兽用抗菌药物PK/PD同步模型研究进展

近年来关于兽用抗菌药物的药代动力学/药效学（Pharmacokinetics/Pharmacodynamics,PK/PD）同步模型的研究取得较大进展。了解PK/PD同步模型的基本概念,利用PK/PD同步模型优化给药方案,可以增强药物的抗菌效果,减少耐药性的发生。该文介绍了PK/PD同步模型的研究方法和应用进展,以及PK/PD同步模型在兽药领域面临的挑战和应用前景,以期提高对兽药PK/PD同步模型及其未来发展趋势的认识,为兽用抗菌药物PK/PD同步模型研究开展提供一定理论基础。     

乳酸恩诺沙星可溶性粉在鸡体内的药动学研究

24只苏禽黄羽肉鸡随机分成2组,分别按10 mg/kg体重剂量静注和内服乳酸恩诺沙星。测定乳酸恩诺沙星在鸡体内的药动学参数和生物利用度。恩诺沙星血药浓度数据用3p87计算机软件处理。静注乳酸恩诺沙星后的血药浓度-时间数据符合二室开放模型,主要动力学参数:t1/2α(0.45±0.16)h,t1/2β(7.02±1.42)h,CL(s)(0.38±0.10)L/kg/h,AUC(23.69±5.56)(mg/L)×h。内服乳酸恩诺沙星的血药浓度时间数据,符合有吸收因素二室模型,主要动力学参数:t1/2ka(0.60±0.01)h,t1/2ke(8.25±1.73)h,tpeak(2.44±0.17)h,Cmax(1.44±0.30)mg/L,AUC(20.74±3.80)(mg/L)×h,F 87.54%。结果表明,乳酸恩诺沙星可溶性粉在鸡体内具有吸收快、分布广、消除较慢以及内服生物利用度高的药动学特征。     

体外药动学模型中恩诺沙星对猪大肠杆菌的药效研究

为使畜禽专用的喹诺酮类药物更合理地应用,通过建立体外模型的方法,研究了恩诺沙星对大肠杆菌的药效.结果,在消除半衰期为3 h的模型内,2MIC（最小抑茵浓度）的恩诺沙星对猪大肠杆菌仅能抑制4 h,模型运行4 h后细菌出现再生长.5MIC和8MIC的恩诺沙星对猪大肠杆菌可抑制6 h,模型运行6 h后细菌出现再生长.16MIC的恩诺沙星可在模型运行期间对猪大肠杆菌产生持续的抑制杀灭作用.在消除半衰期为6.5 h的模型内,2MIC的恩诺沙星对猪大肠杆菌仅能抑制4 h,模型运行4 h后细菌出现再生长.5MIC、8MIC和16MIC的恩诺沙星可在模型运行期间对猪大肠杆菌产生持续的抑制杀灭作用,4 h已经不能检测到猪大肠杆菌的存在.结果表明,若要使恩诺沙星发挥持续的抗菌效果,保持Cmaz/MIC大于一定数值,同时维持有足够高的AUCo→24/MIC是非常必要的.     

恩诺沙星在猪血清和组织液中对大肠杆菌的半体内药动-药效同步模型的研究

为合理应用恩诺沙星治疗猪大肠杆菌感染.本研究采用了体内药动和体外药效联合的方法,研究了恩诺沙星在血清和组织笼液中抗大肠杆菌的活性.体外测定结果显示,恩诺沙星在血清和组织笼液中对猪大肠杆菌的MIC均为0.4 μg·mL-1.如果在血清和组织液中添加更多的细菌,则需要高于MIC药物浓度才能持续抑制细菌的生长.猪按5 mg·kg-1的剂量肌内注射恩诺沙星后,血清中半效浓度(EC50)为77.67±31.12,即恩诺沙星血清药物浓度为1.29μg·mL-1时可产生50%最大效应;组织液中恩诺沙星的半效浓度(EC50)为15.78±4.99,即组织液药物浓度为0.26μg·mL-1时可产生50%最大效应.结果提示,临床应用恩诺沙星治疗大肠杆菌感染时,应适当提高给药的剂量,不应仅以高于MIC作为制定给药间隔的标准.     

药动/药效同步模型在兽用抗菌药物研究的应用概况

药动/药效同步模型是将药动学和药效学结合,用于研究药理效应随时间变化规律的一种模型。药动/药效同步模型在药理学和毒理学研究、临床应用及新药评价等领域得到越来越广泛的应用。随着抗菌药物的发展,耐药性问题日益成为全球关注的焦点。将药动/药效同步模型引入兽药研究中,不仅能够优化给药方案,避免细菌耐药性的产生,也能够为新药的开发提供研究基础。论文对兽用抗菌药物的分类、药动/药效同步模型的研究方法及其在国内外兽药研究中的应用现状进行综述,以期为药动/药效同步模型的兽医临床应用提供参考。     

药动药效同步模型在兽药领域应用的研究进展

兽用药物在预防以及治疗动物疾病中有着非常重要的作用,对动物健康生长起到了重要的保障作用.但随着兽药的广泛使用,临床分离菌株对于兽药的耐药性问题逐渐显现出来.这就给动物疾病的预防以及治疗带来了极大困难.如何合理地使用兽药并减少耐药性问题的出现成为了亟待解决的问题.随着研究的逐渐加深,药动药效同步模型又称为PK/PD模型,...     

基于生理药动学模型预测口服给药后氟苯尼考在肉鸡体内的残留

为预测肉鸡多次灌胃氟苯尼考后各可食性组织中的残留药物浓度,研究利用文献检索获得的肉鸡生理学和解剖学参数,建立了一个包含11个组织在内的血流限速型生理药动学(PBPK)模型,模型中包含了氟苯尼考的口服给药、胃肠道吸收、肾脏排泄、肝脏代谢及肝肠循环模块,该PBPK模型成功预测了肉鸡连续5d灌胃氟苯尼考(30mg/kg·d)后各组织中的药物浓度。结果表明,多次灌胃给药后,氟苯尼考在肉鸡体内吸收迅速、分布广泛、消除缓慢,其中在肾脏中分布最多,而在胆汁中消除最慢。     

基于防突变浓度的新型药动学-药效学-突变选择窗同步模型在临床用药上的指导作用

文章综述了抗菌药药动学/药效学(PK/PD)模型的发展,详细阐述新型药动物学/药效学模型在抑制细菌耐药突变上的作用,为合理用药及新药研发提供指导,并指出了临床应用所存在的问题。     

Pharmacokinetics and Dosage Regimen of Enrofloxacin in Buffalo Bulls after Intramuscular Administration

The disposition kinetics and dosage regimen of enrofloxacin were investigated in breeding buffalo bulls following a single intramuscular administration of 5 mg/kg. The absorption half-life, half-life of the terminal phase, apparent volume of distribution and total body clearance were 0.262±0.099 h, 1.97±0.23 h, 0.61±0.13 L/kg and 210.2±18.6 ml/(kg.h), respectively. Therapeutic plasma levels (1 g/ml) were maintained for up to 6 h. A satisfactory intramuscular dosage regimen for enrofloxacin in buffalo bulls would be 8.5 mg/kg followed by 8.0 mg/kg at 8 h intervals.     

恩诺沙星在鸡体中的排泄及其在鸡粪中的降解

检测了在不同给药剂量下,健康鸡服用恩诺沙星后,在不同时间粪尿中恩诺沙星及其主要代谢产物的含量变化,并对在不同光照条件下鸡粪中恩诺沙星的降解进行了研究。结果表明,健康鸡灌服恩诺沙星后,主要以恩诺沙星原形、其次以环丙沙星的形式随粪(尿)排出体外。2.5 mg/kg体重剂量组和5 mg/kg体重剂量组在给药后6h恩诺沙星的排泄量达到最高峰;环丙沙星达到峰浓度的时间为4 h。7.5 mg/kg体重剂量组恩诺沙星排泄量达到最高峰的时间为9 h;环丙沙星达到峰浓度的时间为6 h。至给药后第10天时鸡粪中检不出恩诺沙星和环丙沙星。鸡粪中恩诺沙星的降解速率受光照条件的影响,在避光条件下,鸡粪中恩诺沙星几乎很少降解;在自然光照下,鸡粪中恩诺沙星的降解较快,其变化趋势符合一级动力学方程Ct=C0e-kt,并由此求得鸡粪中恩诺沙星在自然光照下的降解半衰期为(2.23±0.25)d。     

HPLC-MS/MS法研究恩诺沙星在鸡蛋中残留消除规律

建立了高效液相色谱—串联质谱法（HPLC-MS/MS）检测鸡蛋中恩诺沙星、环丙沙星残留的方法。鸡蛋样品经1%乙酸乙腈提取、正己烷除脂, 用HPLC-MS/MS进行检测。恩诺沙星、环丙沙星在0.5~500 ng/mL浓度时线性关系良好（r≥0.999）;恩诺沙星回收率为87.7%~99.1%、环丙沙星的回收率为89.1%~101.4%, 检测限为0.5 μg/kg, 定量限为1.0 μg/kg。应用该方法初步研究了恩诺沙星及其代谢物环丙沙星在鸡蛋中的残留消除规律。结果表明, 给药后鸡蛋中恩诺沙星及其代谢物蓄积迅速, 停药8 d后痕量恩诺沙星代谢缓慢, 25 d后恩诺沙星代谢完全。     

Determination of a dosage regimen of colistin by pharmacokinetic/pharmacodynamic integration and modeling for treatment of G.I.T. disease in pigs

Colistin is an antimicrobial drug of the polymyxin group and COLIVET SOLUTION is an aqueous solution containing colistin sulphate (2 × 10⁶ IU/mL), formulated for oral administration. The target species is the pig, particularly the suckling and post weaning animal. This investigation was undertaken to provide pharmacokinetic and pharmacodynamic data on which to base the selection of dosage rate and interval of the solution for the treatment of porcine colibacillosis.Colistin absorption from the gastrointestinal tract of young pigs, when administered at dosage rates of 25,000, 50,000 and 1,00,000 IU/kg, was slight or absent. The drug was therefore restricted almost entirely to the required site of action. The colistin concentration-time profile within the jejunum and ileum was established, and this enabled determination of the pharmacokinetic variables, maximum concentration (C_max) and area under curve (AUC) and derivation of the surrogate indices of antibacterial activity, C_max/minimum inhibitory concentration (MIC) and AUC/MIC through integration of in vivo data with the results of in vitro potency studies for four strains of Escherichia coli.In the in vitro bacterial growth inhibition studies colistin acted by a concentration-dependent killing mechanism. Numerical values for the surrogate parameter AUC/MIC producing bactericidal and eradication effects of colistin against four strains of E. coli were established by PK-PD modeling based on the sigmoidal E_max equation. These data were used to predict a daily dosage regimen for colistin.     

Pharmacokinetics of enrofloxacin HCl‐2H2O (ENRO‐C), PK/PD,and Monte Carlo modeling vs. Leptospira spp. in cows

The pharmacokinetics, PK/PD ratios, and Monte Carlo modeling of enrofloxacin HCl‐2H₂O (Enro‐C) and its reference preparation (Enro‐R) were determined in cows. Fifty‐four Jersey cows were randomly assigned to six groups receiving a single IM dose of 10, 15, or 20 mg/kg of Enro‐C (Enro‐C₁₀, Enro‐C₁₅, Enro‐C₂₀) or Enro‐R. Serial serum samples were collected and enrofloxacin concentrations quantified. A composite set of minimum inhibitory concentrations (MIC) of Leptospira spp. was utilized to calculate PK/PD ratios: maximum serum concentration/MIC (C_max/MIC₉₀) and area under the serum vs. time concentration of enrofloxacin/MIC (AUC_0‐24/MIC₉₀). Monte Carlo simulations targeted C_max/MIC = 10 and AUC_0‐24/MIC = 125. Mean C_max obtained were 6.17 and 2.46 μg/ml; 8.75 and 3.54 μg/ml; and 13.89 and 4.25 μg/ml, respectively for Enro‐C and Enro‐R. C_max/MIC₉₀ ratios were 6.17 and 2.46, 8.75 and 3.54, and 13.89 and 4.25 for Enro‐C and Enro‐R, respectively. Monte Carlo simulations based on C_max/MIC₉₀ = 10 indicate that only Enro‐C₁₅ and Enro‐C₂₀ may be useful to treat leptospirosis in cows, predicting a success rate ≥95% when MIC₅₀ = 0.5 μg/ml, and ≥80% when MIC₉₀ = 1.0 μg/ml. Although Enro‐C₁₅ and Enro‐C₂₀ may be useful to treat leptospirosis in cattle, clinical trials are necessary to confirm this proposal.     

Pharmacokinetic/pharmacodynamic integration of cefquinome against Pasteurella Multocida in a piglet tissue cage model

To explore the in vivo antimicrobial activity of cefquinome against Pasteurella multocida in piglets, a piglet tissue cage infection model was used in this study. After the population of P. multocida reached 10⁷ CFU/mL in a tissue cage, piglets received an intramuscular administration of cefquinome at 0.2, 0.4, 0.8, 1, 2, and 4 mg/kg once daily for 3 days. To assess the tissue cage pharmacokinetics (PKTCF) of cefquinome, tissue cage fluid was collected for cefquinome analysis at 1, 3, 6, 9, 12, and 24 hr after each of the 3 daily drug administrations. Bacteria were counted every 24 hr after drug administration and at 48 and 72 hr after the last administration. Evaluation of the relationship between pharmacokinetic/pharmacodynamic (PK/PD) parameters and the antibacterial effect showed that the surrogate of %T > minimum inhibitory concentration (MIC) (R² = 0.981) was the best PK/PD index that correlated with effectiveness of cefquinome against P. multocida. The respective values of %T > MIC required for continuous 1/3‐log, 1/2‐log, and 1‐log reductions were 14.23, 34.45, and 73.44%, respectively, during each 24‐hr treatment period. In conclusion, cefquinome exhibited a potent antibacterial effect against P. multocida. When %T > MIC reached 73.44%, cefquinome exhibited a bactericidal effect against P. multocida after three successive daily administrations.     

抗菌药物药动、药效同步信息在兽医临床上应用的研究进展

总结了抗菌药物药动药效同步信息的研究方法，并回顾了各类抗菌药物药动-药效同步信息在兽医临床上应用的研究概况及存在问题，认为使用药动-药效联合研究的方法，确定畜禽抗菌药物最佳给药方案将成为临床兽药研究的新方向。     

应用计算机和气象资料对草场上马歇尔线虫数量季节消长预测技术的研究

根据土源性寄生线虫体外发育期间受温度、湿度、季节和宿主动物影响的原理,采用电子计算机对上述因子和马歇尔线虫从虫卵发育到侵袭性幼虫的速度、数量进行分析回归,制定出模拟模型,设计出草场上该种线虫从虫卵发育到侵袭性幼虫数量的预测预报公式。将气象资料代入公式计算出侵袭性幼虫季节消长曲线,并与草场上羊体内成虫数量消长曲线相互对比。研究初步显示,可以采用气象资料通过计算机计算处理预测草场上马歇尔线虫侵袭性幼虫数量的季节动态,从而为制订防治措施提供科学依据。     

The use of Markov chain Monte Carlo for analysis of correlated binary data: patterns of somatic cells in milk and the risk of clinical mastitis in dairy cows

Two analytical approaches were used to investigate the relationship between somatic cell concentrations in monthly quarter milk samples and subsequent, naturally occurring clinical mastitis in three dairy herds. Firstly, cows with clinical mastitis were selected and a conventional matched analysis was used to compare affected and unaffected quarters of the same cow. The second analysis included all cows, and in order to overcome potential bias associated with the correlation structure, a hierarchical Bayesian generalised linear mixed model was specified. A Markov chain Monte Carlo (MCMC) approach, that is Gibbs sampling, was used to estimate parameters.

The results of both the matched analysis and the hierarchical modelling suggested that quarters with a somatic cell count (SCC) in the range 41,000–100,000 cells/ml had a lower risk of clinical mastitis during the next month than quarters <41,000 cell/ml. Quarters with an SCC >200,000 cells/ml were at the greatest risk of clinical mastitis in the next month. There was a reduced risk of clinical mastitis between 1 and 2 months later in quarters with an SCC of 81,000–150,000 cells/ml compared with quarters below this level. The hierarchical modelling analysis identified a further reduced risk of clinical mastitis between 2 and 3 months later in quarters with an SCC 61,000–150,000 cells/ml, compared to other quarters.

We conclude that low concentrations of somatic cells in milk are associated with increased risk of clinical mastitis, and that high concentrations are indicative of pre-existing immunological mobilisation against infection. The variation in risk between quarters of affected cows suggests that local quarter immunological events, rather than solely whole cow factors, have an important influence on the risk of clinical mastitis. MCMC proved a useful tool for estimating parameters in a hierarchical Bernoulli model. Model construction and an approach to assessing goodness of model fit are described.