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Abstract

Objective—To compare the in vitro imMunosuppressive effects of cyclosporine and 4 novel immunosuppressive drugs on lymphocytes in whole blood collected from healthy cats.

Sample Population—Whole blood samples collected from 10 healthy adult domestic shorthair cats.

Procedure—Mitogen-stimulated lymphocyte proliferation in whole blood incubated with and without various concentrations of cyclosporine, tacrolimus, sirolimus, mycophenolic acid (MPA), or A771726 was measured by use of [3H]thymidine incorporation. Drug concentrations that resulted in a 50% inhibition of mitogen-induced proliferation (IC50) were calculated. Lymphocyte viability was determined by use of the trypan blue dye exclusion method.

Results—An obvious dose-response relationship for the antiproliferative effects of each drug was detected. Mean IC50 determined with concanavalin A was 46 nMfor cyclosporine, 9 nMfor tacrolimus, 12 nM for sirolimus, 16 nM for MPA, and 30 mM for A771726, whereas with pokeweed mitogen, mean IC50 was 33 nM for cyclosporine, 5 nMfor tacrolimus, 15 nM for sirolimus, 14 nM for mycophenolic acid, and 25 mM for A771726. Mitogen-stimulated and nonstimulated lymphocytes remained viable, regardless of drug evaluated.

Conclusions and Clinical Relevance—Tacrolimus, sirolimus, MPA, and A771726 inhibited in vitro mitogen- stimulated proliferation of feline lymphocytes in a dose-dependent manner. These novel immunosuppressive drugs may be useful for management of immune-mediated inflamMatory diseases and prevention and treatment of rejection in cats that undergo organ transplantation. (Am J Vet Res 2000;61: 906–909)

Full access
in American Journal of Veterinary Research

Abstract

Objective

To evaluate the disposition of fentanyl after IV and transdermal administrations. The hypothesis was that transdermal administration of fentanyl would result in a measurable plasma opioid concentration.

Design

Each dog received 2 treatments in a randomized, crossover design.

Animals

6 clinically normal Beagles.

Procedure

2 treatments consisting of IV fentanyl (50 μg/kg of body weight) and transdermal fentanyl (50 μg/h) administrations. Plasma fentanyl concentrations were measured at fixed times, and pharmacokinetic values were calculated.

Results

Intravenous pharmacokinetics of fentanyl was similar to those previously described in dogs and provided the distribution and clearance data necessary to calculate the rate of absorption of the transdermally administered opioid. The transdermal fentanyl patch produced average steady-state concentrations of 1.6 ng/ml. The actual rate of delivery of transdermal fentanyl was 35.7 (range, 13.7 to 49.8) μg/h, which represented 71.48% (range, 27.45 to 99.56%) of the theoretical rate of delivery. The mean elimination half-life of fentanyl after patch removal was 1.39 hours.

Conclusions

Transdermally administered fentanyl resulted in fairly constant plasma concentrations, in the range generally considered to be analgesic, from 24 to 72 hours after application of the patch. The rate of drug delivery was less than expected, and there was substantial individual variation.

Clinical Relevance

Transdermally administered fentanyl has the potential to be a clinically useful analgesic regimen in dogs, and further evaluation of its analgesic actions and potential side effects is warranted. (Am J Vet Res 1996; 57:715–719)

Free access
in American Journal of Veterinary Research

Abstract

Objective—To determine whether the active metabolite of leflunomide, A77 1726 (A77), inhibits replication of feline herpesvirus-1 (FHV-1) in cell culture.

Study Population—Crandell Rees feline kidney (CRFK) cell cultures.

Procedures—Cell cultures were inoculated with FHV-1 and treated simultaneously with concentrations of A77 ranging from 0 to 200μM. The antiviral effect of A77 was determined by use of conventional plaque reduction assays. The effect of A77 on viral load was determined via real-time PCR analysis, and transmission electron microscopy was used to evaluate the effect of A77 on viral morphology. To determine whether the antiviral effect was attributable to alterations in CRFK cell viability and number, CRFK cells were treated with various concentrations of A77 and stained with Annexin V and propidium iodide to assess apoptosis and a mitochondrial function assay was used to determine cell viability.

Results—Concentrations of A77 ≥ 20μM were associated with substantial reduction in plaque number and viral load. Concentrations ≥ 100μM were associated with complete suppression of plaque formation. At low concentrations of A77, clusters of intracytoplasmic virus particles that appeared to lack tegument and an external membrane were detected. Treatment of uninfected CRFK cell monolayers with A77 was associated with reduction in mitochondrial function with minimal evidence of apoptosis.

Conclusions and Clinical Relevance—Leflunomide may be an alternative to current calcineurin-based immunosuppressive protocols used in feline organ transplantation because of its antiherpesviral activity.

Full access
in American Journal of Veterinary Research

Abstract

Objective—To use in vitro assays to evaluate the effects of a novel immunosuppressive agent, FTY720, on biological functions (migration, phagocytosis, and production of reactive-oxygen species [ROS]) of feline peripheral neutrophils and determine the cytotoxic effects of FTY720 on feline peripheral neutrophils.

Sample Population—Peripheral neutrophils obtained from 8 healthy cats.

Procedure—Peripheral neutrophils were isolated from blood samples obtained from the 8 cats and exposed to the phosphorylated form of FTY720 (FTY720-P). A fluorescence-based in vitro evaluation of migration was performed. Phagocytosis of microbes and production of ROS were evaluated by use of a 2-color flow cytometry system. Samples of whole blood obtained from the cats were incubated with various concentrations of FTY720-P, fluorescein-labeled Staphylococcus aureus, and dihydroethidium. Cytotoxic effects were evaluated by use of propidium iodide staining.

Results—Addition of FTY720-P caused a slight non-significant decrease in phagocytosis and production of ROS by feline peripheral neutrophils. Migration activity of feline peripheral neutrophils was significantly increased by the addition of FTY720-P. Addition of FTY720-P at concentrations considered for clinical use did not increase the death rate of feline peripheral neutrophils.

Conclusions and Clinical Relevance—FTY720 does not inhibit critical functions of feline peripheral neutrophils in vitro.

Full access
in American Journal of Veterinary Research

Abstract

Objective—To describe pharmacokinetics of multidose oral administration of tacrolimus in healthy cats and evaluate the efficacy of tacrolimus in the prevention of allograft rejection in cats with renal transplants.

Animals—6 healthy research cats.

Procedure—Cats received tacrolimus (0.375 mg/kg, PO, q 12 h) for 14 days. Blood tacrolimus concentrations were measured by a high performance liquid chromatography-mass spectrometry assay. Each cat received an immunogenically mismatched renal allograft and native kidney nephrectomy. Tacrolimus dosage was modified to maintain a target blood concentration of 5 to 10 ng/mL. Cats were euthanatized if plasma creatinine concentration exceeded 7 mg/dL, body weight loss exceeded 20%, or on day 50 after surgery. Kaplan-Meier survival curves were plotted for 6 cats treated with tacrolimus and for 8 cats with renal transplants that did not receive immunosuppressive treatment.

Results—Mean (± SD) values of elimination half-life, time to maximum concentration, maximum blood concentration, and area under the concentration versus time curve from the last dose of tacrolimus to 12 hours later were 20.5 ± 9.8 hours, 0.77 ± 0.37 hours, 27.5 ± 31.8 ng/mL, and 161 ± 168 hours × ng/mL, respectively. Tacrolimus treated cats survived longer (median, 44 days; range, 24 to 52 days) than untreated cats (median, 23 days; range, 8 to 34 days). On histologic evaluation, 3 cats had evidence of acute-active rejection, 1 cat had necrotizing vasculitis, and 2 cats euthanatized at study termination had normal appearing allografts.

Conclusions and Clinical Relevance—Tacrolimus may be an effective immunosuppressive agent for renal transplantation in cats. (Am J Vet Res 2003;64:926–934)

Full access
in American Journal of Veterinary Research

Abstract

Objective—To determine sensitivity and specificity of radiography, ultrasonography, and antegrade pyelography for detection of ureteral obstructions in cats.

Design—Retrospective study.

Animals—11 cats.

Procedure—Medical records of cats that had radiography, ultrasonography, and antegrade pyelography performed for suspected ureteral obstructions were examined. Ultrasound-guided pyelocentesis and fluoroscopic- assisted antegrade pyelography were performed on 18 kidneys in 11 cats. Obstructive ureteral lesions were confirmed in all cats by surgical or necropsy examination. Sensitivity and specificity of survey radiography, ultrasonography, and antegrade pyelography for identification of ureteral obstructions were calculated. Surgical or necropsy findings were used as the standard for comparison.

Results—All cats were azotemic. Mean ± SD serum creatinine and BUN concentrations were 10.2 ± 6.1 and 149 ± 82 mg/dL, respectively. Fifteen of 18 ureters were found to be obstructed at surgery or necropsy. Sensitivity and specificity were 60 and 100% for radiography and 100 and 33% for ultrasonography, respectively, in identification of ureteral obstructions. Leakage of contrast material developed in 8 of 18 kidneys during antegrade pyelography and prevented diagnostic interpretation in 5 of 18 studies. For the 13 diagnostic studies, specificity and sensitivity were 100% by use of the antegrade pyelography technique. Correct identification of the anatomic location of the ureteral obstruction was obtained in 100% of diagnostic antegrade pyelography studies and in 60% of radiography or ultrasonography studies.

Conclusions and Clinical Relevance—Antegrade pyelography can be a useful alternative in the diagnosis and localization of ureteral obstructions in azotemic cats, although leakage of contrast material may prevent interpretation of the study. (J Am Vet Med Assoc 2003;222:1576–1581)

Full access
in Journal of the American Veterinary Medical Association

Abstract

Objective—To determine clinical, clinicopathologic, radiographic, and ultrasonographic abnormalities in cats with ureteral calculi.

Design—Retrospective study.

Animals—163 client-owned cats.

Procedure—Medical records were reviewed, and information on signalment, history, clinical signs, and results of clinicopathologic testing and diagnostic imaging was obtained.

Results—The number of cats in which ureterolithiasis was diagnosed each year increased progressively during the study period. Clinical signs tended to be nonspecific and included inappetence, vomiting, lethargy, and weight loss. A combination of survey radiography and abdominal ultrasonography revealed ureteral calculi in 66 of 73 (90%) cats in which the diagnosis was confirmed at surgery or necropsy. Ultrasonography revealed that ureteral calculi were causing ureteral obstruction in 143 of 155 (92%) cats. One hundred thirty-four of 162 (83%) cats had azotemia, 84 of 156 (54%) had hyperphosphatemia, and 22 of 152 (14%) had hypercalcemia. Urinary tract infection was documented in 10 of 119 (8%). Fifty-eight of 76 (76%) cats with unilateral ureterolithiasis had azotemia and 33 (43%) had hyperphosphatemia, indicating impairment of renal function in the contralateral kidney or prerenal azotemia. Ultrasonographic imaging of the contralateral kidney in cats with unilateral ureteral calculi suggested that preexisting renal parenchymal disease was common in cats with ureterolithiasis. Ninety-one of 93 (98%) ureteral calculi contained calcium oxalate.

Conclusions and Clinical Relevance—Results suggest that abdominal imaging should be performed in all cats with chronic nonspecific signs or with acute or chronic renal failure to rule out ureterolithiasis. Preexisting renal disease may be common in cats with ureteral calculi. (J Am Vet Med Assoc 2005;226: 932–936)

Full access
in Journal of the American Veterinary Medical Association

Objective

To evaluate diagnostic methods, surgical treatment, perioperative management, and renal function of cats with obstructive calcium oxalate ureteroliths.

Design

Retrospective case series.

Animals

11 cats that underwent surgery for removal of calcium oxalate ureteroliths.

Procedure

Medical records were reviewed, and the following information was recorded: signalment; results of physical examination, clinicopathologic analyses, and abdominal imaging; surgical procedure; postoperative management; and results of ureterolith quantitative analysis.

Results

Ureteroliths in the proximal portion of the ureter were removed from 5 cats (pyelotomy, 1 cat; unilateral ureterotomy, 2 cats; bilateral ureterotomies, 2 cats). Calculi in the middle and distal part of the ureter were removed by partial ureterectomy and ureteroneocystostomy (6 cats). Ten cats recovered from surgery and were discharged from the hospital. One cat died from unknown causes 4 months after surgery, and 1 cat had a nephrectomy elsewhere 5 weeks after ureterolith removal. Eight cats were evaluated 12 to 20 months after surgery. Of these, 2 cats that were markedly azotemic before surgery improved after surgery, and 2 cats developed nephroliths after surgery. Also, of 5 cats that had nephroliths that were not removed at the time of surgery, 4 still had visible nephroliths. One cat had recurrent ureteral obstruction from a ureterolith and persistent urinary tract infection. Ureteroliths or ultrasonographic evidence of ureteral obstruction were not detected in other cats.

Clinical Implications

A combination of microsurgical techniques and intensive postoperative care is necessary to minimize morbidity of cats after removal of a ureterolith. Renal function may improve or stabilize after removal of the ureteral obstruction. (J Am Vet Med Assoc 1998;213:1150-1156)

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in Journal of the American Veterinary Medical Association

Abstract

Objective—To document the signalment; history; clinical signs; clinicopathologic, diagnostic imaging, and surgical findings; perioperative complications; and long-term clinical results of ameroid ring constrictor (ARC) placement on single extrahepatic portosystemic shunts (PSS) in cats.

Design—Retrospective study.

Animals—23 cats treated with an ARC on a single extrahepatic PSS.

Procedure—An ARC was placed surgically around the PSS. Portal pressure was measured prior to ARC placement, with complete temporary PSS occlusion, and after ARC placement. Cats were scheduled for recheck transcolonic portal scintigraphy 8 to 10 weeks after surgery. Follow-up information was obtained by telephone interview with the owners.

Results—An ARC was successfully placed in 22 of 23 cats. Intraoperative complications, consisting of PSS hemorrhage, occurred in 2 cats. Mean (± SD) portal pressure (n = 15) was 6.7 ± 2.9 mm Hg before PSS manipulation, 18.6 ± 7.7 mm Hg with complete temporary PSS occlusion, and 6.9 ± 2.7 mm Hg after ARC placement. Postoperative complications developed in 77% (17 of 22) of cats after ARC placement, and included central blindness, hyperthermia, frantic behavior, and generalized motor seizures. Perioperative mortality rate was 4.3% (1 of 23). Persistent shunting was identified in 8 of 14 cats. Overall, 75% (15 of 20) of cats had an excellent longterm outcome.

Conclusions and Clinical Relevance—Placement of an ARC on single extrahepatic PSS in cats resulted in low surgical complication and perioperative mortality rates, but most cats did have substantial postoperative complications. Persistent shunting was common, although many cats with persistent shunting were clinically normal. (J Am Vet Med Assoc 2002;220: 1341–1347)

Full access
in Journal of the American Veterinary Medical Association