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JCI Insight ; 7(5)2022 03 08.
Article in English | MEDLINE | ID: covidwho-1759583


Severe acute lung injury has few treatment options and a high mortality rate. Upon injury, neutrophils infiltrate the lungs and form neutrophil extracellular traps (NETs), damaging the lungs and driving an exacerbated immune response. Unfortunately, no drug preventing NET formation has completed clinical development. Here, we report that disulfiram - an FDA-approved drug for alcohol use disorder - dramatically reduced NETs, increased survival, improved blood oxygenation, and reduced lung edema in a transfusion-related acute lung injury (TRALI) mouse model. We then tested whether disulfiram could confer protection in the context of SARS-CoV-2 infection, as NETs are elevated in patients with severe COVID-19. In SARS-CoV-2-infected golden hamsters, disulfiram reduced NETs and perivascular fibrosis in the lungs, and it downregulated innate immune and complement/coagulation pathways, suggesting that it could be beneficial for patients with COVID-19. In conclusion, an existing FDA-approved drug can block NET formation and improve disease course in 2 rodent models of lung injury for which treatment options are limited.

Acute Lung Injury/drug therapy , COVID-19/complications , Disulfiram/pharmacology , Extracellular Traps/drug effects , Lung/immunology , SARS-CoV-2 , Acetaldehyde Dehydrogenase Inhibitors/pharmacology , Acute Lung Injury/etiology , Animals , COVID-19/virology , Disease Models, Animal , Extracellular Traps/immunology , Rodentia
Eur J Pharmacol ; 904: 174143, 2021 Aug 05.
Article in English | MEDLINE | ID: covidwho-1487708


Disulfiram (DSF) is a well-known anti-alcohol agent that inhibits aldehyde dehydrogenase and results in extreme 'hangover' symptoms when consumed with alcohol. This drug, however, has been suggested as useful in other forms of drug addiction due to its beneficial potential in both drug abuse reduction and withdrawal. However, among other drugs used in alcohol dependence, it carries the greatest risk of pharmacological interactions. Concomitant use of DSF and central nervous system stimulants usually leads to harmful, undesirable effects. To date, there is still limited data regarding the detailed safety profile of DSF as a concomitant drug. In this review article, we outline the current state of knowledge about DSF, its broad pharmacological action, as well as therapeutic effects, with a particular emphasis on the molecular understanding of its potential pharmacodynamic interactions with common addictive substances (e.g., alcohol, cocaine, cannabinoids, opioids) supported by relevant examples.

Acetaldehyde Dehydrogenase Inhibitors/pharmacology , Acetaldehyde Dehydrogenase Inhibitors/therapeutic use , Disulfiram/pharmacology , Disulfiram/therapeutic use , Substance-Related Disorders/drug therapy , Alcohol Drinking/prevention & control , Alcoholism/drug therapy , Animals , Disulfiram/adverse effects , Drug Interactions , Humans
Acta Pharmacol Sin ; 42(11): 1913-1920, 2021 11.
Article in English | MEDLINE | ID: covidwho-1437673


Sepsis is a dysregulated immune response to infection and potentially leads to life-threatening organ dysfunction, which is often seen in serious Covid-19 patients. Disulfiram (DSF), an old drug that has been used to treat alcohol addiction for decades, has recently been identified as a potent inhibitor of the gasdermin D (GSDMD)-induced pore formation that causes pyroptosis and inflammatory cytokine release. Therefore, DSF represents a promising therapeutic for the treatment of inflammatory disorders. Lactoferrin (LF) is a multifunctional glycoprotein with potent antibacterial and anti-inflammatory activities that acts by neutralizing circulating endotoxins and activating cellular responses. In addition, LF has been well exploited as a drug nanocarrier and targeting ligands. In this study, we developed a DSF-LF nanoparticulate system (DSF-LF NP) for combining the immunosuppressive activities of both DSF and LF. DSF-LF NPs could effectively block pyroptosis and inflammatory cytokine release from macrophages. Treatment with DSF-LF NPs showed remarkable therapeutic effects on lipopolysaccharide (LPS)-induced sepsis. In addition, this therapeutic strategy was also applied to treat ulcerative colitis (UC), and substantial treatment efficacy was achieved in a murine colitis model. The underlying mode of action of these DSF-LF-NPs may contribute to efficiently suppressing macrophage-mediated inflammatory responses and ameliorating the complications caused by sepsis and UC. As macrophage pyroptosis plays a pivotal role in inflammation, this safe and effective biomimetic nanomedicine may offer a versatile therapeutic strategy for treating various inflammatory diseases by repurposing DSF.

COVID-19 , Colitis, Ulcerative , Disulfiram/pharmacokinetics , Lactoferrin , Systemic Inflammatory Response Syndrome , Acetaldehyde Dehydrogenase Inhibitors/pharmacology , Animals , Anti-Inflammatory Agents/pharmacology , Biomimetic Materials/pharmacology , COVID-19/drug therapy , COVID-19/immunology , Colitis, Ulcerative/drug therapy , Colitis, Ulcerative/immunology , Disease Models, Animal , Disulfiram/pharmacology , Drug Carriers/pharmacology , Humans , Immunosuppressive Agents/pharmacology , Lactoferrin/metabolism , Lactoferrin/pharmacology , Lipopolysaccharides/immunology , Macrophages/drug effects , Macrophages/immunology , Mice , Mice, Inbred C57BL , Nanoparticles/therapeutic use , Pyroptosis/drug effects , SARS-CoV-2 , Systemic Inflammatory Response Syndrome/drug therapy , Systemic Inflammatory Response Syndrome/immunology , Systemic Inflammatory Response Syndrome/metabolism , Treatment Outcome