Co-administration of midazolam and psilocybin: differential effects on subjective quality versus memory of the psychedelic experience.

Aspects of the acute experience induced by the serotonergic psychedelic psilocybin predict symptomatic relief in multiple psychiatric disorders and improved well-being in healthy participants, but whether these therapeutic effects are immediate or are based on memories of the experience is unclear. To examine this, we co-administered psilocybin (25 mg) with the amnestic benzodiazepine midazolam in 8 healthy participants and assayed the subjective quality of, and memory for, the dosing-day experience. We identified a midazolam dose that allowed a conscious psychedelic experience to occur while partially impairing memory for the experience.

Simulated Target Attainment of Multidose Regimens of Dalbavancin for Prolonged Durations of Therapy.

Background: Dalbavancin is a long-acting lipoglycopeptide antibiotic that is increasingly utilized for infections that require prolonged treatment durations despite the lack of Food and Drug Administration approval for these indications. There is no consensus regarding optimal dosing of dalbavancin for these infections and no available pharmacokinetic studies to identify optimal dosing for long-term use.

Methods: An in silico pharmacokinetic simulation was performed to assess the predicted dalbavancin concentration resulting from commonly utilized dosing regimens, in addition to modified regimens.

Pharmacokinetic analysis of acute and dietary exposure to piperonyl butoxide in the mouse.

Piperonyl butoxide (PBO) is a popular insecticide synergist present in thousands of commercial, agricultural, and household products. PBO inhibits cytochrome P450 activity, impairing the ability of insects to detoxify insecticides. PBO was recently discovered to also inhibit Sonic hedgehog signaling, a pathway required for embryonic development, and rodent studies have demonstrated the potential for PBO exposure to cause structural malformations of the brain, face, and limbs, or more subtle neurodevelopmental abnormalities.

Reference Range of Hydroxychloroquine Blood Levels That Can Reduce Odds of Active Lupus and Prevent Flares.

Objective: Recent data show that lower hydroxychloroquine (HCQ) doses are associated with a two- to six-fold higher risk of lupus flares. Thus, establishing an effective reference range of HCQ blood levels with upper and lower bounds for efficacy may support individualizing HCQ dosing to prevent flares.

Methods: HCQ levels in whole blood and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) were measured during the baseline visit and again during a standard of care routine follow-up visit.

Single-Dose Psilocybin Treatment for Major Depressive Disorder: A Randomized Clinical Trial.

Importance: Psilocybin shows promise as a treatment for major depressive disorder (MDD).

Objective: To evaluate the magnitude, timing, and durability of antidepressant effects and safety of a single dose of psilocybin in patients with MDD.

Design, Setting, And Participants: In this phase 2 trial conducted between December 2019 and June 2022 at 11 research sites in the US, participants were randomized in a 1:1 ratio to receive a single dose of psilocybin vs niacin placebo administered with psychological support.

Phase 2 study of anti-disialoganglioside antibody, dinutuximab, in combination with GM-CSF in patients with recurrent osteosarcoma: A report from the Children's Oncology Group.

Purpose: Novel effective therapies are urgently needed in recurrent osteosarcoma. GD2 is expressed in human osteosarcoma tumours and cell lines. This study evaluated the disease control rate (DCR) in patients with recurrent osteosarcoma treated with the anti-GD2 antibody dinutuximab plus cytokine therapy as compared to historical outcomes.

Clinical utility of a regional precision medicine molecular tumor board and challenges to implementation.

Purpose: Molecular tumor boards provide precision treatment recommendations based on cancer genomic profile. However, practical barriers limit their benefits. We studied the clinical utility of the precision medicine molecular tumor board (PMMTB) and described challenges with PMMTB implementation.

Safety, Pharmacokinetic, and Pharmacodynamic Study of a Sublingual Formula for the Treatment of Vasovagal Syncope.

Background: Vasovagal syncope is a common cause of syncope which, if recurrent, can have multiple negative consequences such as injury and occupational disability. Various medications can be used to decrease the recurrence of vasovagal syncope but there are no drugs that can be used by patients to interrupt a perceived vasovagal episode.

Methods: A phase I study was performed to evaluate the tolerability and safety of a gel formulation containing capsaicin (1 mg), phenylephrine HCL (PE) and caffeine citrate (200 mg) (CPC) in normal adult volunteers.

A Phase 1 and pharmacokinetic study evaluating daily or weekly schedules of the humanized anti-GD2 antibody hu14.18K322A in recurrent/refractory solid tumors.

Hu14.18K322A is a humanized anti-GD2 monoclonal antibody with a single point mutation that reduces complement-mediated cytotoxicity, with a maximum tolerated dose (MTD) of 60 mg/m daily for 4 days in children with recurrent/refractory neuroblastoma. We report additional results of a Phase 1 trial to determine the MTD and safety profile of hu14.

A Two-Dose Oritavancin Regimen Using Pharmacokinetic Estimation Analysis.

Background: Antibiotics for the treatment of complicated, multidrug-resistant Gram-positive infections are limited, especially when prolonged treatment is necessary. Oritavancin is approved for the treatment of serious skin infections as a 1200 mg single-dose regimen, but case reports describe supplemental doses given at weekly intervals ranging from 800 mg to 1200 mg.   OBJECTIVE: This study determined population pharmacokinetic estimates for a 1200 mg single dose with and without an 800 mg dose 1 week apart.

Exposure-Response Analysis to Assess the Concentration-QTc Relationship of Psilocybin/Psilocin.

Psilocybin is being developed for treating major depressive disorder. Psilocybin is readily dephosphorylated to psilocin upon absorption. The potential for psilocin proarrhythmic effect was assessed using a concentration-QTc interval (C-QTc) analysis from an open-label single ascending dose study of psilocybin.

High dose psilocybin is associated with positive subjective effects in healthy volunteers.

Aim: The aim of the current study was to investigate the relationship between escalating higher doses of psilocybin and the potential psilocybin occasioned positive subjective effects.

Methods: Healthy participants ( n=12) were given three escalating doses of oral psilocybin (0.3 mg/kg; 0.

The Adherence Rate Threshold is Drug Specific.

Introduction: Patient adherence to a medication regimen is usually expressed as an adherence rate, defined as the proportion of prescribed doses actually taken. An adherence rate threshold, above which the therapeutic effect is maintained, is typically assigned an arbitrary value, commonly 0.8.

A Pilot Trial of Humanized Anti-GD2 Monoclonal Antibody (hu14.18K322A) with Chemotherapy and Natural Killer Cells in Children with Recurrent/Refractory Neuroblastoma.

Anti-GD2 mAbs, acting via antibody-dependent cell-mediated cytotoxicity, may enhance the effects of chemotherapy. This pilot trial investigated a fixed dose of a unique anti-GD2 mAb, hu14.18K322A, combined with chemotherapy, cytokines, and haploidentical natural killer (NK) cells.

Binge-eating disorder: Clinical and therapeutic advances.

Binge-eating disorder (BED) is the most prevalent eating disorder with estimates of 2-5% of the general adult population. Nonetheless, its pathophysiology is poorly understood. Furthermore, there exist few therapeutic options for its effective treatment.

Dopamine and μ-opioid receptor dysregulation in the brains of binge-eating female rats - possible relevance in the psychopathology and treatment of binge-eating disorder.

Adult, female rats given irregular, limited access to chocolate develop binge-eating behaviour with normal bodyweight and compulsive/perseverative and impulsive behaviours similar to those in binge-eating disorder. We investigated whether (a) dysregulated central nervous system dopaminergic and opioidergic systems are part of the psychopathology of binge-eating and (b) these neurotransmitter systems may mediate the actions of drugs ameliorating binge-eating disorder psychopathology. Binge-eating produced a 39% reduction of striatal D receptors with 22% and 23% reductions in medial and lateral caudate putamen and a 22% increase of striatal μ-opioid receptors.

Investigation of impulsivity in binge-eating rats in a delay-discounting task and its prevention by the d-amphetamine prodrug, lisdexamfetamine.

Freely-fed, female, rats were trained in a two-lever, delay-discounting task: one lever delivered a single chocolate-flavoured pellet immediately and the other a three-pellet reward after increasing delay (0, 4, 8, 16, 32 s). Rats were divided into two groups (i.e.

Pharmacokinetics of Escalating Doses of Oral Psilocybin in Healthy Adults.

Introduction: Psilocybin is a psychedelic tryptamine that has shown promise in recent clinical trials for the treatment of depression and substance use disorders. This open-label study of the pharmacokinetics of psilocybin was performed to describe the pharmacokinetics and safety profile of psilocybin in sequential, escalating oral doses of 0.3, 0.

Immune-driven alterations in mucin sulphation is an important mediator of Trichuris muris helminth expulsion.

Mucins are heavily glycosylated proteins that give mucus its gel-like properties. Moreover, the glycans decorating the mucin protein core can alter the protective properties of the mucus barrier. To investigate whether these alterations could be parasite-induced we utilized the Trichuris muris (T.

CNS Target Identification and Validation: Avoiding the Valley of Death or Naive Optimism?

There are many challenges along the path to the approval of new drugs to treat CNS disorders, one of the greatest areas of unmet medical need with a large societal burden and health-care impact. Unfortunately, over the past two decades, few CNS drug approvals have succeeded, leading many pharmaceutical companies to deprioritize this therapeutic area. The reasons for the failures in CNS drug discovery are likely to be multifactorial.

Lisdexamfetamine reduces the compulsive and perseverative behaviour of binge-eating rats in a novel food reward/punished responding conflict model.

Compulsive and perseverative behaviour in binge-eating, female, Wistar rats was investigated in a novel food reward/punished responding conflict model. Rats were trained to perform the conditioned avoidance response task. When proficient, the paradigm was altered to a food-associated conflict test by placing a chocolate-filled jar (empty jar for controls) in one compartment of the shuttle box.

Synthesis and optimization of N-heterocyclic pyridinones as catechol-O-methyltransferase (COMT) inhibitors.

A series of N-heterocyclic pyridinone catechol-O-methyltransferase (COMT) inhibitors were synthesized. Physicochemical properties, including ligand lipophilic efficiency (LLE) and clogP, were used to guide compound design and attempt to improve inhibitor pharmacokinetics. Incorporation of heterocyclic central rings provided improvements in physicochemical parameters but did not significantly reduce in vitro or in vivo clearance.