Pharmacokinetic report: Pharmacokinetics of a single oral dose of gabapentin in goats (Capra hircus).

Gabapentin is used in goats to treat chronic pain associated with lameness. However, pharmacokinetic data and clinical effectiveness trials are lacking. The objective of the study was to describe the pharmacokinetics of gabapentin in goats following a single oral dose. Six Spanish-crossbred goats were enrolled. Each goat was administered gabapentin at a target dose of 15 mg/kg per os. Serial blood samples were collected out to 60 h post-gabapentin administration for plasma gabapentin concentration determination. Plasma samples were analyzed for gabapentin concentration using ultra-high-pressure liquid chromatography coupled with mass spectroscopy. Individual animal pharmacokinetic outcomes were determined using non-compartmental analysis. Gabapentin was detectable in the plasma of all goats at 60 h post-administration. The mean (±SD) Cmax was 2.01 ± 0.62 µg/mL which occurred at 8.47 ± 1.9 h. The mean terminal half-life (T1/2) and mean resident time were determined to be 8.52 ± 1.8 and 18.7 ± 4.0 h, respectively. This study indicates gabapentin is absorbed from the gastrointestinal tract of goats. Further research is needed to determine an optimal dose for clinical efficacy in goats.

Examination of the pharmacokinetics and differential inhibition of cyclooxygenase isoenzymes in New Zealand white rabbits (Oryctolagus cuniculus) by the Non-Steroidal anti-inflammatory Robenacoxib.

Effective rabbit analgesia is challenging, and there are few studies available on the newer COX-2 selective NSAIDs, such as robenacoxib. This study aimed to establish the pharmacokinetics of oral and subcutaneous robenacoxib, describe its inhibitory actions on COX enzymes, and develop dosing, using six healthy New Zealand white rabbits. Pharmacokinetics were determined from plasma concentrations after oral administration of robenacoxib (0.83-0.96 mg/kg) and also after subcutaneous administration (2 mg/kg). The inhibitory actions of robenacoxib were evaluated by measuring plasma concentrations of thromboxane B2 (TBX2 ) and prostaglandin E2 (PGE2 ) as surrogate markers of cyclooxygenase enzyme isoform inhibition. The mean maximum concentration for oral and subcutaneous administration was 0.23 µg/ml and 5.82 µg/ml, respectively. Oral robenacoxib administration did not demonstrate a significant difference between any time point for PGE2 or TBX2 , though subcutaneous administration did for both. There was no significant difference in PGE2 or TBX2 concentrations at any time point when comparing subcutaneous versus oral routes. Although the results support that plasma robenacoxib exceeds the therapeutic levels compared to dogs and cats, there was little significance in the difference in the changes associated with COX-1 and COX-2 inhibition. Further studies are warranted to determine appropriate dosing, safety, and efficacy in rabbits.

Comparison of firocoxib and meloxicam for pain mitigation in goats undergoing surgical castration.

OBJECTIVE: This study sought to determine whether firocoxib (FIRO) or meloxicam (MEL) was effective at providing analgesia after surgical castration in goats. ANIMALS: 18 intact male crossbred goats (6 to 8 months old) were enrolled with a mean weight of 32.6 (± 2.9) kg. METHODS: Surgical castration was done under injectable anesthesia by a licensed veterinarian. Twelve bucks were surgically castrated and given either FIRO (n = 6) or MEL (n = 6). Six bucks served as controls (CNTLs) and were not castrated. Outcome measurements included visual analogue scale, infrared thermography, plasma cortisol, plasma substance P, and kinetic gait analysis. All outcome measurements were obtained at -24, 4, 8, 24, 48, and 72 hours. RESULTS: All 3 treatments were significantly different from each other at the 24- and 48-hour time points, with MEL animals having lower visual analogue scale scores when compared to FIRO animals; CNTL animals exhibited the lowest plasma cortisol levels (3.19 ng/mL; 95% CI, -1.21 to 7.59 ng/mL) followed by FIRO (7.45 ng/mL; 95% CI, 3.10 to 11.80 ng/mL) and MEL (10.24 ng/mL; 95% CI, 5.87 to 14.60 ng/mL). FIRO had an average mean decrease in gait velocity change (-54.17 cm/s; 95% CI, -92.99 to -15.35 cm/s), while MEL had an increase in gait velocity when compared to baseline values (14.54 cm/s; 95% CI, -24.27 to 53.36 cm/s). Control animals had an average mean of -3.06 cm/s (95% CI, -41.88 to 35.75 cm/s). CLINICAL RELEVANCE: Results from this study showed that there were some analgesic effects from administering MEL when compared to bucks that received a placebo treatment (CNTL).

Measurement of Cyclooxygenase Products in Plasma as Markers for Inhibition of Cyclooxygenase Isoforms by Oral Meloxicam in New Zealand White Rabbits (Oryctolagus cuniculus ).

Pain management in rabbits is a challenging task that is complicated by the rabbit's ability to hide signs of distress and the limited pharmacologic data available for this species. Pharmacokinetic data has shown that in rabbits, meloxicam, a nonsteroidal anti-inflammatory NSAID, reaches plasma concentrations that are known to provide analgesia in dogs and cats; these concentrations could theoretically alleviate pain in rabbits. However, the inhibitory effects of meloxicam on cyclooxygenase (COX) isoforms have not been studied in rabbits. In this study, we measured the products of COX-1 and COX-2 after the oral administration of a single 1 mg/kg dose of meloxicam to New Zealand White rabbits (n = 6). Blood samples were collected before drug administration (T0) and then at predetermined time points over 48 h. Plasma prostaglandin E2 (PGE2 ) and thromboxane (TxB2) concentrations were measured as surrogate markers for COX-1 and COX-2, respectively, by using commercial ELISA kits. After meloxicam administration, both TxB2 and PGE2 plasma concentrations fell significantly below baseline, with maximal mean reductions to 80% and 60% of baseline at 8 h, respectively. The reduction in PGE2 concentrations was followed by a significant increase that moved its mean plasma concentrations toward baseline between 8 and 24 h. Adverse effects such as lethargy, inappetence, or changes in fecal production were not observed in any rabbits. In conclusion, meloxicam appeared to significantly inhibit both COX-1 and COX-2 with a time course similar to previously reported meloxicam plasma concentration-time profiles in rabbits. Our data suggest that a dosage of 1 mg/kg given orally could provide analgesia to rabbits, but a more frequent dosing interval than the currently recommended daily dosing may be required to maintain clinical efficacy.

Optimal lameness induction model development using amphotericin B in meat goats.

Lameness continues to be a critical health and welfare concern associated with goat production. Amphotericin B (amp B) is an antimicrobial successful in inducing transient lameness for research purposes previously in livestock animals. The objectives of this study were to (1) identify which of three varying doses of amp B would be most effective in inducing lameness in meat type goats and (2) develop a facial grimace scale for goats. Lameness was produced by an intra-articular injection of amphotericin B into the left hind lateral claw distal interphalangeal joint with either a 5 mg/0.25 mL (high-low, 5 mg of amphotericin B in a volume of 0.25 mL), 5 mg/0.5 mL (high-high, 5 mg of amphotericin B in a volume of 0.5 mL), or a 2.5 mg/0.25 mL (low-low, 2.5 mg of amphotericin B in a volume of 0.25 mL). A saline treatment of 0.5 mL was used as control (0.9% sterile saline solution). Lameness response was analyzed by infrared thermography (IRT) at the induced joint, mechanical-nociception threshold (MNT), visual lameness scoring (VLS), a visual analogue scale (VAS), kinetic gait analysis (KGA), plasma cortisol (CORT), substance P (Sub P), and behavior scoring. The IRT and MNT values differed by timepoint (P ≤ 0.0001). Results from VLS showed the HL treatment was the most effective at inducing lameness (6/6 goats became lame compared to HH 4/6 and LL 2/6). At 24, 48, and 72 h, VAS scores were significantly higher when comparing HL to all other treatment groups (P = 0.0003). Both behavior observers (1 and 2) reported a significant time effect (P = 0.05), with goats exhibiting more facial grimacing at 24 h post-lameness induction. From these data, an optimal dose for a repeatable lameness induction model in goats was aquired. An effective Goat Grimace Scale (GGS) was also developed to evaluate pain responses in goats.

Short term feeding of industrial hemp with a high cannabidiolic acid (CBDA) content increases lying behavior and reduces biomarkers of stress and inflammation in Holstein steers.

Industrial hemp (IH) is defined as Cannabis sativa containing < 0.3% delta-9 tetrahydrocannabinol (THC) and was legalized in the 2018 Farm Bill. The impact of cannabinoids in IH fed to livestock, especially after repeat exposure, has not been thoroughly investigated. Sixteen male castrated Holstein cattle weighting (± SD) 447 ± 68 kg were enrolled onto the study. Cattle were allocated into two treatment groups either receiving IH (HEMP, n = 8) or a control (CNTL, n = 8). Cattle in the HEMP group were fed 25 g IH mixed in 200 g of grain once a day for 14 days to target a daily dose of 5.5 mg/kg of cannabidiolic acid (CBDA). Behavior was continuously monitored with accelerometers and blood samples were collected at predetermined time points for plasma cannabinoid, serum cortisol, serum haptoglobin, liver enzymes, serum amyloid A, and prostaglandin E2 concentrations. The HEMP group spent a mean 14.1 h/d (95% CI 13.6-14.6 h/d) lying compared to the 13.4 h/d (95% CI 12.9-13.8 h/d) for the CNTL cattle (P = 0.03). Cortisol concentrations in the HEMP group were lower than the CNTL group (P = 0.001). Cattle in the HEMP group demonstrated an 8.8% reduction in prostaglandin E2 concentrations from baseline compared to a 10.2% increase from baseline observed in the CNTL group. No differences for haptoglobin or serum amyloid A were observed. These results suggest that feeding IH with a high CBDA content for 14 days increases lying behavior and decreases biomarkers of stress and inflammation in cattle.

Pharmacokinetics and ex vivo pharmacodynamics of oral firocoxib administration in New Zealand White rabbits (Oryctolagus cuniculus).

OBJECTIVE: To examine the pharmacokinetics and ex vivo pharmacodynamics of oral firocoxib administration in New Zealand White rabbits (Oryctolagus cuniculus). ANIMALS: 6 healthy New Zealand White rabbits. PROCEDURES: Pharmacokinetics were determined from plasma concentrations measured via ultra performance liquid chromatography-tandem mass spectrometry after oral administration of firocoxib at a dose of 3.74 to 4.20 mg/kg. Pharmacokinetic analysis was performed using non compartmental methods. Pharmacodynamics of firocoxib were evaluated by measuring plasma concentrations of thromboxane and prostaglandin via ELISAs as surrogate markers of cyclooxygenase enzyme isoform inhibition. RESULTS: The terminal rate constant was 0.07 hours (range, 0.05 to 0.11 h). The mean maximum concentration (Cmax) and time to Cmax were 0.16 µg/mL and 3.81 hours (range, 2.0 to 8.0 h), respectively. Mean residence time was 15.02 hours. Mean elimination half-life was 9.12 hours. For the pharmacodynamic analysis, firocoxib administration did not demonstrate a significant difference between any time point for prostaglandin E2 and only a significant difference between 24 and 48 hours for thromboxane B2. CLINICAL RELEVANCE: Although the pharmacokinetic research supports that plasma firocoxib concentrations that would be therapeutic in dogs are achieved in rabbits, the pharmacodynamic results do not demonstrate a significant difference in levels of cyclooxygenase-2 inhibition, which indirectly reflects the anti-inflammatory effects of the drug. Further pharmacodynamic studies and multidose studies are warranted to determine the efficacy and safety of this drug in rabbits.

The effect of breed, sex, and oral meloxicam administration on pain biomarkers following hot-iron branding in Hereford and Angus calves.

Hot-iron branding uses thermal injury to permanently identify cattle causing painful tissue damage. The primary objective was to examine the physiological and behavioral effects of oral meloxicam (MEL), compared to a control, administered at the time of hot-iron branding in Angus and Hereford steers and heifers. The secondary objectives were to investigate breed and sex effects on pain biomarkers. A total of 70 yearlings, consisting of 35 heifers and 35 steers (Angus, Hereford, or Angus × Hereford), were enrolled in the study. Animals were blocked by sex, randomized across weight, and assigned to receive MEL (1 mg/kg) or a placebo (CON). Biomarkers were assessed for 48 h after branding and included infrared thermography (IRT), mechanical nociceptive threshold (MNT), accelerometry and a visual analog scale (VAS), and serum cortisol and prostaglandin E2 metabolites (PGEM). Wound healing was assessed for 12 wk. Hair samples to quantify cortisol levels were taken prior to and 30 d post-branding. Responses were analyzed using repeated measures with calf nested in treatment as a random effect, and treatment, time, treatment by time interaction, breed, and sex as fixed effects. There was a treatment by time interaction for PGEM (P < 0.01) with MEL having lower values than CON at 6, 24, and 48 h (MEL: 18.34 ± 3.52, 19.61 ± 3.48, and 22.24 ± 3.48 pg/mL, respectively; CON: 32.57 ± 3.58, 37.00 ± 3.52, and 33.07 ± 3.48 pg/mL; P < 0.01). MEL showed less of a difference in maximum IRT values between the branded (2.27 ± 0.29 °C) and control site (3.15 ± 0.29 °C; P < 0.01). MEL took fewer lying bouts at 0-12 h (4.91 bouts ± 0.56) compared with CON (6.87 bouts ± 0.55; P < 0.01). Compared with Hereford calves, Angus calves exhibited greater serum but lower hair cortisol, greater PGEM, more lying bouts, and less healed wound scores at 3, 4, and 5 wk. Compared with heifers, steers exhibited lower PGEM, lower branding site and ocular IRT, higher MNT, and lower plasma meloxicam levels. Steers spent more time lying, took more lying bouts and had greater VAS pain, and more healed wound scores at 5 wk than heifers. Meloxicam administration at branding reduced branding and control site temperature differences and reduced lying bouts for the first 12 h. Breed and sex effects were observed across many biomarkers. Changes from baseline values for IRT, MNT, lying time, step count, VAS pain, and wound scoring all support that branding cattle is painful.

Hot-iron branding uses thermal injury to permanently identify cattle causing painful tissue damage. The primary objective was to examine the effects of oral meloxicam (MEL), compared with a control, administered at the time of hot-iron branding in Angus and Hereford steers and heifers. The secondary objectives were to investigate breed and sex effects on pain biomarkers. A total of 70 yearlings, consisting of 35 heifers and 35 steers (Angus, Hereford, or Angus × Hereford), were enrolled. Animals were assigned to receive MEL or a placebo. Changes from baseline values for infrared thermography (IRT), mechanical nociceptive threshold, lying time, step count, visual analog scale score, and wound scoring all support that hot-iron branding cattle is painful and investigation into analgesic strategies is needed. MEL administration reduced IRT differences from the branding and control site and reduced lying bouts. Breed and sex effects were observed across a wide range of biomarkers and should be considered in future pain studies. The practicality of administering a nonsteroidal anti-inflammatory drug once at the time of branding is attractive. However, a multimodal approach using a combination of analgesics or longer acting analgesic option warrants further investigation to alleviate pain and discomfort caused by hot-iron branding.

Delivering an Immunocastration Vaccine via a Novel Subcutaneous Implant.

Immunocastration relies on the vaccine-mediated stimulation of an immune response to gonadotropin-releasing hormone (GnRH) in order to interrupt spermatogenesis. This approach offers a less painful alternative to traditional castration approaches but the current, commercially available options require multiple doses of vaccine to maintain sterility. Thus, a series of pilot studies were conducted to determine the feasibility of a single-dose immunocastration vaccine implant. These five studies utilized a total of 44 Holstein bulls to determine the optimal vaccine composition and validate the ability of a stainless-steel subcutaneous implant to deliver a vaccine. Outcome measures included the duration of implant retention, scrotal dimensions and temperature, implant site temperature, anti-GnRH antibodies, and serum testosterone concentration. Over the course of several studies, anti-GnRH antibodies were successfully stimulated by vaccine implants. No significant treatment effects on scrotal dimensions or testosterone were detected over time, but changes in spermatogenesis were detected across treatment groups. Results indicate that a single-dose implantable immunocastration vaccine elicits a humoral immune response and could impact spermatogenesis in bulls. These findings provide opportunities for the refinement of this technology to improve implant retention over longer periods of time. Taken together, this approach will offer producers and veterinarians an alternative to physical castration methods, to improve animal welfare during routine livestock management procedures.

Assessment of pain associated with bovine respiratory disease and its mitigation with flunixin meglumine in cattle with induced bacterial pneumonia.

Pleuritic chest pain from bacterial pneumonia is often reported in human medicine. However, studies investigating pain associated with bovine respiratory disease (BRD) are lacking. The objectives of this study were to assess if bacterial pneumonia elicits a pain response in calves with experimentally induced BRD and to determine the analgesic effects of transdermally administered flunixin. A total of 26 calves, 6-7 mo of age, with no history of BRD were enrolled into one of three treatment groups: 1) experimentally induced BRD + transdermal flunixin at 3.3 mg/kg twice, 24 h apart (BRD + FTD); 2) experimentally induced BRD + placebo (BRD + PLBO); and 3) sham induction + placebo (CNTL + PLBO). Calves induced with BRD were inoculated with Mannheimia haemolytica via bronchoalveolar lavage. Outcomes were collected from -48 to 192 h post-treatment and included serum cortisol, infrared thermography, mechanical nociceptive threshold, substance P, kinematic gait analysis, visual analog scale (VAS), clinical illness score, computerized lung score, average activity and rumination level, prostaglandin E2 metabolite, plasma serum amyloid A, and rectal temperature. Outcomes were evaluated using either a generalized logistic mixed model for categorical variables or a generalized linear mixed model for continuous variables. Right front force differed by treatment (P = 0.01). The BRD + PLBO had lower mean force applied to the right front limb (85.5 kg) compared with BRD + FTD (96.5 kg; P < 0.01). Average VAS differed by a treatment by time interaction (P = 0.01). The VAS scores differed for BRD + PLBO at -48 (3.49 mm) compared with 168 and 192 h (13.49 and 13.64 mm, respectively) (P < 0.01). Activity for BRD + PLBO was higher at -48 h (27 min/h) compared with 48, 72, 120, and 168 h (≤ 22.24 min/h; P < 0.01). Activity differed by a treatment by time interaction (P = 0.01). Activity for BRD + FTD was higher at -48 and 0 h (28.2 and 28.2 min/h, respectively) compared to 48, 72, 96, and 168 h (≤23.7 min/h; P < 0.01). Results show a combination of reduced activity levels, decreased force on the right front limb, and increased VAS pain scores all support that bacterial pneumonia in cattle is painful. Differences in right front force indicate that flunixin transdermal may attenuate certain pain biomarkers in cattle with BRD. These findings suggest that BRD is painful and analgesic drugs may improve the humane aspects of care for cattle with BRD.