本文選題：軟堅消癭顆粒 + 長期毒性��； 參考：《遼寧中醫(yī)藥大學》2014年碩士論文

【摘要】：目的：本課題屬于中藥復方軟堅消癭顆粒的長期毒性研究，基于前期藥學實驗探明軟堅消癭顆粒的制備工藝、質(zhì)量標準及穩(wěn)定性、急性毒性和藥效學基礎上，進一步判斷動物長期服用軟堅消癭顆粒是否發(fā)生毒性反應，描述毒性反應的性質(zhì)和程度（包括毒性起始時間、程度、持續(xù)時間以及可逆性等）和靶器官，確定安全范圍，并探討毒性作用機制。本文重點對大鼠腦、肝、心、脾、肺、腎等主要臟器的組織病理學進行研究探討。 材料與方法： 1.實驗材料 根據(jù)研究需求，實驗動物采用SPF級，體重為120±20g的SD品系大鼠240只，雌雄兩性各半。動物合格證號(SCXKI遼SO10-001)。所有動物均符合國家有關藥物非臨床安全性研究的要求。受試藥物是中藥復方軟堅消癭顆粒（柴胡、當歸、莪術、陳皮、浙貝母、海藻、昆布、赤芍，共8味中藥）。本次藥品由遼寧中醫(yī)藥大學附屬醫(yī)院中醫(yī)藥實驗中心制劑室提供。 2.實驗方法 將240只大鼠在正式開始實驗前于遼寧中醫(yī)藥大學附屬醫(yī)院中醫(yī)藥實驗中心的動物實驗室（溫度18-23℃、濕度40%～60%）適應性常規(guī)飼養(yǎng)1周。將大鼠按照體重、性別分層隨機分配。分為軟堅消癭顆粒低、中、高三個劑量組和生理鹽水對照組，每組60只，雌雄各半。每周按所稱體重計算給藥量。正常對照組生理鹽水1.5ml/100g2次/日；軟堅消癭顆粒低劑量組8g生藥/kg/d（1.51g粉末/kg/d）（1.5ml/100g5%2次/日）；軟堅消癭顆粒中劑量組20g生藥/kg/d（3.77g粉末/kg/d）（1.5ml/100g12.56%2次/日）；軟堅消癭顆粒高劑量組60g生藥/kg/d（11.32g粉末/kg/d）（1.5ml/100g37.68%2次/日）；對照組給予1.5ml/100g生理鹽水灌胃。每日灌胃2次，每周給藥6天，周日停止給藥，連續(xù)給藥6個月。恢復期為2周。在給藥3個月后（中期）、六個月后（末期）、和六個半月后（恢復期）分別隨機抽取1/3數(shù)量大鼠給予25%烏拉坦腹腔注射麻醉，進行取血。取血后對大鼠進行系統(tǒng)尸解，對臟器進行稱重并計算臟器系數(shù)后做組織病理學檢查。 結(jié)果： 1.軟堅消癭顆粒長期毒性試驗過程中，各組大鼠外觀皮毛、行為活動、精神狀態(tài)等未見明顯異常，口、鼻、眼、耳等腺體未見有異樣分泌物。但軟堅消癭顆粒低、中、高劑量組大鼠糞便多呈褐色，其顏色與軟堅消癭顆粒沖劑相近，考慮為藥物本身顏色所致，非毒性引起。 2.軟堅消癭顆粒長期給藥對大鼠攝食量有影響，其中低、中、高劑量組與生理鹽水對照組對比，結(jié)果見表1-1和表1-2，在不同時間階段可出現(xiàn)P＜0.05的情況，有統(tǒng)計學意義。但研究者認為主要影響大鼠攝食量的原因是藥物刺激胃腸消化吸收并占據(jù)了部分胃空間。 3.軟堅消癭顆粒長期毒性試驗中，每周所稱體重，低、中、高劑量組與生理鹽水對照組對比，結(jié)果見表2-1和表2-2。不同時間階段，出現(xiàn)P＜0.05的情況，有統(tǒng)計學意義。但研究者認為多與攝食量關系密切，非毒性所致。 4.軟堅消癭顆粒長期給藥對大鼠臟器系數(shù)有影響，，在中期、末期、恢復期三個階段，其低、中、高劑量組與生理鹽水對照組對比，部分臟器系數(shù)P＜0.05，有統(tǒng)計學意義，但是否為軟堅消癭顆粒長期毒性所致有待進一步的研究。 5.組織病理學檢查顯示，大鼠低、中、高、劑量組與生理鹽水對照組相比，其主要臟器鏡下結(jié)構(gòu)未見明顯異常。 結(jié)論： 1.軟堅消癭顆粒長期服用對大鼠的一般情況無明顯影響。 2.軟堅消癭顆粒長期服用對大鼠日常攝食量有一定影響，但非毒性引起。 3.軟堅消癭顆粒長期服用對大鼠體重有一定影響，但非毒性引起。 4.軟堅消癭顆粒長期服用對大鼠腦、肝、心、脾、肺、腎等器官的臟器系數(shù)略有影響，但多數(shù)恢復期可逆。 5.軟堅消癭顆粒在長期毒性試驗中，組織病理學檢查未見異常。 6.軟堅消癭顆粒長期用藥是基本安全的。
[Abstract]:Objective : To study the long - term toxicity of Chinese traditional Chinese medicine compound soft solid Xiaoying granules . Based on the preparation technology , quality standard and stability , acute toxicity and pharmacodynamics of soft solid Xiaoying granules , the characteristics and extent of toxicity reaction ( including initiation time , degree , duration , reversibility , etc . ) and target organs were further determined , the safety range was determined , and the mechanism of toxic action was discussed . This paper mainly studied the histopathological study of the brain , liver , heart , spleen , lung , kidney and other organs of rats .

Materials and Methods :

1 . Experimental material

According to the research requirements , 240 male and female male and female male and female male and female male and female , 240 male and female male and female male and female male and female were used in the experimental animals . All the animals were in compliance with the requirements of the national drug non - clinical safety study . The tested drugs were Chinese traditional Chinese medicine compound soft solid Xiaoying granules ( Radix Bupleuri , Radix Angelicae Sinensis , Curcumae Rhizoma , Pericarpium Citri Tangerinae , Bulbus Fritillariae Thunbergii , seaweed , kelp , Radix Paeoniae Rubra , and 8 Chinese medicines ) . The medicine is provided by the laboratories of the Central Pharmaceutical Experimental Center of the Affiliated Hospital of Chinese Medical University of Liaoning .

2 . Test Method

The rats were randomly divided into three dosage groups : soft masses , medium , high three dose groups and normal saline control group .
8 g of crude drug / kg / day ( 1.5ml / 100g5 % 2 times per day ) in low - dose group .
20 g crude drug / kg / day ( 3.77 g powder / kg / d ) ( 1.5ml / 100g12 . 56 % 2 times per day ) in the dosage group of soft extract gall granules ;
60 g / kg / day ( 11.32g powder / kg / d ) ( 1.5ml / 100g37.68 % 2 times per day ) .
The control group was given 1.5 ml / 100 g of physiological saline to fill the stomach . The rats were administered twice daily , 6 days a week , dosing on Sunday , 6 months after continuous administration . After 3 months of administration ( mid - term ) , 6 months later ( end ) , and six months later ( recovery period ) , 1 / 3 of rats were randomly selected to inject 25 % uranotan into the abdominal cavity for anesthesia and blood taking . After taking the blood , the rats were subjected to systemic necropsy , the organs were weighed and the organ coefficients were calculated for histopathological examination .

Results :

1 . During the long - term toxicity test , the appearance fur , behavioral activity and mental state of the rats in each group were not obviously abnormal . There were no abnormal secretion in the glands , such as mouth , nose , eye and ear .

2 . The effect of long - term administration on the feeding amount in rats was shown in Table 1 - 1 and Table 1 - 2 . The results were shown in Table 1 - 1 and Table 1 - 2 .

3 . In the long - term toxicity test , the weight , low , medium and high dosage groups were compared with normal saline control group , and the results were shown in Table 2 - 1 and Table 2 - 2 . The results showed that P & lt ; 0.05 had statistical significance in different time periods . However , the researchers thought that there was close relationship between dietary intake and non - toxicity .

4 . The effect of long - term administration on organ coefficients in rats was studied . In the middle , middle and high dose groups , there was a significant difference between the low and middle and high dose groups compared with normal saline control group .

5 . The histopathological examination showed that the lower , medium , and high dose groups of the rats showed no obvious abnormality in the structure of the main organ under the main organ mirror compared with the normal saline control group .

Conclusion :

1 . There was no obvious effect on the general situation of the rats in long - term administration .

2 . The long - term administration of soft - jian Xiaoying granules had some effects on the daily intake of rats , but it was not caused by toxicity .

3 . The long - term administration of soft - jian Xiaoying granules had some effects on the weight of rats , but it was not caused by toxicity .

4 . The long - term administration of soft - jian Xiaoying granules has a slight effect on the organ coefficients of organs such as brain , liver , heart , spleen , lung and kidney , but most of the recovery periods are reversible .

5 . In the long - term toxicity test , the histopathological examination showed no abnormality .

6 . The long - term use of soft - solid Xiaoying granules is basically safe .

【學位授予單位】：遼寧中醫(yī)藥大學
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：R285.5

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