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Journal of Psychosocial Nursing and... Dec 2021Alcohol use disorder (AUD) is a serious, prevalent disorder that affects millions of people. There are numerous evidence-based treatments and strategies to treat AUD,... (Review)
Review
Alcohol use disorder (AUD) is a serious, prevalent disorder that affects millions of people. There are numerous evidence-based treatments and strategies to treat AUD, but they are under-utilized for a variety of reasons, including provider stigma, lack of knowledge, lack of professional support, shortage of willing providers, and patient barriers. Disulfiram, naltrexone, and acamprosate are approved but underused medications for the treatment of AUD. Nonpharmacological strategies and treatments include the use of motivational interviewing when talking to patients about their alcohol use, peer support or mutual help groups, and individualized therapy. Nurses are in a prime position to educate themselves and patients on evidence-based treatments for AUD and to help patients access those treatments. [(12), 7-11.].
Topics: Acamprosate; Alcohol Deterrents; Alcoholism; Disulfiram; Humans; Naltrexone
PubMed: 34846245
DOI: 10.3928/02793695-20211110-01 -
Frontiers in Bioscience (Landmark... Aug 2023The complex formed by disulfiram (DSF) and copper (Cu) is safe and effective for the prevention and treatment of triple-negative breast cancer (TNBC). Although previous...
BACKGROUND
The complex formed by disulfiram (DSF) and copper (Cu) is safe and effective for the prevention and treatment of triple-negative breast cancer (TNBC). Although previous studies have shown that DSF/Cu induces ferroptosis, the mechanism remains unclear.
METHODS
The mitochondrial morphology of TNBC treated with DSF/Cu was observed by transmission microscopy, and intracellular levels of iron, lipid reactive oxygen species (ROS), malondialdehyde, and glutathione were evaluated to detect the presence of ferroptosis. Target genes for the DSF/Cu-activated ferroptosis signaling pathway were examined by transcriptome sequencing analysis. Expression of the target gene, , was detected by qRT-PCR, immunofluorescence and western blot.
RESULTS
The mitochondria of TNBC cells were significantly atrophied following treatment with DSF/Cu for 24 h. Addition of DSF/Cu supplement resulted in significant up-regulation of intracellular iron, lipid ROS and malondialdehyde levels, and significant down-regulation of glutathione levels, all of which are important markers of ferroptosis. Transcriptome analysis confirmed that DSF/Cu activated the ferroptosis signaling pathway and up-regulated several ferroptosis target genes associated with redox regulation, especially heme oxygenase-1 (HMOX-1). Inhibition of ferroptosis by addition of the ROS scavenger N-acetyl-L-cysteine (NAC) significantly increased the viability of DSF/Cu-treated TNBC cells.
CONCLUSIONS
These results show that DSF/Cu increases lipid peroxidation and causes a sharp increase in HMOX1 activity, thereby inducing TNBC cell death through ferroptosis. DSF/Cu is a promising therapeutic drug for TNBC and could lead to ferroptosis-mediated therapeutic strategies for human cancer.
Topics: Humans; Triple Negative Breast Neoplasms; Copper; Disulfiram; Ferroptosis; Reactive Oxygen Species; Cell Line; Glutathione; Lipids
PubMed: 37664913
DOI: 10.31083/j.fbl2808186 -
Alcohol and Alcoholism (Oxford,... Jul 2022
Topics: Disulfiram; Humans; Methemoglobinemia
PubMed: 34047343
DOI: 10.1093/alcalc/agab040 -
Redox Biology Oct 2021Hepatocellular carcinoma (HCC) is one of the paramount causes of cancer-related death worldwide. Despite recent advances have been made in clinical treatments of HCC,...
Hepatocellular carcinoma (HCC) is one of the paramount causes of cancer-related death worldwide. Despite recent advances have been made in clinical treatments of HCC, the general prognosis of patients remains poor. Therefore, it is imperative to develop a less toxic and more effective therapeutic strategy. Currently, series of cellular, molecular, and pharmacological experimental approaches were utilized to address the unrecognized characteristics of disulfiram (DSF), pursuing the goal of repurposing DSF for cancer therapy. We found that DSF/Cu selectively exerted an efficient cytotoxic effect on HCC cell lines, and potently inhibited migration, invasion, and angiogenesis of HCC cells. Importantly, we confirmed that DSF/Cu could intensively impair mitochondrial homeostasis, increase free iron pool, enhance lipid peroxidation, and eventually result in ferroptotic cell death. Of note, a compensatory elevation of NRF2 accompanies the process of ferroptosis, and contributes to the resistance to DSF/Cu. Mechanically, we found that DSF/Cu dramatically activated the phosphorylation of p62, which facilitates competitive binding of Keap1, thus prolonging the half-life of NRF2. Notably, inhibition of NRF2 expression via RNA interference or pharmacological inhibitors significantly facilitated the accumulation of lipid peroxidation, and rendered HCC cells more sensitive to DSF/Cu induced ferroptosis. Conversely, fostering NRF2 expression was capable of ameliorating the cell death activated by DSF/Cu. Additionally, DSF/Cu could strengthen the cytotoxicity of sorafenib, and arrest tumor growth both in vitro and in vivo, by simultaneously inhibiting the signal pathway of NRF2 and MAPK kinase. In summary, these results provide experimental evidence that inhibition of the compensatory NRF2 elevation strengthens HCC cells more vulnerable to DSF/Cu induced ferroptosis, which facilitates the synergistic cytotoxicity of DSF/Cu and sorafenib.
Topics: Carcinoma, Hepatocellular; Cell Line, Tumor; Copper; Disulfiram; Ferroptosis; Humans; Kelch-Like ECH-Associated Protein 1; Liver Neoplasms; NF-E2-Related Factor 2
PubMed: 34482117
DOI: 10.1016/j.redox.2021.102122 -
Journal of Dermatological Science Dec 2022Pyroptosis is a newly discovered type of programmed cell death associated with inflammatory and fibrotic diseases. Macrophages play an important role in inducing early...
BACKGROUND
Pyroptosis is a newly discovered type of programmed cell death associated with inflammatory and fibrotic diseases. Macrophages play an important role in inducing early immune inflammation in systemic sclerosis (SSc).
OBJECTIVE
To investigate the effect of macrophages pyroptosis on fibrosis of SSc.
METHODS
Pyroptosis/inflammatory markers in serum and skin of SSc patients were detected. Bleomycin (BLM) was subcutaneously injected to establish SSc mouse model. The levels of pyroptosis markers, dermal thickness and collagen deposition in skin were assessed before and after the administration of pyroptosis inhibitors, including MCC950, Disulfiram and necrosulfonamide (NSA). Human-derived monocyte-macrophage cell line (THP-1) or mouse bone marrow-derived macrophages (BMDMs) were primed with lipopolysaccharide (LPS) and stimulated by silicon dioxide (SiO) to induce cell pyroptosis. Fibroblasts from patients with SSc were co-cultured with pyroptotic THP-1 cells, and the collagen production was assessed.
RESULTS
Pyroptotic/inflammatory proteins, including NLRP3, cleaved-Caspase (CASP)1, GSDMD-N terminal and IL-18 were increased in the serum, and ASC aggregation and GSDMD were elevated in macrophages in the skin of SSc patients. SSc mice showed increased pyroptosis markers, dermal thickness and collagen deposition in skins, which were alleviated by MCC950, Disulfiram and NSA. Pyroptosis of THP-1 cells and BMDMs was induced by LPS/SiO, and it was reduced by the inhibitors of Cathepsin B, NLRP3, CASP1 and GSDMD. Co-culture with pyroptotic THP-1 cells increased the fibrotic proteins in fibroblasts, which were alleviated by pyroptosis inhibitors.
CONCLUSIONS
SSc patients and BLM-induced mouse model presented increased pyroptosis. LPS/SiO-induced macrophage pyroptosis promoted fibrosis of SSc through Cathepsin B/NLRP3/GSDMD pathway.
Topics: Humans; Mice; Animals; Pyroptosis; NLR Family, Pyrin Domain-Containing 3 Protein; Cathepsin B; Lipopolysaccharides; Disulfiram; Silicon Dioxide; Macrophages; Inflammation; Caspase 1; Disease Models, Animal; Fibrosis; Scleroderma, Systemic; Inflammasomes
PubMed: 36585288
DOI: 10.1016/j.jdermsci.2022.12.006 -
Pharmacogenomics Oct 2020Alcohol use disorder (AUD) is highly prevalent and among the leading causes of morbidity and mortality in the United States. Pharmacotherapies for AUD are limited, thus... (Review)
Review
Alcohol use disorder (AUD) is highly prevalent and among the leading causes of morbidity and mortality in the United States. Pharmacotherapies for AUD are limited, thus making identification of patient subgroups that are most likely to respond favorably crucial. In this article, pharmacogenetic research on US FDA-approved and commonly prescribed off-label medications for the treatment of AUD is comprehensively reviewed. While the field has advanced in understanding pharmacotherapies for AUD and potential genetic moderators of treatment responses, the pharmacogenetic data to guide the prescribing clinician are limited and should be interpreted with caution. Precision medicine for AUD with more beneficial treatment responses and minimal side effects remains a high priority for further research.
Topics: Alcohol Deterrents; Alcoholism; Disulfiram; Humans; Naltrexone; Pharmacogenetics; Pharmacogenomic Testing; Precision Medicine
PubMed: 32807012
DOI: 10.2217/pgs-2020-0079 -
International Journal of Molecular... Feb 2024Disulfiram (DSF) is used to treat non‑small cell lung cancer (NSCLC). DSF significantly increases expression of programmed death‑ligand 1 (PD‑L1), which may...
Disulfiram (DSF) is used to treat non‑small cell lung cancer (NSCLC). DSF significantly increases expression of programmed death‑ligand 1 (PD‑L1), which may enhance immunosuppression and immune escape of tumors. Therefore, the present study aimed to investigate the role of combined treatment of DSF and anti‑PD‑L1 in NSCLC resistance. The viability and apoptosis of A549 cells were detected by the Cell Counting Kit‑8 assay and flow cytometry, respectively. The expression levels of ATPase copper‑transporting β (ATP7B) and PD‑L1 in A549 cells were detected by reverse transcription‑quantitative PCR and western blot analysis. The levels of reactive oxygen species (ROS), malondialdehyde (MDA) and superoxide dismutase (SOD) in A549 cells were detected by respective assay kits. The expression levels of cuproptosis‑associated proteins ferredoxin‑1 (FDX1), ATP7B, solute carrier family 31 member 1 (SLC31A1), succinate dehydrogenase B (SDHB), PD‑L1 and hypoxia inducible factor (HIF)‑1A were analyzed by western blotting in A549 cells. DSF inhibited the viability of A549 cells and promoted expression levels of ATP7B and PD‑L1 at both mRNA and protein levels in A549 cells. The viability of cisplatin (DPP)‑treated A549 cells was increased following DSF treatment. JQ‑1 (a PD‑L1 inhibitor) suppressed the viability of DPP‑treated A549 cells pretreated with DSF. DSF increased expression levels of ATP7B and PD‑L1. The combination treatment of DSF and JQ‑1 in A549 cells increased levels of ROS and MDA, as well as expression levels of FDX1 and SLC31A1; however, combination treatment decreased levels of SOD, as well as expression levels of ATP7B, SDHB, PD‑L1, and HIF‑1A. PX478 (an HIF‑1 inhibitor) acted with DSF to enhance the inhibitory effects on the viability and on the induction of apoptosis of A549 cells. PX478 upregulated the levels of ROS and MDA, while it downregulated levels of SOD in DSF‑treated A549 cells. PX478 promoted expression levels of FDX1 and SLC31A1, while it suppressed expression levels of ATP7B, PD‑L1, and HIF‑1A in DSF‑treated A549 cells. In conclusion, the combined treatment of A549 cells with anti‑PD‑L1 and DSF enhanced the effect of cuproptosis on the inhibition of NSCLC cell viability.
Topics: Humans; B7-H1 Antigen; Carcinoma, Non-Small-Cell Lung; Disulfiram; Reactive Oxygen Species; Lung Neoplasms; Signal Transduction; Superoxide Dismutase; 3,4-Methylenedioxyamphetamine
PubMed: 38186308
DOI: 10.3892/ijmm.2023.5343 -
Current Opinion in Psychiatry Jul 2019Cocaine is a highly addictive substance with serious medical and mental health consequences. Despite these concerns, there are no Food and Drug Administration-approved... (Review)
Review
PURPOSE OF REVIEW
Cocaine is a highly addictive substance with serious medical and mental health consequences. Despite these concerns, there are no Food and Drug Administration-approved medications for the treatment of cocaine use disorder (CUD). Although many medication-assisted treatments (MATs) have been investigated, no clear guidelines exist for clinicians treating patients with CUDs.
RECENT FINDINGS
There are a limited number of recent data examining MATs for CUD. Multiple high-quality reviews of existing literature have been performed with psychostimulants, modafinil, bupropion, topiramate and disulfiram showing the most promise. Evidence is limited by heterogeneity of studies, small sample sizes and inconsistent results.
SUMMARY
The current literature does not strongly support any individual MAT for CUD. Psychosocial interventions, namely contingency management, have the most evidence for treatment of CUD, but it is worth seriously considering MAT for patients who do not respond well to psychosocial interventions alone given limitations in access to care, relatively low risks associated with MAT and significant morbidity associated with CUD. Further research into MAT for CUD is necessary, as the combination of MAT and psychosocial interventions may be better than either alone.
Topics: Anticonvulsants; Antidepressive Agents; Antipsychotic Agents; Central Nervous System Stimulants; Cocaine-Related Disorders; Disulfiram; Humans; Naltrexone
PubMed: 31008728
DOI: 10.1097/YCO.0000000000000518 -
Drug Discovery Today Jun 2020Disulfiram (DSF) is a thiuram derivative that was developed to treat alcoholism but was also found to have antitumor activity. Copper (Cu), as a trace metal, has... (Review)
Review
Disulfiram (DSF) is a thiuram derivative that was developed to treat alcoholism but was also found to have antitumor activity. Copper (Cu), as a trace metal, has important roles in the body. Numerous studies have shown that the combination of DSF and copper (DSF/Cu) greatly enhances its antitumor efficacy. Given that the efficacy of DSF is well established and its safety profile is understood, repurposing DSF as a new anticancer drug is a promising strategy. Here, we summarize the pharmacological effects of DSF and the role of Cu in cancer, and focus on the antitumor effect of DSF/Cu, especially the mechanisms involved in enhancing drug sensibility by targeting specific molecules. We also provide rational strategies for using DSF as a cancer therapy.
Topics: Animals; Antineoplastic Agents; Copper; Disulfiram; Drug Therapy, Combination; Humans; Neoplasms
PubMed: 32320854
DOI: 10.1016/j.drudis.2020.04.003 -
The Cochrane Database of Systematic... Jan 2024Cocaine is a psychostimulant used by approximately 0.4% of the general population worldwide. Cocaine dependence is a chronic mental disorder characterised by the... (Review)
Review
BACKGROUND
Cocaine is a psychostimulant used by approximately 0.4% of the general population worldwide. Cocaine dependence is a chronic mental disorder characterised by the inability to control cocaine use and a host of severe medical and psychosocial complications. There is current no approved pharmacological treatment for cocaine dependence. Some researchers have proposed disulfiram, a medication approved to treat alcohol use disorder. This is an update of a Cochrane review first published in 2010.
OBJECTIVES
To evaluate the efficacy and safety of disulfiram for the treatment of cocaine dependence.
SEARCH METHODS
We updated our searches of the following databases to August 2022: the Cochrane Drugs and Alcohol Group Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL, and PsycINFO. We also searched for ongoing and unpublished studies via two trials registries. We handsearched the references of topic-related systematic reviews and included studies. The searches had no language restrictions.
SELECTION CRITERIA
We included randomised controlled trials that evaluated disulfiram alone or associated with psychosocial interventions versus placebo, no intervention, other pharmacological interventions, or any psychosocial intervention for the treatment of cocaine dependence.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane.
MAIN RESULTS
Thirteen studies (1191 participants) met our inclusion criteria. Disulfiram versus placebo or no treatment Disulfiram compared to placebo may increase the number of people who are abstinent at the end of treatment (point abstinence; risk ratio (RR) 1.58, 95% confidence interval (CI) 1.05 to 2.36; 3 datasets, 142 participants; low-certainty evidence). However, compared to placebo or no pharmacological treatment, disulfiram may have little or no effect on frequency of cocaine use (standardised mean difference (SMD) -0.11 standard deviations (SDs), 95% CI -0.39 to 0.17; 13 datasets, 818 participants), amount of cocaine use (SMD -0.00 SDs, 95% CI -0.30 to 0.30; 7 datasets, 376 participants), continuous abstinence (RR 1.23, 95% CI 0.80 to 1.91; 6 datasets, 386 participants), and dropout for any reason (RR 1.20, 95% CI 0.92 to 1.55; 14 datasets, 841 participants). The certainty of the evidence was low for all these outcomes. We are unsure about the effects of disulfiram versus placebo on dropout due to adverse events (RR 12.97, 95% CI 0.77 to 218.37; 1 study, 67 participants) and on the occurrence of adverse events (RR 3.00, 95% CI 0.35 to 25.98), because the certainty of the evidence was very low for these outcomes. Disulfiram versus naltrexone Disulfiram compared with naltrexone may reduce the frequency of cocaine use (mean difference (MD) -1.90 days, 95% CI -3.37 to -0.43; 2 datasets, 123 participants; low-certainty evidence) and may have little or no effect on amount of cocaine use (SMD 0.12 SDs, 95% CI -0.27 to 0.51, 2 datasets, 123 participants; low-certainty evidence). We are unsure about the effect of disulfiram versus naltrexone on dropout for any reason (RR 0.86, 95% CI 0.56 to 1.32, 3 datasets, 131 participants) and dropout due to adverse events (RR 0.50, 95% CI 0.07 to 3.55; 1 dataset, 8 participants), because the certainty of the evidence was very low for these outcomes.
AUTHORS' CONCLUSIONS
Our results show that disulfiram compared to placebo may increase point abstinence. However, disulfiram compared to placebo or no pharmacological treatment may have little or no effect on frequency of cocaine use, amount of cocaine use, continued abstinence, and dropout for any reason. We are unsure if disulfiram has any adverse effects in this population. Caution is required when transferring our results to clinical practice.
Topics: Humans; Disulfiram; Cocaine-Related Disorders; Naltrexone; Alcoholism; Cocaine
PubMed: 38180268
DOI: 10.1002/14651858.CD007024.pub3