WO2019096144A1 - 片仔癀及其制剂在治疗脑卒中后遗症的用途 - Google Patents

片仔癀及其制剂在治疗脑卒中后遗症的用途 Download PDF

Info

Publication number
WO2019096144A1
WO2019096144A1 PCT/CN2018/115329 CN2018115329W WO2019096144A1 WO 2019096144 A1 WO2019096144 A1 WO 2019096144A1 CN 2018115329 W CN2018115329 W CN 2018115329W WO 2019096144 A1 WO2019096144 A1 WO 2019096144A1
Authority
WO
WIPO (PCT)
Prior art keywords
use according
brain tissue
sequelae
improving
tze huang
Prior art date
Application number
PCT/CN2018/115329
Other languages
English (en)
French (fr)
Inventor
袁慧君
洪绯
于娟
罗志毅
黄进明
殷婷婷
庄毅超
林丽敏
Original Assignee
漳州片仔癀药业股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 漳州片仔癀药业股份有限公司 filed Critical 漳州片仔癀药业股份有限公司
Publication of WO2019096144A1 publication Critical patent/WO2019096144A1/zh

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/37—Digestive system
    • A61K35/413—Gall bladder; Bile
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/55—Glands not provided for in groups A61K35/22 - A61K35/545, e.g. thyroids, parathyroids or pineal glands
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/56—Materials from animals other than mammals
    • A61K35/58—Reptiles
    • A61K35/583—Snakes; Lizards, e.g. chameleons
    • 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)
    • A61K36/25—Araliaceae (Ginseng family), e.g. ivy, aralia, schefflera or tetrapanax
    • A61K36/258—Panax (ginseng)

Definitions

  • the invention belongs to the field of traditional Chinese medicine, and particularly relates to the use of Pien Tze Huang and its preparations in treating sequelae of stroke.
  • the sequela of stroke refers to the symptoms of hemiplegia, unfavorable speech, and crooked eyes left behind after 6 months of treatment.
  • the root cause of the above symptoms is: blood vessels with high blood viscosity, high blood lipids, high blood pressure, high blood sugar, platelet aggregation, etc., and vascular lesions such as atherosclerotic plaque, which are caused by the combination of the two diseases.
  • the formed thrombus blocks the cerebral artery, leading to the interruption of blood flow in the brain and ischemia and hypoxia.
  • the sequela of stroke is also called the sequela of cerebral apoplexy. Compared with the recovery period, the recovery rate and degree are slower.
  • the effective methods to improve the symptoms of stroke sequelae and reduce the high recurrence rate are mainly in the scientific diet and active and passive recovery exercise, combined with drug therapy, not only for the formation of cerebral apoplexy, atherosclerotic plaque formation, high blood viscosity, etc.
  • the basic lesions are effectively treated to prevent the formation of arteriosclerotic thrombus re-formation; and it can improve the blood supply and oxygen supply of the brain tissue, create a good internal environment for the brain tissue, restore the brain nervous system, and then control the movement, language and nervous system signs.
  • the drugs for improving the symptoms of sequelae of stroke have mainly include three methods: traditional Chinese medicine treatment, western medicine treatment, and integrated Chinese and Western medicine treatment.
  • traditional Chinese medicine treatment includes: activating blood circulation and removing blood stasis treatment, aromatherapy treatment, activating blood circulation and removing blood stasis, and aroma treatment.
  • Pien Tze Huang is a national first-class Chinese medicine protection variety. It is made from precious Chinese medicines such as musk, bezoar, snake gall, and Sanqi. It has the effects of clearing away heat and detoxifying, dispersing phlegm and relieving blood, reducing swelling and setting pain. It is commonly used in the treatment of bacterial infectious diseases and viruses. Hepatitis, bronchitis, malignant tumors and other diseases.
  • the present invention proposes the use of Pien Tze Huang and its preparation for treating sequelae of stroke.
  • the present invention provides the use of Pien Tze Huang and its preparations for the treatment of sequelae of stroke.
  • treatment of stroke sequelae refers to: improving blood rheology abnormalities.
  • improving blood rheology abnormality means reducing at least one of the following blood rheology indexes: whole blood viscosity, plasma viscosity, red blood cell deformation index, hematocrit, and maximum platelet aggregation rate.
  • treatment of stroke sequelae refers to: improving energy metabolism disorders in brain tissue.
  • improving energy metabolism disorder in brain tissue means: increasing the content of at least one of the following energy metabolism indicators in brain tissue: ATP and ADP.
  • the above-mentioned use for treating stroke sequelae means: improving neurological dysfunction.
  • improving neurological dysfunction means: increasing the content of at least one of the following neurological indicators in the brain tissue: norepinephrine, dopamine and serotonin.
  • Pien Tze Huang is added to a conventional excipient to prepare a clinically acceptable preparation.
  • the pharmaceutically acceptable excipients are: fillers, disintegrants, lubricants, suspending agents, binders, sweeteners, flavoring agents, preservatives, matrices, and the like.
  • Filling agents include: starch, pregelatinized starch, lactose, mannitol, chitin, microcrystalline cellulose, sucrose, etc.
  • disintegrating agents include: starch, pregelatinized starch, microcrystalline cellulose, sodium carboxymethyl starch, Cross-linked polyvinylpyrrolidone, low-substituted hydroxypropylcellulose, croscarmellose sodium, etc.
  • lubricants include: magnesium stearate, sodium lauryl sulfate, talc, silica, etc.
  • suspending agent Including: polyvinylpyrrolidone, microcrystalline cellulose, sucrose, agar, hydroxypropyl methylcellulose, etc.
  • binders include: starch syrup, polyvinylpyrroli
  • the preparation is selected from the group consisting of a tablet, a tablet, a capsule, a granule, a powder, a pill, an elixir, a wine, a ointment or a mixture.
  • the tablet preparation of the Pien Tze Huang preparation contains 0.3-0.9 g of Pien Tze Huang.
  • Pien Tze Huang has the combined effects of improving blood rheology abnormality, energy metabolism disorder and neurological dysfunction in brain tissue of rats with stroke sequelae, and can promote the damaged brain cells of model rats to some extent. Recovery, and thus restore the dominating function of the lower nervous and muscle functions, and therefore have a better therapeutic effect on stroke sequelae.
  • Pien Tze Huang was produced by Zhangzhou Pien Trick Pharmaceutical Co., Ltd.
  • Pien Tze Huang is prepared into a clinically acceptable lozenge according to a conventional process by adding conventional excipients.
  • Pien Tze Huang is prepared into a clinically acceptable tablet according to a conventional process by adding conventional excipients.
  • Pien Tze Huang is prepared into a clinically acceptable capsule according to a conventional process by adding conventional excipients.
  • Pien Tze Huang is prepared into a clinically acceptable granule according to a conventional process by adding conventional excipients.
  • PA-3210 platelet aggregation instrument LBY-N6K automatic cleaning rotary viscometer, LG-B190 red blood cell deformity instrument, Agilent high performance liquid chromatography system (SPD-10AV ultraviolet detector, L-ECD-6A electrochemical detector).
  • the Pien Tze Huang was pulverized into a fine powder by a grinder as a test drug.
  • Fifty male Wistar rats were randomly divided into normal control group, model control group, low dose group, middle dose group and high dose group, with 10 animals in each group.
  • the neck was dug in the middle of the neck, the left common carotid artery was first ligated, and the right common carotid artery was clipped.
  • the animal was fixed and the rat stereotactic instrument was placed on the right ear edge. Open the skull above the eyelid line, expose the skull, drill a bone window with a diameter of about 2mm, use a miniature electrocoagulation knife to occlude the middle cerebral artery, and use a random random electric pulse random stimulator at 24h after surgery.
  • the stimulation intensity is 50-80V. , 0.5-25Hz, 0.1-1.1ms, after 30 days, the evaluation model is based on whether the Zealonga scoring method is successfully established.
  • the drug was administered 30 days after the operation.
  • the low dose group was given 0.7g/kg Pien Tze Huang
  • the middle dose group was given 1.4g/kg Pien Tze Huang
  • the high dose group was given 2.1g. /kg Pien Tze Huang
  • the above three groups of gastric perfusion capacity were 20mL / (kg ⁇ d); normal control group and model control group were given the same amount of normal saline. Each group was administered continuously for 15 days.
  • 0 points no symptoms of nerve damage
  • 1 point can not completely straighten the contralateral fore paw
  • 2 points turn to the outside
  • 3 points dump to the opposite side
  • 4 points can not be self-issued, consciousness Lost.
  • a score of 1-4 points indicates that the model is successful.
  • the rats were orally administered for 15 days, and the abdominal aorta was taken for blood.
  • the whole blood viscosity at 10 ° -1 , 50 s -1 and 200 -1 at 37 ° C and the plasma viscosity at 100 s -1 were measured by blood viscosity tester.
  • the maximum deformation index of red blood cells was measured by a red blood cell deformity meter; the hematocrit was measured by a micro speed centrifugation method.
  • Blood was taken from the abdominal aorta, anticoagulated with sodium citrate solution (volume ratio 1:9), and centrifuged at 1000 r/min for 10 min to prepare platelet-rich plasma (PRP), and a certain amount was taken for use. Then, the remaining part was centrifuged at 3000r/min for 15min to prepare platelet-poor plasma (PPP). PRP and PPP were mixed in a certain ratio, and the transmittance was adjusted to about 4000 with a platelet meter (the number of platelets at this time was 3 ⁇ 9 12 /L), using ADP as an inducer, the turbidimetric method was used to determine the maximum aggregation rate of platelet aggregation in a certain period of time.
  • PRP platelet-rich plasma
  • PPP platelet-poor plasma
  • the right brain tissue was taken and weighed. 2 mL of 0.4 mol/L acetonitrile was quickly added. The paper tissue was homogenized and homogenized thoroughly with a homogenizer. The mixture was placed in an ice bath for 30 min, centrifuged at 10,000 rpm for 10 min, and the supernatant was taken. After centrifugation at 3000 rpm for 5 min, the supernatant was taken, filtered through a 0.22 ⁇ m aqueous membrane, and stored at -86 ° C, to be tested.
  • SPD-10AV UV detector mobile phase 0.05 mol/L NH 4 H 2 PO 4 buffer (pH 6.0), flow rate 1.6 mL/min, column temperature 25 ° C, detection wavelength 254 nm.
  • the right brain tissue of the rats was weighed and quickly added to an ice-cold 0.05 mol/L perchloric acid solution (containing 0.4 g/L sodium metabisulfite and 0.4 g/L EDTA) to 2 ml, and homogenized in an ice bath for 1 min. Centrifuge at 15000 rpm for 30 min at 4 ° C, remove the supernatant and store at -86 ° C for testing.
  • perchloric acid solution containing 0.4 g/L sodium metabisulfite and 0.4 g/L EDTA
  • L-ECD-6A electrochemical detector mobile phase 80mmol / L NH 4 H 2 PO 4 and 60mmol / L citrate buffer and methanol mixture (8:2), pH 3.4, flow rate 0.6mL / min .
  • each group of rats had hemiplegia symptoms, which showed dull hair, lack of energy, lack of energy, lethargy, reduced feeding and drinking water, left upper extremity adduction, physics, climbing cage
  • the body leans to one side the lower extremity is abducted, the adduction is difficult, and the limp is in a state of walking when jumping or jumping.
  • the rat tail is lifted, the rat cannot normally roll up the body, and the body can only be shaken, and the left testicle of the male rat shrinks.
  • the testicles on both sides are not the same size.
  • the symptoms of hemiplegia in the model rats were observed to be improved to varying degrees in the low-dose, medium-dose, and high-dose groups, and there was a phenomenon of hair moisturization, increased activity, improved diet, and accelerated wound healing.
  • Pien Tze Huang has a comprehensive effect of improving blood rheology abnormality, energy metabolism disorder and neurological dysfunction in brain tissue of rats with stroke sequelae, and can promote the recovery of damaged brain cells in model rats to some extent. It restores the dominating function of the lower limbs and muscles, and therefore has a better therapeutic effect on stroke sequelae.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Cell Biology (AREA)
  • Biomedical Technology (AREA)
  • Zoology (AREA)
  • Virology (AREA)
  • Immunology (AREA)
  • Developmental Biology & Embryology (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Mycology (AREA)
  • Botany (AREA)
  • Medical Informatics (AREA)
  • Microbiology (AREA)
  • Endocrinology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

片仔癀对脑卒中后遗症具有治疗作用，具体为改善脑卒中后遗症模型大鼠的血液流变性异常、脑组织中能量代谢障碍和神经功能障碍等综合效应，一定程度上促进模型大鼠受损脑细胞的恢复。

Description

片仔癀及其制剂在治疗脑卒中后遗症的用途 技术领域
本发明属于中药领域，具体涉及片仔癀及其制剂在治疗脑卒中后遗症的用途。
背景技术
脑卒中后遗症是指脑中风治疗6个月后所遗留的半身不遂、言语不利、口眼歪斜等症状。出现以上症状的根本原因在于：脑血管内部出现血粘度高、血脂高、血压高、血糖高、血小板聚集等血液病变，和动脉粥样硬化斑块形成等血管病变，由两种病变共同作用结果形成的血栓堵塞脑动脉所致，导致脑局部的血流中断和脑组织缺血缺氧坏死。脑卒中后遗症也叫做脑中风后遗症期，与恢复期相比，恢复速度及程度较慢。虽然经过脑卒中急性期和恢复期的规范治疗，多数脑卒中患者的病情可有效控制，并有一定的功能恢复，但患者仍遗留不同程度的残疾，其中重度致残患者可达40％。脑卒中后遗症患者如果在2-3年内采取良好的治疗措施，则有望改善患者功能活动障碍，从而提高患者的生活质量。
目前，改善脑中风后遗症症状、降低高复发率的有效方法主要是在科学饮食和主、被动恢复锻炼的同时，结合药物治疗，不仅可以对脑中风诱因动脉粥样硬化斑块形成、血液粘度高等基础病变进行有效治疗，进而防止动脉硬化血栓再次形成；而且可以改善脑组织供血供氧量，为脑组织创造一个良好的内环境，恢复脑神经系统，进而使其控制的运动、语言神经系统体征得到改善。改善脑中风后遗症症状的药物主要包括：中药治疗、西药治疗、中西医结合治疗三种方法，其 中中药治疗包括：活血化瘀治疗、芳香开窍治疗和活血化瘀、芳香开窍双重治疗三种方法。
片仔癀是国家一级中药保护品种，采用麝香、牛黄、蛇胆、三七等名贵中药精制而成，具有清热解毒、散瘀止血、消肿定痛的功效，临床常用于治疗细菌感染性疾病、病毒性肝炎、支气管炎、恶性肿瘤等疾病。
尽管现有技术有文献报道：片仔癀预防性治疗能够减轻卒中的严重程度并延长卒中的生存时间；但是，未见片仔癀及其制剂用于制备治疗脑卒中后遗症的相关报道。
发明内容
为此，本发明提出片仔癀及其制剂在治疗脑卒中后遗症的用途。
为解决上述技术问题，本发明是通过以下技术方案来实现的：
本发明提供片仔癀及其制剂在治疗脑卒中后遗症的药物中的用途。
优选地，上述用途，治疗脑卒中后遗症是指：改善血液流变性异常。
进一步优选地，上述用途，改善血液流变性异常是指：降低如下血液流变学指标中的至少一种：全血粘度、血浆粘度、红细胞变形指数、红细胞压积和血小板最大聚集率。
优选地，上述用途，治疗脑卒中后遗症是指：改善脑组织中能量代谢障碍。
进一步优选地，上述用途，改善脑组织中能量代谢障碍是指：升高脑组织中至少一种如下能量代谢指标中的含量：ATP和ADP。
优选地，上述用途，治疗脑卒中后遗症是指：改善神经功能障碍。
进一步优选地，上述用途，改善神经功能障碍是指：升高脑组织中至少一种如下神经功能指标中的含量：去甲肾上腺素、多巴胺和5-羟色胺。
进一步优选地，上述用途，片仔癀加入常规辅料，制成临床上可接受的制剂。
所述药学上可接受的辅料为：填充剂、崩解剂、润滑剂、助悬剂、粘合剂、甜味剂、矫味剂、防腐剂、基质等。填充剂包括：淀粉、预胶化淀粉、乳糖、甘露醇、甲壳素、微晶纤维素、蔗糖等；崩解剂包括：淀粉、预胶化淀粉、微晶纤维素、羧甲基淀粉钠、交联聚乙烯吡咯烷酮、低取代羟丙纤维素、交联羧甲基纤维素纳等；润滑剂包括：硬脂酸镁、十二烷基硫酸钠、滑石粉、二氧化硅等；助悬剂包括：聚乙烯吡咯烷酮、微晶纤维素、蔗糖、琼脂、羟丙基甲基纤维素等；粘合剂包括，淀粉浆、聚乙烯吡咯烷酮、羟丙基甲基纤维素等；甜味剂包括：糖精钠、阿斯帕坦、蔗糖、甜蜜素、甘草次酸等；矫味剂包括：甜味剂及各种香精；防腐剂包括：尼泊金类、苯甲酸、苯甲酸钠、山梨酸及其盐类、苯扎溴铵、醋酸氯乙定、桉叶油等；基质包括：PEG6000、PEG4000、虫蜡等。
进一步优选地，上述用途，所述制剂选自锭剂、片剂、胶囊剂、颗粒剂、散剂、丸剂、酊剂、酒剂、煎膏剂或合剂。
进一步优选地，上述应用，片仔癀制剂的每次给药制剂中含片仔癀0.3-0.9g。
本发明的上述技术方案相比现有技术具有以下优点：
本发明通过研究发现，片仔癀具有改善脑卒中后遗症模型大鼠的血液流变性异常、脑组织中能量代谢障碍和神经功能障碍等综合效应，而且可以在一定程度上促进模型大鼠受损脑细胞的恢复，进而恢复对下级神经和肌肉功能的支配功能，因此对脑卒中后遗症具有较好的治疗作用。
具体实施方式
本发明以下实施例和实验例中，片仔癀由漳州片仔癀药业股份有限公司生产。
实施例1
片仔癀按照常规工艺，加入常规辅料制成临床上可接受的锭剂。
实施例2
片仔癀按照常规工艺，加入常规辅料制成临床上可接受的片剂。
实施例3
片仔癀按照常规工艺，加入常规辅料制成临床上可接受的胶囊剂。
实施例4
片仔癀按照常规工艺，加入常规辅料制成临床上可接受的颗粒剂。
实验例1片仔癀对脑卒中后遗症的治疗作用的研究
1、实验目的
研究片仔癀对脑卒中后遗症的治疗作用。
2、实验方法
2.1实验动物
雄性Wistar大鼠，12周龄，体重250±25g，共50只。
2.2实验仪器
PA-3210血小板聚集仪，LBY-N6K自动清洗旋转粘度计，LG-B190型红细胞变形仪，安捷伦高效液相色谱系统(SPD-10AV紫外检测器，L-ECD-6A电化学检测器)。
2.3供试药物
将片仔癀用研磨机粉碎成细粉，作为供试药物。
2.4实验分组
将50只雄性Wistar大鼠随机分为正常对照组、模型对照组、低剂量组、中剂量组、高剂量组，每组动物各10只。
2.5脑卒中后遗症模型的建立及给药方法
大鼠麻醉后，颈部正中划一切口，先结扎左侧颈总动脉，再夹闭右侧颈总动脉，1h后放开，将动物固定与大鼠立体定向仪，在右侧耳缘和眼睑连线上方作一切口，暴露颅骨，钻一直径约2mm的骨窗，用微型电凝刀凝闭大脑中动脉，术后24h使用大鼠随机电脉冲随机刺激仪，刺激强度为50-80V，0.5-25Hz，0.1-1.1ms，30天后评价模型参考Zealonga评分方法是否建立成功。
确认脑卒中后遗症模型建立成功后，在术后30天开始给药，低剂量组灌胃给予0.7g/kg片仔癀，中剂量组灌胃给予1.4g/kg片仔癀，高剂量组灌胃给予2.1g/kg片仔癀，上述三组的灌胃容量均为20mL/(kg·d)；正常对照组和模型对照组均灌胃给予等量生理盐水。各组均连续给药15天。
2.6神经功能缺失评分
参考Zealonga评分方法，各组大鼠均于术后30天进行5分制评分。具体评分标准如下所示：0分：无神经损伤症状；1分：不能完全伸直对侧前爪；2分：向外侧转圈；3分：向对侧倾倒；4分：不能自发行走，意识丧失。评分为1-4分，则表示模型成功。
2.7血液流变学指标测定
大鼠灌胃15天后腹主动脉取血，用血液粘度测试仪测定37℃时10s -1、50s -1、200 -1三种切变率下全血粘度和100s -1下的血浆粘度；用红细胞变形仪测定红细胞最大变形指数；用微量高速离心法测定红细胞压积。
2.8血小板聚集率测定
由腹主动脉取血，枸橼酸钠溶液抗凝(体积比1:9)，1000r/min离心10min，制备富血小板血浆(PRP)，取一定量备用。再将剩余部分以3000r/min离心15min，制备贫血小板血浆(PPP)，将PRP与PPP按一定比例混合，用血小板仪将透光度调至4000左右(此时的血小板数为3×9 12/L)，用ADP为诱导剂，采用比浊法测定一定时间内血小板聚集的最大聚集率。
2.9脑细胞中ATP、ADP含量的测定
(1)样品预处理
大鼠处死后取右侧脑组织并称重，迅速加入0.4mol/L乙腈2mL，用匀浆器手动匀浆纸质组织完全混匀，置冰浴中30min，10000rpm离心10min，取上清液，3000rpm离心5min，取上清液，0.22μm水系膜过滤，置-86℃保存，待测。
(2)色谱条件
SPD-10AV紫外检测器，流动相0.05mol/L NH 4H 2PO 4缓冲液(pH6.0)，流速1.6mL/min，柱温25℃，检测波长254nm。
2.9脑组织中神经递质含量测定
(1)样品预处理
大鼠取右侧脑组织并称重，迅速加入冰冷的0.05mol/L高氯酸溶液中(内含0.4g/L焦亚硫酸钠和0.4g/L EDTA)至2ml，冰浴中匀浆1min，4℃下15000rpm离心30min，取上清液过滤，置-86℃保存，待测。
(2)色谱条件
L-ECD-6A电化学检测器，流动相为80mmol/L NH 4H 2PO 4和60mmol/L柠檬酸缓冲液与甲醇的混合液(8:2)，pH3.4，流速0.6mL/min。
3、实验结果
3.1一般体征观察
与正常对照组相比，造模后，各组大鼠均有偏瘫症状，表现为毛发暗淡无光，精神萎靡不振，嗜睡，摄食和饮水减少，左侧上肢内收，物理，攀爬鼠笼时身体向一侧倾斜，下肢外展，内收困难，走路或跳跃时呈跛行状态，提起鼠尾时大鼠不能正常卷起身体，只能不停抖动身体，雄鼠左侧睾丸萎缩，表现为两侧睾丸大小不一样等。
给药后，低剂量组、中剂量组和高剂量组观察到模型大鼠肢体偏瘫症状有不同程度改善，并且有毛发润泽，活动强度增加，饮食改善，伤口愈合加快等现象。
3.2神经功能缺失评分
各组的神经功能缺失评分结果如表1所示。
表1 各组的神经功能缺失评分结果
组别 神经功能缺失评分
正常对照组 0
模型对照组 2.52±0.47 ##
低剂量组 1.64±0.67 *
中剂量组 1.45±0.83 *
高剂量组 1.31±0.75 *
注：与正常对照组比较， ##P＜0.01；与模型对照组比较， *P＜0.05
由表1可知：(1)模型对照组的评分显著高于正常对照组的评分(p＜0.01)，这表明：脑卒中后遗症模型建立成功，大鼠神经功能受损后均遗留后遗症；
(2)术后30天，各给药组低剂量组、中剂量组、高剂量组的评分均显著低于模型对照组的评分(p＜0.05)，这表明：片仔癀可以改善脑卒中后遗症模型大鼠神经功能，有利于其神经功能的恢复；
(3)各给药组的评分的顺序依次为(从高到低)：低剂量组、中剂量组、高剂量组，这表明：在一定给药剂量范围内，随着片仔癀的给药剂量的增加，神经功能缺失评分有下降趋势。
3.3对大鼠血液流变性的影响
各组大鼠血液流变性实验结果如表2所示。
表2 各组大鼠血液流变性实验结果
Figure PCTCN2018115329-appb-000001
Figure PCTCN2018115329-appb-000002
注：与正常对照组比较， ##p＜0.01， #p＜0.05；与模型对照组比较， **p＜0.01， *p＜0.05
由表2可知：(1)与正常对照组比较，模型对照组的全血粘度、血浆粘度、红细胞压积、血小板最大聚集率等各指标均显著升高(p＜0.05)；
(2)与模型对照组比较，各给药组的全血粘度、血浆粘度、红细胞压积、血小板最大聚集率等各指标均有一定程度的降低，其中以中剂量、高剂量组的全血粘度、血浆粘度、血小板最大聚集率的降低较显著(p＜0.05)；这表明：片仔癀对脑卒中后遗症模型大鼠的血液流变性具有改善作用。
3.4对大鼠脑组织中能量代谢的影响
各组大鼠脑组织中ATP和ADP含量如表3所示。
表3 各组大鼠脑组织中ATP和ADP含量(ng/mL)
组别 ATP ADP
正常对照组 460±112 521±95
模型对照组 84±35# 117±31#
低剂量组 343±56* 385±79**
中剂量组 219±48** 312±43**
高剂量组 241±63** 293±50**
注：与正常对照组比较， #p＜0.001；与模型对照组比较，*p＜0.01，**p＜0.001
由表3可知：(1)模型对照组大鼠脑组织中ATP和ADP含量显著低于正常对照组的ATP和ADP含量(p＜0.001)；
(2)各给药组大鼠脑组织中ATP和ADP含量均显著高于模型对 照组脑组织中ATP和ADP含量(p＜0.001或p＜0.01)；这表明：片仔癀可以升高脑卒中后遗症模型大鼠脑组织中ATP和ADP含量，可以改善脑卒中所导致的能量代谢障碍。
3.5对大鼠脑组织中神经递质的影响
各组大鼠脑组织中NE、DA和5-HT含量如表4所示。
表4 各组大鼠脑组织中NE、DA和5-HT含量(ng/mL)
Figure PCTCN2018115329-appb-000003
注：与正常对照组比较， #p＜0.01， ##p＜0.001；与模型对照组比较， *p＜0.05， **p＜0.01
由表4可知：(1)模型对照组大鼠脑组织中NE、DA、5-HT的含量均显著低于正常对照组大鼠脑组织中NE、DA、5-HT的含量(p＜0.001或p＜0.01)；
(2)各给药组大鼠脑组织中NE、DA、5-HT含量均有不同程度的升高，且各给药组NE含量的升高与模型对照组NE含量相比具有显著性差异(p＜0.01)，中、高剂量组的DA、5-HT含量的升高与模型对照组DA、5-HT含量相比具有显著性差异(p＜0.05)；这表明，片仔癀可以促进脑卒中后遗症模型大鼠神经元的损伤修复，可以改善脑组织神经功能障碍。
4、实验结论
综上，片仔癀具有改善脑卒中后遗症模型大鼠的血液流变性异常、脑组织中能量代谢障碍和神经功能障碍等综合效应，而且可以在一定程度上促进模型大鼠受损脑细胞的恢复，进而恢复对下级神经和肌肉的支配功能，因此对脑卒中后遗症具有较好的治疗作用。
显然，上述实施例仅仅是为清楚地说明所作的举例，而并非对实施方式的限定。对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引伸出的显而易见的变化或变动仍处于本发明创造的保护范围之中。

Claims (15)

  1. 片仔癀及其制剂在治疗脑卒中后遗症的用途。
  2. 根据权利要求1所述的用途，其特征在于，治疗脑卒中后遗症是指：改善血液流变性异常。
  3. 根据权利要求2所述的用途，其特征在于，改善血液流变性异常是指：降低如下血液流变学指标中的至少一种：全血粘度、血浆粘度、红细胞变形指数、红细胞压积和血小板最大聚集率。
  4. 根据权利要求1所述的用途，其特征在于，治疗脑卒中后遗症是指：改善脑组织中能量代谢障碍。
  5. 根据权利要求4所述的用途，其特征在于，改善脑组织中能量代谢障碍是指：升高脑组织中至少一种如下能量代谢指标中的含量：ATP和ADP。
  6. 根据权利要求1所述的用途，其特征在于，治疗脑卒中后遗症是指：改善神经功能障碍。
  7. 根据权利要求6所述的用途，其特征在于，改善神经功能障碍是指：升高脑组织中至少一种如下神经功能指标中的含量：去甲肾上腺素、多巴胺和5-羟色胺。
  8. 根据权利要求1-7任一项所述的用途，其特征在于，片仔癀加入常规辅料，按照常规工艺，制成临床上可接受的制剂。
  9. 根据权利要求8所述的用途，其特征在于，所述制剂选自锭剂、片剂、胶囊剂、颗粒剂、散剂、丸剂、酊剂、酒剂、煎膏剂或合剂。
  10. 根据权利要求1-9任一项所述的应用，其特征在于，片仔癀制剂的每次给药制剂中含片仔癀0.3-0.9g。
  11. 一种片仔癀药物在治疗脑卒中后遗症的用途，其特征在于所述片仔癀药物包括片仔癀或其含片仔癀的组合物。
  12. 根据权利要求11所述的用途，其特征在于，治疗脑卒中后遗症是指：改善血液流变性异常。
  13. 根据权利要求11所述的用途，其特征在于，治疗脑卒中后遗症是指：改善脑组织中能量代谢障碍。
  14. 根据权利要求13所述的用途，其特征在于，改善脑组织中能量代谢障碍是指：升高脑组织中至少一种如下能量代谢指标中的含量：ATP和ADP。
  15. 根据权利要求11所述的用途，其特征在于，治疗脑卒中后遗症是指：改善神经功能障碍。
PCT/CN2018/115329 2017-11-16 2018-11-14 片仔癀及其制剂在治疗脑卒中后遗症的用途 WO2019096144A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201711136929.7A CN107970264A (zh) 2017-11-16 2017-11-16 片仔癀及其制剂在制备治疗脑卒中后遗症的药物中的新用途
CN201711136929.7 2017-11-16

Publications (1)

Publication Number Publication Date
WO2019096144A1 true WO2019096144A1 (zh) 2019-05-23

Family

ID=62013662

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/115329 WO2019096144A1 (zh) 2017-11-16 2018-11-14 片仔癀及其制剂在治疗脑卒中后遗症的用途

Country Status (3)

Country Link
CN (1) CN107970264A (zh)
TW (1) TWI794335B (zh)
WO (1) WO2019096144A1 (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107970264A (zh) * 2017-11-16 2018-05-01 漳州片仔癀药业股份有限公司 片仔癀及其制剂在制备治疗脑卒中后遗症的药物中的新用途

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107970264A (zh) * 2017-11-16 2018-05-01 漳州片仔癀药业股份有限公司 片仔癀及其制剂在制备治疗脑卒中后遗症的药物中的新用途

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107970264A (zh) * 2017-11-16 2018-05-01 漳州片仔癀药业股份有限公司 片仔癀及其制剂在制备治疗脑卒中后遗症的药物中的新用途

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
LI, QIAN ET AL.,: "The effect of pianzaihuang on nerve growth factor (NGF) expression of focal cerebral infarction rats", CHINESE JOURNAL OF NEUROANATOMY, vol. 5, no. 28, 31 May 2012 (2012-05-31), ISSN: 1111-2222 *
LIU, LIXING ET AL.,: "Effect of Pien Tze Huan on the amount of TNF-alpha, ICAM-1 and VCAM-1 of focal cerebral infarction rats", HEBEI JOURNAL OF TRADITIONAL CHINESE MEDICINE, vol. 9, no. 36, 30 September 2014 (2014-09-30), ISSN: 1002-2619 *

Also Published As

Publication number Publication date
TW201922269A (zh) 2019-06-16
TWI794335B (zh) 2023-03-01
CN107970264A (zh) 2018-05-01

Similar Documents

Publication Publication Date Title
CN109939102B (zh) 一种包含丁苯酞和冰片的药物组合物及其应用
WO2019109590A1 (zh) 眼用药物制剂及其应用
CN113413461A (zh) 抗老年痴呆药物及其制备方法
Zhang et al. Electroacupuncture improves neurogenic bladder dysfunction through activation of NGF/TrkA signaling in a rat model
Wan Nuclear factor κB and inhibitor of κB: acupuncture protection against acute focal cerebral ischemia in rodents
WO2019096144A1 (zh) 片仔癀及其制剂在治疗脑卒中后遗症的用途
AU2012381574B2 (en) Compound ambroxol hydrochloride composition and preparation method therefor
JP6663018B2 (ja) 糖尿病性網膜症の治療のための漢方薬組成物
JP2769584B2 (ja) 局所投与用抗アレルギー剤
TW202210090A (zh) 藥學組合物及其於治療肌少症之用途
WO2023168898A1 (zh) 中药组合物在制备防治视网膜色素变性的药物中的应用
CN105125630A (zh) 一种眼药水及制备方法
CN111686175A (zh) 苦黄注射液在治疗或预防眼部炎症中的用途
CN108403740A (zh) 八宝丹及其制剂在制备治疗血精症的药物中的应用
WO2019128511A1 (zh) 片仔癀及其制剂在制备治疗带状疱疹后遗神经痛的药物中的用途
RU2564907C1 (ru) Способ лечения больных красным плоским лишаем
CN115779013B (zh) 一种心肾同治法治疗病态窦房结综合征的中药组合物及其应用
CN103446366B (zh) 一种治疗颈椎病的药物组合物及其制备方法
CN105878276A (zh) 鼻炎制剂及其制备方法
CN106727605B (zh) 环维黄杨星d在制备预防或治疗缺血性脑卒中药物中的应用
CN107793404A (zh) 一种治疗缺血性脑损伤药物组合物及其应用
RU2266737C1 (ru) Препарат для лечения геморрагического инсульта и способ лечения геморрагического инсульта
Leng Vestibular Neuritis (Acute Unilateral Vestibulopathy)
O'Neill et al. Treatment of Choreoathetotic Movements in Chronic Liver Disease with a Dopamine-Blocking Agent Pathophysiologic Implications: Treatment of Choreoathetotic Movements in Chronic Liver Disease with a Dopamine-Blocking Agent Pathophysiologic Implications
Song et al. Clinical study of microvascular decompression for the treatment of trigeminal neuralgia

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18878518

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18878518

Country of ref document: EP

Kind code of ref document: A1