thromboxane-b2 and carprofen

A tissue cage model of inflammation in calves was used to determine the pharmacokinetic and pharmacodynamic properties of individual carprofen enantiomers, following the administration of the racemate. RS(±) carprofen was administered subcutaneously both alone and in combination with intramuscularly administered oxytetracycline in a four-period crossover study. Oxytetracycline did not influence the pharmacokinetics of R(-) and S(+) carprofen enantiomers, except for a lower maximum concentration (Cmax ) of S(+) carprofen in serum after co-administration with oxytetracycline. S(+) enantiomer means for area under the serum concentration-time curve (AUC0-96 h were 136.9 and 128.3 μg·h/mL and means for the terminal half-life (T(1/2) k10 ) were = 12.9 and 17.3 h for carprofen alone and in combination with oxytetracycline, respectively. S(+) carprofen AUC0-96 h in both carprofen treatments and T(1/2) k10 for carprofen alone were lower (P < 0.05) than R(-) carprofen values, indicating a small degree of enantioselectivity in the disposition of the enantiomers. Carprofen inhibition of serum thromboxane B2 ex vivo was small and significant only at a few sampling times, whereas in vivo exudate prostaglandin (PG)E2 synthesis inhibition was greater and achieved overall significance between 36 and 72 h (P < 0.05). Inhibition of PGE2 correlated with mean time to achieve maximum concentrations in exudate of 54 and 42 h for both carprofen treatments for R(-) and S(+) enantiomers, respectively. Carprofen reduction of zymosan-induced intradermal swelling was not statistically significant. These data provide a basis for the rational use of carprofen with oxytetracycline in calves and indicate that no alteration to carprofen dosage is required when the drugs are co-administered.

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Area Under Curve; Carbazoles; Cattle; Cross-Over Studies; Diffusion Chambers, Culture; Dinoprostone; Drug Interactions; Half-Life; Injections, Intramuscular; Injections, Subcutaneous; Male; Oxytetracycline; Thromboxane B2

To determine effects of anti-inflammatory doses of COX-2 selective NSAIDs carprofen, meloxicam, and deracoxib on platelet function in dogs and urine 11-dehydro-thromboxane B2.. Randomized, blocked, crossover design with a 14-day washout period.. Healthy intact female Walker Hounds aged 1-6 years and weighing 20.5-24.2 kg.. Dogs were given NSAIDs for 7 days at recommended doses: carprofen (2.2 mg kg(-1), PO, every 12 hours), carprofen (4.4 mg kg(-1), PO, every 24 hours), meloxicam (0.2 mg kg(-1), PO, on the 1st day then 0.1 mg kg(-1), PO, every 24 hours), and deracoxib (2 mg kg(-1), PO, every 24 hours). Collagen/epinephrine and collagen/ADP PFA-100 cartridges were used to evaluate platelet function before and during and every other day after administration of each drug. Urine 11-dehydro-thromboxane B(2) was also measured before and during administration of each drug.. All NSAIDs significantly prolonged PFA-100 closure times when measured with collagen/epinephrine cartridges, but not with collagen/ADP cartridges. The average duration from drug cessation until return of closure times (collagen/epinephrine cartridges) to baseline values was 11.6, 10.6, 11 and 10.6 days for carprofen (2.2 mg kg(-1) every 12 hours), carprofen (4.4 mg kg(-1) every 24 hours), meloxicam and deracoxib, respectively.. Oral administration of some COX-2 selective NSAIDs causes detectable alterations in platelet function in dogs. As in humans, PFA-100 collagen/ADP cartridges do not reliably detect COX-mediated platelet dysfunction in dogs. Individual assessment of platelet function is advised when administering these drugs prior to surgery, particularly in the presence of other risk factors for bleeding.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Platelets; Carbazoles; Dogs; Female; Hemostasis; Meloxicam; Platelet Aggregation; Sulfonamides; Thiazines; Thiazoles; Thromboxane B2

The pharmacokinetics and pharmacodynamics of the nonsteroidal anti-inflammatory drug (NSAID) carprofen have been evaluated in 6 horses using a model of acute non-immune inflammation. Following intravenous administration of 0.7 mg racemic carprofen/kg bwt, mean values for pharmacokinetic parameters were 18.1 h (elimination half-life); 0.25 l/kg (volume of distribution, Vd[area]); 58.9 ml/min (clearance); and 57.9 micrograms/ml.h (area under plasma concentration time curve). Mean exudate:plasma concentration ratios exceeded 1.0 at all sampling times between 2 and 48 h. Swelling at the site of acute inflammation was significantly reduced but exudate leucocyte numbers were unchanged. Although carprofen produced moderate suppression of serum thromboxane B2 and exudate prostaglandin E2 synthesis, these effects were not related to carprofen concentrations in plasma or exudate. It was concluded that the anti-oedematous action of carprofen was not attributable to inhibition of cyclo-oxygenase.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carbazoles; Cross-Over Studies; Dinoprostone; Exudates and Transudates; Female; Horses; Injections, Intravenous; Leukocyte Count; Male; Thromboxane B2; Time Factors

The effect of indometacin (3 X 50 mg daily), carprofen (Imadyl) (2 X 150 mg daily) and placebo (3 X daily) on gastric juice secretion, acidity, prostanoid concentration (PGE2, PGF2 alpha and TXB2) and excretion of the major urinary metabolite of PGF (PGF-MUM) were investigated in a single-blind cross-over study in nine healthy volunteers after 3-day treatment periods separated by one-week washout periods between treatments. Indometacin proved to be a classical cyclooxygenase inhibitor (strong inhibition of PGE2 and TXB2 before and after pentagastrin stimulation and of PGF-MUM) while carprofen was an atypical inhibitor (weak inhibition of PGE2 before pentagastrin stimulation and no inhibition after, strong inhibition of TXB2 but without influence on PGF-MUM). The weak inhibition of PGE2-biosynthesis by carprofen might be related to its low incidence of gastric side effects.

Topics: Adult; Carbazoles; Dinoprost; Dinoprostone; Gastric Mucosa; Humans; Indomethacin; Male; Prostaglandins; Prostaglandins E; Prostaglandins F; Prostanoic Acids; Thromboxane B2; Time Factors

Whole blood in vitro assays were used to determine the potency and selectivity of carprofen enantiomers for inhibition of the isoforms of cyclooxygenase (COX), COX-1 and COX-2, in the calf. S(+)-carprofen possessed preferential activity for COX-2 inhibition but, because the slopes of inhibition curves differed, the COX-1:COX-2 inhibition ratio decreased from 9.04:1 for inhibitory concentration (IC)10 to 1.84:1 for IC95. R(-) carprofen inhibited COX-2 preferentially only for low inhibition of the COX isoforms (IC10 COX-1:COX-2=6.63:1), whereas inhibition was preferential for COX-1 for a high level of inhibition (IC95 COX-1:COX-2=0.20:1). S(+) carprofen was the more potent inhibitor of COX isoforms; potency ratios S(+):R(-) carprofen were 11.6:1 for IC10 and 218:1 for IC90. Based on serum concentrations of carprofen enantiomers obtained after administration of a therapeutic dose of 1.4 mg/kg to calves subcutaneously, S(+)-carprofen concentrations exceeded the in vitro IC80 COX-2 value for 32 h and the IC20 for COX-1 for 33 h. The findings are discussed in relation to efficacy and safety of carprofen in calves.

Topics: Animals; Carbazoles; Cattle; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Thromboxane B2

To develop and validate in cats suitable in vitro assays for screening and ranking nonsteroidal antiinflammatory drugs (NSAIDs) on the basis of their inhibitory potencies for cyclooxygenase (COX)-1 and COX-2.. 10 cats.. COX-1 and COX-2 activities in heparinized whole blood samples were induced with calcium ionophore and lipopolysaccharide, respectively. For the COX-2 assay, blood was pretreated with aspirin. The COX-1 and COX-2 assays were standardized, such that time courses of incubation with the test compounds and conditions of COX expression were as similar as possible in the 2 assays. Inhibition of thromboxane B2 production, measured by use of a radioimmunoassay, was taken as a marker of COX-1 and COX-2 activities. These assays were used to test 10 to 12 concentrations of a COX-1 selective drug (SC-560) and of 2 NSAIDs currently used in feline practice, meloxicam and carprofen. Selectivities of these drugs were compared by use of classic 50% and 80% inhibitory concentration (ie, IC50 and IC80) ratios but also with alternative indices that are more clinically relevant.. These assay conditions provide a convenient and robust method for the determination of NSAID selectivity. The S(+) enantiomeric form of carprofen was found to be COX-2 selective in cats, but meloxicam was only slightly preferential for this isoenzyme.. In vitro pharmacodynamic and in vivo pharmacokinetic data predict that the COX-2 selectivity of both drugs for cats will be limited when used at the recommended doses. This study provides new approaches to the selection of COX inhibitors for subsequent clinical testing.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carbazoles; Cats; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Female; Inhibitory Concentration 50; Male; Meloxicam; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Radioimmunoassay; Thiazines; Thiazoles; Thromboxane B2

We report on the inhibitory activity of the NSAIDs meloxicam, carprofen, phenylbutazone and flunixin, on blood cyclooxygenases in the horse using in vitro enzyme-linked assays. As expected, comparison of IC50 indicated that meloxicam and carprofen are more selective inhibitors of COX-2 than phenylbutazone and flunixin; meloxicam was the most advantageous for horses of four NSAIDs examined. However at IC80, phenylbutazone (+134.4%) and flunixin (+29.7%) had greater COX-2 selectivity than at IC50, and meloxicam (-41.2%) and carprofen (-12.9%) had lower COX-2 selectivity than at IC50. We therefore propose that the selectivity of NSAIDs should be assessed at the 80% as well as 50% inhibition level.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carbazoles; Clonixin; Cyclooxygenase Inhibitors; Dinoprostone; Female; Horses; In Vitro Techniques; Male; Meloxicam; Phenylbutazone; Thiazines; Thiazoles; Thromboxane B2

Acute Escherichia coli mastitis is one of the major sources of economic loss in the dairy industry due to reduced milk production, treatment costs, discarded milk, and occasional fatal disease. Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used as adjunctive therapy to antibiotics. The objective of the current study was to evaluate the effect of carprofen treatment following infusion of Escherichia coli into the mammary glands of primiparous cows during the periparturient period. Severity of mastitis was scored based on the average milk production in the uninfected quarters on d +2 postinoculation and a clinical severity score. Carprofen was administered intravenously at 9 h postchallenge, when clinical signs of mastitis appeared. In previous work, efficacy of NSAIDs was mainly evaluated using clinical symptoms. In the present study, the effect of carprofen on innate immune response was also assessed by quantification of inflammatory mediators. All primiparous cows reacted as moderate responders throughout the experimental period. Primiparous cows were intramammarily inoculated with 1 x 10(4) cfu of E. coli P4:O32 in 2 left quarters. Analysis of blood and milk parameters, including IL-8, complement component C5a, lipopolysaccharide-binding protein (LBP), soluble CD14, prostaglandin E2, and thromboxane B2 was performed from d 0 to d +6 relative to intramammary inoculation. Rectal temperature in carprofen-treated animals was lower than in control animals at 3 and 6 h posttreatment. Treatment also restored the decreased reticulorumen motility that occurs during E. coli mastitis to preinfection levels faster than in control animals. Carprofen treatment resulted in an earlier normalization of the clinical severity score. Eicosanoid (prostaglandin E2 and thromboxane B2) production in milk tended to be inhibited by carprofen. No significant differences in the kinetic patterns of somatic cell count, IL-8, complement component C5a, LBP, and soluble CD14 were observed. In conclusion, carprofen treatment improved general clinical condition by effective antipyrexia and restoration of reticulorumen motility but did not significantly inhibit eicosanoid production. Carprofen treatment did not result in a significant decrease of chemotactic inflammatory mediators, IL-8 and C5a, and early innate immune molecules, sCD14 and LBP. Therefore, major modulatory effects from NSAID administration were not observed in this mastitis model, although a larger study mig

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carbazoles; Cattle; Cell Count; Colony Count, Microbial; Complement C5a; Dinoprostone; Escherichia coli Infections; Female; Hematocrit; Interleukin-8; Lactation; Leukocyte Count; Lipopolysaccharide Receptors; Mastitis, Bovine; Milk; Parity; Pregnancy; Thromboxane B2

Carprofen is a nonsteroidal anti-inflammatory drug of the 2-arylpropionate subclass. It contains a single chiral centre and exists in two enantiomeric forms. In this study rac-carprofen, at two dosages, 0.7 and 4.0 mg/kg, and placebo were administered i.v. to six New Forest horses in a three period cross-over study. The concentration-time profiles were established for R(-) and S(+)-carprofen for plasma and both inflamed (exudate) and noninflamed (transudate) tissue cage fluids. R(-)-carprofen was the predominant enantiomer in all three fluids, as indicated by plasma area under the curve (AUC) values for R(-) and S(+)-carprofen of 117.4 and 22.6 microg h/mL (low dose carprofen) and 557.5 and 138.1 microg h/mL (high dose carprofen) respectively. Penetration of both enantiomers into exudate was slow and limited and passage into transudate was even lower. The pharmacodynamics of rac-carprofen was investigated at both the molecular level and in terms of the ability to suppress components of the tissue cage inflammatory response. Low dose carprofen produced only moderate and transient inhibition of serum thromboxane (Tx)B2 but failed to affect exudate prostaglandin (PG)E2 concentrations, whilst suppression of exudate leukotriene (LT)B4 and beta-glucuronidase was not significant. High dose carprofen produced greater and more persistent inhibition of serum TxB2 and virtually abolished exudate PGE2 synthesis. Some inhibition of LTB4 and beta-glucuronidase in exudate was also obtained. At both dosages rac-carprofen reduced the swelling produced by intradermal bradykinin injection but only high dose carprofen was anti-inflammatory as indicated by suppression of temperature rise over exudate tissue cages and neither dose affected leucocyte numbers in exudate. When considered in conjunction with previous data on carprofen, the present findings indicate that carprofen is not a selective inhibitor of cyclooxygenase (COX) isoenzymes, COX-1 and COX-2 in the horse, although it may show some preference for COX-2 inhibition. Because low dose carprofen, which is the clinically recommended dosage, produces minimal inhibition of COX, it is likely to achieve its therapeutic effects at least partially through other pathways, possibly including weak to moderate inhibition of 5-lipoxygenase and of enzyme release. The good safety margin of carprofen in clinical use might also be explained by weak COX inhibition and by other actions at the molecular level.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Area Under Curve; Carbazoles; Dinoprostone; Dose-Response Relationship, Drug; Half-Life; Horses; Injections, Intravenous; Male; Metabolic Clearance Rate; Radioimmunoassay; Stereoisomerism; Thromboxane B2

To assess anti-inflammatory effects of carprofen (CPF), CPF enantiomers, and N(G)-nitro-L-arginine methyl ester (LNAME) in sheep.. 8 sheep.. Sheep with SC tissue cages were used. After intracaveal injection of 1% carrageenan, sheep were given single doses of racemic (Rac; 50:50 mixture of S[+] and R[-] enantiomers)-CPF (4.0 mg/kg), R(-)CPF (2.0 mg/kg), S(+)CPF (2.0 mg/kg), LNAME (25 mg/kg), and placebo (PLB) IV in a crossover design.. Rac-CPF and S(+)CPF inhibited serum thromboxane2 (TXB2) and exudate prostaglandin (PG)E2 generation significantly for 32 hours. Maximal inhibitory effect for serum TXB2 was 79+/-3% for Rac-CPF and 68+/-6% for S(+)CPF. The Rac-CPF and S(+)CPF induced 50 to 98% reversible inhibitory effect for exudate PGE2 generation during a 4- to 32-hour period. The R(-)CPF and LNAME attenuated serum TXB2 generation significantly. The R(-)CPF did not affect exudate PGE2 production, whereas L-NAME potentiated exudate, PGE2 generation by 30% during 4 to 32 hours. The S(+)CPF and LNAME increased leukotriene B4 generation and WBC recruitment in exudate although significance was achieved only at a few time points. Increase in skin temperature over inflammatory cages was effectively inhibited by Rac-CPF and S(+)CPF but not by R(-)CPF CONCLUSIONS AND CLINICAL RELEVANCE: Carprofen is a potent cyclooxygenase inhibitor in vivo in sheep, and its anti-inflammatory effects are attributable only to S(+)CPF in Rac-CPF. Nitric oxide may enhance eicosanoid production and accelerate the acute inflammatory process.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carbazoles; Carrageenan; Cross-Over Studies; Dinoprostone; Edema; Enzyme Inhibitors; Exudates and Transudates; Leukotriene B4; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Sheep; Stereoisomerism; Thromboxane B2

To determine potency and selectivity of nonsteroidal anti-inflammatory drugs (NSAID) and cyclooxygenase- (COX-) specific inhibitors in whole blood from horses, dogs, and cats.. Blood samples from 30 healthy horses, 48 healthy dogs, and 9 healthy cats.. Activities of COX-1 and COX-2 were determined by measuring coagulation-induced thromboxane and lipopolysaccharide-induced prostaglandin E2 concentrations, respectively, in whole blood with and without the addition of various concentrations of phenylbutazone, flunixin meglumine, ketoprofen, diclofenac, indomethacin, meloxicam, carprofen, 5-bromo-2[4-fluorophenyl]-3-14-methylsulfonylphenyl]-thiophene (DuP 697), 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl) phenyl-2(5H)-furan one (DFU), 3-(3,4-difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone (MF-tricyclic), and celecoxib. Potency of each test compound was determined by calculating the concentration that resulted in inhibition of 50% of COX activity (IC50). Selectivity was determined by calculating the ratio of IC50 for COX-1 to IC50 for COX-2 (COX-1/COX-2 ratio).. The novel compound DFU was the most selective COX-2 inhibitor in equine, canine, and feline blood; COX-1/COX-2 ratios were 775, 74, and 69, respectively. Carprofen was the weakest inhibitor of COX-2, compared with the other COX-2 selective inhibitors, and did not inhibit COX-2 activity in equine blood. In contrast, NSAID such as phenylbutazone and flunixin meglumine were more potent inhibitors of COX-1 than COX-2 in canine and equine blood.. The novel COX-2 inhibitor DFU was more potent and selective in canine, equine, and feline blood, compared with phenylbutazone, flunixin meglumine, and carprofen. Compounds that specifically inhibit COX-2 may result in a lower incidence of adverse effects, compared with NSAID, when administered at therapeutic dosages to horses, dogs, and cats.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carbazoles; Cats; Clonixin; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; Dogs; Female; Furans; Horses; Inhibitory Concentration 50; Isoenzymes; Male; Phenylbutazone; Prostaglandin-Endoperoxide Synthases; Thromboxane B2

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Platelets; Calcimycin; Carbazoles; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dogs; In Vitro Techniques; Ionophores; Isoenzymes; Prostaglandin-Endoperoxide Synthases; Thromboxane B2

To evaluate the activity of carprofen and other nonsteroidal anti-inflammatory drugs (NSAID) against isozymes of canine cyclooxygenases (COX1 and COX2).. Constitutive COX1 was obtained from washed canine platelets, and COX2 was obtained from a canine macrophage-like cell line that was induced with endotoxin. Activity of carprofen and other NSAID against COX1 and COX2 was compared. Dose-response curves were plotted, and calculations were performed to identify concentrations that caused 50% inhibition (IC50 [microM]) for each isozyme. Ratio of the COX1-to-COX2 IC50 was used as a measure of isozyme selectivity.. Of the compounds evaluated, carprofen had the greatest selectivity for COX2. Potency of carprofen for canine COX2 was more than 100-fold greater than for canine COX1. Inhibition of canine COX2 (IC50, 0.102 microM) for the racemic mixture of carprofen (S and R stereoisomers) was primarily attributable to the S enantiomer (IC50, 0.0371 microM), which was approximately 200-fold more potent than the R enantiomer (IC50, 5.97 microM). Nimesulide had the next highest selectivity for COX2 (38-fold), and tolfenamic acid and meclofenamic acid had 15-fold selectivity for COX2. The other compounds tested did not have substantial selectivity for canine COX2 or were more selective for canine COX1.. Carprofen was found to be a potent inhibitor of canine COX2. Of the compounds tested, carprofen had the highest selectivity for canine COX2.. The selectivity of carprofen for canine COX2 may be an important factor for its use in dogs.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Platelets; Calcimycin; Carbazoles; Cell Line; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dogs; In Vitro Techniques; Ionophores; Isoenzymes; Prostaglandin-Endoperoxide Synthases; Thromboxane B2

The non-steroidal anti-inflammatory drug, carprofen, was administered intravenously as the racemate at a dose rate of 0.7 mg kg-1 to six Friesian bull calves aged 8-10 weeks. Anti-inflammatory properties were indicated by attenuation of temperature rise at sites of intradermal injection of the irritants, carrageenin and dextran, but responses were not statistically significant at most recording times. Carrageenin- and dextran-induced swelling were not significantly reduced by carprofen. Carprofen reduced ex vivo serum thromboxane B2 synthesis but this effect was also not significant at most sampling times. Enantioselective pharmacokinetics of carprofen was demonstrated, plasma concentrations of the R(-) enantiomer predominating at all sampling times. It is concluded that inhibition of cyclo-oxygenase is unlikely to be the sole mechanism of action of carprofen in calves.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carbazoles; Carrageenan; Cattle; Dextrans; Edema; Injections, Intradermal; Injections, Intravenous; Male; Skin Temperature; Thromboxane B2; Time Factors

The pharmacodynamics and enantioselective pharmacokinetics of the arylpropionic acid non-steroidal anti-inflammatory drug, carprofen, were investigated in cats after administration of the racemic mixture (rac-carprofen) at dose rates ranging from 0.7 to 4.0 mg kg-1 intravenously and subcutaneously. A low dose of rac-carprofen (0.7 mg kg-1) partially inhibited the rise in skin temperature at a site of acute inflammation but had no effect on the ex vivo synthesis of serum thromboxane (Tx) B2. A higher dose (4.0 mg kg-1) inhibited oedematous swelling, although the response was statistically significant at only one time, and also reduced the ex vivo synthesis of serum TxB2 for 12 hours after intravenous injection or 24 hours after subcutaneous injection. The main features of carprofen pharmacokinetics were a low distribution volume, a relatively long elimination half-life, the predominance of the R(-) enantiomer and a bioavailability (after subcutaneous dosing) of 100 per cent and 92 per cent, respectively, after doses of 0.7 and 4.0 mg kg-1. On the basis of these data, it is suggested that a dose of 4.0 mg kg-1 by both intravenous and subcutaneous routes should be evaluated in clinical subjects.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carbazoles; Cats; Cross-Over Studies; Female; Half-Life; Injections, Intravenous; Injections, Subcutaneous; Male; Metabolic Clearance Rate; Orchiectomy; Ovariectomy; Skin; Skin Temperature; Stereoisomerism; Thromboxane B2

The non-steroidal anti-inflammatory drug (NSAID) carprofen (CPF) contains a single chiral centre. It was administered orally to Beagle dogs as a racemate (rac-CPF) at a dose of 4 mg per kg body weight and as individual (-)(R) and (+)(S) enantiomers at 2 mg per kg body weight. Each of the enantiomers achieved similar plasma bioavailability following administration as the racemate as they did following their separate administration. Only the administered enantiomers were detectable when the drug was given in the (-)(R) or (+)(S) form, indicating that chiral inversion did not occur in either direction. Higher plasma concentrations of the (-)(R) (Cmax 18 micrograms/ml, AUC0-24 118 micrograms h/ml) than the (+)(S) (Cmax 14 micrograms/ml, AUC0-24 67 micrograms h/ml) enantiomer were achieved following administration of the racemate. Both enantiomers distributed into peripheral subcutaneous tissue cage fluids, but Cmax and AUC values were lower for both transudate (non-stimulated tissue cage fluid) and exudate (induced by the intracaveal administration of the irritant carrageenan) than for plasma. Drug concentrations in transudate and exudate were similar, as indicated by Cmax and AUC values, although CPF penetrated more rapidly into exudate than into transudate. Neither rac-CPF nor either enantiomer inhibited thromboxane B2 (T x B2) generation by platelets in clotting blood (serum T x B2), or prostaglandin E2 (PGE2) and 12-hydroxyeicosatetraenoic acid (12-HETE) synthesis in inflammatory exudate.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carbazoles; Cyclooxygenase Inhibitors; Dinoprostone; Dogs; Exudates and Transudates; Female; Hydroxyeicosatetraenoic Acids; Male; Skin Temperature; Stereoisomerism; Thromboxane B2

We examined the potential contribution of thromboxanes in human monocyte adherence to plastic. Monocyte adherence to plastic could be augmented by various stimuli including lipopolysaccharide, chemotactic peptide, and supernates of antigen-stimulated lymphocytes. Increments in monocyte adhesiveness were suppressed by inhibition of cyclooxygenase, thromboxane synthetase, or by antiserum to thromboxane B2. Neither prostaglandin E2 or F2 alpha significantly affected baseline or lipopolysaccharide-stimulated monocyte adherence. Additional experiments confirmed incremental production of thromboxane B2 by monocytes after incubation with lipopolysaccharide. Thromboxane B2 itself did not stimulate monocyte adhesiveness. These data demonstrate that monocytes release thromboxane A2 following stimulation and suggest that thromboxane A2 may play a significant role in monocyte-substrate attachment.

Topics: Carbazoles; Cell Adhesion; Humans; Imidazoles; Immunologic Techniques; In Vitro Techniques; Indomethacin; Leukocytes, Mononuclear; Lipopolysaccharides; N-Formylmethionine Leucyl-Phenylalanine; Plastics; Thromboxane B2; Thromboxanes

The effects of one-day treatment with nine nonsteroidal anti-inflammatory drugs and prednisolone on human synovial fluid concentrations of prostanoids were studied. The doses were calculated so as to be approximately equipotent according to clinical experience and the recommendations of the manufacturers. Most of the drugs used reduced clearly PGE2 and TxB2 levels in synovial fluid, but only a slight diminution in 6-keto-PGF1 alpha values was found. Carprofen, diclofenac, indomethacin, naproxen and tolfenamic acid reduced significantly the synovial fluid PGE2 concentrations. Diclofenac and indomethacin also reduced significantly the synovial TxB2 concentrations.

Topics: 6-Ketoprostaglandin F1 alpha; Acetaminophen; Anti-Inflammatory Agents; Arthritis, Rheumatoid; Aspirin; Carbazoles; Diclofenac; Dinoprostone; Guanidines; Humans; Indomethacin; Naproxen; ortho-Aminobenzoates; Prednisolone; Prostaglandins; Prostaglandins E; Quinazolines; Synovial Fluid; Thromboxane B2