Page 92 - Clinical Small Animal Internal Medicine

60 Section 2 Endocrine Disease

Ketoconazole of anorexia, vomiting, and weakness occurred in one dog
VetBooks.ir past, its use now is generally in countries where mitotane and medication was withdrawn. Two further dogs devel­
While ketoconazole was used more frequently in the
oped progression of concurrent diseases and medication
and trilostane are not available or when these agents
occurred in four dogs. Moderate to severe elevations in
have failed to correct hypercortisolism or resulted in was stopped in these animals as well. Mild toxicity
adverse reactions. Its systemic use has recently been liver enzymes occurred in all dogs. The efficacy of this
restricted or banned in several countries due to the drug is lower than that observed using mitotane, trilos­
potential of significant hepatoxocity in humans. tane and ketoconazole, and adverse effects limit its use.
Specifically, ketoconazole has been shown to inhibit
cholesterol side‐chain cleavage enzyme, which converts Metyrapone (Metopirone®; Novartis)
cholesterol to pregnenolone, 17‐alpha‐hydroxylase and Metyrapone is a pharmacologic agent used in the diag­
17,20‐lyase, which convert pregnenolone into andro­ nosis of adrenal insufficiency and occasionally in the
gens, and 11‐beta‐hydoxylase, which converts 11‐deoxy­ treatment of Cushing disease in humans. The primary
cortisol to cortisol. inhibitory target is 11‐beta‐hydroxylase and to a lesser
A paper in 2008 examined the safety and efficacy of extent 17‐alpha‐, 18‐, and 19‐hydroxylase. The availabil­
ketoconazole in 48 dogs with PDH. Data collected from ity of metyrapone varies by country.
each record included signalment, clinical signs, results of In dogs, it has been used in patients with Cushing syn­
ACTH stimulation tests before and after treatment with drome in an attempt to distinguish PDH from a func­
ketoconazole (10 mg/kg PO BID), serum alkaline phos­ tional adrenal tumor. No reports exist on its use in
phatase (ALP) and alanine aminotransferase (ALT) treating Cushing syndrome in dogs.
activities, dosage of ketoconazole, clinical response, and
survival time. Forty‐three of 48 (90%) dogs had evidence Etomidate (Amidate®; Hospira)
of clinical improvement during the treatment period. In Etomidate is a short‐acting intravenous hypnotic non­
all dogs, treatment with ketoconazole resulted in signifi­ barbiturate anesthetic agent used for general anesthesia
cantly lower serum cortisol concentrations as measured which suppresses steroidogenesis by dose‐dependent
before and after ACTH stimulation testing; 69% (33/48) inhibition of 11‐beta‐hydroxylase and desmolase. It plays
of serum cortisol concentrations measured after ACTH a particular role in human cases with significant bio­
stimulation were within the basal resting range. Serum chemical disturbance, sepsis and other serious complica­
ALP and ALT activities significantly decreased after tions such as severe psychosis, as well as in patients who
treatment with ketoconazole. have acute contraindications to surgery and cannot tol­
Survival time after diagnosis of PDH ranged from 2 to erate oral medications.
61 months (mean 26.9 months; median 25 months). Its use in canine surgical patients has been reported
Another study evaluating ketoconazole found that after revealing adrenal suppression for 2–6 hours following a
diagnosis, 50% of the dogs died approximately 1.8–2 single bolus injection of 1.5–3.0 mg/kg. Its use as a con­
years (range 0.6–3) after starting therapy. tinuous‐rate infusion (CRI) in the management of
Several other adrenal steroidogenesis inhibitors have Cushing syndrome has not been reported.
been used in man and at times in dogs.
LCI699 (Novartis)
Aminoglutethemide (Cytadren®; Novartis) LCI699 is a potent inhibitor of aldosterone synthase and
Aminoglutethemide blocks the conversion of cholesterol 11‐beta‐hydroxylase. The mechanism of action of LCI699
to pregnenolone by inhibiting the enzyme P450scc and is similar to that of metyrapone, but LCI699 is more
consequently decreases synthesis of all hormonally active potent and has a longer plasma half‐life (approximately 4
steroids. Its use in dogs has been limited. In one study, 10 vs 2 h), which allows for twice‐daily dosing. LCI699 is
dogs were diagnosed with PDH based on clinical and lab­ currently under investigation in a Phase III prospective
oratory data, adrenal function tests, ACTH stimulation safety and efficacy study in human patients with Cushing
test and UCCR combined with a high‐dose oral dexa­ disease. No information on its use in canine patients has
methasone suppression test, and ultrasonographic evalu­ been reported.
ation of the adrenal glands. Aminoglutethimide was
administered daily at a dose of 15 mg/kg body weight for NormoCort (COR‐003; Cortendo)
one month. Median basal cortisol concentration and COR‐003 is a single 2S, 4R enantiomer of ketoconazole
post‐ACTH cortisol concentration one month after treat­ in development as a possible new drug for the treat­
ment were significantly lower than pretreatment values. ment of endogenous Cushing syndrome. This 2S, 4R
Complete response was achieved in one dog, and partial enantiomer of ketoconazole is expected to be a more
response was obtained in three dogs. Severe side‐effects potent inhibitor of key enzymes in the cortisol synthesis