-
Expert Opinion on Emerging Drugs Apr 2024Alcohol Use Disorder (AUD) poses an ongoing significant global health burden. AUD is highly prevalent and affects not only the individuals with AUD, but also their... (Review)
Review
INTRODUCTION
Alcohol Use Disorder (AUD) poses an ongoing significant global health burden. AUD is highly prevalent and affects not only the individuals with AUD, but also their communities and society at large. Even though pharmacotherapy is an integral part of AUD treatment, the few available substances show limited efficacy and limited clinical impact. Thus, there is a need for new innovative pharmacotherapeutic approaches.
AREAS COVERED
This paper provides a comprehensive review of drugs approved for the treatment of AUD as well as those currently in phase II and III development. Data from recent clinical trials has been reviewed and supplemented by additional literature based on a systematic search of the PubMed database and clinical trials registries. Compounds discussed include disulfiram, naltrexone, nalmefene, acamprosat, baclofen, sodium oxybate, doxazosin, varenicline, zonisamide, gabapentin, apremilast, ibudilast, ivermectin, tolcapone, mifepristone, suvorexant, ketamine, psilocybin, semaglutide, oxytocin and cannabidiol.
EXPERT OPINION
Even though the majority of the discussed compounds lack sufficient evidence to support their efficacy, multiple promising new treatment options are currently under investigation. Future research has to consider specific phenotypes and subgroups of AUD as well as a possible enhancement of the effects of psychotherapy through combination with pharmacotherapy. Practitioners should be encouraged to use available compounds to support existing therapeutic regimens.
PubMed: 38606899
DOI: 10.1080/14728214.2024.2342951 -
Gynecologic Oncology Apr 2024Low grade serous ovarian carcinoma (LGSOC) is a distinct histotype of ovarian cancer characterised high levels of intrinsic chemoresistance, highlighting the urgent need...
BACKGROUND
Low grade serous ovarian carcinoma (LGSOC) is a distinct histotype of ovarian cancer characterised high levels of intrinsic chemoresistance, highlighting the urgent need for new treatments. High throughput screening in clinically-informative cell-based models represents an attractive strategy for identifying candidate treatment options for prioritisation in clinical studies.
METHODS
We performed a high throughput drug screen of 1610 agents across a panel of 6 LGSOC cell lines (3 RAS/RAF-mutant, 3 RAS/RAF-wildtype) to identify novel candidate therapeutic approaches. Validation comprised dose-response analysis across 9 LGSOC models and 5 high grade serous comparator lines.
RESULTS
16 hits of 1610 screened compounds were prioritised for validation based on >50% reduction in nuclei counts in over half of screened cell lines at 1000 nM concentration. 11 compounds passed validation, and the four agents of greatest interest (dasatinib, tyrosine kinase inhibitor; disulfiram, aldehyde dehydrogenase inhibitor; carfilzomib, proteasome inhibitor; romidepsin, histone deacetylase inhibitor) underwent synergy profiling with the recently approved MEK inhibitor trametinib. Disulfiram demonstrated excellent selectivity for LGSOC versus high grade serous ovarian carcinoma comparator lines (P = 0.003 for IC50 comparison), while the tyrosine kinase inhibitor dasatinib demonstrated favourable synergy with trametinib across multiple LGSOC models (maximum zero interaction potency synergy score 46.9). The novel, highly selective Src family kinase (SFK) inhibitor NXP900 demonstrated a similar trametinib synergy profile to dasatinib, suggesting that SFK inhibition is the likely driver of synergy.
CONCLUSION
Dasatinib and other SFK inhibitors represent novel candidate treatments for LGSOC and demonstrate synergy with trametinib. Disulfiram represents an additional treatment strategy worthy of investigation.
PubMed: 38582027
DOI: 10.1016/j.ygyno.2024.03.029 -
Aesthetic Surgery Journal Jun 2024Macrophage-mediated inflammatory response in the early post-grafting period restricts fat graft retention. Pyroptosis is a novel type of programmed cell death that...
BACKGROUND
Macrophage-mediated inflammatory response in the early post-grafting period restricts fat graft retention. Pyroptosis is a novel type of programmed cell death that extensively participates in inflammatory pathologies.
OBJECTIVES
This study sought to determine whether macrophage pyroptosis was activated during the inflammatory phase after fat grafting and to investigate the efficacy of a pyroptosis inhibitor, disulfiram (DSF), in fat graft retention.
METHODS
We established a C57BL/6 mice fat grafting model and then analyzed macrophage pyroptosis. DSF (50 mg/kg, every other day) was intraperitoneally injected starting 1 hour before fat grafting and continued for 14 days. An in vitro co-culture system was established in which mouse RAW264.7 macrophages were co-cultured with apoptotic adipocytes to further validate the findings of the in vivo studies and to explore the underlying mechanisms.
RESULTS
Here we reported that macrophage pyroptosis was activated in both fat grafts and in vitro co-culture models. DSF was found to be a potent pyroptosis inhibitor, promoting M2 macrophage polarization. In addition, DSF was demonstrated to enhance vascularization and graft retention.
CONCLUSIONS
Our results suggested that pyroptosis plays a crucial role in the inflammatory cascade within fat grafts. DSF, being a clinically available drug, could be translated into a clinically effective drug for improving fat graft survival by inhibiting macrophage pyroptosis, therefore inducing M2 macrophage polarization and promoting neovascularization.
Topics: Animals; Pyroptosis; Disulfiram; Mice; NLR Family, Pyrin Domain-Containing 3 Protein; Mice, Inbred C57BL; Macrophages; Inflammasomes; Coculture Techniques; RAW 264.7 Cells; Adipose Tissue; Graft Survival; Adipocytes; Male
PubMed: 38567442
DOI: 10.1093/asj/sjae075 -
Journal of the American Heart... Apr 2024Pyroptosis executor GsdmD (gasdermin D) promotes atherosclerosis in mice and humans. Disulfiram was recently shown to potently inhibit GsdmD, but the in vivo efficacy...
BACKGROUND
Pyroptosis executor GsdmD (gasdermin D) promotes atherosclerosis in mice and humans. Disulfiram was recently shown to potently inhibit GsdmD, but the in vivo efficacy and mechanism of disulfiram's antiatherosclerotic activity is yet to be explored.
METHODS AND RESULTS
We used human/mouse macrophages, endothelial cells, and smooth muscle cells and a hyperlipidemic mouse model of atherosclerosis to determine disulfiram antiatherosclerotic efficacy and mechanism. The effects of disulfiram on several atheroprotective pathways such as autophagy, efferocytosis, phagocytosis, and gut microbiota were determined. Atomic force microscopy was used to determine the effects of disulfiram on the biophysical properties of the plasma membrane of macrophages. Disulfiram-fed hyperlipidemic apolipoprotein E mice showed significantly reduced interleukin-1β release upon in vivo Nlrp3 (NLR family pyrin domain containing 3) inflammasome activation. Disulfiram-fed mice showed smaller atherosclerotic lesions (~27% and 29% reduction in males and females, respectively) and necrotic core areas (~50% and 46% reduction in males and females, respectively). Disulfiram induced autophagy in macrophages, smooth muscle cells, endothelial cells, hepatocytes/liver, and atherosclerotic plaques. Disulfiram modulated other atheroprotective pathways (eg, efferocytosis, phagocytosis) and gut microbiota. Disulfiram-treated macrophages showed enhanced phagocytosis/efferocytosis, with the mechanism being a marked increase in cell-surface expression of efferocytic receptor MerTK. Atomic force microscopy analysis revealed altered biophysical properties of disulfiram-treated macrophages, showing increased order-state of plasma membrane and increased adhesion strength. Furthermore, 16sRNA sequencing of disulfiram-fed hyperlipidemic mice showed highly significant enrichment in atheroprotective gut microbiota and a reduction in atherogenic species.
CONCLUSIONS
Taken together, our data show that disulfiram can simultaneously modulate several atheroprotective pathways in a GsdmD-dependent as well as GsdmD-independent manner.
Topics: Male; Female; Mice; Humans; Animals; Disulfiram; Efferocytosis; Endothelial Cells; Gastrointestinal Microbiome; Atherosclerosis; Autophagy
PubMed: 38563369
DOI: 10.1161/JAHA.123.033881 -
International Review of Neurobiology 2024Repurposing drugs for the treatment of alcohol dependence involves the use of drugs that were initially developed for other conditions, but have shown promise in... (Review)
Review
Repurposing drugs for the treatment of alcohol dependence involves the use of drugs that were initially developed for other conditions, but have shown promise in reducing alcohol use or preventing relapse. This approach can offer a more cost-effective and time-efficient alternative to developing new drugs from scratch. Currently approved medications for alcohol use disorder (AUD) include acamprosate, disulfiram, naltrexone, nalmefene, baclofen, and sodium oxybate. Acamprosate was developed specifically for AUD, while disulfiram's alcohol-deterrent effects were discovered incidentally. Naltrexone and nalmefene were originally approved for opioids but found secondary applications in AUD. Baclofen and sodium oxybate were repurposed from neurological conditions. Other drugs show promise. Topiramate and zonisamide, anticonvulsants, demonstrate efficacy in reducing alcohol consumption. Another anticonvulsant, gabapentin has been disappointing overall, except in cases involving alcohol withdrawal symptoms. Varenicline, a nicotinic receptor agonist, benefits individuals with less severe AUD or concurrent nicotine use. Ondansetron, a 5-HT3 antagonist, has potential for early-onset AUD, especially when combined with naltrexone. Antipsychotic drugs like aripiprazole and quetiapine have limited efficacy. Further investigation is needed for potential repurposing of α1 adrenergic receptor antagonists prazosin and doxazosin, glucocorticoid receptor antagonist mifepristone, the phosphodiesterase inhibitor Ibudilast, the cysteine prodrug N-acetylcysteine, and the OX1R and OX2R blocker Suvorexant. This review supports repurposing drugs as an effective strategy for expanding treatment options for AUD.
Topics: Humans; Alcoholism; Acamprosate; Naltrexone; Disulfiram; Sodium Oxybate; Baclofen; Drug Repositioning; Substance Withdrawal Syndrome; Alcohol Drinking
PubMed: 38555115
DOI: 10.1016/bs.irn.2024.02.002 -
Brain, Behavior, and Immunity Jul 2024GSDMD-mediated pyroptosis occurs in the nigrostriatal pathway in Parkinson's disease animals, yet the role of GSDMD in neuroinflammation and death of dopaminergic...
GSDMD-mediated pyroptosis occurs in the nigrostriatal pathway in Parkinson's disease animals, yet the role of GSDMD in neuroinflammation and death of dopaminergic neurons in Parkinson's disease remains elusive. Here, our in vivo and in vitro studies demonstrated that GSDMD, as a pyroptosis executor, contributed to glial reaction and death of dopaminergic neurons across different Parkinson's disease models. The ablation of the Gsdmd attenuated Parkinson's disease damage by reducing dopaminergic neuronal death, microglial activation, and detrimental transformation. Disulfiram, an inhibitor blocking GSDMD pore formation, efficiently curtailed pyroptosis, thereby lessening the pathology of Parkinson's disease. Additionally, a modification in GSDMD was identified in the blood of Parkinson's disease patients in contrast to healthy subjects. Therefore, the detected alteration in GSDMD within the blood of Parkinson's disease patients and the protective impact of disulfiram could be promising for the diagnostic and therapeutic approaches against Parkinson's disease.
Topics: Pyroptosis; Parkinson Disease; Animals; Dopaminergic Neurons; Microglia; Mice; Male; Humans; Phosphate-Binding Proteins; Disulfiram; Mice, Inbred C57BL; Disease Models, Animal; Cell Death; Mice, Knockout; Gasdermins
PubMed: 38552923
DOI: 10.1016/j.bbi.2024.03.038 -
JAMA Network Open Mar 2024US Food and Drug Administration-approved medications for alcohol use disorder (MAUD) are significantly underused. Hospitalizations may provide an unmet opportunity to...
IMPORTANCE
US Food and Drug Administration-approved medications for alcohol use disorder (MAUD) are significantly underused. Hospitalizations may provide an unmet opportunity to initiate MAUD, but few studies have examined clinical outcomes of patients who initiate these medications at hospital discharge.
OBJECTIVE
To investigate the association between discharge MAUD initiation and 30-day posthospitalization outcomes.
DESIGN, SETTING, AND PARTICIPANTS
This cohort study was conducted among patients with Medicare Part D who had alcohol-related hospitalizations in 2016. Data were analyzed from October 2022 to December 2023.
EXPOSURES
Discharge MAUD initiation was defined as oral naltrexone, acamprosate, or disulfiram pharmacy fills within 2 days of discharge.
MAIN OUTCOMES
The primary outcome was a composite of all-cause mortality or return to hospital (emergency department visits and hospital readmissions) within 30 days of discharge. Secondary outcomes included these components separately, return to hospital for alcohol-related diagnoses, and primary care or mental health follow-up within 30 days of discharge. Propensity score 3:1 matching and modified Poisson regressions were used to compare outcomes between patients who received and did not receive discharge MAUD.
RESULTS
There were 6794 unique individuals representing 9834 alcohol-related hospitalizations (median [IQR] age, 54 [46-62] years; 3205 hospitalizations among females [32.6%]; 1754 hospitalizations among Black [17.8%], 712 hospitalizations among Hispanic [7.2%], and 7060 hospitalizations among White [71.8%] patients). Of these, 192 hospitalizations (2.0%) involved discharge MAUD initiation. After propensity matching, discharge MAUD initiation was associated with a 42% decreased incidence of the primary outcome (incident rate ratio, 0.58 [95% CI, 0.45 to 0.76]; absolute risk difference, -0.18 [95% CI, -0.26 to -0.11]). These findings were consistent among secondary outcomes (eg, incident rate ratio for all-cause return to hospital, 0.56 [95% CI, 0.43 to 0.73]) except for mortality, which was rare in both groups (incident rate ratio, 3.00 [95% CI, 0.42 to 21.22]). Discharge MAUD initiation was associated with a 51% decreased incidence of alcohol-related return to hospital (incident rate ratio, 0.49 [95% CI, 0.34 to 0.71]; absolute risk difference, -0.15 [95% CI, -0.22 to -0.09]).
CONCLUSION AND RELEVANCE
In this cohort study, discharge initiation of MAUD after alcohol-related hospitalization was associated with a large absolute reduction in return to hospital within 30 days. These findings support efforts to increase uptake of MAUD initiation at hospital discharge.
Topics: Female; Humans; Aged; United States; Middle Aged; Patient Discharge; Alcoholism; Cohort Studies; Medicare; Hospitals
PubMed: 38551564
DOI: 10.1001/jamanetworkopen.2024.3387 -
Cells Mar 2024Disulfiram (DSF), an anti-alcoholism medicine, exerts treatment effects in patients suffering from persistent Borreliosis and also exhibits anti-cancer effects through...
Disulfiram (DSF), an anti-alcoholism medicine, exerts treatment effects in patients suffering from persistent Borreliosis and also exhibits anti-cancer effects through its copper chelating derivatives and induction of oxidative stress in mitochondria. Since chronic/persistent borreliosis is characterized by increased amounts of pro-inflammatory macrophages, this study investigated opsonin-independent phagocytosis, migration, and surface marker expression of in vivo activated and in vitro cultured human monocyte-derived phagocytes (macrophages and dendritic cells) with and without DSF treatment. Phagocytosis of non-opsonized Dynabeads M-450 and migration of macrophages and dendritic cells were monitored using live cell analyzer Juli™ Br for 24 h, imaging every 3.5 min. To simultaneously monitor phagocyte function, results were analyzed by a newly developed software based on the differential phase contrast images of cells before and after ingestion of Dynabeads. DSF decreased the phagocytic capacities exhibited by in vitro enriched and long-lived phagocytes. Although no chemotactic gradient was applied to the test system, vigorous spontaneous migration was observed. We therefore set up an algorithm to monitor and quantify both phagocytosis and migration simultaneously. DSF not only reduced phagocytosis in a majority of these long-lived phagocytes but also impaired their migration. Despite these selective effects by DSF, we found that DSF reduced the expression densities of surface antigens CD45 and CD14 in all of our long-lived phagocytes. In cells with a high metabolic activity and high mitochondrial contents, DSF led to cell death corresponding to mitochondrial oxidative stress, whereas metabolically inactive phagocytes survived our DSF treatment protocol. In conclusion, DSF affects the viability of metabolically active phagocytes by inducing mitochondrial stress and secondly attenuates phagocytosis and migration in some long-lived phagocytes.
Topics: Humans; Disulfiram; Opsonin Proteins; Phagocytosis; Phagocytes; Macrophages
PubMed: 38534379
DOI: 10.3390/cells13060535 -
Hypertension Research : Official... May 2024This graphic depicts the interplay between copper homeostasis and cuproptosis and their role in cardiovascular diseases. Copper is vital for cardiac mitochondrial... (Review)
Review
This graphic depicts the interplay between copper homeostasis and cuproptosis and their role in cardiovascular diseases. Copper is vital for cardiac mitochondrial function, while its dysregulation induces cuproptosis via Ferredoxin1 (FDX1) and lipoic acid synthase (LIAS). Cuproptosis is linked to myocardial ischemia/reperfusion injury, heart failure, atherosclerosis, and arrhythmias. Copper deficiency impacts atherosclerosis markers. Therapeutic interventions include copper chelators (e.g., ammonium tetrathiomolybdate), and oxidative phosphorylation inhibitors like elesclomol and copper ionophores (CuII(atsm), CuII(gtsm), and disulfiram). These interventions modulate intracellular copper, elevate NO, and reduce inflammatory cytokines, contributing to decreased cardiovascular diseases.
Topics: Animals; Humans; Cardiovascular Diseases; Cell Death; Copper; Homeostasis
PubMed: 38467792
DOI: 10.1038/s41440-024-01636-4