Disulfiram associated with lower risk of Covid-19: a retrospective cohort study

Abstract

In the global COVID-19 pandemic, there is a substantial need for effective, low-cost therapeutics. We investigated the potential effects of disulfiram on the incidence and outcomes of COVID-19 in an observational study in a large database of US Veterans Administration clinical records, the VA Corporate Data Warehouse (CDW). The study is motivated by the unique properties of disulfiram, which has been used as an anti-alcoholism drug since 1948, is non-toxic, easy to manufacture and inexpensive. Disulfiram reduces hyperinflammation in mammalian cells by inhibition of the gasdermin D pore. In a mouse model of sepsis, disulfiram reduced inflammatory cytokines and mortality. Disulfiram also is a low micromolar inhibitor of the Mpro and PLpro viral proteases of SARS-CoV-2. To investigate the potential effects of disulfiram on the incidence and severity of COVID-19, we carried out an epidemiological study in the CDW. The VA dataset used has 944,127 patients tested for SARS-Cov-2, 167,327 with a positive test, and 2,233 on disulfiram, of which 188 had a positive SARS-Cov-2 test. A multivariable Cox regression adjusted for age, gender, race/ethnicity, region, a diagnosis of alcohol use disorders, and Charlson comorbidity score revealed a reduced incidence of COVID-19 with disulfiram use with a hazard ratio of 0.66 and 95% confidence interval of 0.57 to 0.76 (P < 0.001). There were no deaths among the 188 SARS-Cov-2 positive patients treated with disulfiram. The expected number of deaths would have been 5-6 according to the 3% death rate among the untreated (P-value 0.03). Our finding of a lower hazard ratio and less severe outcomes for COVID-19 in patients treated with disulfiram compared to those not treated is a statistical association and does not prove any causative effect of disulfiram. However, the results of this study suggest that there is a pharmacological contribution to the reduced incidence and severity of COVID-19 with the use of disulfiram. Given the known anti-inflammatory and viral anti-protease effects of disulfiram, it is reasonable and urgent to initiate accelerated clinical trials to assess whether disulfiram reduces SARS-CoV-2 infection, disease severity and death.

Inflammasome activation at the crux of severe COVID-19

“…Dimethyl fumarate (DMF), an FDA-approved therapeutic for multiple sclerosis, as well as fumarate, the endogenous Krebs cycle intermediate related to DMF, was recently shown to inhibit GSDMD 168 . Interestingly, a case series of several patients with multiple sclerosis being treated with DMF showed that their SARS-CoV-2 infection was self-limiting without their receiving any specific treatment 169 , and an observational study using a large health-care database revealed a significantly reduced risk of SARS-CoV-2 infection and no death in the group using DSF for alcoholism compared with a control group, but this study has not been fully peer reviewed 170 . DSF is currently being studied in two controlled phase II clinical trials that are testing efficacy in mild to moderate disease (NCT04485130) as well as in patients who are hospitalized (NCT04594343) (Table 1 ).…”

Inflammasomes during SARS-CoV-2 infection and development of their corresponding inhibitors

“…As they have been identified as GSDMD-inhibitors, their clinical trials are ongoing for the treatment of COVID-19 disease (Vora et al, 2021). In fact, COVID-19 patients under DMF treatment against sclerosis or under DSF against alcohol use disorder showed a self-limiting symptoms (Fillmore et al, 2021;Mantero et al, 2021). Therefore, it is being clinically tested against COVID-19 (trial number NCT04594343) with a treatment dose of 120 mg every 12 hours for 2 days or 240 mg every 12 hours for 8 days.…”

Network pharmacology reveals multitarget mechanism of action of drugs to be repurposed for COVID-19

“…This network pharmacology workflow has enabled us to identify some relevant drugs as candidates for drug repurposing for the treatment of COVID-19 progression based on the viral and human protein interactions observed in our networks. Some of the drugs identified in the present study have in fact been proposed as candidates for the treatment of COVID-19 by different authors, for example, 1) disulfiram, where its uses are associated with a lower risk of COVID-19 (Fillmore et al, 2021); 2) auranofin, which inhibits SARS-CoV-2 replication and attenuates inflammation in human cells (Marzo and Messori, 2020;Rothan et al, 2020); 3) suloctidil, which was recommended for the treatment of COVID-19-induced exacerbation of asthma (Guo et al, 2021); and 4) gefitinib, which was reported to inhibit spike-driven fusion (Braga et al, 2021).…”