Exploring Psilocybe spp. mycelium and fruiting body chemistry for potential therapeutic compounds.

Psilocybe mushrooms, otherwise known as "magic" mushrooms, owe their psychedelic effect to psilocin, a serotonin subtype 2A (5-HT2A) receptor agonist and metabolite of psilocybin, the primary indole alkaloid found in Psilocybe species. Metabolomics is an advanced fingerprinting tool that can be utilized to identify the differences among fungal life stages that may otherwise be unaccounted for. In this study, by using targeted and untargeted (metabolomic) multivariate analysis, we demonstrate that the chemical composition of Psilocybe differs among mycelia, grain mycelia, and fruiting bodies. The preferential accumulation of psilocybin, baeocystin, tryptophan, ergothioneine, and phenylethylamine in fruiting bodies differentiated them from mycelia; however, the levels of alpha-glycerylphosphorylcholine (α-GPC), N-acetylglucosamine, and trimethylglycine were found to be proportionally higher in mycelia than in fruiting bodies based on Pareto-scaled data. Considering the wealth of compounds with therapeutic potential that have been isolated from various fungal genera, it would be pertinent to study the compounds found in Psilocybe mycelia as potential naturally derived therapeutic targets.

Comprehensive clinical pharmacology characterization of AZD4635 in healthy participants to support dosing considerations.

AIMS: Two phase 1 studies characterized the oral bioavailability of AZD4635 (potential anticancer therapy) and factors that may influence its pharmacokinetics (PKs; food, smoking, proton-pump inhibitors [PPIs] and CYP1A2 inhibitors) to support continued clinical development of AZD4635. METHODS: Study 1 (comparative PK study; nonsmokers) consists of Part A and Part B. Participants (fasted) in Part A were administered 50 mg of AZD4635 either as nanosuspension or capsule. In Part B, these participants were administered a 50-mg capsule either following a high-fat meal or with a PPI in the fasted state. In Study 2 (CYP1A2 mediated drug-drug interaction study), a 25-mg AZD4635 capsule was administered to smokers and nonsmokers (fasted) with or without 100 mg of fluvoxamine. RESULTS: In Study 1 (N = 21), AZD4635 exposure was comparable between the capsule and nanosuspension. The high-fat meal produced a 12% decrease in AUCinf , a ≥50% reduction in Cmax and delayed absorption (Tmax : 4.0 h vs 1.5 h) for the capsule. The PPI did not affect the oral bioavailability of the AZD4635 capsule. In Study 2 (N = 28), AZD4635 + fluvoxamine (compared with AZD4635 alone) produced ~5-fold increases in AUCinf , 2-fold increases in Cmax and prolonged AZD4635 elimination half-life in smokers (22.7 vs 9.0 h) and nonsmokers (22.4 vs 9.2 h). All treatment regimens were well tolerated. The most common adverse events included dizziness, nausea and headache. CONCLUSIONS: The high-fat meal reduced the rate but not the extent of AZD4635 absorption. The effect of gastric pH on AZD4635 was minimal. Smoking had no effect on the exposure (Cmax and AUCinf ) of AZD4635, while fluvoxamine increased AZD4635 Cmax and total exposure. No new safety concerns were identified.

Pharmacokinetics and Metabolism of Ziritaxestat (GLPG1690) in Healthy Male Volunteers Following Intravenous and Oral Administration.

Ziritaxestat is a novel inhibitor of autotaxin, an enzyme responsible for the production of lysophosphatidic acid, the downstream signaling of which mediates responses to tissue injury and has been implicated in the pathogenesis of fibrotic conditions such as idiopathic pulmonary fibrosis and systemic sclerosis. This study (Clinical Trial Registration: NCT03787186) was designed to assess the absorption, distribution, metabolism, and excretion of orally administered 600-mg ziritaxestat labeled with a carbon-14 tracer (14 C-ziritaxestat). To understand the absolute bioavailability of ziritaxestat, an intravenous 100-µg microdose, labeled with a microtracer amount of 14 C radiation, was administered in a separate part of the study, following an unlabeled 600-mg therapeutic oral dose of ziritaxestat. Six healthy male subjects completed each study part. The majority of the labeled oral dose was recovered in feces (77%), with a total mass balance of 84%. The absolute bioavailability of ziritaxestat was 54%. Ziritaxestat was the main (76%) circulating drug-related product. There were 7 treatment-emergent adverse events, all of which were considered mild and not considered to be related to the study drug.

Characterization of Clinical Absorption, Distribution, Metabolism, and Excretion and Pharmacokinetics of Velsecorat Using an Intravenous Microtracer Combined with an Inhaled Dose in Healthy Subjects.

This open-label, single-period study describes the human absorption, distribution, metabolism, excretion, and pharmacokinetics of velsecorat (AZD7594). Healthy subjects received inhaled velsecorat (non-radiolabeled; 720 µg) followed by intravenous infusion of carbon 14 (14C)-velsecorat (30 µg). Plasma, urine, and feces were collected up to 168 hours post-dose. Objectives included identification and quantification of velsecorat and its metabolites (i.e., drug-related material) in plasma and excreta, and determining the elimination pathways of velsecorat by measuring the rate and route of excretion, plasma half-life (t1/2), clearance, volume of distribution and mean recovery of radioactivity. On average, 76.0% of administered 14C dose was recovered by the end of the sampling period (urine = 24.4%; feces = 51.6%), with no unchanged compound recovered in excreta, suggesting that biliary excretion is the main elimination route. Compared with intravenous 14C-velsecorat, inhaled velsecorat had a longer t1/2 (27 versus 2 hours), confirming that plasma elimination is absorption-rate-limited from the lungs. Following intravenous administration, t1/2 of 14C-drug-related material was longer than for unchanged velsecorat, and 20% of the 14C plasma content was related to unchanged velsecorat. The geometric mean plasma clearance of velsecorat was high (70.7 l/h) and the geometric mean volume of distribution at steady state was 113 l. Velsecorat was substantially metabolized via O-dealkylation of the indazole ether followed by sulfate conjugation, forming the M1 metabolite, the major metabolite in plasma. There were 15 minor metabolites. Velsecorat was well tolerated, and these results support the progression of velsecorat to phase 3 studies. SIGNIFICANCE STATEMENT: This study describes the human pharmacokinetics and metabolism of velsecorat, a selective glucocorticoid receptor modulator, evaluated via co-administration of a radiolabeled intravenous microtracer dose and a non-radiolabeled inhaled dose. This study provides a comprehensive assessment of the disposition of velsecorat in humans. It also highlights a number of complexities associated with determining human absorption, distribution, metabolism, and excretion for velsecorat, related to the inhaled route, the high metabolic clearance, sequential metabolite formation and the low intravenous dose.

Effect of Miricorilant, a Selective Glucocorticoid Receptor Modulator, on Olanzapine-Associated Weight Gain in Healthy Subjects: A Proof-of-Concept Study.

PURPOSE: Antipsychotic medications, including olanzapine, are associated with substantial weight gain and metabolic disturbances. We sought to determine whether coadministration of miricorilant, a selective glucocorticoid receptor modulator, with olanzapine can ameliorate these effects. METHODS: Sixty-six healthy men were enrolled in a 2-week, randomized, double-blind, placebo-controlled trial. The primary objective was to evaluate changes in body weight after 14 days coadministration of olanzapine (10 mg) + miricorilant (600 mg) compared with olanzapine (10 mg) + placebo. Secondary objectives included evaluating (a) the safety and tolerability of the combination; (b) the effects of the combination on glucose, insulin, insulin resistance, and triglycerides; and (c) the impact of the combination on hepatic enzymes. RESULTS: Subjects administered olanzapine + miricorilant gained less weight than subjects administered olanzapine + placebo (mean weight gain on day 15, 3.91 kg vs 4.98 kg; difference between groups, -1.07 kg; 95% confidence interval, -1.94 to -0.19; P = 0.017]). Compared with the placebo group, coadministration of miricorilant with olanzapine was associated with smaller increases in insulin (difference, -3.74 mIU/L; P = 0.007), homeostatic model assessment of insulin resistance (difference, -0.47; P = 0.007), triglycerides (difference, -0.29 mmol/L; P = 0.057), aspartate aminotransferase (difference, -32.24 IU/L; P = 0.009), and alanine aminotransferase (difference, -49.99 IU/L; P = 0.030). CONCLUSIONS: Miricorilant may provide a promising option for ameliorating the detrimental effects of olanzapine, and investigation of this medication in patients affected by antipsychotic-induced weight gain is warranted. Two phase 2 studies of miricorilant in patients with recent and long-standing antipsychotic-induced weight gain are currently in progress.

Nursing curriculum and bullying: An integrative literature review.

OBJECTIVES: The purpose of this integrative review was to identify and synthesize key concepts that inform curriculum which increase nursing students' competence, skills and strategies when addressing bullying. Specifically, the authors sought to examine the concepts informing educational interventions, skills, and strategies, which addressed the bullying of nursing students. DESIGN: Integrative literature review. DATA SOURCES: A search of the electronic databases CINAHL, MEDLINE, ERIC, PsycINFO, Proquest, and PubMed was conducted in January 2016 using search terms such as 'bully' 'nursing student' 'education' and 'curriculum'. REVIEW METHODS: Articles were screened for relevance and eligibility and extracted onto a table. Critical appraisal was conducted using multiple tools. Papers were analysed using constant comparison and concept mapping. RESULTS: 61 articles were included in the synthesis. Concepts identified included: empowerment, socialization, support, self-awareness, awareness about bullying, collaboration, communication, and self-efficacy. All concepts linked to empowerment. Social Cognitive Theory was used by many studies. Active teaching methods which gave students opportunities to practice skills were the most effective. CONCLUSIONS: Empowered nursing students have the potential to address bullying more effectively and competently. Empowerment of nursing students is a powerful concept that educators must consider when developing curriculum and educational interventions to address bullying.

Local versus general anaesthesia for adults undergoing pars plana vitrectomy surgery.

BACKGROUND: Vitrectomy surgery is one of the commonest ophthalmic procedures performed across the world. It may be performed using general or local anaesthesia encompassing regional or topical anaesthesia depending on a number of factors, including patient suitability, and patient, surgeon or anaesthetist preference. There have so far been no evidence-based recommendations on the best form of anaesthesia for this intervention. There is no clear collated evidence base as to the best type of anaesthesia to reduce harm, and provide best surgical conditions and optimal outcome for patients. OBJECTIVES: To compare local with general anaesthesia for adults undergoing pars plana vitrectomy. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library and the reference lists of updated studies on the 25th of July 2016; MEDLINE via Ovid SP (1972 to July 2016) and Embase via Ovid SP (1972 to July 2016). In addition we searched the metaRegister of Controlled Trials (mRCT), ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) in July 2016. We searched the proceedings of the Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO) up to July 2016 for information about other relevant studies.We also searched appropriate databases for ongoing reviews. We did not apply any language restriction. We assessed the search as up-to-date on the 25th of July 2016. SELECTION CRITERIA: We planned to include all published randomized controlled trials (RCTs) involving comparison of different modalities of local anaesthesia with general anaesthesia for pars plana vitrectomy. We considered the following different modalities of local anaesthesia: sub-Tenon's anaesthesia, retrobulbar anaesthesia, topical anaesthesia, peribulbar anaesthesia. We planned to include cluster-randomized controlled trials. We excluded quasi-RCT trials. DATA COLLECTION AND ANALYSIS: Two review authors conducted independent searches and assessed identified studies for inclusion according to the prespecified selection criteria. Two review authors assessed trial quality and planned to extract the data. MAIN RESULTS: We found no eligible studies that met our inclusion criteria and were therefore unable to perform a meta-analysis or conduct a methodological quality assessment. AUTHORS' CONCLUSIONS: This systematic review failed to locate relevant clinical evidence to support or refute a pars plana vitrectomy performed with various modalities of local anaesthesia versus general anaesthesia. Good-quality clinical trials are needed to define the role of local versus general anaesthesia for pars plana vitrectomy.

Effect of Conditioning and Aging on the Bond Strength and Interfacial Morphology of Glass-ionomer Cement Bonded to Dentin.

PURPOSE: To determine the bond stability and the change in interfacial ultrastructure of a conventional glassionomer cement bonded to dentin, with and without pretreatment using a polyalkenoic acid conditioner. MATERIALS AND METHODS: The occlusal dentin surfaces of 10 teeth were ground flat. Glass-ionomer cement was bonded to the surfaces either with or without polyalkenoic acid conditioning. The teeth were sectioned into 1-mm2 stick-shaped specimens. The 200 specimens obtained were randomly assigned to four groups with different periods of storage in water: 1 week, 1 month, 3 months, and 6 months. The microtensile bond strength (µTBS) was determined for each storage time. Additional specimens were prepared for transmission electron microscopy (TEM); they were produced with or without prior polyalkenoic acid conditioning in the same manner as for the µTBS test. RESULTS: There was no significant difference in µTBS to conditioned dentin (p > 0.05). After 6 months of aging, the µTBS to non-conditioned dentin was significantly reduced as compared to the 1-week, 1-month, and 3-month results (p < 0.05). The failures appeared to be of a mixed nature, although aging caused more areas of cohesive than adhesive failure in all groups. TEM observation showed a demineralized layer and an amorphous gel phase in the polyalkenoic acid conditioned group. CONCLUSION: Aging did not reduce the bond strength of the conventional glass-ionomer cement to dentin when the surface was pretreated with a polyalkenoic acid conditioner.

X chromosome inactivation: heterogeneity of heterochromatin.

The silent X chromosome in mammalian females is a classic example of facultative heterochromatin, the term highlighting the compacted and inactive nature of the chromosome. However, it is now clear that the heterochromatin of the inactive X is not homogeneous--as indeed, not all genes on the inactive X are silenced. We summarize known features and events of X inactivation in different mouse and human model systems, and highlight the heterogeneity of chromatin along the inactive X. Characterizing this heterogeneity is likely to provide insight into the cis-acting sequences involved in X chromosome inactivation.