Pharmacokinetics of meloxicam administered orally to rabbits (Oryctolagus cuniculus) for 29 days Katie W. Delk, DVM; James W. Carpenter, MS, DVM; Butch KuKanich, DVM, PhD; Jerome C. Nietfeld, DVM, PhD; Micah Kohles, DVM, MPA
Objective—To determine the pharmacokinetics and safety of meloxicam in rabbits when administered orally for 29 days. Animals—6 healthy rabbits. Procedures—Meloxicam (1.0 mg/kg, PO, q 24 h) was administered to rabbits for 29 days. Blood was collected immediately before (time 0) and 2, 4, 6, 8, and 24 hours after drug administration on days 1, 8, 15, 22, and 29 to evaluate the pharmacokinetics of meloxicam. On day 30, an additional sample was collected 36 hours after treatment. Plasma meloxicam concentrations were quantified with liquid chromatography–mass spectrometry, and noncompartmental pharmacokinetic analysis was performed. Weekly plasma biochemical analyses were performed to evaluate any adverse physiologic effects. Rabbits were euthanatized for necropsy on day 31. Results—Mean ± SD peak plasma concentrations of meloxicam after administration of doses 1, 8, 15, 22, and 29 were 0.67 ± 0.19 µg/mL, 0.81 ± 0.21 µg/mL, 1.00 ± 0.31 µg/mL, 1.00 ± 0.29 µg/mL, and 1.07 ± 0.19 µg/mL, respectively; these concentrations did not differ significantly among doses 8 through 29. Results of plasma biochemical analyses were within reference ranges at all time points evaluated. Gross necropsy and histologic examination of tissues revealed no clinically relevant findings. Conclusions and Clinical Relevance—Plasma concentrations of meloxicam for rabbits in the present study were similar to those previously reported in rabbits that received 1.0 mg of meloxicam/kg, PO every 24 hours, for 5 days. Results suggested that a dosage of 1.0 mg/ kg, PO, every 24 hours for up to 29 days may be safe for use in healthy rabbits. (Am J Vet Res 2014;75:195–199)
P
ain relief is one of the basic tenants of veterinary medicine, and veterinarians are constantly striving to improve their ability to alleviate pain in their patients. One of the most common classes of drugs used by veterinarians for analgesia is NSAIDs.1 These drugs work centrally and peripherally to prevent pain and have analgesic and anti-inflammatory effects.2,3 They are used to prevent and treat postoperative pain, most
AUC0–24
AUCinf Cmax COX
Received June 21, 2013. Accepted September 18, 2013. From the Departments of Clinical Sciences (Delk, Carpenter), Anatomy and Physiology (KuKanich), and Diagnostic Medicine and Pathobiology (Nietfeld), College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506; and Oxbow Animal Health, 29012 Mill Rd, Murdock, NE 68407 (Kohles). Dr. Delk’s present address is Veterinary Teaching Hospital, University of CaliforniaDavis, Davis, CA 95616. Supported by Oxbow Animal Health. Presented in abstract form at the 35th Annual Association of Avian Veterinarians Conference, Jacksonville, Fla, August 2013, and at the 12th Annual Conference of the Association of Exotic Mammal Veterinarians, Indianapolis, Ind, September 2013. The authors thank Christine Hackworth, Robert Martinez, Drew Pearson, Nolan McClain, Amy Guernsey, and Caitlin Kozel for assistance with sample collection and analysis. Address correspondence to Dr. Delk ([email protected]). AJVR, Vol 75, No. 2, February 2014
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ABBREVIATIONS
Area under the plasma concentrationversus-time curve from administration of the last dose to 24 hours after administration of the last dose Area under the plasma concentrationversus-time curve extrapolated to infinity after administration of a single dose Observed maximum plasma concentration Cyclooxygenase
often associated with musculoskeletal disease.4–7 Results of several studies8–10 have indicated that NSAIDs are effective in treating postoperative pain in dogs and cats, without producing adverse effects such as sedation, ileus, dysphoria, and hypothermia, which are typically associated with opioids and can be profound. The NSAIDs reduce inflammation by inhibition of the action of COX enzymes, which convert arachidonic acid into prostanoids.1,4,8 Cyclooxygenase has 2 forms, COX-1 and COX-2. The form associated with homeostasis, COX-1, produces eicosanoids that are often protective. Although COX-2 is the form of the enzyme most often associated with inflammation, homeostatic 195
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effects of COX-2 eicosanoids, including maintenance of gastrointestinal, platelet, and renal function, are also important. Therefore, toxic effects of NSAIDs are most commonly associated with nonselective inhibition of both COX-1 and COX-2, whereas analgesia associated with NSAIDs is primarily attributable to inhibition of COX-2,1,8,10 –14 and an approach to achieving the desired effect of analgesia is to specifically target the inhibition of COX-2 while maintaining activity of COX-1 to provide the beneficial effects of eicosanoids. The adverse effects associated with NSAIDs most commonly involve gastrointestinal tract injury and, occasionally, impairment of renal blood flow.4,11,15 Gastrointestinal perforation, ulceration, and bleeding have been associated with NSAID-induced depression of normal prostaglandin E2-mediated mucosal protective mechanisms as well as direct local irritation.11,15 Because maintenance of gastrointestinal mucosal integrity is largely the result of COX-1 activity, COX-2 selective NSAIDs are associated with fewer gastrointestinal complications.11 Nonsteroidal anti-inflammatory drugs may also cause nephropathy, especially with chronic use.11 Acute hepatic toxicity has been reported in several breeds of dogs but occurs much less frequently than adverse gastrointestinal and renal effects.16 Because NSAIDs have the potential to produce adverse gastrointestinal effects, the concurrent use of other NSAIDs or corticosteroids (which also produce adverse gastrointestinal effects) is not recommended.14 The adverse effects of NSAIDs are usually dose dependent, so it is important to know the pharmacokinetics of each medication before it is used in a particular species.17 Recently, meloxicam, a COX-2 selective NSAID, has become more frequently administered in veterinary medicine. Meloxicam’s anti-inflammatory, analgesic, and antipyretic properties have been established in experimental and clinical studies in dogs and cats.5–10,12 Because of meloxicam’s COX-2 selectivity, its use may be associated with a decreased occurrence of adverse effects such as inhibition of platelet function and adverse gastrointestinal effects.1–3,11 Meloxicam is metabolized extensively in the liver into 4 metabolites, none of which have anti-inflammatory or analgesic properties.3,17 Safe and effective pain relief should ideally be based on sound research that has been conducted to determine a therapeutic dose that does not cause adverse effects. The plasma or serum half-life of meloxicam is species specific, and it is difficult to extrapolate data across species.2,6,11,14,17,18 However, there are very few research studies on the pharmacokinetics of NSAIDS in exotic small animal species. Where data are available, they are often derived from studies in rodents. In particular, despite their popularity as companion animals, few studies on NSAIDs have been performed in rabbits (Oryctolagus cuniculus), and only 3 studies2,17,19 on the pharmacokinetics of meloxicam in this species have been reported. In 1 recent study,19 the pharmacokinetics of meloxicam in rabbits after oral administration (1.0 mg/kg, q 24 h, for 5 days) was determined. The results of that study19 indicated that peak plasma concentrations of meloxicam at the described dose were similar to therapeutic concentrations in other species. 196
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Considering those results, a dose of 1.0 mg/kg, PO, was hypothesized to be necessary to reach therapeutic concentrations of meloxicam in rabbits. However, because of the possibility that meloxicam could accumulate in plasma or tissues with multiple doses, this dosage needed to be evaluated to demonstrate clinical safety beyond 5 days of use. The objectives of the study reported here were to determine the pharmacokinetics and safety of meloxicam in rabbits at a dosage of 1 mg/kg, PO, every 24 hours for a 29-day period. We performed plasma biochemical analysis and gross and histologic examinations to assess possible adverse effects of the drug at this dosage. Our hypotheses were that administration of meloxicam under this regimen would cause high plasma concentrations of the drug and that meloxicam concentrations would accumulate in plasma during the treatment period. We also hypothesized that there would be no adverse biochemical, gross, or histopathologic effects of meloxicam at this dosage. Materials and Methods Animals—Six clinically normal 3-month-old New Zealand white rabbits (Oryctolagus cuniculus; body weight range, 2.55 to 2.71 kg) were included in the study. The rabbits were obtained from a commercial source and were specific pathogen (Pasteurella spp) free. Rabbits were housed individually at the research facilities of the Kansas State University College of Veterinary Medicine with constant temperature (21.11°C) and humidity (60%) and were exposed to cycles of 16 hours of light and 8 hours of darkness/d. Rabbits were fed a timothy-based pelleted dieta and timothy hay.b Water was available ad libitum. Rabbits were acclimated to the facility for 5 days after their arrival and were habituated to handling prior to initiation of the study. Immediately prior to the start of the study, each rabbit underwent a physical examination, including evaluation of a fecal sample, urinalysis, and collection of a blood sample (0.5 mL) from a lateral saphenous vein or auricular artery for determination of Hct, plasma total protein, and biochemical variables (glucose, BUN, creatinine, total protein, albumin, globulin, total calcium, phosphorus, sodium, potassium, chloride, bicarbonate, cholesterol, and total bilirubin concentrations, with creatine kinase, alanine transaminase, and alkaline phosphatase activities). All rabbits were determined to be healthy and behaviorally normal. The study was approved by the Institutional Animal Care and Use Committee of Kansas State University. Experimental design and sample collection— Meloxicam solutionc (1.0 mg/kg, PO) was administered to each rabbit; a 3-mL syringe containing the appropriate dose of meloxicam was inserted into the diastema, and the drug was slowly administered so that none of the medication escaped the oral cavity. Rabbits received meloxicam (1 mg/kg, PO) every 24 hours. The frequency of meloxicam administration in the present study was determined on the basis of results of other studies2,17,19 performed to evaluate pharmacokinetics of meloxicam in rabbits. Also, the use of this meloxicam AJVR, Vol 75, No. 2, February 2014
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administration interval enabled assessment of meloxicam accumulation in plasma over time. Blood samples were collected from a lateral saphenous vein or an auricular artery of each rabbit with a 25-gauge butterfly catheter and a syringe containing heparin. Blood was collected immediately before (0 hours) and 2, 4, 6, 8, and 24 hours after daily meloxicam administration on days 1, 8, 15, 22, and 29. Blood was also collected 36 hours after the final dose of meloxicam was given on day 29. At each time 0 and at the 36-hour time point after dose 29, 1.5 mL of blood was collected to allow for plasma biochemical analysis and evaluation of PCV and total solids as well as pharmacokinetic analysis. At every other time point, 0.5 mL of blood was collected for the pharmacokinetic assay. Therefore, 31 blood samples were collected from each rabbit during the study period for determination of meloxicam concentrations. Within 20 minutes after each collection, blood samples were centrifuged (10 minutes at approx 2,000 X g), and the plasma supernatant was harvested and stored at –70°C until analysis. Behavior, attitude, mentation, activity, urinary and fecal output, and amount of food and water consumed by the rabbits were subjectively monitored by 1 investigator (KWD) on a daily basis. Rabbits were weighed weekly. Plasma biochemical analysis—Plasma biochemical analytes were measured at baseline (before meloxicam administration) and weekly during the study as indicated. These analytes included plasma glucose, BUN, creatinine, total protein, albumin, globulin (calculated), total calcium, phosphorus, sodium, potassium, chloride, bicarbonate, cholesterol, and total bilirubin concentrations and creatine kinase, alanine transaminase, and alkaline phosphatase activities. Postmortem evaluation—All rabbits were euthanatized by administration of pentobarbital sodium (100 mg/kg, IV), and cadavers were transported immediately to a necropsy room where postmortem examinations were initiated ≤ 15 minutes after euthanasia. The rabbits were examined externally and internally for gross abnormalities. As tissues were examined, samples were collected and placed in neutral-buffered 10% formalin solution for subsequent histologic examination. Samples collected from all rabbits included lung, trachea, liver, spleen, kidneys, urinary bladder, salivary glands, mesenteric lymph nodes, esophagus, fundic and pyloric regions of stomach, small intestine, cecum, appendix, large colon, small colon, heart, skeletal muscles, adrenal glands, pancreas, and bone marrow. Multiple sections of each region of the intestine were collected; small intestinal sections with and without Peyer’s patches were included. After fixation for 48 hours, the tissues were trimmed, placed into cassettes, routinely processed, and embedded into paraffin blocks. Tissues were cut at 4-µm thickness, mounted on glass slides, and stained with H&E. A board-certified veterinary pathologist (JCN) examined the slides and performed further testing with special stains when needed. Plasma meloxicam analysis—Plasma concentrations of meloxicam were determined by means of highAJVR, Vol 75, No. 2, February 2014
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pressure liquid chromatographyd and triple quadrupole mass spectrometrye as previously described in detail.19 The plasma standard curve and quality control standards were made with untreated rabbit plasma. The standard curves were linear between 0.025 and 5 µg/mL and accepted if the correlation coefficient was > 0.99 and predicted concentrations were within 15% of the actual concentration for ≥ 5/6 standards. Accuracy of the assay was 99%, 107%, and 102% of the actual concentration in replicates of 5 quality-control samples for meloxicam concentrations of 0.025, 0.5, and 5 µg/mL, respectively. The coefficient of variation was 7%, 6%, and 4% on replicates of 5 quality control samples for concentrations of 0.025, 0.5, and 5 µg/mL, respectively. Pharmacokinetic analysis—Pharmacokinetic parameters of meloxicam were estimated with computer software.f The AUCinf and AUC0–24 were determined by use of the linear trapezoidal rule. The Cmax and time to maximum plasma concentration were determined directly from the data. The terminal half-life after the last dose was determined from meloxicam concentrations measured in samples collected at the last 3 time points (ie, 8, 24, and 36 hours after the final dose of meloxicam on day 29) by means of log linear regression. A standard 2-stage approach was used to present the mean and SD pharmacokinetic parameters. Pharmacokinetic parameters were determined for each individual animal, and then the mean and SD were determined for each dose from the individuals’ pharmacokinetic parameters. Statistical analysis—Results of a Shapiro-Wilk test revealed that pharmacokinetic parameters were normally distributed and of equal variance. Therefore, a 1-way repeated-measures ANOVA was used to assess the data.g A Tukey test was used for the all-pairwise comparison procedure on each day pharmacokinetic parameters were determined. Values of P < 0.05 were considered significant. Results Meloxicam was easily administered to each rabbit, and all rabbits remained apparently healthy during the study. None of the rabbits had changes in behavior, attitude, mentation, amount of activity, amount of food or water consumed, or urinary or fecal production that could be attributed to an adverse drug reaction. All values measured in the plasma biochemical analysis before and during the study were within published reference ranges.20 The mean ± SD body weight of the rabbits at the end of the study was 2.70 ± 0.1 kg. During gross necropsy and histologic evaluation, special attention was given to organs that have been reported to show lesions related to meloxicam toxicosis, including the liver, urinary bladder, gastrointestinal tract, and kidneys.4,11,15 The liver of 1 rabbit had a single irregular white nodule that contained coalescing areas of necrotic debris surrounded by bands of macrophages, lymphocytes, and heterophils. A Gram stain and silver stain did not reveal the presence of bacteria or fungi, including yeast. The inflammation was consistent with a localized infection. No lesions suggestive 197
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ma meloxicam concentrations similar to those reported in a previous study19 where investigators evaluated the shortterm use of meloxicam at a dose of 1.0 mg/kg every 24 hours for 5 days in rabbits. However, the plasma meloxicam concentrations in this study and the previous study were proportionally higher than those attained after administration of the currently recommended2,17 dose (0.2 to 0.3 mg/kg). The clinical efficacy of meloxicam in rabbits was not determined in the present study, and further studies are needed in which the efficacy of orally administered meloxicam at a dose of 1 mg/kg in rabbits is assessed. Results of the study19 in which the pharmacokinetics of meloxicam administered to rabbits by the same route and at the same dosage as in the present study was determined indicated a mean Cmax Figure 1—Mean ± SD plasma concentrations of meloxicam in 6 healthy New Zealand of 0.83 µg/mL and AUCinf of 10.37 white rabbits (Oryctolagus cuniculus) at various time points following administration of the drug (1.0 mg/kg, PO, q 24 h) for 29 days. The time 0 concentrations were h•µg/mL. Results of the present study measured in samples collected immediately before drug administration and were all indicated similar plasma values after 1 below the lower limit of quantitation for the assay. dose of meloxicam (Cmax, 0.67 ± 0.19 µg/mL; AUCinf, 10.14 ± 3.2 h•µg/mL). Table 1—Mean ± SD pharmacokinetic parameters of meloxicam in 6 healthy rabbits following Results for these paramadministration of the drug (1.0 mg/kg, PO, q 24 h) for 29 days. eters in the present study and the previous study19 Dose were both proportionally higher than the Cmax Parameter 1 8 15 22 29 (0.17 ± 0.06 µg/mL) and AUC0–24 (h●µg/mL) 8.81 ± 2.45 10.90 ± 2.93 11.41 ± 2.74 11.69 ± 2.46 12.43 ± 1.61 AUCinf (1.8 ± 0.50 h•µg/ a a Cmax (µg/mL) 0.67 ± 0.19 0.81 ± 0.21 1.00 ± 0.31 1.00 ± 0.29 1.07 ± 0.19 mL) of meloxicam in an Tmax (h) 6.3 ± 0.8a,b 5.3 ± 1.0 4.7 ± 1.0a 5.0 ± 1.1 4.3 ± 0.8b T1/2 (h) NA NA NA NA 7.2 ± 0.6 earlier study,2 in which AUCinf (h●µg/mL) 10.14 ± 3.2 NA NA NA NA a dose of 0.2 mg/kg was investigated in rabbits. NA = Not applicable. T1/2 =Terminal half-life. Tmax = Time to maximum plasma concentration. a,b Within a row, the same superscript letters indicate significant (P < 0.05) differences among time points. These findings indicate that an increase in an orally administered dose of meloxicam from 0.2 to 1.0 mg/ of acute or chronic meloxicam toxicosis were found in kg caused a proportional increase in the plasma conany of the rabbits. centration of the drug. The higher mean Cmax values Mean ± SD plasma concentrations of meloxicam observed in this study and in the previous study19 for in samples collected after doses 1, 8, 15, 22, and 29 the same dose are notable because they are similar to were summarized (Figure 1). Mean ± SD daily Cmax for meloxicam was 0.67 ± 0.19 µg/mL, 0.81 ± 0.21 µg/ the Cmax values for clinically effective doses of meloximL, 1.00 ± 0.31 µg/mL, 1.00 ± 0.29 µg/mL, and 1.07 ± cam in other species.21,22 It is interesting to note that 0.19 µg/mL, respectively (Table 1). There was no unexalthough the plasma concentrations of meloxicam after pected plasma accumulation of meloxicam over the 29administration of clinically effective doses in other speday dosing period. The mean time to maximum plasma cies seem to be similar to those in rabbits after adminisconcentration in samples collected after doses 1, 8, 15, tration at a dose of 1.0 mg/kg, PO, in the present study 22, and 29 was 6.3 ± 0.8 hours, 5.3 ± 1.0 hours, 4.7 and the previous study, the effective doses of meloxi± 1.0 hours, 5.0 ± 1.1 hours, and 4.3 ± 0.8 hours, recam for those other species were much lower than the spectively. There was no significant difference between dose administered to rabbits in our study. Therefore, it doses 8, 15, 22, and 29 for any parameter, indicating no appears necessary to administer a much higher dose of apparent effect of chronic dosing on drug exposure (as meloxicam to rabbits to achieve similar plasma concenmeasured with the area under the plasma concentratrations of meloxicam. Meloxicam appears to have varition-versus-time curve) or on Cmax other than predictable efficacy among species, so extrapolation of data for ed accumulation with multiple-dose administration. other species should be discouraged. Results of plasma biochemical analysis in the presDiscussion ent study did not reveal any values outside of normal reference ranges. The main adverse effects of NSAIDs Findings of the present study indicated that oral occur in the gastrointestinal tract and renal system, so administration of meloxicam at a dose of 1.0 mg/kg special attention was given to BUN and creatinine conevery 24 hours for 29 days to rabbits resulted in plas198
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centrations and alanine aminotransferase and alkaline phosphatase activities, but no clinically important differences were noted among pretreatment plasma samples and samples taken during the treatment period because all remained within the reference ranges. Packed cell volume, total solids, and body weight were all measured weekly, and no appreciable difference was noted in any of the values (other than apparent weight gain). In addition, there were no observable changes in the behavior, appetite, or urinary or fecal output of rabbits during the study. No clinically relevant changes were seen on gross necropsy of the rabbits, and there were no changes attributable to meloxicam found on histologic examination. These results suggest that the dosage of 1.0 mg of meloxicam/kg, PO, every 24 hours may be safe for use in rabbits up to 29 days. However, although no unexpected drug accumulation and no adverse effects were detected in the healthy animals used in our study, sick animals receiving meloxicam must be closely monitored because drug clearance may be impaired. Very few NSAIDs are approved for long-term use in veterinary patients, but animals frequently need pain medication over an extended period of time. Meloxicam is a popular pain medication for use in rabbits because it is available in a palatable liquid formulation, is not a controlled substance, and is well tolerated in most species. In the present study, administration of the drug at 1.0 mg/kg, PO, every 24 hours appeared to be well tolerated, but further study is needed to determine clinical efficacy and clearance at this dose in rabbits.
4.
a.
15.
b. c. d. e. f. g.
Essentials – Young Rabbit Food, Oxbow Animal Health, Murdock, Neb. Western Timothy Hay, Oxbow Animal Health, Murdock, Neb. Metacam, 1.5 mg/mL oral suspension, Boehringer Ingelheim Vetmedica, St Joseph, Mo. Shimadzu Prominence, Shimadzu Scientific Instruments Inc, Columbia, Md. API 2000, Applied Biosystems Inc, Foster City, Calif. WinNonlin, version 5.2, Pharsight Corp, Mountain View, Calif. Sigma Plot 12, Systat Software Corp, Chicago, Ill.
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Streppa HK, Jones CJ, Budsberg SC. Cyclooxygenase selectivity of nonsteroidal anti-inflammatory drugs in canine blood. Am J Vet Res 2002;63:91–94. Carpenter JW, Pollock CG, Koch DE, et al. Single and multiple-dose pharmacokinetics of meloxicam after oral administration to the rabbit (Oryctolagus cuniculus). J Zoo Wildl Med 2009;40:601–606. Davies NM, Skjodt NM. Clinical pharmacokinetics of meloxicam; a cyclo-oxygenase-2 preferential nonsteroidal anti-inflammatory drug. Clin Pharmacokinet 1999;36:115–126.
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Luna SPL, Basilio AC, Steagall PVM, et al. Evaluation of adverse effects of long-term oral administration of carprofen, etodolac, flunixin meglumine, ketoprofen, and meloxicam in dogs. Am J Vet Res 2007;68:258–264. Peterson KD, Keefe TJ. Effects of meloxicam on severity of lameness and other clinical signs of osteoarthritis in dogs. J Am Vet Med Assoc 2004;225:1056–1060. Doig PA, Purbrick KA, Hare JE, et al. Clinical efficacy and tolerance of meloxicam in dogs with chronic osteoarthritis. Can Vet J 2000;41:296–300. Moreau M, Dupuis J, Bonneau NH, et al. Clinical evaluation of a nutraceutical, carprofen and meloxicam for the treatment of dogs with osteoarthritis. Vet Rec 2003;152:323–329. Caulkett N, Read M, Fowler D, et al. A comparison of the analgesic effects of butorphanol with those of meloxicam after elective ovariohysterectomy in dogs. Can Vet J 2003;44:565–570. Carroll GL, Howe LB, Peterson KD. Analgesic efficacy of preoperative administration of meloxicam or butorphanol in onychectomized cats. J Am Vet Med Assoc 2005;226:913–919. Mathews KA, Pettifer G, Foster R, et al. Safety and efficacy of preoperative administration of meloxicam, compared with that of ketoprofen and butorphanol in dogs undergoing abdominal surgery. Am J Vet Res 2001;62:882–888. Jones CJ, Budsberg SC. Physiologic characteristics and clinical importance of the cyclooxygenase isoforms in dogs and cats. J Am Vet Med Assoc 2000;217:721–729. Jones CJ, Streppa HK, Harmon BG, et al. In vivo effects of meloxicam and aspirin on blood, gastric mucosal, and synovial fluid prostanoid synthesis in dogs. Am J Vet Res 2002;63:1527– 1531. Engelhardt G. Pharmacology of meloxicam, a new non-steroidal anti-inflammatory drug with an improved safety profile through preferential inhibition of COX-2. Rheumatology 1996:35(suppl 1):4–12. Curry SL, Cogar SM, Cook JL. Nonsteroidal antiinflammatory drugs: a review. J Am Anim Hosp Assoc 2005;41:298–309. Forsyth SF, Guilford WG, Haslett SJ, et al. Endoscopy of the gastroduodenal mucosa after carprofen, meloxicam and ketoprofen administration in dogs. J Small Anim Pract 1998;39:421–424. MacPhail CM, Lappin MR, Meyer DJ, et al. Hepatocellular toxicosis associated with administration of carprofen in 21 dogs. J Am Vet Med Assoc 1998;212:1895–1901. Turner PV, Chen HC, Taylor MW. Pharmacokinetics of meloxicam in rabbits after single and repeat oral dosing. Comp Med 2006;56:63–67. Toutain PL, Reymond N, Laroute V, et al. Pharmacokinetics of meloxicam in plasma and urine of horses. Am J Vet Res 2004;65:1542–1547. Fredholm DV, Carpenter JW, KuKanich B, et al. Pharmacokinetics of meloxicam in rabbits after oral administration of single and multiple doses. Am J Vet Res 2013;74:636–641. Fiorello CV, Divers SJ. Rabbits. In: Carpenter JW, ed. Exotic animal formulary. 4th ed. St Louis: Elsevier, 2012;517–559. Montoya L, Ambrose L, Kreil V, et al. A pharmacokinetic comparison of meloxicam and ketoprofen following oral administration to healthy dogs. Vet Res Commun 2004;28:415–428. Giraudel JM, Diquelou A, Laroute V, et al. Pharmacokinetic/ pharmacodynamic modelling of NSAIDs in a model of reversible inflammation in the cat. Br J Pharmacol 2005;146:642–653.
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Objective—To determine the pharmacokinetics and safety of meloxicam in rabbits when administered orally for 29 days. Animals—6 healthy rabbits. Procedures—Meloxicam (1.0 mg/kg, PO, q 24 h) was administered to rabbits for 29 days. Blood was collected immediately before (time 0) and 2, 4, 6, 8, and 24 hours after drug administration on days 1, 8, 15, 22, and 29 to evaluate the pharmacokinetics of meloxicam. On day 30, an additional sample was collected 36 hours after treatment. Plasma meloxicam concentrations were quantified with liquid chromatography–mass spectrometry, and noncompartmental pharmacokinetic analysis was performed. Weekly plasma biochemical analyses were performed to evaluate any adverse physiologic effects. Rabbits were euthanatized for necropsy on day 31. Results—Mean ± SD peak plasma concentrations of meloxicam after administration of doses 1, 8, 15, 22, and 29 were 0.67 ± 0.19 µg/mL, 0.81 ± 0.21 µg/mL, 1.00 ± 0.31 µg/mL, 1.00 ± 0.29 µg/mL, and 1.07 ± 0.19 µg/mL, respectively; these concentrations did not differ significantly among doses 8 through 29. Results of plasma biochemical analyses were within reference ranges at all time points evaluated. Gross necropsy and histologic examination of tissues revealed no clinically relevant findings. Conclusions and Clinical Relevance—Plasma concentrations of meloxicam for rabbits in the present study were similar to those previously reported in rabbits that received 1.0 mg of meloxicam/kg, PO every 24 hours, for 5 days. Results suggested that a dosage of 1.0 mg/ kg, PO, every 24 hours for up to 29 days may be safe for use in healthy rabbits. (Am J Vet Res 2014;75:195–199)
P
ain relief is one of the basic tenants of veterinary medicine, and veterinarians are constantly striving to improve their ability to alleviate pain in their patients. One of the most common classes of drugs used by veterinarians for analgesia is NSAIDs.1 These drugs work centrally and peripherally to prevent pain and have analgesic and anti-inflammatory effects.2,3 They are used to prevent and treat postoperative pain, most
AUC0–24
AUCinf Cmax COX
Received June 21, 2013. Accepted September 18, 2013. From the Departments of Clinical Sciences (Delk, Carpenter), Anatomy and Physiology (KuKanich), and Diagnostic Medicine and Pathobiology (Nietfeld), College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506; and Oxbow Animal Health, 29012 Mill Rd, Murdock, NE 68407 (Kohles). Dr. Delk’s present address is Veterinary Teaching Hospital, University of CaliforniaDavis, Davis, CA 95616. Supported by Oxbow Animal Health. Presented in abstract form at the 35th Annual Association of Avian Veterinarians Conference, Jacksonville, Fla, August 2013, and at the 12th Annual Conference of the Association of Exotic Mammal Veterinarians, Indianapolis, Ind, September 2013. The authors thank Christine Hackworth, Robert Martinez, Drew Pearson, Nolan McClain, Amy Guernsey, and Caitlin Kozel for assistance with sample collection and analysis. Address correspondence to Dr. Delk ([email protected]). AJVR, Vol 75, No. 2, February 2014
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ABBREVIATIONS
Area under the plasma concentrationversus-time curve from administration of the last dose to 24 hours after administration of the last dose Area under the plasma concentrationversus-time curve extrapolated to infinity after administration of a single dose Observed maximum plasma concentration Cyclooxygenase
often associated with musculoskeletal disease.4–7 Results of several studies8–10 have indicated that NSAIDs are effective in treating postoperative pain in dogs and cats, without producing adverse effects such as sedation, ileus, dysphoria, and hypothermia, which are typically associated with opioids and can be profound. The NSAIDs reduce inflammation by inhibition of the action of COX enzymes, which convert arachidonic acid into prostanoids.1,4,8 Cyclooxygenase has 2 forms, COX-1 and COX-2. The form associated with homeostasis, COX-1, produces eicosanoids that are often protective. Although COX-2 is the form of the enzyme most often associated with inflammation, homeostatic 195
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effects of COX-2 eicosanoids, including maintenance of gastrointestinal, platelet, and renal function, are also important. Therefore, toxic effects of NSAIDs are most commonly associated with nonselective inhibition of both COX-1 and COX-2, whereas analgesia associated with NSAIDs is primarily attributable to inhibition of COX-2,1,8,10 –14 and an approach to achieving the desired effect of analgesia is to specifically target the inhibition of COX-2 while maintaining activity of COX-1 to provide the beneficial effects of eicosanoids. The adverse effects associated with NSAIDs most commonly involve gastrointestinal tract injury and, occasionally, impairment of renal blood flow.4,11,15 Gastrointestinal perforation, ulceration, and bleeding have been associated with NSAID-induced depression of normal prostaglandin E2-mediated mucosal protective mechanisms as well as direct local irritation.11,15 Because maintenance of gastrointestinal mucosal integrity is largely the result of COX-1 activity, COX-2 selective NSAIDs are associated with fewer gastrointestinal complications.11 Nonsteroidal anti-inflammatory drugs may also cause nephropathy, especially with chronic use.11 Acute hepatic toxicity has been reported in several breeds of dogs but occurs much less frequently than adverse gastrointestinal and renal effects.16 Because NSAIDs have the potential to produce adverse gastrointestinal effects, the concurrent use of other NSAIDs or corticosteroids (which also produce adverse gastrointestinal effects) is not recommended.14 The adverse effects of NSAIDs are usually dose dependent, so it is important to know the pharmacokinetics of each medication before it is used in a particular species.17 Recently, meloxicam, a COX-2 selective NSAID, has become more frequently administered in veterinary medicine. Meloxicam’s anti-inflammatory, analgesic, and antipyretic properties have been established in experimental and clinical studies in dogs and cats.5–10,12 Because of meloxicam’s COX-2 selectivity, its use may be associated with a decreased occurrence of adverse effects such as inhibition of platelet function and adverse gastrointestinal effects.1–3,11 Meloxicam is metabolized extensively in the liver into 4 metabolites, none of which have anti-inflammatory or analgesic properties.3,17 Safe and effective pain relief should ideally be based on sound research that has been conducted to determine a therapeutic dose that does not cause adverse effects. The plasma or serum half-life of meloxicam is species specific, and it is difficult to extrapolate data across species.2,6,11,14,17,18 However, there are very few research studies on the pharmacokinetics of NSAIDS in exotic small animal species. Where data are available, they are often derived from studies in rodents. In particular, despite their popularity as companion animals, few studies on NSAIDs have been performed in rabbits (Oryctolagus cuniculus), and only 3 studies2,17,19 on the pharmacokinetics of meloxicam in this species have been reported. In 1 recent study,19 the pharmacokinetics of meloxicam in rabbits after oral administration (1.0 mg/kg, q 24 h, for 5 days) was determined. The results of that study19 indicated that peak plasma concentrations of meloxicam at the described dose were similar to therapeutic concentrations in other species. 196
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Considering those results, a dose of 1.0 mg/kg, PO, was hypothesized to be necessary to reach therapeutic concentrations of meloxicam in rabbits. However, because of the possibility that meloxicam could accumulate in plasma or tissues with multiple doses, this dosage needed to be evaluated to demonstrate clinical safety beyond 5 days of use. The objectives of the study reported here were to determine the pharmacokinetics and safety of meloxicam in rabbits at a dosage of 1 mg/kg, PO, every 24 hours for a 29-day period. We performed plasma biochemical analysis and gross and histologic examinations to assess possible adverse effects of the drug at this dosage. Our hypotheses were that administration of meloxicam under this regimen would cause high plasma concentrations of the drug and that meloxicam concentrations would accumulate in plasma during the treatment period. We also hypothesized that there would be no adverse biochemical, gross, or histopathologic effects of meloxicam at this dosage. Materials and Methods Animals—Six clinically normal 3-month-old New Zealand white rabbits (Oryctolagus cuniculus; body weight range, 2.55 to 2.71 kg) were included in the study. The rabbits were obtained from a commercial source and were specific pathogen (Pasteurella spp) free. Rabbits were housed individually at the research facilities of the Kansas State University College of Veterinary Medicine with constant temperature (21.11°C) and humidity (60%) and were exposed to cycles of 16 hours of light and 8 hours of darkness/d. Rabbits were fed a timothy-based pelleted dieta and timothy hay.b Water was available ad libitum. Rabbits were acclimated to the facility for 5 days after their arrival and were habituated to handling prior to initiation of the study. Immediately prior to the start of the study, each rabbit underwent a physical examination, including evaluation of a fecal sample, urinalysis, and collection of a blood sample (0.5 mL) from a lateral saphenous vein or auricular artery for determination of Hct, plasma total protein, and biochemical variables (glucose, BUN, creatinine, total protein, albumin, globulin, total calcium, phosphorus, sodium, potassium, chloride, bicarbonate, cholesterol, and total bilirubin concentrations, with creatine kinase, alanine transaminase, and alkaline phosphatase activities). All rabbits were determined to be healthy and behaviorally normal. The study was approved by the Institutional Animal Care and Use Committee of Kansas State University. Experimental design and sample collection— Meloxicam solutionc (1.0 mg/kg, PO) was administered to each rabbit; a 3-mL syringe containing the appropriate dose of meloxicam was inserted into the diastema, and the drug was slowly administered so that none of the medication escaped the oral cavity. Rabbits received meloxicam (1 mg/kg, PO) every 24 hours. The frequency of meloxicam administration in the present study was determined on the basis of results of other studies2,17,19 performed to evaluate pharmacokinetics of meloxicam in rabbits. Also, the use of this meloxicam AJVR, Vol 75, No. 2, February 2014
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administration interval enabled assessment of meloxicam accumulation in plasma over time. Blood samples were collected from a lateral saphenous vein or an auricular artery of each rabbit with a 25-gauge butterfly catheter and a syringe containing heparin. Blood was collected immediately before (0 hours) and 2, 4, 6, 8, and 24 hours after daily meloxicam administration on days 1, 8, 15, 22, and 29. Blood was also collected 36 hours after the final dose of meloxicam was given on day 29. At each time 0 and at the 36-hour time point after dose 29, 1.5 mL of blood was collected to allow for plasma biochemical analysis and evaluation of PCV and total solids as well as pharmacokinetic analysis. At every other time point, 0.5 mL of blood was collected for the pharmacokinetic assay. Therefore, 31 blood samples were collected from each rabbit during the study period for determination of meloxicam concentrations. Within 20 minutes after each collection, blood samples were centrifuged (10 minutes at approx 2,000 X g), and the plasma supernatant was harvested and stored at –70°C until analysis. Behavior, attitude, mentation, activity, urinary and fecal output, and amount of food and water consumed by the rabbits were subjectively monitored by 1 investigator (KWD) on a daily basis. Rabbits were weighed weekly. Plasma biochemical analysis—Plasma biochemical analytes were measured at baseline (before meloxicam administration) and weekly during the study as indicated. These analytes included plasma glucose, BUN, creatinine, total protein, albumin, globulin (calculated), total calcium, phosphorus, sodium, potassium, chloride, bicarbonate, cholesterol, and total bilirubin concentrations and creatine kinase, alanine transaminase, and alkaline phosphatase activities. Postmortem evaluation—All rabbits were euthanatized by administration of pentobarbital sodium (100 mg/kg, IV), and cadavers were transported immediately to a necropsy room where postmortem examinations were initiated ≤ 15 minutes after euthanasia. The rabbits were examined externally and internally for gross abnormalities. As tissues were examined, samples were collected and placed in neutral-buffered 10% formalin solution for subsequent histologic examination. Samples collected from all rabbits included lung, trachea, liver, spleen, kidneys, urinary bladder, salivary glands, mesenteric lymph nodes, esophagus, fundic and pyloric regions of stomach, small intestine, cecum, appendix, large colon, small colon, heart, skeletal muscles, adrenal glands, pancreas, and bone marrow. Multiple sections of each region of the intestine were collected; small intestinal sections with and without Peyer’s patches were included. After fixation for 48 hours, the tissues were trimmed, placed into cassettes, routinely processed, and embedded into paraffin blocks. Tissues were cut at 4-µm thickness, mounted on glass slides, and stained with H&E. A board-certified veterinary pathologist (JCN) examined the slides and performed further testing with special stains when needed. Plasma meloxicam analysis—Plasma concentrations of meloxicam were determined by means of highAJVR, Vol 75, No. 2, February 2014
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pressure liquid chromatographyd and triple quadrupole mass spectrometrye as previously described in detail.19 The plasma standard curve and quality control standards were made with untreated rabbit plasma. The standard curves were linear between 0.025 and 5 µg/mL and accepted if the correlation coefficient was > 0.99 and predicted concentrations were within 15% of the actual concentration for ≥ 5/6 standards. Accuracy of the assay was 99%, 107%, and 102% of the actual concentration in replicates of 5 quality-control samples for meloxicam concentrations of 0.025, 0.5, and 5 µg/mL, respectively. The coefficient of variation was 7%, 6%, and 4% on replicates of 5 quality control samples for concentrations of 0.025, 0.5, and 5 µg/mL, respectively. Pharmacokinetic analysis—Pharmacokinetic parameters of meloxicam were estimated with computer software.f The AUCinf and AUC0–24 were determined by use of the linear trapezoidal rule. The Cmax and time to maximum plasma concentration were determined directly from the data. The terminal half-life after the last dose was determined from meloxicam concentrations measured in samples collected at the last 3 time points (ie, 8, 24, and 36 hours after the final dose of meloxicam on day 29) by means of log linear regression. A standard 2-stage approach was used to present the mean and SD pharmacokinetic parameters. Pharmacokinetic parameters were determined for each individual animal, and then the mean and SD were determined for each dose from the individuals’ pharmacokinetic parameters. Statistical analysis—Results of a Shapiro-Wilk test revealed that pharmacokinetic parameters were normally distributed and of equal variance. Therefore, a 1-way repeated-measures ANOVA was used to assess the data.g A Tukey test was used for the all-pairwise comparison procedure on each day pharmacokinetic parameters were determined. Values of P < 0.05 were considered significant. Results Meloxicam was easily administered to each rabbit, and all rabbits remained apparently healthy during the study. None of the rabbits had changes in behavior, attitude, mentation, amount of activity, amount of food or water consumed, or urinary or fecal production that could be attributed to an adverse drug reaction. All values measured in the plasma biochemical analysis before and during the study were within published reference ranges.20 The mean ± SD body weight of the rabbits at the end of the study was 2.70 ± 0.1 kg. During gross necropsy and histologic evaluation, special attention was given to organs that have been reported to show lesions related to meloxicam toxicosis, including the liver, urinary bladder, gastrointestinal tract, and kidneys.4,11,15 The liver of 1 rabbit had a single irregular white nodule that contained coalescing areas of necrotic debris surrounded by bands of macrophages, lymphocytes, and heterophils. A Gram stain and silver stain did not reveal the presence of bacteria or fungi, including yeast. The inflammation was consistent with a localized infection. No lesions suggestive 197
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ma meloxicam concentrations similar to those reported in a previous study19 where investigators evaluated the shortterm use of meloxicam at a dose of 1.0 mg/kg every 24 hours for 5 days in rabbits. However, the plasma meloxicam concentrations in this study and the previous study were proportionally higher than those attained after administration of the currently recommended2,17 dose (0.2 to 0.3 mg/kg). The clinical efficacy of meloxicam in rabbits was not determined in the present study, and further studies are needed in which the efficacy of orally administered meloxicam at a dose of 1 mg/kg in rabbits is assessed. Results of the study19 in which the pharmacokinetics of meloxicam administered to rabbits by the same route and at the same dosage as in the present study was determined indicated a mean Cmax Figure 1—Mean ± SD plasma concentrations of meloxicam in 6 healthy New Zealand of 0.83 µg/mL and AUCinf of 10.37 white rabbits (Oryctolagus cuniculus) at various time points following administration of the drug (1.0 mg/kg, PO, q 24 h) for 29 days. The time 0 concentrations were h•µg/mL. Results of the present study measured in samples collected immediately before drug administration and were all indicated similar plasma values after 1 below the lower limit of quantitation for the assay. dose of meloxicam (Cmax, 0.67 ± 0.19 µg/mL; AUCinf, 10.14 ± 3.2 h•µg/mL). Table 1—Mean ± SD pharmacokinetic parameters of meloxicam in 6 healthy rabbits following Results for these paramadministration of the drug (1.0 mg/kg, PO, q 24 h) for 29 days. eters in the present study and the previous study19 Dose were both proportionally higher than the Cmax Parameter 1 8 15 22 29 (0.17 ± 0.06 µg/mL) and AUC0–24 (h●µg/mL) 8.81 ± 2.45 10.90 ± 2.93 11.41 ± 2.74 11.69 ± 2.46 12.43 ± 1.61 AUCinf (1.8 ± 0.50 h•µg/ a a Cmax (µg/mL) 0.67 ± 0.19 0.81 ± 0.21 1.00 ± 0.31 1.00 ± 0.29 1.07 ± 0.19 mL) of meloxicam in an Tmax (h) 6.3 ± 0.8a,b 5.3 ± 1.0 4.7 ± 1.0a 5.0 ± 1.1 4.3 ± 0.8b T1/2 (h) NA NA NA NA 7.2 ± 0.6 earlier study,2 in which AUCinf (h●µg/mL) 10.14 ± 3.2 NA NA NA NA a dose of 0.2 mg/kg was investigated in rabbits. NA = Not applicable. T1/2 =Terminal half-life. Tmax = Time to maximum plasma concentration. a,b Within a row, the same superscript letters indicate significant (P < 0.05) differences among time points. These findings indicate that an increase in an orally administered dose of meloxicam from 0.2 to 1.0 mg/ of acute or chronic meloxicam toxicosis were found in kg caused a proportional increase in the plasma conany of the rabbits. centration of the drug. The higher mean Cmax values Mean ± SD plasma concentrations of meloxicam observed in this study and in the previous study19 for in samples collected after doses 1, 8, 15, 22, and 29 the same dose are notable because they are similar to were summarized (Figure 1). Mean ± SD daily Cmax for meloxicam was 0.67 ± 0.19 µg/mL, 0.81 ± 0.21 µg/ the Cmax values for clinically effective doses of meloximL, 1.00 ± 0.31 µg/mL, 1.00 ± 0.29 µg/mL, and 1.07 ± cam in other species.21,22 It is interesting to note that 0.19 µg/mL, respectively (Table 1). There was no unexalthough the plasma concentrations of meloxicam after pected plasma accumulation of meloxicam over the 29administration of clinically effective doses in other speday dosing period. The mean time to maximum plasma cies seem to be similar to those in rabbits after adminisconcentration in samples collected after doses 1, 8, 15, tration at a dose of 1.0 mg/kg, PO, in the present study 22, and 29 was 6.3 ± 0.8 hours, 5.3 ± 1.0 hours, 4.7 and the previous study, the effective doses of meloxi± 1.0 hours, 5.0 ± 1.1 hours, and 4.3 ± 0.8 hours, recam for those other species were much lower than the spectively. There was no significant difference between dose administered to rabbits in our study. Therefore, it doses 8, 15, 22, and 29 for any parameter, indicating no appears necessary to administer a much higher dose of apparent effect of chronic dosing on drug exposure (as meloxicam to rabbits to achieve similar plasma concenmeasured with the area under the plasma concentratrations of meloxicam. Meloxicam appears to have varition-versus-time curve) or on Cmax other than predictable efficacy among species, so extrapolation of data for ed accumulation with multiple-dose administration. other species should be discouraged. Results of plasma biochemical analysis in the presDiscussion ent study did not reveal any values outside of normal reference ranges. The main adverse effects of NSAIDs Findings of the present study indicated that oral occur in the gastrointestinal tract and renal system, so administration of meloxicam at a dose of 1.0 mg/kg special attention was given to BUN and creatinine conevery 24 hours for 29 days to rabbits resulted in plas198
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centrations and alanine aminotransferase and alkaline phosphatase activities, but no clinically important differences were noted among pretreatment plasma samples and samples taken during the treatment period because all remained within the reference ranges. Packed cell volume, total solids, and body weight were all measured weekly, and no appreciable difference was noted in any of the values (other than apparent weight gain). In addition, there were no observable changes in the behavior, appetite, or urinary or fecal output of rabbits during the study. No clinically relevant changes were seen on gross necropsy of the rabbits, and there were no changes attributable to meloxicam found on histologic examination. These results suggest that the dosage of 1.0 mg of meloxicam/kg, PO, every 24 hours may be safe for use in rabbits up to 29 days. However, although no unexpected drug accumulation and no adverse effects were detected in the healthy animals used in our study, sick animals receiving meloxicam must be closely monitored because drug clearance may be impaired. Very few NSAIDs are approved for long-term use in veterinary patients, but animals frequently need pain medication over an extended period of time. Meloxicam is a popular pain medication for use in rabbits because it is available in a palatable liquid formulation, is not a controlled substance, and is well tolerated in most species. In the present study, administration of the drug at 1.0 mg/kg, PO, every 24 hours appeared to be well tolerated, but further study is needed to determine clinical efficacy and clearance at this dose in rabbits.
4.
a.
15.
b. c. d. e. f. g.
Essentials – Young Rabbit Food, Oxbow Animal Health, Murdock, Neb. Western Timothy Hay, Oxbow Animal Health, Murdock, Neb. Metacam, 1.5 mg/mL oral suspension, Boehringer Ingelheim Vetmedica, St Joseph, Mo. Shimadzu Prominence, Shimadzu Scientific Instruments Inc, Columbia, Md. API 2000, Applied Biosystems Inc, Foster City, Calif. WinNonlin, version 5.2, Pharsight Corp, Mountain View, Calif. Sigma Plot 12, Systat Software Corp, Chicago, Ill.
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