Prostaglandin E2 is an unreliable biomarker for inflammation in castrated piglets: a randomized controlled trial assessing pharmaceutical drug efficiency.

OBJECTIVE: To investigate the effect of intranasal (IN) flunixin meglumine (FM) and intra-inguinal (IG) lidocaine on castration inflammation using prostaglandin E2 (PGE2) concentration as a biomarker. METHODS: This randomized controlled trial was conducted in March 2022. Blood was collected at -24, 1, and 24 hours postcastration for PGE2 quantification from 195 piglets that received 1 of 8 treatments: (1) saline (1.5 mL) applied IG and IN (0.2 mL) followed by surgical castration (n = 24); (2) saline (1.5 mL) IG and IN (0.2 mL) followed by sham castration (25); (3) lidocaine (20 mg/kg or 1.5 mL) IG followed by surgical castration (24); (4) lidocaine (20 mg/kg or 1.5 mL) IG followed by sham castration (25); (5) FM (2.2 mg/kg) IN followed by surgical castration (25); (6) FM (2.2 mg/kg) IN followed by sham castration (24); (7) lidocaine (20 mg/kg or 1.5 mL) IG and FM (2.2 mg/kg) IN followed by surgical castration (24); and (8) lidocaine (20 mg/kg or 1.5 mL) IG and FM (2.2 mg/kg) IN followed by sham castration (24). RESULTS: Prostaglandin E2 concentrations did not increase following the castration procedure and were not an effective biomarker of castration inflammation. Piglets that received lidocaine demonstrated no difference in PGE2 levels across all time points. Piglets administered FM had lower PGE2 concentrations at 1 hour and 20 minutes postdrug administration in both the sham and castrated piglets. CONCLUSIONS: Prostaglandin E2 was not an effective biomarker to quantify castration inflammation. Flunixin meglumine was able to reduce PGE2 concentration in piglets regardless of castration procedure, but lidocaine had no impact. Decreased PGE2 levels in FM-treated pigs are likely associated with the drug's ability to mitigate a noncastration-associated inflammatory process occurring independent of the castration procedure. CLINICAL RELEVANCE: Flunixin meglumine reduced circulating PGE2 concentration in the blood, regardless of the castration procedure, indicating a potential for the drug to mitigate an inflammatory process unrelated to castration.

Systemic absorption of triamcinolone acetonide is increased from intrasynovial versus extrasynovial sites and induces hyperglycemia, hyperinsulinemia, and suppression of the hypothalamic-pituitary-adrenal axis.

Steroid-associated laminitis remains a major concern with use of corticosteroids in horses. Individual case factors such as joint pathology, pre-existing endocrinopathies, or corticosteroid type, dose, and timing influencing steroid-induced laminitis risk have not been investigated. This study aimed to determine if systemic absorption of triamcinolone acetonide (TA) varies between intrasynovial (antebrachiocarpal) and extrasynovial (sacroiliac) injection sites, and to determine the effects of TA absorption on glucose, insulin, cortisol, and adrenocorticotropic hormone (ACTH). Twenty adult horses were randomized into antebrachiocarpal or sacroiliac joint injection groups, and each horse received bilateral injections with a total dose of 18 mg triamcinolone. Blood was collected prior to injection and at 1, 2, 4, 6, 8, 10, 12, 16, 20, 24, 36, 48, 60, and 72 h post-injection. Peak TA absorption occurred at 8 h in both groups, and was significantly higher in the intrasynovial group compared to the extrasynovial group (1.397 ng/mL, 0.672 ng/mL, p < 0.05). Plasma TA levels were significantly higher in the intrasynovial group from 8 to 36 h post-injection (p < 0.05). There was no difference in glucose, insulin, cortisol, or ACTH between groups at any time point. Insulin and glucose were significantly increased from baseline at all timepoints from 10-72 h and 1-72 h post-injection, respectively. Horses with elevated baseline insulin values (>20 µU/mL) from both groups experienced a more marked hyperinsulinemia, reaching a mean peak insulin of 197.5 µU/mL as compared to 90.06 µU/mL in those with normal baseline insulin. Cortisol and ACTH were significantly decreased from baseline at timepoints from 4-72 h post-injection in both groups. This study is the first to evaluate drug absorption from the sacroiliac site and demonstrates that drug absorption varies between intrasynovial and extrasynovial injection sites. TA absorption causes metabolic derangements, most notably a marked hyperinsulinemia that is more severe in horses with elevated baseline insulin values. The influence of baseline endocrinopathies on response to corticosteroid administration as well as the effect of corticosteroid-induced metabolic derangements warrant further investigation as risk factors for corticosteroid-associated laminitis.

Pharmacokinetics of a continuous intravenous infusion of hydromorphone in healthy dogs.

Introduction: Dosing recommendations for hydromorphone intravenous constant rate infusion (IV CRI) are derived from simulations following IV bolus administration. While this extrapolated dose regimen has been described clinically, pharmacokinetics (PK) of hydromorphone infusions in dogs are not yet described. The study objective was to describe the PK of hydromorphone in healthy dogs receiving an IV bolus followed by an IV CRI for 48 h. Methods: A prospective, experimental study was performed involving the administration of hydromorphone (0.1 mg/kg IV bolus then IV CRI 0.01 mg/kg/h over a 48 h period) to 6 healthy Beagle dogs. Blood samples were collected at 16 time points between 0 and 58 h relative to the initial bolus. Plasma hydromorphone concentrations were analyzed by high pressure liquid chromatography with tandem mass spectrometry detection. Pharmacokinetic parameter estimates were obtained with compartmental methods using commercially available software. Results: A two-compartment model with first order elimination was used. At the end of the infusion, median (range) plasma hydromorphone concentrations were 6.8 (5.5-19.6) ng/mL. The median total body clearance was 30.4 (19.8-36.7) mL/min/kg; volume of distribution at steady state was 4.5 (3.2-7.8) L/kg; and terminal elimination half-life was 11.2 (7.6-24.3) h. Conclusion: Hydromorphone (0.1 mg/kg IV bolus then IV CRI of 0.01 mg/kg/h) maintained steady-state plasma concentrations above the minimum human analgesic target in healthy Beagle dogs with minimal side effects. Further studies are needed to determine the effective plasma concentrations of hydromorphone in painful dogs.

Pharmacokinetics of subcutaneous ketamine administration via the Omnipod® system in dogs.

Ketamine is an injectable anesthetic agent with analgesic and antidepressant effects that can prevent maladaptive pain. Ketamine is metabolized by the liver into norketamine, an active metabolite. Prior rodent studies have suggested that norketamine is thought to contribute up to 30% of ketamine's analgesic effect. Ketamine is usually administered as an intravenous (IV) bolus injection or continuous rate infusion (CRI) but can be administered subcutaneously (SC) and intramuscularly (IM). The Omnipod® is a wireless, subcutaneous insulin delivery device that adheres to the skin and delivers insulin as an SC CRI. The Omnipod® was used in dogs for postoperative administration of ketamine as a 1 mg/kg infusion bolus (IB) over 1 hour (h). Pharmacokinetics (PK) showed plasma ketamine concentrations between 42 and 326.1 ng/mL. The median peak plasma concentration was 79.5 (41.9-326.1) ng/mL with a Tmax of 60 (30-75) min. After the same infusion bolus, the corresponding norketamine PK showed plasma drug concentrations between 22.0 and 64.8 ng/mL. The median peak plasma concentration was 43.0 (26.1-71.8) ng/mL with a median Tmax of 75 min. The median peak ketamine plasma concentration exceeded 100 ng/mL in dogs for less than 1 h post infusion. The Omnipod® system successfully delivered subcutaneous ketamine to dogs in the postoperatively.

Pharmacokinetics of intranasal and intramuscular flunixin in healthy grower pigs.

Flunixin meglumine is a nonsteroidal anti-inflammatory drug approved to manage pyrexia associated with swine respiratory disease. In the United States, no analgesic drugs are approved for use in swine by the FDA, although they are needed to manage painful conditions. This study evaluated the pharmacokinetics and relative bioavailability of intranasal versus intramuscular flunixin in grower pigs. Six pigs received 2.2 mg/kg flunixin either intranasally via atomizer or intramuscularly before receiving flunixin via the opposite route following a 5-day washout period. Plasma samples were collected over 60 h and analysed using ultra-performance liquid chromatography and tandem mass spectrometry to detect flunixin plasma concentrations. A non-compartmental pharmacokinetic analysis was performed. The median Cmax was 4.0 µg/mL and 2.7 µg/mL for intramuscular and intranasal administration, respectively, while the median AUCinf was 6.9 h µg/mL for intramuscular administration and 4.9 h µg/mL for intranasal administration. For both routes, the median Tmax was 0.2 h, and flunixin was detectable in some samples up to 60 h post-administration. Intranasal delivery had a relative bioavailability of 88.5%. These results suggest that intranasal flunixin has similar, although variable, pharmacokinetic parameters to the intramuscular route, making it a viable route of administration for use in grower swine.

Efficacy of inguinal buffered lidocaine and intranasal flunixin meglumine on mitigating physiological and behavioral responses to pain in castrated piglets.

Managing castration pain on US sow farms is hindered by the lack of Food and Drug Administration (FDA) approved products for mitigating pain. Previous work assessing flunixin meglumine (FM) efficacy in mitigating castration pain has shown the drug to be effective in pigs, meanwhile, results from previous work evaluating lidocaine efficacy are contradictory. Therefore, the objectives of this study were to determine the efficacy of inguinal buffered lidocaine (BL) and FM in mitigating castration pain in piglets. This study was divided into Part I (physiological response) and Part II (behavioral response). For part I piglets were randomly assigned to the following treatments: T1: (C) Castration plus physiological saline; T2: (S) Sham plus physiological saline; T3: (CL) Castration plus BL; T4: (SL) Sham plus BL; T5: (CF) Castration plus FM; T6: (SF) Sham plus FM; T7: (CLF) Castration plus BL and FM; T8: (SLF) Sham plus BL and FM. Blood was collected 24 h prior to castration, 1 h, and 24 h post castration for cortisol quantification. For Part II another cohort of piglets was enrolled and randomly assign to the following treatments: T1: (C) Castration plus physiological saline and T7: (CLF) Castration plus BL and FM. Behavior scoring was obtained in real-time by observing each piglet for 4-min continuously using Unesp-Botucatu pig acute pain scale (UPAPS) at the following timepoints: 1 h before castration (-1 h), immediately post-castration (0 h), and 3 h post-castration (+3 h). Average cortisol concentrations did not differ at -24 h (P > 0.05) or at 24 h post-castration (P > 0.05) between treatments. At 1 h post-castration, castrated piglets (C and CL) demonstrated greater cortisol concentrations (P < 0.05). Castrated piglets in the CF and CLF group had lower cortisol concentrations compared to C and CL-treated pigs (P < 0.05). For behavioral response, there were no differences between treatments on total UPAPS scores (C and CLF, P > 0.05). Intranasal FM was able to effectively reduce the physiological piglet's response immediately post-castration. Inguinal buffered lidocaine had no effect on the either physiological or behavioral response to pain. Long-term research should focus on refining injection techniques for inguinal BL and consider administration frequency and dosing of intranasal FM to control pain for a longer period post-castration.

Pharmacokinetics and pharmacodynamics of intramuscular alfaxalone in central bearded dragons (Pogona vitticeps): effect of injection site.

OBJECTIVE: To evaluate the pharmacodynamic effects and pharmacokinetics of a single intramuscular (IM) injection of alfaxalone in central bearded dragons (Pogona vitticeps) when injected at a cranial versus a caudal site. STUDY DESIGN: Prospective, masked, randomized crossover study. ANIMALS: A total of 13 healthy bearded dragons weighing 0.48 ± 0.1 kg. METHODS: Alfaxalone (10 mg kg-1) was administered IM to 13 bearded dragons in the triceps muscle (cranial treatment) or the quadriceps muscle (caudal treatment) separated by 4 weeks. Pharmacodynamic variables included movement score, muscle tone score and righting reflex. Blood was obtained from the caudal tail vein using a sparse sampling methodology. Plasma alfaxalone concentrations were determined using liquid chromatography-mass spectrometry, and pharmacokinetic analysis was performed using nonlinear mixed-effects modeling. Differences in variables between injection sites were analyzed using a nonparametric Wilcoxon signed-rank test for paired data with significance set at p ≤ 0.05. RESULTS: Time to loss of righting reflex score was not different, median (interquartile range), between cranial and caudal treatments [8 (5-11) and 8 (4-12) minutes, respectively, p = 0.72]. Time to recovery of righting reflex was also not different between cranial and caudal treatments [80 (44-112) and 64 (56-104) minutes, respectively, p = 0.75]. Plasma alfaxalone concentrations were not significantly different between treatments. The population estimate (95% confidence intervals) for volume of distribution per fraction absorbed was 1.0 (0.79-1.20) L kg-1, clearance per fraction absorbed was 9.6 (7.6-11.6) mL minute-1 kg-1, absorption rate constant was 2.3 (1.9-2.8) minute-1 and elimination half-life was 71.9 (52.7-91.1) minutes. CONCLUSIONS AND CLINICAL RELEVANCE: Regardless of the injection site, IM alfaxalone (10 mg kg-1) produced reliable chemical restraint in central bearded dragons, appropriate for nonpainful diagnostic procedures or anesthetic premedication.

Pharmacokinetics and efficacy of orally administered acetaminophen (paracetamol) in adult horses with experimentally induced endotoxemia.

BACKGROUND: Acetaminophen has been evaluated in horses for treatment of musculoskeletal pain but not as an antipyretic. OBJECTIVES: To determine the pharmacokinetics and efficacy of acetaminophen compared to placebo and flunixin meglumine in adult horses with experimentally induced endotoxemia. ANIMALS: Eight university owned research horses with experimentally induced endotoxemia. METHODS: Randomized placebo controlled crossover study. Horses were treated with acetaminophen (30 mg/kg PO; APAP), flunixin meglumine (1.1 mg/kg, PO; FLU), and placebo (PO; PLAC) 2 hours after administration of LPS. Plasma APAP was analyzed via LC-MS/MS. Serial CBC, lactate, serum amyloid A, heart rate and rectal temperature were evaluated. Serum IL-1ß, IL-6, IL-8, IL-10, and TNF-α were evaluated by an equine-specific multiplex assay. RESULTS: Mean maximum plasma APAP concentration was 13.97 ± 2.74 µg/mL within 0.6 ± 0.3 hour after administration. At 4 and 6 hours after treatment, both APAP (P = <.001, P = .03, respectively) and FLU (P = .0045 and P < .001, respectively) had a significantly greater decrease in rectal temperature compared to placebo. FLU caused greater heart rate reduction than APAP at 4 and 6 hours (P = .004 and P = .04), and PLAC at 4 hours (P = .05) after treatment. CONCLUSIONS AND CLINICAL IMPORTANCE: The pharmacokinetics of acetaminophen in endotoxemic horses differ from those reported by previous studies in healthy horses. Acetaminophen is an option for antipyresis in clinical cases, particularly when administration of traditional NSAIDs is contraindicated.

Comparative growth dynamics of bacterial and fungal contaminants in bupivacaine liposomal injectable suspension, bupivacaine 0.5%, and propofol.

OBJECTIVE: To determine whether bupivacaine liposomal injectable suspension (BLIS) supports microbial growth when artificially inoculated and to evaluate liposomal stability in the face of this extrinsic contamination as evidenced by changes in free bupivacaine concentrations. STUDY DESIGN: A randomized, prospective in vitro study in which three vials of each BLIS, bupivacaine 0.5%, and propofol were individually inoculated with known concentrations of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Candida albicans (n = 36) to quantify bacterial and fungal growth was conducted. Over 120 hours, aliquots from contaminated vials were withdrawn, plated, and incubated to determine microbial concentrations. High-pressure liquid chromatography (HPLC) was used to evaluate free bupivacaine concentrations over time in BLIS. Data were analyzed using a mixed effects model with multiple comparisons. SAMPLE POPULATION: Twelve vials of each BLIS, bupivacaine 0.5%, and propofol. RESULTS: BLIS did not support significant growth of Staphylococcus aureus or Candida albicans at any time. BLIS supported significant growth of Escherichia coli and Pseudomonas aeruginosa beginning at the 24 hour time point. Bupivacaine 0.5% did not support significant growth of any organisms. Propofol supported significant growth of all organisms. Free bupivacaine concentrations changed minimally over time. CONCLUSION: Bacterial and fungal contaminant growth in artificially inoculated BLIS is organism dependent. BLIS supports significant growth of Escherichia coli and Pseudomonas aeruginosa. Extra-label handling of BLIS should only be undertaken with caution and with adherence to strict aseptic technique.

Preliminary evaluation of the effects of grapiprant compared with carprofen on acute pain and inflammation following ovariohysterectomy in dogs.

OBJECTIVE: To compare the analgesic efficacy of grapiprant to carprofen for the treatment of postoperative pain and inflammation in dogs following ovariohysterectomy. ANIMALS: 12 purpose-bred adult sexually intact female Beagles. PROCEDURES: Dogs were randomly assigned to 1 of 2 treatment groups: grapiprant (2 mg/kg, PO; n = 6) or carprofen (4.4 mg/kg, PO; n = 6), 1.5 hours prior to ovariohysterectomy (OVH) and every 24 hours afterward for 3 total doses. An ultrafiltration probe was placed within the OVH incision to collect interstitial fluid (ISF). Pain and inflammation were assessed by masked investigators via mechanical nociceptive threshold testing and the short form of the Glasgow Composite Pain Scale before drug administration and at multiple time points for 72 hours following dosing and surgery. ISF samples were collected at the same time points to assess prostaglandin E2 concentrations at the site of inflammation. RESULTS: In both groups, pain scale scores were highest in the immediate postoperative period and decreased over time. In both treatment groups, there were significant (P = 0.003) differences in mechanical nociceptive threshold results over time when compared with baseline, but there was no difference between groups. Prostaglandin E2 concentrations in ISF were higher in dogs receiving grapiprant compared with carprofen (P < 0.001). One dog in the carprofen group required rescue analgesia. CLINICAL RELEVANCE: Results of this preliminary study suggested both carprofen and grapiprant may be effective for postoperative pain following OVH in dogs; however, additional studies are warranted to determine grapiprant's effectiveness in a larger and more diverse population of dogs.