thromboxane-b2 and flunixin-meglumine

Flunixin meglumine is commonly used in horses for the treatment of musculoskeletal injuries. The current ARCI threshold recommendation is 20 ng/mL when administered at least 24 h prior to race time. In light of samples exceeding the regulatory threshold at 24 h postadministration, the primary goal of the study reported here was to update the pharmacokinetics of flunixin following intravenous administration, utilizing a highly sensitive liquid chromatography-mass spectrometry (LC-MS). An additional objective was to characterize the effects of flunixin on COX-1 and COX-2 inhibition when drug concentrations reached the recommended regulatory threshold. Sixteen exercised adult horses received a single intravenous dose of 1.1 mg/kg. Blood samples were collected up to 72 h postadministration and analyzed using LC-MS. Blood samples were collected from 8 horses for determination of TxB(2) and PGE(2) concentrations prior to and up to 96 h postflunixin administration. Mean systemic clearance, steady-state volume of distribution and terminal elimination half-life was 0.767 ± 0.098 mL/min/kg, 0.137 ± 0.12 L/kg, and 4.8 ± 1.59 h, respectively. Four of the 16 horses had serum concentrations in excess of the current ARCI recommended regulatory threshold at 24 h postadministration. TxB(2) suppression was significant for up to 24 h postadministration.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Area Under Curve; Clonixin; Female; Half-Life; Horses; Injections, Intravenous; Male; Physical Exertion; Thromboxane B2

Twelve clinically sound, healthy, athletically conditioned Thoroughbred horses were subjected to an incremental exercise stress test to determine the effects and period of detection of a single dose of flunixin meglumine (1.1 mg/kg by intravenous injection) in serum and urine by ELISA. Flunixin concentrations, performance, and hematologic and clinical chemical parameters were measured. All horses were rotated through four treatment groups of a Latin-square design providing for each horse to serve as its own control. Flunixin meglumine reduced prostaglandin F(1alpha) and thromboxane concentrations that had been increased by intense exercise. Performance parameters did not improve and prostaglandin concentrations did not significantly correlate with total run time. Exercise did not change the flunixin elimination profile in either serum or urine, and concentrations were found to be below the detection limit of the ELISA test within 36 hours in serum and 120 hours in urine.

Topics: Adrenocorticotropic Hormone; Animals; Anti-Inflammatory Agents, Non-Steroidal; beta-Endorphin; Blood Glucose; Clonixin; Creatinine; Dinoprostone; Exercise Test; Female; Horses; Hydrocortisone; Injections, Intravenous; Insulin; Male; Oxygen Consumption; Physical Conditioning, Animal; Prostaglandins; Prostaglandins F; Thromboxane B2

The purpose of this study was to investigate the in vitro effects of flunixin meglumine, a cyclo-oxygenase inhibitor, and ketoprofen, a reported cyclo-oxygenase and lipoxygenase inhibitor, on the synthesis of cyclo-oxygenase end-products thromboxane B2 and prostaglandin E2, lipoxygenase derived 12-hydroxyeicosatetraenoic acid, tumor necrosis factor and tissue factor. Six adult horses were each randomly administered flunixin meglumine (1.1 mg/kg) or ketoprofen (2.2 mg/kg) intravenously every 12 hours with the drug treatments separated by two weeks. Blood samples were obtained prior to initiating treatment, the last day of treatment and for two consecutive days after the termination of treatment for measurement of serum concentrations of thromboxane B2 as well as isolation of peripheral blood monocytes. Quantitation of unstimulated, endotoxin- and calcium ionophore-induced synthesis of thromboxane B2, prostaglandin E2, 12-hydroxyeicosatetraenoic acid, tumor necrosis factor and tissue factor by peripheral blood monocytes was performed in vitro. Both flunixin meglumine and ketoprofen significantly decreased serum concentrations of thromboxane B2 demonstrating in vivo cyclo-oxygenase inhibition. There were no significant differences between drug treatment groups in the in vitro production of thromboxane B2, prostaglandin E2, 12-hydroxy-eicosatetraenoic acid, tumor necrosis factor or tissue factor. This study does not identify significant differences between the effects of flunixin meglumine and ketoprofen.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Calcimycin; Clonixin; Endotoxins; Horse Diseases; Horses; Hydroxyeicosatetraenoic Acids; Ketoprofen; Monocytes; Thromboplastin; Thromboxane B2; Tumor Necrosis Factor-alpha

Non-steroidal anti-inflammatory drugs (NSAID) are a family of chemicals that function to reduce pain, fever, and inflammation, and they are commonly used in people and animals for this purpose. Currently there are no NSAIDs approved for the management of inflammation in swine due to a lack of validated animal models and suitable biomarkers to assess efficacy. A previous in vitro study examining biomarkers of inflammation identified fourteen genes that were significantly altered in response to Escherichia coli lipopolysaccharide (LPS)-induced inflammation. In the present study, five of those fourteen genes were tested in vivo to determine if the same effects observed in vitro were also observed in vivo. Plasma levels of prostaglandin E(2) (PGE(2)), an essential mediator of fever and inflammation, were also determined. Two groups of swine were stimulated with LPS with the second group also treated with flunixin meglumine. Blood was collected at 0, 1, 3, 6, 8, 24, and 48 h post LPS-stimulation. The RNA was extracted from the blood and quantitative real-time-PCR (qRT-PCR) was utilized to determine the expression patterns of CD1, CD4, serum amyloid A2 (SAA2), Caspase 1, and monocyte chemoattractant protein 1 (MCP-1). The LPS-stimulated animals demonstrated a statistically significant alteration in expression of SAA2 and CD1 at 3h post-stimulation. Flunixin meglumine treated animals' demonstrated reduced expression of CD1 in comparison to the LPS-stimulated swine at 24 and 48 h post LPS-stimulation. Flunixin meglumine treated animals exhibited reduced expression of SAA2 at 48 h post-stimulation compared to LPS-stimulated swine. Swine treated with LPS demonstrated statistically significant increases in plasma PGE(2) at 1h post-stimulation. Swine treated with flunixin meglumine had no increase in plasma PGE(2) levels at any time. These results demonstrate that PGE(2) production, along with two out of five genes (SAA2 and CD1) have the potential to serve as early biomarkers of inflammation as well as indicators of NSAID efficacy.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antigens, CD1; Biomarkers; Caspase 1; CD4 Antigens; Chemokine CCL2; Clonixin; Dinoprostone; Enzyme-Linked Immunosorbent Assay; Inflammation; Lipopolysaccharides; Male; Real-Time Polymerase Chain Reaction; Serum Amyloid A Protein; Swine; Swine Diseases; Thromboxane B2

To determine whether treatment of horses with firocoxib affects recovery of ischemic-injured jejunum, while providing effective analgesia.. 18 horses.. Horses (n = 6 horses/group) received saline (0.9% NaCl) solution (1 mL/50 kg, IV), flunixin meglumine (1.1 mg/kg, IV, q 12 h), or firocoxib (0.09 mg/kg, IV, q 24 h) before 2 hours of jejunal ischemia. Horses were monitored via pain scores and received butorphanol for analgesia. After 18 hours, ischemic-injured and control mucosa were placed in Ussing chambers for measurement of transepithelial resistance and permeability to lipopolysaccharide. Histomorphometry was used to determine denuded villus surface area. Western blots for cyclooxygenase (COX)-1 and COX-2 were performed. Plasma thromboxane B(2) and prostaglandin E(2) metabolite (PGEM) concentrations were determined.. Pain scores did not significantly increase after surgery in horses receiving flunixin meglumine or firocoxib. Transepithelial resistance of ischemic-injured jejunum from horses treated with flunixin meglumine was significantly lower than in saline- or firocoxib-treated horses. Lipopolysaccharide permeability across ischemic-injured mucosa was significantly increased in horses treated with flunixin meglumine. Treatment did not affect epithelial restitution. Cyclooxygenase-1 was constitutively expressed and COX-2 was upregulated after 2 hours of ischemia. Thromboxane B(2) concentration decreased with flunixin meglumine treatment but increased with firocoxib or saline treatment. Flunixin meglumine and firocoxib prevented an increase in PGEM concentration after surgery.. Flunixin meglumine retarded mucosal recovery in ischemic-injured jejunum, whereas firocoxib did not. Flunixin meglumine and firocoxib were effective visceral analgesics. Firocoxib may be advantageous in horses recovering from ischemic intestinal injury.

Topics: 4-Butyrolactone; Analysis of Variance; Animals; Anti-Inflammatory Agents, Non-Steroidal; Blotting, Western; Clonixin; Cyclooxygenase 1; Cyclooxygenase 2; Eicosanoids; Electrophoresis, Polyacrylamide Gel; Horse Diseases; Horses; Ischemia; Jejunal Diseases; Sulfones; 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

The anti-inflammatory effects of the non-steroidal anti-inflammatory drugs phenylbutazone (PBZ) and flunixin meglumine (FM) and the relationship between the effects and drug concentration in vivo were studied using a subcutaneous tissue-cage model in sheep. Intracaveal injection of carrageenan induced prostaglandin (PG) E2 production in tissue-cage exudate (maximal concentration, 101 nM) with significant increases in white blood cell (WBC) numbers, skin temperature over the inflamed cage and exudate leukotriene B4 (LTB4) concentration (P < 0.05). Intravenous PBZ, 4.4 mg kg-1 produced mild inhibition of exudate PGE2 generation (10%), but greater inhibition of serum TXB2 (75.3%). The IC50 for TXB2 was 36.0 microM. Phenylbutazone did not alter effects on skin temperature, WBC numbers or exudate LTB4 concentrations. Intravenous FM, 1.1 mg kg-1, significantly inhibited carrageenan-induced exudate PGE2 formation (Emax, 100%, IC50, < 0.4 nM) and serum TXB2 generation (Emax, 100%, IC50, 17 nM) for up to 32 h. Flunixin meglumine significantly inhibited the rise in skin temperature but had a limited effect on exudate WBC. Phenylbutazone and FM have distinct effects on carrageenan-induced cyclooxygenase (COX-2) and platelet COX (COX-1). Flunixin meglumine was a more potent COX inhibitor than PBZ and was more selective for the inducible form of COX in vivo.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Clonixin; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Diffusion Chambers, Culture; Dinoprostone; Inflammation; Isoenzymes; Leukocyte Count; Leukotriene B4; Male; Phenylbutazone; Prostaglandin-Endoperoxide Synthases; Sheep; Skin Temperature; Thromboxane B2

To compare effects of a single dose of pentoxifylline (PTX), flunixin meglumine (FM), and their combination (FM/PTX) in a model of equine endotoxemia.. 24 healthy horses, aged 2 to 15 years.. 4 groups (n = 6/group) received 30 ng of Escherichia coli O55:B5 endotoxin/kg of body weight, i.v., over 30 minutes, and 1 of the following preparations 15 minutes before and 8 hours after endotoxin infusion: FM, 1.1 mg/kg; PTX, 8 mg/kg; FM/PTX, 1.1 mg of FM and 8 mg of PTX/kg; and saline solution bolus (ENDO). Clinical and hematologic variables were measured over 24 hours.. Compared with ENDO, FM given before endotoxin significantly reduced TxB2, and 6-keto-PGF1 concentrations, pulse, rectal temperature, and attitude score. Pentoxifylline given before endotoxin resulted in significantly higher 6-keto-PGF1 concentration at 1.5 hours and significantly lower PAI-1 activity at 12 hours. Tumor necrosis factor and IL-6 activities in horses given PTX alone were not significantly different from values in those given the saline bolus. FM/PTX induced effects similar to those of FM alone on endotoxin-induced changes in temperature and TxB2 concentration, and 6-keto-PGF1 concentration was significantly lower than that in horses of the ENDO group at 1 hour. In horses of the FM group, 6-keto-PGF1 concentration was significantly lower than that in horses of the ENDO group, from 0.5 hour to 2 hours. Horses of the FM and FM/PTX groups had significantly higher IL-6 activity at 1.5 and 2 hours than did horses of the PTX and ENDO groups; those of the FM and FM/PTX groups had significantly lower WBC count than did those of the PTX and ENDO groups.. FM/PTX may help offset deleterious hemodynamic effects of endotoxin more effectively than does either FM or PTX alone.

Topics: 6-Ketoprostaglandin F1 alpha; Analysis of Variance; Animals; Anti-Inflammatory Agents, Non-Steroidal; Body Temperature; Clonixin; Disease Models, Animal; Drug Combinations; Endotoxemia; Escherichia coli; Escherichia coli Infections; Hemodynamics; Horse Diseases; Horses; Interleukin-6; Leukocyte Count; Pentoxifylline; Plasminogen Activator Inhibitor 1; Thromboxane B2; Time Factors; Tissue Plasminogen Activator; Tumor Necrosis Factor-alpha; Vasodilator Agents

In the present study the significance of eicosanoids in the development of shock in horses on the basis of ileus has been investigated using the prostanoids thromboxane B2 (TXB2) and prostaglandine E2 (PGE2) as indicators. The prostanoid synthesis inhibitor flunixin meglumine was to be examined regarding its efficacy in the effective blockade of the synthesis of these mediators within the peri-operative timeframe as well as its effects on clinical signs and laboratory parameters. 21 horses suffering from ileus and ready for surgical intervention received an intravenous flunixin dosis of 1.1 mg/kg body weight immediately after the initial examination and prior to the surgical procedure. 20 colic horses receiving surgical treatment without application of the drug served as control group. Reference data concerning the approximate standard plasma levels of the prostanoids were determined in 10 healthy horses. Plasma levels of thromboxane B2 and prostaglandine E2 in all colic horses, treatment group as well as controls, initially proved to be significantly higher than the reference values in healthy horses. The untreated control group showed plasma levels highly exceeding the standards within the course of investigation. The application of flunixin meglumine resulted in an effective inhibition of the prostanoid synthesis. Post-operatively as well as within the whole period of investigation the plasma levels of PGE2 and TXB2 of the treated group were considerably lower than those of the control group. Flunixin meglumine had a favorable effect on several cardiovascular parameters. The experimental data concerning the effects of flunixin meglumine thus could be validated in a clinical setting, especially the effective inhibition of the cyclooxygenase enzyme system. The application of the prostanoid synthesis inhibitor flunixin meglumine can be judged as being effective in limiting shock progress in the peri-operative setting given reliable diagnosis.

Topics: Animals; Biomarkers; Clonixin; Colic; Dinoprostone; Female; Horse Diseases; Horses; Intestinal Obstruction; Male; Postoperative Period; Prostaglandin Antagonists; Thromboxane B2

Flunixin was highly protein bound in the serum of dogs (92.2 per cent), goats (84.8 per cent) and horses (86.9 per cent). Meclofenamic acid was also highly protein bound, although there were larger differences between the extent of the binding in dogs (90.3 per cent), goats (84.7 per cent) and horses (99.8 per cent). Both flunixin and meclofenamic acid were potent inhibitors of the in vitro generation of thromboxane (Tx) B2 in blood. Flunixin inhibited the generation of TxB2 by 50 per cent of the maximum response (IC50) in dog, goat and horse blood at concentrations of 0.10, 0.02 and 0.04 microM respectively and by 100 per cent (Imax) at 2.07, 0.14 and 2.07 microM respectively. The IC50 values of meclofenamic acid in dogs, goats and horses were 0.77, 0.80 and 0.30 microM respectively and the Imax values were 3.93, 3.63 and 3.56 microM respectively. When the concentrations of flunixin were corrected for protein binding, it was estimated that the IC50 of the unbound fractions in dogs, goats and horses were 0.008, 0.003 and 0.005 microM, respectively. Similarly corrected values for meclofenamic acid were 0.075, 0.122 and 0.001 microM respectively.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Proteins; Clonixin; Dogs; Goats; Horses; Kinetics; Meclofenamic Acid; Protein Binding; Thromboxane B2

Age and species reportedly affect the pharmacokinetic variables of nonsteroidal anti-inflammatory drugs. We determined the effect of age on flunixin pharmacokinetic variables in foals during the first month of life. We also estimated the physiologic activity of the drug in neonatal foals by determining the effect of flunixin on thromboxane production during clotting of blood taken from the foals. Flunixin disposition and clearance were determined after IV administration of 1.1 mg of drug/kg of body weight to 5 healthy foals when they were 24 to 28 hours, 10 to 11 days, and 27 to 28 days old. The area under the curve (2,471 micrograms.min/ml), mean residence time (477 minutes), and zero-time intercept of the elimination phase (4,853 ng/ml) were significantly (P = 0.05) greater, the elimination half-life (339 minutes) and slope of the elimination phase (0.002 L/min) were significantly (P = 0.05) longer, and total body clearance (0.482 ml/min/kg) and zero-time intercept for the distribution phase (2,092 ng/ml) were significantly (P = 0.05) lower at 24 to 28 hours. At each age, a biexponential equation was best fitted to the plasma flunixin concentration from each foal. Thromboxane B2 production during clotting of blood was significantly (P = 0.05) suppressed for 12 hours after flunixin meglumine administration at all ages. Therefore, it appears that although age does alter the disposition and elimination of flunixin in neonatal foals, this effect may be of little consequence because the drug's physiologic activity in foals appears similar to that in mature horses.

Topics: Aging; Analysis of Variance; Animals; Animals, Newborn; Anti-Inflammatory Agents, Non-Steroidal; Blood Coagulation; Blood Specimen Collection; Clonixin; Female; Horses; Male; Metabolic Clearance Rate; Thromboxane B2

Flunixin meglumine and phenylbutazone are nonsteroidal anti-inflammatory drugs commonly used for the management of colic, endotoxemia, and musculoskeletal disorders in equids. Although it is not usually recommended, there appears to be an increasing trend to use nonsteroid anti-inflammatory drugs in combination to enhance or prolong their effects. Therefore, we studied the effect of concurrent administration of flunixin (1.1 mg/kg of body weight, IV) as flunixin meglumine and phenylbutazone (2.2 mg/kg, IV) on the pharmacokinetics of each drug and on in vitro thromboxane B2 production. Pharmacokinetic variables calculated for each drug when given alone and in combination were similar to those reported. Serum thromboxane B2 production was significantly (P = 0.05) suppressed for 12, 8, and 24 hours after administration of flunixin, phenylbutazone, and the drugs in combination, respectively. These results indicate that although concurrent administration of these drugs at the aforementioned dosages does not alter either drug disposition or clearance, it prolongs their pharmacologic effect.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Clonixin; Drug Interactions; Female; Horse Diseases; Horses; In Vitro Techniques; Phenylbutazone; Thromboxane B2

The role of arachidonic acid metabolites in the forestomach stasis induced by Escherichia coli endotoxin was evaluated. Six adult Holstein cows received saline solution; endotoxin at 1, 10, and 100 ng/kg of body weight; flunixin meglumine at 1.1 mg/kg of body weight; and flunixin meglumine at 1.1 mg/kg plus endotoxin at 100 ng/kg. The frequency of reticulorumen contractions, mental attitude, body temperature, respiratory rate, heart rate, and plasma concentration of prostaglandin E2, prostacyclin, and thromboxane were evaluated. Administration of saline solution and endotoxin at 1 ng/kg had no significant effects. Administration of endotoxin at 10 ng/kg did not cause significant clinical effects or alter reticulorumen contractions but enhanced synthesis of thromboxane. Administration of endotoxin at 100 ng/kg caused mild clinical signs of stasis, reduced the frequency of reticulorumen contractions, and enhanced synthesis of thromboxane and prostacyclin. Reticulorumen stasis was not accompanied by an increase in the plasma concentration of prostaglandin E2. Flunixin meglumine abolished endotoxin-induced reticulorumen stasis, tachycardia, and synthesis of arachidonic acid metabolites. Reticulorumen stasis during bovine endotoxemia is caused either by enhanced synthesis of an arachidonic acid metabolite other than prostaglandin E2 or by local synthesis of prostaglandin E2.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Cattle; Cattle Diseases; Clonixin; Dinoprostone; Endotoxins; Escherichia coli; Female; Muscle Contraction; Muscle, Smooth; Prostaglandins F; Reticulum; Rumen; Stomach Diseases; Thromboxane B2

The effects of the intravenous (i.v.) administration of 1.1 mg/kg of flunixin meglumine on thromboxane B2 (TxB2) concentrations were studied in sedentary and 2-year-old horses in training. The baseline TxB2 serum concentrations generated during clotting were 2.89 +/- 0.81, 2.19 +/- 0.25 and 0.88 +/- 0.12 ng/ml for the 2-year-old Thoroughbreds in training, sedentary horses under 10 and over 10 years old, respectively. There was a significant difference in baseline TxB2 concentrations between older and younger horses (P less than 0.005). Significant reduction in TxB2 production from baseline were noted at 1 (P less than 0.01) and 4 h (P less than 0.01) but not at 8 h after flunixin administration. The percent reduction in serum TxB2 concentration at 1 h after the administration of flunixin was 68.6 +/- 7.3 and 45.2 +/- 6.8 for the training and sedentary horses, respectively; the differences were significant (P less than 0.04). Serum concentrations of TxB2 returned to baseline values by 12-16 h after flunixin administration. The results of this study indicate a difference in the TxB2 concentrations of older vs. younger horses and a difference in the suppression of TxB2 after the administration of flunixin in 2-year-old Thoroughbreds in training compared to sedentary horses. The results of this study suggest that the detection of low concentrations of flunixin in urine 24 h post-administration may not represent pharmacologic effective concentrations of flunixin in plasma.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Clonixin; Horses; Injections, Intravenous; Leukocyte Count; Physical Conditioning, Animal; Platelet Count; Thromboxane B2

Topics: Administration, Oral; Animals; Cats; Clonixin; Female; Half-Life; Injections, Intravenous; Male; Thromboxane B2

Flunixin meglumine administered orally to beagle dogs at doses of 0.55, 1.10 or 1.65 mg/kg bodyweight was rapidly absorbed to produce maximum mean plasma concentrations of 2.40 +/- 0.70, 4.57 +/- 1.12 and 7.42 +/- 2.07 micrograms/ml, respectively. Thereafter, the plasma concentrations of flunixin fell rapidly to values less than 0.10 micrograms/ml from 24 hours after drug administration at all dosage levels. The maximum mean inhibition of serum thromboxane B2 was 91.5 per cent after the lowest dose of flunixin and 98.8 per cent for both the intermediate and high dose rates. At plasma concentrations of flunixin above 2 micrograms/ml there was more than 90 per cent inhibition of thromboxane.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Clonixin; Dogs; Feces; Female; Male; Nicotinic Acids; Occult Blood; Platelet Count; Thromboxane B2

Previous work has shown repeated low doses of flunixin meglumine (FM) inhibit thromboxane production in normal horses. Enhanced concentrations of thromboxane in serum occurred after the drug therapy was discontinued. Our study was performed to evaluate the effects of low doses of FM in horses repeatedly challenged with endotoxin. Group I horses received E. coli endotoxin (0.1 microgram/kg IV) at 0 and 90 h. Group II horses received endotoxin and were also treated with FM (0.25 mg/kg IV) at 2, 10, 18, 26, 34, and 42 h after the initial administration of endotoxin. Clinical signs of endotoxemia were observed in all horses, but FM treated horses recovered more rapidly. The leukopenic response after endotoxin was attenuated in Group II following the second dose. Serum thromboxane (TxB2) decreased after the initial administration of endotoxin and remained below baseline values throughout the study. Serum TxB2 concentrations were not different between the groups. Plasma TxB2 and 6-keto-PGF1 alpha concentrations were increased after the initial endotoxin injection. In Group II, plasma TxB2 levels declined rapidly after FM administration and remained low. After the second dose of endotoxin, Group I horses had a mild rise and decline in TxB2 and 6-keto-PGF1 alpha concentrations, respectively. Thromboxane B2 levels in Group II changed little after the second dose of endotoxin, but a dramatic increase in 6-keto-PGF1 alpha concentrations occurred. These results suggest that multiple low doses of FM to horses with endotoxemia cause a selective and sustained suppression of TxB2 production and an enhancement of 6-keto-PGF1 alpha.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Clonixin; Drug Administration Schedule; Endotoxins; Escherichia coli; Horses; Lactates; Nicotinic Acids; Thromboxane B2

Ponies with electromagnetic blood flow transducers implanted around the main pulmonary and left main coronary arteries, were used to evaluate effects of chronic sublethal endotoxin on cardiac output (CO), stroke volume, and left coronary blood flow (LCBF). Plasma thromboxane (TX), as indicated by TXB2, prostacyclin as indicated by 6-keto-prostaglandin (PG) F1 alpha, and hematologic and blood chemical values also were evaluated. Over 24 hours, 2 groups of ponies were given progressively increasing IV and intraperitoneal doses of Escherichia coli lipopolysaccharide (LPS) at 0, 6, 12, and 18 hours. Group 1 was not treated and group 2 was treated with flunixin meglumine, before each LPS insult. Initial LPS inoculation in group 1 led to 10-fold increases in TXB2 and 6-keto-PGF1 alpha values by 30 and 90 minutes, respectively. These eicosanoid values returned to base line by 6 hours after each insult. Although repeated LPS injections stimulated recurring high plasma concentrations of 6-keto-PGF1 alpha, TXB2 production became less with each successive LPS insult. Cardiac output decreased to 55% to 60% of base-line values in association with increased 6-keto-PGF1 alpha values. Left coronary blood flow could not be evaluated accurately. Severe lactic acidosis developed in group 1. Group-2 ponies remained clinically normal, indicating protection of cardiovascular function and peripheral perfusion with flunixin meglumine. Seemingly, flunixin meglumine helped to maintain acceptable cardiovascular function and tissue perfusion during endotoxemia. Flunixin meglumine given to healthy ponies had no effect on cardiovascular function.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cardiac Output; Clonixin; Coronary Circulation; Endotoxins; Escherichia coli; Female; Heart Rate; Hemodynamics; Horses; Lipopolysaccharides; Male; Thromboxane B2

Eicosanoids have been implicated in the pathophysiology of endotoxic shock. Drugs which alter eicosanoid production such as corticosteroids and non-steroidal anti-inflammatory drugs (NSAID) are beneficial in treating endotoxic shock. Experiments were conducted to investigate the efficacy of dexamethasone, a corticosteroid, and/or flunixin meglumine, a NSAID, in treating endotoxin-induced changes in calves. Fourteen male calves were assigned to one of four treatment groups: group 1, endotoxin-untreated; group 2, endotoxin-flunixin meglumine treated; group 3, endotoxin-dexamethasone-treated; group 4, endotoxin-flunixin meglumine and dexamethasone-treated. Each calf was given three intravenous and intraperitoneal injections of E. coli endotoxin. Hemodynamic, blood gas, blood chemical and eicosanoid level determinations were obtained. Thirty minutes after endotoxin injection, pulmonary artery pressure (PAP) increased and cardiac output (CO) decreased compared with baseline, corresponding to increased thromboxaneB2 levels in groups 1 and 3. These groups exhibited a decreased mean arterial pressure (MAP) at three and five hours corresponding to increased 6-keto-prostaglandinF1 alpha. The MAP, PAP and CO of group 4 remained near baseline for the entire six hours, except for a late drop in MAP. Lactic acid levels were significantly increased and arterial bicarbonate levels were reduced by six hours in all groups except for group 4. These results indicate that the combination treatment of flunixin meglumine and dexamethasone prevents many of the metabolic derangements observed during endotoxic shock in calves.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Bicarbonates; Blood Pressure; Cardiac Output; Cattle; Cattle Diseases; Clonixin; Dexamethasone; Drug Therapy, Combination; Endotoxins; Heart Rate; Hydrogen-Ion Concentration; Lactates; Lactic Acid; Male; Nicotinic Acids; Respiration; Shock, Septic; Thromboxane B2

The efficacy of low doses of flunixin meglumine in reducing eicosanoid generation and clinical signs in response to experimentally induced endotoxaemia was investigated. Thromboxane B2 and 6-keto-prostaglandin F1 alpha were measured in serum and plasma by radioimmunoassay. Plasma flunixin concentrations were determined by high performance liquid chromatography and pharmacokinetic parameters derived non-compartmentally. In horses administered flunixin meglumine before endotoxin challenge, a significant suppression in plasma thromboxane B2 and 6-keto-prostaglandin F1 alpha generation was observed. Elevations in blood lactate were significantly suppressed in horses pretreated with 0.25 mg/kg bodyweight flunixin meglumine. Reduction of the clinical signs of endotoxaemia by flunixin meglumine was dose dependent. Low doses of flunixin inhibited eicosanoid production without masking all of the physical manifestations of endotoxaemia necessary for accurate clinical evaluation of the horse's status.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Clonixin; Endotoxins; Horse Diseases; Horses; Kinetics; Lactates; Nicotinic Acids; Random Allocation; Thromboxane B2; Toxemia

Two cyclooxygenase inhibitors (flunixin meglumine and phenylbutazone) and a selective thromboxane synthetase inhibitor were assessed in the management of experimental equine endotoxemia. Drugs or saline solution were administered to 16 horses 15 minutes before administration of a sublethal dose of endotoxin (Escherichia coli 055:B5). Plasma concentrations of thromboxane B2 (TxB2), prostacyclin (6-keto PGF1 alpha), plasma lactate, and hematologic values and clinical appearance were monitored for 3 hours after endotoxin administration. Pretreatment with flunixin meglumine (1 mg/kg of body weight) prevented most of the endotoxin-induced changes and correlated with a significant decrease in plasma TxB2 and 6-keto PGF1 alpha concentrations, compared with concentrations in nontreated horses (ie, pretreated with saline solution). Pretreatment with phenylbutazone (2 mg/kg) attenuated the effects of endotoxin and was associated with a brief, early, significant increase in plasma TxB2 concentrations, but not in plasma 6-keto PGF1 alpha concentrations. Pretreatment with the thromboxane synthetase inhibitor did not appear to clinically benefit the horses involved; however, arachidonic acid metabolism was redirected to prostacyclin production.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Arachidonic Acids; Clonixin; Endotoxins; Escherichia coli; Horses; Imidazoles; Lactates; Male; Nicotinic Acids; Phenylbutazone; Thromboxane B2; Thromboxane-A Synthase

Arachidonic acid metabolites (AAM) were measured in milk and plasma during the course of acute endotoxin-induced mastitis in 12 lactating cows. Mastitis was induced by intramammary challenge exposure with 10 micrograms of Escherichia coli (026:B6) endotoxin. Endotoxin was injected into the teat cistern via the teat canal of a single randomly selected rear quarter of each cow. Concentrations of prostaglandin (PG) F2 alpha and thromboxane (Tx) B2 in fat-free unextracted milk and of 15-keto-13,14-dihydro-PGF2 alpha in plasma were measured by radioimmunoassay. Total production of AAM in milk was determined by measuring quarter milk production. The AAM were compared in 6 cows administered flunixin meglumine (1.1 mg/kg of body weight) and in 6 cows administered saline solution. Concentrations of TxB2 in milk were significantly (P less than 0.001) increased during the early course of acute mastitis in endotoxin-treated quarters of cows not administered flunixin meglumine. Peak concentrations of TxB2 in milk occurred at 8 hours after endotoxin inoculation. Flunixin meglumine treatment produced significant (P less than 0.05) reductions in milk TxB2 and plasma 15-keto-13,14-dihydro-PGF2 alpha concentrations. Concentrations of PGF2 alpha in milk and total PGF2 alpha and TxB2 production per quarter per milking were not significantly influenced by endotoxin challenge or by flunixin meglumine treatment.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Cattle; Clonixin; Dinoprost; Endotoxins; Escherichia coli; Female; Mastitis, Bovine; Milk; Nicotinic Acids; Prostaglandins F; Thromboxane B2

The efficacy of three agents which alter the metabolism of arachidonic acid was investigated in normal, conscious horses. A dose response evaluation was made of flunixin meglumine and phenylbutazone, two cyclo-oxygenase inhibitors, and of a selective thromboxane synthetase inhibitor, UK-38,485. Radioimmunoassay of thromboxane B2 (TxB2) and 6-keto prostaglandin F1 alpha (PGF1 alpha) was used to assess the concentrations of thromboxane A2 (TxA2) and prostacyclin (PGI2) respectively, in serum. Flunixin was the most potent inhibitor of serum TxB2 and 6-keto PGF1 alpha production. UK-38,485 also decreased serum TxB2 generation while significantly increasing serum 6-keto PGF1 alpha levels, thus confirming its selectivity as a thromboxane synthetase inhibitor.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Clonixin; Epoprostenol; Horses; Imidazoles; Male; Nicotinic Acids; Orchiectomy; Phenylbutazone; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

Dispersed equine vascular endothelial cells grown in tissue culture, and freshly isolated neutrophils were used to determine direct effects of endotoxin on cyclooxygenase and lipoxygenase products. Endothelial cells (10(7)/ml) or neutrophils (2 X 10(6)/ml) were incubated with (a) buffer, (b) endotoxin (10 micrograms/ml), (c) endotoxin + flunixin meglumine (10 micrograms/ml), or (d) calcium ionophore, A23187 (10 micrograms/ml). Thromboxane (TxB2), prostacyclin (6-keto-PGF1 alpha), and leukotriene C4 (LTC4) were determined in the incubation fluid by radioimmunoassay. Thromboxane and prostacyclin levels increased in endothelial cells incubated with endotoxin. Treatment with flunixin meglumine prevented the endotoxin-induced release of these cyclooxygenase products to levels below those observed in control cells. Leukotriene production was increased in endothelial cells incubated with endotoxin plus flunixin meglumine. Endotoxin as well as endotoxin plus flunixin meglumine increased the production of prostacyclin and LTC4 by freshly isolated neutrophils. Cells exposed to endotoxin plus flunixin meglumine produced more LTC4 than cells exposed to endotoxin. The data revealed that endotoxin has a direct effect on arachidonic acid metabolism in endothelial cells and neutrophils. Flunixin meglumine reduced the level of cyclooxygenase products but increased the level of lipoxygenase products. Therefore, the well-established beneficial effects of cyclooxygenase inhibitors during endotoxemia may be improved even more if they are used in conjunction with lipoxygenase inhibitors or a combined cyclooxygenase-lipoxygenase inhibitor.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cells, Cultured; Clonixin; Cyclooxygenase Inhibitors; Endothelium; Endotoxins; Escherichia coli; Fatty Acids, Unsaturated; Horses; Neutrophils; Pulmonary Artery; Pulmonary Veins; SRS-A; Thromboxane B2

The pharmacokinetics and inhibition of prostaglandin synthesis in conscious horses given various dosages of flunixin meglumine were studied. Plasma concentrations of flunixin were measured by high-performance liquid chromatography, and serum thromboxane B2 and 6-keto prostaglandin F1 alpha were quantitated by radioimmunoassay. Within the dosage range studied, linear pharmacokinetics were achieved. After IV administration of flunixin (1.1 mg/kg, 0.25 mg/kg, 0.1 mg/kg), significant suppression of serum thromboxane generation persisted for 12, 4, and 3 hours, respectively. Repeated administrations of flunixin (0.25 mg/kg) once every 8 hours maintained significant suppression of thromboxane generation for the duration of treatment. After treatment with flunixin was stopped, serum thromboxane generation exceeded base line (pretreatment values). Among the groups, significant alteration of 6-keto prostaglandin F1 alpha production was not observed.

Topics: Animals; Clonixin; Horses; Kinetics; Nicotinic Acids; Prostaglandin Antagonists; Thromboxane B2

Plasma concentrations of thromboxane and prostaglandin I2 (PGI2) before and after IV injection of endotoxin and resulting hemodynamic changes were evaluated. Effects of flunixin meglumine on plasma concentrations of these prostaglandins and the related hemodynamic changes were also determined. Shock was induced in 2 groups of anesthetized dogs. Four dogs were given endotoxin only and 4 dogs were given endotoxin and then were treated with flunixin meglumine. Arterial blood pressure (BP), cardiac output (CO), and heart rate were measured, and blood samples were collected at postendotoxin hours (PEH) 0, 0.1, 0.25, 0.5, 1, 2, 3, and 4. Plasma thromboxane and PGI2 concentrations were increased in canine endotoxic shock. Thromboxane concentration was highest early in shock, and appeared to be associated with an initial decrease in BP and CO. The increased concentration of PGI2 was associated with systemic hypotension at PEH 1 to 2. Treatment of dogs with flunixin meglumine at PEH 0.07 prevented further increase of thromboxane and blocked the release of PGI2, resulting in an increased CO, BP, and tissue aerobic metabolism.

Topics: Animals; Clonixin; Dog Diseases; Dogs; Endotoxins; Epoprostenol; Escherichia coli; Female; Hemodynamics; Male; Prostaglandins F; Shock, Septic; Thromboxane B2; Thromboxanes

This study had 2 objectives: (i) to correlate plasma thromboxane and prostaglandin I2 (epoprostenol) concentrations with hemodynamic changes occurring in equine endotoxin shock, and (ii) to determine the effects of flunixin meglumine on plasma concentrations of these prostaglandins relative to hemodynamic changes. Shock was induced in 2 groups, each of 4 anesthetized ponies, and in a 3rd group of 2 ponies. Group A ponies were given endotoxin only (and were not treated), and group B ponies were given endotoxin and then treated with flunixin meglumine. Group C ponies were treated with flunixin meglumine 5 minutes before they were fiven endotoxin. Arterial, pulmonary arterial, and central venous pressures were measured and blood samples were collected at 0, 0.1, 0.25, 0.5, 1, 1, 3, and 4 hours after ponies were given the endotoxin. The plasma thromboxane and prostaglandin I2 concentrations were increased in equine endotoxic shock. Increased thromboxane concentration was associated with the high pulmonary arterial and central venous pressures and low arterial blood pressure in the minutes immediately after the ponies were given endotoxin. The increased prostaglandin I2 concentration was associated with systemic hypotension at 1 to 2 hours after endotoxin. Treatment of ponies with flunixin meglumine after endotoxin was given (group B) prevented the prostaglandin I2 rise and the associated hypotension. Treatment with fluixin meglumine before endotoxin was given prevented the increase of the plasma thromboxane and prostaglandin I2 values, along with the associated hemodynamic changes.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents, Non-Steroidal; Clonixin; Epoprostenol; Escherichia coli; Female; Hemodynamics; Horse Diseases; Horses; Male; Primates; Prostaglandin Antagonists; Prostaglandins; Rabbits; Shock, Septic; Thromboxane A2; Thromboxane B2; Thromboxanes