本文選題：痔血膠囊 + 肝毒性�。� 參考：《北京中醫(yī)藥大學(xué)》2017年碩士論文

【摘要】：痔血膠囊是一種純中藥復(fù)方制劑,由苦參和白鮮皮兩味中藥組成,功能主治:清熱解毒、涼血止血。用于Ⅰ、Ⅱ期內(nèi)痔及混合痔所致的便血、肛門(mén)墜脹或墜痛,大便干燥或秘結(jié)等癥。該品種被收入2004年《國(guó)家基本藥物目錄》和《國(guó)家基本醫(yī)療保險(xiǎn)和工傷保險(xiǎn)藥品目錄》。但近年來(lái)國(guó)家藥品不良反應(yīng)中心陸續(xù)收到痔血膠囊涉及的藥品不良反應(yīng)報(bào)告,特別是2008年報(bào)告數(shù)量迅速增加。國(guó)家藥品不良反應(yīng)中心第十七期《藥品不良反應(yīng)信息通報(bào)》報(bào)告了痔血膠囊引起肝損害的不良反應(yīng)情況:截至2008年9月25日,共收到痔血膠囊相關(guān)病例報(bào)告35例。其中21例(60%)不良反應(yīng)名稱描述為肝功能異常、膽汁淤積型肝炎、藥物性肝炎,另有腹痛8例,皮疹4例,過(guò)敏樣反應(yīng)1例,頭暈、頭痛1例。經(jīng)對(duì)報(bào)告病例系統(tǒng)分析后,不能排除痔血膠囊與肝損害事件的關(guān)聯(lián)性。為對(duì)痔血膠囊的肝毒性進(jìn)行全面的研究,本實(shí)驗(yàn)從藥物因素,以及個(gè)體因素,對(duì)痔血膠囊出現(xiàn)肝毒性的原因進(jìn)行了研究,其中藥物因素從痔血膠囊中出現(xiàn)過(guò)單味藥肝損傷報(bào)道的白鮮皮的產(chǎn)地、生產(chǎn)工藝;個(gè)體因素從辨證、辨體、用量、療程等角度進(jìn)行研究。第一部分:藥物因素實(shí)驗(yàn)一、含不同產(chǎn)地白鮮皮痔血膠囊肝毒性的比較性研究目的:觀察分別含不同產(chǎn)地白鮮皮痔血膠囊的長(zhǎng)期低(4.1 g.kg-1)、中(8.3 g·kg-1)、高(16.5g·kg-1)劑量給藥后對(duì)大鼠產(chǎn)生的肝毒性反應(yīng)。方法:Wistar大鼠,隨機(jī)分為正常組、含五個(gè)不同產(chǎn)地白鮮皮痔血膠囊的高中低劑量組,分別灌服蒸餾水、含不同產(chǎn)地白鮮皮痔血膠囊的高中低劑量,連續(xù)給藥30 d。觀察給藥期間的一般表現(xiàn),體重變化等。末次給藥后,檢測(cè)血清肝功能指標(biāo);計(jì)算臟器指數(shù);按照肝臟病理檢驗(yàn)要求,取肝組織,固定,蘇木精-伊紅染色(HE染色)后光鏡下觀察。結(jié)果:大鼠連續(xù)灌胃含不同產(chǎn)地白鮮皮痔血膠囊30 d,給藥期間動(dòng)物活動(dòng)、排便、毛發(fā)等與正常組無(wú)明顯差異;30 d后,與正常組比較,肝臟血生化結(jié)果白蛋白(ALB)、谷氨酰轉(zhuǎn)肽酶(GGT)在個(gè)別組有升高(P0.05);病理切片觀察顯示,分別含五個(gè)不同產(chǎn)地白鮮皮痔血膠囊的動(dòng)物肝臟低、中、高劑量組均可見(jiàn)透明細(xì)胞改變及肝竇擴(kuò)張。結(jié)論:分別含五個(gè)不同產(chǎn)地白鮮皮痔血膠囊均具有明顯的肝毒性。實(shí)驗(yàn)二、痔血膠囊不同工藝提取物肝毒性研究目的:通過(guò)比較痔血膠囊水提取物和乙醇提取物對(duì)大鼠肝毒性的影響,探討工藝因素對(duì)中藥制劑安全性的影響。方法:Wistar大鼠80只,雌雄各半,隨機(jī)分為空白對(duì)照組、全方水提組、全方60%醇提組、全方85%醇提組,除正常組灌服蒸餾水外,其余組按劑量4.1 g·kg-1灌服對(duì)應(yīng)藥物,連續(xù)給藥30 d。末次給藥后,腹腔注射10%水合氯醛溶劑麻醉,腹主動(dòng)脈取血,離心取血清,全自動(dòng)生化儀檢測(cè)血清天門(mén)冬氨酸氨基轉(zhuǎn)移酶(AST)、堿性磷酸酶(ALP)、丙氨酸氨基轉(zhuǎn)移酶(ALT)、總膽紅素(TBIL)等血清肝功能指標(biāo);摘取肝臟,稱取質(zhì)量,計(jì)算臟器指數(shù);取肝臟最大葉同一部位肝組織,10%中性福爾馬林固定48 h,脫水,石蠟包埋,切片,HE染色后,在光學(xué)顯微鏡下進(jìn)行病理檢查。結(jié)果:痔血膠囊全方乙醇提取物存在明確的肝臟毒性,組織病理學(xué)主要表現(xiàn)為肝小葉周邊帶肝細(xì)胞小泡型脂肪變性;并且其肝毒性與提取溶劑中乙醇含量正相關(guān);此外根據(jù)大鼠肝臟小灶狀炎細(xì)胞浸潤(rùn)評(píng)分,發(fā)現(xiàn)痔血膠囊的抗炎作用,水提組明顯優(yōu)于醇提組,說(shuō)明痔血膠囊醇提物較水提物藥效降低。結(jié)論:工藝因素對(duì)中藥復(fù)方制劑的安全性具有重要影響,提示今后新藥研發(fā)應(yīng)關(guān)注現(xiàn)代工藝對(duì)中藥安全性的影響,過(guò)分強(qiáng)調(diào)成分富集存在嚴(yán)重的安全隱患,工藝篩選應(yīng)采用毒效結(jié)合的思路。實(shí)驗(yàn)三、痔血膠囊不同工藝提取物化學(xué)成分差異分析目的:運(yùn)用HPLC-MS聯(lián)用技術(shù),對(duì)痔血膠囊不同工藝提取物化學(xué)成分差異進(jìn)行分析。方法:通過(guò)HPLC-MS對(duì)痔血膠囊水提取物、85%乙醇提取物、60%乙醇提取物進(jìn)行分析,對(duì)三者的主要成分差異進(jìn)行OPLS-DA分析,并通過(guò)2級(jí)圖譜對(duì)主要差異成分進(jìn)行鑒定。結(jié)果:痔血膠囊水提取物、65%醇提取物、85%醇提取物的化學(xué)成分具有明顯的含量差異;并初步鑒定其中的已知化合物,為進(jìn)一步篩選痔血膠囊中的肝毒性成分奠定了基礎(chǔ)。第二部分:個(gè)體因素通過(guò)對(duì)痔病的中醫(yī)證型分布,及其體質(zhì)分布特征與痔血膠囊主治功能進(jìn)行比較、以及痔血膠囊肝損傷病例報(bào)告的回顧,對(duì)造成痔血膠囊肝損傷的個(gè)體因素進(jìn)行分析。發(fā)現(xiàn)痔血膠囊出現(xiàn)肝損傷的個(gè)體因素主要包括用藥辨證不準(zhǔn),用藥未考慮體質(zhì),以及患者超療程、超劑量服用等。本研究通過(guò)對(duì)痔血膠囊中白鮮皮的產(chǎn)地、痔血膠囊的醇提工藝對(duì)其肝毒性的影響進(jìn)行大鼠長(zhǎng)期毒性實(shí)驗(yàn),基本明確痔血膠囊出現(xiàn)肝損傷的主要因素之一為工藝因素。但是辨證是否準(zhǔn)確、是否辨體用藥、以及用藥是否符合療程、用量等個(gè)體因素,也是痔血膠囊造成肝損傷的因素之一。
[Abstract]:The hemorrhoid blood capsule is a pure Chinese medicine compound preparation, composed of two herbs of Radix Sophorae Flavescentis and white fresh skin. It is used for the treatment of blood stasis caused by internal hemorrhoids and mixed hemorrhoids in stage I, II period of internal hemorrhoids and mixed hemorrhoids, anus falling or falling pain, the dry or secret of stool. The variety was paid in 2004 < National Basic Medicine > and national basic medical insurance. In recent years, the national drug adverse reaction center has received reports of adverse drug reactions involved in hemorrhoids and blood capsules, especially in 2008. The seventeenth phase of the national drug adverse reaction center report on the adverse drug reaction information report on the adverse reactions caused by hemorrhoids and blood capsules. Situation: as of September 25, 2008, a total of 35 cases of hemorrhoids and blood capsule related cases were reported. Among them, 21 cases (60%) were described as abnormal liver function, cholestasis hepatitis, drug hepatitis, 8 cases of abdominal pain, 4 cases of skin rash, 1 cases of allergic reaction, dizziness and 1 headache. After systematic analysis of the reported cases, the hemorrhoids and blood capsules can not be excluded from the hemorrhoids capsules and blood capsules and can not be excluded. In order to study the hepatotoxicity of the hemorrhoid blood capsule, we studied the hepatotoxicity of hemorrhoids and blood capsules. From the drug factors and individual factors, the cause of the liver toxicity of hemorrhoid capsule was studied. Research on syndrome differentiation, differentiation, dosage and course of treatment. Part 1: drug factor experiment 1. Comparative study on hepatotoxicity of hemorrhoid capsules containing white fresh skin in different habitats: long-term low (4.1 g.kg-1), medium (8.3 G. Kg-1), and high (16.5g. Kg-1) dosage of high (16.5g. Kg-1), respectively, of different producing areas Methods: Wistar rats were randomly divided into normal group and high and low dose group containing five different areas of white fresh skin hemorrhoids and blood capsules. The low dose of distilled water and high and low doses of white fresh skin hemorrhoid capsule in different areas were given respectively. The general performance and weight change during the period of 30 D. were continuously given. After the last administration, the liver function was detected. Index; calculate the organ index; take the liver tissue, fixed, the hematoxylin eosin staining (HE staining) under the light microscope according to the liver pathological examination requirements. Results: the rats were continuously filled with 30 d capsules containing white fresh skin hemorrhoids and blood, and there was no significant difference between the animal activities, defecation, hair and so on during the period of administration. After 30 d, the liver blood was compared with the normal group. The biochemical results of albumin (ALB) and glutamyl transpeptidase (GGT) were elevated in a few groups (P0.05). Pathological sections showed that the liver of animals with five different areas of white fresh skin hemorrhoid capsules were low, middle and high dose group showed transparent cell changes and hepatic sinusoid dilatation. Significant liver toxicity. Experiment two, study on the hepatotoxicity of different process extracts of hemorrhoid blood capsules. By comparing the effects of water extract and ethanol extract of hemorrhoid Capsule on the liver toxicity of rats, the effect of technological factors on the safety of Chinese medicine preparation was discussed. Methods: 80 Wistar rats were divided into blank control group and the whole water extract group at random. The whole 60% alcohol extraction group and the whole 85% alcohol extract group, except the normal group was filled with distilled water, the other groups were given the corresponding drugs according to the dosage of 4.1 G. Kg-1. After continuous administration of the last dosage of 30 d., the abdominal aorta was injected with chloral chloral solvent anesthesia, the abdominal aorta was taken from the blood, the serum was centrifuged, and the serum aspartate aminotransferase (AST) was detected by the automatic biochemistry analyzer. Phosphatase (ALP), alanine aminotransferase (ALT), total bilirubin (TBIL) and other serum liver function indexes, extract the liver, take the mass, calculate the organ index; take the liver tissue of the same part of the liver of the largest lobe of the liver, 10% neutral Faure Marin fixed 48 h, dehydration, paraffin embedding, slice, HE staining, pathological examination under the optical microscope. Results: hemorrhoids blood There was a clear liver toxicity in the whole capsule ethanol extract of the capsule. Histopathology was mainly manifested by hepatocyte vesicular steatosis in the periphery of the liver lobule, and the liver toxicity was positively correlated with the ethanol content in the extraction solvent. The results showed that the technological factors had an important influence on the safety of Chinese medicine compound preparation, suggesting that the development of new drugs should pay attention to the effect of modern technology on the safety of traditional Chinese medicine, overemphasize the existence of serious safety hidden dangers in the enrichment of ingredients, and the process screening should be combined with toxic effect. Experiment three, the difference analysis of chemical composition of different process extracts of hemorrhoid blood capsule: use HPLC-MS combined technique to analyze the chemical composition difference of different process extracts of hemorrhoid blood capsule. Method: analysis the water extract of hemorrhoid blood capsule, 85% ethanol extract and 60% ethanol extract through HPLC-MS. OPLS-DA analysis was carried out and the main difference components were identified by 2 level atlas. Results: the chemical composition of the water extract of hemorrhoid blood capsule, 65% alcohol extract and 85% alcohol extract had obvious difference, and the preliminary identification of the known compounds was established. Second parts were laid for the further screening of the hepatotoxic components in hemorrhoid blood capsules. The individual factors were compared with the TCM syndrome distribution of hemorrhoids, the distribution characteristics of the constitution of hemorrhoids and the main function of hemorrhoids and blood capsules, and the review of the report on the case of hemorrhoid capsule liver injury, and the individual factors that caused the liver injury of hemorrhoids and blood capsules were analyzed. In this study, the effect of the alcohol extraction process on the liver toxicity of hemorrhoids and blood capsules was carried out in the long-term toxicity test on the liver toxicity of hemorrhoids and blood capsules. Whether or not body identification is used, and whether the medication is in line with the course of treatment and dosage is also one of the factors that cause liver injury caused by hemorrhoids capsule.

【學(xué)位授予單位】：北京中醫(yī)藥大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R285

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