Pharmacokinetics of IV Ketorolac in Horses Undergoing Orchiectomy

Ketorolac (KET) is a nonsteroidal anti-inflammatory drug for human use, with a potent analgesic activity, that is used in the relief of moderate-to-severe postoperative pain. The pharmacokinetics of KET tromethamine was evaluated after single IV injection at 0.5 mg/kg body weight, after intubation and 10 minutes before surgery, to six Arabian colts undergoing orchiectomy. Intraoperative cardiorespiratory variables were monitored. Blood samples were collected for 36 hours, and serum samples were analyzed by high performance liquid chromotography with ultraviolet-visible detection. During surgery, all monitored physiological parameters were stable. Intermittent positive pressure ventilation, and normocapnia were maintained throughout the procedure in all animals. No adverse effects were observed. The kinetics of KET was described by a two-compartment models, and also a noncompartmental analysis was performed. The distribution and elimination half-lives were t_1/2λ1$t_{1/2{\lambda }_1}$ 0.06 ± 0.02 and t_1/2λ2$t_{1/2{\lambda }_2}$ 0.59 ± 0.21 hours, respectively. Body clearance and mean residence time were 339.99 ± 120.19 mL/h/kg and 0.49 ± 0.22 hours, respectively. The volume of distribution at steady state and volume of distribution based on the terminal phase were 218.83 ± 134.26 mL/kg and 522.5 ± 529.3 mL/kg, respectively. The serum protein binding was 75.8 ± 2.9%. The results indicate that KET at 0.5 mg/kg IV was very rapidly eliminated and thus was likely not effective in the postoperative period. However, further studies including a control group and at higher doses are suggested to investigate the KET kinetics and the analgesic efficacy in horse and define the most appropriate dosage scheme.     

The use of force plate measurements to titrate the dosage of a new COX‐2 inhibitor in lame horses

Reasons for performing study: Lameness is a highly prevalent condition in horses and the principal cause of removal from athletic activity. In clinical studies to evaluate nonsteroidal anti‐inflammatory drug therapies, force plates are commonly used to assess improvement of lameness objectively. Hypothesis: To use a force plate to determine the optimal dose of a new COX‐2 inhibitor (firocoxib) that will reduce lameness, when administered orally to horses once daily. Methods: Sixty‐four horses that exhibited chronic lameness presumed due to osteoarthritis, including navicular disease, in at least one of the frontlimbs and at a stable level of severity, were included. Horses were treated per os s.i.d. for 7 days as follows: vehicle control, firocoxib at 0.05, 0.1 or 0.25 mg/kg bwt. Force plate analysis of each horse was done for the selected (most) lame frontlimb at trot. Once between Days ?19 and ?4 (initial examination), and again on Day ?2 or ?1 (baseline), pretreatment force plate assessments were performed, and thereafter horses were assessed on Days 0, 2 and 6, approximately 10 h post treatment each time. Peak vertical force (PVF) and lameness grades at initial examination and at baseline, and their change from baseline in the 4 different treatment groups were analysed statistically at a significance level of P<0.05. Results: The PVF results were found to be superior to vehicle control already at Day 0 for 0.25 mg/kg bwt and at Days 2 and 6 for 0.1 and 0.25 mg/kg bwt (P<0.05). Mean clinical lameness for both concentrations decreased >1 grade at Day 6. Conclusions and clinical relevance: With the dosage of 0.25 mg/kg bwt lameness did not improve more than with 0.1 mg/kg bwt. Thus, 0.1 mg/kg bwt s.i.d. was considered to be the effective dose at reducing chronic lameness in horses presumed due to osteoarthritis, including navicular disease.     

Distribution of flunixin meglumine and firocoxib into aqueous humor of horses

Background: Nonsteroidal anti‐inflammatory drugs (NSAIDs) are commonly used systemically for the treatment of inflammatory ocular disease in horses. However, little information exists regarding the ocular penetration of this class of drugs in the horse. Objective: To determine the distribution of orally administered flunixin meglumine and firocoxib into the aqueous humor of horses. Animals: Fifteen healthy adult horses with no evidence of ophthalmic disease. Methods: Horses were randomly assigned to a control group and 2 treatment groups of equal sizes (n = 5). Horses assigned to the treatment groups received an NSAID (flunixin meglumine, 1.1 mg/kg PO q24h or firocoxib, 0.1 mg/kg PO q24h for 7 days). Horses in the control group received no medications. Concentrations of flunixin meglumine and firocoxib in serum and aqueous humor and prostaglandin (PG) E₂ in aqueous humor were determined on days 1, 3, and 5 and aqueous : serum ratios were calculated. Results: Firocoxib penetrated the aqueous humor to a significantly greater extent than did flunixin meglumine at days 3 and 5. Aqueous : serum ratios were 3.59 ± 3.32 and 11.99 ± 4.62% for flunixin meglumine and firocoxib, respectively. Ocular PGE₂ concentrations showed no differences at any time point among study groups. Conclusions and Clinical Importance: Both flunixin meglumine and firocoxib penetrated into the aqueous humor of horses. This study suggests that orally administered firocoxib penetrates the aqueous humor better than orally administered flunixin meglumine at label dosages in the absence of ocular inflammation. Firocoxib should be considered for the treatment of inflammatory ophthalmic lesions in horses at risk for the development of adverse effects associated with nonselective NSAID administration.     

Effects of zinc-L-carnosine and vitamin E on aspirin-induced gastroduodenal injury in dogs

Background: Nonsteroidal anti‐inflammatory drugs frequently cause gastrointestinal (GI) injury. Zinc‐l ‐carnosine has antioxidant, anti‐inflammatory, mucosal protective, and healing properties in rodent models and in some human studies of GI injury. Hypothesis: The combination of zinc‐l ‐carnosine and vitamin E attenuates aspirin‐induced gastroduodenal mucosal injury. Animals: Eighteen healthy random‐source Foxhound dogs. Methods: In this randomized, double‐blinded, placebo‐controlled study dogs were treated with placebo (n = 6; 0X group), 30 mg/30 IU (n = 6; 1X group), or 60 mg/60 IU (n = 6; 2X group) zinc‐l ‐carnosine/vitamin E orally every 12 hours for 35 days. Between Day 7 and 35, GI mucosal lesions were induced with aspirin (25 mg/kg PO q8h). Mucosal injury lesions (hemorrhage, erosion, and ulcer) were assessed by gastroduodenoscopy on Days 14, 21, and 35 with a 12‐point scoring scale. Results: At baseline (Day ?1) gastroscopy scores were not significantly different between groups (mean ± SD: 0X, 4.4 ± 0.8; group 1X, 4.4 ± 0.6; group 2X, 4.2 ± 0.3; P= .55). Gastroscopy scores increased significantly in all groups between Day ?1 and Days 14, 21, and 35 (P < .0001). On Day 35, gastroscopy scores were 29.2 ± 5.2 (0X), 27.3 ± 3.7 (1X), and 28.6 ± 3.3 (2X). Mean gastroscopy scores were not significantly different among treatment groups on any of the days (P= .61). Conclusions and Clinical Importance: Administration of the combination of zinc‐l ‐carnosine and vitamin E at 1X or 2X dosing did not attenuate aspirin‐induced gastroduodenal mucosal injury.     

Field Trial Validation of the Efficacy and Acceptability of Firocoxib,a Highly Selective Cox-2 Inhibitor,in a Group of 96 Lame Horses

The objective was to generate evidence for clinical efficacy and acceptability of a second generation coxib, firocoxib, administered orally for 14 days to lame horses under field conditions compared with a classic nonsteroidal anti-inflammatory drug, vedaprofen, in a prospective, randomized, controlled, double-blinded, multicenter field trial. Ninety-six client-owned horses with American Association of Equine Practitioners score of at least grade 3 lameness or grade 2 lameness plus at least a score of 2 for either pain on palpation, range of motion, or joint swelling were analyzed. Horses were administered 0.1 mg/kg firocoxib orally at 24 hour intervals (n = 48) or 1.0 mg/kg vedaprofen paste at 12 hour intervals for 14 days (single loading dose of 2.0 mg/kg vedaprofen) (n = 48). Physical examinations and lameness evaluations were conducted on Day 1 (V1, before treatment) and on Days 7 (V2) and 14 (V3). Blood chemistry and hematology profiles were also evaluated. With regard to the primary variable, clinical improvement, 83% of the firocoxib-treated horses improved at V3 compared with 65% of vedaprofen-treated horses improved meeting the criteria defined to demonstrate noninferiority of firocoxib to vedaprofen. Health and behavioral abnormalities for side effect detection occurred at the rate of 2% (1 horse) and 8% (4 horses) for firocoxib- and vedaprofen-treated horses, respectively. Changes in hematology and blood chemistry values from V1 to V3 were not significantly different between treatment groups. Firocoxib, formulated as an oral paste was highly effective, well tolerated, and acceptable for the control of pain and inflammation associated with lameness in horses under field conditions.     

Effects of the NSAIDs Meloxicam and Indomethacin on Cartilage Proteoglycan Synthesis and Joint Responses to Calcium Pyrophosphate Crystals in Dogs

NSAIDs are a major cause for concern for their propensity to cause joint deterioration in canine, as in human, patients receiving these drugs for treatment of pain in osteoarthritis and other acute and chronic painful conditions. To determine the potential effects of the new NSAID meloxicam on cartilage integrity, the effects of this drug on proteoglycan biosynthesis in vitro and ex vivo were compared with those of indomethacin, a known inhibitor of sulphated proteoglycans that accelerates joint injury in human osteoarthritis.In vitro cartilage proteoglycan synthesis from a radiosulphate precursor was unaffected by 0.5–10.0 mol/L meloxicam but was significantly inhibited by 50 mol/L indomethacin after 6 or 24 h incubation of femoral or tibial cartilage explants in organ culture. This is in accord with previous observations in human or porcine articular cartilage under the same culture conditions.Studies were performed in vivo to establish the effects of the NSAIDs on joint integrity. This involved determining cartilage proteoglycan synthesis ex vivo, leukocyte, fluid and protein accumulation, as well as pain relief. Thus, meloxicam (0.2 mg/kg i.v.×3 doses) or indomethacin (0.5 mg/kg i.v.×3 doses) was given for 26 h and the effects were compared with a control (1.0 ml saline i.v.×3 doses) in dogs in which acute inflammation had been induced by intra-articular (i.a.) injection of calcium pyrophosphate dihydrate (CPPD) crystals into the right stifle joint, an equivalent volume of saline being injected into the left stifle joint as a control. No effects were observed of the treatment with the NSAIDs on ex vivo sulphated proteoglycan synthesis. The lack of the expected inhibitory effects of indomethacin may be related to the relatively low plasma concentrations of this drug obtained during the 26 h period of treatment.The pain response, which was elicited up to 6 h following i.a. injection of CPPD crystals, was totally prevented by the treatment with meloxicam and to a lesser extent with indomethacin. There were no effects from the drug treatment on synovial inflammatory reactions (fluid and cell accumulation), although the protein concentration of the exudate was reduced by meloxicam. This indicates that, at the doses given, it was possible to discriminate the analgesic action from the anti-inflammatory action of the two NSAIDs, this being achieved at relatively low plasma concentrations of these drugs.In conclusion, while relatively high therapeutic concentrations of indomethacin inhibit cartilage proteoglycan synthesis, this is not an effect seen even at high concentrations of meloxicam. Furthermore, the lack of effects on proteoglycan synthesis was evident when these two drugs were given in vivo to dogs. However, the signs of pain, but not the inflammation in the joint, were relieved by low plasma concentrations of the drugs. Meloxicam may thus be safely employed for acute analgesia without the potential risks of joint cartilage damage that occurs with indomethacin given at anti-inflammatory doses for long periods of time.     

Strategies for Increasing Reproductive Efficiency in a Commercial Embryo Transfer Program With High Performance Donor Mares Under Training

Exercise stress has a negative impact on embryo transfer efficiency (ET). For example, a 34% embryo recovery rate, 43% incidence of poor quality embryos, and a 29% pregnancy rate after transfer have been reported. Administration of nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the inflammatory response produced after nonsurgical embryo transfer. In addition, progesterone supplementation is commonly administered to some recipient mares to improve uterine conditions before the transfer and to ensure adequate progestational support compatible with pregnancy. The aim of the study was to evaluate embryo recovery rates using BioRelease deslorelin versus hCG and to increase posttransfer pregnancy rates by jointly administering BioRelease progesterone and a NSAID (flunixin or meloxicam) to recipient mares. Seventeen upper-level showjumping mares stabled and in daily training were used as embryo donors. To induce ovulation, 1-mg IM BioRelease deslorelin (BioRelease Technologies, Lexington, KY) was injected in treated cycles (n = 66), or 2500-IU hCG IV (Ovusyn, Syntex, Buenos Aires, Argentina) was given in control cycles (n = 79) when a ≥35 mm follicle was present. Artificial insemination with extended fresh semen (at least 500 × 10⁶ progressively motile sperm) was carried out in both groups immediately after injecting the ovulation induction agent. Day 8 embryos were recovered and nonsurgically transferred using a speculum and a cervical traction forceps. Recipient mares (n = 73) were randomly assigned to one of three groups: Group A received a single injection of 1.5-g IM BioRelease progesterone (Progesterone LA 300, BioRelease Technologies) and 3 IV injections of 0.5 g of flunixin meglumine (Flunix Deltavet, Argentina), one injection administered the day of the transfer and one on each of the next two successive days. Group B received 1.5-g IM BioRelease progesterone and a single dose of 1.5-g IM BioRelease meloxicam (Meloxicam LA, BioRelease Technologies) at the moment of embryo transfer. Group C did not receive any treatment. Pregnancy diagnosis was carried out 7 days after transfer. Results were analyzed using comparisons of proportions. More embryos were recovered per cycle (13% increase) when donor mares in training were induced to ovulate with BioRelease deslorelin (60.6%; 40/66) than with hCG (46.8%; 37 of 79; P < .05). Although both recipient groups given NSAIDs in combination with BioRelease progesterone numerically had higher pregnancy rates (A: 70.8%; 17/24 and B: 75%; 15/20) compared with nontreated control recipients (47.1%; 33/70), pregnancy rates were significantly higher only in recipients given LA meloxicam treatment at the time of transfer (P < .05). The LA meloxicam is released over a 72-hour period making it more practical to use as it requires a single IM injection versus the 3 IV flunixin meglumine injections. Thus, to minimize the effects of exercise stress on ET efficiency, a combination of BioRelease deslorelin to induce ovulation in donors and BioRelease progesterone and LA meloxicam in recipients at the time of transfer may offer an interesting alternative for improving results in commercial ET programs.