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1.
单诺沙星脂质体在蛋雏鸡血浆的药代动力学   总被引:1,自引:0,他引:1  
分别采用静脉注射和内服两种给药途径给予健康蛋雏鸡甲磺酸单诺沙星溶液和甲磺酸单诺沙星脂质体混悬液(剂量为5 mg/kg).结果显示,两种剂型静注给药的药时数据均符合无吸收二室开放模型,主要药动学参数分别为T1/2α 0.349 6、0.351 8 h;T1/2β6.411 4、8.193 2 h;AUC3.799 7、5.066 0 mg/(L·h);CLβ1.723 2、1.131 7 L/(kg·h).两种剂型内服给药的药时数据均符合一级吸收一室开放模型,主要药动学参数分别为T1/2 Ka0.301 7、0.524 4 h;T1/2K 4.479 2、5.021 7 h;AUC 3.284 4、4.610 6 mg/(L·h);Cmax 0.483 8、1.054 8 mg/L;Tp 1.287 3、1.936 2 h;生物利用度分别为86.44%、91.01%.可见这两种剂型的静注与内服给药的体内药动学特征不同.与甲磺酸单诺沙星溶液相比,甲磺酸单诺沙星脂质体血浆半衰期延长,达峰浓度高,有效浓度维持时间持久,内服生物利用度提高.  相似文献   

2.
替米考星明胶微球在兔体内的靶向性研究   总被引:3,自引:0,他引:3  
作者旨在研究替米考星明胶微球在兔体内的靶向性.采用高效液相色谱法测定肌内注射给药不同时间兔体各脏器组织的药物浓度,利用3p97药动学软件无房室模型计算药时曲线下面积,结果显示替米考星明胶微球肺脏的靶向效率较心脏、肌肉、肝脏和肾脏提高了5.18±0.13、3.11±0.06、3.94±0.06和3.74±0.02倍;肺脏、心脏,肌肉、肝脏和肾脏的相对摄取率分别为8.23±0.04、1.59±0.03、2.65±0.04、2.09±0.02和2.20±0.01;肺脏、心脏、肌肉、肝脏和肾脏的峰浓度比分别为2.22±0.04、0.42±0.02、0.46±0.01、0.61±0.02和0.71±0.02.表明替米考星明胶微球具有良好的肺靶向性,同时可以减轻替米考星的心脏毒性.  相似文献   

3.
达氟沙星(Danofloxacin)在鸡体内的组织残留   总被引:5,自引:0,他引:5  
建立了坞组织中达氟沙星(Danonoxacin)的高效液相色谱(HPLC)测定方法,并测定了鸡单次内服(每千克体重5mg)给药后组织中的达氟沙星残留特征。组织样品用含0.015mol/L H3PO4和0.015mol/L HClO4的水-甲醇(50:50)提取,50℃水浴酸性水解90min,离心后取上清液作HPLC检测。色谱枉为Hypersil BDSC18柱;荧光检测器检测,激发波长280nm,发射波长440nm;流动相为含0.015mol/L四丁基溴化铵的水-乙腈(905:95,组织检测时为915:85)混合物,85%磷酸调pH为3.0。血浆、肝脏、肾脏、肺脏、肌肉中达氟沙星的检测限为0.02mg/L或0.02Pg/g,血浆样品回收率大于90%,组织样品回收率均大于74%。鸡单次内服甲磺酸达氟沙星后,在60h内各组奴中均可检出药物,但在48h所有组织中药物残留量均低于相应的MRLs(最高残留限量)。结果表明,达氟沙星在鸡组织中消除相对较慢。  相似文献   

4.
利福平乙基纤维素微球在小鼠体内的组织分布   总被引:1,自引:0,他引:1  
以有机相分散、溶媒扩散二步法制备了利福平乙基纤维素微球,粒径范围2.5-12.5μm,其中粒径2.5-5.0μm的约占63%。采用微生物测定法研究了利福平乙基纤维素微球静脉给药后,利福平在小鼠体内的组织分布,且与游离利福平在小鼠体内组织分布进行了比较,小鼠单剂量静脉注射游离利福平或利福平乙基纤维素微球(相当于利福平原药)10mg/kg,测定0.5、1、3、7、12、24、48、72、120、168h共10个时间点各组织中的药物浓度。结果表明,游离利福平给药组和利福平乙基纤维素微球给药组在12h内均以肝脏中药物浓度为最高,为9.96-22.41μg/g,在3h内微球给药组高于游离药物给药组,7、12h微球给药组的药物浓度迅速下降,低于游离药物给药组;肾脏的药物浓度在12h内微球给药组明显低于游离药物给药组,24-168h微球给药组的药物浓度下降迟缓,显著高于游离药物给药组直到168药物浓度始终是微球给药组高于游离药物给药组,12h游离药物给药组已不能检出药物含量,而微球给药组直到168h仍维持在5.44μg/g,接近游离药物给药组的最高峰值;血清中利福平浓度在48h已不能检出,而微球给药组在168h为1.33mg/L;心脏、用脏微球给药组和游离药物给药组的药物浓度变化无统计学意义,与游离药物相比,利福平微球明显提高了肺脏中的药物分布,降低了利福平对肝脏、肾脏的毒性,并显著延缓了药物代谢,说明利福平微球具有长效、靶向作用。  相似文献   

5.
给药方法     
1.内服给药 多数药物可经内服给药吸收,主要吸收部位是小肠。 2.注射给药 常用的注射给药主要有静脉、肌肉和皮下注射。其他还包括关节内、结膜下腔和硬膜外注射等。快速静注可立即产生药效,并且可以控制用药剂量;静脉滴注是达到和维持稳态浓度的最佳技术,达到稳态浓度的时间还取决于药物的消除速率。药物从肌肉、皮下注射部位吸收一般30min内达峰值,吸收速率取决于注射部位的血管分布状态。  相似文献   

6.
给药方法     
《农业新技术》2008,(2):55-55
1.内服给药 多数药物可经内服给药吸收,主要吸收部位是小肠。 2.注射给药 常用的注射给药主要有静脉、肌肉和皮下注射。其他还包括关节内、结膜下腔和硬膜外注射等。快速静注可立即产生药效,并且可以控制用药剂量;静脉滴注是达到和维持稳态浓度的最佳技术,达到稳态浓度的时间还取决于药物的消除速率。药物从肌肉、皮下注射部位吸收一般30min内达峰值,吸收速率取决于注射部位的血管分布状态。  相似文献   

7.
建立了猪、牛、羊、鸡、兔的肌肉、脂肪、肝脏和肾脏四种组织中环丙沙星、达氟沙星、恩诺沙星、沙拉沙星和二氟沙星残留量检测的高效液相色谱法。试样经磷酸盐溶液提取,C18固相萃取柱浓缩净化后,用高效液相色谱分析,荧光检测器检测,外标法定量。5种药物在0.1~100μg/L浓度范围内线性关系良好。环丙沙星、恩诺沙星、沙拉沙星和二氟沙星在五种动物肌肉、脂肪组织中的定量限为5μg/kg,在肝脏、肾脏组织中的定量限为10μg/kg;达氟沙星在肌肉、脂肪组织中的定量限为1μg/kg,在肝脏、肾脏组织中的定量限为2μg/kg。在指定的三个浓度添加水平下,5种药物在各组织中的平均回收率为62%~103%;批内变异系数为0.30%~18%,批间变异系数为1.0%~17%。该方法操作简单,准确度和精密度好,动物品种及动物组织覆盖范围广,可以很好地满足实际检测工作的需要。  相似文献   

8.
将14日龄艾维茵肉用雏鸡接种感染鸡慢性呼吸道病,然后用禽速康、甲磺酸达氟沙星、罗红霉素、酒石酸泰乐菌素进行混饮给药,比较其疗效.结果试验药物组与感染对照组差异极显著(P<0.01),试验药物对雏鸡慢性呼吸道病有良好的疗效;禽速康对雏鸡慢性呼吸道病的治疗效果与临床上常用的甲磺酸达氟沙星相当(P>0.05),比罗红霉素、酒石酸泰乐菌素要好(P<0.05),且不影响鸡只的正常增重.  相似文献   

9.
【目的】探究马兜铃酸Ⅰ(aristolochic acid Ⅰ,AA-Ⅰ)对大鼠五脏(心脏、肝脏、脾脏、肺脏和肾脏)的毒性及功能影响,为今后马兜铃属类中药临床用药提供参考。【方法】将SD大鼠随机分为AA-Ⅰ给药组和空白对照组,给药组按20 mg/kg灌服AA-Ⅰ,连续7 d。于给药后0.25、0.5、1、2、24 h及停药后15 d,采集大鼠五脏组织。利用HPLC法检测各个时间点五脏组织中的AA-Ⅰ及马兜铃内酰胺Ⅰ(aristolactams-Ⅰ,AL-Ⅰ)含量,并检测大鼠五脏主要生理功能及病理组织学变化。【结果】给药后0.25 h,AA-Ⅰ主要分布于心脏、肝脏、脾脏和肺脏,同时在肝脏和脾脏中检测到AL-Ⅰ;给药后0.5 h,AA-Ⅰ主要分布于心脏、肝脏、脾脏、肺脏和肾脏,除心脏外,其余四脏中AA-Ⅰ含量均达到高峰值,且在肝脏、肺脏、肾脏中检测到AL-Ⅰ;给药后1 h,AA-Ⅰ主要分布于肝脏和肺脏,且在肝脏中检测到AL-Ⅰ;给药后2 h,AA-Ⅰ主要分布于心脏、肝脏、肺脏和肾脏,且在肾脏中检测到AL-Ⅰ;给药后24 h,AA-Ⅰ主要分布于心脏和肝脏,且在肝脏中检测到AL-Ⅰ;停药后15 d,五脏中均未检测到AA-Ⅰ及AL-Ⅰ。功能检测结果显示,大鼠灌服AA-Ⅰ可引起五脏发生氧化应激损伤。【结论】连续7 d给大鼠灌服20 mg/kg AA-Ⅰ,在五脏中均可检测到不同含量的AA-Ⅰ,且在肝脏、肾脏、肺脏及脾脏中检测到AL-Ⅰ。AA-Ⅰ可对五脏造成不同程度的损伤,其损伤与氧化应激有关。  相似文献   

10.
肺靶向利福平脂质体在小鼠体内的分布及抑杀菌效果观察   总被引:4,自引:0,他引:4  
采用薄膜分散法结合冷冻溶融法制备利福平脂质体 (L ip- RFP) ,在脂质体水相层中包入不同单糖作为肺组织的导向分子 ,采用微生物测定法 ,通过测定小鼠肺组织中 RFP含量来确定肺靶向最佳单糖及其浓度 ,并进行组织分布的研究 ;通过体内细菌计数比较了含 5 % D-甘露糖的利福平脂质体 (L ip- RFP- Man)组与 L ip- RFP组对血液及肺组织中细菌的清除能力。结果表明 ,L ip- RFP最佳制备工艺为 :乳化温度 2 0℃ ,氯仿∶ PBS为 1∶ 5 ,药脂比为 1∶ 7,乳化速度4 0 0 r/ min,- 2 0℃冷冻过夜 ,室温融化 ,反复 2~ 3次 ;L ip- RFP- Man呈现最佳肺靶向作用 ;L ip- RFP与游离药物相比 ,对血液中细菌的清除能力明显增强 ,且维持时间延长 ,2 4 h游离组血液中细菌数为 6× 10 3个 / m L ,L ip- RFP组降为5 .2× 10 2 个 / m L;L ip- RFP- Man组与 L ip- RFP组相比 ,对肺组织中细菌的清除能力有显著性差异 (P<0 .0 5 ) ,前者优于后者 ;体内组织分布测定结果表明 ,各时间点的 RFP浓度均以肝脏为最高 ,但 L ip- RFP- Man组较 L ip- RFP组在肝脏中的药物浓度有所下降 ,二者的药物浓度变化有显著性差异 (P<0 .0 5 ) ,而 L ip- RFP- Man组较 L ip- RFP组在肺脏中的 RFP浓度有所上升 ,二者的药物浓度变化也有显著性差异 (P<0 .0  相似文献   

11.
Disposition kinetics of danofloxacin and ciprofloxacin in broiler chickens.   总被引:3,自引:0,他引:3  
Disposition kinetics of danofloxacin and ciprofloxacin were studied in broiler chickens following intravenous, intramuscular and oral administration in a single dose of 5 and 10 mg/kg-1 body weight respectively. In addition, tissue distribution and residual pattern of both drugs were determined. The maximum serum concentration (Cmax) after intramuscular and oral administration were 1.03 and 0.55 mu/ml for danofloxacin and 2.92 and 1.24 mu/ml for ciprofloxacin attained at 0.8 and 2.43 and 0.55 and 1.27 hours for danofloxacin and ciprofloxacin respectively. The volume of distribution and systemic bioavailability were higher for danofloxacin (Vdss 2.21 L/kg and F% 96.56 and 81.4%) as compared with ciprofloxacin (Vdss 1.41 L/kg and F% 75.5 and 29.4%). Data relating to intravenous injection for both drugs were analyzed using a two compartment open model curve fit. Danofloxacin and ciprofloxacin were not detected in the serum of broilers at the 5th and 3rd day respectively following the drugs withdrawal while were detected in liver, kidneys, spleen and lungs. Danofloxacin completely disappeared from all tissues at the 13th day after stopping of the drug medication but ciprofloxacin disappeared after 5 days only.  相似文献   

12.
1. The pharmacokinetic properties of doxycycline were determined in healthy chickens and chickens naturally infected with Mycoplasma gallisepticum after a single intravenous (i.v.) and oral administration of the drug at 20 mg/kg body weight. Tissue residues of the tested drug after an oral dose of 20 mg/kg given twice daily for 5 consecutive days were also estimated in diseased chickens. 2. The plasma concentrations of doxycycline following single i.v. and oral administration were higher in healthy chickens than in diseased ones. Following i.v. injection, the elimination half-life (t1/2beta), distribution half-life and mean residence time (MRT) were longer in healthy chickens than in diseased birds. The values of total body clearance (ClB) and volume of distribution (Vdss) were larger in healthy chickens than in diseased birds. 3. After single oral administration, the absorption half-life (tl/2ab) and the elimination half-life were longer in normal birds than in diseased ones. The maximum plasma concentration of the drug was higher in normal chickens than in diseased ones. 4. Following repeated oral administration, the concentration of doxycycline in all tissues except muscle was higher than the corresponding concentrations in plasma. Concentrations of doxycycline in different tissues were in the following order: kidney > liver > lung > muscle. The drug was detected in liver and kidney in substantial concentrations on d 5 post administration of the last dose whereas, on d 7, its concentration in all tissues was below the lower limit of the sensitivity of the assay method used. Because of the low sensitivity of the microbiological assay method used in this study, a safe withdrawal time for doxycycline in diseased birds could not be estimated for the meanwhile.  相似文献   

13.
In this study, a physiologically based pharmacokinetics (PBPK) model was firstly developed for danofloxacin in healthy broiler chickens after a single oral administration at 5 mg/kg bw. Then, the model extrapolation from healthy chickens to those infected with Pasteurella multocidaones was performed. The healthy model was validated through a comparison of predicted and previously published concentrations, which indicated that the healthy PBPK model had good predictive ability in plasma, lung, muscle, liver, and kidney, especially at the later sampling time points. Multiple dosing of administration was incorporated into the healthy and infected models. In addition, a Monte Carlo simulation (MCS) included 1000 iterations was further incorporated into both models to predict the withdrawal times of danofloxacin in healthy and infected chickens, which were estimated to be 3 and 2 days, respectively.  相似文献   

14.
The plasma pharmacokinetics of danofloxacin and enrofloxacin in broiler chickens was investigated following single intravenous (i.v.) or oral administration (p.o.) and the steady-state plasma and tissue concentrations of both drugs were investigated after continuous administration via the drinking water. The following dosages approved for the treatment of chickens were used: danofloxacin 5 mg/kg and enrofloxacin 10 mg/kg of body weight. Concentrations of danofloxacin and enrofloxacin including its metabolite ciprofloxacin were determined in plasma and eight tissues by specific and sensitive high performance liquid chromatography methods. Pharmacokinetic parameter values for both application routes calculated by noncompartmental methods were similar for danofloxacin compared to enrofloxacin with respect to elimination half-life (t1/2: approximately 6-7 h), mean residence time (MRT; 6-9 h) and mean absorption time (MAT; 1.44 vs. 1.20 h). However, values were twofold higher for body clearance (ClB; 24 vs. 10 mL/min. kg) and volume of distribution at steady state (VdSS; 10 vs. 4 L/kg). Maximum plasma concentration (Cmax) after oral administration was 0.5 and 1.9 micrograms/mL for danofloxacin and enrofloxacin, respectively, occurring at 1.5 h for both drugs. Bioavailability (F) was high: 99% for danofloxacin and 89% for enrofloxacin. Steady-state plasma concentrations (mean +/- SD) following administration via the drinking water were fourfold higher for enrofloxacin (0.52 +/- 0.16 microgram/mL) compared to danofloxacin (0.12 +/- 0.01 microgram/mL). The steady-state AUC0-24 h values of 12.48 and 2.88 micrograms.h/mL, respectively, derived from these plasma concentrations are comparable with corresponding area under the plasma concentration-time curve (AUC) values after single oral administration. For both drugs, tissue concentrations markedly exceeded plasma concentrations, e.g. in the target lung, tissue concentrations of 0.31 +/- 0.07 microgram/g for danofloxacin and 0.88 +/- 0.24 microgram/g for enrofloxacin were detected. Taking into account the similar in vitro activity of danofloxacin and enrofloxacin against important pathogens in chickens, a higher therapeutic efficacy of water medication for enrofloxacin compared to danofloxacin can be expected when given at the approved dosages.  相似文献   

15.
1. Disposition kinetics of doxycycline (doxy) was studied in healthy chickens and chickens experimentally intoxicated with aflatoxin B1 by intravenous, oral or intramuscular (i.m.) injection, in a single dose of 15 mg/kg body weight. In addition, the tissue distribution and residual pattern of the drug were determined in healthy and intoxicated chickens. 2. The maximum serum concentrations of doxy were reached 1.97 and 2.37 h after oral, and 1.57 and 2.92 h after i.m. dosage in healthy and aflatoxic birds, respectively. 3. The volumes of distribution and total body clearances were higher in aflatoxic birds (1.75 l/kg and 14.61 ml/kg/min) than in healthy chickens (0.93 l/kg and 4.6 ml/kg/min). Data relating to intravenous injection were analysed using a two-compartment open model curve fit. 4. Lower values of systemic bioavailability were observed in intoxicated birds (30.9 and 33.9%) than healthy ones (43.7 and 57.3%) after oral and i.m. administration, respectively. 5. The highest concentration of doxy residues were present in liver, kidney and serum followed by heart and muscles. Doxy residue concentrations in edible tissues was below the EEC limit 6 d after cessation of oral or i.m. medication with 15 mg/kg body weight twice daily for 5 successive days.  相似文献   

16.
The study was aimed to evaluate the pharmacokinetics and tissue distribution of forsythiaside liposome in chicks by intravenous administration. The pharmacokinetics of chicks with intravenous administration of forsythiaside liposome and forsythiaside solution 20 mg/kg was studied and the concentrations of forsythiaside in heart, liver, spleen, lung, kidney and plasma were determined by HPLC. The plasma concentration-time curves of forsythiaside liposome and forsythiaside solution were both fit to the two-compartment model and the pharmacokinetic parameters were (1.79±0.050) and (0.11±0.006) h for t1/2β, (39.95±2.32) and (4.26±0.39) (μg·h)/mL for AUC, (0.56±0.04) and (4.73±0.41) mg/(h·kg) for CLs. Compared with the liposome to the solution, the drug distribution in liver, spleen and lung were obviously elevated. Compared with forsythiaside solution, the forsythiaside liposome could significantly prolong the resident time of forsythiaside in the blood circulating system and could be concentrated at the target tissue rich in the reticuloendothelial system.  相似文献   

17.
Avian pathogenic Escherichia coli could cause localized and systemic infection in the poultry, and danofloxacin is usually used to treat avian colibacillosis through oral administration. To promote prudent use of danofloxacin and reduce the emergence of drug‐resistant E. coli strains, it is necessary to understand the population pharmacokinetics (PopPK) of danofloxacin in chicken intestines. In this study, reversed‐phase high performance liquid chromatography (HPLC) with fluorescence detection was used to detect the concentrations of danofloxacin in the contents of duodenum, jejunum, and ileum of the healthy and infected chickens after single oral administration (5 mg/kg body weight). Then, the PopPK of danofloxacin in intestines were analyzed using NONMEM software. As a result, a two‐compartment PK model best described the time‐concentration profile of duodenal, jejunal, and ileal contents. Interestingly, absorption rate (Ka), distribution volume (V), and clearance (CL) for danofloxacin from duodenal, jejunal to ileal contents were sequentially decreased in the healthy chickens. However, the trend of Ka, V, and CL of danofloxacin was changed dramatically in the intestine of infected chickens. Ka and V of danofloxacin in the jejunum were higher than in the ileum and duodenum. Compared with healthy chickens, Ka and V of danofloxacin in the duodenum decreased significantly, while increased in jejunum, respectively. It has been noted that Ka decreased and V increased in the ileum of infected chickens. Besides, CL in the duodenum, jejunum, and ileum of infected chickens was, respectively, lower than those of healthy chickens. Interestingly, the relative bioavailability (F) of danofloxacin in the ileum was relatively higher in both healthy and infected chickens. In addition, F in the duodenal, jejunal, and ileal contents of infected chickens was respectively higher than healthy chickens. In summary, the PopPK for danofloxacin in infected chicken intestines was quite different from healthy chickens. The absorption, distribution, and clearance of danofloxacin in healthy chickens decreased from duodenum to jejunum and to ileum. Moreover, the pharmacokinetic characteristics in the intestine of infected chickens changed significantly, and the pharmacokinetic characteristics in the ileum can be used as a representative of all intestinal segments.  相似文献   

18.
19.
This study investigated the disposition kinetics and plasma availability of erythromycin in broiler chickens after single intravenous (i.v.), intramuscular (i.m.), subcutaneous (s.c.) and oral administrations (p.o.) of 30 mg kg(-1) b. wt. Tissue residue profiles were also studied after multiple intramuscular, subcutaneous, and oral administration of 30 mg kg(-1) b. wt., twice daily for three consecutive days. Plasma and tissue concentrations of erythromycin were determined using microbiological assay methods with Micrococcus luteus as the test organism. Following intravenous injection, plasma concentration-vs-time curves were best described by a two compartment open model. The decline in plasma drug concentration was bi-exponential with half-lives of (t(1/2alpha)) 0.19 h and (t(1/2beta)) 5.3 h for distribution and elimination phases, respectively. After intramuscular, subcutaneous and oral administration erythromycin at the same dose was detected in plasma at 10 min and reached its minimum level 8 h post-administration. The peak plasma concentration (Cmax) were 5.0, 5.3, and 6.9 microg x ml(-1) and were attained at 1.7, 1.4, and 1.3 h (Tmax), respectively. The elimination half-lives (T(1/2el)) were 3.9, 2.6, and 4.1 h and the mean residence times (MRT) were 3.5, 3.2, and 3.6 h, respectively. The systemic bioavailabilities were 92.5, 68.8, and 109.3%, respectively. In vitro protein binding percent of erythromycin in broiler plasma was ranged from 21 to 31%. The limit of quantification (LOQ) for the assay was 0.03 microg x ml(-1) in plasma and tissues. The tissue level concentrations were highest in the liver, and decreased in the following order: plasma > kidney > lung > muscle and heart. No erythromycin residues were detected in tissues and plasma after 24 h except in liver and kidney where it persisted during 48 h following intramuscular and oral administrations.  相似文献   

20.
本研究利用PCR和免疫组化等方法,对FSHR和FSH基因在鸡多个非繁殖系统的组织器官中的mRNA和蛋白水平的表达以及相关性进行了分析.结果显示:在心脏、肝脏、肾脏、肺和十二指肠中FSHR mRNA和蛋白以及FSH蛋白水平具有相同的表达趋势,表达丰度从大到小依次为肝脏、心脏、肾脏、肺和十二指肠.而在脾脏、胃、腿肌和胸肌中未检测到FSHR mRNA和蛋白以及FSH蛋白水平的表达;在检测的9个组织中,均无FSHmRNA的表达.相关性分析结果表明,在肝脏、心脏、肾脏、肺和十二指肠中各组织器官质量与组织中的FSH蛋白水平具有显著或极显著的正相关(P<0.05或P<0.01);各组织中的FSHR mRNA和蛋白水平均与FSH蛋白水平存在显著或极显著正相关(P<0.05或P<0.01).本研究初步证明,机体其他部位表达分泌的促卵泡素,在多个非繁殖组织器官(肝脏、心脏、肾脏、肺和十二指肠)中通过调控促卵泡素受体基因的表达来影响北京油鸡不同组织的发育.  相似文献   

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