A radiopaque marker was injected, using needles of various lengths, into the cervical musculature, the lumbar epaxial musculature, and the cranial and caudal muscular masses of the thighs of anesthetized dogs. After this procedure, the dogs were euthanatized and deep-frozen. The bodies were then sectioned, and the slices were radiographed to determine the fate of the injected material. Material that was injected into the neck or caudal region of the thigh was determined to be located in the muscle bellies or dispensed throughout the intermuscular fascial sheaths. In contrast, material injected into the lumbar area and cranial region of the thigh was located entirely in the muscle bellies. It was concluded that the best sites for injection in dogs are the lumbar epaxial musculature or the quadriceps femoris muscle when IM administration is imperative.

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.

Polioencephalomalacia (PEM) was induced in calves by feeding a semipurified, low-roughage diet of variable copper and molybdenum composition. Two formulations resulting in Cu-insufficient and Cu-sufficient forms of the diet were fed (n = 10 and 4 calves, respectively); both diets induced PEM. Clinical signs of disease developed as early as 15 days after transition to the experimental diets and included impaired vision, decreased response to external stimuli, and abnormal gait. Grossly evident cerebrocortical lesions consisted of laminar areas of cavitation and/or autofluorescence seen under UV illumination. Hepatic Cu concentration was decreased in calves fed the Cu-insufficient diet, but not below normal range. During the course of feeding either diet, rumen pH decreased, rumen volatile fatty acid concentrations increased, rumen and blood lactic acid concentrations increased, and rumen and plasma thiamine concentrations increased. The thiamine pyrophosphate effect on erythrocyte transketolase activitywas unaltered in calves of either diet group. This nutritionally induced form of PEM does not appear to be related to Cu deficiency or reduction in plasmaor rumen thiamine concentration.

We tested the hypothesis that lymphocytes from swine with susceptibility to malignant hyperthermia (MH) had calcium extrusion activity higher than unaffected swine. Cytoplasmic concentration of ionized calcium was determined by use of dual emission spectrofluorometry and measurement of the ratio of free to calcium-bound form of the fluorescent calcium dye indo-1. Net calcium accumulation and unidirectional calcium extrusion rate were dependent on intracellular calcium concentration. Calcium extrusion from calcium-loaded lymphocytes was monitored while calcium influx was inhibited by suspending the cells in calcium-free medium with a calcium chelator. Net calcium accumulation of untreated lymphocytes was monitored in calcium-replete medium. A novel method of calculation of ionized calcium was used. This method confirmed our previous findings of lower ionized calcium concentration (86 +/- 40 and 370 +/- 216 nmol/L; P < 0.01) and slower rates of calcium accumulation (39 +/- 16 and 127 +/- 52 nmol/L/min) in untreated lymphocytes from MH-susceptible swine compared with controls. These changes were attributable to calcium extrusion activity two- to three-fold higher in lymphocytes of MH-susceptible swine (154 +/- 36 and 408 +/- 47 nmol/L/min at 175 nmol/L; 972 +/- 111 and 1,690 +/- 505 nmol/L/min at 425 nmol/L). These data were compatible with our model of higher calcium extrusion activity being a compensatory adaptation of MH-susceptible swine lymphocytes to their hypersensitivity to stimuli that increase cytoplasmic calcium concentration.

Pharmacokinetic variables of etomidate were determined after IV administration of etomidate (3.0 mg/kg of body weight). Blood samples were collected for 6 hours. Disposition of this carboxylated imidazole best conformed to a 2- (n = 2) and a 3- compartment (n = 4) open pharmacokinetic model. The pharmacokinetic values were calculated for the overall best-fitted model, characterized as a mixed 2- and 3-compartmental model. The first and most rapid distribution half-life was 0.05 hour and a second distribution half-life was 0.35 hour. Elimination half-life was 2.89 hours, apparent volume of distribution was 11.87 +/- 4.64 L/kg, apparent volume of distribution at steady state was 4.88 +/- 2.25 L/kg, apparent volume of the central compartment was 1.17 +/- 0.70 L/kg, and total clearance was 2.47 +/- 0.78 L/kg/h.

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.

The pharmacokinetics of flunixin were studied in 6 adult lactating cattle after administration of single IV and IM doses at 1.1 mg/kg of body weight. A crossover design was used, with route of first administration in each cow determined randomly. Plasma and milk concentrations of total flunixin were determined by use of high-pressure liquid chromatography, using an assay with a lower limit of detection of 50 ng of flunixin/ml. The pharmacokinetics of flunixin were best described by a 2-compartment, open model. After IV administration, mean plasma flunixin concentrations rapidly decreased from initial concentrations of > 10 micrograms/ml to nondetectable concentrations at 12 hours after administration. The distribution phase was short (t1/2 alpha, harmonic mean = 0.16 hours) and the elimination phase was more prolonged (t1/2 beta, harmonic mean = 3.14 hours). Mean +/- SD clearance after IV administration was 2.51 +/- 0.96 ml/kg/min. After IM administration, the harmonic mean for the elimination phase (t1/2 beta) was prolonged at 5.20 hours. Bioavailability after IM dosing gave a mean +/- SD (n = 5) of 76.0 +/- 28.0%. Adult lactating cows (n = 6) were challenge inoculated with endotoxin as a model of acute coliform mastitis. After multiple administration (total of 7 doses; first IV, remainder IM) of 1.1 mg/kg doses of flunixin at 8-hour intervals, plasma flunixin concentrations were approximately 1 microgram/ml at 2 hours after each dosing and 0.5 microgram/ml just prior to each dosing. Flunixin was not detected in milk at any sampling during the study. Flunixin concentrations necessary to induce therapeutic effects in cattle are unknown. Results of our study indicate that administration of 1.1 mg/kg doses of flunixin meglumine at 8-hour intervals would produce plasma concentrations similar to those demonstrated to be effective clinically in treatment of equine musculoskeletal disorders and colic.

Using arthroscopic technique, identical diameter defects were created in the proximal articular surface of both intermediate carpal bones of 6 horses. One of each pair of defects was deepened to penetrate the subchondral plate. Removed cartilage was assayed for [35S] sulfate incorporation, total hexosamine content, and DNA content. Six weeks later, cartilage was harvested and similarly analyzed from the distolateral portion of the radius directly opposite the created lesions and the distomedial portion of the radius distant from the lesion. The repair tissue filling the full-thickness defect and the cartilage at the periphery of the partial-thickness lesion also were analyzed. There was a marked increase in synthetic activity (35S sulfate incorporation) opposite the full-thickness defect, compared with the cartilage opposite the partial-thickness defect. A marked decrease in glycosaminoglycan content in the cartilage opposite the full-thickness defect was found as compared with that opposite the partial-thickness defect. The repair tissue filling the full-thickness defect was highly cellular, high in synthetic activity, but low in glycosaminoglycan content. Insignificant changes occurred in the cartilage adjacent to the partial-thickness defect. On the basis of these results, we suggest that full-thickness defects at 6 weeks result in more detrimental change to the cartilage opposite it than do partial-thickness lesions of the same diameter.

Hypochloremic metabolic alkalosis accompanied by hypokalemia and hyponatremia was induced experimentally in 7 adult sheep by diversion (loss) of gastric contents through an Ivan and Johnston cannula placed in the cranial part of the duodenum just distal to the pylorus. Cannula placement was easily accomplished, and cannulae were tolerated well by the sheep. Volume of effluent produced during the 60- to 120-hour period of diversion ranged from 7.7 to 14.9 L and tended to be greatest during the first 24 hours. All sheep became dehydrated, with mean PCV and plasma total protein concentration increases of 94.2 and 61.7%, respectively. Plasma chloride concentration decreased in linear fashion from a prediversion mean of 113 mEq/L (range, 111 to 117 mEq/L) to an end-point mean of 54 mEq/L (range, 45 to 65 mEq/L). Plasma sodium and potassium concentrations also decreased, though potassium concentration increased terminally. There were rapid increases in arterial blood pH and bicarbonate and base excess concentrations during the first 48 hours after diversion. However, during the final stages of diversion, sheep developed superimposed metabolic acidosis with increased plasma lactate concentration and high anion gap.

Low molecular weight polysulfated glycosaminoglycan (PSGAG) stimulated net collagen and glycosaminoglycan synthesis by normal and arthritic equine fetlock cartilage tissues in organ culture. Arthritic tissues were more sensitive to PSGAG stimulation. The rates of cartilage-specific type-II collagen and chondroitin sulfate-rich glycosaminoglycan synthesis by confluent chondrocyte cell cultures obtained from normal and arthritic equine cartilage tissues were increased by 25 and 50 mg of PSGAG/ml. Cells from arthritic cartilage were also more sensitive to the presence of PSGAG. In addition, concentrations of PSGAG (25 and 50 mg/ml) approximate to those in synovial fluid after intra-articular injection of 250 mg of PSGAG inhibited the rate of collagen and glycosaminoglycan degradation in cell culture. These findings suggest that PSGAG may have a role in the healing of mild cartilage degeneration by encouraging the production of replacement hyaline matrix materials, while delaying their subsequent degradation. In contrast, growth of cell cultures was inhibited by PSGAG, suggesting that these compounds may fail to stimulate chondrocyte replication, a prerequisite for tissue regeneration. Nonetheless, these observations provide direct evidence of a truly chondroprotective role for low molecular weight PSGAG in the treatment of equine degenerative joint disease.