COVID-19 and related symptoms in patients under disulfiram for alcohol use disorder

Tamburin, Stefano; Mantovani, Elisa; Bernardis, E. De; Zipeto, Donato; Lugoboni, Fabio; Agostoni, C.; Almasio, Roberta; Avveduti, Paola; Baisini, Ornella; Ballerio, Martina; A, Barbero; Bellinato, Marina; Benevento, Carlo; Bin, Loretta; Bonizzi, Veronica; Borroni, G.; Bove, Angelo; Broccardo, Rita; Bruschi, Sandra; Brusini, Roberta; Cairati, Manuela; Cammarata, Liborio M.; Canale, Andrea; Cantiero, Donatella; Capovilla, Tania; Chiroli, Maria Cristina; Cibin, Mauro; Collesei, Raffaella; Colombo, Daniela; Cuomo, Tiziana; D’Angelo, A.; Dedola, Susanna; Esposti, Marco; Micco, Giovanni De; Stefano, Vincenzo De; Cosmo, Filomena Di; Dio, Tiziana Di; Fazio, C; Dona, Claudia; Fabiano, L.R.F. Lucia Rachele; Fanton, Mariacristina; Fantozzi, F.; Fergonzi, Egle Maria; Finotti, Elena; Fiore, Francesca; Fiorentini, Donatella; Fontana, N.; Franceschini, Laura; Furini, Luciana; Galletta, Paola; Gallo, Francesco; Gardiolo, Marianna; Gaspari, Roberta; Gentile, Nicola; Gervino, Daniela; Ghezzo, Novella; C, Ghidoni; Giubertoni, M.; Giussani, Paola; Gori, Filippo; Groppa, Francesca; Grosina, Cinzia; Guzzetti, Maria Raffaella; Jarre, Paolo; Latino, Giovanna Maria; Lerro, G.; Lobello, S.; Lobrano, Gloria; Lotti, Ilaria Valerida; Malagò, Michael; Mazzo, M; Mellini, Stefano; Meneguzzi, Cristina; Mercuri, Rocco; Migliozzi, Sabrina; Molinaroli, Elena; Mosti, A.; Mussi, Daniela; Novelli, A; Padovani, Anna; Palmigiano, Carmela; Panelli, Elio; Pani, A; Passaretti, Serena; Pavani, Valentina; Pecoraro, Maria; Peroglia, Ivo; Pitasi, Marina; Poli, Roberto; Polidori, Edoardo; Porcu, Anna; Possetto, Davide; Prete, Antonio; Quaresima, Serenella; Rapuzzi, Paola; Recchia, Rosa; Reina, Fábio Tadeu Rodrigues; Riglietta, Marco; Rizzo, Elisabetta; Rugani, Fabio; Salvadori, Maria Adele; Samaia, Stefania; Sanchini, Samantha; Sandrone, Paolo; Sassella, F.; Scala, A; Scarzella, M; Sciutteri, Bruno; Sclaverano, Ivana; Sorce, Massimo; Speranza, Elvira; Staccioli, Maria Caterina; Suardi, L; Talassi, Fiorella; Talluto, Anna; Tinghino, Biagio; Tiso, Sonia; Tosi, Tania; Tusa, Antonella; Ungari, Maria Sabrina; Valenti, Riccardo; Vecchi, Lucia; Vegliach, Alessandro; Vercellone, Rita; Verdelli, Flavio; Vicario, Serena; Vignola, Francesca; Zambon, Cinzia; Zannini, Angela; Zanoni, Ilenia; Zavan, Valeria; Zerbini, Cristina

doi:10.1007/s11739-021-02633-y

Cited by 19 publications

(18 citation statements)

References 4 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Disulfiram, an FDA‐approved drug has also been identified to be a potential therapeutic target for SARS‐CoV‐2 infection. Tamburin et al 93 showed that symptoms compatible with COVID‐19 were significantly less common in patient under disulfiram treatment than control group (not taking disulfiram). Disulfiram is known to be a thiol‐reactive compound that can covalently modify cysteine residues and may also act as a zinc ejector 94 .…”

Section: Papain‐like Protease Inhibitorsmentioning

confidence: 99%

Interactions between SARS coronavirus 2 papain‐like protease and immune system: A potential drug target for the treatment of COVID‐19

Mahmoudvand

Shokri

2021

Scand J Immunol

View full text Add to dashboard Cite

The innate immune system is the first line of defence against viral infection and characterized by production of type I interferons (IFN-α and β). 1 Antiviral response relies on pattern-recognition receptors (PRRs) of the innate immune system which recognize pathogen-associated molecular patterns (PAMPs). 2 The response is initiated by cytoplasmic protein sensors such as RIG-I (retinoic acid-inducible gene I), melanoma differentiation-associated protein 5 (MDA5) and membrane sensors as toll-like receptors (TLR3, 7, 8 and 9). 3 Type I IFNs induce the activation of signal transducer and activator of transcription (STAT) factors that induce the expression of hundreds of IFN-stimulated genes (ISGs) which act as antiviral effectors to control viral replication and spread. 4 Many viruses encode proteins that antagonize both the innate and adapted arms of the immune response. 5 All CoVs encode at least one papain-like protease (PLpro) with deubiquitinating (DUB), deISGylating (deISG) and other activities that elicit the appropriate innate immune response. 6 Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) recently entered the human population at the end of 2019 from Hunnan seafood market in Wuhan, China. 7 The virus causes a pandemic infection in more than 119 million people with a case fatality ratio (CFR) of 1.4% with substantially higher ratios in older age groups, 0.32% in those aged <60 years, 6.4% in those aged ≥60 years and up to 13.4% in those aged 80 years or older. 8,9 This raises an urgent need to develop an effective treatment based on identifying targets for viral factors which blocked or reduced innate immune responses. A majority of the newly reported studies showed that PLpro,

show abstract

Section: Papain‐like Protease Inhibitorsmentioning

confidence: 99%

Interactions between SARS coronavirus 2 papain‐like protease and immune system: A potential drug target for the treatment of COVID‐19

Mahmoudvand

Shokri

2021

Scand J Immunol

View full text Add to dashboard Cite

show abstract

“…Recently, in a preliminary report, Tamburin et al (17) showed individuals taking disulfiram had a significantly lower risk of COVID-19 compatible symptoms, such as fever and dyspnea, compared to a control group. However their study was underpowered to reliably discern a difference in risk for a positive COVID-19 test, rather than just for compatible symptoms, between the groups.…”

Section: Discussionmentioning

confidence: 99%

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

Fillmore

Bell

Shen

et al. 2021

Preprint

View full text Add to dashboard Cite

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.

show abstract

“…Recently, in a preliminary report, Tamburin et al . [ 17 ] showed that patients taking disulfiram had a significantly lower incidence of symptoms compatible with COVID-19, such as fever and dyspnea, compared to a control group. However, their study was underpowered to discern a difference in actual risk of COVID-19 disease.…”

Section: Discussionmentioning

confidence: 99%

Disulfiram use is associated with lower risk of COVID-19: A retrospective cohort study

et al. 2021

View full text Add to dashboard Cite

Effective, low-cost therapeutics are needed to prevent and treat COVID-19. Severe COVID-19 disease is linked to excessive inflammation. Disulfiram is an approved oral drug used to treat alcohol use disorder that is a potent anti-inflammatory agent and an inhibitor of the viral proteases. We investigated the potential effects of disulfiram on SARS-CoV-2 infection and disease severity in an observational study using a large database of clinical records from the national US Veterans Affairs healthcare system. A multivariable Cox regression adjusted for demographic information and diagnosis of alcohol use disorder revealed a reduced risk of SARS-CoV-2 infection with disulfiram use at a hazard ratio of 0.66 (34% lower risk, 95% confidence interval 24–43%). There were no COVID-19 related deaths among the 188 SARS-CoV-2 positive patients treated with disulfiram, in contrast to 5–6 statistically expected deaths based on the untreated population (P = 0.03). Our epidemiological results suggest that disulfiram may contribute to the reduced incidence and severity of COVID-19. These results support carefully planned clinical trials to assess the potential therapeutic effects of disulfiram in COVID-19.

show abstract

COVID-19 and related symptoms in patients under disulfiram for alcohol use disorder

Cited by 19 publications

References 4 publications

Interactions between SARS coronavirus 2 papain‐like protease and immune system: A potential drug target for the treatment of COVID‐19

Interactions between SARS coronavirus 2 papain‐like protease and immune system: A potential drug target for the treatment of COVID‐19

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

Disulfiram use is associated with lower risk of COVID-19: A retrospective cohort study

Contact Info

Product

Resources

About