Medical therapies for canine pituitary-dependent hyperadrenocorticism - Veterinary Medicine
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Medical therapies for canine pituitary-dependent hyperadrenocorticism
Drug administration is usually the only option for treating dogs with PDH. Mitotane is the most common choice, but some alternatives are worth considering.


VETERINARY MEDICINE


Trilostane


Protocol for importing trilostane
Trilostane is used throughout Europe and Asia as a safe, efficacious therapy for canine PDH. Although approved for use in people by the FDA, trilostane is no longer manufactured in the United States. With FDA permission, pet owners in the United States can obtain trilostane from several Internet or overseas pharmacies (see boxed text titled "Protocol for importing trilostane").

Mechanism of action

Trilostane is a synthetic, orally active steroid analogue. It acts as a competitive inhibitor of the 3β-hydroxysteroid dehydrogenase enzyme system, which blocks the production of corticosteroids, mineralocorticoids, and sex hormones (Figure 1).23 The effects of trilostane are largely reversible and are dose-dependent.24

Safety

Trilostane seems to be well-tolerated by dogs. Mild lethargy and decreased appetite are occasionally seen two to four days after initiating therapy, likely due to steroid withdrawal.24,25 Mild hyperkalemia, azotemia, hyperbilirubinemia, and hypercalcemia have been reported but were usually not associated with clinical illness.26 In one study, two of 78 dogs developed hypoadrenocorticism, while a second study involving 30 dogs reported no troubling side effects.25,26 Bilateral adrenal gland enlargement has been reported but was not clinically important.27

Efficacy

Trilostane seems to be highly effective in resolving the signs of PDH.26-28 Polyuria, polydipsia, and polyphagia were ameliorated in 70% of 67 dogs with these clinical signs.26 A marked improvement in dermatologic signs was noted in 62% of 39 dogs.26 Significant reductions in both basal and post-ACTH stimulation cortisol concentrations were observed after a mean of 12.3 days.26 Target cortisol concentrations were achieved in 81% of 73 dogs within the first month of therapy, with an additional 15% achieving target cortisol concentrations subsequently.26 Two other studies reported 82% to 97% efficacy based on resolution of clinical signs and normalization of ACTH stimulation test results.25,27

Administration and monitoring

Pharmacokinetic data for trilostane in dogs are not available, so the optimal dose and frequency interval for treating PDH are unknown. A typical starting dosage for dogs with PDH is 5 to 10 mg/kg given orally once a day, although some dogs respond better to twice-a-day dosing.24 In a study of 30 dogs, 19 mg/kg/day was the mean dosage required to maintain remission.25 Doses up to 40 to 50 mg/kg have been given with no adverse effects.28,29 Similar to mitotane, trilostane should be given with food to increase its absorption.

Careful monitoring is imperative to achieve optimal control of PDH. Perform ACTH stimulation testing and measure serum electrolyte concentrations 10 to 14 days, 30 days, and 90 days after initiating therapy. It is important to perform these tests four to six hours after trilostane administration. If the post-ACTH cortisol concentration is less than 1 g/dl, discontinue the trilostane for 48 hours and then reintroduce it at a lower dose (generally the next lower capsule size).28 If the post-ACTH cortisol concentration is greater than 4.3 g/dl, increase the dose of trilostane to the next higher capsule size.28 If the post-ACTH cortisol concentration is between 1 and 4.3 g/dl, serum electrolyte concentrations are normal, and the dog appears clinically normal, keep the dose as is. After the dosage has been stabilized and the dog is free of clinical signs, ACTH stimulation test results and serum electrolyte concentrations should be monitored every three or four months.28

Ketoconazole

Ketoconazole, commonly used to treat fungal infections, is an imidazole drug that also inhibits steroidogenesis. The expense and twice-a-day dosing of ketoconazole have limited its routine use in treating PDH in dogs. Ketoconazole is more often used to treat dogs with mitotane-resistant adrenocortical tumors, particularly to stabilize patients before adrenalectomy.

Mechanism of action

Ketoconazole interferes with gonadal and adrenal steroid synthesis by inhibiting cytochrome P-450–dependent enzymes.16,30 It inhibits both the cholesterol side-chain cleavage step and the 11β-hydroxylation step (Figure 1).30 Other imidazole antifungal drugs, such as itraconazole, do not inhibit steroidogenesis.31

Safety

In a report of 18 dogs with PDH given ketoconazole, the only adverse effect noted was gastrointestinal upset in one dog.32 Hepatotoxicity has been reported, and thrombocytopenia is rarely encountered. Some dogs treated with ketoconazole will have a reversible lightening of their coats.16 The effects of hypocortisolemia are reversible with discontinuation of the drug, and mineralocorticoid deficiency is not observed.16

Efficacy

The efficacy of ketoconazole in dogs with PDH is debatable. A marked reduction in the serum cortisol concentration can occur within 30 minutes of administration and lasts from eight to 12 hours. In a single small study, 81% of dogs with PDH attained complete remission with ketoconazole.32 However, anecdotal evidence suggests the efficacy may be lower. In a survey of internists and dermatologists, most thought ketoconazole was effective in less than 25% of dogs with PDH.11 Only one of seven surveyed considered the efficacy of ketoconazole similar to that of mitotane.11 Treatment failure has been associated with poor bioavailability of orally administered ketoconazole.32 Assessing serum drug concentrations can differentiate between animals with poor intestinal absorption and those with true treatment failure.32

Administration and monitoring

Ketoconazole is administered initially at a dosage of 5 mg/kg given orally with a small meal twice a day for seven days. If no adverse effects occur, increase the dose to 10 mg/kg twice a day. After three weeks of therapy, perform ACTH stimulation testing within three to six hours of ketoconazole administration. If the basal and post-ACTH stimulation serum cortisol concentrations are not below 5 g/dl and the clinical signs have not resolved, increase the dose by 50% again. Most dogs with PDH will not achieve remission with dosages below 30 mg/kg/day.4

L-Deprenyl

L-Deprenyl, or selegiline hydrochloride, is the only FDA-approved drug for treating PDH in dogs. It is also used to treat canine cognitive dysfunction. Its use for treating PDH is controversial.

Mechanism of action

L-Deprenyl's mechanism of action is irreversible inhibition of monoamine oxidase B, resulting in increased central dopamine concentrations. Several studies have indicated that dopamine can inhibit the release of ACTH by the pars intermedia and, possibly, the pars distalis.33-35 It is hypothesized that L-deprenyl, by increasing dopamine concentrations in the brain, inhibits ACTH secretion (Figure 2).6 Additionally, L-deprenyl may have a suppressive effect on the growth of pituitary adenomas, although more studies are warranted to confirm this.6

Safety

L-Deprenyl is generally quite safe in dogs. Studies to date have demonstrated few adverse effects in healthy dogs or dogs with PDH treated long-term with L-deprenyl.6,7,16,36,37 The most common adverse effects include vomiting, diarrhea, salivation, and anorexia. CNS effects can include restlessness, repetitive movements, or lethargy.16 Mineralocorticoid deficiency does not occur.


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Source: VETERINARY MEDICINE,
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