Clinical pharmacology of nonsteroidal anti-inflammatory drugs in dogs

OBJECTIVES: To discuss the clinical pharmacology of currently licensed veterinary NSAIDs and to review gastrointestinal and renal adverse effects as well as drug-drug interactions that have been reported with these drugs. To review the use of NSAIDs in the peri-operative setting and their use in patients with osteoarthritis. To further review the reported effects of NSAIDs on canine articular cartilage and liver as well as the clinical relevance of a washout period. DATABASES USED: PubMed, CAB abstracts and Google Scholar using dog, dogs, nonsteroidal anti-inflammatory drugs and NSAID(s) as keywords. CONCLUSIONS: A good understanding of the mechanisms by which NSAIDs elicit their analgesic effect is essential in order to minimize adverse effects and drug-drug interactions. Cyclooxygenase (COX) is present in at least two active isoforms in the body and is the primary pharmacologic target of NSAIDs. Inhibition of COX is associated with the analgesic effects of NSAIDs. COX is present in the gastrointestinal tract and kidneys, along with other areas of the body, and is also the likely reason for many adverse effects including gastrointestinal and renal adverse effects. The newer veterinary approved NSAIDs have a lower frequency of gastrointestinal adverse effects in dogs compared to drugs such as aspirin, ketoprofen and flunixin, which may be due to differential effects on the COX isoforms. There are currently no published reports demonstrating that the newer NSAIDs are associated with fewer renal or hepatic adverse effects in dogs. NSAIDs remain the cornerstone of oral therapy for osteoarthritis unless contraindicated by intolerance, concurrent therapies or underlying medical conditions. NSAIDs are also effective and frequently used for the management of post-operative pain.     

Development of in vitro assays for the evaluation of cyclooxygenase inhibitors and predicting selectivity of nonsteroidal anti-inflammatory drugs in cats

OBJECTIVE: 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. ANIMALS: 10 cats. PROCEDURE: 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. RESULTS: 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. CONCLUSIONS AND CLINICAL RELEVANCE: 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.     

非甾体抗炎药的研究进展

传统非甾体抗炎药对环氧化酶的选择性较差,副作用明显,临床应用受限.近年来,一些疗效好、副作用低的新型非甾体抗炎药相继问世,应用于临床.本文主要综述了选择性COX-2抑制剂、一氧化氮释放型非甾体抗炎药以及选择性5-LOX/COX-2双重抑制剂三类非甾体抗炎药中的代表药物的研究进展.     

Changes in platelet function, hemostasis, and prostaglandin expression after treatment with nonsteroidal anti-inflammatory drugs with various cyclooxygenase selectivities in dogs

OBJECTIVE: To determine the effects of nonsteroidal anti-inflammatory drugs of various cyclooxygenase selectivities on hemostasis and prostaglandin expression in dogs. ANIMALS: 8 client-owned dogs with clinical signs of osteoarthritis. PROCEDURES: Dogs received aspirin (5 mg/kg, PO, q 12 h), carprofen (4 mg/kg, PO, q 24 h), deracoxib (2 mg/kg, PO, q 24 h), and meloxicam (0.1 mg/kg, PO, q 24 h) for 10 days each, with an interval of at least 14 days between treatments. On days 0 and 10, blood was collected for platelet aggregation assays, thrombelastography, and measurement of lipopolysaccharide-stimulated prostaglandin E(2), platelet thromboxane B(2) (TXB(2)), and free serum TXB(2) and 6-keto-prostaglandin F (PGF)-1alpha concentrations. RESULTS: Platelet aggregation decreased after treatment with aspirin and carprofen, whereas significant changes from baseline were not detected for the other drugs tested. Thrombelastograms obtained after treatment with carprofen revealed decreased maximum amplitude and alpha-angle, suggesting hypocoagulability. Maximum amplitude and coagulation index increased after treatment with deracoxib. Plasma concentrations of prostaglandin E(2) decreased after treatment with carprofen or deracoxib, and platelet TXB(2) production increased after treatment with aspirin. Serum concentrations of the prostacyclin metabolite 6-keto-PGF-1alpha did not change significantly after treatment with any of the drugs, although the ratio of free TXB(2) to 6-keto-PGF-1alpha decreased slightly after treatment with carprofen and increased slightly after treatment with deracoxib. CONCLUSIONS AND CLINICAL RELEVANCE: At the dosages tested, treatment with meloxicam affected platelet function minimally in dogs with osteoarthritis. Treatment with carprofen decreased clot strength and platelet aggregation. Clot strength was increased after treatment with deracoxib.     

In vitro activity of the nonsteroidal anti-inflammatory drug indomethacin on a scuticociliate parasite of farmed turbot

The scuticociliatosis produced by the endoparasite Philasterides dicentarchi is a severe parasitic infection of farmed turbot (Scophthalmus maximus) characterized by several histopathological effects including extensive inflammation. Indomethacin is a nonsteroidal anti-inflammatory drug that specifically inhibits synthesis of the proinflammatory mediator prostaglandins. The effect of indomethacin on the in vitro growth of P. dicentrarchi was investigated. In vitro growth of the scuticociliate was significantly inhibited by treatment with 100 microM indomethacin for 48 h. Higher concentrations of indomethacin (mM levels) did not affect the gelatinolytic activity of the cysteine proteinases of P. dicentrarchi. In vitro treatment with 25, 50 or 100 microM indomethacin for 3 days did not significantly affect the enzymatic activity of cysteine proteinases, as assayed with p-nitroanilide as substrate. Immunoblot analysis with anti-cysteine proteinase antibodies revealed an increase in proteinase expression (molecular weights of 80, 32 and 40-45 kDa) in parasite lysates originating from in vitro cultures incubated with 25 microM indomethacin for 72 h. Degradation of genomic DNA of the ciliates was observed in cultures incubated with 100 microM indomethacin for 1, 3 and 7 days. The results suggest that indomethacin is capable of inhibiting in vitro growth of the scuticociliate P. dicentrarchi by a mechanism related to the induction of programmed cell death, without affecting the enzymatic activation of parasite proteinases, which demonstrates the potential therapeutic use of this drug in the control of turbot scuticociliatosis.     

Effect of administration of nonsteroidal anti-inflammatory drugs before surgery on renal function in clinically normal dogs

OBJECTIVES: To investigate renal function in clinically normal dogs undergoing general anesthesia for ovariohysterectomies that received nonsteriodal antiinflammatory drugs (NSAID) before surgery. ANIMALS: 40 clinically normal dogs. PROCEDURE: After induction of anesthesia, dogs were given an analgesic. Renal function was assessed before surgery and 24 and 48 hours after surgery by means of serum urea and creatinine concentrations, fractional clearance of sodium (FC(Na)), urine gamma-glutamyltransferase (GGT) and alkaline phosphatase (ALP) activities, and urine analysis. Ten dogs in each of 4 groups received ketorolac tromethamine (0.5 mg/kg of body weight), ketoprofen (1 mg/kg), carprofen (4 mg/kg), or morphine (0.1 mg/kg; control group). RESULTS: Duration of general anesthesia ranged from 1.75 to 5 hours, with a mean of 3 hours. Two ketorolac- and 2 ketoprofen-treated dogs had transient azotemia. A significant decrease in the FC(Na) between before surgery and 24 hours after surgery, and between before surgery and 48 hours after surgery, was found in ketoprofen- and carprofen-treated dogs. Ketorolac-, ketoprofen-, and morphine-treated dogs had a decrease in urine specific gravity. Two ketorolac, 1 ketoprofen-, 1 carprofen-, and 4 morphine-treated dogs had increases in renal tubular epithelial cells on urine sediment examination 24 hours after surgery. CONCLUSIONS AND CLINICAL RELEVANCE: In clinically normal dogs undergoing general anesthesia and elective surgery, the use of NSAID as analgesics is not contraindicated. Compared with ketorolac or ketoprofen, carprofen had the least effect on renal function and integrity.     

In vitro effects of cyclooxygenase inhibitors in whole blood of horses, dogs, and cats.

OBJECTIVE: To determine potency and selectivity of nonsteroidal anti-inflammatory drugs (NSAID) and cyclooxygenase- (COX-) specific inhibitors in whole blood from horses, dogs, and cats. SAMPLE POPULATION: Blood samples from 30 healthy horses, 48 healthy dogs, and 9 healthy cats. PROCEDURE: 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). RESULTS: 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. CONCLUSIONS AND CLINICAL RELEVANCE: 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.     

Cyclooxygenase selectivity of nonsteroidal anti-inflammatory drugs in canine blood

OBJECTIVE: To evaluate cyclooxygenase (COX) selectivity of several nonsteroidal anti-inflammatory drugs (NSAID) in canine blood in vitro. ANIMALS: 11 healthy adult male hound crosses. PROCEDURE: 9 NSAID were studied at 5 concentrations. Thromboxane B2 (TxB2) was assayed as a measure of COX-1 activity in clotted blood. Prostaglandin E2 (PGE2) was assayed as a measure of COX-2 activity in heparinized, lipopolysaccharide (LPS)-stimulated blood. All assays were competitive ELISA tests. Cyclooxygenase selectivity was expressed as a ratio of the concentration of an NSAID that inhibited 50% of the activity (IC50) of COX-1 to the IC50 of COX-2. A separate ratio of the concentration that inhibited 80% of COX activity (IC80) was also determined. A ratio of < 1.0 indicated selectivity for COX-1, whereas a ratio of > 1.0 indicated COX-2 selectivity. RESULTS: Ketoprofen, aspirin, and etodolac were COX-1 selective. Piroxicam, meloxicam, and carprofen had COX-2 selectivity. The IC50 and IC80 values were similar for most NSAID. CONCLUSIONS: This methodology provides repeatable data from individual dogs and is comparable to results of previous in vitro and ex vivo models. Findings are also consistent with those of canine studies performed in vivo, suggesting that this is a viable in vitro assessment of the COX selectivity of NSAID in dogs.     

In vitro investigation of the effects of nonsteroidal anti-inflammatory drugs, prostaglandin E2, and prostaglandin F2alpha on contractile activity of the third compartment of the stomach of llamas

OBJECTIVE: To determine the in vitro effect of prostaglandin (PG) E2, PGF2alpha, and the nonsteroidal anti-inflammatory drugs (NSAIDs) indomethacin, ketoprofen, and nabumetone on the contractile strength of the circular smooth muscle layer of the third compartment of the stomach of llamas. SAMPLE POPULATION: Specimens of the third compartment obtained from 5 healthy adult llamas. PROCEDURE: Full-thickness tissue samples were collected from the third compartment immediately after euthanasia. Specimens were cut into strips oriented along the circular muscle layer and mounted in a tissue bath system. Incremental amounts of ketoprofen, nabumetone, indomethacin, PGE2, and PGF2alpha were added, and contractile strength (amplitude of contractions) was recorded. RESULTS: Generally, PGE2 reduced contractile strength of the circular smooth layer of the third compartment, whereas PGF2alpha, increased the strength of contractions. The activity of the NSAIDs was generally excitatory in a concentration-dependent manner, although significant changes were induced only by administration of indomethacin. CONCLUSIONS AND CLINICAL RELEVANCE: On isolated smooth muscle strips of the third compartment of llamas, exogenous PGE2 and PGF2alpha had a variable effect on contractile strength. Administration of the NSAIDs did not inhibit contractility and would not be likely to induce stasis of the third compartment in the absence of an underlying disease process.     

Cyclooxygenase expression and prostanoid production in pyloric and duodenal mucosae in dogs after administration of nonsteroidal anti-inflammatory drugs

OBJECTIVE: To assess cyclooxygenase (COX) expression and prostanoid concentrations in pyloric and duodenal mucosae of dogs after administration of nonsteroidal anti-inflammatory drugs (NSAIDs). ANIMALS: 8 healthy dogs. PROCEDURES: Each dog received carprofen (4.4 mg/kg, q 24 h), deracoxib (2 mg/kg, q 24 h), aspirin (10 mg/kg, q 12 h), and placebo (1 dog treat, q 24 h) orally for 3 days (4-week interval between treatments). Before study commencement (baseline) and on day 3 of each treatment, pyloric and duodenal mucosal appearance was assessed endoscopically and biopsy specimens were obtained for histologic examination. Cyclooxygenase-1 and COX-2 protein expressions were assessed via western blotting, and prostanoid concentrations were measured via ELISAs. An ANOVA was used to analyze data. RESULTS: Treatments had no effect on mucosal appearance and ulceration was not evident histologically. In pyloric and duodenal mucosae, COX-1 expression was unaffected by treatments. Cyclooxygenase-2 expression remained unchanged in pyloric mucosa; in duodenal mucosa, aspirin significantly increased COX-2 expression, compared with effects of deracoxib and carprofen. At baseline, total prostaglandin and thromboxane B2 concentrations in pyloric mucosa were significantly greater than those in duodenal mucosa. Aspirin significantly decreased both prostanoid concentrations in both mucosal tissues, compared with other treatments. In pyloric mucosa, carprofen administration significantly decreased total prostaglandin and thromboxane B2 concentrations, compared with deracoxib administration. CONCLUSIONS AND CLINICAL RELEVANCE: In dogs, prostanoid synthesis was greater in pyloric mucosa than it was in duodenal mucosa. Nonselective NSAIDs significantly decreased prostanoid concentrations in these mucosae, compared with the effects of a selective COX-2 NSAID.     

Use of nonsteroidal anti-inflammatory drugs in food animal practice.

We attempted to determine the extent to which nonsteroidal anti-inflammatory drugs (NSAID) are used in the treatment of food animals, and whether withdrawal times for milk and slaughter are recommended to clients. A survey questionnaire was mailed to a stratified random sample of 2,000 veterinarians whose practices were at least half food animals. A cross-sectional study was used to examine the responses to determine whether differences existed on the basis of a respondent's geographic location, number of years since graduation from veterinary college, and percentage of practice devoted to beef and dairy cattle. The response rate was 71% (1,424/2,000). Of those practitioners responding, 93% (1,325/1,424) reported using NSAID, with approximately 57 (751/1,322), 24 (327/1,322), and 18% (244/1,322) of respondents reporting use more than once a week, once a week, and 1 to 2 times per month, respectively. Dairy practitioners reported more frequent use than did beef practitioners. Use of flunixin meglumine was reported more frequently than the use of aspirin, phenylbutazone, or dipyrone. Approximately 88% (1,146/1,306) of respondents that used NSAID did so in combination with antibiotics. Withdrawal times for milk and meat were made on the basis of guidelines for the antibiotic. When using NSAID alone, recommendations for withdrawal times for milk and meat varied extensively. Overall, practitioners indicated that NSAID were useful and necessary for the treatment of food-producing animals.     

非甾体类抗炎药前处理及检测方法研究进展

非甾体类抗炎药是目前兽医临床中使用最为广泛的一类药物,但此类药物在动物源性食品中的残留对人类的健康造成严重威胁。通过综述国内外非甾体类抗炎药在动物源性食品中的前处理方法和检测方法的研究现状,总结不同前处理方法的优缺点以及多种检测方法的灵敏度和准确性,对非甾体类药物的残留检测发展趋势进行展望,旨在为今后的检测方法开发提供参考。     

Effect of short-term sequential administration of nonsteroidal anti-inflammatory drugs on the stomach and proximal portion of the duodenum in healthy dogs

OBJECTIVE: To evaluate effects of injection with a nonsteroidal anti-inflammatory drug (NSAID) followed by oral administration of an NSAID on the gastrointestinal tract (GIT) of healthy dogs. ANIMALS: 6 healthy Walker Hounds. PROCEDURES: In a randomized, crossover design, dogs were administered 4 treatments consisting of an SC injection of an NSAID or control solution (day 0), followed by oral administration of an NSAID or inert substance for 4 days (days 1 through 4). Treatment regimens included carprofen (4 mg/kg) followed by inert substance; saline (0.9% NaCl) solution followed by deracoxib (4 mg/kg); carprofen (4 mg/kg) followed by carprofen (4 mg/kg); and carprofen (4 mg/kg) followed by deracoxib (4 mg/kg). Hematologic, serum biochemical, and fecal evaluations were conducted weekly, and clinical scores were obtained daily. Endoscopy of the GIT was performed before and on days 1, 2, and 5 for each treatment. Lesions were scored by use of a 6-point scale. RESULTS: No significant differences existed for clinical data, clinicopathologic data, or lesion scores in the esophagus, cardia, or duodenum. For the gastric fundus, antrum, and lesser curvature, an effect of time was observed for all treatments, with lesions worsening from before to day 2 of treatments but improving by day 5. CONCLUSIONS AND CLINICAL RELEVANCE: Sequential administration of NSAIDs in this experiment did not result in clinically important gastroduodenal ulcers. A larger study to investigate the effect of sequential administration of NSAIDs for longer durations and in dogs with signs of acute and chronic pain is essential to substantiate these findings.     

Transdermal fentanyl combined with nonsteroidal anti-inflammatory drugs for analgesia in horses

This study investigated the pharmcokinetics, efficacy, and safety of the fentanyl transdermal therapeutic system (TTS) in horses in which there was an inadequate analgesic response to nonsteroidal anti-inflammatory drugs (NSAIDs) alone. Nine horses with pain that was refractory to therapeutic doses of phenylbutazone (n = 3) or flunixin meglumine (n = 6) subsequently also received between 39 and 110 microg/kg of transdermal fentanyl. Blood samples were collected at 0, 1, 2, 3, 4, 5, 6, 12, 24, 36, 48, 60, and 72 hours after patch application, and a radioimmunoassay was used to determine serum fentanyl concentrations. Pharmacokinetic values were determined by noncompartmental analysis. Physical examination findings were recorded in all horses, and pain and lameness grading systems were used to assign scores to 8 and 6 horses, respectively. All horses tolerated the administration of fentanyl TTS, in that no clinically significant adverse effects attributable to fentanyl were observed. Use of the TTS resulted in variable serum concentrations of fentanyl, with a peak serum concentration of 2.2+/-1.1 ng/mL (mean+/-SD) and a time to peak serum concentration of 26+/-13 hours. After transdermal fentanyl administration, mean time to reach serum fentanyl concentrations consistent with analgesia in other species (1 ng/mL) was 14 hours. In addition, serum fentanyl concentrations of 1 ng/mL or greater were maintained in all but one horse for at least 18 hours. Pain scores were significantly decreased after fentanyl TTS and NSAID administration (P < .05), but lameness scores were not significantly different (P > .05). Overall, administration of fentanyl TTS had a favorable pharmacokinetic profile in horses with clinical pain, and the fentanyl TTS in combination with NSAIDs appeared to provide safe and effective analgesia in most of the horses with pain that was refractory to NSAID therapy alone.     

In vitro investigation of the effect of prostaglandins and nonsteroidal anti-inflammatory drugs on contractile activity of the equine smooth muscle of the dorsal colon, ventral colon, and pelvic flexure

OBJECTIVES: To determine the in vitro effect of prostaglandin E2 (PGE2), PGF2alpha, PGI2; and nonsteroidal anti-inflammatory drugs (NSAID; ie, flunixin meglumine, ketoprofen, carprofen, and phenylbutazone) on contractile activity of the equine dorsal colon, ventral colon, and pelvic flexure circular and longitudinal smooth muscle. ANIMALS: 26 healthy horses. PROCEDURE: Tissue collected from the ventral colon, dorsal colon, and pelvic flexure was cut into strips and mounted in a tissue bath system where contractile strength was determined. Incremental doses of PGE2, PGF2alpha,, PGI2, flunixin meglumine, carprofen, ketoprofen, and phenylbutazone were added to the baths, and the contractile activity was recorded for each location and orientation of smooth muscle. RESULTS: In substance P-stimulated tissues, PGE2 and PGF2alpha enhanced contractility in the longitudinal smooth muscle with a decrease or no effect on circular smooth muscle activity. Prostaglandin I2 inhibited the circular smooth muscle response with no effect on the longitudinal muscle. The activity of NSAID was predominantly inhibitory regardless of location or muscle orientation. CONCLUSIONS AND CLINICAL RELEVANCE: In the equine large intestine, exogenous prostaglandins had a variable effect on contractile activity, depending on the location in the colon and orientation of the smooth muscle. The administration of NSAID inhibited contractility, with flunixin meglumine generally inducing the most profound inhibition relative to the other NSAID evaluated in substance P-stimulated smooth muscle of the large intestine. The results of this study indicate that prolonged use of NSAID may potentially predispose horses to develop gastrointestinal tract stasis and subsequent impaction.     

Pharmacodynamics and pharmacokinetics of nonsteroidal anti-inflammatory drugs in species of veterinary interest

This review summarises selected aspects of the pharmacokinetics (PK) and pharmacodynamics (PD) of nonsteroidal anti-inflammatory drugs (NSAIDs). It is not intended to be comprehensive, in that it covers neither minor species nor several important aspects of NSAID PD. The limited objective of the review is to summarise those aspects of NSAID PK and PD, which are important to an understanding of PK-PD integration and PK-PD modelling (the subject of the next review in this issue). The general features of NSAID PK are: usually good bioavailability from oral, intramuscular and subcutaneous administration routes (but with delayed absorption in horses and ruminants after oral dosing), a high degree of binding to plasma protein, low volumes of distribution, limited excretion of administered dose as parent drug in urine, marked inter-species differences in clearance and elimination half-life and ready penetration into and slow clearance from acute inflammatory exudate. The therapeutic effects of NSAIDs are exerted both locally (at peripheral inflammatory sites) and centrally. There is widespread acceptance that the principal mechanism of action (both PD and toxicodynamics) of NSAIDs at the molecular level comprises inhibition of cyclooxygenase (COX), an enzyme in the arachidonic acid cascade, which generates inflammatory mediators of the prostaglandin group. However, NSAIDs possess also many other actions at the molecular level. Two isoforms of COX have been identified. Inhibition of COX-1 is likely to account for most of the side-effects of NSAIDs (gastrointestinal irritation, renotoxicity and inhibition of blood clotting) but a minor contribution also to some of the therapeutic effects (analgesic and anti-inflammatory actions) cannot be excluded. Inhibition of COX-2 accounts for most and possibly all of the therapeutic effects of NSAIDs. Consequently, there has been an intensive search to identify and develop drugs with selectivity for inhibition of COX-2. Whole blood in vitro assays are used to investigate quantitatively the three key PD parameters (efficacy, potency and sensitivity) for NSAID inhibition of COX isoforms, providing data on COX-1:COX-2 inhibition ratios. Limited published data point to species differences in NSAID-induced COX inhibition, for both potency and potency ratios. Members of the 2-arylpropionate sub-groups of NSAIDs exist in two enantiomeric forms [R-(-) and S-(+)] and are licensed as racemic mixtures. For these drugs there are marked enantiomeric differences in PK and PD properties of individual drugs in a given species, as well as important species differences in both PK and PD properties.     

Acute effects of anti-inflammatory drugs on neodymium:yttrium aluminum garnet laser-induced uveitis in dogs.

Dogs were treated with flunixin meglumine, a cyclooxygenase inhibitor; L-651,896, a 5-lipoxygenase inhibitor; and matrine, a herbal anti-inflammatory drug. Acute inflammation was induced in the eyes by disruption of the anterior lens capsule, using a neodymium:yttrium aluminum garnet laser. Intraocular pressure, pupil diameter, and eicosanoid production in the aqueous humor were measured. Statistically significant effects were seen in the eyes of flunixin meglumine-treated dogs where mydriasis was maintained and aqueous prostaglandin E2 concentration was reduced.