本文選題：鹽酸氯苯胍 + 恩諾沙星��； 參考：《上海海洋大學(xué)》2017年碩士論文

【摘要】：近年來,異育銀鯽養(yǎng)殖發(fā)展迅速,已成為我國主要的淡水養(yǎng)殖品種之一,然而大規(guī)模集約化養(yǎng)殖帶來了嚴(yán)重的病害問題,尤其是細(xì)菌性疾病和寄生蟲病最為嚴(yán)重。粘孢子蟲可寄生于鯽的鰓、表皮、喉部、腸、肝等多個(gè)部位,其造成的危害已給產(chǎn)業(yè)帶來重大的經(jīng)濟(jì)損失,因此需要一種具有較強(qiáng)殺蟲驅(qū)蟲效果的藥物來減少病害的發(fā)生。越來越嚴(yán)重的細(xì)菌耐藥性問題,對抗菌藥的使用造成了很大麻煩,為了更好的治療疾病和減少耐藥細(xì)菌的產(chǎn)生,進(jìn)行貼近生產(chǎn)的藥物代謝動力學(xué)研究顯得尤為重要。鹽酸氯苯胍是我國國標(biāo)漁藥,關(guān)于鹽酸氯苯胍在異育銀鯽體內(nèi)的藥物代謝動力學(xué)未見有研究報(bào)道。針對我國鯽養(yǎng)殖現(xiàn)狀,本文首先建立了鹽酸氯苯胍在異育銀鯽組織中殘留的檢測方法,又研究了通過藥餌給藥,鹽酸氯苯胍在異育銀鯽體內(nèi)的藥物代謝動力學(xué)研究,確定其在異育銀鯽組織內(nèi)的分布與消除規(guī)律,根據(jù)肌肉可食組織中的消除規(guī)律,結(jié)合相關(guān)國家和組織的最高殘留限量標(biāo)準(zhǔn),確定鹽酸氯苯胍在異育銀鯽體內(nèi)的休藥期,為鯽生產(chǎn)中鹽酸氯苯胍的合理使用提供科學(xué)依據(jù)。1.異育銀鯽組織中鹽酸氯苯胍的反相高效液相色譜法測定方法的建立在比較不同流動相對鹽酸氯苯胍色譜行為影響,以及不同提取方法對鹽酸氯苯胍回收率影響的基礎(chǔ)上,建立了測定異育銀鯽血漿、肝胰臟、肌肉、喉、腎臟、腸、鰓、腦和膽汁等組織中鹽酸氯苯胍含量的反相高效液相色譜法。方法以乙腈和0.1%甲酸水為流動相,色譜柱為Aglient Zorbax SB-C18(4.6×150mm,5μm),柱溫30℃,紫外檢測器波長317nm,進(jìn)樣量20μL,流速1.0 m L·min-1。鹽酸氯苯胍在0.01~10μg·m L-1范圍內(nèi)線性關(guān)系良好,相關(guān)系數(shù)R2=0.9998。采用乙腈提取異育銀鯽血漿、肝胰臟、肌肉、喉、腎臟、腸、鰓、腦和膽汁組織中鹽酸氯苯胍,加標(biāo)回收率為80.06%~102.02%,精密度為2.16%~7.41%,檢測限為0.01μg·m L-1。該方法操作簡單,重現(xiàn)性好,藥峰無干擾,適用于異育銀鯽生物樣品中鹽酸氯苯胍含量的分析。2.鹽酸氯苯胍在異育銀鯽體內(nèi)藥動學(xué)和組織分布與消除研究水溫25±1℃條件下,鹽酸氯苯胍以20 mg·kg-1單劑量拌飼藥餌給藥后在異育銀鯽體內(nèi)藥動學(xué),以及在肝胰臟、肌肉、喉、腎臟、腸、鰓、腦和膽汁中的分布和消除規(guī)律,為其科學(xué)安全使用提供理論支撐。結(jié)果顯示,藥餌給藥后異育銀鯽血漿中鹽酸氯苯胍的藥時(shí)數(shù)據(jù)符合一級吸收二室模型,血藥達(dá)峰時(shí)間(Tmax)為4 h,血藥濃度峰值(Cmax)為1.117 mg·L-1、藥時(shí)曲線下面積(AUC0-∞)為68.39mg·L-1·h和消除半衰期(t1/2β)為56.86 h。鹽酸氯苯胍在異育銀鯽其他組織中分布較廣,Cmax大小依次為:腸(8.53mg·kg-1)、腎臟(4.64mg·kg-1)、肝胰臟(3.27mg·kg-1)、膽汁(2.68mg·kg-1)、鰓(1.38mg·kg-1)、喉(1.17mg·kg-1)、腦(0.82mg·kg-1)、肌肉(0.43mg·kg-1);AUC0-∞大小依次:腸(156.39mg·kg-1·h)、腎臟(122.911mg·kg-1·h)、膽汁(83.772mg·kg-1·h)、肝胰臟(68.444mg·kg-1·h)、喉(53.659mg·kg-1·h)、鰓(39.142mg·kg-1·h)、腦(32.904mg·kg-1·h)、肌肉(12.448mg·kg-1·h);t1/2z大小依次為:腦(85.549h)、鰓(83.263h)、腎臟(76.541h)、喉(69.334h)、肝胰臟(67.197h)、膽汁(55.852h)、肌肉(54.506h)、腸(48.581h)。異育銀鯽攝食藥餌后,鹽酸氯苯胍通過腸道吸收進(jìn)入肝胰臟,經(jīng)血液循環(huán)廣泛分布于各組織器官中,最后主要從腎臟排出,這也與其較大的Vd值相印證。研究還發(fā)現(xiàn),粘孢子蟲感染異育銀鯽的喉、鰓和腦等組織均有鹽酸氯苯胍分布,為該病的治療提供了理論依據(jù)。若以10μg·kg-1為-肌肉中最高殘留限量,在本試驗(yàn)條件下,建議休藥期不少于15 d。3.恩諾沙星臨床用藥藥動學(xué)與藥效評價(jià)本研究深入生產(chǎn)進(jìn)行采樣分析,實(shí)驗(yàn)池塘位于江蘇省鹽城市射陽鹽場鯽大規(guī)模養(yǎng)殖區(qū),選取發(fā)生細(xì)菌性疾病的用藥池塘且按照當(dāng)?shù)赜盟幜?xí)慣進(jìn)行給藥,以獲得更加真實(shí)、可靠的數(shù)據(jù),方便對實(shí)際生產(chǎn)中用藥情況的分析和指導(dǎo)。采樣方法上,在多次用藥前后采集樣品,以獲得藥物在動物體內(nèi)的大致代謝情況和在血漿中可以達(dá)到的最高藥物濃度。結(jié)果顯示,異育銀鯽恩諾沙星最高血藥濃度為1.130μg·m L-1,環(huán)丙沙星的最高濃度為0.026μg·mL-1,恩諾沙星及其代謝產(chǎn)物環(huán)丙沙星在異育銀鯽體內(nèi)消除較慢,存留時(shí)間較長。所得的實(shí)驗(yàn)數(shù)據(jù)表明,池塘的用藥劑量偏小,最高的藥物濃度僅為1.130μg·m L-1,面對日益嚴(yán)重的細(xì)菌耐藥問題,很難達(dá)到良好的治療效果。模擬生產(chǎn)進(jìn)行的30mg/kg的恩諾沙星藥餌多次給藥,獲得的最高血藥濃度為5.600μg·mL-1,已經(jīng)大于多數(shù)細(xì)菌的MIC,理論上可以起到殺滅細(xì)菌并抑制耐藥菌株產(chǎn)生,達(dá)到治療細(xì)菌性疾病的目的。所以,在臨床實(shí)際用藥時(shí),要綜合考慮多種因素,病情的嚴(yán)重程度,科學(xué)的使用一定劑量的藥物來達(dá)到好的治療效果并減少耐藥的發(fā)生。
[Abstract]:In recent years, the culture of crucian carp has been developing rapidly, and it has become one of the main varieties of freshwater aquaculture in our country. However, the large-scale intensive culture has brought serious disease problems, especially the most serious bacterial and parasitic diseases. The parasitic spore can parasitism on the gills, epidermis, larynx, intestines and liver of Carassius auratus. The harm caused by it has been given to the carp. Industry brings great economic loss, so it needs a drug with strong insecticidal and insect repellent effects to reduce the occurrence of disease. More and more serious bacterial resistance problems, and the use of anti bacteria drugs has caused great trouble. In order to better treat disease and reduce the production of drug resistant bacteria, the pharmacokinetics of drug metabolism close to production is carried out. The study appears particularly important. Chlorobenzidine hydrochloride is a national standard fishing drug in China. The pharmacokinetics of chlorobenzidine hydrochloride in the body of crucian carp is not reported. In view of the current situation of carp culture in China, the detection method of chlorphenidine hydrochloride in the tissue of crucian carp is first established, and the drug bait, hydrochloric acid, and hydrochloric acid are also studied. The pharmacokinetics of chlorobenzidine in the crucian carp was studied, and its distribution and elimination in the tissue of the crucian carp were determined. According to the elimination rule in the edible tissues of the muscle and the standard of the highest residue limit of the related countries and organizations, the period of the taking of chlorobenzidine hydrochloride in the crucian carp was determined, and the chlorobenzene hydrochloride in the Carassius auratus production was found. The rational use of guanidine provides a scientific basis for the determination of chlorphenanidine hydrochloride in the tissue of.1. silver crucian carp by reversed phase high performance liquid chromatography (RP HPLC). On the basis of the influence of different flow relative to chlorobenzidine hydrochloride and the effect of different extraction methods on the recovery rate of chlorphenanidine hydrochloride, the determination of plasma and hepatopancreanopancreas of crucian carp was established. The reversed phase high performance liquid chromatography of chlorobenzidine hydrochloride content in tissues such as dirty, muscle, larynx, kidney, intestines, gills, brain and bile. Acetonitrile and 0.1% formate water were used as the mobile phase, the column was Aglient Zorbax SB-C18 (4.6 x 150mm, 5 mu m), the column temperature was 30, the UV detector was 317nm, the sample volume was 20 mu L, and the flow rate 1 m L min-1. hydrochloric guanidine was in 0.01~. The linear relationship between 10 g and m L-1 is good. Correlation coefficient R2=0.9998. uses acetonitrile to extract plasma, hepatopancreas, muscle, muscle, larynx, kidney, intestine, gill, brain and bile of chlorobenzidine hydrochloride, the recovery rate is 80.06%~102.02%, the precision is 2.16%~7.41%, the detection limit is 0.01 mu g. M L-1. this method is simple operation, reproducibility, peak drug peak Analysis of the content of chlorphenanidine hydrochloride in the biological samples of crucian carp (.2.), the pharmacokinetics and tissue distribution of chlorphenidine hydrochloride in the crucian carp were 25 + 1 centigrade, and the pharmacokinetics of chlorphenanidine hydrochloride in the crucian carp with 20 mg kg-1 single dose of chlorphenididine hydrochloride, and in the liver, pancreas, muscle and larynx were studied. The distribution and elimination of the kidney, intestines, gills, brain and bile provide theoretical support for the scientific and safe use of the drug. The results show that the data of chlorphenidine hydrochloride in the plasma of Carassius auratus after drug delivery are in accordance with the first order absorption two compartment model, the peak time of blood drug (Tmax) is 4 h, the peak value of blood drug concentration (Cmax) is 1.117 mg. L-1, under the curve of the drug time The product (AUC0- infinity) is 68.39mg / L-1 / h and the elimination half life (t1/2 beta) is 56.86 h. chlorobenzene guanidine in the other tissues of the crucian carp. The Cmax size is the following: the intestine (8.53mg. Kg-1), the kidney (4.64mg. Kg-1), the hepatopancreas (3.27mg.), the gills, the larynx, the brain and the muscles. Kg-1 (156.39mg. Kg-1. H), kidney (122.911mg. Kg-1. H), bile (83.772mg kg-1 / h), hepatopancreas (68.444mg. H), larynx (H), muscles (veins), gills, kidneys, larynx (69.33) 4h), hepatopancreas (67.197h), bile (55.852h), muscle (54.506h), and intestine (48.581h). Chlorphenanidine hydrochloride is absorbed into the hepatopancreas through intestinal absorption through intestinal absorption, and is widely distributed in the tissues and organs through the blood circulation. Finally, it is mainly discharged from the kidney, which is also evidenced by its larger Vd value. The distribution of chlorphenanidine hydrochloride in the larynx, gills and brain tissues of the Carassius auratus has provided a theoretical basis for the treatment of the disease. If 10 g kg-1 is the highest residual limit in the muscle, it is suggested that the drug pharmacokinetics and efficacy of enrofloxacin are not less than 15 d.3.. The pond is located in the large aquaculture area of the Sheyang salt carp in Yancheng City, Jiangsu province. The drug ponds of the bacterial diseases are selected and given according to the local drug use, so as to obtain more real and reliable data and facilitate the analysis and guidance of the use of drugs in the actual production. The highest concentration of the blood was 1.130 u g. M L-1, the highest concentration of ciprofloxacin was 0.026 G. ML-1, and enrofloxacin and its metabolite ciprofloxacin were slow to be eliminated in the crucian carp and the retention time was more than that in the Carassius auratus. The experimental data showed that the dosage of the drug in the pond was small and the highest drug concentration was only 1.130 G. M L-1. In the face of the increasingly serious bacterial resistance problem, it was difficult to achieve a good therapeutic effect. The 30mg/kg enrofloxacin bait for the simulated production was given many times, the highest concentration of blood drug was 5.600 mu g. ML-1, which was more than a lot. The MIC of several bacteria, in theory, can kill bacteria and inhibit the production of resistant strains to achieve the purpose of treating bacterial diseases. Therefore, in clinical practice, we should consider a variety of factors, the severity of the disease, the scientific use of a certain dose of drugs to achieve good therapeutic effects and reduce the occurrence of drug resistance.

【學(xué)位授予單位】：上海海洋大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：S943

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