兽用广谱抗菌药物氟甲砜霉素

兽用广谱抗菌药物氟甲砜霉素邱银生，吴佳（湖北省医药工业研究所武汉，４３００６１）氟甲砜霉素（Ｆｌｏｒｆｅｎｉｃｏｌ）系新型氯霉素类广谱抗菌药物，由美国先灵－保雅（Ｓｃｈｅｒｉｎｇ－Ｐｌｏｕｇｈ）公司研制，用于鱼类及牛、猪细菌性疾病的治疗，于１９９０年...     

不同温度下甲砜霉素在鲫体内的药物动力学及残留研究

本文对鲫以15 mg/kg·bw的剂量单次口灌甲砜霉素进行药物动力学参数模拟研究,以15 mg/kg·bw的剂量连续口灌给药3 d进行药物残留研究。结果表明甲砜霉素的药—时曲线均较符合有吸收一室开放模型,10℃水温条件下甲砜霉素在鲫体内的主要药物动力学参数为:吸收半衰期(t1/2ka)4.63 h;峰浓度(Cmax)5.71μg/m L;达峰时间(Tmax)10.94 h;消除半衰期(t1/2β)13.68 h;表观分布容积(Vd/F)1.53 L/kg;清除率(CLb)0.08 L/(h·kg);药时曲线下面积(AUC)195.99μg·h/m L。25℃水温条件下甲砜霉素在鲫体内的药物动力学参数为:吸收半衰期(t1/2ka)2.72 h;峰浓度(Cmax)5.60μg/m L;达峰时间(Tmax)6.98 h;消除半衰期(t1/2β)9.87 h;表观分布容积(Vd/F)1.6 4L/kg;清除率(CLb)0.12 L/(h·kg);药时曲线下面积(AUC)130.16μg·h/m L。不同水温条件下甲砜霉素在鲫鱼各组织中的代谢明显不同,表现为水温升高甲砜霉素消除则加快,水温降低甲砜霉素消除则变慢。结果还显示在两个温度下,甲砜霉素在鲫鱼主要组织中消除均较慢,在给药72h后,仍可在在皮肤、肌肉、肾脏组织中检测到甲砜霉素。同时,皮肤中的药物代谢速率相对于其他组织较慢,因此,建议把皮肤作为甲砜霉素药物残留的靶组织。若以15 mg/kg·bw的剂量连续口灌给药甲砜霉素后,建议甲砜霉素在鲫鱼体内的休药期定为:在10℃至少为10d,在25℃至少为6 d。     

鸡肉中甲砜霉素和氟甲砜霉素残留的高效液相色谱法检测

试验将鸡肉样品制成匀浆,用乙酸乙酯提取,正己烷去脂后用乙酸乙酯反萃取,经固相萃取柱(SPE)净化,甲醇洗脱,采用HPLC进行检测。甲砜霉素和氟甲砜霉素在同时检测时的保留时间分别为7.30min和17.60min,测得甲砜霉素与氟甲砜霉素的检测限达10ng/g。在添加浓度为0.005～0.02mg/kg时,平均回收率在65.84%～81.18%之间,相对标准偏差(RSD)在5.6%～13.2%之间(n=5);甲砜霉素、氟甲砜霉素在0.01～1.0mg/L范围内有良好的线性关系。     

液相色谱-荧光检测法检测水产品中甲砜霉素、氟甲砜霉素及代谢物氟甲砜霉素胺残留

建立了以带荧光检测器的液相色谱检测水产品中甲砜霉素、氟甲砜霉素与氟甲砜霉素胺残留的新方法.采用碱性乙酸乙酯-乙腈提取试样中残留的化合物,凝胶渗透色谱(GPC)净化,荧光检测器的激发与发射波长分别为225 nm与295 nm,可疑样品以液相色谱-质谱/质谱进行确证.在添加浓度为0.050～2.0 mg/kg时,平均回收率在86.4%～96.8%之间,相对标准偏差(RSD)在5.63%～9.71%之间(n=5);甲砜霉素、氟甲砜霉素在0.20～5.0 mg/L范围内、氟甲砜霉素胺在0.10～5.0 mg/L范围内有良好的线性关系,甲砜霉素与氟甲砜霉素的检测限达0.020mg/kg、氟甲砜霉素胺的检测限达0.010 mg/kg.     

甲砜霉素在感染多杀性巴氏杆菌鸡体内的药物动力学

30只健康杂交肉鸡随机分成3组,每组10只,雌雄各半,分别进行健康鸡静脉注射、健康和巴氏杆菌感染鸡口服给药的药动学研究。静注和口服的给药剂量按体质量分别为15mg/kg和30mg/kg。以反相HPLC测定血浆中甲砜霉素的质量浓度,药物浓度-时间数据用3P97药动学程序软件处理。健康鸡单剂量静注给药后,血药浓度-时间数据符合无吸收二室开放模型,其主要动力学参数分别为:V(c)为(0.58±0.09)L/kg,t1/2α(0.11±0.03)h,t1/2β(0.95±0.18)h,AUC为(11.99±0.90)mg/(L.h),CL(s)为(1.26±0.10)L/(kg.h)。健康鸡和巴氏杆菌感染鸡单剂量口服给药血药浓度-时间数据均符合一级吸收一室开放模型。健康鸡口服给药的主要动力学参数分别为:Lagtime(0.04±0.02)h,t1/2ka(0.16±0.08)h,t1/2ke(1.64±0.22)h,T(peak)(0.57±0.18)h,C(max)(6.34±0.56)mg/L,AUC为(19.02±1.48)mg/(L.h),F为79.32%。巴氏杆菌感染鸡口服给药的主要动力学参数分别为:Lagtime(0.07±0.02)h,t1/2ka(0.54±0.26)h,t1/2ke(1.74±0.27)h,T(peak)(1.31±0.39)h,C(max)(5.28±0.73)mg/L,AUC为(21.75±1.03)mg/(L.h),F90.70%。与健康鸡相比,甲砜霉素在感染鸡的t1/2(ka)、T(peak)和Lag-time显著延长(P0.05或P0.01),且比健康鸡具有更高的生物利用度。但甲砜霉素在巴氏杆菌感染鸡体内的消除速度未受影响。     

氟甲砜霉素与氯霉素抗菌作用比较

采用试管2倍稀释法,测定了氟甲砜霉素和氯霉素对鸡白痢沙门氏菌、禽巴氏杆菌、猪链球菌、禽大肠杆菌、金黄色葡萄球菌、鸭疫李氏杆菌等6种畜禽常见病原菌的最小抑菌浓度(MIC)。结果表明,氟甲砜霉素对受试菌的抗菌作用与氯霉素基本一致。     

氟甲砜霉素对鸭大肠杆菌病的药效研究

为了探讨氟甲砜霉素对鸭大肠杆菌病的疗效进行了本研究。用试管2倍稀释法测定氟甲砜霉素及对照药氯霉素对大肠杆菌的最小抑菌浓度，然后用氟甲砜霉素，氯霉素进行混饲给药5d的疗效试验，试验结果表明，氟甲砜霉素，氯霉素对大肠杆菌O78株的最小抑菌浓度分别为6mg/L,8mg/L,100,200,400mg/kg氟甲砜霉素混饲给药对鸭大肠杆菌病的有效率分别为30．3％，93．9％，100％,400mg/kg氯霉素的有效率为93．9％，试验各组之间鸭的增重差异不显著。     

氟甲砜霉素对实验性鸡巴氏杆菌病的药效研究

以两倍稀释法测定氟甲砜霉素及甲砜霉素对鸡巴氏杆菌的最小抑菌浓度分别为０．２５μｇ／ｍＬ和１．２５μｇ／ｍＬ。按１０,２０和３０ｍｇ／ｋｇ的氟甲砜霉素及３０ｍｇ／ｋｇ的甲砜霉素分别给实验性巴氏杆菌病患鸡肌注,每天给药一次,共５ｄ。药物对鸡巴氏杆菌病的治愈率分别为９３．３％,１００％,１００％和１００％,而感染对照组鸡全部死亡。用药组与感染对照组间疗效差异极显著     

氯霉素的替代物—氟甲砜霉素

氟甲砜霉素是一种新型化学合成氯霉素类抗菌药，是目前氯霉素很好的替代物，具有抗菌广谱、使用安全、高效、耐药性低等特点，用于畜禽、水产动物等的细菌性疾病，也可作为饲料添加剂使用。     

氟甲砜霉素对鸡大肠杆菌的疗效研究

鸡大肠杆菌病逐年来受到兽医工作者和养殖户的高度关注,被认为是近年来危害集约化养鸡场的重要鸡病.全国每年因大肠杆菌病造成的鸡只死亡高达40％以上.据研究表明大多数抗菌药物对大肠杆菌病都有效,但容易产生耐药性,即使相同成分的药物,因用量不同,效果也各不相同.为此,评价氟甲砜霉素[1]对大肠杆菌病的疗效,采用饮水给药方式进行防治.     

氟苯尼考磺酸盐在肉鸡体内的药物动力学初步研究

研究氟苯尼考磺酸盐在肉鸡体内的血药浓度及药动学特征。将12只健康三黄肉鸡,单次肌肉注射推荐治疗剂量（20mg／kg）的自制2％氟苯尼考磺酸盐。采用高效液相色谱法测定血浆药物浓度,所得数据用3P97药动软件进行分析后发现,血药浓度和时间关系符合一级吸收一室模型,选择的权重为1／C。主要药动学参数为T1／2kα：（0．28±0．04）h,T1/2Ke：（2．06±0．06）h,Cmax：（4．17±0．12）μg／mL,Tmax：（0．92±0．09）h,AUC：（16．89±0,35）μg／mL,V／F（c）：（3．52±0．13）L／kg,CL／F（s）：（1．19±0．03）L／（kg·h）,Ke：（0．34±0．01）／h,kα：（2．57±0．37）／h,A：（6．56±0．38）μg／mL。结果提示,氟苯尼考磺酸盐在肉鸡体内具有吸收迅速,分布广泛、峰浓度较高以及消除较快的动力学特征。     

Pharmacokinetics of florfenicol and thiamphenicol in ducks

The pharmacokinetics of florfenicol (FF) and thiamphenicol (TP) after single intravenous (IV) and oral (PO) administration was investigated in Mulard ducks. Both antibiotics were administered at a dose of 30 mg/kg body weight, and their concentrations in plasma samples were assayed using high‐performance liquid chromatography with ultraviolet detection. Pharmacokinetic parameters were calculated using a noncompartmental method. After IV administration, significant differences were found for the mean residence time (2.25 ± 0.21 hr vs. 2.83 ± 0.50 hr for FF and TP, respectively) and the general half‐life (1.56 ± 0.15 hr vs. 1.96 ± 0.35 hr for FF and TP, respectively) indicating slightly slower elimination of TP as compared to FF. The clearance, however, was comparable (0.30 ± 0.07 L/hr/kg for FF and 0.26 ± 0.04 L/hr/kg for TP). The mean volume of distribution was below 0.7 L/kg for both drugs. Pharmacokinetics after PO administration was very similar for FF and TP suggesting minor clinical importance of the differences found in the IV study. Both antimicrobials showed rapid absorption and bioavailability of more than 70% indicating that PO route should be an efficient method of FF and TP administration to ducks under field conditions.     

氟苯尼考纳米晶在鸡体内的药动学

氟苯尼考(florfenicol, FFC)是新型动物广谱抗菌剂,抗菌效果好,广泛应用于牛、羊、猪、水产及禽类等动物细菌性疾病的防制。本试验旨在研究FFC和氟苯尼考纳米晶(florfenicol nanocrystal, FFC-NC)在鸡体内的生物利用度。采用交叉试验法,鸡用药后,在不同时间点翅下静脉采血,利用高效液相色谱法(high performance liquid chromatography, HPLC)测定血浆中FFC含量。结果显示,此试验所建立的HPLC色谱图基线平稳,血浆峰与FFC峰完全分离。回收率和精密度均符合测定要求,重复性好,适用于鸡血浆FFC含量测定。药动学参数结果显示,与FFC组相比,FFC-NC组的达峰时间t_max为(0.875±0.137) h,峰时缩短,药时曲线下面积AUC₍(0-∞))和峰浓度C_max分别为(23.957±2.338) mg/(L·h)和(8.249±0.713) mg/L,FFC-NC组的相对生物利用度是FFC组的3.6倍。结果表明,FFC-NC的药动学特征较FFC均...     

Pharmacokinetics of florfenicol and its metabolite florfenicol amine in crucian carp (Carassius auratus) at three temperatures after one single intramuscular injection

The pharmacokinetic profiles of florfenicol (FF) or florfenicol amine (FFA) in crucian carp were compared at different water temperatures after single intramuscular administration of FF at 10 mg/kg bodyweight. The concentrations of FF and FFA were determined by a high‐performance liquid chromatography method, and then, the concentration versus time data were subjected to compartmental analysis using a one‐compartment open model. At the water temperatures of 10, 20, and 25°C, the peak concentrations (C_maxs) of FF were 2.28, 2.29, and 2.34 μg/ml, respectively, while those of FFA were 0.42, 0.71, and 0.82 μg/ml, respectively. And the absorption half‐life (t_1/2ka) of FF was 0.21, 0.19, and 0.21 hr, while the elimination half‐life (t_1/2kel) was 31.66, 24.77, and 21.48 hr, respectively. For FFA, the formation half‐life (t_1/2kf) was 3.85, 8.97, and 12.43 hr, while the t_1/2kel was 58.34, 30.27, and 21.22 hr, respectively. The results presented here demonstrated that the water temperature had effects on the elimination of both FF and FFA and the formation of FFA. Based on the T > MIC values calculated here, to treat the infections of bacterial with MIC value ≤ 0.5 μg/ml, FF intramuscularly given at 10 mg/kg bodyweight with a 72‐hr interval is sufficient at the water temperature of 10°C, while the intervals of 60 and 48 hr were needed at 20 and 25°C, respectively. But to treat bacterial with higher MIC values, more FF or FF at 10 mg/kg BW but with shorter intervals should be intramuscularly given to the infected fish.     

Pharmacokinetics of florfenicol in the plasma of Japanese quail

Abstract

AIM: To determine the pharmacokinetics and bioavailability of florfenicol in the plasma of healthy Japanese quail (Coturnix japonica).

METHODS: Sixty-five quail were given an I/V and I/M dose of florfenicol at 30 mg/kg bodyweight (BW). A two-period sequential design was used, with a wash-out period of 2 weeks between the different routes of administration. Concentrations of florfenicol in plasma were determined using high-performance liquid chromatography (HPLC).

RESULTS: A naíve pooled data analysis approach for the plasma concentration-time profile of florfenicol was found to fit a non-compartmental open model. After I/V administration, the mean residence time (MRT), mean volume of distribution at steady state (V_ss), and total body clearance of florfenicol were 12.0 (SD 0.37) h, 8.7 (SD 0.22) L/kg, and 1.3 (SD 0.08) L/h/kg, respectively. After I/M injection, the MRT, mean absorption time (MAT), and bioavailability were 12.3 (SD 0.37) h, 0.2 (SD 0.02) h, and 79.1 (SD 1.79)%, respectively.

CONCLUSIONS: The time for the concentration of florfenicol to fall below the probable effective concentration of 1 µg/ml of approximately 10 h is sufficient for the minimum inhibitory concentration needed for many bacterial isolates. Further pharm acodynamic studies in quail are needed to evaluate a suitable dosage regimen.     

氟苯尼考在红笛鲷体内的药代动力学研究

为研究氟苯尼考在红笛鲷体内的药代动力学特征,在水温(20±2)℃条件下,氟苯尼考以10 mg/kg单剂量腹注和口灌健康红笛鲷(Lutjanus sanguineus),采用HPLC-MS/MS测定组织中的药物浓度,数据用DAS3.0软件分析。结果显示,两种给药方式下红笛鲷血浆药时数据均符合一级吸收二室模型;腹注给药后血浆、肝脏、肾脏和肌肉的峰浓度(C_(max))分别为10.62μg/m L、8.36、22.57和4.76μg/g,达峰时间(T_(max))分别为1.2、1.0、1.0和6.0 h,消除半衰期(t_(1/2β))分别为29.76、17.84、17.23和19.48 h;口灌给药后血浆、肝脏、肾脏和肌肉的C_(max)分别为2.35μg/m L、1.45μg/g、4.06μg/g和1.73μg/g,T_(max)分别为2.69、1.5、1.5和4.0 h,t_(1/2β)分别为40.59、12.29、37.78和47.34 h。结果表明,腹注给药方式下氟苯尼考在红笛鲷体内的吸收快于口灌给药,在血浆和肝脏中的消除快于口灌给药,在肌肉和肾脏中的消除则慢于口灌给药。研究结果为氟苯尼考在临床上的合理应用提供了科学依据。     

不同剂量氟苯尼考对猪血液生化指标及猪瘟抗体的影响

40头70日龄健康猪随机分为高、中、低剂量组和对照组,每组10头,各试验组注射猪瘟弱毒疫苗(2头份/猪),同时高、中、低剂量组分别按每千克体质量于饲料中加入120、60、30 mg氟苯尼考,连续给药7 d,停药后1、8、15、22、29 d,对相关的血液生化指标以及猪瘟抗体水平进行检测分析.结果表明,停药后1、8 d,所有氟苯尼考添加组的猪瘟抗体滴度下降,仅120 mg/kg组差异显著(P<0.05),停药15 d后抗体水平恢复至正常水平;60和120mg/kg给药组TP含量在停药后1、8 d均显著下降(P<0.05);所有给药组的ALT活性在所有检测时间内均显著上升(P<0.05或P<0.01);所有给药组的γGT活性在停药后1 d均显著上升(P<0.05),而60和120 mg/kg组γGT在第8天仍显著上升(P<0.05);所有给药组的BUN含量在停药后1 d均显著升高(P<0.05或P<0.01);AST、LDH、CHE活性和ALB、CRE含量与对照组相比无显著差异(P>0.05);表明每千克体质量60 mg以上氟苯尼考在饲料中饲喂7 d后,对部分生化指标有一定的影响,应引起重视.     

氟苯尼考在猪的群体药动学

收集临床消化道和呼吸道细菌性疾病猪 2 15头 ,其中原种猪 91头 ,杂交商品猪 12 4头 ;公猪 112头 ,母猪 10 3头 ;体重范围 5～ 4 1kg,平均为 18.6 8± 0 .4 7;日龄 6 3～ 117天 ,平均为 85 .2 4± 0 .78。动物随机分为两组 ,第 1组动物数量为总体数量的 2 / 3,共 14 6头 ,为模型组 ,用于建立群体药动学模型 ;第 2组动物数量为总体动物数量的 1/ 3,共 6 9头 ,为验证组。给药前测定每头猪血清生化指标。试验猪颈部肌肉注射 30 %氟苯尼考注射液 ,剂量为 2 0 mg· kg- 1体重。给药前采一次空白血浆及血清 (测定血清生化指标 ) ,给药后随机采样 ,每只猪采样 2～ 4次 ,就整个群体而言使采样时间均匀分布于药物的吸收相、分布相和消除相内 ,采样时间为给药后 0 .183～ 4 8.36 7h,以高效液相色谱法测定血浆药物浓度 ,应用 NONMEM程序处理所收集的数据 ,包括药时数据、猪只的体重、日龄、性别、种属及血清生化指标、对研究组数据拟合发现最佳药动学模型为一级吸收一室模型 ,药动学参数随机效应及自身变异的最佳模型均为对数加法模型。体重对机体清除率、表观分布容积有显著影响 ,机体清除率、表观分布容积随体重的增加而增加 ,基本呈线性关系。种属对吸收速率常数有显著影响。把研究组得到的群体药动学参数值应用     

氟苯尼考注射液对猪的安全性研究

本试验旨在研究肌注氟苯尼考注射液(20%)对靶动物猪的安全性。选取24头健康猪,分为对照组和高、中、低剂量给药组,给药组颈部肌肉注射氟苯尼考注射液分别为每公斤体重100、60和20 mg,且在第1天和第3天连续给药2次。比较给药前后的血常规和血液生化指标,并观察给药后动物的临床表现。结果表明:试验期间,各组猪临床表现正常,只有高剂量组和中剂量组的猪在给药第3天或第4天出现了腹泻现象,但随后亦慢慢恢复正常;各给药组给药后的血常规和血生化指标均在正常范围内波动,与给药前相比无显著性差异性(P>0.05)。本试验结果说明氟苯尼考注射液(20%)通过肌注给药对猪无明显的不良反应,具有较好的安全性。     

Bath immersion pharmacokinetics of florfenicol in Nile tilapia (Oreochromis niloticus)

Drug administration by immersion can be a preferable method in certain conditions especially for treating small-sized, anorexic, or valuable fish. Pharmacokinetic information regarding bath treatment is considerably lacking in comparison to other common administration routes. The current study aimed to investigate if immersion can be an effective route to administer florfenicol (FF) for treatment in Nile tilapia. Nile tilapia reared at 28°C were immersed with FF solution at concentrations of 50, 100, 200, 500, and 500/200 (3 hr/117 hr) ppm for 120 hr and moved to drug-free freshwater for another 24 hr. The serum FF concentration in 100, 200, and 500/200 ppm groups reached steady-state at 12 hr with concentrations of 2.44, 3.04, and 5.26 µg/ml, respectively, which were about 2% of the bathing concentrations. The target therapeutic levels of 1–4 µg/ml were attained and maintained within 1–12 hr, depending on the immersion concentration and the target MIC. Serum FF reached the target with shorter time at higher bathing concentration. Following the 120-hr bath, the serum FF declined with the first-order half-life of approximately 10 hr. A minimum of 100 ppm FF is required for treatment purpose, and an initial high loading concentration followed by maintenance concentration is a plausible way to reach in vivo therapeutic level in short time. Greater than 99% of the residual FF in the bathing water could be removed within 15 min by 0.05% NaOCl. Our results indicated that bath immersion is a promising potential route for FF administration in Nile tilapia.