加味黄芪桂枝五物汤治疗糖尿病周围神经病变的理论、临床和实验研究
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摘要
糖尿病周围神经病变(diabetic peripheral neuropathy,DPN)是糖尿病(diabetes mellitus,DM)最常见的慢性并发症及致残、致死的主要因素之一。其发病机制尚未完全阐明,亦缺乏特异性的治疗方法及药物。寻找有效的治疗方法和药物,揭示药物作用的机理,是当今国内外研究的热点。本研究通过阅读大量古今文献并结合对DPN患者的临床观察,认为气虚血瘀是本病的主要病机,气虚为本,血瘀为标。依据“法随证立”的原则,制定益气活血,温经通络的治疗大法。在本治法指导下,以汉代名医张仲景《伤寒杂病论》中治疗血痹的黄芪桂枝五物汤为基础方,依据导师多年临床经验,组方加味黄芪桂枝五物汤,通过临床观察和实验研究两部分,观察该方对DPN患者的临床疗效,并探讨其治疗DPN的机理。
临床观察
目的：观察加味黄芪桂枝五物汤治疗DPN的临床疗效。
方法：将符合诊断标准的DPN患者40例,按就诊顺序随机分为治疗组和对照组,每组各20例。在控制血糖、血压、血脂的基础上,治疗组给予口服加味黄芪桂枝五物汤治疗,对照组给予口服弥可保(甲钴胺)治疗,8周为1疗程。观察治疗后患者临床症状、神经传导速度及血压、血脂、血糖等指标的变化情况。
结果：治疗组总有效率为90%,对照组总有效率为65%,经Ridit检验,治疗组总有效率优于对照组(P<0.05)；治疗组对患者临床症状,两侧胫运动神经、感觉神经传导速度的改善均优于对照组(P<0.05)；治疗过程中未见明显不良反应。
结论：加味黄芪桂枝五物汤可明显改善DPN患者的临床症状,加快神经传导速度,总体疗效优于目前临床常用西药弥可保。实验研究
目的：探讨加味黄芪桂枝五物汤治疗DPN的作用机理,提供药物临床应用的理论依据,为防治DPN提供新的药物。
方法：200-220g雄性Wistar大鼠,随机取10只为正常对照组,其余用链脲佐菌素(streptozotocin,STZ)诱导制备糖尿病模型,将成模大鼠分为模型组,弥可保组,加味黄芪桂枝五物汤低、中、高剂量组五组,每组10只。大鼠灌胃治疗8周,观察加味黄芪桂枝五物汤对模型大鼠血糖,体重,血清丙二醛(MDA)、谷胱甘肽(GSH),冷、热刺激反应时间,坐骨神经传导速度及坐骨神经NGFmRNA表达的影响,并对糖尿病大鼠坐骨神经组织进行病理学检查。
结果：经加味黄芪桂枝五物汤治疗后,糖尿病大鼠的体重升高,血糖降低,血清MDA含量明显降低,血清GSH含量明显升高,对冷、热刺激反应时间缩短,神经传导速度加快,坐骨神经NGFmRNA表达增强。病理观察表明,该药对坐骨神经组织病变具有改善作用。
结论：
1.加味黄芪桂枝五物汤具有减轻DM大鼠周围神经结构和功能的损伤,延缓神经病变进程的作用。
2.加味黄芪桂枝五物汤可降低大鼠血清MDA水平、提高血清GSH水平,改善神经周围组织的氧化应激状态,可能是该方保护DPN的作用机制之一。
3.加味黄芪桂枝五物汤能增强大鼠坐骨神经NGFmRNA的表达,提高神经生长因子的含量可能是该方保护DPN的又一作用机制。
Diabetic peripheral neuropathy (DPN) is one of the most common chronic complications of diabetes mellitus(DM), and the main cause of disability and death. Its pathogenesis is not understood clearly now and had no good therapeutic. It is an international attention in reseaching good therapeutic and medicines and explanting the pharmacological functions. It is thought Qi deficiency, blood stasis and meridian block is the essential pathogenesis for DPN. Supplying Qi, promoting blood circulation, warming and removing obstruction in channels are basic therapeutic for it. Modify HuangQi GuiZhi WuWu decoction, which come from Zhang Zhongjing's work and my tutor's clinical experience, was studied both on clinical observation and experiment research.
Clinical observation
Objective:to observe effectiveness and mechanism on treatment of DPN with modify HuangQi GuiZhi WuWu decoction.
Methods:Forty patients with DPN were randomly divided into treatment group and control group with 20 case each. In controlling blood sugar, blood pressure, and blood lipids, modify HuangQi GuiZhi WuWu decoction was orally given in treatment group, and Mikebao (Jia Gu An) was taken in control group. The course of treatment was 8 weeks, and the symptoms, nerve conduction velocity and blood pressure, blood lipids and blood sugar were recored.
Results:The total effective rate in treatment group and control group is 90% and 65%. The total effective rate in treatment group is higher than in control group (P<0.05). Improvements of clinical symptoms, both sides'posterior motor nerve, and sensory nerve conduction velocity in treatment group are better than in control group, (P<0.05). There is no side effects are found in both groups.
Conclusion:Modify HuangQi GuiZhi WuWu decoction on the DPN is better than Mikebao in improving clinical symptom, and accelerating nerve conduction velocity.
Experimental study
Objective:To investigate mechanism of the modify HuangQi GuiZhi WuWu decoction in treating DPN and provide the theoretical basis for clinical applications of new drugs.
Methods:Ten of 60 of 200-220g Wistar male rats was randomly taken to the normal control group, Diabetic model was established in rest of 50 rats by induction of streptozotocin, and then was randomly divided into model group, Mikebao gruop, three JiaWei HuangQi GuiZhi WuWu decoction groups in high, medium and low dosage with 10 in each. Body weight, blood sugar, malondialdehyde (MDA), glutathione (GSH), and reaction time, of cold and hot stimulation, sciatic nerve conduction velocity and expression of sciatic nerve growth factor (NGF) were measured after 8 weeks of treatment. Finally diabetic rat sciatic nerve tissue was examined in pathology
Results:Compare with model group, body weight, and blood sugar, the content of MDA significantly reduced; serum levels of serum GSH and NGF increased significantly, reaction time for cold and hot stimulation was shortened and nerve conduction velocity increased significantly. Pathological observation showed pathological changes of sciatic nerve tissue were improved obviously by this drug.
Conclusion:
1 Modify HuangQi GuiZhi WuWu decoction could alleviate peripheral nerve injury, and delay neuropathy process in DM rat
2 Modify HuangQi GuiZhi WuWu decoction can reduce serum MDA level, increase level of serum GSH, and improve the oxidation and stress response of surrounding tissues. The changes may be coused by the protection mechanisms.
3 It could be another protection mechanism for modify HuangQi GuiZhi WuWu decoction in increasing the expression of NGF, and content of NGF.
临床观察
目的：观察加味黄芪桂枝五物汤治疗DPN的临床疗效。
方法：将符合诊断标准的DPN患者40例,按就诊顺序随机分为治疗组和对照组,每组各20例。在控制血糖、血压、血脂的基础上,治疗组给予口服加味黄芪桂枝五物汤治疗,对照组给予口服弥可保(甲钴胺)治疗,8周为1疗程。观察治疗后患者临床症状、神经传导速度及血压、血脂、血糖等指标的变化情况。
结果：治疗组总有效率为90%,对照组总有效率为65%,经Ridit检验,治疗组总有效率优于对照组(P<0.05)；治疗组对患者临床症状,两侧胫运动神经、感觉神经传导速度的改善均优于对照组(P<0.05)；治疗过程中未见明显不良反应。
结论：加味黄芪桂枝五物汤可明显改善DPN患者的临床症状,加快神经传导速度,总体疗效优于目前临床常用西药弥可保。实验研究
目的：探讨加味黄芪桂枝五物汤治疗DPN的作用机理,提供药物临床应用的理论依据,为防治DPN提供新的药物。
方法：200-220g雄性Wistar大鼠,随机取10只为正常对照组,其余用链脲佐菌素(streptozotocin,STZ)诱导制备糖尿病模型,将成模大鼠分为模型组,弥可保组,加味黄芪桂枝五物汤低、中、高剂量组五组,每组10只。大鼠灌胃治疗8周,观察加味黄芪桂枝五物汤对模型大鼠血糖,体重,血清丙二醛(MDA)、谷胱甘肽(GSH),冷、热刺激反应时间,坐骨神经传导速度及坐骨神经NGFmRNA表达的影响,并对糖尿病大鼠坐骨神经组织进行病理学检查。
结果：经加味黄芪桂枝五物汤治疗后,糖尿病大鼠的体重升高,血糖降低,血清MDA含量明显降低,血清GSH含量明显升高,对冷、热刺激反应时间缩短,神经传导速度加快,坐骨神经NGFmRNA表达增强。病理观察表明,该药对坐骨神经组织病变具有改善作用。
结论：
1.加味黄芪桂枝五物汤具有减轻DM大鼠周围神经结构和功能的损伤,延缓神经病变进程的作用。
2.加味黄芪桂枝五物汤可降低大鼠血清MDA水平、提高血清GSH水平,改善神经周围组织的氧化应激状态,可能是该方保护DPN的作用机制之一。
3.加味黄芪桂枝五物汤能增强大鼠坐骨神经NGFmRNA的表达,提高神经生长因子的含量可能是该方保护DPN的又一作用机制。
Diabetic peripheral neuropathy (DPN) is one of the most common chronic complications of diabetes mellitus(DM), and the main cause of disability and death. Its pathogenesis is not understood clearly now and had no good therapeutic. It is an international attention in reseaching good therapeutic and medicines and explanting the pharmacological functions. It is thought Qi deficiency, blood stasis and meridian block is the essential pathogenesis for DPN. Supplying Qi, promoting blood circulation, warming and removing obstruction in channels are basic therapeutic for it. Modify HuangQi GuiZhi WuWu decoction, which come from Zhang Zhongjing's work and my tutor's clinical experience, was studied both on clinical observation and experiment research.
Clinical observation
Objective:to observe effectiveness and mechanism on treatment of DPN with modify HuangQi GuiZhi WuWu decoction.
Methods:Forty patients with DPN were randomly divided into treatment group and control group with 20 case each. In controlling blood sugar, blood pressure, and blood lipids, modify HuangQi GuiZhi WuWu decoction was orally given in treatment group, and Mikebao (Jia Gu An) was taken in control group. The course of treatment was 8 weeks, and the symptoms, nerve conduction velocity and blood pressure, blood lipids and blood sugar were recored.
Results:The total effective rate in treatment group and control group is 90% and 65%. The total effective rate in treatment group is higher than in control group (P<0.05). Improvements of clinical symptoms, both sides'posterior motor nerve, and sensory nerve conduction velocity in treatment group are better than in control group, (P<0.05). There is no side effects are found in both groups.
Conclusion:Modify HuangQi GuiZhi WuWu decoction on the DPN is better than Mikebao in improving clinical symptom, and accelerating nerve conduction velocity.
Experimental study
Objective:To investigate mechanism of the modify HuangQi GuiZhi WuWu decoction in treating DPN and provide the theoretical basis for clinical applications of new drugs.
Methods:Ten of 60 of 200-220g Wistar male rats was randomly taken to the normal control group, Diabetic model was established in rest of 50 rats by induction of streptozotocin, and then was randomly divided into model group, Mikebao gruop, three JiaWei HuangQi GuiZhi WuWu decoction groups in high, medium and low dosage with 10 in each. Body weight, blood sugar, malondialdehyde (MDA), glutathione (GSH), and reaction time, of cold and hot stimulation, sciatic nerve conduction velocity and expression of sciatic nerve growth factor (NGF) were measured after 8 weeks of treatment. Finally diabetic rat sciatic nerve tissue was examined in pathology
Results:Compare with model group, body weight, and blood sugar, the content of MDA significantly reduced; serum levels of serum GSH and NGF increased significantly, reaction time for cold and hot stimulation was shortened and nerve conduction velocity increased significantly. Pathological observation showed pathological changes of sciatic nerve tissue were improved obviously by this drug.
Conclusion:
1 Modify HuangQi GuiZhi WuWu decoction could alleviate peripheral nerve injury, and delay neuropathy process in DM rat
2 Modify HuangQi GuiZhi WuWu decoction can reduce serum MDA level, increase level of serum GSH, and improve the oxidation and stress response of surrounding tissues. The changes may be coused by the protection mechanisms.
3 It could be another protection mechanism for modify HuangQi GuiZhi WuWu decoction in increasing the expression of NGF, and content of NGF.
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