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.

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.

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.
Anti-Infective Agents ; Bacterial Infections ; Drug Residues ; Humans ; Treatment Failure ; Veterinarians