Copper is an essential cofactor for many enzymatic reactions, but excessive tissue and blood copper concentrations can result in life-threatening hepatic failure, neurologic derangements, renal tubular disease, and hemolysis.1–4 Disorders of copper metabolism include Wilson disease in humans, copper toxicosis in sheep, and CACH in dogs. Regardless of the species or pathological process, diseases associated with copper overload are often treated with copper-chelating agents such as d-penicillamine, trientine, or TTM. d-penicillamine has been used to treat Wilson disease since the 1950s,5 but adverse effects frequently occur and can preclude use of this drug for treatment in some cases.2 Since 1989, d-penicillamine has been replaced primarily with trientine and more recently with TTM.2 Although a newer drug in human medicine, TTM has been used to effectively treat sheep with copper toxicosis since the 1980s.3 The copper-chelating effect of molybdenum was first observed in 1943.6
Since the original description of copper toxicosis in Bedlington Terriers in 1975, d-penicillamine has remained the drug of choice for chelation therapy of CACH.7 However, variable therapeutic responses have been observed, and some dogs have minimal or no reduction in hepatic copper concentrations after receiving treatment for several months.8,9 Even in dogs that respond to treatment, the duration of d-penicillamine treatment can range from 2 to 16 months.10 The expense of d-penicillamine prevents some owners from pursuing treatment. Furthermore, gastrointestinal adverse effects occur in approximately 20% of dogs, which has led some authors to recommend coadministration of the drug with a meal.11 However, this practice results in markedly decreased drug absorption.12 Although d-penicillamine remains an effective drug for many dogs with CACH, these limitations warrant evaluation of alternative agents.
Ammonium tetrathiomolybdate has potential value as a chelating agent for CACH. It is unique as a copper chelator because of its additive actions in the intestinal tract, plasma, and hepatic tissue.13 When used for Wilson disease, it has superior therapeutic efficacy, compared with the efficacy for trientine or d-penicillamine.2,14,15 It is specifically indicated for humans with neurologic manifestations of Wilson disease because other treatments often lead to worsening and sometimes irreversible clinical signs.2,14,15 In rodents with experimentally induced Wilson disease, intraperitoneal administration of a single dose of TTM rapidly reduces clinical signs, total hepatic copper concentrations, and liver enzyme activities.16 Given the success of TTM for treating copper overload in other species, critical evaluation of this agent is needed in dogs.
To the authors' knowledge, use of TTM has not been reported in dogs with CACH. The only report of TTM use in dogs was a small study17 of dogs with metastatic neoplasia in which the drug was administered for its antiangiogenic properties. The pharmacokinetics of TTM have been reported in sheep and rats, with discordant results.18,19 Dosages and frequency of administration for the treatment of copper storage diseases also differ widely across species.3,14,17,20,21 Prior to clinical evaluation of TTM in dogs with CACH, pharmacological evaluation of the drug is warranted. The purposes of the study reported here were to determine pharmacokinetics after oral and IV administration of TTM to healthy dogs and to evaluate effects of TTM administration on serum trace mineral concentrations. We hypothesized that serum copper concentrations would increase after TTM administration.
Supported by the Michigan State University College of Veterinary Medicine Endowed Research Funds and the Michigan State University College of Veterinary Medicine Trinket Fund.
Presented in abstract form at the American College of Veterinary Internal Medicine Forum, Nashville, June 2014, and as a poster at the Michigan State University Phi Zeta Research Day, East Lansing, Michigan, October 2013.
The authors declare no conflicts of interest.
The authors thank Justin Zyskowski for technical assistance.
Area under the curve
Copper-associated chronic hepatitis
Inductively coupled plasma mass spectrometry
Time to maximum concentration
Pro Plan Chicken and Rice Adult Maintenance Food, Nestlé Purina PetCare Co, St Louis, Mo.
Sigma-Aldrich Corp, St Louis, Mo.
Cerenia [package insert]. New York: Pfizer Animal Health, 2012.
7500ce inductively coupled plasma mass spectrometer, Agilent Technologies, Santa Clara, Calif.
National Institute of Standards & Technology. Certificate of Analysis for Standard Reference Material SRM 1598a. Inorganic Constituents in Animal Serum. Gaithersburg, Md: National Institute of Standards and Technology. Available at www-s.nist.gov/m-srmors/view_detail.cfm?srm=1598a (last updated 4/8/2014). Accessed Mar 31, 2015.
UV160U spectrophotometer with CPS 240A cell positioner, Shimadzu, Kyoto, Japan.
Varian Vista Pro with radial aligned torch, Agilent Technologies, Santa Clara, Calif.
Avantor Performance Materials, Center Valley, Pa.
National Institute of Standards & Technology. Certificate of Analysis for Standard Reference Material SRM 1573a–Tomato Leaves. Gaithersburg, Md: National Institute of Standards and Technology. Available at www-s.nist.gov/m-srmors/view_detail.cfm?srm=1573a (last updated 10/17/2013). Accessed Mar 31, 2015.
Quality Control-21, Alfa Aesar, Ward Hill, Mass.
PKSolver, version 2.0, China Pharmaceutical University, Nanjing, China.
Prism, version 6.00 for Windows, GraphPad Software Inc, La Jolla, Calif.
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