Treatment of Wilson Disease With Ammonium Tetrathiomolybdate

Brewer, George J.; Hedera, Peter; Kluin, Karen J.; Carlson, Martha; Askari, Fred; Dick, Robert; Sitterly, Julia; Fink, John K.

doi:10.1001/archneur.60.3.379

Cited by 232 publications

(53 citation statements)

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“…We observed two side effects in this study [29]. One was anemia, sometimes accompanied by leukopenia, in six patients.…”

Section: Development Of Tetrathiomolybdate For Wilson's Diseasesupporting

confidence: 48%

“…Only 2 of the 55 patients reached our criteria, or 3.6%, compared with the roughly 50% that worsened on penicillamine therapy [29]. Over the next 2 years, during which the patients were on maintenance zinc therapy, they showed substantial neurologic recovery.…”

Section: Development Of Tetrathiomolybdate For Wilson's Diseasementioning

confidence: 83%

“…Our first trial was an open study that accrued 55 patients [29]. The design included an 8-week admission to the General Clinical Research Center of the University of Michigan Hospital, during which the patient received 20 mg of TM three times daily with meals and 60À350 mg of TM away from food.…”

Section: Development Of Tetrathiomolybdate For Wilson's Diseasementioning

confidence: 99%

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Copper‐lowering therapy with tetrathiomolybdate for cancer and diseases of fibrosis and inflammation

Brewer

2003

J Trace Elements Exper Med

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Angiogenesis is required for tumor growth and is a likely Achilles heel for cancer. However, antiangiogenic agents have been somewhat disappointing in cancer therapy, perhaps because they target a single angiogenic factor, and there is much redundancy in angiogenic systems. Copper is required for high levels of angiogenesis, and many angiogenic factors have a requirement for copper. Thus, anticopper drugs offer the possibility of more global inhibition. Our group has developed tetrathiomolybdate (TM) for the initial treatment of neurologic Wilson's disease. Penicillamine makes about 50% of these patients neurologically worse, and many never recover. Only 2 of 55 (3.6%) patients worsened when treated with TM. Because TM exhibited desirable properties of potency, speed, and safety, we studied it as an antiangiogenic agent. We hypothesize that if copper is lowered to midrange, the cellular requirements for copper are met, but angiogenic cytokine signaling is inhibited. TM has shown strong inhibition of cancer growth in five rodent models, encouraging results in a canine study of advanced and metastatic cancer, and encouraging results in a phase 1/2 study of advanced and metastatic cancer in 42 patients. Finally, we have hypothesized that the pathway of fibrosis involving transforming growth factor beta (TGF-b) and connective tissue growth factor is inhibitable by copper-lowering therapy with TM. This pathway is overactive and dysregulated in many diseases of fibrosis. In animal studies, TM has completely inhibited the pulmonary fibrosis induced by bleomycin, the hepatitis induced by concanavalin A, and the cirrhosis induced by carbon tetrachloride. We find that TM inhibits transforming growth factor beta and inflammatory cytokines tumor necrosis factor alpha and interleukin-1-beta.

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“…We observed two side effects in this study [29]. One was anemia, sometimes accompanied by leukopenia, in six patients.…”

Section: Development Of Tetrathiomolybdate For Wilson's Diseasesupporting

confidence: 48%

Section: Development Of Tetrathiomolybdate For Wilson's Diseasementioning

confidence: 83%

See 1 more Smart Citation

Copper‐lowering therapy with tetrathiomolybdate for cancer and diseases of fibrosis and inflammation

Brewer

2003

J Trace Elements Exper Med

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“…Its fast action and lack of appreciable toxicity has established its utility in this area [10][11][12]. The mechanism of TTM's action is proposed to be the decreasing availability of copper to one or more key systems in the body [13][14][15][16].…”

mentioning

confidence: 99%

“…As TTM is proposed to be used as a drug [10][11][12] it seemed of interest to check whether it reacts with NO and whether this reaction involves nitrosation of TTM.…”

mentioning

confidence: 99%

On the reaction mechanism of MoS42− with nitric oxide

Popivker

Zilbermann

Maimon³

et al. 2010

Inorganic Chemistry Communications

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Treatment of Wilson Disease With Ammonium Tetrathiomolybdate

Brewer¹,

Askari²,

Lorincz³

et al. 2006

Arch Neurol

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281

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Objective: To compare tetrathiomolybdate and trientine in treating patients with the neurologic presentation of Wilson disease for the frequency of neurologic worsening, adverse effects, and degree of neurologic recovery. Design: A randomized, double-blind, controlled, 2-arm study of 48 patients with the neurologic presentation of Wilson disease. Patients either received 500 mg of trientine hydrochloride 2 times per day or 20 mg of tetrathiomolybdate 3 times per day with meals and 20 mg 3 times per day between meals for 8 weeks. All patients received 50 mg of zinc 2 times per day. Patients were hospitalized for 8 weeks, with neurologic and speech function assessed weekly; discharged taking 50 mg of zinc 3 times per day, and returned annually for follow-up. Setting: A university hospital referral setting. Patients: Primarily newly diagnosed patients with Wilson disease presenting with neurologic symptoms who had not been treated longer than 4 weeks with an anticopper drug. Intervention: Treatment with either trientine plus zinc or tetrathiomolybdate plus zinc. Main Outcome Measures: Neurologic function was assessed by semiquantitative neurologic and speech examinations. Drug adverse events were evaluated by blood cell counts and biochemical measures. Results: Six of 23 patients in the trientine arm and 1 of 25 patients in the tetrathiomolybdate arm underwent neurologic deterioration (PϽ.05). Three patients receiving tetrathiomolybdate had adverse effects of anemia and/or leukopenia, and 4 had further transaminase elevations. One patient receiving trientine had an adverse effect of anemia. Four patients receiving trientine died during follow-up, 3 having shown initial neurologic deterioration. Neurologic and speech recovery during a 3-year follow-up period were quite good. Conclusion: Tetrathiomolybdate is a better choice than trientine for preserving neurologic function in patients who present with neurologic disease. ClinicalTrials.gov Identifier: NCT00004339

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Treatment of Wilson Disease With Ammonium Tetrathiomolybdate

Abstract: Tetrathiomolybdate shows excellent efficacy in patients with Wilson disease who present with neurologic manifestations. With rapid escalation of dose, adverse effects from bone marrow suppression or aminotransferase elevations can occur.

Cited by 232 publications

References 20 publications

Copper‐lowering therapy with tetrathiomolybdate for cancer and diseases of fibrosis and inflammation

Copper‐lowering therapy with tetrathiomolybdate for cancer and diseases of fibrosis and inflammation

On the reaction mechanism of MoS42− with nitric oxide

Treatment of Wilson Disease With Ammonium Tetrathiomolybdate

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