Cushing's syndrome refers to all causes of hyperadrenocorticism.
Cushing's syndrome refers to all causes of hyperadrenocorticism with overproduction of cortisol.
1) Cushing's disease: Pituitary hypersecretion of ACTH which results in bilateral adrenal hyperplasia (90% of cases)
2) Ectopic ACTH production: Non-pituitary tumors secreting ACTH resulting in bilateral adrenal hyperplasia. Has not been completely documented in dogs or cats.
b. ACTH independent
1) Adrenocortical adenoma or carcinoma: Hypersecretion of cortisol with atrophy of normal adrenal and suppressed ACTH concentrations (10% of cases).
1) Excessive or prolonged administration of glucocorticoids. Clinically indistinguishable from natural disease. Results in adrenal atrophy and suppressed ACTH levels.
a. Poodles, Dachshunds, Schnauzers, Boston Terriers, Boxers.
b. Middle to old age. Average 12 years; range 6 months to 17 years.
c. No sex predilection.
d. Rare in cats. Usually seen with insulin resistant diabetes mellitus and/or cats with severe dermal atrophy/ulceration.
3. Clinical Signs
a. PU / PD
b. Pendulous, "pot-bellied abdomen": Due to muscle catabolism by glucocorticoids and hepatomegaly.
c. Bilaterally symmetric alopecia: Head and extremities spared.
d. Thin skin
e. Muscle weakness and muscle atrophy; cruciate ruptures
f. Mineralization of skin (calcinosis cutis)
g. Hyperpigmentation: ACTH similar to MSH, co-existing hypothyroidism, chronic skin irritation.
h. Reproductive abnormalities
2. Clitoral hypertrophy
3. Testicular atrophy
4. Perianal adenomas in females and neutered males.
i. Respiratory signs
1. Panting: Pulmonary hypertension and decreased compliance, primary CNS disturbance, pulmonary mineralization.
2. Dyspnea: Rare; seen with pulmonary thromboembolism and concurrent congestive heart failure.
j. Central nervous system
1. Seen with large pituitary tumors (macroadenomas). Present at time of diagnosis or following therapy for Cushing's disease as microscopic pituitary tumors enlarge into macroadenomas.
2. Signs due to compression/invasion of pituitary and/or hypothalamus:
v. Behavior change
vi. Head pressing
4. Diagnosis of Hyperadrenocorticism
a. History and clinical signs
b. R/O iatrogenic disease with questions concerning current or past medications. These medications can include oral, ophthalmic, otic, and topical medications. Make sure the owner tells you about everything and anything that went on or in their pet.
c. Laboratory data
A. Polycythemia (PCV 45-55%)
b. Stress leukogram
3. Neutrophilia (mature)
2. Biochemistry profile
A. Elevations in:
1. Serum alkaline phosphatase (SAP)
3. Serum alanine aminotransferase (ALT)
4. Fasting blood glucose: Diabetes in 5-10%.
3. Thyroid function tests
A. T3 and T4 basal levels are generally decreased.
B. Response to TSH parallels normal.
C. Secondary to negative feedback of cortisol on pituitary.
D. Does not require thyroid supplementation.
4. Blood pressure: 50 – 80% are hypertensive, cause unknown.
A. Recent study demonstrated normal or decreased levels of atrial natriuretic factor (ANF) in dogs with hyperadrenocorticism. Argues against hypervolemia as the etiology of the hypertension.
A. Decreased urine specific gravity.
d. Radiographic abnormalities
1. Thoracic films
i. Bronchial calcification
ii. Metastases from adrenal adenocarcinoma
2. Abdominal films
v. 50% of adrenal tumors are visualized as soft tissue or calcified masses.
vi. Subcutaneous calcification
e. Adrenal function tests
Three tests used to diagnose hyperadrenocorticism. They do not differentiate between PDH or AT.
1. ACTH stimulation test
a) Look for exaggerated cortisol response in response to ACTH.
b) See protocols at the end of this discussion.
c) Diagnostic in 85% of pituitary-dependent cases (PDH)
d) Diagnostic in 70% of adrenal tumors (AT)
e) Overall accuracy 80-85 %
f) A suppressed response to ACTH in animals with clinical signs of hyperadrenocorticism suggests iatrogenic disease.
2. Low-dose dexamethasone suppression test
g) Low doses of dexamethasone inhibit ACTH release from the pituitary via negative feedback and decrease plasma cortisol concentrations in normal dogs.
h) Dogs with Cushing's are more resistant to steroid suppression. Therefore, lack of suppression following dexamethasone = hyperadrenocorticism.
i) Diagnostic in 95% of PDH
j) Diagnostic in 100% of AT
k) Overall 90-95%
l) May also be used to distinguish PDH from AT (see below)
m) See protocols
3. Urine cortisol/creatinine ratio
a) Assessment of cortisol production and excretion rate.
b) Sensitivity of this test is greater than that of the LDDS (some animals with clinical signs of hyperadrenocorticism may have normal LDDS response tests but elevated urine cortisol to creatinine ratios). Used as a screening test.
c) Test is easy to perform.
d) As with all adrenal function tests, elevated results may occur in animals with non-adrenal disease.
e) Positive tests confirmed with a LDDS.
f) Must be performed on urine obtained at home, preferably in the AM
Tests to differentiate PDH from AT (performed after confirming diagnosis of hyperadrenocorticism).
1. High-dose dexamethasone suppression test
a) With PDH, a high dose of dexamethasone results in a decrease in ACTH release from the pituitary and a decrease in plasma cortisol.
b) With AT, the tumor secretes cortisol autonomously thereby suppressing ACTH production. With low ACTH concentrations already present, dexamethasone has no effect on plasma cortisol.
c) 70% of patients with PDH suppress plasma cortisol to less than 50% of the pre-treatment value.
d) 100% of patients with AT do not suppress.
e) Therefore: Suppression = PDH; Lack of suppression = Inconclusive
f) See protocol
2. Endogenous ACTH concentration
a) PDH: Levels normal or high
b) AT: Levels low to undetectable
c) Contact lab regarding sample handling and collection. Use of the preservative (Aprotinin) allows for greater utilization of this test.
d) Excellent method to differentiate PDH from AT.
These are suggested protocols that are used in the evaluation of patients with hyperadrenocorticism. You must use the protocol and normal values from the laboratory to whom you are submitting samples to properly evaluate endocrine tests.
1) ACTH Stimulation Test
a) Synthetic ACTH (Cortrosyn) 5 µg/kg IV or IM; collect serum at 0 and 1 hour, or
b) ACTH gel (Acthar) 2.2 U/kg IM; collect serum at 0 and 2 hours.
c) Hyperadrenocorticism if post-cortisol > 20 µg/dl (530 nmol/L)
2) Low-Dose Dexamethasone Suppression Test
a) 8 A.m: Baseline serum cortisol. Administer 0.01 mg/kg dexamethasone sodium phosphate (0.015 mg/kg dexamethasone) IV.
b) 12 p.m: Collect 4 hour post-dexamethasone cortisol.
c) 4 p.m: Collect 8 hour post-dexamethasone cortisol.
d) In normal animals cortisol suppresses to less than 1.0 µg/dl (27.5 mmol/L) at 8 hours.
e) 50% or greater suppression at either 4 or 8 hours together with lack of suppression at 8 hours is diagnostic for PDH and additional tests are not necessary.
3) Urine Cortisol/Creatinine Ratio
a) First morning urine sample is preferred. Sample should be obtained at home. Requires 1 – 2 mls.
b) Stable at room temperature or refrigerated for 3 days.
c) Normal range 2.8 - 4.8. A normal result effectively rules-out hyperadrenocorticism, an abnormal result should be confirmed with a LDDS or ACTH stimulation test.
Differentiating PDH From AT
1) Low-Dose Dexamethasone Suppression Test
a) See above.
2) High-Dose Dexamethasone Suppression Test
a) 8 a.m: Obtain serum cortisol. Administer 0.1 mg/kg dexamethasone sodium phosphate (0.15 mg/kg dexamethasone) IV.
b) 4 p.m: Collect post-dexamethasone cortisol.
c) Suppression defined as greater than a 50% reduction of cortisol.
d) Suppression = PDH, non-suppression = Inconclusive
3) Endogenous ACTH Concentration
a) Check with lab on sample collection and handling.
b) Normal: 20-100 pg/ml (4.4-22.0 pmol/L)
c) PDH: 40-500 pg /ml (8.8-110 pmol/L)
d) AT: < 20 pg/ml (<4.4 pmol/L)
A. Pituitary-dependent hyperadrenocorticism
1. Surgical management
B. Bilateral adrenalectomy
1. Technically difficult
2. Poor surgical/anesthetic risk
3. Permanently hypoadrenal and require lifelong replacement therapy
1. Technically very difficult
2. Lifelong therapy with thyroid hormone and prednisone necessary.
2. Medical therapy
D. Lysodren (o,p'-DDD)
1. Selective necrosis of adrenal cortical cells producing cortisol (zona fasiculata and reticularis).
2. Zona glomerulosa usually spared maintaining aldosterone secretion.
3. Side-effects (35 – 40%)
E. Neurologic signs
F. Addison's disease (< 5 %)
4. Most commonly used therapy for PDH.
Treatment Protocol For Initiating Lysodren Therapy
Goals of therapy:
A. Eliminate clinical signs
B. Avoid toxicity
C. Pre and post-ACTH plasma cortisols within the normal resting range (<4.0 µg/dl; <100 nmol/L)
1. Owners assess water consumption and appetite at home for 3-5 days.
2. Begin Lysodren at 25 mg/kg PO BID.
3. When water consumption or appetite starts to decrease or following seven consecutive days of therapy (which ever occurs first) the medication is discontinued and an ACTH response test is performed.
4. If an adequate response to therapy is seen (pre and post cortisols within the resting range) maintenance therapy is begun. If an adequate response has not been seen, daily therapy is continued until clinical signs improve or for an additional 7 days and another ACTH stimulation test is performed.
5. If adverse reactions are noted at any time during therapy (reduction in appetite, anorexia, vomiting, diarrhea) therapy should be discontinued and the animal brought in as soon as possible for evaluation. Electrolytes, BUN, and an ACTH stimulation test should be performed. If the animal can not be brought in within the next 12-24 hours, replacement doses of steroids (0.25 mg/kg/day of prednisone) are started and the animal is seen at the earliest possible time. Owners should have 5 mg prednisone tablets at home for emergency use.
1. Lysodren is given at 50 mg/kg once a week or divided twice a week.
2. Watch for clinical signs of returning hyperadrenocorticism.
3. ACTH stimulation test in 4 weeks then every 3-4 months.
4. Electrolytes every 3-4 months. Even though the zona glomerulosa is fairly resistant to the effects of o,p'-DDD, mineralocorticoid deficiency can occur (see treatment for hypoadrenocorticism).
5. Therapy is life-long.
Another protocol that has been used with o,p'-DDD in the management of Cushing's disease is total adrenal ablation. In this protocol, Lysodren is administered at 100 mg/kg/day divided BID for 30 days. Supplemental cortisone acetate (2 mg/kg divided BID) and fludrocorticone tablets (0.1 mg/10 # once a day) are begun beginning on day 1 of Lysodren therapy. The diet is supplemented with 1-5 grams of NaCl per day. One week after the induction phase with o,p'-DDD, the dose of cortisone is reduced to 1 mg/kg/day. Electrolytes and an ACTH stimulation test are performed at the end of the induction period, every six months, and at any time the animal demonstrates signs compatible with either hyperadrenocorticism or hypoadrenocorticism. While this form of therapy may be effective in the management of canine hyperadrenocorticism, is does require close patient monitoring and life-long daily therapy. Close attention must be paid to these animals during times of stress and episodes of non- adrenal illness.
1. Medical therapy (con't)
B. Ketoconazole (Nizoral)
Inhibits adrenal enzymes responsible for the synthesis of cortisol. Enzymatic inhibition is reversible.
No affect on aldosterone.
Does not destroy adrenal tissue.
Can be used for both PDH and AT.
C. Increased liver enzymes.
D. Lightening of hair coat.
A. 10-15 mg/kg BID
B. Assess response to therapy with ACTH stimulation tests just as with Lysodren.
C. Daily therapy must be maintained.
A. Animals not able to tolerate Lysodren.
B. Animals non-responsive to therapy with Lysodren or Anipryl.
C. Pre-operative stabilization prior to adrenalectomy (4-6 weeks).
D. Palliative therapy in animals with metastatic adrenal tumors.
E. Effective in approximately 50% of patients.
5. l-Deprenyl (Anipryl)
l-Deprenyl (Anipryl) is a selective monoamine oxidase-B inhibitor (MAO-B) that is currently approved for the treatment of Parkinson's disease in man and PDH and cognitive dysfunction in the dog. There are several reasons why dopamine depletion and monoamine oxidase inhibitors may play a role in the pathogenesis and treatment of canine PDH. First dopamine concentrations are decreased in canine patients with PDH. Secondly, PDH is a geriatric disease and it is known that the concentration of MAO-B increases with age. Together these events lead to further functional dopamine depletion. Thirdly, treatment with dopamine agonists (man, dog, horses) has been beneficial in some patients with PDH. Dopamine affects the HPA axis primarily through tonic inhibition of ACTH release from the pars intermedia (PI). Based on previous studies, approximately 30% of cases of PDH in the dog arise from adenomas or adenomatous hyperplasia in the PI. In addition, it appears that dopamine depletion also play a role in enhancing corticotropin releasing hormone (CRH) mediated ACTH release. In the dog, treatment with the dopamine antagonist domperidone results in enhanced CRH mediated ACTH release. This suggests that dopamine depletion can impact ACTH release from both the PI and pars distalis (PD) and that dopamine depletion may play a role in the pathogenesis of canine PDH. MAO-B can be effectively and irreversibly inhibited in the dog with chronic, daily oral administration of l-deprenyl with few adverse side effects. Therapy with l-deprenyl has recently been shown to be effective in 4 studies involving 125 dogs with PDH. The drug was administered once a day. Efficacy of therapy was evaluated on the basis of reversal of clinical signs and normalization or a return toward normal in the low dose dexamethasone suppression test. Seventy-five percent of the dogs treated with 1.0 or 2.0 mg/kg, were considered treatment successes based on clinical and biochemical criteria.
6. Radiation therapy
A. Used to treat pituitary macroadenomas
B. Good results in reducing tumor size and decreasing neurologic signs, but frequently poor results on controlling excess tumor secretion of ACTH so medical therapy is still needed.
B. Adrenal tumors
A. Treatment of choice according to the literature. Unfortunately, adrenal tumors, even benign ones, can be very large, highly vascular, and locally invasive (vena cava, aorta, kidney). If you are considering surgical therapy consider referral to someone who does these often and who has the ability to determine extent of disease prior to surgery (CT, ultrasound, angiography). Always remember the goal of therapy is to alleviate clinical signs.
B. Submit all tissue for histopathology and prognosis. 50% of adrenal tumors are malignant and carry a very poor prognosis.
C. Intra and post-operative care is critical to survival.
D. Begin supraphysiologic doses of glucocorticoids during surgery and for the first few days after recovery. The dose is gradually tapered over 4-6 weeks.
A. Responses can be achieved albeit at higher dosages than normally considered for PDH.
B. Induction protocol is the same as for PDH.
C. May require 100-200 mg/kg/day to obtain remission. Maintenance therapy is then started using the effective daily induction dosage given once or twice a week.
D. When used in this fashion you are using Lysodren as a chemotherapeutic drug and the goal is to wipe out all adrenal tissue thereby inducing both glucocorticoid and mineralocorticoid insufficiency.
A. Will decrease cortisol production by the tumor, no good evidence for any effect on destroying tumor tissue.
B. Good medication for palliative therapy.
C. Do not use Lysodren and ketoconazole together.
D. Use dosage and protocol as described for PDH.
Management of Diabetes and Hyperadrenocorticism
As the clinical signs of diabetes mellitus and hyperadrenocorticism are similar, clinical suspicion of hyperadrenocorticism is usually made based on physical examination findings and the occurrence of insulin resistance. The diagnosis of hyperadrenocorticism in a diabetic patient can be difficult. Unregulated or poorly regulated diabetic dogs can have exaggerated cortisol responses to ACTH, an elevated urine cortisol/creatinine ratio, and an abnormal LDDS test, without having hyperadrenocorticism. While well regulated diabetics have normal ACTH response tests, most ACTH response tests on diabetic dogs are being performed because of difficulties with glucose regulation. If you have a diabetic animal in which you suspect hyperadrenocorticism it is probably best to institute insulin therapy (even if it requires high doses) in order to regulate the diabetes. Once an adequate response to insulin therapy has been observed (based on clinical signs and serial blood sugars) adrenal function tests can then be performed. Prior to initiating Lysodren, insulin therapy is reduced to 0.5 to 1.0 U/kg BID. This will help avoid the occurrence of ketoacidosis while helping to prevent severe hypoglycemic reactions that may occur as insulin requirements decrease. Owners are asked to monitor urine sugars 2-3 times a day and if negative readings are obtained the dose of insulin is reduced by 25%. One-third of treated dogs may be able to discontinue insulin therapy entirely following successful management of the hyperadrenocorticism.
A. Start daily Lysodren at 25 mg/kg/day.
B. Insulin requirements may change rapidly. Owner should monitor urine samples 2-3 times a day for glucose. With negative results, insulin dose is lowered 25% at next injection.
C. Cortisol causes insulin antagonism so with resolution of hyperadrenocorticism:
1. Insulin requirements will decrease.
2. Some dogs may be able to stop insulin.
3. These patients may be prone to more severe hypoglycemic reactions due to loss of one of the counter-regulatory hormones, cortisol.
D. Aside from starting with a decreased dose, the protocol is the same as that used for treating PDH without diabetes.
A. Most dogs with PDH live normal lives (average 2.2 years, but remember most are geriatric to begin with.)
A. Recurrence of disease.
B. CNS signs.
C. Pulmonary thromboembolism.
F. Congestive heart failure.
2. Adrenal tumors:
1. Adenomas: Good if no evidence of local invasion.
2. Carcinomas: Guarded to grave with metastases.
Trilostane Therapy of Canine Hyperadrenocorticism
Canine hyperadrenocorticism (HAC) has been most commonly treated with the adrenolytic drug o, p'-DDD (mitotane). However, it is well recognized that mitotane has several side effects, is associated with a high frequency of relapses and is not without risk to owners. Other drugs such as ketoconazole and l-deprenyl (selegeline) have also been investigated for the treatment of HAC. Recently it has been suggested that trilostane was an effective treatment for canine hyperadrenocorticism. Several workers in the field have subsequently used trilostane in canine pituitary dependent and adrenal dependent hyperadrenocorticism, in feline hyperadrenocorticism and in equine Cushing's syndrome. Trilostane is a synthetic, orally active steroid analogue. It can act as a competitive inhibitor of the 3 hydroxysteroid dehydrogenase enzyme system and thereby inhibit the synthesis of several steroids, including cortisol and aldosterone. This blockade is reversible and seems to be dose-related.
Pharmacology of trilostane
Few pharmacokinetic studies have been performed on trilostane. In the rat and monkey trilostane is rapidly absorbed after oral dosing with peak blood concentrations occurring between 0.5-1 hour (rat) and between 2-4 hours (monkey). In human volunteers the peak concentrations were between 2 and 4 hours 5. In dogs peak trilostane concentrations are seen within 1.5 hours and decrease to baseline values in about 18 hours (Arnolds Veterinary Products Limited, UK, data on file). The variability exhibited in systemic levels of trilostane following oral administration is possibly due in part to suboptimal absorption owing to its low water solubility.The decline of trilostane follows a triexponential decrease with trilostane cleared from the blood after 7 hours (rat), 6-8 hours (human) and 48 hours (monkey). Following the administration of trilostane to rats, the metabolite ketotrilostane is formed within a few minutes. Ketotrilostane has about 1.7 times the activity of trilostane in steroid inhibition. Conversely, when ketotrilostane is given to rats, trilostane is rapidly formed, suggesting that these compounds exist in equilibrium in vivo. Trilostane and ketotrilostane are metabolised into any one of 4 further metabolites. Excretion in rats is mainly via faeces, whilst in monkeys urinary excretion is more important 4.
Use in humans
In humans, trilostane has been mainly used for Cushing's syndrome. However the clinical response was rather disappointing with only few patients showing clinical improvement. Decreases in cortisol levels and in blood pressure were even less common. Other conditions in humans treated with trilostane are Conn's disease (primary aldosteronism) and advanced breast cancer. In humans, trilostane is given orally at a dose of 60 mg four times daily for three days with adjustment according to the patient's response. Usually a final dose of 120-480 mg daily in divided doses is required with a maximal dose of 960 mg recommended. Uncommon dose-related side effects of trilostane in humans include flushing, nausea and vomiting, diarrhoea, rhinorhoea and palatal oedema. Acute addisonian episodes have also been reported.
Canine pituitary dependent hyperadrenocorticism (PDH)
The efficacy and safety of trilostane in the treatment of canine PDH were evaluated in a multicentre study at the Royal Veterinary College in London, the Veterinary Teaching Hospital in Dublin and Small Animal Hospital in Glasgow. Seventy-eight dogs with confirmed PDH were treated with trilostane for up to 3 years. The starting dose varied from 1.8 to 20 mg/kg (mean = 5.9 mg/kg).
Trilostane appeared to be well tolerated by almost all dogs with only 2 dogs developing signs and biochemical evidence of hypoadrenocorticism. One of these dogs recovered with appropriate therapy. The other died despite withdrawal of trilostane and administration of appropriate therapy. A further two dogs died within one week of starting trilostane but in neither case could a direct link with the trilostane therapy be established. The low prevalence of side effects compared favourably to those reported with mitotane.
Trilostane was found to be nearly as effective as mitotane in resolving the signs of hyperadrenocorticism. Polyuria, polydipsia and polyphagia had dissipated in 40 dogs within 3 weeks after starting trilostane. Within 2 months, a further 20 dogs showed decreases in their water and food consumption. These improvements were maintained as long as the dogs remained on adequate doses of trilostane. Skin changes resolved in 24 out of 39 (62%) of dogs that initially presented with dermatological signs. All of these improvements were maintained as long as the dogs remained on adequate doses of trilostane. Only 8 dogs that were treated with trilostane for more than 2 months showed poor control of clinical signs. In contrast, mitotane is effective in about 80% of cases of pituitary dependent hyperadrenocorticism (PDH).
Trilostane caused a significant (p<0.001) reduction in both the mean basal and post-ACTH stimulation cortisol concentrations after 10 days of treatment. The post ACTH cortisol concentration decreased to less than 250 nmol/l (9 μg/dl) in 81% of dogs within one month and in another 15% at some time whilst on treatment. These improvements were also maintained in the study population for the duration of the trial.
Thirty-five dogs had at least one dose adjustment over the treatment period. The dose was increased in 23 dogs up to four times the starting dose. In one dog the dose was increased nine fold over a period of six months. The dose was decreased in nine dogs to as low as a quarter of the starting dose.
The mean survival of all trilostane treated dogs was 661 days. Direct comparison with mitotane was difficult as 65% of the dogs were still alive at the time of censor and therefore the mean survival may still increase.By comparison, the mean survival of mitotane treated dogs has been reported to be 810 to 900 days.
Subsequently it has been demonstrated that the effects of trilostane on basal cortisol concentrations are short lived (less than 20 hours) in most dogs with hyperadrenocorticism. Furthermore there are significant differences between the cortisol responses in ACTH stimulation tests performed at 4 and 24 hours post dosing 12. It has also been suggested that adrenal glands increase in size in response to therapy. This may be as a result of an increase in endogenous ACTH during therapy.
Canine adrenal dependent hyperadrenocorticism
Only a few cases of adrenal dependent hyperadrenocorticism (ADH) have been treated with trilostane. A reduction in post-ACTH cortisol concentrations has been demonstrated and extended survival times (more than 2 years) have been achieved in some cases. Insufficient cases have been collected to compare the long-term efficacy of trilostane with that of mitotane. Trilostane is not cytotoxic and it is likely to be inferior to mitotane for the prevention and control of metastatic disease. The value of trilostane for pre-operative therapy before adrenalectomy has not been examined in a systematic fashion. However, given the data presented above, it would suggest that trilostane might be an effective and safer alternative to ketoconazole in this respect.
Clinical studies in other species
Trilostane has been used in 20 cases of equine HAC at a dose of 120-240 mg once daily 14. The drug was effective as assessed by reduction in lethargy, laminitis and polyuria/polydipsia and a corresponding decrease in cortisol response to TRH administration. Some of these horses have been treated for up to one year so far with no side effects noticed. The use of trilostane in feline HAC has not been reported.
Current Recommendations for the Use of Trilostane in Dogs
Many aspects of trilostane use in canine HAC are still under investigation and the following recommendations are therefore likely to change.
Preparations, storage, and handling
Trilostane has been available in 60 mg capsules in the UK since late 2001 under a temporary veterinary product licence as Vetoryl® (Arnolds Pharmaceuticals, Crawley, Surrey, UK). It is also available in 60 mg capsules approved for human use as Modrenal® (Wanskerne Ltd, Billingshurst, West Sussex, UK). With very small dogs, capsules might need to be split into smaller gelatin capsules. A licensed pharmacist should do this. Trilostane capsules should be stored at room temperature in airtight, light-resistant containers. Pregnant women should wear gloves when handling the drug and all users should wash their hands after handling the capsules.
Dosage and administration
As pharmacokinetic data for trilostane are not yet available, the optimal dose rate and frequency interval for the treatment of canine HAC are not yet known. The current suggested starting dose rate for dogs with PDH is 5-10 mg/kg once daily. This needs to be adjusted according to clinical signs and serum cortisol values (see below). Doses up to 40-50 mg/kg (divided twice daily) have been given with no unwanted side effects. In some dogs twice daily dosing may be necessary. The drug is given with food.
Cautions and drug interactions
In dogs only minor side effects are commonly seen such as mild lethargy and decreased appetite 2-4 days from start of therapy (potentially due to steroid withdrawal syndrome) and mild electrolyte abnormalities. Overt hypoadrenocorticism seems to be a rare event despite the marked decrease in serum cortisol values found shortly after trilostane dosing. It has been shown that trilostane terminates pregnancy in rhesus monkeys at a dose of 50mg/monkey at various time points through pregnancy. The drug should therefore not be used in pregnant animals.
As trilostane can cause hyperkalemia through its aldosterone inhibiting effect it is advised to use caution if given together with a potassium-sparing diuretic. No unwanted drug interactions have been seen in dogs on trilostane together with several non-steroidal anti-inflammatory drugs, various antibiotics, insulin and levothyroxine. The effect of angiotensin converting enzyme inhibitors might be potentiated (again due to it's aldosterone inhibiting effect) but no studies have looked into this.
It is important to monitor the clinical and biochemical effects of therapy and to adjust the trilostane dose to achieve optimal control. Dogs are re-examined and an ACTH stimulation test is performed at 10 to 14 days, 30 days and 90 days after starting therapy. It is important that all ACTH stimulation tests are performed 4 to 6 hours after trilostane administration and interpreted in the light of the history and the findings of a thorough physical examination. If the post ACTH cortisol concentration is less than 20 nmol/l (0.7 μg/dl) the trilostane is stopped for 48 hours and then re-introduced at a lower dose. If the post ACTH cortisol concentration is more than 120 nmol/l (4.3 μg/dl) then the dose of trilostane is increased. If the post ACTH cortisol concentration is between these two values and the patient appears to be clinically well controlled then the dose is unaltered. If however the post ACTH cortisol concentration is between these two values and the patient appears not to be clinically well controlled then the trilostane may need to be given twice daily. If an ACTH stimulation test is performed at times other than 4 to 6 hours after trilostane then the post ACTH cortisol concentration should be more than 20 nmol/l (0.7 μg/dl) and less than 250 nmol/l (9 μg/dl).
Once the clinical condition of the animal and the dose rate has been stabilized then dogs should be examined and an ACTH stimulation test performed every 3 to 4 months. Serum biochemistry (especially electrolytes) should be performed periodically to check for hyperkalemia.
It is concluded that trilostane is an acceptable alternative to mitotane for the treatment of canine PDH. However, the optimal dose rate and frequency of administration need to be determined from pharmacokinetic studies. Trilostane may also be useful in canine ADH and equine Cushing's disease but more studies are needed. Its use in any of these diseases does not remove the need for regular veterinary monitoring. As the post-ACTH cortisol concentration is variable depending on the time at which the test is performed it may not be the optimal test for assessing the efficacy of trilostane therapy. However no comparison has yet been made with other tests of adrenal gland function.