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.Primary biliary cirrhosis (PBC) is a serious disease of the liver that is usually progressive, and often fatal within 5-10 years. PBC has a poor prognosis, usually affects adults, and is more common in females. Currently only one treatment, ursodiol, offers some improvement, and that is usually only partial. Usually the disease progresses in spite of ursodiol therapy. In PBC patients already on ursodiol therapy, we propose to test whether a new experimental treatment, with a study drug called tetrathiomolybdate (TM), can halt further progression of PBC, and stabilize or improve liver function. TM is not yet approved by the FDA for use in humans, except for experimental studies such as this. Bleomycin mouse model studies demonstrated an antifibrotic and antiinflammatory effect of tetrathiomolybdate (TM) therapy in the lung. Concanavalin A and carbon tetrachloride mouse model studies demonstrate antifibrotic and antiinflammatory effects in the liver. TM is an anticopper drug developed for Wilson's disease. TM also produces an antiangiogenic effect in non-Wilson's disease patients with cancer, and in animal tumor models, by lowering systemic copper levels. The rationale for a trial of TM in PBC stems from its antifibrotic, and antiinflammatory effects in mouse models. This double blind trial in PBC will follow patients for two years at four-month intervals. Patients will already be on ursodiol, which has shown some benefit in this disease. Patients will be randomized to one of two arms. In one arm patients will receive best current therapy, including ursodiol, plus a TM placebo. In the second arm patients will receive best current therapy, including ursodiol, plus TM therapy. At each visit liver function and other studies will be performed. Liver biopsies will be performed at baseline and at two years. The dose of oral TM will be titrated to keep ceruloplasmin (Cp) at 5-15mg/day, the level required for efficacy without toxicity. Patients will be monitored as appropriate for Cp levels, anemia/leukopenia, and other side effects. Dr. Brewer and Dr. Marrero will be unblinded so they he can manage TM therapy. Dr. Askari and Dr. Conjeevaram will be blinded evaluators. The primary endpoint is preservation of liver function. Research records will be kept in a password protected database. Linkable information for biological specimens obtained will be kept in this computer. Written documents will be kept in a locked study office. Written informed consent will be utilized.'
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