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  • Author or Editor: Gregory F. Grauer x
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Abstract

Objective—To determine whether tepoxalin alters kidney function in dogs with chronic kidney disease (CKD).

Animals—16 dogs with CKD (International Renal Interest Society stage 2 or 3) and osteoarthritis.

Procedures—Kidney function was assessed via serum biochemical analysis, urinalysis, urine protein-to-creatinine concentration ratio, urine γ-glutamyl transpeptidase-to-creatinine concentration ratio, iohexol plasma clearance, and indirect blood pressure measurement twice before treatment. Dogs received tepoxalin (10 mg/kg, PO, q 24 h) for 28 days (acute phase; n = 16) and an additional 6 months (chronic phase; 10). Recheck examinations were performed weekly (acute phase) and at 1, 3, and 6 months (chronic phase). Kidney function variables were analyzed via repeated-measures ANOVA.

Results—There was no difference over time for any variables in dogs completing both phases of the study. Adverse drug events (ADEs) resulting in discontinuation of tepoxalin administration included increased serum creatinine concentration (1 dog; week 1), collapse (1 dog; week 1), increased liver enzyme activities (1 dog; week 4), vomiting and diarrhea (1 dog; week 8), hematochezia (1 dog; week 24), and gastrointestinal ulceration or perforation (1 dog; week 26). Preexisting medical conditions and concomitant drug use may have contributed to ADEs. Kidney function was not affected in the latter 5 dogs. Discontinuation of tepoxalin administration stabilized kidney function in the former dog and resolved the ADEs in 4 of the 5 latter dogs.

Conclusions and Clinical Relevance—Tepoxalin may be used, with appropriate monitoring, in dogs with International Renal Interest Society stage 2 or 3 CKD and osteoarthritis.

Full access
in American Journal of Veterinary Research

Summary

Twelve Beagles were inoculated with concanavalin A, and after a mean ninefold increase in antibody titer, 1 mg of concanavalin A was infused into each renal artery of each dog to induce in situ immune complex glomerulonephritis. Starting 4 weeks after renal arterial infusion, 6 dogs were treated orally 3 times daily with 30 mg of 3-methyl-2 (3 pyridyl)-1-indoleoctanoic acid (CGS 12970)/ kg of body weight, a thromboxane synthetase inhibitor, and 6 dogs (control group) received a gelatin capsule 3 times daily. Endogenous creatinine clearance and 24-hour urinary excretion of protein and thromboxane B2 were determined for each dog prior to renal arterial infusion, at the initiation of treatment and at 2, 4, 6, and 8 weeks after initiation of treatment. In addition, methyoxy-3H inulin clearance was determined at initiation of treatment and 4 and 8 weeks later. Renal specimens were examined histologically at the initiation of treatment and 4 and 8 weeks later. Glomerular mononuclear profiles/μm3 were determined from at least 10 equatorially sectioned glomeruli from each dog. Paired t tests were used to compare mean values at the various time points to the respective mean baseline value and 2-sample t tests were used to evaluate differences between treatment groups.

At the start of treatment (4 weeks after renal arterial infusion of concanavalin A), histologic evaluation of renal specimens revealed glomerular epithelial crescent formation, mononuclear cell proliferation, and infiltration of neutrophils. Mononuclear cell profiles and urinary excretion of protein and thromboxane B2 were significantly increased, but endogenous creatinine clearance values were unchanged. Treatment with CGS 12970 did not affect endogenous creatinine clearance, methyoxy-3H inulin clearance, or glomeruli, however, CGS 12970 treatment significantly decreased urinary excretion of protein and thromboxane B2 when compared with values in the control group. These findings suggested that thromboxane has a role in the pathogenesis of established glomerulonephritis and that thromboxane synthetase inhibition treatment may be beneficial in dogs with established glomerulonephritis.

Free access
in American Journal of Veterinary Research

Abstract

Objective—To evaluate the use of dipstick, sulfosalicylic acid (SSA), and urine protein-tocreatinine ratio (UP:C) methods for use in detection of canine and feline albuminuria.

Design—Evaluation study.

Sample Population—599 canine and 347 feline urine samples.

Procedures—Urine was analyzed by use of dipstick, SSA, and UP:C methods; results were compared with those for a species-specific ELISA to determine sensitivity, specificity, positive predictive value (PPV), negative predictive value, and positive and negative likelihood ratios.

Results—Positive results for dipstick and SSA tests (trace reaction or greater) in canine urine had moderate specificity (dipstick, 81.2%; SSA, 73.3%) and poor PPV (dipstick, 34.0%; SSA, 41.8%). Values improved when stronger positive results (≥ 2+) for the dipstick and SSA tests were compared with ELISA results (specificity, 98.9% and 99.0% for the urine dipstick and SSA tests, respectively; PPV, 90.7% and 90.2% for the dipstick and SSA tests, respectively). Data obtained for cats revealed poor specificity (dipstick, 11.0%; SSA, 25.4%) and PPV (dipstick, 55.6%; SSA, 46.9%). Values improved slightly when stronger positive test results (≥ 2+) were used (specificity, 80.0% and 94.2% for the dipstick and SSA tests, respectively; PPV, 63.5% and 65.2% for the dipstick and SSA tests, respectively). The UP:C had high specificity for albuminuria in dogs and cats (99.7% and 99.2%, respectively) but low sensitivity (28.7% and 2.0%, respectively).

Conclusions and Clinical Relevance—Caution should be used when interpreting a positive test result of a dipstick or SSA test for canine or feline albuminuria.

Full access
in Journal of the American Veterinary Medical Association

SUMMARY

Platelet aggregation and adenosine triphosphate (atp) secretion in response to arachidonic acid (10 μM) or collagen (5 μg/ml) were compared in healthy, adult female Beagles treated with low-dosage aspirin (3.5 mg/kg of body weight, po, q 12 h for 7 treatments) or with CGS 12970, a specific thromboxane synthetase inhibitor (10 mg/kg, po, q 8 h for 10 treatments). Platelet aggregation was assessed in whole blood by use of an electrical impedance method. Baseline values obtained prior to treatment served as controls. Addition of arachidonic acid to blood from nontreated dogs resulted in significantly (P < 0.001) increased impedance, but had no effect in blood from dogs treated with either aspirin or CGS 12970. Treatment with CGS 12970 or aspirin significantly (P < 0.001) decreased platelet atp secretion in response to arachidonic acid, compared with baseline values; however atp secretion in aspirin-treated dogs was significantly (P < 0.01) less than atp secretion in CGS 12970-treated dogs. Differences in platelet aggregation were not observed between control dogs and aspirin- or CGS 12970-treated dogs in response to collagen as an aggregant, however, collagen-induced platelet atp secretion was significantly (P < 0.001) decreased in dogs treated with aspirin, compared with control values and values from dogs treated with CGS 12970. In dogs treated orally with 0.1, 0.2, 1.0, or 10 mg of CGS 12970/kg, dose-dependent inhibition of arachidonic acid-induced platelet aggregation was observed, with impedance changes not observed at the 10-mg/kg dosage and normal platelet aggregation associated with the 0.1-mg/kg dosage. After a single orally administered dosage of 10 mg of CGS 12970/kg, platelet aggregation was maximally inhibited at 1 hour, remained negligible through 12 hours, and returned to normal by 96 hours. Platelet numbers were not affected by treatment with CGS 12970. These results indicate that similar to low-dose aspirin administration, treatment with CGS 12970 decreases arachidonic acid-induced, but not collagen-induced, whole blood platelet aggregation in dogs. Low-dose aspirin administration, however, was more effective than CGS 12970 treatment in reducing arachidonic acid- and collagen-induced platelet atp secretion.

Free access
in American Journal of Veterinary Research

Summary

Eighteen 6-month-old male Beagles with normal renal function were allotted at random to 3 groups of 6 dogs each. For 21 days, each group was fed a diet that was similar except for protein content (high protein, 27.3%; medium protein, 13.7%; and low protein, 9.4%). After the conditioning period, gentamicin was administered at a dosage of 10 mg/kg of body weight, IM, every 8 hours for 8 days, and the respective diet was continued. Clearance of endogenous creatinine, 24-hour urinary excretion of protein and enzymes (γ-glutamyltransferase, and N-acetyl- β-d-glucosaminidase, and fractional clearance of sodium and potassium (%) were determined before and after dietary protein conditioning and on days 2, 4, 6, and 8 of gentamicin administration. Additionally, trough serum gentamicin concentration was determined on days 2, 4, 6, and 8 of gentamicin administration. At the end of the study, all dogs were euthanatized; renal histologic features were graded, using a continuous ranking scale, and renal cortical gentamicin concentrations were measured. Data were ranked and analyzed, using a nonparametric equivalent of a two-way anova; P < 0.05 was considered significant.

After the dietary conditioning period (prior to gentamicin), dogs fed the high-protein diet had higher endogenous creatinine clearance and urinary excretion of protein, compared with dogs fed the low-protein diet. Differences existed among groups after 8 days of gentamicin administration. Dogs fed the high-protein diet had higher creatinine clearance, lower serum creatinine concentration, lower fractional clearance of sodium, lower urinary excretion of N-acetyl-β-d-glucosaminidase and lower trough serum gentamicin concentration, compared with dogs fed the medium- and low-protein diets. Dogs fed the high-protein diet also had lower urinary excretion of protein and lower fractional clearance of potassium, compared with dogs fed the low-protein diet. There was no difference in urinary excretion of γ-gluta-myltransferase among groups on day 8 of the study. Proximal tubular necrosis was more severe in dogs fed the medium-protein diet, compared with dogs fed the high-protein diet; however, there were no differences in renal cortical gentamicin concentrations among groups. In conclusion, feeding the high-protein diet prior to and during gentamicin administration reduced nephrotoxicosis in these dogs.

Free access
in American Journal of Veterinary Research

SUMMARY

A specific thromboxane synthetase inhibitor, 3-methyl- 2 (3-pyridyl)-l-indoleoctanoic acid (CGS 12970) was administered orally to 6 healthy adult Beagles at a dosage of 30 mg/kg of body weight. Blood generation of thromboxane B2 and urinary excretion of thromboxane B2 were measured before and after administration of CGS 12970. Although 97 ± 0.4% inhibition of thromboxane B2 generation was observed within 2 hours after a single dose of CGS 12970 was administered orally, an effect on urinary excretion of thromboxane B2 was not observed. Additionally, oral administration of 30 mg/kg every 12 hours resulted in 80 ± 14% inhibition of thromboxane B2 generation but had no effect on urinary thromboxane B2 excretion.

Free access
in American Journal of Veterinary Research

Objective—

To evaluate safety and efficacy of 4-methylpyrazole (4-MP) treatment in dogs and to determine clinical signs and outcome of, and clinicopathologic abnormalities in, dogs treated in early or late stages of ethylene glycol (EG) intoxication.

Design—

Retrospective study.

Animals—

107 dogs.

Procedure—

For dogs treated with 4-MP, 1 of 2 dosage regimens was usually used: 20 mg/kg of body weight, IV, initially, 15 mg/kg 17 hours later, and 5 mg/kg 25 and 36 hours after the initial dose, or 20 mg/kg, IV, initially, 15 mg/kg 12 and 24 hours later, and 5 mg/kg 36 hours after the initial dose.

Results—

Neither adverse clinical signs nor clinicopathologic abnormalities were associated with the administration of 4-MP except in 1 dog, which developed tachypnea, gagging, excess salivation, and trembling after the second dose of 4-MP was given. Ethylene glycol intoxication was confirmed in 37 dogs. Of these, 21 were azotemic or became azotemic within 18 hours after admission, and only 1 of the 21 survived. All 16 dogs that did not become azotemic survived. Median time from EG ingestion to treatment with 4-MP was 5 hours (range, 2 to 8.5 hours) for dogs that were not azotemic at admission and 14.5 hours (range, 8.5 to 38 hours) for dogs that were azotemic at admission.

Clinical Implications—

4-MP was a safe and effective treatment for EG intoxication when it was given before sufficient quantities of EG had been metabolized to induce renal failure. Dogs treated within 8 hours of EG ingestion had a good prognosis. (J Am Vet Med Assoc 1996;209:1880–1883)

Free access
in Journal of the American Veterinary Medical Association

Abstract

Objective

To evaluate the protective effects of dietary n-3 fatty acid supplementation versus treatment with a thromboxane synthetase inhibitor (TXSI) in dogs given high-dose gentamicin.

Design

Clinicopathologic and renal histopathologic changes induced by gentamicin (10 mg/kg of body weight, IM, q 8 h, for 8 days) were compared in dogs fed an n-3 fatty acid-supplemented diet containing a fatty acid ratio of 5.7:1 (n-6:n-3), dogs treated with CGS 12970 (a specific TXSI given at 30 mg/kg, PO, q 8 h, beginning 2 days prior to gentamicin administration), and control dogs. The TXSI-treated and control dogs were fed a diet with a fatty acid ratio of 51.5:1 (n-6:n-3). Both diets were fed beginning 42 days prior to and during the 8-day course of gentamicin administration.

Animals

Eighteen 6-month-old male Beagles, 6 in each group.

Results

After 8 days of gentamicin administration, differences existed among groups. Compared with n-3-supplemented and control dogs, TXSI-treated dogs had higher creatinine clearance. Both TXSI-treated and n-3-supplemented dogs had higher urinary prostaglandin E2 and E3 (PGE2/3) and 6-keto prostaglandin F (PGF) excretion, compared with control dogs. Urinary thromboxane B2 (TXB2) excretion was higher in n-3-supplemented and control dogs, compared with TXSI-treated dogs. Urine PGE2/3-to-TXB2 and PGF-to-TXB2 ratios were increased in TXSI-treated dogs, compared with n-3-supplemented and control dogs, and these ratios were increased in n-3-supplemented dogs, compared with control dogs. In addition, TXSI-treated and n-3-supplemented dogs had lower urinary protein excretion, compared with control dogs. Proximal tubular necrosis was less severe in TXSI-treated dogs, compared with control dogs.

Conclusion

Treatment with CGS 12970 prior to and during gentamicin administration prevented increases in urinary TXB2 excretion and reduced nephrotoxicosis.

Clinical Relevance

Increased renal production/excretion of thromboxane is important in the pathogenesis of gentamicin-induced nephrotoxicosis. (Am J Vet Res 1996;57:948–956)

Free access
in American Journal of Veterinary Research

SUMMARY

To determine the role of thromboxane A2 in the pathogenesis of experimentally induced immune complex glomerulonephritis, 12 concanavalin A-immunized Beagles were infused with 1 mg of concanavalin A via each renal artery and treated twice daily for 8 days with either 30 mg of CGS 12970/kg, po, a specific thromboxane synthetase inhibitor, or placebo. The effect of treatment was assessed by measuring endogenous creatinine clearance and urine protein and eicosanoid excretion, and by evaluating changes in glomerular morphometric characteristics. On postinfusion day 8, urine protein, thromboxane B2, and 11-dehydro-thromboxane B2 excretion, glomerular epithelial crescent formation, and glomerular cell proliferation in the CGS 12970-treated dogs were significantly decreased when compared with values in the placebo-treated group. Differences were not observed in endogenous creatinine clearance, urine prostaglandin E2 and 6-keto-prostaglandin F excretion, or glomerular polymorphonuclear leukocyte infiltration between groups in this study. These findings suggest thromboxane A2 has a role in the development of immune complex glomerulonephritis and that thromboxane synthetase inhibition may be beneficial in attenuating some of the functional and histologic changes associated with immune complex glomerulonephritis.

Free access
in American Journal of Veterinary Research