THERAPY OF WILSONS DISEASE W/ TETRATHIOMOLYBDATE COMPARISON W/ TRIENTINE

最近FDA批准了醋酸锌，这很好地涵盖了威尔逊病的维持疗法。然而，对表现为神经系统疾病的患者的初始治疗是有问题的。锌的作用相当缓慢，急病患者的病情可能会在锌控制铜中毒之前进展。治疗威尔逊氏病使用时间最长的铜络合剂青霉胺对这些患者来说是极其危险的。我们已经证明，接受青霉胺治疗的患者中有一半神经学恶化，许多人未能恢复，可能是由于铜重新分配到大脑中。铜络合剂曲恩汀的使用有限，但似乎比青霉胺的副作用更少。最初的恶化还没有报道，尽管理论上三丁胺有风险。我们已经推出了一种新的孤儿药物(四硫钼酸盐，或TM)用于这些患者的初步治疗。TM具有快速起效的理想特性，并且不会导致最初的恶化。在孤儿产品办公室的资助下，我们对51名患者进行了一项最初8周的治疗的开放研究。我们已经显示出良好的初始神经功能保存，以及1年和2年后的良好恢复。副作用一直很小，主要发生在高剂量。在这里，我们提出了一项为期3年的、II/III期双盲、两个部位的研究，比较TM和曲宁汀对神经科表现患者的初始治疗。我们计划对90名患者进行试验，每支手臂45名，但功率计算显示，我们可以在60名患者中获得非常有用的数据。需要回答的主要问题是：最初的神经恶化速度是否存在差异？第一年和第二年的神经功能恢复程度有差异吗？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和Trientine有关的问题，而且我们将确定已上市的药物Trientine在最初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.