# Clinicopathologic, gross necropsy, and histologic findings after intramuscular injection of carprofen in a pigeon (Columba livia) model.

Abstract: To evaluate the pathologic effects of carprofen in a pigeon model (Columba livia), 52 young adult pigeons were used in a randomized control study design. Sixteen pigeons were randomly assigned to 1 of 3 treatment groups and received carprofen by intramuscular injection at dosages of either 2, 5, or 10 mg/kg once daily for 7 days. Four pigeons served as saline-injected controls. Four pigeons from each group and 1 control pigeon were randomly selected on days 2, 4, 6, and 8 to obtain blood samples and then were euthanatized and submitted for necropsy. Histologic lesions in pectoral muscle, liver, kidney, and digestive tract tissue samples were ranked in severity as 0, normal/not present; 1, minimal; 2, mild; 3, mild to moderate; 4, moderate; 5, moderate to marked; and 6, marked pathologic changes. Two-way analysis of variance (day x dose) and pairwise t tests revealed significant (P [less than or equal to] .05) mild decreases in total protein and glucose concentrations and marked increases in aspartate arninotransferase and alanine aminotransferase enzyme activities after carprofen treatments. Gross lesions in carprofen-treated pigeons were pale injection sites (23/48 [47.9%]), mottled yellow livers (9/48 [18.8%]), and congestion of small intestines (7/48 [14.6%]). Liver, kidney, and muscle injection sites had significantly increased (P [less than or equal to] .05) severity of histologic lesions. In pigeons, intramuscular administration of carprofen is associated with increased aspartate aminotransferase and alanine aminotransferase enzyme concentrations, gross lesions in muscle injection sites and liver, and histologic lesions in liver and muscle.Key words: anti-inflammatory drugs, nonsteroidal anti-inflammatory drugs, NSAID, carprofen, avian pathology, avian, pigeon, Columba livia

Introduction

Prostaglandin synthesis is controlled by 1 of 2 isoforms of cyclooxygenase (COX) enzymes: COX-1 or COX-2. The COX-1 enzyme is constantly present during normal physiologic events (1,2) that produce cytoprotective prostaglandins in tissues such as gastric mucosa, kidneys, and the reproductive tract. Carprofen (Rimadyl, Pfizer Animal Health, New York, NY, USA) is predominately a COX-2 inhibitor in the propionic acid class of nonsteroidal anti-inflammatory drugs (NSAID) commonly used in veterinary medicine, specifically in dogs, to decrease inflammation and alleviate pain. Carprofen has been recommended for pain relief in avian species (1,3) and published dosages range from 1 to 10 mg/kg every 12 to 24 hours when administered intramuscularly (IM). (4) There are few reports, however, on the efficacy of carprofen for pain relief or the potential to cause pathologic effects in birds.

A pharmacokinetic study in broiler chickens indicated that peak plasma levels of carprofen were achieved between 1 and 2 hours after subcutaneous injections at 1 mg/kg. (5) The pain threshold was considered raised for at least 90 minutes after receiving these injections. In a study performed in Hispaniolan Amazon parrots (Amazona ventralis), carprofen administered at a 3 mg/kg dose was not as effective as long-acting opioid analgesics in relieving pain in birds with arthritis induced by microcrystalline sodium urate. (6) Results of another study, in chickens given carprofen at 10-200 mg/kg, showed that the minimum effective dose for pain relief from arthritis induced with microcrystalline sodium urate was 30 mg/kg, but higher doses resulted in physiologic stress and nonresponsive behavior. (7) The purpose of this study was to evaluate the hematologic alterations and pathologic effects, if any, of carprofen administered IM short term (up to a week) at 3 different doses in avian species by using pigeons (Columba livia) as a model. Preliminary study findings were presented at the American Association of Zoo Veterinarians. (8) The purpose of this report is to present the full study findings.

Materials and Methods

All procedures and protocols used in this study were reviewed and approved by the Institution Animal Care and Use Committee, Oklahoma State University, (Protocol VM0414).

Animals

Fifty-two clinically healthy young adult pigeons ([less than or equal to] 1 year of age) of mixed sex were purchased from a private breeder and housed in a laboratory animal research approved facility. The pigeons were randomly divided into 3 treatment groups of 16 birds each and assigned numbers 1 16, 17-32, and 3348, respectively, with 4 control birds, numbered 49-52. Eight pigeons were housed in each of 6 cages, 2 cages per treatment group, and the 4 controls were housed in a seventh cage. The cages were cleaned daily, and the pigeons were fed a commercial dove seed diet (Wild Delight, Dove and Quail Food, Stephen, MN, USA) daily with water available ad libitum. The pigeons were allowed a 1-week acclimation period before the initiation of this study.

Pretreatment

Before the study began, physical examinations were performed, and pretreatment blood samples were obtained for the measurement of packed cell volume (PCV), total plasma solids (TPS), estimated white blood cell (WBC) count, and plasma biochemical analysis. All the pigeons used in this study were considered clinically normal and weighed a mean 554 [+ or -] 106 g, with a range of 382 to 713 g. Blood samples [greater than or equal to] 1.0 mL were obtained without anticoagulant by ulnar venipuncture. Aliquots in duplicate were placed in 75 mm x 1.1 1.2-mm-diameter heparinized microhematocrit tubes to determine the PCV and TPS concentrations. Duplicate blood smears were made on glass slides for estimated WBC counts. The balance of each sample was placed in 1.0-mL lithium heparin blood tubes (BD Microtainer tubes, BD Vacutainer Systems, Franklin Lakes, N J, USA) for biochemical profile analyses. The microhematocrit tubes were centrifuged at 12 100g for 5 minutes, and the PCV was reported as a percentage. The TPS (an estimate of total plasma protein) was determined by refractometer and reported in g/dL. Estimated WBC counts were determined on blood smear slides stained with a modified Wright-Giemsa stain.9 Blood samples in lithium heparin tubes were centrifuged at 2800g for 5 minutes to separate the plasma; plasma biochemical values were determined by an autoanalyzer (VITROS 250, Ortho-Clinical Diagnostics, Rochester, NY, USA). The composition of avian biochemical profiles was established by the reference laboratory (Clinical Pathology Laboratory, Veterinary Medical Teaching Hospital, Oklahoma Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK, USA) and included sodium, potassium, chloride, calcium, glucose, urea nitrogen, creatinine, urea nitrogen:creatinine ratio (calculated), uric acid, total protein, albumin, globulin, albumin:globulin ratio (calculated), total carbon dioxide (C[O.sub.2]), anion gap (calculated), total bilirubin, and alkaline phosphatase, aspartate transaminase (AST), and alanine transaminase (ALT) enzyme concentrations. Urea nitrogen, creatinine, and total bilirubin are not considered useful biochemical analytes in avian species, (10-12) and, along with the calculated values for alburuin : globulin, urea : nitrogen ratios, and anion gap, were omitted from the results.

Treatments

The pigeons in treatment groups were treated with carprofen by IM injection with a microliter syringe. Each pigeon was dosed according to its respective weight at 2 mg/kg for treatment group 1, 5 mg/kg for treatment group 2, and 10 mg/kg for treatment group 3. The doses were selected to encompass the recommended IM doses of carprofen for use in birds. (4) The 4 control pigeons were injected with 0.9% sodium chloride solution at volumes that corresponded to treatment group 2. The pigeons received one IM injection in either the left or right pectoral muscles every afternoon on days 1 through 7, alternating the sides of injection. Twenty-four hours after IM injections, 13 pigeons were randomly selected on days 2, 4, 6, and 8, four from each of the 3 treatment groups and 1 from the control group, to obtain blood samples by ulnar venipuncture for hematologic testing and biochemical analyses as described above. These pigeons then were euthanatized by intravenous injection of 0.3 mL of pentobarbital sodium and phenytoin sodium (Beuthanasia D, Intervet/Schering-Plough Animal Health, Merck & Co Inc, White House Station, N J, USA) for postmortem examination. Necropsies were performed on all the pigeons within 1 hour of euthanasia by 1 investigator (T.J.Z.), and tissue samples were taken from the ingluvies, proventriculus, ventriculus, small intestine, pancreas, liver, kidneys, and pectoral muscle injection sites of each pigeon. These tissue samples were fixed in 10% neutral buffered formalin, embedded in paraffin, sectioned at 15-[micro]m thickness, mounted on glass slides, and stained with hematoxylin and eosin for histologic examination by 1 pathologist (C.A.S.), who was blinded to the treatments. Histologic examination findings were ranked for statistical analyses by the severity of the histopathologic changes seen: 0, within normal limits/ not present; 1, minimal; 2, mild; 3, mild to moderate; 4, moderate; 5, moderate to marked; and 6, marked pathologic changes.

Statistical methods

The study was a randomized 2 factorial design (carprofen dose and number of days administered). The hemogram and plasma biochemical data were analyzed by 2-way analysis of variance (ANOVA) by using SAS Version 9.1 (PROC MIXED, SAS Institute, Cary, NC, USA). The day by dose interactions were analyzed with a SLICE options in an LSMEANS statement. Simple effects of one factor given the other were considered statistically significant at P [less than or equal to] .05. Protected pairwise t test comparisons were performed when these simple effects were significant. The pretreatment values for each of the respective pigeons served as the reference values for these paired comparisons by dose and by day. The Fisher exact test was used to compare the frequency of gross postmortem lesions seen by day euthanatized and by dose administered, with an alpha level of [less than or equal to] .05 considered significant. The histologic data constituted an ordinal (and not continuous) response variable. The relationship of these responses to dose and day were assessed with gamma statistics applied to ordinal-by-ordinal contingency tables. The gamma statistic performed was a correlation-like statistic that measures the likelihood of concordance for dose (or day) in relation to the histologic score. P values associated with the gamma statistic calculated for the contingency tables were considered significant at P [less than or equal to] .05.

Results

The 16 pigeons in group 3 appeared to eat less of the commercial diet fed during the study and declined (P < .05) in body weight by a mean of 15 [+ or -] 7.4 g at euthanasia. The pigeons in groups 1 and 2 appeared to eat well and maintained their weights. No other behavioral or physical changes were appreciated during this study.

Clinical pathology

Two-way ANOVA (day x dose) for hemograms revealed no significant differences in the mean PCV or estimated WBC count among the 3 treatment groups or within these groups over days when compared with their pretreatment values (Table 1). However, there was a mild significant decrease in the mean TPS with increased dose and duration of treatment. Results of protected pairwise t tests confirmed significantly lower TPS on days 6 and 8 for all doses administered. Two-way ANOVA of biochemical values revealed decreases in mean glucose, chloride, and total protein concentrations in the 3 treatment groups and within these groups over time when compared with their pretreatment values (Table 2). Results of protected pairwise t tests confirmed significant decreases for treated pigeons in mean glucose concentration on day 8 and for total protein and chloride concentrations on days 6 and 8 for all doses administered. The mean total C[O.sub.2] concentration increased significantly on days 4 and 8, AST enzyme concentrations increased significantly for all doses on all days, and ALT enzyme concentrations increased significantly for all doses on days 4, 6, and 8. The decrease in total protein concentration of treated pigeons corresponded with the significant decreases in mean globulin levels on days 6 and 8. In the 4 saline-injected control pigeons, the mean concentrations of pretreatment hemogram values and biochemical analytes did not differ significantly from means at the time of euthanasia. The pre- and post--saline-injection mean values for those hemogram and biochemical analyte concentrations of control pigeons that were significantly different from those of treated pigeons after carprofen injections were as follows: total C[O.sub.2], 25.5 [+ or -] 1.3 mEq/L (pre) and 27.0 + 2.0 mEq/ L (post); AST, 105 [+ or -] 22 IU/L (pre) and 112 + 32 IU/L (post); ALT, 19 [+ or -] 15 IU/L (pre) and 31 [+ or -] 22 IU/L (posO; and total protein, 3.4 [+ or -] 0.3 g/dL (pre) and 3.1 [+ or -] 0.2 g/dL (post).

Gross pathology

In 23 pigeons treated with carprofen, pectoral muscle injection sites had focally extensive pale areas that occasionally extended betwecn the fasial planes: these were 6 of 16 (38%) from group 1, 8 of 16 (50%) from group 2, and 9 of 16 (56%) from group 3 (Table 3). No gross lesions in the pectoral muscles were found in the control pigeons. The frequency of muscle lesions seen did not differ significantly by dose of carprofen administered (P = .85). Pale areas at the injection sites were not seen in any of the 12 treated pigeons euthanatized on day 2 but were present in 7 of 12 treated pigeons (58%) euthanatized on day 4, 8 of 12 (67%) on day 6, and 8 of 12 (67%) on day 8. The increase in frequency of muscle lesions seen by days of carprofen administration was significant (P = .001).

Mottled yellow livers were observed in 10 of the 52 study pigeons total (19%): 2 of 16 (13%) from group 1, 3 of 16 (19%) from group 2, and 4 of 16 (25%) from group 3, as well as 1 of 4 (25%) control pigeons (Table 3). The frequency of liver lesions seen did not differ significantly by carprofen dose administered (P = .85). The 10 pigeons with mottled livers were comprised of 5 (38%) of 13 pigeons euthanatized on day 2, 1 (8%) of 13 euthanatized on day 4, 1 (8%) of 13 euthanatized on day 6, and 2 (15%) of 13 euthanatized on day 8. These 9 pigeons were treatment pigeons. The 10th pigeon with a mottled liver was a control pigeon and was 1 of 13 pigeons (8%) euthanatized on day 4. The frequency ofliver lesions seen by days of carprofen administration was not significant (P = .23).

The small intestines appeared congested (erythematous) in 7 of the 48 treatment pigeons (15%), with no gross lesions seen in the control pigeons: 3 of 16 pigeons (19%) from group 1, 2 of 16 (13%) from group 2, and 2 of 16 (13%) from group 3 (Table 3). The frequency of small intestinal lesions seen did not differ significantly by carprofen dose administered (P = 1.0). Of the 7 carprofen-treated pigeons with congested small intestines, none were euthanatized on days 2 or 4, one (14%) was euthanatized on day 6, and the remaining 6 (86%) were euthanatized on day 8. The increase in frequency of small intestinal lesions seen by days of carprofen administration was significant (P < .001). All other organs appeared grossly normal in all pigeons.

Histopathology

Significant differences in the histologic rankings were found in pigeon tissue samples from the liver, kidney, and pectoral injection site musculature both by group (dose) and by day. Lesions in the digestive system of study pigeons (ingluvies, proventriculus, ventriculus, small intestine, and pancreas) were predominately absent (0) to occasionally minimal (1) in severity and were not statistically significant (all, P > .05).

Analysis by dose revealed significant increases in rank of lesion severity of acute lymphoid necrosis (P = .02) and random necrosis (P < .001) in treated pigeon livers, reactive diffuse lymphoid tissue (P = .002) and acute diffuse congestion (P = .001) in treated pigeon kidneys, and myoregeneration (P = .009) in the pectoral muscle injection sites of treated pigeons (Table 4). The dose-related increase in acute lymphoid hepatic necrosis was observed in 10 of 48 carprofen-treated pigeons (21%), all of which had hepatic lipidosis. Dose-related increases in diffuse reactive lymphoid tissue were seen in the kidneys of carprofen-treated pigeons. Acute lymphoid hepatic necrosis, reactive diffuse lymphoid renal tissue, and myoregeneration were not seen in the control pigeons.

Analysis by day (duration of treatment) revealed significant increases in the rank of lesion severity for diffuse hepatocellular hydropic change (P < .001), mixed diffuse vacuolar change (P = .033), mixed portal hepatitis (P = .035), and random necrosis (P = .027) in treated pigeon livers (Table 5). Although statistically significant, random hepatic necrosis with a rank of 1 only occurred in 1 of 4 group 1 pigeons on day 6. Conversely, hepatic lipidosis was the predominate liver lesion seen and occurred in 46 of 52 study pigeons (88%) but only approached statistical significance (P = .05) in treated pigeons by day. Significant pectoral muscle lesions in treated pigeons by day included myodegeneration (P < .001), mixed myositis (P < .001), myoregeneration (P < .001), fibrosis/fibroplasia (P < .001), dystrophic mineralization (P = .015), and hemorrhage (P = .008). Although statistically significant, muscle hemorrhage, when present, was only minimal to mild, except for moderate hemorrhage in one group 3 pigeon on day 8. A significant dose by day interaction for hepatic lipidosis (P = .008) was present. The most severe lesions occurred in 3 of 4 group 3 pigeons on day 8 (2 ranked 4 [moderate], and 1 ranked 5 [moderate to marked]).

Diseussion

Injectable carprofen presents an option to manage acute pain and inflammation in birds with an NSAID. The physiologic effects of short-term use of many NSAIDs have not been well documented in avian species, although there are some reports specifically for flunixin meglumine and ketoprofenYTM This study was done to evaluate any adverse effects of IM administration of carprofen in pigeons as a avian model. Carprofen administration at 2 mg/kg, 5 mg/kg, and 10 mg/kg IM daily for up to a week in pigeons appears to be associated with increases in mean plasma AST and ALT enzyme concentrations; mottled yellow livers, pale muscle injection sites, and small intestinal vascular congestion on gross pathologic examination; and histologic changes in the kidney (acute vascular congestion and reactive lymphoid tissue), liver (hepatic lipidosis, necrosis, portal hepatitis, and hepatocellular hydropic changes), and muscle injection sites (myodegeneration, myoregeneration, myositis, and fibrosis/fibroplasia).

A study in budgerigars (Melopsittacus undulatus) evaluated the renal effects of flunixin meglumine, ketoprofen, and meloxicam. (15) No changes in plasma uric acid or protein concentrations were found after treatment for 3 or 7 days with these 3 NSAIDs, but increases in glomerular mesangial matrix synthesis and tubular necrosis were reported. Although carprofen analgesia studies in chicken, (5,7) and Hispaniolan parrots6 have been reported, and published dosages are available for carprofen in birds, (4) there are no reports on the clinicopathologic or pathologic effects of carprofen in an avian species. Administration of carprofen to control pain has been reported to produce adverse pathologic effects in mammals; the most common are gastrointestinal irritation and ulceration, hepatic changes, and nephritis. (16) Carprofen has been associated with increases in liver enzyme activities of dogs. (17)

The pretreatment hemogram and biochemical values of study pigeons were very similar to the reference values reported for pigeons in the International Species Information System (ISIS), (18) with the exception of somewhat lower mean uric acid, potassium, and albumin concentrations, much lower mean alkaline phosphatase enzyme activities, and higher mean chloride concentrations in the study pigeons. These differences may represent a difference in the laboratories that performed the analyses. A1though several mean biochemical values of treated pigeons differed significantly by dose and day from their respective mean pretreatment values, most of these posttreatment mean concentrations remained similar to those reported for pigeons by ISIS (within reference intervals). The decreases in TPS and total plasma protein concentrations in the biochemical profile of treated pigeons on days 6 and 8 corresponded with the significant decreases in mean globulin concentrations and nonsignificant decreases in albumin concentrations. We do not have an explanation for the consistent and significantly lower mean chloride concentrations for all doses on days 6 and 8. In the other measured anions, no corresponding significant increases in mean albumin concentrations were found, but mean total C[O.sub.2] concentration increased significantly for all doses on days 4 and 8 but not for any doses on Day 6.

Perhaps the most significant biochemical alterations were the marked increases in mean AST and ALT enzyme activities for all 3 treatment groups after treatment (Table 2). These means were significantly higher than the means of the saline-injected control pigeons and the pretreatment means of pigeons for all 3 groups, and considerably higher than the ISIS normal reference intervals for pigeons. The mean activities of both AST and ALT enzymes increased as the dose of IM carprofen was increased, but the mean activities of AST or ALT enzymes did not increase significantly with an increase in the days of treatment, which suggests that these increases were not additive.

The biochemical changes seen in this study appeared to correspond with the gross and histologic postmortem findings. The cytosol of avian hepatocytes and myocytes both contain ALT and AST enzyme activity, and neither enzyme is specific for either tissue. (11,12) The grossly pale areas in the pectoral musculature injection sites of carprofen-treated pigeons observed at necropsy (Table 3) suggested ischemia and corresponded with the muscle damage seen on histologic examination (Tables 4 and 5) and appeared strongly associated with the increases in mean AST and ALT enzyme concentrations (Table 2). These lesions were absent to minimal in the saline-injected controls in which no increases in mean AST or ALT enzyme concentrations were present. Increases in mean AST and ALT enzyme concentrations also appeared strongly associated with the hepatic necrosis and lipidosis seen on histologic examination in the carprofen-treated pigeons. These lesions were absent to minimal in the saline-injected controls in which there were no increases in AST or ALT enzyme concentrations. The increased mean AST and ALT enzyme concentrations, along with the pectoral IM injection site lesions (myositis with myodegeneration) and liver lesions (necrosis and hepatic lipidosis) found on histologic examination, suggest that carprofen injections could have caused the muscle or hepatic damage, or both. Unfortunately, plasma concentrations of creatinine kinase (creatinine phosphokinase) enzyme from muscle that may have better clarified the origin of these increases in enzyme concentrations were not measured in this study.

The AST enzyme appears to be more readily detected and reliable than ALT on avian biochemical profiles and is preferred for clinical evaluation of hepatic disease in avian species. (11,12) The increased enzyme concentrations with increased IM carprofen dose seen in this study, but without a significant increase over days, suggests a dose rather than duration of treatment, dependant hepatic response (Table 2). An apparently idiosyncratic, rather than predictable and dose-related (intrinsic) hepatocellular toxicosis, has been associated with carprofen administration in dogs. (17) In our study, the increases in both AST and ALT enzyme concentrations appeared to be intrinsic, dose-related responses in the carprofen-treated pigeons.

Hepatic lipidosis was suspected on gross inspection (mottled yellow livers) at necropsy and was confirmed on histologic examinations in 46 of 52 pigeons in this study (88%), including the 10 with acute lymphoid necrosis (21%). Although just failing to be statistically significant (P = .052), hepatic lipidosis was found after all treatments (days) and at all 3 doses as well as in 1 of the 4 untreated control pigeons. Treated pigeons in group 3 (10 mg/kg) had more severe hepatic lipidosis then those in either group 1 (2 mg/kg) or group 2 (5 mg/kg) pigeons or in the saline-solution controls, and the 3 affected pigeons on day 8 had the highest histologic rankings, ranging in severity from moderate (4) to moderate to marked (5). Reduced consumption of the commercial diet with mobilization of body fat stores for energy may also have played a part in the development of hepatic lipidosis in group 3 pigeons, but repeated IM injections of carprofen at the highest dose may have contributed to the increased hepatic lipidosis seen. The degree of hepatic lipidosis found, such as the increases seen in AST and ALT enzyme concentrations, appears more consistent with an intrinsic rather than idiosyncratic response to carprofen administration in study pigeons.

Although carprofen is predominately a COX-2 inhibitor, some COX-1 effects have been reported, and inhibition of COX-1 may result in gastric ulceration, prolonged blood clotting times, and reduced renal blood flow, which lead to renal damage and failure. (16,19) Minimal or mild acute, diffuse congestion of the kidney vessels was observed in all 3 treatment groups as well as in the controls. However, most mean uric acid concentrations in these birds were lower than ISIS reference values and did not differ significantly from the respective paired pretreatment values, except for a significantly lower mean uric acid concentration for group 3 pigeons on day 6 and significantly higher means for all 3 groups on day 8. The absence of significant increases in mean uric acid concentrations over treatments, along with the minimal-to-mild histologic changes seen without the increases in glomerular mesangial matrix synthesis and tubular necrosis reported in budgerigars treated with flunixin meglumine, (15) suggests that clinical nephritis would not develop in the kidneys of pigeons treated with carprofen at the doses administered and durations used in this study. Digestive tract lesions, other than minimal to mild congestion of small intestines in some pigeons, were notably lacking. It does not appear likely that the intestinal lesions (ulcers) associated with NSAID administration reported primarily in dogs (17,19) would develop in pigeons at the doses and durations of carprofen administration used in this study.

Other than a possible reduced food consumption and mild weight loss in treatment group 3, no clinical signs developed with IM administration of carprofen in pigeons in this study, which suggests that IM carprofen may best be reserved for short term use in birds with acute injuries or after painful procedures. Further investigation is necessary to determine if long-term administration or higher doses of carprofen administered to control chronic inflammation and pain will result in more severe pathologic changes with clinical signs.

Acknowledgments: We thank Dr Armando G Burgos-Rodrigues for his assistance in conducting this study. Funding for this study was provided by the College of Veterinary Medicine and the Department of Veterinary Clinical Sciences, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK, USA.

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Tawina J. Zollinger, DVM, John P. Hoover, MS, DVM, Dipl ABVP, Dipl ACVIM, Mark E. Payton, PhD, and Chris A. Schiller, DVM, Dipl ACVP

From the Department of Veterinary Clinical Sciences, Center for Veterinary Health Sciences (Zollinger, Hoover) and the Department of Statistics (Payton), Oklahoma State University, Stillwater, OK 74078, USA; and Antech Diagnostics, 2121 N Union Rd, Stillwater, OK 74075, USA (Schiller). Present address (Zollinger): Cosley Zoo and Animal Medical Clinic-Wheaton, 1768 S Blanchard Rd, Wheaton, IL 60189, USA.

Table 1. Hemogram values, mean [+ or -] SD, of pigeons before and 2, 4, 6, and 8 days after daily intramuscular injections with carprofen at 2, 5, and 10 mg/kg. Carprofen dose, Analyte mg/kg Day 2 PCV % Pretreatment 52.9 [+ or -] 4.1 (hematocrit) (n = 12) (a) 2 (n = 4) 52.5 [+ or -] 1.7 5 (n=4) 53.8 [+ or -] 3.0 10 (n=4) 52.5 [+ or -] 1.3 Total plasma Pretreatment 4.9 [+ or -] 1.4 solids (g/dL) (n = 12) (a) 2 (n = 4) 4.7 [+ or -] 0.4 5 (n = 4) 4.7 [+ or -] 0.3 10 (n = 4) 5.0 [+ or -] 0.3 Estimated WBC Pretreatment 9.0 [+ or -] 2.0 (x [10.sup.3] (n = 12) (a) /[micro] L) 2 (n = 4) 7.6 [+ or -] 1.0 5 (n = 4) 7.0 [+ or -] 1.6 10 (n = 4) 6.6 [+ or -] 1.1 Carprofen dose, Analyte mg/kg Day 4 PCV % Pretreatment 53.0 [+ or -] 4.9 (hematocrit) (n = 12) (a) 2 (n = 4) 54.3 [+ or -] 3.3 5 (n=4) 54.0 [+ or -] 3.4 10 (n=4) 53.8 [+ or -] 1.3 Total plasma Pretreatment 5.0 [+ or -] 0.7 solids (g/dL) (n = 12) (a) 2 (n = 4) 4.9 [+ or -] 0.3 5 (n = 4) 4.6 [+ or -] 0.5 10 (n = 4) 4.7 [+ or -] 0.2 Estimated WBC Pretreatment 9.9 [+ or -] 2.0 (x [10.sup.3] (n = 12) (a) /[micro] L) 2 (n = 4) 9.1 [+ or -] 2.0 5 (n = 4) 9.2 [+ or -] 1.7 10 (n = 4) 8.5 [+ or -] 0.5 Carprofen dose, Analyte mg/kg Day 6 PCV % Pretreatment 53.5 [+ or -] 4.8 (hematocrit) (n = 12) (a) 2 (n = 4) 52.3 [+ or -] 2.6 5 (n=4) 52.8 [+ or -] 4.6 10 (n=4) 52.5 [+ or -] 3.8 Total plasma Pretreatment 4.9 [+ or -] 0.4 solids (g/dL) (n = 12) (a) 2 (n = 4) 4.3 [+ or -] 0.1 (b) 5 (n = 4) 4.1 [+ or -] 0.1 (b) 10 (n = 4) 4.4 [+ or -] 0.4 (b) Estimated WBC Pretreatment 8.5 [+ or -] 1.7 (x [10.sup.3] (n = 12) (a) /[micro] L) 2 (n = 4) 8.5 [+ or -] 1.0 5 (n = 4) 7.4 [+ or -] 0.3 10 (n = 4) 8.0 [+ or -] 0.4 Carprofen dose, Analyte mg/kg Day 8 PCV % Pretreatment 52.4 [+ or -] 3.0 (hematocrit) (n = 12) (a) 2 (n = 4) 51.3 [+ or -] 2.8 5 (n=4) 49.8 [+ or -] 2.5 10 (n=4) 52.5 [+ or -] 1.7 Total plasma Pretreatment 4.7 [+ or -] 0.5 solids (g/dL) (n = 12) (a) 2 (n = 4) 4.1 [+ or -] 0.1 (b) 5 (n = 4) 4.2 [+ or -] 0.3 (b) 10 (n = 4) 4.0 [+ or -] 0.4 (b) Estimated WBC Pretreatment 8.9 [+ or -] 1.7 (x [10.sup.3] (n = 12) (a) /[micro] L) 2 (n = 4) 8.1 [+ or -] 1.1 5 (n = 4) 9.7 [+ or -] 1.0 10 (n = 4) 8.1 [+ or -] 1.6 Carprofen dose, ISIS reference values Analyte mg/kg (min-max) PCV % Pretreatment 47.6--5.0 (36.0-62.6) (hematocrit) (n = 12) (a) 2 (n = 4) -- 5 (n=4) -- 10 (n=4) -- Total plasma Pretreatment NA solids (g/dL) (n = 12) (a) 2 (n = 4) -- 5 (n = 4) -- 10 (n = 4) -- Estimated WBC Pretreatment 13.9 [+ or -] 9.4 (2.5-47.6) (x [10.sup.3] (n = 12) (a) /[micro] L) 2 (n = 4) -- 5 (n = 4) -- 10 (n = 4) -- Abbreviations: ISIS indicates International Species Inventory System; min-max, minimum-maximum; PCV, packed cell volume; NA, no value available; WBC, white blood cell. (a) Pretreatment values of carprofen-treated birds on that sample day (n = 12). (b) Values of pigeons on this sample day and dose of carprofen (n=4) are significantly different (P < .05) by protected pairwise t tests from the respective pretreatment values of those pigeons. Table 2. Biochemical values, mean [+ or -] SD, of pigeons before and 2, 4, 6, and 8 days after daily intramuscular injections with carprofen at 2, 5, and 10 mg/kg. Carprofen dose, Analyte mg/kg (a) Day 2 Albumin (g/dL) Pretreatment 1.0 [+ or -] 0.2 (n = 12) (a) 2 (n = 4) 1.0 [+ or -] 0.1 5 (n = 4) 1.0 [+ or -] 0.1 10 (n = 4) 1.2 [+ or -] 0.1 ALP (IU/L) Pretreatment 124 [+ or -] 40 (n = 12) (a) 2 (n = 4) 79 [+ or -] 18 5 (n = 4) 91 [+ or -] 25 10 (n = 4) 57 [+ or -] 20 ALT (IU/L) Pretreatment 19 [+ or -] 17 (n = 12) (a) 2 (n = 4) 56 [+ or -] 39 5 (n = 4) 106 [+ or -] 17 (b) 10 (n = 4) 237 [+ or -] 137 (b) AST (IU/L) Pretreatment 102 [+ or -] 27 (n = 12) (a) 2 (n = 4) 311 [+ or -] 171 (b) 5 (n = 4) 481 [+ or -] 103 (b) 10(n = 4) 370 [+ or -] 249 (b) Calcium (mg/dL) Pretreatment 9.3 [+ or -] 0.5 (n = 12) (a) 2 (n = 4) 9.2 [+ or -] 0.5 5 (n = 4) 9.4 [+ or -] 0.4 10 (n = 4) 9.2 [+ or -] 0.4 Chloride (mEq/L) Pretreatment 120 [+ or -] 3 (n = 12) (a) 2 (n = 4) 119 [+ or -] 3 5 (n = 4) 121 [+ or -] 2 10 (n = 4) 119 [+ or -] 2 Globulin (g/dL) Pretreatment 2.3 [+ or -] 0.2 (n = 12) (a) 2 (n = 4) 2.2 [+ or -] 0.3 5 (n = 4) 2.4 [+ or -] 0.1 10 (n = 4) 2.5 [+ or -] 0.4 Glucose (mg/dL) Pretreatment 340 [+ or -] 19 (n = 12) (a) 2 (n = 4) 319 [+ or -] 19 (b) 5 (n = 4) 306 [+ or -] 7 (b) 10 (n = 4) 319 [+ or -] 5 (b) Potassium (mEq/L) Pretreatment 1.1 [+ or -] 0.2 (n = 12) (a) 2 (n = 4) 1.0 [+ or -] 0.1 5 (n = 4) 1.1 [+ or -] 0.1 10 (n = 4) 2.1 [+ or -] 0.1 (b) Sodium (mEq/L) Pretreatment 144 [+ or -] 2 (n = 12) (a) 2 (n = 4) 144 [+ or -] 2 5 (n = 4) 145 [+ or -] 2 10 (n = 4) 143 [+ or -] 3 Total C[O.sub.2] Pretreatment 26.4 [+ or -] 1.4 (mEq/L) (n = 12) (a) 2 (n = 4) 27.3 [+ or -] 0.5 5 (n = 4) 26.3 [+ or -] 1.0 10 (n = 4) 25.5 [+ or -] 1.7 Total protein Pretreatment 3.3 [+ or -] 0.4 (g/dL) (n = 12) (a) 2 (n = 4) 3.3 [+ or -] 0.4 5 (n = 4) 3.4 [+ or -] 0.2 10 (n = 4) 3.7 [+ or -] 0.5 Uric acid (mg/dL) Pretreatment 3.8 [+ or -] 1.5 (n = 12) (a) 2 (n = 4) 2.0 [+ or -] 0.8 5 (n = 4) 2.0 [+ or -] 0.4 10 (n = 4) 2.5 [+ or -] 0.6 Carprofen dose, Analyte mg/kg (a) Day 4 Albumin (g/dL) Pretreatment 1.0 [+ or -] 0.1 (n = 12) (a) 2 (n = 4) 1.2 [+ or -] 0.1 5 (n = 4) 1.1 [+ or -] 0.1 10 (n = 4) 1.0 [+ or -] 0.1 ALP (IU/L) Pretreatment 163 [+ or -] 107 (n = 12) (a) 2 (n = 4) 88 [+ or -] 42 5 (n = 4) 74 [+ or -] 32 (b) 10 (n = 4) 89 [+ or -] 67 ALT (IU/L) Pretreatment 13 [+ or -] 10 (n = 12) (a) 2 (n = 4) 156 [+ or -] 25 (b) 5 (n = 4) 456 [+ or -] 150 (b) 10 (n = 4) 499 [+ or -] 54 (b) AST (IU/L) Pretreatment 109 [+ or -] 26 (n = 12) (a) 2 (n = 4) 302 [+ or -] 37 (b) 5 (n = 4) 561 [+ or -] 141 (b) 10(n = 4) 797 [+ or -] 213 (b) Calcium (mg/dL) Pretreatment 9.5 [+ or -] 0.8 (n = 12) (a) 2 (n = 4) 10.1 [+ or -] 2.2 5 (n = 4) 10.1 [+ or -] 1.9 10 (n = 4) 9.1 [+ or -] 0.3 Chloride (mEq/L) Pretreatment 120 [+ or -] 2 (n = 12) (a) 2 (n = 4) 118 [+ or -] 3 5 (n = 4) 118 [+ or -] 1 10 (n = 4) 119 [+ or -] 2 Globulin (g/dL) Pretreatment 2.3 [+ or -] 0.2 (n = 12) (a) 2 (n = 4) 2.4 [+ or -] 0.3 5 (n = 4) 2.3 [+ or -] 0.4 10 (n = 4) 2.2 [+ or -] 0.2 Glucose (mg/dL) Pretreatment 342 [+ or -] 19 (n = 12) (a) 2 (n = 4) 314 [+ or -] 86 5 (n = 4) 315 [+ or -] 14" 10 (n = 4) 321 [+ or -] 13 Potassium (mEq/L) Pretreatment 1.2 [+ or -] 0.2 (n = 12) (a) 2 (n = 4) 1.3 [+ or -] 0.4 5 (n = 4) 1.3 [+ or -] 0.2 10 (n = 4) 1.1 [+ or -] 0.1 Sodium (mEq/L) Pretreatment 144 [+ or -] 2 (n = 12) (a) 2 (n = 4) 145 [+ or -] 3 5 (n = 4) 144 [+ or -] 1 10 (n = 4) 144 [+ or -] 1 Total C[O.sub.2] Pretreatment 25.5 [+ or -] 1.9 (mEq/L) (n = 12) (a) 2 (n = 4) 28.8 [+ or -] 2.5 (b) 5 (n = 4) 29.8 [+ or -] 1.O (b) 10 (n = 4) 27.3 [+ or -] 1.9 (b) Total protein Pretreatment 3.3 [+ or -] 0.3 (g/dL) (n = 12) (a) 2 (n = 4) 3.6 [+ or -] 0.3 5 (n = 4) 3.3 [+ or -] 0.4 10 (n = 4) 3.2 [+ or -] 0.2 Uric acid (mg/dL) Pretreatment 3.5 [+ or -] 0.9 (n = 12) (a) 2 (n = 4) 4.3 [+ or -] 1.9 5 (n = 4) 1.9 [+ or -] 0.5 10 (n = 4) 2.5 [+ or -] 1.2 Carprofen dose, Analyte mg/kg (a) Day 6 Albumin (g/dL) Pretreatment 1.0 [+ or -] 0.1 (n = 12) (a) 2 (n = 4) 0.9 [+ or -] 0.1 5 (n = 4) 0.8 [+ or -] 0.1 10 (n = 4) 1.0 [+ or -] 0.1 ALP (IU/L) Pretreatment 158 [+ or -] 85 (n = 12) (a) 2 (n = 4) 68 [+ or -] 14 5 (n = 4) 151 [+ or -] 24 10 (n = 4) 83 [+ or -] 29 ALT (IU/L) Pretreatment 19 [+ or -] 15 (n = 12) (a) 2 (n = 4) 300 [+ or -] 30 (b) 5 (n = 4) 318 [+ or -] 103 (b) 10 (n = 4) 394 [+ or -] 139 (b) AST (IU/L) Pretreatment 117 [+ or -] 39 (n = 12) (a) 2 (n = 4) 355 [+ or -] 112 (b) 5 (n = 4) 630 [+ or -] 163 (b) 10(n = 4) 657 [+ or -] 258 (b) Calcium (mg/dL) Pretreatment 9.2 [+ or -] 0.4 (n = 12) (a) 2 (n = 4) 8.0 [+ or -] 0.3 (b) 5 (n = 4) 8.0 [+ or -] 0.5 (b) 10 (n = 4) 8.6 [+ or -] 0.2 Chloride (mEq/L) Pretreatment 120 [+ or -] 3 (n = 12) (a) 2 (n = 4) 113 [+ or -] 1 (b) 5 (n = 4) 113 [+ or -] 2 (b) 10 (n = 4) 115 [+ or -] 1 (b) Globulin (g/dL) Pretreatment 2.3 [+ or -] 0.2 (n = 12) (a) 2 (n = 4) 1.9 [+ or -] 0.2 (b) 5 (n = 4) 1.8 [+ or -] 0.1 (b) 10 (n = 4) 2.0 [+ or -] 0.2 Glucose (mg/dL) Pretreatment 347 [+ or -] 30 (n = 12) (a) 2 (n = 4) 293 [+ or -] 11 (b) 5 (n = 4) 306 [+ or -] 14 (b) 10 (n = 4) 297 [+ or -] 25 (b) Potassium (mEq/L) Pretreatment 1.1 [+ or -] 0.1 (n = 12) (a) 2 (n = 4) 1.1 [+ or -] 0.1 5 (n = 4) 1.4 [+ or -] 0.3 10 (n = 4) 1.4 [+ or -] 0.2 Sodium (mEq/L) Pretreatment 146 [+ or -] 2 (n = 12) (a) 2 (n = 4) 147 [+ or -] 2 5 (n = 4) 150 [+ or -] 5 (b) 10 (n = 4) 148 [+ or -] 2 Total C[O.sub.2] Pretreatment 26.2 [+ or -] 2.0 (mEq/L) (n = 12) (a) 2 (n = 4) 25.3 [+ or -] 1.0 5 (n = 4) 28.0 [+ or -] 1.4 10 (n = 4) 25.3 [+ or -] 1.3 Total protein Pretreatment 3.3 [+ or -] 0.3 (g/dL) (n = 12) (a) 2 (n = 4) 2.8 [+ or -] 0.2 (b) 5 (n = 4) 2.7 [+ or -] 0.1 (b) 10 (n = 4) 3.0 [+ or -] 0.3 (b) Uric acid (mg/dL) Pretreatment 4.3 [+ or -] 2.5 (n = 12) (a) 2 (n = 4) 3.1 [+ or -] 1.5 5 (n = 4) 6.1 [+ or -] 1.8 10 (n = 4) 2.2 [+ or -] 0.1 (b) Carprofen dose, Analyte mg/kg (a) Day 8 Albumin (g/dL) Pretreatment 1.0 [+ or -] 0.2 (n = 12) (a) 2 (n = 4) 0.9 [+ or -] 0.1 5 (n = 4) 0.9 [+ or -] 0.1 10 (n = 4) 0.9 [+ or -] 0.2 ALP (IU/L) Pretreatment 146 [+ or -] 56 (n = 12) (a) 2 (n = 4) 205 [+ or -] 133 (b) 5 (n = 4) 188 [+ or -] 58 10 (n = 4) 188 [+ or -] 129 ALT (IU/L) Pretreatment 21 [+ or -] 18 (n = 12) (a) 2 (n = 4) 188 [+ or -] 46 (b) 5 (n = 4) 306 [+ or -] 88 (b) 10 (n = 4) 374 [+ or -] 217 (b) AST (IU/L) Pretreatment 121 [+ or -] 49 (n = 12) (a) 2 (n = 4) 455 [+ or -] 164 (b) 5 (n = 4) 426 [+ or -] 58 (b) 10(n = 4) 641 [+ or -] 277 (b) Calcium (mg/dL) Pretreatment 8.8 [+ or -] 0.6 (n = 12) (a) 2 (n = 4) 8.4 [+ or -] 0.4 5 (n = 4) 9.0 [+ or -] 0.1 10 (n = 4) 8.7 [+ or -] 0.6 Chloride (mEq/L) Pretreatment 120 [+ or -] 3 (n = 12) (a) 2 (n = 4) 117 [+ or -] 4 (b) 5 (n = 4) 116 [+ or -] 2 (b) 10 (n = 4) 116 [+ or -] 1 (b) Globulin (g/dL) Pretreatment 2.2 [+ or -] 0.2 (b) (n = 12) (a) 2 (n = 4) 1.9 [+ or -] 0.2 (b) 5 (n = 4) 1.9 [+ or -] 0.1 (b) 10 (n = 4) 1.9 [+ or -] 0.1 (b) Glucose (mg/dL) Pretreatment 341 [+ or -] 32 (n = 12) (a) 2 (n = 4) 304 [+ or -] 18 (b) 5 (n = 4) 323 [+ or -] 11 10 (n = 4) 330 [+ or -] 27 Potassium (mEq/L) Pretreatment 1.5 [+ or -] 0.8 (n = 12) (a) 2 (n = 4) 1.3 [+ or -] 0.1 5 (n = 4) 1.4 [+ or -] 0.3 10 (n = 4) 2.1 [+ or -] 0.4 (b) Sodium (mEq/L) Pretreatment 145 [+ or -] 3 (n = 12) (a) 2 (n = 4) 150 [+ or -] 2 (b) 5 (n = 4) 147 [+ or -] 2 10 (n = 4) 147 [+ or -] 3 Total C[O.sub.2] Pretreatment 25.4 [+ or -] 2.4 (mEq/L) (n = 12) (a) 2 (n = 4) 28.5 [+ or -] 1.3 (b) 5 (n = 4) 29.5 [+ or -] 2.1 (b) 10 (n = 4) 28.0 [+ or -] 2.2 (b) Total protein Pretreatment 3.2 [+ or -] 0.4 (g/dL) (n = 12) (a) 2 (n = 4) 2.8 [+ or -] 0.3 (b) 5 (n = 4) 2.8 [+ or -] 0.2 (b) 10 (n = 4) 2.8 [+ or -] 0.3 (b) Uric acid (mg/dL) Pretreatment 3.6 [+ or -] 1.7 (n = 12) (a) 2 (n = 4) 10.3 [+ or -] 1.7 (b) 5 (n = 4) 5.2 [+ or -] 3.2 (b) 10 (n = 4) 6.5 [+ or -] 3.3 (b) Carprofen dose, ISIS reference values Analyte mg/kg (a) (min-max) Albumin (g/dL) Pretreatment 1.3 [+ or -] 0.3 (0.5-2.0) (n = 12) (a) 2 (n = 4) -- 5 (n = 4) -- 10 (n = 4) ALP (IU/L) Pretreatment 437 [+ or -] 388 (62-1580) (n = 12) (a) 2 (n = 4) -- 5 (n = 4) -- 10 (n = 4) -- ALT (IU/L) Pretreatment 28 [+ or -] 9 (13-50) (n = 12) (a) 2 (n = 4) -- 5 (n = 4) -- 10 (n = 4) -- AST (IU/L) Pretreatment 127 [+ or -] 89 (24-620) (n = 12) (a) 2 (n = 4) -- 5 (n = 4) -- 10(n = 4) -- Calcium (mg/dL) Pretreatment 9.4 [+ or -] 2.7 (4.0-19.0) (n = 12) (a) 2 (n = 4) -- 5 (n = 4) -- 10 (n = 4) -- Chloride (mEq/L) Pretreatment 113 [+ or -] 4 (105-120) (n = 12) (a) 2 (n = 4) -- 5 (n = 4) -- 10 (n = 4) -- Globulin (g/dL) Pretreatment 1.7 [+ or -] 0.7 (1.0-3.7) (n = 12) (a) 2 (n = 4) -- 5 (n = 4) -- 10 (n = 4) -- Glucose (mg/dL) Pretreatment 336 [+ or -] 93 (212-646) (n = 12) (a) 2 (n = 4) -- 5 (n = 4) -- 10 (n = 4) -- Potassium (mEq/L) Pretreatment 2.0 [+ or -] 0.8 (1.2-3.9) (n = 12) (a) 2 (n = 4) -- 5 (n = 4) -- 10 (n = 4) -- Sodium (mEq/L) Pretreatment 146- [+ or -] - 8 (134-164) (n = 12) (a) 2 (n = 4) -- 5 (n = 4) -- 10 (n = 4) -- Total C[O.sub.2] Pretreatment 26.3 [+ or -] 2.6 (23.0-32.0) (mEq/L) (n = 12) (a) 2 (n = 4) -- 5 (n = 4) -- 10 (n = 4) -- Total protein Pretreatment 3.0 [+ or -] 0.7 (2.1-5.5) (g/dL) (n = 12) (a) 2 (n = 4) -- 5 (n = 4) -- 10 (n = 4) -- Uric acid (mg/dL) Pretreatment 6.2 [+ or -] 2.9 (2.2-16.0) (n = 12) (a) 2 (n = 4) -- 5 (n = 4) -- 10 (n = 4) -- Abbreviations: ISIS indicates International Species Inventory System; min-max, minimum-maximum; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; C[O.sub.2], carbon dioxide. (a) Pretreatment values of carprofen-treated birds on that sample day (n = 12). (b) Biochemical values of pigeons on this sample day and dose of carprofen (n = 4) are significantly different (P < .05) by protected pairwise t tests from the respective pretreatment values of those pigeons. Table 3. Frequency of gross lesions seen at necropsy in pigeons at 2, 4, 6, and 8 days after daily intramuscular injections with carprofen at 2, 5, and 10 mg/kg. Carprofen-treated pigeons Controls (saline Group 1 Organ lesion Day solution) (2 mg/kg) Pectoral muscles Pale injection 2 0/1 0/4 sites 4 0/1 2/4 6 0/1 1/4 8 0/1 3/4 Totals by dose (%) 0/4 (0%) 6/16 (37.5%) (a) Liver Mottled yellow 2 0/1 I/4 (diffuse) 4 1/1 I/4 6 0/1 0/4 8 0/1 0/4 Totals by dose (%) 1/4 (25.0%) 2/16 (12.5%) (a) Small intestines Congestion 2 0/1 0/4 (erythema) 4 0/1 0/4 6 0/1 0/4 8 0/1 3/4 Totals by dose (%) 0/4 (0%) 3/16 (18.8%) (a) Carprofen-treated pigeons Group 2 Group 3 Organ lesion Day (5 mg/kg) (10 mg/kg) Pectoral muscles Pale injection 2 0/4 0/4 sites 4 2/4 3/4 6 4/4 3/4 8 2/4 3/4 Totals by dose (%) 8/16 (50.0%) (a) 9/16 (56.3%) (a) Liver Mottled yellow 2 2/4 2/4 (diffuse) 4 0/4 0/4 6 0/4 1/4 8 1/4 1/4 Totals by dose (%) 3/16 (18.8%) (a) 4/16 (25.0%) (a) Small intestines Congestion 2 0/4 0/4 (erythema) 4 0/4 0/4 6 0/4 1/4 8 2/4 1/4 Totals by dose (%) 2/16 (12.5%) (a) 2/16 (12.5%) (a) Totals by day Organ lesion Day (%) Pectoral muscles Pale injection 2 0/12 (0) (a) sites 4 7/12 (58.3) (b) 6 8/12 (66.7) (b) 8 8/12 (66.7) (b) Totals by dose (%) 23/48 (47.9) Liver Mottled yellow 2 5/12 (41.6) (a) (diffuse) 4 2/12 (16.7) (a) 6 1/12 (8.3) (a) 8 2/12 (16.7) (a) Totals by dose (%) 9/48 (18.8) Small intestines Congestion 2 0/12 (0) (a) (erythema) 4 0/12 (0) (a) 6 1/12 (8.3) (a) 8 6/12 (50.0) (b) Totals by dose (%) 7/48 (14.6) (a,b) Totals for frequency of lesions seen by days and by treatment (dose) with different superscript letters are significantly different (P < .05). Table 4. Histologic rankings, mean [+ or -] SD (range) by dose for lesions seen in pigeon tissues after daily intramuscular injections with carprofen at 2, 5, and 10 mg/kg. Controls, dose Histologic lesion 0 mg/kg (n = 4) Liver Hepatocellular 2.0 [+ or -] 1.4 (1-4) lipidosis (diffuse) Hepatocellular 0.3 [+ or -] 0.5 (0-1) hydropic change (diffuse) Mixed vacuolar 0.3 [+ or -] 0.5 (0-1) change (diffuse) EMH, portal, 0.5 [+ or -] 0.6 (0-1) primarily heterophilic EMH, portal, mixed 0.5 [+ or -] 0.6 (0-1) Hepatitis, portal, mixed 1 NA (1) Reactive lymphoid tissue 0 NA (0) (diffuse) Acute lymphoid necrosis 0 NA (0) Acute congestion 2.3 [+ or -] 0.5 (2-3) (diffuse) Necrosis, random 0 NA (0) Kidneys Reactive lymphoid tissue 0 NA (0) (diffuse) Acute congestion 1.5 [+ or -] 1.0 (0-2) (diffuse) Interstitial nephritis, 0.5 [+ or -] 0.6 (0-1) nonsuppurative Pectoral muscles Myodegeneration 0.5 [+ or -] 0.6 (0-1) Myositis, mixed 0.5 [+ or -] 0.6 (0-1) Myoregeneration 0 NA (0) Fibrosis-fibroplasia 0 NA (0) Dystrophic 0 NA (0) mineralization Hemorrhage 0.5 [+ or -] 1.0 (0-2) Digestive tract Ingluvies: lymphocytic 1.0 [+ or -] 1.2 (0-2) mucosal infiltrate Proventriculus 0 NA (0) Ventriculus 1.0 [+ or -] 2.0 (0-4) Small intestine: acute 0 NA (0) congestion (diffuse) Pancreas: pancreatitis, 0 NA (0) Carprofen-treated pigeons Group 1, dose Histologic lesion 2 mg/kg (n = 16) Liver Hepatocellular 2.2 [+ or -] 1.6 (1-5) lipidosis (diffuse) Hepatocellular 0.2 [+ or -] 0.4 (0-1) hydropic change (diffuse) Mixed vacuolar 0.2 [+ or -] 0.5 (0-2) change (diffuse) EMH, portal, 0.6 [+ or -] 1.0 (0-3) primarily heterophilic EMH, portal, mixed 0.8 [+ or -] 0.6 (0-2) Hepatitis, portal, mixed 1.3 [+ or -] 0.6 (0-2) Reactive lymphoid tissue 0.4 [+ or -] 0.7 (0-2) (diffuse) Acute lymphoid necrosis 0.1 [+ or -] 0.3 (0-1) (b) Acute congestion 1.8 [+ or -] 0.9 (0-3) (diffuse) Necrosis, random 0.1 [+ or -] 0.3 (0-1) (b) Kidneys Reactive lymphoid tissue 0.1 [+ or -] 0.3 (0-1) (b) (diffuse) Acute congestion 1 NA (1) (diffuse) Interstitial nephritis, 0.3 [+ or -] 0.5 (0-1) nonsuppurative Pectoral muscles Myodegeneration 2.4 [+ or -] 1.6 (0-4) Myositis, mixed 2.1 [+ or -] 1.3 (0-4) Myoregeneration 0.8 [+ or -] 1.0 (0-3) (b) Fibrosis-fibroplasia 1.3 [+ or -] 1.4 (0-4) Dystrophic 0.4 [+ or -] 0.7 (0-2) mineralization Hemorrhage 0.3 [+ or -] 0.7 (0-2) Digestive tract Ingluvies: lymphocytic 0.9 [+ or -] 0.7 (0-2) mucosal infiltrate Proventriculus 0 NA (0) Ventriculus 0 NA (0) Small intestine: acute 0.4 [+ or -] 0.8 (0-2) congestion (diffuse) Pancreas: pancreatitis, 0.3 [+ or -] 1.0 (0-4) Carprofen-treated pigeons Group 2, dose Histologic lesion 5 mg/kg (n = 16) Liver Hepatocellular 1.6 [+ or -] 1.4 (0-5) lipidosis (diffuse) Hepatocellular 0.6 [+ or -] 1.0 (0-3) hydropic change (diffuse) Mixed vacuolar 0.5 [+ or -] 1.0 (0-3) change (diffuse) EMH, portal, 0.3 [+ or -] 0.7 (0-2) primarily heterophilic EMH, portal, mixed 0.9 [+ or -] 0.4 (0-2) Hepatitis, portal, mixed 1.2 [+ or -] 0.7 (0-3) Reactive lymphoid tissue 0.5 [+ or -] 0.5 (0-1) (diffuse) Acute lymphoid necrosis 0.4 [+ or -] 0.5 (0-1) (b) Acute congestion 2.0 [+ or -] 1.0 (1-4) (diffuse) Necrosis, random 0 NA (0) Kidneys Reactive lymphoid tissue 0.2 [+ or -] 0.6 (0-2)1 (diffuse) Acute congestion 1.4 [+ or -] 0.5 (1-2) (diffuse) Interstitial nephritis, 0.3 [+ or -] 0.6 (0-2) nonsuppurative Pectoral muscles Myodegeneration 2.6 [+ or -] 1.4 (0-4) Myositis, mixed 2.2 [+ or -] 1.2 (0-4) Myoregeneration 1.0 [+ or -] 1.0 (0-3) (b) Fibrosis-fibroplasia 1.1 [+ or -] 1.1 (0-3) Dystrophic 0.5 [+ or -] 1.0 (0-3) mineralization Hemorrhage 0.2 [+ or -] 0.4 (0-1) Digestive tract Ingluvies: lymphocytic 1.4 [+ or -] 0.6 (1-3) mucosal infiltrate Proventriculus 0 NA (0) Ventriculus 0 NA (0) Small intestine: acute 0.4 [+ or -] 0.7 (0-2) congestion (diffuse) Pancreas: pancreatitis, 0 NA (0) Carprofen-treated pigeons Group 3, dose P Histologic lesion 10 mg/kg (n = 16) value (a) Liver Hepatocellular 3.0 [+ or -] 1.6 (0-5) .15 lipidosis (diffuse) Hepatocellular 0.3 [+ or -] 0.7 (0-2) .94 hydropic change (diffuse) Mixed vacuolar 0.1 [+ or -] 0.5 (0-2) .56 change (diffuse) EMH, portal, 0.9 [+ or -] 1.3 (0-4) .52 primarily heterophilic EMH, portal, mixed 0.7 [+ or -] 0.7 (0-2) .91 Hepatitis, portal, mixed 1.3 [+ or -] 0.6 (0-2) .66 Reactive lymphoid tissue 0.5 [+ or -] 0.9 (0-3) .3 (diffuse) Acute lymphoid necrosis 0.3 [+ or -] 0.6 (0-3) (b) .02 (b) Acute congestion 2.3 [+ or -] 0.7 (1-3) .14 (diffuse) Necrosis, random 0 NA (0) <.001 (b) Kidneys Reactive lymphoid tissue 0.6 [+ or -] 0.7 (0-2)1 .002 (b) (diffuse) Acute congestion 1.9 [+ or -] 0.5 (1-3)1 .001 (b) (diffuse) Interstitial nephritis, 0.3 [+ or -] 0.5 (0-1) .58 nonsuppurative Pectoral muscles Myodegeneration 2.9 [+ or -] 1.5 (0-5) .12 Myositis, mixed 2.3 [+ or -] 1.4 (0-4) .17 Myoregeneration 1.6 [+ or -] 1.4 (0-3) (b) .009 (b) Fibrosis-fibroplasia 1.5 [+ or -] 1.4 (0-3) .25 Dystrophic 0.3 [+ or -] 0.7 (0-2) .79 mineralization Hemorrhage 0.7 [+ or -] 1.1 (0-4) .36 Digestive tract Ingluvies: lymphocytic 1.1 [+ or -] 0.8 (0-3) .44 mucosal infiltrate Proventriculus 0 NA (0) NA Ventriculus 0 NA (0) NA Small intestine: acute 0.4 [+ or -] 0.7 (0-2) 1.0 congestion (diffuse) Pancreas: pancreatitis, 0 NA (0) NA adjacent steatitis Abbreviations: EMH indicates extramedullary hematopoiesis; NA, no value available (lesions for all birds sampled in the group had the same value and no variability could be calculated). (a) Probability of an increase in lesion histologic rank in severity with dose of carprofen treatment. (b) Values represent significantly increased (P < .05) rank severity of lesions in pigeons (n = 16) with an increase in the dose of intramuscular carprofen administered compared with the untreated controls (n = 4). Table 5. Histologic rankings, mean [+ or -] SD (range) by day for lesions seen in pigeon tissues after daily intramuscular injections with carprofen on days 2, 4, 6, and 8. Histologic lesion Controls (n = 4) Liver Hepatocellular 2.0 [+ or -] 1.4 (1-4) lipidosis (diffuse) Hepatocellular 0.3 [+ or -] 0.5 (0-1) hydropic change (diffuse) Mixed vacuolar change (diffuse) 0.3 [+ or -] 0.5 (0-1) EMH, portal, 0.5 [+ or -] 0.6 (0-1) primarily heterophilic EMH, portal, mixed 0.5 [+ or -] 0.6 (0-1) Hepatitis, portal, mixed 1 NA (1) Reactive lymphoid tissue 0 NA (0) (diffuse) Acute lymphoid necrosis 0 NA (0) Acute congestion 2.3 [+ or -] 0.5 (2-3) (diffuse) Necrosis, random 0 NA (0) Kidneys Reactive lymphoid tissue 0 NA (0) (diffuse) Acute congestion 1.5 [+ or -] 1.0 (0-2) (diffuse) Interstitial nephritis, 0.5 [+ or -] 0.6 (0-1) nonsuppurative Pectoral muscles Myodegeneration 0.5 [+ or -] 0.6 (0-1) Myositis, mixed 0.5 [+ or -] 0.6 (0-1) Myoregeneration 0 NA (0) Fibrosis-fibroplasia 0 NA (0) Dystrophic 0 NA (0) mineralization Hemorrhage 0.5 [+ or -] 1.0 (0 -2) Digestive tract Ingluvies: lymphocytic 1.0 [+ or -] 1.2 (0-2) mucosal infiltrate Proventriculus 0 NA (0) Ventriculus 1.0 [+ or -] 2.0 (0-4) Small intestine: acute 0 NA (0) congestion (diffuse) Pancreas: pancreatitis, 0 NA (0) adjacent steatitis Carprofen-treated pigeons Histologic lesion Day 2 (n = 12) Liver Hepatocellular 2.7 [+ or -] 1.4 (2-5) lipidosis (diffuse) Hepatocellular 0.2 [+ or -] 0.6 (0-2) hydropic change (diffuse) Mixed vacuolar change (diffuse) 0.2 [+ or -] 0.6 (0-2) EMH, portal, 0.6 [+ or -] 1.0 (0-3) primarily heterophilic EMH, portal, mixed 0.8 [+ or -] 0.6 (0-2) Hepatitis, portal, mixed 0.9 [+ or -] 0.7 (0-2) Reactive lymphoid tissue 0.7 [+ or -] 0.7 (0-1) (diffuse) Acute lymphoid necrosis 0.2 [+ or -] 0.4 (0 -1) Acute congestion 1.5 [+ or -] 0.7 (0-2) (diffuse) Necrosis, random 0 NA (0) Kidneys Reactive lymphoid tissue 0.3 [+ or -] 0.7 (0-2) (diffuse) Acute congestion 1.2 [+ or -] O.4 (12) (diffuse) Interstitial nephritis, 0.3 [+ or -] 0.5 (0-1) nonsuppurative Pectoral muscles Myodegeneration 0.8 [+ or -] 1.0 (0-2) (b) Myositis, mixed 0.7 [+ or -] 0.9 (0-2) (b) Myoregeneration 0 NA (0) Fibrosis-fibroplasia 0 NA (0) Dystrophic 0.3 [+ or -] 0.7 (0-2) (b) mineralization Hemorrhage 0 NA (0) Digestive tract Ingluvies: lymphocytic 1.1 [+ or -] 0.8 (0-3) mucosal infiltrate Proventriculus 0 NA (0) Ventriculus 0 NA (0) Small intestine: acute 0.2 [+ or -] 0.4 (0-1) (b) congestion (diffuse) Pancreas: pancreatitis, 0 NA (0) adjacent steatitis Carprofen-treated pigeons Histologic lesion Day 4 (n = 12) Liver Hepatocellular 2.5 [+ or -] 1.5 (0-5) lipidosis (diffuse) Hepatocellular 0 NA (0) hydropic change (diffuse) Mixed vacuolar change (diffuse) 0 NA (0) EMH, portal, 0.4 [+ or -] 0.9 (0-2) primarily heterophilic EMH, portal, mixed 0.8 [+ or -] 0.5 (0-2) Hepatitis, portal, mixed 1.3 [+ or -] 0.7 (1-3) (b) Reactive lymphoid tissue 0.1 [+ or -] 0.4 (0-1) (diffuse) Acute lymphoid necrosis 0.1 [+ or -] 0.4 (0-1) Acute congestion 2.2 [+ or -] 0.8 (1-4) (diffuse) Necrosis, random 0 NA (0) Kidneys Reactive lymphoid tissue 0.3 [+ or -] 0.6 (0-2) (diffuse) Acute congestion 1.5 [+ or -] 0.5 (1-2) (diffuse) Interstitial nephritis, 0.3 [+ or -] 0.5 (0-1) nonsuppurative Pectoral muscles Myodegeneration 3.3 [+ or -] 1.0 (1-5) (b) Myositis, mixed 2.6 [+ or -] 1.2 (0-4) (b) Myoregeneration 0.5 [+ or -] 1.1 (0-3) (b) Fibrosis-fibroplasia 0.6 [+ or -] 0.7 (0-2) (b) Dystrophic 1.2 [+ or -] 1.1 (0-3) (b) mineralization Hemorrhage 0.3 [+ or -] 0.5 (0-1) Digestive tract Ingluvies: lymphocytic 0.9 [+ or -] 0.7 (0-2) mucosal infiltrate Proventriculus 0 NA (0) Ventriculus 0 NA (0) Small intestine: acute 0 NA (0) congestion (diffuse) Pancreas: pancreatitis, 0 NA (0) adjacent steatitis Carprofen-treated pigeons Histologic lesion Day 6 (n = 12) Liver Hepatocellular 2.2 [+ or -] 1.5 (0-5) lipidosis (diffuse) Hepatocellular 0.5 [+ or -] 0.7 (0-2) (b) hydropic change (diffuse) Mixed vacuolar change (diffuse) 0.5 [+ or -] 0.8 (0-2) (b) EMH, portal, 0.8 [+ or -] 1.4 (0-4) primarily heterophilic EMH, portal, mixed 0.8 [+ or -] 0.7 (0-2) Hepatitis, portal, mixed 1.5 [+ or -] 0.5 (1-2) (b) Reactive lymphoid tissue 0.6 [+ or -] 0.9 (0-3) (diffuse) Acute lymphoid necrosis 0.5 [+ or -] 0.7 (0-2) Acute congestion 2.5 [+ or -] 0.8 (1-4) (diffuse) Necrosis, random 0.1 [+ or -] 0.3 (0-1) (b) Kidneys Reactive lymphoid tissue 0.2 [+ or -] 0.6 (0-2) (diffuse) Acute congestion 1.6 [+ or -] 0.7 (1-3) (diffuse) Interstitial nephritis, 0.3 [+ or -] 0.7 (0-2) nonsuppurative Pectoral muscles Myodegeneration 3.3 [+ or -] 0.9 (1-4) (b) Myositis, mixed 2.7 [+ or -] 0.7 (1-3) (b) Myoregeneration 1.7 [+ or -] 1.0 (0-3) (b) Fibrosis-fibroplasia 2.0 [+ or -] 0.9 (1-3) (b) Dystrophic 0.1 [+ or -] 0.3 (0-1) (b) mineralization Hemorrhage 0.6 [+ or -] 0.9 (0-2) (b) Digestive tract Ingluvies: lymphocytic 1.3 [+ or -] 0.7 (0-2) mucosal infiltrate Proventriculus 0 NA (0) Ventriculus 0 NA (0) Small intestine: acute 0.3 [+ or -] 0.7 (0-2) (b) congestion (diffuse) Pancreas: pancreatitis, 0 NA (0) adjacent steatitis Carprofen-treated pigeons Histologic lesion Day 8 (n = 12) Liver Hepatocellular 2.8 [+ or -] 1.9 (0-5) lipidosis (diffuse) Hepatocellular 0.8 [+ or -] 1.0 (0-3) (b) hydropic change (diffuse) Mixed vacuolar change (diffuse) 0.5 [+ or -] 1.0 (0-3) (b) EMH, portal, 0.6 [+ or -] 0.9 (0-2) primarily heterophilic EMH, portal, mixed 0.8 [+ or -] 0.6 (0-2) Hepatitis, portal, mixed 1.3 [+ or -] 0.5 (0-2) (b) Reactive lymphoid tissue 0.7 [+ or -] 0.8 (0-2) (diffuse) Acute lymphoid necrosis 0.3 [+ or -] 0.5 (0-1) Acute congestion 2.0 [+ or -] 1.0 (0-3) (diffuse) Necrosis, random 0 NA (0) Kidneys Reactive lymphoid tissue 0.3 [+ or -] 0.5 (0-1) (diffuse) Acute congestion 1.4 [+ or -] 0.5 (1-2) (diffuse) Interstitial nephritis, 0.3 [+ or -] 0.5 (0-1) nonsuppurative Pectoral muscles Myodegeneration 3.0 [+ or -] 1.3 (0-4) (b) Myositis, mixed 2.6 [+ or -] 1.0 (0-4) (b) Myoregeneration 2.1 [+ or -] 0.9 (0-3) (b) Fibrosis-fibroplasia 2.3 [+ or -] 1.1 (0-4) (b) Dystrophic 0.1 [+ or -] 0.3 (0-1) (b) mineralization Hemorrhage 0.7 [+ or -] 1.2 (0-4) (b) Digestive tract Ingluvies: lymphocytic 1.3 [+ or -] 0.9 (0-3) mucosal infiltrate Proventriculus 0 NA (0) Ventriculus 0 NA (0) Small intestine: acute 1.1 [+ or -] 1.0 (0-2) (b) congestion (diffuse) Pancreas: pancreatitis, 0.3 [+ or -] 1.2 (0-4) adjacent steatitis Histologic lesion P value (a) Liver Hepatocellular 0.05 lipidosis (diffuse) Hepatocellular <.O01 (b) hydropic change (diffuse) Mixed vacuolar change (diffuse) 0.03 (b) EMH, portal, 0.91 primarily heterophilic EMH, portal, mixed 0.86 Hepatitis, portal, mixed 0.04 (b) Reactive lymphoid tissue 0.10 (diffuse) Acute lymphoid necrosis 0.19 Acute congestion 0.15 (diffuse) Necrosis, random 0.03 (b) Kidneys Reactive lymphoid tissue 0.79 (diffuse) Acute congestion 0.36 (diffuse) Interstitial nephritis, 0.72 nonsuppurative Pectoral muscles Myodegeneration <.001 (b) Myositis, mixed <.001 (b) Myoregeneration <.001 (b) Fibrosis-fibroplasia <.001 (b) Dystrophic 0.02 (b) mineralization Hemorrhage 0.008 (b) Digestive tract Ingluvies: lymphocytic 0.08 mucosal infiltrate Proventriculus NA Ventriculus NA Small intestine: acute 0.001 (b) congestion (diffuse) Pancreas: pancreatitis, NA adjacent steatitis Abbreviations: EMH indicates extramedullary hematopoiesis; NA, no value available (lesions for all birds sampled in this group had the same value and no variability could be calculated). (a) Probability of an increase in lesion histologic rank in severity with days of carprofen treatment. (b) Values represent significantly increased (P < .05) rank severity of lesions in pigeons (n = 12) with an increase in the days of intramuscular carprofen administration compared with the untreated controls (n = 4).

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Author: | Zollinger, Tawina J.; Hoover, John P.; Payton, Mark E.; Schiller, Chris A. |
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Publication: | Journal of Avian Medicine and Surgery |

Article Type: | Report |

Geographic Code: | 1USA |

Date: | Sep 1, 2011 |

Words: | 10470 |

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