Use of Trilostane Administered Twice Daily for the Treatment of Hyperadrenocorticism
*Facultad Veterinaria Madrid (Hospital Clinico), Universidad Complutense de Madrid
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.
The aim of this study was to evaluate the efficacy (dosage and duration of effect) and toxicity of Trilostane (4a ,5-epoxi-17 b - hydroxy-3-oxo-5a - androstane- 2a carbonitrile) in the treatment of canine hyperadrenocorticism. Trilostane (Modrenal®) competitively inhibits the enzyme 3 b hydroxysteroid dehydrogenase which processes the conversion of pregnenolone to progesterone, reducing steroid hormone levels. Clinical signs, laboratorial data and adrenal functional tests were evaluated one week and one month after treatment. The occurrence of adverse effects was also registered.
Eight dogs with clinical signs of hyperadrenocorticism were included in the study. Seven were non-spayed females and one was an intact male. Age ranged from 6 to 11 years (mean ± SD,7.80± 1.69). Two dogs were mixed breed and the following breeds were represented by one dog: Fox terrier, Schnauzer, Boxer, Yorkshire terrier, Beagle and Dachshund. The clinical diagnosis was based on clinical history, physical exam, routine laboratory tests including CBC, biochemical profile and urinalysis. Diagnosis was confirmed with an ACTH stimulation test and a low dose dexamethasone suppression test in all cases. High dose dexamethasone suppression test, endogenous ACTH level and/or abdominal ultrasound were used to differentiate pituitary dependant(7 dogs) from adrenal dependant hyperadrenocorticism(1 dog).Trilostane was initially administered at a dose of 6 mg/kg/day BID. This dosage was then adjusted to maintain the post ACTH cortisol concentrations between 1-5 ìg/dl. Final dosage ranged from 3-16 mg/kg/day BID. Animals were followed-up one week and one month after the beginning of the treatment. At each recheck data was taken, including clinical signs, physical examination, laboratory tests and ACTH stimulation test. To evaluate the efficacy of the treatment, on the first week the ACTH stimulation test was performed 4-6 hours after taking the trilostane. Once an adequate response was achieved, a second recheck was scheduled at a month period. In order to evaluate the duration of the effect at this second recheck, the ACTH test was run 12 hours after the administration of the treatment.
Clinical signs: PU/ PD was presented in all patients at diagnosis, and it improved or resolved at the first week in all cases. Polyphagia decreased as well in the 6 dogs initially polyphagic, however one dog without polyphagia initially develop transient increased appetite during the first two weeks of treatment. Weakness and lethargy initially presented by 5 and 3 dogs, respectively, also improved or resolved on the first week. None of these dogs presented PU/PD, polyphagia, weakness or lethargy at one month recheck. Six dogs presented abdominal distension initially, none of them showed variation on first week recheck but all improved at one month recheck.
Laboratorial findings: Hematological data before and after treatment were not significantly different. On biochemistry profile, alkaline phosphatase (ALP) and alanine transaminase (ALT) significantly (p< 0.05) decreased at one month
Adrenal functional tests. Both one week and one month recheck showed significant decrease (p< 0.05) on post ACTH cortisol concentration. Pre-treatment basal cortisol (mean ± SD) was 3.47 ± 3.14 µg/dl, and post-ACTH cortisol was 24.45 ± 15.94 µg/dl. One week recheck (4-6 hours post capsule) basal cortisol 1.93 ± 3.70, and post-ACTH cortisol was 2.57± 4.43 µg/dl. At one month, basal cortisol was 3.48 ± 1.47 µg/dl and cortisol post-ACTH was 7.17± 3.18 µg/dl. However, 4 of 8 dogs had at one month a post-ACTH cortisol concentration between 6-11 µg/dl.
Based on our results, the dosage of 6 mg/kg/day, divided twice daily results in an adequate initial treatment protocol as showed by resolution of clinical signs and routine laboratory abnormalities found on all of these dogs. However, some dogs would eventually need higher dosages to achieve a good response. ACTH stimulation tests response was adequate in all dogs after one week of treatment. An ACTH stimulation test performed at one month visit, showed that the duration of the effect did not reach 12 hours in half of these dogs. Despite the short duration of suppression of basal cortisol showed with trilostane, reported by other authors, in the ACTH stimulation test performed after 12 hours of administration, the mean cortisol pre-ACTH was lower than 6 ìg/dl. Based on these results, we consider that the administration of trilostane should be administered twice daily. No adverse effects were observed during the one month period of the study. Trilostane can be considered a good alternative for the treatment of canine hyperadrenocorticism. Its efficacy resolving the clinical signs and its fewer adverse effects makes it a good option to treat this disease compared to less effective or more toxic medical treatments.