Page 93 - Clinical Small Animal Internal Medicine

7 Pituitary-Dependent Hyperadrenocorticism in Dogs and Cats 61

pathway, and also a less potent inhibitor of a metabolic We recently evaluated nine client‐owned dogs with
VetBooks.ir enzyme, cholesterol 7‐alpha‐hydroxylase (Cyp7a), than PDH and macroadenoma in which PDH had been suc­
cessfully managed with adrenal‐directed treatment (trilos­
its counterpart. COR‐003 is presently in Phase III studies
in humans though no information is available regarding
kg [0.014 mg/lb], SC, q12h) for six months, while adrenal‐
its use in dogs. tane or mitotane). Dogs were given pasireotide (0.03 mg/
directed treatment was continued. Physical examination,
basic clinicopathologic testing, ACTH stimulation testing,
Pituitary‐Directed Therapy
and plasma ACTH concentration measurement were per­
Recent work on somatostatin and dopaminergic recep­ formed before (baseline) and three and six months after
tor changes in humans and dogs with Cushing disease treatment began. Measurements of pituitary gland vol­
has opened the door to targeted therapy of pituitary ume and pituitary gland‐to‐brain ratio were performed
tumors. Such therapies result not only in decreased via MRI at baseline and six months after treatment
ACTH production but also a reduction in tumor size. began. No dog developed neurologic abnormalities or
Several agents have been studied or are in clinical trials. signs of adverse effects during the study period. No dif­
ferences from baseline were identified in clinicopatho­
Pasireotide (SOM230; Signifor®; Novartis) logic values, ACTH stimulation test results, or plasma
Pasireotide is a somatostatin receptor (SSR) ligand with ACTH concentration at the three‐ or six‐month assess­
high binding affinity for multiple receptor isoforms ment points. After six months of pasireotide treatment,
(SST1‐3 and SST5). SST5 and SST2 are highly expressed six dogs had decreases in MRI‐measured values, and three
in ACTH pituitary adenomas, and animal studies docu­ had increases. Pasireotide as administered in this study
mented that SSR mediates inhibition of cAMP and regu­ had no noted adverse effects on dogs with PDH and mac­
lation of ACTH secretion. While SST5 is most commonly roadenoma successfully managed with standard treat­
overexpressed in humans, SST2 appears to be most com­ ment. Placebo‐controlled, randomized studies are needed
mon in dogs. Pasireotide has recently been approved for to determine whether pasireotide protects from the devel­
use in humans for the treatment of adult patients with opment of neurologic signs or improves outcome in dogs
Cushing disease for whom pituitary surgery is not an with pituitary macroadenomas.
option or has not been curative. As mentioned, while dogs seem to overexpress the
SOM230 was tested in dogs suffering from Cushing SST2 receptor, a recent paper showed no decrease in
disease (10 animals were treated continuously during six cortisol concentrations in dogs treated with octreotide, a
months, and another 10 were treated with three cycles selective SST2 receptor antagonist.
consisting of two months of treatment followed by a two‐
month rest period). The dose was 0.03 mg/kg SOM230, Cabergoline (Dostinex®; Pfizer)
SC q12h. Clinical and biochemical variables were evalu­ Cabergoline is a dopamine D2 receptor agonist with a
ated at different times: before treatment and at three higher affinity and a longer half‐life than bromocriptine.
and six months of treatment. MRI studies at three and In humans, its effectiveness and tolerance in the treat­
six months were performed. A significant decrease in ment of prolactinomas and growth‐hormone secreting
ACTH, urinary cortisol creatinine ratio, adenoma size adenomas have been demonstrated. Pivonello described
(magnetic nuclear resonance), and improvement of reduction in size of the aggressive corticotroph adenoma,
clinical signs were obtained, without side‐effects. In this which causes Nelson syndrome, while the antineoplastic
study, tumor size did not decrease in patients whose effects of cabergoline have been reported in the treat­
tumors were >7 mm, but there was no increase either, ment of nonfunctional tumors of corticotroph cells.
and there were variations in the paramagnetic signal A study with follow‐up for over four years was con­
intensities, becoming isointense. AtT20 cells treated ducted in 40 dogs with PDH that were treated with
with SOM230 suppressed proopiomelanocortin (POMC) cabergoline (0.07 mg/kg/week). Out of the 40 dogs, 17
promoter activity through SSTR2, via the G i alpha‐subu­ responded to cabergoline (42.5%). A year after the
nit, and reduced Nur77/Nurr1 transcriptional activity. It treatment, there was a significant decrease in ACTH (P
was concluded that SOM230, in addition to its well‐ <0.0001), alpha‐MSH (P <0.01), UCCR (P <0.001), and
described antisecretory effects, inhibits, as shown in tumor size (P <0.0001) evaluated by nuclear magnetic
AtT20 cells, ACTH synthesis at the POMC transcrip­ resonance. Dogs responding to cabergoline lived signifi­
tional level, an effect mediated mainly through SSTR2, cantly longer (P <0.001) than those in the control group
and limits tumor growth. The controlled Cushing dis­ (ketoconazole). Cabergoline may be useful in 42.5% of
ease in the dogs that received the treatment indicates dogs with PDH, justifying its use as a treatment especially
that SOM230 has a potential therapeutic use in dogs suf­ if a pars intermedia tumor is documented or suspected
fering from Cushing disease. based on hormonal (elevated MSH) and imaging data.