6-ketoprostaglandin-f1-alpha and flunixin-meglumine

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

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

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

A study was performed to identify prostacyclin (PGI2) in equine aqueous humor, demonstrate an increase in PGI2 following anterior chamber paracentesis, and determine the effects of subconjunctival injection of flunixin meglumine on PGI2 accumulation. Twenty ponies were found to be normal upon ocular examination and were placed under general anesthesia. Anterior chamber paracentesis was performed in both eyes (right and left); immediately afterward, 25 mg of flunixin meglumine was injected (subconjunctivally) in the left eye. Aqueous paracentesis was performed 1.5 hours later (both eyes). Aqueous humor samples were assayed for 6-keto PGF1alpha, the stable, inactive metabolite of PGI2. Eyes treated with flunixin meglumine contained less 6-keto PGF1alpha than did control eyes.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents, Non-Steroidal; Clonixin; Eye; Horses; Paracentesis

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