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Use of Trilostane Administered Twice Daily for the Treatment of Hyperadrenocorticism
*Carolina Arenas Bermejo, Carlos Melian Liminana, Dolores Perez Alenza
*Facultad Veterinaria Madrid (Hospital Clinico), Universidad Complutense de Madrid Madrid, ES

Mitotane has been considered as treatment of choice for canine hyperadrenocorticism. However, this drug has potential severe side effects and, therefore, safer alternatives for treatment of hyperadrenocorticism are needed. Other described medical options (ketoconazole, l-deprenyl, aminoglutethimide) are quite less effective. In some pilot studies, trilostane seemed to be safe and effective for the management of hyperadrenocorticism. However, it is still necessary to know the dosage and the duration of the effect, in order to establish a protocol of use in the management of this disease.
Vet Rec 2002 Jun 29;150(26):799-804 : Trilostane treatment of 78 dogs with pituitary-dependent hyperadrenocorticism.
Neiger R, Ramsey I, O'Connor J, Hurley KJ, Mooney CT.
Department of Veterinary Clinical Sciences, Royal Veterinary College, Hatfield.

The efficacy of trilostane in the treatment of canine pituitary-dependent hyperadrenocorticism (PDH) was evaluated in 78 dogs with the condition which were treated for up to three years. The drug appeared to be well tolerated by almost all the dogs, and only two developed clinical signs and biochemical evidence of hypoadrenocorticism. Polyuria and polydipsia completely resolved in 70 per cent of the dogs that had these problems, and skin changes resolved in 62 per cent of the dogs that had skin abnormalities. There was a significant reduction (P<0.001 in each case) in both the mean basal and post-adrenocorticotrophic hormone (ACTH) cortisol concentrations after a mean of 12.3 days of treatment. The post-ACTH cortisol concentration decreased to less than 250 nmol/litre in 81 per cent of the dogs within one month of the start of treatment and in another 15 per cent at some later time. The median survival time of the 26 dogs which died was 549 days, and 51 of the dogs were alive at the completion of the study. One was lost to follow up after 241 days treatment.
J Am Vet Med Assoc 2002 Jun 1;220(11):1643-9 : Diagnosis of hyperadrenocorticism in dogs: a survey of internists and dermatologists.
Behrend EN, Kemppainen RJ, Clark TP, Salman MD, Peterson ME.
Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, AL 36849, USA.

OBJECTIVE: To determine testing protocols used by board-certified internists and dermatologists for diagnosis of hyperadrenocorticism (HAC) in dogs. DESIGN: Survey. STUDY POPULATION: Board-certified internists and dermatologists. PROCEDURE: A questionnaire was mailed to 501 specialists to gather information pertaining to diagnosis of HAC. RESULTS: 206 surveys were returned. Only 26% of respondents indicated they would screen a dog for HAC if the dog had only a few laboratory abnormalities consistent with HAC and no clinical signs consistent with the disease; 31% indicated they would not, and 43% indicated they would sometimes. Overall, 55% of respondents indicated they preferred to use the low-dose dexamethasone suppression test for routine screening of dogs suspected to have HAC. However, many respondents indicated they would use a different screening test than usual in particular circumstances. Sixty-eight percent of respondents indicated they would perform a second screening test for confirmation if results of an initial screening test were positive but there were few clinical or laboratory abnormalities consistent with HAC. Most respondents used some sort of test to differentiate pituitary-dependent HAC from HAC secondary to an adrenal tumor (AT), but no 1 test was clearly preferred. Ultrasonography was commonly used, whereas computed tomography and magnetic resonance imaging were not, even if available. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that the low-dose dexamethasone suppression test is the test most commonly used to screen dogs for HAC but that other tests may be used in certain circumstances. A variety of tests were used to differentiate pituitary-dependent HAC from HAC secondary to an AT.
Am J Vet Res 2002 Apr;63(4):506-12 : Results of clinical examinations, laboratory tests, and ultrasonography in dogs with pituitary-dependent hyperadrenocorticism treated with trilostane.
Ruckstuhl NS, Nett CS, Reusch CE.
Clinic for Small Animal Internal Medicine, University of Zurich, Switzerland.

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.
J Small Anim Pract 2002 Mar;43(3):104-8 : Use of aminoglutethimide in the treatment of pituitary-dependent hyperadrenocorticism in the dog.
Perez AM, Guerrero B, Melian C, Ynaraja E, Pena L.
Hospital Clinico Veterinario, Facultad de Veterinaria, Universidad Complutense de Madrid, Spain.

The aim of this study was to evaluate the efficacy and safety of aminoglutethimide in the treatment of dogs with pituitary-dependent hyperadrenocorticism (PDH). Ten dogs were diagnosed with PDH based on clinical and laboratory data, adrenal function tests (adrenocorticotropic hormone [ACTH] stimulation test and urinary cortisol/creatinine ratio [UCCR] combined with a high dose oral dexamethasone suppression test) and ultrasonographic evaluation of the adrenal glands. Aminoglutethimide was administered daily at a dose of 15 mg/kg bodyweight for one month. Median basal cortisol concentration and post-ACTH cortisol concentration one month after treatment were significantly lower than pretreatment values. Complete response was achieved in one dog, and partial response was obtained in three dogs. Severe side effects of anorexia, vomiting and weakness occurred in one dog and medication was withdrawn. Two further dogs developed decompensations of concurrent diseases and medication was stopped in these animals as well. Mild toxicity occurred in four dogs. Moderate to severe elevations in liver enzymes occurred in all dogs. The efficacy of this drug is lower than that observed using mitotane and ketoconazole, and adverse effects limit its use. Aminoglutethimide, using the protocol described, cannot be recommended for long-term management of PDH in the dog.
Progress in transsphenoidal hypophysectomy for treatment of pituitary-dependent hyperadrenocorticism in dogs and cats.
Meij B, Voorhout G, Rijnberk A.
Dept of Clin Sci Comp Anim,Fac of Vet Med,Utrecht Univ, PO Box 80.154,NL-3508 TD,Utrecht,The Netherlands
Mol Cell Endocrinol 2002 Nov 29;197(1-2):89-96
Cushing's disease or pituitary-dependent hyperadrenocorticism (PDH) is common in dogs and rare in cats. PDH is caused by a pituitary tumor producing adrenocorticotropin (ACTH). Pituitary imaging with computed tomography (CT) or magnetic resonance imaging (MRI) is required to assess the size and location of the pituitary adenoma in relation to the surgical landmarks. In a specialized veterinary institution, microsurgical transsphenoidal hypophysectomy has proven to be a safe and effective treatment for dogs (n=84) and cats (n=7) with Cushing's disease. Pituitary surgery requires a team approach and the neurosurgeon performing hypophysectomies must master a learning curve. The surgical results compared favorably with those for dogs with PDH treated medically with mitotane at the same institution. The recurrence rate after initially successful surgery increases with longer follow up-times. Pituitary function testing in 39 dogs with PDH treated with hypophysectomy revealed that, much more so than the other adenohypophyseal cell types, residual corticotropes present in the sella turcica after surgery are functional. Such normal ACTH secreting cells may maintain normocorticism whereas residual adenoma cells may lead to mild recurrence after relatively long periods of remission. Microsurgical transsphenoidal hypophysectomy is an effective treatment for canine and feline Cushing's disease.
Medical Therapy of Canine Cushings-Syndrome
EN Behrend, RJ Kemppainen
Auburn Univ Dept Anat Physiol & Pharmacol Auburn,AL 36849 USA
Compendium on Continuing Education for the Practicing Veterinarian,20,6 (JUN 1998) 679
Cushing's syndrome (GS) can result from excess adrenocorticotropin secretion from-the anterior or intermediate lobe of the pituitary or cortisol secretion from the adrenal glands. Therapy ideally targets the underlying abnormality, but this is not always possible. Intermediate lobe function is inhibited by dopamine; therefore, medications such as monoamine oxidase (MAO) inhibitors that increase dopamine-levels may be effective. However; no medications clearly affect the anterior lobe. The role dopamine plays in anterior pituitary function is unknown; thus the potential of MAO inhibitors as therapeutic agents for pituitary anterior lobe-dependent CCS: is unclear and; based on current knowledge, may be limited. It CCS results from an anterior lobe tumor destruction of the adrenal gland with mitotane or decreasing cortisol secretory ability with ketoconazole may be the two best options. Mitotane is usually preferred because ketoconazole has relatively low efficacy. However, the use of ketoconazole should be considered under certain circumstances. For adrenal tumors, agents (e.g., mitotane, ketoconazole that directly affect the adrenal glands are optimal. Because adrenal tumors may be resistant to the effects of mitotane, a different protocol should be used when treating pituitary-dependent CCS versus adrenal tumors