WO2019014851A1 - 大麻二酚在治疗肺动脉高压中的应用 - Google Patents

大麻二酚在治疗肺动脉高压中的应用 Download PDF

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WO2019014851A1
WO2019014851A1 PCT/CN2017/093367 CN2017093367W WO2019014851A1 WO 2019014851 A1 WO2019014851 A1 WO 2019014851A1 CN 2017093367 W CN2017093367 W CN 2017093367W WO 2019014851 A1 WO2019014851 A1 WO 2019014851A1
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pulmonary hypertension
pharmaceutically acceptable
cannabidiol
caused
pulmonary
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PCT/CN2017/093367
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English (en)
French (fr)
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张可
谭昕
于朝晖
李向东
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汉义生物科技（北京）有限公司
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Priority to AU2017424129A priority Critical patent/AU2017424129B2/en
Priority to JP2020502341A priority patent/JP6893012B2/ja
Priority to US16/630,428 priority patent/US11666542B2/en
Priority to CA3068879A priority patent/CA3068879C/en
Priority to EP17918496.5A priority patent/EP3650018B1/en
Priority to PCT/CN2017/093367 priority patent/WO2019014851A1/zh
Publication of WO2019014851A1 publication Critical patent/WO2019014851A1/zh
Priority to US18/188,162 priority patent/US11872196B2/en

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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
    • A61K31/05—Phenols
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/191—Carboxylic acids, e.g. valproic acid having two or more hydroxy groups, e.g. gluconic acid
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
    • 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
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5578—Eicosanoids, e.g. leukotrienes or prostaglandins having a pentalene ring system, e.g. carbacyclin, iloprost
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • A61P9/12—Antihypertensives

Definitions

  • the invention belongs to the field of medicine and relates to the application of cannabidiol in the treatment of pulmonary hypertension.
  • Pulmonary hypertension is complex and is caused by a variety of heart, lung or pulmonary vascular diseases. Pulmonary hypertension is characterized by pulmonary vascular remodeling and pulmonary vascular smooth muscle proliferation. It is characterized by increased pulmonary circulation pressure and resistance, increased right heart load, right heart dysfunction, and reduced pulmonary blood flow, resulting in a series of clinical manifestations. Pulmonary hypertension often progresses progressively during the course of the disease. In particular, it is a disease that seriously threatens the health of human life by enhancing right heart failure caused by pulmonary artery vascular tone.
  • Pulmonary hypertension is divided into primary and secondary. With the gradual deepening of understanding of pulmonary hypertension, the World Health Organization (WHO) “Pulmonary Hypertension Conference” classified the pulmonary hypertension according to the etiology, pathophysiology, treatment plan and prognosis. In 2004, the American College of Chest Physicians (ACCP) This was revised with the European Society for Cardiovascular Disease (ESC), which is instructive for the treatment of patients with pulmonary hypertension. It is generally believed that pulmonary arterial hypertension is detected by a right heart catheter in a calm state when the mean pulmonary artery pressure is ⁇ 25 mmHg (Badesch et al., 2009). Pulmonary hypertension can be graded according to resting PAPm, mildly 26-35 mm Hg; moderate 36-45 mm Hg; severe > 45 mm Hg.
  • WHO World Health Organization
  • Pulmonary hypertension mainly involves the pulmonary artery and right heart, which is characterized by right ventricular hypertrophy and right atrial dilatation.
  • the trunk of the pulmonary artery is dilated and the surrounding pulmonary arterioles are sparse.
  • pulmonary hypertension Other manifestations of pulmonary hypertension include elevation of the pulmonary adventitia and venous hypertrophy and TGF- ⁇ expression, and increased expression of matrix proteins such as elastin, fibronectin, cytochrome c, and mucopolysaccharide.
  • Pulmonary hypertension is a disease that can be treated, but there is currently no specific cure.
  • Traditional treatments include oxygen inhalation, cardiotonic, diuretic, calcium channel blockers, and anticoagulant adjuvant therapies, mainly to relieve symptoms.
  • cannabidiol can effectively inhibit pulmonary hypertension, and is particularly suitable for treating pulmonary hypertension caused by hypoxemia.
  • One aspect of the invention relates to the use of any one of (1) to (3) below for the preparation of a medicament for the treatment and/or prevention of pulmonary hypertension:
  • a plant extract containing cannabidiol preferably, the plant extract is a cannabis extract such as an industrial cannabis extract, and
  • composition comprising cannabidiol or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable excipients.
  • the use, wherein the pulmonary hypertension is primary pulmonary hypertension or secondary pulmonary hypertension; preferably, arterial pulmonary hypertension (eg, idiopathic pulmonary hypertension, Hereditary pulmonary hypertension, pulmonary hypertension caused by drugs and poisons, or persistent pulmonary hypertension in the newborn, and pulmonary hypertension associated with left heart disease (eg pulmonary hypertension caused by systolic dysfunction, pulmonary hypertension caused by diastolic dysfunction, valvular disease)
  • Pulmonary hypertension caused by pulmonary diseases such as pulmonary hypertension caused by chronic obstructive pulmonary disease, pulmonary hypertension caused by emphysema or pulmonary hypertension caused by pulmonary interstitial disease
  • High pressure for example, pulmonary hypertension caused by sleep apnea syndrome, pulmonary hypertension caused by chronic high altitude disease such as high altitude heart disease) or chronic thromboembolic pulmonary hypertension; more preferably, pulmonary hypertension caused
  • Cannabisdiol is one of the cannabinoids and its structural formula is as follows. I shows:
  • the cannabidiol a compound of formula I, can be purchased commercially (for example from Sigma, etc.) or synthesized using commercially available starting materials by the prior art. After the synthesis, it can be further purified by column chromatography, liquid-liquid extraction, molecular distillation or crystallization. In addition, cannabidiol can also be extracted from cannabis, especially industrial cannabis.
  • the present inventors have found through experiments that the cannabidiol of the present invention and the above compounds have obvious therapeutic effects on animal models of pulmonary hypertension induced by hypoxia and drugs.
  • compositions of cannabidiol include, but are not limited to, organic ammonium salts, alkali metal salts (sodium salts, potassium salts), alkaline earth metal salts (magnesium salts, barium salts, calcium salts), and the like.
  • the pharmaceutically acceptable salt of cannabidiol may be cannabinol (CBD) with sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, aluminum hydroxide, or hydroxide.
  • CBD cannabinol
  • the pharmaceutically acceptable ester of cannabidiol may be a monoester of cannabidiol and a C 0 -C 6 alkyl carboxylic acid, or may be the same as two of cannabidiol or different diesters of C 0- C 6 alkyl carboxylic acids, the C 0 -C 6 alkyl carboxylic acids may be straight-chain alkyl carboxylic acid, branched alkyl or cycloalkyl carboxylic acid,
  • the cannabis extract may be marijuana containing cannabidiol, especially an extract of industrial cannabis, for example Such as ethanol extract, extract and so on.
  • the content of cannabidiol is not particularly limited, and the content of cannabidiol in the cannabis extract can be further increased by means known to those skilled in the art such as concentration.
  • the cannabis extract is an extract, preferably wherein the content of cannabidiol is from 18% to 25%.
  • Another aspect of the present invention relates to the preparation of a drug for inhibiting inflammation, a drug for inhibiting the expression of an inflammatory factor, or a gene for promoting inflammation inhibition (for example, a Mgl 2 gene), which is selected from any one of (1) to (3) below.
  • a drug for inhibiting inflammation a drug for inhibiting the expression of an inflammatory factor
  • a gene for promoting inflammation inhibition for example, a Mgl 2 gene
  • a plant extract containing cannabidiol preferably, the plant extract is a cannabis extract, and
  • composition comprising cannabidiol or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable excipients.
  • the use, wherein the inflammation is chronic low-grade inflammation.
  • the use, wherein the inflammatory factor is selected from the group consisting of TNF-[alpha] and IL-6, particularly human TNF-[alpha] and human IL-6.
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising cannabidiol or a pharmaceutically acceptable salt or ester thereof, or a plant extract comprising cannabidiol or a pharmaceutically acceptable salt or ester thereof (for example, cannabis extract), and one or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition in one embodiment of the invention, is the sole active ingredient. In another embodiment of the invention, the cannabidiol is used in combination with one or more other known active ingredients for the prevention and treatment of pulmonary hypertension.
  • the pharmaceutical composition wherein the pharmaceutical composition further comprises a prostacyclin selected from the group consisting of a prostacyclin, an endothelin receptor antagonist, a phosphodiesterase-5 inhibitor, and a soluble Any one or more of a guanylate cyclase agonist, a serotonin transporter inhibitor, a growth factor inhibitor, and a Rho kinase inhibitor.
  • a prostacyclin selected from the group consisting of a prostacyclin, an endothelin receptor antagonist, a phosphodiesterase-5 inhibitor, and a soluble Any one or more of a guanylate cyclase agonist, a serotonin transporter inhibitor, a growth factor inhibitor, and a Rho kinase inhibitor.
  • the pharmaceutical composition wherein
  • the prostacyclin is selected from any one or more of Benapnost, Treprostinil, iloprost, and Ventavis;
  • the endothelin receptor antagonist is Bosentan; and/or
  • the phosphodiesterase-5 inhibitor is selected from the group consisting of Sildenafil, Vardenafil, and Tadalafil.
  • the pharmaceutical composition may be in the form of any pharmaceutically acceptable dosage form, including: tablets, sugar-coated tablets, film-coated tablets, enteric coated tablets, capsules, hard capsules, soft capsules, Oral liquid, oral preparation, granules, granules, pills, powders, ointments, dans, suspensions, powders, solutions, injections, suppositories, ointments, plasters, creams, sprays, drops, stickers Oral dosage forms such as capsules, tablets, oral liquids, granules, pills, powders, granules, ointments and the like.
  • the oral dosage form may contain conventional excipients such as a binder, a filler, a diluent, a tablet, a lubricant, a disintegrant, a coloring agent, a flavoring agent, and a humectant, and if necessary, a tablet Carry out the coating.
  • suitable fillers include cellulose, mannitol, lactose and other similar fillers;
  • suitable disintegrating agents include starch, polyvinylpyrrolidone and starch derivatives, such as sodium starch glycolate;
  • suitable lubricants include, for example, hard Magnesium citrate.
  • Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulfate.
  • the pharmaceutical composition is an oral preparation.
  • the inventors have found through experiments that the drugs prepared by the cannabidiol are orally administered to mice suffering from pulmonary hypertension, and have obvious therapeutic effects.
  • the therapeutically and/or prophylactically effective amount of the pharmaceutical composition of the present invention is between 0.1 and 200 mg/kg body weight per day.
  • a preferred effective amount of the pharmaceutical composition of the present invention is between 0.1 and 100 mg/kg body weight per day; more preferably between 0.1 and 50 mg/kg body weight per day.
  • a preferred effective amount of the pharmaceutical composition recommended for use in humans is between 0.1 and 50 mg/kg body weight per day; more preferably between 0.5 and 30 mg/kg body weight per day.
  • the "therapeutic and/or prophylactically effective amount" can be used for single or combination therapy of the relevant disease.
  • the pharmaceutical composition (agent) for treating pulmonary hypertension is preferably administered orally, preferably at a dose of 0.5-30 mg/kg per day.
  • Another aspect of the invention relates to a combination product, including product 1 and product 2, wherein:
  • the product 1 is selected from the products of any one of (1) to (3) below:
  • a plant extract containing cannabidiol preferably, the plant extract is a cannabis extract, and
  • composition comprising cannabidiol or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable excipients;
  • the product 2 is selected from the group consisting of prostacyclin, endothelin receptor antagonist, phosphodiesterase-5 inhibitor, soluble guanylate cyclase agonist, serotonin transporter inhibitor, growth factor inhibitor And any one or more of Rho kinase inhibitors;
  • both Product 1 and Product 2 are in the form of an oral formulation.
  • the prostacyclin is selected from any one or more of Benapnost, Treprostinil, iloprost, and Ventavis;
  • the endothelin receptor antagonist is Bosentan; and/or
  • the phosphodiesterase-5 inhibitor is selected from the group consisting of Sildenafil, Vardenafil, and Tadalafil.
  • a further aspect of the invention relates to a product selected from any one of (1) to (3) for treating and/or preventing pulmonary hypertension:
  • a plant extract containing cannabidiol preferably, the plant extract is a cannabis extract, and
  • composition comprising cannabidiol or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable excipients.
  • the product wherein the pulmonary hypertension is primary pulmonary hypertension or secondary pulmonary hypertension; preferably, arterial pulmonary hypertension (eg, idiopathic pulmonary hypertension, Hereditary pulmonary hypertension, pulmonary hypertension caused by drugs and poisons, or persistent pulmonary hypertension in the newborn, and pulmonary hypertension associated with left heart disease (eg pulmonary hypertension caused by systolic dysfunction, pulmonary hypertension caused by diastolic dysfunction, valvular disease) Pulmonary hypertension caused by pulmonary disease (such as chronic obstruction) Pulmonary hypertension caused by pulmonary disease, pulmonary hypertension caused by emphysema or pulmonary hypertension caused by pulmonary interstitial disease), pulmonary hypertension caused by hypoxemia (such as pulmonary hypertension caused by sleep apnea syndrome, chronic high altitude disease) Pulmonary hypertension (such as high altitude heart disease) or chronic thromboembolic pulmonary hypertension; more preferably, pulmonary hypertension caused by hypoxemia
  • hypoxemia such as
  • a further aspect of the invention relates to a product according to any one of (1) to (3), which is for inhibiting inflammation, inhibiting expression of an inflammatory factor or promoting expression of a gene inhibiting inflammation (for example, Mgl 2 gene) :
  • a plant extract containing cannabidiol preferably, the plant extract is a cannabis extract, and
  • composition comprising cannabidiol or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable excipients.
  • the product, wherein the inflammatory factor is selected from the group consisting of TNF-[alpha] and IL-6, particularly human TNF-[alpha] and human IL-6.
  • a further aspect of the invention relates to a method of treating and/or preventing pulmonary hypertension comprising administering to a subject in need thereof an effective amount of a product selected from any one of (1) to (3) below step:
  • a plant extract containing cannabidiol preferably, the plant extract is a cannabis extract, and
  • composition comprising cannabidiol or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable excipients;
  • the method wherein the subject is a mammal, particularly a human.
  • the method wherein the pulmonary hypertension is primary pulmonary hypertension or secondary pulmonary hypertension; preferably, arterial pulmonary hypertension (eg, idiopathic pulmonary hypertension, Hereditary pulmonary hypertension, pulmonary hypertension caused by drugs and poisons, or persistent pulmonary hypertension in the newborn, and pulmonary hypertension associated with left heart disease (eg pulmonary hypertension caused by systolic dysfunction, pulmonary hypertension caused by diastolic dysfunction, valvular disease) Pulmonary hypertension caused by pulmonary disease (such as chronic obstruction) Pulmonary hypertension caused by pulmonary disease, pulmonary hypertension caused by emphysema or pulmonary hypertension caused by pulmonary interstitial disease), pulmonary hypertension caused by hypoxemia (such as pulmonary hypertension caused by sleep apnea syndrome, chronic high altitude disease) Pulmonary hypertension (such as high altitude heart disease) or chronic thromboembolic pulmonary hypertension; more preferably, pulmonary hypertension caused by hypoxemia
  • hypoxemia such as
  • a further aspect of the invention relates to a method of inhibiting inflammation, inhibiting expression of an inflammatory factor or promoting expression of a gene (e.g., Mgl 2 gene) that inhibits inflammation, comprising administering to a subject in need thereof an effective amount selected from the group consisting of The steps of the product of any of 1) to (3):
  • a plant extract containing cannabidiol preferably, the plant extract is a cannabis extract, and
  • composition comprising cannabidiol or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable excipients.
  • the method wherein the inflammation is chronic low-grade inflammation.
  • the method wherein the inflammatory factor is selected from the group consisting of TNF- ⁇ and IL-6.
  • the dosage and method of administration of the active ingredient cannabidiol depends on a number of factors, including the patient's age, weight, sex, natural health status, nutritional status, activity intensity of the compound, time of administration, rate of metabolism, and condition of the disease. Severity and subjective judgment of the doctor.
  • the dose (effective amount) of using cannabidiol is between 0.1 and 50 mg/kg body weight/day, more preferably 0.5 mg/kg to 30 mg/kg body weight/day, 0.5 mg/kg to 20 mg/kg body weight/day, 5 mg/kg to 30 mg/kg body weight/day or 5 mg/kg to 20 mg/kg body weight/day, further preferably 0.5 mg/kg to 10 mg/kg body weight/day, particularly preferably 0.5 mg/kg to 5 mg/kg body weight/ day.
  • the administration is by oral administration.
  • the term "effective amount” refers to a dose that can achieve treatment, prevention, alleviation and/or alleviation of the disease or condition of the invention in a subject.
  • subject can refer to a patient or other animal that receives the composition of the invention to treat, prevent, ameliorate and/or alleviate the disease or condition of the invention, particularly a mammal, such as a human, a dog, a monkey, a cow, Horse and so on.
  • disease and/or condition refers to a physical state of the subject that is associated with the disease and/or condition described herein.
  • the term "pulmonary hypertension” and the so-called hypertension are two distinct diseases.
  • the human heart is divided into the left heart system and the right heart system.
  • the high blood pressure refers to the increase of arterial pressure from the left heart system to the whole body.
  • the arteries from the right heart system are specifically responsible for the lungs.
  • the blood supply is called the pulmonary artery, and this part of the arterial pressure is called pulmonary hypertension.
  • Pulmonary arterial hypertension is a disease or pathophysiological syndrome in which abnormal pressure in the pulmonary arteries is caused by known or unknown causes. There is a pulmonary circulatory disorder and a high right heart load, which can lead to right heart failure and even death, and PAH. The patient may develop hypotension due to cardiac ejection dysfunction later.
  • hypotension refers to the increase in systemic arterial blood pressure (systolic and/or diastolic blood pressure) (systolic blood pressure ⁇ 140 mm Hg, diastolic blood pressure ⁇ 90 mm Hg), which may be accompanied by heart and brain. Clinical syndrome of functional or organic damage of organs such as kidneys.
  • TNF- ⁇ refers to Tumor necrosis factor- ⁇ , a cytokine involved in systemic inflammation, and is also one of many cytokines that cause acute phase reactions, mainly by giants. Phagocyte secretion. The main role of tumor necrosis factor alpha is to regulate the function of immune cells.
  • TNF- ⁇ refers to a protein represented by GenBank Accession No.: NP_038721.1, or a fragment having TNF- ⁇ function, unless otherwise specified.
  • the nucleic acid sequence of the TNF-[alpha] gene is shown as Gene ID: 21926 or its degenerate sequence.
  • IL-6 refers to Interleukin 6 which is a cytokine and belongs to the class of interleukins. It can be produced by fibroblasts, monocytes/macrophages, T lymphocytes, B lymphocytes, epithelial cells, keratinocytes or various tumor cells. Interleukin 6 stimulates cells involved in the immune response to proliferate, differentiate and enhance their function.
  • IL-6 refers to a protein of GenBank Accession No.: NP_001300983.1, or a fragment thereof having IL-6 function.
  • the nucleic acid sequence of the IL-6 gene is set forth in Gene ID: 16193 or its degenerate sequence.
  • Mgl 2 refers to the macrophage galactose N-acetyl-galactosamine specific lectin 2 (macrophage galactose N-acetyl-galactosamine specific lectin 2).
  • Mgl 2 refers to a protein of GenBank Accession No.: NP_660119.1, or a fragment thereof having Mgl 2 function.
  • the nucleic acid sequence of the Mgl 2 gene is set forth in Gene ID: 216864 or its degenerate sequence.
  • the product 1 and the product 2 are merely for the sake of clarity and do not have the meaning of order unless otherwise specified.
  • the cannabis is preferably industrial cannabis unless otherwise specified; the cannabis extract is preferably an industrial cannabis extract.
  • the invention discovers the effect of cannabidiol on inhibiting pulmonary hypertension through experimental research, and proves that cannabidiol has a good therapeutic effect on pulmonary hypertension, and is particularly suitable for treating pulmonary hypertension caused by hypoxemia.
  • CBD reduces hypoxia-induced elevation of right ventricular systolic blood pressure.
  • N 10 / group, the value is the mean ⁇ standard error, with the normoxic wild group as a reference, *** P ⁇ 0.001; the hypoxic wild group as a reference, ### P ⁇ 0.001.
  • FIG. 2 CBD reduces right ventricular hypertrophy caused by hypoxia.
  • N 10 / group, the value is the mean ⁇ standard error, with the normoxic wild group as a reference, *** P ⁇ 0.001; the hypoxic wild group as a reference, ### P ⁇ 0.001.
  • Figure 3 Results of HE staining of pulmonary arterioles ( Figures 3A-3D) and elastic fiber staining ( Figures 3E-3H).
  • the samples of FIGS. 3A-3D are in turn the paraffin sections of the lung tissue of the first group to the fourth group.
  • the samples of FIGS. 3E-3H were sequentially paraffin sections of mouse lung tissue of Group 1 - Group 4.
  • CBD reduces the rate of vascular remodeling caused by hypoxia.
  • N 10/group, the values were mean ⁇ standard error, with the normoxic wild group as the reference, *** P ⁇ 0.001; the hypoxic wild group as the reference, ### P ⁇ 0.01.
  • CBD inhibits LPS-induced primary alveolar macrophage activation in vitro. Values were mean ⁇ standard error, with negative control as reference, * P ⁇ 0.05, ** P ⁇ 0.01; LPS treated group as reference, # P ⁇ 0.05, ## P ⁇ 0.01.
  • Example 1 Effect of cannabidiol on pulmonary hypertension induced by hypoxia
  • Group 1 normal oxygen wild type, as a control group: under normal oxygen conditions, 10 female mice and 10 male rats;
  • Group 2 (anoxic wild type, as a control group): 10 female rats and 10 male rats under hypoxic conditions;
  • Group 3 (10 mg/kg, experimental group): intragastric administration under hypoxic conditions, 10 10 mg/kg female mice and 10 male rats;
  • Group 4 gavage treatment under hypoxic conditions, 10 female mice at 50 mg/kg, and 10 male rats.
  • mice were placed in a normal-pressure hypoxic animal breeding cabin to maintain a cabin oxygen concentration of 9%-11% and a cabin temperature of 22-26 °C.
  • Group 1 mice inhaled atmospheric air, and other conditions were the same as those in groups 2-4.
  • mice can maintain a model of pulmonary hypertension with a significant increase in right ventricular systolic blood pressure for 14 days (Ricard, N., Tu, L., Le Hiress, M., Huertas, A., Phan, C., Thuillet, R., Sattler, C., Fadel, E., Seferian, A., Montani, D., et al. (2014). Increased pericyte coverage mediated by endothelial-derived fibroblast growth Factor-2 and interleukin-6is a source of smooth muscle-like cells in pulmonary hypertension. Circulation 129, 1586-1597.).
  • mice In order to investigate whether CBD has a therapeutic effect on pulmonary hypertension, the inventors first treated mice with a continuous hypoxic environment for 14 days, established a model of pulmonary hypertension (Groups 2-4), and then administered by intragastric administration. The administration was started on the 15th day until the 21st day, once a day, and the mice were treated daily for 7 days (Groups 3-4), and were detected on the 21st day.
  • Multi-channel recording physiological instrument (BE-EH4) Beijing Baianji Technology Co., Ltd.; OLYMPUS microscope (CX4) Olympus (China) Co., Ltd. (OCN); anoxic tank (CJ-DO2) Changsha Changjin Technology Co., Ltd.; Fluorescence quantitative PCR instrument (Light Cycler 480II) Roche Applied Science.
  • RVSP right ventricular systolic pressure
  • mice were anesthetized with sodium pentobarbital (35 mg/kg) by intraperitoneal injection, see Song et al. (Song, Y., Jones, JE, Beppu, H., Keaney, JF, Jr., Loscalzo, J). ., Zhang, YY (2005). Increased susceptibility to pulmonary hypertension in heterozygous BMPR2-mutant mice. Circulation 112, 553-562.) Reported right heart catheterization, right ventricular systolic pressure was measured with a physiologic instrument.
  • a multi-channel physiological recorder signal acquisition and processing system is connected to the end of the catheter to determine the position of the catheter tip based on the blood pressure value displayed by the monitor and the transition of the pressure curve waveform. After the catheter is inserted into the right ventricle, the RVSP is measured and recorded.
  • RVH right ventricular hypertrophy index
  • mice were anesthetized, the thoracic cavity was opened, the heart was removed, all blood vessels and ventricles were dissected, the right ventricle was cut, the weight of the right ventricle and the weight of the left ventricle were weighed, and the left ventricle was divided by the left.
  • the combined weight of the ventricle and sputum RV/(LV+S)).
  • the cut paraffin sections were placed in a 55 ° C oven for 10 min.
  • the nucleus is blue-violet and the cytoplasm is pink.
  • Xylene I 10 min; xylene II: 10 min; 100% ethanol: 5 min; 90% ethanol: 5 min; tap water: 5 min; 0.5% potassium permanganate 5 min; tap water rinse for 2-3 min; 1% oxalic acid solution 2-3 min (bleaching can be); tap water for 2-3min; 95% ethanol for 2-3min; Elastic dye solution for 2h; 95% ethanol to wash the dye solution; tap water for 2-3min; Van Gieson dye solution for 1min; rapid dehydration: 80 % ethanol 1 min, 90% ethanol 1 min, absolute ethanol I 5 min, absolute ethanol II 5 min, xylene I 5 min, xylene II 5 min.
  • Keegan et al. Kerman, A., Morecroft, I., Smillie, D., Hicks, M.N., and MacLean, M.R. (2001). Contribution of the 5-HT (1B) receptor to Hypoxia-induced pulmonary hypertension: converging evidence using5-HT(1B)-receptor knockout mice and the 5-HT(1B/1D)-receptor antagonist GR127935.Circulation research 89,1231-1239), pulmonary paraffin with front-dyed elastic fibers The sections were counted, 50-100 ⁇ m were selected, and the pulmonary arterioles away from the airway were counted, and the remodeling part exceeding the vessel circumference by 1/2 or more was recorded as a remodeling vessel.
  • the measurement data were expressed as mean ⁇ standard error, and statistical processing was performed using SPSS 22.0. The statistical tests were based on the two-tailed T test.
  • the mean right ventricular systolic pressure of the hypoxic model control group was (25.55 ⁇ 2.29) mmHg, which was significantly higher than that of the normoxic control group (17.54 ⁇ 1.48) mmHg, and the difference was statistically significant (P ⁇ 0.001).
  • the mean right ventricular systolic pressure was (16.90 ⁇ 2.31) mmHg in the experimental group of 10 mg/kg, which was significantly lower than that in the hypoxic model control group (P ⁇ 0.001); the experimental group of 50 mg/kg The mean right ventricular systolic pressure was (17.92 ⁇ 2.37) mmHg, which was also significantly lower than the model group, but there was no significant difference between the two dose treatment groups (10 mg/kg and 50 mg/kg).
  • the right ventricular hypertrophy index of the model group was (32.62 ⁇ 1.41)%, which was significantly higher than that of the normoxic control group (25.99 ⁇ 1.17)%.
  • the right heart index of the mice in the 10 mg/kg and 50 mg/kg groups was (30.18 ⁇ 1.01)%, (29.90 ⁇ 1.19)%, which was significantly lower than the model group, and the difference was statistically significant (P ⁇ 0.001). ), but there were no significant differences between the different dose treatment groups.
  • the wall of the mice was significantly thickened and remodeled significantly.
  • the pulmonary arteriole remodeling was significantly reduced, and the remodeling rate was significantly decreased.
  • Both doses of cannabidiol can reduce right ventricular systolic pressure and inhibit right ventricular (RV) hypertrophy; pathological weight Plastics have an improved effect, including reducing the thickness ratio of the middle layer of the artery, the cross-sectional area ratio of the middle wall of the tube wall, and reducing the right ventricular hypertrophy.
  • Example 2 In vitro experiment of treatment of macrophages induced by LPS with cannabidiol
  • Cannabisdiol (CBD, Yunnan Hansu Biotechnology Co., Ltd.)
  • mice Primary alveolar macrophages were isolated according to the method of Yang et al. (Yang, HM, Ma, JY, Castranova, V., and Ma, JK (1997). Effects of diesel exhaust particles on the release of interleukin-1 and tumor necrosis factor -alpha from rat alveolar macrophages.Experimental lung research 23, 269-284.): 2 months old mice were anesthetized with pentobarbital by intraperitoneal injection. Fix it on the back, disinfect the neck, cut the neck skin, peel off the gland muscles, and expose the trachea.
  • the alveolar macrophages of the mice were randomly divided into six treatment groups (about 5 ⁇ 10 6 cells in each group), the first group was a negative control; the second group was induced with 100 ng/mL LPS (addition in the medium) LPS), modeled the in vivo inflammatory response model; the third group was the CBD control group (5 ⁇ M CBD was added to the medium); the fourth group was pretreated with 0.5 ⁇ M CBD for 0.5 h, and 100 ng/mL LPS was added (in the medium). 0.5 ⁇ M CBD and 100 ng/mL LPS) were added.
  • the fifth group was pretreated with 1 ⁇ M of CBD for 0.5 h, and then induced with 100 ng/mL of LPS (1 ⁇ M CBD and 100 ng/mL LPS were added to the medium).
  • the sixth group was pretreated with 5 ⁇ M of CBD for 0.5 h, and then induced with 100 ng/mL of LPS (5 ⁇ M CBD and 100 ng/mL LPS were added to the medium). After 5 hours of treatment, the cells were collected, and the expression changes of inflammatory factors TNF- ⁇ , IL-6 and Mgl 2 in each group were detected by fluorescence quantitative PCR.
  • Reverse primer GCTACGACGTGGGCTACAG (SEQ ID NO: 2)
  • Reverse primer AAGTGCATCGTTGTTCATACA (SEQ ID NO: 4)
  • Reverse primer AGTTGACCACCACCACCAGGTGAGAAT (SEQ ID NO: 6)
  • CBD can significantly inhibit the expression of inflammation-associated TNF- ⁇ and IL-6 induced by LPS in a dose-dependent manner, and promote the expression of the gene Mgl 2 which inhibits inflammation.

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Abstract

本发明属于医药领域，涉及大麻二酚(Cannabidiol，CBD)在治疗肺动脉高压中的应用。所述大麻二酚可作为唯一活性成分或者与其它活性成分联用制备治疗肺动脉高压的药物。具体地，本发明涉及选自如下的(1)至(3)中的任一项在制备治疗和/或预防肺动脉高压的药物中的用途：(1)大麻二酚，(2)一种植物提取物，其含有大麻二酚；优选地，所述植物提取物为大麻提取物，和(3)一种药物组合物，其含有大麻二酚，以及一种或多种药学上可接受的辅料。本发明通过试验研究发现了大麻二酚抑制肺动脉高压的作用，尤其适合治疗低氧血症所致的肺动脉高压。

Description

大麻二酚在治疗肺动脉高压中的应用 技术领域
本发明属于医药领域，涉及大麻二酚在治疗肺动脉高压中的应用。
背景技术
肺动脉高压(pulmonary arterial hypertension，PAH)病因复杂，由多种心、肺或肺血管疾病引起。肺动脉高压以肺小动脉血管重构、肺动脉血管平滑肌增殖为病理特征，表现为肺循环压力和阻力增加，可出现右心负荷增大，右心功能不全，肺血流减少，从而引起一系列临床表现；病程中肺动脉高压常呈进行性发展。特别是增强肺动脉血管张力导致的右心衰，是严重威胁人类生命健康的疾病。
肺动脉高压分为原发性和继发性两类。随着对肺动脉高压认识的逐步深入，2003年世界卫生组织(WHO)“肺动脉高压会议”按照病因、病理生理、治疗方案及预后特点对肺动脉高压进行分类，2004年美国胸科医师学院(ACCP)和欧洲心血管病学会(ESC)对此进行了修订，该分类方法对肺动脉高压患者的治疗具有指导意义。一般认为，平静状态下右心导管检测肺动脉平均压≥25mmHg时即为肺动脉高压(Badesch et al.,2009)。根据静息PAPm可将肺动脉高压进行分级，轻度为26－35mmHg；中度为36－45mmHg；重度>45mmHg。
肺动脉高压主要累及肺动脉和右心，表现为右心室肥厚，右心房扩张。肺动脉主干扩张，周围肺小动脉稀疏。肺小动脉内皮细胞、平滑肌细胞增生肥大，血管内膜纤维化增厚，中膜肥厚，管腔狭窄，闭塞，扭曲变形，呈丛状改变。肺小静脉也可以出现内膜纤维增生和管腔阻塞。肺动脉高压患者的其它表现还包括肺动脉外膜以及静脉的肥大和TGF-β的表达升高，以及弹性蛋白、纤连蛋白、细胞色素C和粘多糖等基质蛋白表达升高。
肺动脉高压是一种能够治疗的疾病，但目前尚无特效的治愈方法。传统的治疗方法包括吸氧、强心、利尿、钙通道阻滞剂和抗凝剂辅助治疗剂等，主要起到症状的缓解作用。
近年来，靶向治疗药物的研发与推广使用(主要包括前列环素类药物、内皮素受 体拮抗剂、磷酸二酯酶-5抑制剂以及新近探索的可溶性鸟苷酸环化酶激动剂、5-羟色胺转运子抑制剂、生长因子抑制剂、Rho激酶抑制剂等)以及活体肺移植等治疗方法大大改善了患者的预后。
尽管这些药物能在一定程度上缓解PAH的症状，肺动脉高压目前仍然是一种无法治愈且病死率较高的疾病，患者接受治疗情况下的中位生存时间仅为2.7年，目前肺动脉高压仍缺乏特效的治愈方法，因此，寻找新的特异性治疗药物显得尤为迫切。
发明内容
本发明人经过深入的研究和创造性的劳动，惊奇地发现，大麻二酚能够有效地抑制肺动脉高压，尤其适合治疗低氧血症所致的肺动脉高压。由此提供了下述发明：
本发明的一个方面涉及选自如下的(1)至(3)中的任一项在制备治疗和/或预防肺动脉高压的药物中的用途：
(1)大麻二酚或其药学上可接受的盐或酯，
(2)一种植物提取物，其含有大麻二酚；优选地，所述植物提取物为大麻提取物例如工业大麻提取物，和
(3)一种药物组合物，其含有大麻二酚或其药学上可接受的盐或酯，以及一种或多种药学上可接受的辅料。
在本发明的一个实施方案中，所述的用途，其中，所述肺动脉高压为原发性肺动脉高压或继发性肺动脉高压；优选地，为动脉性肺动脉高压(例如特发性肺动脉高压、可遗传性肺动脉高压、药物和毒物所致肺动脉高压或新生儿持续性肺动脉高压)、左心疾病相关性肺动脉高压(例如心脏收缩功能不全所致肺动脉高压、舒张功能不全所致肺动脉高压、瓣膜病所致肺动脉高压)、肺部疾病所致肺动脉高压(例如慢性阻塞性肺疾病所致肺动脉高压、肺气肿所致肺动脉高压或肺间质性疾病所致肺动脉高压)、低氧血症所致肺动脉高压(例如睡眠呼吸暂停综合征所致肺动脉高压、慢性高原病所致肺动脉高压比如高原性心脏病)或者慢性血栓栓塞性肺动脉高压；更优选地，为低氧血症所致肺动脉高压。
大麻二酚(Cannabidiol,CBD)是大麻素类物质中的一种，其结构式如下面的式 I所示：
Figure PCTCN2017093367-appb-000001
所述大麻二酚即式I化合物可通过商业途径购买(例如购自Sigma等)或者利用市售原料，通过现有技术合成。合成后可以通过柱色谱法、液液萃取法、分子蒸馏方法或结晶等方式进一步纯化。此外，大麻二酚还可以从大麻，尤其是工业大麻中提取得到。
本发明通过实验研究发现，本发明所述大麻二酚与上述化合物对低氧和药物诱导所致的肺动脉高压动物模型有明显的治疗作用。
大麻二酚的药学上可接受的盐，包括但不限于：有机铵盐、碱金属盐(钠盐、钾盐)、碱土金属盐(镁盐、锶盐、钙盐)等。
在本发明的一些实施方式中，大麻二酚的药学上可接受的盐可以为大麻二酚(CBD)与氢氧化钠、氢氧化钾、氢氧化钙、氢氧化镁、氢氧化铝、氢氧化锂、氢氧化锌、氢氧化钡、氨、甲胺、二甲胺、二乙胺、甲基吡啶、乙醇胺、二乙醇胺、三乙醇胺、乙二胺、赖氨酸、精氨酸、鸟氨酸、胆碱、N，N′-二苯甲基乙二胺、氯普鲁卡因、二乙醇胺、普鲁卡因、N-苯甲基苯乙胺、N-甲基葡糖胺哌嗪、三(羟基甲基)-氨基甲烷等形成的盐。
在本发明的一些实施方式中，大麻二酚药学上可接受的酯可以为大麻二酚与一个C0-C6烷基羧酸形成的单酯，也可以为大麻二酚与两个相同或不同的C0-C6烷基羧酸形成的二酯，所述的C0-C6烷基羧酸可以是直链烷基羧酸、支链烷基羧酸或环烷基羧酸，例如HCOOH、CH3COOH、CH3CH2COOH、CH3(CH2)2COOH、CH3(CH2)3COOH、CH3(CH2)4COOH、(CH3)2CHCOOH、(CH3)3CCOOH、(CH3)2CHCH2COOH、(CH3)2CH(CH2)2COOH、(CH3)2CH(CH3)CHCOOH、(CH3)3CCH2COOH、CH3CH2(CH3)2CCOOH、环丙烷羧酸、环丁烷羧酸、环戊烷羧酸。
所述的大麻提取物，可以是含有大麻二酚的大麻，尤其是工业大麻的提取物，例 如乙醇提取液、浸膏等。其中，大麻二酚的含量并不特别限定，而且可以通过本领域技术人员知悉的手段例如浓缩等来进一步提高大麻提取物中大麻二酚的含量。在本发明的一个实施方案中，所述的大麻提取物，其为浸膏，优选地，其中大麻二酚的含量为18％－25％。
本发明的另一方面涉及选自如下的(1)至(3)中的任一项在制备抑制炎症的药物、抑制炎症因子表达的药物或者促进抑制炎症的基因(例如Mgl2基因)的表达的药物中的用途：
(1)大麻二酚或其药学上可接受的盐或酯，
(2)一种植物提取物，其含有大麻二酚；优选地，所述植物提取物为大麻提取物，和
(3)一种药物组合物，其含有大麻二酚或其药学上可接受的盐或酯，以及一种或多种药学上可接受的辅料。
在本发明的一个实施方案中，所述的用途，其中，所述炎症是慢性低度炎症。
在本发明的一个实施方案中，所述的用途，其中，所述炎症因子选自TNF-α和IL-6特别是人TNF-α和人IL-6。
本发明的另一方面涉及一种药物组合物，其包含大麻二酚或其药学上可接受的盐或酯，或者包含含有大麻二酚或其药学上可接受的盐或酯的植物提取物(例如大麻提取物)，以及一种或多种药学上可接受的辅料。
在本发明的一个实施方案中，所述的药物组合物，大麻二酚是唯一活性成分。在本发明的另一个实施方案中，大麻二酚与一种或多种其它已知的用于防治肺动脉高压的活性成分联用。
在本发明的一个实施方案中，所述的药物组合物，其中，所述药物组合物还包含选自前列环素类药物、内皮素受体拮抗剂、磷酸二酯酶-5抑制剂、可溶性鸟苷酸环化酶激动剂、5-羟色胺转运子抑制剂、生长因子抑制剂以及Rho激酶抑制剂中的任意一种或几种。
在本发明的一个实施方案中，所述的药物组合物，其中，
所述前列环素类药物选自贝前列素(Benapnost)、曲前列素(Treprostinil)、伊洛前列素(iloprost)和万他维(Ventavis)中的任意一种或者几种；
所述内皮素受体拮抗剂为波生坦(Bosentan)；和/或
所述磷酸二酯酶-5抑制剂选自西地那非(Sildenafil)、伐地那非(Vardenafil)和他达那非(Tadalafil)。
所述药物组合物的制剂形式可以是任何可药用的剂型，这些剂型包括：片剂、糖衣片剂、薄膜衣片剂、肠溶衣片剂、胶囊剂、硬胶囊剂、软胶囊剂、口服液、口含剂、颗粒剂、冲剂、丸剂、散剂、膏剂、丹剂、混悬剂、粉剂、溶液剂、注射剂、栓剂、软膏剂、硬膏剂、霜剂、喷雾剂、滴剂、贴剂；优选口服剂型，如：胶囊剂、片剂、口服液、颗粒剂、丸剂、散剂、丹剂、膏剂等。所述的口服剂型可含有常用的赋形剂，诸如粘合剂、填充剂、稀释剂、压片剂、润滑剂、崩解剂、着色剂、调味剂和湿润剂，必要时可对片剂进行包衣。适宜的填充剂包括纤维素、甘露糖醇、乳糖和其它类似的填充剂；适宜的崩解剂包括淀粉、聚乙烯吡咯烷酮和淀粉衍生物，例如羟基乙酸淀粉钠；适宜的润滑剂包括，例如硬脂酸镁。适宜的药物可接受的湿润剂包括十二烷基硫酸钠。
优选地，所述药物组合物为口服制剂。本发明人经试验发现，将所述大麻二酚制备的药物经口灌胃患肺动脉高压的小鼠，具有明显的治疗效果。
本发明所述药物组合物的治疗和/或预防有效用量介于0.1－200mg/kg体重/天之间。本发明所述药物组合物的优选有效用量介于0.1－100mg/kg体重/天之间；更优选为0.1－50mg/Kg体重/天之间。建议用在人体的所述药物组合物的优选有效用量介于0.1－50mg/kg体重/天之间；更优选为0.5－30mg/Kg体重/天之间。所述的“治疗和/或预防有效用量”可用于相关疾病的单一用药或联合用药治疗。
所述治疗肺动脉高压的药物组合物(药剂)优选使用方法为口服，优选的剂量为每天0.5－30mg/Kg。
本发明的另一方面涉及一种组合产品，包括产品1和产品2，其中：
所述产品1选自如下的(1)至(3)中的任一项的产品：
(1)大麻二酚或其药学上可接受的盐或酯，
(2)一种植物提取物，其含有大麻二酚；优选地，所述植物提取物为大麻提取物，和
(3)一种药物组合物，其含有大麻二酚或其药学上可接受的盐或酯，以及一种或多种药学上可接受的辅料；
所述产品2选自前列环素类药物、内皮素受体拮抗剂、磷酸二酯酶-5抑制剂、可溶性鸟苷酸环化酶激动剂、5-羟色胺转运子抑制剂、生长因子抑制剂以及Rho激酶抑制剂中的任意一种或几种；
并且所述产品1和产品2是各自独立包装的；
优选地，所述产品1和产品2均为口服制剂形式。
在本发明的一个实施方案中，所述的组合产品，其中，
所述前列环素类药物选自贝前列素(Benapnost)、曲前列素(Treprostinil)、伊洛前列素(iloprost)和万他维(Ventavis)中的任意一种或者几种；
所述内皮素受体拮抗剂为波生坦(Bosentan)；和/或
所述磷酸二酯酶-5抑制剂选自西地那非(Sildenafil)、伐地那非(Vardenafil)和他达那非(Tadalafil)。
本发明的再一方面涉及选自如下的(1)至(3)中的任一项的产品，其用于治疗和/或预防肺动脉高压：
(1)大麻二酚或其药学上可接受的盐或酯，
(2)一种植物提取物，其含有大麻二酚；优选地，所述植物提取物为大麻提取物，和
(3)一种药物组合物，其含有大麻二酚或其药学上可接受的盐或酯，以及一种或多种药学上可接受的辅料。
在本发明的一个实施方案中，所述的产品，其中，所述肺动脉高压为原发性肺动脉高压或继发性肺动脉高压；优选地，为动脉性肺动脉高压(例如特发性肺动脉高压、可遗传性肺动脉高压、药物和毒物所致肺动脉高压或新生儿持续性肺动脉高压)、左心疾病相关性肺动脉高压(例如心脏收缩功能不全所致肺动脉高压、舒张功能不全所致肺动脉高压、瓣膜病所致肺动脉高压)、肺部疾病所致肺动脉高压(例如慢性阻塞 性肺疾病所致肺动脉高压、肺气肿所致肺动脉高压或肺间质性疾病所致肺动脉高压)、低氧血症所致肺动脉高压(例如睡眠呼吸暂停综合征所致肺动脉高压、慢性高原病所致肺动脉高压比如高原性心脏病)或者慢性血栓栓塞性肺动脉高压；更优选地，为低氧血症所致肺动脉高压。
本发明的再一方面涉及选自如下的(1)至(3)中的任一项的产品，其用于抑制炎症、抑制炎症因子表达或者促进抑制炎症的基因(例如Mgl2基因)的表达：
(1)大麻二酚或其药学上可接受的盐或酯，
(2)一种植物提取物，其含有大麻二酚；优选地，所述植物提取物为大麻提取物，和
(3)一种药物组合物，其含有大麻二酚或其药学上可接受的盐或酯，以及一种或多种药学上可接受的辅料。
在本发明的一个实施方案中，所述的产品，其中，所述炎症因子选自TNF-α和IL-6特别是人TNF-α和人IL-6。
本发明的再一方面涉及一种治疗和/或预防肺动脉高压的方法，包括给予有需求的受试者以有效量的选自如下的(1)至(3)中的任一项的产品的步骤：
(1)大麻二酚或其药学上可接受的盐或酯，
(2)一种植物提取物，其含有大麻二酚；优选地，所述植物提取物为大麻提取物，和
(3)一种药物组合物，其含有大麻二酚或其药学上可接受的盐或酯，以及一种或多种药学上可接受的辅料；
在本发明的一个实施方案中，所述的方法，其中，所述受试者为哺乳动物特别是人。
在本发明的一个实施方案中，所述的方法，其中，所述肺动脉高压为原发性肺动脉高压或继发性肺动脉高压；优选地，为动脉性肺动脉高压(例如特发性肺动脉高压、可遗传性肺动脉高压、药物和毒物所致肺动脉高压或新生儿持续性肺动脉高压)、左心疾病相关性肺动脉高压(例如心脏收缩功能不全所致肺动脉高压、舒张功能不全所致肺动脉高压、瓣膜病所致肺动脉高压)、肺部疾病所致肺动脉高压(例如慢性阻塞 性肺疾病所致肺动脉高压、肺气肿所致肺动脉高压或肺间质性疾病所致肺动脉高压)、低氧血症所致肺动脉高压(例如睡眠呼吸暂停综合征所致肺动脉高压、慢性高原病所致肺动脉高压比如高原性心脏病)或者慢性血栓栓塞性肺动脉高压；更优选地，为低氧血症所致肺动脉高压。
本发明的再一方面涉及一种抑制炎症、抑制炎症因子表达或者促进抑制炎症的基因(例如Mgl2基因)的表达的方法，包括给予有需求的受试者以有效量的选自如下的(1)至(3)中的任一项的产品的步骤：
(1)大麻二酚或其药学上可接受的盐或酯，
(2)一种植物提取物，其含有大麻二酚；优选地，所述植物提取物为大麻提取物，和
(3)一种药物组合物，其含有大麻二酚或其药学上可接受的盐或酯，以及一种或多种药学上可接受的辅料。
在本发明的一个实施方案中，所述的方法，其中，所述炎症是慢性低度炎症。
在本发明的一个实施方案中，所述的方法，其中，所述炎症因子选自TNF-α和IL-6。
需要指出的是，活性成分大麻二酚的使用剂量和使用方法取决于诸多因素，包括患者的年龄、体重、性别、自然健康状况、营养状况、化合物的活性强度、服用时间、代谢速率、病症的严重程度以及诊治医师的主观判断。优选的使用大麻二酚的剂量(有效量)介于0.1－50mg/kg体重/天，更优选为0.5mg/kg－30mg/kg体重/天、0.5mg/kg－20mg/kg体重/天、5mg/kg－30mg/kg体重/天或者5mg/kg－20mg/kg体重/天，进一步优选为0.5mg/kg－10mg/kg体重/天，特别优选为0.5mg/kg－5mg/kg体重/天。优选地，通过口服进行给药。
本发明中，术语“有效量”是指可在受试者中实现治疗、预防、减轻和/或缓解本发明所述疾病或病症的剂量。
术语“受试者”可以指患者或者其它接受本发明组合物以治疗、预防、减轻和/或缓解本发明所述疾病或病症的动物，特别是哺乳动物，例如人、狗、猴、牛、马等。
术语“疾病和/或病症”是指所述受试者的一种身体状态，该身体状态与本发明所述疾病和/或病症有关。
本发明中，术语“肺动脉高压“与通常所说的高血压是两种截然不同的疾病。人的心脏分为左心系统和右心系统，平时我们所说的高血压是指从左心系统发出的给全身供血的动脉压力升高；而从右心系统发出的动脉专门负责给肺部供血，被称为肺动脉，而这部分动脉压力升高则被称为肺动脉高压。
肺动脉高压(pulmonary arterial hypertension，PAH)是由已知或未知原因引起肺动脉内压力异常升高的疾病或病理生理综合征，存在肺循环障碍与右心高负荷，可导致右心衰竭甚至死亡，而且PAH病人后期因为心脏射血功能障碍，可能发展为低血压。
术语“高血压”(hypertension)是指以体循环动脉血压(收缩压和/或舒张压)增高为主要特征(收缩压≥140毫米汞柱，舒张压≥90毫米汞柱)，可伴有心、脑、肾等器官的功能或器质性损害的临床综合征。
术语“TNF-α”是指肿瘤坏死因子(Tumor necrosis factor-α)，是一种涉及到系统性炎症的细胞因子，同时也是属于引起急相反应的众多细胞因子中的一员，主要由巨噬细胞分泌。肿瘤坏死因子α的主要作用是调节免疫细胞的功能。本发明中，如果没有特别说明，TNF-α是指GenBank登录号：NP_038721.1所示的蛋白，或其具有TNF-α功能的片段。在本发明的一个实施方案中，TNF-α基因的核酸序列如Gene ID:21926或其简并序列所示。
术语“IL-6”是指白介素6(Interleukin 6)，是一种细胞因子，属于白细胞介素的一种。它可以由纤维母细胞、单核/巨噬细胞、T淋巴细胞、B淋巴细胞、上皮细胞、角质细胞或者多种瘤细胞所产生。白介素6能够刺激参与免疫反应的细胞增殖、分化并提高其功能。本发明中，如果没有特别说明，IL-6是指GenBank登录号：NP_001300983.1的蛋白，或其具有IL-6功能的片段。在本发明的一个实施方案中，IL-6基因的核酸序列如Gene ID:16193或其简并序列所示。
术语“Mgl2”是指巨噬细胞半乳糖N-乙酰半乳糖胺特异性凝集素2(macrophage galactose N-acetyl-galactosamine specific lectin 2)。本发明中，如果没有特别说明，Mgl2是指GenBank登录号：NP_660119.1的蛋白，或其具有Mgl2功能的片段。在本发明的一个实施方案中，Mgl2基因的核酸序列如Gene ID:216864或其简并序列所示。
本发明中，如果没有特别说明，所述产品1、产品2仅仅是为了指代清楚，并不具有次序的含义。
本发明中，如果没有特别说明，大麻优选为工业大麻；大麻提取物优选为工业大麻提取物。
发明的有益效果
本发明通过试验研究发现了大麻二酚抑制肺动脉高压的作用，证明了大麻二酚对肺动脉高压具有良好的治疗作用，尤其适合治疗低氧血症所致的肺动脉高压。
附图说明
图1：CBD降低缺氧引起的右心室收缩压升高。N＝10/组，数值为平均值±标准误，以常氧野生组作为参照，***P＜0.001；以缺氧野生组作为参照，###P＜0.001。
图2：CBD降低缺氧引起的右心室肥大。N＝10/组，数值为平均值±标准误，以常氧野生组作为参照，***P＜0.001；以缺氧野生组作为参照，###P＜0.001。
图3：肺小动脉血管HE染色(图3A-3D)和弹性纤维染色(图3E-3H)结果。其中，图3A-3D的样品依次为第1组-第4组的小鼠肺组织石蜡切片。其中，图3E-3H的样品依次为第1组-第4组的小鼠肺组织石蜡切片。
图4：CBD降低缺氧引起的血管重塑率。N＝10/组，数值为平均值±标准误，以常氧野生组作为参照，***P＜0.001；以缺氧野生组作为参照，###P＜0.01。
图5：CBD抑制体外LPS诱导的原代肺泡巨噬细胞激活。数值为平均值±标准误，以阴性对照组作为参照，*P＜0.05，**P＜0.01；以LPS处理组作为参照，#P＜0.05，##P＜0.01。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述，但是本领域技术人员将会理解，下列实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
实施例1：大麻二酚对低氧所致肺动脉高压的影响试验
1.实验动物、试剂和仪器
(1)实验动物
4－6周龄健康活泼、毛色光泽，体重(25.15±2.15)g，C57BL/6(军事科学医学院实验动物中心，SPF级)。分为四组：
第1组(常氧野生型，作为对照组)：常氧条件下，雌鼠10只，雄鼠10只；
第2组(缺氧野生型，作为对照组)：缺氧条件下，雌鼠10只，雄鼠10只；
第3组(10mg/kg，实验组)：缺氧条件下灌胃处理，10mg/kg雌鼠10只，雄鼠10只；
第4组(50mg/kg，实验组)：缺氧条件下灌胃处理，50mg/kg雌鼠10只，雄鼠10只。
(2)给药方法
将第2－4组小鼠置于常压低氧动物饲养舱内，维持舱内氧浓度在9％－11％，保持舱内温度为22－26℃。第1组小鼠吸入常压空气，其它条件同第2－4组小鼠。
以前的研究结果表明，小鼠持续缺氧14天，就可建成以右心室收缩压明显升高为标准的肺动脉高压模型(Ricard,N.,Tu,L.,Le Hiress,M.,Huertas,A.,Phan,C.,Thuillet,R.,Sattler,C.,Fadel,E.,Seferian,A.,Montani,D.,et al.(2014).Increased pericyte coverage mediated by endothelial-derived fibroblast growth factor-2and interleukin-6is a source of smooth muscle-like cells in pulmonary hypertension.Circulation 129,1586-1597.)。为了探究CBD是否对肺动脉高压有治疗作用，本发明人先用持续缺氧的环境处理小鼠14天，建立起肺动脉高压的模型(第2－4组)，然后采用灌胃的给药方式，在第15天开始给药一直到第21天，每天给药一次，持续7天每天处理小鼠(第3－4组)，在第21天检测。
具体检测步骤如下面第2部分“实验方法”所描述。
(3)实验试剂
戊巴比妥钠(sigma)；大麻二酚(云南汉素生物科技有限公司)；结晶紫、维多利亚蓝B(国药集团化学试剂有限公司)；新品红(东京化成工业株式会社)。
(4)实验仪器
多道记录生理仪(BE-EH4)北京拜安吉科技有限公司；OLYMPUS显微镜(CX4)奥林巴斯(中国)有限公司(OCN)；缺氧箱(CJ-DO2)长沙长锦科技有限公司；荧光定量PCR仪(Light Cycler480Ⅱ)罗氏应用科学部。
2.实验方法
(1)右心室收缩压(RVSP)测定
在第21天，小鼠用戊巴比妥钠(35mg/kg)腹腔注射麻醉，参照Song等(Song,Y.,Jones,J.E.,Beppu,H.,Keaney,J.F.,Jr.,Loscalzo,J.,and Zhang,Y.Y.(2005).Increased susceptibility to pulmonary hypertension in heterozygous BMPR2-mutant mice.Circulation 112,553-562.)报道的右心导管插入术，用生理仪配套导管测右心室收缩压。导管末端连接多道生理记录仪信号采集处理系统，根据监视器所显示的血压值与压力曲线波型的移行变化判断导管尖端的位置。待导管进人右心室后，测定并记录RVSP。
(2)右心室肥大指数(RVH)测定
按照Ryan等的方法，小鼠麻醉后，开胸腔，摘取心脏，剥离所有血管和心室，剪下右心室，分别称量右心室重量和左心室加膈的重量，用右心室重除以左心室和膈的合重(RV/(LV+S))。
(3)HE染色
样品：小鼠肺组织的石蜡切片。
目的：看肺组织病理，是否有血管壁增厚的现象。
将切好的石蜡切片放入55℃烘箱中10min。
①石蜡切片经脱蜡下行至70％乙醇；
二甲苯I：15min
二甲苯II：7min
1：1二甲苯乙醇溶液：5min
各级乙醇：各5min
②苏木精溶液染色10-15min；
③自来水冲洗2min；
④0.5％盐酸酒精溶液分化8s；
⑤自来水返蓝10min；
⑥70％酒精→80％酒精各2min；
⑦0.5％伊红酒精染液50-70s；
⑧90％乙醇，95％乙醇分色各3min；
⑨无水乙醇I、II脱水各3min；
⑩无水乙醇：二甲苯(1:1)3min；
Figure PCTCN2017093367-appb-000002
二甲苯I 3min；
Figure PCTCN2017093367-appb-000003
二甲苯II 3min；
中性树胶封片；
染色完成后，胞核呈蓝紫色，胞质呈粉红色。
(4)弹性纤维染色(Elastic染色)
样品：小鼠肺组织的石蜡切片。
染液配制：维多利亚蓝B 1g。
新品红1g，结晶紫1g。
200ml热水溶解，按顺序加入间二苯酚4g，糊精4g，30％氯化铁50ml(现用现配)，煮5min过滤，沉淀和滤纸用200ml 95％乙醇溶解，煮沸15min－20min过滤(水浴)，95％乙醇补至200ml，最后加2ml浓盐酸。密封，避光保存。
染色方法：
二甲苯I：10min；二甲苯II：10min；100％乙醇：5min，；90％乙醇：5min；自来水：5min；0.5％高锰酸钾5min；自来水冲洗2－3min；1％草酸溶液2－3min(漂白即可)；自来水冲洗2－3min；95％乙醇2-3min；Elastic染液染2h；95％乙醇洗去染液；自来水冲洗2－3min；Van Gieson染液染1min；快速脱水：80％乙醇1min，90％乙醇1min，无水乙醇I 5min，无水乙醇II 5min，二甲苯I 5min，二甲苯II 5min。
(5)血管重塑率
采用Keegan等的方法(Keegan,A.,Morecroft,I.,Smillie,D.,Hicks,M.N.,and MacLean,M.R.(2001).Contribution of the 5-HT(1B)receptor to  hypoxia-induced pulmonary hypertension:converging evidence using5-HT(1B)-receptor knockout mice and the 5-HT(1B/1D)-receptor antagonist GR127935.Circulation research 89,1231-1239)，用前面染弹性纤维的肺石蜡切片进行计数，选取50-100μm，远离大气道的肺小动脉血管进行计数，重塑部分超过血管周长1/2及以上的记为重塑血管。
(6)统计学处理
计量资料以均数±标准误表示，采用SPSS 22.0进行统计处理，统计检验均基于双尾T检验。
3.实验结果
(1)PAH小鼠右心室收缩压
结果如图1所示。
持续缺氧21天后，缺氧模型对照组平均右心室收缩压为(25.55±2.29)mmHg，较常氧对照组(17.54±1.48)mmHg显著升高，差异有统计学意义(P＜0.001)。
经CBD治疗后，10mg/kg的实验组平均右心室收缩压为(16.90±2.31)mmHg，较缺氧模型对照组显著降低，差异有统计学意义(P＜0.001)；50mg/kg的实验组平均右心室收缩压为(17.92±2.37)mmHg，较模型组也有显著降低，但两个剂量处理组(10mg/kg和50mg/kg)的结果没有显著差异。
(2)CBD处理显著抑制PAH小鼠右心室肥大指数
结果如图2所示。
模型组小鼠右心室肥大指数为(32.62±1.41)％，明显高于常氧对照组小鼠(25.99±1.17)％。经CBD治疗后，10mg/kg和50mg/kg实验组小鼠右心指数分别为(30.18±1.01)％、(29.90±1.19)％，显著低于模型组，差异有统计学意义(P＜0.001)，但不同剂量治疗组间没有显著差异。
(3)肺小动脉病理学改变
结果如图3A－3H和图4所示。
缺氧模型组小鼠管壁显著增厚，重构明显。CBD治疗后显著降低肺小动脉重塑，重塑率显著下降。
大麻二酚两个剂量组都能降低右心室收缩压，抑制右心室(RV)肥厚指标；病理重 塑有改善作用，包括减小动脉中层壁厚比，管壁中层横截面积比以及降低右心室肥大。
实施例2：大麻二酚处理LPS诱导的巨噬细胞的体外实验
1.实验动物、试剂和仪器
2月龄C57BL/6小鼠(军事科学医学院实验动物中心，SPF级)
RPMI-1640(Sigma)
大麻二酚(CBD，云南汉素生物科技有限公司)
LPS(Sigma)
荧光定量PCR仪(Roche)
2.实验方法
按照Yang等人的方法分离原代肺泡巨噬细胞(Yang,H.M.,Ma,J.Y.,Castranova,V.,and Ma,J.K.(1997).Effects of diesel exhaust particles on the release of interleukin-1and tumor necrosis factor-alpha from rat alveolar macrophages.Experimental lung research 23,269-284.)：取2月龄小鼠，腹腔注射戊巴比妥麻醉动物。仰卧固定，消毒颈部，剪开颈部皮肤，剥离腺体肌肉，暴露气管。在气管上部剪开一个小口，不要剪断，用1ml枪头插一个小白枪头，吸取4℃1ml PBS(无Ca2+，无Mg2+，0.6mM EDTA)[50ml PBS+0.00876g EDTA]从开口吹入肺中，吹打进后吸出。再拿新的PBS吹入，吸出，反复3－4次。将收集的肺泡灌洗液以200×g离心5分钟，去上清液。用无血清RPMI-1640培养液洗涤细胞一次，以200×g离心5分钟。加入有血清的RPMI-1640重悬，接种。贴壁2h，用PBS洗三次。加入有血清的RPMI-1640，在5％二氧化碳，37℃条件下培养。
取小鼠的肺泡巨噬细胞，随机分为六个处理组(每组约5×106个细胞)，第一组为阴性对照；第二组用100ng/mL的LPS诱导(培养基中添加LPS)，模拟体内炎症反应模型；第三组为CBD对照组(培养基中添加5μM CBD)；第四组用0.5μM的CBD预处理0.5h后，加100ng/mL的LPS诱导(培养基中添加0.5μM CBD和100ng/mL LPS)。第五组用1μM的CBD预处理0.5h后，加100ng/mL的LPS诱导(培养基中添加1μM CBD和100ng/mL LPS)。第六组用5μM的CBD预处理0.5h后，加100ng/mL的LPS诱导(培养基中添加5μM CBD和100ng/mL LPS)。处理5h后收集细胞，利用荧光 定量PCR仪检测各组细胞炎症因子TNF-α、IL-6和Mgl2的表达变化。
检测TNF-α的引物：
正向引物：CCCTCACACTCAGATCATCTTCT(SEQ ID NO:1)
反向引物：GCTACGACGTGGGCTACAG(SEQ ID NO:2)
检测IL-6的引物：
正向引物：GAGGATACCACTCCCAACAGACC(SEQ ID NO:3)
反向引物：AAGTGCATCGTTGTTCATACA(SEQ ID NO:4)
检测Mgl2的引物：
正向引物：AGGCAGCTGCTATTGGTTCTCTGA(SEQ ID NO:5)
反向引物：AGTTGACCACCACCAGGTGAGAAT(SEQ ID NO:6)
3.实验结果
结果如图5所示。
结果显示，CBD能够剂量依赖性地显著抑制LPS引起的炎症相关TNF-α和IL-6的表达，促进抑制炎症的基因Mgl2的表达。
尽管本发明的具体实施方式已经得到详细的描述，本领域技术人员将会理解。根据已经公开的所有教导，可以对那些细节进行各种修改和替换，这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。

Claims (22)

  1. 选自如下的(1)至(3)中的任一项在制备治疗和/或预防肺动脉高压的药物中的用途：
    (1)大麻二酚或其药学上可接受的盐或酯，
    (2)一种植物提取物，其含有大麻二酚；优选地，所述植物提取物为大麻提取物，和
    (3)一种药物组合物，其含有大麻二酚或其药学上可接受的盐或酯，以及一种或多种药学上可接受的辅料。
  2. 根据权利要求1所述的用途，其中，所述肺动脉高压为原发性肺动脉高压或继发性肺动脉高压；优选地，为动脉性肺动脉高压(例如特发性肺动脉高压、可遗传性肺动脉高压、药物和毒物所致肺动脉高压或新生儿持续性肺动脉高压)、左心疾病相关性肺动脉高压(例如心脏收缩功能不全所致肺动脉高压、舒张功能不全所致肺动脉高压、瓣膜病所致肺动脉高压)、肺部疾病所致肺动脉高压(例如慢性阻塞性肺疾病所致肺动脉高压、肺气肿所致肺动脉高压或肺间质性疾病所致肺动脉高压)、低氧血症所致肺动脉高压(例如睡眠呼吸暂停综合征所致肺动脉高压、慢性高原病所致肺动脉高压比如高原性心脏病)或者慢性血栓栓塞性肺动脉高压；更优选地，为低氧血症所致肺动脉高压。
  3. 选自如下的(1)至(3)中的任一项在制备抑制炎症的药物、抑制炎症因子表达的药物或者促进抑制炎症的基因(例如Mgl2基因)的表达的药物中的用途：
    (1)大麻二酚或其药学上可接受的盐或酯，
    (2)一种植物提取物，其含有大麻二酚；优选地，所述植物提取物为大麻提取物，和
    (3)一种药物组合物，其含有大麻二酚或其药学上可接受的盐或酯，以及一种或多种药学上可接受的辅料。
  4. 根据权利要求3所述的用途，其中，所述炎症是慢性低度炎症。
  5. 根据权利要求3所述的用途，其中，所述炎症因子选自TNF-α和IL-6。
  6. 一种药物组合物，其包含大麻二酚或其药学上可接受的盐或酯，或者包含含有大麻二酚或其药学上可接受的盐或酯的植物提取物(例如大麻提取物)，以及一种或多种药学上可接受的辅料；优选地，所述药物组合物为口服制剂。
  7. 根据权利要求6所述的药物组合物，其中，所述药物组合物还包含选自前列环素类药物、内皮素受体拮抗剂、磷酸二酯酶-5抑制剂、可溶性鸟苷酸环化酶激动剂、5-羟色胺转运子抑制剂、生长因子抑制剂以及Rho激酶抑制剂中的任意一种或几种。
  8. 根据权利要求7所述的药物组合物，其中，
    所述前列环素类药物选自贝前列素、曲前列素、伊洛前列素和万他维中的任意一种或者几种；
    所述内皮素受体拮抗剂为波生坦；和/或
    所述磷酸二酯酶-5抑制剂选自西地那非、伐地那非和他达那非。
  9. 一种组合产品，包括产品1和产品2，其中：
    所述产品1选自如下的(1)至(3)中的任一项的产品：
    (1)大麻二酚或其药学上可接受的盐或酯，
    (2)一种植物提取物，其含有大麻二酚；优选地，所述植物提取物为大麻提取物，和
    (3)一种药物组合物，其含有大麻二酚或其药学上可接受的盐或酯，以及一种或多种药学上可接受的辅料；
    所述产品2选自前列环素类药物、内皮素受体拮抗剂、磷酸二酯酶-5抑制剂、可溶性鸟苷酸环化酶激动剂、5-羟色胺转运子抑制剂、生长因子抑制剂以及Rho激酶抑制剂中的任意一种或几种；
    并且所述产品1和产品2是各自独立包装的；
    优选地，所述产品1和产品2均为口服制剂。
  10. 根据权利要求9所述的组合产品，其中，
    所述前列环素类药物选自贝前列素、曲前列素、伊洛前列素和万他维中的任意一种或者几种；
    所述内皮素受体拮抗剂为波生坦；和/或
    所述磷酸二酯酶-5抑制剂选自西地那非、伐地那非和他达那非。
  11. 选自如下的(1)至(3)中的任一项的产品，其用于治疗和/或预防肺动脉高压：
    (1)大麻二酚或其药学上可接受的盐或酯，
    (2)一种植物提取物，其含有大麻二酚；优选地，所述植物提取物为大麻提取物，和
    (3)一种药物组合物，其含有大麻二酚或其药学上可接受的盐或酯，以及一种或多种药学上可接受的辅料。
  12. 根据权利要求11所述的产品，其中，所述肺动脉高压为原发性肺动脉高压或继发性肺动脉高压；优选地，为动脉性肺动脉高压(例如特发性肺动脉高压、可遗传性肺动脉高压、药物和毒物所致肺动脉高压或新生儿持续性肺动脉高压)、左心疾病相关性肺动脉高压(例如心脏收缩功能不全所致肺动脉高压、舒张功能不全所致肺动脉高压、瓣膜病所致肺动脉高压)、肺部疾病所致肺动脉高压(例如慢性阻塞性肺疾病所致肺动脉高压、肺气肿所致肺动脉高压或肺间质性疾病所致肺动脉高压)、低氧血症所致肺动脉高压(例如睡眠呼吸暂停综合征所致肺动脉高压、慢性高原病所致肺动脉高压比如高原性心脏病)或者慢性血栓栓塞性肺动脉高压；更优选地，为低氧血症所致肺动脉高压。
  13. 选自如下的(1)至(3)中的任一项的产品，其用于抑制炎症、抑制炎症因子表达或者促进抑制炎症的基因(例如Mgl2基因)的表达：
    (1)大麻二酚或其药学上可接受的盐或酯，
    (2)一种植物提取物，其含有大麻二酚；优选地，所述植物提取物为大麻提取物，和
    (3)一种药物组合物，其含有大麻二酚或其药学上可接受的盐或酯，以及一种或多种药学上可接受的辅料。
  14. 根据权利要求13所述的产品，其中，所述炎症是慢性低度炎症。
  15. 根据权利要求13所述的产品，其中，所述炎症因子选自TNF-α和IL-6。
  16. 一种治疗和/或预防肺动脉高压的方法，包括给予有需求的受试者以有效量的选自如下的(1)至(3)中的任一项的产品的步骤：
    (1)大麻二酚或其药学上可接受的盐或酯，
    (2)一种植物提取物，其含有大麻二酚；优选地，所述植物提取物为大麻提取物，和
    (3)一种药物组合物，其含有大麻二酚或其药学上可接受的盐或酯，以及一种或多种药学上可接受的辅料。
  17. 根据权利要求16所述的方法，其中，所述肺动脉高压为原发性肺动脉高压或继发性肺动脉高压；优选地，为动脉性肺动脉高压(例如特发性肺动脉高压、可遗传性肺动脉高压、药物和毒物所致肺动脉高压或新生儿持续性肺动脉高压)、左心疾病相关性肺动脉高压(例如心脏收缩功能不全所致肺动脉高压、舒张功能不全所致肺动脉高压、瓣膜病所致肺动脉高压)、肺部疾病所致肺动脉高压(例如慢性阻塞性肺疾病所致肺动脉高压、肺气肿所致肺动脉高压或肺间质性疾病所致肺动脉高压)、低氧血症所致肺动脉高压(例如睡眠呼吸暂停综合征所致肺动脉高压、慢性高原病所致肺动脉高压比如高原性心脏病)或者慢性血栓栓塞性肺动脉高压；更优选地，为低氧血症所致肺动脉高压。
  18. 一种抑制炎症、抑制炎症因子表达或者促进抑制炎症的基因(例如Mgl2基因)的表达的方法，包括给予有需求的受试者以有效量的选自如下的(1)至(3)中的任一项的产品的步骤：
    (1)大麻二酚或其药学上可接受的盐或酯，
    (2)一种植物提取物，其含有大麻二酚；优选地，所述植物提取物为大麻提取物，和
    (3)一种药物组合物，其含有大麻二酚或其药学上可接受的盐或酯，以及一种或多种药学上可接受的辅料。
  19. 根据权利要求18所述的方法，其中，所述炎症是慢性低度炎症。
  20. 根据权利要求18所述的方法，其中，所述炎症因子选自TNF-α和IL-6。
  21. 根据权利要求16至20中任一权利要求所述的方法，其中，大麻二酚的剂量介于0.1－50mg/kg体重/天，更优选为0.5mg/kg－30mg/kg体重/天、0.5mg/kg－20mg/kg体重/天、5mg/kg－30mg/kg体重/天或者5mg/kg－20mg/kg体重/天，进一步优选为0.5mg/kg－10mg/kg体重/天，特别优选为0.5mg/kg－5mg/kg体重/天。
  22. 根据权利要求16至20中任一权利要求所述的方法，其中，通过口服给药。
PCT/CN2017/093367 2017-07-18 2017-07-18 大麻二酚在治疗肺动脉高压中的应用 WO2019014851A1 (zh)

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