@article{nixon_chittenden_baynes_messenger_2022, title={Pharmacokinetic/pharmacodynamic modeling of ketoprofen and flunixin at piglet castration and tail-docking}, volume={7}, ISSN={["1365-2885"]}, url={https://doi.org/10.1111/jvp.13083}, DOI={10.1111/jvp.13083}, abstractNote={Abstract This study performed population‐pharmacokinetic/pharmacodynamic (pop‐PK/PD) modeling of ketoprofen and flunixin in piglets undergoing routine castration and tail‐docking, utilizing previously published data. Six‐day‐old male piglets (8/group) received either ketoprofen (3.0 mg/kg) or flunixin (2.2 mg/kg) intramuscularly. Two hours post‐dose, piglets were castrated and tail docked. Inhibitory indirect response models were developed utilizing plasma cortisol or interstitial fluid prostaglandin E2 (PGE2) concentration data. Plasma IC50 for ketoprofen utilizing PGE2 as a biomarker was 1.2 μg/ml, and ED50 for was 5.83 mg/kg. The ED50 calculated using cortisol was 4.36 mg/kg; however, the IC50 was high, at 2.56 μg/ml. A large degree of inter‐individual variability (124.08%) was also associated with the cortisol IC50 following ketoprofen administration. IC50 for flunixin utilizing cortisol as a biomarker was 0.06 μg/ml, and ED50 was 0.51 mg/kg. The results show that the currently marketed doses of ketoprofen (3.0 mg/kg) and flunixin (2.2 mg/kg) correspond to drug responses of 33.97% (ketoprofen‐PGE2), 40.75% (ketoprofen‐cortisol), and 81.05% (flunixin‐cortisol) of the maximal possible responses. Given this information, flunixin may be the best NSAID to use in mitigating castration and tail‐docking pain at the current label dose.}, journal={JOURNAL OF VETERINARY PHARMACOLOGY AND THERAPEUTICS}, publisher={Wiley}, author={Nixon, Emma and Chittenden, Jason T. and Baynes, Ronald E. and Messenger, Kristen M.}, year={2022}, month={Jul} }
 @article{meira_wiloch_nixon_yeatts_sheela_smith_baynes_2022, title={The pharmacokinetics of transdermal flunixin in lactating dairy goats}, volume={105}, ISSN={["1525-3198"]}, url={https://doi.org/10.3168/jds.2021-20460}, DOI={10.3168/jds.2021-20460}, abstractNote={Flunixin is a nonsteroidal anti-inflammatory drug approved for use in cattle to manage pyrexia associated with bovine respiratory disease, mastitis, and endotoxemia. In the United States, no nonsteroidal anti-inflammatory drugs are approved for use in goats, but analgesics are needed for management of painful conditions to improve animal welfare. The objective of this study was to evaluate the pharmacokinetics of transdermal flunixin in dairy goats to determine a milk withdrawal interval (WDI) to avoid violative residue contamination in the food supply. Six adult lactating dairy goats received 3.3 mg/kg of transdermal flunixin before milk, interstitial fluid (ISF), and blood samples were collected at various time points for 360 h. The samples were analyzed using tandem mass spectrometry to detect flunixin as well as the flunixin marker metabolite, 5-hydroxyflunixin followed by a pharmacokinetic WDI calculation using the US Food and Drug Administration tolerance limit method to propose safe residue levels in goat milk. The mean flunixin apparent plasma half-life was 21.63 h. The apparent milk half-life for 5-hydroxyflunixin was 17.52 h. Our findings provide a milk WDI of 60 h using the US Food and Drug Administration tolerance of 0.002 µg/mL (established for bovine milk) and a more conservative WDI of 96 h using a limit of quantification of 0.001 µg/mL following the extralabel use of transdermal flunixin in dairy goats.}, number={1}, journal={JOURNAL OF DAIRY SCIENCE}, publisher={American Dairy Science Association}, author={Meira, Enoch B. de S., Jr Jr and Wiloch, Emily E. and Nixon, Emma and Yeatts, James L. and Sheela, Farha Ferdous and Smith, Geof W. and Baynes, Ronald E.}, year={2022}, month={Jan}, pages={549–559} }
 @article{graham_cheong_furniss_nixon_smith_yang_fruengel_hussain_tchorzewska_ragione_et al._2021, title={Antiviral Efficacy of Metal and Metal Oxide Nanoparticles against the Porcine Reproductive and Respiratory Syndrome Virus}, url={https://doi.org/10.3390/nano11082120}, DOI={10.3390/nano11082120}, abstractNote={Porcine reproductive and respiratory syndrome viruses (PRRSV) are responsible for one of the most economically important diseases affecting the global pig industry. On-farm high-efficiency particulate air (HEPA) filtration systems can effectively reduce airborne transmission of PRRSV and the incidence of PRRS, but they are costly, and their adoption is limited. Therefore, there is a need for low-cost alternatives, such as antimicrobial filters impregnated with antiviral nanoparticles (AVNP). During the past 10 years, tailored intermetallic/multi-elemental AVNP compositions have demonstrated effective performance against human viruses. In this study, a panel of five AVNP was evaluated for viricidal activity against PRRSV. Three AVNP materials: AVNP2, copper nanoparticles (CuNP), and copper oxide nanoparticles (CuONP), were shown to exert a significant reduction (>99.99%) in virus titers at 1.0% (w/v) concentration. Among the three, CuNP was the most effective at lower concentrations. Further experiments revealed that AVNP generated significant reductions in viral titers within just 1.5 min. For an optimal reduction in viral titers, direct contact between viruses and AVNP was required. This was further explained by the inert nature of these AVNP, where only negligible leaching concentrations of Ag/Cu ions (0.06–4.06 ppm) were detected in AVNP supernatants. Real-time dynamic light scatting (DLS) and transmission electron microscopic (TEM) analyses suggested that the mono-dispersive hydrodynamic behavior of AVNPs may have enhanced their antiviral activity against PRRSV. Collectively, these data support the further evaluation of these AVNP as candidate nanoparticles for incorporation into antimicrobial air-filtration systems to reduce transmission of PRRSV and other airborne pathogens.}, journal={Nanomaterials}, author={Graham, Simon P. and Cheong, Yuen-Ki and Furniss, Summer and Nixon, Emma and Smith, Joseph A. and Yang, Xiuyi and Fruengel, Rieke and Hussain, Sabha and Tchorzewska, Monika A. and Ragione, Roberto M. La and et al.}, year={2021}, month={Aug} }
 @article{nixon_carlson_routh_hernandez_almond_baynes_messenger_2021, title={Comparative effects of nonsteroidal anti-inflammatory drugs at castration and tail-docking in neonatal piglets}, volume={16}, ISSN={["1932-6203"]}, url={https://doi.org/10.1371/journal.pone.0254409}, DOI={10.1371/journal.pone.0254409}, abstractNote={This study assessed the efficacy of meloxicam, flunixin, and ketoprofen in piglets undergoing routine castration and tail-docking. Six-day-old male piglets (8/group) received one of five randomized treatments: intramuscular saline (SAL PROC), meloxicam (MEL; 0.4 mg/kg), flunixin (FLU; 2.2 mg/kg), ketoprofen (KETO; 3.0 mg/kg) or sham (SAL SHAM; saline injection, no processing). Two hours post-dose, piglets were castrated and tail-docked. Plasma cortisol, interstitial fluid (ISF) prostaglandin E2 (PGE2) and activity levels via Actical® monitoring were used to estimate pain. SAL SHAM and FLU exhibited lower cortisol concentrations than SAL PROC at the time of processing (p = 0.003 and p = 0.049, respectively), and all NSAIDs exhibited lower PGE2 than SAL PROC at 3.69 hours (MEL p = 0.050; FLU p = 0.043 and KETO p = 0.031). While not statistically significant, PGE2 was higher in SAL PROC piglets vs. other treatment groups at most time points. There was also a high degree of variability between piglets, especially for SAL PROC. Activity levels were significantly decreased at multiple time points in SAL PROC and MEL piglets following processing. However, FLU and KETO piglets had increased activity levels closer to that of the SAL SHAM group, suggesting that these NSAIDs are more effective than MEL in providing analgesia. These results demonstrate that management strategies including administration of intramuscular flunixin or ketoprofen to reduce pain associated with processing will likely improve piglet health and welfare in the United States.}, number={11}, journal={PLOS ONE}, author={Nixon, Emma and Carlson, Alexandra R. and Routh, Patricia A. and Hernandez, Liliana and Almond, Glen W. and Baynes, Ronald E. and Messenger, Kristen M.}, editor={Loor, Juan J.Editor}, year={2021}, month={Nov} }
 @article{smith_bublitz_nixon_yeatts_ball_baynes_2021, title={EVALUATION OF THE PHARMACOKINETIC BEHAVIOR OF TULATHROMYCIN (DRAXXIN) IN FLORIDA MANATEES (TRICHECHUS MANATUS LATIROSTRIS) UNDERGOING MEDICAL REHABILITATION}, volume={52}, ISSN={["1937-2825"]}, url={http://dx.doi.org/10.1638/2021-0025}, DOI={10.1638/2021-0025}, abstractNote={Abstract: Florida manatees (Trichechus manatus latirostris) frequently present to rehabilitation care facilities for various conditions, including boat strike trauma, cold stress syndrome, and brevetoxicosis. Throughout the course of treatment, antimicrobial use to treat respiratory disease is frequently warranted. To date, clinicians have extrapolated dosages based on established information available in bovine and equine medicine. The routes of administration, efficacy, and treatment intervals are considerations in dealing with critical wild animals. The use of tulathromycin, a triamilide antibiotic, has been studied in multiple domestic species of economic importance, including cattle, small ruminants, and swine, and has revealed efficacy against respiratory diseases. Given this information, this antibiotic has also been used in manatees with positive clinical outcomes. This study employed sparse sampling and evaluated banked plasma samples at various time intervals post–tulathromycin administration obtained during the clinical treatment course of nine animals during their rehabilitation. Preliminary pharmacokinetic analysis following administration of a single dose estimated a half-life of 33.75 h and volume of distribution per fraction absorbed (Vz/F = 4.29 L/kg). The pharmacokinetic behavior of tulathromycin in Florida manatees can be used to optimize dosage regimens in this species.}, number={3}, journal={JOURNAL OF ZOO AND WILDLIFE MEDICINE}, publisher={American Association of Zoo Veterinarians}, author={Smith, Lauren N. and Bublitz, Claire and Nixon, Emma and Yeatts, James and Ball, Ray L. and Baynes, Ronald E.}, year={2021}, month={Sep}, pages={880–885} }
 @article{wagner_nixon_robles_baynes_coetzee_pairis-garcia_2021, title={Non-Steroidal Anti-Inflammatory Drugs: Pharmacokinetics and Mitigation of Procedural-Pain in Cattle}, volume={11}, ISSN={["2076-2615"]}, url={https://www.mdpi.com/2076-2615/11/2/282}, DOI={10.3390/ani11020282}, abstractNote={Simple Summary Castration and disbudding, common husbandry procedures used in cattle livestock production industries, are recognized as being painful. In the United States (U.S.), these procedures are frequently performed without pain relief. Although non-steroidal anti-inflammatory drugs (NSAIDs) are used in food-animal production systems, no such pain relief drugs are federally approved in the U.S. for controlling procedural pain in cattle to date. Recent increases in consumer, retailer and producer commitment to improving the welfare of food-animals necessitate a closer look into pain control efforts for livestock. Therefore, this review comprehensively evaluated existing literature to summarize three NSAIDs (meloxicam, flunixin and aspirin) (1) pharmacokinetics and (2) administration outcome in regard to pain control during castration and disbudding procedures, in cattle. The sample size contained notable variability and a general deficiency of validated and replicated methodologies for assessing pain in cattle represent on-going challenges. Future research should prioritize replication of pain assessment techniques across different experimental conditions to close knowledge gaps identified by the present study and facilitate examination of the effectiveness of pain relief drugs. Abstract Common routine management practices in cattle, such as castration and disbudding, are recognized as being painful. In the United States (U.S.), these procedures are frequently performed without pain mitigation and there are currently no drugs federally approved for such use. Non-steroidal anti-inflammatory drugs, such as meloxicam, flunixin meglumine and aspirin, are the most commonly used analgesics in U.S. food-animal production systems. However, the body of research investigating the effectiveness of these pharmaceuticals to control pain in cattle at castration and disbudding has not been comprehensively evaluated. Therefore, this review examined existing literature to summarize meloxicam, flunixin and aspirin (1) pharmacokinetics (PK) and (2) administration outcome in regard to pain control during castration and disbudding procedures, in cattle. Following systematic searches and screening, 47 PK and 44 publications were extracted for data and are presented. The sample size contained notable variability and a general deficiency of validated and replicated methodologies for assessing pain in cattle remain substantial challenges within this research area. Future research should prioritize replication of pain assessment methodologies across different experimental conditions to close knowledge gaps identified by the present study and facilitate examination of analgesic efficacy.}, number={2}, journal={ANIMALS}, publisher={MDPI AG}, author={Wagner, Brooklyn K. and Nixon, Emma and Robles, Ivelisse and Baynes, Ronald E. and Coetzee, Johann F. and Pairis-Garcia, Monique D.}, year={2021}, month={Feb} }
 @article{robles_arruda_nixon_johnstone_wagner_edwards-callaway_baynes_coetzee_pairis-garcia_2021, title={Producer and Veterinarian Perspectives towards Pain Management Practices in the US Cattle Industry}, volume={11}, ISSN={["2076-2615"]}, url={https://www.mdpi.com/2076-2615/11/1/209}, DOI={10.3390/ani11010209}, abstractNote={Simple Summary A key aspect to improve animal welfare is to reduce pain experienced by the animal. However, pain management practices have not been widely adopted in the United States (US) cattle industry. Furthermore, for a veterinarian or producer to relieve pain in cattle, analgesics must be provided in an extra-label drug manner. Currently, research describing pain mitigation strategies used by cattle producers and the study of barriers to implement those strategies from a producer or veterinarian perspective is limited. Understanding challenges faced by these stakeholders is key in improving on-farm pain management strategies. Therefore, the objectives of this study were to explore producer and veterinarian perspectives on pain. Albeit analgesia use increased in the past ten years for some producers and the majority of veterinarians, administering analgesics for pain management on US cattle farms remains a challenge. From a producer perspective, drug cost, availability and logistics for administration. From a veterinarian perspective, lack of Food and Drug Administration (FDA) products hinders the support of on-farm protocols requiring extra-label drug use. Future steps to improve analgesic use on-farm include identifying and approving drugs that demonstrate efficacy for managing pain and disseminating educational resources to support stakeholders in both the implementation and drug withdrawal process. Abstract Producers and veterinarians are considered responsible for improving animal welfare, as they are responsible for implementing practices that directly impact the animal’s well-being. Most husbandry procedures performed in cattle do not include pain mitigation, and understanding challenges faced by these stakeholders to use analgesics is key in improving on-farm pain management strategies. Therefore, the objectives of this study were to explore producer and veterinarian perspectives on pain management practices by (1) exploring inquires received by Food Animal Residue Avoidance Databank (FARAD) regarding analgesic use in cattle and (2) using a survey instrument to identify factors that impact pain management implementation in the US cattle industry. Albeit analgesia use increased in the past ten years for some producers and the majority of veterinarians, administering analgesics for pain management on US cattle farms remains a challenge. From a producer perspective, drug cost, availability and logistics for administration. From a veterinarian perspective, lack of Food and Drug Administration (FDA) products hinders the support of on-farm protocols requiring extra-label drug use. Future steps to improve analgesic use on-farm include identifying and approving drugs that demonstrate efficacy for managing pain in cattle and disseminating educational resources to support stakeholders in both the implementation and drug withdrawal process.}, number={1}, journal={ANIMALS}, author={Robles, Ivelisse and Arruda, Andreia G. and Nixon, Emma and Johnstone, Elizabeth and Wagner, Brooklyn and Edwards-Callaway, Lily and Baynes, Ronald and Coetzee, Johann and Pairis-Garcia, Monique}, year={2021}, month={Jan} }
 @article{nixon_almond_baynes_messenger_2020, title={Comparative Plasma and Interstitial Fluid Pharmacokinetics of Meloxicam, Flunixin, and Ketoprofen in Neonatal Piglets}, volume={7}, ISSN={["2297-1769"]}, DOI={10.3389/fvets.2020.00082}, abstractNote={Piglet castration and tail-docking are routinely performed in the United States without analgesia. Pain medications, predominately non-steroidal anti-inflammatory drugs, are used in the EU/Canada to decrease pain associated with processing and improve piglet welfare, however, past studies have shown the efficacy and required dose remain controversial, particularly for meloxicam. This study assessed the pharmacokinetics of three NSAIDs (meloxicam, flunixin, and ketoprofen) in piglets prior to undergoing routine castration and tail-docking. Five-day-old male piglets (8/group) received one of 3 randomized treatments; meloxicam (0.4 mg/kg), flunixin (2.2 mg/kg), ketoprofen (3.0 mg/kg). Two hours post-dose, piglets underwent processing. Drug concentrations were quantified in plasma and interstitial fluid (ISF) and pharmacokinetic parameters were generated by non-compartmental analysis. Time to peak concentration (Tmax) of meloxicam, flunixin, and S(–)-ketoprofen in plasma were 1.21, 0.85, and 0.59 h, compared to 2.81, 3.64, and 2.98 h in the ISF, respectively. The apparent terminal half-life of meloxicam, flunixin and S(–)-ketoprofen were 4.39, 7.69, and 3.50 h, compared to 11.26, 16.34, and 5.54 h, respectively in the ISF. If drug concentrations in the ISF are more closely related to efficacy than the plasma, then the delay between the Tmax in plasma and ISF may be relevant to the timing of castration in order to provide the greatest analgesic effect.}, journal={FRONTIERS IN VETERINARY SCIENCE}, author={Nixon, Emma and Almond, Glen W. and Baynes, Ronald E. and Messenger, Kristen M.}, year={2020}, month={Feb} }
 @article{nixon_mays_routh_yeatts_fajt_hairgrove_baynes_2020, title={Plasma, urine and tissue concentrations of Flunixin and Meloxicam in Pigs}, volume={16}, ISSN={["1746-6148"]}, DOI={10.1186/s12917-020-02556-4}, abstractNote={The objective of this study was to determine the renal clearance of flunixin and meloxicam in pigs and compare plasma and urine concentrations and tissue residues. Urine clearance is important for livestock show animals where urine is routinely tested for these drugs. Fourteen Yorkshire/Landrace cross pigs were housed in individual metabolism cages to facilitate urine collection. This is a unique feature of this study compared to other reports. Animals received either 2.2 mg/kg flunixin or 0.4 mg/kg meloxicam via intramuscular injection and samples analyzed by mass spectrometry. Pigs were euthanized when drugs were no longer detected in urine and liver and kidneys were collected to quantify residues.Drug levels in urine reached peak concentrations between 4 and 8 h post-dose for both flunixin and meloxicam. Flunixin urine concentrations were higher than maximum levels in plasma. Urine concentrations for flunixin and meloxicam were last detected above the limit of quantification at 120 h and 48 h, respectively. The renal clearance of flunixin and meloxicam was 4.72 ± 2.98 mL/h/kg and 0.16 ± 0.04 mL/h/kg, respectively. Mean apparent elimination half-life in plasma was 5.00 ± 1.89 h and 3.22 ± 1.52 h for flunixin and meloxicam, respectively. Six of seven pigs had detectable liver concentrations of flunixin (range 0.0001-0.0012 µg/g) following negative urine samples at 96 and 168 h, however all samples at 168 h were below the FDA tolerance level (0.03 µg/g). Meloxicam was detected in a single liver sample (0.0054 µg/g) at 72 h but was below the EU MRL (0.065 µg/g).These data suggest that pigs given a single intramuscular dose of meloxicam at 0.4 mg/kg or flunixin at 2.2 mg/kg are likely to have detectable levels of the parent drug in urine up to 2 days and 5 days, respectively, after the first dose, but unlikely to have tissue residues above the US FDA tolerance or EU MRL following negative urine testing. This information will assist veterinarians in the therapeutic use of these drugs prior to livestock shows and also inform livestock show authorities involved in testing for these substances.}, number={1}, journal={BMC VETERINARY RESEARCH}, author={Nixon, Emma and Mays, Travis P. and Routh, Patricia A. and Yeatts, James L. and Fajt, Virginia R. and Hairgrove, Thomas and Baynes, Ronald E.}, year={2020}, month={Sep} }
 @article{carlson_nixon_jacob_messenger_2020, title={Sterility and concentration of liposomal bupivacaine single-use vial when used in a multiple-dose manner}, volume={49}, ISSN={["1532-950X"]}, DOI={10.1111/vsu.13380}, abstractNote={OBJECTIVE
To evaluate the sterility of bupivacaine liposome injectable suspension (Nocita®) used in a multiple-dose fashion for 5 days.


STUDY DESIGN
Triplicate liposomal bupivacaine vials were stored under two conditions, (1) room temperature (24°C) and (2) refrigerated temperature (5°C). A 3-mL aliquot was withdrawn from each vial daily. Samples were inoculated in tryptic soy broth in triplicate and then incubated for 24 hours at 37°C and subcultured every 48 hours onto blood agar and Sabouraud dextrose agar, respectively. Separate 1.5-mL aliquots of liposomal bupivacaine were centrifuged at 3500 g to separate liposome-encapsulated bupivacaine from the solution. Concentration of unencapsulated bupivacaine was analyzed via high-pressure liquid chromatography. Data were analyzed by using mixed effects procedure with multiple comparisons.


SAMPLE POPULATION
Ten 20-mL vials of bupivacaine liposome injectable suspension stored under two conditions, (1) room temperature (24°C) and (2) refrigerated temperature (5°C).


RESULTS
Five days of repeated withdrawal from the single-use vials yielded no bacterial growth. One control vial, which was opened and punctured once on the last day of the experiment, yielded fungal growth of an Aspergillus spp, likely an environmental contaminant. The concentration of free bupivacaine did not significantly differ until the fifth day of sampling.


CONCLUSION
When aseptic technique was used, liposomal bupivacaine remained sterile for 5 days. Concentrations of free bupivacaine were unchanged from baseline for 4 days in both refrigerated and room temperature conditions.


CLINICAL SIGNIFICANCE
Single-use liposomal bupivacaine vials can be used extralabel in a multiple-dose fashion for up to 4 days when stored either refrigerated or room temperature when sterile technique is used.}, number={4}, journal={VETERINARY SURGERY}, author={Carlson, Alexandra R. and Nixon, Emma and Jacob, Megan E. and Messenger, Kristen M.}, year={2020}, month={May}, pages={772–777} }
 @article{nixon_brooks_routh_chittenden_baynes_2017, title={Pharmacokinetics of C-14-ortho-phenylphenol following intravenous administration in pigs}, volume={37}, ISSN={["1099-1263"]}, url={https://doi.org/10.1002/jat.3380}, DOI={10.1002/jat.3380}, abstractNote={Workers in the USA are exposed to industrial formulations, which may be toxic. These formulations often contain preservatives or biocides such as ortho‐phenylphenol (OPP). There are limited data describing OPP following intravenous administration to assess truly the clearance of this chemical in humans and other species. In vivo experiments were conducted in pigs to determine related pharmacokinetic parameters. 14C‐OPP was administered as an intravenous bolus dose. Blood, feces, urine and tissue samples were collected for analysis by liquid scintillation. Data were analyzed using non‐compartmental and compartmental pharmacokinetic model approaches. These data fitted a three‐compartment model and showed that the half‐life of 14C‐OPP following the intravenous bolus in pigs was 46.26 ± 10.01 h. The kidneys play a crucial role in clearance of 14C‐OPP with a large percentage of the dose being found in the urine (70.3 ± 6.9% dose). Comparisons with other species suggest that 14C‐OPP clearance in pigs (2.48 ml h–1 kg–1) is less than that in humans (18.87 ml h–1 kg–1) and rats (35.51 ml h–1 kg–1). Copyright © 2016 John Wiley & Sons, Ltd.}, number={4}, journal={JOURNAL OF APPLIED TOXICOLOGY}, author={Nixon, Emma and Brooks, James D. and Routh, Patricia A. and Chittenden, Jason T. and Baynes, Ronald E.}, year={2017}, month={Apr}, pages={508–512} }