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. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that causes progressive weakness and wasting of limb, breathing, and swallowing muscles. Death usually occurs within 5 years of symptom onset. No treatment reverses the weakness caused by ALS. An ideal candidate for treatment of ALS would be an agent that can interfere with the programmed cell death seen in ALS, could block glutamate receptors, supress reactive oxygen species, and inhibit the caspase cascade. In the mouse model of ALS, inhibition of caspase 1 and 3 by intrathecal injection of specific caspase 3 inhibitors, prolonged life by 22% (from 126 to 155 days). A dose-dependent response was observed. Therefore, inhibition of a component of the caspase system would seem to be a promising line of research to pursue. Unfortunately there are no pharmaceutical agents known to inhibit caspase that can be given by any route other than intrathecally. Disulfiram is a drug product being developed by Odyssey Pharmaceuticals, Inc., a subsidiary of Pliva, Inc., for the treatment of patients with amyotrophic lateral sclerosis (ALS) under IND 63,907. Disulfiram is currently marketed by Odyssey Pharmaceuticals, Inc. in the US under the trade name, Antabuse as an aid in the management of selected chronic alcoholic patients who are attempting to remain in a state of enforced sobriety. The general safety and tolerability of disulfiram in the doses used in this protocol are well established by decades of clinical experience. Recent findings in a tissue culture system have shown that disulfiram can dramatically inhibit caspase 3. However, disulfiram has other effects on the cell death pathway. It also stabilizes mitochondrial membrane potentials as well as suppressing reactive oxygen species. In light of this information, a preliminary exploration of the clinical effects of disulfiram in ALS is justified. This protocol will be a pilot study to futher explore safety and tolerability in the specific context of ALS. The present study will prepare the way for a full clinical program by providing an initial pilot evaluation of the safety of disulfiram in patients with ALS.
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