帕病1号治疗帕金森病的临床疗效观察及作用机制探讨
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摘要
第一部分帕病1号治疗帕金森病的临床疗效观察
目的：
观察帕病1号治疗少动和强直型PD的临床疗效。
方法：
采用前瞻性随机对照研究方法,将56例早中期少动和强直型PD患者随机分为2组。治疗组29例,在美多巴基础治疗的基础上,加用帕病1号颗粒剂(主要药物：乌梅、山茱萸、山药、附子、川芎、生地黄、白芍、葛根、甘草等组成)；对照组27例,用美多巴治疗。治疗3个月后观察两组临床疗效,同时观察两组治疗前后症状改善情况。
结果：
治疗组总有效率为62.69%,对照组总有效率为51.85%,两组比较,差异无统计学意义(P>0.05),但治疗组病人经治疗,临床症状及UPDRSⅡ、Ⅲ部分评分有改善,差异有统计学意义,表明治疗组在一定程度上改善病情,缓解或减轻病人的症状,而且在改善患者口常生活及运动功能方面,治疗组疗效优于对照组。
两组病人经治疗后PDQ-39评分,差异有统计学意义,说明帕病1号在改善患者生存质量方面优于单纯西药组,考虑除与改善患者日常生活、运动功能有关外,尚与改善患者睡眠障碍、便秘等非运动症状有关。
结论：
帕病1号治疗少动和强直型PD的临床研究结果表明,帕病1号能明显改善少动和强直型PD的临床症状、日常活动和运动功能,因此可以提高患者的生活质量,疗效优于单纯西药组。但限于样本含量较小、观察周期较短等因素,尚不能将研究结果推及PD的全过程,有待进一步扩大试验,更可靠地证实其临床疗效。
第二部分帕病1号对帕金森病模型大鼠脑内多巴胺的影响
目的：
观察帕病1号对PD模型大鼠神经行为的改善作用及PD模型大鼠脑内多巴胺的含量及黑质细胞的形态学变化的影响,探讨其作用机制。
方法：
1.PD大鼠模型的建立：采取左侧纹状体两点单次注射法。参照文献方法绘制大鼠脑立体定位图谱,确定左侧纹状体两点坐标,前注射点为前囟嘴侧1.6mm,中线左侧2.8mm,深度5.Omm,后注射点坐标为前囟尾侧1.Omm,中线左侧旁开4.5mm,深度5.0mm,计算出注射点的相对坐标进行标记定位后,在相应部位用三角钻钻透颅骨,用微量注射器吸取6-OHDA,缓慢进针达预定深度,每点以1ul/min速度将6-OHDA(含0.2%抗坏血酸的生理盐水配制成5ug/2.5u1)2.5ul注入左侧纹状体。术后第1、2、3周行为学检测,每次给受试大鼠腹腔注射APO0.5mg/kg(溶于生理盐水),以诱发大鼠向健侧单向旋转,每次在注射APO10分钟后开始记录,共记录30分钟内诱导转圈数,若大鼠恒定转向右侧,且平均转速大于7转/分钟,视为PD大鼠模型制作成功。
2.治疗方法：将PD模型大鼠随机分为模型组和帕病1号低剂量组、帕病1号高剂量组,低剂量组、高剂量组分别给予帕病1号颗粒8.558g/kg、17.116g/kg,正常组、模型组、假手术组灌蒸馏水3ml/只,以上各组均每天给药1次(高剂量组分上、下午分开两次给药),连续32天。
3.检测指标：行为学观察(旋转实验)、大鼠毁损侧纹状体内多巴胺含量测定、大鼠黑质组织形态学观察。
结果：
1.帕病1号对PD模型大鼠旋转行为的影响：与治疗前比较,高剂量组与低剂量组平均转速均有改善(P<0.05),且高剂量组、低剂量组治疗后的平均转速与模型组比较均有统计学意义(P<0.05),说明帕病1号有改善PD模型大鼠症状的作用。
高剂量组治疗后平均转数少于低剂量组,提示帕病1号改善PD模型大鼠的症状的作用有量效关系。
2.帕病1号对PD模型大鼠毁损侧纹状体多巴胺含量测定：与正常组比较,造模的三组大鼠毁损侧纹状体DA的含量均明显下降(P均<0.05),而且高剂量组高于低剂量、高于模型组,差异有统计学意义(P均>0.05),提示帕病1号能提高PD模型大鼠纹状体系统内多巴胺的含量,疗效有量效关系。
3.帕病1号对PD模型大鼠脑组形态学影响：模型组、低剂量组、高剂量组均存在黑质细胞的变性坏死,胶质细胞增生的病理特点,提示造模成功,而且帕病1号治疗后,神经细胞的数目增加,树突、轴突的长度、数量增加,而且高剂量组的黑质色素细胞数目、树突轴突的长度和数目较低剂量组明显增加。
结论：
帕病1号能改善PD模型大鼠的旋转行为,其作用机制可能是通过保护黑质神经细胞、促进黑质神经细胞修复,改善黑质纹状体的分泌功能,提高脑组织中多巴胺的含量达到其治疗作用的。
Part One
The Clinical Obersevation of PD NO.1on Parkinson Disease
Object i ve
Study the curative effect of PD NO.1to Hypokinesia Type and Rigid Type Parkinson.
Methods
Under the guide of Randomized control study method, I divided56eary-middle Hypokinesia Type and Rigid Type Parkinson patients into two groups, treatment group and control group. There was29patients in treatment group and27patients in control group respectively. We treated the first group with dopa plus PD NO.1(made up of:Ebony, Dogwood, Yam, Aconitem, Rehmanniae, Root of herbaceous peony, Licorice et al) and the second group with dopa only. We recorded the observation and improvement of the two groups and analysed the curative effects of PD NO.1.
Results
There is no statistical significant between the curative percentage of two groups.The curative percentage of treatment group is62.69%while the corresponding number is51.85related to control group.But the improvement of treatment group is dominant when we take clinical sympotoms and UPDRSⅡ、 Ⅲ estimate into consideration. It is illustrated that treatment group is better than control group at the level of recovery and the ability of daily life. We estimated the two groups with PDQ-39and got a statistical significant result. All these show that PD NO.1has great effects on improving the life quality of PD patients including movement and nonmovement aspects(constipation, dizzness and sleep).
Conclusion
The clinical study demonstrated that PD NO.1has prominent effects on improving the clinical sympotoms and daily movemnt of Hypokinesia Type and Rigid Type Parkinson patients. It means that PD NO.1can improve the life quality of PD patients. Some factors such as sample population limitation and experimental period made it impossible to get a solid conclusion of PD NO.1on curing PD patients. We need more experiments and further study.
Part two
The effects of PD NO.1on Dopa level of PD Model Mice
Objective
To see the stimulative effect of PD NO.1on nerve behavior, Dopa level and Substantia nigra cell's morphology of PD Model mice. To invistigate the mechanism of PD NO.1on PD model.
Methods
1. Generate PD mice model
Using the left side of the striatum two single-injection method. Firstly, we protracted mice head three-dimensional positioning map according references:make sure the two-point coordinate of left side of the striatum. We fixed the head inject point at1.6mm of skull rostral side and2.8mm of left side of middle line. It's deapth is5. Omm. The back inject point at1.0mm of anterior fontanelle tail and4.5mm of middle line. It's deapth is5.0mm too. Secondly, we marked the coordinate of the two points. Thirdly, we digged a hole at the marked point and injiected mice with micro injection. We injiected2.5ul6-OHDA to a mice at lul/min.
In order to finish the behavior detection of mice weekly after treatment, we injiected the mice with APO0.5mg/kg(prepared in sodium) to induce one-way rotation. If the mice rotated rigth more than7times one minute, we thought the model was generated sucessfully.
2. Treatment
We divided PD model mice into four groups randomly:model, PD NO.1low dose (8.558g/kg), PD NO.1high dose (17.116g/kg), and normal group. We fed mice with PD NO.1+dopa, dopa or ddH20one time/day continuously for32days. The PD NO.1high dose group was fed2times/day.
3.Measurement
Behavior detection (rotation experiment), dopa level measuring, histological morphology of corpus striatum and substantia nigra
Results
1.The effect of PD NO.1on mice rotation performance:
By comparing after or before treatment, both low and high group mice were improverd(P<0.05).The differences between low or high dose group and model group were statisticaly significant (P<0.05). It means that PD NO.1is helpful to PD mice.
The difference between low and high dose group was statisticaly significant after treatment at the meanwhile.
2.The effects of PD NO.1on dopa level of damaged corpus striatum:
Comparing with control group, the other three groups all had low DA content in corpus striatum(P<0.05). The effect of PD NO.1on DA content was dose dependent because high dose group had higher DA level than low dose group and model group(P<0.05).
3. The effect of PD NO.1on mice brain histological morphology:
It was confrimed that we generated PD mice model sucessfully because of cell necrosis of substantia nigra in model, low dose and high dose groups. Mice treated with PD NO.1had more nerve cells and the number and the length of dendritic and axons were all increased daramtically. The high dose group had more dominant increase than the low dose group at the same time.
Conclusion
PD NO.1can improve PD modle mice in the aspect of rotation movement. It's crutive function is dose dependent. The mechanism is not very clear now. But our experiments results show that PD NO.1can promote nerve cell renew and increase secretion ability of corpus striatum in damaged substantia nigra.
目的：
观察帕病1号治疗少动和强直型PD的临床疗效。
方法：
采用前瞻性随机对照研究方法,将56例早中期少动和强直型PD患者随机分为2组。治疗组29例,在美多巴基础治疗的基础上,加用帕病1号颗粒剂(主要药物：乌梅、山茱萸、山药、附子、川芎、生地黄、白芍、葛根、甘草等组成)；对照组27例,用美多巴治疗。治疗3个月后观察两组临床疗效,同时观察两组治疗前后症状改善情况。
结果：
治疗组总有效率为62.69%,对照组总有效率为51.85%,两组比较,差异无统计学意义(P>0.05),但治疗组病人经治疗,临床症状及UPDRSⅡ、Ⅲ部分评分有改善,差异有统计学意义,表明治疗组在一定程度上改善病情,缓解或减轻病人的症状,而且在改善患者口常生活及运动功能方面,治疗组疗效优于对照组。
两组病人经治疗后PDQ-39评分,差异有统计学意义,说明帕病1号在改善患者生存质量方面优于单纯西药组,考虑除与改善患者日常生活、运动功能有关外,尚与改善患者睡眠障碍、便秘等非运动症状有关。
结论：
帕病1号治疗少动和强直型PD的临床研究结果表明,帕病1号能明显改善少动和强直型PD的临床症状、日常活动和运动功能,因此可以提高患者的生活质量,疗效优于单纯西药组。但限于样本含量较小、观察周期较短等因素,尚不能将研究结果推及PD的全过程,有待进一步扩大试验,更可靠地证实其临床疗效。
第二部分帕病1号对帕金森病模型大鼠脑内多巴胺的影响
目的：
观察帕病1号对PD模型大鼠神经行为的改善作用及PD模型大鼠脑内多巴胺的含量及黑质细胞的形态学变化的影响,探讨其作用机制。
方法：
1.PD大鼠模型的建立：采取左侧纹状体两点单次注射法。参照文献方法绘制大鼠脑立体定位图谱,确定左侧纹状体两点坐标,前注射点为前囟嘴侧1.6mm,中线左侧2.8mm,深度5.Omm,后注射点坐标为前囟尾侧1.Omm,中线左侧旁开4.5mm,深度5.0mm,计算出注射点的相对坐标进行标记定位后,在相应部位用三角钻钻透颅骨,用微量注射器吸取6-OHDA,缓慢进针达预定深度,每点以1ul/min速度将6-OHDA(含0.2%抗坏血酸的生理盐水配制成5ug/2.5u1)2.5ul注入左侧纹状体。术后第1、2、3周行为学检测,每次给受试大鼠腹腔注射APO0.5mg/kg(溶于生理盐水),以诱发大鼠向健侧单向旋转,每次在注射APO10分钟后开始记录,共记录30分钟内诱导转圈数,若大鼠恒定转向右侧,且平均转速大于7转/分钟,视为PD大鼠模型制作成功。
2.治疗方法：将PD模型大鼠随机分为模型组和帕病1号低剂量组、帕病1号高剂量组,低剂量组、高剂量组分别给予帕病1号颗粒8.558g/kg、17.116g/kg,正常组、模型组、假手术组灌蒸馏水3ml/只,以上各组均每天给药1次(高剂量组分上、下午分开两次给药),连续32天。
3.检测指标：行为学观察(旋转实验)、大鼠毁损侧纹状体内多巴胺含量测定、大鼠黑质组织形态学观察。
结果：
1.帕病1号对PD模型大鼠旋转行为的影响：与治疗前比较,高剂量组与低剂量组平均转速均有改善(P<0.05),且高剂量组、低剂量组治疗后的平均转速与模型组比较均有统计学意义(P<0.05),说明帕病1号有改善PD模型大鼠症状的作用。
高剂量组治疗后平均转数少于低剂量组,提示帕病1号改善PD模型大鼠的症状的作用有量效关系。
2.帕病1号对PD模型大鼠毁损侧纹状体多巴胺含量测定：与正常组比较,造模的三组大鼠毁损侧纹状体DA的含量均明显下降(P均<0.05),而且高剂量组高于低剂量、高于模型组,差异有统计学意义(P均>0.05),提示帕病1号能提高PD模型大鼠纹状体系统内多巴胺的含量,疗效有量效关系。
3.帕病1号对PD模型大鼠脑组形态学影响：模型组、低剂量组、高剂量组均存在黑质细胞的变性坏死,胶质细胞增生的病理特点,提示造模成功,而且帕病1号治疗后,神经细胞的数目增加,树突、轴突的长度、数量增加,而且高剂量组的黑质色素细胞数目、树突轴突的长度和数目较低剂量组明显增加。
结论：
帕病1号能改善PD模型大鼠的旋转行为,其作用机制可能是通过保护黑质神经细胞、促进黑质神经细胞修复,改善黑质纹状体的分泌功能,提高脑组织中多巴胺的含量达到其治疗作用的。
Part One
The Clinical Obersevation of PD NO.1on Parkinson Disease
Object i ve
Study the curative effect of PD NO.1to Hypokinesia Type and Rigid Type Parkinson.
Methods
Under the guide of Randomized control study method, I divided56eary-middle Hypokinesia Type and Rigid Type Parkinson patients into two groups, treatment group and control group. There was29patients in treatment group and27patients in control group respectively. We treated the first group with dopa plus PD NO.1(made up of:Ebony, Dogwood, Yam, Aconitem, Rehmanniae, Root of herbaceous peony, Licorice et al) and the second group with dopa only. We recorded the observation and improvement of the two groups and analysed the curative effects of PD NO.1.
Results
There is no statistical significant between the curative percentage of two groups.The curative percentage of treatment group is62.69%while the corresponding number is51.85related to control group.But the improvement of treatment group is dominant when we take clinical sympotoms and UPDRSⅡ、 Ⅲ estimate into consideration. It is illustrated that treatment group is better than control group at the level of recovery and the ability of daily life. We estimated the two groups with PDQ-39and got a statistical significant result. All these show that PD NO.1has great effects on improving the life quality of PD patients including movement and nonmovement aspects(constipation, dizzness and sleep).
Conclusion
The clinical study demonstrated that PD NO.1has prominent effects on improving the clinical sympotoms and daily movemnt of Hypokinesia Type and Rigid Type Parkinson patients. It means that PD NO.1can improve the life quality of PD patients. Some factors such as sample population limitation and experimental period made it impossible to get a solid conclusion of PD NO.1on curing PD patients. We need more experiments and further study.
Part two
The effects of PD NO.1on Dopa level of PD Model Mice
Objective
To see the stimulative effect of PD NO.1on nerve behavior, Dopa level and Substantia nigra cell's morphology of PD Model mice. To invistigate the mechanism of PD NO.1on PD model.
Methods
1. Generate PD mice model
Using the left side of the striatum two single-injection method. Firstly, we protracted mice head three-dimensional positioning map according references:make sure the two-point coordinate of left side of the striatum. We fixed the head inject point at1.6mm of skull rostral side and2.8mm of left side of middle line. It's deapth is5. Omm. The back inject point at1.0mm of anterior fontanelle tail and4.5mm of middle line. It's deapth is5.0mm too. Secondly, we marked the coordinate of the two points. Thirdly, we digged a hole at the marked point and injiected mice with micro injection. We injiected2.5ul6-OHDA to a mice at lul/min.
In order to finish the behavior detection of mice weekly after treatment, we injiected the mice with APO0.5mg/kg(prepared in sodium) to induce one-way rotation. If the mice rotated rigth more than7times one minute, we thought the model was generated sucessfully.
2. Treatment
We divided PD model mice into four groups randomly:model, PD NO.1low dose (8.558g/kg), PD NO.1high dose (17.116g/kg), and normal group. We fed mice with PD NO.1+dopa, dopa or ddH20one time/day continuously for32days. The PD NO.1high dose group was fed2times/day.
3.Measurement
Behavior detection (rotation experiment), dopa level measuring, histological morphology of corpus striatum and substantia nigra
Results
1.The effect of PD NO.1on mice rotation performance:
By comparing after or before treatment, both low and high group mice were improverd(P<0.05).The differences between low or high dose group and model group were statisticaly significant (P<0.05). It means that PD NO.1is helpful to PD mice.
The difference between low and high dose group was statisticaly significant after treatment at the meanwhile.
2.The effects of PD NO.1on dopa level of damaged corpus striatum:
Comparing with control group, the other three groups all had low DA content in corpus striatum(P<0.05). The effect of PD NO.1on DA content was dose dependent because high dose group had higher DA level than low dose group and model group(P<0.05).
3. The effect of PD NO.1on mice brain histological morphology:
It was confrimed that we generated PD mice model sucessfully because of cell necrosis of substantia nigra in model, low dose and high dose groups. Mice treated with PD NO.1had more nerve cells and the number and the length of dendritic and axons were all increased daramtically. The high dose group had more dominant increase than the low dose group at the same time.
Conclusion
PD NO.1can improve PD modle mice in the aspect of rotation movement. It's crutive function is dose dependent. The mechanism is not very clear now. But our experiments results show that PD NO.1can promote nerve cell renew and increase secretion ability of corpus striatum in damaged substantia nigra.
引文
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