New Developments in Treatment of Insulinoma By Deborah

New Developments in Treatment of Insulinoma By Deborah Cottrell DVM westendanimal. com

Insulinoma Overview • Incidence in older ferrets may be close to 50% • May be related to diet, but this is still speculation • MEN 1 syndrome known to be hereditary in people • Article by May Van Dahm: Results of a Four Year Study on Light Sensitivity in Ferrets

Insulinoma Overview • Early warnings: drooling, staring into space, ataxia, muscle twitching • Progressing to screaming, seizuring, and death if untreated • Unlike dogs, most are benign, but almost always multiple and recurring • Timing of symptoms not related to food intake, since insulinomas secrete large amounts insulin in unpredictable cycles

Diagnosis • Fast ferret four hours if possible, no more than six • Fasting blood glucose of less than 70 mg/dl is pretty diagnostic • Insulin/glucose ratio probably not necessary • Radiographs to rule out gastric foreign body as cause

Easy Blood Draw Technique

Foreign Bodies • Can lower blood glucose if they don’t completely occlude pylorus or small intestine and cause classic symptoms of blockage.

Standard Treatments • • • Surgical treatment: nodulectomy Surgical treatment: partial pancreatectomy Medical treatment: Prednisolone Medical treatment: Diazoxide Combining surgical and medical treatment can buy another two years of quality life

Nodulectomy • Advantage: Quick and easy • Disadvantage: Less time without symptoms

Partial Pancreatectomy • Advantage: Longer time without symptoms • Disadvantages: Can create diabetes, occasionally permanently • Cannot remove right lobe near pylorus due to presence of bile duct

Pancreatic Duct/Bile Duct

Medical Treatment • Prednisone or Prednisolone Body converts prednisone to prednisolone Ferrets can tolerate high doses Mobilizes carb stores to raise glucose level • Diazoxide Also well-tolerated, but efficacy is erratic Expensive

Investigative Treatments • • Verapamil/Amlodipine Streptozotocin Doxorubicin (Adriamycin) Octreotide

Verapamil/Amlodipine • • • Based on one case report in human Unknown efficacy in animals Normally used for hypertension Verapamil is anti-arrhythmic Amlodipine is calcium channel blocker

Streptozotocin • Specifically toxic to pancreatic beta cells • May be carcinogenic • Originally an antibiotic derived from the microorganism Streptomyces achromogenes • Not tested in ferrets • Dog data two studies with mixed results • Dosed at 500 mg/m 2 every three weeks

Streptozotocin Warning • Recent anecdotal evidence and small numbers of trial cases have shown this drug to be very toxic to ferrets at the previously recommended dose. If you wish to try it, it is suggested you use 200 mg/m 2

Doxorubicin (Adriamycin) • Dose used in ferrets much lower than people— humans=60 mg/m 2; ferrets=5 mg/m 2 • Dog dose for insulinoma=30 mg/m 2 • Dose of 1 mg per ferret given IV every three weeks for four treatments • Few side effects at this dose • Consider increasing dose to increase effectiveness

Octreotide • Analog of somatostatin, a natural hormone • Once daily dose of 50 micrograms subcutaneously was used in both humans and dogs • Results extremely encouraging • Efficacy in ferrets not well-known, but appears safe and well tolerated • Cost is $15 -20 per 50 mcg vial

Alternative/Complementary Treatments • Glucosamine: warnings exist about diabetics taking it, because it has potential to raise blood sugar. May be helpful, and also relieve mild arthritis • Brewer’s yeast: Chromium may help, but evidence is conflicting. • Xiao Yao San: Widely used in TCM, but I found NO evidence.

Drug Doses • Pred: start at 0. 25 mg/lb p. o. sid. Go up to 2 mg/lb bid with few problems • Diazoxide: start at 5 mg/lb p. o. bid. Go up to 15 mg/lb bid with few problems • Streptozotocin: extrapolate from dog dose of 500 mg/m 2 iv • Adriamycin: 30 mg/m 2 iv standard dose • Doxorubicin: 1 mg iv standard dose • Verapamil: 1 mg/kg p. o. bid • Amlodipine: 0. 1 mg/kg p. o. bid • Octreotide: 1 -2 mcg/kg sub. Q bid-tid

References • • • Eastman RC, Come SE, Strewler GJ, Gorden P, Kahn CR. Adriamycin Therapy for Advanced Insulinoma. J Clin Endocrinol Metab. 1977 Jan; 44(1): 142 -8. Dobson J and Gorman T. Cancer Chemotherapy in Small Animal Practice. Blackwell Scientific Publications. 1993, p 20. Shimada A, Morita T, Ikeda N, Torii S, Haruna A. Hypoglycemic Brain Lesions in a Dog with Insulinoma. J Comp Pathol 2000 Jan; 122 (1): 67 -71. Moertel CG, Lavin PT, Hahn RG. Phase II Trial of Doxorubicin Therapy for Advanced Islet Cell Carcinoma. Cancer Treat Rep. 1982 Jul; 66(7); 1567 -9. Dutton M. Case Studies of Doxorubicin for the Treatment of Ferret Insulinoma (12 Cases). Exotic Mammal Medicine & Surgery 2004 May; 2. 1. Caplan ER, Peterson ME, Mullen HS, Quesenberry KE, Rosenthal KL, Hoefer HL, Moroff SD. Diagnosis and Treatment of Insulin-secreting Pancreatic Islet Cell Tumors in Ferrets: 57 cases (1986 -1994). J Am Vet Med Assoc. 1996 Nov 15; 209(10); 1741 -5.

References • • • Igaz P, Igaz I, Racz K, Tulassay Z. Hereditary Tumors of the Endocrine Pancreas. Orv Hetil. 2006 Feb 5; 147(5): 195 -200. Robben JH, vad den Brom WE, Mol JA, van Haeften TW, Rijnberk A. Effect of Octreotide on Plasma Concentrations of Glucose, Insulin, Glucagon, Growth Hormone, and Cortisol in Healthy Dogs and Dogs with Insulinoma. Res Vet Sci. 2006 Feb; 80(1): 25 -32. Kishakawa H, Okada Y, Hirose A, Tanikawa T, Kanda K, Tanaka Y. Successful Treatment of Insulinoma by a Single Daily Dose of Octreotide in Two Elderly Female Patients. Endocr J. 2006 Feb; 53(1): 79 -85. Weiss CA, Williams BH, Scott MV. Insulinoma in the Ferret: Clinical Findings and Treatment Comparison of 66 Cases. J Am Anim Hosp Assoc. 1998 Nov-Dec; 34(6): 471 -5. Bell R, Mooney CT, Mansfield CS, Jones BR. Treatment of Insulinoma in a Springer Spaniel with Streptozotocin. J Small Anim Prac. 2005 May; 46(5): 247 -50.

References • • • Owecki M, Sowinski J. Successful Pharmacological Treatment of Hyperinsulinemic Hypoglycemia with Verapamil and Amlodipine-Case Report. Pol Merkuriusz Lek. 2005 Aug; 19(110): 196 -8. Eatwell K. Two Unusual Tumors in a Ferret (Mustela putorius furo). J Small Anim Prac. 2004 Sept; 45(9); 454 -9. Van Dahm M. Results of a 4 Year Study on Light Sensitivity in Ferrets.