The effect of premedication with phenylbutazone on systemic hemodynamic and diuretic effects of furosemide was examined in 6 healthy, conscious, mares. Mares were instrumented for measurement of systemic hemodynamics, including cardiac output and pulmonary arterial, systemic arterial, and intracardiac pressures, and urine flow. Each of 3 treatments was administered in a randomized, blinded study; furosemide (1 mg/kg of body weight, IV) only, phenylbutazone (8.8 mg/kg PO, at 24 hours and 4.4 mg/kg IV, 30 minutes before furosemide) and furosemide, or 0.9% NaCl. Phenylbutazone administration significantly attenuated, but did not abolish, the diuretic effect of furosemide. Phenylbutazone completely inhibited the immediate effect of furosemide on cardiac output, stroke volume, total peripheral resistance, and right ventricular peak pressure. Premedication with phenylbutazone did not inhibit equally the diuretic and hemodynamic effects of furosemide, indicating that some of furosemide's hemodynamic effects are mediated by an extrarenal activity of furosemide.

Objective-To assess gene expressions of cyclooxygenase-1 and -2 in oral, glandular gastric, and urinary bladder mucosae and determine the effect of oral administration of phenylbutazone on those gene expressions in horses. Animals-12 healthy horses. Procedures-Horses were allocated to receive phenylbutazone or placebo (6 horses/group); 1 placebo-treated horse with a cystic calculus was subsequently removed from the study, and those data were not analyzed. In each horse, the stomach and urinary bladder were evaluated for ulceration via endoscopy before and after experimental treatment. Oral, glandular gastric, and urinary bladder mucosa biopsy specimens were collected by use of a skin punch biopsy instrument (oral) or transendoscopically (stomach and bladder) before and after administration of phenylbutazone (4.4 mg/kg, PO, q 12 h) in corn syrup or placebo (corn syrup alone) for 7 days. Cyclooxygenase-1 and -2 gene expressions were determined (via quantitative PCR techniques) in specimens collected before and after the 7-day treatment period and compared within and between groups. Prior to commencement of treatment, biopsy specimens from 7 horses were used to compare gene expressions among tissues. Results-The cyclooxygenase-1 gene was expressed in all tissues collected. The cyclooxygenase-2 gene was expressed in the glandular gastric and bladder mucosae but not in the oral mucosa. Cyclooxygenase gene expressions were unaffected by phenylbutazone administration. Conclusions and Clinical Relevance-Cyclooxygenase-2 was constitutively expressed in glandular gastric and bladder mucosae but not in the oral mucosa of healthy horses. Oral administration of phenylbutazone at the maximum recommended dosage daily for 7 days did not affect cyclooxygenase-1 or -2 gene expression.

The effect of premedication with phenylbutazone on systemic hemodynamic and diuretic effects of furosemide was examined in 6 healthy, conscious, mares. Mares were instrumented for measurement of systemic hemodynamics, including cardiac output and pulmonary arterial, systemic arterial, and intracardiac pressures, and urine flow. Each of 3 treatments was administered in a randomized, blinded study; furosemide (1 mg/kg of body weight, IV) only, phenylbutazone (8.8 mg/kg PO, at 24 hours and 4.4 mg/kg IV, 30 minutes before furosemide) and furosemide, or 0.9% NaCl. Phenylbutazone administration significantly attenuated, but did not abolish, the diuretic effect of furosemide. Phenylbutazone completely inhibited the immediate effect of furosemide on cardiac output, stroke volume, total peripheral resistance, and right ventricular peak pressure. Premedication with phenylbutazone did not inhibit equally the diuretic and hemodynamic effects of furosemide, indicating that some of furosemide's hemodynamic effects are mediated by an extrarenal activity of furosemide.

Single doses (2.2 mg/kg of body weight) of phenylbutazone (PBZ) were administered IV to 6 neonatal horses (5 to 17 hours old at time of dosing). Plasma concentrations of PBZ and its metabolite oxyphenbutazone were monitored serially for 120 hours after drug administration. Pharmacokinetic variables were calculated, using 1- and 2-compartment open models. Descriptive equations from the best model for each foal were then used to derive model-independent variables describing PBZ disposition. Median volume of distribution at steady-state was 0.274 L/kg (range, 0.190 to 0.401 L/kg). Median terminal half-life was 7.4 (6.4 to 22.1) hours, and median total plasma clearance of PBZ for foals in this study was 0.018 L/kg/h (range, 0.013 to 0.038 L/kg/h). Volume of distribution was larger, half-life was longer, and total clearance was lower, compared with similar values reported for administration of PBZ to adult horses.

Six mature Holstein bulls were given an 8-day course of phenylbutazone (PBZ) orally (loading dose, 12 mg of PBZ/kg of body weight and 7 maintenance doses of 6 mg of PBZ/kg, q 24 h). Plasma concentration-vs-time data were analyzed, using nonlinear regression modeling. The harmonic mean +/- pseudo-SD of the biologic half-life of PBZ was 61.8 +/- 12.8 hours. The arithmetic mean +/- SEM of the total body clearance and apparent volume of distribution were 0.0021 +/- 0.0001 L/h/kg and 0.201 +/- 0.009 L/kg, respectively. The predicted mean minimal plasma concentration of PBZ with this dosage regimen was 75.06 +/- 4.05 microgram/ml. The predicted minimal plasma drug concentration was compared with the observed minimal plasma drug concentration in another group of bulls treated with PBZ for at least 60 days. Sixteen mature Holstein bulls were given approximately 6 mg of PBZ/kg, PO, daily for various musculoskeletal disorders. The mean observed minimal plasma concentration of PBZ in the 16 bulls was 76.10 +/- 2.04 microgram/ml, whereas the mean predicted minimal plasma concentration was 74.69 +/- 3.10 microgram/ml. Dosages of 4 to 6 mg of PBZ/kg, q 24 h, or 10 to 14 mg of PBZ/kg, q 48 h, provided therapeutic plasma concentrations of PBZ with minimal steady-state concentrations between 50 and 70 microgram/ml.

Six mature Holstein bulls were each given 10 mg of phenylbutazone (PBZ)/kg of body weight, PO. Of the 6 bulls, 3 were given 10 mg of PBZ/kg by rapid IV administration 4 weeks later. Plasma concentration-vs-time data were analyzed, using nonlinear regression modeling (sum of exponential functions). The harmonic mean of the biologic half-life of PBZ was 62.6 +/- 12.9 hours after oral administration and 61.6 +/- 7.2 hours after IV administration. The mean residence time was 94.61 +/- 8.44 hours and 90.49 +/- 8.93 hours for oral and IV administration, respectively. The mean total body clearance was 0.0015 +/- 0.0003 L/h/kg, with the mean apparent volume of distribution 0.134 +/- 0.021 L/kg. Mean bioavailability was 73 +/- 2% after oral administration. Phenylbutazone was adequately absorbed from the gastrointestinal tract in bulls. The apparent volume of distribution was small, indicating that PBZ distributed mainly into plasma and extracellular fluid. The total body clearance was also small, which accounted for the long half-life of PBZ in bulls.

Objective—To compare the effects of 2 NSAIDs (phenylbutazone and meloxicam) on renal function in horses. Animals—9 Thoroughbred or Standardbred mares (mean ± SD age, 5.22 ± 1.09 years [range, 2 to 12 years]; mean body weight, 470 ± 25 kg [range, 442 to 510 kg]). Procedures—A randomized blinded placebo-controlled crossover study was conducted to examine the effects of treatment with phenylbutazone, meloxicam, or a placebo (control solution) on renal responses to the administration of furosemide, dobutamine, and exercise (15 minutes at 60% of maximum heart rate). Renal function was assessed by use of bilateral ureteral catheterization for simultaneous determination of creatinine clearance, sodium excretion, and urine flow rate. Results—Both phenylbutazone and meloxicam attenuated diuresis and natriuresis and reduced glomerular filtration rate, compared with results for the control solution, when horses were treated with furosemide. Mean arterial blood pressure, urine flow rate, and glomerular filtration rate were increased during or after (or both) dobutamine infusion. Both NSAIDs reduced urine flow rate and sodium excretion associated with dobutamine infusion and exercise but had no effect on glomerular filtration rate. Conclusions and Clinical Relevance—Responses to meloxicam, a cyclooxygenase (COX)-2 preferential agent, appeared comparable to those detected after phenylbutazone treatment, which suggested that COX-2 was the mediator of prostanoid-induced changes to renal function in horses and indicated that COX-2–preferential agents would be likely to have adverse renal effects similar to those for nonselective COX inhibitors in volume-depleted horses.

Objective-To determine the effects of recombinant equine interleukin -1beta (reIL-1beta) and 4 anti-inflammatory compounds on the expression and activity of cyclooxygenase (COX)-2 in cultured equine chondrocytes. Sample Population-Articular cartilage from 9 young adult horses. Procedure-Reverse transcriptase-polymerase chain reaction methods were used to amplify a portion of equine COX-2 to prepare a cDNA probe. Northern blot analysis was used to quantify the expression of COX-2 in first-passage cultures of equine articular chondrocytes propagated in media containing dexamethasone (DEX), phenylbutazone (PBZ), polysulfated glycosaminoglycan, and hyaluronan, each at concentrations of 10 and 100 micrograms/ml and each with or without reIL-1beta. A commercial immunoassay was used to determine prostaglandin E2 (PGE2) concentrations in conditioned medium of similarly treated cells to quantify COX-2 activity. Results-Addition of reIL-1beta increased the expression of COX-2 in a dose-dependent manner, which was paralleled by an increased concentration of PGE2 in culture medium. Concentration of PGE2 in spent medium from reIL-1beta-treated chondrocytes was significantly reduced by DEX and PBZ; however, only DEX significantly reduced gene expression of COX-2. Conclusions and Clinical Relevance-Prostaglandin E2 is considered to be an important mediator in the pathophysiologic processes of arthritis, and cultured chondrocytes respond to interleukin-1 with enhanced expression and activity of COX-2. Palliative relief in affected horses is probably attributable, in part, to inhibition of PGE2 synthesis; however, analysis of these data suggests that of the 4 compounds tested, only DEX affects pretranslational regulation of the COX-2 gene in cultured equine chondrocytes.