INITIAL THERAPY OF WILSON'S DISEASE

背景：威尔逊病是一种常染色体隐性遗传疾病，无论种族，每30，000人中就有1人发病。 青霉胺是开发用于治疗这些患者的第一种口服药物，然而，在治疗的初始阶段，用青霉胺治疗威尔逊病的神经系统表现导致10-50%的神经系统恶化。 虽然许多人通过持续治疗康复，但有些患者留下永久性严重残疾。 另外两种口服螯合剂已被用于治疗威尔逊氏病，四硫代钼酸盐（TM），一种正在评估的实验药物，和Trientine，一种批准用于青霉胺不耐受患者的替代剂。 锌是另一种通过阻断铜吸收而起作用的口服药物，但其起效缓慢，因此在治疗的初始阶段不太可能有效。研究目的：本研究的目的是通过比较四硫代钼酸盐（TM）（一种实验性铜螯合剂）与Trientine，确定威尔逊病神经系统表现患者的最佳初始治疗模式。 该研究的设计是给予患者TM或Trientine沿着锌，锌是一种本身阻止铜吸收但不直接清除铜储存的药物。 这些方案的有效性将通过监测非血浆铜蓝蛋白结合铜和尿铜排泄的减少以及肝功能异常（如果在开始时存在）的正常化进行生化测定。 在8周治疗期间，还将通过每周一次的神经学和言语检查对患者进行临床监测。 每周进行血液学和生化筛查;以排除药物毒性。 如果患者在两周的检查期内表现出神经系统恶化，或者如果发生严重的血液学或生化异常，则患者将退出方案。治疗后，患者将继续接受锌治疗，并根据需要每两年或更频繁地进行监测。 入组本研究的患者将被怀疑患有威尔逊氏病作为其神经系统疾病的病因，并且作为研究的一部分完成了对这种疾病的评估，或者通过适当的测试被诊断为患有威尔逊氏病并用青霉胺治疗不到两周。

Background: Wilson's disease is an autosomal recessive disorder that affects 1 in 30,000 individuals regardless of ethnicity. Penicillamine was the first oral agent developed for treatment of these patients, however treatment with Penicillamine for neurologic manifestations of Wilson's disease causes neurologic worsening in 10-50% during the initial phase of treatment. While many recover with continued treatment, some patients are left with permanent severe disabilities. Two other oral chelating agents have been utilized for treatment of Wilson's disease, tetrathiomolybdate (TM), an experimental drug under evaluation, and Trientine, an alternative agent approved for use in Penicillamine intolerant patients. Zinc is another oral agent that acts by blocking copper absorption, however its onset of action is slow and therefore is less likely to be efficacious in the initial phase of treatment. Study Objective: The objective of the study is to determine the best initial mode of therapy for patients with neurologic manifestations of Wilson's disease by comparing tetrathiomolybdate (TM), an experimental copper-chelator with Trientine. The design of the study is to give patients either TM or trientine along with zinc, an agent that itself blocks copper absorption but does not directly remove copper stores. The effectiveness of these regimens will be determined biochemically by monitoring for reductions in non-ceruloplasmin bound copper and in urine copper excretion, and for normalization of abnormal liver functions if present at the outset. Patients will also be monitored clinically by neurologic and speech examinations performed on a weekly basis for the eight weeks of treatment. Hematologic and biochemical screening will be performed weekly; to exclude drug toxicity. Patients will be withdrawn from the protocol if they manifest neurologic worsening over a two week period of examination or if serious hematologic or biochemical abnormalities occur. Following this treatment, patients will be maintained on zinc therapy and monitored biannually or more frequently as necessary. Patients to be enrolled in this study will either have been suspected of having Wilson's disease as the etiology of their neurologic disease, and the evaluation for this disorder completed as part of the study, or have been diagnosed as having Wilson's disease with appropriate testing and treated for less than two weeks with Penicillamine.