The dose regimen formulation of doxycycline hydrochloride and florfenicol injection based on ex vivo pharmacokinetic-pharmacodynamic modeling against the Actinobacillus pleuropneumoniae in pigs

Doxycycline hydrochloride and florfenicol combination(DoxHcl&FF)is an effective treatment for respiratory diseases.In the study,our objective Was to evaluate the activity of DoxHcl&FF against Actinobacillus pleuropneumoniae(APP)in porcine pulmonary epithelial lining fluid(PELF)and the optimal dosage scheme to avoid the development of resistance.The DoxHcl&FF Was administered intramuscularly(IM)at 20mg/kg,and the PELF was collected at differ-ent time points.The minimum inhibitory concentration(MIC)and time-mortality curves were also included in the study.Based on the sigmoid Emax equation and dose equations,the study integrated the in vivo pharmacokinetic data of infected pigs and ex vivo pharmacodynamic data to obtain the area under concentration time curve(AUCo-24h)MIC values in PELF and achieve bacteriostatic activity,bactericidal activity and the virtual eradication of bacteria.The study showed that the combination of DoxHcl and FF caused no significant changes in PK parameters.The peak concentration(Cmax)of FF in healthy and diseased pigs was 8.87±0.08 and 8.67±0.07μg/mL,the_AUCo-24h were.172.75±2.52 and 18022±3.13 h-μg/mL,the Cmax of DoxHcl was 7.91±0.09 and 7.99±0.05μg/mL,and the AUCo-24h was 129.96±3.70 h-μg/mL and 169.82±4.38 h-μg/mL.DoxHcl&FF showed strong concentra-tion-dependent tendencies.The bacteriostatic,bactericidal,and elimination activity were calculated as 5.61,18.83 and 32.68 h,and the doses were 1.37(bacteriostatic),4.59(bactericidal)and 7.99(elimination)mg/kg.These findings indicated that the calculated recommended dose could assist in achieving more precise administration,increasing the effectiveness of DoxHcl&FF treatment for APP infections.

氟甲砜霉素(Florfenicol)在猪体内的药物动力学

健康猪 6头 ,体重 ( 2 4 .7± 1 .0 ) kg,单剂量静注、肌注、内服氟甲砜霉素 ( Florfenicol) 2 0 mg/ kg,用高效液相色谱法测定其血药浓度 ,实验所得的血药浓度 -时间数据采用非房室模型统计矩原理分析处理。静注给药的主要药物动力学参数为 :AUC 90 .1 3mg/ ( L· h) ,MRT 6.84 h,Cl B0 .2 3L/ ( kg· h) ,Vd(SS) 1 .53L/ kg,t1 / 2β 6.72 h。肌注给药的主要药物动力学参数为 :AUC 84 .31 mg/ ( L· h) ,MRT 2 6.88h,t1 / 2β 1 7.1 8h,F96.86% ,校正 F* 4 2 .50 %。内服给药的主要药物动力学参数为 :AUC1 32 .0 8mg/ ( L· h) ,MRT1 4 .2 3h,t1 / 2β 9.98h,F 1 4 8.53% ,校正 F* 1 0 8.51 %。试验结果表明 ,氟甲砜霉素在猪体内的主要药动学特征为 :静注给药表观分布容积大 ,消除半衰期长 ,血药浓度高 ;肌注给药吸收不规则 ,吸收和消除缓慢 ;内服给药吸收迅速完全 。

氟甲砜霉素(florfenicol)对禽败血支原体病的药效学

以试管两倍稀释法测得体外氟甲砜霉素 (florfenicol)及对照药物恩诺沙星对禽败血支原体 (MG)的最小抑菌质量浓度分别为 1.2 5、0 .0 195 mg/ L。体内药效试验表明 ,氟甲砜霉素以 30 0、40 0、5 0 0 mg/ kg饲料混饲给药 ,连用 5 d,对实验性感染 MG的鸡具有显著的保护作用 ,与感染对照组的死亡率 (2 5 %)差异显著 (P<0 .0 1)。氟甲砜霉素及对照药物的增重效果显著高于感染对照组 (P<0 .0 1) ,中、高剂量组还能显著减少气囊损伤率 (P<0 .0 1) ,但氟甲砜霉素各用药组都不能减少抗体反应的阳性率。

Effects of florfenicol exposure on growth,development and antioxidant capacity of flounder Paralichthys olivaceus larvae at different developmental stages

Antibiotics are widespread in various environmental media,and may pose a potential threat to aquatic ecosystems and non-target aquatic organisms.Florfenicol(FLO)is one of the most commonly used antibiotics in aquaculture,and extensively used to substitute chloramphenicol with its strong sterilization and low adverse ef fect.In this study,flounder Paralichthys olivaceus,an important economic fish species in seawater was used as an experimental subject.Five exposure concentrations of FLO(including environmentrelated concentrations)were set at 0,0.01,0.1,1,and 10 mg/L.Ef fects of FLO exposure for 168 h on growth and development,motor behavior,antioxidant enzyme activity,malondialdehyde(MDA)content,and thyroid hormone level of P.olivaceus larvae were studied in pre-larvae(1 dpf)and post-larvae(20 dpf).The results show that the short-term FLO exposure could promote the larvae growth to some degrees,but inhibit them as the exposure time prolonged.For pre-larvae,FLO at 0.01 mg/L could stimulate the motor nerve system and increase the swimming ability,but inhibited it at 1 mg/L.With the increasing dosage of FLO,the superoxide dismutase(SOD)and MDA contents were elevated,reaching the maximum in the 1 mg/L FLO group.The pre-larvae were more sensitive than the post-larvae to FLO in the environment,and the growth and immune resistance could be damaged with long exposure.Post-larvae were more tolerant to external pollutants,FLO at 1 mg/L could promote the motor behavior and reduce SOD and MDA contents.Therefore,FLO can be used as an antibiotic at a proper concentration but as a drug to prevent disease in a long-term way.

E-beam degradation of thiamphenicol and florfenicol

Thiamphenicol(THA) and florfenicol(FLO) aqueous solutions were irradiated to different doses by 1 MeV electron beams,and redox reactions of THA/FLO and radicals of OH,e_(eq)^- and ~·H were investigated under various conditions.The results showed that at 8 kGy,the decomposition rate of THA and FLO was 97.2%and 98.5%, respectively.Quantitative and qualitative analysis indicated that OH played a key role in E-beam degradation of the THA and FLO in aqueous solutions,and e_(eq)^- and ~·H radicals could initiate the degradation,too.Seven primary products of the THA and FLO degradation were identified.These indicate that E-beam radiation is an effective method to reduce THA and FLO in aqueous solutions.

3D-printed MoS_(2)/Ni electrodes with excellent electro-catalytic performance and long-term stability for dechlorination of florfenicol

Here,we report the production of 3D-printed MoS_(2)/Ni electrodes(3D-MoS_(2)/Ni)with longterm stability and excellent performance by the selective laser melting(SLM)technique.As a cathode,the obtained 3D-MoS_(2)/Ni could maintain a degradation rate above 94.0%for forfenicol(FLO)when repeatedly used 50 times in water.We also found that the removal rate of FLO by 3D-MoS_(2)/Ni was about 12 times higher than that of 3D-printed pure Ni(3D-Ni),attributed to the improved accessibility of H^(*).In addition,the electrochemical characterization results showed that the electrochemically active surface area of the 3D-MoS_(2)/Ni electrode is about 3-fold higher than that of the 3D-Ni electrode while the electrical resistance is 4 times lower.Based on tert-butanol suppression,electron paramagnetic resonance and triple quadrupole mass spectrometer experiments,a“dual path”mechanism and possible degradation pathway for the dechlorination of FLO by 3D-MoS_(2)/Ni were proposed.Furthermore,we also investigated the impacts of the cathode potential and the initial pH of the solution on the degradation of FLO.Overall,this study reveals that the SLM 3D printing technique is a promising approach for the rapid fabrication of high-stability metal electrodes,which could have broad application in the control of water contaminants in the environmental field.

Enhanced degradation of florfenicol by microscale SiC/Fe:Dechlorination via hydrogenolysis

Herein,the degradation of florfenicol(FLO)over zero-valent iron(ZVI)enhanced by SiC was systematically investigated.It was found that 5 g/L of ZVI/SiC(1:3)at pH 3.0 could completely degrade 20 mg/L of FLO within 1 h,with a Kobsvalue of 0.0873 min^(-1),12.5 times greater than that of pure ZVI(0.0069 min^(-1)).Vibrating sample magnetometer(VSM)characterizations revealed that the use of SiC supporter reduces the magnetic intensity of ZVI,which mitigates iron particle agglomeration,increases Brunauer-Emmett-Teller(BET)surface area,and enhances FLO degradation efficiency.Furthermore,ZVI/SiC exhibits a much lower hydrogen evolution potential(HEP)and significantly higher corrosion currents compared to pure ZVI.FLO was proposed to undergo degradation via reductive dechlorination,involving a hydrogenolysis mechanism that entails the cleavage of theσbond.This study provides new insights into the reduction hydrogenation mechanism of ZVI.

氟苯尼考在泰和乌鸡可食性组织中残留消除规律研究

为研究氟苯尼考可溶性粉在泰和乌鸡体内可食性组织的残留变化规律,试验选择64只110日龄健康泰和乌鸡(公母各半),按推荐剂量0.5 g可溶性氟苯尼考粉/L饮用水连续给药5 d。在停药后第0.16、1、3、5、7、9、12、15天随机屠宰4只公鸡和4只母鸡,分别采集肌肉、肝脏、肾脏、皮脂样本,采用超高效液相色谱-串联质谱联用法测定组织中氟苯尼考和氟苯尼考胺残留量,并利用WT1.4软件计算氟苯尼考在泰和乌鸡体内的休药期。结果显示,氟苯尼考和氟苯尼考胺在泰和乌鸡肌肉、肝脏、肾脏组织内残留消除较为迅速,而在皮脂组织消除相对缓慢;氟苯尼考可溶性粉在泰和乌鸡肌肉、肝脏、肾脏、皮脂中的休药时间分别为4.36 d、0.00 d、0.00 d、9.81 d。研究表明,为保证泰和乌鸡产品质量安全,氟苯尼考在泰和乌鸡体内的推荐休药期应大于10 d。

氟苯尼考残留对海洋小球藻生长及抗氧化系统的影响

随着水产养殖业的集约化发展,养殖尾水中抗生素残留可能对水生生态系统造成严重威胁,已引起全球性的关注。笔者以水产养殖中常用的饵料微藻——海洋小球藻为研究对象,探究氟苯尼考对其可能的作用效应。分析不同质量浓度氟苯尼考暴露72 h后,海洋小球藻细胞生长、色素含量、活性氧含量、丙二醛及抗氧化酶活性的响应变化。试验结果显示,海洋小球藻在氟苯尼考暴露72 h后藻细胞表现出“低促高抑”现象,藻细胞的叶绿素含量随氟苯尼考质量浓度增加呈倒“U”型趋势,0.100 mg/L组叶绿素含量最高,与对照组相比提高了74.6%;氟苯尼考胁迫会对微藻细胞膜产生氧化损伤,20 mg/L氟苯尼考暴露导致藻细胞丙二醛含量升高,是对照组的2.45倍,诱导合成类胡萝卜素,参与抵抗氧化损伤。试验质量浓度下,谷胱甘肽、超氧化物歧化酶、过氧化氢酶活性受到显著抑制作用。与球等鞭金藻相比,海洋小球藻对氟苯尼考表现出较高的耐受性。本试验结果可为养殖尾水中抗生素残留的处理提供理论依据。

畜禽组织中甲氧苄啶和氟苯尼考的同时免疫层析检测方法研究

针对动物源性食品中甲氧苄啶(TMP)和氟苯尼考(FF)复配使用残留的问题,以乳胶微球作为示踪信号探针,建立了同时检测鸡肉和猪肉样品中甲氧苄啶和氟苯尼考的乳胶微球侧流免疫层析方法(LMs-LFIA)。基于特异性单克隆抗体7E6和SF15,通过逐步优化策略考察了探针制备条件、试纸条工作缓冲液以及样品垫处理液缓冲体系等对LMs-LFIA性能的影响。结果表明:在优化条件下,所建立的LMs-LFIA对鸡肉和猪肉样品中甲氧苄啶和氟苯尼考的可视化检出限分别为8 ng/g和12 ng/g,检测时间为8 min,且与甲氧苄啶和氟苯尼考的结构及功能类似物无明显交叉反应,方法特异性良好。所建方法对鸡、猪肉盲样的检测结果与超高效液相色谱-串联质谱(UPLC-MS/MS)仪器确证方法一致,适用于畜禽组织样本中甲氧苄啶和氟苯尼考残留的同时检测。

基于G-四链体/硫黄素T无标记荧光适配体传感器快速检测氟苯尼考

硫黄素T(ThT)通过非共价相互作用与G-四链体结合,形成G-四链体/ThT复合物,呈现出较强荧光强度,而游离ThT荧光十分微弱。当存在氟苯尼考(FF)时,具有G-四链体结构的适配体(Apt)对靶标的高亲和力,使得Apt/FF复合物形成并释放ThT,荧光强度降低。基于这一特点,本研究设计一种灵敏快速的现场检测体系,用于检测氟苯尼考,即基于G-四链体/硫黄素T的无标记荧光适配体传感器。该适配体传感器的检测范围为0.0128~200 ng/mL,实际检出限0.0128 ng/mL,检测总时长10 min。同时,对实际加标样品(牛奶和鸡蛋)进行回收率计算,加标回收率在91.2%~117.1%之间。所建立的无标记荧光适配体传感器具有高特异性、成本低、耗时短等优点,可用于实际样品的现场检测。

流动注射-鲁米诺-KMnO_(4)化学发光抑制法测定鸡蛋中氟苯尼考残留含量

在碱性条件下,基于氟苯尼考会抑制鲁米诺-KMnO4化学发光,并且随着氟苯尼考浓度的增加,其抑制化学发光强度随之增强,从而建立流动注射-鲁米诺-KMnO4化学发光体系检测氟苯尼考的方法。分别探讨试剂用量、蠕动泵流速等参数条件对该发光强度的影响。优化条件下,在1.0×10^(-6)℃~1.0×10^(-4)g·mL^(-1)质量浓度范围内,氟苯尼考质量浓度与相对化学发光强度呈良好的线性关系,方法检出限(3σ)3.0×10^(-7)g·mL^(-1);对质量浓度8.0×10^(-5)g·mL^(-1)的氟苯尼考平行测定11次,RSD为4.88%。结果表明,建立的流动注射-化学发光分析方法简单快速,并将该方法应用于动物源性食品鸡蛋样中兽药氟苯尼考残留的分析,方法灵敏、准确、可靠,结果令人满意。

氟苯尼考/二甲基-β-环糊精包合物的制备及评价

目的 以2,6-二甲基-β-环糊精(DM-β-CD)为包合材料制备氟苯尼考(florfenicol,FF)包合物FF/DM-β-CD,以改善FF的溶解度和溶出速度,提高其生物利用度。方法 在应用分子对接结合相溶解度法筛选合适的环糊精(CD)后,采用加热搅拌法制备FF/DM-β-CD,并使用DSC、PXRD、FT-IR对包合物进行物相鉴别,对其溶解性、溶液稳定性和体外溶出进行考察,同时进行了FF/DM-β-CD在鸡体内的药动学研究。结果 FF与HP-β-CD、DM-β-CD和SBE-β-CD对接后的模型较稳定,DM-β-CD改善FF溶解度的效果最好。选择DM-β-CD作为包合材料,加热搅拌法制备了FF/DM-β-CD,DSC、PXRD和FT-IR结果证实FF/DM-β-CD的形成。FF/DM-β-CD可显著增加FF的溶解度,在标准硬水、自来水、去离子水和纯化水中的溶解度均大于FF的55.0倍。FF/DM-β-CD溶液在25℃放置1 d后,自来水中无析出,标准硬水、纯化水和去离子水中有微量析出;随着时间增加,析出逐渐增多,7 d后,以自来水中析出最少;FF含量无明显变化。FF/DM-β-CD在不同水质水中的溶出无明显差异,25℃、5 min时均已完全溶出,为FF原料药的17.09倍。与FF相比,FF/DM-β-CD能明显提高FF在鸡体内的生物利用度(Fr=165.24%)。结论 以DM-β-CD为包合材料制备FF/DM-β-CD,可显著提高FF的溶解度、溶出度和生物利用度。

QuEChERS-超高效液相色谱-串联三重四极杆质谱联用法快速测定羊肉中氯霉素、甲砜霉素、氟苯尼考的残留量

目的建立QuEChERS-超高效液相色谱-串联三重四极杆质谱法测定羊肉中氯霉素、甲砜霉素、氟苯尼考残留量的分析方法。方法样品经研磨机匀浆后用乙腈提取,提取液经QuEChERS-1010,QuEChERS-0101净化,采用电喷雾负离子扫描,多反应监测模式,内标法定量。结果氯霉素、甲砜霉素、氟苯尼考在4~50μg/L范围内具有良好的线性关系,相关系数均大于0.998,3种药物在5.0,10.0,30.0μg/kg浓度水平加标回收率在93.17%~109.91%范围内,相对标准偏差(RSD)为2.33%~6.14%。方法的检出限为0.01~0.03μg/kg,定量限为0.02~0.09μg/kg。结论该方法具有操作简单,准确度和灵敏度高等特点,满足测定羊肉中氯霉素、甲砜霉素、氟苯尼考残留量的检测要求。

CoFe_(2)O_(4)nanoparticles anchored on waste eggshell for catalytic oxidation of florfenicol via activating peroxymonosulfate

Eggshell-loaded CoFe_(2)O_(4) catalyst was synthesized via a convenient hydrothermal method during our work,then the surface morphology and elemental composition of the composites were systematically investigated.Performance of CoFe_(2)O_(4)/eggshell-activated peroxymonosulfate(PMS)system was evaluated by selecting florfenicol(FF)as the model pollutant,and effects of operating parameters and water matrices on the FF removal efficiency in this system were investigated.In addition,main radicals involved in FF degradation were identified by EPR tests and radical quenching experiments,and possible mechanism was proposed.The reduction of toxicity during FF degradation was confirmed,and in combination with HP-LC tests,it was found that dehalogenation and defluorination were effectively carried out during FF degradation.In addition,the prepared CoFe_(2)O_(4)polyvinylidene fluoride(PVDF)membrane effectively improved the stability of the material and reduced the precipitation of metals.

二硫化钼负载泡沫镍铁电极降解水中氟苯尼考的研究

以二硫化钼(MoS_(2))为载体,通过水热法负载泡沫镍铁制备MoS_(2)负载泡沫镍铁电极(MoS_(2)@Ni-Fe-Foam)并用于降解水中的氟苯尼考(FLO)。利用X-射线衍射仪(XRD)、扫描电子显微镜(SEM)和X-射线光电子能谱仪(XPS)对电极的表面形貌和元素分布进行表征,采用循环伏安法和电化学阻抗谱对其电化学性能进行表征,通过电子顺磁共振检测(EPR)、高效液相色谱-三重四极杆质谱仪、离子色谱及电化学检测研究了不同条件对FLO降解效果的影响,并对降解产物和降解机理进行了分析。结果表明,当FLO质量浓度为25 mg/L、电流密度为30 mA/cm^(2)、初始pH为3、Na_(2)SO_(4)浓度为30 mmol/L时对FLO的降解速率最快,降解率达到96%。自由基淬灭实验表明,·O_(2)^(-)在降解过程中发挥主要作用,其次是^(1)O_(2),而·OH的影响较弱。最后,通过三重四极杆质谱仪分析得到4种FLO降解产物,并提出FLO的降解机理。

氟苯尼考原料药及制剂在大鼠体内的药代动力学及绝对生物利用度研究

对氟苯尼考制剂不同给药方式在大鼠体内的药动学特征和体内生物利用度进行了研究,以评价β-环糊精包合工艺对氟苯尼考体内生物利用度的影响。选取15只健康大鼠平行随机分为3组,分别静脉注射氟苯尼考原药,口服灌胃氟苯尼考物理混合物,口服灌胃包合工艺氟苯尼考粉,采用高效液相色谱法测定大鼠血浆中氟苯尼考的浓度,利用药代动力学软件PKSovler软件中非房室统计矩分析模型,计算药动学参数并进行药动学数据分析。结果显示,静脉注射组药物消除为半衰期(t_(1/2))为(367.04±159.85)min、平均药时曲线下面积AUC_(0-)为6622.16±927.55。包合工艺氟苯尼考组达峰时间(T max)为(40.00±14.14)min、达峰浓度(C_(max))为(28.82±4.00)μg/mL、半衰期(t_(1/2))为(378.40±226.34)min,平均药时曲线下面积AUC_(0-)为5627.60±1442.41。物理混合物组达峰时间(T max)为(68.00±30.33)min、达峰浓度(C_(max))为(15.64±4.40)μg/mL、半衰期(t_(1/2))为(288.29±52.25)时曲线下面积AUC_(0-)为4543.56±761.34。氟苯尼考粉物理混合组体内绝对生物利用度为68.6%,包合工艺氟苯尼考组在体内绝对生物利用度为85.0%。综上可判定包合工艺法氟苯尼考组能显著提高氟苯尼考达峰浓度和氟苯尼考体内吸收程度,生物利用度高。

气相色谱法测定氟苯尼考中二乙胺和三乙胺残留

建立气相色谱法测定氟苯尼考中二乙胺和三乙胺残留的方法。采用Inert Cap for Amines毛细管胺类测试柱,经惰性处理的衬管,载气为氮气,流速3.0 mL/min,分流比为5∶1,检测器为FID。结果表明:该方法中二乙胺、三乙胺与其相邻峰完全分离;对照峰面积RSD均小于2%;二乙胺的检测限浓度为1.84μg/mL,定量限浓度为3.67μg/mL,在3.67~13.76μg/mL浓度范围内线性相关系数r为0.995 9;三乙胺的检测限浓度为0.50μg/mL,定量限浓度为1.50μg/mL,在1.50~374.63μg/mL浓度范围内线性相关系数r为0.998 6;二乙胺的回收率90.7%~103.0%,三乙胺的回收率90.8%~97.3%;小幅改变色谱条件,耐用性良好。方法操作简单、准确度高、重复性好,适用于氟苯尼考中二乙胺、三乙胺残留的测定。

氟苯尼考可溶性粉含量测定的不确定度分析

为分析评定氟苯尼考可溶性粉含量测定的不确定度,通过高效液相色谱(HPLC)法进行测定,选用C_(18)色谱柱,乙腈-水-冰醋酸(100∶197∶3)为流动相,224 nm波长下检测,并建立HPLC法测定氟苯尼考可溶性粉含量的数学模型。分析各因素引入的标准不确定度,评定置信概率95%时测定结果的扩展不确定度,给出不确定度评定报告。测定结果表明,含量测定的不确定度主要源于称量、溶液配制及峰面积测定过程。含量测定的标准不确定度为1.16%,扩展不确定度为2.32%。含量测定结果表示为(97.3±2.32)%,包含因子k=2。该方法适用于HPLC法测定氟苯尼考可溶性粉含量的不确定度评定,可为氟苯尼考可溶性粉的质量控制和客观评价提供参考。