宁动颗粒治疗抽动—秽语综合征的临床与分子机制研究
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摘要
背景
抽动-秽语综合征(Tourette's syndrome, TS)是一种好发于儿童,以无意识的、无目的的、反复的运动性或声音性抽动为特征的慢性神经精神性疾病。发病率在儿童、青少年群体中较高,约0.4-3.8%。临床表现为头面、躯干及四肢不自主的抽动,喉部发出奇异叫声或骂詈不避亲疏。抽动症状有不规则的发作间歇期,可因转移注意力而减轻,睡眠时症状消失,压力过大、精神紧张时症状加重。除抽动症状外,常常伴有强迫(Obsessive-compulsive disorder,OCD)、多动、冲动及注意力缺陷症状,其中强迫障碍发生率为50%。TS及伴发的OCD症状交替出现,反复发作,迁延不愈,严重影响着处于生长发育阶段儿童及青少年的生活和学习。因此,尽早采取安全有效的干预措施和治疗方法具有十分重要的意义。
长期以来,典型性抗精神病药物(氟哌啶醇、哌咪清、氟奋乃静等)常作为治疗TS的标准疗法,尤其是氟哌啶醇常作为第一选择。但长期应用后的副作用,如嗜睡、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,让许多患者无法忍受。近年来,应用非典型抗精神病药物(如利哌酮、喹硫平、奥氮平等)已经成为TS治疗的一种新趋势,临床疗效不稳定,而且具有一定的副作用,如镇静、体重增加、抑郁等。选择性5-羟色胺再摄取抑制剂(Selective serotonin reuptake inhibitors, SSRI),如氟西汀、帕罗西汀、氟伏沙明等,主要用于TS伴发OCD的治疗。
宁动颗粒是根据导师多年来治疗TS的验方采用现代科学工艺研制的中药复方制剂。动物实验表明,宁动颗粒对阿朴吗啡(Apomorphine, Apo)诱导的TS大鼠模型的刻板活动具有明显抑制作用。但宁动颗粒治疗TS及伴发OCD的临床疗效,以及与SSRI类药物疗效比较尚不明确。为此,进行了宁动颗粒和氟西汀治疗TS及伴发OCD的对照临床研究。
目的
1.探讨宁动颗粒和氟西汀治疗TS及伴发OCD症状的疗效及安全性。
2.评价宁动颗粒和氟西汀治疗TS及伴发OCD的相对价值。
方法
将符合诊断标准的66例患者随机分成宁动颗粒组和氟西汀组各33例。宁动颗粒组予宁动颗粒1g/kg/d；氟西汀组予氟西汀,初始剂量10mg/d,最大剂量60mg/d。既往药物治疗史者,经4周清洗期后给予上述治疗。两组均治疗半年。参照美国耶鲁综合抽动严重程度量表(Yale Global Tic Severity Scale, YGTSS)和耶鲁-布朗强迫量表(Yale-Brown Obsessive Compulsive Scale, Y-BOCS),分别于治疗前、后,进行综合抽动、强迫障碍严重程度量化评估,以评定疗效。记录不良反应,治疗前、后检测血、尿、大便三大常规,肝肾功能,心电图,体重指数(Body mass index, BMI),以评价安全性。
结果
1.一般资料
在符合诊断标准的66例TS伴发OCD患者中有4例患者治疗过程中退出研究,其中宁动颗粒组1例,氟西汀组3例,在统计分析时将其剔除。两组剩余62例患者在年龄、性别、体重指数、药物治疗史、基线YGTSS积分及Y-BOCS评分方面比较,差异均无统计学意义,具有可比性(P>0.05)。
2.抽动评分比较
与治疗前总抽动、运动性抽动、声音性抽动评分比较,两组治疗后均显著降低(P<0.01)；宁动颗粒组总抽动和运动性抽动评分降低更显著,较氟西汀组差异具有统计学意义(P<0.05或P<0.01)；治疗前后声音性抽动评分变化,两组间比较无统计学意义(P>0.05)。
3.抽动整体损害评分比较
与治疗前抽动整体损害评分相比,两组病例治疗后均明显降低(P<0.01)；治疗前后抽动整体损害评分变化,两组之间比较差异无统计学意义。
4.综合抽动总有效率比较
宁动颗粒组综合抽动抑制总有效率71.9%(23/32)显著优于氟西汀组46.7%(14/30)(P<0.05)。
5.两组病例强迫障碍严重程度评分比较与治疗前Y-BOCS评分相比,两组治疗后均明显降低(P<0.01)；氟西汀组Y-BOCS评分降低较宁动颗粒组更显著(P=0.01)。
6.强迫症状好转有效率
氟西汀组强迫症状好转有效率为80.0%(24/30)明显优于宁动颗粒组56.2%(18/32)(P<0.05)。
7.不良反应
宁动颗粒组中出现不良反应者2例,分别为厌食和便秘。氟西汀组出现不良反应者9例,主要表现为恶心、厌食、失眠、焦虑、躁狂等。宁动颗粒组不良反应发生率6.1%(2/33)明显低于氟西汀组30%(9/30)(P<0.05)。两组均未发现肝肾功能损害、心脏毒性和体重指数异常。
结论
宁动颗粒和氟西汀均能有效改善TS抽动及伴发OCD症状。宁动颗粒抑制TS抽动的疗效优于氟西汀,但氟西汀抑制OCD症状的疗效更显著。宁动颗粒临床应用安全性优于氟西汀。
背景
抽动-秽语综合征(Tourette's syndrome, TS)是一种以无意识的、无目的的、反复的运动性或声音性抽动为特征的慢性神经精神性疾病。TS的病因及发病机制目前尚不十分清楚。其发病可能与遗传因素、中枢神经递质失衡、神经生化异常和精神因素等诸多方面有关。目前普遍认为,中枢神经递质失衡在TS发病过程中的起着重要作用。
有动物和临床实验表明,TS患者存在多巴胺(Dopamin, DA)系统功能过度活跃。不但中枢DA活性过度,而且有突触后受体超敏感,超敏感的受体引起效应细胞的反应活动过度。我们前期动物实验表明,阿朴吗啡(Apomorphine, Apo)诱导的TS大鼠模型纹状体确实存在DA系统活性增强。在基底神经节-丘脑皮层回路中,5-羟色胺(5-hydroxytryptamine,5-HT)系统伴随DA系统,共同控制机体运动、认知、感情。5-HT系统对于脑的高级部位和精神活动方面起着普遍的抑制和稳定作用。临床上应用选择性5-羟色胺再摄取抑制剂(selective serotonin reuptake inhibitors, SSRI)治疗TS有效,尤其是治疗TS伴随强迫障碍(Obsessive-compulsive, OCD)疗效肯定,进一步表明TS在病理生理方面可能存在5-HT能系统功能相对或绝对不足。第一部分临床研究结果显示,宁动颗粒可以有效改善TS抽动症状以及伴发的OCD症状。前期动物实验表明,宁动颗粒可以抑制TS大鼠模型纹状体DA系统活性,但对5-HT系统的影响尚不明确。
目的
1.探讨TS大鼠模型纹状体5-HT系统变化。
2.探讨宁动颗粒对TS大鼠模型纹状体5-HT系统的影响,以进一步明确宁动颗粒治疗TS的作用机制。
方法
1.研究对象：4周龄雄性Wistar大鼠64只,随机分为4组,每组16只：(1)正常对照组(Control),16只；(2)阿朴吗啡组(Apo),16只；(3)宁动颗粒低剂量组(NGL),16只；(4)宁动颗粒高剂量组(NGH),16只。常对照组腹腔注射生理盐水3 ml/(kg-d),其余3组腹腔注射Apo2.0mg/(kg-d)。连续注射4周。NGL组给予宁动颗粒1.8g/(kg-d)；NGH组给予宁动颗粒3.6g/(kg·d)；正常对照组及Apo组分别给予等量蒸馏水。各组大鼠均灌胃给药,每日9：00和16：00分别给药1次,连续给药12周。末次给药后禁食24 h,不禁水。3%戊巴比妥钠(30mmg/kg,腹腔注射)麻醉。多聚甲醛全身灌注,留纹状体固定备用,另取新鲜脑组织,-80℃保存备用。然后进行后续实验。
2.研究内容：(1)免疫组织化学染色法检测纹状体内5-HT2AR蛋白表达；(2)实时定量PCR(Real time PCR, RT-PCR)法检测纹状体内5-HT2AR mRNA表达；(3)蛋白印记法(Western blot, WB)检测纹状体内TPH2蛋白表达；(4)酶联免疫吸附剂测定法(Enzyme linked immunosorbent assay, ELISA)检测纹状体中5-HT、5-HIAA含量。
结果
1.大鼠纹状体5-HT2AR:蛋白表达比较
与正常对照组大鼠相比,Apo组大鼠纹状体5-HT2AR蛋白表达明显升高(143.10±8.01vs127.43±6.72,P<0.01)。治疗后大鼠纹状体5-HT2AR蛋白表达随宁动颗粒剂量加大进一步升高。与Apo组大鼠比较,NGL组大鼠纹状体5-HT2AR蛋白表达有所升高(153.69±9.38 vs 143.10±8.01,P<0.05)；NGH组大鼠纹状体5-HT2AR蛋白表达显著升高(166.33±9.21 vs 143.10±8.01,P<0.01)。治疗组间比较差异具有统计学意义(166.33±9.21 vs 153.69±9.38,P<0.01)。
2.大鼠纹状体5-HT2AR mRNA表达比较
与正常对照组大鼠相比,Apo组大鼠纹状体5-HT2AR mRNA表达有所升高[1.52(0.93-2.46)vs 1.00(0.77-1.3),P<0.05]。给药后,大鼠纹状体5-HT2AR mRNA表达进一步升高。与Apo组大鼠比较,NGL组大鼠纹状体5-HT2AR mRNA表达有所升高[2.53(1.36-4.72)vs 1.52(0.93-2.46),P<0.05]；NGH组大鼠纹状体5-HT2AR mRNA表达显著升高[3.10(1.69-5.66)vs 1.52(0.93-2.46),P<0.01]。NGL组与NGH组相比差异无统计学意义(P>0.05)
3.大鼠纹状体TPH2蛋白表达比较
与正常对照组大鼠比较,Apo组大鼠纹状体TPH2蛋白表达有所升高(0.41±0.046 vs0.34±0.034,P<0.05)。给药后,大鼠纹状体TPH2蛋白表达进一步升高。与Apo组大鼠比较,NGL组大鼠纹状体TPH2蛋白表达明显升高(0.65±0.040 vs 0.41±0.046,P<0.01)；NGH组大鼠纹状体5-HT2AR mRNA表达进一步升高(0.81±0.051 vs 0.41±0.046,P<0.01)。NGL组与NGH组相比差异具有统计学意义(P<0.01)。
4.大鼠纹状体中5-HT含量比较
与正常对照组大鼠比较,Apo组大鼠纹状体5-HT含量有所升高(1.98±0.14 vs 1.78±0.10 ng/ml,P<0.05)。给药后NGL组较Apo组大鼠纹状体中5-HT含量无明显变化(2.05±0.17 vs 1.98±0.14ng/ml,P>0.05)。NGH组较Apo组大鼠纹状体中5-HT含量明显升高(2.20±0.14 vs 1.98±0.14ng/ml,P<0.05)。两治疗组间比较无统计学意义(P>0.05)。
5.大鼠纹状体中5-HIAA含量比较
与正常对照组大鼠比较,Apo组大鼠纹状体5-HIAA含量变化无统计学意义(0.94±0.12 vs 0.97±0.10ng/ml,P>0.05)。给药后NGL组和NGH组与Apo组相比大鼠,纹状体中5-HIAA含量均明显降低(0.77±0.10 vs 0.94±0.12,P<0.05；0.58±0.08 vs0.94±0.12,P<0.01)。两治疗组间比较具有明显差异(P＜0.01)。
结论
1.在Apo诱导的TS大鼠模型中证实了5-HT系统活性增强的存在,但其活性增强可能仍相对不足。
2.宁动颗粒治疗TS的作用机制与其促进纹状体内5-HT合成,抑制其代谢,上调5-HT2AR表达,增强纹状体内5-HT系统兴奋性有关。
Background
Tourette's syndrome (TS) is a chronic, childhood-onset neuropsychiatric disorder, which is characterized by multiple motor and vocal tics, including involuntary or semi-voluntary, sudden, brief, intermittent, repetitive movements or sounds. The prevalence of TS is estimated to be 0.4-3.8%for children and adolescents. 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 decrease by divert attention, vanish after sleep, and aggravate after actuation. In addition to tics, it often associates with obsessive-compulsive disorder (OCD), motor tics and attention-deficit hyperactivity disorder (ADHD), in which the incidence of OCD is 25-60%. The symptoms are alternating, recurrent, persistent unhealed, which seriously affect the children and adolescents'lives and study in the growth and developmental stages. Therefore, it is important to treat TS early and effectively.
For a long time, typical antipsychotics (e.g. haloperidol, pimozide, and fluphenazine) are the standard therapy for TS, and haloperidol is the first-choice neuroleptic. Many patients treated with haloperidol experience adverse events, such as akathisia, bradykinesia, dystonia, Parkinsonism, and somnolence. Only a minority of patients continue to use haloperidol for extended periods. Recently, several atypical antipsychotics (e.g. risperidone, olanzapine, and quetiapine) have recently been used instead of classical antipsychotics in an attempt to improve the clinical course of TS and to minimize side-effects. None of these atypical antipsychotics are curative and all have some common and troublesome side-effects, such as sedation, increasing body weight, and depression. Thus, there is a need for alternative effective and mild side effects pharmacotherapy for TS. Selective serotonin reuptake inhibitors (SSRI), such as fluoxetine, paroxetine, fluvoxamine, are primarily used for the treatment of OCD associated with TS.
ND granule, a Chinese herbal compound preparation, was made by modern technology according my advisor's prescription for TS. Previous research by the authors demonstrated that ND granule improved the stereotypical behaviour of apomorphine-induced TS rats, an animal model of TS, by suppressing the dopamine (DA) system. However, the efficacy of ND granule for OCD associated with TS and comparison with the efficacy of SSRI drugs remain unknown. Thus, the controlled clinical trial was done.
Objective
1. To investigate the effect and security of ND granule and fluoxetine on TS and OCD associated with it.
2. To evaluate relative value of ND granule and fluoxetine on TS and OCD associated with it.
Method
66 patients of TS with OCD were randomly divided into 2 groups.33 patients in the ND granule group were treated with ND granule lg/kg/d, and 33 patients in the fluoxetine group were treated with fluoxetine, the initial dose of fluoxetine was 10mg/d, and maximum dose was 60mg/d. All of the participants with history of medication had to be medication-free for≥4 weeks prior to the study. In order to investigate the effect of ND granule and fluoxetine on TS and OCD, the severity of tics and OCD were evaluated at baseline and at end point, with Yale Global Tic Severity Scale (YGTSS) and Yale-Brown Obsessive Compulsive Scale (Y-BOCS). To evaluate the security of ND granule and fluoxetine on TS and OCD, Side-effects were evaluated according to an adverse event chart produced by this study team. Alanine transferase (ALT), aspartate transaminase (AST), blood urea nitrogen (BUN), creatinine, electrocardiogram, and body mass index (BMI) were measured at baseline and at end point.
Results
1. Study population
Sixty-six subjects were recruited to participate in this study. One patient in the ND granule group and two patients in the fluoxetine group missed the full course of treatment, so they were excluded from this analysis. The remaining subjects in the two groups were similar with regard to age, gender, BMI, previous use of pharmacotherapy for tics, baseline YGTSS total tic score and Y-BOCS score (P> 0.05).
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 both two groups at end point reduced significantly (P< 0.01). Compared with fluoxetine group, the YGTSS total tic score and motor tic score in ND granule group reduced more significantly (P<0.05或P <0.01). The difference of YGTSS vocal tic score reduction between the two groups was not significant.
3. Comparison of YGTSS overall impairment scores
Compared with overall impairment score at baseline, the scores of both two groups at end point reduced significantly (P< 0.01). The difference of YGTSS overall impairment scores reduction between the two groups was not significant.
4. Comparison of total effective rate of tics
The total effective rate (66.7%) in ND granule group were higher than that (46.7%) in fluoxetine group (P< 0.01).
5. Comparison of Y-BOCS score
Compared with Y-BOCS score at baseline, in the trail group, Y-BOCS score after 6 months medication significantly decreased (P<0.05). the reduction of Y-BOCS score in fluoxetine group was more significant than that in ND granule (P= 0.01)
6. Comparison of total effective rate of OCD
The total effective rate (80.0%) in fluoxetine granule group were higher than that (56.2%) in ND group (P< 0.05)
6. Side effects
Only two subjects reported loss of appetite and constipation in the ND granule, while 9 subjects experienced adverse reactions, Nausea, anorexia, insomnia, anxiety, mania, etc., in fluoxetine group. The incidence of adverse reactions in ND granule was lower than that in in fluoxetine group. Moreover, no abnormalities on the liver or renal function tests, or cardiac toxicity were observed after administration of ND granule.
Conclusion
Both ND granule and fluoxetine could improve the syndrome of tics and OCD associated with TS. ND granule exhibited better effect on TS, while fluoxetine show better effect on OCD associated with TS. ND granule was superior to fluoxetine in the clinical application security.
Background
Tourette's syndrome (TS) is a chronic, childhood-onset neuropsychiatric disorder, which is characterized by multiple motor and vocal tics. The etiology and pathogenesis of TS is not yet clear. Genetic factors, central nervous system neurotransmitter imbalances, neurological and biochemical abnormalities and psychological factors may be associated with TS. It has been generally recognized that neurotransmitter imbalances of central nervous system plays an important role on pathogenesis of TS.
Some animal and clinical researches indicate that over-active function of dopamine system exhibit in TS. Central DA activity is not only excessive, but also post-synaptic receptor super-sensitive, ultra-sensitive receptors caused by excessive effector cell over response. Our previous animal study also shows that over-active function of dopamine system exhibit in TS rat model. In the basal ganglia-thalamic cortical loop,5-hydroxytryptamine (5-hydroxytryptamine,5-HT) systems can be associated with DA systems, joint control body movement, cognitive, emotional.5-HT system plays a widespread role of suppression and stability in central parts of the brain and mental activities. Selective serotonin reuptake inhibitors (SSRI) is a effective medication for TS, particularly OCD associated with TS, which further shows that relative or absolute lack-activity of 5-HT system plays an important role in the pathophysiology of TS. Our clinical study shows that ND granule could significantly improve the tics and OCD syndrome with TS. Previous animal study also shows that ND granule could suppress the dopamine (DA) system, but the impact of ND granule on 5-HT system remains unknown.
Objective
1. Investigate the change of 5-HT system of striatum in TS rat.
2. Investigate the impact of ND granule on 5-HT system, in order to further clarify the mechanism of ND granule for TS.
Methods
Sixty-four male (4 weeks old) wistar rats were randmy divided into 4 groups (n=16):the control group, the model (Apo) group, the low dosage NDG (NGL) group, and the high dosage (NGH) group. TS rat models were induced by intraperitoneal injection (i.p.) with Apo (2mg/kg) in the experimental groups last 4 weeks. Rats in the control group were injected with normal saline (0.9%) (3ml/kg, i.p.). After the injection of Apo (i.p.), rats were treated by intragastric administration (i.g.) with ND granule at 1.8g/(kg-d) in NGL group, with ND granule at 3.6g/(kg-d) in NGH group, with distilled water at equal Volume in Control group and Apo group, respectively, twice a day at 9am and 4 pm for 12 successive weeks.
After the last administration,all rats were fasted with free access to water for 24 h, and anesthetized with intraperitoneal injection of 3% pentobarbital (30 mg/kg) which was followed by other experiments. The detection conten (1) Analysis the 5-HT2aAR protein expression by Immunohistochemical method; (2) Analysis the 5-HT2AR mRNA expression by RT-PCR; (3) Analysis the TPH2 protein expression by Western blot. (4) Determination of the content of 5-HT and 5-HIAA in striatum by Enzyme linked immunosorbent assay (ELISA);
Results
Comparison of the expression of 5-HT2AR protein
The level of the expression of 5-HT2AR protein in striatum in Apo group was significant higher than that in the control group (143.10±8.01 vs 127.43±6.72, P< 0.01). The level of the expression of 5-HT2AR protein became higher after medication with ND granule. The level of the expression of 5-HT2AR protein in Both NDL group and NDH group significantly increased Compared with in Apo group (P<0.05或P<0.01). The level of the expression of 5-HT2AR protein in NDH group significantly increased, compared with that in NDL group (P <0.01)
Comparison of the expression of 5-HT2AR mRNA in striatum
The level of the expression of 5-HT2AR mRNA in striatum in Apo group was significant higher than that in the control group[1.52(0.93-2.46) vs 1.00(0.77-1.3), P<0.05]. After treatment, the level of the expression of 5-HT2AR mRNA in both NDL group and NDH group became higher than that in Apo group(P<0.05或P<0.01). The difference between NDL group and NDH group was not significant (P>0.05).
Comparison of the expression of TPH2 protein
The level of the expression of TPH2 protein in Apo group was significant higher than that in the control group[1.52(0.93-2.46) vs 1.00(0.77-1.3), P<0.05]. After treatment, the level of the expression of TPH2 protein in both NDL group and NDH group became higher than that in Apo group(P<0.05或P<0.01). The level of the expression of TPH2 protein in NDH group significantly increased, compared with that in NDL group (P<0.01).
Comparison of level of 5-HT in striatum
The level of 5-HT in striatum in Apo group was significant higher than that in the control group(1.98±0.14 vs 1.78±0.10 ng/ml, P<0.05). The difference between Apo group and NDL group was not significant (P>0.05). The level of 5-HT in NDH group became higher than that in Apo group(2.20±0.14 vs 1.98±0.14ng/ml, P<0.05). No difference was shown in comparison between NGL group and NDH group (P> 0.05)
Comparison of level of 5-HIAA in striatum
No difference was shown in comparison of level of 5-HIAA in striatum between Apo group and control group(0.94±0.12 vs 0.97±0.10ng/ml, P>0.05). The level of 5-HIAA in both NDL group and NDH group became lower than that in Apo group (0.77±0.10 vs 0.94±0.12, P<0.05; 0.58±0.08 vs 0.94±0.12, P<0.01). the difference between NGL group and NDH group was significant(P<0.01).
Conclusion
1. Activity of 5-HT system enhanced in Apo-induced TS rat model; however, the enhanced activity may still be relatively insufficient.
2. The mechanism of ND granule treating TS was associated with promotion of 5-HT synthesis in the striatum, depression of the 5-HT metabolism, up-regulation expression of 5-HT2AR, enhancing activity of 5-HT system and improving the activity insufficient of 5-HT system.
抽动-秽语综合征(Tourette's syndrome, TS)是一种好发于儿童,以无意识的、无目的的、反复的运动性或声音性抽动为特征的慢性神经精神性疾病。发病率在儿童、青少年群体中较高,约0.4-3.8%。临床表现为头面、躯干及四肢不自主的抽动,喉部发出奇异叫声或骂詈不避亲疏。抽动症状有不规则的发作间歇期,可因转移注意力而减轻,睡眠时症状消失,压力过大、精神紧张时症状加重。除抽动症状外,常常伴有强迫(Obsessive-compulsive disorder,OCD)、多动、冲动及注意力缺陷症状,其中强迫障碍发生率为50%。TS及伴发的OCD症状交替出现,反复发作,迁延不愈,严重影响着处于生长发育阶段儿童及青少年的生活和学习。因此,尽早采取安全有效的干预措施和治疗方法具有十分重要的意义。
长期以来,典型性抗精神病药物(氟哌啶醇、哌咪清、氟奋乃静等)常作为治疗TS的标准疗法,尤其是氟哌啶醇常作为第一选择。但长期应用后的副作用,如嗜睡、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,让许多患者无法忍受。近年来,应用非典型抗精神病药物(如利哌酮、喹硫平、奥氮平等)已经成为TS治疗的一种新趋势,临床疗效不稳定,而且具有一定的副作用,如镇静、体重增加、抑郁等。选择性5-羟色胺再摄取抑制剂(Selective serotonin reuptake inhibitors, SSRI),如氟西汀、帕罗西汀、氟伏沙明等,主要用于TS伴发OCD的治疗。
宁动颗粒是根据导师多年来治疗TS的验方采用现代科学工艺研制的中药复方制剂。动物实验表明,宁动颗粒对阿朴吗啡(Apomorphine, Apo)诱导的TS大鼠模型的刻板活动具有明显抑制作用。但宁动颗粒治疗TS及伴发OCD的临床疗效,以及与SSRI类药物疗效比较尚不明确。为此,进行了宁动颗粒和氟西汀治疗TS及伴发OCD的对照临床研究。
目的
1.探讨宁动颗粒和氟西汀治疗TS及伴发OCD症状的疗效及安全性。
2.评价宁动颗粒和氟西汀治疗TS及伴发OCD的相对价值。
方法
将符合诊断标准的66例患者随机分成宁动颗粒组和氟西汀组各33例。宁动颗粒组予宁动颗粒1g/kg/d；氟西汀组予氟西汀,初始剂量10mg/d,最大剂量60mg/d。既往药物治疗史者,经4周清洗期后给予上述治疗。两组均治疗半年。参照美国耶鲁综合抽动严重程度量表(Yale Global Tic Severity Scale, YGTSS)和耶鲁-布朗强迫量表(Yale-Brown Obsessive Compulsive Scale, Y-BOCS),分别于治疗前、后,进行综合抽动、强迫障碍严重程度量化评估,以评定疗效。记录不良反应,治疗前、后检测血、尿、大便三大常规,肝肾功能,心电图,体重指数(Body mass index, BMI),以评价安全性。
结果
1.一般资料
在符合诊断标准的66例TS伴发OCD患者中有4例患者治疗过程中退出研究,其中宁动颗粒组1例,氟西汀组3例,在统计分析时将其剔除。两组剩余62例患者在年龄、性别、体重指数、药物治疗史、基线YGTSS积分及Y-BOCS评分方面比较,差异均无统计学意义,具有可比性(P>0.05)。
2.抽动评分比较
与治疗前总抽动、运动性抽动、声音性抽动评分比较,两组治疗后均显著降低(P<0.01)；宁动颗粒组总抽动和运动性抽动评分降低更显著,较氟西汀组差异具有统计学意义(P<0.05或P<0.01)；治疗前后声音性抽动评分变化,两组间比较无统计学意义(P>0.05)。
3.抽动整体损害评分比较
与治疗前抽动整体损害评分相比,两组病例治疗后均明显降低(P<0.01)；治疗前后抽动整体损害评分变化,两组之间比较差异无统计学意义。
4.综合抽动总有效率比较
宁动颗粒组综合抽动抑制总有效率71.9%(23/32)显著优于氟西汀组46.7%(14/30)(P<0.05)。
5.两组病例强迫障碍严重程度评分比较与治疗前Y-BOCS评分相比,两组治疗后均明显降低(P<0.01)；氟西汀组Y-BOCS评分降低较宁动颗粒组更显著(P=0.01)。
6.强迫症状好转有效率
氟西汀组强迫症状好转有效率为80.0%(24/30)明显优于宁动颗粒组56.2%(18/32)(P<0.05)。
7.不良反应
宁动颗粒组中出现不良反应者2例,分别为厌食和便秘。氟西汀组出现不良反应者9例,主要表现为恶心、厌食、失眠、焦虑、躁狂等。宁动颗粒组不良反应发生率6.1%(2/33)明显低于氟西汀组30%(9/30)(P<0.05)。两组均未发现肝肾功能损害、心脏毒性和体重指数异常。
结论
宁动颗粒和氟西汀均能有效改善TS抽动及伴发OCD症状。宁动颗粒抑制TS抽动的疗效优于氟西汀,但氟西汀抑制OCD症状的疗效更显著。宁动颗粒临床应用安全性优于氟西汀。
背景
抽动-秽语综合征(Tourette's syndrome, TS)是一种以无意识的、无目的的、反复的运动性或声音性抽动为特征的慢性神经精神性疾病。TS的病因及发病机制目前尚不十分清楚。其发病可能与遗传因素、中枢神经递质失衡、神经生化异常和精神因素等诸多方面有关。目前普遍认为,中枢神经递质失衡在TS发病过程中的起着重要作用。
有动物和临床实验表明,TS患者存在多巴胺(Dopamin, DA)系统功能过度活跃。不但中枢DA活性过度,而且有突触后受体超敏感,超敏感的受体引起效应细胞的反应活动过度。我们前期动物实验表明,阿朴吗啡(Apomorphine, Apo)诱导的TS大鼠模型纹状体确实存在DA系统活性增强。在基底神经节-丘脑皮层回路中,5-羟色胺(5-hydroxytryptamine,5-HT)系统伴随DA系统,共同控制机体运动、认知、感情。5-HT系统对于脑的高级部位和精神活动方面起着普遍的抑制和稳定作用。临床上应用选择性5-羟色胺再摄取抑制剂(selective serotonin reuptake inhibitors, SSRI)治疗TS有效,尤其是治疗TS伴随强迫障碍(Obsessive-compulsive, OCD)疗效肯定,进一步表明TS在病理生理方面可能存在5-HT能系统功能相对或绝对不足。第一部分临床研究结果显示,宁动颗粒可以有效改善TS抽动症状以及伴发的OCD症状。前期动物实验表明,宁动颗粒可以抑制TS大鼠模型纹状体DA系统活性,但对5-HT系统的影响尚不明确。
目的
1.探讨TS大鼠模型纹状体5-HT系统变化。
2.探讨宁动颗粒对TS大鼠模型纹状体5-HT系统的影响,以进一步明确宁动颗粒治疗TS的作用机制。
方法
1.研究对象：4周龄雄性Wistar大鼠64只,随机分为4组,每组16只：(1)正常对照组(Control),16只；(2)阿朴吗啡组(Apo),16只；(3)宁动颗粒低剂量组(NGL),16只；(4)宁动颗粒高剂量组(NGH),16只。常对照组腹腔注射生理盐水3 ml/(kg-d),其余3组腹腔注射Apo2.0mg/(kg-d)。连续注射4周。NGL组给予宁动颗粒1.8g/(kg-d)；NGH组给予宁动颗粒3.6g/(kg·d)；正常对照组及Apo组分别给予等量蒸馏水。各组大鼠均灌胃给药,每日9：00和16：00分别给药1次,连续给药12周。末次给药后禁食24 h,不禁水。3%戊巴比妥钠(30mmg/kg,腹腔注射)麻醉。多聚甲醛全身灌注,留纹状体固定备用,另取新鲜脑组织,-80℃保存备用。然后进行后续实验。
2.研究内容：(1)免疫组织化学染色法检测纹状体内5-HT2AR蛋白表达；(2)实时定量PCR(Real time PCR, RT-PCR)法检测纹状体内5-HT2AR mRNA表达；(3)蛋白印记法(Western blot, WB)检测纹状体内TPH2蛋白表达；(4)酶联免疫吸附剂测定法(Enzyme linked immunosorbent assay, ELISA)检测纹状体中5-HT、5-HIAA含量。
结果
1.大鼠纹状体5-HT2AR:蛋白表达比较
与正常对照组大鼠相比,Apo组大鼠纹状体5-HT2AR蛋白表达明显升高(143.10±8.01vs127.43±6.72,P<0.01)。治疗后大鼠纹状体5-HT2AR蛋白表达随宁动颗粒剂量加大进一步升高。与Apo组大鼠比较,NGL组大鼠纹状体5-HT2AR蛋白表达有所升高(153.69±9.38 vs 143.10±8.01,P<0.05)；NGH组大鼠纹状体5-HT2AR蛋白表达显著升高(166.33±9.21 vs 143.10±8.01,P<0.01)。治疗组间比较差异具有统计学意义(166.33±9.21 vs 153.69±9.38,P<0.01)。
2.大鼠纹状体5-HT2AR mRNA表达比较
与正常对照组大鼠相比,Apo组大鼠纹状体5-HT2AR mRNA表达有所升高[1.52(0.93-2.46)vs 1.00(0.77-1.3),P<0.05]。给药后,大鼠纹状体5-HT2AR mRNA表达进一步升高。与Apo组大鼠比较,NGL组大鼠纹状体5-HT2AR mRNA表达有所升高[2.53(1.36-4.72)vs 1.52(0.93-2.46),P<0.05]；NGH组大鼠纹状体5-HT2AR mRNA表达显著升高[3.10(1.69-5.66)vs 1.52(0.93-2.46),P<0.01]。NGL组与NGH组相比差异无统计学意义(P>0.05)
3.大鼠纹状体TPH2蛋白表达比较
与正常对照组大鼠比较,Apo组大鼠纹状体TPH2蛋白表达有所升高(0.41±0.046 vs0.34±0.034,P<0.05)。给药后,大鼠纹状体TPH2蛋白表达进一步升高。与Apo组大鼠比较,NGL组大鼠纹状体TPH2蛋白表达明显升高(0.65±0.040 vs 0.41±0.046,P<0.01)；NGH组大鼠纹状体5-HT2AR mRNA表达进一步升高(0.81±0.051 vs 0.41±0.046,P<0.01)。NGL组与NGH组相比差异具有统计学意义(P<0.01)。
4.大鼠纹状体中5-HT含量比较
与正常对照组大鼠比较,Apo组大鼠纹状体5-HT含量有所升高(1.98±0.14 vs 1.78±0.10 ng/ml,P<0.05)。给药后NGL组较Apo组大鼠纹状体中5-HT含量无明显变化(2.05±0.17 vs 1.98±0.14ng/ml,P>0.05)。NGH组较Apo组大鼠纹状体中5-HT含量明显升高(2.20±0.14 vs 1.98±0.14ng/ml,P<0.05)。两治疗组间比较无统计学意义(P>0.05)。
5.大鼠纹状体中5-HIAA含量比较
与正常对照组大鼠比较,Apo组大鼠纹状体5-HIAA含量变化无统计学意义(0.94±0.12 vs 0.97±0.10ng/ml,P>0.05)。给药后NGL组和NGH组与Apo组相比大鼠,纹状体中5-HIAA含量均明显降低(0.77±0.10 vs 0.94±0.12,P<0.05；0.58±0.08 vs0.94±0.12,P<0.01)。两治疗组间比较具有明显差异(P＜0.01)。
结论
1.在Apo诱导的TS大鼠模型中证实了5-HT系统活性增强的存在,但其活性增强可能仍相对不足。
2.宁动颗粒治疗TS的作用机制与其促进纹状体内5-HT合成,抑制其代谢,上调5-HT2AR表达,增强纹状体内5-HT系统兴奋性有关。
Background
Tourette's syndrome (TS) is a chronic, childhood-onset neuropsychiatric disorder, which is characterized by multiple motor and vocal tics, including involuntary or semi-voluntary, sudden, brief, intermittent, repetitive movements or sounds. The prevalence of TS is estimated to be 0.4-3.8%for children and adolescents. 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 decrease by divert attention, vanish after sleep, and aggravate after actuation. In addition to tics, it often associates with obsessive-compulsive disorder (OCD), motor tics and attention-deficit hyperactivity disorder (ADHD), in which the incidence of OCD is 25-60%. The symptoms are alternating, recurrent, persistent unhealed, which seriously affect the children and adolescents'lives and study in the growth and developmental stages. Therefore, it is important to treat TS early and effectively.
For a long time, typical antipsychotics (e.g. haloperidol, pimozide, and fluphenazine) are the standard therapy for TS, and haloperidol is the first-choice neuroleptic. Many patients treated with haloperidol experience adverse events, such as akathisia, bradykinesia, dystonia, Parkinsonism, and somnolence. Only a minority of patients continue to use haloperidol for extended periods. Recently, several atypical antipsychotics (e.g. risperidone, olanzapine, and quetiapine) have recently been used instead of classical antipsychotics in an attempt to improve the clinical course of TS and to minimize side-effects. None of these atypical antipsychotics are curative and all have some common and troublesome side-effects, such as sedation, increasing body weight, and depression. Thus, there is a need for alternative effective and mild side effects pharmacotherapy for TS. Selective serotonin reuptake inhibitors (SSRI), such as fluoxetine, paroxetine, fluvoxamine, are primarily used for the treatment of OCD associated with TS.
ND granule, a Chinese herbal compound preparation, was made by modern technology according my advisor's prescription for TS. Previous research by the authors demonstrated that ND granule improved the stereotypical behaviour of apomorphine-induced TS rats, an animal model of TS, by suppressing the dopamine (DA) system. However, the efficacy of ND granule for OCD associated with TS and comparison with the efficacy of SSRI drugs remain unknown. Thus, the controlled clinical trial was done.
Objective
1. To investigate the effect and security of ND granule and fluoxetine on TS and OCD associated with it.
2. To evaluate relative value of ND granule and fluoxetine on TS and OCD associated with it.
Method
66 patients of TS with OCD were randomly divided into 2 groups.33 patients in the ND granule group were treated with ND granule lg/kg/d, and 33 patients in the fluoxetine group were treated with fluoxetine, the initial dose of fluoxetine was 10mg/d, and maximum dose was 60mg/d. All of the participants with history of medication had to be medication-free for≥4 weeks prior to the study. In order to investigate the effect of ND granule and fluoxetine on TS and OCD, the severity of tics and OCD were evaluated at baseline and at end point, with Yale Global Tic Severity Scale (YGTSS) and Yale-Brown Obsessive Compulsive Scale (Y-BOCS). To evaluate the security of ND granule and fluoxetine on TS and OCD, Side-effects were evaluated according to an adverse event chart produced by this study team. Alanine transferase (ALT), aspartate transaminase (AST), blood urea nitrogen (BUN), creatinine, electrocardiogram, and body mass index (BMI) were measured at baseline and at end point.
Results
1. Study population
Sixty-six subjects were recruited to participate in this study. One patient in the ND granule group and two patients in the fluoxetine group missed the full course of treatment, so they were excluded from this analysis. The remaining subjects in the two groups were similar with regard to age, gender, BMI, previous use of pharmacotherapy for tics, baseline YGTSS total tic score and Y-BOCS score (P> 0.05).
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 both two groups at end point reduced significantly (P< 0.01). Compared with fluoxetine group, the YGTSS total tic score and motor tic score in ND granule group reduced more significantly (P<0.05或P <0.01). The difference of YGTSS vocal tic score reduction between the two groups was not significant.
3. Comparison of YGTSS overall impairment scores
Compared with overall impairment score at baseline, the scores of both two groups at end point reduced significantly (P< 0.01). The difference of YGTSS overall impairment scores reduction between the two groups was not significant.
4. Comparison of total effective rate of tics
The total effective rate (66.7%) in ND granule group were higher than that (46.7%) in fluoxetine group (P< 0.01).
5. Comparison of Y-BOCS score
Compared with Y-BOCS score at baseline, in the trail group, Y-BOCS score after 6 months medication significantly decreased (P<0.05). the reduction of Y-BOCS score in fluoxetine group was more significant than that in ND granule (P= 0.01)
6. Comparison of total effective rate of OCD
The total effective rate (80.0%) in fluoxetine granule group were higher than that (56.2%) in ND group (P< 0.05)
6. Side effects
Only two subjects reported loss of appetite and constipation in the ND granule, while 9 subjects experienced adverse reactions, Nausea, anorexia, insomnia, anxiety, mania, etc., in fluoxetine group. The incidence of adverse reactions in ND granule was lower than that in in fluoxetine group. Moreover, no abnormalities on the liver or renal function tests, or cardiac toxicity were observed after administration of ND granule.
Conclusion
Both ND granule and fluoxetine could improve the syndrome of tics and OCD associated with TS. ND granule exhibited better effect on TS, while fluoxetine show better effect on OCD associated with TS. ND granule was superior to fluoxetine in the clinical application security.
Background
Tourette's syndrome (TS) is a chronic, childhood-onset neuropsychiatric disorder, which is characterized by multiple motor and vocal tics. The etiology and pathogenesis of TS is not yet clear. Genetic factors, central nervous system neurotransmitter imbalances, neurological and biochemical abnormalities and psychological factors may be associated with TS. It has been generally recognized that neurotransmitter imbalances of central nervous system plays an important role on pathogenesis of TS.
Some animal and clinical researches indicate that over-active function of dopamine system exhibit in TS. Central DA activity is not only excessive, but also post-synaptic receptor super-sensitive, ultra-sensitive receptors caused by excessive effector cell over response. Our previous animal study also shows that over-active function of dopamine system exhibit in TS rat model. In the basal ganglia-thalamic cortical loop,5-hydroxytryptamine (5-hydroxytryptamine,5-HT) systems can be associated with DA systems, joint control body movement, cognitive, emotional.5-HT system plays a widespread role of suppression and stability in central parts of the brain and mental activities. Selective serotonin reuptake inhibitors (SSRI) is a effective medication for TS, particularly OCD associated with TS, which further shows that relative or absolute lack-activity of 5-HT system plays an important role in the pathophysiology of TS. Our clinical study shows that ND granule could significantly improve the tics and OCD syndrome with TS. Previous animal study also shows that ND granule could suppress the dopamine (DA) system, but the impact of ND granule on 5-HT system remains unknown.
Objective
1. Investigate the change of 5-HT system of striatum in TS rat.
2. Investigate the impact of ND granule on 5-HT system, in order to further clarify the mechanism of ND granule for TS.
Methods
Sixty-four male (4 weeks old) wistar rats were randmy divided into 4 groups (n=16):the control group, the model (Apo) group, the low dosage NDG (NGL) group, and the high dosage (NGH) group. TS rat models were induced by intraperitoneal injection (i.p.) with Apo (2mg/kg) in the experimental groups last 4 weeks. Rats in the control group were injected with normal saline (0.9%) (3ml/kg, i.p.). After the injection of Apo (i.p.), rats were treated by intragastric administration (i.g.) with ND granule at 1.8g/(kg-d) in NGL group, with ND granule at 3.6g/(kg-d) in NGH group, with distilled water at equal Volume in Control group and Apo group, respectively, twice a day at 9am and 4 pm for 12 successive weeks.
After the last administration,all rats were fasted with free access to water for 24 h, and anesthetized with intraperitoneal injection of 3% pentobarbital (30 mg/kg) which was followed by other experiments. The detection conten (1) Analysis the 5-HT2aAR protein expression by Immunohistochemical method; (2) Analysis the 5-HT2AR mRNA expression by RT-PCR; (3) Analysis the TPH2 protein expression by Western blot. (4) Determination of the content of 5-HT and 5-HIAA in striatum by Enzyme linked immunosorbent assay (ELISA);
Results
Comparison of the expression of 5-HT2AR protein
The level of the expression of 5-HT2AR protein in striatum in Apo group was significant higher than that in the control group (143.10±8.01 vs 127.43±6.72, P< 0.01). The level of the expression of 5-HT2AR protein became higher after medication with ND granule. The level of the expression of 5-HT2AR protein in Both NDL group and NDH group significantly increased Compared with in Apo group (P<0.05或P<0.01). The level of the expression of 5-HT2AR protein in NDH group significantly increased, compared with that in NDL group (P <0.01)
Comparison of the expression of 5-HT2AR mRNA in striatum
The level of the expression of 5-HT2AR mRNA in striatum in Apo group was significant higher than that in the control group[1.52(0.93-2.46) vs 1.00(0.77-1.3), P<0.05]. After treatment, the level of the expression of 5-HT2AR mRNA in both NDL group and NDH group became higher than that in Apo group(P<0.05或P<0.01). The difference between NDL group and NDH group was not significant (P>0.05).
Comparison of the expression of TPH2 protein
The level of the expression of TPH2 protein in Apo group was significant higher than that in the control group[1.52(0.93-2.46) vs 1.00(0.77-1.3), P<0.05]. After treatment, the level of the expression of TPH2 protein in both NDL group and NDH group became higher than that in Apo group(P<0.05或P<0.01). The level of the expression of TPH2 protein in NDH group significantly increased, compared with that in NDL group (P<0.01).
Comparison of level of 5-HT in striatum
The level of 5-HT in striatum in Apo group was significant higher than that in the control group(1.98±0.14 vs 1.78±0.10 ng/ml, P<0.05). The difference between Apo group and NDL group was not significant (P>0.05). The level of 5-HT in NDH group became higher than that in Apo group(2.20±0.14 vs 1.98±0.14ng/ml, P<0.05). No difference was shown in comparison between NGL group and NDH group (P> 0.05)
Comparison of level of 5-HIAA in striatum
No difference was shown in comparison of level of 5-HIAA in striatum between Apo group and control group(0.94±0.12 vs 0.97±0.10ng/ml, P>0.05). The level of 5-HIAA in both NDL group and NDH group became lower than that in Apo group (0.77±0.10 vs 0.94±0.12, P<0.05; 0.58±0.08 vs 0.94±0.12, P<0.01). the difference between NGL group and NDH group was significant(P<0.01).
Conclusion
1. Activity of 5-HT system enhanced in Apo-induced TS rat model; however, the enhanced activity may still be relatively insufficient.
2. The mechanism of ND granule treating TS was associated with promotion of 5-HT synthesis in the striatum, depression of the 5-HT metabolism, up-regulation expression of 5-HT2AR, enhancing activity of 5-HT system and improving the activity insufficient of 5-HT system.
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19. Heinz A, Knable MB, Wolf SS, et al. Tourette's syndrome: [I-123]beta-CIT SPECT correlates of vocal tic severity. Neurology,1998; 51:1069-1074.
20. Wong DF, Singer HS, Brandt J, et al. D2-tike dopamine receptor density in Tourete syndrome measured by PET. J Nucl Med,1997; 38:1243-1247.
21. Pollack MA, Cohen NL, Friedhoff AJ. Gilles de la Tourrette's syndrome Famillial occurrence and precipitation by metrylphenidate therary. Ann Neurol, 1977; 3:630.
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