Formulation of a rational dosage regimen of ceftiofur hydrochloride oily suspension by pharmacokineticpharmacodynamic (PK-PD) model for treatment of swine Streptococcus suis infection

Background@#Our previously prepared ceftiofur (CEF) hydrochloride oily suspension shows potential wide applications for controlling swine Streptococcus suis infections, while the irrational dose has not been formulated. @*Objectives@#The rational dose regimens of CEF oily suspension against S. suis were systematically studied using a pharmacokinetic-pharmacodynamic model method. @*Methods@#The healthy and infected pigs were intramuscularly administered CEF hydrochloride oily suspension at a single dose of 5 mg/kg, and then the plasma and pulmonary epithelial lining fluid (PELF) were collected at different times. The minimum inhibitory concentration (MIC), minimal bactericidal concentration, mutant prevention concentration (MPC), post-antibiotic effect (PAE), and time-killing curves were determined. Subsequently, the area under the curve by the MIC (AUC 0–24h /MIC) values of desfuroylceftiofur (DFC) in the PELF was obtained by integrating in vivo pharmacokinetic data of the infected pigs and ex vivo pharmacodynamic data using the sigmoid E max (Hill) equation. The dose was calculated based on the AUC 0–24h /MIC values for bacteriostatic action, bactericidal action, and bacterial elimination. @*Results@#The peak concentration, the area under the concentration-time curve, and the time to peak for PELF's DFC were 24.76 ± 0.92 µg/mL, 811.99 ± 54.70 μg·h/mL, and 8.00 h in healthy pigs, and 33.04 ± 0.99 µg/mL, 735.85 ± 26.20 μg·h/mL, and 8.00 h in infected pigs, respectively. The MIC of PELF's DFC against S. suis strain was 0.25 µg/mL. There was strong concentration-dependent activity as determined by MPC, PAE, and the time-killing curves. The AUC 0–24h /MIC values of PELF's DFC for bacteriostatic activity, bactericidal activity, and virtual eradication of bacteria were 6.54 h, 9.69 h, and 11.49 h, respectively. Thus, a dosage regimen of 1.94 mg/kg every 72 h could be sufficient to reach bactericidal activity. @*Conclusions@#A rational dosage regimen was recommended, and it could assist in increasing the treatment effectiveness of CEF hydrochloride oily suspension against S. suis infections.

Pharmacokinetics/Pharmacodynamics models of veterinary antimicrobial agents

Misuse and abuse of veterinary antimicrobial agents have led to an alarming increase in bacterial resistance, clinical treatment failure, and drug residues. To address these problems, consistent and appropriate dosage regimens for veterinary antimicrobial agents are needed. Pharmacokinetics/Pharmacodynamics (PK/PD) models have been widely used to establish rational dosage regimens for veterinary antimicrobial agents that can achieve effective prevention and treatment of bacterial diseases and avoid the development of bacterial resistance. This review introduces building methods for PK/PD models and describes current PK/PD research progress toward rational dosage regimens for veterinary antimicrobial agents. Finally, the challenges and prospects of PK/PD models in the design of dosage regimens for veterinary antimicrobial agents are reviewed. This review will help to increase awareness of PK/PD modeling among veterinarians and hopefully promote its development and future use.

Simultaneous Determination of 12 Nonsteroidal Anti-inflammatory Drugs Illegally Added into Antirheumatic TCM Preparations by UPLC-MS/MS / 中国药房

OBJECTIVE:To develop a method for simultaneous determination of 12 nonsteroidal anti-inflammatory drugs (NSAIDs) illegally added into antirheumatic TCM preparations.METHODS:UPLC-MS/MS was adopted.The determination was performed on Hypersil Golden C18 column with mobile phase consisted of 5 mmol/L ammonium formate solution-methanol (gradient elution) at the flow rate of 0.2 mL/min.The column temperature was 40 ℃,and the sample size was 2 μL.A tandem quadrupole mass spectrometer equipped with electrospray ionization source was used in positive-negative ion mode:curtain gas of 25 kPa,atomizing gas of 60 kPa,auxiliary gas of 55 kPa,electrospray voltage of 4 500 V,ion source temperature of 650 ℃.The multiple reaction monitoring mode was performed.RESULTS:The linear ranges of acetaminophen,acetylsalicylic acid,aminopyrine,meloxicam,ibuprofen,naproxen,lam acid,nimesulide,diclofenac,indomethacin,ketoprofen and celecoxib were 0.01-2.0 μg/ rnL (r=0.995 6),0.05-5.0 μg/mL (r=0.997 6),0.01-2.0 μg/mL (r =0.998 7),0.02-5.0 μg/mL (r=0.995 0),0.02-5.0 μg/mL (r =0.995 3),0.02-5.0 μg/mL(r=0.996 5),0.05-5.0 μg/mL(r=0.995 4),0.02-5.0 μg/mL(r=0.996 0),0.05-5.0 μg/mL(r=0.995 9),0.02-5.0 μg/mL(r=0.995 7),0.02-5.0 μg/mL(r=0.996 8),0.01-2.0 μg/mL(r=0.998 7),respectively.The limits of quantitation were no more than 0.20 mg/g,and the limits of detection were no more than 0.05 mg/g.RSDs of precision,stability and reproducibility tests were all lower than 5.0％.The recoveries were 80.8％-114.2％ (RSD was 3.85％-7.32％,n=9).CONCLUSIONS:The established method is simple,accurate,stable and reproducible,and can be used for simultaneous determination of 12 NSAIDs illegally added into antirheumatic TCM preparations.

Simultaneous Determination of 12 Nonsteroidal Anti-inflammatory Drugs Illegally Added into Antirheumatic TCM Preparations by UPLC-MS/MS / 中国药房

OBJECTIVE:To develop a method for simultaneous determination of 12 nonsteroidal anti-inflammatory drugs (NSAIDs) illegally added into antirheumatic TCM preparations.METHODS:UPLC-MS/MS was adopted.The determination was performed on Hypersil Golden C18 column with mobile phase consisted of 5 mmol/L ammonium formate solution-methanol (gradient elution) at the flow rate of 0.2 mL/min.The column temperature was 40 ℃,and the sample size was 2 μL.A tandem quadrupole mass spectrometer equipped with electrospray ionization source was used in positive-negative ion mode:curtain gas of 25 kPa,atomizing gas of 60 kPa,auxiliary gas of 55 kPa,electrospray voltage of 4 500 V,ion source temperature of 650 ℃.The multiple reaction monitoring mode was performed.RESULTS:The linear ranges of acetaminophen,acetylsalicylic acid,aminopyrine,meloxicam,ibuprofen,naproxen,lam acid,nimesulide,diclofenac,indomethacin,ketoprofen and celecoxib were 0.01-2.0 μg/ rnL (r=0.995 6),0.05-5.0 μg/mL (r=0.997 6),0.01-2.0 μg/mL (r =0.998 7),0.02-5.0 μg/mL (r=0.995 0),0.02-5.0 μg/mL (r =0.995 3),0.02-5.0 μg/mL(r=0.996 5),0.05-5.0 μg/mL(r=0.995 4),0.02-5.0 μg/mL(r=0.996 0),0.05-5.0 μg/mL(r=0.995 9),0.02-5.0 μg/mL(r=0.995 7),0.02-5.0 μg/mL(r=0.996 8),0.01-2.0 μg/mL(r=0.998 7),respectively.The limits of quantitation were no more than 0.20 mg/g,and the limits of detection were no more than 0.05 mg/g.RSDs of precision,stability and reproducibility tests were all lower than 5.0％.The recoveries were 80.8％-114.2％ (RSD was 3.85％-7.32％,n=9).CONCLUSIONS:The established method is simple,accurate,stable and reproducible,and can be used for simultaneous determination of 12 NSAIDs illegally added into antirheumatic TCM preparations.

Metabolic Disposition and Elimination of Cyadox in Pigs, Chickens, Carp, and Rats.

The metabolism, distribution, and elimination of cyadox (CYA) is investigated in pigs, chickens, carp, and rats to identify the marker residue and target tissue of CYA in food animals for food safety concerns. Following a single oral gavage of [(3)H]-CYA, the total radioactivity was rapidly excreted, with more than 95% of the dose excreted within 14 days in the four species. Fecal excretion of the total radioactivity was 66.2% and 51.6%, and urinary excretion of the total radioactivity was 28.35% and 44.3% in rats and pigs, respectively. Radioactivity was observed in nearly all of the tissues in the first 6 h after 7 days of consecutive oral dosing. The highest radioactivity and longest persistence were in the livers and kidneys, where the majority of the radioactivity was cleared within 7 days. A total of 15 metabolites were identified in rats, pigs, chickens, and carp, and eight new metabolites were identified for the first time in vivo. No parent drug could be detected in the tissues of rats and pigs. The major metabolites of CYA were Cy1, Cy3, and Cy6 in pigs, Cy1, Cy5, and Cy6 in chickens, Cy1, Cy2, and Cy4 in carp, and Cy1, Cy2, Cy4, and Cy5 in rats. Cy1 was suggested to be the marker residue, and the kidneys were identified as the target tissue of CYA in pigs and chickens. These results provide comprehensive information for the food safety evaluation of CYA in food animals and will improve the understanding of the pharmacology and toxicology of CYA in animals.

Evaluation of matrix solid-phase dispersion extraction for 11 ß-agonists in swine feed by liquid chromatography with electrospray ionization tandem mass spectrometry.

A sensitive liquid chromatography with tandem mass spectrometry method was developed for the determination of 11 ß-agonists (clenbuterol, salbutamol, ractopamine, terbutaline, fenoterol, cimaterol, isoxsuprine, mabuterol, mapenterol, clenproperol, and tulobuterol) in swine feed. This rapid, simple, and effective extraction method was based on matrix solid-phase dispersion. The limit of quantification of clenbuterol, cimaterol, mabuterol, salbutamol, terbutaline, mapenterol, clenproperol, and tulobuterol was 1 µg/kg and that of ractopamine, fenoterol, and isoxsuprine was 2 µg/kg. The recoveries of ß-agonists spiked in swine feeds at a concentration range of 1-8 µg/kg were >83.1% with relative standard deviations <9.3%. This rapid and reliable method can be used to efficiently separate, characterize, and quantify the residues of 11 ß-agonists in swine feeds with advantages of simple pretreatment and environmental friendliness.

Development of an accelerated solvent extraction, ultrasonic derivatisation LC-MS/MS method for the determination of the marker residues of nitrofurans in freshwater fish.

A rapid method using accelerated solvent extraction (ASE) and ultrasound enhanced derivatisation has been developed for the quantitative determination of metabolites of nitrofurans, namely 3-amino-2-oxalidinone (AOZ), 5-morpholinomethyl-3-amino-2-oxalidinone (AMOZ), 1-amino-hydantoin (AHD) and semicarbazide (SEM), in muscle and skin of carp and finless eel. The target analytes were extracted using ASE, ultrasonic derivatisation for 1 h and then purified by solid phase extraction. Averaged decision limits (CCα) and detection capability (CCß) of the method were in the range of 0.07-0.13 and 0.31-0.49 µg kg⁻¹ in carp and finless eel, respectively. The accuracy in terms of recovery was in the range 77.2-97.4%. The simplified and traditional methods were compared with incurred residue samples. The simplified method reduced the derivatisation time and has been applied to the determination of nitrofurans residues in fish.