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

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。我们过去的研究已经导致FDA批准锌用于威尔逊病的维持治疗。锌现在可以取代毒性更大的青霉胺和曲恩汀。锌对于治疗威尔逊病患者来说作用太慢，当他们首次出现铜中毒疾病时。这些患者可能是急性或慢性病，脑损伤或肝损伤。对于大脑（神经）发育的患者，我们沿着在开发一种新的药物，四硫代钼酸盐（TM），这是安全的，快速起效，有效。然而，没有工作已经做了确定最好的方法来治疗最初出现肝脏疾病的患者，这些患者来自威尔逊病中的铜毒性，并且已经发展出肝脏问题。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9名病人，每一个病例都已经康复。现在，我们相信我们可以通过对这些患者的TM治疗取得更多成就。TM在拯救铜中毒的羊方面取得了巨大的成功，否则这些羊会死于肝功能衰竭。我们有机会用TM治疗一名同时伴有神经系统症状和肝功能衰竭的威尔逊病患者，该患者的肝功能恢复速度是用曲恩汀和锌治疗的9名患者的两倍。我们将纳入所有患者（包括儿童），包括男性和女性，本研究中的所有种族。他们将被随机分配接受TM、曲恩汀或青霉胺治疗。所有患者也将获得锌。患者将在密歇根大学医院的综合临床研究中心接受约6周的治疗，然后在家中接受另外18周的药物治疗。每周在家中抽血进行持续评估。24周后，患者将接受锌维持治疗。如果这项研究表明TM是这类患者的上级治疗方法，它将减少患者的风险期，允许更多的患者保留自己的肝脏，而不是接受肝脏移植，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的数量。

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.