摘要
上消化道出血是一临床常见病和多发病，同时也是内科急重症之一。发病率成年人中大约为1／1000(每年)，占内科住院病人数的2.43％，其死亡率约为8％-14％，而由消化性溃疡引起的出血占40％-50％，如未能及时有效治疗，会导致一些严重的全身性损害如：失血性休克、缺血再灌注损伤、各种脏器功能衰竭，甚至死亡。因此研究一种行之有效的止血方法、止血药物是治疗消化性溃疡出血病人的迫切需要。
目前临床上有很多常用的止血药如：通过影响某些凝血因子，促进或恢复凝血过程而止血的维生素K、凝血质、止血敏等；通过抑制纤维蛋白溶解系统而止血的6-氨基乙酸、止血芳酸等；通过降低毛细血管通透性而止血的安络血。但这些药物存在着不可忽视的缺点包括作用特异性差易引发高凝状态，水溶性差临床使用受限，给药途径单一使用不方便等。中药止血具有悠久的历史，大黄止血最早文献记载于汉代张仲景《伤寒论》，临床运用于各种血证，故有“血证要药”之称，其有效的止血成分为单体d-儿茶素和没食子酸。根据中药“烧炭存性”的原理，我们在现代高科技与传统炮制技术相结合的基础上研制出新型中药-微米大黄炭，在保持大黄原有药性的基础上又最大限度的提高药物的吸收和生物利用度，缩短了药物的起效时间。本课题拟从临床观察及实验研究两方面全方位揭示微米大黄炭的止血作用及其机制，为开发新型中药制剂奠定药理学基础。
1微米大黄炭胃镜下喷洒治疗消化性溃疡出血的临床观察
目的：观察胃镜下喷洒微米大黄炭治疗消化性溃疡出血的临床疗效。
方法：90例消化性溃疡并出血的患者随机分为微米大黄炭组(治疗组)和去甲肾上腺素组(对照组)两组，各45例，采用胃镜下喷洒的方法观察胃镜下两组患者的平均止血时间和止血成功率以及术后患者黑便、呕血的次数、血红蛋白量及止血有效率。
结果：治疗组较对照组胃镜下止血平均止血时间明显减少(P＜0.01)而止血成功率明显升高(P＜0.01)，达到96％；治疗组治疗后平均黑便、呕血的次数较对照组明显减少(P＜0.05)；而两组患者平均血红蛋白量比较无统计学差异(P＞0.05)；治疗组止血疗效高于对照组(P＜0.01)，且无明显不良反应，安全性好。
结论：胃镜下喷洒微米大黄炭是治疗消化性溃疡出血一种安全有效的治疗方法，值得临床运用和推广。
2微米大黄炭对家兔胃组织局部止血作用的实验研究
目的：观察微米大黄炭对家免胃出血的局部止血作用以判断该药物动物实验的有效性。
方法：以家兔为研究对象，按4组4×4拉丁方设计，记录家兔胃组织局部出血后喷洒微米大黄炭、云南白药、去甲肾上腺素及生理盐水后的止血时间。
结果：各用药组均能缩短家免胃组织平均出血时间，与生理盐水组比较，有显著统计学差异(P＜0.01)，与云南白药组比较NA作用优于云南白药(P＜0.05)，而微米大黄效果最明显(P＜0.01)；各用药组局部出血时间与生理盐水组比较均有显著统计学差异(P＜0.01)，与云南白药组比较微米大黄炭效果最佳(P＜0.05)。
结论：微米大黄炭对家免胃组织局部出血作用明显，止血效果优于云南白药和去甲肾上腺素。
3微米大黄炭止血作用的机制研究
目的：通过观察微米大黄炭对动物出凝血时间、血液凝固系统、纤溶系统、血小板功能的影响，探讨微米大黄炭的止血作用及其作用机理，为临床用药提供理论依据，为开发新型中药制剂奠定药理学基础。
方法：以昆明种小鼠和SD大鼠为研究对象，将动物分为空白对照组、云南白药组和微米大黄炭大、中、小剂量组共5组，分别给药6天后，采用毛细玻璃管法和断尾法测定小鼠出、凝血时间；采用ACL-200型血液凝集仪测定大鼠凝血酶原时间(PT)和活化部分凝血活酶时间(APTT)；用酶联免疫分析法(ELISA)测定组织纤溶酶原激活物(t-PA)和纤溶酶原激活物抑制剂(PAI-1)的活性；用MC-190型血小板聚集仪测定ADP诱导大鼠的血小板聚集。
结果：(1)微米大黄炭大、中、小剂量组和云南白药组均能缩短小鼠出、凝血时间，与对照组相比较差异显著(P＜0.01)；与云南白药组比较，微米大黄炭大剂量组作用明显(P＜0.05)。(2)微米大黄炭大、中、小剂量组和云南白药组均能缩短大鼠PT、APTT(P＜0.01)；与云南白药组比较，微米大黄炭中、大剂量组PT小于云南白药组(P＜0.05)。(3)云南白药组能降低大鼠组织纤溶酶原激活物(t-PA)的活性(p＜0.05)，提高纤溶酶原激活物抑制剂(AI-1)的活性(P＜0.05)；而微米大黄炭各组对t-PA及PAI-1含量变化无影响。(4)用药各组均能明显提高ADP诱导的大鼠血小板聚集性(P＜0.05)，其中微米大黄炭大、中剂量组作用非常显著(P＜0.01)；与云南白药组相比，微米大黄炭大剂量组提高ADP诱导的大鼠血小板聚集性有统计学意义(P＜0.05)。
结论：微米大黄炭止血作用是通过激活内源性和外源性途径的多种凝血因子而促进凝血过程中的凝血酶原和凝血活酶的生成，同时增加血小板的聚集性，而与纤维蛋白溶解活性无关。
总之，本研究表明内镜下喷洒微米大黄炭能够起到有效的止血作用，而实验研究亦证实了这一结果。对其作用机制的实验研究证实微米大黄炭能够显著缩短小鼠出、凝血时间、PT和APTT，同时提高血小板聚集性，而对t-PA及PAI-1活性无明显影响，因此通过激活内源性和外源性途径的多种凝血因子而促进凝血过程中的凝血酶原和凝血活酶的生成，同时增加血小板的聚集性可能是微米大黄炭止血作用的重要作用机制。
The peptic ulcer hemorrhage is a clinical common disease andfrequently-occurring disease, simultaneously also is a internal medicine departmentacute disease. In the UGH disease incidence rate adult probably is 1/1000 (every year),accounts for 2.43％which the internal medicine department in-patient counts, itsmortality rate is approximately 8％-14％, gastric ulcer and other digestive the ulcerscause the upper gastrointestinal hemorrhage occupies 40％-50％, if has not been ablethe prompt effective treatment, it will be able to cause some serious body-wide harm,for example: the hemorrhagic shock, ischemical reperfusion injury, each kind ofinternal organs function failure, even died. Therefore searching for each effectivehematischesis method, the hematischesis medicine is the urgent need which saves thepeptic ulcer hemorrhage patients.
There is many commonly used hemorrhage on clinical at present, for instance:vitamin K, thromboplastin, Aglumin etc. which through influencing some bloodcoagulation factor, promote or resume blood coagulation course to stops blooding;6-Aminoacetic Acid and Aminomethylbenzoic Acid, etc. which through inhibiting thefibrinolytic system to stops blooding; Carbazochrome which through reducing thecapillary penetratingly to stops blooding. But the classical styptic medicine haveshortcoming including being easy to initiate high state of congealing while poorfunction specific that can't ignore, water-solubility is used badly and clinicallylimitedly, the medicine route is single and inconvenient to use that give. It has a longhistory that traditional Chinese medicine arrests blood,《Treatise on Febrile Diseases》written by zhang zhongjing Hart Dynasty is the earliest literature that records rhubarbcan be used to stop blooding and apply clinically to various blood cards, so known ascard key medicine of blood. Single d- catechu Amoxcillinand Gallic acid which is effective styptic composition of rhubarb, offer material basis for explaining the stypticfunction of rhubarb. According to the principle of the traditional Chinese medicine"Bum the charcoal keep nature", we adopt the way that combining modern Hi-Techwith tradition technology together to develop new traditional Chinese medicine:micron rhubarb charcoal, enable it improve absorption of the medicine and biologyavailability maximumly on the basis of keeping original nature, shortened the gettingup for time of result of the medicine at the same time. This subject plans to exploreomni-directional styptic function and mechanism of micron rhubarb charcoal throughclinical observation and experiment study, establish the pharmacology foundation fordeveloping new traditional Chinese medicine preparation.
1 Clinical observation on the endoscopic treatment of hemorrhage of pepticulcer spraying micron rhubarb charcoal
Objective: To observe the endoscopic treatment of peptic ulcer hemorrhage sprayingmicron rhubarb charcoal.
Methods: 90 cases of peptic ulcer hemorrhage patients were randomly divided intomicron rhubarb charcoal group (treatment group) and norepinephrine (control group),each having 45 cases. Using gastroscope spraying method to observe the average timeand the success rate of hemostasis; the number of melena and hematemesis,hemoglobin and hemostasis efficient after endoscopic treatment between two groups.
Results: Endoscopic hemostatic therapy group compared with the control groupaverage hemostasis time is significantly reduced (P＜0.01) and significantly highersuccess rate hemostatic (P＜0.01), reaching anaverage of 96％;After treatment in thetherapy group the average number of melena and hematemesis is significantly lessthan the control group (P＜0.05); and the two groups compare to the averagehemoglobin was no statistically significant difference (P＞0.05); Hemostatic efficacy of the treatment group were higher than control group (P＜0.01), no significantadverse reactions, is safe.
Conclusion: Endoscopic sprinkler micron rhubarb charcoal is a safe and effectivetreatment for patients of peptic ulcer hemorrhage, be worthy to clinical applicationand promotion.
2 Experiment study on Micron rhubarb making domestic rabbit's gastric tissuehemostasis locally
Objective: To observe local hemostatic effects of micron rhubarb charcoal tax ondomestic rabbit gastric bleeding in order to determine the validity of animalexperiments.
Methods: The rabbits were studied by four Group 4 x 4 Latin square design. Recordsthe bleeding time of rabbit whose gastric tissue local bleeding after spraying microncarbon rhubarb, Yunnan Baiyao, Norepinephrine and Physiological saline.
Results: Each drug group could shorten the average time of stomach blooding,compared with the Physiological saline group, there was a significant difference (P＜0.01) Compared with the Yunnan Baiyao NA superior to Yunnan Baiyao (P＜0.05),and micron rhubarb charcoal has the most obvious effect (P＜0.01); the difference ofbleeding time between the drug groups and Physiological saline group weresignificantly (P＜0.01); compared with the Yunnan B aiyao, micron rhubarb charcoalis the better one(P＜0.05).
Conclusion: micron rhubarb charcoal have obvious effect in treating stomach localbleeding of rabbit, hemostatic effect is better than Yunnan Baiyao and norepinephrine.
3 Effects of micron rhubarb charcoal on the hemostatic mechanism in rat
Objective: Through observing the influence of micron rhubarb charcoal on theblooding and hemoglutination time, the blood coagulation system, fibrinolysis systemand faction of platelet to discuss its function and mechanism of stops bleeding, forproviding the theory basis with the medicine clinical, lays the Pharmacologyfoundation for the development new Chinese native medicine preparation.
Methods: SD rats were divided into contral gruop、Yunan Baiyao group and micronrhubarb charcoal high、normal and low dosage gruop, ig six days. We studied theeffects of micron rhubarb charcoal on the coagulation time(CT), bleeding time (BT),the prothrombin time(PT) and the active partial thromboplastin time (APTT), tissueplasmiongen activity (t-PA)and Plasm inogen activator inhibiter (PAI-1), plateletaggregation induced by ADP were also tested.
Results: (1) The micron rhubarb charcoal high、normal and low dosage gruop andYunan Baiyao group could obviously reduce the BT, CT, the difference is prominentcompared with control group(P＜0.01). Compared with Yunan Baiyao group, functionof micron rhubarb charcoal high dosage gruop is obvious (P＜0.05)(2) The micronrhubarb charcoal high、normal and low dosage gruop and Yunan Baiyao group couldobviously reduce the PT and APTT (P＜0.01); compared with Yunan Baiyao group, themicron rhubarb charcoal high、normal dosage gruop less than Yunan Baiyao group onPT (P＜0.05). (3) Yunan Baiyao group can reduce activity of t-PA (P＜0.05);andadvance the activity of PAI-1 (P＜0.05); Every group of micron rhubarb charcoal hasnot influenced the change of t-PA and PAI-1 content. (4) Medicine each group canobviously enhance the nature of platelet aggregation inducted by ADP (P＜0.05),inwhich the function of the micron rhubarb charcoal high、normal dosage group areobvious (P＜0.01); compared with Yunan Baiyao group, there is a statistics meaningthat micron rhubarb charcoal high dosage gruop enhance the nature of plateletaggregation inducted by ADP(P＜0.05). Conclusion: The main hemostasia mechanism of micron rhubarb charcoal was to produce prothrombin and thrombin by activatingboth endogenous and exogenous blood coagulation factor in the course of bloodcoagulation. And increase the gathering of the blood platelet at the same time, havenothing to do with the fibrinolysis activity.
In brief, this research indicated that the endoscopic treatment of hemorrhage ofpeptic ulcer spraying micron rhubarb charcoal be able to play the role in hemostaticeffectively, and the experimental study also confirmed this result. Experimental studyof its mechanism verifies that micron rhubarb charcoal can remarkably reduce theblooding and hemoglutination time, PT and APTT, enhances platelet aggregationsimultaneously, but has not affected activeness of t-PA and PAI-1. Therefore, it ispossibly the vital mechanism that producing prothrombin and thrombin by activatingboth endogenous and exogenous blood coagulation factor in the course of bloodcoagulation, and increases platelet aggregation in course of the micron rhubarbcharcoal stopping bleeding.
引文
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