Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in veterinary medicine. They are used in pain control and in anti-inflammatory and antipyretic therapies. Some NSAIDs, e.g piroxicam, also have a documented anticancer effect. The objective of this study was to evaluate which of the commonly used NSAIDs (etodolac, flunixin, tolfenamic acid, carprofen, and ketoprofen) are cytotoxic to the D-17 cell line of canine osteosarcoma. The viability of the cells was evaluated using the MTT assay. Four independent repetitions were performed and the results are given as the average of these values; EC₅₀ values (half maximal effective concentration) were also calculated. The analysis of results showed that carprofen and tolfenamic acid displayed the highest cytotoxicity. Other drugs either did not provide such effects or they were very poor. For carprofen, it was possible to determine an EC₅₀ which fell within the limits of concentrations obtainable in canine serum after the administration of routinely used doses. The results are promising but further studies should be conducted to confirm them, since this study is only preliminary. The possibility of introducing carprofen and tolfenamic acid into the routine treatment of osteosarcoma in dogs should be considered.

OBJECTIVE: To assess the analgesic efficacy of an IV constant rate infusion (CRI) of a morphine-lidocaine-ketamine (MLK) combination in calves undergoing umbilical herniorrhaphy. ANIMALS: 20 weaned Holstein calves with umbilical hernias. PROCEDURES: Calves were randomly assigned to receive a CRI of an MLK solution (0.11 mL/kg/h; morphine, 4.8 μg/kg/h; lidocaine, 2.1 mg/kg/h; and ketamine, 0.42 mg/kg/h) for 24 hours (MLK group) or 2 doses of flunixin meglumine (1.1 mg/kg, IV, q 24 h) and a CRI of saline (0.9% NaCl) solution (0.11 mL/kg/h) for 24 hours (control group). The assigned CRI was begun after anesthesia induction. A pain-scoring system and incisional algometry were used to assess pain, and blood samples were obtained to measure serum cortisol concentration at predetermined times for 120 hours after CRI initiation. RESULTS: Mean pain scores did not differ significantly between the MLK and control groups at any time. Mean algometry score for the MLK group was significantly greater (calves were less responsive to pressure) than that for the control group at 4 hours after CRI initiation. Mean cortisol concentration decreased over time for both groups and was significantly greater for the MLK group than the control group at 1, 4, and 18 hours after CRI initiation. CONCLUSIONS AND CLINICAL RELEVANCE: A CRI of MLK provided adequate postoperative analgesia to calves that underwent umbilical herniorrhaphy. However, the technical support required for CRI administration limits its use to hospital settings. Kinetic analyses of MLK infusions in cattle are necessary to establish optimal dosing protocols and withdrawal intervals.

OBJECTIVE To describe plasma pharmacokinetic parameters and tissue elimination of flunixin in veal calves. ANIMALS 20 unweaned Holstein calves between 3 and 6 weeks old. PROCEDURES Each calf received flunixin (2.2 mg/kg, IV, q 24 h) for 3 days. Blood samples were collected from all calves before the first dose and at predetermined times after the first and last doses. Beginning 24 hours after injection of the last dose, 4 calves were euthanized each day for 5 days. Plasma and tissue samples were analyzed by ultraperformance liquid chromatography. Pharmacokinetic parameters were calculated by compartmental and noncompartmental methods. RESULTS Mean ± SD plasma flunixin elimination half-life, residence time, and clearance were 1.32 ± 0.94 hours, 12.54 ± 10.96 hours, and 64.6 ± 40.7 mL/h/kg, respectively. Mean hepatic and muscle flunixin concentrations decreased to below FDA-established tolerance limits (0.125 and 0.025 μg/mL, respectively) for adult cattle by 3 and 2 days, respectively, after injection of the last dose of flunixin. Detectable flunixin concentrations were present in both the liver and muscle for at least 5 days after injection of the last dose. CONCLUSIONS AND CLINICAL RELEVANCE The labeled slaughter withdrawal interval for flunixin in adult cattle is 4 days. Because administration of flunixin to veal calves represents extralabel drug use, any detectable flunixin concentrations in edible tissues are considered a violation. Results indicated that a slaughter withdrawal interval of several weeks may be necessary to ensure that violative tissue residues of flunixin are not detected in veal calves treated with that drug.

The pharmacokinetic aspects of tulathromycin (2.5 mg/kg b.w.) were studied following intravenous administration alone and in combination with flunixin meglumine (2.2 mg/kg b.w) in apparently healthy goats. Tulathromycin concentrations in serum were determined by microbiological assay technique using Bacillus subtiles (ATCC 66343) as test organism. The half-lives of distribution and elimination (t0.5(a)and to.5(p)) were 0.071, 0.046 and 6.43, and 5.05 h. following intravenous injection of tulathromycin alone and in combination with flunixin, respectively. Volume of distribution at steady state (Vdss) was 0.249 and 0.96l/kg., mean residence time (MRT) was 6.27 and 5.99 h and total body clearance (ClB) was 0.046 and 0.17 l/kg/hr., respectively. It was concluded that flunixin significantly altered the pharmacokinetics of tulathromycin by increase its distribution and accelerate its elimination from body. Therefore care should be taken during use of tulathromycin in goats concurrently with flunixin.

OBJECTIVE To evaluate ex vivo cyclooxygenase (COX) inhibition and compare in vitro and ex vivo COX-1 inhibition by flunixin meglumine and firocoxib in horses. ANIMALS 4 healthy horses for in vitro experiments and 12 healthy horses (6 males and 6 females; 5 Thoroughbreds, 5 Warmbloods, and 2 ponies) undergoing elective surgery for ex vivo experiments. PROCEDURES 12 horses received flunixin meglumine (1.1 mg/kg, IV, q 12 h) or firocoxib (0.09 mg/kg, IV, q 24 h). Blood samples were collected before (baseline) and 2 and 24 hours after NSAID administration. Prostanoids (thromboxane B2, prostaglandin E2, and prostaglandin E metabolites) served as indicators of COX activity, and serum drug concentrations were measured by use of high-performance liquid chromatography. An in vitro coagulation-induced thromboxane B2 assay was used to calculate drug concentration-COX-1 inhibition curves. Effect of time and treatment on COX activity was determined. Agreement between in vitro and ex vivo measurement of COX activity was assessed with Bland-Altman analysis. RESULTS At 2 and 24 hours after NSAID administration, COX-1 activity was reduced, compared with baseline activity, for the flunixin meglumine group only and relative COX-1 activity was significantly greater for the firocoxib group, compared with that for the flunixin meglumine group. There was no significant change in COX-2 activity after surgery for either group. Bland-Altman analysis revealed poor agreement between in vitro and ex vivo measurement of COX-1 activity. CONCLUSIONS AND CLINICAL RELEVANCE Compared with flunixin meglumine, firocoxib had COX-1-sparing effects ex vivo in equine patients that underwent elective surgery.

A rabbit serosal scarification model was utilized to compare the ability of four drugs, previously administered peri-operatively to horses undergoing exploratory celiotomy, to prevent the development of postoperative intestinal adhesions. The substances compared were 32% Dextran 70 (7 mL/kg), 1% sodium carboxymethylcellulose (7 mL/kg), trimethoprim-sulfadiazine (30 mg/kg), and flunixin meglumine (1 mg/kg). The first two were administered intra-abdominally following surgery, while the latter two were administered systemically in the peri-operative period. Fibrous adhesions were evident in all animals in the untreated serosal scarification group. No significant difference in the number of animals with adhesions was found between the untreated control group and any treatment group, nor among the treatment groups. Microscopic examination of adhesions collected at postmortem examination revealed fibers consistent with cotton, surrounded by a giant-cell reaction and ongoing acute inflammation. The source of the fibers was likely the cotton laparotomy sponges used to scarify the intestinal surface, since the pattern in the granuloma and sponge fibers appeared similar under polarized light. Though consistent intestinal adhesion formation was produced in the rabbit, the presence of foreign body granulomas may prevent consideration of this model for future research. The drugs tested were ineffective in preventing the formation of postoperative small intestinal adhesions in this model.

A high-performance liquid chromatography method was developed for determination of flunixin in bovine plasma. The extraction procedure was easily performed and made it possible to detect low concentrations of flunixin with high accuracy. The limit of quantitation was 7 ng/ml (relative standard deviation = 18%, n = 10). The analytic method permits processing of 60 samples/d. Flunixin, as well as the internal standard (diclofenac sodium), belong to the group of nonsteroidal anti-inflammatory drugs, which are known to have a high degree of binding to plasma proteins. Therefore, an evaluation of several buffer systems was undertaken to optimize analytic conditions. Cattle were given 2.2 mg of flunixin meglumine/kg of body weight. In experiment 1, single injections were administered IV to q cow and IM to 1 heifer (7 days apart), and pharmacokinetic variables were calculated. The IV data were best described by a two-compartment model. The half-life after single IV or IM administration was around 4.0 hours. In experiment 2, the decreasing flunixin concentration was determined after the last of either 4 IM injections daily (n = 3 cows) or 2 IM injections daily (n = 3 cows) administered during a 14-day postpartum period. The half-life, determined between 48 and 96 hours after the last dose, was approximately 26 hours in both groups, and flunixin could be detected in plasma up to 8 days, on average. The protein binding of flunixin was studied, using the method of equilibrium dialysis. Flunixin was found to have a high degree of protein binding (ie, 99.4 +/- 0.2%) at a flunixin concentration in plasma of 3 to micrograms/ml. Differences in protein binding between cattle were not found.

Pharmacokinetic and pharmacodynamic variables of flunixin were studied in calves after IV administration of the drug at a dose rate of 2.2 mg/kg of body weight. The anti-inflammatory properties of flunixin were investigated, using a model of acute inflammation; this involved surgically implanting tissue cages at subcutaneous sites and stimulating the tissue cage granulation tissue by intracavitary injection of carrageenan. The actions of flunixin on exudate concentrations of several substances related to the inflammatory process, including proteases (metalloprotease [active and total] and cysteine and serine proteases), enzymes (lactate dehydrogenase, acid phosphatase, and beta-glucuronidase [beta-glu]), eicosanoid (prostaglandin E2 [PGE2], leukotriene B4, and serum thromboxane B2 [TXB2]) concentrations, and bradykinin (BK)-induced edema, were investigated. Flunixin had a long elimination half-life--6.87 +/- 0.49 hours--and volume of distribution was 2.11 +/- 0.37 L/kg, indicating extensive distribution of the drug in the body. Body clearance was 0.20 +/- 0.03 L/kg/h. Flunixin exerted inhibitory effects on serum TXB2 and exudate PGE2 concentrations, B-glu activity, and BK-induced swelling. Other enzymes and inflammatory mediators were not significantly affected. Pharmacokinetic/pharmacodynamic modeling of the data revealed similar mean concentration producing 50% of the maximal effect values for inhibition of exudate PGE2 and beta-glu and of BK-induced swelling (0.070 +/- 0.006, 0.064 +/- 0.040, and 0.061 +/- 0.030 microgram/ml), respectively). A lower concentration producing 50% of the maximal effect value was obtained for inhibition of serum TXB2 concentration (0.023 +/- 0.004 microgram/ml). Differences also were observed in equilibration half-life for these actions, suggesting the existence of 3 distribution compartments correlating with 3 sites of action--a central compartment and shallow and deep peripheral compartments. Pharmacokinetic/pharmacodynamic modeling proved to be a useful analytical method, providing a quantitative description of in vivo drug pharmacodynamics and indicating possible mechanisms of action.

Saline (0.9% NaCl) solution or 1 of 3 nonsteroidal anti-inflammatory drugs (NSAID) was administered IV to 5 neonatal calves 15 minutes after the start of a 3-hour IV infusion of Escherichia coli lipopolysaccharide (LPS; 2 micrograms/kg/h). Four additional calves were given a 3-hour IV infusion of saline solution alone. Clinical attitude, mean arterial blood pressure, PCV, WBC, and plasma lactate, glucose, and eicosanoid concentrations (thromboxane B2, 6-keto-PGF(1 alpha)) were monitored for 12 hours. Flunixin meglumine (1.1 mg/kg of body weight, IV), ketoprofen (2.2 mg/kg, IV), and ketorolac tromethamine (1.1 mg/kg, IV) each ameliorated the clinical signs of endotoxemia and LPS-induced lacticemia, but failed to significantly alter the degree of leukopenia or hypoglycemia associated with infusion of LPS. Although the 3 NSAID prevented eicosanoid production, they provided only partial protection against LPS-induced hypotension. Each NSAID modified the response to LPS, but none was clearly superior to the others in modulating the clinical signs or physiologic alterations induced by infusion of LPS in neonatal calves.

Dogs were treated with the cyclo-oxygenase inhibitors flunixin meglumine IV or flurbiprofen topically. Acute inflammation was induced in the eyes by disruption of the anterior lens capsule, using a neodymium:yttrium aluminum garnet laser. Pupil diameter and intraocular pressure were measured before and after inducing ocular inflammation. Both drugs maintained mydriasis and increased intraocular pressure in the inflamed eyes, compared with untreated controls.