Flunixin inhibits prostaglandin E2 production in equine inflammation

Lees, P.; Higgins, A.J.

doi:10.1016/s0034-5288(18)31876-9

Cited by 69 publications

(39 citation statements)

References 4 publications

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“…Previous studies in this laboratory have shown that, in the horse, 2‐arylpropionate (ketoprofen and carprofen) and other NSAIDs (phenylbutazone, flunixin and meloxicam) penetrate readily into and are slowly cleared from inflammatory exudate (Higgins et al ., 1984b, 1986, 1987; Lees & Higgins, 1984; Lees et al ., 1986, 1991a, b, 1994a; Landoni & Lees, 1995, 1996a). Penetration has been shown to be particularly high for both S(+) and R(–) ketoprofen enantiomers, with exudate: plasma AUC ratios of the order of 15 : 1 (Landoni & Lees, 1995, 1996a).…”

Section: Discussionmentioning

confidence: 99%

A pharmacodynamic and pharmacokinetic study with vedaprofen in an equine model of acute nonimmune inflammation

Lees

May

Hoeijmakers³

et al. 1999

Vet Pharm & Therapeutics

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The pharmacodynamics and enantioselective pharmacokinetics of vedaprofen were studied in six ponies in a two period cross-over study, in which a mild acute inflammatory reaction was induced by carrageenan soaked sponges implanted subcutaneously in the neck. Vedaprofen, administered intravenously at a dosage of 1 mg/kg, produced significant and prolonged inhibition of ex vivo serum thromboxane B2 (TXB2) synthesis and short-lived inhibition of exudate prostaglandin E2 (PGE2) and TXB2 synthesis. Vedaprofen also partially inhibited oedematous swelling and leucocyte infiltration into exudate. Vedaprofen displayed enantioselective pharmacokinetics, plasma concentrations of the R(-) enantiomer exceeding those of S(+) vedaprofen. The plasma concentration ratio, R:S, increased from 69:31 at 5 min to 96:4 at 3 h and plasma mean AUC values were 7524 and 1639 ng x h/mL, respectively. Volume of distribution was greater for S(+) vedaprofen, whilst elimination half-life (t(1/2beta)) and mean residence time were greater for R(-) vedaprofen. The penetration of vedaprofen into inflammatory exudate was also enantioselective. For R(-) and S(+) vedaprofen maximum concentration (Cmax) values were 2950 and 1534 ng/mL, respectively, and corresponding AUC values were 9755 and 4400 ng x h/mL. Vedaprofen was highly protein bound (greater than 99%) in both plasma and exudate. The significance of these data for the therapeutic use of vedaprofen is discussed.

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Section: Discussionmentioning

confidence: 99%

A pharmacodynamic and pharmacokinetic study with vedaprofen in an equine model of acute nonimmune inflammation

Lees

May

Hoeijmakers³

et al. 1999

Vet Pharm & Therapeutics

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“…For most NSAIDs their antiinflammatory effects last longer than would be expected from the plasma drug disposition. Previous studies in horses (Lees & Higgins, 1984; Lees et al ., 1987), donkeys (Cheng et al ., 1996) and calves (Landoni et al ., 1995) showed that FM and PBZ have greater penetration into inflamed tissue fluid (exudate) than into non‐inflamed transudate and are eliminated more slowly from the exudate than from plasma. These findings indicate that the relationships between plasma concentrations and effects are complex and that tissue kinetics in exudate may provide useful information.…”

Section: Introductionmentioning

confidence: 95%

Pharmacokinetic studies of flunixin meglumine and phenylbutazone in plasma, exudate and transudate in sheep

Cheng

McKeller

Nolan

1998

Vet Pharm & Therapeutics

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Flunixin meglumine (FM, 1.1 mg/kg) and phenylbutazone (PBZ, 4.4 mg/kg) were administered intravenously (i.v.) as a single dose to eight sheep prepared with subcutaneous (s.c.) tissue-cages in which an acute inflammatory reaction was stimulated with carrageenan. Pharmacokinetics of FM, PBZ and its active metabolite oxyphenbutazone (OPBZ) in plasma, exudate and transudate were investigated. Plasma kinetics showed that FM had an elimination half-life (t1/2beta) of 2.48 +/- 0.12 h and an area under the concentration - time curve (AUC) of 30.61 +/- 3.41 Lg/mL x h. Elimination of PBZ from plasma was slow (t1/2beta = 17.92 +/- 1.74 h, AUC = 968.04 +/- microg/mL x h). Both FM and PBZ distributed well into exudate and transudate although penetration was slow, indicated by maximal drug concentration (Cmax) for FM of 1.82 +/- 0.22 microg/mL at 5.50 +/- 0.73 h (exudate) and 1.58 +/- 0.30 microg/mL at 8.00 h (transudate), and Cmax for PBZ of 22.32 +/- 1.29 microg/mL at 9.50 +/- 0.73 h (exudate) and 22.07 +/- 1.57 microg/mL at 11.50 +/- 1.92 h (transudate), and a high mean tissue-cage fluids:plasma AUClast ratio obtained in the FM and PBZ groups (80-98%). These values are higher than previous reports in horses and calves using the same or higher dose rates. Elimination of FM and PBZ from exudate and transudate was slower than from plasma. Consequently the drug concentrations in plasma were initially higher and subsequently lower than in exudate and transudate.

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“…[36][37][38][39][40] In contrast, the inability of KTP treatments to attenuate the skin temperature increase over exudate tissue cages was more surprising. Moreover, studies in our laboratory using tissue cage and sponge models of inflammation reveal that several NSAID administered at clinical dosage in a number of species fail to affect WBC count in exudate.…”

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confidence: 99%