Effects of firocoxib, meloxicam, and tepoxalin on prostanoid and leukotriene production by duodenal mucosa and other tissues of osteoarthritic dogs

OBJECTIVE: To evaluate the in vivo effects of firocoxib, meloxicam, and tepoxalin on prostaglandin (PG) and leukotriene production in duodenal mucosa and other target tissues in dogs with chronic osteoarthritis (OA). ANIMALS: 8 dogs with chronic, unilateral OA of the stifle joint. PROCEDURES: In a crossover design, each dog received placebo (no treatment), firocoxib, meloxicam, or tepoxalin for 7 days, followed by a 21-day washout period. On the first day of treatment (day 0; baseline) and days 2, 4, and 7, samples of whole blood, synovial fluid, and gastric and duodenal mucosae were collected. Prostaglandin E2 concentrations were measured in synovial fluid of the stifle joint and after ex vivo stimulation of whole blood samples. Synthesis of PGE1 and PGE2 was measured in samples of gastric and duodenal mucosae. Concentrations of thromboxane B2 (TxB2) were measured in whole blood samples. Leukotriene B4 (LTB4) concentrations were measured in samples of whole blood (ex vivo stimulation) and gastric and duodenal mucosae. RESULTS: Firocoxib, meloxicam, and tepoxalin significantly suppressed whole blood concentrations of PGE2, compared with baseline and placebo concentrations, at days 2, 4, and 7. Tepoxalin significantly suppressed serum TxB2 concentrations, compared with baseline, firocoxib, meloxicam, and placebo, at all 3 time points. Production of PGE1 and PGE2 was significantly lower in duodenal versus gastric mucosa. Tepoxalin significantly decreased rates of PGE1 and PGE2 in duodenal and gastric mucosae, compared with baseline rates. CONCLUSIONS AND CLINICAL RELEVANCE: PG production was lower in the duodenum than in the stomach. Firocoxib had a COX-1-sparing effect in vivo.     

In vivo effects of meloxicam and aspirin on blood,gastric mucosal,and synovial fluid prostanoid synthesis in dogs

OBJECTIVE: To evaluate in vivo activity in dogs of meloxicam or aspirin, previously shown in vitro to be a selective cyclooxygenase-2 (COX-2) inhibitor (COX-1 sparing drug), or a nonselective COX inhibitor, respectively. ANIMALS: 12 male dogs with unilateral osteoarthritis of the stifle joint. PROCEDURE: Each dog was treated in a crossover design with aspirin or meloxicam for 21 days. Prostaglandin E2 (PGE2) concentrations were measured at days 0 (baseline), 7, and 21 of each treatment period in lipopolysaccharide (LPS)-stimulated blood, synovial fluid collected by arthrocentesis, and endoscopic gastric mucosal biopsy specimens. Thromboxane B2 (TXB2) was evaluated in blood on days 0, 7, and 21 of each treatment period. RESULTS: Aspirin administration significantly suppressed PGE2 concentrations in blood, gastric mucosa, synovial fluid, and suppressed TXB2 concentration in blood at days 7 and 21. Meloxicam administration significantly suppressed PGE2 concentrations in blood and synovial fluid at days 7 and 21, but had no effect on concentrations of TXB2 in blood or PGE2 in gastric mucosa. Suppression of LPS-stimulated PGE2 concentrations in blood and synovial fluid by aspirin and meloxicam administration is consistent with activity against the COX-2 isoenzyme. Suppression of concentrations of PGE2 in the gastric mucosa and TXB2 in blood by aspirin administration is consistent with activity against COX-1. Meloxicam, in contrast, had a minimal effect on functions mediated by COX-1. CONCLUSIONS AND CLINICAL RELEVANCE: Meloxicam acts in vivo in dogs as a COX-1 sparing drug on target tissues by sparing gastric PGE2 synthesis while retaining antiprostaglandin effects within inflamed joints.     

In vivo effects of carprofen, deracoxib, and etodolac on prostanoid production in blood, gastric mucosa, and synovial fluid in dogs with chronic osteoarthritis

OBJECTIVE: To evaluate in vivo activity of carprofen, deracoxib, and etodolac on prostanoid production in several target tissues in dogs with chronic osteoarthritis. ANIMALS: 8 dogs with chronic unilateral osteoarthritis of the stifle joint. PROCEDURE: Each dog received carprofen, deracoxib, or etodolac for 10 days with a 30- to 60-day washout period between treatments. On days 0, 3, and 10, prostaglandin (PG) E2 concentrations were measured in lipopolysaccharide-stimulated blood, synovial fluid, and gastric mucosal biopsy specimens; PGE1 concentrations were measured in gastric mucosal biopsy specimens; and thromboxane B2 (TXB2) was evaluated in blood. RESULTS: Carprofen and deracoxib significantly suppressed PGE2 concentrations in blood at days 3 and 10, compared with baseline, whereas etodolac did not. None of the drugs significantly suppressed TXB2 concentrations in blood or gastric PGE1 synthesis at any time point. All 3 drugs significantly decreased gastric synthesis of PGE2 at day 3 but not day 10 of each treatment period. All 3 drugs decreased synovial fluid PGE2 concentrations in the affected and unaffected stifle joints at days 3 and 10. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicate that carprofen and deracoxib act in vivo on target tissues as COX-1-sparing drugs by sparing gastric PGE1 and PGE2 synthesis and production of TXB2 by platelets. Etodolac also appears to be COX-1 sparing but may have variable effects on COX-2 depending on the tissue. In gastric mucosa and synovial fluid, there were no significant differences in PG production between compounds at recommended concentrations.     

Correlation of prostaglandin E2 concentrations in synovial fluid with ground reaction forces and clinical variables for pain or inflammation in dogs with osteoarthritis induced by transection of the cranial cruciate ligament

OBJECTIVE: To evaluate the temporal pattern of prostaglandin (PG) E2 concentrations in synovial fluid after transection of the cranial cruciate ligament (CCL) in dogs and to correlate PGE2 concentrations with ground reaction forces and subjective clinical variables for lameness or pain. ANIMALS: 19 purpose-bred adult male Walker Hounds. PROCEDURE: Force plate measurements, subjective clinical analysis of pain or lameness, and samples of synovial fluid were obtained before (baseline) and at various time points after arthroscopic transection of the right CCL. Concentrations of PGE2 were measured in synovial fluid samples, and the PGE2 concentrations were correlated with ground reaction forces and clinical variables. RESULTS: The PGE2 concentration increased significantly above the baseline value throughout the entire study, peaking 14 days after transection. Peak vertical force and vertical impulse significantly decreased by day 14 after transection, followed by an increase over time without returning to baseline values. All clinical variables (eg, lameness, degree of weight bearing, joint extension, cumulative pain score, effusion score, and total protein content of synovial fluid, except for WBC count in synovial fluid) increased significantly above baseline values. Significant negative correlations were detected between PGE2 concentrations and peak vertical force (r, -0.5720) and vertical impulse (r, -0.4618), and significant positive correlations were detected between PGE2 concentrations and the subjective lameness score (r, 0.5016) and effusion score (r, 0.6817). CONCLUSIONS AND CLINICAL RELEVANCE: Assessment of the acute inflammatory process by measurement of PGE2 concentrations in synovial fluid may be correlated with the amount of pain or lameness in dogs.     

Oral administration of tepoxalin in the horse: a PK/PD study

Tepoxalin is a non-steroidal anti-inflammatory drug with analgesic, anti-inflammatory, and antipyretic properties and has been recently introduced into veterinary medicine. The aim of this study was to evaluate the pharmacokinetic/pharmacodynamic (PK/PD) profile of tepoxalin to assess whether it would be suitable for clinical use in horses. Six female fasting/fed horses were given 10mg/kg tepoxalin orally in a cross-over study. After administration, tepoxalin underwent rapid and extensive hydrolytic conversion to its carboxylic acid metabolite RWJ-20142. In animals that had been fed, the plasma concentrations of tepoxalin were undetectable, whereas in fasting animals they were close to the limit of quantification of the method. No differences between the fasting/fed groups in RWJ-20142 plasma concentrations were shown. Tepoxalin showed a strong and long-lasting ex vivo inhibitory activity against cyclooxygenase (COX)-1, mainly due to its main metabolite RWJ-20142. Tepoxalin and RWJ-20142 do not seem to possess either COX-2 or 5-lipoxygenase inhibitory activity in the horse. These features suggest that the drug is a selective COX-1 inhibitor in horses, with no significant anti-inflammatory activity. Thus, its long term use in equine practice could be of concern.     

Pro-apoptotic effects of tepoxalin, a cyclooxygenase/lipoxygenase dual inhibitor, on canine synovial fibroblasts

Canine osteoarthritis occurs frequently and causes secondary synovitis. Administration of nonsteroidal anti-inflammatory drugs (NSAIDs) is one of the major therapeutic options for pain management of joint diseases. Tepoxalin has an unique property as an NSAIDs that suppresses both cyclooxygenase and lipoxygenase. The purpose of this study was to evaluate antiproliferative effects of tepoxalin on cultured canine synovial cells. Cytotoxic effects of tepoxalin, carprofen, meloxicam and AA-861 on cultured canine synoviocytes were evaluated by MTT colorimetric assay. Apoptosis was detected by morphological observations with Giemsa or annexin V/Hoechst 33342 staining and by the inhibition of caspase-3 activity with N-Ac-Asp-Glu-Val-Asp-CHO (Ac-DEVD-CHO). Cytotoxic effects of tepoxalin were evident in comparison with the effects of carprofen or meloxicam. The same tendency of cytotoxicity was observed when 5-lipoxygenase was inhibited by AA-861. The morphological findings and contradictory effects of Ac-DEVD-CHO with regard to the cytotoxicity proved the proapoptotic effects of tepoxalin. In conclusion, tepoxalin might control osteoarthritic synovitis by inducing apoptosis in proliferating synoviocytes, while most NSAIDs that selectively inhibit cyclooxygenase-2 most likely would not suppress synovial proliferation.     

Prostaglandin and thromboxane concentrations in plasma and lung lavage fluids during sequential infection of vaccinated and nonvaccinated calves with bovine respiratory syncytial virus

The potential action of immunologic reactions and mediators released during the course of bovine respiratory syncytial virus infection in pathogenesis of the ensuing disease process was examined in an experimental infection study. Prostaglandin (PG) E2, PGF2 alpha 6-keto-PGF1 alpha, and thromboxane B2 (TxB2) concentrations were quantitated in plasma and lung lavage fluid by radioimmunoassay at 3- to 4-day intervals during a primary and secondary virus infection of vaccinated, nonvaccinated, and control (mock-infected) calves. A significant increase in the plasma PGE2 concentration for the nonvaccinated calves was noticed on day 3 after primary infection and on day 7 after secondary infection. The PGF2 alpha plasma concentrations increased significantly for the nonvaccinated groups on day 10 after primary infection. Plasma 6-keto-PGF1 alpha concentrations increased for nonvaccinated and vaccinated calves 3 days after the secondary infection. Plasma TxB2 concentrations during the primary exposure did not vary significantly. However, 14 days after the secondary exposure, both experimental groups had concentrations significantly greater than did the control group. Lung lavage fluid concentrations of TxB2 had peaks of activity 7 days after primary and secondary viral infections for the nonvaccinated group. Increases in plasma PG concentrations corresponded variably with disease expression, whereas plasma TxB2 concentrations did not have any correlation with disease expression. However, there was a significant correlation between TxB2 concentration in lung lavage fluid of the nonvaccinated group with disease expression 7 days after primary and secondary virus infection.(ABSTRACT TRUNCATED AT 250 WORDS)     

Single and multiple-dose pharmacokinetics of tepoxalin and its active metabolite after oral administration to rabbits (Oryctolagus cuniculus)

The anti-inflammatory agent, tepoxalin, was administered to eight healthy 6-month-old female New Zealand white rabbits once daily at an oral dose of 10 mg/kg. Blood samples were obtained immediately before and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 h postadministration on days 1 and 10. Tepoxalin and its active metabolite, RWJ 20142, concentrations were determined in plasma by use of high-performance liquid chromatography with mass spectrometry. C _max of the parent compound was reached between 3 and 8 h of drug administration, with a harmonic mean t _1/2 of 3.6 h. Peak tepoxalin plasma concentrations were 207 ± 49 ng/mL. After oral administration, the metabolite RWJ 20142 achieved C _max in plasma 2–8 h after administration, with a t _1/2 of 1.9–4.8 h (harmonic mean 2.8 h). Peak plasma concentrations of RWJ 20142 on day 1 were 2551 ± 1034 ng/mL.     

Changes in the levels of eicosanoids in cats naturally and experimentally infected with Dirofilaria immitis

Feline heartworm (Dirofilaria immitis) infection is a severe, life-threatening disease. The eicosanoids are lipid mediators derived from the metabolism of the arachidonic acid, involved in the regulation of the immune response and of inflammatory reactions. In this study, naturally infected cats showed significant higher levels of prostaglandin E(2) (PGE2), thromboxane B(2) (TXB(2)) and leukotriene B(4) (LTB4) than uninfected cats. Changes in the levels of eicosanoids during the infection were observed in experimentally infected cats. PGE2 increased significantly during the first 60 days post-infection, then progressively decreased until day 180 post-infection. At this time, PGE2 values are still significantly higher than those observed before the infection. TxB2 and LTB4 increased progressively from the beginning of infection and reached their maximum levels 180 days post-infection. In experimentally infected, ivermectin-treated cats, 15 days after treatment (45 days after infection) both PGE2 and LTB4 levels were similar to those observed in experimentally infected, untreated cats. No significant differences of PGE2 levels were found before the infection and at the end of the experiment (165 days post-treatment, 195 days post-infection). Increased levels of LTB4 were found 15 days post-treatment, afterward they progressively decreased. These data show that D. immitis infection influences the production of intravascular eicosanoids in cats. The high levels of PGE2 observed in the early phase of infection could be related to the survival of the worms, while those of TxB2 and LTB4 detected at the end of the study could mediate the inflammatory reactions and thrombi formation during the feline dirofilariosis.     

Synovial Fluid Cytokines and Eicosanoids as Markers of Joint Disease in Horses

OBJECTIVE: To evaluate the value of various synovial fluid cytokines and eicosanoids to diagnose joint disease or categories of joint disease. STUDY DESIGN: Prospective acquisition of clinicopathologic data. ANIMALS OR SAMPLE POPULATION: Client-owned or donated horses: 50 joints with no evidence of disease; 28 joints with acute disease; 32 joints with chronic disease; 9 joints with cartilage damage and no other signs of joint disease. METHODS: Concentrations of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), prostaglandin E(2) (PGE(2)), thromboxane B(2) (TXB(2)), prostaglandin F1-alpha (PGF(1)-alpha), and leukotriene B(4) (LTB(4)), were measured in equine synovial fluid by immunoassay and categorized according to duration and degree of joint disease. Any test value for a given category that was different from normal was further analyzed for sensitivity (S), specificity (Sp), and operating point (most valid test cutoff value). Likelihood ratios and predictive values were calculated at the operating point. Mediator concentrations were correlated to synovial fluid white blood cell count. Tests were reported as poor, fair, good, or excellent based on predictive values of <.25,.25-.5,.5-.75, or >.75, respectively. RESULTS: TNF synovial fluid concentration as a predictor of joint disease was good, and the value of TNF (maximum S and Sp) indicating joint disease was >36 pg/mL. IL-1beta as a predictor of joint disease was good, and the value of IL-1beta indicating joint disease was >4.5 pg/mL. IL-6 concentration was an excellent predictor of joint disease. Any IL-6 in synovial fluid indicated joint disease and correlated highly with synovial fluid white blood cell count (P <.0001). PGE(2) was a good-excellent predictor of disease (positive predictive value [PPV] = 0.75), and the concentration indicating joint disease was >22.5 pg/mL. The diagnostic PGF(1)-alpha concentration indicating severe chronic joint disease was identified to be >16.5 pg/mL with very high sensitivity (S = 1) and specificity (Sp =.89). PGF(1)-alpha concentrations > 9.5 pg/mL had a good PPV (.69) and NPV (.6) for any joint disease. TBX(2) concentrations below 31.5 pg/mL (S =.57; Sp =.61) were a very good predictor of joint disease (PPV =.72). LTB(4) concentration appeared to be greater in severe acute joint disease than normal joints; this was not significant (P =.15) and correlated highly with synovial fluid white blood cell count (P =.0001). CONCLUSIONS: The ability of a single value from a joint in an adult horse predicting the presence of joint disease was often good (.5-.75), and was excellent (> or =.75) for IL-6 and PGE(2). TNF-alpha and IL-1beta were no more effective than white blood cell count in screening for joint disease. IL-6 was the most sensitive and specific for joint disease and could be an excellent screening test for the presence of joint disease when lameness is difficult to identify or is intermittent. PGE(2) would be a functional screening test for the presence of any joint disease and offers a differentiating feature because values were not influenced by white blood cell count. PGF(1)-alpha values > 16.5 pg/mL identified chronic severe joint disease and may be clinically useful when there are minimal radiographic changes but substantial articular cartilage degradation.     

Effect of tepoxalin on renal function and hepatic enzymes in dogs exposed to hypotension with isoflurane

ObjectiveTo evaluate the possible renal and hepatic toxicity of tepoxalin in dogs exposed to hypotension during isoflurane anesthesia.Study designProspective, randomized experimental study.AnimalsTwenty adult mixed-breed dogs, weighing 18.8 ± 2.8 kg.MethodsThe animals received 10 mg kg^?1 tepoxalin orally 2 hours before the anesthetic procedure (PRE; n = 6), or 30 minutes after anesthesia (POST; n = 6), along with a control group (CON; n = 8), which were only anesthetized. The PRE and POST groups also received the same dose of tepoxalin for 5 days post-procedure. All dogs were anesthetized with propofol and maintained with isoflurane and the end-tidal isoflurane (Fe’Iso) was increased until mean arterial pressure decreased to 50–60 mmHg. These pressures were maintained for 60 minutes. Heart rate, arterial pressures and Fe’Iso were recorded at 0, 10 and every 10 minutes up to 60 minutes of hypotension. Blood gases, pH, electrolytes and bleeding time were analyzed before and at 30 and 60 minutes of hypotension. Renal and hepatic changes were quantified by serum and urinary biochemistry and creatinine clearance.ResultsSerum concentrations of alanine amino transferase (ALT), alkaline phosphatase (ALP) and σ-glutamyl transferase (GGT), blood urea nitrogen (BUN) and creatinine (Cr), and urinary output, urinary Cr, Cr clearance, and GGT:Cr ratio remained stable throughout the evaluations. During the anesthetic procedure there were no important variations in the physiological parameters. No side effects were observed in any of the groups.Conclusions and clinical relevanceTepoxalin did not cause significant effects on renal function or cause hepatic injury in healthy dogs exposed to hypotension with isoflurane, when administered pre- or postanesthetic and continued for five consecutive days.     

Evaluation of postceliotomy peritoneal drain fluid volume, cytology, and blood-to-peritoneal fluid lactate and glucose differences in normal dogs

Objective: To describe peritoneal drain fluid volume, fluid cytology, and blood‐to‐peritoneal fluid lactate and glucose concentration differences after exploratory celiotomy in normal dogs. Study Design: Prospective study. Animals: Healthy Beagle dogs (n=10). Methods: After exploratory celiotomy, a peritoneal drain was placed, and peritoneal fluid was recorded every 6 hours for 7 days. Fluid was submitted for cytologic examination, and fluid and blood glucose and lactate concentrations were recorded every 12 hours. On day 7, drains were removed and drain tips submitted for aerobic bacterial culture. Results: Mean peritoneal fluid volume decreased from 2.8 mL/kg/day (day 1) to 0.6 mL/kg/day (day 7). All dogs had degenerate neutrophils in peritoneal fluid throughout the 7 days. Four dogs developed contaminated drains. Blood‐to‐peritoneal glucose concentration differences>20 mg/dL occurred after day 4. By day 7, 5 of 7 dogs with patent drains had blood‐to‐peritoneal lactate concentration differences70% of dogs had differences consistent with septic peritonitis each day. Postoperative blood‐to‐peritoneal fluid glucose and lactate difference may not be reliable indicators of septic peritonitis when evaluating abdominal fluid collected with closed suction drains.     

Effects of Firocoxib and Tepoxalin on Healing in a Canine Gastric Mucosal Injury Model

Background: Little is known about the effect of dual cyclooxygenase (COX) and lipoxygenase inhibition on canine gastric mucosal healing.
Objective: This study compares the effects of putative dual COX and 5-lipoxygenase inhibition with that of COX-2 selective inhibition on gastric mucosal lesion healing in dogs.
Animals: Six normal adult mixed-breed research dogs.
Methods: Gastric body and pyloric lesions were induced by endoscopic biopsy. Dogs were treated with tepoxalin, firocoxib, or placebo for 7 days in a randomized 3-way crossover study design. Healing was evaluated on days 2, 4, and 7 of treatment by endoscopic lesion scoring. Eicosanoid concentrations in plasma and at the lesion margins were determined on days 2, 4, and 7. Repeated measures analyses were performed. All hypothesis tests were 2-sided with P < .05. Multiple comparisons were adjusted using Tukey's test.
Results: Significant treatment differences were noted in the pyloric lesion area measurements. Overall, the firocoxib group had larger lesions than the placebo ( P = .0469) or tepoxalin ( P = .0089) groups. Despite larger pyloric lesions in the firocoxib group, mucosal prostaglandin production did not differ significantly from placebo. In contrast, the tepoxalin group had significantly lower pyloric mucosal prostaglandin production compared with the firocoxib ( P < .0001) or the placebo ( P < .0001) groups but pyloric lesions were not significantly larger than those of the placebo group ( P = .7829).
Conclusion: COX-2 inhibition by firocoxib slowed wound healing by a mechanism independent of prostaglandin synthesis. Suppression of mucosal prostaglandin production by tepoxalin did not alter mucosal lesion healing compared with placebo.     

Effect of dietary fat on oral bioavailability of tepoxalin in dogs

A pharmacokinetic study was conducted to compare the oral bioavailability of tepoxalin and its pharmacologically active acid metabolite in fasted dogs and dogs fed either a low-fat or high-fat commercial diet. Using a cross-over design, six beagles were administered tepoxalin (10 mg/kg) intravenously (i.v.) and orally (p.o.) after being fed one of three diets (fasted, low-fat, or high-fat). Thereafter, blood samples were collected at frequent intervals, concentrations of tepoxalin and acid metabolite in plasma were determined by high performance liquid chromatography, and pharmacokinetic parameters were estimated. After i.v. dosing, the mean (+/-SD) half-life of elimination (t(1/2(beta))) was 2.45 +/- 1.47 h. After p.o. administration, plasma concentrations of acid metabolite were consistently higher than corresponding concentrations of the parent tepoxalin, indicating that tepoxalin is subject to a substantial first-pass effect. Mean (+/-SD) peak concentrations of tepoxalin were significantly higher after feeding of low-fat (1.08 +/- 0.37 microg/mL) and high-fat (1.19 +/- 0.29 microg/mL) diets than in fasted dogs (0.53 +/- 0.20 microg/mL), suggesting that feeding improves oral bioavailability.     

Effect of 1- and 10-day administration of tepoxalin on minimum alveolar concentration of isoflurane and sevoflurane in dogs

Analgesics given preoperatively have the potential to decrease the amount of inhalant anesthetics required intraoperatively (i.e., to decrease the minimum alveolar concentration, or MAC, for the inhalant). Tepoxalin is an NSAID approved for the treatment of arthritis in dogs in the United States and, hence, could be administered to patients undergoing anesthesia. In this study, administration of a single dose or a 10-day course of tepoxalin did not affect the MAC for isoflurane or sevoflurane.     

Effect of preoperative administration of tepoxalin on induction dose of injectable anesthetics in dogs

Medications given preoperatively have the potential to affect the induction dose of injectable anesthetics, which could result in an anesthetic overdose. Tepoxalin is an NSAID approved for the treatment of arthritis in dogs in the United States and hence could be administered in patients requiring anesthesia. In this study, administration of a single dose or a 10-day course of tepoxalin did not affect the induction dose (dose that allowed intubation) of propofol, thiopental, or ketamine-diazepam and also did not affect the time required for dogs to recover from anesthesia.     

Serum and synovial fluid concentrations of keratan sulfate and hyaluronan in dogs with induced stifle joint osteoarthritis following cranial cruciate ligament transection

OBJECTIVE: To examine longitudinal changes in serum and synovial fluid concentrations of keratan sulfate (KS) and hyaluronan (HA) after cranial cruciate ligament (CCL) transection in dogs. ANIMALS: 12 clinically normal adult mixed-breed dogs. PROCEDURE: Following CCL transection in the right stifle joint, KS and HA concentrations were determined in serum and neat (undiluted) synovial fluid prior to and 1, 2, 3, and 12 months after surgery. Postsurgical dilution of synovial fluid was corrected by use of urea as a passive marker. RESULTS: Synovial fluid KS and HA concentrations decreased at 1, 2, and 3 months after surgery in operated stifle joints, compared with baseline values. Synovial fluid KS concentration decreased in unoperated stifle joints at 1 month. A decrease in synovial fluid KS concentration was found in operated stifle joints, compared with unoperated stifle joints, at 2 and 3 months, and a decrease in synovial fluid HA concentrations was also found in operated stifle joints, compared with unoperated stifle joints, at 1, 2, and 3 months. Serum KS concentrations increased from baseline values at 3 months after surgery. Hyaluronan concentrations in operated stifle joints were lower than baseline values at 1, 2, and 3 months. Urea-adjusted synovial fluid concentrations revealed that dilution did not account for the decline in biomarker concentrations. CONCLUSIONS AND CLINICAL RELEVANCE: The initial decrease and subsequent increase in synovial fluid concentrations of HA and KS may be caused by an acute inflammatory response to surgical intervention that negatively affects cartilage metabolism or an increase in production of immature proteoglycans.     

高乌甲素对犬术后血浆PGE_2含量的影响及其镇痛机理

选取18只健康杂交雌犬,随机分为A、B、C、D、E、F共6个组,每组3只。A、B、C、D、E组均实施子宫卵巢摘除术制作动物疼痛模型;F组不做手术作为对照组。A、B、C组分别一次性皮下注射高乌甲素0.2、0.4、0.8 mg/kg,D组口服卓比林（20 mg/kg）;E组不给与镇痛治疗。各组动物均在术前、术毕、术后2、6、12、24 h等时间点进行疼痛评分并采血测定血浆中前列腺素E2（PGE2）含量。结果显示：E组术后PGE2含量随时间增加而显著升高;高乌甲素能显著降低术后血浆PGE2含量（P〈0.05）,B组效果最佳;D组与B组无显著差异（P〉0.05）。术后各组的疼痛评分,D组与B组差异不显著（P〉0.05）。结果表明,高乌甲素的镇痛效果与卓比林相当,且其镇痛机理可能是通过抑制PGE2生成来实现的。     

Effects of polyunsaturated fatty acids on the proliferation of mitogen stimulated bovine peripheral blood mononuclear cells

The present study aimed at analysis of the effects of polyunsaturated fatty acid (PUFA), linoleic acid (LA, C18:2n - 6) and linolenic acid (LNA, C18:3n - 3) on bovine peripheral blood mononuclear cells (PBMC) in vitro. Both mitogen (ConA)-induced proliferative lymphocyte responsiveness during 4 days of culture and eicosanoid (prostaglandin E(2) (PGE(2)) and leukotriene B(4) (LTB(4))) production during 36 h were determined in relation to the absence or presence of various concentrations of LA and LNA (0, 1, 5, 25, 125 and 250 microM). Mitogen-driven proliferative responses of lymphocytes tended to be uninfluenced in the presence of lower concentrations of LA, whereas significant inhibition was observed at the higher concentrations of LA (125 and 250 microM). However, increasing amounts of LNA did not affect the proliferation. ConA stimulation induced a clear PGE(2) response, which significantly decreased in the presence of 250 microM of LA. In addition, increasing amounts of LNA, but not LA, led to a significant decrease in LTB(4) levels. However, The production of LTB(4) did not alter due to mitogenic stimulation. In conclusion, the present study shows that bovine mononuclear cells may functionally be influenced by the presence of PUFA in their environment. Further studies need to be conducted to clarify in vivo consequences of these findings in a situation of PUFA enriched rations in ruminants.