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JAMA Aug 2018Alcohol consumption is associated with 88 000 US deaths annually. Although routine screening for heavy alcohol use can identify patients with alcohol use disorder... (Review)
Review
IMPORTANCE
Alcohol consumption is associated with 88 000 US deaths annually. Although routine screening for heavy alcohol use can identify patients with alcohol use disorder (AUD) and has been recommended, only 1 in 6 US adults report ever having been asked by a health professional about their drinking behavior. Alcohol use disorder, a problematic pattern of alcohol use accompanied by clinically significant impairment or distress, is present in up to 14% of US adults during a 1-year period, although only about 8% of affected individuals are treated in an alcohol treatment facility.
OBSERVATIONS
Four medications are approved by the US Food and Drug Administration to treat AUD: disulfiram, naltrexone (oral and long-acting injectable formulations), and acamprosate. However, patients with AUD most commonly receive counseling. Medications are prescribed to less than 9% of patients who are likely to benefit from them, given evidence that they exert clinically meaningful effects and their inclusion in clinical practice guidelines as first-line treatments for moderate to severe AUD. Naltrexone, which can be given once daily, reduces the likelihood of a return to any drinking by 5% and binge-drinking risk by 10%. Randomized clinical trials also show that some medications approved for other indications, including seizure disorder (eg, topiramate), are efficacious in treating AUD. Currently, there is not sufficient evidence to support the use of pharmacogenetics to personalize AUD treatments.
CONCLUSIONS AND RELEVANCE
Alcohol consumption is associated with a high rate of morbidity and mortality, and heavy alcohol use is the major risk factor for AUD. Simple, valid screening methods can be used to identify patients with heavy alcohol use, who can then be evaluated for the presence of an AUD. Patients receiving a diagnosis of the disorder should be given brief counseling and prescribed a first-line medication (eg, naltrexone) or referred for a more intensive psychosocial intervention.
Topics: Acamprosate; Alcohol Deterrents; Alcoholism; Counseling; Disulfiram; Humans; Naltrexone; Taurine
PubMed: 30167705
DOI: 10.1001/jama.2018.11406 -
Drugs Feb 2022Alcohol use disorder (AUD) is a highly prevalent but severely under-treated disorder, with only three widely-approved pharmacotherapies. Given that AUD is a very... (Review)
Review
Alcohol use disorder (AUD) is a highly prevalent but severely under-treated disorder, with only three widely-approved pharmacotherapies. Given that AUD is a very heterogeneous disorder, it is unlikely that one single medication will be effective for all individuals with an AUD. As such, there is a need to develop new, more effective, and diverse pharmacological treatment options for AUD with the hopes of increasing utilization and improving care. In this qualitative literature review, we discuss the efficacy, mechanism of action, and tolerability of approved, repurposed, and novel pharmacotherapies for the treatment of AUD with a clinical perspective. Pharmacotherapies discussed include: disulfiram, acamprosate, naltrexone, nalmefene, topiramate, gabapentin, varenicline, baclofen, sodium oxybate, aripiprazole, ondansetron, mifepristone, ibudilast, suvorexant, prazosin, doxazosin, N-acetylcysteine, GET73, ASP8062, ABT-436, PF-5190457, and cannabidiol. Overall, many repurposed and novel agents discussed in this review demonstrate clinical effectiveness and promise for the future of AUD treatment. Importantly, these medications also offer potential improvements towards the advancement of precision medicine and personalized treatment for the heterogeneous AUD population. However, there remains a great need to improve access to treatment, increase the menu of approved pharmacological treatments, and de-stigmatize and increase treatment-seeking for AUD.
Topics: Acamprosate; Alcohol Deterrents; Alcoholism; Baclofen; Disulfiram; Humans; Naltrexone; Topiramate
PubMed: 35133639
DOI: 10.1007/s40265-021-01670-3 -
The American Journal of Psychiatry Aug 2023Alcohol is regularly consumed throughout most of the world, including by nearly half the U.S. population age 12 or older. Heavy drinking, which is also common,... (Review)
Review
Alcohol is regularly consumed throughout most of the world, including by nearly half the U.S. population age 12 or older. Heavy drinking, which is also common, contributes to multiple adverse medical, psychiatric, and social outcomes and more than 140,000 deaths annually in the United States. It is the major risk factor for alcohol use disorder (AUD), whose current U.S. prevalence is 11%. However, AUD is undertreated, with less than 15% of individuals with a lifetime diagnosis receiving any treatment. Risk of AUD is nearly equally genetic and environmental. AUD is responsive to psychosocial treatments, including cognitive-behavioral therapy and motivational enhancement therapy. Alcohol affects multiple neurotransmitter systems, and thus pharmacotherapy for AUD is also effective. The three medications approved in the United States to treat AUD-disulfiram, naltrexone (oral and long-acting injectable formulations), and acamprosate-are underprescribed, despite being considered first-line treatments in clinical practice guidelines. Two medications not approved for treating AUD, topiramate and gabapentin, have shown efficacy in treating the disorder and are used off-label. Recent studies of novel drug candidates, including psychedelics and phosphodiesterase-4 inhibitors, are promising additions for the treatment of AUD, although they require further evaluation before being used clinically. Despite the growing availability of efficacious psychosocial and pharmacological treatments for AUD, it remains a highly stigmatized condition. Research aimed at enhancing the identification and treatment of AUD, including precision therapeutics, could broaden the acceptability of AUD treatment, benefiting affected individuals and their families and reducing the stigma associated with the disorder.
Topics: Humans; United States; Child; Alcoholism; Alcohol Deterrents; Acamprosate; Disulfiram; Naltrexone; Ethanol
PubMed: 37525595
DOI: 10.1176/appi.ajp.20230488 -
Nature Communications Nov 2022Nonalcoholic steatohepatitis (NASH) has been linked with the gut-liver axis. Here, we investigate the potential for repurposing disulfiram (DSF), a drug commonly used to... (Clinical Trial)
Clinical Trial
Nonalcoholic steatohepatitis (NASH) has been linked with the gut-liver axis. Here, we investigate the potential for repurposing disulfiram (DSF), a drug commonly used to treat chronic alcoholism, for NASH. Using a mouse model, we show that DSF ameliorates NASH in a gut microbiota-dependent manner. DSF modulates the gut microbiota and directly inhibits the growth of Clostridium. Administration of Clostridium abolishes the ameliorating effects of DSF on NASH. Mechanistically, DSF reduces Clostridium-mediated 7α-dehydroxylation activity to suppress secondary bile acid biosynthesis, which in turn activates hepatic farnesoid X receptor signaling to ameliorate NASH. To assess the effect of DSF on human gut microbiota, we performed a self-controlled clinical trial (ChiCTR2100048035), including 23 healthy volunteers who received 250 mg-qd DSF for 7 days. The primary objective outcomes were to assess the effects of the intervention on the diversity, composition and functional profile of gut microbiota. The pilot study shows that DSF also reduces Clostridium-mediated 7α-dehydroxylation activity. All volunteers tolerated DSF well and there were no serious adverse events in the 7-day follow-up period. Transferring fecal microbiota obtained from DSF-treated humans into germ-free mice ameliorates NASH. Collectively, the observations of similar ameliorating effects of DSF on mice and humans suggest that DSF ameliorates NASH by modulating the gut microbiota and bile acid metabolism.
Topics: Humans; Bile Acids and Salts; Clostridium; Disulfiram; Gastrointestinal Microbiome; Liver; Non-alcoholic Fatty Liver Disease; Pilot Projects
PubMed: 36369291
DOI: 10.1038/s41467-022-34671-1 -
Nature Cell Biology Jan 2022Poly (ADP-ribose) polymerase (PARP) inhibitors elicit antitumour activity in homologous recombination-defective cancers by trapping PARP1 in a chromatin-bound state. How...
Poly (ADP-ribose) polymerase (PARP) inhibitors elicit antitumour activity in homologous recombination-defective cancers by trapping PARP1 in a chromatin-bound state. How cells process trapped PARP1 remains unclear. Using wild-type and a trapping-deficient PARP1 mutant combined with rapid immunoprecipitation mass spectrometry of endogenous proteins and Apex2 proximity labelling, we delineated mass spectrometry-based interactomes of trapped and non-trapped PARP1. These analyses identified an interaction between trapped PARP1 and the ubiquitin-regulated p97 ATPase/segregase. We found that following trapping, PARP1 is SUMOylated by PIAS4 and subsequently ubiquitylated by the SUMO-targeted E3 ubiquitin ligase RNF4, events that promote recruitment of p97 and removal of trapped PARP1 from chromatin. Small-molecule p97-complex inhibitors, including a metabolite of the clinically used drug disulfiram (CuET), prolonged PARP1 trapping and enhanced PARP inhibitor-induced cytotoxicity in homologous recombination-defective tumour cells and patient-derived tumour organoids. Together, these results suggest that p97 ATPase plays a key role in the processing of trapped PARP1 and the response of tumour cells to PARP inhibitors.
Topics: Cell Line, Tumor; Chromatin; Disulfiram; HCT116 Cells; HeLa Cells; Humans; MCF-7 Cells; Neoplasms; Nuclear Proteins; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Poly-ADP-Ribose Binding Proteins; Protein Inhibitors of Activated STAT; Sumoylation; Transcription Factors; Ubiquitination; Valosin Containing Protein
PubMed: 35013556
DOI: 10.1038/s41556-021-00807-6 -
Nature Cancer Feb 2020Anti-cancer uses of non-oncology drugs have occasionally been found, but such discoveries have been serendipitous. We sought to create a public resource containing the...
Anti-cancer uses of non-oncology drugs have occasionally been found, but such discoveries have been serendipitous. We sought to create a public resource containing the growth inhibitory activity of 4,518 drugs tested across 578 human cancer cell lines. We used PRISM, a molecular barcoding method, to screen drugs against cell lines in pools. An unexpectedly large number of non-oncology drugs selectively inhibited subsets of cancer cell lines in a manner predictable from the cell lines' molecular features. Our findings include compounds that killed by inducing PDE3A-SLFN12 complex formation; vanadium-containing compounds whose killing depended on the sulfate transporter SLC26A2; the alcohol dependence drug disulfiram, which killed cells with low expression of metallothioneins; and the anti-inflammatory drug tepoxalin, which killed via the multi-drug resistance protein ABCB1. The PRISM drug repurposing resource (https://depmap.org/repurposing) is a starting point to develop new oncology therapeutics, and more rarely, for potential direct clinical translation.
Topics: Cell Line; Disulfiram; Drug Repositioning; Humans; Neoplasms
PubMed: 32613204
DOI: 10.1038/s43018-019-0018-6 -
Nature Dec 2017Cancer incidence is rising and this global challenge is further exacerbated by tumour resistance to available medicines. A promising approach to meet the need for...
Cancer incidence is rising and this global challenge is further exacerbated by tumour resistance to available medicines. A promising approach to meet the need for improved cancer treatment is drug repurposing. Here we highlight the potential for repurposing disulfiram (also known by the trade name Antabuse), an old alcohol-aversion drug that has been shown to be effective against diverse cancer types in preclinical studies. Our nationwide epidemiological study reveals that patients who continuously used disulfiram have a lower risk of death from cancer compared to those who stopped using the drug at their diagnosis. Moreover, we identify the ditiocarb-copper complex as the metabolite of disulfiram that is responsible for its anti-cancer effects, and provide methods to detect preferential accumulation of the complex in tumours and candidate biomarkers to analyse its effect on cells and tissues. Finally, our functional and biophysical analyses reveal the molecular target of disulfiram's tumour-suppressing effects as NPL4, an adaptor of p97 (also known as VCP) segregase, which is essential for the turnover of proteins involved in multiple regulatory and stress-response pathways in cells.
Topics: Adult; Alcohol Deterrents; Alcoholism; Animals; Antineoplastic Agents; Copper; Denmark; Disulfiram; Drug Repositioning; Female; Heat-Shock Response; Humans; Male; Mice; Middle Aged; Molecular Targeted Therapy; Neoplasms; Nuclear Proteins; Protein Aggregates; Protein Binding; Proteolysis
PubMed: 29211715
DOI: 10.1038/nature25016 -
JAMA Feb 2021
Topics: Acamprosate; Alcohol Deterrents; Alcoholics Anonymous; Alcoholism; Cognitive Behavioral Therapy; Disulfiram; Humans; Naltrexone
PubMed: 33560323
DOI: 10.1001/jama.2020.2012 -
Photothermally Triggered Copper Payload Release for Cuproptosis-Promoted Cancer Synergistic Therapy.Angewandte Chemie (International Ed. in... Mar 2023Cuproptosis is a new form of programmed cell death and exhibits enormous potential in cancer treatment. However, reducing the undesirable Cu ion release in normal tissue...
Cuproptosis is a new form of programmed cell death and exhibits enormous potential in cancer treatment. However, reducing the undesirable Cu ion release in normal tissue and maximizing the copper-induced therapeutic effect in cancer sites are two main challenges. In this study, we constructed a photothermally triggered nanoplatform (Au@MSN-Cu/PEG/DSF) to realize on-demand delivery for synergistic therapy. The released disulfiram (DSF) chelated with Cu in situ to generate highly cytotoxic bis(diethyldithiocarbamate)copper (CuET), causing cell apoptosis, and the formed Cu species promoted toxic mitochondrial protein aggregation, leading to cell cuproptosis. Synergistic with photothermal therapy, Au@MSN-Cu/PEG/DSF could effectively kill tumor cells and inhibit tumor growth (inhibition rate up to 80.1 %). These results provide a promising perspective for potential cancer treatment based on cuproptosis, and may also inspire the design of advanced nano-therapeutic platforms.
Topics: Humans; Antineoplastic Agents; Cell Line, Tumor; Copper; Disulfiram; Ditiocarb; Neoplasms; Apoptosis
PubMed: 36585379
DOI: 10.1002/anie.202213922 -
Cell Death & Disease Sep 2023Gasdermin D (GSDMD)-mediated pyroptosis has a significant pro-inflammation characteristic due to dramatic secretion of pro-inflammatory substances. However, its role...
Gasdermin D (GSDMD)-mediated pyroptosis has a significant pro-inflammation characteristic due to dramatic secretion of pro-inflammatory substances. However, its role remains unclear in psoriasis as one chronic inflammatory skin disorder with high prevalence. We found that N-terminal GSDMD (N-GSDMD) was aberrantly expressed in epidermis of skin lesion in psoriasis patients and imiquimod-induced psoriasis-like dermatitis (IIPLD) mice. In epidermis of IIPLD mice and M5 (simulating psoriatic inflammatory challenge)-treated keratinocytes cultured in vitro, cleavage products of caspase-1, GSDMD and IL-1β were increased. M5-stimulated keratinocyte presented typical pyroptosis morphology accompanied with PI-staining. Gsdmd keratinocytes could not present pyroptosis morphology while stimulated with M5. Electroporation of recombinant N-GSDMD could make the pyroptosis morphology reappear. In Gsdmd mice or keratinocyte-specific Gsdmd conditional knockout mice, we observed the alleviation of psoriatic inflammation and epidermal aberrant expression of Ki-67 and differentiation markers (loricrin and keratin 5) after imiquimod stimulation. Transplanting skin tissue from control mice to Gsdmd mice can evoke the response to imiquimod stimulation in the background of Gsdmd mice (not limited in transplanting area). In M5-stimulated keratinocytes, disulfiram or GSDMD siRNA transfection can inhibit pyroptosis and eliminate disproportionate increases of Ki-67 and PI. We further validated that topically application of disulfiram (pyroptosis inhibitor) also alleviated IIPLD in mice. These findings indicate a novel mechanism that GSDMD-mediated keratinocyte pyroptosis facilitates hyperproliferation and aberrant differentiation induced by immune microenvironment in psoriatic skin inflammation, which contributes to pathogenesis of psoriasis. Our study provides an innovative insight that targeting pyroptosis can be considered as a therapeutic strategy against psoriasis.
Topics: Animals; Mice; Gasdermins; Disulfiram; Imiquimod; Ki-67 Antigen; Pyroptosis; Keratinocytes; Psoriasis; Dermatitis; Inflammation
PubMed: 37673869
DOI: 10.1038/s41419-023-06094-3