Results of clinical examinations, laboratory tests, and ultrasonography in dogs with pituitary-dependent hyperadrenocorticism treated with trilostane

OBJECTIVE: To determine the efficacy of trilostane, a 3beta-hydroxysteroid dehydrogenase inhibitor, in dogs with pituitary-dependent hyperadrenocorticism (PDH). ANIMALS: 11 dogs with PDH. PROCEDURE: The initial dose of trilostane was 30 mg, PO, q 24 h for dogs that weighed < 5 kg and 60 mg, PO, q 24 h for dogs that weighed > or = 5 kg. A CBC count, serum biochemical analyses, urinalysis, ACTH stimulation test, and ultrasonographic evaluation of the adrenal glands were performed in each dog 1, 3 to 4, 6 to 7, 12 to 16, and 24 to 28 weeks after initiation of treatment. RESULTS: All dogs responded well to treatment. All had reductions in polyuria-polydipsia and panting and an increase in activity. Polyphagia decreased in 9 of 10 dogs, and 9 of 11 dogs had improvement of coat quality and skin condition. Concentration of cortisol after ACTH stimulation significantly decreased by 1 week after initiation of treatment. After treatment for 6 months, clinical signs resolved in 9 dogs. In the other 2 dogs, marked clinical improvement was reported for 1 dog, and moderate improvement was reported in the other dog. Ultrasonographically, there was a considerable change in the parenchyma and an increase in size of the adrenal glands. Adverse effects consisted of 1 dog with transient lethargy and 1 dog with anorexia. CONCLUSIONS AND CLINICAL RELEVANCE: Trilostane is an efficacious and safe medication for treatment of dogs with PDH. Additional studies in a larger group of dogs and characterization of progressive changes in adrenal glands are needed.     

The use of trilostane for the treatment of alopecia X in Alaskan malamutes

Three Alaskan malamutes with hair loss and slightly elevated blood concentrations of 17-hydroxyprogesterone after stimulation with adrenocorticotropic hormone (ACTH) were treated with trilostane. Trilostane, an inhibitor of 3 beta-hydroxysteroid dehydrogenase, was given twice daily at a dose of 3.0 to 3.6 mg/kg per day orally for 4 to 6 months. Routine ACTH stimulation tests were performed over 8 months to evaluate the degree of adrenal function suppression. Treatment with trilostane led to complete hair regrowth in all three dogs within 6 months. No adverse effects associated with trilostane were recognized.     

Histological evaluation of the adrenal glands of seven dogs with hyperadrenocorticism treated with trilostane

The lesions in the adrenal glands of seven dogs with hyperadrenocorticism that had been treated with trilostane were studied histologically. The glands of the six dogs with pituitary-dependent hyperadrenocorticism had moderate to severe cortical hyperplasia that was either diffuse or nodular. The lesions were more pronounced in the zona fasciculata than in the zona reticularis, and the zona glomerulosa was normal. In the dog with a functional adrenal tumour the non-tumour bearing adrenal gland showed mild nodular hyperplasia. Five of the seven dogs had variable degrees of adrenal necrosis, which was severe in two of them. The terminal deoxynucleotidyl transferase-mediated DUTP nick-end labelling (TUNEL) reaction specified areas of cell death as apoptosis in three of the dogs, and was positive in one of the dogs without visible areas of cell death. There were variable degrees of cortical haemorrhage in three of the dogs. In some of the dogs the lesions were severe enough to lead to hypoadrenocorticism.     

Trilostane-induced inhibition of cortisol secretion results in reduced negative feedback at the hypothalamic–pituitary axis

Cushing's disease caused by pituitary corticotroph adenoma in dogs is usually treated by medical treatment, and the efficacy of this treatment has been reported. However, controversy remains as to whether reduced negative feedback through the inhibition of cortisol secretion, similar to Nelson's syndrome, may appear as an adverse effect. The purpose of this study was to investigate the effect of reduced negative feedback through the inhibition of cortisol secretion by daily trilostane administration on the pituitary–adrenal axis in clinically normal dogs. Dogs were administered 5 mg/kg trilostane twice a day every day for 8 weeks (n = 8) or 16 weeks (n = 3). After the initiation of trilostane administration, plasma adrenocorticotropic hormone (ACTH) concentrations were increased remarkably. As assessed by magnetic resonance imaging (MRI) during administration, the pituitary became enlarged. After trilostane administration, the cytoplasmic areas of the pituitary corticotrophs were increased and the ratio of pituitary corticotrophs to all cells in the anterior lobe was greater in the trilostane-treated dogs than that in untreated animals. In addition, histological examinations revealed bilateral adrenal cortical hyperplasia. Using real-time PCR quantification, the expression of proopiomelanocortin (POMC) mRNA in the pituitary and ACTH receptor (ACTH-R) mRNA in the adrenal gland was greater in the dogs treated with trilostane than in untreated dogs. These results indicate that reduced negative feedback induced hyperfunction of the pituitary corticotrophs and pituitary enlargement in healthy dogs. These changes suggest that the inhibition of cortisol secretion by trilostane may increase the risk for accelerating the growth of corticotroph adenomas in dogs with Cushing's disease.     

The influence of trilostane on steroid hormone metabolism in canine adrenal glands and corpora lutea—an in vitro study

Trilostane is widely used to treat hyperadrenocorticism in dogs. Trilostane competitively inhibits the enzyme 3-beta hydroxysteroid dehydrogenase (3β-HSD), which converts pregnenolone (P5) to progesterone (P4) and dehydroepiandrosterone (DHEA) to androstendione (A4). Although trilostane is frequently used in dogs, the molecular mechanism underlying its effect on canine steroid hormone biosynthesis is still an enigma. Multiple enzymes of 3β–HSD have been found in humans, rats and mice and their presence might explain the contradictory results of studies on the effectiveness of trilostane. We therefore investigated the influence of trilostane on steroid hormone metabolism in dogs by means of an in vitro model. Canine adrenal glands from freshly euthanized dogs and corpora lutea (CL) were incubated with increasing doses of trilostane. Tritiated P5 or DHEA were used as substrates. The resulting radioactive metabolites were extracted, separated by thin layer chromatography and visualized by autoradiography. A wide variety of radioactive metabolites were formed in the adrenal glands and in the CL, indicating high metabolic activity in both tissues. In the adrenal cortex, trilostane influences the P5 metabolism in a dose- and time-dependent manner, while DHEA metabolism and metabolism of both hormones in the CL were unaffected. The results indicate for the first time that there might be more than one enzyme of 3β-HSD present in dogs and that trilostane selectively inhibits P5 conversion to P4 only in the adrenal gland.     

Persistent isolated hypocortisolism following brief treatment with trilostane

A 12‐year‐old male neutered Miniature Poodle with confirmed pituitary‐dependent hyperadrenocorticism was treated with trilostane. After three doses, it developed clinical and laboratory changes suggestive of isolated hypocortisolism (‘atypical hypoadrenocorticism’), which persisted and progressed for more than 3 months despite immediate withdrawal of the trilostane. The clinical signs of hyperadrenocorticism resolved without further trilostane. After 3 months, prednisolone treatment was started and the clinical signs of hypocortisolism resolved. Prednisolone therapy was required for more than 1 year. Ultrasonography initially demonstrated large hypoechoic adrenal cortices, typical of dogs with hyperadrenocorticism, which then became small and heteroechoic, consistent with the development of adrenal necrosis. Persistent isolated hypocortisolism has not been reported previously as a complication of trilostane therapy. The case is also remarkable for the very short duration of trilostane therapy that elicited this complication. Clinicians should be aware that trilostane therapy may result in adrenal necrosis, even in the very earliest stages of therapy, but prompt action can prevent a life‐threatening situation.     

CHANGES IN ULTRASONOGRAPHIC APPEARANCE OF ADRENAL GLANDS IN DOGS WITH PITUITARY-DEPENDENT HYPERADRENOCORTICISM TREATED WITH TRILOSTANE

Trilostane, a 3beta-hydroxysteroid dehydrogenase inhibitor, has been used successfully over the last few years for the treatment of canine pituitary-dependent hyperadrenocorticism. In a prospective study of 19 dogs with pituitary-dependent hyperadrenocorticism, the adrenal glands were measured before and at least 6 months after initiation of trilostane therapy. Right adrenal gland length and caudal pole thickness and left adrenal gland caudal pole thickness increased significantly (p < or = 0.05); there was no significant change in left adrenal gland length. Enlargement of adrenal glands during trilostane therapy may occur as a result of suppression of the negative feedback mechanism affecting cortisol production.     

Effect of trilostane on serum concentrations of aldosterone, cortisol, and potassium in dogs with pituitary-dependent hyperadrenocorticism

OBJECTIVE: To evaluate the effect of trilostane on serum concentrations of aldosterone, cortisol, and potassium in dogs with pituitary-dependent hyperadrenocorticism (PDH), compare the degree of reduction of aldosterone with that of cortisol, and compare aldosterone concentrations of healthy dogs with those of dogs with PDH. ANIMALS: 17 dogs with PDH and 12 healthy dogs. PROCEDURE: For dogs with PDH, the initial dose of trilostane was selected in accordance with body weight. A CBC count, serum biochemical analyses, and ACTH stimulation tests were performed in each dog. Dogs were evaluated 1, 3 to 4, 6 to 8, and 10 to 12 weeks after initiation of treatment. Healthy dogs were evaluated only once. RESULTS: Serum aldosterone concentrations before ACTH stimulation did not change significantly after initiation of treatment with trilostane. At each evaluation after initiation of treatment, serum aldosterone concentrations after ACTH stimulation were significantly lower than corresponding concentrations before initiation of treatment. The overall effect of trilostane on serum aldosterone concentration was less pronounced than the effect on serum cortisol concentration. Median potassium concentrations increased slightly after initiation of treatment with trilostane. Dogs with PDH had significantly higher serum aldo sterone concentrations before and after ACTH stimulation than healthy dogs. CONCLUSIONS AND CLINICAL RELEVANCE: Treatment with trilostane resulted in a reduction in serum cortisol and aldosterone concentrations in dogs with PDH, although the decrease for serum aldosterone concentration was smaller than that for serum cortisol concentration. There was no correlation between serum concentrations of aldosterone and potassium during treatment.     

Cortisol, aldosterone, cortisol precursor, androgen and endogenous ACTH concentrations in dogs with pituitary-dependant hyperadrenocorticism treated with trilostane

Trilostane is thought to be a competitive inhibitor of the 3beta-hydroxysteroid dehydrogenase (3beta-HSD), an essential enzyme system for the synthesis of cortisol, aldosterone and androstenedione. Due to its reliable clinical efficacy, trilostane is increasingly used to treat dogs with pituitary-dependant hyperadrenocorticism (PDH). The objective of our study was to investigate the effect of trilostane on precursor concentrations located before (17alpha-OH-pregnenolone, dehydroepiandrostenedione) and after (17alpha-OH-progesterone, androstenedione, 11-deoxycortisol, 21-deoxycortisol) the proposed enzyme inhibition, on end products of steroid biosynthesis (cortisol and aldosterone) and on endogenous adrenocorticotrophic hormone (ACTH) concentrations in dogs with PDH. Hormones of the steroid biosynthesis pathway were evaluated in 15 dogs before and 1h after injection of synthetic ACTH prior to (t(0)), in weeks 1-2 (t(1)) and in weeks 3-7 (t(2)) of trilostane treatment. Endogenous ACTH concentrations were measured at the same time points before performing the ACTH stimulation test. During trilostane treatment baseline and post-stimulation cortisol concentrations decreased significantly. Baseline serum aldosterone levels showed a significant increase; post-stimulation values decreased. Baseline and post-stimulation 17alpha-OH-pregnenolone and dehydroepiandrostenedione concentrations increased significantly. 17alpha-OH-progesterone and androstenedione levels did not change. Post-stimulation 21-deoxycortisol concentrations decreased significantly, baseline 11-deoxycortisol concentrations increased significantly. Endogenous ACTH levels showed a significant increase. The significant increase in 17alpha-OH-pregnenolone and dehydroepiandrostenedione concentrations confirms an inhibitory effect of trilostane on the 3beta-HSD. Since 17alpha-OH-progesterone concentrations did not change, but cortisol concentrations markedly decreased, trilostane seems to influence additional enzymes of the hormone cascade, like the 11beta-hydroxylase and possibly the 11beta-hydroxysteroid dehydrogenase.     

Ultrasonographic examination of the adrenal gland and evaluation of the hypophyseal-adrenal axis in 20 cats

The adrenal glands of 20 healthy, non-sedated cats were examined ultrasonographically; visualisation and assessment was possible in all cases. In comparison with the surrounding tissue, the adrenal glands were hypoechoic and two distinct zones could be differentiated in six of the cats. The length and width of the adrenal glands varied from 0.45 to 1.37 cm and 0.29 to 0.53 cm, respectively, and both dimensions could be reliably reproduced. The adrenal glands did not differ between male and female cats, and, in comparison to dogs, those of cats are more easily visualised ultrasonographically. The basal cortisol value ranged from 2.0 to 79 micrograms/litre. Values 30 and 60 minutes after administration of ACTH (0.125 mg/cat intramuscularly) varied from 36 to 126 micrograms/litre. The basal value of aldosterone ranged from 4 to 618 pg/ml. Values 30 and 60 minutes after administration of ACTH varied from 100 to 832 pg/ml. In all cats, suppression of the cortisol value below the level of detection (< 2.0 micrograms/litre) occurred four and eight hours after the administration of dexamethasone (0.1 mg/kg intravenously).     

Pituitary response to thyrotropin, corticotropin, and gonadotropin-releasing hormones in lactating cows treated with sometribove for a fourth consecutive lactation

The effect of chronic treatment with recombinant methionyl bovine somatotropin (USAN, sometribove) on anterior pituitary secretions and its target organs was investigated in six control and six sometribove-treated British Friesian cows. Cows averaged 112 and 119 d postpartum in their fourth lactation of treatment and, except for one control, had active corpora lutea. During each lactation, treated cows received sometribove injections (500 mg) every 2 wk (injection cycle) starting 60 ± 3 d postpartum. On Day 9 of one injection cycle, blood was sampled for 390 min, starting 30 min before an intravenous injection of thyrotropin (TRH, 0.33 μg/kg), corticotropin (100 μg), and gonadotropin (GnRH, 200 μg)-releasing hormones. Baseline somatotropin (bST) and adrenocorticotropin (ACTH) were higher in sometribove-treated cows vs. controls (3.27 vs. 1.03 ng/ml and 35.24 vs. 19.28 pg/ml, respectively). Baseline total thyroxine, free thyroxine, triiodothyronine, prolactin, follicle stimulating and luteinizing hormones, estradiol, and progesterone (P4) were similar across treatments. Circulating cortisol levels did not differ between control and sometribove cows, indicating a reduced adrenal ACTH responsiveness in the latter. Releasing factors induced similar changes across treatments in hormones studied with the following exceptions: a bST spike was seen in control cows only, cortisol response to ACTH was reduced in treated cows, and a significantly higher P4 concentration was detected in the plasma of sometribove-treated cows, suggesting increased ovarian responsiveness to GnRH-stimulated P4 output. The study demonstrated reduced bST response to TRH, consistent with physiologic feedback mechanisms, whereas the release profiles of the other pituitary hormones were unaffected. Target tissue responses affected by chronic sometribove treatment appear to be adrenal cortisol and ovarian P4 output.     

Evaluation of twice-daily, low-dose trilostane treatment administered orally in dogs with naturally occurring hyperadrenocorticism

OBJECTIVE: To evaluate the effects of twice-daily oral administration of a low-dose of trilostane treatment and assess the duration of effects after once-daily trilostane administration in dogs with naturally occurring hyperadrenocorticism (NOH). DESIGN: Prospective study. ANIMALS: 28 dogs with NOH. PROCEDURES: 22 dogs received 0.5 to 2.5 mg of trilostane/kg (0.23 to 1.14 mg/lb) orally every 12 hours initially. At intervals, dogs were reevaluated; owner assessment of treatment response was recorded. To assess drug effect duration, 16 of the 22 dogs and 6 additional dogs underwent 2 ACTH stimulation tests 3 to 4 hours and 8 to 9 hours after once-daily trilostane administration. RESULTS: After 1 to 2 weeks, mean trilostane dosage was 1.4 mg/kg (0.64 mg/lb) every 12 hours (n = 22 dogs; good response [resolution of signs], 8; poor response, 14). Four to 8 weeks later, mean dosage was 1.8 mg/kg (0.82 mg/lb) every 12 or 8 hours (n = 21 and 1 dogs, respectively; good response, 15; poor response, 5; 2 dogs were ill). Eight to 16 weeks after the second reevaluation, remaining dogs had good responses (mean dosages, 1.9 mg/kg [0.86 mg/lb], q 12 h [n = 13 dogs] and 1.3 mg/kg [0.59 mg/lb], q 8 h [3]). At 3 to 4 hours and 8 to 9 hours after once-daily dosing, mean post-ACTH stimulation serum cortisol concentrations were 2.60 and 8.09 Pg/dL, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: In dogs with NOH, administration of trilostane at low doses every 12 hours was effective, although 2 dogs became ill during treatment. Drug effects diminished within 8 to 9 hours. Because of potential adverse effects, lower doses should be evaluated.     

Study of the effects of once daily doses of trilostane on cortisol concentrations and responsiveness to adrenocorticotrophic hormone in hyperadrenocorticoid dogs

The effects of trilostane, a 3beta-hydroxysteroid dehydrogenase inhibitor on basal cortisol concentrations and the results of ACTH stimulation tests in dogs with pituitary-dependent hyperadrenocorticism were investigated. In eight of nine dogs trilostane suppressed the concentration of cortisol below the lower limit of the reference range (<50 nmol/l) for a mean (sd) of 3.5 (2.3) hours during the day, but for no longer than 13 hours. In another 10 dogs, there was a clear difference between the post ACTH cortisol concentrations observed four and 24 hours after the administration of trilostane. Furthermore, in the six dogs whose clinical signs were poorly controlled the post-ACTH concentrations observed four and 24 hours after the administration of trilostane were always higher than the equivalent cortisol concentrations in the four dogs whose clinical signs were controlled. A short duration of drug action may be responsible for the failure of some dogs to respond adequately to once daily trilostane administration.     

Administration of ACTH to restrained, pregnant sows alters their pigs' hypothalamic-pituitary-adrenal (HPA) axis

This study was designed to examine the physiology and behavior of pigs whose dams were snared and then injected with ACTH during gestation. Administration of ACTH to dams during pregnancy has been shown to replicate the effects of prenatal stress in other species. Control sows (n = 8) were given no treatment, whereas the treatment sows (ACTH, n = 8) were immobilized by snaring the snout and then administered an i.v. injection of ACTH (1 IU/kg BW) weekly from 6 to 12 wk of gestation. A pig was killed from each sow at 1, 30, and 60 d of age. The hypothalamus, pituitary gland, adrenal glands, and liver were immediately obtained to determine the amounts of corticotropin-releasing hormone (CRH), beta-endorphin, and mRNA for pro-opiomelanocorticotropin (POMC), the ACTH receptor (ACTH-R), and insulin-like growth factor I (IGF-I). Pituitary corticotrope and somatotrope cell numbers and adrenal cortex-to-medulla area ratios (CORT:MED) were also determined. Pigs' behaviors were recorded at 6 and 8 wk of age. At 75 d of age, a blood sample was taken and a biopsy puncture was created on one pig from each litter, then pigs were stressed by mixing. Blood was sampled every other day for 10 d to determine plasma cortisol concentrations and differential leukocyte counts. Biopsy damage was evaluated for healing. At 1 d of age, control pigs tended to weigh more (P = .09), have a lower expression of ACTH-R mRNA (P = .01) and IGF-I mRNA (P = .01), and a lower CORT:MED (P = .04) than ACTH pigs. At 30 d of age, control pigs had a greater concentration of beta-endorphin (P = .01) and tended to have a lower concentration of CRH (P = .09) and IGF-I mRNA (P = .10) than ACTH pigs. At 60 d of age, control pigs tended to have lighter pituitary glands (P = .08), a lower expression of POMC mRNA (P = .02), and a CORT:MED (P = .003) than ACTH pigs. At 8 wk of age, control pigs performed a higher frequency of belly nosing (P = .07) and oral vice behaviors (P = .01) than ACTH pigs. In response to mixing stress, control pigs had lesser concentrations of plasma cortisol (P = .03) and healed faster (P = .006) than ACTH pigs. Thus, exogenous ACTH and restraint during gestation alters the HPA axis of the sow's offspring, and during stressful situations later in life health, and therefore welfare, may be compromised.     

Urinary Corticoid : Creatinine Ratios in Dogs with Pituitary-Dependent Hypercortisolism during Trilostane Treatment

Background: The adrenocorticotropic hormone (ACTH) stimulation test is used to evaluate trilostane treatment in dogs with hypercortisolism.
Hypothesis: The urinary corticoid : creatinine ratio (UCCR) is a good alternative to the ACTH stimulation test to determine optimal trilostane dose.
Animals: Eighteen dogs with pituitary-dependent hypercortisolism.
Methods: In this prospective study, the dose of trilostane was judged to be optimal on the basis of resolution of clinical signs of hypercortisolism and results of an ACTH stimulation test. The owners collected urine for determination of UCCR at 2-week intervals for at least 8 weeks after achieving the optimal trilostane dose.
Results: The UCCRs were significantly higher before treatment (11.5–202.0 × 10⁻⁶; median, 42.0 × 10⁻⁶) than at rechecks 2 months after optimal dosing, but they did not decrease below the upper limit of the reference range in the majority of dogs. The UCCRs of 11 dogs that initially were dosed insufficiently (range, 7.5–79.0 × 10⁻⁶; median, 31.0 × 10⁻⁶) did not differ significantly from UCCRs when the dosage was optimal (8.2–72.0 × 10⁻⁶; median, 33.0 × 10⁻⁶). Post-ACTH cortisol concentrations did not correlate significantly with UCCRs at rechecks during trilostane treatment. Long-term follow-up indicated that the decrease in UCCR below the upper limit of the reference was associated with hypocortisolism.
Conclusion and Clinical Importance: The UCCR cannot be used as an alternative to the ACTH stimulation test to determine the optimal dose of trilostane, but might be helpful in detecting dogs at risk for developing hypocortisolism during trilostane treatment.     

Diagnosis and treatment of naturally occurring hypoadrenocorticism in 42 dogs

Hypoadrenocorticism was diagnosed in 42 dogs over a two-and-a-half-year period. The disease occurred more commonly in young to middle-aged dogs, with a female:male ratio of 2:1. Most dogs had chronic intermittent signs (eg, poor appetite, lethargy and vomiting), but more than a third were in acute adrenal crisis at the time of diagnosis. Serum biochemical testing revealed azotaemia, hyperphosphataemia, hyper-kalaemia and hyponatraemia in almost all the dogs. In all dogs, results of adrenocorticotrophic hormone (ACTH) stimulation testing revealed a low to low-normal serum baseline Cortisol concentration that failed to increase after ACTH administration. In two dogs with persistently normal serum electrolytes concentration, one had a markedly high plasma ACTH concentration diagnostic for primary hypoadrenocorticism, whereas the other had a low concentration confirming secondary hypoadrenocorticism. Fludrocortisone acetate was initially used for mineralocorticoid replacement in 33 of the 37 treated dogs withprimary hypoadrenocorticism (final median dosage, 27-0 μg/kg/day), but supplementation was changed to desoxycorticos-terone pivalate (DOCP) in four dogs because of poor response or adverse effects. Seven dogs with primary hypoadrenocorticism were treated with DOCP (final median dosage, 2-02 mg/kg/month). Prednisone, initially administered to 36 dogs, was discontinued in 11 dogs because of side effects. Of the dogs treated with fludrocortisone, the response was considered good to excellent in 26 dogs (78.8 per cent), fair in three, and poor in four. All dogs treated with DOCP responded well.     

Treatment of Blastomycosis With Itraconazole in 112 Dogs

One hundred twelve client-owned dogs with blastomycosis were treated with itraconazole, 5 or 10 mg/kg/d. The first group of 70 dogs treated in 1987 and 1988 received 10 mg/kg/d (group 1), and the second group of 42 dogs treated after October 1988 received 5 mg/kg/d (group 2). Even though the groups were treated at different times, the dogs were similar in age and gender distribution, number of sites involved, and percent and severity of pulmonary involvement. The proportion of dogs cured with a 60–day course of itraconazole was similar for both groups (53.6% versus 54.3%) and for a second historical control group treated with amphotericin B (57%); the recurrence rate was also similar, 20%, 21.4%, and 20%, respectively. Dogs treated with itraconazole had similar mortality rates (25.7% at 5 mg/kg/d; 25% at 10 mg/kg/day) to those treated with amphotericin B (23%). Seventeen of the 23 dogs that died (74%), did so during the first week of treatment; these early deaths were usually attributed to respiratory failure. The only site of infection that was significantly associated with failure (death or recurrence) was the brain. There was a marked difference in survival times between dogs without lung disease or with mild lung disease compared with dogs with moderate or severe lung disease. Serum itraconazole concentrations reached steady state by 14 days of treatment. Dogs receiving 5 mg/kg/d of itraconazole (group 2) had mean serum concentrations of 3.55 ± 2.81 mg/mL (range, 0.67 to 10.8 μg/mL), whereas dogs receiving 10 μg/kg/d (group 1) had mean concentrations of 13.46 ± 8.49 μg/mL (range, 1.8 to 28 μg/mL) (P ≤ .001). There was no association between cure and serum itraconazole concentrations. Dogs in group 1 had significantly more adverse effects than dogs in group 2 (P= .046). Anorexia was the most common adverse effect, occurring in 14.9% of dogs in group 1. Only 8% of dogs in group 2 had adverse effects. Serum concentrations of itraconazole were positively correlated with serum alkaline phosphatase and alanine aminotransferase activities. Our findings indicate that itraconazole administered at a dose of 5 mg/kg/d is the drug of choice for blastomycosis in dogs.     

Retrospective evaluation of the effect of trilostane on insulin requirement and fructosamine concentration in eight diabetic dogs with hyperadrenocorticism

Objectives : To describe the effect of trilostane on insulin requirements and serum fructosamine in dogs with diabetes mellitus (DM) and hyperadrenocorticism (HAC). Methods : Observational retrospective study of eight dogs. Results : Median fructosamine concentration at presentation was 401 μmol/L (range 244 to 554 μmol/L). Median insulin dose at presentation was 1·1 IU/kg/dose (0·4 to 2·1 IU/kg/dose) administered twice daily in five animals and once in three. Four dogs had their insulin dose prospectively reduced at the start of trilostane therapy. The HAC was controlled within 28 days in seven dogs. The remaining case was controlled by 17 weeks. Two dogs died within 40 days of starting trilostane. The median fructosamine concentration was 438 μmol/L (range 325 to 600 μmol/L) after stabilisation of the HAC. One case had a consistent reduction in serum fructosamine concentration over the first four months. The median insulin dose after stabilisation of HAC was 1·5 IU/kg dose (range 0·25 to 3·0 IU/kg/dose). Insulin requirements were reduced in two cases after treatment with trilostane. Four dogs required increased insulin doses. Clinical Significance : Insulin requirements and fructosamine concentrations do not consistently reduce during trilostane treatment for HAC. Prospective studies are required to provide recommendations regarding reductions in insulin doses with trilostane treatment.     

Chronic effects of recombinant porcine growth hormone on adrenal weight and activity in pigs

This study was conducted to examine serum cortisol concentrations and adrenal cortisol output in pigs treated chronically with recombinant pGH (rpGH) at a maximally effective anabolic dose. Recombinant pGH (140 micrograms/kg body weight) was administered daily to eight barrows for 77 d. At slaughter, adrenal glands were removed, weighed and sliced; slices of fresh adrenal tissue were incubated for 1 h in the presence or absence of ACTH. Recombinant pGH increased adrenal weight by 39%. This change was accompanied by an inversely proportional reduction of in vitro cortisol output per gram of tissue, with the net result that total cortisol output per adrenal per kilogram of BW was unaltered, as was cortisol output in the presence of ACTH. Serum cortisol concentrations were measured in 10 barrows fitted with femoral artery catheters and treated daily with 0 or 140 micrograms rpGH/kg BW for 8 d. Basal and ACTH-stimulated cortisol concentrations were not altered by rpGH treatment. These results do not support our earlier speculation that a pGH-dependent increase in adrenal weight is associated with a chronic increase in adrenal activity, but rather demonstrate that corticosteroid output is tightly regulated and remains constant despite a marked increase in the size of the adrenal glands.     

Hyperadrenocorticism in a dog due to ectopic secretion of adrenocorticotropic hormone

Spontaneous hyperadrenocorticism in dogs is known to be the result of excessive secretion of adrenocorticotropic hormone (ACTH) by the pituitary gland or excessive autonomous glucocorticoid secretion by an adrenocortical tumor. Here, we report on an 8-year-old German shepherd dog in which ACTH-dependent hyperadrenocorticism was a result of ectopic ACTH secretion and could be related to an abdominal neuroendocrine tumor. Hyperadrenocorticism was diagnosed on the basis of the history, clinical signs, and elevated urinary corticoid/creatinine ratios (UCCRs; 236 and 350 x 10(-6); reference range < 10 x 10(-6)). The UCCR remained elevated (226 x 10(-6)) after three oral doses of dexamethasone (0.1 mg/kg body weight) at 8-h intervals. Ultrasonography revealed two equivalently enlarged adrenal glands, consistent with adrenocortical hyperplasia. Plasma ACTH concentration was clearly elevated (159 and 188 ng/l; reference range 5-85 ng/l). Computed tomography (CT) revealed that the pituitary was not enlarged. These findings were interpreted as indicating dexamethasone-resistant pituitary-dependent hyperadrenocorticism. Transsphenoidal hypophysectomy was performed but within 2 weeks after surgery, there was exacerbation of the clinical signs of hyperadrenocorticism. Plasma ACTH concentration (281 ng/l) and UCCRs (1518 and 2176 x 10(-6)) were even higher than before surgery. Histological examination of the pituitary gland revealed no neoplasia. Stimulation of the pituitary with corticotropin-releasing hormone did not affect plasma ACTH and cortisol concentrations. Treatment with trilostane was started and restored normocorticism. CT of the pituitary fossa, 10 months after hypophysectomy, revealed an empty sella. Hence, it was presumed that there was ectopic secretion of ACTH. CT of the abdomen revealed a mass in the region of the pancreas and a few nodules in the liver. Partial pancreatectomy with adjacent lymph node extirpation was performed and the liver nodules were biopsied. Histological examination revealed a metastasized neuroendocrine tumor. Abdominal surgery was not curative and medical treatment with trilostane was continued. At 18 months after the abdominal surgery, the dog is still in good condition. In conclusion, the combination of (1) severe dexamethasone-resistant hyperadrenocorticism with elevated circulating ACTH levels, (2) definitive demonstration of the absence of pituitary neoplasia, and (3) an abdominal neuroendocrine tumor allowed the diagnosis of ectopic ACTH secretion.