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

BACKGROUND: Cushing'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. METHODS: ATR-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 3 mg/kg PO once daily for one week, followed by 30 mg/kg PO once daily for one (n = 4) or three (n = 6) weeks. Clinical, biochemical, adrenal hormonal, and pharmacokinetic data were obtained weekly for study duration. RESULTS: ATR-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 mean ± standard deviation reduction in cortisol levels of 50 ± 17% 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. CONCLUSIONS: This 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.

Serum concentrations of gastrin after famotidine and omeprazole administration to dogs.

BACKGROUND: The duration of antacid-induced hypergastrinemia after cessation of administration of omeprazole and famotidine apparently has not been determined in dogs. HYPOTHESIS: That serum gastrin will return to basal concentrations by 7 days after cessation of famotidine or omeprazole administration. ANIMALS: Nine healthy, adult, male, research colony dogs. METHODS: Randomized, cross-over design. Serum gastrin was determined daily for 7 days to establish baseline concentrations. Famotidine (1.0 mg/kg q24h) or omeprazole (1.0 mg/kg q24h) was administered PO for 7 days followed by a 14-day washout. Serum concentrations of gastrin were determined daily during 7 days of administration and daily for 7 days after cessation of administration. Each drug was evaluated in 8 of the 9 dogs. RESULTS: Omeprazole caused a significant increase in serum gastrin concentration (37.2 ± 7.3 to 71.3 ± 19.0 ng/L; P = .006). Famotidine induced a transient increase in serum gastrin (37.2 ± 7.3 to 65.5 ± 38.5 ng/L; P = .02) that peaked at administration day 3 and declined thereafter. By day 7 after cessation of both drugs, there was no difference in serum gastrin concentrations compared to those before administration (famotidine P = .99; omeprazole P = .99). During or after administration, gastrin concentrations above 3 times the upper reference range were rare (12 of 224 samples). CONCLUSIONS AND CLINICAL IMPORTANCE: A 7-day withdrawal from short-term administration of famotidine or omeprazole is sufficient for serum gastrin to return to baseline concentrations. Withholding famotidine or omeprazole for longer before investigating pathologic causes of hypergastrinemia is unnecessary.

Myocardial function in small dogs with chronic mitral regurgitation and severe congestive heart failure.

Systolic myocardial function was assessed in 16 dogs with severe congestive heart failure due to chronic mitral valve fibrosis. End-systolic diameters were measured on echocardiograms and end-systolic volume indices were calculated. Thirteen of the 16 dogs (81%) had normal or only mildly abnormal myocardial function. These data suggested that myocardial failure is not a prominent factor contributing to signs of heart failure in dogs with mitral regurgitation. Because of these data, the routine use of digitalis glycosides to increase cardiac contractility is seriously questioned in dogs with heart failure secondary to chronic mitral regurgitation.