Pet Endocrinology: Diabetes, Thyroid & Adrenal Disease Compounding
Low Dose Trilostane for Canine Cushing’s Disease
Cushing’s Disease (hyperadrenocorticism) is a common condition in older dogs, often mistaken for the aging process itself. Dogs get pot bellies, lose hair, drink and eat excessively, urinate in the house, and make owners begin to prematurely consider euthanasia. Yet, Cushing’s disease is treatable and that treatment can result in a longer, more comfortable life for the dog and its owner.
Trilostane is the most promising FDA-approved treatment for canine Cushing’s disease. Current FDA approved labeling for trilostane (Vetoryl™) lists the recommended dose at 3-6mg/kg body weight orally once daily, and Vetoryl™ capsules are available in strengths of 10mg, 30mg and 60mg. Several studies conducted prior to US-approval of trilostane referenced effective doses ranging from 6-12mg/kg orally per day. After noting that many dogs treated with trilostane at the labeled dose demonstrated symptoms of hypoadrenocorticism (Addison’s Disease), clinical endocrinologists at the University of California Davis College of Veterinary Medicine evaluated the safety and efficacy of lower doses of trilostane. Investigators in this trial administered trilostane to dogs diagnosed with Cushing’s disease at doses ranging from 0.5-2.5mg/kg orally every 12 hours and evaluated dogs for therapeutic progress at 3 different treatment intervals over a total treatment period of 8-16 weeks. After 1 to 2 weeks, mean trilostane dosage was 1.4 mg/kg (0.64 mg/lb) every 12 hours (n = 22 dogs; good response [resolution of signs], 8; poor response, 14). Four to 8 weeks later, mean dosage was 1.8 mg/kg (0.82 mg/lb) every 12 or 8 hours (n = 21 and 1 dogs, respectively; good response, 15; poor response, 5; 2 dogs were ill). Eight to 16 weeks after the second reevaluation, remaining dogs had good responses (mean dosages, 1.9 mg/kg [0.86 mg/lb], q 12 h [n = 13 dogs] and 1.3 mg/kg [0.59 mg/lb], q 8 h [n =3]).
Since many dogs that develop Cushing’s disease are smaller breed dogs weighing less than 9kg (e.g. terriers and poodles), the commercially available capsules (10mg, 30mg and 60mg) are too large for appropriate therapy. As a result of the UC-Davis study, many veterinarians are requesting compounding pharmacists to compound smaller doses of trilostane as capsules or oral suspensions. On September 11, 2009, the Center for Veterinary Medicine division of the Food and Drug Administration issued a statement to veterinarians and pharmacists that “trilostane can only be legally compounded by using FDA-approved VETORYL™ as the starting material”, and that “…trilostane should not be imported from other countries or compounded from (the) bulk (chemical)”. As Vetoryl™ is only available for sale to licensed veterinarians in the US, and use of the bulk chemical to compound trilostane will not be tolerated by FDA, veterinarians and pharmacists are advised to collaborate to ensure availability of safe and legal compounded dosage forms of trilostane for dogs requiring lower doses than are commercially available.
J Am Vet Med Assoc 2008;232:1321–1328.
Evaluation of twice-daily, low dose trilostane treatment in dogs with naturally occurring hyperadrenocorticism.
Click here to access the abstract of this article.
Phenoxybenzamine for Dogs with Pheochromocytoma
Some studies in dogs undergoing adrenalectomy for pheochromocytoma suggest that anesthetic complications and perioperative mortality are common. In humans, surgical outcome has improved with the use of phenoxybenzamine (PBZ) before adrenalectomy. Therefore, at the School of Veterinary Medicine, University of California, Davis, it was hypothesized that dogs treated with PBZ before adrenalectomy have increased survival compared with untreated dogs, and they conducted a retrospective medical record review of 48 dogs that underwent adrenalectomy for pheochromocytoma from January 1986 through December 2005. Twenty-three of 48 dogs were pretreated with PBZ (median dosage: 0.6 mg/kg PO q12h) for a median duration of 20 days before adrenalectomy. Duration of anesthesia and surgery, percentage of dogs with pheochromocytoma involving the right versus left adrenal gland, size of tumor, and presence of vascular invasion were similar for PBZ-treated and untreated dogs. Thirty-three (69%) of 48 dogs survived adrenalectomy in the perioperative period. PBZ-treated dogs had a significantly decreased mortality rate compared with untreated dogs (13 versus 48%, respectively). Additional significant prognostic factors for improved survival included younger age, lack of intraoperative arrhythmias, and decreased surgical time. Results from this retrospective study support treatment with PBZ before surgical removal of pheochromocytoma in dogs.
J Vet Intern Med. 2008 Nov-Dec;22(6):1333-9.
Predictive factors and the effect of phenoxybenzamine on outcome in dogs undergoing adrenalectomy for pheochromocytoma.
Click here to access the PubMed abstract of this article.
Transdermal Carbimazole Gel for the Treatment of Feline Hyperthyroidism
The aim of a study conducted by Buijtels et al. of Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, The Netherlands, and presented at the 16th ECVIM-CA Congress, 2006, was to develop a carbimazole gel for application at the inner pinna of the ear and to study its effectiveness in cats with hyperthyroidism. The results of this study indicate that twice daily administration of carbimazole gel at the inner pinna of the ear is an effective treatment of cats with hyperthyroidism.
Tijdschrift voor Diergeneeskunde. 2006; 131(13):478-82
[Transdermal carbimazole for the treatment of feline hyperthyroidism]
Click here to read the PubMed abstract of this article.
PZI and Low-Dose Insulin
The commercial production of traditional beef &/or pork insulins has declined as most human diabetic patients (the majority of the consumers) are being switched to human insulin products because of the reduced risk of allergic reactions. Protamine zinc insulin occurs as a sterile suspension of insulin modified by the addition of protamine sulfate and zinc chloride, and has a long duration of action (up to 30 hours). Therefore, treatment of many dogs and cats has been accomplished with once daily dosing of PZI.
U-20 and U-40 insulin allow for more accurate measurement of smaller doses required by many pets and birds. Use of U-100 insulin can result in morbidity or mortality caused by dosing errors.
Oral Anti-Diabetic Drugs
“may be appropriate for cats that are in good overall health with early or mild clinical signs of diabetes and those with owners who are unwilling or unable to administer insulin injections.”1 The oral hypoglycemic medication, glipizide, provides a viable therapeutic alternative to conventional insulin therapy with a positive therapeutic response in approximately 50% of diabetic cats with non-insulin-dependent disease. Response to glipizide therapy or lack thereof usually is evident within the first 4 to 6 weeks of treatment. Adverse side effects occurred in less than 10% of patients. The existence of residual beta cell function is necessary for response to glipizide therapy. Discontinuation of diabetogenic medications that may be contributing to insulin resistance is important.2
According to Deborah S. Greco, DVM, Ph.D., diplomate ACVIM, glipizide has been used successfully to treat diabetes mellitus in cats at a dosage of 2.5 to 5 mg two times daily, when combined with dietary fiber therapy. Dr. Greco recommends evaluating the patient weekly or every two weeks for a period of 2 to 3 months. If the fasting blood sugar decreases to less than 200 mg/dL, the glipizide should be continued at the same dosage and the cat reevaluated in 3 to 6 months. If the fasting blood glucose remains >200 mg/dL after 2 to 3 months of therapy and the cat is still symptomatic (polyuria, polydipsia, weight loss), glipizide should be discontinued and insulin therapy instituted. If the blood glucose remains >200 mg/dL and the cat becomes asymptomatic, glipizide should be continued indefinitely and the cat rechecked in 3-6 months.3
1 Compendium 23(7), July 2001, 633-640
2 Vet Clin North Am Small Anim Pract 1995 May;25(3):599-615
NIDDM in the cat: treatment with the oral hypoglycemic medication, glipizide.
Click here to access the PubMed abstract of this article.
3 presented at the 1999 Southern California VMA Seminar and the 116th Indiana VMA Seminar
Methimazole for Feline Hyperthyroid Disease
“Methimazole is the drug of choice for the medical management of feline hyperthyroid disease. It is safer and more potent than propylthiouracil in blocking thyroid hormone synthesis. Use of the drug generally will bring serum T4 into normal ranges within 2 to 3 weeks… Adverse effects have been observed in approximately 15% of cats and generally are transient. Anorexia, vomiting, and transient lethargy have been reported. Serum antinuclear antibodies develop in many cats with long-term use of the drug. A glucocorticoid-responsive pruritus involving the face, ears, and neck may occur. In less than 2% of cases, thrombocytopenia or agranulocytosis have been reported in cats treated with [methimazole]. Withdrawal of the drug and provision of care for thrombocytopenia or agranulocytosis generally results in resolution… Cats on chronic methimazole therapy should be rechecked every 3 to 6 months to assay serum T4 levels and to check for signs of drug toxicity.”
Handbook of Veterinary Drugs, 2nd edition, ©1998, pp. 239-240
According to the International Journal of Pharmaceutical Compounding (Vol. 5, No. 2, March/April 2001, p. 96), “it could be theorized that transdermal administration would produce a … higher blood level of methimazole than that resulting from oral administration of the drug. A higher blood level of [methimazole] might result in a slightly greater risk of adverse effects, so drug therapy might need to be initiated at a slightly lower dose than that of the traditional oral dose.” The author of the article (GiGi Davidson, R.Ph., DICVP, North Carolina State University, College of Veterinary Medicine) states that anecdotal evidence indicates that this is true of “most transdermally administered doses of methimazole. The most measurable parameter for efficacy is the response of the serum T4 level.”
Note: Methimazole is also used to decrease renal toxicity of cisplatin in dogs.
Transdermal Methimazole Applied to Ear of Hyperthyroid Cats
Francis Arsenault, D.V.M., New Brunswick
The following six cats have received methimazole in a pluronic lecithin organogel (PLO) which the owners apply to the inner side of the ear. Overall, we have found this to be very effective therapy with good compliance. Transdermal administration can be particularly helpful for owners who have arthritis and those who have great difficulty “pilling” the cat. Methimazole doses have ranged from 2.5mg to 12.5 mg daily, divided into two doses.
Cat #1 (S.A.): 17 years old, has been on methimazole 1.25mg/0.1 ml PLO to inside of ear twice daily for nine months. The owner reports that the medicine is easy to administer and absorbs well. I am pleased with the clinical results.
Cat #2 (A.L.): 18 years old, has been using methimazole for six months. This cat was started on 3.5mg/0.1ml PLO BID. Several dosage adjustments were necessary. We increased the concentration of the transdermal gel to 5.0mg/0.1ml PLO, and the owner now applies 7.5mg/0.15ml PLO in the AM and 5mg/0.1ml in the PM. She places plastic wrap over her finger before applying the medication, which she has found to be much easier to use than pills, with no stress to the pet. She states the measurements on the topical dispenser are easy to read, and she needs to wash the cat’s ear to remove the coating left by the medication.
Cat #3 (B.M.): was started on methimazole eight months ago at 5mg/0.1ml PLO BID. The dose was decreased to 2.5mg BID. The cat’s owner stated the medication was very easy to use. B.M. improved clinically and gained weight, and is no longer on the med.
Cat #4 (S.O.): used medication once only.
Cat #5 (D.O.): same owner as cat #4, received methimazole 2.5mg/0.05ml PLO BID for two months. No longer on medication.
Cat #6 (M.B.): 19 years old, has received methimazole 1.25mg/0.1ml PLO BID for four months. The owner says the medication is easy to apply, and alternates ears. It is necessary to wipe the ear each day as the medication does leave a residue.
Adrenal Disease in Male Ferrets
Adrenal gland disease is a common problem in middle-aged to older ferrets. The disease results in one or both of the adrenal glands producing abnormal amounts of androgens and/or estrogens, and can cause hair loss, itching, vulvar enlargement in females, prostate enlargement in male ferrets which can block the flow of urine, and in rare cases, bone marrow suppression. Although not usually a serious health concern, ferrets may have no relief from the itching that is associated with this disease if it is not treated.
Flutamide is an androgen blocker that may help relieve prostatic enlargement. It is dosed at 10 mg/kg, PO, every 12-24 hours. Liver enzymes should be checked at one month and every six months thereafter. Mitotane may be effective in younger ferrets but may cause nausea and lethargy. Ketoconazole is usually ineffective.1
1 Evelyn Ivey, DVM, Dip ABVP, San Diego Co VMA Conf Procd, Sep 2000
Mitotane for Canine Hyperadrenocorticism
In veterinary medicine, mitotane is used primarily for the medical treatment of pituitary-dependent hyper-adrenocorticism (PDH) and palliative therapy of adrenal carcinoma, usually in dogs. Systemic drug availability has been found to be very poor from intact tablets in fasted dogs, and best when the powdered drug is mixed in oil and poured on dog food. The interaction between food and mitotane probably contributes to the variation in clinical response of dogs treated with the drug, because it appears that the efficacy is improved considerably when the drug is given with food. Because of the potentially severe toxicity associated with mitotane, clients should be instructed to wear gloves during and wash their hands after administering the medication, and to keep the medication out of reach of children or pets. Dogs with concurrent diabetes mellitus may have rapidly changing insulin requirements during the initial treatment period, and should be closely monitored until they are clinically stable. Clients should be advised of the symptoms of acute hypoadrenocorticism. Because of the potential severe toxicity associated with mitotane, clients should be instructed to wash their hands after administration and to keep the medication out of reach of children or pets.
Res Vet Sci 1987 Sep;43(2):160-5
Systemic availability of o,p’-DDD in normal dogs, fasted and fed, and in dogs with hyperadrenocorticism.
Click here to access the PubMed abstract of this article.
Veterinary Drug Handbook, 2nd Edition, by Donald C. Plumb