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JAMA Network Open Mar 2023Disulfiram has demonstrated broad antitumoral effect in several preclinical studies. One of the proposed indications is for the treatment of glioblastoma. (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Disulfiram has demonstrated broad antitumoral effect in several preclinical studies. One of the proposed indications is for the treatment of glioblastoma.
OBJECTIVE
To evaluate the efficacy and safety of disulfiram and copper as add-on to alkylating chemotherapy in patients with recurrent glioblastoma.
DESIGN, SETTING, AND PARTICIPANTS
This was a multicenter, open-label, randomized phase II/III clinical trial with parallel group design. Patients were recruited at 7 study sites in Sweden and 2 sites in Norway between January 2017 and November 2020. Eligible patients were 18 years or older, had a first recurrence of glioblastoma, and indication for treatment with alkylating chemotherapy. Patients were followed up until death or a maximum of 24 months. The date of final follow-up was January 15, 2021. Data analysis was performed from February to September 2022.
INTERVENTIONS
Patients were randomized 1:1 to receive either standard-of-care (SOC) alkylating chemotherapy alone, or SOC with the addition of disulfiram (400 mg daily) and copper (2.5 mg daily).
MAIN OUTCOMES AND MEASURES
The primary end point was survival at 6 months. Secondary end points included overall survival, progression-free survival, adverse events, and patient-reported quality of life.
RESULTS
Among the 88 patients randomized to either SOC (n = 45) or SOC plus disulfiram and copper (n = 43), 63 (72%) were male; the mean (SD) age was 55.4 (11.5) years. There was no significant difference between the study groups (SOC vs SOC plus disulfiram and copper) in 6 months survival (62% [26 of 42] vs 44% [19 of 43]; P = .10). Median overall survival was 8.2 months (95% CI, 5.4-10.2 months) with SOC and 5.5 months (95% CI, 3.9-9.3 months) with SOC plus disulfiram and copper, and median progression-free survival was 2.6 months (95% CI, 2.4-4.6 months) vs 2.3 months (95% CI, 1.7-2.6 months), respectively. More patients in the SOC plus disulfiram and copper group had adverse events grade 3 or higher (34% [14 of 41] vs 11% [5 of 44]; P = .02) and serious adverse events (41% [17 of 41] vs 16% [7 of 44]; P = .02), and 10 patients (24%) discontinued disulfiram treatment because of adverse effects.
CONCLUSIONS AND RELEVANCE
This randomized clinical trial found that among patients with recurrent glioblastoma, the addition of disulfiram and copper to chemotherapy, compared with chemotherapy alone, resulted in significantly increased toxic effects, but no significant difference in survival. These findings suggest that disulfiram and copper is without benefit in patients with recurrent glioblastoma.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02678975; EUDRACT Identifier: 2016-000167-16.
Topics: Humans; Male; Middle Aged; Female; Glioblastoma; Copper; Disulfiram; Quality of Life; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37000452
DOI: 10.1001/jamanetworkopen.2023.4149 -
Kidney International Dec 2022Activated monocytes/macrophages promote glomerular injury, including crescent formation, in anti-glomerular basement membrane (GBM) glomerulonephritis. Disulfiram, an...
Activated monocytes/macrophages promote glomerular injury, including crescent formation, in anti-glomerular basement membrane (GBM) glomerulonephritis. Disulfiram, an alcohol-aversion drug, inhibits monocyte/macrophage migration by inhibiting FROUNT, a cytosolic protein that enhances chemokine receptor signaling. Our study found that disulfiram at a human equivalent dose successfully blocked albuminuria and crescent formation with podocyte loss, and later stage kidney fibrotic lesions, in a rat model of anti-GBM glomerulonephritis. A disulfiram derivative, DSF-41, with more potent FROUNT inhibition activity, inhibited glomerulonephritis at a lower dose than disulfiram. Disulfiram markedly reduced the number of monocytes or macrophages at the early stage of glomerulonephritis and that of CD3 and CD8 lymphocytes at the established stage. Impaired pseudopodia formation was observed in the glomerular monocytes/macrophages of the disulfiram group; consistent with the in vitro observation that disulfiram blocked chemokine-dependent pseudopodia formation and chemotaxis of bone marrow-derived monocytes/macrophages. Furthermore, disulfiram suppressed macrophage activation as revealed by reduced expression of inflammatory cytokines and chemokines (TNF-α, CCL2, and CXCL9) and reduced CD86 and MHC class II expressions in monocytes/macrophages during glomerulonephritis. The dramatic reduction in monocyte/macrophage number might have resulted from disulfiram suppression of both the chemotactic response of monocytes/macrophages and their subsequent activation to produce cytokines and chemokines, which further recruit monocytes. Additionally, FROUNT was expressed in CD68 monocytes/macrophages infiltrating the crescentic glomeruli in human anti-GBM glomerulonephritis. Thus, disulfiram can be a highly effective and safe drug for the treatment of glomerulonephritis by blocking the chemotactic responses of monocytes/macrophages and their activation status in the glomerulus.
Topics: Rats; Humans; Animals; Disulfiram; Rats, Inbred WKY; Chemokines; Glomerulonephritis; Glomerulonephritis, Membranoproliferative; Cytokines
PubMed: 36049642
DOI: 10.1016/j.kint.2022.07.031 -
Nihon Ishinkin Gakkai Zasshi = Japanese... 2007Disulfiram, an alcohol antagonistic drug has been on the market since 1949 with 80% bioavailability and an established safety profile. Recently it has been reported as a... (Review)
Review
Disulfiram, an alcohol antagonistic drug has been on the market since 1949 with 80% bioavailability and an established safety profile. Recently it has been reported as a P-glycoprotein efflux pump modulator. Herein we report its antifungal potential. The MIC50 and MIC90 of disulfiram for yeast isolates is 4 and 8 microg/ml, respectively, and the MIC range is 1-16 micro g/ml for both fluconazole sensitive and resistant strains. Interestingly, disulfiram also showed fungicidal activity on Aspergillus spp. with MIC50 and MIC90 of 2 and 8 microg/ml, respectively.
Topics: Antifungal Agents; Aspergillus; Disulfiram; Microbial Sensitivity Tests; Yeasts
PubMed: 17667894
DOI: 10.3314/jjmm.48.109 -
The American Journal of Medicine Jun 1990For 40 years, disulfiram has been the alcohol-aversive drug used most frequently by American physicians in the treatment of alcohol dependency disorders. We reviewed the... (Review)
Review
PURPOSE
For 40 years, disulfiram has been the alcohol-aversive drug used most frequently by American physicians in the treatment of alcohol dependency disorders. We reviewed the clinical literature regarding the risks, benefits, indications, and efficacy of this controversial drug and summarized current knowledge of this therapy.
CONCLUSIONS
Disulfiram will produce an aversive reaction with ethanol, usually at a dose between 250 mg/day and 500 mg/day, although some patients may not have an aversive reaction at this level. Cardiac, hepatic, and neurologic toxicity can also occur within this dosage range. If disulfiram is to be used, the patient must clearly understand the risks of drinking while taking the drug, and the physician and patient must agree about the need for continued clinical supervision and monitoring for efficacy and side effects. The physician must also recognize that disulfiram is only an adjunctive therapy and that continued support, supervision, and other therapeutic measures are required. Disulfiram is probably effective in reducing the frequency of alcohol consumption in the compliant patient over the short term (e.g., 6 months). Certain subgroups of patients, such as those who are older, those who are more socially stable, and those who are well-motivated, may experience a beneficial effect for longer periods. The drug may be most effective in reducing short-term alcohol consumption when the compliance of the patient is supervised, although consideration of this kind of therapy includes the practical problems of supervising the patient and concerns that the supervising person may be placed in a difficult position. Prescription of disulfiram without accompanying education, counseling, and concomitant alcoholism therapy is not beneficial. Disulfiram has no proven effect on the long-term outcome of alcoholism.
Topics: Alcoholism; Disulfiram; Ethanol; Humans
PubMed: 2189310
DOI: 10.1016/0002-9343(90)90534-k -
Critical Care (London, England) Jul 2022The release of neutrophil extracellular traps (NETs) is associated with inflammation, coagulopathy, and organ damage found in severe cases of COVID-19. However, the...
BACKGROUND
The release of neutrophil extracellular traps (NETs) is associated with inflammation, coagulopathy, and organ damage found in severe cases of COVID-19. However, the molecular mechanisms underlying the release of NETs in COVID-19 remain unclear.
OBJECTIVES
We aim to investigate the role of the Gasdermin-D (GSDMD) pathway on NETs release and the development of organ damage during COVID-19.
METHODS
We performed a single-cell transcriptome analysis in public data of bronchoalveolar lavage. Then, we enrolled 63 hospitalized patients with moderate and severe COVID-19. We analyze in blood and lung tissue samples the expression of GSDMD, presence of NETs, and signaling pathways upstreaming. Furthermore, we analyzed the treatment with disulfiram in a mouse model of SARS-CoV-2 infection.
RESULTS
We found that the SARS-CoV-2 virus directly activates the pore-forming protein GSDMD that triggers NET production and organ damage in COVID-19. Single-cell transcriptome analysis revealed that the expression of GSDMD and inflammasome-related genes were increased in COVID-19 patients. High expression of active GSDMD associated with NETs structures was found in the lung tissue of COVID-19 patients. Furthermore, we showed that activation of GSDMD in neutrophils requires active caspase1/4 and live SARS-CoV-2, which infects neutrophils. In a mouse model of SARS-CoV-2 infection, the treatment with disulfiram inhibited NETs release and reduced organ damage.
CONCLUSION
These results demonstrated that GSDMD-dependent NETosis plays a critical role in COVID-19 immunopathology and suggests GSDMD as a novel potential target for improving the COVID-19 therapeutic strategy.
Topics: Animals; Disulfiram; Extracellular Traps; Mice; Neutrophils; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35799268
DOI: 10.1186/s13054-022-04062-5 -
Vojnosanitetski Pregled May 2012Disulfiram is used in the treatment of chronic alcoholism, because of the unpleasant symptoms produced after ethanol intake. Although it is well tolerated in most...
INTRODUCTION
Disulfiram is used in the treatment of chronic alcoholism, because of the unpleasant symptoms produced after ethanol intake. Although it is well tolerated in most patients, one in 15,000 patients will develop peripheral neuropathy every year, which is frequently misdiagnosed as alcoholic neuropathy.
CASE REPORT
We report clinical, laboratory, electrophysiological and histopathological features in a 19-year-old patient who developed an acute distal sensorymotor neuropathy during the treatment of alcoholism. At the end of 4-month treatment with disulfiram 250 mg/day, the patient complained of weakness in distal segments of the lower limbs associated with burning dysesthesias, numbness and pain in the soles of the feet and the legs below the knees; reduction in foot strength, the absence of ankle jerk tendon reflexes, and tactile stocking pin-pick and vibratory sensory impairment in the lower limbs below the knee. Recovery was successful after treatment cessation.
CONCLUSION
The significance of toxic neuropathy is shown by the fact that the recognition of clinical picture, identifying etiological factors and its elimination may prevent the evolution of polyneuropathy. This allows for more effective treatment of these neuropathies as apposite to idiopathic ones which can be treated only symptomatically. Our case report indicates the possibilities during a period with no serious damage to the axons manifested.
Topics: Alcohol Deterrents; Alcoholism; Disulfiram; Humans; Male; Peripheral Nervous System Diseases; Young Adult
PubMed: 22764551
DOI: 10.2298/vsp1205453v -
Scientific Reports Nov 2023We report a multi-resonant terahertz (THz) metamaterial perfect absorber (MPA)-based biosensor in the working frequency range of [Formula: see text] for sensing of...
We report a multi-resonant terahertz (THz) metamaterial perfect absorber (MPA)-based biosensor in the working frequency range of [Formula: see text] for sensing of microorganisms (such as fungi, yeast) and wheat pesticides. Nearly [Formula: see text] absorption is realized at [Formula: see text] and [Formula: see text]. We designed our THz MPA sensor making resonators' gap area compatible with the microorganisms' size. To obtain optimum performance of the MPA, a mapping of amplitudes and shifts in the absorption resonance peaks with different structural parameters of the resonators is carried out. A very high-frequency shift is obtained for microorganisms such as Penicillium chrysogenum (fungi), yeast, and pesticides (Imidacloprid, N, N-Diethyldithiocarbamate sodium salt trihydrate, Daminozide, N, N-Diethyldithiocarbamate sodium salt hydrate, and Dicofol). An equivalent circuit model using Advance Design System (ADS) software is developed. The calculated results through the model show similar trends as obtained in the simulations using CST. Investigations of the effect of incidence angle of THz wave on the absorption spectra of the MPA are also carried out. It is found that incidence angle does not impact the stability of the lower resonance absorption peak (1.79THz). Due to the wide working frequency range, the proposed sensor is extremely suitable for the detection of all range of pesticides because their specific absorption fingerprint lies in the frequency range of 0-3.8THz. We believe that our sensor could be a potential detection tool for detecting pesticide residues in agriculture and food products. The THz MPA-based biosensor is capable of detecting a very small change in the effective dielectric constant of the MPA environment. Therefore, it can also offer huge opportunities in label-free biosensing for future biomedical applications.
Topics: Saccharomyces cerevisiae; Pesticides; Yeast, Dried; Ditiocarb; Sodium
PubMed: 37952035
DOI: 10.1038/s41598-023-46787-5 -
Molecules (Basel, Switzerland) Jan 2022Aldehyde dehydrogenase-1a1 (ALDH1a1), the enzyme responsible for the oxidation of retinal into retinoic acid, represents a key therapeutic target for the treatment of...
Aldehyde dehydrogenase-1a1 (ALDH1a1), the enzyme responsible for the oxidation of retinal into retinoic acid, represents a key therapeutic target for the treatment of debilitating disorders such as cancer, obesity, and inflammation. Drugs that can inhibit ALDH1a1 include disulfiram, an FDA-approved drug to treat chronic alcoholism. Disulfiram, by carbamylation of the catalytic cysteines, irreversibly inhibits ALDH1a1 and ALDH2. The latter is the isozyme responsible for important physiological processes such as the second stage of alcohol metabolism. Given the fact that ALDH1a1 has a larger substrate tunnel than that in ALDH2, replacing disulfiram ethyl groups with larger motifs will yield selective ALDH1a1 inhibitors. We report herein the synthesis of new inhibitors of ALDH1a1 where (hetero)aromatic rings were introduced into the structure of disulfiram. Most of the developed compounds retained the anti-ALDH1a1 activity of disulfiram; however, they were completely devoid of inhibitory activity against ALDH2.
Topics: Acetaldehyde Dehydrogenase Inhibitors; Aldehyde Dehydrogenase 1 Family; Aldehyde Dehydrogenase, Mitochondrial; Disulfiram; Humans; Molecular Docking Simulation; Recombinant Proteins; Retinal Dehydrogenase
PubMed: 35056791
DOI: 10.3390/molecules27020480 -
Canadian Medical Association Journal Jul 1980Disulfiram (Antabuse) can produce neuropathy in daily doses of less than the usually recommended 500 mg. The four recent cases reported in this paper emphasize the need...
Disulfiram (Antabuse) can produce neuropathy in daily doses of less than the usually recommended 500 mg. The four recent cases reported in this paper emphasize the need for greater recognition of this condition. Nerve biopsies showed axonal degeneration. The neuropathy is difficult to distinguish from that associated with ethanol abuse. Disulfiram neuropathy occurs after a variable latent period (mean 5 to 6 months) and progresses steadily. Slow improvement may occur when the drug's use is stopped; often there is complete recovery eventually.
Topics: Adult; Disulfiram; Female; Humans; Male; Middle Aged; Peripheral Nerves; Peripheral Nervous System Diseases
PubMed: 6266628
DOI: No ID Found -
Current Oncology (Toronto, Ont.) Jun 2021Multiple myeloma (MM) is a malignant disease of the plasma cells representing approximately 10% of all hemato-oncological diseases. Detection of the disease is most... (Review)
Review
Multiple myeloma (MM) is a malignant disease of the plasma cells representing approximately 10% of all hemato-oncological diseases. Detection of the disease is most probable at around 65 years of age, and the average survival of patients is estimated to be 5-10 years, specifically due to frequent relapses and resistance to the therapy used. Thus, the search for new therapeutic approaches is becoming a big challenge. Disulfiram (DSF), a substance primarily known as a medication against alcoholism, has often been mentioned in recent years in relation to cancer treatment for its secondary anti-cancer effects. Recent studies performed on myeloma cell lines confirm high inhibition of the cell growth activity if a complex of disulfiram and copper is used. Its significant potential is now being seen in the cure of haematological malignities.
Topics: Cell Line, Tumor; Copper; Disulfiram; Humans; Multiple Myeloma; Neoplasm Recurrence, Local
PubMed: 34205025
DOI: 10.3390/curroncol28030193