Daniel K. Langlois

Evaluation of Basal Serum or Plasma Cortisol Concentrations for the Diagnosis of Hypoadrenocorticism in Dogs.

Background Previous studies that included limited numbers of affected dogs have suggested basal cortisol concentrations ≤55 nmol/L (2 μg/dL) are sensitive, but nonspecific, for a diagnosis of hypoadrenocorticism. A detailed assessment of the diagnostic utility of basal cortisol concentrations is warranted. Hypothesis/Objectives To evaluate the utility of basal cortisol concentrations for the diagnosis of hypoadrenocorticism in a large number of dogs, including those with and without serum electrolyte abnormalities. Animals Five hundred and twenty‐two dogs, including 163 dogs with hypoadrenocorticism, 351 dogs with nonadrenal gland illness, and 8 dogs with equivocal results. Methods Retrospective study. Basal and post‐ACTH cortisol concentrations and sodium and potassium concentrations were collected from medical records. A receiver operating characteristic (ROC) curve was constructed for basal cortisol concentrations by standard methodologies. Sensitivity, specificity, and predictive values were determined for various cut‐points. Results The area under the ROC curve was 0.988 and was similarly excellent regardless of serum electrolyte concentrations. At the most discriminatory cut‐point of 22 nmol/L (0.8 μg/dL), sensitivity and specificity were 96.9 and 95.7%, respectively. A basal cortisol concentration of ≤55 nmol/L (2 μg/dL) resulted in a sensitivity of 99.4%. Conversely, a basal cortisol concentration of ≤5.5 nmol/L (0.19 μg/dL) resulted in a specificity of 99.1%. Conclusions and Clinical Importance Similar to findings in previous studies, basal cortisol concentrations >55 nmol/L (2 μg/dL) are useful in excluding a diagnosis of hypoadrenocorticism. Interestingly, excellent specificities and positive predictive values were observed at lower cut‐point cortisol concentrations.

Acquired Proximal Renal Tubular Dysfunction in 9 Labrador Retrievers with Copper-Associated Hepatitis (2006–2012)

BACKGROUNDnCopper-associated hepatitis (CAH) has been well described in Labrador Retrievers. However, the association of CAH with proximal renal tubular dysfunction in this breed has not been characterized.nnnOBJECTIVESnTo report clinical features, hepatic and renal histopathologic findings, tissue copper concentrations, and outcome of Labradors with CAH and proximal renal tubular disease.nnnANIMALSnNine Labrador Retrievers with renal glucosuria and biopsy-confirmed CAH.nnnMETHODSnClinical, clinicopathologic, and light microscopic findings were retrospectively reviewed. Rhodanine staining or atomic emission spectroscopy was performed on all hepatic samples and available renal tissue (4 dogs) to assess copper concentrations.nnnRESULTSnEight dogs had a history of polyuria and polydipsia, and all dogs had increased serum bilirubin concentrations. Five dogs had hyperchloremic metabolic acidosis. Three dogs with acidemia had paradoxical alkalinuria. All renal specimens had increased copper concentrations. Renal tubular vacuolization, degeneration, and regeneration were observed on light microscopy. Four dogs died within 10 days of diagnosis. One dog survived 2 months; 4 dogs survived more than 1 year. In long-term survivors, including 2 that did not undergo immediate copper chelation, resolution of renal tubular dysfunction occurred within weeks to months.nnnCONCLUSIONS AND CLINICAL IMPORTANCEnLabrador Retrievers with CAH can develop clinical and laboratory evidence of renal tubular dysfunction in association with increased renal copper concentrations. Given the rarity of renal tubular disorders, detection of renal glucosuria and increased ALT activity in a Labrador Retriever is suggestive of CAH. Although renal tubular dysfunction may indicate advanced disease, successful long-term outcome is possible with a variety of therapies.

Clinical, Morphological, and Molecular Characterization of Penicillium canis sp. nov., Isolated from a Dog with Osteomyelitis

ABSTRACT Infections caused by Penicillium species are rare in dogs, and the prognosis in these cases is poor. An unknown species of Penicillium was isolated from a bone lesion in a young dog with osteomyelitis of the right ilium. Extensive diagnostic evaluation did not reveal evidence of dissemination. Resolution of lameness and clinical stability of disease were achieved with intravenous phospholipid-complexed amphotericin B initially, followed by long-term combination therapy with terbinafine and ketoconazole. A detailed morphological and molecular characterization of the mold was undertaken. Sequence analysis of the internal transcribed spacer revealed the isolate to be closely related to Penicillium menonorum and Penicillium pimiteouiense. Additional sequence analysis of β-tubulin, calmodulin, minichromosome maintenance factor, DNA-dependent RNA polymerase, and pre-rRNA processing protein revealed the isolate to be a novel species; the name Penicillium canis sp. nov. is proposed. Morphologically, smooth, ovoid conidia, a greenish gray colony color, slow growth on all media, and a failure to form ascomata distinguish this species from closely related Penicillium species.

Pharmacokinetics and relative bioavailability of D-penicillamine in fasted and nonfasted dogs.

BACKGROUNDnD-Penicillamine is the most commonly used copper-chelating agent in the treatment of copper-associated hepatitis in dogs. Response to therapy can be variable, and there is a lack of pharmacokinetic information available for dogs. Coadministering the drug with food to alleviate vomiting has been recommended for dogs, which contradicts recommendations for drug administration to humans.nnnHYPOTHESISnCoadministration of d-penicillamine with food decreases relative bioavailability and maximum plasma drug concentrations (C(max)) in dogs.nnnANIMALSnNine purpose-bred dogs with a median body weight of 17.0 kg.nnnMETHODSnDogs received D-penicillamine (12.5 mg/kg PO) fasted and with food in a randomized, crossover design. Blood samples were collected before and 0.25, 0.5, 1, 2, 3, 4, 8, 12, and 24 hours after dosing. Total d-penicillamine concentrations were measured using liquid chromatography coupled with tandem quadrupole mass spectrometry. Pharmacokinetic parameters were calculated for each dog.nnnRESULTSnTwo fasted dogs (22%) vomited after receiving d-penicillamine. Mean C(max) ± standard deviation (SD) was 8.7 ± 3.1 μg/mL (fasted) and 1.9 ± 1.6 μg/mL (fed). Mean area under the plasma concentration curve ± SD was 16.9 ± 5.9 μg/mL·h (fasted) and 4.9 ± 3.4 μg/mL·h (fed). There were significant reductions in relative bioavailability and C(max) in fed dogs (P < .001).nnnCONCLUSIONS AND CLINICAL IMPORTANCEnCoadministration of d-penicillamine with food significantly decreases plasma drug concentrations in dogs. Decreased drug exposure could result in decreased copper chelation efficacy, prolonged therapy, additional cost, and greater disease morbidity. Administration of d-penicillamine with food cannot be categorically recommended without additional studies.

Pharmacokinetics and Relative Bioavailability of Orally Administered Innovator‐Formulated Itraconazole Capsules and Solution in Healthy Dogs

Background Itraconazole is commonly used for treatment of systemic and cutaneous mycoses in veterinary medicine. Two formulations, capsule and solution, are used interchangeably in dogs. However, marked differences in bioavailability have been reported in other species. Similar investigations have not been performed in dogs. Objective To determine and compare pharmacokinetics of itraconazole in dogs after oral administration of commercially available capsule and solution formulations intended for use in humans. Animals Eight healthy, adult, purpose‐bred dogs. Methods Dogs received approximately 10 mg/kg of innovator‐formulated itraconazole solution and capsule PO in randomized, crossover design with a 10‐day washout period. To ensure maximal absorption, solution was administered to fasted dogs, whereas capsules were co‐administered with food. Blood samples were collected at predetermined time points, and plasma drug concentrations were measured using high‐pressure liquid chromatography. Pharmacokinetic parameters were determined with compartmental analysis. Results The mean relative bioavailability of the capsule was 85% that of the solution, but drug absorption was variable, and overall drug concentrations were similar between formulations. Mean elimination half‐lives of both formulations were nearly identical at approximately 33 hours. Regardless of formulation, simulations suggest that a loading dose of 20 mg/kg, followed by 10 mg/kg once every 24 hours, will result in plasma concentrations considered to be adequate in most dogs. Conclusions and Clinical Importance Contrary to findings reported in other species, overall drug exposures after capsule and solution administration are not substantially different in dogs. Despite some pharmacokinetic differences between itraconazole capsule and solution, formulation‐specific dosages do not appear to be necessary.

Pharmacologic evaluation of ammonium tetrathiomolybdate after intravenous and oral administration to healthy dogs

OBJECTIVEnTo evaluate pharmacokinetics of ammonium tetrathiomolybdate (TTM) after IV and oral administration to dogs and effects of TTM administration on trace mineral concentrations.nnnANIMALSn8 adult Beagles and Beagle crossbreds (4 sexually intact males and 4 sexually intact females).nnnPROCEDURESnDogs received TTM (1 mg/kg) IV and orally in a randomized crossover study. Serum molybdenum and copper concentrations were measured via inductively coupled plasma mass spectrometry in samples obtained 0 to 72 hours after administration. Pharmacokinetics was determined via noncompartmental analysis.nnnRESULTSnFor IV administration, mean ± SD terminal elimination rate constant, maximum concentration, area under the curve, and half-life were 0.03 ± 0.01 hours(-1), 4.9 ± 0.6 μg/mL, 30.7 ± 5.4 μg/mL•h, and 27.7 ± 6.8 hours, respectively. For oral administration, mean ± SD terminal elimination rate constant, time to maximum concentration, maximum concentration, area under the curve, and half-life were 0.03 ± 0.01 hours(-1), 3.0 ± 3.5 hours, 0.2 ± 0.4 μg/mL, 6.5 ± 8.0 μg/mL•h, and 26.8 ± 8.0 hours, respectively. Oral bioavailability was 21 ± 22%. Serum copper concentrations increased significantly after IV and oral administration. Emesis occurred after IV (2 dogs) and oral administration (3 dogs).nnnCONCLUSIONS AND CLINICAL RELEVANCEnPharmacokinetics for TTM after a single IV and oral administration was determined for clinically normal dogs. Absorption of TTM after oral administration was variable. Increased serum copper concentrations suggested that TTM mobilized tissue copper. Further studies will be needed to evaluate the potential therapeutic use of TTM in copper-associated chronic hepatitis of dogs.

Successful Treatment of Intracardiac and Intraocular Blastomycosis in a Dog with Combination Azole Therapy

A 4 yr old spayed female Labrador retriever with clinical signs of blindness, cutaneous lesions, coughing, inappetence, and lethargy was diagnosed with disseminated blastomycosis based on cytologic (skin and lymph node aspirates) and histopathologic (skin biopsy) examinations of tissue samples. The dog deteriorated clinically during hospitalization and developed sustained ventricular tachycardia. Echocardiography revealed pericardial effusion, a nodule associated with the left ventricular papillary muscle, and a right atrial mural lesion. Therapy for myocardial performance and glaucoma was initiated. A combination of itraconazole and fluconazole successfully treated the dog. The dog regained vision in the left eye (oculus sinister [OS]) and had no residual cardiac disease detectable by either electrocardiography or echocardiography. This report is unique in documenting survival from intracardiac blastomycosis and in the use of combination azole therapy for treating disseminated disease with intraocular involvement.

Radioactive iodine uptake in hyperthyroid cats after administration of recombinant human thyroid stimulating hormone

Background Radioactive iodine therapy is considered the treatment of choice for hyperthyroidism in cats, but the availability of this modality is limited by costs and hospitalization requirements. Administration of recombinant human thyroid stimulating hormone (rh‐TSH) to humans with thyroid neoplasia or nodular goiter can increase thyroidal iodine uptake, thereby allowing the use of lower radioactive iodine doses for treatment. Veterinary studies of this subject are limited, and results are conflicting. Objective To investigate the effects of rh‐TSH administration on thyroidal iodine uptake in hyperthyroid cats. Animals Ten client‐owned hyperthyroid cats. Methods In this prospective clinical study, cats were administered saline (placebo), 50 μg rh‐TSH (low‐dose), and 100 μg rh‐TSH (high‐dose) in randomized crossover design with treatments separated by 7‐10 days. After each treatment, thyroid scintigraphy was performed by administering 300 μCi 123I and assessing radionuclide uptake 8 and 24 hours later. Serum thyroid hormone concentrations were measured at each visit. Results Thyroidal percent iodine uptakes (mean ± SD at 8 and 24 hours) in cats treated with placebo (25.2 ± 13.4%, 30.0 ± 12.8%), low‐dose (24.1 ± 12.5%, 29.4 ± 13.7%), and high‐dose rh‐TSH (24.2 ± 16.3%, 30.8 ± 15.3%) were not different (P = .76). Independent of rh‐TSH administration, percent iodine uptakes were positively correlated with serum thyroid hormone concentrations. Conclusions and Clinical Importance One‐time administration of rh‐TSH, even at high doses, would not be expected to lower radioactive iodine doses needed for treatment of hyperthyroidism in cats. Investigations of alternate strategies to increase thyroidal uptake of radioactive iodine are warranted.

Hepatic copper concentrations in 546 dogs (1982-2015)

Background Copper associated hepatitis (CAH) has been increasingly recognized in dogs, and speculation exists that hereditary defects in copper metabolism have been exacerbated by increased environmental copper exposure. However, no broad epidemiological investigations have been performed to investigate quantitative hepatic copper concentrations ([Cu]H) over time in both dogs that are (predisposed breed [PB]), and are not (non‐predisposed breed [NPB]), considered at‐risk for CAH. Objectives To investigate [Cu]H in dogs and explore temporal, demographic, and histologic associations spanning 34 years. Animals 546 archived liver specimens. Methods Retrospective study. Searches of the Michigan State University Veterinary Diagnostic Laboratory database identified dogs that had undergone hepatic histopathologic assessment. Cases with archived tissue were reviewed and classified by breed, time period, and presence or absence of hepatitis. Inductively coupled plasma mass spectrometry was used to determine [Cu]H. Results In time period 2009–2015, median [Cu]H were 101 μg/g and 313 μg/g greater than median [Cu]H in time period 1982–1988 for NPB and PB dogs, respectively (P < .001 for both comparisons). The proportion of dogs with [CU]H > 300 μg/g increased in NPB (28% to 49%) and PB dogs (48% to 71%) during these periods (P = .002 for both comparisons). Median [Cu]H in dogs with hepatitis increased 3‐fold over time in both NPB (P = .004) and PB populations (P < .001). Conclusions and Clinical Importance The frequent recognition of CAH in recent years is likely due to the observed increases in [Cu]H over time. Importantly, effects are not limited to PB dogs.

ATR-101, a selective ACAT1 inhibitor, decreases ACTH-stimulated cortisol concentrations in dogs with naturally occurring Cushing’s syndrome

BackgroundCushing’s syndrome in humans shares many similarities with its counterpart in dogs in terms of etiology (pituitary versus adrenal causes), clinical signs, and pathophysiologic sequelae. In both species, treatment of pituitary- and adrenal-dependent disease is met with limitations. ATR-101, a selective inhibitor of ACAT1 (acyl coenzyme A:cholesterol acyltransferase 1), is a novel small molecule therapeutic currently in clinical development for the treatment of adrenocortical carcinoma, congenital adrenal hyperplasia, and Cushing’s syndrome in humans. Previous studies in healthy dogs have shown that ATR-101 treatment led to rapid, dose-dependent decreases in adrenocorticotropic hormone (ACTH) stimulated cortisol levels. The purpose of this clinical study was to investigate the effects of ATR-101 in dogs with Cushing’s syndrome.MethodsATR-101 pharmacokinetics and activity were assessed in 10 dogs with naturally-occurring Cushing’s syndrome, including 7 dogs with pituitary-dependent disease and 3 dogs with adrenal-dependent disease. ATR-101 was administered at 3xa0mg/kg PO once daily for one week, followed by 30xa0mg/kg PO once daily for one (nu2009=u20094) or three (nu2009=u20096) weeks. Clinical, biochemical, adrenal hormonal, and pharmacokinetic data were obtained weekly for study duration.ResultsATR-101 exposure increased with increasing dose. ACTH-stimulated cortisol concentrations, the primary endpoint for the study, were significantly decreased with responders (9 of 10 dogs) experiencing a meanu2009±u2009standard deviation reduction in cortisol levels of 50u2009±u200917% at study completion. Decreases in pre-ACTH-stimulated cortisol concentrations were observed in some dogs although overall changes in pre-ACTH cortisol concentrations were not significant. The compound was well-tolerated and no serious drug-related adverse effects were reported.ConclusionsThis study highlights the potential utility of naturally occurring canine Cushing’s syndrome as a model for human disease and provides proof of concept for ATR-101 as a novel agent for the treatment of endocrine disorders like Cushing’s syndrome in humans.