宁动颗粒治疗抽动—秽语综合征的临床及分子机制研究

发布时间：2018-06-22 02:30

本文选题：宁动颗粒 + 抽动-秽语综合征　；参考：《山东大学》2012年博士论文

【摘要】：背景抽动-秽语综合征(Tourette's syndrome, TS)是一种无意识的、无目的的、重复的刻板活动为特征的神经精神性疾病。临床表现为头面、腹部及四肢不自主的抽动,喉部发出奇特叫声或者谩骂不避亲疏为特征。TS有不规则的发作间歇期,有时可因转移注意力而减轻,精神紧张时症状加重,睡眠时症状消失。 TS诊断标准为：1.具有多种运动性抽动及一种或多种发声性抽动,有时不一定在同一时间出现。2.抽动每天发作多次,通常为一阵阵发作,病情持续或间断发作已超过一年,其无抽动间歇期连续不超过三个月。3.上述症状引起明显的不安,显著地影响社交、就业和其他重要领域的活动。4.发病于18岁前。5.上述症状不是直接由某些药物(如兴奋剂)或内科疾病(如亨廷顿舞蹈病或病毒感染后脑炎)引起。尽管TS是一种轻症的神经精神疾病,但病程迁延,反复发作,影响正常的生活和学习。氟哌啶醇(Haloperidol, Hal)为DRD2阻滞剂,至今仍为治疗TS的有效药物。但氟哌啶醇的副作用相对较大,常见的副作用有嗜睡、镇静、乏力、头昏、椎体外系反应(如肌张力障碍、静坐不能、帕金森氏病样震颤等),服用数月后,可能出现类帕金森氏病的症状,如震颤、肌肉僵直等,长期应用氟哌啶醇可导致迟发性运动障碍的发生,表现为不自主的刻板运动,并具有持续性。有如此多的副作用,一定程度上限制了该药物的临床应用。宁动颗粒(Ningdong granule, NDG)是临床治疗TS的中药复方制剂,已应用于临床多年,并显示出良好的效果。前期研究表明,NDG可以明显抑制TS症状的发生,但尚未与一线药物氟哌啶醇及临床常用的中西药合用的疗法进行系统的对比观察,遂行此番研究。目的 1.观察宁动颗粒、氟哌啶醇及中西药合用对TS患儿抽动行为的影响。 2.三种治疗方法在副反应上有何异同,以期找出较为安全可靠的治疗方案。方法将符合诊断标准的120(6-18岁)例患儿随机分成NDG、Hal、NDG+Hal及control组各30例。NDG组予宁动颗粒5mg/kg/d;氟哌啶醇,Hal组开始剂量为0.75mg/d,每2个星期增加1.5-3.0mg/d,最高剂量不超过4.5mg/d; NDG+Hal组予以同等剂量NDG与Hal合用,control组给予安慰剂治疗,四组组均治疗八周。参照美国耶鲁综合抽动严重程度量表(Yale Global Tic Severity Scale, YGTSS)分别于治疗的第0,2,4,6,8周进行抽动严重程度量化评估,以评定疗效并记录不良反应。结果 1.一般资料在符合诊断标准的120例TS患儿中有3例患者治疗过程中退出研究,其中control组2例,NDG组1例,在统计分析时将其剔除。两组剩余117例患者在年龄、性别,差异均无统计学意义,具有可比性(P0.05)。 2. YGTSS评分比较与治疗前总抽动、运动性抽动、声音性抽动评分比较,NDG与Hal组治疗后均显著降低(P0.05),NDG+Hal组总抽动,发声性抽动和运动性抽动评分降低更显著,较control组差异具有统计学意义(P0.01)。 3.不良反应 Hal组与NDG+Hal组出现镇静作用、锥体外系反应与QT间期延长的副反应明显高于NDG组与control组(P0.05),NDG+Hal组中出现食欲亢进、头痛的几率明显高于control组(P0.05),Hal组出现焦虑症状的几率较NDG组高(P0.05)。结论 NDG与Hal均能有效改善TS抽动症状。两者合用疗效优单一治疗,但宁动颗粒临床应用副反应小于氟哌啶醇。背景抽动-秽语综合征(Tourette's syndrome, TS)是一种无意识的、无目的的、重复的刻板活动为特征的神经精神性疾病。临床表现为头面、腹部及四肢不自主的抽动,喉部发出奇特叫声或者谩骂不避亲疏为特征。TS有不规则的发作间歇期,有时可因转移注意力而减轻,精神紧张时症状加重,睡眠时症状消失。目前,有关TS的病因及发病原因尚不十分明确,一般认为TS的发病与遗传基因和神经递质系统异常相关,脑外伤、感染、母亲孕期的生活事件等生物、心理及环境因素也不可忽视,也有学者认为该病具有明显的家族聚集性,Leckman等提出遗传因素、其它危险和保护性因素与神经生物学发育因素相互作用导致抽动、强迫及其他抽动相关症状的观点。有关TS病理生理以及神经生化研究,目前认为发病与多巴胺或5-羟色胺及γ-氨基丁酸等神经递质代谢异常相关。或与相应受体、载体功能异常或在大脑纹状体表达异常关系密切。临床治疗TS的中药复方制剂宁动颗粒(Ningdong granule, NDG),已经应用于临床多年,效果良好。前期研究证明,NDG可以明显抑制TS症状,但尚未与一线药物氟哌啶醇及临床常用的中西药合用的疗法进行系统的对比观察,遂行此番研究。目的 1.观察TS患儿血清中DA、5-TH、HVA、5-HIAA及GABA含量的变化,从神经递质角度推断TS的病因 2.观察宁动颗粒对TS患儿血清中DA、5-TH、HVA、5-HIAA及GABA含量的影响。探讨宁动颗粒治疗TS的作用机制。 3.观察NDG与氟哌啶醇的副作用及毒理作用。方法将符合诊断标准的120(6-18岁)例患儿随机分成NDG、Hal、NDG+Hal及control组各30例。NDG组予宁动颗粒5mg/kg/d;氟哌啶醇,Hal组开始剂量为0.75mg/d,每2个星期增加1.5-3.0mg/d,最高剂量不超过4.5mg/d; NDG+Hal组予以同等剂量NDG与Hal合用,control组给予安慰剂治疗,四组组均治疗八周。记录不良反应,治疗后检测肝肾功能,以评价安全性。另募集30例健康查体患儿作为空白对照组。结果 1.一般资料在符合诊断标准的120例TS患儿中有4例患者治疗过程中退出研究,其中control组2例,NDG组1例,Hal组1例,在统计分析时将其剔除。五组剩余146例儿童在年龄、性别,差异均无统计学意义,具有可比性(P0.05)。 2.血清中DA和HVA含量比较五组儿童血清中DA含量在治疗后无明显差异(P0.05),而NDG+Hal (66.25±12.88ng/ml)、NDG (67.07±16.01ng/ml)及Hal (60.88±11.71ng/ml)组中HVA含量明显高于control组(47.13±7.58ng/ml), control组中HVA含量显著高于空白对照组(37.25±5.06ng/ml)(P0.05), NDG+Hal组与NDG组有显著差异(p0.01)。NDG+Hal组中HVA含量亦高于Hal组(p0.05)。 3.血清中5-TH与5-HIAA含量的比较经研究表明,control、NDG、Hal及NDG+Hal四组儿童血清中5-TH与5-HIAA的含量均无显著性差异(P0.05)。Control组血清中5-HIAA含量(11.41±1.61ng/ml)明显高于空白对照组(7.66±1.08ng/m1)P0.05,两组中5-TH无显著性差异(P0.05)。 4.血清中GABA的含量比较 ELSAL结果显示,NDG+Hal (166.22±41.91pmol/ml)、NDG (123.69±38.47pmol/ml)及Hal (113.97±36.23pmol/ml)组中GABA含量明显高于control组(85.63±33.69pmol/ml)(P0.05), NDG+Hal组与NDG组有显著差异(p0.01)。NDG+Hal组中GABA含量亦高于Hal组(p0.05)。control组中GABA含量显著高于空白对照组(52.1655±29.78pmol/ml)(p0.05) 5.肝肾功能检测 Hal与NDG+Hal组血清中ALT含量明显高于control组(p0.05)。结论： 1.TS的发病与DA,5-TH及GABA系统存在联系。 2.经NDG与Hal治疗后,患儿血清中HVA及GABA含量均升高,可推测,NDG与Hal对TS的治疗机制可能是增加了DA的代谢,并直接或间接地兴奋GABA系统。
[Abstract]:background
Tourette's syndrome (TS) is a neuropsychiatric disorder characterized by an unconscious, aimless, repeated stereotyped activity. The clinical manifestation is the head, the involuntary twitch of the abdomen and extremities, the unusual cries or abuses of the larynx, and the irregular intermittence of the.TS. Attentions were relieved, symptoms increased during mental stress, and symptoms disappeared during sleep.
The TS diagnostic criteria are: 1. with multiple motor movements and one or more vocal twitches, sometimes not necessarily at the same time.2. seizures many times a day, usually a array of episodes, continuous or intermittent episodes for more than one year, and the absence of tash intermittence for no more than three months.3.. A significant impact on social, employment, and other important areas of activity.4. onset before the age of 18, the above symptoms of.5. are not directly caused by certain drugs (such as stimulants) or internal medical diseases (such as Huntington chorea or viral encephalitis). Although TS is a mild neuropsychiatric disease, the course of the disease is prolonged, repeated attacks, affecting normal life. And study.
Haloperidol (Hal) is a DRD2 blocker and is still an effective drug for the treatment of TS. However, the side effects of haloperidol are relatively large. The common side effects are somnolence, sedative, fatigue, dizziness, extrapycorp reaction (such as dystonia, sitting cannot, Parkinson's disease like tremor, etc.). After taking a few months, it may appear like Parkinson's disease. Symptoms such as tremor, muscle stiffness and so on, long term use of haloperidol can lead to the occurrence of delayed dyskinesia, characterized by involuntary stereotyped exercise and persistent. There are so many side effects that limit the clinical application of the drug to a certain extent.
Ningdong granule (NDG) is a traditional Chinese medicine compound preparation for the clinical treatment of TS. It has been applied to clinical years and has shown good results. Earlier studies have shown that NDG can obviously inhibit the occurrence of TS symptoms, but it has not been compared with the first-line haloperidol and the commonly used traditional Chinese and Western medicine. This is the study.
objective
1. to observe the effects of Ningdong granule, haloperidol and Chinese and Western Medicine on TiC behavior in children with TS.
2. what is the difference between the three treatments on side effects in order to find a safer and more reliable treatment plan?
Method
120 (6-18 year old) children were randomly divided into NDG, Hal, NDG+Hal and group control, 30 cases of.NDG group were given Ningjing granule 5mg/kg/d, haloperidol, Hal group began to dose 0.75mg/d, increase 1.5-3.0mg/d every 2 weeks, the highest dose was not more than 4.5mg/d. Treatment, the four groups were treated for eight weeks. Yale Global Tic Severity Scale (YGTSS) was used to evaluate the severity of aspiration severity on week 0,2,4,6,8, respectively, to evaluate the efficacy and record adverse reactions.
Result
1. general information
In 120 cases of TS children with diagnostic criteria, 3 cases were withdrawn during the treatment process, of which 2 cases in group control and 1 cases in group NDG were eliminated in statistical analysis. The remaining 117 patients in the two group were not statistically significant in age, sex, and had comparability (P0.05).
2. YGTSS score comparison
Compared with the total aspiration before treatment, motor aspiration and sound aspiration score, the NDG and Hal groups were significantly decreased after treatment (P0.05). The total aspiration of group NDG+Hal, sounding aspiration and motor drive score decreased more significantly, compared with the control group, the difference was statistically significant (P0.01).
3. adverse reactions
Group Hal and group NDG+Hal had a sedative effect. The side effects of the extrapyramidal reaction and the prolongation of QT interval were significantly higher than those in the group NDG and the control group (P0.05). The incidence of hyperactivity in the NDG+Hal group was higher than that of the control group (P0.05), and the risk of anxiety in the Hal group was higher than that in the NDG group (P0.05).
conclusion
Both NDG and Hal can effectively improve TS tic symptoms. The combination of them is effective and single treatment, but the side effect of Ningdong granule is less than haloperidol.
background
Tourette's syndrome (TS) is a neuropsychiatric disorder characterized by an unconscious, aimless, repeated stereotyped activity. The clinical manifestation is the head, the involuntary twitch of the abdomen and extremities, the unusual cries or abuses of the larynx, and the irregular intermittence of the.TS. Attentions were relieved, symptoms increased during mental stress, and symptoms disappeared during sleep.
At present, the causes and causes of TS are still not very clear. It is generally believed that the pathogenesis of TS is associated with genetic and neurotransmitter systems, brain trauma, infection, life events in the mother's pregnancy and other biological, psychological and environmental factors, and some scholars believe that the disease has obvious familial aggregation, Leckman and so on. Factors, other risk and protective factors that interact with neurobiological developmental factors that lead to twitch, compulsion, and other aspiration related symptoms. TS pathophysiology and neurobiochemical studies are currently considered to be associated with abnormal metabolic abnormalities such as dopamine or 5- serotonin and gamma aminobutyric acid. Abnormal body function or abnormal expression in the striatum of the brain is closely related.
Ningdong granule (NDG), a Chinese medicine compound, has been used for many years in clinical treatment of TS, and has been applied for many years. The previous study has proved that NDG can obviously inhibit the symptoms of TS, but it has not been compared with the first-line haloperidol and the commonly used Chinese and Western Medicine.
objective
1. to observe the changes of DA, 5-TH, HVA, 5-HIAA and GABA contents in serum of children with TS, and to deduce the etiology of TS from the angle of neurotransmitters.
2. to observe the effect of Ningdong Granule on the contents of DA, 5-TH, HVA, 5-HIAA and GABA in serum of children with TS, and to explore the mechanism of Ningdong granule in treating TS.
3. to observe the side effects and toxicological effects of NDG and haloperidol.
Method
120 (6-18 year old) children were randomly divided into NDG, Hal, NDG+Hal and group control, 30 cases of.NDG group were given Ningjing granule 5mg/kg/d, haloperidol, Hal group began to dose 0.75mg/d, increase 1.5-3.0mg/d every 2 weeks, the highest dose was not more than 4.5mg/d. Treatment, the four groups were treated for eight weeks. The adverse reactions were recorded, the liver and kidney function was detected after treatment, and the safety was evaluated. 30 cases of healthy children were collected as the blank control group.
Result
1. general information
In 120 cases of TS children with diagnostic criteria, 4 patients withdrew from the treatment process, of which 2 cases in group control, 1 in group NDG and 1 in group Hal were eliminated in statistical analysis. The remaining 146 children in the five group were not statistically significant in age, sex, and had comparability (P0.05).
Comparison of the content of DA and HVA in 2. serum
There was no significant difference in the serum DA content between the five groups (P0.05), while NDG+Hal (66.25 + 12.88ng/ml), NDG (67.07 + 16.01ng/ml) and Hal (60.88 + 11.71ng/ml) groups were significantly higher than the control group (47.13 + 7.58ng/ml), and the content of the control group was significantly higher than that in the blank control group (37.25 +). Significant difference (P0.01) in group.NDG+Hal, the content of HVA was also higher than that in group Hal (P0.05).
Comparison of the content of 5-TH and 5-HIAA in 3. serum
The results showed that there was no significant difference between the serum levels of 5-TH and 5-HIAA in the four groups of children with control, NDG, Hal and NDG+Hal (P0.05), the content of 5-HIAA (11.41 + 1.61ng/ml) in the serum of.Control group was significantly higher than that of the blank control group (7.66 + 1.08ng/m1) P0.05, and there was no significant difference in the two groups.
Comparison of the content of GABA in 4. serum
The results of ELSAL showed that the content of GABA in NDG+Hal (166.22 + 41.91pmol/ml), NDG (123.69 + 38.47pmol/ml) and Hal (113.97 + 36.23pmol/ml) group was significantly higher than that of the control group (85.63 + 33.69pmol/ml), and the content of the NDG+Hal group was significantly higher than that of the empty group. White control group (52.1655 + 29.78pmol/ml) (P0.05)
5. liver and kidney function test
Serum ALT levels in group Hal and group NDG+Hal were significantly higher than those in group control (P0.05).
Conclusion:
The incidence of 1.TS is associated with the DA, 5-TH and GABA systems.
2. after the treatment of NDG and Hal, the serum levels of HVA and GABA increased in the children. It is possible to speculate that the mechanism of NDG and Hal for TS may be to increase the metabolism of DA and to stimulate the GABA system directly or indirectly.
【学位授予单位】：山东大学
【学位级别】：博士
【学位授予年份】：2012
【分类号】：R749.94

【参考文献】