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Anthony T. Blikslager - One of the best experts on this subject based on the ideXlab platform.
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The pharmacokinetics and in vitro cyclooxygenase selectivity of Deracoxib in horses
Journal of veterinary pharmacology and therapeutics, 2011Co-Authors: Jennifer Davis, Anthony T. Blikslager, John F. Marshall, Mark G. Papich, Nigel B. CampbellAbstract:Davis, J. L., Marshall, J. F., Papich, M. G., Blikslager, A. T., Campbell, N. B. The pharmacokinetics and in vitro cyclooxygenase selectivity of Deracoxib in horses. J. vet. Pharmacol. Therap.34, 12–16. The purpose of this study was to determine the pharmacokinetics of Deracoxib following oral administration to horses. In addition, in vitro equine whole blood cyclooxygenase (COX) selectivity assays were performed. Six healthy adult horses were administered Deracoxib (2 mg/kg) orally. Plasma samples were collected prior to drug administration (time 0), and 10, 20, 40 min and 1, 1.5, 2, 4, 6, 8, 12, 24, and 48 h after administration for analysis with high pressure liquid chromatography using ultraviolet detection. Following PO administration, Deracoxib had a long elimination half-life (t1/2k10) of 12.49 ± 1.84 h. The average maximum plasma concentration (Cmax) was 0.54 μg/mL, and was reached at 6.33 ± 3.44 h. Bioavailability was not determined because of the lack of an IV formulation. Results of in vitro COX selectivity assays showed that Deracoxib was selective for COX-2 with a COX-1/COX-2 ratio of 25.67 and 22.06 for the IC50 and IC80, respectively. Dosing simulations showed that concentrations above the IC80 for COX-2 would be maintained following 2 mg/kg PO q12h, and above the IC50 following 2 mg/kg PO q24h. This study showed that Deracoxib is absorbed in the horse after oral administration, and may offer a useful alternative for anti-inflammatory treatment of various conditions in the horse.
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effects of cyclooxygenase inhibitors flunixin and Deracoxib on permeability of ischaemic injured equine jejunum
Equine Veterinary Journal, 2010Co-Authors: J E Tomlinson, Anthony T. BlikslagerAbstract:Summary Reasons for performing study: Recent studies have shown that flunixin prevented recovery of equine jejunum post ischaemia. However, the use of a purported cyclooxygenase (COX)-2 preferential inhibitor, etodolac, also prevented recovery. These findings may have implications for the use of nonsteroidal anti-inflammatory drugs in colic patients. Objective: To compare the effects of Deracoxib, a highly selective canine COX-2 inhibitor, with flunixin on in vitro recovery of ischaemic-injured equine jejunum. Methods: Six horses underwent 2 h jejunal ischaemia, after which mucosa was mounted in Ussing chambers and recovered for 240 mins. Transepithelial electrical resistance (TER) and mucosal-to-serosal fluxes of 3H-mannitol were monitored as indices of barrier function in the presence of flunixin or Deracoxib. Results: The TER of ischaemic-injured tissue recovered significantly over 240 mins in the presence of no treatment, but not in the presence of flunixin or Deracoxib. In addition, flunixin-treated ischaemic jejunum was significantly more permeable to mannitol when compared with untreated tissue by the end of the recovery period, whereas Deracoxib treatment did not increase permeability. Addition of the PGE1 analogue misoprostol to flunixin-treated tissue restored recovery of TER. Conclusions and potential relevance: Treatment of horses with ischaemic jejunal disease with flunixin may result in a prolonged permeability defect in recovering mucosa. Addition of misoprostol or replacement of flunixin with Deracoxib may ameliorate effects of COX inhibitors on recovering mucosa.
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Effect of nonsteroidal anti-inflammatory drugs with varied cyclooxygenase-2 selectivity on cyclooxygenase protein and prostanoid concentrations in pyloric and duodenal mucosa of dogs.
American journal of veterinary research, 2009Co-Authors: Jenna G. Wooten, Anthony T. Blikslager, Steve L. Marks, J. Mac Law, Elizabeth C. Graeber, B. Duncan X. LascellesAbstract:Objective—To assess in vivo effects of short-term administration of NSAIDs with varied cyclooxygenase (COX)-2 selectivity on pyloric and duodenal mucosa. Animals—8 healthy dogs. Procedures—Each dog received Deracoxib (2 mg/kg, PO, q 24 h for 3 days), firocoxib (5 mg/kg, PO, q 24 h for 3 days), meloxicam (0.2 mg/kg, PO, q 24 h for 1 day followed by 0.1 mg/kg, PO, q 24 h for 2 days), or placebo orally for 3 days; there was a 4-week interval between successive treatments. Prior to and on day 3 of drug administration, pyloric and duodenal mucosae were assessed endoscopically and biopsy specimens obtained for histologic examination. Cyclooxygenase-1 and -2 protein expressions were assessed (western blotting) and prostanoid concentrations measured (ELISAs). Data were analyzed by use of an ANOVA. Results—Drug administration did not significantly affect endoscopic mucosal scores, histologic scores, or COX-1 or -2 protein expression. The COX-1 protein expression was significantly higher in the pylorus than in the ...
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Cyclooxygenase expression and prostanoid production in pyloric and duodenal mucosae in dogs after administration of nonsteroidal anti-inflammatory drugs.
American journal of veterinary research, 2008Co-Authors: Jenna Gray Wooten, Anthony T. Blikslager, Kathleen A. Ryan, Steve L. Marks, J. Mac Law, B. Duncan X. LascellesAbstract:Objective—To assess cyclooxygenase (COX) expression and prostanoid concentrations in pyloric and duodenal mucosae of dogs after administration of nonsteroidal anti-inflammatory drugs (NSAIDs). Animals—8 healthy dogs. Procedures—Each dog received carprofen (4.4 mg/kg, q 24 h), Deracoxib (2 mg/kg, q 24 h), aspirin (10 mg/kg, q 12 h), and placebo (1 dog treat, q 24 h) orally for 3 days (4-week interval between treatments). Before study commencement (baseline) and on day 3 of each treatment, pyloric and duodenal mucosal appearance was assessed endoscopically and biopsy specimens were obtained for histologic examination. Cyclooxygenase-1 and COX-2 protein expressions were assessed via western blotting, and prostanoid concentrations were measured via ELISAs. An ANOVA was used to analyze data. Results—Treatments had no effect on mucosal appearance and ulceration was not evident histologically. In pyloric and duodenal mucosae, COX-1 expression was unaffected by treatments. Cyclooxygenase-2 expression remained unc...
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Gastrointestinal tract perforation in dogs treated with a selective cyclooxygenase-2 inhibitor: 29 cases (2002-2003).
Journal of the American Veterinary Medical Association, 2005Co-Authors: B. Duncan X. Lascelles, Anthony T. Blikslager, Steven M. Fox, Doug ReeceAbstract:Objective—To identify factors associated with gastrointestinal tract perforation in dogs being treated with a selective cyclooxygenase-2 (COX-2) inhibitor (Deracoxib). Design—Retrospective study. Animals—29 dogs. Procedure—The Novartis Animal Health pharmacovigilance database was searched for records of dogs treated with Deracoxib in which gastrointestinal tract perforation was documented. Results—16 of the 29 (55%) dogs had received Deracoxib at a dosage higher than that approved by the FDA for the particular indication being treated, with 25 (86%) dogs having received Deracoxib at a dosage > 2 mg/kg/d (0.9 mg/lb/d). Seventeen (59%) dogs had received at least 1 other nonsteroidal anti-inflammatory drug (NSAID) or a corticosteroid in close temporal association (within 24 hours) with Deracoxib administration (ie, immediately before or following). In all, 26 (90%) dogs had received Deracoxib at a higher-than-approved dosage or had received at least 1 other NSAID or corticosteroid in close temporal associati...
Deborah W Knapp - One of the best experts on this subject based on the ideXlab platform.
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antitumor effects of Deracoxib treatment in 26 dogs with transitional cell carcinoma of the urinary bladder
Javma-journal of The American Veterinary Medical Association, 2011Co-Authors: Sarah K Mcmillan, Pedro A Boria, George E Moore, William R Widmer, Patty L Bonney, Deborah W KnappAbstract:Objective—To evaluate the antitumor activity and toxic effects of Deracoxib, a selective cyclooxygenase-2 inhibitor, in dogs with transitional cell carcinoma (TCC) of the urinary bladder. Design—Clinical trial. Animals—26 client-owned dogs with naturally occurring, histologically confirmed, measurableTCC of the urinary bladder. Procedures—Dogs were treated PO with Deracoxib at a dosage of 3 mg/kg/d (1.36 mg/lb/d) as a single-agent treatment for TCC. Tumor response was assessed via radiography, abdominal ultrasonography, and ultrasonographic mapping of urinary bladder masses. Toxic effects of Deracoxib administration in dogs were assessed through clinical observations and hematologic and biochemical analyses. Results—Of 24 dogs for which tumor response was assessed, 4 (17%) had partial remission, 17 (71%) had stable disease, and 3 (13%) had progressive disease; initial response could not be assessed in 2 of 26 dogs. The median survival time was 323 days. Median time to progressive disease was 133 days. Ren...
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Effect of cyclooxygenase inhibitors in a xenograft model of canine mammary tumours
Veterinary and comparative oncology, 2010Co-Authors: K. Sonzogni-desautels, Deborah W Knapp, Eva A. Sartin, M. DoréAbstract:Inhibition of cyclooxygenase-2 (COX-2) represents a possible avenue for the prevention and/or treatment of some cancers. Our goal was to compare the effect of a selective inhibitor of COX-2, Deracoxib, and a COX-1 and -2 inhibitor, piroxicam, on the growth of canine mammary tumours in a murine model. CMT-9 was used to induce xenografts in nude mice. Mice were treated with piroxicam (0.6 mg kg(-1)), Deracoxib (6 mg kg(-1)) or a control solution. Tumour volumes between 0 and 24 days post-treatment showed no significant difference between all groups. A second series of experiments was performed with a higher dose of piroxicam (0.9 mg kg(-1)). Tumour volumes between 14 and 21 days post-treatment were significantly smaller in piroxicam-treated mice compared with controls. These results demonstrate that COX inhibition reduced the growth of canine mammary cancer xenografts in mice, suggesting that COX inhibitors could have a positive effect in dogs.
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Abstract A48: In vivo evaluation of Cox‐2 inhibition to prevent the progression of invasive urinary bladder cancer
Chemoprevention and Biological Therapies, 2010Co-Authors: Sarah K Mcmillan, Patty L Bonney, Susan Biolsi, Jane C. Stewart, Deborah W KnappAbstract:Background: Invasive transitional cell carcinoma (InvTCC) of the urinary bladder has a propensity to metastasize, is only partially responsive to chemotherapy, and causes > 14,000 deaths yearly in the United States. The development of effective means to prevent the development and progression of InvTCC is crucial. Cyclooxygenase‐2 (Cox‐2) is over‐expressed in InvTCC in humans and animals. In a pilot study, a Cox‐2 inhibitor induced apoptosis of InvTCC in humans. Cox‐2 inhibitors may offer an avenue for prevention of InvTCC progression. The purpose of this study was to determine the effects of Cox‐2 inhibitor treatment in preventing the progression of InvTCC in a highly relevant animal model, canine InvTCC. Naturally‐occurring InvTCC in dogs closely mimics human InvTCC in cellular and molecular features (including Cox‐2 expression), sites and frequency of metastasis, and response to therapy. Methods: Dogs with histologically confirmed InvTCC who failed or whose owner declined standard chemotherapy protocols, and with expected survival of > 6 weeks were prospectively enrolled. The Cox‐2 inhibitor Deracoxib (Novartis, Greensboro, NC) was given as a single agent with a planned dose of 3mg/kg/day orally. Dogs were evaluated prior to and during therapy with abdominal ultrasound including mapping of the urinary bladder masses, thoracic radiographs, complete blood count, serum biochemistry profiles and urinalyses. Toxicity was assessed by clinical signs and serial blood work. Tumor response was defined as: complete remission (CR), no evidence of disease detected; partial remission (PR) ≥ 50% reduction in tumor volume; stable disease (SD) Results: Thirty‐nine dogs with InvTCC received Deracoxib at a mean dose of 2.79 mg/kg/day (range 1.18 mg/kg/day to 4.08mg/kg/day). Of 39 dogs, 1 had nodal metastasis, and 3 had distant metastasis at diagnosis. Initial responses in 30 dogs with measurable disease included PR in 4 dogs (13%), SD in 17 dogs (57%), and PD in 3 dogs (10%); and in 6 dogs, response to therapy has not been determined. Mean time to subsequent PD (n=20) was 167 days (range 36 – 482 days). After PD was noted, 10 dogs went on to receive other therapy (leukeran, mitoxantrone, mitomycin‐C, 5 azacitidine, carboplatin). Of the 39 dogs treated, 9 had microscopic residual disease after surgical intervention. Of these 9 dogs, 4 had relapse (median time to relapse, 221 days), and 3 had not relapsed at the time of death from other causes (median time to death 772 days). The median survival times for dogs with measurable disease and microscopic disease were 349 and 772 days, respectively. Conclusion: The results of this work help justify further study of the use of Cox‐2 inhibitors in preventing the progression of InvTCC. Citation Information: Cancer Prev Res 2010;3(1 Suppl):A48.
Linda Lee-ambrose - One of the best experts on this subject based on the ideXlab platform.
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The effect of Deracoxib and piroxicam on viability of canine osteosarcoma cells in vitro
Veterinary and Comparative Oncology, 2005Co-Authors: Stephen R. Royals, James P. Farese, Rowan J. Milner, Linda Lee-ambroseAbstract:Introduction: Cyclooxygenase-2 (COX-2) inhibitors are being used increasingly in cancer therapy. Although the effects of COX-2 inhibitors have been evaluated extensively in carcinomas, less is known about their effects in sarcomas. Since the majority of dogs with appendicular osteosarcoma (OSA) are treated for pain with a non-steroidal anti-inflammatory drug (some COX-2 selective) prior to definitive treatment, it is important to determine the effects that commonly used NSAIDS have on tumor cell growth. Methods: Established canine osteosarcoma (POS, HMPOS and COS31) and canine fibroblast cell lines were maintained in culture under standard conditions. Cells were incubated with either Deracoxib (1 uM to 500 uM) or piroxicam (1 uM to 1000 uM). Cell viability was assessed at 72 hours by cell counts and the MTT assay. The DNA fragmentation analysis was utilized to assess for apoptosis induction. Results: Deracoxib concentrations ≥100 uM and piroxicam concentrations ≥500 uM significantly reduced mean cell viability of all three OSA cell lines (lowest cell viability percentages 20% and 32%, respectively). Deracoxib concentrations ≥250 uM and piroxicam concentrations ≥500 uM also reduced viability of fibroblasts; however, the cell viability percent was reduced to only 54% and 68%, respectively, of the control value. Exposure of OSA cells to cytotoxic concentrations of Deracoxib and piroxicam did not result in DNA fragmentation. Conclusions: Deracoxib and piroxicam demonstrated a cytotoxic effect on canine osteosarcoma cells. There was no evidence of apoptosis induction at the concentrations evaluated. Further investigation will need to be performed to determine whether either drug exhibits anti-tumor effects in vivo.
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Investigation of the effects of Deracoxib and piroxicam on the in vitro viability of osteosarcoma cells from dogs.
American journal of veterinary research, 2005Co-Authors: Stephen R. Royals, James P. Farese, Rowan J. Milner, Linda Lee-ambrose, James M. Van GilderAbstract:Objective—To determine whether exposure of canine osteosarcoma cells to Deracoxib or piroxicam results in decreased viability, whether the cytotoxic effects of Deracoxib and piroxicam involve induction of apoptosis, and whether Deracoxib is a more potent inhibitor of osteosarcoma cell growth than piroxicam. Sample Population—1 fibroblast and 3 osteosarcoma cell lines. Procedure—Cell counts and viability assays were performed using osteosarcoma cells (POS, highly metastatic POS, and canine osteosarcoma cell 31) and fibroblasts after 72 hours of incubation with Deracoxib at concentrations of 0.5µM to 500µM or piroxicam at concentrations of 1µM to 1,000µM. Percentage viability was determined for each concentration. A DNA fragmentation analysis was performed to assess drug-induced apoptosis. Results—Concentration of Deracoxib required for 50% inhibition of cell viability (IC50) was reached in all 3 osteosarcoma cell lines and ranged from 70 to 150µM, whereas the IC50 for piroxicam was only reached in the POS ...
Peter Lees - One of the best experts on this subject based on the ideXlab platform.
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In vitro and ex vivo inhibition of canine cyclooxygenase isoforms by robenacoxib: A comparative study
Research in veterinary science, 2009Co-Authors: Jonathan N. King, C. Rudaz, L. Borer, Martin Jung, W. Seewald, Peter LeesAbstract:Abstract In vitro whole blood canine assays were used to quantify the inhibitory actions of the novel non-steroidal anti-inflammatory drug (NSAID) robenacoxib on the cyclooxygenase (COX) isoenzymes, COX-1 and COX-2, in comparison with other drugs of the NSAID class. COX-1 activity was determined by measuring serum thromboxane (Tx)B 2 synthesis in blood samples allowed to clot at 37 °C for 1 h. COX-2 activity was determined by measuring prostaglandin (PG)E 2 synthesis in blood samples incubated at 37 °C for 24 h in the presence of lipopolysaccharide. The rank order of selectivity for inhibition of COX-2 versus COX-1 (IC 50 COX-1:IC 50 COX-2) for veterinary drugs was highest with robenacoxib (128.8) compared to Deracoxib (48.5), nimesulide (29.2), S+ carprofen (17.6), meloxicam (7.3), etodolac (6.6), R− carprofen (5.8) and ketoprofen (0.88). Selectivity expressed as the clinically relevant ratio IC 20 COX-1:IC 80 COX-2 was highest for robenacoxib (19.8) compared to Deracoxib (2.3), S+ carprofen (2.5), R− carprofen (2.1), nimesulide (1.8), etodolac (0.76), meloxicam (0.46) and ketoprofen (0.21). An in vivo pharmacokinetic ex vivo pharmacodynamic study in the dog established dosage and concentration–effect relationships for single oral doses of robenacoxib over the dosage range 0.5–8.0 mg/kg. Values of C max and AUC were linearly related to dosage over the tested range. Robenacoxib did not inhibit serum TxB 2 synthesis (COX-1) ex vivo at dosages of 0.5–4.0 mg/kg and produced only transient inhibition (at the 1 h and 2 h sampling times) at the 8 mg/kg dosage. All dosages of robenacoxib (0.5–8 mg/kg) produced marked, significant and dose related inhibition of PGE 2 synthesis (COX-2) ex vivo. The data demonstrate that in the dog robenacoxib is a highly selective inhibitor of the COX-2 isoform of COX, and significantly inhibits COX-2 and spares COX-1 in vivo when administered orally over the dosage range 0.5–4.0 mg/kg.
Stephen R. Royals - One of the best experts on this subject based on the ideXlab platform.
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The effect of Deracoxib and piroxicam on viability of canine osteosarcoma cells in vitro
Veterinary and Comparative Oncology, 2005Co-Authors: Stephen R. Royals, James P. Farese, Rowan J. Milner, Linda Lee-ambroseAbstract:Introduction: Cyclooxygenase-2 (COX-2) inhibitors are being used increasingly in cancer therapy. Although the effects of COX-2 inhibitors have been evaluated extensively in carcinomas, less is known about their effects in sarcomas. Since the majority of dogs with appendicular osteosarcoma (OSA) are treated for pain with a non-steroidal anti-inflammatory drug (some COX-2 selective) prior to definitive treatment, it is important to determine the effects that commonly used NSAIDS have on tumor cell growth. Methods: Established canine osteosarcoma (POS, HMPOS and COS31) and canine fibroblast cell lines were maintained in culture under standard conditions. Cells were incubated with either Deracoxib (1 uM to 500 uM) or piroxicam (1 uM to 1000 uM). Cell viability was assessed at 72 hours by cell counts and the MTT assay. The DNA fragmentation analysis was utilized to assess for apoptosis induction. Results: Deracoxib concentrations ≥100 uM and piroxicam concentrations ≥500 uM significantly reduced mean cell viability of all three OSA cell lines (lowest cell viability percentages 20% and 32%, respectively). Deracoxib concentrations ≥250 uM and piroxicam concentrations ≥500 uM also reduced viability of fibroblasts; however, the cell viability percent was reduced to only 54% and 68%, respectively, of the control value. Exposure of OSA cells to cytotoxic concentrations of Deracoxib and piroxicam did not result in DNA fragmentation. Conclusions: Deracoxib and piroxicam demonstrated a cytotoxic effect on canine osteosarcoma cells. There was no evidence of apoptosis induction at the concentrations evaluated. Further investigation will need to be performed to determine whether either drug exhibits anti-tumor effects in vivo.
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Investigation of the effects of Deracoxib and piroxicam on the in vitro viability of osteosarcoma cells from dogs.
American journal of veterinary research, 2005Co-Authors: Stephen R. Royals, James P. Farese, Rowan J. Milner, Linda Lee-ambrose, James M. Van GilderAbstract:Objective—To determine whether exposure of canine osteosarcoma cells to Deracoxib or piroxicam results in decreased viability, whether the cytotoxic effects of Deracoxib and piroxicam involve induction of apoptosis, and whether Deracoxib is a more potent inhibitor of osteosarcoma cell growth than piroxicam. Sample Population—1 fibroblast and 3 osteosarcoma cell lines. Procedure—Cell counts and viability assays were performed using osteosarcoma cells (POS, highly metastatic POS, and canine osteosarcoma cell 31) and fibroblasts after 72 hours of incubation with Deracoxib at concentrations of 0.5µM to 500µM or piroxicam at concentrations of 1µM to 1,000µM. Percentage viability was determined for each concentration. A DNA fragmentation analysis was performed to assess drug-induced apoptosis. Results—Concentration of Deracoxib required for 50% inhibition of cell viability (IC50) was reached in all 3 osteosarcoma cell lines and ranged from 70 to 150µM, whereas the IC50 for piroxicam was only reached in the POS ...