α-硫辛酸与丹参治疗糖尿病下肢血管病变的疗效比较及可能机制探讨
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摘要
[背景]
近年来,糖尿病患者的发病率逐年增加,糖尿病并发症的发生也随之不断增加。糖尿病并发下肢血管病变(diabetic lower extremity arterial disease, DLEAD)是非糖尿病患者的7-10倍[1，2],部分患者在诊断糖尿病时即已存在,并随年龄、病程的增加而发病增多[3,4]。常见症状为间歇性跛行,表现为肢体运动时疼痛、不适或疲劳,休息后缓解。然而仅1/3的DLEAD患者具有典型的间歇性跛行症状,>50%患者无症状或症状不典型,其余DLEAD患者则症状较严重,可表现为静息痛、组织坏死或坏疽。患者由于存在周围神经病变,肢体感觉减退,症状往往比非糖尿病患者更不明显,仅表现出下肢疲劳感、步行速度减慢等[5，6]。DLEAD患者下肢病理改变较非糖尿病下肢动脉疾病患者更严重,病变范围更弥漫,更容易向肢体远端发展。无论对糖尿病还是非糖尿病患者,下肢动脉疾病是下肢截肢的主要危险因素。即使患者无症状,下肢动脉疾病也是全身心血管、脑血管疾病的标志。因此早期发现糖尿病下肢血管疾病,早期进行干预治疗,可减轻患者临床症状,降低临床DLEAD的致残率和截肢率、心血管事件的发生率[7,8,9],提高患者生活质量,改善远期预后。
糖尿病下肢血管病变的治疗是多方面的,以缓解症状、减慢动脉粥样硬化进程和控制危险因素为原则。其中包括外科治疗、介入治疗[10,11,12,13]、内科治疗[14,15,16]等。内科治疗包括危险因素的控制,如戒烟、减轻体质量、降压、降脂、控制血糖等。抗血小板治疗,如阿司匹林、氯吡格雷的应用,血管扩张药物治疗等等[17]。
研究表明,硫辛酸(lipoic acid,LA),亦称α-硫辛酸(a-lipoic acid, ALA),有改善动脉粥样硬化患者血管内皮功能的作用。丹参(Salvia miltiorrhiza Bunge)可扩张血管,改善循环。
硫辛酸是一种天然的二硫化合物,在体内可以转变为二氢硫辛酸(DHLA,还原型),LA和DHLA都具有很强的抗氧化性,它们在体内协同作用,是已知天然抗氧剂中效果最强的一种[19,20]。研究表明,硫辛酸使动脉粥样硬化患者血浆纤溶酶原激活剂-1(Plasminogen Activator Inhibitor-1,PAI-1),白介素-6等炎症因素减少,脂质氧化终产物MDA减少,抗氧化物质谷胱甘肽(L-Glutathione, GSH)增加,从而降低氧化应激水平,减少机体炎症因素,改善NO介导的血管舒张,改善血管内皮细胞的功能[21,22,23,24]。硫辛酸是否能改善糖尿病下肢血管病变患者下肢血管舒张功能?这在以往的研究中未见报道。
丹参的主要有效成分为丹参酮等脂溶性成分和丹酚酸等水溶性成分两部分。药理研究结果表明丹参具有扩张冠状动脉、增加冠脉血流量、防止心肌缺血、改善微循环等[25]。丹参能否改善糖尿病下肢血管病变患者下肢血管舒张功能?与硫辛酸相比较,疗效如何?目前尚未见有研究报道。
糖尿病血管病变早期以血管内皮依赖性舒张功能受损为主,可能是糖尿病血管病变发生的始动因素和基本病理生理改变[26],核心为血管内皮细胞功能障碍。内皮细胞是血液和血管平滑肌之间的重要屏障,分泌的多种活性物质处于精密的平衡状态,维持血管正常的生理功能。当内皮细胞功能紊乱、分泌活性物质失衡时,则造成血管的病理改变[27,28,29]。
氧化应激为糖尿病并发症的共同基础。氧化应激能够改变血浆脂质蛋白谱、凝血系统。主要机制如下：一高糖加重低密度脂蛋白(low density lipoprotein,LDL)氧化的易感性。氧化低密度脂蛋白(oxDL)破坏单核细胞、平滑肌细胞特异性LDL受体的识别能力,导致变性LDL通过胞吞途径在胞内不断积累,最终形成泡沫细胞。后者是形成动脉粥样硬化的关键。二活性氧(reactiveoxygen spicies,ROS)作用于花生四烯酸,分别通过环氧化和醋氧化反应产生前列腺素和白三烯,趋化白细胞浸润,诱导炎性反应的发生。通过不同机制导致血栓和血液高凝状态,包括诱导前列腺素产生、凝血酶激活等,从而诱发血管病变。硫辛酸及丹参是否能改变糖尿病下肢血管病变患者氧化应激相关因素如MDA, GSH?如果能改变,该两种药物是否有差异?以往的研究未曾涉及。
炎症是糖尿病血管病变的原因之一。糖尿病患者促炎因子如白细胞介素(inter-leukin,IL)-1,-6、活性氧、C反应蛋白(C-reactive protein,CRP)等表达明显增加,促进黏附分子表达,增加炎症趋化因子和凝固蛋白,如：血浆纤溶酶原激活剂-1(PAI-1)、纤溶酶原激活物和组织因子分泌,诱导血管调节物释放,造成血管功能改变。硫辛酸及丹参能否改变糖尿病下肢血管病变患者炎症相关因素：如白介素-6,血管细胞粘附分子-1(vascular cell adhesion molecule1, VCAM-1), PAI-1?如果有影响,该两种药物是否有差异?我们还不得而知。
步行受损问卷(Waling Impairment Questionnare,WIQ)可用于评价下肢血管病变患者的行走能力、生活质量、治疗效果,是一种简便、经济、实用性强的可靠评分方法,在国外广泛应用。
基于对以上已有研究的思考,本实验共分为四部分。本实验拟比较α-硫辛酸及丹参对糖尿病下肢血管病变患者WIQ评分的影响,临床症状的改善,及是否对造成血管内皮功能改变的氧化应激相关因素、炎症相关因素有所改善进行探讨。
第一部分：α-硫辛酸与丹参治疗糖尿病下肢血管病变临床疗效观察
[目的]
观察α-硫辛酸、丹参对糖尿病下肢血管病变的临床疗效。
[方法]
1、以糖尿病下肢血管病变患者为研究对象,排除严重心、肝、肾功能不全者,均符合1999年WHO糖尿病诊断标准,ABI<0.9。入院后均使用胰岛素控制血糖。
2、入院后测量血压、体重指数(BMI)、踝肱指数(ABI)、空腹测血脂、血糖、糖化血红蛋白(HbA1C)等。
3、分组：1)α-硫辛酸+丹参组(A组,n=20,α-硫辛酸600mg/d,丹参40mg/d, iv by drip,共21天),2)丹参组(B组,n=20,丹参40mg/d,iv by drip,共21天)
5、根据步行受损问卷(walking impairment questionare,WIQ)评分,观察各组用药前后评分的变化。
6、根据临床症状评分,观察各组用药前后评分的变化。
[结果]
1.各组治疗前WIQ量表评分比较无显著统计学差异(P>0.05)。
2.各组治疗前后WIQ量表评分比较差异有显著性统计学意义。分别为：A组治疗前后比较,差异有显著性统计学意义(P<0.001),B组治疗前后比较,差异有显著性统计学意义(P<0.001)。。
3.各组治疗后WIQ量表评分变化比较差异有显著性统计学意义(P<0.001)。A组较B组显著增高。
4.各组治疗前症状评分差异无显著性统计学差异(P>0.05)。
5.各组治疗前后症状评分比较差异有显著性统计学意义,分别为：麻木感：A组治疗前后比较,差异有显著性统计学意义(P<0.001),B组治疗前后比较,差异有显著性统计学意义(P=0.008)。冷感：麻木感：A组治疗前后比较,差异有显著性统计学意义(P<0.001),B组治疗前后比较,差异有显著性统计学意义(P=0.008)。静息痛：A组治疗前后比较,差异有显著性统计学意义(P<0.001),B组治疗前后比较,差异有显著性统计学意义(P=0.005)。
6.两组治疗后症状评分变化比较差异有显著性统计学意义,其中分别为：麻木感变化：A组较B组高,差异有显著性统计学意义(P=0.002)。冷感变化比较, A组较B组高,差异有显著性统计学意义(P=0.004)。静息痛变化比较, A组较B组高,差异有显著性统计学意义(P=0.002)。
[结论]
1.在纠正患者代谢紊乱后,糖尿病下肢血管病变患者WIQ及症状评分可得到改善。
2.a-硫辛酸+丹参显著改善糖尿病下肢血管病变患者WIQ评分。
3.丹参可改善糖尿病下肢血管病变患者WIQ评分,但α-硫辛酸+丹参显著优于丹参。
4.α-硫辛酸+丹参显著改善糖尿病下肢血管病变患者症状评分。
5.丹参可改善糖尿病下肢血管病变患者症状评分,但α-硫辛酸+丹参改善患者WIQ评分显著优于丹参。
第二部分：α-硫辛酸与丹参对糖尿病下肢血管病变患者血流介导的血管舒张变化(FMD)
[目的]
观察α-硫辛酸、丹参对糖尿病下肢血管病变患者内皮依赖的血管舒张功能(flow-mediated dilation,FMD)的影响。
[方法]
1、以糖尿病下肢血管病变患者为研究对象,排除严重心、肝、肾功能不全者。均符合1999年WHO糖尿病诊断标准。ABI<0.9。
2、分组：1)α-硫辛酸+丹参组(A组,n=20)2)丹参组(B组,n=20)
3、采用12MHz高频线阵探头的彩色多普勒超声诊断仪测量肱动脉舒张期末血管内径。
4.用带袖套式充气止血带的血压计加压300mmHg,持续4—5分钟,迅速放气,放气后45—60s于同样部位再测舒张期末血管内径。
[结果]
1、各组治疗前后肱动脉内径比较差异无显著性统计学意义(P>0.05)。
2、各组治疗前后FMD比较差异有显著性统计学意义(P<0.001)。分别为：A组治疗前后比较,差异有显著性统计学意义(P<0.001),B组治疗前后比较,差异有显著性统计学意义(P<0.001)。
3、两组治疗后FMD比较差异有显著性统计学意义(P<0.001)。A组较B组显著增高。
[结论]
1、在纠正患者代谢紊乱后,糖尿病下肢血管病变患者内皮依赖的血管舒张功能可得到改善。
2、α-硫辛酸+丹参可显著改善糖尿病下肢血管病变患者内皮依赖的血管舒张功能。
3、丹参可改善糖尿病下肢血管病变患者内皮依赖的血管舒张功能,但α-硫辛酸+丹参改善内皮依赖的血管舒张功能显著优于丹参。
第三部分：α-硫辛酸及丹参对糖尿病下肢血管病变氧化应激相关因素的影响
[目的]
观察α-硫辛酸、丹参对糖尿病下肢血管病变患者血清氧化应激因素的影响。
[方法]
1、以糖尿病下肢血管病变患者为研究对象,排除严重心、肝、肾功能不全者。均符合1999年WHO糖尿病诊断标准。ABI<0.9。
2、分组：1)α-硫辛酸+丹参组(A组,n=20)2)丹参组(B组,n=20)
3、采用硫代巴比妥酸法测定MDA。
4、采用二硫代二硝基苯甲酸反应法测定GSH。
[结果]
1.各组治疗前血浆GSH浓度比较差异无显著性统计学意义(P>0.05)。
2.各组治疗前后血浆GSH浓度比较,差异有显著性统计学意义,分别为：A组治疗前后比较,差异有显著性统计学意义(P<0.001),B组治疗前后比较,差异有显著性统计学意义(P<0.001)。
3.两组治疗后血浆GSH浓度比较差异有显著性统计学意义(P<0.001)。A组较B组显著增高。
4.各组治疗前血浆MDA浓度比较差异无显著性统计学意义(P>0.05)。
5.各组治疗后血浆MDA浓度比较,差异有显著性统计学意义,分别为：A组治疗前后比较,差异有显著性统计学意义(P<0.001),B组治疗前后比较,差异有显著性统计学意义(P<0.001)。
6.两组治疗后血浆MDA浓度比较差异有显著性统计学意义(P<0.001)。A组较B组显著增高。
[结论]
1.在纠正患者代谢紊乱后,糖尿病下肢血管病变患者血浆GSH浓度升高,MDA浓度降低。
2.α-硫辛酸+丹参可显著增加血浆GSH浓度。
3.丹参可增加血浆GSH浓度,但α-硫辛酸+丹参增加血浆GSH浓度显著优于丹参。
4.α-硫辛酸+丹参可显著降低血浆MDA浓度。
5.丹参可降低血浆MDA浓度,但α-硫辛酸+丹参降低血浆MDA浓度显著优于丹参。
第四部分：α-硫辛酸及丹参对糖尿病下肢血管病变患者炎症相关因素的影响
[目的]
观察α-硫辛酸、丹参对糖尿病下肢血管病变患者炎症相关因子的影响。
[方法]
1、以糖尿病下肢血管病变患者为研究对象,排除严重心、肝、肾功能不全者。均符合1999年WHO糖尿病诊断标准。ABI<0.9。
2、分组：1)α-硫辛酸+丹参组(A组,n=20)2)丹参组(B组,n=20)
3、使用Elisa法检测血浆IL-6。
4、使用Elisa法检测血浆VCAM-1。
5、使用Elisa法检测血浆PAI-1。
[结果]
1.各组血浆IL-6浓度比较差异无显著性统计学意义(P>0.05)。
2.各组治疗前后血浆IL-6浓度比较,差异有显著性统计学意义,分别为：A组治疗前后比较,差异有显著性统计学意义(P=0.001),B组治疗前后比较,差异有显著性统计学意义(P=0.010)。
3.两组治疗后血浆IL-6浓度变化比较差异有显著性统计学意义(P=0.001)。A组较B组显著降低。
4.各组治疗前血浆VCAM-1浓度比较差异无显著性统计学意义(P>0.05)。
5.各组治疗后血浆VCAM-1浓度比较,差异有显著性统计学意义,分别为：A组治疗前后比较,差异有显著性统计学意义(P<0.001),B组治疗前后比较,差异有显著性统计学意义(P<0.001)。
6.两组治疗后血浆VCAM-1浓度比较差异有显著性统计学意义(P<0.001)。A组较B组显著降低。
7.各组治疗前血浆PAI-1浓度比较差异无显著性统计学意义(P>0.05)。
8.各组治疗后血浆PAI-1浓度比较,差异有显著性统计学意义,分别为：A组治疗前后比较,差异有显著性统计学意义(P<0.001),B组治疗前后比较,差异有显著性统计学意义(P<0.001)。
9.两组治疗后血浆PAI-1浓度比较差异有显著性统计学意义(P<0.001)。A组较B组显著降低。
[结论]
1.在纠正患者代谢紊乱后,糖尿病下肢血管病变患者血浆IL-6、VCAM-1、PAI-1浓度降低。
2.α-硫辛酸+丹参可降低血浆IL-6浓度。
3.丹参可降低血浆IL-6浓度,但α-硫辛酸+丹参降低血浆IL-6浓度显著优于丹参。
4.α-硫辛酸+丹参及丹参可降低血浆VCAM-1浓度。
5.丹参可降低血浆VCAM-1浓度,但α-硫辛酸+丹参降低血浆VCAM-1浓度显著优于丹参。
6.α-硫辛酸+丹参及丹参可降低血浆PAI-1浓度
7.丹参可降低血浆PAI-1浓度,但α-硫辛酸+丹参降低血浆PAI-1浓度显著优于丹
[background]
In recent years, the incidence of diabetes increased year by year, diabetes complications are also increasing. Diabetes concurrent lower limb vascular lesions (diabetic lower extremity arterial disease, DLEAD) are7to10times as patients with diabetes mellitus. Some patients are diagnosed diabetes that already exist, and inctrease with the growth of age, duration. Common symptom is intermittent claudication, performance of one body motion pain, discomfort, or fatigue, after the break to alleviate. Only a third of the DLEAD patients with typical intermittent limp symptoms,>50%of patients without symptoms or atypical symptoms, the rest DLEAD patients with severe symptoms, by resting pain, gangrene or gangrene. But since there are patients peripheral neuropathy, body feeling decline, DLEAD symptoms of diabetes more often not obvious, the only show are lower limbs on foot, fatigue or slow down, etc. DLEAD patients pathological changes is more serious than patients with the lower extremities diabetes lower limb artery disease,and more diffuse disease extent, more easily to limbs far end development. Whether to diabetic patients or those withoutdiabetes, lower limb artery disease is the main factor of limb amputations, even if patients are without symptoms, lower limb artery disease is the the sign of whole body cardiovascular and cerebrovascular diseases. So early detection of diabetes lower limb vascular disease, early intervention treatment, can reduce the clinical symptoms and reduce the DLEAD clinical morbidity and amputation rate, the incidence of cardiovascular events, and improve the quality of life of the patients, improve the long-term prognosis.
the treatment of Diabetes lower limbs of vascular lesions t is various, to alleviate the symptoms, slow down the process of atherosclerosis and control risk factors is the principle, inncluding surgery, interventional treatment, medical treatment, etc. Medical treatment includes the control of the risk factors, such as quit smoking, reduce body quality, step-down, fall fat, control blood sugar, etc.,anti-platelet therapy, such as aspirin, clopidogrel, application of vessels to dilate drug therapy, and so on.
Lipoic acid (LA) also called alpha lipoic acid (ALA), is a natural two sulfur compounds, in body,which can be transformed for the two hydrogen lipoic acid (DHLA, reduced), LA and DHLA both have the very strong oxidation resistance, they in body, synergy, is known to be one of the strongest effectin natural antioxidants. Research shows that lipoic acid that atherosclerosis plasma fiber melts the patients with plasminogen activator inhibitor1(PAI-1), interleukin (IL)-6, reduce inflammation factors, lipid oxidation end-products of MDA reduce, GSH increase, so as to reduce oxidatie stress level,andimprove NO mediated diastolic blood vessels, improving the function of endothelial cells.
Salvia miltiorrhiza Bunge, the main effective ingredients are such as for Dan CanTong fat soluble constituents and Dan phenolic acids water-soluble ingredients such as two parts. The pharmacological research results show that salvia miltiorrhiza has dilating coronary artery, increase coronary blood flow, prevent myocardial ischemia, microcirculation, fall hematic fat, etc.
The primarily diastolic function damage of Diabetes vascular lesions with endothelial dependence may be diabetes vascular lesions occurr tumor-initiating factors and the fundamental pathological physiology change, the core for endothelial cells of dysfunction. Endothelial cells and vascular smooth muscle blood is an important barrier between, the secretion of various active substances in precision balance, and maintain normal physiological function of blood vessels. When endothelial function disorder makes the secretory activity material imbalanceed, the pathological changes cause blood vessels leision. Patients with diabetes to promote inflammation factors interleukin (inter-leukin IL)-1,6, active oxygen (reactive oxygen spicies, ROS) c-reactive protein (C-reactive protein, CRP) express significantly increased, promote adhesion molecule expression, increase inflammation and solidification chemotactic agent protein (PAI-1, fibrinolytic enzyme that the activation and tissue factor) secretion, induction blood vessels that regulation (endothelial NO gentle shock peptide) release, cause blood vessel function damage.
How do alpha-lipoic acid and Salvia miltiorrhiza improve the clinicial symptoms of diabetic patients with vascular lesions? what is the effect of the above two drugs on oxidative stress factors, such as GSH,MDA of diabetic patients with lower extremities vascular lesions? what is the effect of the above two drugs on inflammatory factors:plasma fiber melts the enzyme activators-1, interleukin (il)6, The past research has not been concerned.
Based on the above thinking, this experiment is divided into four parts. This experiment is to compare clinical effect of alpha lipoic acid and Salvia miltiorrhiza on patients with lower extremities vascular lesions, and inflammation factors and oxidative stress and related factors are discussed.
Part1:clinical curative effect observation of alpha lipoic acid and salvia miltiorrhiza on the treatment of diabetes lower limb vascular lesions
[objective]
Observation the clinical clinical curative effect of alpha lipoic acid and Salvia miltiorrhiza on diabetes with vascular lesions of lower extremities.
[methods]
1. Diabetic patients with vascular lesions work as the research object, eliminate those whose heart, liver and kidney function is not complete. Which conform to the 1999WHO diabetes diagnosis standard. ABI<0.9. All insulin after admission control blood sugar.
2. After admission measure blood pressure, body mass index (BMI), fasting blood sugar, blood fat, the glycated hemoglobin (HbA1C), etc.
3. Group:1) a-lipoic acid±salvia miltiorrhiza group (group A, n=20, a-lipoic acid600mg/d,iv by drip andSalvia miltiorrhiza,40mg/d,iv by drip,21days)2) salvia miltiorrhiza group (group B, n=20, SalviamiltiorrhizaBunge,40mg/d,iv by drip,21days).
4. According to the clinical symptom scores, observe the clinical scoring change of the three group self before and after treatment.
5. According to clinical symptom scores, observe the clinical scoring change of the two groups before and after treatment.
6. According to WIQ score, observe the clinical scoring change before and after treatment.
[results]
1. WIQ scores were not significant different between the two groups (P>0.05)
2. WIQ scores were significant different before and after treatment of the two groups.Group A was significant different before and after treatment,(P<0.001) Group B was significant different before and after treatment,(P<0.001) respectively.
3. WIQ scores were significant different between the two groups before and after treatment. Group A was higher than group B (P<0.001)
4. Clinical symptom scores were not significant different between the two groups before treatment (P>0.05)
5. Clinical symptom scores were significant different before and after treatment of the two groups. Numbness:Group A was significant different before and after treatment,(P<0.001), Group B was significant different before and after treatment,(P=0.008), respectively, cold:Group A was significant different before and after treatment,(P<0.001), Group B was significant different before and after treatment, (P=0.008), rest pain:Group A was significant different before and after treatment,(P<0.001), Group B was significant different before and after treatment,(P=0.005), respectively.
6. Clinical symptom scores were significant different before and after treatment between the two groups (P<0.05). Numbness:Group A was higher than group B (P=0.002).Cold:Group A was higher than group B (P=0.004). Rest pain:Group A was lower than group B (P=0.002), respectively.
[conclusion]
1. WIQ scores of diabetic patients with vascular lesions were significant improved after correcting of metabolic disorder.
2. WIQ scores of diabetic patients with vascular lesions were improved by using of alpha lipoic acid plusSalvia miltiorrhiza.
3. WIQ scores of diabetic patients with vascular lesions were improved by using ofSalvia miltiorrhiza. But alpha lipoic acid plusSalvia miltiorrhiza are better thanSalvia miltiorrhiza according WIQ scores improving,
4. Clinical symptom scores of diabetic patients with vascular lesions were improved by using of alpha lipoic acid plusSalvia miltiorrhiz.
5. Clinical symptom scores of diabetic patients with vascular lesions were improved by using ofSalvia miltiorrhiza. But Alpha lipoic acid plus Salvia miltiorrhiza Bunge was better thanSalvia miltiorrhiza according Clinical symptom scores improving.
Part2:alpha lipoic acid and salvia miltiorrhiza mediated flood mediated diastolic function of diabetic patients with lower extremities vascular lesion.
[objective]
Observe the influence of diastolic function of vascular endothelial dependent alpha lipoic acid andSalvia miltiorrhiza on diabetic patients with lower extremities vascular lesions.
[methods]
1. Diabetic patients with vascular lesions work as the research object, and eliminate those whose heart, liver and kidney function is not complete. Which conform to the1999WHO diabetes diagnosis standard. ABI<0.9.
2. Group:1) lipoic acid+salvia miltiorrhiza group (group A, n=20)2) salvia miltiorrhiza group (group B, n=20).
3.The12MHz high frequency line of probe array of color doppler ultrasound diagnostic instrument was used to measure the diameter of humerus artery diastolic blood vessels.
4.Use pneumatic tourniquet to takes type of blood pressure300mmHg for4-5minutes, quickly deflated, the cuff was released after60-45second at the same area and measure the inner diameter of diastolic blood vessels.
[results]
1. The diameter and flow velocity of humerus artery diastolic blood vessels was not significant different between the two groups before treatment (P>0.05)
2. FMD was significant different before and after treatment of the two groups.Group A was significant different before and after treatment,(P<0.001).Group B was significant different before and after treatment (P<0.001), respectively.
3. FMD was significant different between the two groups before and after treatment. Group A was higher than group B (P<0.001)
[conclusion]
1. FMD of diabetic patients with vascular lesions was significant improved after correcting of metabolic disorder.
2. FMD of diabetic patients with vascular lesions were improved by using of alpha lipoic acid plusSalvia miltiorrhiza.
3. FMD of diabetic patients with vascular lesions were improved by using ofSalvia miltiorrhiza.But alpha lipoic acid plusSalvia miltiorrhiza are better thanSalvia miltiorrhiza according FMD improving.
Part3:Influence of alpha lipoic acid and salvia miltiorrhiza on oxidative stress factors of diabetes with lower extremities vascular lesions
[objective]
Observation how alpha lipoic acid influent serum oxidative stress factors of diabetic patients with lower extremities vascular lesions and comparing withSalvia miltiorrhiza.
[methods]
1. Diabetic patients with vascular lesions wok as the research object, persons of whom heart, liver and kidney function is not complete are eliminated. Which conform to the1999WHO diabetes diagnosis standard. ABI<0.9.
2. Group:1) lipoic acid+salvia miltiorrhiza group (1group, n=20)2) salvia miltiorrhiza group (2groups, n=20).
3. The content and the method to determine the inflicting MDA.
4. Determine GSH.
[results]
1. GSH concentration was not significant different between the two groups before treatment (P>0.05)
2. GSH concentration was significant different before and after treatment of the two groups.Group A was significant different before and after treatment,(P<0.001) Group B was significant different before and after treatment,(P<0.001) respectively.
3. GSH concentration was significant different between the two groups before and after treatment. Group A was higher than group B (P<0.001)
4. MDA concentration was not significant different between the two groups before treatment (P>0.05)
5. MDA concentration was significant different before and after treatment of the two groups.Group A was significant different before and after treatment,(P<0.001), Group B was significant different before and after treatment,(P<0.001), respectively.
6. MDA concentration was significant different between the two groups before and after treatment. Group A was lower than group B (P<0.001)
[conclusion]
1. GSH concentration of diabetic patients with vascular lesions was significant high after correcting of metabolic disorder, meanwhile, MDA concentration of diabetic patients with vascular lesions was significant low.
2. GSH concentration was high after using of alpha lipoic acid plus salvia miltiorrhiza.
3. GSH concentration was high after using of alpha lipoic acid plus salvia miltiorrhiza. But alpha lipoic acid plus salvia miltiorrhiza was better than salvia miltiorrhiza according GSH concentration improving.
4. MDA concentration was low after using of alpha lipoic acid plus salvia miltiorrhiza.
5. MDA concentration was low after using of salvia miltiorrhiza.But alpha lipoic acid plus salvia miltiorrhiza was better than salvia miltiorrhiza according MDA concentration reducing.
Part4:Influlence of inflammation factors of alpha lipoic acid and salvia miltiorrhiza on diabetic patients with lower extremities vascular lesions
[objective]
Observation inflammation factors of alpha lipoic acid lower extremities to diabetic patients with vascular lesions and the comparison with prostaglandin E1.
[methods]
1. Diabetic patients with vascular lesions perform as the research object,and eliminate those whose heart, liver and kidney function is not complete. Which conform to the1999WHO diabetes diagnosis standard. ABI<0.9.
2. Group:1) lipoic acid+salvia miltiorrhiza group (1group, n=20)2) salvia miltiorrhiza group (2groups, n=20).
3. Use Elisa test plasma IL-6.
4. Use Elisa test plasma VCAM-1.
5. Use Elisa test plasma PAI-1.
[results]
1. IL-6concentration was not significant different between the two groups before treatment (P>0.05)
2. IL-6concentration was significant different before and after treatment of the two groups.Group A was significant different before and after treatment,(P=0.001), Group B was significant different before and after treatment,(P=0.010)
3. IL-6concentration was significant different between the two groups before and after treatment. Group A was lower than group B (P<0.001)
4. VCAM-1concentration was not significant different between the two groups before treatment (P>0.05)
5. VCAM-1concentration was significant different before and after treatment of the two groups.Group A was significant different before and after treatment,(P<0.001), Group B was significant different before and after treatment,(P<0.001) respectively.
6. VCAM-1concentration was significant different between the two groups before and after treatment (P<0.001). Group A was lower than group B.
7. PAI-1concentration was not significant different between the two groups before treatment (P>0.05)
8. PAI-1concentration was significant different before and after treatment of the two groups.Group A was significant different before and after treatment,(P<0.001) Group B was significant different before and after treatment,(P<0.001) respectively.
9. PAI-1concentration was significant different between the two groups before and after treatment (P<0.001). Group A was lower than group B.
[conclusion]
1. IL-6,VCAM-1,PAI-1concentration of diabetic patients with vascular lesions was significant low after correcting of metabolic disorder,
2. IL-6concentration was low after using of alpha lipoic acid plus salvia miltiorrhiza.
3. IL-6concentration was low after using of salvia miltiorrhiza.But alpha lipoic acid plus salvia miltiorrhiza were better than salvia miltiorrhiza according IL-6concentration reducing.
4. VCAM-1concentration was low after using of alpha lipoic acid plus salvia miltiorrhiza.
5. VCAM-1concentration was low after using of salvia miltiorrhiza. But alpha lipoic acid plus salvia miltiorrhiza were better than salvia miltiorrhiza according VCAM-1concentration reducing.
6. PAI-1concentration was low after using of alpha lipoic acid plus salvia miltiorrhiza.
7. PAI-1concentration was low after using of salvia miltiorrhiza. But alpha lipoic acid plus salvia miltiorrhiza were better than salvia miltiorrhiza according PAI-1concentration reducing.
近年来,糖尿病患者的发病率逐年增加,糖尿病并发症的发生也随之不断增加。糖尿病并发下肢血管病变(diabetic lower extremity arterial disease, DLEAD)是非糖尿病患者的7-10倍[1，2],部分患者在诊断糖尿病时即已存在,并随年龄、病程的增加而发病增多[3,4]。常见症状为间歇性跛行,表现为肢体运动时疼痛、不适或疲劳,休息后缓解。然而仅1/3的DLEAD患者具有典型的间歇性跛行症状,>50%患者无症状或症状不典型,其余DLEAD患者则症状较严重,可表现为静息痛、组织坏死或坏疽。患者由于存在周围神经病变,肢体感觉减退,症状往往比非糖尿病患者更不明显,仅表现出下肢疲劳感、步行速度减慢等[5，6]。DLEAD患者下肢病理改变较非糖尿病下肢动脉疾病患者更严重,病变范围更弥漫,更容易向肢体远端发展。无论对糖尿病还是非糖尿病患者,下肢动脉疾病是下肢截肢的主要危险因素。即使患者无症状,下肢动脉疾病也是全身心血管、脑血管疾病的标志。因此早期发现糖尿病下肢血管疾病,早期进行干预治疗,可减轻患者临床症状,降低临床DLEAD的致残率和截肢率、心血管事件的发生率[7,8,9],提高患者生活质量,改善远期预后。
糖尿病下肢血管病变的治疗是多方面的,以缓解症状、减慢动脉粥样硬化进程和控制危险因素为原则。其中包括外科治疗、介入治疗[10,11,12,13]、内科治疗[14,15,16]等。内科治疗包括危险因素的控制,如戒烟、减轻体质量、降压、降脂、控制血糖等。抗血小板治疗,如阿司匹林、氯吡格雷的应用,血管扩张药物治疗等等[17]。
研究表明,硫辛酸(lipoic acid,LA),亦称α-硫辛酸(a-lipoic acid, ALA),有改善动脉粥样硬化患者血管内皮功能的作用。丹参(Salvia miltiorrhiza Bunge)可扩张血管,改善循环。
硫辛酸是一种天然的二硫化合物,在体内可以转变为二氢硫辛酸(DHLA,还原型),LA和DHLA都具有很强的抗氧化性,它们在体内协同作用,是已知天然抗氧剂中效果最强的一种[19,20]。研究表明,硫辛酸使动脉粥样硬化患者血浆纤溶酶原激活剂-1(Plasminogen Activator Inhibitor-1,PAI-1),白介素-6等炎症因素减少,脂质氧化终产物MDA减少,抗氧化物质谷胱甘肽(L-Glutathione, GSH)增加,从而降低氧化应激水平,减少机体炎症因素,改善NO介导的血管舒张,改善血管内皮细胞的功能[21,22,23,24]。硫辛酸是否能改善糖尿病下肢血管病变患者下肢血管舒张功能?这在以往的研究中未见报道。
丹参的主要有效成分为丹参酮等脂溶性成分和丹酚酸等水溶性成分两部分。药理研究结果表明丹参具有扩张冠状动脉、增加冠脉血流量、防止心肌缺血、改善微循环等[25]。丹参能否改善糖尿病下肢血管病变患者下肢血管舒张功能?与硫辛酸相比较,疗效如何?目前尚未见有研究报道。
糖尿病血管病变早期以血管内皮依赖性舒张功能受损为主,可能是糖尿病血管病变发生的始动因素和基本病理生理改变[26],核心为血管内皮细胞功能障碍。内皮细胞是血液和血管平滑肌之间的重要屏障,分泌的多种活性物质处于精密的平衡状态,维持血管正常的生理功能。当内皮细胞功能紊乱、分泌活性物质失衡时,则造成血管的病理改变[27,28,29]。
氧化应激为糖尿病并发症的共同基础。氧化应激能够改变血浆脂质蛋白谱、凝血系统。主要机制如下：一高糖加重低密度脂蛋白(low density lipoprotein,LDL)氧化的易感性。氧化低密度脂蛋白(oxDL)破坏单核细胞、平滑肌细胞特异性LDL受体的识别能力,导致变性LDL通过胞吞途径在胞内不断积累,最终形成泡沫细胞。后者是形成动脉粥样硬化的关键。二活性氧(reactiveoxygen spicies,ROS)作用于花生四烯酸,分别通过环氧化和醋氧化反应产生前列腺素和白三烯,趋化白细胞浸润,诱导炎性反应的发生。通过不同机制导致血栓和血液高凝状态,包括诱导前列腺素产生、凝血酶激活等,从而诱发血管病变。硫辛酸及丹参是否能改变糖尿病下肢血管病变患者氧化应激相关因素如MDA, GSH?如果能改变,该两种药物是否有差异?以往的研究未曾涉及。
炎症是糖尿病血管病变的原因之一。糖尿病患者促炎因子如白细胞介素(inter-leukin,IL)-1,-6、活性氧、C反应蛋白(C-reactive protein,CRP)等表达明显增加,促进黏附分子表达,增加炎症趋化因子和凝固蛋白,如：血浆纤溶酶原激活剂-1(PAI-1)、纤溶酶原激活物和组织因子分泌,诱导血管调节物释放,造成血管功能改变。硫辛酸及丹参能否改变糖尿病下肢血管病变患者炎症相关因素：如白介素-6,血管细胞粘附分子-1(vascular cell adhesion molecule1, VCAM-1), PAI-1?如果有影响,该两种药物是否有差异?我们还不得而知。
步行受损问卷(Waling Impairment Questionnare,WIQ)可用于评价下肢血管病变患者的行走能力、生活质量、治疗效果,是一种简便、经济、实用性强的可靠评分方法,在国外广泛应用。
基于对以上已有研究的思考,本实验共分为四部分。本实验拟比较α-硫辛酸及丹参对糖尿病下肢血管病变患者WIQ评分的影响,临床症状的改善,及是否对造成血管内皮功能改变的氧化应激相关因素、炎症相关因素有所改善进行探讨。
第一部分：α-硫辛酸与丹参治疗糖尿病下肢血管病变临床疗效观察
[目的]
观察α-硫辛酸、丹参对糖尿病下肢血管病变的临床疗效。
[方法]
1、以糖尿病下肢血管病变患者为研究对象,排除严重心、肝、肾功能不全者,均符合1999年WHO糖尿病诊断标准,ABI<0.9。入院后均使用胰岛素控制血糖。
2、入院后测量血压、体重指数(BMI)、踝肱指数(ABI)、空腹测血脂、血糖、糖化血红蛋白(HbA1C)等。
3、分组：1)α-硫辛酸+丹参组(A组,n=20,α-硫辛酸600mg/d,丹参40mg/d, iv by drip,共21天),2)丹参组(B组,n=20,丹参40mg/d,iv by drip,共21天)
5、根据步行受损问卷(walking impairment questionare,WIQ)评分,观察各组用药前后评分的变化。
6、根据临床症状评分,观察各组用药前后评分的变化。
[结果]
1.各组治疗前WIQ量表评分比较无显著统计学差异(P>0.05)。
2.各组治疗前后WIQ量表评分比较差异有显著性统计学意义。分别为：A组治疗前后比较,差异有显著性统计学意义(P<0.001),B组治疗前后比较,差异有显著性统计学意义(P<0.001)。。
3.各组治疗后WIQ量表评分变化比较差异有显著性统计学意义(P<0.001)。A组较B组显著增高。
4.各组治疗前症状评分差异无显著性统计学差异(P>0.05)。
5.各组治疗前后症状评分比较差异有显著性统计学意义,分别为：麻木感：A组治疗前后比较,差异有显著性统计学意义(P<0.001),B组治疗前后比较,差异有显著性统计学意义(P=0.008)。冷感：麻木感：A组治疗前后比较,差异有显著性统计学意义(P<0.001),B组治疗前后比较,差异有显著性统计学意义(P=0.008)。静息痛：A组治疗前后比较,差异有显著性统计学意义(P<0.001),B组治疗前后比较,差异有显著性统计学意义(P=0.005)。
6.两组治疗后症状评分变化比较差异有显著性统计学意义,其中分别为：麻木感变化：A组较B组高,差异有显著性统计学意义(P=0.002)。冷感变化比较, A组较B组高,差异有显著性统计学意义(P=0.004)。静息痛变化比较, A组较B组高,差异有显著性统计学意义(P=0.002)。
[结论]
1.在纠正患者代谢紊乱后,糖尿病下肢血管病变患者WIQ及症状评分可得到改善。
2.a-硫辛酸+丹参显著改善糖尿病下肢血管病变患者WIQ评分。
3.丹参可改善糖尿病下肢血管病变患者WIQ评分,但α-硫辛酸+丹参显著优于丹参。
4.α-硫辛酸+丹参显著改善糖尿病下肢血管病变患者症状评分。
5.丹参可改善糖尿病下肢血管病变患者症状评分,但α-硫辛酸+丹参改善患者WIQ评分显著优于丹参。
第二部分：α-硫辛酸与丹参对糖尿病下肢血管病变患者血流介导的血管舒张变化(FMD)
[目的]
观察α-硫辛酸、丹参对糖尿病下肢血管病变患者内皮依赖的血管舒张功能(flow-mediated dilation,FMD)的影响。
[方法]
1、以糖尿病下肢血管病变患者为研究对象,排除严重心、肝、肾功能不全者。均符合1999年WHO糖尿病诊断标准。ABI<0.9。
2、分组：1)α-硫辛酸+丹参组(A组,n=20)2)丹参组(B组,n=20)
3、采用12MHz高频线阵探头的彩色多普勒超声诊断仪测量肱动脉舒张期末血管内径。
4.用带袖套式充气止血带的血压计加压300mmHg,持续4—5分钟,迅速放气,放气后45—60s于同样部位再测舒张期末血管内径。
[结果]
1、各组治疗前后肱动脉内径比较差异无显著性统计学意义(P>0.05)。
2、各组治疗前后FMD比较差异有显著性统计学意义(P<0.001)。分别为：A组治疗前后比较,差异有显著性统计学意义(P<0.001),B组治疗前后比较,差异有显著性统计学意义(P<0.001)。
3、两组治疗后FMD比较差异有显著性统计学意义(P<0.001)。A组较B组显著增高。
[结论]
1、在纠正患者代谢紊乱后,糖尿病下肢血管病变患者内皮依赖的血管舒张功能可得到改善。
2、α-硫辛酸+丹参可显著改善糖尿病下肢血管病变患者内皮依赖的血管舒张功能。
3、丹参可改善糖尿病下肢血管病变患者内皮依赖的血管舒张功能,但α-硫辛酸+丹参改善内皮依赖的血管舒张功能显著优于丹参。
第三部分：α-硫辛酸及丹参对糖尿病下肢血管病变氧化应激相关因素的影响
[目的]
观察α-硫辛酸、丹参对糖尿病下肢血管病变患者血清氧化应激因素的影响。
[方法]
1、以糖尿病下肢血管病变患者为研究对象,排除严重心、肝、肾功能不全者。均符合1999年WHO糖尿病诊断标准。ABI<0.9。
2、分组：1)α-硫辛酸+丹参组(A组,n=20)2)丹参组(B组,n=20)
3、采用硫代巴比妥酸法测定MDA。
4、采用二硫代二硝基苯甲酸反应法测定GSH。
[结果]
1.各组治疗前血浆GSH浓度比较差异无显著性统计学意义(P>0.05)。
2.各组治疗前后血浆GSH浓度比较,差异有显著性统计学意义,分别为：A组治疗前后比较,差异有显著性统计学意义(P<0.001),B组治疗前后比较,差异有显著性统计学意义(P<0.001)。
3.两组治疗后血浆GSH浓度比较差异有显著性统计学意义(P<0.001)。A组较B组显著增高。
4.各组治疗前血浆MDA浓度比较差异无显著性统计学意义(P>0.05)。
5.各组治疗后血浆MDA浓度比较,差异有显著性统计学意义,分别为：A组治疗前后比较,差异有显著性统计学意义(P<0.001),B组治疗前后比较,差异有显著性统计学意义(P<0.001)。
6.两组治疗后血浆MDA浓度比较差异有显著性统计学意义(P<0.001)。A组较B组显著增高。
[结论]
1.在纠正患者代谢紊乱后,糖尿病下肢血管病变患者血浆GSH浓度升高,MDA浓度降低。
2.α-硫辛酸+丹参可显著增加血浆GSH浓度。
3.丹参可增加血浆GSH浓度,但α-硫辛酸+丹参增加血浆GSH浓度显著优于丹参。
4.α-硫辛酸+丹参可显著降低血浆MDA浓度。
5.丹参可降低血浆MDA浓度,但α-硫辛酸+丹参降低血浆MDA浓度显著优于丹参。
第四部分：α-硫辛酸及丹参对糖尿病下肢血管病变患者炎症相关因素的影响
[目的]
观察α-硫辛酸、丹参对糖尿病下肢血管病变患者炎症相关因子的影响。
[方法]
1、以糖尿病下肢血管病变患者为研究对象,排除严重心、肝、肾功能不全者。均符合1999年WHO糖尿病诊断标准。ABI<0.9。
2、分组：1)α-硫辛酸+丹参组(A组,n=20)2)丹参组(B组,n=20)
3、使用Elisa法检测血浆IL-6。
4、使用Elisa法检测血浆VCAM-1。
5、使用Elisa法检测血浆PAI-1。
[结果]
1.各组血浆IL-6浓度比较差异无显著性统计学意义(P>0.05)。
2.各组治疗前后血浆IL-6浓度比较,差异有显著性统计学意义,分别为：A组治疗前后比较,差异有显著性统计学意义(P=0.001),B组治疗前后比较,差异有显著性统计学意义(P=0.010)。
3.两组治疗后血浆IL-6浓度变化比较差异有显著性统计学意义(P=0.001)。A组较B组显著降低。
4.各组治疗前血浆VCAM-1浓度比较差异无显著性统计学意义(P>0.05)。
5.各组治疗后血浆VCAM-1浓度比较,差异有显著性统计学意义,分别为：A组治疗前后比较,差异有显著性统计学意义(P<0.001),B组治疗前后比较,差异有显著性统计学意义(P<0.001)。
6.两组治疗后血浆VCAM-1浓度比较差异有显著性统计学意义(P<0.001)。A组较B组显著降低。
7.各组治疗前血浆PAI-1浓度比较差异无显著性统计学意义(P>0.05)。
8.各组治疗后血浆PAI-1浓度比较,差异有显著性统计学意义,分别为：A组治疗前后比较,差异有显著性统计学意义(P<0.001),B组治疗前后比较,差异有显著性统计学意义(P<0.001)。
9.两组治疗后血浆PAI-1浓度比较差异有显著性统计学意义(P<0.001)。A组较B组显著降低。
[结论]
1.在纠正患者代谢紊乱后,糖尿病下肢血管病变患者血浆IL-6、VCAM-1、PAI-1浓度降低。
2.α-硫辛酸+丹参可降低血浆IL-6浓度。
3.丹参可降低血浆IL-6浓度,但α-硫辛酸+丹参降低血浆IL-6浓度显著优于丹参。
4.α-硫辛酸+丹参及丹参可降低血浆VCAM-1浓度。
5.丹参可降低血浆VCAM-1浓度,但α-硫辛酸+丹参降低血浆VCAM-1浓度显著优于丹参。
6.α-硫辛酸+丹参及丹参可降低血浆PAI-1浓度
7.丹参可降低血浆PAI-1浓度,但α-硫辛酸+丹参降低血浆PAI-1浓度显著优于丹
[background]
In recent years, the incidence of diabetes increased year by year, diabetes complications are also increasing. Diabetes concurrent lower limb vascular lesions (diabetic lower extremity arterial disease, DLEAD) are7to10times as patients with diabetes mellitus. Some patients are diagnosed diabetes that already exist, and inctrease with the growth of age, duration. Common symptom is intermittent claudication, performance of one body motion pain, discomfort, or fatigue, after the break to alleviate. Only a third of the DLEAD patients with typical intermittent limp symptoms,>50%of patients without symptoms or atypical symptoms, the rest DLEAD patients with severe symptoms, by resting pain, gangrene or gangrene. But since there are patients peripheral neuropathy, body feeling decline, DLEAD symptoms of diabetes more often not obvious, the only show are lower limbs on foot, fatigue or slow down, etc. DLEAD patients pathological changes is more serious than patients with the lower extremities diabetes lower limb artery disease,and more diffuse disease extent, more easily to limbs far end development. Whether to diabetic patients or those withoutdiabetes, lower limb artery disease is the main factor of limb amputations, even if patients are without symptoms, lower limb artery disease is the the sign of whole body cardiovascular and cerebrovascular diseases. So early detection of diabetes lower limb vascular disease, early intervention treatment, can reduce the clinical symptoms and reduce the DLEAD clinical morbidity and amputation rate, the incidence of cardiovascular events, and improve the quality of life of the patients, improve the long-term prognosis.
the treatment of Diabetes lower limbs of vascular lesions t is various, to alleviate the symptoms, slow down the process of atherosclerosis and control risk factors is the principle, inncluding surgery, interventional treatment, medical treatment, etc. Medical treatment includes the control of the risk factors, such as quit smoking, reduce body quality, step-down, fall fat, control blood sugar, etc.,anti-platelet therapy, such as aspirin, clopidogrel, application of vessels to dilate drug therapy, and so on.
Lipoic acid (LA) also called alpha lipoic acid (ALA), is a natural two sulfur compounds, in body,which can be transformed for the two hydrogen lipoic acid (DHLA, reduced), LA and DHLA both have the very strong oxidation resistance, they in body, synergy, is known to be one of the strongest effectin natural antioxidants. Research shows that lipoic acid that atherosclerosis plasma fiber melts the patients with plasminogen activator inhibitor1(PAI-1), interleukin (IL)-6, reduce inflammation factors, lipid oxidation end-products of MDA reduce, GSH increase, so as to reduce oxidatie stress level,andimprove NO mediated diastolic blood vessels, improving the function of endothelial cells.
Salvia miltiorrhiza Bunge, the main effective ingredients are such as for Dan CanTong fat soluble constituents and Dan phenolic acids water-soluble ingredients such as two parts. The pharmacological research results show that salvia miltiorrhiza has dilating coronary artery, increase coronary blood flow, prevent myocardial ischemia, microcirculation, fall hematic fat, etc.
The primarily diastolic function damage of Diabetes vascular lesions with endothelial dependence may be diabetes vascular lesions occurr tumor-initiating factors and the fundamental pathological physiology change, the core for endothelial cells of dysfunction. Endothelial cells and vascular smooth muscle blood is an important barrier between, the secretion of various active substances in precision balance, and maintain normal physiological function of blood vessels. When endothelial function disorder makes the secretory activity material imbalanceed, the pathological changes cause blood vessels leision. Patients with diabetes to promote inflammation factors interleukin (inter-leukin IL)-1,6, active oxygen (reactive oxygen spicies, ROS) c-reactive protein (C-reactive protein, CRP) express significantly increased, promote adhesion molecule expression, increase inflammation and solidification chemotactic agent protein (PAI-1, fibrinolytic enzyme that the activation and tissue factor) secretion, induction blood vessels that regulation (endothelial NO gentle shock peptide) release, cause blood vessel function damage.
How do alpha-lipoic acid and Salvia miltiorrhiza improve the clinicial symptoms of diabetic patients with vascular lesions? what is the effect of the above two drugs on oxidative stress factors, such as GSH,MDA of diabetic patients with lower extremities vascular lesions? what is the effect of the above two drugs on inflammatory factors:plasma fiber melts the enzyme activators-1, interleukin (il)6, The past research has not been concerned.
Based on the above thinking, this experiment is divided into four parts. This experiment is to compare clinical effect of alpha lipoic acid and Salvia miltiorrhiza on patients with lower extremities vascular lesions, and inflammation factors and oxidative stress and related factors are discussed.
Part1:clinical curative effect observation of alpha lipoic acid and salvia miltiorrhiza on the treatment of diabetes lower limb vascular lesions
[objective]
Observation the clinical clinical curative effect of alpha lipoic acid and Salvia miltiorrhiza on diabetes with vascular lesions of lower extremities.
[methods]
1. Diabetic patients with vascular lesions work as the research object, eliminate those whose heart, liver and kidney function is not complete. Which conform to the 1999WHO diabetes diagnosis standard. ABI<0.9. All insulin after admission control blood sugar.
2. After admission measure blood pressure, body mass index (BMI), fasting blood sugar, blood fat, the glycated hemoglobin (HbA1C), etc.
3. Group:1) a-lipoic acid±salvia miltiorrhiza group (group A, n=20, a-lipoic acid600mg/d,iv by drip andSalvia miltiorrhiza,40mg/d,iv by drip,21days)2) salvia miltiorrhiza group (group B, n=20, SalviamiltiorrhizaBunge,40mg/d,iv by drip,21days).
4. According to the clinical symptom scores, observe the clinical scoring change of the three group self before and after treatment.
5. According to clinical symptom scores, observe the clinical scoring change of the two groups before and after treatment.
6. According to WIQ score, observe the clinical scoring change before and after treatment.
[results]
1. WIQ scores were not significant different between the two groups (P>0.05)
2. WIQ scores were significant different before and after treatment of the two groups.Group A was significant different before and after treatment,(P<0.001) Group B was significant different before and after treatment,(P<0.001) respectively.
3. WIQ scores were significant different between the two groups before and after treatment. Group A was higher than group B (P<0.001)
4. Clinical symptom scores were not significant different between the two groups before treatment (P>0.05)
5. Clinical symptom scores were significant different before and after treatment of the two groups. Numbness:Group A was significant different before and after treatment,(P<0.001), Group B was significant different before and after treatment,(P=0.008), respectively, cold:Group A was significant different before and after treatment,(P<0.001), Group B was significant different before and after treatment, (P=0.008), rest pain:Group A was significant different before and after treatment,(P<0.001), Group B was significant different before and after treatment,(P=0.005), respectively.
6. Clinical symptom scores were significant different before and after treatment between the two groups (P<0.05). Numbness:Group A was higher than group B (P=0.002).Cold:Group A was higher than group B (P=0.004). Rest pain:Group A was lower than group B (P=0.002), respectively.
[conclusion]
1. WIQ scores of diabetic patients with vascular lesions were significant improved after correcting of metabolic disorder.
2. WIQ scores of diabetic patients with vascular lesions were improved by using of alpha lipoic acid plusSalvia miltiorrhiza.
3. WIQ scores of diabetic patients with vascular lesions were improved by using ofSalvia miltiorrhiza. But alpha lipoic acid plusSalvia miltiorrhiza are better thanSalvia miltiorrhiza according WIQ scores improving,
4. Clinical symptom scores of diabetic patients with vascular lesions were improved by using of alpha lipoic acid plusSalvia miltiorrhiz.
5. Clinical symptom scores of diabetic patients with vascular lesions were improved by using ofSalvia miltiorrhiza. But Alpha lipoic acid plus Salvia miltiorrhiza Bunge was better thanSalvia miltiorrhiza according Clinical symptom scores improving.
Part2:alpha lipoic acid and salvia miltiorrhiza mediated flood mediated diastolic function of diabetic patients with lower extremities vascular lesion.
[objective]
Observe the influence of diastolic function of vascular endothelial dependent alpha lipoic acid andSalvia miltiorrhiza on diabetic patients with lower extremities vascular lesions.
[methods]
1. Diabetic patients with vascular lesions work as the research object, and eliminate those whose heart, liver and kidney function is not complete. Which conform to the1999WHO diabetes diagnosis standard. ABI<0.9.
2. Group:1) lipoic acid+salvia miltiorrhiza group (group A, n=20)2) salvia miltiorrhiza group (group B, n=20).
3.The12MHz high frequency line of probe array of color doppler ultrasound diagnostic instrument was used to measure the diameter of humerus artery diastolic blood vessels.
4.Use pneumatic tourniquet to takes type of blood pressure300mmHg for4-5minutes, quickly deflated, the cuff was released after60-45second at the same area and measure the inner diameter of diastolic blood vessels.
[results]
1. The diameter and flow velocity of humerus artery diastolic blood vessels was not significant different between the two groups before treatment (P>0.05)
2. FMD was significant different before and after treatment of the two groups.Group A was significant different before and after treatment,(P<0.001).Group B was significant different before and after treatment (P<0.001), respectively.
3. FMD was significant different between the two groups before and after treatment. Group A was higher than group B (P<0.001)
[conclusion]
1. FMD of diabetic patients with vascular lesions was significant improved after correcting of metabolic disorder.
2. FMD of diabetic patients with vascular lesions were improved by using of alpha lipoic acid plusSalvia miltiorrhiza.
3. FMD of diabetic patients with vascular lesions were improved by using ofSalvia miltiorrhiza.But alpha lipoic acid plusSalvia miltiorrhiza are better thanSalvia miltiorrhiza according FMD improving.
Part3:Influence of alpha lipoic acid and salvia miltiorrhiza on oxidative stress factors of diabetes with lower extremities vascular lesions
[objective]
Observation how alpha lipoic acid influent serum oxidative stress factors of diabetic patients with lower extremities vascular lesions and comparing withSalvia miltiorrhiza.
[methods]
1. Diabetic patients with vascular lesions wok as the research object, persons of whom heart, liver and kidney function is not complete are eliminated. Which conform to the1999WHO diabetes diagnosis standard. ABI<0.9.
2. Group:1) lipoic acid+salvia miltiorrhiza group (1group, n=20)2) salvia miltiorrhiza group (2groups, n=20).
3. The content and the method to determine the inflicting MDA.
4. Determine GSH.
[results]
1. GSH concentration was not significant different between the two groups before treatment (P>0.05)
2. GSH concentration was significant different before and after treatment of the two groups.Group A was significant different before and after treatment,(P<0.001) Group B was significant different before and after treatment,(P<0.001) respectively.
3. GSH concentration was significant different between the two groups before and after treatment. Group A was higher than group B (P<0.001)
4. MDA concentration was not significant different between the two groups before treatment (P>0.05)
5. MDA concentration was significant different before and after treatment of the two groups.Group A was significant different before and after treatment,(P<0.001), Group B was significant different before and after treatment,(P<0.001), respectively.
6. MDA concentration was significant different between the two groups before and after treatment. Group A was lower than group B (P<0.001)
[conclusion]
1. GSH concentration of diabetic patients with vascular lesions was significant high after correcting of metabolic disorder, meanwhile, MDA concentration of diabetic patients with vascular lesions was significant low.
2. GSH concentration was high after using of alpha lipoic acid plus salvia miltiorrhiza.
3. GSH concentration was high after using of alpha lipoic acid plus salvia miltiorrhiza. But alpha lipoic acid plus salvia miltiorrhiza was better than salvia miltiorrhiza according GSH concentration improving.
4. MDA concentration was low after using of alpha lipoic acid plus salvia miltiorrhiza.
5. MDA concentration was low after using of salvia miltiorrhiza.But alpha lipoic acid plus salvia miltiorrhiza was better than salvia miltiorrhiza according MDA concentration reducing.
Part4:Influlence of inflammation factors of alpha lipoic acid and salvia miltiorrhiza on diabetic patients with lower extremities vascular lesions
[objective]
Observation inflammation factors of alpha lipoic acid lower extremities to diabetic patients with vascular lesions and the comparison with prostaglandin E1.
[methods]
1. Diabetic patients with vascular lesions perform as the research object,and eliminate those whose heart, liver and kidney function is not complete. Which conform to the1999WHO diabetes diagnosis standard. ABI<0.9.
2. Group:1) lipoic acid+salvia miltiorrhiza group (1group, n=20)2) salvia miltiorrhiza group (2groups, n=20).
3. Use Elisa test plasma IL-6.
4. Use Elisa test plasma VCAM-1.
5. Use Elisa test plasma PAI-1.
[results]
1. IL-6concentration was not significant different between the two groups before treatment (P>0.05)
2. IL-6concentration was significant different before and after treatment of the two groups.Group A was significant different before and after treatment,(P=0.001), Group B was significant different before and after treatment,(P=0.010)
3. IL-6concentration was significant different between the two groups before and after treatment. Group A was lower than group B (P<0.001)
4. VCAM-1concentration was not significant different between the two groups before treatment (P>0.05)
5. VCAM-1concentration was significant different before and after treatment of the two groups.Group A was significant different before and after treatment,(P<0.001), Group B was significant different before and after treatment,(P<0.001) respectively.
6. VCAM-1concentration was significant different between the two groups before and after treatment (P<0.001). Group A was lower than group B.
7. PAI-1concentration was not significant different between the two groups before treatment (P>0.05)
8. PAI-1concentration was significant different before and after treatment of the two groups.Group A was significant different before and after treatment,(P<0.001) Group B was significant different before and after treatment,(P<0.001) respectively.
9. PAI-1concentration was significant different between the two groups before and after treatment (P<0.001). Group A was lower than group B.
[conclusion]
1. IL-6,VCAM-1,PAI-1concentration of diabetic patients with vascular lesions was significant low after correcting of metabolic disorder,
2. IL-6concentration was low after using of alpha lipoic acid plus salvia miltiorrhiza.
3. IL-6concentration was low after using of salvia miltiorrhiza.But alpha lipoic acid plus salvia miltiorrhiza were better than salvia miltiorrhiza according IL-6concentration reducing.
4. VCAM-1concentration was low after using of alpha lipoic acid plus salvia miltiorrhiza.
5. VCAM-1concentration was low after using of salvia miltiorrhiza. But alpha lipoic acid plus salvia miltiorrhiza were better than salvia miltiorrhiza according VCAM-1concentration reducing.
6. PAI-1concentration was low after using of alpha lipoic acid plus salvia miltiorrhiza.
7. PAI-1concentration was low after using of salvia miltiorrhiza. But alpha lipoic acid plus salvia miltiorrhiza were better than salvia miltiorrhiza according PAI-1concentration reducing.
引文
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[20]Manning PJ, Sutherland WH, Williams SM, et al. The effect of lipoic acid and vitamin E therapies in individuals with the metabolic syndrome. Nutr Metab Cardiovasc Dis.2012 Mar 6. [Epub ahead of print]
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[50]Mirjana M, Jelena A, Aleksandra U, et al. Alpha-lipoic acid preserves the structural and functional integrity of red blood cells by adjusting the redox disturbance and decreasing O-GlcNAc modifications of antioxidant enzymes and heat shock proteins in diabetic rats. Eur J Nutr.2011 Nov 18. [Epub ahead of print]
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[56]El-Latif MA, Makhlouf AA, Moustafa YM, Gouda TE et al. Diagnostic value of nitric oxide, lipoprotein(a), and malondialdehyde levels in the peripheral venous and cavernous blood of diabetics with erectile dysfunction. Int J Impot Res.2006; 18(6):544-9.
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[7]Aerden D, Haentjens P, von Kemp K, et al. The surgical history of the amputated limb according to the indication for revascularization:diabetic foot, acute ischaemia, aneurysmal disease, chronic arterial occlusive disease. Acta ChirBelg.2011;111(6):384-8.
[8]Van Den Berg J, Waser S, Trelle S, et al. Lesion characteristics of patients with chronic critical limb ischemia that determine choice of treatment modality. J Cardiovasc Surg (Torino).2012;53(1):45-52.
[9]Parekh N, Nanjundappa A, Dieter RS. Pharmacological interventions on critical limb ischemia in diabetic patients. J Cardiovasc Surg (Torino). 2012;53(1):39-43.
[10]Alexandrescu V, Hubermont G. The challenging topic of diabetic foot revascularization:does the angiosome-guided angioplasty may improve outcome. J Cardiovasc Surg (Torino).2012;53(1):3-12.
[11]Garg PK, Liu K, Ferrucci L, et al. Lower extremity nerve function, calf skeletal muscle characteristics, and functional performance in peripheral arterial disease. J Am Geriatr Soc.2011;59(10):1855-63..
[12]Manzi M, Cester G, Palena LM, et al. Vascular imaging of the foot:the first step toward endovascular recanalization. Radiographics.2011;31 (6):1623-36.
[13]Faglia E. Characteristics of peripheral arterial disease and its relevance to the diabetic population. Int J Low Extrem Wounds.2011;10(3):152-66.
[14]Manzi M, Palena L, Cester G. Endovascular techniques for limb salvage in diabetics with crural and pedal disease. J Cardiovasc Surg (Torino). 2011;52(4):485-92.
[15]Van Belle E, Nikol S, Norgren L, et al. Insights on the role of diabetes and geographic variation in patients with critical limb ischaemia. Eur J Vasc Endovasc Surg.2011;42(3):365-73.
[16]Wang J, Zhu YQ, Li MH, et al. Batroxobin plus aspirin reduces restenosis after angioplasty for arterial occlusive disease in diabetic patients with lower-limb ischemia. J Vasc Interv Radiol.2011;22(7):987-94.
[17]Sixt S, Scheinert D, Rastan A, et al. One-year outcome after percutaneous rotational and aspiration atherectomy in infrainguinal arteries in patient with and without type 2 diabetes mellitus. Ann Vasc Surg.2011;25(4):520-9.
[18]Chen WL, Kang CH, Wang SG, et al. a-Lipoic acid regulates lipid metabolism through induction of sirtuin 1 (SIRT1) and activation of AMP-activated protein kinase. Diabetologia.2012 Mar 30. [Epub ahead of print]
[19]Chen P, Ma QG, Ji C, et al. Dietary lipoic Acid influences antioxidant capability and oxidative status of broilers. Int J Mol Sci.2011;12(12):8476-88.
[20]Manning PJ, Sutherland WH, Williams SM, et al. The effect of lipoic acid and vitamin E therapies in individuals with the metabolic syndrome. Nutr Metab Cardiovasc Dis.2012 Mar 6. [Epub ahead of print]
[21]Mittermayer F, Pleiner J, Francesconi M, et al. Treatment with alpha-lipoic acid reduces asymmetric dimethylarginine in patients with type 2 diabetes mellitus. Transl Res.2010;155(1):6-9.
[22]Guangda Xiang, Jinhui Pu, Ling Yue, et al. a-Lipoic acid can improve endothelial dysfunction in subjects withimpaired fasting glucose. Metabolism Clinical and Experimental.2011; 60:480-485.
[23]Heinisch BB, Francesconi M, Mittermayer F, et al. Alpha-lipoic acid improves vascular endothelial function in patients with type 2 diabetes:a placebo-controlled randomized trial. Eur J Clin Invest.2010;40(2):148-54.
[24]Sola S, Mir MQ, Cheema FA, et al. Irbesartan and lipoic acid improve endothelial function and reduce markers of inflammation in the metabolic syndrome:results of the Irbesartan and Lipoic Acid in Endothelial Dysfunction (ISLAND) study. Circulation.2005; 111(3):343-8.
[25]Wang T, Fu F, Han B, et al. Danshensu ameliorates the cognitive decline in streptozotocin-induced diabetic mice by attenuating advanced glycation end product-mediated neuroinflammation. J Neuroimmunol.2012 Mar 12. [Epub ahead of print]
[26]Carter A, Murphy MO, Turner NJ, et al. Intimal neovascularisation is a prominent feature of atherosclerotic plaques in diabetic patients with critical limb ischaemia Eur J Vasc Endovasc Surg.2007;33(3):319-24.
[27]Wilson AM, O'Neal D, Nelson CL, et al. Comparison of arterial assessments in low and high vascular disease risk groups. Am J Hypertens. 2004;17(4):285-91.
[28]Selvaraju V, Joshi M, Suresh S, et al. Diabetes, oxidative stress, molecular mechanism, and cardiovascular disease-an overview. Toxicol Mech Methods. 2012 Mar 17. [Epub ahead of print]
[29]Huang A, Yang YM, Feher A, et al. Exacerbation of endothelial dysfunction during the progression of diabetes:role of oxidative stress. Am J Physiol Regul Integr Comp Physiol.2012;302(6):R674-81.
[30]Aso Y, Okumura K, Inoue T, et al. Results of blood inflammatory markers are associated more strongly with toe-brachial index than with ankle-brachial index in patients with type 2 diabetes. Diabetes Care.2004;27(6):1381-6.
[31]Mendiz OA, Fava CM, Valdivieso LR, et al. Angioplasty for treatment of isolated below-the-knee arterial stenosis in patients with critical limb ischemia. Angiology.2011;62(5):359-64.
[32]Matsuo H, Shigematsu H. Patient-based outcomes using the Walking Impairment Questionnaire for patients with peripheral arterial occlusive disease treated with Lipo-PGE1. Circ J.2010;74(2):365-70.
[33]Xiao L, Huang DS, Tong JJ, et al. Efficacy of endoluminal interventional therapy in diabetic peripheral arterial occlusive disease:a retrospective trial. Cardiovasc Diabetol.2012;11:17.
[34]Zhang H, Li XY, Si YJ, et al. Manifestation of lower extremity atherosclerosis in diabetic patients with high ankle-brachial index. Chin Med J (Engl). 2010;123(7):890-4.
[35]Garg PK, Liu K, Ferrucci L, Guralnik JM et al. Lower extremity nerve function, calf skeletal muscle characteristics, and functional performance in peripheral arterial disease. J Am Geriatr Soc.2011;59(10):1855-63.
[36]Edmundsson D, Toolanen G. Chronic exertional compartment syndrome in diabetes mellitus. Diabet Med.2011;28(1):81-5.
[37]Van Den Berg J, Waser S, Trelle S, et al. Lesion characteristics of patients with chronic critical limb ischemia that determine choice of treatment modality. J Cardiovasc Surg (Torino).2012;53(1):45-52.
[38]Chen NX, Moe SM. Vascular Calcification:Pathophysiology and Risk Factors. Curr Hypertens Rep.2012 Apr 3. [Epub ahead of print]
[39]Kang P, Tian C, Jia C. Association of RAGE gene polymorphisms with type 2 diabetes mellitus, diabetic retinopathy and diabetic nephropathy. Gene.2012 Mar 23. [Epub ahead of print]
[40]Zhu W, Li W, Silverstein RL. Advanced glycation end products induce a prothrombotic phenotype in mice via interaction with platelet CD36. Blood. 2012 Mar 19. [Epub ahead of print]
[41]Lin N, Zhang H, Su Q. Advanced glycation end-products induce injury to pancreatic beta cells through oxidative stressDiabetes Metab.2012 Feb 29. [Epub ahead of print].
[42]Win MT, Yamamoto Y, Munesue S, et al. Regulation of RAGE for attenuating progression of diabetic vascular complications. Exp Diabetes Res. 2012;2012:894605. Epub 2011 Oct 29.
[43]Kovacic P, Somanathan R. Cell signaling and receptors in toxicity of advanced glycation end products (AGEs):a-dicarbonyls, radicals, oxidative stress and antioxidants. J Recept Signal Transduct Res.2011;31(5):332-9.
[44]Aerden D, Haentjens P, von Kemp K, et al. The surgical history of the amputated limb according to the indication for revascularization:diabetic foot, acute ischaemia, aneurysmal disease, chronic arterial occlusive disease. Acta ChirBelg.2011;111(6):384-8.
[45]Owens CD, Ridker PM, Belkin M, et al. Elevated C-reactive protein levels are associated with postoperative events in patients undergoing lower extremity vein bypass surgery. J Vasc Surg.2007;45(1):2-9.
[46]Galasko DR, Peskind E, Clark CM, et al. Antioxidants for Alzheimer Disease: A Randomized Clinical Trial With Cerebrospinal Fluid Biomarker Measures. Arch Neurol.2012 Mar 19. [Epub ahead of print]
[47]Abdel-Hafeez EH, Ahmad AK, Abdulla AM, et al. Therapeutic effect of alpha lipoic acid combined with praziquantel on liver fibrosis induced by Schistosoma mansoni challenged mice. Parasitol Res.2012 Mar 8. [Epub ahead of print]
[48]Yao Y, Li R, Ma Y, et al. a-Lipoic acid increases tolerance of cardiomyoblasts to glucose/glucose oxidase-induced injury via ROS-dependent ERK1/2 activation. Biochim Biophys Acta.2012;1823(4):920-9..
[49]McNeilly AM, Davison GW, Murphy MH, et al. Effect of a-lipoic acid and exercise training on cardiovascular disease risk in obesity with impaired glucose tolerance. Lipids Health Dis.2011;10:217.
[50]Mirjana M, Jelena A, Aleksandra U, et al. Alpha-lipoic acid preserves the structural and functional integrity of red blood cells by adjusting the redox disturbance and decreasing O-GlcNAc modifications of antioxidant enzymes and heat shock proteins in diabetic rats. Eur J Nutr.2011 Nov 18. [Epub ahead of print]
[51]Hafez T, Moussa M, Nesim I, et al. The effect of intraportal prostaglandin E1 on adhesion molecule expression, inflammatory modulator function, and histology in canine hepatic ischemia/reperfusion injury. J Surg Res. 2007;138(1):88-99.
[52]Alexandrescu V, Hubermont G. The challenging topic of diabetic foot revascularization:does the angiosome-guided angioplasty may improve outcome.J Cardiovasc Surg (Torino).2012;53(1):3-12.
[53]Ahn JH, Kim TY, Kim YJ, et al. Lipo-prostaglandin E1 in combination with steroid therapy is effective for treatment of sudden sensorineural hearing loss in Korean patients with Type 2 diabetes. Diabet Med.2006;23(12):1339-43.
[54]Wang H, Deng JL, Yue J, et al. Prostaglandin El for preventing the progression of diabetic kidney disease. Cochrane Database Syst Rev. 2010;(5):CD006872.
[55]Abularrage CJ, Conrad MF, Hackney LA, et al. Long-term outcomes of diabetic patients undergoing endovascular infrainguinal interventions. J Vase Surg.2010;52(2):314-22.
[56]El-Latif MA, Makhlouf AA, Moustafa YM, Gouda TE et al. Diagnostic value of nitric oxide, lipoprotein(a), and malondialdehyde levels in the peripheral venous and cavernous blood of diabetics with erectile dysfunction. Int J Impot Res.2006; 18(6):544-9.
[57]Santo SS, Sergio N, Luigi DP, et al. Effect of PLC on functional parameters and oxidative profile in type 2 diabetes-associated PAD. Diabetes Res Clin Pract.2006;72(3):231-7.
[58]Arthurs ZM, Bishop PD, Feiten LE, et al.Evaluation of peripheral atherosclerosis:a comparative analysis of angiography and intravascular ultrasound imaging. J Vase Surg.2010;51(4):933-8.
[59]Lookstein R, Ward T, Kim E, et al. Value of drug-eluting stents after failed percutaneous transluminal angioplasty in the infrapopliteal vessels for the treatment of critical limb ischemia:favorable mid-term patency and limb salvage results. J Cardiovasc Surg (Torino).2011;52(4):461-6.62
[60]Van Belle E, Nikol S, Norgren L, et al. Belch J. Insights on the role of diabetes and geographic variation in patients with critical limb ischaemia. Eur J Vasc Endovasc Surg.2011;42(3):365-73.
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