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.

Twenty newborn Holstein calves were allotted at random to 4 groups: group A received 0.9% sterile saline solution; group B received phenylbutazone (5 mg/kg of body weight, IV) and 0.9% sterile saline solution; group C received progressively increasing doses of endotoxin (0.1 to 15 micrograms/kg); and group D received phenylbutazone and endotoxin similarly as did calves of groups B and C, respectively. Phenylbutazone was given once daily and saline solution or endotoxin were given every 8 hours for 5 days. Clinical variables-PCV, plasma total protein and fibrinogen concentrations, platelet count, prothrombin time, activated partial thromboplastin time, and fibrin degradation products concentration were measured at 24-hour intervals. Necropsy was performed on each calf. Phenylbutazone suppressed the clinical response to endotoxin challenge until large doses (7.5 to 15 micrograms/kg) were administered. Calves of groups C and D remained stable until they abruptly developed severe dyspnea necessitating euthanasia. Thrombocytopenia and leukopenia developed after the initial endotoxin dose. Prothrombin time was prolonged and PCV suddenly decreased at 96 hours. Necropsy revealed consistent lesions in the vascular endothelium and lungs. Phenylbutazone administration did not enhance or ameliorate endotoxin-induced hemostatic alterations or pathologic lesions.

Ten healthy sedentary male Thoroughbreds with previous race training experience were studied for 14 weeks. Horses were trained for 9 weeks, using a program designed after those used commonly in the United States. Horses were trained conventionally by slow trotting (250 m/min) for 2 weeks and galloping (390 to 450 m/min) for 4 weeks, followed by 3 weeks of galloping (440 to 480 m/min) and intermittent sprinting exercises (breezes) at distances between 600 and 1,000 m (900 to 950 m/min). The horses were then pasture rested for 5 weeks. A standardized exercise test (SET) involving an 800-m gallop at 800 m/min was administered before and after the 9-week training period and after the 5-week detraining period. Heart rate (HR) was monitored during exercise and at standardized intervals after exercise for 60 minutes. Venous blood for determination of plasma lactate concentration was obtained at 5 minutes after exercise. Heart rate was monitored daily at rest, during exercise, and through the first 60 minutes of recovery. Venous plasma samples (for lactate determination) were obtained 5 minutes after the sprinting exercises. Horses were observed daily before exercise for signs of lameness and were not allowed to train if lame. Differences after 9 weeks' training were seen in the SET recovery HR at 0.5 through 5 minutes after exercise (P < 0.05 to P < 0.01). Differences after detraining were seen in the SET recovery HR at 40 and 60 minutes after exercise (P < 0.05 to P < 0.01). Neither training nor detraining resulted in differences in plasma lactate concentration after the SET gallop. A training-induced resting bradycardia was not observed. The mean maximal HR (HRmax) during workouts was 238 +/- 3.4 beats/min (n = 9). When exercise HR was expressed as a function of HRmax, 22% of trotting, 89% of galloping, and 100% of sprinting workouts were performed at the greater than or equalto 60% HRmax value characterized by the onset of blood lactate accumulation. Plasma lactate concentration further documented that all the sprinting exercises were performed with concentration above the point of onset of blood lactate accumulation. Mean postsprinting lactate concentration was not different over time and ranged from 13.4 +/- 0.9 to 15.6 +/- 0.6 mmol/l. As training progressed, some of the horses had days on which they were lame after exercise. Some lameness was judged sufficient to warrant phenylbutazone (PBZ) administration. Retrospective analysis of the daily HR data indicated that there were no differences in HR during workouts for lame horses given PBZ, compared with those not given PBZ. Using analysis of variance, HR for horses that were lame during workouts was significantly higher than that for horses that were sound during workouts, during and 0.5 minutes after trotting; 0.5, 1, 2, 20, 40, and 60 minutes after galloping; and 0.5 and 20 minutes after sprinting (P < 0.05 to P < 0.01).

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.

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.

The objectives of this experiment were to determine serum concentrations of triiodothyronine (T3), thyroxine (T4), and free thyroxine (fT4) at rest, following thyroid-stimulating hormone (TSH) administration, and following phenylbutazone administration in healthy horses. This was done to determine which available laboratory test can best be used for diagnosis of hypothyroid conditions in horses. Serum T3, T4, and fT4 concentrations in serum samples obtained before and after TSH stimulation and following phenylbutazone administration for 7 days were determined. Baseline values ranged from 0.21 to 0.80 ng of T3/ml, 6.2 to 25.1 ng of T4/ml, and 0.07 to 0.47 ng of fT3/dl. After 5 IU of TSH was administered IV, serum T3 values increased to 6 times baseline values in 2 hours. Thyroxine values increased to 3 times baseline values at 4 hours and remained high at 6 hours. Free T4 values increased to 4 times baseline values at 4 hours and remained high at 6 hours. Administration of 4.4 mg of phenylbutazone/kg, every 12 hours for 7 days significantly decreased T4 and fT4 values, but did not significantly affect serum T3 concentrations, It was concluded that a TSH stimulation test should be performed when hypothyroidism is suspected. Measurement of serum fT4 concentrations, by the single-stage radioimmunoassay, does not provide any additional information about thyroid gland function over that gained by measuring T4 concentrations. Phenylbutazone given at a dosage of 4.4 mg/kg every 24 hours, for 7 days did significantly decrease resting T4 and fT4 concentrations, but did not significantly affect T3 concentrations in horses.

The pattern of vertical ground reaction force redistribution among limbs during episodes of acute synovitis of the stifle in 12 mixed-breed dogs was investigated as an adjunct to a blinded nonsteroidal anti-inflammatory drug efficacy study. Without regard to drug efficacy groupings, the redistribution of vertical forces before and during the acute synovitis episode was evaluated by analysis of gait, using a force platform. Acute synovitis was induced by intrasynovial injection of sodium urate crystals. Simultaneously, each dog was given 1 of 4 treatment regimens, including IV injection of sterile saline solution (as a negative control), phenylbutazone (as a positive control), or 1 of 2 proprietary nonsteroidal anti-inflammatory drugs. Postinjection analyses took place at 2, 4, 8, 12, 24, and 36 hours. The peak vertical force redistribution in the 3 untreated limbs of the dogs was described. The greatest redistribution sm observed 4 hours after substance injection when the synovitis was clinically at maximum. Thereafter, there was steady improvement and the dogs had a clinically normal gait 24 hours after substance injection. During synovitis, peak vertical force increased in the contralateral hind limb. During the more severe synovitis episodes, force was decreased in both forelimbs. There was good correlation between severity of lameness and peak vertical force response in the contralateral hind limb. Results of the study indicate that the untreated limbs of the same animal should not be used as a control during acute lameness studies.