31 research outputs found
In Vivo Pharmacodynamic Studies of the Disulfiram Metabolite S-Methyl N,N-Diethylthiolcarbamate Sulfoxide:Inhibition of Liver Aldehyde Dehydrogenase
Application of a High Performance Liquid Chromatography Method for Screening of Aldehyde Dehydrogenase Isozyme Deficiency in Hair Roots from Different Ethnic Groups
Roles of FMO and CYP450 in the Metabolism in Human Liver Microsomes of S-Methyl-N, N-Diethyldithiocarbamate, a Disulfiram Metabolite
Quantification of breath carbon disulphide and acetone following a single dose of disulfiram (Antabuse) using selected ion flow tube mass spectrometry (SIFT-MS)
A phase I study to repurpose disulfiram in combination with temozolomide to treat newly diagnosed glioblastoma after chemoradiotherapy
Disulfiram, a generic alcohol aversion drug, has promising preclinical activity against glioblastoma (GBM). This phase I study aims to evaluate its safety, maximum tolerated dose (MTD), pharmacodynamic effect, and preliminary efficacy when combined with adjuvant temozolomide in GBM patients after standard chemoradiotherapy. Patients received disulfiram 500–1000 mg once daily, in combination with 150–200 mg/m2 temozolomide. A modified 3 + 3 dose-escalation design was used to determine the MTD. The pharmacodynamic effect of proteasome inhibition was assessed using fluorometric 20S proteasome assay on peripheral blood cells. The MTD was determined based on the dose-limiting toxicities (DLTs) within the first month of therapy. Twelve patients were enrolled to two dose levels: 500 and 1000 mg. Two DLTs of grade 3 delirium occurred after 15 days of administration at 1000 mg per day. Other possible grade 2–3 DSF-related toxicities included fatigue, ataxia, dizziness, and peripheral neuropathy. The toxicities were self-limiting or resolved after discontinuing DSF. The MTD was determined to be 500 mg per day. Limited proteasome inhibition was observed at week 4 and showed an increased trend with escalated disulfiram. Median progression-free survival with 500 mg of DSF was 5.4 months from the start of disulfiram and 8.1 months from the start of chemoradiotherapy. Disulfiram can be safely combined with temozolomide but can cause reversible neurological toxicities. The MTD of disulfiram with adjuvant temozolomide appears to produce limited proteasome inhibition on peripheral blood cells