In pharmacodynamic studies, the methods used included net copper balance and radiolabeled copper uptake in Wilson’s disease patients. These studies showed that a regimen of 50 mg t.i.d. of zinc acetate was effective in inducing a negative mean copper balance (-0.44 mg/day) and an adequate mean 64Cu uptake (0.82% of the administered dose). A regimen of 25 mg t.i.d. of zinc acetate was also pharmacodynamically active but fewer patients have been treated with this regimen than 50 mg t.i.d.
Clinical Trials
In the single center United States trial, 60 patients with Wilson’s disease (31 male, 29 female) who had adequate detoxification of copper after initial chelation therapy were entered into a copper balance study of various dose regimens of zinc acetate. Patients were hospitalized to carefully control food and liquid intake. Food, urine and feces were analyzed for copper content, and copper balance was defined as the difference between copper intake and copper elimination/excretion over a 10-day period. A patient was considered in adequate copper balance if the result was less than +0.25 mg copper/day. Results for the groups in each dose regimen tested and for adequacy of individual results are provided in the following table.
Number of Patients
Inadequately
Dose Regimen Mean Copper Controlled/Total
(mg zinc x number Balance number of patients
of daily doses) N* (mg/day) studied
*N = number of copper balance studies. Some patients had more than one balance study, at different doses or at the same dose at widely separated intervals.
50 x 3 70 -0.36 6/70
50 x 2 5 -0.16 0/5
25 x 4 5 -0.21 0/5
25 x 3 11 -0.18 1/11
37.5 x 2 4 -0.02 1/4
75 x 1 8 0.16 2/8
25 x 2 4 0.15 1/4
25 x 1 10 -0.37 2/10
25 x 6 12 0.05 4/12
50 x 1 1 0.1 0/1
50 x 5 11 -0.3 1/11
0 6 0.52 –
While all zinc acetate regimens appeared better than no therapy, there was little experience with doses other than 50 mg t.i.d. Once daily dosing did not appear to give satisfactory control in many cases, and would be inadequate in patients with poor compliance. Based on the limited data available 25 mg t.i.d. was also thought to be an adequate dose regimen, and not shown to be inferior to 50 mg t.i.d. Dose related toxicity was not found in this study.
Symptomatic Patients Initially Treated With a Chelating Drug
Clinical parameters such as neuropsychiatric status including eva luation of speech, and liver function tests were followed as the patients continued therapy on an adequate zinc acetate dose regimen. One hundred and thirty-three patients were followed for up to 14 years. There was no deterioration of neuropsychiatric function including speech and biochemical liver function tests, including bilirubin, transaminases, alkaline phosphatase and lactic dehydrogenase. The liver function tests remained either within normal range or slightly above the upper limit of normal for up to 9 years of treatment.
Pre-symptomatic Patients
In this study 30 pre-symptomatic patients were followed for up to 10 years. Diagnosis of the pre-symptomatic Wilson’s disease was made on the basis of a liver copper value greater than 200 μg of copper per gram dry weight of tissue.
Non-ceruloplasmin copper levels, 64Cu balance studies, and clinical parameters were assessed. No patient developed symptoms of Wilson’s disease in this cohort. Since the cloning and sequencing of the abnormal genes in Wilson’s disease patients, many mutati |
