WO2020200305A1 - 一种含羟基脲的药物组合物的应用 - Google Patents

一种含羟基脲的药物组合物的应用 Download PDF

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WO2020200305A1
WO2020200305A1 PCT/CN2020/083159 CN2020083159W WO2020200305A1 WO 2020200305 A1 WO2020200305 A1 WO 2020200305A1 CN 2020083159 W CN2020083159 W CN 2020083159W WO 2020200305 A1 WO2020200305 A1 WO 2020200305A1
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hydroxyurea
aspirin
atherosclerosis
pharmaceutical composition
clopidogrel bisulfate
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PCT/CN2020/083159
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English (en)
French (fr)
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佟倩
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吉林大学
中国医学科学院药物研究所
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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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
    • 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 invention belongs to the technical field of medicine, and in particular relates to the application of a pharmaceutical composition including hydroxyurea or its salt.
  • cardiovascular disease has become the number one killer of human beings.
  • cardiovascular and cerebrovascular diseases such as coronary heart disease, cerebral infarction, and peripheral vascular disease
  • atherosclerosis seriously harms
  • the prevalence and mortality rates are still increasing.
  • Atherosclerosis is a progressive disease characterized by accumulation of lipids and complex carbohydrates in the inner wall of blood vessels, proliferation and calcification of fibrous tissue, thickening and hardening of blood vessel walls, and stenosis of blood vessel lumen.
  • Clinically, arteriography, Doppler ultrasound, X-ray examination and other methods can be used for detection.
  • the disease begins in children or youth, usually in middle-aged or middle-aged and continues to progress. In severe cases, it can cause arterial lumen blockage, as well as ischemia or necrosis of the supplied tissues or organs, and even life-threatening.
  • Atherosclerosis is a complex metabolic disorder process.
  • the main risk factors include high blood pressure, hyperlipidemia, heavy smoking, diabetes, obesity and genetics.
  • the clinical treatment plan for the prevention/treatment of atherosclerosis and the prognosis of surgery is usually controlled by reducing its risk factors: such as the combined use of antiplatelet aggregation drugs aspirin and clopidogrel bisulfate (double-antibody therapy ), or its combined treatment with statins.
  • Hydroxyurea has been reported to be a nucleoside diphosphate reductase inhibitor, which prevents the reduction of nucleotides to deoxynucleotides, interferes with the biosynthesis of purine and pyrimidine bases, thereby selectively hindering DNA synthesis. Hydroxyurea has a long history of antiviral and antitumor clinical application, and it is still the first-line drug for many diseases, including the treatment of polycythemia vera, essential thrombocythemia, chronic myeloid leukemia and primary bone marrow fibers Myeloproliferative diseases such as chemistry.
  • the inventor has proposed a pharmaceutical composition containing hydroxyurea for the preparation of drugs for the prevention and/or treatment of atherosclerosis, and its effect is far superior to the current clinical treatment programs. Due to the complexity of the etiology of atherosclerosis, the curative effect of current clinical treatment programs is still very limited.
  • the combination of oral hydroxyurea, aspirin and clopidogrel bisulfate, and the combination of hydroxyurea, aspirin, clopidogrel bisulfate, and atorvastatin calcium provided by this technical solution can significantly improve atherosclerosis.
  • Therapeutic effect the area of plaque is reduced by 85% and 91% compared with the model group
  • the efficacy is significantly better than the most effective aspirin and sulfuric acid at present
  • the drug combination of clopidogrel and atorvastatin calcium (the plaque area was reduced by 64% compared with the model group).
  • the clinically effective dose of hydroxyurea is converted to approximately 1.1 mg/kg, which is far lower than the current clinically applied anti-tumor therapeutic dose (20 mg/kg) and the published hydroxyurea alone
  • the effective dose of atherosclerosis during use (130mg/kg, Comparative Medicine, 59: 567-572). Because the toxic and side effects of the drug can disappear as the dose is reduced, the effective dose is reduced by 130 times, indicating this drug combination Outstanding technical effect in the treatment/prevention of atherosclerosis. Based on these findings, the inventor came up with the present invention.
  • the purpose of the present invention is to provide an application of a pharmaceutical composition including hydroxyurea or its salt, which can significantly improve and basically cure atherosclerosis.
  • the present invention provides an application of a pharmaceutical composition containing hydroxyurea or a pharmaceutically acceptable salt thereof in preparing a medicine for preventing and/or treating atherosclerosis.
  • the pharmaceutically acceptable salt includes hydrochloride, sulfate, hydrobromide, hydroiodide, formate, acetate or oxalate;
  • the present invention provides an application of the pharmaceutical composition of the above technical scheme in the preparation of a medicine for the prevention and/or treatment of atherosclerosis.
  • the pharmaceutical composition includes hydroxyurea or a pharmaceutically acceptable salt thereof.
  • ,Also includes:
  • the oral mass ratio of hydroxyurea, aspirin and clopidogrel bisulfate in the pharmaceutical composition is 5-150:4-22:7-25;
  • the mass ratio of urea, aspirin and clopidogrel bisulfate when used in combination is 5-60:4-11:7-25.
  • the mass ratio is 5-24:4-6:25.
  • the mass ratio of hydroxyurea, aspirin and clopidogrel hydrogen sulfate is 10:5:25 or 20:5:25.
  • the present invention provides an application of a pharmaceutical composition in the preparation of a medicine for preventing and/or treating atherosclerosis.
  • a pharmaceutical composition in addition to including hydroxyurea or a pharmaceutically acceptable salt thereof, the pharmaceutical composition also includes:
  • the oral mass ratio of hydroxyurea, atorvastatin calcium, aspirin and clopidogrel bisulfate when the four drugs are combined is 5 ⁇ 150:3 ⁇ 12:4 ⁇ 22 : 7-25;
  • the mass ratio when the four drugs of hydroxyurea, atorvastatin calcium, aspirin and clopidogrel bisulfate are combined is 5-60: 3-7: 4-11: 7-25;
  • the mass ratio is 5-24:4-6:4-6:25; most preferably, when the hydroxy
  • the mass ratio of urea, atorvastatin calcium, aspirin and clopidogrel bisulfate is 10:5:5:25.
  • the hydroxyurea has the structure of formula I:
  • the aspirin has the structure of formula II:
  • the clopidogrel hydrogen sulfate has a structure of formula III:
  • the atorvastatin calcium has the structure of formula IV:
  • the pharmaceutical composition further includes a pharmaceutically acceptable carrier and/or a pharmaceutically acceptable excipient.
  • Oral administration of the above-mentioned pharmaceutical composition significantly reduced the blood glucose, triglycerides, total cholesterol, and low-density lipoprotein cholesterol levels of the atherosclerosis model ApoE -/- mice, and significantly reduced the area of atherosclerotic plaques. Improve and basically cure atherosclerosis.
  • the atherosclerosis of the present invention is caused by the abnormalities of blood glucose, triglycerides, total cholesterol, or low-density lipoprotein cholesterol and other factors.
  • Vascular diseases such as necrotic lesions.
  • the present invention uses a pharmaceutical composition containing hydroxyurea or a pharmaceutically acceptable salt thereof to prepare a medicine for preventing and/or treating atherosclerosis.
  • the experimental results showed that the high-fat diet induced by 21% fat, 0.15% cholesterol and 78.85% basal feed formula induced apolipoprotein E gene (ApoE) knockout mice, their blood glucose, triglycerides, total cholesterol, low The density lipoprotein cholesterol concentration was significantly higher than that of the normal control group, and fat accumulation and atherosclerotic lesions appeared in the aortic intima; the results indicated that the high-fat diet-induced ApoE -/- knockout mice had abnormal glucose and lipid metabolism and produced Atherosclerosis.
  • ApoE apolipoprotein E gene
  • Oral hydroxyurea (much lower than its current clinical dose) and a combination of aspirin and clopidogrel bisulfate, or oral hydroxyurea (far below its current clinical dose), aspirin, clopidogrel bisulfate and atova
  • statin calcium compared with the model and aspirin and clopidogrel bisulfate drug combination group, the aortic intima fat and atherosclerotic lesion area were significantly reduced and basically disappeared, atherosclerosis was basically cured, and the drug effect It is also significantly better than the three-drug combination of oral aspirin, clopidogrel bisulfate and atorvastatin calcium.
  • the above results indicate that the pharmaceutical composition can synergistically exert pharmacological effects, improve the severity of atherosclerosis, and effectively treat and basically cure atherosclerosis.
  • Figure 1 is a picture of coronary angiography before and after the patient undergoes coronary angiography and treated with hydroxyurea and other drugs;
  • Figure 2 shows the results of HE pathological section of the aorta after treatment of atherosclerosis model mice with hydroxyurea and other pharmaceutical compositions
  • Figure 3 shows the pathological section results of aortic oil red O in atherosclerosis model mice treated with hydroxyurea and other pharmaceutical compositions
  • Figure 4 shows the statistical results of corrected plaque area in the aorta after treatment with hydroxyurea and other pharmaceutical compositions in atherosclerosis model mice;
  • Figure 5 shows the results of full-length oil red O staining of the aorta after treatment of atherosclerosis model mice with hydroxyurea and other pharmaceutical compositions
  • Figure 6 shows the results of serum glucose measurement in atherosclerosis model mice treated with hydroxyurea and other pharmaceutical compositions
  • Figure 7 shows the results of serum triglyceride determination in atherosclerosis model mice treated with hydroxyurea and other pharmaceutical compositions
  • Figure 8 shows the results of serum total cholesterol measurement in atherosclerosis model mice treated with hydroxyurea and other pharmaceutical compositions
  • Figure 9 is the measurement result of serum low-density lipoprotein cholesterol after treatment with hydroxyurea and other pharmaceutical compositions in atherosclerosis model mice;
  • Figure 10 shows the results of serum alanine aminotransferase determination in atherosclerosis model mice after treatment with hydroxyurea and other pharmaceutical compositions
  • Figure 11 shows the results of serum aspartate aminotransferase determination in atherosclerosis model mice treated with hydroxyurea and other pharmaceutical compositions
  • Figure 12 shows the measurement results of serum creatinine in atherosclerosis model mice after treatment with hydroxyurea and other pharmaceutical compositions.
  • Example 1 Clinical patients were treated with hydroxyurea and conventional drugs (statins and anticoagulant drugs) to significantly improve the degree of atherosclerotic stenosis
  • Coronary angiography is an important method to check the degree of vascular stenosis clinically.
  • a patient with a previous diagnosis of acute coronary syndrome who was diagnosed with severe atherosclerotic stenosis of the anterior descending artery by coronary angiography and also suffered from essential thrombocythemia is being treated with aspirin, clopidogrel bisulfate and statins At the same time, he took hydroxyurea (100mg ⁇ 1/day).
  • coronary angiography showed an unexpected improvement in the atherosclerotic lesions, the original stenosis area disappeared, the blood vessel wall became smooth, and the normal state was basically restored. See Figure 1.
  • Figure 1 is a picture of coronary angiography before and after the patient undergoes coronary angiography and treated with hydroxyurea and other drugs.
  • Example 2 Therapeutic effect of a pharmaceutical composition containing hydroxyurea in ApoE -/- mice, a model of atherosclerosis induced by a high-fat diet
  • Aortic oil red O pathological section, aortic HE pathological section, and aortic full-length oil red O staining image comparison are important indicators to evaluate the therapeutic effect of atherosclerosis.
  • Blood glucose content, triglyceride content, total cholesterol content, and low-density lipoprotein cholesterol content are important indicators for evaluating risk factors for atherosclerosis.
  • Blood alanine aminotransferase (ALT), aspartate aminotransferase (AST), and creatinine content are one of the important indicators for evaluating liver and kidney function in atherosclerotic animals.
  • mice (8 weeks old) and ApoE -/- mice (8 weeks old) were purchased from Beijing Weitong Lihua Animal Technology Co., Ltd.
  • the animals were kept in an SPF environment (21 ⁇ 2°C, 12 hours light cycle) , Free eating and drinking during the experiment.
  • Atorvastatin calcium, aspirin, and hydroxyurea >98%) were purchased from Soleibao Biotechnology Co., Ltd.
  • clopidogrel bisulfate (>98%) was purchased from Tichia (Shanghai) Chemical Industry Development Co., Ltd., saturated Oil red O mother solution, OCT frozen section embedding agent, 4% tissue cell fixative were purchased from Soleibao Biotechnology Co., Ltd.
  • Pathology section technical support is provided by the Pathology Research Group of the Institute of Materia Medica, Chinese Academy of Medical Sciences.
  • Pathological staining of aortic oil red O The aortic tissue was fixed in 4% tissue cell fixative (4% paraformaldehyde) for 24 hours, dehydrated overnight, embedded in OCT embedding agent, and made into frozen sections.
  • the oil red O working fluid is obtained by mixing the saturated oil red O mother liquor prepared by isopropanol with double distilled water 3:2 and filtering it with filter paper. Place the frozen sections in Oil Red O working solution for 6 hours at room temperature. Take out the sections and rinse them in 60% isopropanol for 3 times. After rinsing with tap water, they are counter-stained with hematoxylin for 1-2 minutes, rinsed back to blue, and dried at room temperature. , Glycerin gelatin mount, microscopic examination, photo recording.
  • Aortic full-length oil red O staining the tissue around the aorta of the animal after sacrifice is removed, taken out, dehydrated in 20% sucrose solution overnight, rinsed in PBS solution, and stained in oil red O working solution at room temperature for 6 hours. Take out the stained aortic blood vessel, the plaque was stained red, rinsed 3 times in 60% isopropanol. After soaking in PBS, cut the blood vessel and place the blood vessel on a silica gel pad, take a picture, and save the picture.
  • HE staining of the aorta After fixing the aortic tissue in 4% tissue cell fixative (4% paraformaldehyde) for 24 hours, it is dehydrated by an automatic dehydrator for 16 hours. After conventional embedding with a paraffin embedding machine, HE staining is carried out. Check, take photos and record.
  • Corrected plaque area (%) namely pathological section plaque area/pathological section blood vessel area.
  • the statistical result of the corrected plaque area of each aorta is the average of the corrected plaque area obtained by oil red O pathological staining and HE pathological staining for each animal.
  • Serum glucose, triglycerides, total cholesterol, and low-density lipoprotein cholesterol were determined using a test kit, which was purchased from Zhongsheng Beikong Biotechnology Co., Ltd., and the specific methods are detailed in the instructions.
  • Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and creatinine were determined using a test kit.
  • the kit was purchased from Nanjing Jiancheng Biotechnology Co., Ltd. The specific methods are detailed in the instructions.
  • mice The experimental animals were divided into 7 groups, including normal control group, atherosclerosis model group, model double antibody treatment group, hydroxyurea low-dose combination treatment group, hydroxyurea high-dose combination treatment group, and positive drug treatment group.
  • Combination treatment group The normal control group was C57 BL/6 mice, and the model and treatment groups were ApoE -/- mice. Model establishment starts with 8-week-old mice. After one week of normal feed, the model group and drug treatment group are modeled with high-fat feed for 4 weeks, and then the model is given for 8 weeks at the same time. The normal control group is given normal feed. feed. The model feed is 21% fat, 0.15% cholesterol and 78.85% basic formula. After the experiment, the animals take fasting serum. Six aortic vessels in each group were used for pathological section staining statistics, and the rest were used for full-length aortic staining.
  • Normal control group normal feed feeding + oral normal saline 0.2mL;
  • Atherosclerosis model group model feed feeding + oral normal saline 0.2mL;
  • Model double-antibody treatment group model feed feeding + oral aspirin 5mg/kg/day + clopidogrel bisulfate 25mg/kg/day;
  • Hydroxyurea low-dose combination treatment group model feed feeding + oral aspirin 5mg/kg/day + clopidogrel bisulfate 25mg/kg/day + hydroxyurea 10mg/kg/day;
  • Hydroxyurea high-dose combination treatment group model feed feeding + oral aspirin 5mg/kg/day + clopidogrel bisulfate 25mg/kg/day + hydroxyurea 20mg/kg/day;
  • Positive drug treatment group model feed feeding + oral aspirin 5 mg/kg/day + clopidogrel bisulfate 25 mg/kg/day + atorvastatin calcium 5 mg/kg/day.
  • Drug combination treatment group model feed feeding + oral aspirin 5mg/kg/day + clopidogrel bisulfate 25mg/kg/day + atorvastatin calcium 5mg/kg/day + hydroxyurea 10mg/kg/day .
  • the staining results of HE pathological sections and oil red O pathological sections showed that after 8 weeks of oral administration of aspirin and clopidogrel bisulfate (bi-antibody therapy), the area of atherosclerotic plaques was reduced to a certain extent compared with the model group; in addition, oral aspirin and hydrogen sulfate After the combined treatment of clopidogrel and the lipid-lowering drug atorvastatin calcium, although the corrected plaque area of the aortic intima was further reduced, the effect was not significantly enhanced.
  • the aortic intima corrected plaque area was further reduced, the drug effect was significant and the symptoms of atherosclerosis were basically reversed, indicating that the drug mixture is effective
  • the efficacy of the treatment of atherosclerosis is very significant (P ⁇ 0.001 compared to the model group).
  • the model animal was already in a state of disorder of glucose and lipid metabolism, but the symptoms of atherosclerosis were not obvious. Because it is a continuously progressive disease, those skilled in the art It is believed that the pharmaceutical composition also has a certain effect in preventing atherosclerosis.
  • the combined HE pathological section and oil red O pathological section staining results, after 8 weeks of oral hydroxyurea, aspirin, and clopidogrel bisulfate treatment, (hydroxyurea low and high dose combination treatment group) artery
  • the corrected area of atherosclerotic plaque was reduced by 76% and 85% respectively compared with the model group, and was significantly reduced compared with double antibody therapy (52%) (P ⁇ 0.05).
  • the corrected plaque area of the aortic intima was further reduced significantly, which was reduced by 91% compared with the model group (significant drug effect Better than the positive drug control group, P ⁇ 0.001).
  • the effect of the drug combination containing hydroxyurea on atherosclerosis is significantly better than the clinical routine treatment program-aspirin, clopidogrel bisulfate and atorvastatin calcium positive drug control group (64%, P ⁇ 0.01, P ⁇ 0.001), and basically reversed the symptoms of atherosclerosis. Because atherosclerosis itself is difficult to control and treat, the proposed pharmaceutical composition containing hydroxyurea has obvious advantages in preparing drugs for the prevention/treatment of atherosclerosis.
  • the full-length aortic oil red O staining results are consistent with the pathological section staining results.
  • the model group had more lipid-containing lesions and obvious plaques in the aorta of mice in the model group.
  • the block has been basically eliminated, indicating that the efficacy of the pharmaceutical composition containing hydroxyurea is significantly better than the three-drug combination of aspirin, clopidogrel bisulfate and atorvastatin calcium, further confirming that the pharmaceutical composition is effective in preventing/treatment of atherosclerosis Good medicinal effect for sarcoidosis.
  • the serum glucose, triglyceride, total cholesterol, and low-density lipoprotein cholesterol concentrations in the model group were significantly higher than those in the normal control group, indicating that the model group ApoE -/- mouse glucose and lipid metabolism abnormal.
  • the combined treatment group of hydroxyurea, aspirin, and clopidogrel bisulfate, and the combined treatment group of oral hydroxyurea, aspirin, clopidogrel bisulfate and atorvastatin calcium the serum glucose and lipid levels were average It is significantly lower than the model group, which proves that the metabolism of glucose and lipid in animals is improved after the drug combination treatment.
  • the serum alanine aminotransferase activity of the model group was higher than that of the normal control group, indicating that the liver function of the ApoE -/- mice in the model group was impaired.
  • the drug combination treatment group of hydroxyurea, aspirin, and clopidogrel bisulfate had no significant changes in alanine aminotransferase activity compared with the double antibody treatment group; hydroxyurea, aspirin, and clopidogrel bisulfate
  • the atorvastatin calcium drug combination treatment group has no significant changes in alanine aminotransferase activity.
  • the drug combination treatment group of hydroxyurea, aspirin, and clopidogrel bisulfate had no significant changes in the activity of aspartate aminotransferase compared with the double antibody treatment group;
  • the drug combination treatment group of hydroxyurea, aspirin, clopidogrel bisulfate, and atorvastatin calcium showed no significant difference in aspartate aminotransferase activity compared to the double antibody treatment group and the combination treatment group with atorvastatin calcium Variety.

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Abstract

提供了一种含羟基脲的药物组合物的应用，将含羟基脲或其药学上可接受的盐用于制备预防和/或治疗动脉粥样硬化症的药物。实验结果表明：口服羟基脲及阿司匹林、硫酸氢氯吡格雷的组合后，主动脉内膜脂肪及粥糜样病灶区域明显缩小，对动脉粥样硬化症的药效十分明显(斑块抑制程度85％)，血中葡萄糖，甘油三酯，总胆固醇，低密度脂蛋白胆固醇浓度降低，糖脂代谢紊乱显著改善；口服羟基脲、阿司匹林、硫酸氢氯吡格雷及阿托伐他汀钙的组合后，主动脉内膜脂肪及粥糜样病灶区域进一步明显缩小并基本治愈动脉粥样硬化症(斑块抑制程度91％)。该剂量下的药物组合在预防和/或治疗动脉粥样硬化症中具有突出的治疗效果。

Description

一种含羟基脲的药物组合物的应用
本申请要求于2019年04月04日提交中国专利局、申请号为201910270431.2、发明名称为“一种含羟基脲的药物组合物的应用”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明属于医药技术领域，尤其涉及一种包括羟基脲或其盐在内的药物组合物的应用。
背景技术
随着经济的发展,人们生活水平的提高，心血管疾病已经成为人类的头号杀手，而作为冠心病、脑梗死、外周血管病等心脑血管疾病的共同病理学基础，动脉粥样硬化严重危害着人类健康，且患病率及死亡率仍呈上升趋势。动脉粥样硬化症是一种表现为血管内壁的脂质和复合糖类积累，纤维组织增生钙化，血管壁增厚变硬、血管腔狭窄等的进展性疾病。临床上可采用动脉造影、多普勒超声波检查、X线检查等方法检测。本病始发儿童或青年时期，通常在中年或者中老年出现症状并持续进展，严重时可导致动脉管腔阻塞，及所供应的组织或器官缺血或坏死，甚至危及生命。
动脉粥样硬化发病原因尚不明确。虽然许多学者曾提出不同学说以尝试阐明动脉粥样硬化的发病机制，如脂质渗入学说、损伤应答学说、炎性反应学说及免疫学说等，但尚无一种学说可较全面地解释其机制。目前普遍认为，动脉粥样硬化症是一个复杂的代谢紊乱过程，主要危险因素包括高血压、高血脂、大量吸烟、糖尿病、肥胖和遗传等。而临床上用于动脉粥样硬化症的预防/治疗、及手术预后的治疗方案通常是通过降低其危险因素给予控制：如抗血小板 聚集药物阿司匹林和硫酸氢氯吡格雷的联合使用(双抗疗法)，或其与他汀类降血脂药物的合用治疗。但是，在临床上该治疗方案的药效有限，在后期随访中，冠脉造影时均未见明确的粥样硬化斑块退化或逆转，且用药后不良反应明显，严重时需停止用药。因此，需要探索和研究新的安全、有效的动脉粥样硬化症预防/治疗药物或治疗方案。
羟基脲已被报道是一种核苷二磷酸还原酶抑制剂，可阻止核苷酸还原为脱氧核苷酸，干扰嘌呤及嘧啶碱基生物合成，从而选择性地阻碍DNA的合成。羟基脲在抗病毒、抗肿瘤方面的临床应用已有悠久历史，目前仍为许多疾病的一线用药，包括治疗真性红细胞增多症、原发性血小板增多症、慢性粒细胞白血病和原发性骨髓纤维化等骨髓增殖性疾病。此外，它也应用于恶性黑色素瘤、胃癌、肠癌、复发性转移性卵巢癌的治疗以及放射增敏等，临床上尚未将其用于治疗动脉粥样硬化症。2009年，在《比较医学杂志》(Comparative Medicine，59：567-572)的文章中，报道了口服400mg/kg的羟基脲能够减轻内皮损伤所致的兔动脉粥样硬化的症状并缩小其斑块面积。经换算，该剂量约为目前临床最高使用剂量的7倍，在此剂量下斑块面积减少了40％，提示了高剂量羟基脲对于血管动脉粥样硬化狭窄具有一定的治疗作用。
发明人通过长期探索，提出了一种含羟基脲的药物组合物在制备预防和/或治疗动脉粥样硬化症药物中的应用，其效果远优于目前临床使用的治疗方案。由于动脉粥样硬化症病因的复杂性，目前现有的临床治疗方案治疗效果还非常有限。当单独给药药效到达一定程度后，合用其他药物以增强药效是非常困难的，如口服阿司匹林和硫酸氢氯吡格雷的组合，或单独口服阿托伐他汀钙，动脉粥样硬化斑块面积均可呈现一定程度的降低(不足或约为50％)，而当三种药物合用时，疗效较前两药合用仅增加了10％左右，疗效已基本到达平台期，无协同增效及药效的叠加作用。而本技术方案提供的口服羟基脲与阿司匹林和 硫酸氢氯吡格雷的组合，及羟基脲与阿司匹林、硫酸氢氯吡格雷、阿托伐他汀钙的组合，能够非常显著地提高动脉粥样硬化的治疗效果(斑块面积与模型组相比缩小85％，91％)，明显缩小动脉粥样硬化斑块面积并基本治愈动脉粥样硬化症，且药效明显优于目前最为有效的阿司匹林、硫酸氢氯吡格雷及阿托伐他汀钙的药物组合(斑块面积与模型组相比缩小64％)。另外，本技术方案所提供的组合物中，羟基脲的临床有效剂量经换算约为1.1mg/kg，远低于目前临床应用的抗肿瘤治疗剂量(20mg/kg)及已公开的羟基脲单独使用时动脉粥样硬化的有效剂量(经折算130mg/kg，Comparative Medicine，59：567-572)，因药物的毒副作用可以随剂量降低而消失，所以有效剂量降低130倍表明了这种药物组合在治疗/预防动脉粥样硬化症中的突出技术效果。基于这些发现，发明人提出了本发明。
发明内容
有鉴于此，本发明的目的在于提供了一种包括羟基脲或其盐在内的药物组合物的应用，其能够明显改善并基本治愈动脉粥样硬化症。
本发明提供了一种含羟基脲或其药学上可接受的盐的药物组合物在制备预防和/或治疗动脉粥样硬化症药物中的应用。
在本发明中，所述药学上可接受的盐包括盐酸盐、硫酸盐、氢溴酸盐、氢碘酸盐、甲酸盐、乙酸盐或草酸盐；
本发明提供了一种上述技术方案所述药物组合物在制备预防和/或治疗动脉粥样硬化症药物中的应用，所述的药物组合物除包括羟基脲或其药学上可接受的盐外，还包括：
阿司匹林；
硫酸氢氯吡格雷。
在本发明中，所述药物组合物中，当羟基脲、阿司匹林与硫酸氢氯吡格雷 三种药物合用时的口服质量比为5～150：4～22：7～25；优选地，当羟基脲、阿司匹林与硫酸氢氯吡格雷三种药物合用时的质量比为5～60：4～11：7～25。更优选地，当羟基脲、阿司匹林与硫酸氢氯吡格雷三种药物合用时的质量比为5～24：4～6：25。最优选地，羟基脲、阿司匹林与硫酸氢氯吡格雷的质量比为10：5：25或20：5：25。
本发明提供了一种药物组合物在制备预防和/或治疗动脉粥样硬化症药物中的应用，所述的药物组合物除包括羟基脲或其药学上可接受的盐外，还包括：
阿司匹林；
硫酸氢氯吡格雷；
阿托伐他汀钙。
在本发明中，所述药物组合物中，当羟基脲、阿托伐他汀钙、阿司匹林与硫酸氢氯吡格雷四种药物合用时的口服质量比为5～150：3～12：4～22：7～25；优选地，当羟基脲、阿托伐他汀钙、阿司匹林与硫酸氢氯吡格雷四种药物合用时的质量比为5～60：3～7：4～11：7～25；更优选地，当羟基脲、阿托伐他汀钙、阿司匹林与硫酸氢氯吡格雷四种药物合用时的质量比为5～24：4～6：4～6：25；最优选地，当羟基脲、阿托伐他汀钙、阿司匹林与硫酸氢氯吡格雷合用时的质量比为10：5：5：25。
在本发明中，所述羟基脲具有式I结构：
Figure PCTCN2020083159-appb-000001
在本发明中，所述阿司匹林具有式II结构：
Figure PCTCN2020083159-appb-000002
在本发明中，所述硫酸氢氯吡格雷具有式III结构：
Figure PCTCN2020083159-appb-000003
在本发明中，所述阿托伐他汀钙具有式Ⅳ结构：
Figure PCTCN2020083159-appb-000004
在本发明中，所述药物组合物还包括药学上可接受的载体和/或药学上可 接受的赋形剂。
口服上述药物组合物显著降低了动脉粥样硬化模型ApoE -/-小鼠血葡萄糖，甘油三酯，总胆固醇，低密度脂蛋白胆固醇水平，并显著地缩小动脉粥样硬化斑块面积，可明显改善并基本治愈动脉粥样硬化症。
本发明所述动脉粥样硬化症是由血葡萄糖，甘油三酯，总胆固醇，或低密度脂蛋白胆固醇异常等因素所致的动脉内膜有脂质等血液成分的沉积，粥糜样含脂坏死病灶等血管病变。
本发明将含羟基脲或其药学上可接受的盐的药物组合物用于制备预防和/或治疗动脉粥样硬化症的药物。实验结果表明：使用21％脂肪，0.15％胆固醇及78.85％基础饲料配方的高脂饮食诱导的载脂蛋白E基因(ApoE)敲除小鼠，其血中葡萄糖，甘油三酯，总胆固醇，低密度脂蛋白胆固醇浓度显著性高于正常对照组，主动脉内膜出现脂肪堆积及粥糜样病灶；结果说明高脂饮食诱导的ApoE -/-基因敲除小鼠糖脂代谢出现异常，并产生了动脉粥样硬化症。口服羟基脲(远低于其目前临床使用剂量)及阿司匹林、硫酸氢氯吡格雷的组合，或口服羟基脲(远低于其目前临床使用剂量)、阿司匹林、硫酸氢氯吡格雷及阿托伐他汀钙的组合后，相比模型及阿司匹林、硫酸氢氯吡格雷的药物合用组，主动脉内膜脂肪及粥糜样病灶区域显著缩小并基本消失，动脉粥样硬化症基本治愈，且药效也明显优于口服阿司匹林、硫酸氢氯吡格雷及阿托伐他汀钙的三药组合。上述结果说明，所述药物组合物可以协同地发挥药效，改善动脉粥样硬化严重程度，有效治疗并基本治愈动脉粥样硬化症。
附图说明
图1为患者行冠脉造影术经羟基脲等药物治疗前后冠状动脉造影图片；
图2为动脉粥样硬化模型小鼠经羟基脲等药物组合物治疗后主动脉HE病理切片结果；
图3为动脉粥样硬化模型小鼠经羟基脲等药物组合物治疗后主动脉油红O病理切片结果；
图4为动脉粥样硬化模型小鼠经羟基脲等药物组合物治疗后主动脉校正斑块面积统计结果；
图5为动脉粥样硬化模型小鼠经羟基脲等药物组合物治疗后主动脉全长油红O染色结果；
图6为动脉粥样硬化模型小鼠经羟基脲等药物组合物治疗后血清葡萄糖测定结果；
图7为动脉粥样硬化模型小鼠经羟基脲等药物组合物治疗后血清甘油三酯测定结果；
图8为动脉粥样硬化模型小鼠经羟基脲等药物组合物治疗后血清总胆固醇测定结果；
图9为动脉粥样硬化模型小鼠经羟基脲等药物组合物治疗后血清低密度脂蛋白胆固醇测定结果；
图10为动脉粥样硬化模型小鼠经羟基脲等药物组合物治疗后血清丙氨酸氨基转移酶测定结果；
图11为动脉粥样硬化模型小鼠经羟基脲等药物组合物治疗后血清天门冬氨酸氨基转移酶测定结果；
图12为动脉粥样硬化模型小鼠经羟基脲等药物组合物治疗后血清肌酐测 定结果。
具体实施方式
下面对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例1.临床患者经羟基脲及常规药物(他汀及抗凝血药物)联用治疗明显改善动脉粥样硬化狭窄程度
冠脉造影术是临床上检查血管狭窄程度的重要方法。一名既往诊断为急性冠脉综合征，且行冠脉造影证实前降支存在严重粥样硬化狭窄，同时患有原发性血小板增多症的患者，在进行阿司匹林、硫酸氢氯吡格雷及他汀治疗的同时，服用了羟基脲(100mg×1/日)。治疗后，冠脉造影显示其血管粥样硬化病变出现了意想不到的好转，原狭窄区域程度消失，血管壁变得光滑，基本恢复正常状态。见图1，图1为患者行冠脉造影术经羟基脲等药物治疗前后冠状动脉造影图片。
目前，当通过冠脉造影术明确患者冠状动脉存在粥样硬化斑块时，排除服用他汀类药物的禁忌后，无论性别或年龄，临床医生均建议患者行半年以上的他汀治疗：阿托伐他汀20mg×1/日或瑞舒伐他汀10mg×1/日，及联用阿司匹林/硫酸氢氯吡格雷。在随访中，患者血清低密度脂蛋白胆固醇水平显著下降，心血管不良事件的发生率较前显著降低；但是冠脉造影时均未见明确的粥样硬化斑块退化或逆转的病例。因此，含羟基脲的药物组合物对动脉粥样硬化症的显著疗效从临床上被证实。
实施例2.含羟基脲的药物组合物在高脂饮食诱导的动脉粥样硬化模型 ApoE -/-小鼠中的治疗作用
主动脉油红O病理切片，主动脉HE病理切片，主动脉全长油红O染色图像比较是评价动脉粥样硬化症治疗效果的重要指标。血中葡萄糖含量、甘油三酯含量，总胆固醇含量、低密度脂蛋白胆固醇含量，是评价动脉粥样硬化症危险因素的重要指标。血丙氨酸氨基转移酶(ALT)，天门冬氨酸氨基转移酶(AST)，及肌酐的含量是评价动脉粥样硬化症动物肝肾功能的重要指标之一。
1、实验动物、仪器及药品试剂
C57小鼠(8周龄)及ApoE -/-小鼠(8周龄)从北京维通利华动物技术有限公司购买，动物饲养在SPF级环境下(21±2℃，12小时光照周期)，在实验期间自由饮食和饮水。阿托伐他汀钙，阿司匹林，羟基脲(>98％)从索莱宝生物科技有限公司购买，硫酸氢氯吡格雷(>98％)购于梯希爱(上海)化成工业发展有限公司，饱和油红O母液，OCT冷冻切片包埋剂，4％组织细胞固定液从索莱宝生物科技有限公司购买。病理切片技术支持由中国医学科学院药物研究所病理课题组提供。
2、分析方法
主动脉油红O病理染色：主动脉组织于4％组织细胞固定液(4％多聚甲醛)中固定24小时后，脱水过夜，OCT包埋剂包埋后，制成冰冻切片。油红O工作液由异丙醇配制的饱和油红O母液与双蒸水3：2混合，滤纸过滤而得。在室温下将冰冻切片置于油红O工作液中染色6h，取出切片，在60％异丙醇中漂洗3次，自来水冲洗后，苏木素复染1-2min，冲洗返蓝，室温晾干后，甘油明胶封片，镜检，拍照记录。
主动脉全长油红O染色：将处死后动物的主动脉血管周围组织剔除，取出，于20％蔗糖溶液中脱水过夜，PBS溶液漂洗，将其置于油红O工作液中室温染色6h，取出染色完的主动脉血管，可见斑块被染成红色，于60％异丙醇中漂洗3次。浸泡于PBS后，剪开血管后将血管放置于硅胶垫上，拍照，保存图片。
主动脉HE病理染色：主动脉组织于4％组织细胞固定液(4％多聚甲醛)中固定24小时后，自动脱水机脱水16小时，用石蜡包埋机常规包埋后进行HE染色，镜检，拍照记录。
校正斑块面积(％)，即病理切片斑块面积/病理切片血管面积。各主动脉校正斑块面积统计结果为每只动物油红O病理染色及HE病理染色所得校正斑块面积的平均值。
血清葡萄糖，甘油三酯，总胆固醇及低密度脂蛋白胆固醇的测定采用检测试剂盒测定，试剂盒购于中生北控生物科技股份有限公司，具体方法详见说明书。
血清丙氨酸氨基转移酶(ALT)，天门冬氨酸氨基转移酶(AST)，及肌酐的测定采用测试盒测定，试剂盒购于南京建成生物科技有限公司，具体方法详见说明书。
3.实验设计及动物分组
实验设计：实验动物分为7组，包括正常对照组、动脉粥样硬化模型组、模型双抗治疗组、羟基脲低剂量组合治疗组、羟基脲高剂量组合治疗组、阳性药治疗组，药物组合治疗组。正常对照组为C57 BL/6小鼠，模型及治疗组为ApoE -/-小鼠。模型建立从8周龄小鼠开始，普通饲料适应性喂养一周后，模型组及药物治疗组采用高脂饲料造模4周，之后在造模的同时给药8周，正常对照组用普通饲料喂养。造模饲料为21％脂肪，0.15％胆固醇及78.85％的基础配方。实验结束后，动物取空腹血清。各组动物主动脉血管6只用于病理切片染色统计，其余用于主动脉全长染色。
动物分组：
(1)正常对照组：正常饲料喂养+口服生理盐水0.2mL；
(2)动脉粥样硬化模型组：造模饲料喂养+口服生理盐水0.2mL；
(3)模型双抗治疗组：造模饲料喂养+口服阿司匹林5mg/kg/天+硫酸氢氯吡格雷25mg/kg/天；
(4)羟基脲低剂量组合治疗组：造模饲料喂养+口服阿司匹林5mg/kg/天+硫酸氢氯吡格雷25mg/kg/天+羟基脲10mg/kg/天；
(5)羟基脲高剂量组合治疗组：造模饲料喂养+口服阿司匹林5mg/kg/天+硫酸氢氯吡格雷25mg/kg/天+羟基脲20mg/kg/天；
(6)阳性药治疗组：造模饲料喂养+口服阿司匹林5mg/kg/天+硫酸氢氯吡格雷25mg/kg/天+阿托伐他汀钙5mg/kg/天。
(7)药物组合治疗组：造模饲料喂养+口服阿司匹林5mg/kg/天+硫酸氢氯吡格雷25mg/kg/天+阿托伐他汀钙5mg/kg/天+羟基脲10mg/kg/天。
4.结果
如图2，图3及表1，表2所示，建模12周(即药物治疗8周)后，模型组小鼠主动脉的含脂病变及斑块明显，正常对照组无动脉硬化斑块，说明模型建立成功。HE病理切片及油红O病理切片染色结果显示，口服阿司匹林，硫酸氢氯吡格雷(双抗疗法)8周后，动脉硬化斑块面积较模型组一定程度地缩小；另外，口服阿司匹林、硫酸氢氯吡格雷及降脂药阿托伐他汀钙组合治疗后，主动脉内膜校正斑块面积虽进一步有所缩小，但疗效增强并不显著。原因在于，动脉粥样硬化症本身的复杂性，使得通过控制动脉硬化危险因素的常规临床方案(抗凝血药物阿司匹林、硫酸氢氯吡格雷与降血脂药物阿托伐他汀钙)难以有效治疗及逆转动脉粥样硬化症状。尤其是当药效到达一定程度后，合用药物以增强药效是非常困难的。而在口服阿司匹林，硫酸氢氯吡格雷及羟基脲组合治疗8周后，(羟基脲高、低剂量组合治疗组)动脉粥样硬化斑块校正面积与双抗治疗组及双抗联合阿托伐他汀钙组相比，均显著缩小，且羟基脲10mg/kg/天、20mg/kg/天两组治疗结果呈剂量依赖性，证明口服羟基脲及阿司匹林、硫酸氢氯吡格雷的组合对动脉粥样硬化症的良好药效(相比模型组P<0.001)。另外，口服羟基脲、阿司匹林、硫酸氢氯吡格雷及阿托伐他汀钙后主动脉内膜校正斑块面积进一步缩小，药效显著并基本逆转了动脉粥样硬化症状，说明了该药物混合物对治疗动脉粥样硬化症药效非常显著(相比模型组P<0.001)。另外，本案例实施过程中，于药物组合治疗的初始，模型动物已处于糖脂代谢紊乱的状态，但动脉粥样硬化症状并不明显，因其本身是一种持续进展性疾病，本领域人员认为该药物组合物在预防动脉粥样硬化症中也具有一定的效果。
如图4，表3所示，综合HE病理切片及油红O病理切片染色结果，口服羟基脲及阿司匹林、硫酸氢氯吡格雷治疗8周后，(羟基脲低、高剂量组合治疗组)动脉粥样斑块校正面积分别相比模型组降低了76％和85％，相比双抗疗法(52％)显著缩小(P<0.05)。除此之外，口服低剂量的羟基脲、阿司匹林、硫酸氢氯吡格雷及阿托伐他汀钙后主动脉内膜校正斑块面积进一步明显缩小，相比模型组降低了91％(药效明显优于阳性药对照组，P<0.001)。含羟基 脲的药物组合对动脉粥样硬化症的效果均明显优于临床常规治疗方案——阿司匹林、硫酸氢氯吡格雷及阿托伐他汀钙的阳性药对照组(64％，P<0.01，P<0.001)，并基本逆转了动脉粥样硬化症状。因动脉粥样硬化症本身难以控制及治疗，由此提出的含羟基脲的药物组合物在制备预防/治疗动脉粥样硬化症药物中的优势明显。
如图5所示，主动脉全长油红O染色结果与病理切片染色结果一致。建模12周(即药物治疗8周)后，模型组小鼠主动脉的含脂病变数量多，斑块明显，正常对照组无动脉硬化斑块，说明模型建立成功。口服阿司匹林，硫酸氢氯吡格雷及羟基脲的组合治疗，以及口服羟基脲、阿司匹林、硫酸氢氯吡格雷及阿托伐他汀钙的组合治疗，主动脉斑块数量及面积均显著缩小，或斑块已基本消除，说明含羟基脲的药物组合物药效均明显优于阿司匹林、硫酸氢氯吡格雷及阿托伐他汀钙的三药合用，进一步证实了其药物组合物对预防/治疗动脉粥样硬化症的良好药效。
如图6-9，表4-7所示，模型组血清葡萄糖、甘油三酯、总胆固醇及低密度脂蛋白胆固醇浓度显著高于正常对照组，说明模型组ApoE -/-小鼠糖脂代谢异常。药物治疗8周后，羟基脲及阿司匹林，硫酸氢氯吡格雷的药物合用治疗组，及口服羟基脲、阿司匹林、硫酸氢氯吡格雷及阿托伐他汀钙药物合用治疗组，血清糖脂水平均显著低于模型组，证明药物组合治疗后动物体内糖脂代谢得到改善。
如图10，表8所示，模型组血清丙氨酸氨基转移酶活性高于正常对照组，说明模型组ApoE -/-小鼠肝功能受损。药物治疗8周后，羟基脲及阿司匹林，硫酸氢氯吡格雷的药物组合治疗组相比双抗治疗组，丙氨酸氨基转移酶活性无显著性变化；羟基脲及阿司匹林，硫酸氢氯吡格雷，阿托伐他汀钙的药物组合治疗组相比双抗治疗组与阿托伐他汀钙合用治疗组，丙氨酸氨基转移酶活性也无显著性变化。如图11，表9所示，药物治疗8周后，羟基脲及阿司匹林，硫酸氢氯吡格雷的药物组合治疗组相比双抗治疗组，天门冬氨酸氨基转移酶活性无显著性变化；羟基脲及阿司匹林，硫酸氢氯吡格雷，阿托伐他汀钙的药物组合治疗组相比双抗治疗组及与阿托伐他汀钙合用治疗组，天门冬氨酸氨基转移酶活性也无显著性变化。以上两组实验证明加入羟基脲的药物组合治疗未引 起肝功能异常，提示了该剂量下组合物的安全性。
如图12，表10所示，药物治疗8周后，含羟基脲的药物组合治疗后无明显肾毒性。
表1 动脉粥样硬化模型小鼠经药物治疗8周后主动脉HE病理校正斑块面积测定结果(％，n＝6)
Figure PCTCN2020083159-appb-000005
表2 动脉粥样硬化模型小鼠经药物治疗8周后主动脉油红O病理校正斑块面积测定结果(％，n＝6)
Figure PCTCN2020083159-appb-000006
表3 动脉粥样硬化模型小鼠经药物治疗8周后校正斑块面积统计结果(％，n＝6)
Figure PCTCN2020083159-appb-000007
Figure PCTCN2020083159-appb-000008
表4 动脉粥样硬化模型小鼠经药物治疗8周后血葡萄糖测定结果(mmol/L，n＝8)
Figure PCTCN2020083159-appb-000009
表5 动脉粥样硬化模型小鼠经药物治疗8周后血甘油三酯测定结果(mmol/L，n＝8)
Figure PCTCN2020083159-appb-000010
Figure PCTCN2020083159-appb-000011
表6 动脉粥样硬化模型小鼠经药物治疗8周后血总胆固醇测定结果(mmol/L，n＝8)
Figure PCTCN2020083159-appb-000012
表7 动脉粥样硬化模型小鼠经药物治疗8周后血低密度脂蛋白胆固醇测定结果(mmol/L，n＝8)
Figure PCTCN2020083159-appb-000013
表8 动脉粥样硬化模型小鼠经药物治疗8周后血丙氨酸氨基转移酶测定结果(U/L，n＝8)
Figure PCTCN2020083159-appb-000014
Figure PCTCN2020083159-appb-000015
*：为可疑数据已排除统计。
表9 动脉粥样硬化模型小鼠经药物治疗8周后血天门冬氨酸氨基转移酶测定结果(U/L，n＝8)
Figure PCTCN2020083159-appb-000016
*：为可疑数据已排除统计。
表10 动脉粥样硬化模型小鼠经药物治疗8周后血肌酐测定结果(μmol/L，n＝8)
Figure PCTCN2020083159-appb-000017
Figure PCTCN2020083159-appb-000018
*：为可疑数据已排除统计。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (7)

  1. 一种含羟基脲或其药学上可接受的盐的药物组合物在制备预防和/或治疗动脉粥样硬化症药物中的应用。
  2. 根据权利要求1所述的应用，其特征在于，所述药学上可接受的盐包括盐酸盐、硫酸盐、氢溴酸盐、氢碘酸盐、甲酸盐、乙酸盐或草酸盐。
  3. 一种药物组合物在制备预防和/或治疗动脉粥样硬化症药物中的应用，其特征在于，所述的药物组合物除包括羟基脲或其药学上可接受的盐外，还包括阿司匹林和硫酸氢氯吡格雷。
  4. 根据权利要求3所述的应用，其特征在于，所述药物组合物中，当羟基脲、阿司匹林与硫酸氢氯吡格雷三种药物合用时的口服质量比为5～150：4～22：7～25；优选地，当羟基脲、阿司匹林与硫酸氢氯吡格雷三种药物合用时的质量比为5～60：4～11：7～25；更优选地，当羟基脲、阿司匹林与硫酸氢氯吡格雷三种药物合用时的质量比为5～24：4～6：25；最优选地，羟基脲、阿司匹林与硫酸氢氯吡格雷的质量比为10：5：25或20：5：25。
  5. 一种药物组合物在制备预防和/或治疗动脉粥样硬化症药物中的应用，其特征在于，所述的药物组合物除包括羟基脲或其药学上可接受的盐外，还包括阿司匹林、硫酸氢氯吡格雷和阿托伐他汀钙。
  6. 根据权利要求5所述的应用，其特征在于，所述药物组合物中，当羟基脲、阿托伐他汀钙、阿司匹林与硫酸氢氯吡格雷四种药物合用时的口服质量比为5～150：3～12：4～22：7～25；优选地，当羟基脲、阿托伐他汀钙、阿司匹林与硫酸氢氯吡格雷四种药物合用时的质量比为5～60：3～7：4～11：7～25；更 优选地，当羟基脲、阿托伐他汀钙、阿司匹林与硫酸氢氯吡格雷四种药物合用时的质量比为5～24：4～6：4～6：25；最优选地，当羟基脲、阿托伐他汀钙、阿司匹林与硫酸氢氯吡格雷合用时的质量比为10：5：5：25。
  7. 根据权利要求1、3、5任一项所述的应用，其特征在于，药物组合物还包括药学上可接受的载体和/或药学上可接受的赋形剂。
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