Firocoxib

Firocoxib(ML 1785713) is a potent and selective cyclooxygenase (COX)-2 inhibitor with IC50 of 0.13 uM, 58 fold sensitivity for COX2 VSCOX1. IC50 value: 0.13 uM [1] Target: COX2 inhibitor in vitro: Blood concentrations resulting in 50% inhibition of COX-1 and COX-2 activity in vitro were 75 +/- 2 microM and 0.13 +/- 0.03 microM, respectively, and selectivity for inhibiting COX-2 relative to COX-1 was 58. Firocoxib had moderate to high oral bioavailability (54% to 70%), low plasma clearance (4.7 to 5.8 mL/min/kg), and an elimination half-life of 8.7 to 12.2 hours [1]. in vivo: Administration of firocoxib did not cause any adverse effects on GI, or hematological or serum biochemical variables and appears to have been well tolerated by dogs [2]. Firocoxib (0.5 mg/kg) was initially administered i.v. to calves, and following a 14-day washout period, animals received firocoxib orally prior to cautery dehorning. Firocoxib concentrations were determined by liquid chromatography-tandem mass spectrometry [3]. Firocoxib 5 mg/kg was given orally once daily for 180 days to five dogs with clinical signs and histopathological lesions consistent with solar dermatitis/actinic keratosis. On days 0, 50 and 180, the severity of erythema, skin shine, induration and the number of comedones were evaluated by a clinical scoring system [4].

References:
[1]. McCann ME, et al. In vitro effects and in vivo efficacy of a novel cyclooxygenase-2 inhibitor in cats with lipopolysaccharide-induced pyrexia. Am J Vet Res. 2005 Jul;66(7):1278-84. [2]. Steagall PV, et al. Evaluation of the adverse effects of oral firocoxib in healthy dogs. J Vet Pharmacol Ther. 2007 Jun;30(3):218-23. [3]. Stock ML, et al. Pharmacokinetics of firocoxib in preweaned calves after oral and intravenous administration. J Vet Pharmacol Ther. 2014 Oct;37(5):457-63. [4]. Albanese F, et al. Clinical outcome and cyclo-oxygenase-2 expression in five dogs with solar dermatitis/actinic keratosis treated with firocoxib. Vet Dermatol. 2013 Dec;24(6):606-12, e147.

Analgesic efficacy of oral firocoxib in ovariohysterectomized cats.[Pubmed:27515266]

J Vet Sci. 2017 Jun 30;18(2):175-182.

The postoperative analgesic effects of Firocoxib in ovariohysterectomized cats were observed. Twenty-four cats were divided into 3 groups: control (no medicine), Firocoxib-1 (1 mg/kg/day) and Firocoxib-3 (3 mg/kg/day). Colorado pain scale scores (CPSS), composite pain scores (CPS), and buccal mucosal bleeding times (BMBT) were recorded in blinded fashion before induction and 2, 5, 8, 24, 30, and 48 h post-operation. The average CPSS (mean +/- SEM) over 2 to 48 h post-operation in Firocoxib-3 (0.4 +/- 0.1) was significantly lower than that of the control (0.7 +/- 0.2; p = 0.004), but that of Firocoxib-1 (0.5 +/- 0.2) was not different from that of the control (p = 0.40). The mean CPS of Firocoxib-3 was significantly lower than that of the control at 24 h post-operation (p = 0.04); nonetheless, there was no significant difference in mean CPS between Firocoxib-1 and control groups at all intervals. BMBT and body temperature were within normal limits in all groups. However, reversible azotemia was identified in two Firocoxib-3 cats at 72 h post-operation. One Firocoxib-3 cat vomited once at 48 h post-operation. In conclusion, Firocoxib-3 is helpful for postoperative pain control in cats; however, gastrointestinal irritation and renal function side effects may occur.

Effects of Firocoxib, Flunixin Meglumine, and Phenylbutazone on Platelet Function and Thromboxane Synthesis in Healthy Horses.[Pubmed:27731498]

Vet Surg. 2016 Nov;45(8):1087-1094.

OBJECTIVE: Determine the effects of nonsteroidal anti-inflammatory drugs (NSAID) on platelet function and thromboxane synthesis immediately after drug administration and following 5 days of NSAID administration in healthy horses. STUDY DESIGN: Randomized cross-over study. ANIMALS: Healthy adult horses (n=9; 6 geldings and 3 mares). METHODS: Horses received either flunixin meglumine (1.1 mg/kg IV every 12 hours), phenylbutazone (2.2 mg/kg IV every 12 hours), or Firocoxib (loading dose of 0.27 mg/kg IV on day 1, then 0.09 mg/kg IV every 24 hours for 4 days) for a total of 5 days. Blood samples were collected prior to drug administration (day 0), 1 hour after initial NSAID administration (day 1), and then 1 hour post-NSAID administration on day 5. Platelet function was assessed using turbidimetric aggregometry and a platelet function analyzer. Serum thromboxane B2 concentrations were determined by commercial ELISA kit. A minimum 14 day washout period occurred between trials. RESULTS: At 1 hour and 5 days postadministration of Firocoxib, flunixin meglumine, or phenylbutazone, there was no significant effect on platelet aggregation or function using turbidimetric aggregometry or a platelet function analyzer. There was, however, a significant decrease in thromboxane synthesis at 1 hour and 5 days postadministration of flunixin meglumine and phenylbutazone that was not seen with Firocoxib. CONCLUSION: Preoperative administration of flunixin meglumine, phenylbutazone, or Firocoxib should not inhibit platelet function based on our model. The clinical implications of decreased thromboxane B2 synthesis following flunixin meglumine and phenylbutazone administration are undetermined.

Analgesic Efficacy of Firocoxib, a Selective Inhibitor of Cyclooxygenase 2, in a Mouse Model of Incisional Pain.[Pubmed:26224441]

J Am Assoc Lab Anim Sci. 2015 Jul;54(4):405-10.

Pain management in laboratory animals is generally accomplished by using opioids and NSAIDs. However, opioid use is hindered by controlled substance requirements and a relatively short duration of action. In this study, we compared the analgesic efficacy of Firocoxib (a cyclooxygenase-2-selective NSAID) with that of buprenorphine in the mouse model of plantar incisional pain by objective measurement of mechanical allodynia and thermal hyperalgesia using von Frey and Hargreaves equipment, respectively. Our experimental design included 5 treatment groups: Firocoxib at 10 mg/kg IP every 24 h (F10 group); Firocoxib at 20 mg/kg IP every 24 h (F20); buprenorphine at 0.2 mg/kg SC every 8 h; intraperitoneal normal saline every 24 h; and sham group (anesthesia, no incision) treated with Firocoxib at 20 mg/kg IP every 24 h (sham+F20). All mice underwent nociceptive assays at 24 h before and 4, 24, 48, and 72 h after surgery. Buprenorphine alleviated allodynia at all time points after incision. The F10 treatment alleviated allodynia at 4, 24, and 48 h, whereas F20 alleviated allodynia at 24, 48, and 72 h. None of the treatments alleviated thermal hyperalgesia at 4h. Except for F10 and buprenorphine at 24 h, all treatments alleviated thermal hyperalgesia at 24, 48, and 72 h. No significant differences were noted between the 2 doses of Firocoxib and buprenorphine regarding mechanical allodynia and thermal hyperalgesia at all time points. In conclusion, the analgesic efficacy of Firocoxib is comparable to that of buprenorphine in this mouse pain model.

Effect of firocoxib on cyclooxygenase 2, microsomal prostaglandin E2 synthase 1, and cytosolic phospholipase A2 gene expression in equine mononuclear cells.[Pubmed:26618729]

Am J Vet Res. 2015 Dec;76(12):1051-7.

OBJECTIVE: To validate primer sets for use in reverse transcription quantitative PCR assays to measure gene expression of cytosolic phospholipase A2 (cPLA2) and microsomal prostaglandin E2 synthase 1 (mPGES1) in equine mononuclear cells and determine the effects of Firocoxib, a selective cyclooxygenase 2 (COX-2) inhibitor, on COX-2, cPLA2, and mPGES1 gene expression following incubation of mononuclear cells with lipopolysaccharide (LPS). ANIMALS: 8 healthy adult horses. PROCEDURES: Peripheral blood mononuclear cells were isolated by density gradient centrifugation and incubated at 37 degrees C with medium alone, Firocoxib (100 ng/mL), LPS (1 ng/mL or 1 mug/mL), or combinations of Firocoxib and both LPS concentrations. After 4 hours, supernatants were collected and tested for prostaglandin E2 (PGE2) concentration with an enzyme inhibition assay, and gene expression in cell lysates was measured with PCR assays. RESULTS: Primer pairs for cPLA2 and mPGES1 yielded single products on dissociation curve analyses, with mean assay efficiencies of 102% and 100%, respectively. Incubation with Firocoxib and LPS significantly decreased PGE2 supernatant concentrations and significantly reduced COX-2 and mPGES1 gene expression, compared with values following incubation with LPS alone. CONCLUSIONS AND CLINICAL RELEVANCE: Primer sets for mPGES1 and cPLA2 gene expression in equine mononuclear cells were successfully validated. Firocoxib significantly decreased LPS-induced COX-2 and mPGES1 expression, suggesting that it may be useful in the control of diseases in which expression of these genes is upregulated.

Firocoxib (ML 1785713) is a potent, selective and orally active COX-2 inhibitor with an IC50 of 0.13 μM. Firocoxib shows 58-fold more selective for COX-2 than COX-1 (IC50 of 7.5 μM). Firocoxib has anti-inflammatory effects.

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