ATTM的体内抗菌、毒理学及药物代谢动力学研究
发布时间：2018-08-21 11:12
【摘要】：14-O-[(2-氨基-1,3,4,-噻二唑-5基)巯乙酰基]姆体林(ATTM)是中国农业科学院兰州畜牧与兽药研究所兽用天然药物创新团队自主研发的具有新型化学结构的截短侧耳素类衍生物。该化合物具有良好的体外抑菌效果,因此本文进行了一系列试验,包括ATTM的体内抗菌试验、ATTM的急性毒性、28天亚慢性毒性试验和肉鸡体内的药动学研究,对ATTM进行评价。1.ATTM的合成化合物ATTM的合成步骤为,第一步反应先用TsCl将截短侧耳素的C-22羟基活化,在碱性条件下将产生的磺化截短侧耳素再与KI反应,形成中间体—14-O-(碘乙酰基)姆体林,与2-氨基-5-巯基-1,3,4,-噻二唑反应形成ATTM。2.ATTM的体内抗菌研究采用感染MRSE的动物模型(即模拟临床细菌感染疾病)通过记录存活小鼠的数量来评价ATTM的体内抗菌活性,延胡索酸泰妙菌素作为阳性对照药物。结果:ATTM和延胡索酸泰妙菌素的ED50分别为5.74和5.95 mg/kg b.w.。95%的可信限分别为3.75~8.78 mg/kg和3.59~9.87 mg/kg。试验表明ATTM对全身感染MRSA的小鼠模型具有治疗作用,且效果优于延胡索酸泰妙菌素。3.ATTM的急性毒性研究急性毒性试验按改良寇氏法设计,实验分6组,在预实验的基础上,设5个给药剂量组以及灌服DMSO阴性对照组,给药后连续观察14天并做记录,统计死亡动物数,用改良寇氏法计算LD50。对死亡的小鼠及试验结束处死的小鼠进行解剖并观察病理变化,推测可能的毒性靶器官。结果:LD50为2304.4mg/kg;LD50的95%的可信限为1861.4~2870.5 mg/kg。按照外源化合物急性毒性分级(Copplestcme J,1988)标准判定:ATTM为低毒化合物。4.ATTM亚慢性毒性研究100只健康的SD大鼠(140~160 g),雌雄各半,随机分成5组,分别为高、中、低给药组,溶剂组和生理盐水组,采用灌胃给药方法,连续喂养28天观察ATTM对大鼠毒性反应。体重、饲料消耗和血常规没有显著性差异。高剂量组的肝的脏器系数和血生化指标中的ALP、CR和GLU与空白组具有显著性差异,病理学检查中显示肝、肾和脾有病理变化,推断ATTM对大鼠的毒性靶器官可能是肝脏、肾脏和脾脏。5.ATTM在肉鸡体内的药动学研究本文建立了ATTM在肉鸡血浆中HPLC分析方法,该方法具有灵敏、准确、特异性高和可重复性优点。本方法第一次成功的应用于检测肉鸡血浆中的ATTM。健康肉鸡单剂量(30mg/kg b.w.)静脉、肌肉和口服给予ATTM。用PK solver程序的非房室模型分析ATTM的药动学参数。ATTM在肉鸡体内表现良好的药动学特性,比如分布广泛、吸收快、消除速度适中。
[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.
【学位授予单位】：中国农业科学院
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：S859.79
本文编号：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.
【学位授予单位】：中国农业科学院
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：S859.79
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