PHASE III TRIAL OF TETRATHIOMOLYBDATE IN INITIAL HEPATIC WILSON'S DISEASE

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中出现。列出的机构是中心的机构，不一定是研究者的机构。我们过去的研究导致 FDA 批准锌用于威尔逊病的维持治疗。锌现在可以替代毒性更大的青霉胺和曲恩汀。当威尔逊氏病患者首次出现铜中毒症状时，锌对于治疗其作用太慢。这些患者可能因脑损伤或肝损伤而患有急性或慢性疾病。对于患有大脑（神经系统）发育的患者，我们正在开发一种安全、快速、有效的新药四硫代钼酸盐 (TM)。然而，尚未开展工作来确定治疗最初因威尔逊病铜中毒而出现肝病并已出现肝脏问题的患者的最佳方法。根据经验，我们使用曲恩汀和锌的组合来治疗这些患者。我们已经治疗了九名患者，每一位患者都已康复。现在，我们相信通过TM治疗这些患者可以取得更多成果。 TM 非常成功地拯救了铜中毒的羊，否则它们会死于肝功能衰竭。我们有机会用TM治疗了一位患有威尔逊氏病的患者，该患者同时出现神经系统症状和肝功能衰竭，该患者的肝功能恢复速度是用曲恩汀和锌治疗的九名患者的两倍。我们将包括所有患者（包括儿童），包括男性和女性、所有种族群体。他们将被随机分配接受 TM、曲恩汀或青霉胺治疗。所有患者也将接受锌治疗。患者将在密歇根大学医院综合临床研究中心住院约6周，然后在家接受药物治疗18周。每周都会在家抽血以进行持续评估。 24 周后，患者将接受锌维持治疗。如果这项研究表明TM对于这类患者来说是一种更好的治疗方法，那么它将降低患者的风险期，让更多的患者保留自己的肝脏，而不是接受肝移植，并保存供体肝脏以挽救其他生命。它还可以减少永久性肝损伤和由此产生的并发症。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our past research has led to the development of an FDA approval of zinc for maintenance therapy of Wilson's disease. Zinc can now replace penicillamine and trientine, which have much more toxicity. Zinc is too slow acting for treating Wilson's disease patients when they first present with copper toxicity illness. These patients may be acutely or chonically ill from brain damage or liver damage. For the patients presenting with brain (neurologic) development, we are well along on developing a new drug, tetrathiomolybdate (TM), which is safe, fast-acting, and effective. However, no work has been done on identifying the best way to treat patients who intially present with liver disease from copper toxicity in Wilson's disease, and have developed liver problems. Empirically, we have used a combination of trientine and zinc to treat these patients. We have treated nine patients and in each case, they have recovered. Now, we believe we can accomplish even more with TM treatment of these patients. TM is dramatically successful in saving copper poisoned sheep, who otherwise die of liver failure. We had occasion to treat one Wilson's disease patient who came in with both neurologic symptoms and liver failure with TM, and the liver function recovered twice as fast in that patient as in the nine treated with trientine and zinc. We will include all patients (including children), both males and females, all ethnic groups in this study. They will be randomly assigned to TM, trientine, or penicillamine therapy. All patients will receive zinc as well. Patients will be in the General Clinical Research Center of University of Michigan Hospital for about 6 weeks, then receive the drugs at home for another 18 weeks. Blood will be drawn every week at home for continuing evaluation. After 24 weeks, patients will be placed on zinc maintenance therapy. If this study shows TM to be a superior treatment for this kind of patient, it will decrease the risk period for the patient, allow more patients to retain their own livers, as opposed to receiving a liver transplant, and save donor livers to save other lives. It may also decrease the amount of permanent liver damage and resulting complications.