A µ-opioid receptor modulator that works cooperatively with naloxone.

The µ-opioid receptor (µOR) is a well-established target for analgesia1, yet conventional opioid receptor agonists cause serious adverse effects, notably addiction and respiratory depression. These factors have contributed to the current opioid overdose epidemic driven by fentanyl2, a highly potent synthetic opioid. µOR negative allosteric modulators (NAMs) may serve as useful tools in preventing opioid overdose deaths, but promising chemical scaffolds remain elusive. Here we screened a large DNA-encoded chemical library against inactive µOR, counter-screening with active, G-protein and agonist-bound receptor to 'steer' hits towards conformationally selective modulators. We discovered a NAM compound with high and selective enrichment to inactive µOR that enhances the affinity of the key opioid overdose reversal molecule, naloxone. The NAM works cooperatively with naloxone to potently block opioid agonist signalling. Using cryogenic electron microscopy, we demonstrate that the NAM accomplishes this effect by binding a site on the extracellular vestibule in direct contact with naloxone while stabilizing a distinct inactive conformation of the extracellular portions of the second and seventh transmembrane helices. The NAM alters orthosteric ligand kinetics in therapeutically desirable ways and works cooperatively with low doses of naloxone to effectively inhibit various morphine-induced and fentanyl-induced behavioural effects in vivo while minimizing withdrawal behaviours. Our results provide detailed structural insights into the mechanism of negative allosteric modulation of the µOR and demonstrate how this can be exploited in vivo.

Characterization of Antithrombotic Regimens for Patients with Nonvalvular Atrial Fibrillation and Obesity Discharged from Cardiology Wards.

Background: Despite data derived from observational studies, optimal anticoagulation strategies have yet to be established for patients with nonvalvular atrial fibrillation and obesity. Objective: To describe direct oral anticoagulant (DOAC) regimens prescribed for adult patients with nonvalvular atrial fibrillation who weighed more than 120 kg. Methods: This single-centre, retrospective cohort study, conducted in the Saskatchewan Health Authority - Regina Area, involved adult patients with body weight greater than 120 kg who had an indication for oral anticoagulation to treat nonvalvular atrial fibrillation and were discharged by a cardiologist between June 2019 and July 2021. Results: A total of 62 patients were included (median weight 135 kg). At discharge, DOACs were prescribed for 57 (92%) of the patients and warfarin for 5 (8%). In numeric terms, patients receiving warfarin were at higher risk of thromboembolism or thrombosis; however, the small sample size limited the ability to draw conclusions. Conclusions: Practice patterns in the Saskatchewan Health Authority - Regina Area indicated substantial use of DOACs for patients with body weight greater than 120 kg; however, for those with the highest weights, warfarin was still in use.

Contexte: Malgré les données dérivées d'études observationnelles, les stratégies d'anticoagulation optimales n'ont pas été consolidées pour les patients atteints de fibrillation auriculaire non valvulaire et d'obésité. Objectif: Décrire les schémas thérapeutiques d'anticoagulants oraux (ACO) prescrits aux patients adultes atteints de fibrillation auriculaire non valvulaire et qui pesaient plus de 120 kg. Méthodes: Cette étude de cohorte rétrospective monocentrique menée dans l'office de la santé de la Saskatchewan à Regina a porté sur des patients adultes pesant plus de 120 kg qui avaient une indication de traitement anticoagulant oral pour traiter la fibrillation auriculaire non valvulaire et qui ont été renvoyés par un cardiologue entre juin 2019 et juillet 2021. Résultats: Au total, 62 patients ont été inclus (poids médian, 135 kg). Au congé, des ACO ont été prescrits à 57 (92 %) des patients et de la warfarine à 5 (8 %) d'entre eux. En termes numériques, les patients traités par warfarine présentaient un risque plus élevé de thromboembolie ou de thrombose; cependant, la petite taille de l'échantillon a limité la capacité de tirer des conclusions. Conclusions: Les modèles de pratique de l'office de la santé de la Saskatchewan à Regina indiquaient une utilisation importante des ACO pour les patients dont le poids corporel était supérieur à 120 kg; cependant, pour les personnes ayant le poids le plus élevé, la warfarine était toujours utilisée.

Acute iris vascular tuft hemorrhage treated successfully with intravitreal bevacizumab and pressure patching in a patient with branch retinal vein occlusion.

Purpose: To report the presentation and management of active iris vascular tuft (IVT) hemorrhage and spontaneous hyphema in an eye with previous branch retinal vein occlusion (BRVO). Observations: A 74-year-old male with a history of BRVO in the left eye presented with spontaneous hyphema and blurred vision. Clinical examination confirmed the presence of an actively bleeding IVT at the pupillary margin in the left eye. Sustained hemostasis was achieved following intravitreal bevacizumab injection and pressure patching of the eye. Conclusions and Importance: This is the first case report to demonstrate pressure patching as a non-invasive, effective method of achieving hemostasis in the acute setting of IVT hemorrhage. Intravitreal vascular endothelial growth factor antagonists such as bevacizumab may also be useful in decreasing the risk of IVT hemorrhage in eyes with chronic ischemia, although further investigation is warranted.

Cognitive enhancing supplements and medications in United States Resident Physicians.

BACKGROUND: The use of cognitive-enhancing medications and supplements among healthy adults continues to rise. Limited data exists on their use among resident physicians. Given their highly competitive and stressful lifestyle, we sought to evaluate the prevalence, motivations, and side effects of using cognitive-enhancing supplements and medications among resident physicians at a large United States academic institution. METHODS: An anonymous web-based survey was circulated to resident physicians inquiring about using cognitive-enhancing supplements and medications, as well as personal characteristics such as gender, marital and parental status, medical diagnoses, and medical specialty. Before circulation, we performed a pilot study. Weighted logistic regression analyses estimated the impact of personal characteristics on the probability of using both supplements and medications. RESULTS: Survey response rate was 46.4%. Of respondents, 48.6% were female, 45.9% were married, 70.9% were without children, and 67.2% were in a non-surgical medical specialty. Few respondents had a related medical diagnosis, with attention deficit hyperactivity disorder being the most common (7.1%). Male, non-married, surgical residents were more likely to take supplements (odds ratio (OR) = 1.06, 1.05, and 1.05). Males, without children, and those who felt pressure to perform well, were afraid of being left behind, felt pressure because colleagues take them, or felt they could not reach their current level of training without medications were more likely to take medications (OR = 1.11, 1.04, 1.05, and 1.08). Adverse effects with medications were common. CONCLUSION: Supplement and medication use for cognitive enhancement was high among resident physicians at a single institution despite few having a related medical diagnosis. This study raises awareness of the growing pressure in competitive residency environments to use cognitive enhancement regardless of the potential side effects.

Stereoisomers of an Aryl Pyrazole Glucocorticoid Receptor Agonist Scaffold Elicit Differing Anti-inflammatory Responses.

Glucocorticoids (GCs) are heavily prescribed to control inflammation in various human diseases; however, side effects associated with GCs are well documented and lead to serious metabolic and immunological complications with long-term use. The paradigm for GC function includes two well described modes of activity: dimer formation of the glucocorticoid receptor (GR) promotes transactivation, while monomeric interaction with co-regulators promotes transrepression. Previously, a set of aryl pyrazole-derived glucocorticoid receptor agonists (APGRAs) with potency rivaling current commercially available glucocorticoids were described. In this study, a further series of existing and novel stereopure APGRAs were thoroughly examined for biological activity and evaluated for structure-activity relationships (SARs). The si isomers with an upward OH moiety were ∼70% more active on average than the re isomers. Additionally, AP13 was found to elicit 79% transrepression of dexamethasone while eliciting less than half the transactivation response in 832/13 cells, a rat insulinoma cell line.

Potent Anti-Inflammatory, Arylpyrazole-Based Glucocorticoid Receptor Agonists That Do Not Impair Insulin Secretion.

Glucocorticoids (GCs) are widely used in medicine for their role in the treatment of autoimmune-mediated conditions, certain cancers, and organ transplantation. The transcriptional activities GCs elicit include transrepression, postulated to be responsible for the anti-inflammatory activity, and transactivation, proposed to underlie the undesirable side effects associated with long-term use. A GC analogue that could elicit only transrepression and beneficial transactivation properties would be of great medicinal value and is highly sought after. In this study, a series of 1-(4-substituted phenyl)pyrazole-based GC analogues were synthesized, biologically screened, and evaluated for SARs leading to the desired activity. Activity observed in compounds bearing an electron deficient arylpyrazole moiety showed promise toward a dissociated steroid, displaying transrepression while having limited transactivation activity. In addition, compounds 11aa and 11ab were found to have anti-inflammatory efficacy comparable to that of dexamethasone at 10 nM, with minimal transactivation activity and no reduction of insulin secretion in cultured rat 832/13 beta cells.

Metabolite discovery through global annotation of untargeted metabolomics data.

Liquid chromatography-high-resolution mass spectrometry (LC-MS)-based metabolomics aims to identify and quantify all metabolites, but most LC-MS peaks remain unidentified. Here we present a global network optimization approach, NetID, to annotate untargeted LC-MS metabolomics data. The approach aims to generate, for all experimentally observed ion peaks, annotations that match the measured masses, retention times and (when available) tandem mass spectrometry fragmentation patterns. Peaks are connected based on mass differences reflecting adduction, fragmentation, isotopes, or feasible biochemical transformations. Global optimization generates a single network linking most observed ion peaks, enhances peak assignment accuracy, and produces chemically informative peak-peak relationships, including for peaks lacking tandem mass spectrometry spectra. Applying this approach to yeast and mouse data, we identified five previously unrecognized metabolites (thiamine derivatives and N-glucosyl-taurine). Isotope tracer studies indicate active flux through these metabolites. Thus, NetID applies existing metabolomic knowledge and global optimization to substantially improve annotation coverage and accuracy in untargeted metabolomics datasets, facilitating metabolite discovery.

Adult Versus Pediatric Relapse and Recurrence in Orbital Inflammatory Syndrome.

PURPOSE: Orbital inflammatory syndrome (OIS) is a diagnosis of exclusion that has a variable presentation and unpredictable course. Many studies report incomplete or lack of OIS resolution with high recurrence and relapse rates. No studies to date have investigated the characteristics of both recurrence and relapse in OIS. We sought to determine this in both pediatric and adult patients. METHODS: A retrospective chart review of 56 patients with OIS was performed between 2004 and 2018. Forty-one patients were identified as adults greater than 18 years of age and 15 were identified as pediatric patients less than 18 years of age. RESULTS: Among 56 (41 adult and 15 pediatric) cases of OIS, 18 cases of recurrent disease (32.1%) were identified and 15 (26.8%) patients experienced relapses. All 6 (100%) pediatric patients that had recurrent disease initially suffered from relapses. In contrast, only 1 of the 12 (8.3%) recurrent adult cases initially experienced relapse. Of the 18 patients with recurrent disease, 9 (50%) had multiple recurrences. Underlying etiologies were confirmed in 5 of 18 recurrent cases (27.8%) and 5 of 38 (13.2%) non-recurrent cases. Of the 5 patients with recurrent OIS and an identified etiology, all 5 (100%) demonstrated multiple recurrences. CONCLUSIONS: In pediatric cases, relapse was more common and prior episodes of relapse were predictive of later recurrence. Recurrence was relatively common in both groups with half of the patients having multiple recurrences. Identifiable underlying etiologies were more common in patients with recurrent OIS and those cases all demonstrated multiple recurrences.

Safety and pharmacokinetics of naringenin: A randomized, controlled, single-ascending-dose clinical trial.

AIMS: To evaluate the safety and pharmacokinetics of naringenin in healthy adults consuming whole-orange (Citrus sinensis) extract. METHODS AND METHODS: In a single-ascending-dose randomized crossover trial, 18 adults ingested doses of 150 mg (NAR150), 300 mg (NAR300), 600 mg (NAR600) and 900 mg (NAR900) naringenin or placebo. Each dose or placebo was followed by a wash-out period of at least 1 week. Blood safety markers were evaluated pre-dose and 24 hours post-dose. Adverse events (AEs) were recorded. Serum naringenin concentrations were measured before and over 24 hours following ingestion of placebo, NAR150 and NAR600. Four- and 24-hour serum measurements were obtained after placebo, NAR300 and NAR900 ingestion. Data were analysed using a mixed-effects linear model. RESULTS: There were no relevant AEs or changes in blood safety markers following ingestion of any of the naringenin doses. The pharmacokinetic variables were: maximal concentration: 15.76 ± 7.88 µM (NAR150) and 48.45 ± 7.88 µM (NAR600); time to peak: 3.17 ± 0.74 hours (NAR150) and 2.41 ± 0.74 hours (NAR600); area under the 24-hour concentration-time curve: 67.61 ± 24.36 µM × h (NAR150) and 199.05 ± 24.36 µM × h (NAR600); and apparent oral clearance: 10.21 ± 2.34 L/h (NAR150) and 13.70 ± 2.34 L/h (NAR600). Naringenin half-life was 3.0 hours (NAR150) and 2.65 hours (NAR600). After NAR300 ingestion, serum concentrations were 10.67 ± 5.74 µM (4 hours) and 0.35 ± 0.30 µM (24 hours). After NAR900 ingestion, serum concentrations were 43.11 ± 5.26 µM (4 hours) and 0.24 ± 0.30 µM (24 hours). CONCLUSIONS: Ingestion of 150 to 900 mg doses of naringenin is safe in healthy adults, and serum concentrations are proportional to the dose administered. Since naringenin (8 µM) is effective in primary human adipocytes, ingestion of 300 mg naringenin twice/d will likely elicit a physiological effect.