Safety of reduced-dosage ketoprofen for long-term oral administration in healthy dogs

Tatsuya Narita Department of Clinical Veterinary Science, The United Graduate School of Veterinary Sciences, Gifu University, Gifu, Gifu 501-1193
Department of Small Animal Surgery, Faculty of Agriculture, Iwate University, Morioka, Iwate 020-8550, Japan.

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Reeko Sato Department of Veterinary Internal Medicine, Faculty of Agriculture, Iwate University, Morioka, Iwate 020-8550, Japan.

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Nobuyuki Tomizawa Department of Small Animal Surgery, Faculty of Agriculture, Iwate University, Morioka, Iwate 020-8550, Japan.

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Kenji Tani Department of Small Animal Surgery, Faculty of Agriculture, Iwate University, Morioka, Iwate 020-8550, Japan.

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Shinobu Komori Department of Small Animal Surgery, Faculty of Agriculture, Iwate University, Morioka, Iwate 020-8550, Japan.

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Shigeo Hara Department of Small Animal Surgery, Faculty of Agriculture, Iwate University, Morioka, Iwate 020-8550, Japan.

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Abstract

Objective—To evaluate the safety of reduced-dosage ketoprofen (RDKET) for long-term oral administration in healthy dogs.

Animals—14 healthy Beagles.

Procedures—Racemic ketoprofen (0.25 mg/kg, PO) and gelatin capsules, as a drug-free placebo, were each administered to 7 dogs for 30 days. Dogs were periodically monitored via physical examination, blood analyses, endoscopic examinations, fecal occult blood tests (tetramethylbenzidine and guaiac methods), renal function tests (effective renal plasma flow and glomerular filtration rate), urinalyses, urinary enzyme indices (N-acetyl-β-D-glucosaminidase and γ-glutamyl-transferase), and hemostatic function tests (buccal mucosa bleeding time, cuticle bleeding time, prothrombin time, activated partial thromboplastin time, and fibrinogen concentration).

Results—Pyloric antrum lesion grade was significantly higher in the RDKET group on day 28, compared with the pretreatment and control group grades. Fecal occult blood grade measured by use of the tetramethylbenzidine method was significantly higher in the RDKET group on day 30, compared with the pretreatment grade. No other significant differences were detected between treatment groups.

Conclusions and Clinical Relevance—RDKET induced mild to moderate gastric mucosal injuries especially in the pyloric antrum in healthy Beagles, whereas no adverse effects were observed in renal function or hemostasis. Fecal occult blood tests may be useful as screening tests for adverse gastrointestinal effects induced by RDKET in dogs.

Abstract

Objective—To evaluate the safety of reduced-dosage ketoprofen (RDKET) for long-term oral administration in healthy dogs.

Animals—14 healthy Beagles.

Procedures—Racemic ketoprofen (0.25 mg/kg, PO) and gelatin capsules, as a drug-free placebo, were each administered to 7 dogs for 30 days. Dogs were periodically monitored via physical examination, blood analyses, endoscopic examinations, fecal occult blood tests (tetramethylbenzidine and guaiac methods), renal function tests (effective renal plasma flow and glomerular filtration rate), urinalyses, urinary enzyme indices (N-acetyl-β-D-glucosaminidase and γ-glutamyl-transferase), and hemostatic function tests (buccal mucosa bleeding time, cuticle bleeding time, prothrombin time, activated partial thromboplastin time, and fibrinogen concentration).

Results—Pyloric antrum lesion grade was significantly higher in the RDKET group on day 28, compared with the pretreatment and control group grades. Fecal occult blood grade measured by use of the tetramethylbenzidine method was significantly higher in the RDKET group on day 30, compared with the pretreatment grade. No other significant differences were detected between treatment groups.

Conclusions and Clinical Relevance—RDKET induced mild to moderate gastric mucosal injuries especially in the pyloric antrum in healthy Beagles, whereas no adverse effects were observed in renal function or hemostasis. Fecal occult blood tests may be useful as screening tests for adverse gastrointestinal effects induced by RDKET in dogs.

Nonsteroidal anti-inflammatory drugs have been commonly used in veterinary medicine for musculoskeletal diseases such as osteoarthritis1 to relieve pain and improve quality of life. Racemic ketoprofen (S[+]- and R[−]-ketoprofen) has potent analgesic, antipyretic, and anti-inflammatory effects in dogs1–3 and also provides central analgesia, in addition to peripheral analgesic effects, by acting at the supraspinal level.4,5 Although there is little information about the analgesic effect of RDKET (0.25 mg/kg), improvement of the vertical force in the hind limb with long-term (28 days) orally administered RDKET in dogs with chronic pain disorders was reported.6 That study also found no adverse effects of the treatment, such as vomiting and diarrhea, and the authors postulated that RDKET had minimal or no harmful effects on the gastrointestinal mucosa of dogs.6 Conversely, a previous study7 found that oral administration of ketoprofen (1 mg/kg) over 30 days, a dosage used for acute pain control, also caused no clinical signs such as vomiting, diarrhea, and anorexia in dogs. However, mild to moderate gastric mucosal lesions were observed, mostly in the pyloric antrum, and were confirmed by use of endoscopy and fecal occult blood tests. Likewise, decreased ERPF and abnormal enzymuria with exfoliated renal tubular cells in the urine of a clinically healthy Beagle receiving 1 mg/kg of ketoprofen for 30 days were detected.7

Racemic ketoprofen, including both enantiomers, is a nonspecific COX inhibitor used in dogs that was thought to be less safe than specific COX-2 inhibitors.8 Reducing dosage was expected to improve safety, although the only clinical effects involved the digestive tract. Previous evaluations of adverse effects from longterm administration of a reduced dosage in dogs were insufficient because some gastrointestinal effects develop without overt clinical signs. Furthermore, renal failure9–11 and hemostatic disorders12 are well-known adverse effects of NSAIDs in humans and other animals. However, little is known about ERPF, GFR, bleeding time, gastrointestinal endoscopic findings, or fecal occult blood test results in dogs treated with RDKET. To the authors' knowledge, few studies have investigated the safety of RDKETs, although cautious systemic examinations are needed to evaluate adverse effects associated with NSAIDs. Therefore, further investigations are needed before RDKETs can be safely administered over long periods in dogs. The purpose of the present study was to evaluate the safety of RDKET (0.25 mg/kg, PO, for 30 days) with regard to the gastrointestinal tract, kidneys, and platelets of healthy Beagles.

Materials and Methods

Dogs—Fourteen healthy Beagles (sexually intact females) were used. Dogs ranged in age from 8 to 26 months (mean ± SD, 18.1 ± 5.7 months) and weighed from 6.9 to 12.2 kg (mean ± SD, 8.8 ± 1.7 kg). The study was approved by the Animal Research Committee of Iwate University.

Experimental design—The dogs were randomly assigned to 2 groups. Dogs in the RDKET group (dogs 1 to 7; body weight; 9.2 ± 1.3 kg) received racemic ketoprofena (0.25 mg/kg, PO, q 24 h), and dogs in the control group (dogs 8 to 14; body weight, 8.1 ± 0.9 kg) received empty gelatin capsulesb (1 capsule, PO, q 24 h) as a drug-free negative control. Treatments were carried out for 30 days and given at 8:00 to 9:00 AM. All dogs were housed in cages and fed a commercial dog foodc once per day after drug administration in the morning. Water was given ad libitum. Physical examinations, including observation for anorexia, vomiting, diarrhea, and signs of depression or abdominal pain, were performed on both groups once per day before and every day after starting the treatments. Venous blood analyses, including CBC, and serum biochemical analyses, including analyses for alanine aminotransferase, alkaline phosphatase, GGT, BUN, creatinine, lactate dehydrogenase, total cholesterol, total protein, albumin, globulin, total bilirubin, calcium, and phosphate, were performed on an automatic analyzerd for both groups before and every 10 days after starting the treatment.

Endoscopic examination—Endoscopic examination of the gastrointestinal mucosa was performed in both groups before and every 7 days after starting the treatment. Food was withheld for 24 hours, and water was withheld for 6 hours before anesthesia. Anesthesia was induced with propofole (6 mg/kg, IV bolus), and an endotracheal tube was placed. Anesthesia was maintained with isofluranef in oxygen for the duration of the endoscopic examination. The gastrointestinal tract was examined with a videoendoscope,g and images of the mucosa were photographed. The number and size of the mucosal lesions were recorded and graded according to the scale reported by Forsyth et al.13,14 Briefly, the mucosal lesions were graded from 0 to 6. In this grading scale, grade 0 indicates no lesions and grades 1 to 4 indicate 1 to 5 (grade 1), 6 to 15 (grade 2), 16 to 25 (grade 3), or > 25 (grade 4) punctate erosions, hemorrhages, or both, respectively. Furthermore, 1 to 5 invasive erosions were observed in grade 4 and > 5 invasive erosions were observed in grade 5. Grade 6 indicated that ulcers were present. On the basis of these criteria, invasive erosions were defined as extensive hemorrhages or erosions with evidence of invasion as indicated by detectable depth and breadth substantially greater than a pinhead-size discontinuation of the mucosal epithelium. An ulcer was defined as a lesion that caused a wide discontinuity of the mucosa and had a craterlike center.

Fecal occult blood tests—A test for fecal occult blood in fresh feces was performed in both groups before and every 5 days after treatment was started. A commercially available kith that included the tetramethylbenzidine and guaiac methods was used in the present study. Analysis was performed and graded according the manufacturer's instructions. In the grading scale, grade 0 indicated negative results for fecal occult blood, grade 1 indicated the sample had weakly positive results, grade 2 indicated positive results, grade 3 indicated moderately positive results, and grade 4 indicated strongly positive results.

Renal function tests—Renal function was assessed by determination of ERPF and GFR in both groups before and every 10 days after starting the treatment. Para-aminohippurate sodiumi clearance and endogenous creatinine clearance were measured to assess ERPF and GFR, respectively. The ClPAH and ClCre were analyzed simultaneously by use of methods reported by Narita et al.7 The ClPAH and ClCre were estimated by use of the following formulae:

article image

Urinalyses and urinary enzyme indices—Urinalysis, including specific gravity, dipstick analysis, and urinary sediment examination, were performed in both groups before and every 5 days after starting treatment. In addition, urinary enzyme activities, including NAG and GGT, were measured in both groups before and every 5 days after treatment was started. Urinalysis was performed with a urine dipstick,j and the specific gravity of urine was assayed with a refractometer.k Microscopic evaluation of urine was performed on urine sediment stained with Sternheimer-Malbin stain.l Urine for the measurement of NAG activity, GGT activity, and creatinine concentration was collected aseptically by use of a sterilized silicone-elastomer–coated Foley catheterm and centrifuged at 500 Xg for 15 minutes at 4°C to obtain the supernatant. The samples for NAG activity and creatinine concentration were immediately stored at −20°C, and samples for GGT activity were immediately stored at 4°C. Measurements were performed within a week of collection. Urinary NAG and GGT activities were determined by use of the method reported by Narita et al.7 Urinary creatinine concentration was measured by use of the modified Folin method.15 Urinary NAG and GGT indices were calculated by use of the following formulae:

article image

Hemostatic function tests—Buccal mucosa bleeding time and CBT tests were measured as the primary hemostatic function tests, and PT, APTT, and fibrinogen concentration were measured as the secondary hemostatic function tests in both groups, before and every 7 days after starting the treatment. Before endoscopic examination, by use of a 21-gauge, thin-walled needle, 1.8 mL of blood was withdrawn by venipuncture from the jugular vein into a polypropylene syringe containing 0.2 mL of 3.8% trisodium citrate to obtain a final anticoagulant-to-blood ratio of 1:9. The coagulation panel (PT and APTT) and fibrinogen concentration were determined on an automatic analyzer.n After endoscopic examination, BMBT and CBT were measured by use of the method described by Jergens et al12 and Giles et al,16 respectively.

Statistical analysis—Endoscopic grade data and fecal occult blood grade data were analyzed by use of nonparametric statistical methods. Steel-Dwass nonparametric multiple comparison tests were used to compare differences between treatments at each time period and within treatments over time. For all nonparametric analyses, a value of P < 0.05 was considered significant; data are reported as median, interquartile range (25th to 75th percentile), and 10th percentile point (10th to 90th percentile).

Results of CBC, serum blood biochemical analyses, ERPF, GFR, NAG index, GGT index, BMBT, CBT, PT, APTT, and fibrinogen concentration were analyzed by use of parametric statistical methods. These data were analyzed by use of 2-factor repeatedmeasures ANOVA. For all parametric analyses, a value of P < 0.05 was considered significant; data are reported as mean ± SD.

Results

Physical examinations revealed no abnormalities in either group after starting the treatment. Clinical signs of gastrointestinal disorder, such as anorexia, vomiting, diarrhea and abdominal pain, were not observed. No significant differences were observed between preand posttreatment values in blood variables in either group.

No lesions were observed in the esophagus, cardia, fundus, stomach body, body-antrum junction, angular ventriculi, or duodenum of any dog during the experimental period. Over the course of the study, 2 dogs in the RDKET group developed mucosal erosions in the pylorus. In the RDKET group, all 7 dogs had several lesions on day 28 in the pyloric antrum, of which 5 dogs developed small mucosal erosions and hemorrhages and 2 dogs developed invasive erosions or extensive hemorrhages, whereas 6 dogs had no lesions and only 1 dog in the control group developed a small mucosal erosion on day 28 in the pyloric antrum. The pyloric antrum lesion grade was significantly higher in the RDKET group on day 28, compared with that at pretreatment, and a significant difference was observed between the RDKET and control groups on day 28 in the pyloric antrum (P = 0.028 and 0.044, respectively; Figure 1).

Figure 1—
Figure 1—

Endoscopic lesion grades for the pyloric antrum from pretreatment to 28 days in healthy dogs that received RDKET (0.25 mg/kg, PO, q 24 h [n = 7]) or gelatin capsules PO (control [7]) for 30 days. Box indicates interquartile range, thick line indicates median, and whiskers indicate 10th to 90th percentile. A significant (P < 0.05) difference was observed between pretreatment and day 28 in the RDKET group and between the RDKET and control groups on day 28.

Citation: American Journal of Veterinary Research 67, 7; 10.2460/ajvr.67.7.1115

Fecal occult blood grade typically increased with time, regardless of analytical method, especially in the RDKET group. Dogs 2 and 3 in the RDKET group had the highest recorded grades (grade 2 via both methods) on day 30. These dogs also had the highest endoscopic grades in the pyloric antrum on day 28 (grades 4 and 5). Six dogs in the RDKET group and 2 dogs in the control group had positive fecal occult blood results on day 30, as determined by either method. The fecal occult blood grade determined by use of the tetramethylbenzidine method was significantly (P = 0.043) higher in the RDKET group on day 30, compared with pretreatment. However, no significant differences were detected at any time for either method between the RDKET and control groups (Figure 2).

Figure 2—
Figure 2—

Fecal occult blood grades determined by use of 2 methods in the same dogs as in Figure 1. See Figure 1 for key.

Citation: American Journal of Veterinary Research 67, 7; 10.2460/ajvr.67.7.1115

The reference ranges for ERPF and GFR, determined in a preliminary study, were 12.7 ± 2.3 mL/min/kg and 4.5 ± 1.0 mL/min/kg, respectively. The ERPF and GFR were within reference ranges at all times in both groups, and no significant differences were observed in ERPF and GFR between the RDKET and the control groups (Table 1). No changes were observed in specific gravity, results of dipstick analysis, or urinary sediment examination in either group. The reference range for NAG index in the dogs was 3.2 ± 2.4 U/g, which was reported by Sato et al,17 and the reference range for GGT index in the dogs was 31.6 ± 10.4 U/g, which was determined in a preliminary study with 40 samples from healthy female dogs. No significant differences were detected in NAG and GGT indices between the RDKET and control groups (Table 1).

Table 1—

Results of ERPF, GFR, NAG index, and GGT in the same dogs as in Figure 1.

VariableGroupPretreatmentDay 5Day 10Day 15Day 20Day 25Day 30
ERPF (mL/min/kg)RDKET13.55 ± 0.53ND14.03 ± 0.43ND13.78 ± 0.96ND13.85 ± 1.02
Control13.15 ± 1.30ND13.00 ± 1.27ND12.91 ± 1.23ND13.20 ± 1.32
GFR (mL/min/kg)RDKET5.38 ± 0.32ND5.40 ± 0.64ND5.08 ± 0.74ND5.11 ± 0.72
Control4.60 ± 0.59ND4.69 ± 0.26ND5.04 ± 0.69ND4.55 ± 0.34
NAG index (U/g)RDKET2.39 ± 1.193.02 ± 1.152.85 ± 2.693.29 ± 1.144.01 ± 2.142.58 ± 0.621.64 ± 1.41
Control3.72 ± 1.642.52 ± 0.551.93 ± 0.604.16 ± 3.211.96 ± 0.983.02 ± 1.352.72 ± 1.04
GGT index (U/g)RDKET26.8 ± 7.822.7 ± 9.532.4 ± 12.420.0 ± 4.025.6 ± 11.018.9 ± 2.322.9 ± 5.3
Control32.3 ± 8.524.1 ± 6.021.2 ± 10.219.6 ± 4.020.6 ± 8.116.8 ± 7.928.3 ± 6.9

Data are reported as mean ± SD

ND = Not determined

The BMBT and CBT were within reference ranges in both groups at all times, and no significant differences were detected in either variable. The reference ranges of PT, APTT, and fibrinogen concentration, determined in a preliminary study with 29 samples from healthy dogs, were 5.8 to 7.9 seconds, 11.6 to 18.3 seconds, and 160 to 254.5 mg/dL, respectively. The PT, APTT, and fibrinogen concentration were within reference ranges in both groups at all times, and no significant differences were detected in these variables. In addition, significant differences were not detected in hemostatic variables between the RDKET and control groups (Table 2).

Table 2—

Results of measurements of BMBT, CBT, PT, APTT, and FC in the same dogs as in Figure 1.

VariableGroupPretreatmentDay 7Day 14Day 21Day 28
BMBT (min)RDKET1.96 ± 0.251.81 ± 0.471.83 ± 0.471.78 ± 0.441.94 ± 0.52
Control2.20 ± 0.602.08 ± 0.442.12 ± 0.352.30 ± 0.352.36 ± 0.32
CBT (min)RDKET3.14 ± 0.692.86 ± 0.693.14 ± 0.383.29 ± 0.493.29 ± 0.49
Control3.57 ± 0.533.43 ± 0.533.29 ± 0.493.57 ± 0.793.71 ± 0.76
PT (s)RDKET6.18 ± 0.676.62 ± 0.356.66 ± 0.486.90 ± 0.846.16 ± 0.75
Control6.30 ± 0.756.88 ± 0.426.74 ± 0.476.94 ± 0.496.72 ± 0.31
APTT (s)RDKET16.68 ± 4.2317.44 ± 3.9916.98 ± 1.9815.24 ± 2.5716.50 ± 3.80
Control13.56 ± 1.0614.38 ± 1.7914.42 ± 1.4514.42 ± 1.9914.84 ± 2.00
FC (mg/dL)RDKET180.8 ± 39.1179.8 ± 34.1175.0 ± 35.8186.2 ± 32.2199.4 ± 37.6
Control193.0 ± 32.4178.6 ± 32.2172.2 ± 19.3176.4 ± 31.7207.0 ± 60.7

Data are reported as mean ± SD.

FC = Fibrrinogen.

Discussion

In humans, NSAID use has been associated with gastrointestinal tract complications (upper and lower portions; bleeding, ulceration, and perforation) with approximately 1% to 2% annual incidence in patients who used these drugs for 6 to 12 months, and gastroduodenal ulcers have been reported in approximately 30% to 50% of patients taking NSAIDs with regularity.18 In veterinary medicine, there is an epidemiologic report19 indicating that treatments with NSAIDs are the most common (10/43 dogs) predisposing factor for gastroduodenal ulceration in dogs. Results of a previous study7 that used 1 mg of ketoprofen/kg suggested that oral administration of the drug induced mild to moderate gastric mucosal injuries mostly in the pyloric antrum and caused positive fecal occult blood results. Ketoprofen, a chiral NSAID used therapeutically, exists as a racemic mixture of the enatiomeric forms S(+)- and R(−)-ketoprofen, with S(+)-ketoprofen being primarily responsible for inhibition of COX, whereas R(−)-ketoprofen is devoid of such activity.20 Results of a previous report21 have indicated that although both enantiomers have less ulcerogenic effects than the racemic mixture, they have comparable gastric toxicity. In addition, R(−)-enantiomers in racemic ketoprofen can enhance the intestinal ulcerogenicity of S(+)-enantiomers.22 Therefore, racemic ketoprofen is thought to be less safe than S(+)-ketoprofen (dexketoprofen).23 Adverse effects induced by NSAIDs, including the nonspecific COX inhibitor ketoprofen, on the gastrointestinal tract are associated mainly with selective COX-1 inhibition24–26 and may be influenced by administration dosage and period. Therefore, RDKET is expected to result in fewer adverse effects on the gastrointestinal mucosa. Hazewinkel et al6 suggested that RDKET had minimal or no harmful effects on the gastrointestinal mucosa of dogs, as indicated by clinical signs. However, other results indicated that 0.25 mg of ketoprofen/kg administered for 30 days to healthy dogs still induced mild to moderate gastric mucosal injuries mostly in the pyloric antrum, although the adverse gastric effects involved no overt clinical signs, such as vomiting or diarrhea, as was reported in a previous study.6 Furthermore, the gastric mucosal lesion grades on days 21 and 28 in the present study were similar to the findings on day 21 and 28 in a previous study7 in which the gastrointestinal mucosa was evaluated after administration of 1 mg of ketoprofen/kg to healthy dogs for 30 days, whereas the gastric mucosal lesion grades on days 7 and 14 in the present study were lower than the findings on days 7 and 14 in dogs given 1 mg of ketoprofen/kg for 30 days.7 Therefore, our results suggest that 0.25 mg of ketoprofen/kg is safer for the gastrointestinal tract than 1 mg/kg through 14 days of use in dogs. The reason that most severe NSAID-induced gastric lesions are in the pyloric antrum is unknown. However, stomach shape or a direct irritation of NSAIDs to the gastric mucosa may influence lesion formation.

In the present study, fecal occult blood tests, including those that used tetramethylbenzidine and guaiac methods, were investigated as screening tools for adverse gastrointestinal effects. Fecal occult blood testing has been most commonly used in evaluation of gastrointestinal disorders.27,28 However, these tests could be influenced by diet,29,30 and accordingly, tests for fecal occult blood do not have 100% sensitivity and specificity. In the present study, dogs were fed a meatfree (especially mutton and beef-free), low-peroxidase dry diet during the experimental period to minimize false-positive results. Two dogs in the control group had weakly positive results for fecal blood, and one of these dogs had a small mucosal erosion on day 28 in the pyloric antrum. The cause of gastric mucosal erosion and fecal occult blood in the control group was unknown; however, it was similar to findings of a previous study7 in which gastric mucosal injuries and weakly positive fecal occult blood results were detected in the small number of dogs in a gelatin placebo group and another study13 in which a small number of pinpoint gastric hemorrhages were observed in a gelatin placebo group. Therefore, we speculate that fecal occult blood and gastric injuries in the control group may have been caused by several stressors such as capsule administration or anesthesia. With RDKET, positive fecal occult blood tests were observed, especially by use of the tetramethylbenzidine method, and the results were correlated with lesion grades identified via endoscopic examinations of the pyloric antrum. Therefore, results suggest that fecal occult blood tests, especially via the tetramethylbenzidine method, are useful for evaluating gastrointestinal bleeding disorders in dogs treated with NSAIDs.

In previous studies,9,11,31 adverse effects of NSAIDs on the kidney in humans and dogs have been reported. The most common adverse renal effect related to the use of NSAIDs was renal insufficiency. Although renal insufficiency associated with NSAIDs is reversible, if NSAIDs are administered to dogs without monitoring the severity of renal hypofunction, severe renal disorders may result. Therefore, monitoring adverse renal and gastrointestinal tract effects is important during long-term administration of ketoprofen. Assessment of ERPF reflects certain pathophysiologic events in the kidney,32,33 and GFR is presently considered the best quantitative variable of overall renal function in veterinary medicine.34 Although a previous study35 revealed that 1 mg of ketoprofen/kg caused a temporary decrease in ERPF, in the study reported here, no significant changes in ERPF or GFR were observed in dogs treated with 0.25 mg of ketoprofen/kg or in control dogs. In humans and dogs, reports10,34,36 have attributed several unique nephropathies, including acute interstitial nephritis and papillary necrosis, to NSAID administration.

Recently, a report37 indicated that indomethacin induced free radical formation in the kidney and impaired structure and function of renal brush-border membranes (microvillus membranes) in epithelial cells of renal tubules. The authors postulated that occurrence of free radicals in the kidney may be important in the pathogenesis of NSAID-induced nephropathy,37 and in the present study, urinary NAG and GGT were measured as markers of renal tubular cell injuries to achieve further analysis of renal changes. The NAG and GGT enzymes are located in proximal tubular epithelium cells and in brush-border membranes, respectively. Excretion of these renal enzymes increases in urine of dogs with renal proximal tubular cell injuries.17,38 In the present study, abnormal increases of these enzymes or exfoliation of renal tubular cells in urinary sediments was not detected in treated or control dogs. These results suggested that 0.25 mg of ketoprofen/kg administered for 30 days has no adverse effects on renal function or renal tubular cells in healthy dogs.

Platelets are the only cells that exclusively express COX-1 in dogs39; COX-1 forms thromboxane A2 through the endogenous arachidonic acid pathway, which in turn produces primary platelet plugs. Bleeding time tests (BMBT and CBT) were used in the present study to assess several aspects of primary platelet plug formation.12,40 The BMBT and CBT may not be specific for defects in primary hemostasis because some coagulation defects may result in prolonged BMBT and CBT.12,16 Thus, simultaneous measurement of PT, APTT, and fibrinogen concentration was performed to assess the status of the coagulation cascade. In the present study, no abnormalities were detected in BMBT, CBT, PT, APTT, or fibrinogen concentration in dogs receiving 0.25 mg of ketoprofen/kg. However, Lemke et al41 also reported that 2 mg of ketoprofen/kg inhibited whole-blood platelet aggregation but did not alter BMBT in dogs undergoing ovariohysterectomy, and they suggested that ketoprofen can be given before surgery to healthy dogs, provided that dogs are screened for potential bleeding problems during surgery. Therefore, we suggest that administration of 0.25 mg of ketoprofen/kg for 30 days may inhibit platelet aggregation but that it has no adverse effects on bleeding time in healthy dogs, potentially making a periodic screening test for bleeding problems as well as gastrointestinal complications necessary.

ABBREVIATIONS

RDKET

Reduced-dosage ketoprofen

ERPF

Effective renal plasma flow

COX

Cyclooxygenase

NSAID

Nonsteroidal anti-inflammatory drug

GFR

Glomerular filtration rate

GGT

γ-Glutamyltransferase

ClPAH

Clearance of para-aminohippurate sodium

ClCre

Clearance of endogenous creatinine

NAG

n-acetyl-β-D-glucosaminidase

CBT

Cuticle bleeding time

PT

Prothrombin time

APTT

Activated partial thromboplastin time

BMBT

Buccal mucosa bleeding time

a.

Ketoprofen, Merial Japan Co Ltd, Fukushima, Japan.

b.

Empty gelatin capsules, Kobayashi Capsulae Inc, Hyogo, Japan.

c.

Eukanuba Original, Iams Japan Inc, Tokyo, Japan.

d.

Hitachi Automatic Analyzer 7060, Hitachi Inc, Tokyo, Japan.

e.

Rapinovet, Takeda Schering-Plough Animal Health Co Ltd, Osaka, Japan.

f.

Forane, Dainabot Co Ltd, Tokyo, Japan.

g.

Olympus ves, Olympus AVS Co Ltd, Tokyo, Japan.

h.

Occult Blood Slide Shionogi, Shionogi Co Ltd, Osaka, Japan.

i.

P-aminohippurate sodium, Daiichi Pharmaceutical Co Ltd, Tokyo, Japan.

j.

Aution Sticks 5EA, Arkray Inc, Kyoto, Japan.

k.

Clinical refractometer T2-NE, Atago Co Ltd, Tokyo, Japan.

l.

URI-CEL, Cambridge Diagnostic Products Inc, Fort Lauderdale, Fla.

m.

Ruschi Ultrasil, Rushi Asia Pacific Sdn Bhd, Tokyo, Japan.

n.

COAG 2, A & T Co Ltd, Kanagawa, Japan.

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