Ghrelin decreases sensitivity to negative feedback and increases prediction-error related caudate activity in humans, a randomized controlled trial.

The stomach-derived hormone ghrelin plays not only a role in feeding, starvation, and survival, but it has been suggested to also be involved in the stress response, in neuropsychiatric conditions, and in alcohol and drug use disorders. Mechanisms related to reward processing might mediate ghrelin's broader effects on complex behaviors, as indicated by animal studies and mostly correlative human studies. Here, using a within-subject double-blind placebo-controlled design with intravenous ghrelin infusion in healthy volunteers (n = 30), we tested whether ghrelin alters sensitivity to reward and punishment in a reward learning task.

Sex difference in alcohol withdrawal syndrome: a scoping review of clinical studies.

Background: We conducted a review of all studies comparing clinical aspects of alcohol withdrawal syndrome (AWS) between men and women.

Methods: Five databases (PubMed, Cochrane, EMBASE, Scopus and Clinical Trials) were searched for clinical studies using the keywords "alcohol withdrawal syndrome" or "delirium tremens" limited to "sex" or "gender" or "sex difference" or "gender difference." The search was conducted on May 19, 2023.

A randomized controlled experimental medicine study of ghrelin in value-based decision making.

BACKGROUNDThe stomach-derived hormone ghrelin stimulates appetite, but the ghrelin receptor is also expressed in brain circuits involved in motivation and reward. We examined ghrelin effects on decision making beyond food or drug reward using monetary rewards.METHODSThirty participants (50% women and 50% men) underwent 2 fMRI scans while receiving i.

Are carboxyhaemoglobin levels and distance of the corpse from the site of explosion linked? Results from the retrospective analysis of a terroristic attack.

We present a retrospective analysis of a terrorist attack with incendiary grenades. We tried to analyse the correlation between carboxyhaemoglobin levels and distance of the corpse from the explosion site to check whether there is a direct relationship between them. In most fatal cases caused by grenade explosions reported in literature, death results from disruptive injuries or following multiorgan complications of the trauma, but here the terrorists used incendiary grenades causing serious burns to the victims with flames at the site of explosion.

Stigma and policy preference toward individuals who transition from prescription opioids to heroin.

Background: There is a lack of understanding of what contributes to attitudes toward individuals with an opioid addiction and preferences for policies that support them.

Methods: This study aimed to investigate stigmatization of an opioid addiction and support for publicly funded drug treatment. A randomized, between-subjects case vignette study (N = 1998) was conducted with a nation-wide online survey.

Development of a Physiologically Based Pharmacokinetic Model for Prediction of Ethanol Concentration-Time Profile in Different Organs.

Aims: A physiologically based pharmacokinetic (PBPK) modeling approach was used to simulate the concentration-time profile of ethanol (EtOH) in stomach, duodenum, plasma and other tissues upon consumption of beer and whiskey under fasted and fed conditions.

Methods: A full PBPK model was developed for EtOH using the advanced dissolution, absorption and metabolism (ADAM) model fully integrated into the Simcyp Simulator® 15 (Simcyp Ltd., Sheffield, UK).

A Population Pharmacokinetic Analysis of PF-5190457, a Novel Ghrelin Receptor Inverse Agonist in Healthy Volunteers and in Heavy Alcohol Drinkers.

Background And Objectives: The ghrelin receptor (GHS-R1a) is a potential target for alcohol use disorders. PF-5190457 is the first inverse agonist of GHS-R1a to progress to clinical development with potential to treat alcohol use disorder. We present a population pharmacokinetic model for PF-5190457 in non-heavy (alcohol consumption status = 0) and heavy alcohol drinkers (alcohol consumption status = 1), and identify relevant factors that can influence its pharmacokinetics.

Lack of Smoking Effects on Pharmacokinetics of Oral Paliperidone-analysis of a Naturalistic Therapeutic Drug Monitoring Sample.

Introduction: Major smoking effects have been reported for a series of psychotropic agents, mainly including substrates of CYP450 1A2, although smoking may also affect alternative metabolic pathways. To our knowledge, smoking effects on paliperidone pharmacokinetics have not been assessed yet.

Methods: We compared plasma concentrations of paliperidone as well as dose-corrected-plasma concentrations (C/D) from a naturalistic database between smokers and nonsmokers using nonparametrical tests, such as the Mann-Whitney U-test (MWU).

Leveraging genetic data to investigate molecular targets and drug repurposing candidates for treating alcohol use disorder and hepatotoxicity.

Background: Novel treatments for alcohol use disorder (AUD) and alcohol-related liver disease (ALD) are greatly needed. Genetic information can improve drug discovery rates by facilitating the identification of novel biological targets and potential drugs for repurposing.

Methods: The present study utilized a recently developed Bayesian approach, Integrative Risk Gene Selector (iRIGS), to identify additional risk genes for alcohol consumption using SNPs from the largest alcohol consumption GWAS to date (N = 941,280).

Labeled oxytocin administered via the intranasal route reaches the brain in rhesus macaques.

Oxytocin may have promise as a treatment for neuropsychiatric disorders. Its therapeutic effect may depend on its ability to enter the brain and bind to the oxytocin receptor. To date, the brain tissue penetrance of intranasal oxytocin has not been demonstrated.

Blood Levels to Optimize Antipsychotic Treatment in Clinical Practice: A Joint Consensus Statement of the American Society of Clinical Psychopharmacology and the Therapeutic Drug Monitoring Task Force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie.

Objective: The quantification of antipsychotic levels in blood, also known as therapeutic drug monitoring (TDM), is a potentially useful tool of modern personalized therapy that can be applied to augment antipsychotic use and dosing decisions. The application of TDM for antipsychotics can be helpful in numerous challenging clinical scenarios, such as lack of therapeutic response, relapse, or adverse drug reactions (ADRs) related to antipsychotic treatment. The benefits of TDM may be particularly evident in the treatment of highly vulnerable patient subgroups, such as children, adolescents, pregnant women, and the elderly.

Regulatory peptides and systems biology: A new era of translational and reverse-translational neuroendocrinology.

Recently, there has been a resurgence in regulatory peptide science as a result of three converging trends. The first is the increasing population of the drug pipeline with peptide-based therapeutics, mainly in, but not restricted to, incretin-like molecules for treatment of metabolic disorders such as diabetes. The second is the development of genetic and optogenetic tools enabling new insights into how peptides actually function within brain and peripheral circuits to accomplish homeostatic and allostatic regulation.

Peptide-Liganded G Protein-Coupled Receptors as Neurotherapeutics.

Peptide-liganded G protein-coupled receptors (GPCRs) are a growing fraction of GPCR drug targets, concentrated in two of the five major GPCR structural classes. The basic physiology and pharmacology of some within the rhodopsin class, for example, the enkephalin (μ opioid receptor, MOR) and angiotensin (ATR) receptors, and most in class B, all the members of which are peptide receptors, are well-known, whereas others are less so. Furthermore, with the notable exception of opioid peptide receptors, the ability to translate from peptide to "drug-like" (i.

The future of translational research on alcohol use disorder.

In March 2019, a scientific meeting was held at the University of California, Los Angeles (UCLA) Luskin Center to discuss approaches to expedite the translation of neurobiological insights to advances in the treatment of alcohol use disorder (AUD). A guiding theme that emerged was that while translational research in AUD is clearly a challenge, it is also a field ripe with opportunities. Herein, we seek to summarize and disseminate the recommendations for the future of translational AUD research using four sections.

Understanding plasma treatment effect on human acyl-ghrelin concentrations.

Objective: We evaluated the effect of different concentrations of the esterase inhibitor, AEBSF, and acid treatment on acyl-ghrelin stability in human plasma samples subjected to a freeze/thaw cycle.

Materials And Methods: Four plasma samples were collected from each donor and treated with the following concentrations of AEBSF: 2 mg/ml, 1 mg/ml, 0.6 mg/ml, and 0 mg/ml.

Plasma Risperidone-related Measures in Children and Adolescents with Oppositional Defiant/Conduct Disorders.

Objective: Therapeutic drug monitoring helps clinicians in choosing the right drug and adjust its dose in specific patients. To this end, we aimed to assess time patterns of risperidone and its metabolite, 9-hydroxyrisperidone, in children and adolescents with oppositional defiant and/or conduct disorder.

Methods: We measured plasma concentrations of risperidone and 9-hydroxyrisperidone, their sum (active moiety, AM) and ratio, as well as plasma concentrations corrected for daily dose (C/D), from 140 children/adolescents with the above-mentioned disorders.

Alcohol Tolerance in Human Laboratory Studies for Development of Medications to treat Alcohol Use Disorder.

Aims: Human laboratory studies have contributed extensively in the research and development of novel medications to treat alcohol use disorder (AUD). Alcohol tolerance may represent one additional variable that can be utilized to expand the understanding of the AUD wide phenotypic profile and provide support to the medication development process. Tolerance is characterized as an individual's subjective response to alcohol and has been recognized as a predictor of AUD progression.

Development and validation of an assay for a novel ghrelin receptor inverse agonist PF-5190457 and its major hydroxy metabolite (PF-6870961) by LC-MS/MS in human plasma.

PF-5190457 is a selective and potent ghrelin receptor inverse agonist presently undergoing clinical trials to treat alcohol use disorder (AUD). We describe the development and validation of a selective and sensitive liquid chromatography-tandem mass spectrometry-based method for quantification of PF-5190457 and its recently discovered hydroxy metabolite PF-6870961 in human plasma. Analytes were extracted after simple protein precipitation using methanol (2.

Opioid Craving in Human Laboratory Settings: a Review of the Challenges and Limitations.

There are many factors that need to be taken into consideration when measuring craving in a human laboratory study. This review summarizes and discusses some of the major challenges researchers are faced with when assessing opioid craving in clinical research. First, there are wide range of available assessments that have been developed for measuring craving and depending on the research questions or the underlying constructs targeted, some may be more appropriate than others.

Medication Development for Alcohol Use Disorder: A Focus on Clinical Studies.

Compared to other medical disorders, including other brain diseases, the number of medications approved for alcohol use disorder (AUD) is very small. Disulfiram, naltrexone (oral and long-acting), and acamprosate are approved by the US Food and Drug Administration (FDA) to treat patients with AUD. These medications are also approved in other countries, including in Europe, where the European Medicines Agency (EMA) also approved nalmefene for AUD.