THERAPY OF WILSONS DISEASE W/ TETRATHIOMOLYBDATE COMPARISON W/ TRIENTINE

威尔逊病的维持治疗现在很好地涵盖了最近FDA批准的醋酸锌。 然而，神经系统疾病患者的初始治疗存在问题。 锌是相当缓慢的作用和疾病的急性病患者可能进展之前，锌控制铜毒性。 铜螯合剂，已被用于威尔逊病，青霉胺，是非常危险的，这些患者。 我们已经证明，一半的青霉胺治疗的患者神经系统恶化，许多未能恢复，可能是由于铜重新分配到大脑。 铜螯合剂trientine的使用有限，但似乎比青霉胺的副作用更少。 目前还没有关于初始恶化的报道，尽管理论上Trientine有这种风险，我们已经引入了一种新的孤儿药（四硫代钼酸盐，或TM）用于这些患者的初始治疗。 TM具有理想的快速作用特性，且不会引起初始恶化。 在孤儿产品办公室的赠款下，我们在51名患者中进行了一项为期8周的开放式研究。 我们已经表现出良好的神经功能的初始保存，并在1年和2年的良好恢复。 副作用很小，主要发生在高剂量下。 在此，我们提出了一项为期3年、II/III期、双盲、两个中心的研究，比较TM与曲恩汀用于神经系统疾病患者的初始治疗。 我们计划对90名患者进行试验，每组45名，但功效计算表明，我们可以从60名患者中获得非常有用的数据。 需要回答的主要问题是：初始神经功能恶化的速度是否存在差异？ 第1年和第2年的神经学恢复程度是否有差异？ 严重副作用的发生率是否存在差异？ 在研究完成时，我们不仅将回答与TM vs. Trientine相关的问题，还将表征Trientine（一种已上市的药物）在初始治疗环境中的疗效和毒性。

The maintenance therapy of Wilson's disease is now well covered with the recent FDA approval of zinc acetate. However, the initial therapy of patients presenting with neurologic disease is problematic. Zinc is rather slow-acting and the disease of the acutely ill patient may progress prior to zinc controlling copper toxicity. The copper chelator that has been used the longest for Wilson's disease, penicillamine, is extremely dangerous for these patients. We've shown that half of penicillamine treated patients deteriorate neurologically, with many failing to recover, probably due to redistribution of copper into the brain. The copper chelator, trientine, has seen limited use, but seems to have fewer side effects than penicillamine. Initial worsening has not yet been reported, although it is a theoretical risk with trientine.We have introduced a new orphan drug (tetrathiomolybdate, or TM) for the initial treatment of these patients. TM has ideal properties of fast action, and doesn't cause initial worsening. Supported by grants from the Orphan Products Office, we have carried out an open study of an initial 8 weeks of therapy in 51 patients. We have shown excellent initial preservation of neurological function, and excellent recovery at 1 and 2 years. Side effects have been minimal and have occurred primarily at high doses. Here we propose a 3 year, phase II/III double blind, two site, study comparing TM to trientine for initial therapy of neurologically presenting patients. We project a trial of 90 patients, 45 in each arm, but power calculations show that we can get very useful data with 60 patients. The major questions to be answered are: Is there a difference in the rate of initial neurological deterioration? Is there a difference in degree of neuological recovery at years 1 and 2? Are there differences in the incidence of serious side effects? At the completion of the study, we will not only have answered the questions relating to TM vs. trientine, but we will have characterized the efficacy and toxicity of trientine, a drug already on the market, in the initial treatment setting.