Summary The analgesic effects of the nonsteroidal anti‐inflammatory drugs, ketoprofen (2.2 and 3.63 mg/kg bwt) and phenylbutazone (4.4 mg/kg bwt) were compared in 7 horses with chronic laminitis. Hoof pain was quantified objectively by means of an electronic hoof tester and lameness was subjectively graded on a modified Obel scale. Ketoprofen at a dose of 3.63 mg/kg bwt (phenylbutazone equimolar dose) reduced hoof pain and lameness to a greater extent than the 2.2 mg/kg dose and phenylbutazone. These effects were still present at 24 h in 3 of the 4 pain tests, including lameness grade. These data suggest that ketoprofen at the dosage rate of 1.65 times the recommended therapeutic dose was more potent than phenylbutazone in alleviating chronic pain and lameness in horses.

The pharmacokinetic properties of a single intravenous dose of ketoprofen (2.2 mg/kg) in plasma and synovial fluid were compared in four healthy animals and four horses with experimentally induced acute synovitis. Synovitis was induced by the injection of a 1% solution of sterile carrageenan into the left intercarpal joint. Ketoprofen was administered at the same time as carrageenan infection. The plasma disposition followed a biexponential equation or a two-compartment model in most horses. The plasma harmonic mean half-life in healthy horses (0.88 h) was longer than in horses with synovitis (0.55 h). Synovial fluid concentrations of ketoprofen in healthy horses approximated those in plasma by 3 h post-dose. In horses with synovitis, synovial fluid concentrations approximated plasma concentrations by 1 h. Synovial fluid concentrations of ketoprofen in horses with synovitis were 6.5 times higher than those in healthy horses at 1 h. The area under the synovial fluid concentration curve for horses with synovitis was greater than in healthy horses. These data suggest that the inflamed joint serves as a site of sequestration for ketoprofen. Furthermore, these results indicate that plasma pharmacokinetics may be altered by inflammation in a peripheral compartments such as the joint.

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BackgroundGlioblastoma (GBM) is a highly aggressive malignant primary brain tumor, characterized by rapid growth, diffuse infiltration of cells into both adjacent and remote brain regions, and a generalized resistance to currently available treatment modalities. Recent reports in the literature suggest that Signal Transducers and Activators of Transcription (STATs) play important roles in the regulation of GBM pathophysiology.MethodsSTAT6 protein expression was analyzed by Western blotting in GBM cell lines and by immunohistochemistry in a tissue microarray (TMA) of glioma patient tissues. We utilized shRNA against STAT6 to investigate the effects of prolonged STAT6 depletion on the growth and invasion of two STAT6-positive GBM cell lines. Cell proliferation was assessed by measuring 3H-Thymidine uptake over time. Invasion was measured using an in vitro transwell assay in which cells invade through a type IV collagen matrix toward a chemoattractant (Fetal Bovine Serum). Cells were then stained and counted. Kaplan-Meyer survival curves were generated to show the correlation between STAT6 gene expression and patient survival in 343 glioma patients and in a subset of patients with only GBM. Gene expression microarray and clinical data were acquired from the Rembrandt [1] public data depository (https://caintegrator.nci.nih.gov/rembrandt/). Lastly, a genome-wide expression microarray analysis was performed to compare gene expression in wild-type GBM cells to expression in stable STAT6 knockdown clones.ResultsSTAT6 was expressed in 2 GBM cell lines, U-1242MG and U-87MG, and in normal astrocytes (NHA) but not in the U-251MG GBM cell line. In our TMA study, STAT6 immunostaining was visible in the majority of astrocytomas of all grades (I-IV) but not in normal brain tissue. In positive cells, STAT6 was localized exclusively in the nuclei over 95% of the time.STAT6-deficient GBM cells showed a reduction in 3H-Thymidine uptake compared to the wild-type. There was some variation among the different shRNA- silenced clones, but all had a reduction in 3H-Thymidine uptake ranging from 35%- 70% in U-1242MG and 40- 50% in U-87MG cells. Additionally, STAT6- depleted cells were less invasive than controls in our in vitro transmembrane invasion assay. Invasiveness was decreased by 25-40% and 30-75% in U-1242MG and U-87MG cells, respectively. The microarray analysis identified matrix metalloproteinase 1 (MMP-1) and urokinase Plasminogen activator (uPA) as potential STA6 target genes involved in the promotion of GBM cell invasion. In a Kaplan-Meier survival curve based on Rembrandt [1] gene expression microarray and clinical data, there was a significant difference in survival (P < 0.05) between glioma patients with up- and down-regulated STAT6. Decreased STAT6 expression correlated with longer survival times. In two subsets of patients with either grade IV tumors (GBM) or Grade II/III astrocytomas, there was a similar trend that however did not reach statistical significance.ConclusionsTaken together, these findings suggest a role fo...

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