Pharmacokinetics and pharmacodynamics of A77 1726 and leflunomide in domestic cats.

The pharmacokinetics and pharmacodynamics of A77 1726 and leflunomide after intravenous (i.v.) and oral (p.o.) administration were evaluated in adult cats. Three treatments were administered: a single i.v. dose of A77 1726 (4 mg/kg), a single oral dose of leflunomide (4 mg/kg), and multiple oral doses of leflunomide (2 mg/kg). Mean pharmacokinetic parameter values after a single i.v. dose of A77 1726 were distribution (A) and elimination (B) intercepts (15.2 µg/mL and 34.5 µg/mL, respectively), distribution and elimination half-lives (1.5 and 71.8 h, respectively), area under the curve (AUC(0 → ∞); 3723 µg*h/mL), mean residence time (MRT; 93 h), clearance (Cl(obs); 1.1 mL/kg/h), and volume of distribution at steady state (Vd(ss); 97 mL/kg). Mean pharmacokinetic parameter values after a single oral dose of leflunomide were absorption and elimination rate constants (0.3 1/h and 0.01 1/h, respectively), absorption and elimination half-lives (2.3 and 59.1 h, respectively), AUC(0 → ∞) (3966 µg*h/mL), and maximum observed plasma concentration (C(max); 38 µg/mL). The bioavailability after a single oral dose of leflunomide was 100%. The mean ± SD A77 1726 concentration that inhibited 50% lymphocytes (EC(50) ) was 16 ± 13.5 µg/mL. The mean ± SD maximum A77 1726 concentration (EC(max)) was 61.0 ± 23.9 µg/mL.

Oral pharmacokinetic and pharmacodynamic effects of FTY720 in cats.

The aim of the study was to determine pharmacokinetic and pharmacodynamic profiles of FTY720 in cats and identify any toxic side effects. Six adult cats were used for the experimental study. Single oral dosages were tested at 0.05, 0.3 and 1.0 mg/kg. Whole blood drug concentration, total white blood cell and differential counts were monitored. Flow cytometry evaluated the effects on lymphocyte subsets. A toxicity study consisted of cats receiving a dose of 0.15 mg/kg daily for 30 days. Daily observation, physical examination and bloodwork were evaluated to assess for toxicity. All single doses resulted in > or =80% reduction in circulating lymphocytes within 12 h after administration, with the duration of lymphopenia being dose dependent. CD4+ and CD5+ T cells were specifically depleted. Peripheral neutrophils declined by approximately 70% at all dosages tested. No other toxic side effects were observed. Results of this study suggest that FTY720 is effective at inducing a peripheral lymphopenia in cats without any toxic side effects. Currently, cats appear to be the only species in which FTY720 induces a neutropenia. This study provides the foundation for future clinical transplantation trials using FTY720 in cats. By using combination therapy of FTY720 and low dose cyclosporine, the incidence of serious side effects may be reduced while still preventing allograft rejection.

Indicators of malignancy of canine adrenocortical tumors: histopathology and proliferation index.

Tumors of the adrenal cortex account for 10-20% of the naturally occurring Cushing's syndrome diagnosed in dogs. Differentiating between adrenocortical adenoma and carcinomas is often difficult. The purposes of this study were to determine which histopathologic criteria can be used as markers for malignancy in canine adrenocortical tumors and the relevance of the proliferation marker, Ki-67, for differentiation between cortical adenomas and carcinomas. Twenty-six adrenocortical carcinomas, 23 adenomas, and 11 normal adrenal glands were examined. Morphologic criteria significantly associated with adrenocortical carcinomas included a size larger than 2 cm in diameter, peripheral fibrosis, capsular invasion, trabecular growth pattern, hemorrhage, necrosis, and single-cell necrosis, whereas hematopoiesis, fibrin thombi, and cytoplasmic vacuolation were significantly associated with adrenocortical adenomas. The mean (+/- SD) proliferation index, measured by immunohistochemistry for the Ki-67 antigen, was 9.3 +/- 6.3% in carcinomas, 0.76 +/- 0.83% in adenomas, and 0.58 +/- 0.57% in normal adrenal glands. The Ki-67 proliferation index was significantly higher in carcinomas compared with adenomas and normal adrenal glands. A threshold value of the proliferation index of 2.4% reliably separated carcinomas from adenomas. Based on these results, it appears that thorough evaluation of morphologic features combined with immunohistochemical assessment of the proliferation index is extremely useful for differentiating between adrenocortical adenomas and carcinomas in dogs.

Histopathologic findings and classification of feline renal transplants.

Seventy-seven feline transplant kidney specimens, obtained from 1 to 3,183 days (9 years) after transplantation, were reevaluated histologically and classified on the basis of the Banff '97 guidelines for human renal transplant kidneys. Overall, this classification system appeared useful in detecting rejection reactions and confirmed the finding in humans that biopsies can diagnose subclinical rejection and therefore are an important diagnostic tool for the follow up of renal transplants. However, on the basis of serum creatinine values, the severity of the acute or active and chronic lesions was not accurately reflected by this scoring system. This is thought to be due to the significant differences in histologic rejection patterns, especially in acute or active rejection, in cats when compared with humans. Tubulitis, lymphocytic glomerulitis, and vasculitis, which are the main pillars of the Banff '97 acute or active rejection scoring system, are either rare or not found in cats. The presence of significant necrotizing glomerulitis and vasculitis in feline renal transplants might imply that the rejection is complicated by acute antibody-mediated rejection. Alternatively, cyclosporine toxicity also should be considered because some of these kidneys show other signs of cyclosporine toxicity. Finally, the significance of subcapsular and interlobular phlebitis, rarely described in human rejection reactions but a distinct entity in cats, is unknown. From this study, it is clear that there are significant differences in the histology of acute or active rejection between humans and cats and that a better understanding of the histologic appearance of renal allografts will be especially beneficial for treatment and prognostic purposes.

Disposition of cyclosporine after intravenous and multi-dose oral administration in cats.

The aim of this study was to evaluate the disposition of cyclosporine after intravenous (i.v.) and oral administration and to evaluate single sampling times for therapeutic monitoring of cyclosporine drug concentrations in cats. Six adult male cats (clinically intact) were used. Two treatments consisting of a single i.v. cyclosporine (1 mg/kg) and multiple oral cyclosporine (3 mg/kg b.i.d p.o. for 2 weeks) doses. Whole blood cyclosporine concentrations were measured at fixed times by high performance liquid chromatography and pharmacokinetic values were calculated. Mean values for the i.v. data included AUC (7413 ng/mL.h), t1/2 distribution and elimination (0.705 and 9.7 h, respectively), Cmax (1513 ng/mL), and Vd(ss) (1.71 L/kg). Mean values for the oral data included AUC (6243 ng/mL.h), t1/2 of absorption and elimination (0.227 and 8.19 h, respectively), and Cmax (480.0 ng/mL). Bioavailability of orally administered cyclosporine was 29 and 25% on days 7 and 14 respectively. Whole blood comment cyclosporine concentration 2 h after administration (C2) better correlated with AUC on days 7 and 14 than trough plasma concentration (C12). The rate of oral cyclosporine absorption was less than expected and there was substantial individual variation. Therapeutic drug monitoring strategies for cyclosporine in cats should be re-evaluated.

Diagnostic predictors of complications and survival after renal transplantation in cats.

OBJECTIVE: To identify preoperative diagnostic results that predict postoperative complications and survival in feline renal-transplant recipients. STUDY DESIGN: Retrospective clinical study. ANIMALS: Sixty-one feline renal allograft recipients. METHODS: Medical records for 61 consecutive cats that underwent renal allograft transplantation between January 1, 1996, and December 1, 1999, were reviewed. Age, diagnosis, body weight, body condition score, preoperative medical treatment, systolic blood pressure, packed cell volume, biochemical parameters at admission and at the time of surgery, postoperative complications, and postoperative survival were recorded. Associations of preoperative data with the occurrence of postoperative complications were determined using logistic regression. Postoperative survival was graphed using a Kaplan-Meier cumulative-survival plot. Associations of covariates with postoperative survival were analyzed using Cox proportional hazards analysis. RESULTS: Two parameters were significantly associated with occurrence of postoperative central nervous system (CNS) disorders: blood urea nitrogen concentration (odds ratio = 1.083; 95% CI = 1.018 to 1.148) and serum creatinine concentration (odds ratio = 1.8; 95% CI = 1.413 to 2.187) at the time of surgery. Postoperative survival 6 months after transplantation was 59%, though 3-year survival remained at 42%. Of all covariates investigated, only recipient age (relative hazard = 1.183; 95% CI = 1.039 to 1.334) was significantly associated with survival. CONCLUSION AND CLINICAL RELEVANCE: Standard measures of preoperative renal dysfunction do not predict postoperative survival in cats after renal transplantation, although an increase in the degree of preoperative azotemia is associated with an increased risk of CNS disorders after surgery. Increased recipient age is associated with decreased survival after renal transplantation.

Fluvastatin in combination with rad significantly reduces graft vascular disease in rat cardiac allografts.

BACKGROUND: RAD is a potent immunosuppressive agent that has been shown to be effective in preventing acute and chronic allograft rejection in animal models. The HMGCoA reductase inhibitors have been found to reduce the incidence of graft vascular disease (GVD) in heart transplant patients and in animal models. This study was designed to investigate the effects of fluvastatin or pravastatin in a rodent model of GVD produced using low doses of RAD to prevent acute rejection. METHODS: Hearts from Fisher 344 rats were heterotopically transplanted to Lewis rat recipients. RAD was administered orally at 0.5 mg/kg per day for days 0 to 14 and then 0.25 mg/kg per day for an additional 85 days to prevent acute rejection but allow for the development of GVD. Pravastatin (20 mg/kg per day) or fluvastatin (2 or 6 mg/kg per day) was added to the RAD treatment. At the end of a 100-day treatment period, the hearts were harvested for morphometric and histopathologic examinations. RESULTS: Rats treated with fluvastatin, at either dose, had a significant (P< or =0.0239) decrease in coronary arterial intimal thickening (GVD) of approximately 43%. Rats treated with pravastatin had a 22% reduction in GVD that did not reach statistical significance. Treatment with fluvastatin, but not pravastatin, decreased the degree of endomyocardial mononuclear cell infiltration seen with RAD administered alone. CONCLUSIONS: Fluvastatin significantly decreased GVD in a rat model produced using low-dose RAD immunosuppression. To a lesser extent, pravastatin also decreased GVD in this model. These data lend further support for the study of fluvastatin, pravastatin, and other HMG-CoA reductase inhibitors for the prevention of GVD in cardiac transplant patients.

Nontraumatic rupture of an adrenal gland tumor causing intra-abdominal or retroperitoneal hemorrhage in four dogs.

Diagnosis and surgical management of intra-abdominal or retroperitoneal hemorrhage in 4 dogs with rupture of an adrenal gland tumor were determined. All 4 dogs were lethargic and weak with pale mucous membranes on initial examination. Three dogs did not have any history of clinical signs of hyperadrenocorticism or pheochromocytoma prior to examination. In 3 of the dogs, a mass in the area of the adrenal gland was identified with ultrasonography prior to surgery. All dogs developed ventricular premature contractions before or during anesthesia. Three dogs survived adrenalectomy; 1 dog was euthanatized during surgery because of an inability to achieve adequate hemostasis. The remaining 3 dogs all survived more than 5 months after surgery; 1 was euthanatized 9 months after surgery because of rupture of a hepatic mass. On the basis of these results, we suggest that hemodynamic stabilization followed by adrenalectomy is the treatment of choice for dogs with nontraumatic rupture of an adrenal gland tumor and resulting life-threatening hemorrhage.

Evaluation of interoperator variance in shunt fraction calculation after transcolonic scintigraphy for diagnosis of portosystemic shunts in dogs and cats.

OBJECTIVE: To determine interoperator variance in shunt fraction calculation. DESIGN: Case series. SAMPLE POPULATION: 101 transrectal portoscintigraphic studies. PROCEDURE: Results of dynamic portoscintigraphic studies were reviewed by 4 radiologists without knowledge of signalment, history, or medical profile. Results were judged to be negative or positive on the basis of the dynamic scan. Composite images were formulated, and hand-drawn regions of interest were determined for the heart and liver. Time-activity curves were generated, time-zero points were selected, curves were integrated during a 10-second interval, and shunt fractions were calculated. RESULTS: Radiologists were in agreement regarding positive versus negative results for 99 of 101 studies. Interoperator variance in shunt fraction calculation ranged from 0.4 to 59.6%. For 51 studies with positive results, variance ranged from 2.5 to 59.6% (mean +/- SD, 22.8 +/- 14.5%); differences among reviewers were significant. For 48 studies with negative results, variance in shunt fraction ranged from 0.4 to 25.9% (mean, 5.3 +/- 5.8%); significant differences among reviewers were not detected. Shunt fraction calculations were not exactly reproducible among radiologists in 94 and 100% of studies with negative or positive results, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that shunt fraction values are not reproducible among operators. Range in variability was greater in studies with positive results. This factor may be of particular clinical importance in reassessment of patients after incomplete shunt ligation.

Evaluation of a portocaval venograft and ameroid ring for the occlusion of intrahepatic portocaval shunts in dogs.

OBJECTIVE: To evaluate the use of a portocaval venograft and ameroid constrictor in the surgical management of intrahepatic portosystemic shunts (PSS). STUDY DESIGN: Prospective, clinical study. ANIMAL POPULATION: Ten client-owned dogs with intrahepatic PSS. METHODS: Portal pressure was measured after temporary suture occlusion of the intrahepatic PSS. In dogs with an increase in portal pressure greater than 8 mm Hg, a single extrahepatic portocaval shunt was created using a jugular vein. An ameroid ring was placed around the venograft and the intrahepatic PSS was attenuated. Transcolonic pertechnetate scintigraphy was performed before surgery, 5 days after surgery, and 8 to 10 weeks after surgery. Dogs with continued portosystemic shunting were evaluated further by laparotomy or portography. Clinical outcome and complications were recorded. RESULTS: Mean (+/- SD) portal pressure increased from 6 +/- 3 to 19 +/- 6 mm Hg with PSS occlusion; in all 10 dogs, the increase in portal pressure was greater than 8 mm Hg. There were no intraoperative complications, and, after creation of the portocaval shunt, the intrahepatic PSS could be completely ligated in 8 of 10 dogs. The final portal pressure was 9 +/- 4 mm Hg. Postoperative complications included coagulopathy and death (1 dog), ascites (3 dogs), and incisional discharge (3 dogs). Five of 8 dogs had continued portosystemic shunting at 8 to 10 weeks after surgery. Multiple extrahepatic PSS were demonstrated in 4 of these dogs. Clinical outcome was excellent in all 9 surviving dogs. CONCLUSIONS AND CLINICAL SIGNIFICANCE: The surgical technique resulted in a high incidence of multiple extrahepatic PSS. Short-term clinical results were promising, but long-term outcome must be evaluated further.

Comparison of the in vitro antiproliferative effects of five immunosuppressive drugs on lymphocytes in whole blood from cats.

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 nM for cyclosporine, 9 nM for 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 nM for 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.

Renal transplantation in cats.

Feline renal transplantation can offer long-term survival with a normal quality of life for cats with renal failure. However, it is important to remember that renal transplantation is a treatment option and not a cure. Renal transplantation is never performed on an emergency basis or prophylactically. Feline renal transplantation requires special microvascular instruments and an operating microscope. Careful patient selection and perioperative monitoring have improved the success rate. The new microemulsified form of cyclosporine is recommended for immunosuppression. As survival times have steadily improved, long-term complications, such as diabetes and neoplasia, are now being recognized.

Management of hypertension controls postoperative neurologic disorders after renal transplantation in cats.

OBJECTIVES: To determine the prevalence and describe the management of hypertension and central nervous system (CNS) complications after renal transplantation in cats. We also compared the prevalence of CNS complications between cats monitored and treated for postoperative hypertension and a previously described, historical control group of cats not monitored or treated for postoperative hypertension. STUDY DESIGN: Retrospective clinical study. ANIMALS OR SAMPLE POPULATION: A total of 34 client-owned cats that received renal allografts for the treatment of end-stage renal failure. METHODS: Medical records were reviewed. Data obtained included preoperative and postoperative systolic blood pressures, antihypertensive therapy, response to treatment, neurologic signs, and clinical outcome. The results were compared with a historical control group of feline renal allograft recipients that were neither monitored nor treated for postoperative hypertension. RESULTS: Severe postoperative hypertension occurred in 21 of 34 of cats. Hypertension was treated in all 21 cats with subcutaneously administered hydralazine which reduced systolic blood pressure to less than 170 mm Hg in 15 minutes in 20 of 21 cats; hydralazine produced hypotension in one cat and failed to control hypertension in 1 cat. After transplantation, seizures were observed in one cat and other neurologic complications (stupor, ataxia, and central blindness) were observed in three cats. The prevalence of seizures and neurologic complication-related deaths after transplantation was significantly reduced with treatment of postoperative hypertension. CONCLUSIONS AND CLINICAL RELEVANCE: Hypertension is a major contributing factor to postoperative seizure activity after renal transplantation in cats; treatment of hypertension reduces the frequency of neurologic complications.

Duodenal perforation in a cat following the administration of nonsteroidal anti-inflammatory medication.

A one-year-old, female domestic shorthair was presented for septic peritonitis 10 days following a routine ovariohysterectomy and subsequent oral administration of carprofen. Exploratory laparotomy revealed a perforated duodenum which was treated with a gastroduodenostomy (Billroth I) and open abdomen management. Etiology of the duodenal perforation was most likely due to the administration of carprofen, a nonsteroidal anti-inflammatory drug approved for oral use in dogs only.

Diagnosis and surgical management of obstructive ureteral calculi in cats: 11 cases (1993-1996).

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.