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Molecules (Basel, Switzerland) Aug 2022Disulfiram (DS), known as an anti-alcoholism drug, has shown a potent antiviral activity. Still, the potential clinical application of DS is limited by its low water...
Disulfiram (DS), known as an anti-alcoholism drug, has shown a potent antiviral activity. Still, the potential clinical application of DS is limited by its low water solubility and rapid metabolism. Cyclodextrins (CDs) have been widely used to improve the solubility of drugs in water. In this study, five concentrations of hydroxypropyl β-cyclodextrin (HP) and sulfobutyl ether β-cyclodextrin (SBE) were used to form inclusion complexes of DS for enhanced solubility. Solutions were freeze-dried, and the interaction between DS and CD was characterized using differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and Fourier transform infrared spectroscopy (FTIR). In addition, the nebulization properties of the DS-CD solutions were studied. The aqueous solubility of DS increased significantly when loaded to either of both CDs. The phase solubility of both complexes was a linear function of the CD concentration (A type). Furthermore, physicochemical characterization studies showed a potent inclusion of the drug in the CD-DS complexes. Aerosolization studies demonstrated that these formulations are suitable for inhalation. Overall, the CD inclusion complexes have great potential for the enhancement of DS solubility. However, further studies are needed to assess the efficacy of DS-CD inclusion complexes against SARS-CoV-2 via nebulization.
Topics: 2-Hydroxypropyl-beta-cyclodextrin; Calorimetry, Differential Scanning; Cyclodextrins; Disulfiram; Humans; SARS-CoV-2; Solubility; Spectroscopy, Fourier Transform Infrared; Water; X-Ray Diffraction; beta-Cyclodextrins; COVID-19 Drug Treatment
PubMed: 36080368
DOI: 10.3390/molecules27175600 -
Cells Feb 2021The poor prognosis of locally advanced and metastatic head and neck squamous cell carcinoma (HNSCC) is primarily mediated by the functional properties of cancer stem...
The poor prognosis of locally advanced and metastatic head and neck squamous cell carcinoma (HNSCC) is primarily mediated by the functional properties of cancer stem cells (CSCs) and resistance to chemoradiotherapy. We investigated whether the aldehyde dehydrogenase (ALDH) inhibitor disulfiram (DSF) can enhance the sensitivity of therapy. Cell viability was assessed by the 1-(4,5-dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT) and apoptosis assays, and the cell cycle and reactive oxygen species (ROS) levels were evaluated by fluorescence-activated cell sorting (FACS). The radio-sensitizing effect was measured by a colony formation assay. The synergistic effects were calculated by combination index (CI) analyses. The DSF and DSF/Cu inhibited the cell proliferation (inhibitory concentration 50 (IC) of DSF and DSF/Cu were 13.96 μM and 0.24 μM). DSF and cisplatin displayed a synergistic effect (CI values were < 1). DSF or DSF/Cu abolished the cisplatin-induced G2/M arrest (from 52.9% to 40.7% and 41.1%), and combining irradiation (IR) with DSF or DSF/Cu reduced the colony formation and attenuated the G2/M arrest (from 53.6% to 40.2% and 41.9%). The combination of cisplatin, DSF or DSF/Cu, and IR enhanced the radio-chemo sensitivity by inducing apoptosis (42.04% and 32.21%) and ROS activity (46.3% and 37.4%). DSF and DSF/Cu enhanced the sensitivity of HNSCC to cisplatin and IR. Confirming the initial data from patient-derived tumor xenograft (PDX) supported a strong rationale to repurpose DSF as a radio-chemosensitizer and to assess its therapeutic potential in a clinical setting.
Topics: Acetaldehyde Dehydrogenase Inhibitors; Animals; Apoptosis; Cell Line, Tumor; Disulfiram; Head and Neck Neoplasms; Heterografts; Humans; Mice; Squamous Cell Carcinoma of Head and Neck
PubMed: 33671083
DOI: 10.3390/cells10030517 -
Acta Pharmacologica Sinica Nov 2021Sepsis is a dysregulated immune response to infection and potentially leads to life-threatening organ dysfunction, which is often seen in serious Covid-19 patients....
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.
Topics: Acetaldehyde Dehydrogenase Inhibitors; Animals; Anti-Inflammatory Agents; Biomimetic Materials; COVID-19; Colitis, Ulcerative; Disease Models, Animal; Disulfiram; Drug Carriers; Humans; Immunosuppressive Agents; Lactoferrin; Lipopolysaccharides; Macrophages; Mice; Mice, Inbred C57BL; Nanoparticles; Pyroptosis; SARS-CoV-2; Systemic Inflammatory Response Syndrome; Treatment Outcome; COVID-19 Drug Treatment
PubMed: 34561552
DOI: 10.1038/s41401-021-00770-w -
Oncology Research 2023Various therapeutic strategies have been developed to overcome ovarian cancer. However, the prognoses resulting from these strategies are still unclear. In the present...
Various therapeutic strategies have been developed to overcome ovarian cancer. However, the prognoses resulting from these strategies are still unclear. In the present work, we screened 54 small molecule compounds approved by the FDA to identify novel agents that could inhibit the viability of human epithelial ovarian cancer cells. Among these, we identified disulfiram (DSF), an old alcohol-abuse drug, as a potential inducer of cell death in ovarian cancer. Mechanistically, DSF treatment significantly reduced the expression of the anti-apoptosis marker B-cell lymphoma/leukemia-2 (Bcl-2) and increase the expression of the apoptotic molecules Bcl2 associated X (Bax) and cleaved caspase-3 to promote human epithelial ovarian cancer cell apoptosis. Furthermore, DSF is a newly identified effective copper ionophore, thus the combination of DSF and copper was used to reduce ovarian cancer viability than DSF single treatment. Combination treatment with DSF and copper also led to the reduced expression of ferredoxin 1 and loss of Fe-S cluster proteins (biomarkers of cuproptosis). , DSF and copper gluconate significantly decreased the tumor volume and increased the survival rate in a murine ovarian cancer xenograft model. Thus, the role of DSF revealed its potential for used as a viable therapeutic agent for the ovarian cancer.
Topics: Animals; Female; Humans; Mice; Carcinoma, Ovarian Epithelial; Cell Death; Copper; Disulfiram; Drug Repositioning; Ovarian Neoplasms; Apoptosis
PubMed: 37305383
DOI: 10.32604/or.2023.028694 -
Cells May 2020Drug repurposing appears to offer an attractive alternative in finding new anticancer agents. Their applicability seems to have multiple benefits, among which are the...
Drug repurposing appears to offer an attractive alternative in finding new anticancer agents. Their applicability seems to have multiple benefits, among which are the potential of immediate efficacy assessment in clinical trials and the existence of patient safety and tolerability evidence. Nevertheless, their effective application in terms of tumor-type targeting requires accurate knowledge of their exact mechanism of action. In this review, we present such a successful drug, namely Disulfiram (commercially known as Antabuse), and discuss its recently uncovered mode of anticancer action through DNA damage.
Topics: Animals; Cell Proliferation; DNA Damage; Disulfiram; Drug Repositioning; Humans; Neoplasms
PubMed: 32414147
DOI: 10.3390/cells9051210 -
Journal of Substance Abuse Treatment Jan 2023Alcohol use disorder (AUD) represents the most prevalent addiction in the United States. Integration of AUD treatment in primary care settings would expand care access.... (Review)
Review
BACKGROUND
Alcohol use disorder (AUD) represents the most prevalent addiction in the United States. Integration of AUD treatment in primary care settings would expand care access. The objective of this scoping review is to examine models of AUD treatment in primary care that include pharmacotherapy (acamprosate, disulfiram, naltrexone).
METHODS
The team undertook a search across MEDLINE, PsycINFO, CINAHL, the Cochrane Central Register of Controlled Trials, and Web of Science on May 21, 2021. Eligibility criteria included: patient population ≥ 18 years old, primary care-based setting, US-based study, presence of an intervention to promote AUD treatment, and prescription of FDA-approved AUD pharmacotherapy. Study design was limited to controlled trials and observational studies. We assessed study bias using a modified Oxford Centre for Evidence-based Medicine Rating Framework quality rating scheme.
RESULTS
The qualitative synthesis included forty-seven papers, representing 25 primary studies. Primary study sample sizes ranged from 24 to 830,825 participants and many (44 %) were randomized controlled trials. Most studies (80 %) included a nonpharmacologic intervention for AUD: 56 % with brief intervention, 40 % with motivational interviewing, and 12 % with motivational enhancement therapy. A plurality of studies (48 %) included mixed pharmacologic interventions, with administration of any combination of naltrexone, acamprosate, and/or disulfiram. Of the 47 total studies included, 68 % assessed care initiation and engagement. Fewer studies (15 %) explored practices surrounding screening for or diagnosing AUD. Outcome measures included receipt of pharmacotherapy and alcohol consumption, which about half of studies included (53 % and 51 %, respectively). Many of these outcomes showed significant findings in favor of integrated care models for AUD.
CONCLUSIONS
The integration of AUD pharmacotherapy in primary care settings may be associated with improved process and outcome measures of care. Future research should seek to understand the varied experiences across care integration models.
Topics: Humans; United States; Adolescent; Alcoholism; Acamprosate; Naltrexone; Disulfiram; Alcohol Drinking; Primary Health Care; Randomized Controlled Trials as Topic
PubMed: 36332528
DOI: 10.1016/j.jsat.2022.108919 -
British Journal of Cancer May 2011Previous studies indicate that disulfiram (DS), an anti-alcoholism drug, is cytotoxic to cancer cell lines and reverses anticancer drug resistance. Cancer stem cells...
BACKGROUND
Previous studies indicate that disulfiram (DS), an anti-alcoholism drug, is cytotoxic to cancer cell lines and reverses anticancer drug resistance. Cancer stem cells (CSCs) are the major cause of chemoresistance leading to the failure of cancer chemotherapy. This study intended to examine the effect of DS on breast cancer stem cells (BCSCs).
METHODS
The effect of DS on BC cell lines and BCSCs was determined by MTT, western blot, CSCs culture and CSCs marker analysis.
RESULTS
Disulfiram was highly toxic to BC cell lines in vitro in a copper (Cu)-dependent manner. In Cu-containing medium (1 μM), the IC(50) concentrations of DS in BC cell lines were 200-500 nM. Disulfiram/copper significantly enhanced (3.7-15.5-fold) cytotoxicity of paclitaxel (PAC). Combination index isobologram analysis demonstrated a synergistic effect between DS/Cu and PAC. The increased Bax and Bcl2 protein expression ratio indicated that intrinsic apoptotic pathway may be involved in DS/Cu-induced apoptosis. Clonogenic assay showed DS/Cu-inhibited clonogenicity of BC cells. Mammosphere formation and the ALDH1(+VE) and CD24(Low)/CD44(High) CSCs population in mammospheres were significantly inhibited by exposure to DS/Cu for 24 h. Disulfiram/copper induced reactive oxygen species (ROS) generation and activated its downstream apoptosis-related cJun N-terminal kinase and p38 MAPK pathways. Meanwhile, the constitutive NFκB activity in BC cell lines was inhibited by DS/Cu.
CONCLUSION
Disulfiram/copper inhibited BCSCs and enhanced cytotoxicity of PAC in BC cell lines. This may be caused by simultaneous induction of ROS and inhibition of NFκB.
Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Copper; Disulfiram; Electrophoretic Mobility Shift Assay; Female; Humans; Mitogen-Activated Protein Kinases; NF-kappa B; Neoplastic Stem Cells; Reactive Oxygen Species
PubMed: 21487404
DOI: 10.1038/bjc.2011.126 -
The American Journal of Drug and... 2009Pharmacogenetics uses genetic variation to predict individual differences in response to medications and holds much promise to improve treatment of addictive disorders. (Review)
Review
BACKGROUND
Pharmacogenetics uses genetic variation to predict individual differences in response to medications and holds much promise to improve treatment of addictive disorders.
OBJECTIVES
To review how genetic variation affects responses to cocaine, amphetamine, and methamphetamine and how this information may guide pharmacotherapy.
METHODS
We performed a cross-referenced literature search on pharmacogenetics, cocaine, amphetamine, and methamphetamine.
RESULTS
We describe functional genetic variants for enzymes dopamine-beta-hydroxylase (DbetaH), catechol-O-methyltransferase (COMT), and dopamine transporter (DAT1), dopamine D4 receptor, and brain-derived neurotrophic factor (BDNF). A single nucleotide polymorphism (SNP; C-1021T) in the DbetaH gene is relevant to paranoia associated with disulfiram pharmacotherapy for cocaine addiction. Individuals with variable number tandem repeats (VNTR) of the SLC6A3 gene 3'-untranslated region polymorphism of DAT1 have altered responses to drugs. The 10/10 repeat respond poorly to methylphenidate pharmacotherapy and the 9/9 DAT1 variant show blunted euphoria and physiological response to amphetamine. COMT, D4 receptor, and BDNF polymorphisms are linked to methamphetamine abuse and psychosis.
CONCLUSIONS
Disulfiram and methylphenidate pharmacotherapies for cocaine addiction are optimized by considering polymorphisms affecting DbetaH and DAT1 respectively. Altered subjective effects for amphetamine in DAT1 VNTR variants suggest a 'protected' phenotype.
SCIENTIFIC SIGNIFICANCE
Pharmacogenetic-based treatments for psychostimulant addiction are critical for successful treatment.
Topics: Amphetamine; Amphetamine-Related Disorders; Cocaine-Related Disorders; Disulfiram; Dopamine Uptake Inhibitors; Enzyme Inhibitors; Humans; Methamphetamine; Methylphenidate; Pharmacogenetics; Polymorphism, Single Nucleotide
PubMed: 19462300
DOI: 10.1080/00952990902825447 -
Social Work in Public Health 2013In this article, the authors briefly review the pharmacotherapeutic agents that are currently available for the treatment of substance use disorders. Nicotine... (Review)
Review
In this article, the authors briefly review the pharmacotherapeutic agents that are currently available for the treatment of substance use disorders. Nicotine replacement therapies are most effective for tobacco cessation. Naltrexone, acamprosate, and disulfiram are effective for reducing alcohol use. The most effective pharmacotherapies for opiate use disorders are agonist therapies, including methadone and buprenorphine. The authors also examine recent advances in medication development for other substance use disorders such as stimulant addiction. The role of medication adherence and behavioral treatments and the integration of behavioral and pharmacotherapeutic interventions are also discussed.
Topics: Alcohol Deterrents; Alcoholism; Analgesics, Opioid; Behavior Therapy; Behavior, Addictive; Buprenorphine; Disulfiram; Humans; Naltrexone; Narcotic Antagonists; Secondary Prevention; Smoking Cessation; Substance Withdrawal Syndrome; Substance-Related Disorders; Tobacco Use Disorder
PubMed: 23731419
DOI: 10.1080/19371918.2013.759031 -
Journal of Studies on Alcohol and... 2014Modern pharmacotherapy for alcohol dependence has its roots in the failure of National Prohibition in the United States and the rise of the disease model of alcoholism... (Review)
Review
Modern pharmacotherapy for alcohol dependence has its roots in the failure of National Prohibition in the United States and the rise of the disease model of alcoholism (embodied in Alcoholics Anonymous). In 1948, disulfiram was the first medication approved by the U.S. Food and Drug Administration (FDA) to treat alcohol dependence, but its efficacy has not been supported by randomized controlled trials. In the 1960s, benzodiazepines replaced older treatments for alcohol withdrawal, but sedative and dependence-producing effects limit their utility in the postwithdrawal period. In the 1980s, the focus shifted to the treatment of co-occurring psychiatric disorders and medications that modify negative mood states, which contribute to relapse to heavy drinking. In the 1990s, developments in neurobiology implicated specific neurotransmitter systems underlying alcohol's effects, culminating in the 1994 approval by the FDA of the opioid antagonist naltrexone to treat alcohol dependence. In 2006, the FDA approved a long-acting formulation of naltrexone. Recently, nalmefene, another opioid receptor antagonist, was approved in Europe for as-needed use to reduce heavy drinking. Acamprosate, an amino acid derivative, first approved in France in 1989, received FDA approval in 2004. However, the beneficial effects of the approved medications are only modestly greater than those of placebo, and their use is limited. Topiramate, currently under investigation for alcohol dependence, has greater efficacy but a variety of adverse effects. In addition to the identification of novel compounds, the future of alcohol dependence pharmacotherapy will depend on developments in pharmacogenetics, in which genetic variation that moderates treatment efficacy and adverse effects is used to personalize treatment.
Topics: Acamprosate; Alcohol Deterrents; Alcohol-Related Disorders; Disulfiram; Fructose; Humans; Hypnotics and Sedatives; Narcotic Antagonists; Pharmacogenetics; Taurine; Topiramate
PubMed: 24565314
DOI: No ID Found