Posaconazole Pharmacokinetics in Healthy Cats after Oral and Intravenous Administration.

BACKGROUND: Posaconazole is the most active available azole antifungal drug, but absorption and pharmacokinetics are not available to guide dosing regimens in cats. OBJECTIVE: To determine the pharmacokinetics of posaconazole in cats given an IV solution and PO suspension. ANIMALS: Six healthy, adult research cats. METHODS: After a 12-hour fast, each cat received 15 mg/kg of posaconazole PO suspension with food. Four cats also received 3 mg/kg IV posaconazole after a 7-day washout period. Plasma was collected at predetermined intervals for analysis using high-pressure liquid chromatography (HPLC). Concentration data were analyzed using a 2-compartment pharmacokinetic analysis for IV administration data and a 1-compartment analysis with first-order input for PO administration data using Phoenix® software. RESULTS: After IV dosing, volume of distribution (VSS ) was 1.9 (0.3) L/kg (mean, standard deviation), terminal half-life (T½ ) was 57.7 (28.4) hours, and clearance was 28.1 (17.3) mL/kg/h. After PO dosing, peak concentration (CMAX ) was 1.2 (0.5) µg/mL and T½ was 38.1 (15.0) hours. Bioavailability of PO suspension was 15.9% (8.6). No adverse effects were observed with either route of administration. CONCLUSION AND CLINICAL IMPORTANCE: Despite low PO absorption, these data allow for simulation of PO dosage regimens that could be explored in clinical studies. Two regimens can be considered to maintain targeted trough concentrations of 0.5-0.7 µg/mL as extrapolated from studies in humans: (1) 30 mg/kg PO loading dose followed by 15 mg/kg q48h, or (2) 15 mg/kg PO loading dose followed by 7.5 mg/kg q24h.

Serum cortisol concentrations in dogs with pituitary-dependent hyperadrenocorticism and atypical hyperadrenocorticism.

BACKGROUND: Atypical hyperadrenocorticism (AHAC) is considered when dogs have clinical signs of hypercortisolemia with normal hyperadrenocorticism screening tests. HYPOTHESIS/OBJECTIVES: To compare cortisol concentrations and adrenal gland size among dogs with pituitary-dependent hyperadrenocorticism (PDH), atypical hyperadrenocorticism (AHAC), and healthy controls. ANIMALS: Ten healthy dogs, 7 dogs with PDH, and 8 dogs with AHAC. METHOD: Dogs were prospectively enrolled between November 2011 and January 2013. Dogs were diagnosed with PDH or AHAC based on clinical signs and positive screening test results (PDH) or abnormal extended adrenal hormone panel results (AHAC). Transverse adrenal gland measurements were obtained by abdominal ultrasound. Hourly mean cortisol (9 samplings), sum of hourly cortisol measurements and adrenal gland sizes were compared among the 3 groups. RESULTS: Hourly (control, 1.4 ± 0.6 µg/dL; AHAC, 2.9 ± 1.3; PDH, 4.3 ± 1.5) (mean, SD) and sum (control, 11.3 ± 3.3; AHAC, 23.2 ± 7.7; PDH, 34.7 ± 9.9) cortisol concentrations differed significantly between the controls and AHAC (P < .01) and PDH (P < .01) groups. Hourly (P < .01) but not sum (P = .27) cortisol concentrations differed between AHAC and PDH dogs. Average transverse adrenal gland diameter of control dogs (5.3 ± 1.2 mm) was significantly less than dogs with PDH (6.4 ± 1.4; P = .02) and AHAC (7.2 ± 1.5; P < .01); adrenal gland diameter did not differ (P = .18) between dogs with AHAC and PDH. CONCLUSIONS AND CLINICAL IMPORTANCE: Serum cortisol concentrations in dogs with AHAC were increased compared to controls but less than dogs with PDH, while adrenal gland diameter was similar between dogs with AHAC and PDH. These findings suggest cortisol excess could contribute to the pathophysiology of AHAC.

Canine pancreatic-specific lipase concentrations in clinically healthy dogs and dogs with naturally occurring hyperadrenocorticism.

BACKGROUND: Specificity of canine pancreatic lipase immunoreactivity (cPLI) assays in dogs with hyperadrenocorticism (HAC) is unknown. HYPOTHESIS: Results of cPLI assays differ for clinically healthy dogs and dogs with HAC. ANIMALS: Seventeen healthy dogs and 20 dogs with HAC diagnosed by ACTH stimulation test results without evidence of clinical pancreatitis. METHODS: Dogs were enrolled between December 2009 and November 2010. Serum cPLI concentrations were determined by quantitative (Spec cPL test, SPEC) and semiquantitative (SNAP cPL test, SNAP) assays. Results were categorized as normal, equivocal, or abnormal (SPEC) or negative or positive (SNAP). Associations between group and cPLI were assessed using Fisher's exact test or the Mann-Whitney U-test. Spearman rank correlation coefficients (ρ) were determined for SNAP and SPEC results. Significance was set at P < .05. RESULTS: Spec cPL test concentrations were significantly (P < .001) higher in dogs with HAC (491.1 µg/L) than in healthy dogs (75.2 µg/L), with more abnormal SPEC results in HAC dogs (P < .001). There were more (P = .002) positive SNAP results in dogs with HAC (55%) than in healthy dogs (6%). SNAP and SPEC results were highly correlated (ρ = 0.85; P < .001). CONCLUSIONS AND CLINICAL IMPORTANCE: Dogs with HAC had higher SPEC concentrations and more positive SNAP results than clinically healthy dogs with normal ACTH stimulation test results. Specificity of SPEC and SNAP assays in HAC dogs without clinical pancreatitis were 65 and 45%, respectively. Pending further study, SNAP and SPEC results should be interpreted cautiously in dogs with HAC to avoid false diagnosis of concurrent pancreatitis.

Bioequivalence of orally administered generic, compounded, and innovator-formulated itraconazole in healthy dogs.

BACKGROUND: Itraconazole is commonly used to treat systemic fungal infections in dogs, but problems exist with absorption and cost. OBJECTIVE: To determine oral bioequivalence of generic and compounded itraconazole compared to original innovator (brand name) itraconazole in healthy dogs. ANIMALS: Nine healthy, adult research Beagle dogs. METHODS: A randomized, 3-way, 3-period, crossover design with an 8-day washout period. After a 12-hour fast, each dog received 100 mg (average: 10.5 mg/kg) of either innovator itraconazole, an approved human generic capsule, or compounded itraconazole (compounded using a commercially available compounding vehicle) with a small meal. Plasma was collected at predetermined intervals for high pressure liquid chromatography analysis. Concentration data were analyzed using noncompartmental pharmacokinetics to determine area under the curve (AUC), peak concentration (C(MAX)), and terminal half-life. Bioequivalence tests compared generic and compounded itraconazole to the reference formulation. RESULTS: Average ratios of compounded and generic formulations to the reference formulation of itraconazole for AUC were 5.52% and 104.2%, respectively, and for C(MAX) were 4.14% and 86.34%, respectively. A test of bioequivalence using 2 one-sided tests and 90% confidence intervals did not meet bioequivalence criteria for either formulation. CONCLUSION AND CLINICAL IMPORTANCE: Neither generic nor compounded itraconazole is bioequivalent to the reference formulation in dogs. However, pharmacokinetic data for generic formulation were similar enough that therapeutic concentrations could be achieved. Compounded itraconazole produced such low plasma concentrations, it is unlikely to be effective; therefore, compounded itraconazole should not be used in dogs.

Associations among albuminuria, C-reactive protein concentrations, survival predictor index scores, and survival in 78 critically ill dogs.

BACKGROUND: Microalbuminuria and C-reactive protein (CRP) are predictors of morbidity and survival in critically ill human patients. HYPOTHESIS/OBJECTIVES: To evaluate results of microalbuminuria assays (untimed single-sample urine albumin concentration [U-ALB] and the urine albumin:creatinine ratio [UACR]), serum CRP, and survival predictor index (SPI2) scores as predictors of survival in critically ill dogs. ANIMALS: Seventy-eight dogs admitted to intensive care units at University of Tennessee (UT) and Colorado State University (CSU). METHODS: Prospective observational study. Critically ill dogs were eligible for enrollment, unless euthanized because of financial constraints. Samples were collected within 3 hours of admission. Spearman's rank-correlation coefficients were determined for U-ALB, UACR, CRP, and SPI2. U-ALB, UACR, CRP, and SPI2 were assessed for associations with 7- and 30-day survival by Mann-Whitney U-tests and receiver operating characteristic (ROC) curves. P-values < .0125 were considered significant. RESULTS: UT (n = 49) and CSU (n = 29) patients did not differ significantly. Forty percent (31/78) of dogs died. SPI2 was inversely correlated with U-ALB (r(s) = -0.39, P < .001) and UACR (r(s) = -0.41, P < .001). CRP was not correlated with SPI2 (P = .019), U-ALB (P > .1), or UACR (P > .1). U-ALB and UACR had very high correlation (r(s) = 0.95, P < .001). SPI2, U-ALB, and UACR differed significantly for survivors and nonsurvivors. SPI2, U-ALB, and UACR had areas under the ROC curve (AUC) from 0.68 to 0.74 for survival prediction. CONCLUSIONS AND CLINICAL IMPORTANCE: Albuminuria and SPI2, but not CRP, are associated with survival in critically ill dogs. Suboptimal AUCs limit the value of microalbuminuria testing for clinical risk assessment. Additional studies are necessary to determine the usefulness of microalbuminuria testing in patient risk stratification for prospective research.

Complications of ileal cannulation in cats.

BACKGROUND AND PURPOSE: The anatomic position of the ileum is such that use of simple, noninvasive sampling techniques is difficult. Sampling of ileal contents by use of a cannula provides information about those contents-digestibility and fermentation patterns; however, complications with use of cannulas in horses and dogs have been reported. Therefore, cats were chosen as a laboratory model in which to study ileal cannulation. METHODS: Simple T-piece cannulas were surgically placed in the ileum of six adult cats. RESULTS: Postsurgical complications included cannula displacement and leakage, with subsequent abscessation and skin inflammation. Owing to these complications, the cannulas were removed from four of the six cats. Similar complications developed after removal of the cannulas. In the only attempt to collect a sample, obtaining a 0.5-ml sample of ileal fluid from one cannula took 3 h. Of the six cats, four died or were euthanized. CONCLUSION: Use of cannulas is not a viable technique of collecting ileal fluid samples in cats.

Pharmacological relaxation of the urethra in male cats: a study of the effects of phenoxybenzamine, diazepam, nifedipine and xylazine.

Urethral pressure profiles (UPPs) were recorded in ten adult healthy male cats before and after administration of either phenoxybenzamine, diazepam, nifedipine or xylazine. A significant decrease (p less than 0.05) in urethral pressure at the level of the prostate was observed following treatment with all drugs. Xylazine produced a significant decrease in urethral pressure 4 to 7 cm from the tip of the penis in healthy male cats. None of the drugs used decreased urethral pressure in the zones of pure striated muscle or pure smooth muscle in these cats, making current recommendations for pharmacological management of urethral spasm suspect. Further studies are necessary to evaluate clinical cases of urethral spasm and to study the effects of these drugs on the urethral pressure of cats suffering from this spasm.