肠激安胶囊的主要药效学及干预腹泻型IBS的作用机理研究
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摘要
1研究目的
肠激安胶囊主要由党参、木香、救必应等组成,具有健脾疏肝、清热祛湿、涩肠止泻的功效,主治腹泻型IBS、慢性结肠炎等。该药经广州中医药大学第一附属医院近二十多年的临床使用及观察,证实其临床疗效确切。
本研究的开展是为开发该新药提供实验依据,达到国家6类新药临床前研究的要求,申请临床研究批文。作用机理的研究则是为阐明该制剂治疗IBS的作用机制及为深度开发该药提供有意义的研究成果。
2研究方法
本课题主要分两部分进行研究;第一部分为文献研究:以查阅国内外文献为基础,研究IBS的中西医发病机制,中西医治疗研究进展,IBS的基础实验研究等。第二部分为实验研究,包括:主要药效学研究、急性毒性实验研究、作用机制研究。(1)以小鼠热板法、对番泻叶腹泻模型的影响、小鼠小肠推进运动实验、小鼠腹腔毛细血管通透性试验进行肠激安胶囊治疗腹泻型IBS的药效学研究。(2)通过急性毒性试验、小鼠灌胃最大耐受量测定、大鼠灌胃最大耐受量测定对肠激安胶囊治疗腹泻型IBS进行系统的安全性评价。(3)通过考察胃肠激素CGRP、SP变化探讨肠激安胶囊干预腹泻型IBS的作用机理。
3研究结果
3.1文献研究结果
文献研究表明,对于IBS,西医疗效常不满意,且西药的毒副作用大。祖国医学在治疗胃肠疾病方面积累了几千年的丰富经验和大量有效方剂,中医药治疗IBS方面有其优势,疗效肯定,副作用小,越来越受到国内外市场重视,对该类制剂的开发前景良好。
3.2实验研究结果
(1)药效学实验研究表明,肠激安胶囊能明显提高昆明小鼠基础痛阈值,其止痛效果强弱有呈量效关系的趋势;能减少番泻叶腹泻模型昆明小鼠的排便次数和黑粪数,止泻作用与临床观察一致;可减弱小肠蠕动运动;抗炎实验表明具有明显的抗炎作用。
(2)安全性评价实验,通过小鼠灌胃的急性毒性试验结果显示,按照最大剂量,成人日用量的500倍灌胃给药,观察动物体重变化,各组小鼠给药后未出现明显毒性反应,小鼠精神稍有萎靡,毛发正常,活动减少,体重并未减轻,最高剂量出现一只死亡。给药后共观察7d,第一天出现死亡2只,第2天后未见动物死亡,存活小鼠精神状态未见异常,无法测出肠激安胶囊的半数致死量(LD_(50)),提示该药使用安全。小鼠灌胃最大耐受量测定结果表明:动物2次ig给药后,进食、饮水、行为方式、排便等均未见异常。连续观察7d动物无一只死亡,其进食、饮水、行为方式、排便等均未见异常,体重刚开始有所减小,之后均有不同程度的增长,可能是由于给药剂量过大缘故,t检验两组小鼠体重差异无统计学意义,第8天后处死小鼠进行尸体解剖,均未有肉眼可见的病变。通过大鼠灌胃最大耐受量测定:本品大鼠ig给药的最大耐受量为22.2g/kg,相当于成人日口服剂量的250倍(成人体重按50kg计)。
(3)机制研究结果,用光学显微镜(10×200倍)观察结肠粘膜中CGRP、SP免疫阳性纤维的分布,用北航医学病理图像分析系统,计算随机4个视野结肠粘膜中CGRP、SP阳性纤维的平均OD值,分别代表CGRP、SP含量的多少,OD值越大,表示CGRP、SP含量越多。各实验组结肠粘膜中均见CGRP、SP阳性纤维,其分布未见显著性改变;给药组、空白组与模型组相比较,三组的分布也均无差异。三组之间结肠粘膜中的CGRP、SP阳性纤维数目(根/100μm×100μm)均无差别。模型组结肠粘膜中CGRP、SP的平均OD值分别较正常组及给药组显著要高(P值均＜0.05)。正常组与给药组及肠激安低、中、高剂量组及补脾益肠丸组相比无统计学意义。
4研究结论
本文主要药效学试验、急性毒性试验以及干预腹泻型IBS机理研究表明肠激安胶囊对具有良好的止痛、止泻、抗炎等作用,与其“健脾疏肝,清热祛湿、涩肠止泻”这中医疗效表述相一致的,是其治疗腹泻型IBS的疗效基础,且具有安全性高的优点,试验结果提示其在正常口服剂量的情况下,对机体各方面的影响是十分轻微甚至没有,符合新药开发高效、低毒、安全的要求。本次研究机理部分所考察的指标尚未全面,还需进一步的研究。
1 The objects
The capsule of Changji' an is composed of many Chinese herb which called Chinese medicine,it has a good effect for the spleen the sparse liver, the refrigeration dispel the effect which wet, the astringent intestines stop flow swiftly(has special Chinese medical meaning), especially treats diarrhea IBS(Irritable bowel syndrome), the chronic colitis and so on. This medicine has been tested through clinical usage and observation by the first affiliated hospital of Guangzhou University of Chinese medicine more than 20 years. It proves that the capsule of Changji' an has the function that treats diarrhea IBS indeedly .
The research is to provide the capsule of Changji' an to meet the clinical, study of requirements which the national standards of 6 th of new medicines include. the research of mechanism of the capsule of Changji' an is to expound that this preparation treats IBS the function mechanism and develops this medicine for the depth research results.
2 The methods
This research is mainly divided two parts. the first part is the literature search including the domestic and foreign literature as the foundation of the research . The second part is the experimental study, including: Main pharmacodynamics research, acute toxicity experimental study, function mechanism research. (1) by the Hot pan (using the mouse as experiment animal) testing the function of relieving pain of the capsule of Changji' an, Value the influence on the model which caused by Fanxieye , a Chinese herb, the experiment of mouse small intestine propelling movement, the experiment of mouse abdominal cavity blood capillary permeability carries on the intestines to the capsule of Changji' an treatment diarrhea IBS pharmacodynamics research. (2) secure appraisal by the test of toxicity , the test of maximum volume of the endurece through filling mouse stomach without dead . (3) through inspecting the change of gastrointestinal hormone CGRP and SP, it can be found the mechanism of the capsule of Changji' an intervents diarrhea IBS .
3 Results
3.1 Literature search result
The literature search indicated that regarding IBS, the modern medicine curative effect is often unsatisfied, and the poisonous side effect is big. The Chinese medicine gained experience richly by several thousand year . compared two medicine in treating the IBS , it concluded tha the Chinese medicine has its superiority, because its curative effect be proofed firmly and its side effect is small, and it has the reseach value in future .
3. 2 Experimental study result
(1) pharmacodynamics experimental indicated that the capsule of Changji' an be able to enhance the threshold value of Kunming mouse feeling painful obviously, its pain-relieving' s effect strong and the weak, presents certain quantity effect relations tendency. and it Can reduce the times that diarrhea model Kunming mouse' s bowel move and the quantities of black excrement of the model. Its function is consistent with the clinical observation; it also can weaken the small intestine creeping motion movement; The anti-inflammatory experiment indicated that has the obvious anti- inflammatory function.
(2) the acute toxicity experiment: through filling the mouse stomach by the most large dose which is equl to 500 times of a adult dosage everyday . through observating animal body weight change, after each group of mice for medicine, has not presented the obvious toxicity to respond, the mouse spirit has the dispirited slightly, the hair is normal, the activity reduces, the body weight has not reduced, the biggest dosage presents one to die. After for medicine, altogether observes 7d, the first day appears dies 2, the 2nd day later has not seen the animal death, the survival mouse state of mind has not seen exceptionally, is unable to determine the median lethal doses (LD50) of the capsule of Changji' an . from the experiment it can conclude tha the Chinese medicine which called capsule of Changji' an can be used security, mouse endures the quantity for the medicine is 22. 2g/kg most greatly, is equal in adult date oral administration dosage 250 times (adult body weight according to the 50kg idea).
(3) through mechanism experiment it found that: (10×200 time) observes CGRP, SP immunity fiber distribution in the colon mucous membrane with the optical microscope made in Beijing University of Aeronautics and Astronautics medicine pathology image analysis system, in computation stochastic 4 field of vision colon mucous membrane CGRP, SP fiber average OD value, on behalf of CGRP, SP quantity, the OD value is separately bigger, indicated that CGRP and SP are more. CGRP, the SP fiber can be seen in various experimental groups colon mucous membrane, its distribution has not seen the significance change; For the medicine group, the blank group and the model group compare, three groups of distributions also do not have the difference. In three group of between colon mucous membrane' s CGRP, SP fiber number (root /100μm×100μm) do not have the difference. In the model group colon mucous membrane CGRP, SP the average OD value distinction normal group (P value <0. 05). The normal group compared with capsule of Changji' an low, middle and high group , medicine group and BuPiYiChangWan pill group , there is non-statistics meaning.
4 Research conclusion
The reseach including pharmacodynamics experiment, the acute toxicity test as well as the intervention diarrhea IBS mechanism indicated that the capsule of Changji' an have the functions of well pain-relieving, to stop flow swiftly , to anti - inflammatory and so on . It show tha the capsule of Chuangji' an is accordance with the modern medicine function of r the spleening the sparse liver , the refrigeration dispels, the astringent intestines to stop wet flows swiftly . this Chinese medicine has the merit of the rang of safe is big. the test result prompts it in the normal oral administration dosage situation, is small to the organism poisonous side effect, conforms to the new medicine development highly effective, low poisonous, the safe request. This research mechanism part inspects the target is not yet comprehensive, but must the further research..
肠激安胶囊主要由党参、木香、救必应等组成,具有健脾疏肝、清热祛湿、涩肠止泻的功效,主治腹泻型IBS、慢性结肠炎等。该药经广州中医药大学第一附属医院近二十多年的临床使用及观察,证实其临床疗效确切。
本研究的开展是为开发该新药提供实验依据,达到国家6类新药临床前研究的要求,申请临床研究批文。作用机理的研究则是为阐明该制剂治疗IBS的作用机制及为深度开发该药提供有意义的研究成果。
2研究方法
本课题主要分两部分进行研究;第一部分为文献研究:以查阅国内外文献为基础,研究IBS的中西医发病机制,中西医治疗研究进展,IBS的基础实验研究等。第二部分为实验研究,包括:主要药效学研究、急性毒性实验研究、作用机制研究。(1)以小鼠热板法、对番泻叶腹泻模型的影响、小鼠小肠推进运动实验、小鼠腹腔毛细血管通透性试验进行肠激安胶囊治疗腹泻型IBS的药效学研究。(2)通过急性毒性试验、小鼠灌胃最大耐受量测定、大鼠灌胃最大耐受量测定对肠激安胶囊治疗腹泻型IBS进行系统的安全性评价。(3)通过考察胃肠激素CGRP、SP变化探讨肠激安胶囊干预腹泻型IBS的作用机理。
3研究结果
3.1文献研究结果
文献研究表明,对于IBS,西医疗效常不满意,且西药的毒副作用大。祖国医学在治疗胃肠疾病方面积累了几千年的丰富经验和大量有效方剂,中医药治疗IBS方面有其优势,疗效肯定,副作用小,越来越受到国内外市场重视,对该类制剂的开发前景良好。
3.2实验研究结果
(1)药效学实验研究表明,肠激安胶囊能明显提高昆明小鼠基础痛阈值,其止痛效果强弱有呈量效关系的趋势;能减少番泻叶腹泻模型昆明小鼠的排便次数和黑粪数,止泻作用与临床观察一致;可减弱小肠蠕动运动;抗炎实验表明具有明显的抗炎作用。
(2)安全性评价实验,通过小鼠灌胃的急性毒性试验结果显示,按照最大剂量,成人日用量的500倍灌胃给药,观察动物体重变化,各组小鼠给药后未出现明显毒性反应,小鼠精神稍有萎靡,毛发正常,活动减少,体重并未减轻,最高剂量出现一只死亡。给药后共观察7d,第一天出现死亡2只,第2天后未见动物死亡,存活小鼠精神状态未见异常,无法测出肠激安胶囊的半数致死量(LD_(50)),提示该药使用安全。小鼠灌胃最大耐受量测定结果表明:动物2次ig给药后,进食、饮水、行为方式、排便等均未见异常。连续观察7d动物无一只死亡,其进食、饮水、行为方式、排便等均未见异常,体重刚开始有所减小,之后均有不同程度的增长,可能是由于给药剂量过大缘故,t检验两组小鼠体重差异无统计学意义,第8天后处死小鼠进行尸体解剖,均未有肉眼可见的病变。通过大鼠灌胃最大耐受量测定:本品大鼠ig给药的最大耐受量为22.2g/kg,相当于成人日口服剂量的250倍(成人体重按50kg计)。
(3)机制研究结果,用光学显微镜(10×200倍)观察结肠粘膜中CGRP、SP免疫阳性纤维的分布,用北航医学病理图像分析系统,计算随机4个视野结肠粘膜中CGRP、SP阳性纤维的平均OD值,分别代表CGRP、SP含量的多少,OD值越大,表示CGRP、SP含量越多。各实验组结肠粘膜中均见CGRP、SP阳性纤维,其分布未见显著性改变;给药组、空白组与模型组相比较,三组的分布也均无差异。三组之间结肠粘膜中的CGRP、SP阳性纤维数目(根/100μm×100μm)均无差别。模型组结肠粘膜中CGRP、SP的平均OD值分别较正常组及给药组显著要高(P值均＜0.05)。正常组与给药组及肠激安低、中、高剂量组及补脾益肠丸组相比无统计学意义。
4研究结论
本文主要药效学试验、急性毒性试验以及干预腹泻型IBS机理研究表明肠激安胶囊对具有良好的止痛、止泻、抗炎等作用,与其“健脾疏肝,清热祛湿、涩肠止泻”这中医疗效表述相一致的,是其治疗腹泻型IBS的疗效基础,且具有安全性高的优点,试验结果提示其在正常口服剂量的情况下,对机体各方面的影响是十分轻微甚至没有,符合新药开发高效、低毒、安全的要求。本次研究机理部分所考察的指标尚未全面,还需进一步的研究。
1 The objects
The capsule of Changji' an is composed of many Chinese herb which called Chinese medicine,it has a good effect for the spleen the sparse liver, the refrigeration dispel the effect which wet, the astringent intestines stop flow swiftly(has special Chinese medical meaning), especially treats diarrhea IBS(Irritable bowel syndrome), the chronic colitis and so on. This medicine has been tested through clinical usage and observation by the first affiliated hospital of Guangzhou University of Chinese medicine more than 20 years. It proves that the capsule of Changji' an has the function that treats diarrhea IBS indeedly .
The research is to provide the capsule of Changji' an to meet the clinical, study of requirements which the national standards of 6 th of new medicines include. the research of mechanism of the capsule of Changji' an is to expound that this preparation treats IBS the function mechanism and develops this medicine for the depth research results.
2 The methods
This research is mainly divided two parts. the first part is the literature search including the domestic and foreign literature as the foundation of the research . The second part is the experimental study, including: Main pharmacodynamics research, acute toxicity experimental study, function mechanism research. (1) by the Hot pan (using the mouse as experiment animal) testing the function of relieving pain of the capsule of Changji' an, Value the influence on the model which caused by Fanxieye , a Chinese herb, the experiment of mouse small intestine propelling movement, the experiment of mouse abdominal cavity blood capillary permeability carries on the intestines to the capsule of Changji' an treatment diarrhea IBS pharmacodynamics research. (2) secure appraisal by the test of toxicity , the test of maximum volume of the endurece through filling mouse stomach without dead . (3) through inspecting the change of gastrointestinal hormone CGRP and SP, it can be found the mechanism of the capsule of Changji' an intervents diarrhea IBS .
3 Results
3.1 Literature search result
The literature search indicated that regarding IBS, the modern medicine curative effect is often unsatisfied, and the poisonous side effect is big. The Chinese medicine gained experience richly by several thousand year . compared two medicine in treating the IBS , it concluded tha the Chinese medicine has its superiority, because its curative effect be proofed firmly and its side effect is small, and it has the reseach value in future .
3. 2 Experimental study result
(1) pharmacodynamics experimental indicated that the capsule of Changji' an be able to enhance the threshold value of Kunming mouse feeling painful obviously, its pain-relieving' s effect strong and the weak, presents certain quantity effect relations tendency. and it Can reduce the times that diarrhea model Kunming mouse' s bowel move and the quantities of black excrement of the model. Its function is consistent with the clinical observation; it also can weaken the small intestine creeping motion movement; The anti-inflammatory experiment indicated that has the obvious anti- inflammatory function.
(2) the acute toxicity experiment: through filling the mouse stomach by the most large dose which is equl to 500 times of a adult dosage everyday . through observating animal body weight change, after each group of mice for medicine, has not presented the obvious toxicity to respond, the mouse spirit has the dispirited slightly, the hair is normal, the activity reduces, the body weight has not reduced, the biggest dosage presents one to die. After for medicine, altogether observes 7d, the first day appears dies 2, the 2nd day later has not seen the animal death, the survival mouse state of mind has not seen exceptionally, is unable to determine the median lethal doses (LD50) of the capsule of Changji' an . from the experiment it can conclude tha the Chinese medicine which called capsule of Changji' an can be used security, mouse endures the quantity for the medicine is 22. 2g/kg most greatly, is equal in adult date oral administration dosage 250 times (adult body weight according to the 50kg idea).
(3) through mechanism experiment it found that: (10×200 time) observes CGRP, SP immunity fiber distribution in the colon mucous membrane with the optical microscope made in Beijing University of Aeronautics and Astronautics medicine pathology image analysis system, in computation stochastic 4 field of vision colon mucous membrane CGRP, SP fiber average OD value, on behalf of CGRP, SP quantity, the OD value is separately bigger, indicated that CGRP and SP are more. CGRP, the SP fiber can be seen in various experimental groups colon mucous membrane, its distribution has not seen the significance change; For the medicine group, the blank group and the model group compare, three groups of distributions also do not have the difference. In three group of between colon mucous membrane' s CGRP, SP fiber number (root /100μm×100μm) do not have the difference. In the model group colon mucous membrane CGRP, SP the average OD value distinction normal group (P value <0. 05). The normal group compared with capsule of Changji' an low, middle and high group , medicine group and BuPiYiChangWan pill group , there is non-statistics meaning.
4 Research conclusion
The reseach including pharmacodynamics experiment, the acute toxicity test as well as the intervention diarrhea IBS mechanism indicated that the capsule of Changji' an have the functions of well pain-relieving, to stop flow swiftly , to anti - inflammatory and so on . It show tha the capsule of Chuangji' an is accordance with the modern medicine function of r the spleening the sparse liver , the refrigeration dispels, the astringent intestines to stop wet flows swiftly . this Chinese medicine has the merit of the rang of safe is big. the test result prompts it in the normal oral administration dosage situation, is small to the organism poisonous side effect, conforms to the new medicine development highly effective, low poisonous, the safe request. This research mechanism part inspects the target is not yet comprehensive, but must the further research..
引文
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