【作者】 崔英子；

【导师】 黄永生；

【作者基本信息】 长春中医药大学 ， 中医内科学， 2010， 博士

【摘要】 从“先天伏寒”论治冠心病及其与神经内分泌免疫相关因子关系的研究冠状动脉粥样硬化性心脏病(以下简称冠心病)为心血管系统常见病、多发病,是临床和基础研究的热点和焦点。导师黄永生教授通过多年的临床实践,基于任继学教授对伏邪理论的深入认识,提出“男女媾精,阳气不足,寒伏于内”假说,创立“先天伏寒”病因学说,并总结出与之相应的有效治法和方药,在临床上从“先天伏寒”角度治疗冠心病收效确切。本文从理论探讨、临床研究和神经内分泌免疫网络相关因子的检测等不同侧面对冠心病从“先天伏寒”论治进行探讨和分析。理论探讨论述了“先天伏寒”病因学说提出的临床实践基础;运用中医理论,结合证候学研究的最新进展,对“先天伏寒”证候“气(阳)虚气滞、寒热错杂”的特点进行了探讨;阐述了“先天伏寒”病因学说提出的临床意义;对治疗“先天伏寒”证候的主方-伏寒方的立法组方用药特点进行了分析。冠心病心绞痛“先天伏寒”证的临床表征回顾性研究目的:采用数理统计多因素分析方法,结合临床实践,探讨“先天伏寒”证候特点,分析其主要症状和体征,以期为临床辨证规范化和标准化提供参考。方法:采用黄永生教授收治的冠心病心绞痛患者门诊病案记录,按照标准入选病例,根据黄永生教授的当场判别,以“先天伏寒”证的有无分为试验组和对照组。对收集的症状和体征采用频数分析、因子分析、聚类分析和Logistic回归分析进行分析和处理。结果:①“先天伏寒”证候患者均有足凉或手足凉的症状,以及特征性的演变病史。②“先天伏寒”证候以气(阳)虚气滞,寒热错杂为共性的特征,临床实际中也可以同时兼有血瘀、痰浊等不同的个性特征。③疲乏,善太息,心烦易怒,口干,舌淡隐青,脉沉对于“先天伏寒”证候的辨证具有较大的贡献度。结论:运用中医理论对数理统计的结果进行分析,能够得出相对客观的“先天伏寒”证候临床表征信息,是进行辨证规范化和标准化研究的一种有效方法,值得深入探索。伏寒颗粒干预冠心病心绞痛的临床研究试验1冠心病心绞痛“先天伏寒”兼血瘀证候的临床研究目的:通过随机对照病例观察,评价伏寒颗粒合血府逐瘀颗粒对“先天伏寒”兼血瘀证候患者的治疗效应,并从方证相应角度,进一步探讨“先天伏寒”证候的临床表征特点。方法:选取冠心病心绞痛“先天伏寒”兼血瘀证候患者60例,采用随机对照研究方法,分为试验组和对照组,试验组30例给予伏寒颗粒合血府逐瘀颗粒的混合制剂,1袋、2次/日;对照组给予金匮肾气丸10粒,2次/日,血府逐瘀颗粒1袋、2次/日;给药28天。观察心绞痛症状,“先天伏寒”证候和“血瘀”证候的症状、体征,心电图、不良反应及安全性指标(血尿常规、肝肾功能)。结果:对疾病疗效、心绞痛疗效、不同时点心绞痛症状积分的改善,试验组均优于对照组;在心电图疗效、硝酸甘油停减情况方面,试验组与对照组比较无统计学意义,对于中医证候疗效、心血瘀阻证候积分、“先天伏寒”证候积分、中医总证候积分的改善,试验组优于对照组。试验组可明显改善胸痛、胸闷的冠心病心绞痛“血瘀”证候症状和足凉或手足凉、疲乏、太息、口干、心烦、胃痛或胀的“先天伏寒”证候症状,优于对照组。无明显不良反应,安全性指标无异常变化。结论:从方证角度印证了“先天伏寒”证候临床表征与回顾性研究的一致性。“先天伏寒”证候-气(阳)虚气滞,寒热错杂-阴阳合治,寒热共调-伏寒方,在证-理-法-方-药的链条上存在着内在逻辑性和合理性。临床如能够针对“先天伏寒”证候特点进行治疗,会收到较好的疗效。试验2冠心病心绞痛阳虚血瘀证候的临床研究目的:通过随机对照病例观察,评价伏寒颗粒合血府逐瘀颗粒对阳虚血瘀证候患者的治疗效应。方法:选取冠心病心绞痛阳虚血瘀证候患者60例,采用随机对照研究方法,分为试验组和对照组,试验组30例给予伏寒颗粒合血府逐瘀颗粒的混合制剂,1袋、2次/日;对照组给予金匮肾气丸10粒,2次/日,血府逐瘀颗粒1袋、2次/日;给药28天。观察心绞痛症状,阳虚血瘀证候的症状、体征,心电图、不良反应及安全性指标(血尿常规、肝肾功能)。结果:对疾病疗效、心绞痛疗效、不同时点心绞痛症状积分、中医证候疗效、心电图疗效、硝酸甘油停减情况的改善,试验组与对照组比较无统计学意义。在改善阳虚血瘀证候症状方面,试验组可明显改善心悸、气短、疲乏症状,优于对照组。无明显不良反应,安全性指标无异常变化。结论:伏寒颗粒合血府逐瘀颗粒对阳虚血瘀证候的治疗效应与金匮肾气丸合血府逐瘀颗粒相当,同时可以更好的改善心悸、气短、疲乏等症状。考虑可能与伏寒颗粒组方中专有针对气虚病机而设的药物组分,故疗效要相对明显。小结:应用数理统计方法对回顾性临床资料分析得出的“先天伏寒”的证候特点可从方证相应角度与临床实际相互印证。在临证中,如能够同时针对“先天伏寒”病因进行治疗,可明显提高临床疗效。冠心病“先天伏寒”证候与神经内分泌免疫相关因子关系的研究目的:观察冠心病“先天伏寒”兼有血瘀证患者与冠心病阳虚血瘀证患者、亚健康状态“先天伏寒”证患者和健康对照组人群血液神经内分泌免疫相关因子的差异,探讨冠心病“先天伏寒”与神经内分泌免疫网络相关因子的关系。方法:选择“伏寒颗粒干预冠心病心绞痛的临床研究”中纳入的冠心病心绞痛“先天伏寒”兼有血瘀证试验组和对照组共60例患者和冠心病心绞痛阳虚血瘀证患者30例,另外纳入亚健康状态的“先天伏寒”证候患者30例,健康对照组30例。用酶联免疫吸附法检测各组(包括冠心病心绞痛“先天伏寒”兼有血瘀证患者给药前后)血清hs-CRP、TNF-α、IL-6、ACTH和皮质醇含量。用RT-PCR法检测外周血细胞总RNA中TNF-α和IL-6 mRNA表达。结果:将所有治疗前冠心病患者的结果整合为一组时,与健康组比较,冠心病组患者的血清IL-6、TNF-α、hs-CRP水平均有有明显升高,血清ACTH、皮质醇含量明显下降;冠心病组患者的全血TNF-αmRNA、IL-6 mRNA的表达增强;亚健康组血清IL-6、TNF-α明显升高,血清皮质醇、ACTH均有明显降低。将所有治疗前冠心病“先天伏寒”兼有血瘀证候患者的结果整合到一组时,与冠心病阳虚血瘀证组比较,冠心病“先天伏寒”兼有血瘀证组血清hs-CRP含量升高显著,血清皮质醇、ACTH均显著下降。冠心病先天伏寒证候组给药后两组均可改善上述指标,但试验组对于血清TNF-α、皮质醇、ACTH含量和全血TNF-αmRNA表达的改善更为明显。结论:“先天伏寒”证候的亚健康人群具有潜在性冠心病发病倾向和HPA轴功能低下。hs-CRP、ACTH、皮质醇紊乱可能为其证候特征的一部分。更多还原

【Abstract】 Study on dealing with the treatment of coronary heart disease according to congenital latent cold and its correlated with correlative factors of neuro-endocrine-immunity networkCoronary heart disease(CHD) is a common and frequent disease of Cardiovascular System. It becomes the hotspot and focal point of fundamental and clinical research. Based on many years of clinical practice experience, professor huang yonghseng has put forward hypothesis as“men and women conbine together, deficiency of yang , cold hidden in the asthenia part”and proposed the etiology of chinese medicine theory: congenital latent cold. He also evolved corresponding therapeutic methods and Herbs. Such methods and herbs had definite therapeutic effect on CHD. This article sudy the“congenital latent cold”of CHD on such aspects as theory study, Retrospective Clinical Analysis, and detect correlation factor of neuro-endocrine-immunity network. Theoretical discussionThis part has discussed the clinical fundation of the proposal on“congenital latent cold”etiology theory according to clinical practice . applying the chinese medicine theory and reference to the recent development on science of syndrome , we discuss the the syndrome characteristics of pathogenic incubative cold, that is Qi(yang) Deficiency and Qi Stagnation, mixture of cold and heat syndrome. We also described the theoretical and clinical significance about the proposal of pathogenic incubative cold. and at last we analyzed the composing prescriptions and drug administering characteristics of fu han prescription which is the main clinical study treating the pathogenic incubative cold syndrome.1. Retrospective studies on clinical characteristics of congenital latent cold Syndrome in coronary heart disease with angina pectoris.Purpose: according to clinical practice, study the syndrome characteristics of“congenital latent cold”syndrome, analysis the main symptoms and signs,by using clinical epidemiological and mathematical statistics methods. To provide reference for differentiation of symptoms and signs of standardization.Method: :adopt patient service case of Coronary atherosclerotic heart disease, according to the decide of professor huang yongsheng, divided into experiment group and control group according to if the patient has Pathogenic Incubative cold syndrome. Gathet the symptoms and signs, adopt frequence analysis, factor analysis, cluster analysis and Logistic regression analysis.Result:①Patients of“congenital latent cold”syndrome have cold feet or cold limbs,and distinctive age rule.②the syndrome characteristics of“congenital latent cold”is Qi(yang) Deficiency and Qi Stagnation, mixture of cold and heat syndrome. It also can combine with blood stasis and phlegm.③Some symptom such as vexation, mouth dryness, preference for sighing, light purplish tongue, fatigue, pulse deep and weakened have a biggish contribution degree for differentiate the syndrome characteristics of“congenital latent cold”.Conclusion: by analyzing the results of mathematical statistics using chinese medicine theory, we can obtain the relatively objective clinical manifestation of“congenital latent cold”syndrome. The method is an effective method for differentiation of symptoms and signs of standardization. It worth further explore.2. Clinical mechanism studies of fu han granular preparation on treatment of coronary heart disease with angina pectoris1) Clinical studies of congenital latent cold and blood stasis syndrome. of coronary heart disease with Angina PectorisPurpose: through randomized controlled trial, to evaluate the effects of fu han with xuefuzhuyu granular preparation in the treatment of CHD with angina pectoris of“congenital latent cold”syndrome,according to Prescription-Syndrome Corresponding Theory, study the clinical manifestation of Pathogenic Incubative cold syndrome.Method: 60 patients with stable angina pectoris accoreded with diagnostic standards were selected and divided by randomly single blind into experiment group (30 cases), control group (30 cases),Fu han granulationes and xuefuzhuyu granulationes was dosed twice a day in experiment group,30 cases in experiment group were given Fu Han granulationes and XueFu ZhuYu granulationes 1 bag, twice a day. Fu Han granulationes and XueFu ZhuYu granulationes was dosed twice a day, JinKui ShenQi pills 10 pills was dosed twice a day in control group.30 cases in control group were given Fu Han granulationes and XueFu ZhuYu granulationes, 1 bag, twice a day ,JinKui ShenQi pills,10 pills,twice a day.The treatment courses of the two groups lasted 28 days.To observe the sings and symptoms of angina pectoris, Pathogenic Incubative cold syndrome and blood stasis syndrome, electrocardiogram(ECG), the adverse effect, security test.Result: Experiment group has a better effect than control group in The clinical curative effect, and The clinical curative effect of angina pectoris, and The Symptom score of angina pectoris before treatment ,14days and28 days. The clinical curative effect of ECG and discontinue rate of nitroglycerin, The experiment group compare with the control group,there was no significant difference. experiment group has a better effect than control group in The curative effect in clinical symptoms of traditional chinese medicine, and The Symptom score of congential latent cold syndrome and blood stasis syndrome. experiment group has good effects on improving the clinical symptoms of congential latent cold syndrome and blood stasis syndrome such as chest pain, dyspnea, cold feet,fatigue ,vexation, preference for sighing,mouth dryness, soreness of waist, stomachache. All the patients in two groups have no obvious adverse effects .Conclusion: according to Prescription-Syndrome Corresponding Theory, the clinical manifestation of congential latent cold syndrome in accord with the results of retrospective studies. congential latent cold syndrome- Qi(yang)Deficiency and Qi Stagnation, mixture of cold and heat syndrome-adjust yin and yang ,regulate cold and heat-fu han prescription,it is a logical chain. If considering the importance of congential latent cold, we Can improve the clinical effects of CHD. 2) Clinical studies of yang Deficiency and blood stasis syndrome of coronary heart disease with angina pectorisPurpose: through randomized controlled trial, to evaluate the effects of Fu Han with XueFu ZhuYu granular preparation in the treatment of coronary heart disease with angina pectoris of yang Deficiency and blood stasis syndrome.Method: 60 patients of stable angina pectoris accoreded with diagnostic standards were selected and divided by randomly into experiment group (30 cases), control group (30 cases),Fu Han granulationes and XueFu ZhuYu granulationes was dosed twice a day in experiment group,30 cases in experiment group were given Fu Han granulationes and XueFu ZhuYu granulationes 1 bag, twice a day .Fu Han granulationes and XueFu ZhuYu granulationes was dosed twice a day,JinKui ShenQi pills ,10 pills was dosed twice a day in control group.30 cases in control group were given Fu Han granulationes and XueFu ZhuYu granulationes, 1 bag,twice a day, JinKui ShenQi pills, 10 pills, twice a day. The treatment courses of the two groups lasted 28 days. To observe the sings and symptoms of angina pectoris, yang deficiency and blood stasis syndrome, electrocardiogram(ECG), the adverse effect, security test.Result: Compare The clinical curative effect, and The clinical curative effect of angina pectoris, and The Symptom score of angina pectoris before treatment ,14 days and 28 days. The clinical curative effect of ECG and discontinue rate of nitroglycerin, The curative effect in clinical symptoms of traditional chinese medicine, there was no significant difference in two groups. experiment group has good effects on improving the clinical symptoms of yang Deficiency and blood stasis syndrome such as palpitations, breathe hard ,fatigue ,All patients in two groups have no obvious adverse effects .Conclusion: Fu Han with XueFu ZhuYu granular preparation has a similar curative effect in the treatment of CHD with angina pectoris of yang Deficiency and blood stasis syndrome with JinKui ShenQi pills plus XueFu ZhuYu granular preparation. it has good effects on improving the clinical symptoms of yang deficiency and blood stasis syndrome such as palpitations, breathe hard ,fatigue. 3. Study on the relationship between congenital latent cold and blood stasis Syndrome of CHD and correlative factors of neuro-endocrine-immunity networkPurpose: observe and investigate the correlative factors of neuro-endocrine-immunity network in blood of patients of congenital latent cold and blood stasis syndrome, yang deficiency and blood stasis syndrome. Sub-health and health people,study the the relationship between congenital latent cold syndrome of CHD and correlative factors of neuro-endocrine-immunity network.Method: 60 patients of stable angina pectoris accorded with congenital latent cold and blood stasis syndrome , 30 patients of stable angina pectoris accoreded with yang deficiency and blood stasis syndrome, 30 sub-health people accoreded with congenital latent cold and blood stasis syndrome , 30 heallth people as control group. to detect the serum level of hs-CRP, TNF-α, ACTH, IL-6 and Cortisolwith the ELISA Examination, to detect the gene expressive content of IL-6 and TNF-αin blood with Reverse Transcription–poly merasechain reaction(RT-PCR).Result: Compare with the health control group , all CHD patients have a higher serum level of IL-6,TNF-α,hs-CRP and a lower serum level of ACTH and Cortisol,they alos have a more obvious gene expressive content of IL-6 and TNF-αin blood. Sub-health people also have a higer serum level of IL-6, TNF-αand a lower serum level of ACTH and Cortisol. Compare with the group of yang Deficiency and blood stasis syndrome, all patients of congenital latent cold and blood stasis syndrome have a higher serum level of hs-CRP and a lower serum level of ACTH and Cortisol. The group which given the treatment all improve the serum level ,but the experiment group which given the Fu Han with XueFu ZhuYu granular preparation has better effect on improve the serum level of TNF-α, Cortisol, ACTH and gene expressive content of TNF-αin blood.Conclusion: The sub-health people with Pathogenic Incubative cold syndrome have potential outbreak of CHD and hypofunction of hypothalamic-pituitary-adre-nal axis, disorder of hs-CRP, ACTH, Cortisol may be part of the character of Pathogenic Incubative cold syndrome.更多还原