This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor 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.'
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