In veterinary medicine, piroxicam has been shown to reduce the size of tumors such as transitional cell carcinoma in dogs. Specific COX-2 inhibitors may prove useful as a primary or adjunctive therapy in the management of cancer. However, food can impair the oral absorption of some NSAIDs eg, phenylbutazone, meclofenamate, flunixin, and robenacoxib. Some parenteral formulations are highly alkaline eg, phenylbutazone and may cause tissue necrosis if injected perivascularly.
NSAIDs may also compete for binding sites with other highly protein-bound compounds, leading to some drug displacement; however, this displacement has little therapeutic consequence because it does not affect the concentration of the free drug. Consequently, their duration of action typically exceeds that predicted by elimination half-life. Most NSAIDs are biotransformed in the liver to inactive metabolites that are excreted either by the kidney via glomerular filtration and tubular secretion or by the bile.
Mavacoxib is an exception, mostly being excreted unchanged in the bile. Biotransformation and elimination half-lives vary significantly by species and in some cases by breed or strain, as is the case for some COX-2 inhibitors in Beagles , so it is not possible to safely extrapolate dosages from one species or animal to another. Some NSAIDs, including naproxen, etodolac, and meclofenamic acid, undergo extensive enterohepatic recirculation in some species, resulting in prolonged elimination half-lives.
Many reactions to NSAIDs are dose-related and are typically reversible with discontinuation of therapy and supportive care. Vomiting is the most common adverse effect. GI ulceration is the most common life-threatening adverse effect. Loss of GI protective mechanisms results from inhibition of constitutive prostaglandins that regulate blood flow to the gastric mucosa and stimulate bicarbonate and mucus production.
This disrupts the alkaline protective barrier of the gut, allowing diffusion of gastric acid back into the mucosa, injuring cells and blood vessels and causing gastritis and ulceration. The enterohepatic recirculation of certain NSAIDs may result in high biliary concentrations that increase ulcerogenic potential in the gut.
NSAID-induced GI bleeding may be occult, leading to iron-deficiency anemia, or be more severe, resulting in vomiting, hematemesis, and melena.
Horses may develop oral, lingual, or colonic ulceration with accompanying signs of colic, weight loss, and diarrhea. Because TXA 2 inhibition causes prolonged bleeding, evaluation of buccal mucosal bleeding time is advised in animals for which surgery is anticipated. Acetaminophen paracetamol administration in cats is associated with Heinz body anemia, methemoglobinemia, hepatic failure, and death. Bone marrow dyscrasias associated with phenylbutazone administration have also been reported.
Animals with underlying renal compromise receiving NSAIDs could experience exacerbation or decompensation of their disease. It is important to maintain hydration and renal perfusion in animals receiving NSAIDs, especially those undergoing anesthesia or surgery and in horses with colic.
NSAID administration routinely induces mild hepatic changes characterized primarily by increases in liver enzymes without clinical signs or hepatic dysfunction. Rare reports of idiosyncratic reactions resulting in hepatic dysfunction or failure have been reported in people acetaminophen and others , dogs acetaminophen, carprofen, etodolac , and horses phenylbutazone.
Cytopathic hepatocellular injury, necrosis , cholestatic, and mixed histopathologic patterns of injury have been documented. NSAIDs should be used with caution in animals with preexisting hepatic disease. Based on structure, most NSAIDs can be divided into two broad groups: carboxylic acid and enolic acid derivatives. The main subgroups of enolic acids are the pyrazolones phenylbutazone and the oxicams meloxicam, piroxicam.
Carboxylic acid subgroups include the salicylates aspirin , propionic acids ibuprofen, naproxen, carprofen, ketoprofen, and vedaprofen , fenemates tolfenamic and meclofenamic acids , phenylacetic acids acetaminophen , and aminonicotinic acids flunixin. The newer coxib class of selective COX-2 inhibitors includes a diaryl-substituted pyrazole celecoxib and a diaryl-substituted isoxazole valdecoxib , both available for human use.
Four NSAIDs of the coxib class, deracoxib, firocoxib, robenacoxib, and mavacoxib have been introduced in veterinary medicine. By far the most widely used NSAID in people, aspirin is primarily used in veterinary medicine for relief of mild to moderate pain associated with musculoskeletal inflammation or osteoarthritis.
The salicylic ester of acetic acid, aspirin acetylsalicylic acid is available in several different dosage forms, including bolus for cattle , oral paste for horses , oral solution for poultry , and tablets for dogs. Enteric-coated products used in human medicine are not recommended in dogs, because gastric retention may lead to erratic plasma exposure. After PO administration, aspirin is rapidly absorbed from the stomach and upper small intestine.
Aspirin is subjected to a large, first-pass effect in the liver to yield salicylic acid, its main active metabolite. After oral aspirin administration, salicylic acid is considered the main active substance in the systemic circulation. In addition, aspirin may irreversibly bind to COX-1 through acetylation of a serine residue near the enzyme active site. Depending on its route of administration, aspirin may have different pharmacologic effects.
For irreversible platelet COX-1 inhibition to treat a thromboembolic condition , aspirin given IV is more efficient than aspirin given PO because, for the same dose, aspirin exposure is greater for the IV route of administration. After absorption, both aspirin and salicylate are widely distributed through most tissues and fluids and readily cross the placental barrier.
Metabolism and elimination is via hepatic conjugation with glucuronic acid, followed by renal excretion. Cats, which lack glucuronyl transferase, metabolize salicylates slowly. In addition, salicylate metabolism is saturable and, if overexposure due to an aspirin overdose occurs, plasma salicylate elimination may follow a zero order and slower elimination kinetics. Because aspirin is not approved for veterinary use, definitive efficacy studies have not been performed to establish effective dosages.
Adverse effects are common after aspirin administration and appear to be dosage dependent. Vomiting and melena may be seen at higher doses.
Aspirin overdose in any species can result in salicylate poisoning, characterized by severe acid-base abnormalities, hemorrhage, seizures, coma, and death.
Acetaminophen paracetamol is a para-aminophenol derivative with analgesic and antipyretic effects similar to those of aspirin, but it has weaker anti-inflammatory effects than does aspirin and other NSAIDs.
Acetaminophen does not inhibit neutrophil activation, has little ulcerogenic potential, and has no effect on platelets or bleeding time. Dose-dependent adverse effects include depression, vomiting, and methemoglobinemia. Use in cats is contraindicated because of their deficiency of glucuronyl transferase, which makes them susceptible to methemoglobinemia and centrilobular hepatic necrosis. One of the earliest NSAIDs approved for use in horses and dogs, phenylbutazone PBZ is a pyrazolone derivative available in tablet, paste, gel, and parenteral formulations.
When given PO, PBZ adsorbs to hay in the diet, to then be released during fermentation in the hindgut. Although this potentially may reduce GI absorption and bioavailability, the clinically relevant effect is a delay in absorption. PBZ is metabolized by the liver to several active oxyphenbutazone and inactive metabolites, which are excreted in urine. One of the major therapeutic uses of PBZ is to treat acute laminitis in horses. Laminitis is treated initially with injectable PBZ at dosages up to 8.
Because the therapeutic index for PBZ is relatively narrow PBZ exhibits zero order metabolism , the dosage should be adjusted to the minimum possible to maintain comfort and avoid toxicity. GI effects eg, anorexia and depression are the most frequent adverse effects associated with PBZ. Ulcers may develop in the mouth, stomach, cecum, and right dorsal colon. The ulcerogenic potential of PBZ in horses is greater than that of flunixin and ketoprofen. In dogs, PBZ has been associated with bleeding dyscrasias, hepatopathies, nephropathies, and rare cases of irreversible bone marrow suppression.
Meclofenamic acid is a fenemate anthranilic acid NSAID available for horses as a granular preparation and for dogs as an oral tablet. The recommended dosage is 2. In horses, meclofenamic acid is rapidly absorbed, but feeding before dosing may delay absorption.
The onset of action is slow, requiring 2—4 days of dosing for a clinical effect. Although it is effective in the treatment of chronic laminitis, meclofenamic acid has a therapeutic index that may be lower than that of other NSAIDs. Upon flare, the patient was scheduled for baseline evaluation and initiation of treatment.
Once treatment was initiated, efficacy and safety evaluations were performed at 2, 4, 8, and 12 weeks or at early termination. Diclofenac was chosen as an active comparator to establish sensitivity of the efficacy end points based on its' known efficacy and frequent clinical use. Meloxicam and placebo were given once in the morning after food, and diclofenac was administered in the morning and in the evening after food.
The trial was approved by the appropriate ethics committees and was conducted in accordance with the latest version of the Declaration of Helsinki and under the guidelines for good clinical practice. All patients gave written informed consent. Tolerability was assessed by recording the incidence, duration, and intensity of all adverse events and patient withdrawals due to adverse events.
For each adverse event, the investigator assessed whether or not the event was drug related. The need for treatment of the adverse event and the action taken with the study drug subsequent to the adverse event also were recorded.
Safety was further assessed by vital signs, physical examinations, and clinical laboratory tests, including hematologic analysis and standard chemistry tests uric acid, phosphorus, and calcium , serum creatinine levels, serum urea nitrogen levels, and both aspartate and alanine aminotransferase levels, to identify any effects on renal or hepatic function.
In addition, a hour urine collection was done prior to administering the first study medication and at the trial conclusion to determine the patient's creatinine clearance.
Several primary and secondary variables were used to evaluate efficacy. Primary variables included the Western Ontario and McMaster University Osteoarthritis WOMAC index and the following flare criteria end points: patient's and investigator's global assessment of disease activity and patient's overall assessment of pain.
In addition to the WOMAC subscale for pain, the patient's overall pain for the prior 24 hours was assessed using a mm VAS 0, no pain; , worst pain. A mm VAS was also used in the patient's global assessments of disease activity, with the best outcome fixed at 0 and the worst outcome fixed at The investigator's global assessment of disease activity used a 5-point verbal rating scale ranging from 0 to 4: none, mild, moderate, severe, and very severe and was performed after and blinded to the patient's global assessment.
Secondary efficacy variables included assessment of pain both at rest and on movement for the previous 24 hours in the target joint. As in the primary efficacy end point for pain, a mm VAS was used.
Use of rescue medication acetaminophen was permitted, and the rate of consumption on treatment was included as a secondary efficacy variable. At 12 weeks or with early termination, a final global assessment of efficacy was performed by the patient and the investigator using a 4-point verbal rating scale good, satisfactory, not satisfactory, and poor.
In addition, the patient's status with regard to the change in arthritic condition was determined by asking the patient to rate his or her current condition compared with the condition at the start of the trial as improved, unchanged, or deteriorated. Time to first GI adverse event was analyzed with log-rank tests and Kaplan-Meier estimates. Primary efficacy analyses were performed based on the intent-to-treat principle, including all treated patients with at least one on-treatment evaluation.
Both the patient's last visit assessment last observation carried forward and the weighted mean of all on-trial assessments were analyzed. Analysis of variance models, including treatment, target joint, and center, were used for all variables assessed by VAS, as well as for the WOMAC index for pain, stiffness, physical function, and total score. These variables were analyzed as change from baseline intensity of flare. Secondary efficacy variables were also analyzed applying the intent-to-treat principle.
For those variables assessed by VAS pain on movement and pain at rest , analyses were performed using analysis of variance on data for change from baseline in a manner similar to that for the primary analyses.
For rescue medication use, analysis of covariance was performed, with weekly average use as the dependent variable and use during flare as a covariate. The patients' and investigators' final global assessment of efficacy and the patients' assessment of change in arthritic condition were analyzed using stratified rank sum test procedures, stratified by center.
Time to early discontinuation overall, for adverse events, and for lack of efficacy was analyzed with log-rank tests and Kaplan-Meier estimates. Time to first GI adverse event was analyzed with adjustment for exposure by applying log-rank tests and the Kaplan-Meier algorithm.
Among a total of patients enrolled and screened by 61 study centers, patients were randomized into the trial, and patients initiated treatment.
The demographic and disease characteristics were similar across the treatment groups Table 1. The incidence of all adverse events was comparable among the 3 meloxicam groups Meloxicam did not demonstrate any dose-dependent increase in total adverse events or adverse events grouped by preferred terms Table 2 based on the World Health Organization adverse event coding thesaurus World Health Organization Adverse Event Dictionary , September Gastrointestinal adverse events were the most frequently reported events by system organ class Table 2.
Likewise, the percentage of withdrawals as a result of GI adverse events was similar among the meloxicam groups 3. A serious adverse event was defined as any fatal or immediately life-threatening clinical experience or disabling event, or one that required prolonged inpatient hospitalization, whether or not it was judged to be related to treatment.
Only 1 GI event was considered to be a serious adverse event and also thought to be related to study medication. There was 1 death in this trial, in the 3. There were no reported occurrences of upper GI tract perforations, ulcerations, or peptic ulcer bleedings in any of the treatment groups. There were no statistically significant changes in mean laboratory values in any of the active treatment groups compared with placebo.
There was a slight increase in alanine aminotransferase and aspartate aminotransferase mean values with diclofenac that was not observed in the meloxicam treatment groups or the placebo group. Baseline values flare were similar across all treatment groups for each efficacy end point and demonstrated worsening from the values recorded at screening during prior NSAID use.
Efficacy of meloxicam and diclofenac became evident early in treatment 2 weeks Figure 2. Efficacy is evident by 28 days in comparing the withdrawals due to lack of efficacy in the placebo group with the withdrawals in the meloxicam and diclofenac treatment groups Table 4.
The difference between the 3. Withdrawal rates due to lack of efficacy were also significantly lower for meloxicam, 7. Both meloxicam and diclofenac produce symptomatic reductions to below pre-flare levels, while placebo patients are less successful in recovering from NSAID withdrawal Figure 2. The WOMAC index consists of a total score and 3 subscales for pain, physical function, and stiffness. At the final visit Figure 3 and Table 5 and for on-treatment weighted means data not shown , meloxicam, 7.
The 3. Similar results were obtained for the patient's overall assessment of pain and the patient's global assessment of disease activity. The VAPs were maintained with a heparinized saline solution I. The sample size of this study was based on the minimum number of experimental units used in exploratory metabolomics studies Randomization of the treatments was done using R studio V 3.
All cats were treated subcutaneously with a volume of saline at 0. Then, cats in the meloxicam group were treated subcutaneously with meloxicam at a dosage of 0. Meloxicam at 0. Cats in the control group received a 0. The remaining cats in each group were euthanized 2 weeks after stopping the administration of the treatments. Blood 1. Immediately upon collection, blood and urine samples were placed on ice. The lipidome was determined in urine and plasma samples collected before the administration of the first treatment time 1, baseline , and at 4 time 2 , 9 time 3 and 13 time 4 and 17 time 5 days after the first administration of meloxicam.
We evaluated the lipidome up to 17 days after the first administration of meloxicam because we were interested only in early plasma and urine lipidome changes. The definition of this sampling period was based on abnormal changes in serum creatinine and BUN concentrations in the meloxicam-treated cats. The extraction 40 and chromatographic 41 methods used to determine feline plasma and urine lipids are reported in Supplementary Method S1. Concentrations of the internal standards spiked in plasma and urine samples can be found in Supplementary Table S7.
Lipids were identified based on their retention time, mass spectral information and the Lipidblast library The data were analyzed using a 3-phase approach as shown in Fig.
The data were analyzed by comparing the lipidome between the meloxicam and saline groups. In addition, we assessed the lipidome changes in the meloxicam-treated cats by comparing the lipidome at each sampling time after the administration of meloxicam against the baseline lipidome of the same group. Experimental workflow to identify biomarker candidates for discriminating meloxicam and saline-treated cats.
The workflow was applied to all the time points evaluated: pre-treatment time 1 , urine and plasma samples collected before the administration of the first treatment, and at 4 time 2 , 9 time 3 and 13 time 4 and 17 time 5 days after the first administration of meloxicam.
As it is recommended, the peak intensities of each detected lipid were log base 2 transformed to stabilize the variance before the comparison of the lipidome. In addition, the data was auto scaled mean-centered and divided by the standard deviation of each variable All the analyses done in this study were performed using Metaboanalyst 4.
Two-factor independent samples: two-way between subjects analysis of variance ANOVA was used to compare the data from the control and meloxicam groups over time. Benjamini-Hochberg false discovery rate method was used for multiple testing correction The heatmaps were created using Euclidean distance and the Ward method of hierarchical clustering. Partial least square-discriminatory analysis PLS-DA was used to determine variation between datasets for both, between and within groups, and at each time point.
The predicting and fitting performance was assessed using the values of Q 2 and R 2 , respectively R 2 measures the goodness of fit while Q 2 measures the predictive ability of the model The model was internally validated based on leave-one-out cross validation Variable importance in projection VIP value was used to select the most representative biomarker candidates.
Random forest was applied to classify lipids according to their contributions to the phenotype classification accuracy 35 , The parameters used for the analysis included trees, 7 predictors and randomness. Receiving operating curves were used to evaluate the diagnostic performance of biomarker candidates. Receiving operating characteristic curves were summarized using the area under the curve AUC as a measure of how well a parameter can distinguish between cats in the control and meloxicam groups.
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