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Treatment of Wilson's Disease With Ammonium Tetrathiomolybdate: I. Initial Therapy in 17 Neurologically Affected Patients

Treatment of Wilson's Disease With Ammonium Tetrathiomolybdate: I. Initial Therapy in 17... Abstract Objective: To test the efficacy and toxicity of a new drug, ammonium tetrathiomolybdate, in the initial treatment of a relatively large series of patients presenting with neurologic signs and symptoms caused by Wilson's disease. The key aspect of efficacy was to preserve the neurologic function present at the onset of therapy. Design: An open study of 17 patients treated for 8 weeks each. Neurologic function was evaluated by frequent quantitative neurologic and speech examinations. Several copper-related variables were studied to evaluate the effect of the drug on copper, and a large number of biochemical and clinical variables were studied to evaluate potential toxicity. Patients were then followed up at yearly intervals, with follow-up periods of 1 to 5 years reported. Setting: A university hospital referral setting. Intervention: Patients were generally treated for 8 weeks with tetrathiomolybdate, followed by zinc maintenance therapy. Main Outcome Measures: Neurologic function was evaluated by quantitative neurologic and speech examinations. Results: None of the patients suffered a loss of neurologic function. Copper status and potential further toxic effects were generally well controlled quickly. No toxic effects resulted from administration of tetrathiomolybdate. During the ensuing period of follow-up of 1 to 5 years, neurologic recovery in most patients was good to excellent. Conclusions: Tetrathiomolybdate appears to be an excellent form of initial treatment in patients with Wilson's disease presenting with neurologic signs and symptoms. In contrast to penicillamine therapy, initial treatment with tetrathiomolybdate does not result in further, often irreversible neurologic deterioration. References 1. Brewer GJ, Terry CA, Aisen AM, Hill GM. Worsening of neurological syndrome in patients with Wilson's disease with initial penicillamine therapy . Arch Neurol . 1987;44:490-494.Crossref 2. Brewer GJ, Dick RD, Yuzbasiyan-Gurkan V, Tankanow R, Young AB, Kluin KJ. Initial therapy of Wilson's disease patients with tetrathiomolybdate . Arch Neurol . 1991;48:42-47.Crossref 3. Brewer GJ, Yuzbasiyan-Gurkan V. Wilson's disease . Medicine . 1992;71:139-164.Crossref 4. Brewer GJ, Hill GM, Prasad AS, Cossack ZT, Rabbani P. Oral zinc therapy for Wilson's disease . Ann Intern Med . 1983;99:314-320.Crossref 5. Hill GM, Brewer GJ, Prasad AS, Hydrick CR, Hartmann DE. Treatment of Wilson's disease with zinc, I: oral zinc therapy regimens . Hepatology . 1987;7:522-528.Crossref 6. Ferguson WS, Lewis AL, Waterson SJ. The teart pastures of Somerset, I: the cause and cure of teartness . J Agri Sci . 1943;33:44.Crossref 7. Dick AT, Bull LB. Some preliminary observations of the effect of molybdenum on copper metabolism in herbivorous animals . Aust Vet J . 1945;21:70-72.Crossref 8. Miller RF, Engel RW. Interrelations of copper, molybdenum and sulfate sulfur in nutrition . Fed Proc . 1960;19:666-677. 9. Marcilese Ammerman CB, Valsecchi RM, Dunavant BG, Davis GK. Effect of dietary molybdenum and sulfate upon copper metabolism in sheep . J Nutr . 1969;99:177-183. 10. Mills CF, Monty KJ, Ichihara A, Pearson PB. Metabolic effects of molybdenum toxicity in the rat . J Nutr . 1958;65:129-142. 11. Cox DH, Davis GK, Shirley RL, Jack FH. Influence of excess dietary molybdenum on rat and calf liver and heart enzymes . J Nutr . 1960;70:63-68. 12. Dick AT, Dewey DW, Gawthorne JM. Thiomolybdates and the copper-molybdenum-sulphur interaction in ruminant nutrition . J Agri Sci . 1975;85:567-568.Crossref 13. Mason J. The biochemical pathogenesis of molybdenum-induced copper deficiency syndromes in ruminants: towards the final chapter . Ir Vet J . 1990;43: 18-21. 14. McQuaid A, Mason J. A comparison of the effects of penicillamine, trientine, and trithiomolybdate on [35S]-labeled metallothionein in vitro: the implications for Wilson's disease therapy . J Inorg Biochem . 1991;41:87-92.Crossref 15. Mills CF, El-Gallad TT, Bremner I. Effects of molybdate, sulfide, and tetrathiomolybdate on copper metabolism in rats . J Inorg Biochem . 1981;14:189-207.Crossref 16. Bremner I, Mills CF, Young BW. Copper metabolism in rats given di- or trithiomolybdates . J Inorg Biochem . 1982;16:109-119.Crossref 17. Mills CF, El-Gallad TT, Bremner I, Wenham G. Copper and molybdenum absorption by rats given ammonium tetrathiomolybdate . J Inorg Biochem . 1981; 14:163-175.Crossref 18. Gooneratne SR, Howell JM, Gawthorne JM. An investigation of the effects of intravenous administration of thiomolybdate on copper metabolism in chronic Cu-poisoned sheep . Br J Nutr . 1981;46:469-480.Crossref 19. Young AB, Shoulson I, Penney JB, et al. Huntington's disease in Venezuela: neurologic features and functional decline . Neurology . 1986;36:244-249.Crossref 20. Brewer GJ, Hill GM, Dick RD, et al. Treatment of Wilson's disease with zinc, III: prevention of reaccumulation of hepatic copper . J Lab Clin Med . 1987;109: 526-531. 21. Brewer GJ, Hill GM, Prasad AS, Dick RD. The treatment of Wilson's disease with zinc, IV: efficacy monitoring using urine and plasma copper . Proc Soc Exp Biol Med . 1987;7:446-455.Crossref 22. Jacob RA, Sandstead HH, Munoz JM, Klevay LM, Milne DB. Whole body surface loss of trace metals in normal males . Am J Clin Nutr . 1981;34:1379-1383. 23. Brewer GJ, Yuzbasiyan-Gurkan V, Dick R. Zinc therapy of Wilson's disease, VIII: dose response studies . Trace Elem Exp Med . 1990;3:227-234. 24. Harper PI, Walshe JM. Reversible pancytopenia secondary to treatment with tetrathiomolybdate . Br J Haematol . 1986;64:851-853.Crossref 25. Brewer GJ. Thiomolybdates in the treatment of Wilson's disease . Arch Neurol . 1992;49:132-133.Crossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Neurology American Medical Association

Treatment of Wilson's Disease With Ammonium Tetrathiomolybdate: I. Initial Therapy in 17 Neurologically Affected Patients

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References (29)

Publisher
American Medical Association
Copyright
Copyright © 1994 American Medical Association. All Rights Reserved.
ISSN
0003-9942
eISSN
1538-3687
DOI
10.1001/archneur.1994.00540180023009
Publisher site
See Article on Publisher Site

Abstract

Abstract Objective: To test the efficacy and toxicity of a new drug, ammonium tetrathiomolybdate, in the initial treatment of a relatively large series of patients presenting with neurologic signs and symptoms caused by Wilson's disease. The key aspect of efficacy was to preserve the neurologic function present at the onset of therapy. Design: An open study of 17 patients treated for 8 weeks each. Neurologic function was evaluated by frequent quantitative neurologic and speech examinations. Several copper-related variables were studied to evaluate the effect of the drug on copper, and a large number of biochemical and clinical variables were studied to evaluate potential toxicity. Patients were then followed up at yearly intervals, with follow-up periods of 1 to 5 years reported. Setting: A university hospital referral setting. Intervention: Patients were generally treated for 8 weeks with tetrathiomolybdate, followed by zinc maintenance therapy. Main Outcome Measures: Neurologic function was evaluated by quantitative neurologic and speech examinations. Results: None of the patients suffered a loss of neurologic function. Copper status and potential further toxic effects were generally well controlled quickly. No toxic effects resulted from administration of tetrathiomolybdate. During the ensuing period of follow-up of 1 to 5 years, neurologic recovery in most patients was good to excellent. Conclusions: Tetrathiomolybdate appears to be an excellent form of initial treatment in patients with Wilson's disease presenting with neurologic signs and symptoms. In contrast to penicillamine therapy, initial treatment with tetrathiomolybdate does not result in further, often irreversible neurologic deterioration. References 1. Brewer GJ, Terry CA, Aisen AM, Hill GM. Worsening of neurological syndrome in patients with Wilson's disease with initial penicillamine therapy . Arch Neurol . 1987;44:490-494.Crossref 2. Brewer GJ, Dick RD, Yuzbasiyan-Gurkan V, Tankanow R, Young AB, Kluin KJ. Initial therapy of Wilson's disease patients with tetrathiomolybdate . Arch Neurol . 1991;48:42-47.Crossref 3. Brewer GJ, Yuzbasiyan-Gurkan V. Wilson's disease . Medicine . 1992;71:139-164.Crossref 4. Brewer GJ, Hill GM, Prasad AS, Cossack ZT, Rabbani P. Oral zinc therapy for Wilson's disease . Ann Intern Med . 1983;99:314-320.Crossref 5. Hill GM, Brewer GJ, Prasad AS, Hydrick CR, Hartmann DE. Treatment of Wilson's disease with zinc, I: oral zinc therapy regimens . Hepatology . 1987;7:522-528.Crossref 6. Ferguson WS, Lewis AL, Waterson SJ. The teart pastures of Somerset, I: the cause and cure of teartness . J Agri Sci . 1943;33:44.Crossref 7. Dick AT, Bull LB. Some preliminary observations of the effect of molybdenum on copper metabolism in herbivorous animals . Aust Vet J . 1945;21:70-72.Crossref 8. Miller RF, Engel RW. Interrelations of copper, molybdenum and sulfate sulfur in nutrition . Fed Proc . 1960;19:666-677. 9. Marcilese Ammerman CB, Valsecchi RM, Dunavant BG, Davis GK. Effect of dietary molybdenum and sulfate upon copper metabolism in sheep . J Nutr . 1969;99:177-183. 10. Mills CF, Monty KJ, Ichihara A, Pearson PB. Metabolic effects of molybdenum toxicity in the rat . J Nutr . 1958;65:129-142. 11. Cox DH, Davis GK, Shirley RL, Jack FH. Influence of excess dietary molybdenum on rat and calf liver and heart enzymes . J Nutr . 1960;70:63-68. 12. Dick AT, Dewey DW, Gawthorne JM. Thiomolybdates and the copper-molybdenum-sulphur interaction in ruminant nutrition . J Agri Sci . 1975;85:567-568.Crossref 13. Mason J. The biochemical pathogenesis of molybdenum-induced copper deficiency syndromes in ruminants: towards the final chapter . Ir Vet J . 1990;43: 18-21. 14. McQuaid A, Mason J. A comparison of the effects of penicillamine, trientine, and trithiomolybdate on [35S]-labeled metallothionein in vitro: the implications for Wilson's disease therapy . J Inorg Biochem . 1991;41:87-92.Crossref 15. Mills CF, El-Gallad TT, Bremner I. Effects of molybdate, sulfide, and tetrathiomolybdate on copper metabolism in rats . J Inorg Biochem . 1981;14:189-207.Crossref 16. Bremner I, Mills CF, Young BW. Copper metabolism in rats given di- or trithiomolybdates . J Inorg Biochem . 1982;16:109-119.Crossref 17. Mills CF, El-Gallad TT, Bremner I, Wenham G. Copper and molybdenum absorption by rats given ammonium tetrathiomolybdate . J Inorg Biochem . 1981; 14:163-175.Crossref 18. Gooneratne SR, Howell JM, Gawthorne JM. An investigation of the effects of intravenous administration of thiomolybdate on copper metabolism in chronic Cu-poisoned sheep . Br J Nutr . 1981;46:469-480.Crossref 19. Young AB, Shoulson I, Penney JB, et al. Huntington's disease in Venezuela: neurologic features and functional decline . Neurology . 1986;36:244-249.Crossref 20. Brewer GJ, Hill GM, Dick RD, et al. Treatment of Wilson's disease with zinc, III: prevention of reaccumulation of hepatic copper . J Lab Clin Med . 1987;109: 526-531. 21. Brewer GJ, Hill GM, Prasad AS, Dick RD. The treatment of Wilson's disease with zinc, IV: efficacy monitoring using urine and plasma copper . Proc Soc Exp Biol Med . 1987;7:446-455.Crossref 22. Jacob RA, Sandstead HH, Munoz JM, Klevay LM, Milne DB. Whole body surface loss of trace metals in normal males . Am J Clin Nutr . 1981;34:1379-1383. 23. Brewer GJ, Yuzbasiyan-Gurkan V, Dick R. Zinc therapy of Wilson's disease, VIII: dose response studies . Trace Elem Exp Med . 1990;3:227-234. 24. Harper PI, Walshe JM. Reversible pancytopenia secondary to treatment with tetrathiomolybdate . Br J Haematol . 1986;64:851-853.Crossref 25. Brewer GJ. Thiomolybdates in the treatment of Wilson's disease . Arch Neurol . 1992;49:132-133.Crossref

Journal

Archives of NeurologyAmerican Medical Association

Published: Jun 1, 1994

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