WO2016188091A1 - 烟酰胺单核苷酸在制备防治动脉硬化、心脑血管疾病的药物中的应用及其药物 - Google Patents

烟酰胺单核苷酸在制备防治动脉硬化、心脑血管疾病的药物中的应用及其药物 Download PDF

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WO2016188091A1
WO2016188091A1 PCT/CN2015/097072 CN2015097072W WO2016188091A1 WO 2016188091 A1 WO2016188091 A1 WO 2016188091A1 CN 2015097072 W CN2015097072 W CN 2015097072W WO 2016188091 A1 WO2016188091 A1 WO 2016188091A1
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arteriosclerosis
nicotinamide mononucleotide
nicotinamide
cardiovascular
cerebrovascular diseases
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PCT/CN2015/097072
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English (en)
French (fr)
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傅荣昭
蔡岩岩
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邦泰生物工程(深圳)有限公司
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Priority to PCT/CN2015/097072 priority Critical patent/WO2016188091A1/zh
Priority to US15/317,848 priority patent/US20170165282A1/en
Priority to CN201580030068.7A priority patent/CN106659729A/zh
Publication of WO2016188091A1 publication Critical patent/WO2016188091A1/zh

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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • 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

  • nicotinamide mononucleotide in preparing medicine for preventing and treating arteriosclerosis, cardiovascular and cerebrovascular diseases and drugs thereof
  • the present invention relates to the field of use of nicotinamide mononucleotides, and in particular to the use of nicotinamide mononucleotides in the field of biomedicine.
  • Arteriosclerosis is a non-inflammatory disease of the arteries, which can thicken and harden the arterial wall, lose elasticity, and narrow the lumen.
  • the main types can be divided into small arteriosclerosis, arteriosclerosis and arterial atherosclerosis. These three types of atherosclerosis, atherosclerosis is the most common type of arteriosclerosis, the main cause of myocardial infarction and cerebral infarction.
  • Arteriosclerosis is a vascular disease that occurs with the age of a person. The regularity usually occurs during adolescence, and it is aggravated and morbid in the middle-aged and elderly, and more men than women. In recent years, the incidence of the disease has gradually increased in China, and it has become one of the main causes of death among the elderly. Arteriosclerosis is also the main cause of cardiovascular disease, and cardiovascular disease is a common disease that seriously threatens the health of human beings, especially those over the age of 50. Even with the most advanced and sophisticated treatments available, there are still 50 More than 100% of survivors of cerebrovascular accidents can't take care of themselves.
  • statin lipid-lowering drugs such as simvastatin, pravastatin, and lovastatin. It is well known that such chemically synthesized drugs often have great toxic and side effects, and long-term or high-dose administration can cause great harm to the body. For example, simvastatin has been warned by the State Food and Drug Administration that unexpected muscle pain, tenderness, and weakness may occur after taking it. In severe cases, rhabdomyolysis may occur, which is a worse for the patient. . In addition, the prices of these statin lipid-lowering drugs are generally higher.
  • Nicotinamide mononucleotide (abbreviated to NMN) is biologically fine A biochemical substance in the cell plays an important role in the energy production of human cells. It is involved in the synthesis of nicotinamide adenine dinucleotide (NAD, an important coenzyme for cell energy conversion) in the cell, and is harmless to the human body.
  • NAD nicotinamide adenine dinucleotide
  • nicotinamide mononucleotides in the field of biomedicine has been carried out. It has also been reported about nicotinamide mononucleotides in delaying aging, treating Parkinson's disease, etc., but not yet on nicotinamide. Any report of single nucleotides in the treatment of arteriosclerosis.
  • the object of the present invention is to solve the technical defects of the existing drugs for treating arteriosclerosis mentioned in the above background, which have large toxic side effects and high price, and provide nicotinamide mononucleotides in the field of biomedicine.
  • a new use especially in the field of prevention and treatment of arteriosclerosis and cardiovascular and cerebrovascular diseases caused by arteriosclerosis, in order to obtain an inexpensive, safe and effective prevention and treatment of arteriosclerosis and heart caused by arteriosclerosis A drug for cerebrovascular disease.
  • the inventors conducted long-term and intensive research on the use of nicotinamide mononucleotide in medical use, and surprisingly found that it has a certain preventive and therapeutic effect on atherosclerosis, and therefore, the present invention provides A use of a nicotinamide mononucleotide for the preparation of a medicament for the prevention and treatment of arteriosclerosis and cardiovascular and cerebrovascular diseases caused by arteriosclerosis.
  • nicotinamide mononucleotides can be prepared by yeast fermentation, chemical synthesis or in vitro enzymatic catalysis.
  • the nicotinamide mononucleotide used in the present invention is prepared by an in vitro enzymatic method, and the nicotinamide mononucleotide prepared by the in vitro enzymatic method has high purity, no solvent residue, and no chirality.
  • the problem is that it has the advantages of the same type of ⁇ - ⁇ in the body, and thus it has the advantages of quick action, high curative effect, stable efficacy, and no harm to the human body when it is used as a medicine for preventing and treating arteriosclerosis.
  • the nicotinamide mononucleotide prepared by this method is inexpensive, and can greatly reduce the cost of administration of the patient.
  • the nicotinamide mononucleotide can be prepared as an active ingredient and different pharmaceutically acceptable excipients by various conventional preparation methods, such as granules, powders, tablets, pills, capsules,
  • the oral solution, the injection, and the like are administered to the patient. Oral administration is more convenient and has minimal harm to the human body.
  • the drug is preferably administered orally.
  • the dose of the nicotinamide mononucleotide may vary greatly depending on various conditions of the patient's condition, age, body weight, and self-traits.
  • the nicotinamide The dose of the single nucleotide is preferably 0. l-20 mg / k g body weight / day.
  • the medicament further comprises niacinamide ribose.
  • nicotinamide riboside (abbreviated to NR) is also a biochemical substance present in biological cells, which is preceded by vitamin B 3 and nicotinamide adenine dinucleotide. Body plays an important role in human cell energy production. The inventors have found that when a small amount of nicotinamide ribose is used together with a nicotinamide mononucleotide as a main active ingredient, the effect of preventing and treating arteriosclerosis can be improved to some extent. Similarly, the nicotinamide ribose used in the present invention is also prepared by an in vitro enzymatic method.
  • the nicotinamide ribose is administered at a dose of 0.5% of the dose of the nicotinamide mononucleotide.
  • the present invention provides a medicament for preventing and treating arteriosclerosis and cardiovascular and cerebrovascular diseases caused by arteriosclerosis, characterized in that the medicament comprises an active ingredient nicotinamide mononucleotide.
  • the drug is an oral preparation
  • various pharmaceutical dosage forms such as granules, powders, tablets, pills, capsules, oral liquids and the like can be prepared by a conventional preparation process.
  • the nicotinamide mononucleotide is administered at a dose of 0. l-20mg / k g body weight / day.
  • the medicament further comprises niacinamide ribose.
  • the nicotinamide ribose is administered at a dose of 0.5% of the dose of the nicotinamide mononucleotide.
  • the present invention is the first to use a nicotinamide mononucleotide as an active ingredient in the preparation of a medicament for preventing and treating arteriosclerosis and cardiovascular and cerebrovascular diseases caused by arteriosclerosis.
  • nicotinamide mononucleotide and nicotinamide ribose are biochemical substances existing in biological cells. The use of these self-produced substances not only has a good effect of preventing and treating atherosclerosis, but also does not cause any poison. Side effects, extremely safe. It has been proved by animal experiments that nicotinamide mononucleotide as an active ingredient has an effect on arteriosclerosis.
  • the nicotinamide mononucleotide used in the present invention is prepared by an in vitro enzymatic method, and the nicotinamide mononucleotide prepared by the in vitro enzymatic method has high purity and no solvent residue. There is no chiral problem and it is prepared with the same type of ⁇ - ⁇ in the body, so it has a fast effect as a drug for preventing and treating arteriosclerosis and cardiovascular and cerebrovascular diseases caused by arteriosclerosis. It has the advantages of high curative effect, stable efficacy and no harm to the human body. Moreover, the nicotinamide mononucleotide prepared by this method is inexpensive, and can greatly reduce the cost of administration of the patient.
  • nicotinamide mononucleotide ( ⁇ ) and nicotinamide ribose (NR) in the following examples were all prepared by in vitro enzymatic catalysis.
  • NMN low-dose group feeding high-fat diet, starting from the 7th week, daily administration of NMN 0. lmg / kg body weight, free drinking water
  • 5 NMN middle dose group feeding high fat diet, starting from the 7th week, daily administration of NMN lOmg / kg body weight, free drinking water;
  • NMN high-dose group feeding high-fat diet, starting from the 7th week, daily administration of NMN 20mg/k g body weight, free drinking water;
  • NMN + NR injection group feeding high-fat diet, starting from the 7th week, intramuscular injection of NMN 10mg / kg body weight and NR 5mg / kg body weight, free drinking water. .
  • the above high fat diet is formulated as: 83% basic feed, 2% cholesterol, and 15% lard.
  • the oldest, the shortest course of the disease is 1. 5 years, the longest is 7 years, and the average duration is 4. 6 years.
  • Patients were randomly divided into three groups, group A, group B, and group C, with 100 patients in each group.
  • Group A Oral administration of NMN lOmg/kg body weight per day, taken before or after meals, and controlled diet as required.
  • Group B Oral administration of NMN 10 m g /k g body weight and NR 2m g /kg body weight per day, taken before or after meals, and controlled diet as required.
  • Group C NMN 10 m g /k g body weight and NR 3 mg/kg body weight were administered intramuscularly daily, and the diet was controlled as required.
  • Group A Patients with milder disease were cured 7 days after taking the drug. One month later, 100 patients who participated in the trial were markedly effective in 67 cases, effective in 28 cases, ineffective in 4 cases, and 1 case in the middle of the trial. The total effective rate is 96
  • Group B Those who were milder were cured after 5 days of treatment, and one month later, 100 patients who participated in the trial were markedly effective 7
  • Group C Patients with milder disease were cured after 3 days of administration, and one month later, 100 patients who participated in the trial were markedly effective 8

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Abstract

一种以烟酰胺单核苷酸为活性成分的药物，以及烟酰胺单核苷酸在制备用于预防和治疗动脉硬化、和动脉硬化引起的心脑血管疾病的药物中的应用。

Description

烟酰胺单核苷酸在制备防治动脉硬化、 心脑血管疾病的 药物中的应用及其药物
技术领域
[0001] 本发明涉及烟酰胺单核苷酸的用途技术领域， 特别涉及烟酰胺单核苷酸在生物 医药领域中的用途。
背景技术
[0002] 动脉硬化是动脉的一种非炎症性病变， 可使动脉管壁增厚、 变硬， 失去弹性、 管腔变狭小， 其主要类型可分为细小动脉硬化、 动脉中层硬化以及动脉粥样硬 化这三种， 其中， 动脉粥样硬化是动脉硬化中最为常见的类型， 为心肌梗塞和 脑梗塞的主要病因。
[0003] 动脉硬化是随着人年龄的增长而出现的一种血管疾病， 其规律通常是在青少年 时期发生， 至中老年时期加重、 发病， 男性较女性多。 近年来该病在我国的发 病率逐渐增多， 已经成为老年人死亡的主要原因之一。 动脉硬化还是引起心血 管疾病的主要诱因， 而心血管疾病是一种严重威胁人类， 特别是 50岁以上中老 年人健康的常见病， 即使应用目前最先进、 完善的治疗手段， 仍可有 50%以上的 脑血管意外幸存者生活不能完全自理， 全世界每年死于心脑血管疾病的人数高 达 1500万人， 居各种死因首位。 因此， 我们需要寻求一种预防和治疗动脉硬化 的特效药， 以远离心血管疾病的侵害， 保持健康的身体。
[0004] 动脉硬化的发病机制较为复杂， 是多种因素长期共同作用的结果。 目前用于治 疗动脉硬化的药物多为他汀类降脂药， 如辛伐他汀、 普伐他汀、 洛伐他汀等。 众所周知， 此类化学合成的药物往往具有很大的毒副作用， 长期或者大剂量服 用， 会对身体造成很大的伤害。 如辛伐他汀就曾被国家食品药品监督管理局发 出警示， 服用后可能会出现非预期的肌肉痛、 触痛以及虚弱无力， 严重时可发 生横纹肌溶解症， 这对患者来说无异于雪上加霜。 另外， 这些他汀类降脂药的 价格也普遍较高。
[0005] 烟酰胺单核苷酸 （ β -Nicotinamide mononucleotide, 缩写成 NMN) 是生物细 胞内存在的一种生化物质， 在人体细胞能量生成中扮演重要角色， 它参与细胞 内烟酰胺腺嘌呤二核苷酸 （NAD, 细胞能量转化的重要辅酶） 的合成， 对人体无 危害。 目前， 对于烟酰胺单核苷酸在生物医药领域的用途的研究工作已经展开 ， 也已见关于烟酰胺单核苷酸在延缓衰老、 治疗帕金森病等方面的报道， 但尚 未见关于烟酰胺单核苷酸在治疗动脉硬化方面的任何报道。
发明概述
技术问题
[0006] 本发明的目的在于解决上述背景技术中提到的治疗动脉硬化的现有药物多存在 很大的毒副作用且价格较高的技术缺陷， 提供烟酰胺单核苷酸在生物医药领域 的一种新用途， 特别是在预防和治疗动脉硬化以及由动脉硬化引起的心脑血管 疾病领域中的用途， 以期获得一种价格低廉、 安全有效的预防和治疗动脉硬化 以及由动脉硬化引起的心脑血管疾病的药物。
问题的解决方案
技术解决方案
[0007] 为实现上述目的， 发明人针对烟酰胺单核苷酸在医药用途方面进行了长期深入 的研究， 惊喜地发现其对动脉硬化症具有一定的预防和治疗作用， 因此， 本发 明提供了一种烟酰胺单核苷酸在制备用于预防和治疗动脉硬化以及由动脉硬化 引起的心脑血管疾病的药物中的应用。
[0008] 目前， 烟酰胺单核苷酸可通过酵母菌发酵、 化学合成或者体外酶催化的方式制 备得到。 本发明中使用的烟酰胺单核苷酸是采用体外酶催化方式制备得到的， 通过该体外酶催化方式制备得到的烟酰胺单核苷酸具备纯度高、 不含机溶剂残 留、 不存在手性问题且制备出的是和机体内同型的 β -ΝΜΝ等优点， 因而将其作 为预防和治疗动脉硬化的药物应用时， 具有起效快、 疗效高、 功效稳定、 对人 体无危害等优点。 另外通过该方式制备得到的烟酰胺单核苷酸价格低廉， 可以 在很大程度上降低患者的用药成本。
[0009] 可将烟酰胺单核苷酸作为有效成分与药学上可接受的不同辅料采用常规的制备 工艺制成各种不同的药物剂型， 如颗粒剂、 散剂、 片剂、 丸剂、 胶囊剂、 口服 液、 注射剂等对患者给药。 因口服方式给药较为方便且对人体危害最小， 故所 述药物优选通过口服方式给药。
[0010] 根据患者的病情、 年龄、 体重以及自身特质等种种条件的不同， 所述烟酰胺单 核苷酸的给药剂量会有很大程度的改变， 对一个成人而言， 所述烟酰胺单核苷 酸的给药剂量优选为 0. l-20mg/kg体重 /天。
[0011] 优选地， 所述药物还包含烟酰胺核糖。
[0012] 与烟酰胺单核苷酸一样， 烟酰胺核糖 （nicotinamide riboside, 缩写成 NR) 也是生物细胞内存在的一种生化物质， 它是维生素 B 3和烟酰胺腺嘌呤二核苷酸 的前体， 在人体细胞能量生成中扮演着重要的角色。 发明人研究发现， 将少量 的烟酰胺核糖与作为主要活性成分的烟酰胺单核苷酸配合使用时， 能够在一定 程度上提高预防和治疗动脉硬化的效果。 同样的， 本发明中使用的烟酰胺核糖 也是采用体外酶催化方式制备得到的。
[0013] 更优选地， 所述烟酰胺核糖的给药剂量为所述烟酰胺单核苷酸的给药剂量的 0.
1-0. 5倍。
[0014] 另外， 本发明还提供了一种预防和治疗动脉硬化以及由动脉硬化引起的心脑血 管疾病的药物， 其特征在于： 所述药物包含活性成分烟酰胺单核苷酸。
[0015] 优选地， 所述药物为口服制剂， 可采用常规的制备工艺制成各种不同的药物剂 型， 如颗粒剂、 散剂、 片剂、 丸剂、 胶囊剂、 口服液等。
[0016] 优选地， 所述烟酰胺单核苷酸的给药剂量为 0. l-20mg/kg体重 /天。
[0017] 优选地， 所述药物还包含烟酰胺核糖。
[0018] 更优选地， 所述烟酰胺核糖的给药剂量为所述烟酰胺单核苷酸的给药剂量的 0.
1-0. 5倍。
发明的有益效果
有益效果
[0019] 本发明首次将烟酰胺单核苷酸作为活性成分应用于制备预防和治疗动脉硬化以 及由动脉硬化引起的心脑血管疾病的药物中。 烟酰胺单核苷酸及烟酰胺核糖都 是生物细胞内自身存在的一种生化物质， 使用这些体内自产的物质不仅具有很 好的预防和治疗动脉硬化症的效果， 而且不会出现任何毒副作用， 具有极高的 安全性。 经动物实验证明： 烟酰胺单核苷酸作为活性成分对动脉硬化的发生具 有极好的预防和治疗效果， 如若再辅以少量的烟酰胺核糖， 则效果更佳。 经临 床试验证明： 由动脉硬化引起的心脑血管疾病患者在口服烟酰胺单核苷酸一个 月后的总有效率可达 96%， 而同时口服烟酰胺单核苷酸和烟酰胺核糖一个月后的 总有效率更高达 98%， 肌肉注射烟酰胺单核苷酸和烟酰胺核糖一个月后的总有效 率高达 99%。
[0020] 另外， 本发明中使用的烟酰胺单核苷酸是采用体外酶催化方式制备得到的， 通 过该体外酶催化方式制备得到的烟酰胺单核苷酸具备纯度高、 不含机溶剂残留 、 不存在手性问题且制备出的是和机体内同型的 β -ΝΜΝ等优点， 因而将其作为 预防和治疗动脉硬化以及由动脉硬化引起的心脑血管疾病的药物应用时， 具有 起效快、 疗效高、 功效稳定、 对人体无危害等优点。 而且通过该方式制备得到 的烟酰胺单核苷酸价格低廉， 可以在很大程度上降低患者的用药成本。
发明实施例
本发明的实施方式
[0021] 下面结合具体实施例对本发明做进一步的详细说明， 以下实施例是对本发明的 解释， 本发明并不局限于以下实施例。
[0022] 以下实施例中的烟酰胺单核苷酸 （ΝΜΝ) 及烟酰胺核糖 （NR) 均采用体外酶催 化方式制备得到。
[0023] 实施例 1
[0024] 动物实验资料
[0025] 1、 实验方法：
[0026] 选取健康豚鼠 80只， SPF级， 雌雄各半， 体重 250-300克， 随机分成 8组， 每组 1
0只， 分组如下：
[0027] ①正常对照组， 喂养基础饲料， 期间自由饮水；
[0028] ②高脂对照组， 喂养高脂饲料， 期间自由饮水；
[0029] ③高脂预防组， 喂养高脂饲料， 每天灌胃给药丽 N lOmg/kg体重， 期间自由饮 水；
[0030] ④ NMN低剂量组， 喂养高脂饲料， 第 7周开始， 每天灌胃给药 NMN 0. lmg/kg体重 ， 期间自由饮水； [0031] ⑤ NMN中剂量组， 喂养高脂饲料， 第 7周开始， 每天灌胃给药 NMN lOmg/kg体重 ， 期间自由饮水；
[0032] ⑥ NMN高剂量组， 喂养高脂饲料， 第 7周开始， 每天灌胃给药 NMN 20mg/kg体重 ， 期间自由饮水；
[0033] ⑦ NMN+NR灌胃组， 喂养高脂饲料， 第 7周开始， 每天灌胃给药 NMN lOmg/kg体重 以及 NR lmg/kg体重， 期间自由饮水
[0034] ⑧ NMN+NR注射组， 喂养高脂饲料， 第 7周开始， 每天肌肉注射给药 NMN 10mg/kg 体重以及 NR 5mg/kg体重， 期间自由饮水。 。
[0035] 上述高脂饲料的配方为： 83%基础饲料、 2%胆固醇以及 15%猪油。
[0036] 第 10周末， 将上述所有实验豚鼠禁食 （不禁水） 12小时后处死， 分离主动脉， 沿前壁中线纵行剖开， 用 SudanlV染色， 用肉眼观察主动脉病变情况， 定量病理 学测量病变面积及内膜总面积， 以病变面积占主动脉内膜总面积的百分比表示 动脉硬化的程度。
[0037] 统计学分析： 所有实验数据应用 SPSS13. 0统计软件， 计量资料以
¾·土、； S'
表示， 采用 t 检验， P<0. 05为差异有统计学意义。
[0038] 2、 实验结果：
[0039] 经肉眼观察， 正常对照组豚鼠的主动脉内膜光滑完整、 无病变； 喂养高脂饲料 组的豚鼠的主动脉均见内膜增厚、 变粗糙， 内膜表面突出有针尖至绿豆大小的 圆形或不规则黄色斑块或脂质条纹， 但是高脂对照组的豚鼠的主动脉的上述病 变情况较其余灌胃给药组的豚鼠的病变情况明显严重。 各组豚鼠的主动脉病变 情况的定量数据见表 1所示。
[0040] 表 1 [表 1]
Figure imgf000007_0001
[0041] 实施例 2
[0042] 临床试验资料
[0043] 1、 病例选择
[0044] 随机选择已确诊为由动脉硬化引起的心脑血管疾病患者 300 例作为临床观察对 象， 其中， 男女各 150例， 年龄为 35〜78 岁， 平均年龄 57. 5
岁， 病程最短者 1. 5年， 最长者 7年， 平均病程 4. 6年。 将患者随机分成三组， 分 别为 A组、 B组和 C组， 每组 100例。
[0045] 2、 给药方法
[0046] A组： 每天口服给药 NMN lOmg/kg体重， 饭前或饭后服用， 并按要求控制饮食。
[0047] B组： 每天口服给药 NMN 10mg/kg体重以及 NR 2mg/kg体重， 饭前或饭后服用， 并按要求控制饮食。
[0048] C组： 每天肌肉注射给药 NMN 10mg/kg体重以及 NR 3mg/kg体重， 并按要求控制 饮食。
[0049] 3、 疗效评定标准
[0050] (1) 显效： 体质增强， 身上有劲， 血脂、 血压下降到正常水平， 心悸、 胸痛 、 胸闷、 头痛、 头晕、 视力降低、 记忆力下降、 失眠多梦等临床症状明显缓解 [0051] (2) 有效： 体质增强， 血脂、 血压有所下降， 心悸、 胸痛、 胸闷、 头痛、 头晕 、 视力降低、 记忆力下降、 失眠多梦等临床症状有所缓解。
[0052] (3) 无效： 临床症状无明显改善。
[0053] 4、 临床试验结果
[0054] A组： 病情较轻者服药 7天后即治愈， 一个月后， 100例参与试验的患者中显效 6 7例、 有效 28例、 无效 4例、 中途退出试验者 1例， 剔除中途退出者总有效率为 96
%。
[0055] B组： 病情较轻者服药 5天后即治愈， 一个月后， 100例参与试验的患者中显效 7
3例、 有效 25例、 无效 2例、 总有效率为 98%。
[0056] C组： 病情较轻者给药 3天后即治愈， 一个月后， 100例参与试验的患者中显效 8
1例、 有效 17例、 无效 1例、 总有效率为 99%。

Claims

权利要求书
[权利要求 1] 烟酰胺单核苷酸在制备用于预防和治疗动脉硬化以及由动脉硬化引起 的心脑血管疾病的药物中的应用。
[权利要求 ] 根据权利要求 1所述的应用， 其特征在于： 所述烟酰胺单核苷酸采用 体外酶催化方式制备。
[权利要求 3] 根据权利要求 1所述的应用， 其特征在于： 所述烟酰胺单核苷酸的给 药剂量为 0. l-20mg/kg体重 /天。
[权利要求 4] 根据权利要求 1所述的应用， 其特征在于： 所述药物还包含烟酰胺核
[权利要求 5] 根据权利要求 4所述的应用， 其特征在于： 所述烟酰胺核糖的给药剂 量为所述烟酰胺单核苷酸的给药剂量的 0. 1-0. 5倍。
[权利要求 6] 一种预防和治疗动脉硬化以及由动脉硬化引起的心脑血管疾病的药物
， 其特征在于： 所述药物包含活性成分烟酰胺单核苷酸。
[权利要求 7] 根据权利要求 6所述的药物， 其特征在于： 所述药物为口服制剂。
[权利要求 8] 根据权利要求 6所述的药物， 其特征在于： 所述烟酰胺单核苷酸的给 药剂量为 0. l-20mg/kg体重 /天。
[权利要求 9] 根据权利要求 6所述的药物， 其特征在于： 所述药物还包含烟酰胺核
[权利要求 10] 根据权利要求 9所述的药物， 其特征在于： 所述烟酰胺核糖的给药剂 量为所述烟酰胺单核苷酸的给药剂量的 0. 1-0. 5倍。
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