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Tetrathiomolybdate versus Trientine in the Initial Treatment of Neurologic Wilson's Disease

Published online by Cambridge University Press:  08 June 2007

George J. Brewer ,
Fred Askari ,
Matthew T. Lorincz ,
Martha Carlson ,
Michael Schilsky ,
Karen J. Kluin ,
Peter Hedera ,
Paolo Moretti ,
John K. Fink  and
Roberta Tankanow
...Show all authors
George J. Brewer
Affiliation:
Department of Human Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Email: brewergj@umich.edu
Fred Askari
Affiliation:
Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Email: faskari@med.umich.edu
Matthew T. Lorincz
Affiliation:
Department of Neurology, University of Michigan, Ann Arbor, MI, USA; Email: lorincz@umich.edu
Martha Carlson
Affiliation:
Department of Pediatrics-Neurology, University of Michigan, Ann Arbor, MI, USA; Email: marthac@umich.edu
Michael Schilsky
Affiliation:
Department of Internal Medicine, Cornell University, New York, NY, USA; Email: mls2003@med.cornell.edu
Karen J. Kluin
Affiliation:
Department of Neurology, Department of Speech Pathology, University of Michigan, Ann Arbor, MI, USA; Email: niulk@umich.edu
Peter Hedera
Affiliation:
Department of Neurology, Vanderbilt University, Nashville, TN, USA; Email: peter.hedera@Vanderbilt.Edu
Paolo Moretti
Affiliation:
Departments of Neurology and Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Email: pmoretti@bcm.tmc.edu
John K. Fink
Affiliation:
Department of Neurology, University of Michigan, Ann Arbor, MI, USA; Email: jkfink@umich.edu
Roberta Tankanow
Affiliation:
College of Pharmacy, University of Michigan, Ann Arbor, MI, USA; Email: robertat@umich.edu
Robert B. Dick
Affiliation:
Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA; Email: bobdick@umich.edu
Julia Sitterly
Affiliation:
Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA; Email: sitterly@umich.edu
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Extract

ABSTRACT

Background: The initial treatment of the neurologic presentation of Wilson's disease is problematic. Penicillamine, used for years on most patients, causes neurologic worsening in up to half of such patients, and half of those who worsen never recover. Zinc, ideal for maintenance therapy, is too slow for these acutely ill patients. We have developed tetrathiomolybdate (TM) for this type of patient, and it has worked well in open label studies. Trientine, another anticopper drug on the market approved for penicillamine intolerant patients, had not been tried in this type of patient. Here, we report on a double blind trial of TM versus trientine in the neurologically presenting Wilson's disease patient. Design and Methods: The study was a double blind design in which patients received either TM plus zinc, or trientine plus zinc, for 8 weeksThis study was originally published in reference 1. Patients were accepted if they presented with neurologic symptoms from Wilson's disease, if they had not been treated longer than 4 weeks with penicillamine or trientine. Patients were followed in the hospital for the 8 weeks of treatment with weekly semiquantitative neurologic and speech examinations, to evaluate possible neurologic worsening. They also had blood and urine studies done weekly. At discharge from hospital they were continued on zinc maintenance therapy, and returned at yearly intervals for 3 years for further evaluation. Results: Twenty-three patients were entered into the trientine arm and 6 reached criteria for neurologic deterioration, while 25 patients were entered into the TM arm and only 1 deteriorated (p < 0.05). One patient on trientine had an adverse event while 7 on TM had adverse events. All adverse events were mild. Four patients in the trientine arm died during follow-up, 3 having shown initial neurologic deterioration, 2 patients in the TM arm died. In those patients who did not deteriorate or die, neurologic and speech recovery over 3 years was good. Interpretation: TM is a superior choice to trientine for the initial therapy of neurologic Wilson's disease.

Keywords

copper toxicitydouble blind trialneurologic damagetetrathiomolybdatetrientineWilson's disease
Type
Research Article
Information
Progress in Neurotherapeutics and Neuropsychopharmacology , Volume 3 , Issue 1 , January 2008 , pp. 153 - 165
Copyright
© 2008 Cambridge University Press

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References

Akil, M., Schwartz, J.A., Dutchak, D., Yuzbasiyan-Gurkan, V., & Brewer, G.J. (1991). The psychiatric presentations of Wilson's disease. The Journal of Neuropsychiatry and Clinical Neurosciences, 3, 377–382.Google Scholar
Askari, F.K., Greenson, J., Dick, R.D., Johnson, V.D., & Brewer, G.J. (2003). Treatment of Wilson's disease with zinc. XVIII. Initial treatment of the hepatic decompensation presentation with trientine and zinc. The Journal of Laboratory and Clinical Medicine, 142, 385–390.Google Scholar
Bremner, I., Mills, C.F., & Young, B.W. (1982). Copper metabolism in rats given di- or trithiomolybdates. Journal of Inorganic Biochemistry, 16, 109–119.Google Scholar
Brewer, G.J. (2001). Wilson's Disease: A Clinician's Guide to Recognition, Diagnosis, and Management. Boston, MA: Kluwer Academic Publishers.
Brewer, G.J. (2004). Wilson's disease. In: Kasper, D.L., Braunward, E., Fauci, A.S., Hauser, S.L., Longo, D.L., & Jameson, J.L. (eds.), Harrison's Principles of Internal Medicine. New York, NY: McGraw-Hill Companies, Inc, pp. 2313–2315.
Brewer, G.J. (2005a). Neurologically presenting Wilson's disease: epidemiology, pathophysiology and treatment. CNS Drugs, 19, 185–192.Google Scholar
Brewer, G.J. (2005b). Behavioral abnormalities in Wilson's disease. In: Weiner, W.J., Lang, A.E., & Anderson, K.E. (eds.), Behavioral Neurology of Movement Disorders. Philadelphia: Lippincott, Williams & Wilkins, pp. 262–274.
Brewer, G.J. (2006). Novel therapeutic approaches to the treatment of Wilson's disease. Expert Opinion on Pharmacotherapy, 7, 317–324.Google Scholar
Brewer, G.J., & Askari, F.K. (2005). Wilson's disease: clinical management and therapy. Journal of Hepatology, 42, S13–S21.Google Scholar
Brewer, G.J., & Yuzbasiyan-Gurkan, V. (1992). Wilson disease. Medicine, 71, 139–164.Google Scholar
Brewer, G.J., Hill, G.M., Prasad, A.S., Cossack, Z.T., & Rabbani, P. (1983). Oral zinc therapy for Wilson's disease. Annals of Internal Medicine, 99, 314–319.Google Scholar
Brewer, G.J., Hill, G., Prasad, A., & Dick, R. (1987a). The treatment of Wilson's disease with zinc. IV. Efficacy monitoring using urine and plasma copper. Proceedings of the Society for Experimental Biology and Medicine, 184, 446–455.Google Scholar
Brewer, G.J., Terry, C.A., Aisen, A.M., & Hill, G.M. (1987b). Worsening of neurologic syndrome in patients with Wilson's disease with initial penicillamine therapy. Archives of Neurology, 44, 490–493.Google Scholar
Brewer, G.J., Dick, R.D., Yuzbasiyan-Gurkan, V., Tankanow, R., Young, A.B., & Kluin, K.J. (1991). Initial therapy of patients with Wilson's disease with tetrathiomolybdate. Archives of Neurology, 48, 42–47.Google Scholar
Brewer, G.J., Yuzbasiyan-Gurkan, V., Johnson, V., Dick, R.D., & Wang, Y. (1993). Treatment of Wilson's disease with zinc XII: dose regimen requirements. The American Journal of the Medical Sciences, 305, 199–202.Google Scholar
Brewer, G.J., Dick, R.D., Johnson, V., Wang, Y., Yuzbasiyan-Gurkan, V., Kluin, K., et al. (1994a). Treatment of Wilson's disease with ammonium tetrathiomolybdate. I. Initial therapy in 17 neurologically affected patients. Archives of Neurology, 51, 545–554.Google Scholar
Brewer, G.J., Dick, R.D., Yuzbasiyan-Gurkan, V., Johnson, V., & Wang, Y. (1994b). Treatment of Wilson's disease with zinc. XIII: therapy with zinc in presymptomatic patients from the time of diagnosis. The Journal of Laboratory and Clinical Medicine, 123, 849–858.Google Scholar
Brewer, G.J., Johnson, V., Dick, R.D., Kluin, K.J., Fink, J.K., & Brunberg, J.A. (1996). Treatment of Wilson disease with ammonium tetrathiomolybdate. II. Initial therapy in 33 neurologically affected patients and follow-up with zinc therapy. Archives of Neurology, 53, 1017–1025.Google Scholar
Brewer, G.J., Dick, R.D., Johnson, V.D., Brunberg, J.A., Kluin, K.J., & Fink, J.K. (1998). Treatment of Wilson's disease with zinc: XV long-term follow-up studies. The Journal of Laboratory and Clinical Medicine, 132, 264–278.Google Scholar
Brewer, G.J., Hedera, P., Kluin, K.J., Carlson, M., Askari, F., Dick, R.B., et al. (2003). Treatment of Wilson disease with ammonium tetrathiomolybdate: III. Initial therapy in a total of 55 neurologically affected patients and follow-up with zinc therapy. Archives of Neurology, 60, 379–385.Google Scholar
Brewer, G.J., Askari, F., Lorincz, M.T., Carlson, M., Schilsky, M., Kluin, K.J., et al. (2006). Treatment of Wilson disease with ammonium tetrathiomolybdate: IV. Comparison of tetrathiomolybdate and trientine in a double-blind study of treatment of the neurologic presentation of Wilson disease. Archives of Neurology, 63, 521–527.Google Scholar
Bull, P.C., Thomas, G.R., Rommens, J.M., Forbes, J.R., & Cox, D.W. (1993). The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. Nature Genetics, 5, 327–337.Google Scholar
Fink, J.K., Hedera, P., & Brewer, G.J. (1999). Hepatolenticular degeneration (Wilson's disease). The Neurologist, 5, 171–185.Google Scholar
Gooneratne, S.R., Howell, J.M., & Gawthorne, J.M. (1981). An investigation of the effects of intravenous administration of thiomolybdate on copper metabolism in chronic Cu-poisoned sheep. The British Journal of Nutrition, 46, 469–480.Google Scholar
Hill, G.M., Brewer, G.J., Prasad, A.S., Hydrick, C.R., & Hartmann, D.E. (1987). Treatment of Wilson's disease with zinc. I. Oral zinc therapy regimens. Hepatology, 7, 522–528.Google Scholar
Hoogenraad, T.U., Koevoet, R., & de Ruyter Korver, E.G. (1979). Oral zinc sulphate as long-term treatment in Wilson's disease (hepatolenticular degeneration). European Neurology, 18, 205–211.Google Scholar
Hoogenraad, T.U., Van Hattum, J., & Van den Hamer, C.J.A. (1987). Management of Wilson's disease with zinc sulfate. Experience in a series of 27 patients. Journal of the Neurological Sciences, 77, 137–146.Google Scholar
Mason, J. (1990). The biochemical pathogenesis of molybdenum-induced copper deficiency syndromes in ruminants: towards the final chapter. Irish Veterinary Journal, 43, 18–21.Google Scholar
Mills, C.F., El-Gallad, T.T., & Bremner, I. (1981a). Effects of molybdate, sulfide, and tetrathiomolybdate on copper metabolism in rats. Journal of Inorganic Biochemistry, 14, 189–207.Google Scholar
Mills, C.F., El-Gallad, T.T., Bremner, I., & Weham, G. (1981b). Copper and molybdenum absorption by rats given ammonium tetrathiomolybdate. Journal of Inorganic Biochemistry, 14, 163–175.Google Scholar
Scheinberg, I.H., & Sternlieb, I. (1998). Wilson's disease. In: Smith, L.H.J. (ed.), Major Problems in Internal Medicine. Philadelphia: W.B. Saunders Company, pp. 1–171.
Schilsky, M.L. (1996). Wilson disease: genetic basis of copper toxicity and natural history. Seminars in Liver Disease, 16, 83–95.Google Scholar
Tanzi, R.E., Petrukhin, K., Chernov, I., Pellequer, J.L., Wasco, W., Ross, B., et al. (1993). The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Nature Genetics, 5, 344–350.Google Scholar
Walshe, J.M. (1956). Penicillamine, a new oral therapy for Wilson's disease. American Journal of Medicine, 21, 487–495.Google Scholar
Walshe, J.M. (1982). Treatment of Wilson's disease with trientine (triethylene tetramine) dihydrochloride. Lancet, 1, 643–647.Google Scholar
Yamaguchi, Y., Heiny, M.E., & Gitlin, J.D. (1993). Isolation and characterization of a human liver cDNA as a candidate gene for Wilson disease. Biochemical and Biophysical Research Communications, 197, 271–277.Google Scholar
Yuzbasiyan-Gurkan, V., Grider, A., Nostrant, T., Cousins, R.J., & Brewer, G.J. (1992). Treatment of Wilson's disease with zinc: X. Intestinal metallothionein induction. The Journal of Laboratory and Clinical Medicine, 120, 380–386.Google Scholar