Acute exposure to hypoxia can lead to cognitive impairment. Therefore, hypoxia may become a safety concern for occupational or recreational settings at altitude. Cognitive tests are used as a tool to assess the degree to which hypoxia affects cognitive performance.
View Article and Find Full Text PDFBr J Clin Pharmacol
January 2024
Aims: To characterise the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single ascending doses of oxathridine, a first-in-class histamine-3 receptor partialagonist, in healthy male volunteers.
Methods: A randomised, double-blind, placebo-controlled study including the NeuroCart, consisting of a battery of drug sensitive neurophysiological tests, was performed. Oxathridine was administered orally as an aqueous solution.
JNJ-54175446 is a selective purine P2X7 receptor (P2X7R) antagonist that attenuates microglial IL-1β/IL-18 release. In healthy volunteers, JNJ-54175446 suppressed peripheral interleukin (IL)-1β release, and attenuated dexamphetamine-induced improvements of mood and (visuo)motor performance in a human dexamphetamine-challenge paradigm. In depression, P2X7R inhibition may dampen immune-related dysregulation of mood.
View Article and Find Full Text PDFThe primary purpose of this study was to assess the translatability of preclinical to early clinical tolerable and pharmacologically active dose ranges for central nervous system (CNS) active drugs. As a part of this, IBs were reviewed on reporting quality. Investigator's Brochures (IBs) of studies performed at the Centre for Human Drug Research (CHDR) reporting statistically significant results of CNS activity related to the drug's mechanism of action were included.
View Article and Find Full Text PDFThe anti-inflammatory agents dexamethasone (corticosteroid), and tocilizumab and sarilumab (IL6-inhibitors) are effective in the treatment of late COVID-19. Other anti-inflammatory agents, like anakinra (IL1-inhibitor), baricitinib and tofacitinib (JAK-inhibitors) and lenzilumab (GM-CSF-inhibitor) have also shown positive results in late COVID-19. For the treatment of early COVID-19, the inhalation corticosteroid budesonide is regarded as an off-label treatment option.
View Article and Find Full Text PDFAims: ALKS 7119 is a novel compound with in vitro affinity highest for the SERT, and for μ receptor, α -adrenoceptor, α -adrenoceptor, NMDA receptor and sigma non-opioid intracellular receptor 1. This first-in-human study evaluated safety and PK/PD effects of single ascending doses (SAD) of ALKS 7119 in healthy males and compared effects with neurotransmitter modulators with partially overlapping targets.
Methods: In 10 cohorts (n = 10 subjects each), PK, safety and PD (NeuroCart tests, measuring neurophysiologic effects [pupillometry, pharmaco-EEG (pEEG)], visuomotor coordination, alertness, [sustained] attention [saccadic peak velocity, adaptive tracking], subjective drug effects [VAS Bowdle and VAS Bond and Lader] and postural stability [body sway]) were evaluated.
During the outbreak of the COVID-19 pandemic many clinical trials were abruptly halted. Measures to contain the pandemic are currently taking effect and societies in general and healthcare systems in particular are considering how to return to normalcy. This opens up the discussion when and how clinical trials should be restarted while the COVID-19 pandemic has not yet resolved, and what should happen in case of a resurgence of the virus in the coming months.
View Article and Find Full Text PDFThis research was planned to build a Pharmacokinetic/Pharmacodynamic (PK/PD) model of 5-hydroxytryptophan (5-HTP) challenge study including a circadian rhythm component of cortisol and to predict serum cortisol based on saliva cortisol. Data from three 5-HTP challenge studies in healthy volunteers were collected. Serum 5-HTP, saliva, and serum cortisol were sampled as PK and PD marker.
View Article and Find Full Text PDFBackground: To date, no symptomatic treatment is available for patients with vascular cognitive impairment (VCI). In the proof-of-principle study Symptomatic Treatment of Vascular Cognitive Impairment (STREAM-VCI), we investigated whether a single dose of a monoaminergic drug (methylphenidate) improves executive functioning and whether a single dose of a cholinergic drug (galantamine) improves memory in VCI patients.
Methods: STREAM-VCI is a single-center, double-blind, three-way crossover trial.
Disruption of cholinergic and serotonergic neurotransmitter systems is associated with cognitive, emotional and behavioural symptoms of Alzheimer's disease (AD). To investigate the responsiveness of these systems in AD we measured the effects of a single-dose of the selective serotonin reuptake inhibitor citalopram and acetylcholinesterase inhibitor galantamine in 12 patients with AD and 12 age-matched controls on functional brain connectivity with resting state functional magnetic resonance imaging. In this randomized, double blind, placebo-controlled crossover study, functional magnetic resonance images were repeatedly obtained before and after dosing, resulting in a dataset of 432 scans.
View Article and Find Full Text PDFInvestigating potential pharmacodynamic effects in an early phase of central nervous system (CNS) drug research can provide valuable information for further development of new compounds. A computerized and thoroughly validated battery of neuropsychological and neurophysiological tests has been shown to be sensitive to detect drug-induced effects of multiple new and existing compounds. The test battery covers the main CNS domains, which have been shown to respond to drug effects and can be repeatedly administered following drug administration to characterize the concentration-effect profile of a drug.
View Article and Find Full Text PDFAims: In previous studies, the histamine-3 receptor antagonist CEP-26401 had a subtle effect on spatial working memory, with the best effect seen at the lowest dose tested (20 μg), and a dose-dependent disruption of sleep. In the current study, 3 low-dose levels of CEP-26401 were compared with modafinil and donepezil.
Methods: In this double-blind, placebo- and positive-controlled, randomized, partial 6-way cross-over study, 40 healthy subjects received single doses of placebo, CEP-26401 (5, 25 or 125 μg) or modafinil 200 mg or donepezil 10 mg.
Parkinsonism Relat Disord
March 2019
Background: As the disease progresses, patients with Huntington's disease (HD), an inherited neurodegenerative disorder, become less independent in their daily life activities and have to consider if they can still drive a car. For most patients, the decision to quit driving is difficult and affects their independence and social activities.
Objective: To investigate if cognitive, motor, or psychiatric symptoms can predict driving performance in HD gene carriers using a simulator situation.
Objective: In clinical practice, patients with Huntington's disease (HD) often decide to solely drive in their own familiar neighborhoods and not on a motorway or in an unknown area. The aim of the study was to identify differences in driving performance between HD gene carriers and healthy individuals in simulated urban and motorway environments.
Methods: This cross-sectional study included 87 participants (28 premanifest HD, 30 manifest HD, 29 controls).
Eur Neuropsychopharmacol
September 2018
Numerous novel neuroscience-based drug targets have been identified in recent years. However, it remains unclear how these targets relate to the expression of symptoms in central nervous system (CNS) disorders in general and psychiatric disorders in particular. To discuss this issue, a New Frontiers Meetings of European College of Neuropsychopharmacology (ECNP) was organized to address the challenges in translational neuroscience research that are impeding the effective development of new treatments.
View Article and Find Full Text PDFObjective: To develop a self-test to measure clinical fitness to perform in surgical residents, with alcohol-induced impairment as reference.
Design: Observational, exploratory study to evaluate night shift-induced impaired performance in surgical residents followed by a randomized blinded, placebo-controlled, crossover study to evaluate impaired performance as a result of ethanol intoxication. Impairment was quantified using the Mini-NeuroCart, a psychomotor and cognitive test battery for assessment of subjective and objective measures of alertness, concentration, eye-hand coordination, mood, and self-assessed ability to perform.
Aims: Establishing a pharmacological challenge model could yield an important tool to understand the complex role of the nicotinic cholinergic system in cognition and to develop novel compounds acting on the nicotinic acetylcholine receptor.
Methods: This randomized, double-blind, double-dummy, placebo-controlled, four-way crossover study examined the effects of the nicotinic antagonist mecamylamine on a battery of cognitive and neurophysiological test with coadministration of a placebo, nicotine or galantamine in order to reverse the cognitive impairment caused by mecamylamine.
Results: Thirty-three healthy subjects received a single oral dose of 30 mg of mecamylamine (or placebo) in combination with either 16 mg of oral galantamine or 21 mg of transdermal nicotine (or its double-dummy).
Aging is accompanied by changes in neurotransmission. To advance our understanding of how aging modifies specific neural circuitries, we examined serotonergic and cholinergic stimulation with resting state functional magnetic resonance imaging (RS-fMRI) in young and older adults. The instant response to the selective serotonin reuptake inhibitor citalopram (30 mg) and the acetylcholinesterase inhibitor galantamine (8 mg) was measured in 12 young and 17 older volunteers during a randomized, double blind, placebo-controlled, crossover study.
View Article and Find Full Text PDFAims: Inflammation and organ failure have been reported to have an impact on cytochrome P450 (CYP) 3A-mediated clearance of midazolam in critically ill children. Our aim was to evaluate a previously developed population pharmacokinetic model both in critically ill children and other populations, in order to allow the model to be used to guide dosing in clinical practice.
Methods: The model was evaluated externally in 136 individuals, including (pre)term neonates, infants, children and adults (body weight 0.
Aims: The aims of the present study were to investigate the role of pharmacology in the design of first-in-man (FIM) trials in the Netherlands, and to evaluate the change in design approaches between 2007 and 2015.
Methods: All FIM drug trials approved by all Dutch Institutional Review Boards (IRBs) in 2007 and in 2015 were selected. The original trial protocols, investigator's brochures and investigational medicinal product dossiers were the data sources.
Monitoring effects of disease or therapeutic intervention on brain function is increasingly important for clinical trials, albeit hampered by inter-individual variability and subtle effects. Here, we apply complementary biomarker algorithms to electroencephalography (EEG) recordings to capture the brain's multi-faceted signature of disease or pharmacological intervention and use machine learning to improve classification performance. Using data from healthy subjects receiving scopolamine we developed an index of the muscarinic acetylcholine receptor antagonist (mAChR) consisting of 14 EEG biomarkers.
View Article and Find Full Text PDFBoth normal aging and Alzheimer's disease (AD) have been associated with a reduction in functional brain connectivity. It is unknown how connectivity patterns due to aging and AD compare. Here, we investigate functional brain connectivity in 12 young adults (mean age 22.
View Article and Find Full Text PDFAims: The muscarinic acetylcholine receptor antagonist scopolamine is often used for proof-of-pharmacology studies with pro-cognitive compounds. From a pharmacological point of view, it would seem more rational to use a nicotinic rather than a muscarinic anticholinergic challenge to prove pharmacology of a nicotinic acetylcholine receptor agonist. This study aims to characterize a nicotinic anticholinergic challenge model using mecamylamine and to compare it to the scopolamine model.
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