脑震宁可降低脑外伤相关症状的持续风险

编辑翻译：菁菁

译文校对：奇奇

（本文作者为振东北京光明研究院心脑临床总监Alsanabani Hani，文中介绍了当前关于脑震宁的临床研究，阐述了这一药物改善脑外伤患者持续症状的药理机制）

脑外伤（TBI）是导致死亡和残疾的重要原因之一，也是年轻人死亡的主要原因。在全球范围内，据估计每年有超过5000万人患有TBI。因此，它为公共卫生带来挑战，也造成了沉重的社会负担。相关组织迫切需要减轻TBI因缺乏预防、评估和管理而产生的巨大负担和社会成本。TBI没有唯一定义。但在ICD-11中，损伤通常定义为由于身体与能量互相作用时，能量传递的数量或速率超出耐受，从而造成的身体上或生理上的伤害。TBI的另一个主要定义是运动组脑震荡，该定义将脑震荡定义为脑损伤，并定义为由生物机械力引起的、影响大脑的复杂病理生理过程。依据CISG定义，“轻度脑外伤”（mTBI）和脑震荡在体育比赛中经常互换使用，尤其是在美国。

有几种标准可用来衡量TBI的严重性。最常用的标准是格拉斯哥昏迷量表（GCS），它可以评估意识水平。GCS量表的评分范围是3到15。当GCS评分在13到15之间时，认为患者患有mTBI。关于mTBI的定义并不统一。世界卫生组织的神经创伤工作组将mTBI定义为，对头部的打击或摇动导致的脑功能急性破坏，表现为短暂的意识丧失（<30分钟），精神错乱或创伤后遗症（<24小时），不包括心理创伤或酒精/药物中毒等因素的影响。大多数TBI都为mTBI，统计显示mTBI占所有TBI病例的70-90%。这表明，mTBI是重要的健康问题。

西医（WM）治疗mTBI主要针对症状，如镇痛药、镇静剂、安眠药、抗抑郁药、改善脑循环的药物，以及其它针对患者症状的药物等。从中医的角度来看，这些药物对单一症状都有疗效，但长期服用容易产生药物依赖和一些副作用。然而，在这一领域尚没有中药能够更好地控制mTBI并降低与mTBI相关症状的持续风险（SPR）。

脑震宁颗粒（NZN）是专为TBI患者设计的中药，由11种药材组成：地黄、当归、炒酸枣仁、柏子仁、茯苓、陈皮、丹参、川芎、地龙、牡丹皮、竹茹。在该制剂中，丹参、当归、川芎、地龙、牡丹皮是主要的活性成分。根据中医理论，丹参具有活血化瘀的功效，当归具有滋养血液、缓解疼痛的作用，川芎理气活血，地龙养经活血、缓解疼痛，牡丹皮凉血滋阴、促进循环。酸枣仁、柏种子仁、茯苓主要功效为养心、养肝、安神。温干陈皮及竹茹则和胃止吐。早在1985年，NZN颗粒就开始用于脑震荡、脑损伤综合征，以及术后康复的临床治疗。临床观察表明，该药对头痛、头晕、烦躁、失眠、健忘、心悸、恶心、呕吐等症状有改善作用。

药理和毒理学体内研究表明，NZN具有镇静、镇痛、止吐作用。NZN降低了小鼠的自主活动，增强了戊巴比妥钠的抑制作用。不仅如此，NZN还增加了小鼠的疼痛阈值，改善了小鼠的学习和记忆功能，并减轻了犬实验中的呕吐。

基于网络药理学对NZN机理的分析表明，NZN包括33种药理作用的成分。这些成分由DRAR-CPI预测并通过CooLGeN数据库查询，用于脑震荡，脑损伤和神经保护。神经再生目标的比较分析获得了34种潜在靶标，这些靶标包括信号分子，受体，蛋白质蛋白质（免疫蛋白，钙结合蛋白等），酶（蛋白酶，水解酶等），激酶，转移酶，氧化还原酶等。它们表明NZN成分可协调不同的靶标共同发挥作用。根据节点相关性分析，MAPK1，CASP3，GSK3B，JAK2，PLG，TNF和其他靶标密切相关。然后，对34个靶标进行生物学功能注释，发现NZN可能参与了活性氧的生物合成过程，平滑肌细胞的正调控，凝血的外源性途径，神经递质分解代谢过程。相互作用分析发现，NZN可能通过16种途径发挥作用以实现其临床功效。

NZN临床研究主要是临床实验研究和随机对照研究。研究结果表明，NZN颗粒对头痛和头晕有明显的治疗作用，且可以有效改善TBI引起的头痛和其他症状。但是，当前大多数临床研究的质量并不高，希望未来有高质量的研究。

中医临床研究通常采用简单的疗效量表来评价中药疗效，主要分为三个等级。上等是显著等级，包括了得到根治的患者。中等是有效等级，包括了得到明显缓解的患者。下等是不良等级，包括了未取得良好疗效的患者。得到根治的患者和疗效良好的患者加总后占整体患者的比例，称为药物的有效率（ER）。回顾在2000年后进行的NZN临床研究，有两项研究针对创伤后头痛（PTH）。NZN对PTH疗效的ER结果分别为90%和92%。回顾一项针对PTH的RCT研究，在创伤后3天到3周开始使用NZN，NZN的ER结果为86%。另一项RCT结果中，NZN对创伤后综合征（PTS）的ER结果为94%。

考虑到这些临床试验中协变量的控制较弱且研究规模较小，它们提供了粗略估算NZN临床价值的线索。它们体现了开展更多高质量临床试验以证明NZN功效、阐明其临床价值的必要性。

英文原文

Nao Zhen Ning Improves Traumatic Brain Injury Associated Symptoms Persistence Risk (SPR)

Traumatic brain injury (TBI) is one of the major causes of death and disability and the leading cause of mortality in young adults. Globally, TBI is a public health challenge with heavy social burden as it estimated that more than 50 million people have a TBI each year [1], it has been estimated that TBI costs the global economy approximately 400 billion USD annually[2], related organization urgently need to reduce the huge burden and societal costs of TBI as this clinical situation has lack in the prevention, assessment and management. There is no single definition of TBI but in the ICD-11, injury commonly defined as a physical or physiological bodily harm resulting from interaction of the body with energy in an amount, or at a rate of transfer, that exceeds physical or physiological tolerance. The other main definition of TBI is the Concussion in Sport Group (CISG) [3] definition which define concussion as a brain injury and is defined as a complex pathophysiological process affecting the brain, induced by biomechanical forces, CISG indicated that the terms mild TBI (mTBI) and concussion are often used interchangeably in the sporting context and particularly in the U.S.

There are several criteria used to index severity of TBI. One of the most commonly used is the Glasgow Coma Scale (GCS)[4], which assesses the level of consciousness. GCS scores can range from 3 to 15; and mTBI is defined as a GCS score of 13-15. Definitions of mTBI vary; the World Health Organization Neurotrauma Task Force defines mTBI as a blow to or jolting of the head causing an acute disruption of brain function, manifested by a brief loss of consciousness(< 30minutes), confusion, or posttraumatic amnesia (<24hours) not accounted for by factors such as psychological trauma or alcohol/drug intoxication[5]. mTBI form the major portion of TBI with 70-90% of all kind of TBI [4.6], this demonstrating that mTBI is a major health issue.

Western Medicine (WM) (the modern medicine is known in china as western medicine to differentiate it from the Traditional Chinese Medicine, TCM) treatment of mTBI mainly targeting symptoms, such as analgesics, sedatives and sleeping drugs, antidepressants and drugs for improving cerebral circulation and other symptoms related medicine. From the perspective of Chinese medicine, these drugs have effect on a single symptom, long-term use is prone to drug dependence and certain side effects. On the other hand, there are no Chinese medicines yet in this field with satisfactory efficacy to better control mTBI and to decrease mTBI related symptoms persistence risk (SPR).

Naozhenning granules (NZN) is a traditional Chinese medicine designed specifically to treat TBI patients, it composed of 11 kinds of traditional Chinese medicine include：Rehmannia glutinosa, angelica, fried jujube kernel, cypress seed kernel, tuckahoe, tangerine peel, salviae miltiorrhiza, chuanxiong, lumbricus, peony peel, bamboo shavings. In this preparation, Salvia miltiorrhiza, angelica, chuanxiong, lumbricus, and Danpi is the main active ingredients. Their efficacy，according to Chinese medicine theories, Danshen promotes blood circulation and removes blood stasis, Angelica sinensis nourishes blood and relieves pain, Chuanxiong smoothes qi and promotes blood circulation, lumbricus relieves menstruation and relieves pain, and Danpi cools blood to nourish yin and promote fluid. Suanzaoren, Baiziren, Poria nourishes the heart and nourishes the liver, calms the mind, warms the dried tangerine peel to stop vomiting, and Zhuru and the stomach stop vomiting. As early as 1985, NZN granules began to be used in clinical treatment of concussion, brain injury syndrome and post-operative rehabilitation. Clinical observations show that this medicine has ameliorating effect on various symptoms, such as headache, dizziness, irritability, insomnia, forgetfulness, palpitations, nausea and vomiting.

The in-vivo, pharmacological and toxicological studies proof that NZN has sedative, analgesic and antiemetic effects[8], NZN reducing the autonomous activities[00] of mice and enhancing the inhibitory effect of pentobarbital sodium[00]. Not only that, NZN also increased the pain threshold of mice [00], and improve the learning and memory function of mice[00]，NZN also relief vomiting in dogs experiment [00].

Analysis of the Mechanism of NZN Based on Network Pharmacology shows [14] that the NZN has 33 ingredients that may have pharmacological effects which were predicted by (DRAR-CPI) and queried with the CooLGeN database for concussion, brain injury, and neuroprotection , The comparative analysis of the targets of nerve regeneration has obtained 34 possible potential targets. The targets include signal molecules, receptors, proteins (immune proteins, calcium binding proteins, etc.), enzymes (proteases, hydrolases, etc.), Kinases, transferases, oxidoreductases, etc.), indicating that NZN ingredients work together through different target types. According to the analysis of node correlation, MAPK1, CASP3, GSK3B, JAK2, PLG, TNF and other targets are closely related to each other. Then, the 34 targets obtained were subjected to biological function annotation analysis, and it was found that NZN may participate in the Reactive oxygen species biosynthetic process (reactive oxygen biosynthesis process), positive regulation of smooth muscle cell proliferation (smooth muscle cell proliferation), blood coagulation extrinsic pathway (extrinsic pathway of blood coagulation), neurotransmitter catabolic process (neurotransmitter decomposition). Interaction analysis discover 16 pathways that NZN may act through these pathways to achieve its clinical efficacy.

Clinical studies have shown that NZN granules has obvious therapeutic effects on headache and dizziness, and can effectively improve patients' headache and other symptoms caused by TBI. However, the quality of most of the studies is not high, hope in the near future high quality studies will be available. NZN clinical studies mainly are investigational studies and randomized controlled studies (RCT).

Clinical studies in TCM usually use simple efficacy scale to evaluate the efficacy of Chinese medicine, mainly divided into three grades, the top one is significant grade include radically treated patients, the meddle grade is effective grade include the patient got obvious relief, the bottom grade is poor grade include the patients whom did not get good treatment efficacy. The proportion of the sum of the patients who radically got treated and the patients who got good efficacy called efficacy rate (ER) of the medicine. Reviewing the investigational studies of NZN underwent after 2000, NZN had many investigational clinical studies, two of these studies targeted post traumatic headache (PTH), the ER result of NZN was 90%[14],92%[18] respectively, demonstrating the efficacy of NZN on PTH. Reviewing RCT, one study targeted post traumatic headache (PTH), and the use of NZN start 3d-3w after trauma, the ER result of NZN was 86%[9], Other RCT targeted post traumatic syndrome (PTS) and the ER result of NZN was 94%[7].

Taking into the consideration that the control of covariant in these clinical trials was weak and the studies size were small, these trials at least give us a clue to roughly estimate the clinical value of NZN, increasing the need of more high quality clinical trials to proof the efficacy of NZN and to make clear of its clinical value.

参考文献

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[9]王学建,季炜鹏.脑震宁治疗脑外伤后头痛53例疗效观察[J].中华神经创伤外科电子杂志,2017,3(05):292-293.

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