WO2020042719A1 - 肌苷在防治抑郁症中的应用 - Google Patents

肌苷在防治抑郁症中的应用 Download PDF

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WO2020042719A1
WO2020042719A1 PCT/CN2019/090844 CN2019090844W WO2020042719A1 WO 2020042719 A1 WO2020042719 A1 WO 2020042719A1 CN 2019090844 W CN2019090844 W CN 2019090844W WO 2020042719 A1 WO2020042719 A1 WO 2020042719A1
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depression
inosine
preparation
lps
medicine
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French (fr)
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谢鹏
刘兰香
李雯雯
周婵娟
王海洋
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四川科瑞德制药股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—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
    • A61K31/7064—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 containing condensed or non-condensed pyrimidines
    • A61K31/7076—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 containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

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  • the invention belongs to the technical field of medicine, in particular to the application of inosine in the prevention of depression.
  • Depression is a heterogeneous major mental illness caused by multiple factors. It is characterized by a significant and lasting depression. Its morbidity and lethality are high. According to the World Health Organization, the annual global incidence of depression is about 6%, the lifetime prevalence is about 16%, and there are about 350 million people with depression worldwide. The prevalence of depression in China is about 6.87%, that is, about 90 million people are affected. Prolonged and persistent depressive symptoms can lead to severe cognitive dysfunction, placing a heavy disease burden on patients, families, and society. 50% to 60% of depression patients are suicidal, and 15% to 20% of patients eventually commit suicide. According to the World Health Organization, depression will become the world's largest burden disease by 2030. Therefore, it is urgent to strengthen the prevention and treatment of depression.
  • Inosine is hypoxanthine nucleoside. It is produced by adenosine catabolism. It is a metabolite of the body's nucleotides. It is an endogenous nucleoside.
  • inosine is mainly used to treat various Leukopenia, thrombocytopenia, various heart diseases, acute and chronic hepatitis, cirrhosis, etc. caused by this cause. No inosine has been reported to prevent or treat depression.
  • the technical problem solved by the present invention is to provide the application of inosine in the prevention and treatment of depression, provide a new use for inosine, and also provide a new and effective way for the prevention and treatment of depression.
  • the invention provides the application of inosine in the preparation of a medicament for treating and / or preventing depression.
  • the depression is endogenous depression, reactive depression, psychotic depression, substance / drug-induced depression, and depression caused by other diseases.
  • the medicine is a preparation prepared by using inosine as an active ingredient and a pharmaceutically acceptable auxiliary material or auxiliary component.
  • the preparation is an injection preparation.
  • the unit preparation of the injection preparation contains 300 mg to 600 mg of inosine.
  • the unit preparation of the injection preparation contains 600 mg of inosine.
  • the medicine is a medicine for mammals.
  • the medicine is a human medicine.
  • the unit preparation refers to the amount of the drug contained in the basic production unit (per capsule, tablet, gram, milliliter, pill), and is usually calculated as an adult of 60 kg.
  • the dose of inosine is 50 mg / kg to 100 mg / kg, the curative effect is excellent.
  • the dose of inosine should be 5 mg / kg to 10 mg / kg.
  • the daily dose is 300 mg to 600 mg. Therefore, the prepared unit preparation contains 300 mg to 600 mg of inosine.
  • the test of the present invention confirms that inosine can increase the sugar and water preference value of experimental mice and reduce the resting time of forced swimming in experimental mice, indicating that inosine can improve depression-like behavior, thereby preventing and treating depression, and provides a method for clinical prevention and treatment of depression. New, effective options.
  • FIG. 1 is an experimental flowchart of the present invention.
  • Figure 3 shows the results of a forced swimming test showing that inosine improves depression-like behavior.
  • Figure 4 shows the results of the sugar-water preference test to demonstrate that inosine improves depression-like behavior.
  • LPS Lipopolysaccharide
  • Escherichia Escherichia, coliserotype, 0127: B8, from Sigma, USA.
  • the injection dose was 0.83mg / kg.
  • Inosine (Inosine, from Sigma, USA). Dissolved in sterile physiological saline at injection doses of 10, 50, 100 and 300 mg / kg.
  • Transparent glass bucket open field box
  • high-definition camera small animal behavior science video acquisition and analysis system.
  • mice were injected with LPS (0.83mg / kg, i.p.) intraperitoneally to prepare a depression-like behavior model.
  • the experimental mice were divided into two groups, and sterile saline (1 mL / kg, ip) and LPS (0.83 mg / kg, ip) were injected by intraperitoneal injection.
  • the mice injected with LPS were the experimental group (LPS group).
  • Mice injected with sterile saline were used as a control group (CON group).
  • CON group The sugar water preference test, forced swimming test and tail suspension test were performed on two groups of experimental mice.
  • mice were placed in a transparent glass bucket (10cm ⁇ 25cm) with a water temperature of 25 ⁇ 1 ° C. and a water depth of 19cm, and the observation was performed for 6 minutes.
  • the cumulative resting time of forced swimming reflects the depression-like behavior of the mice, and its value is shortened, indicating that the depression-like behavior is improved.
  • a normal control group (CON) was set up: intraperitoneal injection of sterile saline at a concentration of 1 mL / kg to experimental mice; LPS group (LPS): intraperitoneal injection of LPS at a concentration of 0.83 mg / kg to experimental mice; inosine Group (INO): Intraperitoneal injection of inosine at a concentration of 10, 50, 100, and 300 mg / kg to experimental mice; Inosine + LPS group (INO + LPS): Intraperitoneal injection of 100 mg / kg to experimental mice Inosine was injected intraperitoneally after 30 minutes with LPS at a concentration of 0.83mg / kg.
  • CON normal control group
  • a sugar water preference test and a forced swimming test were performed on the experimental mice of each group to evaluate the depression-like behavior of the experimental groups of mice.
  • the INO + LPS group was administered with different inosine concentrations.
  • concentrations of 50mg / kg and 100mg / kg inosine can significantly shorten the time of immobility in forced swimming; the concentration of inosine at 100mg / kg was injected for 30 minutes and 60 minutes. After minutes, the antidepressant effect was significant.
  • inosine 100 mg / kg
  • LPS low-density polystyrene
  • inosine can significantly shorten the time of immobility of forced swimming and significantly reduce the decrease of the sugar and water preference caused by LPS, which indicates that it can effectively prevent depression.
  • the dosage is 50-100 mg / kg The effect is obvious.

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  • Animal Behavior & Ethology (AREA)
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Abstract

本发明公开了肌苷在制备治疗和/或预防抑郁症的药物中的应用。本发明经动物实验证明腺苷具有显著逆转抑郁样行为的作用，故腺苷可用于抑郁症的预防和治疗，为临床治疗抑郁症提供新的方法和手段。

Description

肌苷在防治抑郁症中的应用 技术领域
本发明属于医药技术领域，特别是肌苷在防御抑郁症中的应用。
背景技术
抑郁症是一种多因素导致的异质性重大精神疾病，以显著而持久的心境低落为主要临床特征。其发病率、致死率高。世界卫生组织资料显示，全球抑郁障碍年发病率大约为6％，终生患病率大约为16％，全球约有3.5亿抑郁症患者。我国抑郁症的患病率约为6.87％，即约有9000万人受累。长期持续的抑郁症状可导致严重的认知功能障碍，给患者、家庭以及社会带来了沉重的疾病负担。有50％～60％的抑郁症患者伴有自杀倾向，而有15％～20％患者最终自杀身亡。据世界卫生组织预测，到2030年抑郁症将成为世界第一大负担疾病。因此，加强抑郁症的防治迫在眉睫。
肌苷(Inosine,INO)即次黄嘌呤核苷，由腺苷分解代谢产生，是机体核苷酸的代谢产物，它是一种内源性核苷，目前，肌苷主要被用于治疗各种原因引起的白细胞减少症、血小板减少症、各种心脏疾病、急性及慢性肝炎、肝硬化等。未见肌苷预防或者治疗抑郁症的报道。
发明内容
本发明所解决的技术问题在于提供肌苷在防治抑郁症中的应用，为肌苷提供了一种新的用途，也为抑郁症的防治提供了一种新的、有效的方式。
本发明提供了肌苷在制备治疗和/或预防抑郁症的药物中的应用。
其中，所述抑郁症为内源性抑郁症、反应性抑郁症、精神病性抑郁症、物质/药物引起的抑郁症、其他疾病导致的抑郁症。
其中，所述药物是以肌苷为活性成分，加上药学上可接受的辅料或者辅助性成分制备而成的制剂。
其中，所述制剂是注射制剂。
其中，所述注射制剂的单位制剂含有300mg～600mg肌苷。
其中，所述注射制剂的单位制剂含有600mg肌苷。
其中，所述药物是哺乳动物用药物。
其中，所述药物是人用药物。
单位制剂指基本生产单位(每粒、片、克、毫升、丸)药品中含有药物的量，通常均是以60kg的成人计算。
根据本发明实验发现，对于小鼠，肌苷的给药量为50mg/kg～100mg/kg 时，疗效优良。根据小鼠与人的剂量换算关系，对于人，肌苷的给药量应为5mg/kg～10mg/kg，以60kg的成人计算，每日用量为300mg～600mg，由于给药方式是一天一次，因此，制成的单位制剂含有300mg～600mg肌苷。
本发明试验证实，肌苷能提高实验小鼠糖水偏好值、减少实验小鼠强迫游泳静止不动时间，说明肌苷可以改善抑郁样行为，从而防治抑郁症，为临床防治抑郁症提供了一种新的、有效的选择。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1本发明的实验流程图。
图2 LPS导致小鼠抑郁样行为结果图，数据以均值±标准差表示(n＝10只/组)，**p<0.01，***p<0.001：A：糖水偏好值；B：强迫游泳试验。
图3证明肌苷改善抑郁样行为的强迫游泳试验结果图，数据以均值±标准差(n＝6只/组)，**p<0.01，***p<0.001(LPS vs.CON)，#p<0.05，##p<0.01(INO+LPS vs.LPS)：A：INO+LPS组给予不同的肌苷浓度；B：100mg/kg浓度的肌苷注射不同时间。
图4证明肌苷改善抑郁样行为的糖水偏好试验结果图，数据以均值±标准差表示(n＝9～11只/组)，**p<0.01(LPS vs.CON)，#p<0.05，(INO+LPS vs.LPS)。
具体实施方式
实施例1本发明肌苷预防抑郁症的实验
1、实验动物的准备
选用35～40g健康雄性Crl:CD1小鼠(由重庆医科大学实验动物中心提供)。饲养环境温度23±1℃，湿度50±5％，12小时/12小时光/暗周期(光照时间为08:00～20:00)，除糖水测试期间，只有摄食和饮水。正式实验之前，进行为期2周的环境适应。
2、实验试剂和实验材料的准备
实验试剂：
①脂多糖(Lipopolysaccharide,LPS,Escherichia coli serotype 0127:B8，来自美国Sigma公司)。溶于无菌生理盐水，肌苷注射30分钟以后，经腹腔注射，注射剂量为0.83mg/kg。
②肌苷(Inosine，来自美国Sigma公司)。溶于无菌生理盐水，注射剂量为10、50、100和300mg/kg。
实验材料：
透明玻璃桶，旷场箱，高清摄像机、小动物行为学视频采集与分析系统。
3、实验方法
实验流程如图1所示：
(1)抑郁样行为的模型制备方法
通过对实验小鼠腹腔注射LPS(0.83mg/kg,i.p.)制备抑郁样行为模型。将实验小鼠分为两组，通过腹腔注射方式分别注射无菌生理盐水(1mL/kg,i.p.)和LPS(0.83mg/kg,i.p.)，注射LPS的小鼠为实验组(LPS组)，注射无菌生理盐水的小鼠为对照组(CON组)。并对两组实验小鼠进行糖水偏好试验、强迫游泳试验和悬尾试验。
糖水偏好试验：
实验前2周，对实验小鼠进行糖水(2％)训练。第1周进行三次糖水基线测试，第2周进行两次糖水基线测试。注射LPS后进行24小时糖水偏好测试。计算24小时糖水偏好度，计算公式为糖水偏好度＝糖水消耗量/(糖水消耗量+清水消耗量)。
强迫游泳试验：
将小鼠置于水温25±1℃、水深19cm的透明玻璃桶(10cm×25cm)中，观察6分钟，记录最后5分钟内累计静止不动时间。强迫游泳的累计静止不动时间反映小鼠的抑郁样行为，其值缩短，说明抑郁样行为改善。
(2)本发明肌苷防治抑郁症
实验分别设置正常对照组(CON)：对实验小鼠腹腔注射浓度为1mL/kg的无菌生理盐水；LPS组(LPS)：对实验小鼠腹腔注射浓度为0.83mg/kg的LPS；肌苷组(INO)：分别对实验小鼠腹腔注射浓度为10、50、100和300mg/kg的肌苷；肌苷+LPS组(INO+LPS)：先对实验小鼠腹腔注射浓度为100mg/kg的肌苷，30分钟后腹腔注射浓度为0.83mg/kg的LPS。
对各组实验小鼠进行糖水偏好试验和强迫游泳试验，评价各实验组小鼠的抑郁样行为。
4、实验结果
如图2所示，与对照组相比，LPS组糖水偏好值显著降低，强迫游泳试验显著延长，说明注射LPS可导致小鼠抑郁样行为，本发明造模成功。
如图3所示，INO+LPS组给予不同的肌苷浓度，50mg/kg和100mg/kg肌苷浓度可显著缩短强迫游泳静止不动时间；浓度为100mg/kg的肌苷注射30分钟和60分钟后，抗抑郁作用显著。
图4的糖水偏好试验中，肌苷(100mg/kg)可显著拮抗LPS导致的糖水偏好值降低。
由图3和图4可知，肌苷可以显著缩短强迫游泳静止不动时间，显著拮抗LPS导致的糖水偏好值降低，说明其可以有效预防抑郁症，其中，给药剂量为50～100mg/kg时，效果明显。
实验结果说明，本发明肌苷可以有效预防抑郁症，为临床治疗抑郁症提供了一种新的选择。

Claims (8)

  1. 肌苷在制备治疗和/或预防抑郁症的药物中的应用。
  2. 根据权利要求1所述的应用，其特征在于：所述抑郁症为内源性抑郁症、反应性抑郁症、精神病性抑郁症、物质/药物引起的抑郁症、其他疾病导致的抑郁症。
  3. 根据权利要求2所述的应用，其特征在于：所述药物是以肌苷为活性成分，加上药学上可接受的辅料或者辅助性成分制备而成的制剂。
  4. 根据权利要求3所述的应用，其特征在于：所述制剂是注射制剂。
  5. 根据权利要求4所述的应用，其特征在于：所述注射制剂的单位制剂含有300mg～600mg肌苷。
  6. 根据权利要求5所述的应用，其特征在于：所述注射制剂的单位制剂含有600mg肌苷。
  7. 根据权利要求1～6任意一项所述的应用，其特征在于：所述药物是哺乳动物用药物。
  8. 根据权利要求7任意一项所述的应用，其特征在于：所述药物是人用药物。
PCT/CN2019/090844 2018-08-31 2019-06-12 肌苷在防治抑郁症中的应用 WO2020042719A1 (zh)

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