ATTM的體內(nèi)抗菌、毒理學(xué)及藥物代謝動(dòng)力學(xué)研究
發(fā)布時(shí)間：2018-08-21 11:12
【摘要】：14-O-[(2-氨基-1,3,4,-噻二唑-5基)巰乙�；鵠姆體林(ATTM)是中國農(nóng)業(yè)科學(xué)院蘭州畜牧與獸藥研究所獸用天然藥物創(chuàng)新團(tuán)隊(duì)自主研發(fā)的具有新型化學(xué)結(jié)構(gòu)的截短側(cè)耳素類衍生物。該化合物具有良好的體外抑菌效果,因此本文進(jìn)行了一系列試驗(yàn),包括ATTM的體內(nèi)抗菌試驗(yàn)、ATTM的急性毒性、28天亞慢性毒性試驗(yàn)和肉雞體內(nèi)的藥動(dòng)學(xué)研究,對(duì)ATTM進(jìn)行評(píng)價(jià)。1.ATTM的合成化合物ATTM的合成步驟為,第一步反應(yīng)先用TsCl將截短側(cè)耳素的C-22羥基活化,在堿性條件下將產(chǎn)生的磺化截短側(cè)耳素再與KI反應(yīng),形成中間體—14-O-(碘乙�；�)姆體林,與2-氨基-5-巰基-1,3,4,-噻二唑反應(yīng)形成ATTM。2.ATTM的體內(nèi)抗菌研究采用感染MRSE的動(dòng)物模型(即模擬臨床細(xì)菌感染疾病)通過記錄存活小鼠的數(shù)量來評(píng)價(jià)ATTM的體內(nèi)抗菌活性,延胡索酸泰妙菌素作為陽性對(duì)照藥物。結(jié)果:ATTM和延胡索酸泰妙菌素的ED50分別為5.74和5.95 mg/kg b.w.。95%的可信限分別為3.75~8.78 mg/kg和3.59~9.87 mg/kg。試驗(yàn)表明ATTM對(duì)全身感染MRSA的小鼠模型具有治療作用,且效果優(yōu)于延胡索酸泰妙菌素。3.ATTM的急性毒性研究急性毒性試驗(yàn)按改良寇氏法設(shè)計(jì),實(shí)驗(yàn)分6組,在預(yù)實(shí)驗(yàn)的基礎(chǔ)上,設(shè)5個(gè)給藥劑量組以及灌服DMSO陰性對(duì)照組,給藥后連續(xù)觀察14天并做記錄,統(tǒng)計(jì)死亡動(dòng)物數(shù),用改良寇氏法計(jì)算LD50。對(duì)死亡的小鼠及試驗(yàn)結(jié)束處死的小鼠進(jìn)行解剖并觀察病理變化,推測可能的毒性靶器官。結(jié)果:LD50為2304.4mg/kg;LD50的95%的可信限為1861.4~2870.5 mg/kg。按照外源化合物急性毒性分級(jí)(Copplestcme J,1988)標(biāo)準(zhǔn)判定:ATTM為低毒化合物。4.ATTM亞慢性毒性研究100只健康的SD大鼠(140~160 g),雌雄各半,隨機(jī)分成5組,分別為高、中、低給藥組,溶劑組和生理鹽水組,采用灌胃給藥方法,連續(xù)喂養(yǎng)28天觀察ATTM對(duì)大鼠毒性反應(yīng)。體重、飼料消耗和血常規(guī)沒有顯著性差異。高劑量組的肝的臟器系數(shù)和血生化指標(biāo)中的ALP、CR和GLU與空白組具有顯著性差異,病理學(xué)檢查中顯示肝、腎和脾有病理變化,推斷ATTM對(duì)大鼠的毒性靶器官可能是肝臟、腎臟和脾臟。5.ATTM在肉雞體內(nèi)的藥動(dòng)學(xué)研究本文建立了ATTM在肉雞血漿中HPLC分析方法,該方法具有靈敏、準(zhǔn)確、特異性高和可重復(fù)性優(yōu)點(diǎn)。本方法第一次成功的應(yīng)用于檢測肉雞血漿中的ATTM。健康肉雞單劑量(30mg/kg b.w.)靜脈、肌肉和口服給予ATTM。用PK solver程序的非房室模型分析ATTM的藥動(dòng)學(xué)參數(shù)。ATTM在肉雞體內(nèi)表現(xiàn)良好的藥動(dòng)學(xué)特性,比如分布廣泛、吸收快、消除速度適中。
[Abstract]:14-O- [(2-Amino -1C3O3C4C4TZ-5) mercaptoacetyl] (ATTM) is a new chemical structure of truncated Pleurotus derivatives developed by the animal natural medicine innovation team of Lanzhou Institute of Animal Husbandry and Veterinary Medicine, Chinese Academy of Agricultural Sciences. The compound has a good antibacterial effect in vitro, so a series of experiments have been carried out in this paper, including the in vivo antimicrobial test of ATTM and the 28 days subchronic toxicity test of ATTM and the pharmacokinetics study in broilers. The synthetic steps of ATTM, a synthetic compound of ATTM, were as follows: the first step was to activate the C-22 hydroxyl group of truncated Pleurodin with TsCl, and then to react with Ki in alkaline condition. Forming the intermediate -14-O- (iodoacetyl) mestin, In vivo Antibacterial activity of ATTM.2.ATTM by reaction with 2-Amino-5-mercapto-1-thiadiazole; Antibacterial activity of ATTM in vivo was evaluated by recording the number of surviving mice in an animal model of MRSE infection (that is, mimicking a clinical bacterial infection disease). Tymiao fumarate was used as a positive control drug. Results the confidence limits of ED50 were 5.74 and 5.95 mg/kg b.w.95% for the two groups, respectively, and the confidence limits were 3.758.78 mg/kg and 3.599.87 mg / kg, respectively. The results showed that ATTM had a therapeutic effect on the mice model of systemic infection with MRSA, and the effect was better than that of Tymione fumarate. 3. The acute toxicity test was designed according to the modified Kou's method. The experiment was divided into 6 groups, and on the basis of the pre-experiment, the acute toxicity test was designed. Five dosage groups and DMSO negative control group were divided into 5 groups. The animals were observed and recorded for 14 days after administration. LD50 was calculated by modified Coll's method. The dead mice and the mice killed at the end of the experiment were dissected and pathological changes were observed to speculate the possible toxic target organs. Results the 95% confidence limit of the LD50 of 2 304.4 mg / kg LD50 was 1861. 4 mg / kg. Acute toxicity classification of exogenous compounds (Copplestcme JJ, 1988): 1. ATTM as a low toxic compound. 4. Study on subchronic toxicity of ATTM; 100 healthy SD rats (140 ~ 160 g), male and female) were randomly divided into 5 groups: high, middle and low administration groups. In the solvent group and saline group, the toxicity of ATTM to rats was observed by oral administration for 28 days. There was no significant difference in body weight, feed consumption and blood routine. There were significant differences in liver organ coefficient and ALP CR and GLU between the high dose group and the blank group. Pathological examination showed pathological changes in liver, kidney and spleen. It was inferred that the toxic target organ of ATTM to rats might be liver. Pharmacokinetic study of kidney and spleen. 5. The pharmacokinetics of ATTM in broiler plasma was established. The method is sensitive, accurate, specific and reproducible. This method was successfully applied to the detection of ATTM in broiler plasma for the first time. Single dose of healthy broiler (30mg/kg b.w.) Intravenous, muscular and oral administration of ATTM. The pharmacokinetic parameters of ATTM in broilers were analyzed by the non-atrioventricular model of competitive solver program. The pharmacokinetic characteristics of ATTM in broilers were analyzed, such as wide distribution, fast absorption and moderate elimination speed.
【學(xué)位授予單位】：中國農(nóng)業(yè)科學(xué)院
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2015
【分類號(hào)】：S859.79
本文編號(hào)：2195538
[Abstract]:14-O- [(2-Amino -1C3O3C4C4TZ-5) mercaptoacetyl] (ATTM) is a new chemical structure of truncated Pleurotus derivatives developed by the animal natural medicine innovation team of Lanzhou Institute of Animal Husbandry and Veterinary Medicine, Chinese Academy of Agricultural Sciences. The compound has a good antibacterial effect in vitro, so a series of experiments have been carried out in this paper, including the in vivo antimicrobial test of ATTM and the 28 days subchronic toxicity test of ATTM and the pharmacokinetics study in broilers. The synthetic steps of ATTM, a synthetic compound of ATTM, were as follows: the first step was to activate the C-22 hydroxyl group of truncated Pleurodin with TsCl, and then to react with Ki in alkaline condition. Forming the intermediate -14-O- (iodoacetyl) mestin, In vivo Antibacterial activity of ATTM.2.ATTM by reaction with 2-Amino-5-mercapto-1-thiadiazole; Antibacterial activity of ATTM in vivo was evaluated by recording the number of surviving mice in an animal model of MRSE infection (that is, mimicking a clinical bacterial infection disease). Tymiao fumarate was used as a positive control drug. Results the confidence limits of ED50 were 5.74 and 5.95 mg/kg b.w.95% for the two groups, respectively, and the confidence limits were 3.758.78 mg/kg and 3.599.87 mg / kg, respectively. The results showed that ATTM had a therapeutic effect on the mice model of systemic infection with MRSA, and the effect was better than that of Tymione fumarate. 3. The acute toxicity test was designed according to the modified Kou's method. The experiment was divided into 6 groups, and on the basis of the pre-experiment, the acute toxicity test was designed. Five dosage groups and DMSO negative control group were divided into 5 groups. The animals were observed and recorded for 14 days after administration. LD50 was calculated by modified Coll's method. The dead mice and the mice killed at the end of the experiment were dissected and pathological changes were observed to speculate the possible toxic target organs. Results the 95% confidence limit of the LD50 of 2 304.4 mg / kg LD50 was 1861. 4 mg / kg. Acute toxicity classification of exogenous compounds (Copplestcme JJ, 1988): 1. ATTM as a low toxic compound. 4. Study on subchronic toxicity of ATTM; 100 healthy SD rats (140 ~ 160 g), male and female) were randomly divided into 5 groups: high, middle and low administration groups. In the solvent group and saline group, the toxicity of ATTM to rats was observed by oral administration for 28 days. There was no significant difference in body weight, feed consumption and blood routine. There were significant differences in liver organ coefficient and ALP CR and GLU between the high dose group and the blank group. Pathological examination showed pathological changes in liver, kidney and spleen. It was inferred that the toxic target organ of ATTM to rats might be liver. Pharmacokinetic study of kidney and spleen. 5. The pharmacokinetics of ATTM in broiler plasma was established. The method is sensitive, accurate, specific and reproducible. This method was successfully applied to the detection of ATTM in broiler plasma for the first time. Single dose of healthy broiler (30mg/kg b.w.) Intravenous, muscular and oral administration of ATTM. The pharmacokinetic parameters of ATTM in broilers were analyzed by the non-atrioventricular model of competitive solver program. The pharmacokinetic characteristics of ATTM in broilers were analyzed, such as wide distribution, fast absorption and moderate elimination speed.
【學(xué)位授予單位】：中國農(nóng)業(yè)科學(xué)院
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2015
【分類號(hào)】：S859.79
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