British Journal of Pharmacology

BACKGROUND AND PURPOSE: The single layer of cells lining all blood vessels, the endothelium, is a sophisticated signal co-ordination centre that controls a wide range of vascular functions including the regulation of blood pressure and blood flow. To co-ordinate activities, communication among cells is required for tissue level responses to emerge. While a significant form of communication occurs by the propagation of signals between cells, the mechanism of propagation in the intact endothelium is unresolved...

AIMS: Our previous 3-period crossover study in healthy volunteers comparing the pharmacokinetics of nalbuphine nasal spray Apain with parenteral nalbuphine solution demonstrated high bioavailability of the nasal spray and close similarity of pharmacokinetic profiles after intranasal and intramuscular administration, especially within 30 min postdose. The aim of the present study was a noninferiority assessment of nalbuphine nasal spray vs. intramuscular injection for pain relief in postoperative patients...

AIMS: Many transgender and gender diverse (TGD) individuals have expressed concerns about the potential for oral pre-exposure prophylaxis to affect hormonal concentrations achieved from taking gender-affirming hormone therapy (GAHT). The purpose of this study was to understand the bidirectional effects between hormone and intraerythrocytic tenofovir diphosphate concentrations when switching from tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) to tenofovir alafenamide/emtricitabine (TAF/FTC) in TGD users/nonusers of GAHT...

BACKGROUND AND PURPOSE: Whereas biased agonism on the 5-HT2A receptor has been ascribed to hallucinogenic properties of psychedelics, no information about biased inverse agonism on this receptor is available. In schizophrenia, increased 5-HT2A receptor constitutive activity has been suggested, highlighting the therapeutic relevance of inverse agonism. This study characterized the modulation of G protein activity promoted by different drugs, commonly considered as 5-HT2A receptor antagonists, in post-mortem human brain cortex...

BACKGROUND AND PURPOSE: White adipose tissue (WAT) is involved in rheumatoid arthritis (RA). This study explored its potential as an antirheumatic target. EXPERIMENTAL APPROACH: WAT status of healthy and adjuvant-induced arthritis (AIA) rats were compared. The contribution of WAT to RA pathology was evaluated by pre-adipocyte transplant experiments and by dissecting perirenal fat pads of AIA rats. The impact of RA on WAT was investigated by culturing pre-adipocytes...

BACKGROUND AND PURPOSE: Methamphetamine (METH) use disorder has risen dramatically over the past decade, and there are currently no FDA-approved medications due, in part, to gaps in our understanding of the pharmacological mechanisms related to METH action in the brain. EXPERIMENTAL APPROACH: Here, we investigated whether transient receptor potential ankyrin 1 (TRPA1) mediates each of several METH abuse-related behaviours in rodents: self-administration, drug-primed reinstatement, acquisition of conditioned place preference, and hyperlocomotion...

BACKGROUND AND PURPOSE: Statins are competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGCR), and exert adverse effects on mitochondrial function, although the mechanisms underlying these effects remain unclear. We used a tamoxifen-induced Hmgcr-knockout (KO) mouse model, a multi-omics approach and mitochondrial function assessments to investigate whether decreased HMGCR activity impacts key liver energy metabolism pathways. EXPERIMENTAL APPROACH: We established a new mouse strain using the Cre/loxP system, which enabled whole-body deletion of Hmgcr expression...

BACKGROUND AND PURPOSE: Chymotrypsin is a pancreatic protease secreted into the lumen of the small intestine to digest food proteins. We hypothesized that chymotrypsin activity may be found close to epithelial cells and that chymotrypsin signals to them via protease-activated receptors (PARs). We deciphered molecular pharmacological mechanisms and gene expression regulation for chymotrypsin signalling in intestinal epithelial cells. EXPERIMENTAL APPROACH: The presence and activity of chymotrypsin were evaluated by Western blot and enzymatic activity tests in the luminal and mucosal compartments of murine and human gut samples...

The Health and Environmental Sciences Institute (HESI) Cardiac Safety Committee designed and created a publicly accessible database with an initial set of 128 pharmacologically defined pharmaceutical agents, many with known cardiotoxic properties. The database includes specific information about each compound that could be useful in evaluating hypotheses around mechanisms of drug-induced cardiac toxicity or for development of novel cardiovascular safety assays. Data on each of the compounds was obtained from published literature and online sources (e...

Changes in structure and dynamics elicited by agonist ligand binding at the extracellular side of G protein coupled receptors (GPCRs) must be relayed to the cytoplasmic G protein binding side of the receptors. To decipher the role of water-mediated hydrogen-bond networks in this relay mechanism, we have developed graph-based algorithms and analysis methodologies applicable to datasets of static structures of distinct GPCRs. For a reference dataset of static structures of bovine rhodopsin solved at the same resolution, we show that graph analyses capture the internal protein-water hydrogen-bond network...

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BACKGROUND AND PURPOSE: Transient hypofunction of the NMDA receptor represents a convergence point for the onset and further development of psychiatric disorders, including schizophrenia. Although the cumulative evidence indicates dysregulation of the hippocampal formation in schizophrenia, the integrity of the synaptic transmission and plasticity conveyed by the somatosensorial inputs to the dentate gyrus, the perforant pathway synapses, have barely been explored in this pathological condition...

AIMS: Pre-emptive prediction to avoid myelosuppression and harmful sequelae is difficult given the complex interplay among patients, drugs and treatment protocols. This study aimed to model plasma and bone marrow concentrations and the likelihood of myelotoxicity following administration of 5-fluorouracil (5-FU) by diverse intravenous (IV) bolus or continuous infusion (cIF) regimens. METHODS: Using physicochemical, in vitro and clinical data obtained from the literature consisting of various regimens and patient cohorts, a 5-FU physiologically based pharmacokinetic (PBPK) model was developed...

The rise of psychedelics in contemporary medicine has sparked interest in their potential therapeutic applications. While traditionally associated with countercultural movements and recreational use, recent research has shed light on the potential benefits of psychedelics in various mental health conditions. In this review, we explore the possible role of psychedelics in the management of chronic pain and opioid use disorder (OUD), 2 critical areas in need of innovative treatment options. Pain control remains a significant clinical challenge, particularly for individuals with OUD and those who receive long-term opioid therapy who develop marked tolerance to opioid-induced analgesia...

Thirst is a complex physiological compensatory mechanism but could also be associated with drugs. This association was poorly investigated previously. Using the WHO global pharmacovigilance database, Vigibase®, disproportionality analyses potential associations between exposure to drugs and thirst reports were performed. All reports of thirst in adults between 01/01/2000 and 31/12/2023 were included. Results are expressed as reporting odds ratio (ROR). Analysis of the 3186 reports of thirst (978 'serious') allowed, first, to confirm the association between thirst and exposure to vasopressin antagonists (tolvaptan), lithium, gliflozins (dapagliflozin, empagliflozin), pregabalin and antimuscarinic drugs (glycopyronium, oxybutynin, tiotropium)...

BACKGROUND AND PURPOSE: Neuropathic pain, a debilitating condition with unmet medical needs, can be characterised as hyperexcitability of nociceptive neurons caused by dysfunction of ion channels. Voltage-gated potassium channels type 7 (Kv7), responsible for maintaining neuronal resting membrane potential and thus excitability, reside under tight control of G protein-coupled receptors (GPCRs). Calcium-sensing receptor (CaSR) is a GPCR that regulates the activity of numerous ion channels, but whether CaSR can control Kv7 channel function has been unexplored until now...

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder with effective pharmacological treatments that improve symptoms and reduce complications. NICE guidelines recommend primary care practitioners prescribe medication for adult ADHD under shared care agreements with adult mental health services (AMHS). However, provision remains uneven, with some practitioners reporting a lack of support. AIM: This study aimed to describe supportive elements (prescribing, shared care, AMHS availability) of primary care prescribing for adult ADHD medication in England, to inform service improvement and improve access for this underserved population...

We aimed to address factors contributing to the pharmacokinetic changes of nirmatrelvir/ritonavir in renal impaired (RI) patients and recommend dosing adjustment via a physiologically-based pharmacokinetic (PBPK) modelling approach. A PBPK model of nirmatrelvir/ritonavir was developed via Simcyp® Simulator. Sensitivity analysis of the influence of hepatic CYP3A4 intrinsic clearance and abundance, as well as hepatic non-CYP3A4 metabolism (other human liver microsomes [HLM] CLint ) was performed to evaluate the effects of RI on oral clearance of nirmatrelvir...

AIMS: Genetic testing can be used to improve the safety and effectiveness of commonly prescribed medicines-a concept known as pharmacogenetics. This study aimed to quantify members of the UK public's preferences for a pharmacogenetic service to be delivered in primary care in the National Health Service. METHODS: Members of the UK population were surveyed via an online panel company. Respondents completed 1 of 2 survey versions, asking respondents to select their preferred pharmacogenetic testing service in the context of a presentation of low mood or pain...

BACKGROUND AND PURPOSE: There is a need for effective anti-COVID-19 treatments, mainly for individuals at risk of severe disease such as the elderly and the immunosuppressed. Drug repositioning has proved effective in identifying drugs that can find a new application for the control of coronavirus disease, in particular COVID-19. The purpose of the present study was to find synergistic antiviral combinations for COVID-19 based on lethal mutagenesis. EXPERIMENTAL APPROACH: The effect of combinations of remdesivir and ribavirin on the infectivity of SARS-CoV-2 in cell culture has been tested...