宁动颗粒治疗抽动—秽语综合征的临床及分子机制研究
|
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(P>0.05)。
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(P<0.05),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(P<0.01)。
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(P<0.05),NDG+Hal组中出现食欲亢进、头痛的几率明显高于control组(P<0.05),Hal组出现焦虑症状的几率较NDG组高(P<0.05)。
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(P>0.05)。
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(P>0.05),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)(P<0.05), NDG+Hal组与NDG组有显著差异(p<0.01)。NDG+Hal组中HVA含量亦高于Hal组(p<0.05)。
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(P>0.05)。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)P<0.05,两组中5-TH无显著性差异(P>0.05)。
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)(P<0.05), NDG+Hal组与NDG组有显著差异(p<0.01)。NDG+Hal组中GABA含量亦高于Hal组(p<0.05)。control组中GABA含量显著高于空白对照组(52.1655±29.78pmol/ml)(p<0.05)
5.肝肾功能检测
Hal与NDG+Hal组血清中ALT含量明显高于control组(p<0.05)。
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。
Background
Tourette's syndrome (TS) is a neuropsychiatric disorder characterized by stereotypic, involuntary, purposeless and repetitive movements. The motor tics include headshakes, violent clonic tics consisting of thrusting head jerks and orofacial tics such as facial grimacing, eye blinking and throat clearing. It dosen't occur regularity. The symptoms will aggravate after actuation, vanish after sleep, and decrease by divert attention.
The diagnostic criteria of TS are1. The character of TS are motor tics and vocal tics, the two symptoms often occur not at the same time.2. Tics break out several times every day. It can last more than1year, and the period with no tics less than3months.3. The tics can cause conspicuouse restlessness, which can influence social intercourse, employment and some other social activities.4. It often occur before the age of18years.5. The symptoms are not cause by some drugs (such as stimulant), and morbus internus (such as Humtington's chorea and viral encephalitis).
As the inhibitor of DRD2, Haloperidol (Hal) is regarded as the effective medicine in treatment of TS. Although haloperidol is efficacious for the treatment of TS, a very high proportion of patients eventually discontinue the therapy because of the side effects. It's side effects are concerned with the dosage. The commen side effects include lethargy, sedation, debilitation, dizziness and extrapyramidal symptoms (such as dysmyotonia, akathisia, thrill like Parkinson's disease, et al). Tardive dyskinesia will occur after take this medicine for a long time. It will appear heteronomous stereotypy behaviors. Such side effects limited the usage of haloperidol.
Ningdong granule (NDG), a TCM preparation, has been revealed to tranquilize and allay excitement in Tourette syndrome (TS). However, the present data were limited for lack of a double-blind and control trial, and the mechanism of NDG on TS children also remains obscure. This study therefore aimed to evaluate NDG's short-term efficacy and safety in the treatment of TS children as an alternative medication.
Objective
1. To evaluate the efficiency of NDG and Haloperidol.
2. To evaluate the differences in side effects of the three treatments, in order to identify more safe and reliable treatment options.
Methods
120children (6-18years) were equally divided into NDG group (n=30), Hal group (n=30), NDG+Hal (n=30) and control group(n=30) by a randomized computer-generated code. NDG group were assigned to receive NDG5mg/kg/day for8weeks. Patients in the haloperidol group were started at a dose of0.75mg/d and increased in1.5-3.0mg/day increments every2weeks to a maximum tolerated dose of4.5mg/d.;NDG+Hal group were assigned both of them. Control group was given placebo.As previously noted, the Yale Global Tic Severity Score (YGTSS), We rated the scores at the first clinic visit as the baseline scores and then every2weeks vocal for a total of8weeks of follow-up. Side effects were systematically recorded.
Results
1. Study population
One hundred and twenty children were recruited to participate in this study. One patient in the control group and two patients in the NDG group missed the full course of treatment, so they were excluded from this analysis. The remaining subjects in the four groups were similar with regard to age, gender.
2. Comparison of YGTSS tic scores
Compared with YGTSS total tic score, YGTSS motor tic score and YGTSS vocal tic score at baseline, the scores of NDG and Hal groups at end point reduced significantly (P<0.05). Compared with control group, the scores of NDG+Hal group reduced more significantly (P<0.01)
3. Side effects control
The incidence of sedation, extrapyramidal and QT prolongation reactions in Hal group and NDG+Hal group were lower than that in NDG and control group (P<0.05). The incidence of nausea and headache reactions in NDG+Hal group were lower than that in control group (P<0.05). The incidence of anxiety in NDG+Hal group were lower than that in NDG group (P<0.05).
Conclusion
Both NDG and Hal could improve the syndrome of tics in TS, morewhile, NDG+Hal have better effect on TS. But the NDG have less side effects than Hal.
Background
Tourette's syndrome (TS) is a neuropsychiatric disorder characterized by stereotypic, involuntary, purposeless and repetitive movements. The motor tics include headshakes, violent clonic tics consisting of thrusting head jerks and orofacial tics such as facial grimacing, eye blinking and throat clearing. It dosen't occur regularity. The symptoms will aggravate after actuation, vanish after sleep, and decrease by divert attention.
At present, the etiology and causes of the TS is not yet very clear, is generally believed that the pathogenesis of TS and genetic and neurological neurotransmitter system abnormalities, traumatic brain injury, infection, and the mother during pregnancy, life events and other biological, psychological and environmental factors can not be ignoredSome scholars believe that the disease has a significant familial aggregation, Leckman genetic factors, other risk and protective factors and the neurobiology of developmental factors interact to cause twitching, coercion and other tic-related symptoms of view. For TS pathophysiology and neurochemistry, that incidence with dopamine or5-hydroxytryptamine and y-aminobutyric acid neurotransmitter metabolic abnormalities. Or with the corresponding receptors, the vector function abnormalities or anomalies are closely related to expression in the striatum.
Ningdong granule (NDG), a TCM preparation, has been revealed to tranquilize and allay excitement in Tourette syndrome (TS). However, the present data were limited for lack of a double-blind and control trial, and the mechanism of NDG on TS children also remains obscure. This study therefore aimed to evaluate NDG's short-term efficacy and safety in the treatment of TS children as an alternative medication.
Objective
To evaluate the efficiency, safety, and possible mechanism of NDG.
Observed side effects and toxicological effects of NDG and haloperidol
Methods
120children (6-18years) were equally divided into NDG group (n=30), Hal group(n=30), NDG+Hal(n=30) and control group (n=30) by a randomized computer-generated code. NDG group were assigned to receive NDG5mg/kg/day for8weeks. Patients in the haloperidol group were started at a dose of0.75mg/d and increased in1.5-3.0mg/day increments every2weeks to a maximum tolerated dose of4.5mg/d;NDG+Hal group were assigned both of them. Control group was given placebo. Mean while liver and renal tests were monitored as well.
Results
1. Study population
One hundred and twenty children were recruited to participate in this study. four patient missed the full course of treatment, so they were excluded from this analysis. The remaining subjects in the four groups were similar with regard to age, gender.
2. Contents of DA and HVA in sera by ELISA
The content of DA in sera was no significant different in the five groups (P>0.05). After treatment the HVA content in the NDG+Hal (66.25±12.88ng/ml)、NDG (67.07±16.01ng/ml)and Hal group (60.88±11.71ng/ml) were increased in different degree compared with the control group (47.13±7.58ng/ml)(P<0.05), The HVA content were more higher in the NDG+Hal group than in the NDG and Hal group (P<0.01, P<0.05).
3. Contents of5-TH and5-HIAA in sera by ELISA
The content of5-TH and5-HIAA in sera were no significant differents in the four groups (P>0.05)
4. Contents of GABA in sera by ELISA
After treatment, the GABA content in the NDG+Hal (166.22±41.91pmol/ml)、 NDG(123.69±38.47pmol/ml)and Hal group(113.97±36.23pmol/ml) were increased in different degree compared with the control group (85.63±33.69pmol/ml)(P<0.05), The content of GABA were more higher in the NDG+Hal group than in the NDG and Hal group (P<0.01, P<0.05).
5-Liver and kidney function tests
The content of ALT in sera were higher were more higher in the NDG+Hal group and Hal group than control group (P<0.05)
Conclusion
After NDG and Hal treatment, serum levels of HVA and GABA content were increased, it can be inferred that NDG and Hal therapeutic mechanism of TS may be an increase of DA metabolism, and excited the GABA system.
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(P>0.05)。
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(P<0.05),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(P<0.01)。
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(P<0.05),NDG+Hal组中出现食欲亢进、头痛的几率明显高于control组(P<0.05),Hal组出现焦虑症状的几率较NDG组高(P<0.05)。
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(P>0.05)。
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(P>0.05),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)(P<0.05), NDG+Hal组与NDG组有显著差异(p<0.01)。NDG+Hal组中HVA含量亦高于Hal组(p<0.05)。
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(P>0.05)。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)P<0.05,两组中5-TH无显著性差异(P>0.05)。
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)(P<0.05), NDG+Hal组与NDG组有显著差异(p<0.01)。NDG+Hal组中GABA含量亦高于Hal组(p<0.05)。control组中GABA含量显著高于空白对照组(52.1655±29.78pmol/ml)(p<0.05)
5.肝肾功能检测
Hal与NDG+Hal组血清中ALT含量明显高于control组(p<0.05)。
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。
Background
Tourette's syndrome (TS) is a neuropsychiatric disorder characterized by stereotypic, involuntary, purposeless and repetitive movements. The motor tics include headshakes, violent clonic tics consisting of thrusting head jerks and orofacial tics such as facial grimacing, eye blinking and throat clearing. It dosen't occur regularity. The symptoms will aggravate after actuation, vanish after sleep, and decrease by divert attention.
The diagnostic criteria of TS are1. The character of TS are motor tics and vocal tics, the two symptoms often occur not at the same time.2. Tics break out several times every day. It can last more than1year, and the period with no tics less than3months.3. The tics can cause conspicuouse restlessness, which can influence social intercourse, employment and some other social activities.4. It often occur before the age of18years.5. The symptoms are not cause by some drugs (such as stimulant), and morbus internus (such as Humtington's chorea and viral encephalitis).
As the inhibitor of DRD2, Haloperidol (Hal) is regarded as the effective medicine in treatment of TS. Although haloperidol is efficacious for the treatment of TS, a very high proportion of patients eventually discontinue the therapy because of the side effects. It's side effects are concerned with the dosage. The commen side effects include lethargy, sedation, debilitation, dizziness and extrapyramidal symptoms (such as dysmyotonia, akathisia, thrill like Parkinson's disease, et al). Tardive dyskinesia will occur after take this medicine for a long time. It will appear heteronomous stereotypy behaviors. Such side effects limited the usage of haloperidol.
Ningdong granule (NDG), a TCM preparation, has been revealed to tranquilize and allay excitement in Tourette syndrome (TS). However, the present data were limited for lack of a double-blind and control trial, and the mechanism of NDG on TS children also remains obscure. This study therefore aimed to evaluate NDG's short-term efficacy and safety in the treatment of TS children as an alternative medication.
Objective
1. To evaluate the efficiency of NDG and Haloperidol.
2. To evaluate the differences in side effects of the three treatments, in order to identify more safe and reliable treatment options.
Methods
120children (6-18years) were equally divided into NDG group (n=30), Hal group (n=30), NDG+Hal (n=30) and control group(n=30) by a randomized computer-generated code. NDG group were assigned to receive NDG5mg/kg/day for8weeks. Patients in the haloperidol group were started at a dose of0.75mg/d and increased in1.5-3.0mg/day increments every2weeks to a maximum tolerated dose of4.5mg/d.;NDG+Hal group were assigned both of them. Control group was given placebo.As previously noted, the Yale Global Tic Severity Score (YGTSS), We rated the scores at the first clinic visit as the baseline scores and then every2weeks vocal for a total of8weeks of follow-up. Side effects were systematically recorded.
Results
1. Study population
One hundred and twenty children were recruited to participate in this study. One patient in the control group and two patients in the NDG group missed the full course of treatment, so they were excluded from this analysis. The remaining subjects in the four groups were similar with regard to age, gender.
2. Comparison of YGTSS tic scores
Compared with YGTSS total tic score, YGTSS motor tic score and YGTSS vocal tic score at baseline, the scores of NDG and Hal groups at end point reduced significantly (P<0.05). Compared with control group, the scores of NDG+Hal group reduced more significantly (P<0.01)
3. Side effects control
The incidence of sedation, extrapyramidal and QT prolongation reactions in Hal group and NDG+Hal group were lower than that in NDG and control group (P<0.05). The incidence of nausea and headache reactions in NDG+Hal group were lower than that in control group (P<0.05). The incidence of anxiety in NDG+Hal group were lower than that in NDG group (P<0.05).
Conclusion
Both NDG and Hal could improve the syndrome of tics in TS, morewhile, NDG+Hal have better effect on TS. But the NDG have less side effects than Hal.
Background
Tourette's syndrome (TS) is a neuropsychiatric disorder characterized by stereotypic, involuntary, purposeless and repetitive movements. The motor tics include headshakes, violent clonic tics consisting of thrusting head jerks and orofacial tics such as facial grimacing, eye blinking and throat clearing. It dosen't occur regularity. The symptoms will aggravate after actuation, vanish after sleep, and decrease by divert attention.
At present, the etiology and causes of the TS is not yet very clear, is generally believed that the pathogenesis of TS and genetic and neurological neurotransmitter system abnormalities, traumatic brain injury, infection, and the mother during pregnancy, life events and other biological, psychological and environmental factors can not be ignoredSome scholars believe that the disease has a significant familial aggregation, Leckman genetic factors, other risk and protective factors and the neurobiology of developmental factors interact to cause twitching, coercion and other tic-related symptoms of view. For TS pathophysiology and neurochemistry, that incidence with dopamine or5-hydroxytryptamine and y-aminobutyric acid neurotransmitter metabolic abnormalities. Or with the corresponding receptors, the vector function abnormalities or anomalies are closely related to expression in the striatum.
Ningdong granule (NDG), a TCM preparation, has been revealed to tranquilize and allay excitement in Tourette syndrome (TS). However, the present data were limited for lack of a double-blind and control trial, and the mechanism of NDG on TS children also remains obscure. This study therefore aimed to evaluate NDG's short-term efficacy and safety in the treatment of TS children as an alternative medication.
Objective
To evaluate the efficiency, safety, and possible mechanism of NDG.
Observed side effects and toxicological effects of NDG and haloperidol
Methods
120children (6-18years) were equally divided into NDG group (n=30), Hal group(n=30), NDG+Hal(n=30) and control group (n=30) by a randomized computer-generated code. NDG group were assigned to receive NDG5mg/kg/day for8weeks. Patients in the haloperidol group were started at a dose of0.75mg/d and increased in1.5-3.0mg/day increments every2weeks to a maximum tolerated dose of4.5mg/d;NDG+Hal group were assigned both of them. Control group was given placebo. Mean while liver and renal tests were monitored as well.
Results
1. Study population
One hundred and twenty children were recruited to participate in this study. four patient missed the full course of treatment, so they were excluded from this analysis. The remaining subjects in the four groups were similar with regard to age, gender.
2. Contents of DA and HVA in sera by ELISA
The content of DA in sera was no significant different in the five groups (P>0.05). After treatment the HVA content in the NDG+Hal (66.25±12.88ng/ml)、NDG (67.07±16.01ng/ml)and Hal group (60.88±11.71ng/ml) were increased in different degree compared with the control group (47.13±7.58ng/ml)(P<0.05), The HVA content were more higher in the NDG+Hal group than in the NDG and Hal group (P<0.01, P<0.05).
3. Contents of5-TH and5-HIAA in sera by ELISA
The content of5-TH and5-HIAA in sera were no significant differents in the four groups (P>0.05)
4. Contents of GABA in sera by ELISA
After treatment, the GABA content in the NDG+Hal (166.22±41.91pmol/ml)、 NDG(123.69±38.47pmol/ml)and Hal group(113.97±36.23pmol/ml) were increased in different degree compared with the control group (85.63±33.69pmol/ml)(P<0.05), The content of GABA were more higher in the NDG+Hal group than in the NDG and Hal group (P<0.01, P<0.05).
5-Liver and kidney function tests
The content of ALT in sera were higher were more higher in the NDG+Hal group and Hal group than control group (P<0.05)
Conclusion
After NDG and Hal treatment, serum levels of HVA and GABA content were increased, it can be inferred that NDG and Hal therapeutic mechanism of TS may be an increase of DA metabolism, and excited the GABA system.
引文
1. Cortese S, Lecendreux M, Bernardo BD, et al. Attention-deficit/hyperactivity disorder, Tourette's syndrome, and restless legs syndrome:The iron hypothesis. Med Hypotheses,2008; 70:1128-1132.
2. Peterson BS, Leckman JF. The temporal dynamics of tics in Gilles de la Tourette syndrome. Biol Psychiatry,1998; 44:1337-1348.
3. Grimaldi BL. The central role of magnesium deficiency in Tourette's syndrome: causal relationships between magnesium deficiency, altered biochemical pathways and symptoms relating to Tourette's syndrome and several reported comorbid conditions. Med Hypotheses,2002; 58:47-60.
4.金嵘,郑荣远,黄文武等.浙江省温州地区7-16岁人群Tourette综合征患病率调查.中华流行病学杂志,2004;25:131-133.
5.刘智胜主编.小儿多发性抽动症.北京：人民卫生出版社,2002:240.4. Leckman JF. Tourette's syndrome. Lancet 2002;360:1577-86.
7. Yao Y, Ma HW. Neurobiology development of Tourette syndrome. Foreign Med Sci (Pediatr),2005; 32:137-140.
8. Leckman JF, Riddle MA, Hardin MT, et al. The Yale Global Tic Severity Scale: initial testing of a clinician-rated scale of tic severity. J Am Acad Child Adolesc Psychiatry 1989; 28:566-573.
9. Roselei F, Jardel GV, Caroline W, et al. Valeriana officinalis does not alter the orofacial dyskinesia induced by haloperidol in rats:Role of dopamine transporter. Neuro-Psychopharmacology & Bio Psychiatry,2007; 31:1478-1486.
10..Saldana M, Bonastre M, Aguilar E, et al. Differential nigral expression of Bcl-2 protein family in chronically haloperidol and clozapine-treated rats:Role in neurotoxicity and stereotyped behavior. Exp Neurol,2007; 203:302-308.
11. Creese I, Burt DR, Snyder SH. Dopamine Receptor Binding Predicts Clinical and Pharmacological Potencies of Antischizophrenic Drugs. SCIENCE,1976; 192: 481-483.
12. Yoo HK, Kim JY, Kim CY. A Pilot Study of Aripiprazole in Children and Adolescents with Tourette's Disorder. J Child Adolesc Psychopharmacol,2006; 16:505-506.
13. Lv H, Li A, Ma H, et al. Effects of Ningdong granule on the dopamine system of Tourette's syndrome rat models.
14. Jijun L, Zaiwang L, Anyuan L, Shuzhen W, Fanghua Q, Lin Z, Hong L.Abnormal expression of dopamine and serotonin transporters associated with the pathophysiologic mechanism of Tourette syndrome. Neurol India.2010 Jul-Aug;58(4):523-9.
15. Li AY, Cong S, Lu H, Li JJ, Zhao L. Clinical observation on treatment of Tourette syndrome by integrative medicine.Chin J Integr Med.2009 Aug;15(4):261-5. Epub 2009 Aug 18.
16. Leckman JF, Riddle MA, Hardin MT, et al. The Yale Global Tic Severity Scale: initial testing of a clinician-rated scale of tic severity. J Am Acad Child Adolesc Psychiatry 1989; 28:566-573.
17.王文革,孟宪军,汪受传.汪受传治疗小儿多发性抽动症的经验.辽宁中医杂志,2004;31：182-181.
18.朱先康,韩新民,张永春.息风豁痰法治疗小儿多发性抽动症30例.河北中医,2005；27：96-97.
19.吴上彬,马融。马融治疗小儿多发性抽动症经验.辽宁中医杂志,2007;34:396-397
20.刘弼臣,王俊宏,陈丹等.中医药治疗抽动秽语综合征临床研究述评。中国医学理论与实践,2001;5:590-592.
21.王志学,李安源.李安源教授治疗小儿多发性抽动症的学术思想.云南中医中药杂志2011；32(8)：11-13
22.李安源,吕红,孙蓉,吕丽莉,张希林,王平.宁动颗粒治疗抽动秽语综合征的药效学研究.中国中西医结合儿科学.2009;1(1):48-50
23. Singer HS, Brown J, Quaskey S, Rosenberg LA, Mellits ED,Denckla MB. The treatment of attention-deficit hyperactivity disorder in Tourette's syndrome:a double-blind placebo-controlled study with clonidine and desipramine. Pediatrics, 1995; 95:74-81
24. Eggers C, Rothenberger A, Berghaus U. Clinical and neurobiological findings in children suffering from tic disease following treatment with tiapride. Eur Arch Psychiatry Neurol Sci,1988; 237:223-229.
25. Shapiro E, Shapiro AK, Fulop G, et al. Controlled study of haloperidol, pimozide and placebo for the treatment of Gilles de la Tourette's syndrome. Arch Gen Psychiatry,1989; 46:722-730.
26. Sallee FR, Nesbitt L, Jackson C, Sine L, Sethuraman G. Relative efficacy of haloperidol and pimozide in children and adolescents with Tourette's disorder. Am J Psychiatry,1997; 154:1057-1062.
27. Shapiro AK, Shapiro E. Controlled study of pimozide vs placebo in Tourette's syndrome. J Am Acad Child Psychiatry 1984; 23:161-173.
28. Sallee FR, Kurlan R, Goetz CG, et al. Ziprasidone treatment of children and adolescents with Tourette's syndrome:a pilot study.J Am Acad Child Adolesc Psychiatry,2000; 39:292-399.
29. Bruggeman R, van der Linden C, Buitelaar JK, et al. Risperidone versus pimozide in Tourette's disorder:a comparative double-blind parallel-group study. J Clin Psychiatry 2001; 62:50-56.
30. Robertson MM, Schnieden V, Lees AJ. Management of Gilles de la Tourette syndrome using sulpiride. Clin Neuropharmacol 1990; 13:229-235.
31. George MS, Trimble MR, Robertson MM. Fluvoxamine and sulpiride in comorbid obsessive-compulsive disorder and Gilles de la Tourette syndrome. Hum Psychopharmacol 1993; 8:327-334.
32. Shapiro AK, Shapiro E:Controlled study of pimozide vs. placebo in Tourette syndrome. J Am Acad Child Psychiatry,1984; 23:161-173.
33. Dion Y, Annable L, Sandor P, et al. Risperidone in the treatment of Tourette syndrome:a double-blind, placebo-controlled trial. J Clin Psychopharmacol,2002; 22:31-39.
34. Scahill L, Leckman JF, Schultz RT, et al. A placebo-controlled trial of risperidone in Tourette syndrome. Neurology,2003; 60:1130-1135.
35. Bruun RD, Budman CL. Risperidone as a treatment for Tourette's syndrome. J Clin Psychiatry.1996; 57(1):29-31.
36. Leckman JF, Hardin MT, Riddle MA, Stevenson J, Ort SI, Cohen DJ. Clonidine treatment of Tourette's syndrome. Arch Gen Psychiatry,1991; 48:324-28.
37. Tourette Syndrome Study Group. Treatment of ADHD in children with tics:a randomized controlled trial. Neurology 2002; 58:527-536.
38. Shapiro AK, Shapiro E. Controlled study of pimozide vs placebo in Tourette's syndrome. J Am Acad Child Psychiatry 1984; 23:161-173.
39. Zhao L, Li AY, Lv H, Liu FY, Qi FH. Traditional Chinese medicine Ningdong granule:the beneficial effects in Tourette's disorder. J Int Med Res.2010 Jan-Feb;38(1):169-75.
1. Wen-Juh Hwang, Wei-Jen Yao et al.[99mTc]TRODAT-1/[123I]IBZM SPECT studies of the dopaminergic system in Tourette syndrome, Psychiatry Research: Neuroimaging 162 (2008) 159-166.
2. Kano Y, Ohta M, Nagai Y, et al. A family study of Tourette syndrome in Japan. Am J Med Genet,2001,28(4):238
3. Freeman RD, Fast DK, Burd L, et al. Aninter national perspective on Tourette syndrome:selected findings from 3500 individuals in 22 coutries. Dev Med Child Neurol,2000,42(7):436.
4. 刘智胜Tourette综合征的问题与回答.实用儿科临床杂志[J],1998,13(6)：347.
5. 刘慎如.抽动-秽语综合征38例综合报告.中华儿科杂志[J],1996,24(3)：81-85.
6. Leckman JF, Cohen DJ. Tourette's Syndrome-Tics, Obsessions, Compulsions. New York, John Wiley&Sons,Inc,1999.155.
7. Emna SJ. Neuroleptics:Neurochemical Behavioral and Clinical Perspectives. New York:Raven Press New York,1983,65.
8. Roger L, Albin,Jonathan W. Mink. Recent advances in Tourette syndrome research. tRENDS in neurosciences:2006,29(3):175-182.
9. Comings DE. Blood serotonin and tryplophan in Tourette syndrome.[J] Am J Med Genet,1990,36:418-430.
10. Mihara K, Kondo T, Yasui-Furukori N, et al. Dopamine D2 receptor gene polymorphisms and clinical response to selective dopamine receptor antagonists. International Congress Series,2002,1244(1):77-83.
11. Aw aad Y, M ichon AM, M inarik S. Use of levetiracetam to treat tics in children and adolescents with Tourette syndrome[J]. MovDiscord,2005,20(6): 714
12. Harvey S. Singer, Christina Morris' Marco Grados. Glutamatergicmodulatorytherapy for Tourettesyndrome.Medical HypothesesVolume 74, Issue 5, May 2010, Pages 862-867.
13. Tian Y, Gunther JR, Liao IH, Liu D, Ander BP, Stamova BS, Lit L, Jickling GC, Xu H, Zhan X, Sharp FR.GABA-and acetylcholine-related gene expression in blood correlate with tic severity and microarray evidence for alternative splicing in Tourette syndrome:a pilot study. Brain Res.2011 Mar 24;1381:228-36. Epub 2011 Jan 15.
14. Freeman RD,Fast DK,Burd L,et al.An international perspective on Tourette Syndrom:selected findings from 3500 individuals in 22 countries[J].Dev Med Child Neural,2000,42:436-447.
15.李继君.李安源教授治疗多发性抽动症经验,中医杂志[J].2009,10(1)15-17.
16.李安源,马瑞萍等.宁动颗粒治疗抽动-秽语综合症临床研究.山东中医药大学学报[J],2008,32(1)：33-35.
17.[9]马瑞萍,李安源.养阴柔肝法论治小儿抽动-秽语综合征.云南中医学院学报[J],2005,28(4)：58.
18.[10]李继君,王淑臻,李安源等.126例抽动-秽语综合征患儿中医证候学研究.中医杂志[J].2010.
19.刘智胜主编.小儿多发性抽动症.北京：人民卫生出版社,2002：240.
20. Singer HS, Hahn IH, Moran TH. Abnormal dopamine uptake sites in postmortem striatum from patients with Tourette's syndrome. Ann Neurol,1991; 30:558-62.
21. Emna SJ. Neuroleptics. Neurochemical Behavioral and Clinical Perspectives. Raven Press New York,1983:65.
22. Emilien G, Maloteaux JM, Geurts M, et al. Dopamine receptors-physiological understanding to therapeutic intervention potential. Pharmacol Ther,1999; 84: 133-156.
23. Singer HS, Hahn IH, Moran TH. Abnormal dopamine uptake sites in postmortem striatum from patients with Tourette's syndrome. Ann Neurol,1991; 30:558-62.
24. Wong DF, Bras JR, Singer HS. Mechanisms of Dopaminergic and Serotonergic Neurotransmission in Tourette Syndrome:Clues from an In Vivo Neurochemistry Study with PET. Neuropsychopharmacology,2008; 33: 1239-1251.
25. Jijun L, Zaiwang L, Anyuan L, Shuzhen W, Fanghua Q, Lin Z, Hong L. Abnormal expression of dopamine and serotonin transporters associated with the pathophysiologic mechanism of Tourette syndrome. Neurol India.2010,58: 523-529.
26. Liu X, Wang Y, Li D, Ju X (2008) Transplantation of rat neural stem cells reduces stereotypic behaviors in rats after intrastriatal microinfusion of Tourette syndrome sera. Behav Brain Res 186:84-90.
27.隆红艳,张骠;,谈碹忠等.静安口服液对小儿多发性抽动症模型大鼠抽动行为及脑组织、血浆5-羟色胺含量的影响.中国中医基础医学杂志2010;(8)：675-676,695
28. Sallee FR. Gilbert DL. Vinks AA, ct al. Pharmaoxtyrurnics of ziprasidon e in childTen and addescents.-impact on dopmnine transmissionlj J. j Am Aead Child Adolesc Psychiatry,2003,42(8):902-907.
29.赵春玲,李蔷华.中药熄风祛痰汤治疗小儿多发性抽动症60例[J]. 中医儿科杂志,2006；2(1)：33-34.
30.曾红英.针药合治抽动—秽语综合征30例[J].辽宁中医杂志,2003,(30);665-666.
31. Ju GC. Progress in studies of pharmacological activities and clinical applications of preparations of Gastrodia elata Blume. Chin Phar,2008; 17: 64-66.
32. Yingfang Tian, Joan R. Gunther, Isaac H. Liao, Dazhi Liu, Bradley P. Ander, Boryana S. Stamova, Lisa Lit, Glen C. Jickling, Huichun Xu, Xinhua Zhan, Frank R. Sharp. GABA- and acetylcholine-related gene expression in blood correlate with tic severity and microarray evidence for alternative splicing in Tourette syndrome:A pilot study. Brain research.2011; 28-236.
33. Roselei F, Jardel GV, Caroline W, et al. Valeriana officinalis does not alter the orofacial dyskinesia induced by haloperidol in rats:Role of dopamine transporter. Neuro-Psychopharmacology & Bio Psychiatry,2007; 31: 1478-1486.
34. Jijun L, Zaiwang L, Anyuan L, Shuzhen W, Fanghua Q, Lin Z, Hong L.Abnormal expression of dopamine and serotonin transporters associated with the pathophysiologic mechanism of Tourette syndrome. Neurol India.2010 Jul-Aug;58(4):523-9.
35. Li AY, Cong S, Lu H, Li JJ, Zhao L. Clinical observation on treatment of Tourette syndrome by integrative medicine.Chin J Integr Med.2009 Aug;15(4):261-5. Epub 2009 Aug 18.
36. Sandor P. Pharmacological management of tics in patients with TS. J Psycholinguist Res,2003; 55:41-48.
37. Fachinetto R, Villarinho JG, Wagner C, et al. Valeriana officinalis does not alter the orofacial dyskinesia induced by haloperidol in rats:Role of dopamine transporter. Prog NeuroPsychopharmacology & Biol Psychiatry,2007; 31: 1478-1486.
38.艾小文,赵玉屏.中西药治疗儿童抽动-秽语综合征疗效比较.中华中医药杂志,2005;20：746-747.
39. Dustin YY, Colin DG, James FL, et al. Frontal dopaminergic abnormality in Tourette syndrome:A postmortem analysis. J Neurol Sci,2007; 255:50-56.
40. Agnes L, Auclair & Alexandra Galinier. Putative antipsychotics with pronounced agonism at serotonin 5-HT1A and partial agonist activity at dopamine D2 receptors disrupt basal PPI of the startle reflex in rats. Psychopharmacology,2007; 193:45-54.
41. Yoo HK, Kim JY, Kim CY. A Pilot Study of Aripiprazole in Children and Adolescents with Tourette's Disorder. J Child Adolesc Psychopharmacol,2006; 16:505-506.
42. L iu J Mori A. Antioxidant and free radical scavenging activities of Gastrodia elata BL. and Uncaria rhynchophylla (Miq.) Jacks [J]. Neuropharmacology, 1992,31(12):1287.
43. L iu J Mori A. Antioxidant and pro-oxidant activities of phydroxybenzyl alcohol and vanillin:effects on free radicals, brain peroxidation and degradation of benzoate, deoxyribose, amino acids and DNA [J]. Neuropharmacology.1993 32(7):659
44. Hsieh C L, Chang S Y. Cheng K S, et al. Anticonvulsive and free radical scavenging activities of Gastrodia elata BL in kainic acid-treated rats [J]. Am J Chin Med,2001,29(2):331.
45. Hsieh C L, Chang C H, Chiang S Y, et al. Anticonvulsive and free radical scavenging activities of vanillyl alcohol in ferric chloride-induced epileptic seizures in Sprague-Dawley rats [J].Life Sci,2000,67(10):1185.
46. H a J H, Lee D U, Lee J T et al.4-Hydroxybenzaldehyde from Gastrodia elata BI. is active in the antioxidation and GABAergic neurom odulation of the rat brain[J]. J EthnophamacoL,2000,73(1-2):329.
47. K im H j, Moom K D, Oh S Y, et al. Ether fraction of methanol extracts of Gastrodia elata, a traditional medicinal herb,protects against k a in ic acid-induced neuronal damage in the mouse hippocampus[J]. Neurosci Lett, 2001,314(1-2):65.]
48. H ssieh C L, Chen C L, Tang N Y, et al. Gastrodia elata BL mediates the suppression of nNOS and microglia activation to protect against neuronal damage in k a in ic acid-treated rats[J]. Am J Chin Med,2005,33(4):599.
49. Lee Y S, H a J H, Yong C S, et al. Inhibitory effects of constituents of Gastrodia elata BL on glutamate-induced apoptosis in IMR-32 human neuroblastoma cells[J]. Arch Pharm Res,1999,22 (4):404.
50. TANG QINGXIU, CHENG GUOQUAN, ZHANG XIAOWEN. Effects of Polysaccharides from Radix Codonopsis and Dangshenjing on Immune Function in C57BL/6 Mice [J]. Endemic Diseases Bulletin,1996, 11(supp.): 1-3 (in Chinese).
51. LI YAN, SUN PING, LIU XIA, et al. Extraction, Determination and effect on Immune Function of Polysaccharides from Codonopsis clematidea (schrenk) Clarke [J]. Chinese Traditional Patent Medicine,2005,27(7):839-840(in Chinese).
52. CAO LI, LUO CHONGNIAN, BIAN QINGYA, et al. Promotive effect of Codonopsis pilosula polysaccharide on IL-2 inductive activity and lymphocyte proliferative reaction in chickens [J]. Journal of Traditional Chinese Veterinary Medicine,2004,1:3-4 (in Chinese).
53. YANG GUANG, LI FASHENG, LIU HUI, et al. Effects of Polysaccharides from Radix Codonopsis on Immune Function in Mice [J]. Pharmacology and Clinics of Chinese Materia Medica,2005,21(4):39(in Chinese).
54. ZHANG XIAOJUN, ZHU CHENCHEN, HU LI, et al. Pharmacological Action of Polysaccharides from Radix Codonopsis on Immune Function and Hematopoiesie in Mice [J]. Traditional Chinese Drug Research & Clinical Pharmacology,2003,14(3):174-176 (in Chinese).
55.黄涛,唐瑛,邹瑞,等,党参水煎提取物对化学药品诱导小鼠学习记忆障碍的影响(J),华南国防医学杂志,2007,21(2)：10-12
56.张天红,张馨,耿爱萍。.潞党参药理实验研究[J].时珍国医国药2001,12(6)：489
57.黄丽亚,党参、维生素C对氟哌啶醇诱导老化大鼠抗氧化酶表达作用的比较研究[J].陕西中医,2006,27(12)：1585
58.周世文,徐传福.多糖的免疫药理作用[J].中国生化药物杂志,1994,15(2)：143
59.汤军,黄琦,徐志瑛,等.麦冬多糖的免疫活性研究[J].中国中医基础医学杂志,1998,4(9)：4
60.舒琦瑾,吴良村.新加沙参麦冬汤抗肿瘤的实验研究[J].中国中医基础医学杂志,2002,8(4)：34
61.彭丽娟,鲍扬漪,朱晓梅,等SM-EDTMP与麦冬注射液联合治疗骨转移癌[J].安徽医科大学学报,1999,10(5)：383
62.汤军,钱华,黄琦,等.麦冬多糖平喘和抗过敏作用研究[J].中国现代应用药学杂志,1999,16(2)：16-19.
63.余伯阳,殷霞,张春红,等.麦冬多糖的免疫活性研究[J].中国药科大学学报,1991,22(5)：286-288
64.汤军,黄琦,徐志瑛,等.麦冬多糖的免疫活性研究[J].中国中医基础医学杂志,1998,4(9)：44-46
65.黄厚才,倪正.麦冬对小鼠小鼠耳廓微循环的影响[J].2003,23(1)：57-58.
66.黄厚才,倪正,蔡雪珠.麦冬对大鼠血小板聚集率的影响[J].上海实验动物科学,2001,21(3)：167-
67.
68.昔谷爱子.芍药的药理及药效[j].国外医学·中医中药分册,1992,14(5)：15
69.王永样.亳白芍芍药总甙的药理作用[j].安徽医科大学学报,1986(1)：11
70.木村正康.芍药甘草汤对骨骼肌松弛作用的机理[j].国外医学·中医中药分册,1983(6)：21
71.张艳,明亮,王瑜,等,白芍总苷的抗惊厥作用[J].中国药理学通报,1994,10(5)：372-374
72.李俊,梁君山,周爱武,等.白芍总甙对B淋巴细胞增殖和白介素1生成的调节作用[J].中国药理学与毒理学杂志,1994,8(1)：53-55
73.李俊,陈敏珠,徐叔云.白芍总甙对大鼠腹腔巨噬细胞产生前列腺素E2的作用及部分机制研究[J].中国药理学通报,1994,10(4)：267-270
74.王斌,陈敏珠,徐叔云.白芍总甙对佐剂性关节炎大鼠滑膜细胞功能和脾细胞增殖反应的影响[J].中国药理与毒理学杂志,8(2)：128-131
75.李俊,汤晓林,陈敏珠,等.白芍总甙对佐剂性关节炎人鼠的免疫调节机制[J].中国药理学通报,1995,11(6)：475-478
76.周辉,张安平,陈敏珠,等.白芍总甙对应激大鼠下丘脑-垂体-肾上腺轴和免疫功能的调节[J].中国药理学通报,1994,10(6)：429-432
77.曹治权,等.微量元素与中医药[M].北京：中国中医药出版社,1993.125
78.江明性.药理学[M].北京：人民卫生出版社,1985.12
79.傅永怀,等,微量元素与临床[M].北京：中国医药科技出版社,1997.126-127
80.李光华,周旭,贺戈,等.龙骨对小鼠镇静与抗惊厥作用的初步研究[J].宁夏医学院学报2002.24(3)：163-165
81.孙长伏.锌与骨代谢[J].解剖科学进展.1995;1(4)：4
82.马金风.微量元素铁与一此疾病关系的研究[J],微量元素与健康研究,1999：16(3)：72
83.董泽平,硒与肿瘤研究的一些进展[J],国外医学·医学地理分册,1995：16(2)：49
84.王少为.人体必需微量元素一硒[J].广东微量元素科学1999;6(6)：50
85.李光华,周旭,贺戈,等,龙骨免疫作用的实验研究[J],江苏中医药,2003年第24卷第4期54-55
86.戴筱青,陈江华,刘玉生.牡蛎提取物对小鼠T淋巴细胞功能的影响[J].第军医大学学报1997年17卷第2期：149
87.王俊,姚澄,张建鹏,等.牡蛎多糖的制备和生物学活性研究[J].医学研究生学报,2006年第19卷第3期：217-220
88.修丽,陈江华,陈育尧.牡蛎提取物对脾虚模型小鼠免疫功能的影响及抗应激反应实验研究[J].深圳中西医结合杂志,1997年第7卷第4期:22-23
89.阎淑芳,张凤琴,李晶,等.赤子爱胜蚯蚓纤溶酶的研究VIII纤溶酶活性组分的确证[J].黑龙江医药,1999,12(5)：263-264.
90. Oumi T, Ukena K, Matsushima O, et al. The GGNG peptides:no-vel myoactive peptides isolated from the gut and the whole body of the earthworm[J].Biochem Biophys Res Commun,1995,216 (3):1072-1078.
91.陈云锋,张凤春,苏颜玲,等.地龙促进大白兔创伤模型愈合的形态学观察[J].中国中药杂志,1998,23(5):305-307.
92.张凤春,陈云峰,苏颜珍,等.地龙对巨噬细胞免疫活性的增强作用[J].中国药学杂志,1998,33(9)：532-535.
93.吴朝晖,张国平,张明,等.蚯蚓制剂(普恩复)对小鼠游泳时间和丙二醛影响的初步研究[J].中国微循环.1998,2(2)：82-84.
94.南景一,王忠,杨正娟,等.穿山龙对小鼠免疫功能的影响[J]中草药,1988,19(3)： 22.
95.唐小云,梁再赋,杨丽群,等,地龙肽对小鼠免疫功能的影响[J].中国医科大学学报,2003,32(2)：21-23
96.刘国军,浅述甘草的药理作用及化学成分[J].陕西中医1997,18(8)371-372
97. LEUNG D T, MOREFIELD S, WILLERFORD D M. Regulation of lymphoid homeostasis by IL-2 receptor signals in viv [J]. Immunol, 2000,164(7):3527-3534.
98. MALEK T R, YU A, MNCEK V, et al. CD4+ regulatory T cells prevent lethal autoimmunity in IL-2R, deficient mice:implications for the non-redundant function of IL-2[J].Immunity,2002,17(2):167-178.
99. ALMEIDA A R, LEGRAND N, PAPIERMK M, et al. Homeostasis of peripberal CD4+T cells:IL 2R alpha and IL-2 shape a population of regul-atory cells that controls CD4+T cell numbers[J].J Immunol,2002,169(9):4850-4860.
100.WOLF M, SCHI MPL A, HuNiG T. Control of T cell hyperactivation in IL 2-deficient mice by CD4+CD5+ and CD4+CD5+Tcells:Evidence for two distinct regulatory mechanism[J]. Eur J Immunol,2001,31(6):1637-1645.
101.程安玮,金征宇,万发春,甘草多糖对小鼠脾淋巴细胞的免疫作用[J].安徽农业科学,2007,35(6)：1660-1661
102. 木村正康.芍药甘草汤对骨骼肌松弛作用的机理[j].国外医学中医中药分册,1983,(6)：2
103. 细野史郎.“芍药甘草汤”的临床药理[J].上海中医药杂志,1987,(10)：449
1. Kan Y, Ohta M, Nagai Y, et al。 A family study of Tourette's syndrome in Japan,Am J Med Genet,2001,105(5):414.
2.杨宏宇,皇甫恩,谭庆荣.抽动秽语综合征的遗传学研究进展.国外医学精神病学分册,2001,28(4):238.
3.刘智胜,Tourette综合征的遗传学研究进展,国外医学神经病学神经外科学分册,1998；25；5；255-257.
4. Tourette Syndrome Association International Consortium on Genet-ics.A genome-wide scan of Gillesde la Tourette syndrome [J].Am JHum Genet,2005, Supp:1288.
5. Verkerk AL,Cath DC,Van derLindeHC, et a.l Genetic and clini-cal analysis of a large Dutch Gilles de la Tourette family[J].Mol Psychiatry,2006,10:954-964.
6. David L, Pauls.An update on the genetics ofGills de la Tourette syndrome[J]. J PsychoRes,2003,55:7-12.
7. Chou IC, Tsai CH, Lee CC, et al. Association analysis between Tourette's syndrome and dopamine D1 receptor gene in Taiwanese children. Psychiatr Genet,2004,14(4):219-221.
8. Lee CC, Chou IC, Tsai CH, et al. Dopamine receptor D2 gene polymorphisms are associated in Taiwanese children with Tourette syndrome.Pediatr Neurol,2005,33(4):272-276.
9. Diaz-Anzaldua A, Joober R, Riviere JB, et al. Tourette syndrome and dopaminergic genes:a family-based association study in the French Canadian founder population[J].Mol Psychiatry,2004,9(3):272-277.
10. Ozbay F, Wigg KG, Turanli ET,et al. Analysis of the dopamine beta hydroxylase gene in Gilles de la Tourette syndrome. Am J Med Genet B Neuropsychiatr Genet,2006,141B(6):673-677.
11. Yoon DY, Rippel CA, Kobets AJ,et al. Dopaminergic polymer phisms in Tourette syndrome:association with the DAT gene (SLC6A3). Am J Med Genet B Neuropsychiatr Genet,2007,144B(5):605-610.
12. Brett PM,Curtis D,Robertson MM,et al. Exclusion of the 5-HT1A serotonin neuroreceptor and tryptophan oxygenase genes in a large British kindred multiply affected with Tourette's syndrome,chronic motor tics,and obsessive-compulsive behavior[J]. Am J Psychiatry,1995,152:437-440.
13. Huang Y,Liu X,Li T,et al. Cases-Control association study and transmission disequilibrium test of T102C polymorphism in 5HT2A and Tourette's syndrome[J]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi,2001,18(1):11-3.
14.13 Xu C,Ozbay F,Wigg K,et al. Evaluation of the genes for the a-drenergic receptors alpha 2A and alpha 1C and Gilles de la Tourette syndrome[J]. Am J Med Genet,2003,119B(1):54-9.
15. Schoenian S,Konig I,Oertel W,et al. HLA-DRB genotyping in Gilles de la Tourette patients and their parents[J]. Am J Med Genet,2003,119B(1):60-4
16. Gadzicki D,Muller-Vahl KR,Heller D,et al. Tourette syndrome is not caused by mutations in the central cannabinoid receptor (CNR1) gene[J]. Am J Med Genet,2004,127B(1):97-103
17. Abelson, J.F. (2005) Sequence variants in SLITRK1 are associated with Tourette's syndrome. Science 310,317-320
18. Curtis D,Brett P,Dearlove AM, et al. Genome scan of Tourette syndrome in a single large pedigree shows some support for linkage to regions of chromosomes 5,10 and 13[J]. Psychiatr Genet,2004,14(2):83-7
19. Diaz-Anzaldua A,Joober R,Riviere JB,et al. Association between 7q31 markers and Tourette syndrome[J]. Am J Med Genet,2004,127A(1):17-20
20. Romstad A,Dupont E,Krag-Olsen B,et al. Dopa-responsive dys-tonia and Tourette syndrome in a large danish family[J]. Arch Neurol,2003,60:618-622
21. Muller-Vahl KR,BerdingG,BruckeT,et al.Dopamine transporter binding in Gilles de la Tourette syndrome[J].J Neurol,2000,247(7):514-520.
22. Singer HS,Szymanski S,Giuliano J,et al.Elevated intrasynaptic dopamine release in Tourette's syndrome measured by PET[J].Am J Psychiatry,
23. Wong DF,Singer HS,Brandt J,et al.D2-like dopamine receptor density in Tourette syndrome measured by PET[J].J Nucl Med,1997,38(8):1243-1247.
24. Heinz A,Knable MB,Wolf SS, et al.Tourette's syndrome:[I-123]-β-CIT SPECTcorrelates of vocal tic severity[J].Neurology,1998,51(4):1069-1074.
25. Sallee FR,Gilbert DL,Vinks AA,et al.Pharmacodynamics of ziprasidone in children and adolescents:impact on dopamine transmission[J].J Am Acad Child Adolesc Psychiatry,2003,42(8):902-907.
26. Bornstein R A, Baker G B, BazylewichT, et a.l Tourette syndrome and neuropsychological performance [J]. Acta Psychiatr Scand,1991,84 (3) 212-216.
27. JonesMD,Hess EJ.Norepinephrine regulates locomotor hyperactivity in the mouse mutant coloboma[J].Pharmacol Biochem Behav,2003,75(1):209-216.
28.刘智胜,静进.儿童心理行为障碍[M].北京：人民卫生出版社,2007:143-146.
29.刘健,霍展样.谷氨酸对多发性抽动症发病的影响[J].实用儿科学临床杂志,2005,20(5)：460-462.
30.唐洪丽,刘放南.儿奄抽动障碍血浆兴奋性氨基酸水平与行为心理的相关性研究[J].江苏医药杂志,2003,29(10)：725-727.
31.唐洪丽,刘放南,龚建平.儿童Tourette综合征与兴奋性氨基酸及性激素水平的相关性研究[J].中国实用儿科杂志,2004,19(5)：301-302.
32.张风华,魏书珍Tourette综合征患儿血清催乳素水平及神经心理功能的对照研究,中国行为医学科学,2002,11(6):645-647.
33.唐洪丽,刘放南,龚建平.儿童Tourette综合征与兴奋性氨基酸及性激素水平的相关性研究[J].中国实用儿科杂志,2004,19(5):301-302.
34.陈文,林广裕,吴毅.低铁血症对小儿多发性抽动症发病的影响.广东医学.2003.24(6)：615-616
35. Lekman JF,KatsorichL,Kawikova I, etal. Increased serum levels of interleukin-12 and tumor necrosis factor-alpha in Tourette syndrome[J]. BiolPsychiatry,2005, 57(6):667-673.
36. Trifiletti RP,Packard AM.Immune mechanisms in pediatric neu-ropsychiatric disorders. Tourette's syndrome,OCD,and Tourette's syndrome,OCD and PANDAS.Child Adolesc Psychiatr Clinic NAm,1999,8(4):767
37.阮毅燕等,Tourette综合征患儿链球菌感染及其免疫功能检测,中国实用儿科 杂,2007,22(3)：182-185.
38. Dalton R, Behrman RE, Kliegman RM, Jenson HB. Habit disorders.In:Nelson Textbook of Pediatrics.16th ed, Philadelphia:WB SAUNDERS,2000.75
39.卢银平,董继华,刘朝,管世鹤.抽动-秽语综合征儿童巨细胞病毒感染的意义初探,中华神经医学杂志,2006,5(11)：1175-1176.
40. Hogan MB, Wilson NW. Tourette syndromr mimicking asthma. JAsthma,1999,36(3):253
41.李树华,庞保东,徐应军,曹丽华,刘寅,吴家骅,抽动秽语综合征危险因素的病例对照研究,中国儿童保健杂志2004,12(5)：412-414
2. Peterson BS, Leckman JF. The temporal dynamics of tics in Gilles de la Tourette syndrome. Biol Psychiatry,1998; 44:1337-1348.
3. Grimaldi BL. The central role of magnesium deficiency in Tourette's syndrome: causal relationships between magnesium deficiency, altered biochemical pathways and symptoms relating to Tourette's syndrome and several reported comorbid conditions. Med Hypotheses,2002; 58:47-60.
4.金嵘,郑荣远,黄文武等.浙江省温州地区7-16岁人群Tourette综合征患病率调查.中华流行病学杂志,2004;25:131-133.
5.刘智胜主编.小儿多发性抽动症.北京：人民卫生出版社,2002:240.4. Leckman JF. Tourette's syndrome. Lancet 2002;360:1577-86.
7. Yao Y, Ma HW. Neurobiology development of Tourette syndrome. Foreign Med Sci (Pediatr),2005; 32:137-140.
8. Leckman JF, Riddle MA, Hardin MT, et al. The Yale Global Tic Severity Scale: initial testing of a clinician-rated scale of tic severity. J Am Acad Child Adolesc Psychiatry 1989; 28:566-573.
9. Roselei F, Jardel GV, Caroline W, et al. Valeriana officinalis does not alter the orofacial dyskinesia induced by haloperidol in rats:Role of dopamine transporter. Neuro-Psychopharmacology & Bio Psychiatry,2007; 31:1478-1486.
10..Saldana M, Bonastre M, Aguilar E, et al. Differential nigral expression of Bcl-2 protein family in chronically haloperidol and clozapine-treated rats:Role in neurotoxicity and stereotyped behavior. Exp Neurol,2007; 203:302-308.
11. Creese I, Burt DR, Snyder SH. Dopamine Receptor Binding Predicts Clinical and Pharmacological Potencies of Antischizophrenic Drugs. SCIENCE,1976; 192: 481-483.
12. Yoo HK, Kim JY, Kim CY. A Pilot Study of Aripiprazole in Children and Adolescents with Tourette's Disorder. J Child Adolesc Psychopharmacol,2006; 16:505-506.
13. Lv H, Li A, Ma H, et al. Effects of Ningdong granule on the dopamine system of Tourette's syndrome rat models.
14. Jijun L, Zaiwang L, Anyuan L, Shuzhen W, Fanghua Q, Lin Z, Hong L.Abnormal expression of dopamine and serotonin transporters associated with the pathophysiologic mechanism of Tourette syndrome. Neurol India.2010 Jul-Aug;58(4):523-9.
15. Li AY, Cong S, Lu H, Li JJ, Zhao L. Clinical observation on treatment of Tourette syndrome by integrative medicine.Chin J Integr Med.2009 Aug;15(4):261-5. Epub 2009 Aug 18.
16. Leckman JF, Riddle MA, Hardin MT, et al. The Yale Global Tic Severity Scale: initial testing of a clinician-rated scale of tic severity. J Am Acad Child Adolesc Psychiatry 1989; 28:566-573.
17.王文革,孟宪军,汪受传.汪受传治疗小儿多发性抽动症的经验.辽宁中医杂志,2004;31：182-181.
18.朱先康,韩新民,张永春.息风豁痰法治疗小儿多发性抽动症30例.河北中医,2005；27：96-97.
19.吴上彬,马融。马融治疗小儿多发性抽动症经验.辽宁中医杂志,2007;34:396-397
20.刘弼臣,王俊宏,陈丹等.中医药治疗抽动秽语综合征临床研究述评。中国医学理论与实践,2001;5:590-592.
21.王志学,李安源.李安源教授治疗小儿多发性抽动症的学术思想.云南中医中药杂志2011；32(8)：11-13
22.李安源,吕红,孙蓉,吕丽莉,张希林,王平.宁动颗粒治疗抽动秽语综合征的药效学研究.中国中西医结合儿科学.2009;1(1):48-50
23. Singer HS, Brown J, Quaskey S, Rosenberg LA, Mellits ED,Denckla MB. The treatment of attention-deficit hyperactivity disorder in Tourette's syndrome:a double-blind placebo-controlled study with clonidine and desipramine. Pediatrics, 1995; 95:74-81
24. Eggers C, Rothenberger A, Berghaus U. Clinical and neurobiological findings in children suffering from tic disease following treatment with tiapride. Eur Arch Psychiatry Neurol Sci,1988; 237:223-229.
25. Shapiro E, Shapiro AK, Fulop G, et al. Controlled study of haloperidol, pimozide and placebo for the treatment of Gilles de la Tourette's syndrome. Arch Gen Psychiatry,1989; 46:722-730.
26. Sallee FR, Nesbitt L, Jackson C, Sine L, Sethuraman G. Relative efficacy of haloperidol and pimozide in children and adolescents with Tourette's disorder. Am J Psychiatry,1997; 154:1057-1062.
27. Shapiro AK, Shapiro E. Controlled study of pimozide vs placebo in Tourette's syndrome. J Am Acad Child Psychiatry 1984; 23:161-173.
28. Sallee FR, Kurlan R, Goetz CG, et al. Ziprasidone treatment of children and adolescents with Tourette's syndrome:a pilot study.J Am Acad Child Adolesc Psychiatry,2000; 39:292-399.
29. Bruggeman R, van der Linden C, Buitelaar JK, et al. Risperidone versus pimozide in Tourette's disorder:a comparative double-blind parallel-group study. J Clin Psychiatry 2001; 62:50-56.
30. Robertson MM, Schnieden V, Lees AJ. Management of Gilles de la Tourette syndrome using sulpiride. Clin Neuropharmacol 1990; 13:229-235.
31. George MS, Trimble MR, Robertson MM. Fluvoxamine and sulpiride in comorbid obsessive-compulsive disorder and Gilles de la Tourette syndrome. Hum Psychopharmacol 1993; 8:327-334.
32. Shapiro AK, Shapiro E:Controlled study of pimozide vs. placebo in Tourette syndrome. J Am Acad Child Psychiatry,1984; 23:161-173.
33. Dion Y, Annable L, Sandor P, et al. Risperidone in the treatment of Tourette syndrome:a double-blind, placebo-controlled trial. J Clin Psychopharmacol,2002; 22:31-39.
34. Scahill L, Leckman JF, Schultz RT, et al. A placebo-controlled trial of risperidone in Tourette syndrome. Neurology,2003; 60:1130-1135.
35. Bruun RD, Budman CL. Risperidone as a treatment for Tourette's syndrome. J Clin Psychiatry.1996; 57(1):29-31.
36. Leckman JF, Hardin MT, Riddle MA, Stevenson J, Ort SI, Cohen DJ. Clonidine treatment of Tourette's syndrome. Arch Gen Psychiatry,1991; 48:324-28.
37. Tourette Syndrome Study Group. Treatment of ADHD in children with tics:a randomized controlled trial. Neurology 2002; 58:527-536.
38. Shapiro AK, Shapiro E. Controlled study of pimozide vs placebo in Tourette's syndrome. J Am Acad Child Psychiatry 1984; 23:161-173.
39. Zhao L, Li AY, Lv H, Liu FY, Qi FH. Traditional Chinese medicine Ningdong granule:the beneficial effects in Tourette's disorder. J Int Med Res.2010 Jan-Feb;38(1):169-75.
1. Wen-Juh Hwang, Wei-Jen Yao et al.[99mTc]TRODAT-1/[123I]IBZM SPECT studies of the dopaminergic system in Tourette syndrome, Psychiatry Research: Neuroimaging 162 (2008) 159-166.
2. Kano Y, Ohta M, Nagai Y, et al. A family study of Tourette syndrome in Japan. Am J Med Genet,2001,28(4):238
3. Freeman RD, Fast DK, Burd L, et al. Aninter national perspective on Tourette syndrome:selected findings from 3500 individuals in 22 coutries. Dev Med Child Neurol,2000,42(7):436.
4. 刘智胜Tourette综合征的问题与回答.实用儿科临床杂志[J],1998,13(6)：347.
5. 刘慎如.抽动-秽语综合征38例综合报告.中华儿科杂志[J],1996,24(3)：81-85.
6. Leckman JF, Cohen DJ. Tourette's Syndrome-Tics, Obsessions, Compulsions. New York, John Wiley&Sons,Inc,1999.155.
7. Emna SJ. Neuroleptics:Neurochemical Behavioral and Clinical Perspectives. New York:Raven Press New York,1983,65.
8. Roger L, Albin,Jonathan W. Mink. Recent advances in Tourette syndrome research. tRENDS in neurosciences:2006,29(3):175-182.
9. Comings DE. Blood serotonin and tryplophan in Tourette syndrome.[J] Am J Med Genet,1990,36:418-430.
10. Mihara K, Kondo T, Yasui-Furukori N, et al. Dopamine D2 receptor gene polymorphisms and clinical response to selective dopamine receptor antagonists. International Congress Series,2002,1244(1):77-83.
11. Aw aad Y, M ichon AM, M inarik S. Use of levetiracetam to treat tics in children and adolescents with Tourette syndrome[J]. MovDiscord,2005,20(6): 714
12. Harvey S. Singer, Christina Morris' Marco Grados. Glutamatergicmodulatorytherapy for Tourettesyndrome.Medical HypothesesVolume 74, Issue 5, May 2010, Pages 862-867.
13. Tian Y, Gunther JR, Liao IH, Liu D, Ander BP, Stamova BS, Lit L, Jickling GC, Xu H, Zhan X, Sharp FR.GABA-and acetylcholine-related gene expression in blood correlate with tic severity and microarray evidence for alternative splicing in Tourette syndrome:a pilot study. Brain Res.2011 Mar 24;1381:228-36. Epub 2011 Jan 15.
14. Freeman RD,Fast DK,Burd L,et al.An international perspective on Tourette Syndrom:selected findings from 3500 individuals in 22 countries[J].Dev Med Child Neural,2000,42:436-447.
15.李继君.李安源教授治疗多发性抽动症经验,中医杂志[J].2009,10(1)15-17.
16.李安源,马瑞萍等.宁动颗粒治疗抽动-秽语综合症临床研究.山东中医药大学学报[J],2008,32(1)：33-35.
17.[9]马瑞萍,李安源.养阴柔肝法论治小儿抽动-秽语综合征.云南中医学院学报[J],2005,28(4)：58.
18.[10]李继君,王淑臻,李安源等.126例抽动-秽语综合征患儿中医证候学研究.中医杂志[J].2010.
19.刘智胜主编.小儿多发性抽动症.北京：人民卫生出版社,2002：240.
20. Singer HS, Hahn IH, Moran TH. Abnormal dopamine uptake sites in postmortem striatum from patients with Tourette's syndrome. Ann Neurol,1991; 30:558-62.
21. Emna SJ. Neuroleptics. Neurochemical Behavioral and Clinical Perspectives. Raven Press New York,1983:65.
22. Emilien G, Maloteaux JM, Geurts M, et al. Dopamine receptors-physiological understanding to therapeutic intervention potential. Pharmacol Ther,1999; 84: 133-156.
23. Singer HS, Hahn IH, Moran TH. Abnormal dopamine uptake sites in postmortem striatum from patients with Tourette's syndrome. Ann Neurol,1991; 30:558-62.
24. Wong DF, Bras JR, Singer HS. Mechanisms of Dopaminergic and Serotonergic Neurotransmission in Tourette Syndrome:Clues from an In Vivo Neurochemistry Study with PET. Neuropsychopharmacology,2008; 33: 1239-1251.
25. Jijun L, Zaiwang L, Anyuan L, Shuzhen W, Fanghua Q, Lin Z, Hong L. Abnormal expression of dopamine and serotonin transporters associated with the pathophysiologic mechanism of Tourette syndrome. Neurol India.2010,58: 523-529.
26. Liu X, Wang Y, Li D, Ju X (2008) Transplantation of rat neural stem cells reduces stereotypic behaviors in rats after intrastriatal microinfusion of Tourette syndrome sera. Behav Brain Res 186:84-90.
27.隆红艳,张骠;,谈碹忠等.静安口服液对小儿多发性抽动症模型大鼠抽动行为及脑组织、血浆5-羟色胺含量的影响.中国中医基础医学杂志2010;(8)：675-676,695
28. Sallee FR. Gilbert DL. Vinks AA, ct al. Pharmaoxtyrurnics of ziprasidon e in childTen and addescents.-impact on dopmnine transmissionlj J. j Am Aead Child Adolesc Psychiatry,2003,42(8):902-907.
29.赵春玲,李蔷华.中药熄风祛痰汤治疗小儿多发性抽动症60例[J]. 中医儿科杂志,2006；2(1)：33-34.
30.曾红英.针药合治抽动—秽语综合征30例[J].辽宁中医杂志,2003,(30);665-666.
31. Ju GC. Progress in studies of pharmacological activities and clinical applications of preparations of Gastrodia elata Blume. Chin Phar,2008; 17: 64-66.
32. Yingfang Tian, Joan R. Gunther, Isaac H. Liao, Dazhi Liu, Bradley P. Ander, Boryana S. Stamova, Lisa Lit, Glen C. Jickling, Huichun Xu, Xinhua Zhan, Frank R. Sharp. GABA- and acetylcholine-related gene expression in blood correlate with tic severity and microarray evidence for alternative splicing in Tourette syndrome:A pilot study. Brain research.2011; 28-236.
33. Roselei F, Jardel GV, Caroline W, et al. Valeriana officinalis does not alter the orofacial dyskinesia induced by haloperidol in rats:Role of dopamine transporter. Neuro-Psychopharmacology & Bio Psychiatry,2007; 31: 1478-1486.
34. Jijun L, Zaiwang L, Anyuan L, Shuzhen W, Fanghua Q, Lin Z, Hong L.Abnormal expression of dopamine and serotonin transporters associated with the pathophysiologic mechanism of Tourette syndrome. Neurol India.2010 Jul-Aug;58(4):523-9.
35. Li AY, Cong S, Lu H, Li JJ, Zhao L. Clinical observation on treatment of Tourette syndrome by integrative medicine.Chin J Integr Med.2009 Aug;15(4):261-5. Epub 2009 Aug 18.
36. Sandor P. Pharmacological management of tics in patients with TS. J Psycholinguist Res,2003; 55:41-48.
37. Fachinetto R, Villarinho JG, Wagner C, et al. Valeriana officinalis does not alter the orofacial dyskinesia induced by haloperidol in rats:Role of dopamine transporter. Prog NeuroPsychopharmacology & Biol Psychiatry,2007; 31: 1478-1486.
38.艾小文,赵玉屏.中西药治疗儿童抽动-秽语综合征疗效比较.中华中医药杂志,2005;20：746-747.
39. Dustin YY, Colin DG, James FL, et al. Frontal dopaminergic abnormality in Tourette syndrome:A postmortem analysis. J Neurol Sci,2007; 255:50-56.
40. Agnes L, Auclair & Alexandra Galinier. Putative antipsychotics with pronounced agonism at serotonin 5-HT1A and partial agonist activity at dopamine D2 receptors disrupt basal PPI of the startle reflex in rats. Psychopharmacology,2007; 193:45-54.
41. Yoo HK, Kim JY, Kim CY. A Pilot Study of Aripiprazole in Children and Adolescents with Tourette's Disorder. J Child Adolesc Psychopharmacol,2006; 16:505-506.
42. L iu J Mori A. Antioxidant and free radical scavenging activities of Gastrodia elata BL. and Uncaria rhynchophylla (Miq.) Jacks [J]. Neuropharmacology, 1992,31(12):1287.
43. L iu J Mori A. Antioxidant and pro-oxidant activities of phydroxybenzyl alcohol and vanillin:effects on free radicals, brain peroxidation and degradation of benzoate, deoxyribose, amino acids and DNA [J]. Neuropharmacology.1993 32(7):659
44. Hsieh C L, Chang S Y. Cheng K S, et al. Anticonvulsive and free radical scavenging activities of Gastrodia elata BL in kainic acid-treated rats [J]. Am J Chin Med,2001,29(2):331.
45. Hsieh C L, Chang C H, Chiang S Y, et al. Anticonvulsive and free radical scavenging activities of vanillyl alcohol in ferric chloride-induced epileptic seizures in Sprague-Dawley rats [J].Life Sci,2000,67(10):1185.
46. H a J H, Lee D U, Lee J T et al.4-Hydroxybenzaldehyde from Gastrodia elata BI. is active in the antioxidation and GABAergic neurom odulation of the rat brain[J]. J EthnophamacoL,2000,73(1-2):329.
47. K im H j, Moom K D, Oh S Y, et al. Ether fraction of methanol extracts of Gastrodia elata, a traditional medicinal herb,protects against k a in ic acid-induced neuronal damage in the mouse hippocampus[J]. Neurosci Lett, 2001,314(1-2):65.]
48. H ssieh C L, Chen C L, Tang N Y, et al. Gastrodia elata BL mediates the suppression of nNOS and microglia activation to protect against neuronal damage in k a in ic acid-treated rats[J]. Am J Chin Med,2005,33(4):599.
49. Lee Y S, H a J H, Yong C S, et al. Inhibitory effects of constituents of Gastrodia elata BL on glutamate-induced apoptosis in IMR-32 human neuroblastoma cells[J]. Arch Pharm Res,1999,22 (4):404.
50. TANG QINGXIU, CHENG GUOQUAN, ZHANG XIAOWEN. Effects of Polysaccharides from Radix Codonopsis and Dangshenjing on Immune Function in C57BL/6 Mice [J]. Endemic Diseases Bulletin,1996, 11(supp.): 1-3 (in Chinese).
51. LI YAN, SUN PING, LIU XIA, et al. Extraction, Determination and effect on Immune Function of Polysaccharides from Codonopsis clematidea (schrenk) Clarke [J]. Chinese Traditional Patent Medicine,2005,27(7):839-840(in Chinese).
52. CAO LI, LUO CHONGNIAN, BIAN QINGYA, et al. Promotive effect of Codonopsis pilosula polysaccharide on IL-2 inductive activity and lymphocyte proliferative reaction in chickens [J]. Journal of Traditional Chinese Veterinary Medicine,2004,1:3-4 (in Chinese).
53. YANG GUANG, LI FASHENG, LIU HUI, et al. Effects of Polysaccharides from Radix Codonopsis on Immune Function in Mice [J]. Pharmacology and Clinics of Chinese Materia Medica,2005,21(4):39(in Chinese).
54. ZHANG XIAOJUN, ZHU CHENCHEN, HU LI, et al. Pharmacological Action of Polysaccharides from Radix Codonopsis on Immune Function and Hematopoiesie in Mice [J]. Traditional Chinese Drug Research & Clinical Pharmacology,2003,14(3):174-176 (in Chinese).
55.黄涛,唐瑛,邹瑞,等,党参水煎提取物对化学药品诱导小鼠学习记忆障碍的影响(J),华南国防医学杂志,2007,21(2)：10-12
56.张天红,张馨,耿爱萍。.潞党参药理实验研究[J].时珍国医国药2001,12(6)：489
57.黄丽亚,党参、维生素C对氟哌啶醇诱导老化大鼠抗氧化酶表达作用的比较研究[J].陕西中医,2006,27(12)：1585
58.周世文,徐传福.多糖的免疫药理作用[J].中国生化药物杂志,1994,15(2)：143
59.汤军,黄琦,徐志瑛,等.麦冬多糖的免疫活性研究[J].中国中医基础医学杂志,1998,4(9)：4
60.舒琦瑾,吴良村.新加沙参麦冬汤抗肿瘤的实验研究[J].中国中医基础医学杂志,2002,8(4)：34
61.彭丽娟,鲍扬漪,朱晓梅,等SM-EDTMP与麦冬注射液联合治疗骨转移癌[J].安徽医科大学学报,1999,10(5)：383
62.汤军,钱华,黄琦,等.麦冬多糖平喘和抗过敏作用研究[J].中国现代应用药学杂志,1999,16(2)：16-19.
63.余伯阳,殷霞,张春红,等.麦冬多糖的免疫活性研究[J].中国药科大学学报,1991,22(5)：286-288
64.汤军,黄琦,徐志瑛,等.麦冬多糖的免疫活性研究[J].中国中医基础医学杂志,1998,4(9)：44-46
65.黄厚才,倪正.麦冬对小鼠小鼠耳廓微循环的影响[J].2003,23(1)：57-58.
66.黄厚才,倪正,蔡雪珠.麦冬对大鼠血小板聚集率的影响[J].上海实验动物科学,2001,21(3)：167-
67.
68.昔谷爱子.芍药的药理及药效[j].国外医学·中医中药分册,1992,14(5)：15
69.王永样.亳白芍芍药总甙的药理作用[j].安徽医科大学学报,1986(1)：11
70.木村正康.芍药甘草汤对骨骼肌松弛作用的机理[j].国外医学·中医中药分册,1983(6)：21
71.张艳,明亮,王瑜,等,白芍总苷的抗惊厥作用[J].中国药理学通报,1994,10(5)：372-374
72.李俊,梁君山,周爱武,等.白芍总甙对B淋巴细胞增殖和白介素1生成的调节作用[J].中国药理学与毒理学杂志,1994,8(1)：53-55
73.李俊,陈敏珠,徐叔云.白芍总甙对大鼠腹腔巨噬细胞产生前列腺素E2的作用及部分机制研究[J].中国药理学通报,1994,10(4)：267-270
74.王斌,陈敏珠,徐叔云.白芍总甙对佐剂性关节炎大鼠滑膜细胞功能和脾细胞增殖反应的影响[J].中国药理与毒理学杂志,8(2)：128-131
75.李俊,汤晓林,陈敏珠,等.白芍总甙对佐剂性关节炎人鼠的免疫调节机制[J].中国药理学通报,1995,11(6)：475-478
76.周辉,张安平,陈敏珠,等.白芍总甙对应激大鼠下丘脑-垂体-肾上腺轴和免疫功能的调节[J].中国药理学通报,1994,10(6)：429-432
77.曹治权,等.微量元素与中医药[M].北京：中国中医药出版社,1993.125
78.江明性.药理学[M].北京：人民卫生出版社,1985.12
79.傅永怀,等,微量元素与临床[M].北京：中国医药科技出版社,1997.126-127
80.李光华,周旭,贺戈,等.龙骨对小鼠镇静与抗惊厥作用的初步研究[J].宁夏医学院学报2002.24(3)：163-165
81.孙长伏.锌与骨代谢[J].解剖科学进展.1995;1(4)：4
82.马金风.微量元素铁与一此疾病关系的研究[J],微量元素与健康研究,1999：16(3)：72
83.董泽平,硒与肿瘤研究的一些进展[J],国外医学·医学地理分册,1995：16(2)：49
84.王少为.人体必需微量元素一硒[J].广东微量元素科学1999;6(6)：50
85.李光华,周旭,贺戈,等,龙骨免疫作用的实验研究[J],江苏中医药,2003年第24卷第4期54-55
86.戴筱青,陈江华,刘玉生.牡蛎提取物对小鼠T淋巴细胞功能的影响[J].第军医大学学报1997年17卷第2期：149
87.王俊,姚澄,张建鹏,等.牡蛎多糖的制备和生物学活性研究[J].医学研究生学报,2006年第19卷第3期：217-220
88.修丽,陈江华,陈育尧.牡蛎提取物对脾虚模型小鼠免疫功能的影响及抗应激反应实验研究[J].深圳中西医结合杂志,1997年第7卷第4期:22-23
89.阎淑芳,张凤琴,李晶,等.赤子爱胜蚯蚓纤溶酶的研究VIII纤溶酶活性组分的确证[J].黑龙江医药,1999,12(5)：263-264.
90. Oumi T, Ukena K, Matsushima O, et al. The GGNG peptides:no-vel myoactive peptides isolated from the gut and the whole body of the earthworm[J].Biochem Biophys Res Commun,1995,216 (3):1072-1078.
91.陈云锋,张凤春,苏颜玲,等.地龙促进大白兔创伤模型愈合的形态学观察[J].中国中药杂志,1998,23(5):305-307.
92.张凤春,陈云峰,苏颜珍,等.地龙对巨噬细胞免疫活性的增强作用[J].中国药学杂志,1998,33(9)：532-535.
93.吴朝晖,张国平,张明,等.蚯蚓制剂(普恩复)对小鼠游泳时间和丙二醛影响的初步研究[J].中国微循环.1998,2(2)：82-84.
94.南景一,王忠,杨正娟,等.穿山龙对小鼠免疫功能的影响[J]中草药,1988,19(3)： 22.
95.唐小云,梁再赋,杨丽群,等,地龙肽对小鼠免疫功能的影响[J].中国医科大学学报,2003,32(2)：21-23
96.刘国军,浅述甘草的药理作用及化学成分[J].陕西中医1997,18(8)371-372
97. LEUNG D T, MOREFIELD S, WILLERFORD D M. Regulation of lymphoid homeostasis by IL-2 receptor signals in viv [J]. Immunol, 2000,164(7):3527-3534.
98. MALEK T R, YU A, MNCEK V, et al. CD4+ regulatory T cells prevent lethal autoimmunity in IL-2R, deficient mice:implications for the non-redundant function of IL-2[J].Immunity,2002,17(2):167-178.
99. ALMEIDA A R, LEGRAND N, PAPIERMK M, et al. Homeostasis of peripberal CD4+T cells:IL 2R alpha and IL-2 shape a population of regul-atory cells that controls CD4+T cell numbers[J].J Immunol,2002,169(9):4850-4860.
100.WOLF M, SCHI MPL A, HuNiG T. Control of T cell hyperactivation in IL 2-deficient mice by CD4+CD5+ and CD4+CD5+Tcells:Evidence for two distinct regulatory mechanism[J]. Eur J Immunol,2001,31(6):1637-1645.
101.程安玮,金征宇,万发春,甘草多糖对小鼠脾淋巴细胞的免疫作用[J].安徽农业科学,2007,35(6)：1660-1661
102. 木村正康.芍药甘草汤对骨骼肌松弛作用的机理[j].国外医学中医中药分册,1983,(6)：2
103. 细野史郎.“芍药甘草汤”的临床药理[J].上海中医药杂志,1987,(10)：449
1. Kan Y, Ohta M, Nagai Y, et al。 A family study of Tourette's syndrome in Japan,Am J Med Genet,2001,105(5):414.
2.杨宏宇,皇甫恩,谭庆荣.抽动秽语综合征的遗传学研究进展.国外医学精神病学分册,2001,28(4):238.
3.刘智胜,Tourette综合征的遗传学研究进展,国外医学神经病学神经外科学分册,1998；25；5；255-257.
4. Tourette Syndrome Association International Consortium on Genet-ics.A genome-wide scan of Gillesde la Tourette syndrome [J].Am JHum Genet,2005, Supp:1288.
5. Verkerk AL,Cath DC,Van derLindeHC, et a.l Genetic and clini-cal analysis of a large Dutch Gilles de la Tourette family[J].Mol Psychiatry,2006,10:954-964.
6. David L, Pauls.An update on the genetics ofGills de la Tourette syndrome[J]. J PsychoRes,2003,55:7-12.
7. Chou IC, Tsai CH, Lee CC, et al. Association analysis between Tourette's syndrome and dopamine D1 receptor gene in Taiwanese children. Psychiatr Genet,2004,14(4):219-221.
8. Lee CC, Chou IC, Tsai CH, et al. Dopamine receptor D2 gene polymorphisms are associated in Taiwanese children with Tourette syndrome.Pediatr Neurol,2005,33(4):272-276.
9. Diaz-Anzaldua A, Joober R, Riviere JB, et al. Tourette syndrome and dopaminergic genes:a family-based association study in the French Canadian founder population[J].Mol Psychiatry,2004,9(3):272-277.
10. Ozbay F, Wigg KG, Turanli ET,et al. Analysis of the dopamine beta hydroxylase gene in Gilles de la Tourette syndrome. Am J Med Genet B Neuropsychiatr Genet,2006,141B(6):673-677.
11. Yoon DY, Rippel CA, Kobets AJ,et al. Dopaminergic polymer phisms in Tourette syndrome:association with the DAT gene (SLC6A3). Am J Med Genet B Neuropsychiatr Genet,2007,144B(5):605-610.
12. Brett PM,Curtis D,Robertson MM,et al. Exclusion of the 5-HT1A serotonin neuroreceptor and tryptophan oxygenase genes in a large British kindred multiply affected with Tourette's syndrome,chronic motor tics,and obsessive-compulsive behavior[J]. Am J Psychiatry,1995,152:437-440.
13. Huang Y,Liu X,Li T,et al. Cases-Control association study and transmission disequilibrium test of T102C polymorphism in 5HT2A and Tourette's syndrome[J]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi,2001,18(1):11-3.
14.13 Xu C,Ozbay F,Wigg K,et al. Evaluation of the genes for the a-drenergic receptors alpha 2A and alpha 1C and Gilles de la Tourette syndrome[J]. Am J Med Genet,2003,119B(1):54-9.
15. Schoenian S,Konig I,Oertel W,et al. HLA-DRB genotyping in Gilles de la Tourette patients and their parents[J]. Am J Med Genet,2003,119B(1):60-4
16. Gadzicki D,Muller-Vahl KR,Heller D,et al. Tourette syndrome is not caused by mutations in the central cannabinoid receptor (CNR1) gene[J]. Am J Med Genet,2004,127B(1):97-103
17. Abelson, J.F. (2005) Sequence variants in SLITRK1 are associated with Tourette's syndrome. Science 310,317-320
18. Curtis D,Brett P,Dearlove AM, et al. Genome scan of Tourette syndrome in a single large pedigree shows some support for linkage to regions of chromosomes 5,10 and 13[J]. Psychiatr Genet,2004,14(2):83-7
19. Diaz-Anzaldua A,Joober R,Riviere JB,et al. Association between 7q31 markers and Tourette syndrome[J]. Am J Med Genet,2004,127A(1):17-20
20. Romstad A,Dupont E,Krag-Olsen B,et al. Dopa-responsive dys-tonia and Tourette syndrome in a large danish family[J]. Arch Neurol,2003,60:618-622
21. Muller-Vahl KR,BerdingG,BruckeT,et al.Dopamine transporter binding in Gilles de la Tourette syndrome[J].J Neurol,2000,247(7):514-520.
22. Singer HS,Szymanski S,Giuliano J,et al.Elevated intrasynaptic dopamine release in Tourette's syndrome measured by PET[J].Am J Psychiatry,
23. Wong DF,Singer HS,Brandt J,et al.D2-like dopamine receptor density in Tourette syndrome measured by PET[J].J Nucl Med,1997,38(8):1243-1247.
24. Heinz A,Knable MB,Wolf SS, et al.Tourette's syndrome:[I-123]-β-CIT SPECTcorrelates of vocal tic severity[J].Neurology,1998,51(4):1069-1074.
25. Sallee FR,Gilbert DL,Vinks AA,et al.Pharmacodynamics of ziprasidone in children and adolescents:impact on dopamine transmission[J].J Am Acad Child Adolesc Psychiatry,2003,42(8):902-907.
26. Bornstein R A, Baker G B, BazylewichT, et a.l Tourette syndrome and neuropsychological performance [J]. Acta Psychiatr Scand,1991,84 (3) 212-216.
27. JonesMD,Hess EJ.Norepinephrine regulates locomotor hyperactivity in the mouse mutant coloboma[J].Pharmacol Biochem Behav,2003,75(1):209-216.
28.刘智胜,静进.儿童心理行为障碍[M].北京：人民卫生出版社,2007:143-146.
29.刘健,霍展样.谷氨酸对多发性抽动症发病的影响[J].实用儿科学临床杂志,2005,20(5)：460-462.
30.唐洪丽,刘放南.儿奄抽动障碍血浆兴奋性氨基酸水平与行为心理的相关性研究[J].江苏医药杂志,2003,29(10)：725-727.
31.唐洪丽,刘放南,龚建平.儿童Tourette综合征与兴奋性氨基酸及性激素水平的相关性研究[J].中国实用儿科杂志,2004,19(5)：301-302.
32.张风华,魏书珍Tourette综合征患儿血清催乳素水平及神经心理功能的对照研究,中国行为医学科学,2002,11(6):645-647.
33.唐洪丽,刘放南,龚建平.儿童Tourette综合征与兴奋性氨基酸及性激素水平的相关性研究[J].中国实用儿科杂志,2004,19(5):301-302.
34.陈文,林广裕,吴毅.低铁血症对小儿多发性抽动症发病的影响.广东医学.2003.24(6)：615-616
35. Lekman JF,KatsorichL,Kawikova I, etal. Increased serum levels of interleukin-12 and tumor necrosis factor-alpha in Tourette syndrome[J]. BiolPsychiatry,2005, 57(6):667-673.
36. Trifiletti RP,Packard AM.Immune mechanisms in pediatric neu-ropsychiatric disorders. Tourette's syndrome,OCD,and Tourette's syndrome,OCD and PANDAS.Child Adolesc Psychiatr Clinic NAm,1999,8(4):767
37.阮毅燕等,Tourette综合征患儿链球菌感染及其免疫功能检测,中国实用儿科 杂,2007,22(3)：182-185.
38. Dalton R, Behrman RE, Kliegman RM, Jenson HB. Habit disorders.In:Nelson Textbook of Pediatrics.16th ed, Philadelphia:WB SAUNDERS,2000.75
39.卢银平,董继华,刘朝,管世鹤.抽动-秽语综合征儿童巨细胞病毒感染的意义初探,中华神经医学杂志,2006,5(11)：1175-1176.
40. Hogan MB, Wilson NW. Tourette syndromr mimicking asthma. JAsthma,1999,36(3):253
41.李树华,庞保东,徐应军,曹丽华,刘寅,吴家骅,抽动秽语综合征危险因素的病例对照研究,中国儿童保健杂志2004,12(5)：412-414
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |