2-莰醇、其药学上可接受的盐或酯、其代谢物、其前药、和其溶剂合物中的一种或其组合，所述缺血性脑卒中的NIHSS评分≥6分。
在某些实施方式中，所述缺血性脑卒中可以选自6≤NIHSS评分≤20分的缺血性脑卒中。在另一些实施方式中，所述缺血性脑卒中可以选自NIHSS评分＞20分的缺血性脑卒中。
例如，所述缺血性脑卒中的评分可以为6、7、8、9、10、11、12、13、14、15、16、17、 18、19、20或更高。
在某些实施方式中，所述药物仅包含(+)-2-莰醇作为活性成分。
在某些实施方式中，还包括将所述药物与静脉溶栓药、抗血小板药、抗凝药、降纤药、扩容药、改善微循环药、神经保护剂中的任一种或其组合联合使用。
在某些实施方式中，其中所述预防和/或治疗效果选自缓解症状、改善预后、减轻神经功能缺损程度、提高患者日常活动能力的任一种或其组合。
在某些实施方式中，所述活性成分的效果选自：调节能量代谢与氧化还原代谢，提高缺血损伤神经元存活率，降低缺血性脑卒中所致脑梗死面积，改善缺血性脑卒中神经行为学特征的任一种或其组合。
另一方面，本申请提供一种降低或避免缺血性脑卒中预防和/或治疗过程中产生的不良反应的方法，包括向有需要的受试者仅施用有效量的药物，所述药物的活性成分选自(+)-2-莰醇、其药学上可接受的盐或酯、其前药、其代谢物、和其溶剂合物中的一种或其组合，所述缺血性脑卒中的NIHSS评分≥6分。
在某些实施方式中，其中所述的降低或避免缺血性脑卒中防治过程中的不良反应的方式选自：替代其他药物、减少患者使用其他药物的种类和/或使用剂量、为患者在脑卒中防治全程中提供持续稳定治疗的任一种或其组合。
在某些实施方式中，所述的其他药物选自静脉溶栓药、抗血小板药、抗凝药、降纤药、扩容药、改善微循环药、和神经保护剂的任一种或其组合联合使用。
本申请还提供了一下具体实施方式：
1.(+)-2-莰醇在制备用于预防和/或治疗缺血性脑卒中药物中的用途，其中所述缺血性脑卒中的NIHSS评分≥6分。
2.(+)-2-莰醇在制备用于提高缺血性脑卒中预防和/或治疗效果的药物中的用途，其中所述缺血性脑卒中的NIHSS评分≥6分。
3.根据实施方式2所述的用途，其中所述预防和/或治疗效果选自缓解症状、改善预后、减轻神经功能缺损程度、提高患者日常活动能力的任一种或其组合。
4.根据实施方式2所述的用途，所述(+)-2-莰醇的效果选自：调节能量代谢与氧化还原代谢，提高缺血损伤神经元存活率，降低缺血性脑卒中所致脑梗死面积，改善缺血性脑卒中神经行为学特征的任一种或其组合。
5.(+)-2-莰醇在制备用于降低或避免缺血性脑卒中预防和/或治疗过程中产生的不良反应的药物中的用途，其中所述缺血性脑卒中的NIHSS评分≥6分。
6.根据实施方式5所述的用途，所述的降低或避免缺血性脑卒中防治过程中的不良反应的方式选自：替代其他药物、减少患者使用其他药物的种类和/或使用剂量、为患者在脑卒中防治全程中提供持续稳定治疗的任一种或其组合。
7.根据实施方式5所述的用途，所述的其他药物选自静脉溶栓药、抗血小板药、抗凝药、降纤药、扩容药、改善微循环药、神经保护剂的任一种或其组合联合使用。
8.根据实施方式1-7中任一项所述的用途，其中所述缺血性脑卒中选自6≤NIHSS评分≤20分的缺血性脑卒中。
9.(+)-2-莰醇在制备用于预防和/或治疗缺血性脑卒中药物中的用途，其中所述缺血性脑卒中选自中度、中-重度或重度型缺血性脑卒中患者的任一种。
10.根据实施方式1-9中任一项所述的用途，所述药物仅包含(+)-2-莰醇作为活性成分。
11.根据实施方式1-10中任一项所述的用途，所述药物中(+)-2-莰醇的含量为约5mg至约40mg。
12.根据实施方式1-11中任一项所述的用途，所述药物中(+)-2-莰醇的含量为约5mg，或约10mg，或约20mg，或约30mg，或约40mg。
13.根据实施方式1-12中任一项所述的用途，所述(+)-2-莰醇还包括其药学上可接受的盐或酯，其代谢物，其前药，或其溶剂合物。
14.一种预防和/或治疗缺血性脑卒中的方法，包括向有需要的受试者仅施用有效量的药物，所述药物的活性成分选自(+)-2-莰醇、其药学上可接受的盐或酯、其代谢物、其前药、和其溶剂合物中的一种或其组合，所述缺血性脑卒中的NIHSS评分≥6分。
15.根据实施方式14所述的方法，还包括将所述药物与静脉溶栓药、抗血小板药、抗凝药、降纤药、扩容药、改善微循环药、神经保护剂中的任一种或其组合联合使用。
16.一种提高缺血性脑卒中预防和/或治疗效果的方法，包括向有需要的受试者仅施用有效量的药物，所述药物的活性成分选自(+)-2-莰醇、其药学上可接受的盐或酯、其前药、其代谢物、和其溶剂合物中的一种或其组合，所述缺血性脑卒中的NIHSS评分≥6分。
17.根据实施方式16所述的方法，其中所述预防和/或治疗效果选自缓解症状、改善预后、减轻神经功能缺损程度、提高患者日常活动能力的任一种或其组合。
18.根据实施方式16所述的方法，所述活性成分的效果选自：调节能量代谢与氧化还原代谢，提高缺血损伤神经元存活率，降低缺血性脑卒中所致脑梗死面积，改善缺血性脑卒中神经行为学特征的任一种或其组合。
19.一种降低或避免缺血性脑卒中预防和/或治疗过程中产生的不良反应的方法，包括向 有需要的受试者仅施用有效量的药物，所述药物的活性成分选自(+)-2-莰醇、其药学上可接受的盐或酯、其前药、其代谢物、和其溶剂合物中的一种或其组合，所述缺血性脑卒中的NIHSS评分≥6分。
不欲被任何理论所限，下文中的实施例仅仅是为了阐释本申请的药物、制备方法和用途等，而不用于限制本申请发明的范围。
实施例
实施例1 (+)-2-莰醇抗急性脑缺血剂量与效应关系
本试验采用大鼠局灶性脑缺血模型(MCAO)，选用120只SD大鼠，雄性，随机分为12个组，分别为溶剂对照组(60％的1,2-丙二醇，静脉注射，5mL/kg)，阳性对照组(尼莫地平注射液，尾静脉注射，25、50、100、500、1000μg/kg)及(+)-2-莰醇注射液剂量组(剂量分别为0.5、1、2、4、6、8mg/kg，静脉注射)，每组10只SD大鼠，全雄。溶剂对照组、阳性对照组及(+)-2-莰醇注射液组SD大鼠按上述剂量设计MCAO脑缺血后分别给药1次。观察给药后脑梗死面积及脑梗后24h神经学行为评分。
结果显示(见表1)，溶剂对照组大鼠脑梗死面积为39.7％，行为学评分为2.5±0.53；(+)-2-莰醇起始剂量为0.5mg/kg，脑梗死面积为33.8％，与溶剂对照组比较，梗死面积减少了15.0％，随着剂量的增加，脑梗死面积进一步缩小，行为学评分也相应降低，与溶剂对照组比较其减少梗死面积的百分比逐渐增大，显示出在剂量与效应之间有良好的量效关系存在。但当剂量达到6mg/kg和8mg/kg时，脑梗面积不再随着剂量的增加而降低，6mg/kg和8mg/kg两个剂量组的脑梗死面积均为20.3％。因此，(+)-2-莰醇用1mg/kg、2mg/kg和4mg/kg作为大鼠的低、中、高剂量进行其他试验较为合适。
同时阳性对照药尼莫地平5个给药剂量组结果显示，阳性对照药的最大效应出现在1000μg/kg，再增加剂量，脑梗死面积将无显著降低，在该剂量，大鼠脑梗死面积为25.3％，与溶剂对照组比较，脑梗死面积减少最大效应为36.2％，所有治疗组的行为学评分也明显低于溶剂对照组。
对(+)-2-莰醇与阳性对照药进行比较发现，(+)-2-莰醇抗大鼠急性脑缺血的药物效价强度较尼莫地平注射液略低，但最大效应明显优于尼莫地平注射液。
表1 (+)-2-莰醇注射液对大鼠脑梗死的影响(单位：脑梗死面积
Figure PCTCN2022125421-appb-000006
n＝10)
组别 剂量 行为学评分 脑梗面积(％) 脑梗面积减少(％)
溶剂对照组 溶剂5ml/kg 2.5±0.53 39.7±3.3 /
(+)-2-莰醇组 0.5mg/kg 2.1±0.88 33.8±4.4** 15.0
(+)-2-莰醇组 1mg/kg 2.1±0.57 30.2±2.3*** 24.0
(+)-2-莰醇组 2mg/kg 2.0±0.82* 26.2±2.0*** 33.9
(+)-2-莰醇组 4mg/kg 1.9±0.57* 21.8±2.0*** 45.2
(+)-2-莰醇组 6mg/kg 1.8±0.79* 20.3±2.2*** 48.9
(+)-2-莰醇组 8mg/kg 1.7±0.48** 20.3±2.5*** 48.9
阳性对照组 25μg/kg 2.2±0.63 34.0±5.7* 14.3
阳性对照组 50μg/kg 1.9±0.57* 32.2±4.5** 19.0
阳性对照组 100μg/kg 1.8±0.42** 27.3±4.1*** 31.3
阳性对照组 500μg/kg 1.4±0.52*** 26.2±3.2*** 33.9
阳性对照组 1000μg/kg 1.5±0.53*** 25.3±3.3*** 36.2
*P<0.05，**P<0.01,***P<0.001vs溶剂对照组
实施例2 (+)-2-莰醇对局灶性缺血再灌注脑损伤的保护作用
本试验采用颈内动脉线栓法制备大鼠脑缺血再灌注模型，于缺血再灌注后2h尾静脉注射给药1次。(+)-2-莰醇设4个给药剂量组，分别为0.25、0.5、1.0、2.0mg/kg；依达拉奉也设4个给药剂量组，分别为0.75、1.5、3.0、6.0mg/kg。脑缺血再灌注48h后观察所试药物对脑缺血大鼠的神经缺陷症状、脑梗死面积及死亡率的影响。结果显示(见表2-1至表2-3)，依达拉奉均呈剂量依赖性减少脑缺血再灌注损伤，起效剂量为6mg/kg，(+)-2-莰醇在0.25～2.0mg/kg剂量范围内呈剂量依赖性减少脑缺血再灌注损伤，起效剂量为1.0mg/kg，且(+)-2-莰醇药效强度优于依达拉奉。
表2-1.(+)-2-莰醇对神经缺陷症状的影响
Figure PCTCN2022125421-appb-000007
均值±标准误。 *P<0.05，与模型组比较。
表2-2 依达拉奉对神经缺陷症状的影响
Figure PCTCN2022125421-appb-000008
均值±标准误。 *P<0.05，与模型组比较。
表2-3 不同效应水平两药的脑梗死面积影响和量效关系
Figure PCTCN2022125421-appb-000009
实施例3 (+)-2-莰醇在缺血性脑卒中患者中的临床试验研究
临床试验设计：多中心、随机、双盲、安慰剂对照、平行试验设计。
临床试验方法
受试人群：18岁(最小年龄)至85岁(最大年龄)，男女均可；根据《中国急性缺血性脑卒中诊治指南2018》诊断为急性缺血性脑卒中患者；从“最后看起来正常的时间”到开始研究药物治疗≤24小时，对于醒后卒中或因失语、意识障碍等原因无法准确获得症状出现时间时，应以患者最后表现正常的时间为准；首次发病或上次发病后愈后良好(mRS评分0-1分)再次发病(复发)的患者；就诊时5分≤NIHSS评分≤20分，且NIHSS第五项上肢和第六项下肢评分之和≥2分；理解并遵守研究流程，自愿参加，并签署知情同意书(知情同意书由本人或法定代理人自愿签署)。
试验药组：(+)-2-莰醇，低剂量10mg(单次给药剂量)和高剂量20mg(单次给药剂量)。
安慰剂组：与试验药组区别在于其不含活性成分(+)-2-莰醇。
给药方式：与250ml生理盐水配伍后静脉滴注
给药次数及间隔：1天给药2次，每次间隔12小时。
治疗周期：连续给药7天
主要疗效终点指标：第90±7天mRS 0-1比例。
注：脑卒中临床试验的主要目的是判断特定干预措施的疗效，已有多种功能评估量表可供选择使用，其中被大力推荐作为脑卒中临床试验终点指标的是改良Rankin评分量表(modified Rankin scale，mRS)。在国内外脑卒中临床试验中，mRS是现今最常使用的功能结局评估量表。
mRS评分又称为改良Rankin评分量表(表3)，是用来评价脑卒中患者神经功能恢复状态的量表，共分为七级。
表3 mRS评分量表
症状 评分
完全无症状 0
尽管有症状，但无明显功能障碍，能完成所有日常职责和活动 1
轻度残疾，不能完成病前所有活动，但不需要帮助，能照顾自己的事务 2
中度残疾，要求一些帮助，但行走不需要帮助 3
重度残疾，不能独立行走，无他人帮助不能满足自身需求 4
严重残疾，不能独立行走，无他人帮助不能满足自身需求 5
死亡 6
“第90±7天mRS 0-1比例”代表卒中患者从入院时基线mRS评分≥2(即轻度残疾或中度残疾或重度残疾或严重残疾)经治疗在90±7天后恢复至mRS评分为0-1(即完全无症状或无明显功能障碍)的比例，通常以百分比表示。
结果
3.1(+)-2-莰醇在不同NIHSS评分的卒中患者中的治疗效果
表4 治疗第90±7天mRS评分0-1分患者比例分析(FAS)-组(不同NIHSS评分)
Figure PCTCN2022125421-appb-000010
Figure PCTCN2022125421-appb-000011
注：脑卒中严重程度通常采用NIHSS评分界定，卒中严重程度影响疗效评估。
N代表样本人数，n代表治疗第90±7天mRS评分0-1分的患者人数，％代表治疗第90±7天mRS评分0-1分的患者比例。
通过试验药组与安慰剂组在不同NIHSS卒中患者中的绝对效应差值结果分析(见表中“试验药组与安慰剂组的绝对效应差值”)，表4结果显示(+)-2-莰醇在NIHSS评分＝5分型卒中患者中的治疗效果不明显，甚至较安慰剂更差(试验药组与安慰剂组的绝对效应差值为负值，即-7.6％)；但当NIHSS评分＝6分，(+)-2-莰醇注射液疗效显现(试验药组与安慰剂组的绝对效应差值为3.3％)，并呈现出患者NIHSS越大(卒中程度越严重)治疗效果越显著(如在NIHSS评分≥6分型卒中患者中试验药组与安慰剂组的绝对效应差值为10.3％；在NIHSS评分≥7分型卒中试验药组与安慰剂组的绝对效应差值为11.0％；在NIHSS评分≥8分型卒中患者中试验药组与安慰剂组的绝对效应差值为16.0％)。
以上结果说明，(+)-2-莰醇在不同NIHSS评分的患者中，疗效具有选择性。具体的，(+)-2-莰醇对NIHSS评分＝5分的卒中患者无效或效果不明显或效果更差，而在NIHSS评分为6分的患者中开始起效/获益，且呈现患者NIHSS越大(卒中程度越严重)治疗效果越显著(体现在试验药组与安慰剂组的绝对效应差值越大)，这种治疗效果也就是NIHSS评分≥6的卒中患者从入院时基线mRS评分≥2(即轻度残疾或中度残疾或重度残疾或严重残疾)经试验药治疗比安慰剂治疗在90±7天后恢复至mRS评分为0-1(即完全无症状或无明显功能障碍)的比例更高。试验药组与安慰剂组的绝对效应差值从3.3％至16.0％，具有重大的临床价值，明显减少了患者残疾的发生。
3.2(+)-2-莰醇在卒中患者中的安全性
表5 严重不良反应按系统器官分类及首选术语汇总列表(SS)
Figure PCTCN2022125421-appb-000012
安全性统计结果显示，三个组别受试者在服药后发生的不良事件和与药物相关的不良事件，在发生例数、严重程度、症状上均无明显差别，三个组别均未见严重不良反应，也未见本品具有肝肾毒性，说明本品人体安全性良好。
依达拉奉右莰醇(依达拉奉30mg与(+)-2-莰醇7.5mg联用)药品说明书中，明确指出：“重度肾功能衰竭的患者禁忌使用(有致自功能表竭加重的可能)”、“轻、中度肾功能损害的患者慎用”、“肝功能损害患者慎用”、“心脏疾病患者慎用”、“高龄患者恨用”。“因有使用本品有效成分之一依达拉奉，加重急性肾功能不全或肾功能衰竭而致死的病例，因此在本品给药过程中应进行多次肾功能检测，同时在给药结束后继续留切观察，出现肾功能下降的表现或少原等症状的情况下，立即停止给药，进行适当处理。”
可见，单独(+)-2-莰醇作为活性成分治疗脑卒中能够有效的避免联用其他活性成分在缺血性脑卒中预防和/或治疗过程中产生的严重不良反应(如联用依达拉奉使用因依达拉奉成分带来的肝肾毒性)。此外，(+)-2-莰醇单独作为活性成分可提高(+)-2-莰醇的人体用药剂量(如与依达拉奉联用受依达拉奉毒性的限制，(+)-2-莰醇单次使用剂量限制在7.5mg)，如单次10mg或单次20mg，进而提高缺血性脑卒中预防和/或治疗效果。

Claims (11)

  1. (+)-2-莰醇在制备用于预防和/或治疗缺血性脑卒中药物中的用途，其中所述缺血性脑卒中的NIHSS评分≥6分。
  2. (+)-2-莰醇在制备用于提高缺血性脑卒中预防和/或治疗效果的药物中的用途，其中所述缺血性脑卒中的NIHSS评分≥6分。
  3. 根据权利要求1-2任一项中所述的用途，其中所述缺血性脑卒中选自NIHSS评分≥7分的缺血性脑卒中。
  4. 根据权利要求1-2任一项中所述的用途，其中所述缺血性脑卒中选自NIHSS评分≥8分的缺血性脑卒中。
  5. 根据权利要求1-2任一项中所述的用途，其中所述缺血性脑卒中选自NIHSS评分≥9分的缺血性脑卒中。
  6. 根据权利要求1-2任一项中所述的用途，其中所述缺血性脑卒中选自6≤NIHSS评分≤20分的缺血性脑卒中。
  7. 根据权利要求1-2任一项中所述的用途，其中所述缺血性脑卒中选自7≤NIHSS评分≤20分的缺血性脑卒中。
  8. 根据权利要求1-2任一项中所述的用途，其中所述缺血性脑卒中选自8≤NIHSS评分≤20分的缺血性脑卒中。
  9. 根据权利要求1-2任一项中所述的用途，其中所述缺血性脑卒中选自9≤NIHSS评分≤20分的缺血性脑卒中。
  10. (+)-2-莰醇在制备用于预防和/或治疗缺血性脑卒中药物中的用途，其中所述缺血性脑卒中包括中度、中-重度或重度型缺血性脑卒中。
  11. 根据权利要求1-10任一项中所述的用途，所述药物仅包含(+)-2-莰醇作为活性成分。
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