化瘀健脾防石汤对泌尿系结石患者尿中主要结石抑制物影响的研究

发布时间：2018-07-06 16:05

本文选题：化瘀健脾防石汤 + 结石抑制物　；参考：《中国中医科学院》2016年博士论文

【摘要】：泌尿系结石是最常见的泌尿科疾病之一。近年来,随着气候变暖及高血脂、高血糖、高血压等代谢性疾病患者的增加,泌尿系路结石发病率呈明显增长趋势。泌尿系结石是一个高复发疾病,10年复发率达到50%。如此高的复发率不但增加了患者的痛苦及经济负担,多次的ESWL及手术治疗可导致输尿管狭窄、肾萎缩、及肾脏功能损害等并发症。因此,针对其病因的诊断和预防性治疗越来越受到重视。由于泌尿系结石的病因非常复杂,是多种因素共同作用的结果。所以结石的预防是一个系统工程,很多人非常注意基础预防,但结石仍然复发,长期服用枸橼酸盐类药物会造成胃肠道刺激等副作用,无法长期坚持。中草药对泌尿系结石的预防确有疗效,且副作用小,并可以整体调理,改善患者的易成石体质,但仍然需要系统的临床及基础研究进行验证。基于中医“治未病”的思想,继承发展名老中医防治泌尿系结石的经验,我们将刘猷枋教授、张亚强教授破血行气、化瘀软坚的治疗尿石症的思想与高荣林教授调理脾胃、化湿消滞的防治泌尿系结石经验加以总结综合。在化瘀尿石汤的基础上化裁出化瘀健脾防石汤。在临床应用中表现出良好的预防泌尿系结石的疗效。传统观点认为尿液结晶盐过饱和是结石形成的首要因素。然而,目前大量研究表明,人体内的一些成分在抑制尿液中晶体的成核,聚集和生长方面起到了至关重要的作用,称为结石抑制物。在正常人的尿液中结石抑制物具有较高的浓度及活性,所以结石不容易形成。但当尿中结石抑制物浓度下降或结构改变时,对成石的抑制能力就会下降,就容易导致结石的生成。尿中枸橼酸盐、尿镁离子的浓度及THP, OPN和ITIH3的表达在结石的发生、发展过程中起重要作用。而化瘀健脾防石汤也是以活血化瘀,健脾利湿为立法,通过整体调理改善患者的易成石体质。基于此,我们推测化瘀健脾防石汤对尿路结石的防治机理可能与调控结石抑制物的浓度及表达有关。因此,在高荣林老师、张亚强老师的指导下设计了以下临床试验进行验证。研究目的：验证化瘀健脾防石汤对泌尿系结石患者尿中主要小分子结石抑制物枸橼酸盐、镁,大分子结石抑制物THP蛋白、骨桥蛋白(0PN)、间α-胰蛋白酶抑制物重链H3(ITIH3)的影响。探索化瘀健脾防石汤预防泌尿系结石的作用机制。为临床用药及进一步研究提供依据。研究方法：总体设计采用随机单盲安慰剂对照的方法,选择广安门医院2015年1月至2015年8月期间,60例经治疗后结石全部排出的临床痊愈患者,随机分成化瘀健脾防石汤治疗组和安慰剂对照组,每组30人。经过4周的治疗,进入最后的疗效分析。1.纳入病例标准：(1)年龄18-60岁(2)曾诊断为泌尿系结石(上尿路)(3)符合泌尿系结石(上尿路)治愈标准(4)符合气滞血瘀脾虚湿阻证的辩证标准(5)签署知情同意书2.排除病例标准：(1)合并肾或输尿管畸形、输尿管狭窄的患者(2)合并泌尿系统肿瘤的患者(3)合并肾盂肾炎及输尿管炎等上尿路感染的患者(4)合并有严重心脑血管疾病,肝肾及造血系统严重原发病的患者(5)甲状旁腺功能亢进的患者(6)过敏体质者3.治疗方法：(1)治疗组：化瘀健脾防石汤一次1袋一日2次。连续服用4周(2)对照组：化瘀健脾防石汤安慰剂一次1袋一日2次。连续服用4周4.疗程：4周5.观测指标(1)主要疗效指标(入组、服药4周后各检测、记录一次)：①24小时尿尿枸橼酸、尿镁②ELISA检尿液中THP、OPN、ITIH3的蛋白表达③中医证侯评分(2)次要疗效指标(入组、服药4周后各检测一次)①尿PH值②24小时尿尿钙、尿磷、尿草酸、尿尿酸③血钙、血磷、血镁、血尿酸研究结果：1.可比性分析：入选时两组间年龄、病程、男女比例、尿TH蛋白、骨桥蛋白、间a-胰蛋白酶抑制物重链H3、尿PH值、24小时尿钙、尿磷、尿草酸、尿尿酸、尿镁、尿枸橼酸、血钙、血磷、血镁、血尿酸及中医证候评分比较,差异均无统计学意义(P均0.05),具有可比性。2.疗效分析结论：2.1主要疗效指标2.1.1对主要结石抑制物疗效24小时尿枸橼酸的排泄总量治疗组组内治疗前后比较差别有统计学意义(P0.01),治疗组与对照组疗后比较差别有统计学意义(P0.01)。24小时尿枸橼酸的排泄总量较疗前明显增加。24小时尿镁的总量治疗组与对照组治疗前后组内比较差别无统计学意义(P0.05),治疗后两组组间比较差别无统计学意义(P0.05)。说明本方对24小时尿镁的排泄量无影响。尿TH蛋白的浓度在治疗组组内治疗前后的比较中,表现出统计学差异(P0.01)。治疗组与对照组疗后比较的差异也有统计学意义(P0.05)。TH蛋白的浓度较治疗前有所下降。尿OPN蛋白浓度在治疗组治疗前后的组内比较中,差别无统计学意义(P0.05)。疗后治疗组与对照组比较差别无统计学意义(P0.05)。尿间α-胰蛋白酶抑制物重链H3浓度在治疗组组内治疗前后的比较中,表现出统计学差异(P0.01)。治疗组与对照组疗后比较的差异也有统计学意义(P0.05)。间α-胰蛋白酶抑制物重链H3浓度较治疗前下降说明化瘀尿石汤确实有预防结石复发的作用。化瘀健脾防石汤可以增加小分子结石抑制物尿枸橼酸的排泄量,可以下调泌尿系结石治愈患者尿TH蛋白和尿间α-胰蛋白酶抑制物重链H3的异常表达。2.1.2中医证候评分疗效化瘀健脾防石汤能够明显降低治疗组患者的中医证候评分,总有效率达到79.3%,与安慰剂对照组28.6%的有效率比较,差别有显著统计学意义(P0.01)。说明化瘀健脾防石汤可改善气滞血瘀脾虚湿阻证患者的主要临床症状,降低中医证候评分,纠正患者血瘀、脾虚、湿阻的易成石体质。从根本上预防泌尿系结石的复发。2.2次要疗效指标疗后治疗组尿PH值呈上高趋势,与治疗前组内比较,差异有统计学意义意义(P0.01)；治疗组与对照组疗后比较差异有统计学意义(P0.01)。疗后治疗组尿钙呈下降趋势。治疗组尿钙组内治疗前后比较,差异有统计学意义(P0.01)；疗后治疗组与对照组比较,差异有统计学意义(P0.01)。对24小时尿草酸、尿尿酸、尿磷、血钙、血磷、血镁、血尿酸的疗效,治疗组治疗前后的组内比较中,差别无统计学意义(P0.05)。疗后治疗组与对照组比较差别无统计学意义(P0.05)。说明本药物对以上指标物无影响。研究结论：从整个临床试验看,化瘀健脾防石汤可以增加小分子结石抑制物尿枸橼酸的排泄量,可以下调泌尿系结石治愈患者尿TH蛋白和尿间α-胰蛋白酶抑制物重链H3的异常表达。并有提高患者尿PH值,降低24小时尿钙总排泄量的作用。同时,化瘀健脾防石汤能够改善气滞血瘀、脾虚湿阻证患者的主要临床症状,降低中医证候评分,纠正患者血瘀、脾虚、湿阻的易成石体质。说明化瘀健脾防石汤可以调节泌尿系结石患者尿中主要结石抑制物的浓度及表达。并有一定的代谢调节作用。这些作用都对泌尿系结石复发的预防有重要的积极意义。说明化瘀健脾防石汤有进一步观察研究的价值。下一步针对化瘀健脾防石汤的研究应该从两方面入手,首先,本方虽然组方时间仅有3年,但在临床应用中也表现出了很好的预防结石复发的疗效。但观察的病例数和观察的时间都有欠缺。所以其疗效需要一个大样本、多中心、随机对照、观察时间在3年以上的临床试验的支持。其次,本试验只是初步观察了化瘀健脾防石汤对人尿中主要结石抑制物的影响。无法了解其对肾组织内结石抑制物表达的影响及其调控结石抑制物的主要机理。也不了解其是否对肾小管上皮细胞的损伤有修复作用。因此需要一个设计完善的模型动物试验及体外晶体模型抑制试验的支持。只有这样才能全面评价化瘀健脾防石汤对泌尿系结石复发的预防作用。
[Abstract]:Urolithiasis is one of the most common urological diseases. In recent years, with the increasing of the climate warming and the increase of metabolic diseases such as hyperlipidemia, hyperglycemia and hypertension, the incidence of urinary calculi is obviously increasing. Urolithiasis is a highly recurrent disease. The recurrence rate of such high recurrence rate of 10 years has increased not only in the 10 year recurrence rate. The pain and economic burden of the people, multiple ESWL and surgical treatment can lead to complications such as ureteral stenosis, renal atrophy, and renal dysfunction. Therefore, the diagnosis and preventive treatment of the causes are becoming more and more important. Because the cause of urinary calculi is very complicated, it is the result of multiple factors. So the prevention of calculus It is a systematic project. Many people pay great attention to basic prevention, but the stones still relapse. Long term use of citrate salts can cause gastrointestinal irritation and other side effects, which can not be persisted for a long time. Chinese herbal medicine has a good effect on the prevention of urinary calculi, with small side effects and can improve the Yi Chengshi constitution of the patient as a whole, but still need to improve the patient's constitution. To verify the clinical and basic research of the system, based on the idea of "treating the disease without disease" and inheriting the experience of developing the old traditional Chinese medicine to prevent and cure urolithiasis, we will teach professor Liu Youfang, Professor Zhang Yaqiang to break blood gas, the thought of treating urolithiasis in the treatment of blood stasis and soft backbone, and the treatment of the spleen and stomach by Gao Rong Lin, and the prevention and treatment of urinary calculi. Experience is summarized and comprehensive. On the basis of Huayu urolithiasis soup, Huayu Jianpi prevention stone soup is cut out. In clinical application, it shows a good effect on the prevention of urinary calculi. The traditional view holds that the supersaturation of urine crystal salt is the primary factor for the formation of stones. However, a large number of studies have shown that some of the ingredients in the human body are inhibiting the urine. The nucleation, aggregation and growth of medium crystals play a vital role, known as stone inhibitors. Stone inhibitors have high concentration and activity in normal human urine, so stones are not easy to form. But when the concentration of stone inhibitors decreases or structural changes in urine, the ability to inhibit the formation of stones will be reduced and easy to guide. The formation of lithiasis. The concentration of urinary citrate, urine magnesium ion and the expression of THP, OPN and ITIH3 play an important role in the occurrence and development of the stone, and the Huayu Jianpi anti stone soup is also the legislation of promoting blood circulation to remove blood stasis and invigorating the spleen and dampness, and improving the patient's easy stone constitution through the whole conditioning. Based on this, we speculate that the Huayu Jianpi anti stone soup is used. The mechanism of prevention and control of urinary calculi may be related to the control of the concentration and expression of stone inhibitors. Therefore, the following clinical trials were designed under the guidance of teacher Gao Ronglin and Mr. Zhang Yaqiang. The effect of macromolecular stone inhibitor THP protein, osteopontin (0PN) and inter alpha trypsin inhibitor heavy chain H3 (ITIH3). To explore the mechanism of the effect of Huayu Jianpi anti stone Decoction on the prevention of urinary calculi, and to provide the basis for clinical use and further study. The overall design is a randomized, single blind, placebo-controlled method for choosing Guanganmen. During the period from January 2015 to August 2015, 60 patients with all the clinical healed stones after treatment were randomly divided into the treatment group of Huayu Jianpi anti stone soup and the placebo control group, with 30 people in each group. After 4 weeks of treatment, the final curative effect analysis.1. was included in the case standard: (1) the age 18-60 years (2) had been diagnosed as urinary calculi (upper urinary tract). ) (3) conforming to the standard of urolithiasis (upper urinary tract) cure (4) the dialectical standard of syndrome of stagnation of blood stasis and spleen deficiency syndrome (5) signing informed consent 2. exclusion criteria: (1) patients with renal or ureteral malformation, ureteral stricture (2) patients with urinary system swelling (3) combined with pyelonephritis and uretertis and other upper urinary tract infections Patients (4) combined with severe cardio cerebrovascular disease, liver, kidney and hematopoietic system severe primary disease (5) patients with hyperparathyroidism (6) allergic constitution 3. treatment methods: (1) treatment group: Huayu Jianpi prevention stone soup 1 bags a day 2 times a day, 4 weeks (2) control group: Huayu Jianpi prevention stone soup placebo once 1 bags a day 2 a day. Continued use of 4 weeks and 4. courses of treatment: 4 weeks 5. observation index (1) main curative effect index (group, medicine 4 weeks after examination, record one time): (1) 24 hours urination of citric acid, urine magnesium (ELISA) urine THP, OPN, ITIH3 protein expression (2) secondary curative effect index (group, medicine for 4 weeks after each test) 1) urine pH value in 24 hours urine urine The results of calcium, urine phosphorus, urine oxalic acid, urinary calcium, blood phosphorus, blood magnesium, blood uric acid: 1. comparability analysis: the age of two groups, the course of the disease, the ratio of men and women, urinary TH protein, osteopontin, a- trypsin inhibitor heavy chain H3, urine pH, 24 hours of urine calcium, urine phosphorus, urine oxalic acid, ururic acid, urinary magnesium, urinary citric acid, calcium, blood phosphorus, blood magnesium, blood The difference of uric acid and TCM syndrome score was not statistically significant (P 0.05), and there was a comparable result of.2. effect analysis: 2.1 the main curative effect index 2.1.1 had a significant difference before and after treatment in the total total of 24 hours urinary citrate excretion in the treatment group (P0.01), and the ratio of the treatment group to the control group was compared with the control group after treatment. The difference was statistically significant (P0.01) the total amount of excretion of citric acid in.24 hours was significantly increased by.24 hours before treatment. There was no significant difference between the total and the control group before and after treatment (P0.05). There was no significant difference between the two groups after treatment (P0.05). The concentration of urine TH protein in the treatment group before and after treatment was statistically significant (P0.01). The difference in the comparison between the treatment group and the control group was also statistically significant (P0.05), the concentration of.TH protein was lower than that before the treatment. The difference of urine OPN protein concentration in the treatment group was not statistically significant (P 0.05). There was no significant difference between the treatment group and the control group (P0.05). The urinary alpha trypsin inhibitor heavy chain H3 concentration in the treatment group was significantly different in the treatment group before and after the treatment (P0.01). The difference of the comparison between the treatment group and the control group was also significant (P0.05). The concentration of a trypsin inhibitor heavy chain H3 concentration between the treatment group and the control group was also significant. The function of Huayu Jianpi anti stone soup can increase the excretion of urinary citric acid in small molecular calculi inhibitor, and can reduce the abnormal expression of urinary TH protein and urinary alpha trypsin inhibitor heavy chain H3 in patients with urinary calculi and the curative effect of.2.1.2 TCM syndrome score. Huayu Jianpi prevention stone soup can obviously reduce the TCM syndrome score in the treatment group, the total effective rate is 79.3%, compared with the placebo control group 28.6%, the difference has significant statistical significance (P0.01). It shows that the Huayu Jianpi anti stone decoction can improve the main clinical symptoms of qi stagnation and blood stasis spleen deficiency syndrome patients, and reduce the TCM syndrome score, To correct the Yi Chengshi constitution of blood stasis, spleen deficiency and dampness resistance. The secondary therapeutic effect index of urinary calculi was fundamentally prevented from the recurrence of.2.2 in the treatment group. The urine pH value of the treatment group was higher, compared with the pre treatment group, the difference was statistically significant (P0.01); the difference between the treatment group and the control group was statistically significant (P0.01). After treatment, the treatment group was significantly different from the treatment group. The difference in urine calcium in the treatment group was statistically significant (P0.01), and the difference was statistically significant (P0.01) compared with the control group (P0.01). The curative effect of 24 hours urine oxalic acid, urinic acid, urine phosphorus, blood calcium, blood phosphorus, blood magnesium, blood uric acid, and the comparison of the treatment group before and after treatment were not statistically different. Significance (P0.05). There was no significant difference between the treatment group and the control group (P0.05). It showed that the drug had no effect on the above indexes. The abnormal expression of alpha trypsin inhibitor heavy chain H3 in urine can improve the urine pH value and decrease the total excretion of urinary calcium by 24 hours. Meanwhile, the Huayu Jianpi anti stone decoction can improve the main clinical symptoms of qi stagnation and blood stasis, the main clinical symptoms of spleen deficiency syndrome, reduce the score of TCM syndrome, and correct the Yi Chengshi constitution of blood stasis, spleen deficiency and damp resistance. The Ming Huayu Jianpi anti stone decoction can regulate the concentration and expression of the main calculi inhibitors in urine of patients with urinary calculi, and have a certain metabolic regulation effect. These effects have important positive significance for the prevention of recurrence of urinary calculi. The study of anti stone soup should start with two aspects. First of all, although the prescription time is only 3 years, the clinical application also shows a good effect on preventing the recurrence of stone. However, the number of cases observed and the time of observation are short. So the curative effect needs a large sample, multi center, random control, the observation time is over 3 years. Secondly, the effect of Huayu Jianpi anti stone soup on the main stone inhibitors in human urine was observed, and the effect of its effect on the expression of stone inhibitor in the kidney tissue and the main mechanism of controlling the stone inhibitor were not understood. This requires a well-designed model animal test and in vitro crystal model inhibition test. Only in this way can we comprehensively evaluate the preventive effect of Huayu Jianpi anti stone soup on the recurrence of urinary calculi.
【学位授予单位】：中国中医科学院
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R691.4

【参考文献】