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1.
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.  相似文献   

2.
Cyclooxygenase (COX) inhibitors and the intestine   总被引：1，自引：0，他引：1  
Nonsteroidal anti-inflammatory drugs (NSAIDs) have long been used for the treatment of pain and inflammation because of their inhibitory effects on cyclooxygenase (COX). For almost as long as NSAIDs have been in use, multiple adverse effects have been noted. Assessment of many of these adverse effects have been complicated because of the discovery of multiple splice variants of the cox gene, and a greater array of COX inhibitors, especially the COX-2 selective inhibitors have become available. Some of these adverse effects cannot be readily explained by the effect of these drugs on COX. This has sparked a new field of investigation into the COX-independent effects of the COX inhibitors. The major noncyclooxygenase targets of the COX inhibitors of particular relevance to inflammation and the gastrointestinal tract are phosphatidylinositol 3'-kinase Akt signaling, uncoupling of oxidative phosphorylation, PPARgamma, nuclear factor KB, mitogen activated protein kinases, and heat shock proteins.  相似文献   

3.
Objective: Five canine cases of gastrointestinal (GI) perforation and septic peritonitis associated with the routine use of meloxicam are reviewed. Series summary: Selective cyclooxygenase‐2 (COX‐2) non‐steroidal anti‐inflammatory drugs (NSAIDs) are being used more extensively and routinely for acute and chronic pain as well as for perioperative management of pain. These medications are safe and effective but can be associated with known GI and renal side effects. The patients in this case series had no significant concurrent illness, were not on any concurrent medication known to potentiate the ulcerogenic effects of NSAIDs, and in most cases did not display clinical signs that were apparent to the owners until the time of perforation. New or unique information provided: Despite the preferential selectivity for COX‐2, newer NSAIDs still carry the risk of GI performation. The incidence of GI perforation may be increased with inappropriate dosing regimens, with use of non‐veterinary products and in animals that are at high risk for toxicity. Early signs of toxicity may include alteration in appetite, and subtle signs of nausea during treatment. Warning owners to monitor their pet for vomiting, melena, and hematemesis may not be sufficient to avoid the potential disastrous consequences of GI ulceration.  相似文献   

4.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to manage a wide variety of conditions in horses, including management of colic. Flunixin meglumine is by far the most commonly used drug in the control of colic pain and inflammation and has become a go-to for not only veterinarians but also horse-owners and nonmedical equine professionals. NSAID use, however, has always been controversial in critical cases due to a high risk of adverse effects associated with their potent cyclo-oxygenase (COX) inhibition. There are two important COX isoenzymes: COX-1 is generally beneficial for normal renal and gastrointestinal functions and COX-2 is associated with the pain and inflammation of disease. Newer selective NSAIDs can target COX-2-driven pathology while sparing important COX-1-driven physiology, which is of critical importance in horses with severe gastrointestinal disease. Emerging research suggests that firocoxib, a COX-2-selective NSAID labelled for use in horses, may be preferable for use in colic cases in spite of the decades-long dogma that flunixin saves lives.  相似文献   

5.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are substances other than steroids that inhibit a component of the inflammatory cascade. This article is dedicated to those substances which specifically inhibit cyclooxygenase. NSAIDs are used extensively in the veterinary field. This article discusses their pharmacologic mechanism of action, indications, and toxicity. The two isoforms of cyclooxygenase (COX-1 and COX-2) are reviewed along with the newer NSAID which are more effective and less toxic due to more specific COX-2 inhibition. Specific effects on soft tissue, bone, cartilage, and synovium are summarized. Pain modulation is extensively reviewed as well as the antiendotoxic and antithrombotic uses.  相似文献   

6.
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.  相似文献   

7.
Over the past decade, there have been several nonsteroidal anti-inflammatory drugs (NSAIDS) introduced in veterinary medicine with an increased gastrointestinal safety profile consistent with a cyclooxygenase (COX)-1-sparing effect. More recently, an NSAID with additional 5-lipoxygenase (5-LOX) activity has also been approved for use. Although it is tempting to equate in vitro COX-2/COX-1 and 5-LOX inhibition to overall in vivo safety, the data do not support this approach. The true overall safety for any individual compound is based on its evaluation in laboratory margin-of-safety studies, reproductive safety studies, and blind multicenter field studies in client-owned animals. Therefore, when choosing a COX-2-selective or dual-inhibitor NSAID for clinical use, all in vivo data must be taken into account to understand comparative safety, and continued use must be based on the drug's performance in the individual being treated. Until head-to-head trials in multicenter blind studies are published, comments on comparative safety and effectiveness must be reserved.  相似文献   

8.
Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenases (COX), and the inhibition of COX-2 rather than COX-1 can limit the onset of NSAID-related adverse effects. The pharmacodynamic properties of eltenac, naproxen, tepoxalin, SC-560 and NS 398 in healthy horses were investigated using an in vitro whole blood assay. To predict COX selectivity in clinical use, eltenac and naproxen were also studied ex vivo after intravenous administration. SC-560 acted as a selective COX-1 inhibitor, tepoxalin as a dual inhibitor with potent activity against COX-1, and NS 398 as a preferential COX-2 inhibitor. Eltenac was a preferential COX-2 inhibitor in vitro but un-selective in the ex vivo study. Naproxen maintained its non-selectivity both in vitro and ex vivo. These findings have demonstrated that in vitro studies may not accurately predict in vivo NSAID selectivity for COX and should be confirmed using an ex vivo whole blood assay.  相似文献   

9.
NSAIDs are the most widely used analgesics in veterinary medicine, and all have some toxic potential. The most common adverse class effects are gastrointestinal, renal, hepatic, and coagulation disorders. When treating chronic pain associated with osteoarthritis, the effectiveness of NSAIDs can be enhanced by physical therapy, use of chondroprotective agents, certain adjunctive drugs, and diet and exercise to control weight. To treat acute perioperative pain, NSAIDs are more effective when used preemptively, in the context of balanced (multimodal) analgesia, and in well-hydrated patients with normal blood pressure and renal function. Screening and monitoring to identify high-risk candidates for NSAID treatment should include a physical examination and patient history, identification of preexisting diseases or conditions, obtaining baseline and periodic hematologic and clinical chemistry values, and ensuring that other NSAIDs or contraindicated drugs are not used concurrently. When switching a patient from one NSAID to another (when no side effects have been seen), a washout period of 5 to 7 days minimizes chances for adverse drug interactions. Informing clients of the potential adverse effects of NSAID therapy and signs of NSAID toxicity greatly increases the likelihood of safe use of this class of drugs.  相似文献   

10.
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11.
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.  相似文献   

12.
This pilot study was designed to determine whether cyclooxygenase (COX)-1, COX-2, or both are expressed in normal turtle tissues and whether level of expression changes when tissue becomes inflamed. Five eastern box turtles, Terrapene carolina carolina, that either died or were euthanatized due to disease or injuries were used for this work. Tissues were obtained from the five turtles. Western blot analysis was used to evaluate tissues for COX-1 and COX-2 proteins. Densiometric analysis was used to compare Western blot bands within each turtle. COX-1 and COX-2 were found in the liver, kidney, grossly normal muscle, and grossly traumatized (inflamed) muscle of all study turtles. In all cases, COX-1 and COX-2 proteins were increased in traumatized muscle over grossly normal nontraumatized muscle. The highest levels of COX-1 and COX-2 proteins were found in kidney and liver. There was no statistical difference between the amount of COX-1 protein in liver and kidney, but traumatized muscle compared with grossly normal muscle had significantly greater COX-1 but not COX 2 protein concentrations. There was no statistical difference between the amount of COX-2 protein in liver and kidney. Traumatized muscle expressed nonstatistically significant greater amounts of COX-2 compared with grossly normal muscle. COX-1 and COX-2 proteins are expressed in turtle tissues, and both isoforms are upregulated during inflammation of muscle tissue. Traditional nonsteroidal anti-inflammatory drugs (NSAIDs) that block both COX isoforms might be more efficacious than COX-2-selective drugs. This work suggests that NSAIDs should be evaluated for potential liver and kidney toxicity in turtles.  相似文献   

13.
A potential adverse effect of cyclo-oxygenase (COX) inhibitors (nonsteroidal anti-inflammatory drugs [NSAIDs]) in horses is colitis. In addition, we have previously shown an important role for COX-produced prostanoids in recovery of ischaemic-injured equine jejunum. It was hypothesised that the nonselective COX inhibitor flunixin would retard repair of bile-injured colon by preventing production of reparative prostaglandins, whereas the selective COX-2 inhibitor, etodolac would not inhibit repair as a result of continued COX-1 activity. Segments of the pelvic flexure were exposed to 1.5 mmol/l deoxycholate for 30 min, after which they were recovered for 4 h in Ussing chambers. Contrary to the proposed hypothesis, recovery of bile-injured colonic mucosa was not affected by flunixin or etodolac, despite significantly depressed prostanoid production. However, treatment of control tissue with flunixin led to increases in mucosal permeability, whereas treatment with etodolac had no significant effect. Therefore, although recovery from bile-induced colonic injury maybe independent of COX-elaborated prostanoids, treatment of control tissues with nonselective COX inhibitors may lead to marked increases in permeability. Alternatively, selective inhibition of COX-2 may reduce the incidence of adverse effects in horses requiring NSAID therapy.  相似文献   

14.
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15.
Objective: The objective of this review is to summarize what is known in human and veterinary patients regarding the potential interactions of non‐steroidal anti‐inflammatory drugs (NSAIDs) with clinically important drugs. Data sources: Relevant articles as identified through searches of Medline, 1985 to present. Human data synthesis: Hemodynamic drug interactions are most likely to cause clinically relevant problems in humans, in which NSAIDs blunt the response to anti‐hypertensive agents and diuretics in patients with cardiovascular disease, or cause renal decompensation in patients with hypovolemia. In addition, NSAIDs enhance the ulcerogenic effects of glucocorticoids or other recently administered NSAIDs, and can increase bleeding from anti‐coagulant drugs or from herbs with platelet inhibitory activities. Veterinary data synthesis: Although there are numerous studies examining the safety and efficacy of various NSAIDs in healthy or arthritic dogs, there are very few studies that address the safety of these agents in veterinary patients receiving medication for other acute or chronic conditions. Conclusions: Based upon what is known in humans, more studies are needed in veterinary patients to assess the safety of NSAIDs in those animals being treated with anti‐hypertensive, diuretic or anti‐coagulant drugs.  相似文献   

16.
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.  相似文献   

17.
Synovitis in horses is frequently treated by administration of non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit cyclooxygenase isoforms (COX-1 and COX-2). Constitutively expressed COX-1 is involved in physiologic functions such as maintenance of gastric mucosal integrity, whereas COX-2 is up-regulated at sites of inflammation. Thus, COX-2 inhibitors reduce inflammation with reduced gastrointestinal side effects as compared to non-selective COX inhibitors. The objective of the present study was to compare the anti-inflammatory effects of the preferential COX-2 inhibitor etodolac with the non-selective COX inhibitor phenylbutazone in horses with lipopolysaccharide (LPS)-induced synovitis. Three groups of horses (n=6) received no treatment, phenylbutazone (4.4 mg/kg, IV, q12h), or etodolac (23 mg/kg, IV, q12h), respectively, 2-h following injection of LPS into one middle carpal joint. Synovial fluid was analyzed for white blood cell (WBC) count, and TXB2 and PGE2 levels. Phenylbutazone and etodolac significantly reduced WBC count 6 and 24-h following injection of LPS compared to untreated horses. In addition, both drugs significantly reduced PGE2 levels (P<0.05) 6-h following LPS injection, whereas the probable COX-1 prostanoid TXB2 was significantly reduced by phenylbutazone (P<0.05), but not etodolac. Etodolac may serve as a more selective anti-inflammatory agent than phenylbutazone for treatment of equine synovitis.  相似文献   

18.
Much useful information relevant to elucidation of mechanism of action of nonsteroidal anti-inflammatory drugs (NSAIDs) at the molecular level can be obtained from integrating pharmacokinetic (PK) and pharmacodynamic (PD) data, such data being obtained usually, although not necessarily, in separate studies. Integrating PK and PD data can also provide a basis for selecting clinically relevant dosing schedules for subsequent evaluation in disease models and clinical trials. The principles underlying and uses of PK-PD integration are illustrated in this review for phenylbutazone in the horse and cow, carprofen and meloxicam in the horse, carprofen and meloxicam in the cat and nimesulide in the dog. In the PK-PD modelling approach for NSAIDs, the PK and PD data are generated (usually though not necessarily) in vivo in the same investigation and then modelled in silico, usually using the integrated effect compartment or indirect response models. Drug effect is classically modelled with the sigmoidal E(max) (Hill) equation to derive PD parameters which define efficacy, potency and sensitivity. The PK-PD modelling approach for NSAIDs can be undertaken at the molecular level using surrogates of inhibition of cyclooxygenase (COX) isoforms (or indeed other enzymes e.g. 5-lipoxygenase). Examples are provided of the generation of PD parameters for several NSAIDs (carprofen, ketoprofen, vedaprofen, flunixin and tolfenamic acid) in species of veterinary interest (horse, calf, sheep and goat), which indicate that all drugs investigated except vedaprofen were non-selective for COX-1 and COX-2 in the four species investigated under the experimental conditions used, vedaprofen being a COX-1 selective NSAID. In these studies, plasma concentration was linked to COX inhibitory action in the biophase using an effect compartment model. Data for S-(+)-ketoprofen have been additionally subjected to inter-species modelling and allometric scaling of both PK and PD parameters. For several species values of four PK parameters were highly correlated with body weight, whilst values for PD parameters based on COX inhibition lacked allometric relationship with body weight. PK-PD modelling of NSAIDs has also been undertaken using clinical end-points and surrogates for clinical end-points in disease models. By measurement of clinically relevant indices in clinically relevant models, data generated for PD parameters have been used to set dosages and dose intervals for evaluation and confirmation in clinical trials. PK-PD modelling of NSAIDs is likely to prove superior to conventional dose titration studies for dosage schedule determination, as it sweeps the whole of the concentration-effect relationship for all animals and therefore permits determination of genuine PD parameters. It also introduces time as a second independent variable thus allowing prediction of dosage interval. Using indirect response models and clinically relevant indices, PD data have been determined for flunixin, phenylbutazone and meloxicam in the horse, nimesulide in the dog and meloxicam in the cat.  相似文献   

19.
OBJECTIVE: To evaluate cyclooxygenase isozyme distribution in tissues from dogs and determine the differential sensitivity of canine cyclooxygenase (COX)-1 and -2 isozymes to nonsteroidal anti-inflammatory drugs (NSAIDs). SAMPLE POPULATION: Canine tissue samples (stomach, duodenum, ileum, jejunum, colon, spleen, cerebral cortex, lung, ovary, kidney, and liver) were obtained from 2 dogs for northern and western blot analyses, and blood for whole blood COX assays was obtained from 15 dogs. PROCEDURE: 11 NSAIDs were evaluated to determine their COX-2 selectivity in whole blood assays. The concentrations of the drug needed to inhibit 50% of enzyme activity (IC50) were then calculated for comparison. Expression and tissue distribution of COX isozymes were determined by northern and western blot analysis. RESULTS: Aspirin, diclofenac, indomethacin, ketoprofen, meclofenamic acid, and piroxicam had little selectivity toward COX isozymes, whereas NS398, carprofen, tolfenamic acid, nimesulide, and etodolac had more than 5 times greater preference for inhibiting COX-2 than COX-1. All canine tissues examined, including those from the gastrointestinal tract, coexpressed COX-1 and -2 mRNA, although protein expression was observed only for COX-1. CONCLUSIONS AND CLINICAL RELEVANCE: Canine COX-2 was selectively inhibited by etodolac, nimesulide, and NS398; tolfenamic acid and carprofen also appeared to be preferential COX-2 inhibitors in dogs. The roles of COX-1 as a constitutive housekeeping enzyme and COX-2 as a proinflammatory inducible enzyme (as determined in humans) appear to apply to dogs; therefore, COX-2-selective inhibitors should prove useful in reducing the adverse effects associated with nonselective NSAIDs.  相似文献   

20.
The pharmacodynamics of non-steroidal anti-inflammatory drugs (NSAIDs) are for the most part well-understood. All NSAIDs inhibit the enzyme cyclooxygenase (COX), and for this reason prostaglandin synthesis. Two isoforms of COX could be isolated. COX-1 is detectable in most tissues on a constant level and is responsible for the synthesis of prostaglandins with cytoprotective effects. COX-2 is induced through inflammation and supports the inflammatory process by producing pro-inflammatory prostaglandins. The desired effects of NSAIDs are related to inhibition of COX-2, whereas inhibition of COX-1 has been linked to the typical side-effects of NSAIDs, especially in the stomach and kidney. The great differences between effects and side-effects in the numerous substances can be explained because of different interactions of the NSAIDs on COX-1 and COX-2. In various test systems meloxicam has been shown to be a preferential inhibitor of COX-2. There are also large differences between the individual NSAIDs with regard to pharmacokinetics. Meloxicam is completely absorbed from the gastrointestinal tract and has an elimination half-life of 24 hours in the dog. It is excreted in faeces and urine. The metabolites, detectable in urine are biologically inactive and do not influence the prostaglandin synthesis in the kidney. In the underlying study, plasma concentration of meloxicam was determined after a subcutaneous injection of 0.2 mg/kg b. w. (day 1) followed by oral treatment of 0.1 mg/kg b. w. (days 2-14). The results confirm the recommended dosage regime of meloxicam with its initial loading dose and the subsequent maintenance dose. This dosing regime results in a very favourable curve of concentrations with a very rapidly attained steady state after roughly two days, without accumulation even in long-term treatment.  相似文献   

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