Disulfiram: Mechanisms, Applications, and Challenges.

Background: Since disulfiram's discovery in the 1940s and its FDA approval for alcohol use disorder, other indications have been investigated. This review describes potential clinical applications, associated risks, and challenges. Methods: For this narrative review, a PubMed search was conducted for articles addressing in vivo studies of disulfiram with an emphasis on drug repurposing for the treatment of human diseases. The key search terms were "disulfiram" and "Antabuse". Animal studies and in vitro studies highlighting important mechanisms and safety issues were also included. Results: In total, 196 sources addressing our research focus spanning 1948-2022 were selected for inclusion. In addition to alcohol use disorder, emerging data support a potential role for disulfiram in the treatment of other addictions (e.g., cocaine), infections (e.g., bacteria such as Staphylococcus aureus and Borrelia burgdorferi, viruses, parasites), inflammatory conditions, neurological diseases, and cancers. The side effects range from minor to life-threatening, with lower doses conveying less risk. Caution in human use is needed due to the considerable inter-subject variability in disulfiram pharmacokinetics. Conclusions: While disulfiram has promise as a "repurposed" agent in human disease, its risk profile is of concern. Animal studies and well-controlled clinical trials are needed to assess its safety and efficacy for non-alcohol-related indications.

Sex and the G Protein-Coupled Estrogen Receptor Impact Vascular Stiffness.

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Current and Emerging Therapeutic Options for Hairy Cell Leukemia Variant.

Hairy cell leukemia variant (HCL-v) is a rare B-cell lymphoproliferative disorder with distinct immunophenotypic and molecular characteristics when compared to classical hairy cell leukemia (HCL-c). In contrast to the enormous progress in therapeutic options for HCL-c, HCL-v remains a therapeutic challenge due to inferior outcomes with standard chemoimmunotherapy and BCR signaling pathway inhibitors, and due to the fact that HCL-v has limited molecular therapeutic targets. In addition, because of the rarity of the disease, there is a paucity of later phase studies or multicenter trials to guide treatment decisions. In this article, we briefly review the diagnostic criteria and clinical characteristics of HCL-v and present a comprehensive overview of current therapeutic options in HCL-v.

mGlu2 and mGlu3 Negative Allosteric Modulators Divergently Enhance Thalamocortical Transmission and Exert Rapid Antidepressant-like Effects.

Non-selective antagonists of metabotropic glutamate receptor subtypes 2 (mGlu2) and 3 (mGlu3) exert rapid antidepressant-like effects by enhancing prefrontal cortex (PFC) glutamate transmission; however, the receptor subtype contributions and underlying mechanisms remain unclear. Here, we leveraged newly developed negative allosteric modulators (NAMs), transgenic mice, and viral-assisted optogenetics to test the hypothesis that selective inhibition of mGlu2 or mGlu3 potentiates PFC excitatory transmission and confers antidepressant efficacy in preclinical models. We found that systemic treatment with an mGlu2 or mGlu3 NAM rapidly activated biophysically unique PFC pyramidal cell ensembles. Mechanistic studies revealed that mGlu2 and mGlu3 NAMs enhance thalamocortical transmission and inhibit long-term depression by mechanistically distinct presynaptic and postsynaptic actions. Consistent with these actions, systemic treatment with either NAM decreased passive coping and reversed anhedonia in two independent chronic stress models, suggesting that both mGlu2 and mGlu3 NAMs induce antidepressant-like effects through related but divergent mechanisms of action.

Dorsal BNST α2A-Adrenergic Receptors Produce HCN-Dependent Excitatory Actions That Initiate Anxiogenic Behaviors.

Stress is a precipitating agent in neuropsychiatric disease and initiates relapse to drug-seeking behavior in addicted patients. Targeting the stress system in protracted abstinence from drugs of abuse with anxiolytics may be an effective treatment modality for substance use disorders. α2A-adrenergic receptors (α2A-ARs) in extended amygdala structures play key roles in dampening stress responses. Contrary to early thinking, α2A-ARs are expressed at non-noradrenergic sites in the brain. These non-noradrenergic α2A-ARs play important roles in stress responses, but their cellular mechanisms of action are unclear. In humans, the α2A-AR agonist guanfacine reduces overall craving and uncouples craving from stress, yet minimally affects relapse, potentially due to competing actions in the brain. Here, we show that heteroceptor α2A-ARs postsynaptically enhance dorsal bed nucleus of the stria terminalis (dBNST) neuronal activity in mice of both sexes. This effect is mediated by hyperpolarization-activated cyclic nucleotide-gated cation channels because inhibition of these channels is necessary and sufficient for excitatory actions. Finally, this excitatory action is mimicked by clozapine-N-oxide activation of the Gi-coupled DREADD hM4Di in dBNST neurons and its activation elicits anxiety-like behavior in the elevated plus maze. Together, these data provide a framework for elucidating cell-specific actions of GPCR signaling and provide a potential mechanism whereby competing anxiogenic and anxiolytic actions of guanfacine may affect its clinical utility in the treatment of addiction.SIGNIFICANCE STATEMENT Stress affects the development of neuropsychiatric disorders including anxiety and addiction. Guanfacine is an α2A-adrenergic receptor (α2A-AR) agonist with actions in the bed nucleus of the stria terminalis (BNST) that produces antidepressant actions and uncouples stress from reward-related behaviors. Here, we show that guanfacine increases dorsal BNST neuronal activity through actions at postsynaptic α2A-ARs via a mechanism that involves hyperpolarization-activated cyclic nucleotide gated cation channels. This action is mimicked by activation of the designer receptor hM4Di expressed in the BNST, which also induces anxiety-like behaviors. Together, these data suggest that postsynaptic α2A-ARs in BNST have excitatory actions on BNST neurons and that these actions can be phenocopied by the so-called "inhibitory" DREADDs, suggesting that care must be taken regarding interpretation of data obtained with these tools.

Isonitrile Formation by a Non-Heme Iron(II)-Dependent Oxidase/Decarboxylase.

The electron-rich isonitrile is an important functionality in bioactive natural products, but its biosynthesis has been restricted to the IsnA family of isonitrile synthases. We herein provide the first structural and biochemical evidence of an alternative mechanism for isonitrile formation. ScoE, a putative non-heme iron(II)-dependent enzyme from Streptomyces coeruleorubidus, was shown to catalyze the conversion of (R)-3-((carboxymethyl)amino)butanoic acid to (R)-3-isocyanobutanoic acid through an oxidative decarboxylation mechanism. This work further provides a revised scheme for the biosynthesis of a unique class of isonitrile lipopeptides, of which several members are critical for the virulence of pathogenic mycobacteria.

Development of the CNS TAP tool for the selection of precision medicine therapies in neuro-oncology.

The number of targeted therapies utilized in precision medicine are rapidly increasing. Neuro-oncology offers a unique challenge due to the varying blood brain barrier (BBB) penetration of each agent. Neuro-oncologists face a difficult task weighing the growing number of potential targeted therapies and their likelihood of BBB penetration. We developed the CNS TAP Working Group and performed an extensive literature review for the evidence-based creation of the CNS TAP tool, which was retrospectively validated by analyzing brain tumor patients who underwent therapy targeted based on genomic results from an academic sequencing study (MiOncoseq, n = 17) or private molecular profiling (Foundation One, n = 7). The CNS TAP tool scores relevant targeted agents by applying multiple variables (i.e., pre-clinical data, clinical data, BBB permeability) to patient specific genomic information and clinical trial availability. In the Michigan cohort, the CNS TAP tool predicted the selected agent 85.7% of the time. The CNS TAP tool predicted the agent independently selected by pediatric neuro-oncologists in the Colorado cohort 50% of the time. Patients with recurrent brain tumors treated with agents predicted by the CNS TAP tool demonstrated a median progression-free survival of 4 months and four patients with recurrent high-grade glioma maintained ongoing partial responses of at least 6 months. The CNS TAP tool is a formalized algorithm to assist clinicians select the optimal targeted therapy for neuro-oncology patients. The CNS TAP tool has relatively high concordance with selected therapies and clinical outcomes in patients receiving targeted therapy in this heterogeneous retrospective cohort were promising.

Mechanism of action and efficacy of RX-111, a thieno[2,3-c]pyridine derivative and small molecule inhibitor of protein interaction with glycosaminoglycans (SMIGs), in delayed-type hypersensitivity, TNBS-induced colitis and experimental autoimmune encephalomyelitis.

OBJECTIVE AND DESIGN: Elucidate the mechanism of action of the small molecule inhibitor of protein binding to glycosaminoglycans, RX-111 and assay its anti-inflammatory activity in animal models of inflammatory disease. MATERIALS: The glycosaminoglycan, heparin, was used in the mechanism of action study of RX-111. Human T lymphocytes and umbilical vein endothelial cells were used to assay the in vitro activity of RX-111. Mouse and rat models of disease were used to assay the anti-inflammatory activity of RX-111 in vivo. METHODS: Circular dichroism and UV/Vis absorption spectroscopy were used to study the binding of RX-111 to the glycosaminoglycan, heparin. T lymphocyte rolling on endothelial cells under shear flow was used to assay RX-111 activity in vitro. Delayed-type hypersensitivity (DTH) and tri-nitrobenzene sulfonic acid (TNBS)-induced colitis in mice and experimental autoimmune encephalomyelitis (EAE) in rats were used to assay anti-inflammatory activity of RX-111 in vivo. RESULTS: RX-111 was shown to bind directly to heparin. It inhibited leukocyte rolling on endothelial cells under shear flow and reduced inflammation in the mouse model of DTH. RX-111 was efficacious in the mouse model of inflammatory bowel disease, TNBS-induced colitis and the rat model of multiple sclerosis, EAE. CONCLUSIONS: RX-111 exercises its broad spectrum anti-inflammatory activity by a singular mechanism of action, inhibition of protein binding to the cell surface GAG, heparan sulfate. RX-111 and related thieno[2,3-c]pyridine derivatives are potential therapeutics for the treatment of inflammatory and autoimmune diseases.

Patterns and correlates of cannabis use among individuals with HIV/AIDS in Maritime Canada.

BACKGROUND: The prevalence of cannabis use in HIV-infected individuals is high and its long-term effects are unclear. METHODS: The prevalence, perceived benefits and consequences, and predictors of cannabis use were studied using a cross-sectional survey in two immunodeficiency clinics in Maritime Canada. RESULTS: Current cannabis use was identified in 38.5% (87 of 226) of participants. Almost all cannabis users (85 of 87 [97.7%]) acknowledged its use for recreational purposes, with 21.8% (19 of 87) reporting medicinal cannabis use. The majority of patients enrolled in the present study reported mild or no symptoms related to HIV (n=179). Overall, 80.5% (70 of 87) of the cannabis-using participants reported a symptom-relieving benefit, mostly for relief of stress, anorexia or pain. Participants consumed a mean (± SD) of 18.3±21.1 g of cannabis per month and spent an average of $105.15±109.87 on cannabis per month. Cannabis use was associated with rural residence, lower income level, driving under the influence of a substance, and consumption of ecstasy and tobacco. Income level, ecstasy use and tobacco use were retained as significant predictors in regression modelling. Cannabis use was not associated with adverse psychological outcomes. DISCUSSION: Prolonged previous cannabis consumption and the substantial overlap between recreational and medicinal cannabis use highlight the challenges in obtaining a tenable definition of medicinal cannabis therapy.

HISTORIQUE: La prévalence de consommation de cannabis est élevée chez les personnes infectées par le VIH, mais on n'en connaît pas les effets à long terme. MÉTHODOLOGIE: Les chercheurs ont étudié la prévalence, les avantages perçus et les conséquences et prédicteurs de consommation de cannabis au moyen d'un sondage transversal mené dans deux cliniques d'immunodéficience des Maritimes, au Canada. RÉSULTATS: Les chercheurs ont constaté une consommation courante de cannabis chez 38,5 % des participants (87 sur 226). Presque tous les consommateurs de cannabis (85 sur 87 [97,7 %]) admettaient en prendre pour des fins récréatives, et 21,8 % (19 sur 87) indiquaient en prendre pour des fins médicinales. La majorité des patients qui participaient à la présente étude a déclaré des symptômes du VIH légers, sinon inexistants (n=179). Dans l'ensemble, 80,5 % des participants consommateurs de cannabis (70 sur 87) ont affirmé remarquer un soulagement des symptômes, particulièrement le stress, l'anorexie ou la douleur. Les participants consommaient en moyenne 18,3±21,1 g de cannabis par mois et dépensaient en moyenne 105,15±109,87 $ par mois pour se le procurer. La consommation de cannabis était liée à un logement en milieu rural, à un niveau de revenu plus bas, à la conduite sous l'influence d'une substance et à la consommation d'ecstasy et de tabac. Le niveau de revenu, la consommation d'ecstasy et la consommation de tabac étaient considérés comme des prédicteurs importants selon le modèle de régression. La consommation de cannabis ne s'associait pas à des résultats psychologiques indésirables. EXPOSÉ: Une consommation antérieure prolongée de cannabis et le chevauchement important entre la consommation de cannabis à des fins récréatives et médicinales font ressortir la difficulté d'obtenir une définition viable du traitement médicinal par le cannabis.

An exploratory study of the influence of clinico-demographic variables on swallowing and swallowing-related quality of life in a cohort of oral and oropharyngeal cancer patients treated with primary surgery.

There are insufficient data on swallowing and the consequences of its dysfunction in patients with cancers of the oral cavity (OC) and oropharynx (OP) that are treated with primary surgery. The study attempts to explore the effect of important clinico-demographic variables on post-treatment swallowing and related quality of life (QOL) in post-surgical OC and OP cancer patients. Sixty-two consecutive OC and OP cancer patients completed the MD Anderson Dysphagia Inventory (MDADI) questionnaire. Mean scores were computed. Comparison of scores based on mean ranks were performed using Mann-Whitney U test or Kruskal-Wallis test. Level of significance was set at P ≤ 0.02. Adjustments were made for multiple comparisons. Significantly worse mean (SD) QOL scores were observed in late T-stage (T3/T4) versus early T-stage (T1/T2) patients for global domain, physical domain, functional domain and emotional domains [44.4 (21.9) vs. 78.7 (22.7) (P < 0.001); 50.0 (9.4) vs. 75.9 (16.3), (P < 0.0001); 57.8 (20.6) vs. 84.1 (16.7), (P < 0.001) and 55.2 (18.0) vs. 78.5 (16.3), (P < 0.001)], respectively. Patients undergoing reconstruction versus without reconstruction had worse QOL scores; 58.8 (26.9) versus 79.5 (22.8), (P < 0.01); 61.2 (15.1) versus 76.4 (17.5), (P = 0.002); 65.4 (20.5) versus 86.3 (15.9), (P < 0.0001) and 63.3 (18.8) versus 79.8 (16.3), (P < 0.01), respectively, for global, physical, functional and emotional domains. Advanced T-stage, reconstruction, younger age and base of tongue tumours have a negative impact on post-treatment swallow function and related QOL in these patients.

Extrusion of metal radiological marker from a total ankle replacement insert: a case report.

Total ankle arthroplasty has become an increasingly performed procedure for the treatment of ankle arthritis. Failures related to polyethylene inserts can result from uncorrected deformities or malalignment of the components. We report a case of a 63-year-old man who underwent total ankle arthroplasty for osteoarthritis of the ankle. The talar component was placed in neutral alignment. Initial postoperative recovery and rehabilitation were unremarkable. At 9 months postoperatively, plain radiographs of the ankle showed worsening varus tilt when compared with radiographs taken earlier. There was also radiographic evidence of separation of the posterior metal marker, suggestive of a fracture of the polyethylene insert. Revision surgery to correct the varus tilt and replace the polyethylene insert was performed. At operation, the polyethylene insert was found to be intact with no evidence of fracture. The posterior metal marker of the polyethylene insert was found to be extruded from the insert. Small degrees of ankle prosthesis malalignment can lead to various degrees of polyethylene liner failure, such as metal marker extrusion. This article also shows that these metal markers may not be accurate indicators of the integrity of the polyethylene insert.

Bone anchors or interference screws? A biomechanical evaluation for autograft ankle stabilization.

BACKGROUND: Autograft stabilization uses free semitendinosus tendon grafts to anatomically reconstruct the anterior talofibular ligament. Study aims were to evaluate the biomechanical properties of Mitek GII anchors compared with the Arthrex Bio-Tenodesis Screw for free tendon reconstruction of the anterior talofibular ligament. NULL HYPOTHESIS: There are no differences in load to failure and percentage specimen elongation at failure between the 2 methods. STUDY DESIGN: Controlled laboratory study using porcine models. METHODS: Sixty porcine tendon constructs were failure tested. Re-creating the pull of the anterior talofibular ligament, loads were applied at 70 degrees to the bones. Thirty-six tendons were fixed to porcine tali and tested using a single pull to failure; 10 were secured with anchors and No. 2 Ethibond, 10 with anchors and FiberWire, 10 with screws and Fiberwire, and 6 with partially gripped screws. Cyclic preloading was conducted on 6 tendons fixed by anchors and on 6 tendons fixed by screws before failure testing. Two groups of 6 components fixed to the fibula were also tested. RESULTS: The talus single-pull anchor group produced a mean load of 114 N and elongation of 37% at failure. The talus single-pull screw group produced a mean load of 227 N and elongation of 22% at failure (P <.05). Cyclic preloading at 65% failure load before failure testing produced increases in load and decreases in elongation at failure. Partially gripped screws produced a load of 133 N and elongation of 30% at failure. The fibula model produced significant increases in load to failure for both. The human anterior talofibular ligament has loads of 139 N at failure with instability occurring at 20% elongation. CONCLUSIONS: Interference screw fixation produced significantly greater failure strength and less elongation at failure than bone anchors. CLINICAL RELEVANCE: The improved biomechanics of interference screws suggests that these may be more suited to in vivo reconstruction of the anterior talofibular ligament than are bone anchors.

Preclinical evaluation of the anticancer activity and toxicity of 9-nitro-20(S)-camptothecin (Rubitecan).

The purpose of this study is to establish the maximum tolerated dose of rubitecan in mice, dogs and men and to establish the anticancer activity of such dose against human tumors xenografted in nude mice. Nude mice received increasing doses of Rubitecan by intrastomach injection until the maximum tolerated dose (MTD) had been established for both the single dose and the multiple doses at the schedule of 5 days on, 2 days off. Extrapolating from the mouse data, MTD was determined for oral administration in dogs and man. Levels of the drug in plasma were determined by high pressure liquid chromatography (HPLC). Using maximum tolerated multiple doses, the sensitivity of human cancer xenografts in nude mice to Rubitecan was determined. MTD of Rubitecan in mice for multiple doses intrastomach at the schedule of 5+,2- was 1 mg/kg/day. MTD in dogs was also 1 mg/kg/day, administered orally but at the schedule of 4+,3-. In man, it was 1 mg/m2/day at the schedule of 5+,2-. Treatment of human cancer xenografts in nude mice with MTD of Rubitecan resulted in 100% growth inhibition of 30/30 tumors tested and in 24/30 in their total disappearance. These 30 tumors comprised all the most common human cancers: lung, colorectal, breast, pancreatic, ovarian, prostate, stomach, melanoma and a leukemia. From the data collected, it appears that rubitecan is a very promising anticancer drug with high potency against a wide spectrum of human cancers. These cancers growing as xenografts in nude mice are always growth inhibited (30/30) and frequently (24/30) totally destroyed by the administration of non-toxic doses of Rubitecan.