Treatment of Wilson Disease With Ammonium Tetrathiomolybdate

Abstract

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

Worsening of Wilson Disease following Penicillamine Therapy

“…It was found that tetrathiomolybdate was superior to trientine. In this study, 6 out of 23 (26%) patients on trientine deteriorated [23,24]. The patients who deteriorated on penicillamine are a great challenge and the safety and efficacy of alternative drugs including trientine needs to be explored.…”

Role of Oxidative Stress in the Worsening of Neurologic Wilson Disease Following Chelating Therapy

“…Value in mean ± SD or median (range) (Brewer et al 1987). In another randomized controlled trial, 6 out of 23 patients on trientine had deterioration and 3 of them died, whereas only 1 out of 25 deteriorated on tetrathiomolybdate (Brewer et al 2006). Asymptomatic WD patients are less likely to have worsening compared to symptomatic patients.…”

“…The exact mechanism of neurologic deterioration following chelating therapy is not known, but studies have suggested redistribution of Cu from the hepatic and visceral organs to the brain (Bruha et al 2012;Chen et al 2012;Choi and Zheng 2009;Halliwell 2001;Stuerenburg 2000;Gromadzka et al 2014;Brewer et al 2003Brewer et al , 2006Brewer et al , 2009. Moreover, there may be shifting of Cu from various intra-neuronal locale following chelating treatment (Chen et al 2012).…”

Triethylene tetramine dihydrochloride (trientine) in children with Wilson disease: experience at King’s College Hospital and review of the literature

“…A total of 14 studies were identified [2,3,5,9,11,13,15,[18][19][20][21][23][24][25]. These are summarised in Table 4.…”

“…None of the studies had a sample size calculation. Only one study was a randomised controlled trial [5], but the outcome was not clearly defined and many participants had previous exposure to other chelation, which had not been controlled for (level IC). Three studies were prospective evaluations of copper clearance comparing trientine to penicillamine (level IIIB).…”