Ex vivo COX-1 and COX-2 inhibition in equine blood by phenylbutazone,flunixin meglumine,meloxicam and firocoxib: Informing clinical NSAID selection

Newer cyclo-oxygenase-2 (COX-2) selective nonsteroidal anti-inflammatory drugs (NSAIDs), such as firocoxib, are proposed to reduce inhibition of cyclo-oxygenase-1 (COX-1) and avoid undesirable side effects, while continuing to inhibit inflammation associated with COX-2. However, COX selectivity is typically based on in vitro testing, which may not provide sufficient information critical for treatment selection. This study investigated the pharmacokinetics and ex vivo COX-1 and COX-2 inhibition of phenylbutazone, flunixin meglumine, meloxicam and firocoxib. Horses (n = 3) were administered one of the four drugs, in a randomised cross-over design, with 3-week washout periods. For each drug, three doses were given and sampling performed. Drug plasma concentrations, thromboxane B₂ (TXB₂) and prostaglandin E₂ (PGE₂) were determined. After one dose, TXB₂ and PGE₂ levels were significantly higher in horses administered firocoxib compared to flunixin meglumine. Following the third dose, TXB₂ levels in horses administered firocoxib and meloxicam were significantly higher compared to flunixin meglumine or phenylbutazone; all drugs reduced PGE₂ to a similar degree. The mean plasma half-lives were 5.97 ± 0.47, 4.74 ± 0.14, 8.24 ± 3.74 and 47.42 ± 7.41 h for phenylbutazone, flunixin meglumine, meloxicam and firocoxib, respectively. Firocoxib and meloxicam exhibited significantly less COX-1 inhibition compared to flunixin meglumine and phenylbutazone; all drugs inhibited COX-2. The plasma half-life of firocoxib was longer than the other NSAIDs, including meloxicam. Data from this study have important clinical relevance and should be used to inform practitioners’ drug selection of a COX-1 sparing or traditional NSAID and dose selection and to provide knowledge of the duration for the four NSAIDs studied.     

解热镇痛药的发展概况

解热镇痛类药物包括传统的非甾体类抗炎药(COX-1抑制剂)、非传统的非甾体类抗炎药(COX-2抑制剂和一氧化氮释放型NSAIDs)。文章分析其国内外市场状况,并指出临床应用所存在的问题。总结了常用解热镇痛药的不良反应,提出了应用时应注意的事项。预计在今后的一段时期内,研究COX-2选择性抑制剂,发现新结构类型的高活性化合物仍是主攻方向,而且开发NO-NSAIDs也会成为降低NSAIDs的不良反应,增加其疗效的途径之一。     

Sparing the gut: COX-2 inhibitors herald a new era for treatment of horses with surgical colic

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.     

Pharmacometabolomics with a combination of PLS-DA and random forest algorithm analyses reveal meloxicam alters feline plasma metabolite profiles

Repeated administration of meloxicam to cats is often limited by the potential damage to multiple organ systems. Identifying molecules that predict the adverse effects of meloxicam would help to monitor and individualize its administration, maximizing meloxicam's beneficial effects. The objectives of this study were to (a) determine if the repeated administration of meloxicam to cats alters the plasma metabolome and (b) identify plasma metabolites that may serve to monitor during the administration of meloxicam in cats. Purpose bred young adult cats (n = 12) were treated with meloxicam at 0.3 mg/kg or saline subcutaneously once daily for up to 17 days. An untargeted metabolomics approach was applied to plasma samples collected prior to and at designated time points after meloxicam or saline administration. To refine the discovery of biomarkers, the machine-learning algorithms, partial least squares discriminant analysis (PLS-DA) and random forest (RF), were trained and validated using a separate unrelated group of meloxicam- and saline-treated cats (n = 8). A total of 74 metabolites were included in the statistical analysis. Metabolomic analysis shows that the repeated administration of meloxicam alters multiple substances in plasma, including nonvolatile organic acids, aromatic amino acids, monosaccharides, and inorganic compounds as early as four days following administration of meloxicam. Seventeen plasma molecules were able to distinguish meloxicam-treated from saline-treated cats. The metabolomic changes discovered in this study may help to unveil unknown mechanisms of NSAID-induced side effects. In addition, some metabolites could be valuable for individualizing the administration of meloxicam to cats to mitigate adverse effects.     

Comparison of Force Plate Gait Analysis and Owner Assessment of Pain Using the Canine Brief Pain Inventory in Dogs with Osteoarthritis

Background

Lameness assessment using force plate gait analysis (FPGA) and owner assessment of chronic pain using the Canine Brief Pain Inventory (CBPI) are valid and reliable methods of evaluating canine osteoarthritis. There are no studies comparing these 2 outcome measures.

Objective

Evaluate the relationship between CBPI pain severity (PS) and interference (PI) scores with the vertical forces of FPGA as efficacy measures in canine osteoarthritis.

Animals

Sixty‐eight client‐owned dogs with osteoarthritis (50 hind limb and 18 forelimb).

Methods

Double‐blind, randomized. Owners completed the CBPI, and dogs underwent FPGA on days 0 and 14. Dogs received carprofen or placebo on days 1 through 14. The change in PS and PI scores from day 0 to 14 were compared to the change in peak vertical force (PVF) and vertical impulse (VI).

Results

PS and PI scores significantly decreased in carprofen‐ compared with placebo‐treated dogs (P = .002 and P = .03, respectively). PVF and VI significantly increased in carprofen‐ compared with placebo‐treated dogs (P = .006 and P = .02, respectively). There was no correlation or concordance between the PS or PI score changes and change in PVF or VI.

Conclusions and Clinical Importance

In these dogs with hind limb or forelimb osteoarthritis, owner assessment of chronic pain using the CBPI and assessment of lameness using FPGA detected significant improvement in dogs treated with carprofen. The lack of correlation or concordance between the change in owner scores and vertical forces suggests that owners were focused on behaviors other than lameness when making efficacy evaluations in their dogs.     

Cyclooxygenase-2 expression in canine appendicular osteosarcomas

Osteosarcoma is the most common primary bone tumor in dogs and it has a high mortality rate from distant metastatic disease. Targeted adjuvant therapies are needed to prolong currently achievable survival times. The role of cyclooxygenase-2 (COX-2) in carcinogenesis has been attributed to the production of prostaglandins and involvement in apoptosis, immune surveillance, and angiogenesis. COX-2 is up-regulated in a number of different human and animal epithelial tumors, but data about its function in mesenchymal tumors is lacking. The purpose of this study was to evaluate COX-2 expression in canine appendicular osteosarcomas and to identify if a relationship exists between the intensity of COX-2 expression and clinicopathologic outcome. Of 44 osteosarcomas analyzed, 34 (77.3%) were positive for COX-2 expression. Most of the positive cases (88%) had poor to moderate COX-2 staining. Dogs that had strong COX-2 expression had significantly decreased overall survival time (P = .0107). The median survival times for dogs with negative (n = 10), poor (n = 19), moderate (n = 11), and strong (n = 4) expression were 423, 399, 370, and 86 days, respectively. Additional studies are warranted to further evaluate COX-2 in osteosarcoma for its prognostic value and as a target for adjuvant therapy.     

Understanding the effect of repeated administration of meloxicam on feline renal cortex and medulla: A lipidomics and metabolomics approach

Repeated administration of meloxicam can cause kidney damage in cats by mechanisms that remain unclear. Metabolomics and lipidomics are powerful, noninvasive approaches used to investigate tissue response to drug exposure. Thus, the objective of this study was to assess the effects of meloxicam on the feline kidney using untargeted metabolomics and lipidomics approaches. Female young‐adult purpose‐breed cats were allocated into the control (n = 4) and meloxicam (n = 4) groups. Cats in the control and meloxicam groups were treated daily with saline and meloxicam at 0.3 mg/kg subcutaneously for 17 days, respectively. Renal cortices and medullas were collected at the end of the treatment period. Random forest and metabolic pathway analyses were used to identify metabolites that discriminate meloxicam‐treated from saline‐treated cats and to identify disturbed metabolic pathways in renal tissue. Our results revealed that the repeated administration of meloxicam to cats altered the kidney metabolome and lipidome and suggest that at least 40 metabolic pathways were altered in the renal cortex and medulla. These metabolic pathways included lipid, amino acid, carbohydrate, nucleotide and energy metabolisms, and metabolism of cofactors and vitamins. This is the first study using a pharmacometabonomics approach for studying the molecular effects of meloxicam on feline kidneys.