Clonazepam repurposing in patients through conventional RCT and N-of-1 trials: an experimental strategy for orphan disease development.

Background: Clinical trials for rare disorders have unique challenges due to low prevalence, patient phenotype variability and high expectations. These challenges are highlighted by our study on clonazepam in patients, a common cause of intellectual disability. Previous studies on Arid1b-haploinsufficient mice showed positive effects of clonazepam on various cognitive aspects.

Administration of oxathridine, a first-in-class histamine-3 receptor partial agonist in healthy male volunteers: Central nervous system depression and pseudo-hallucinations.

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.

Pharmacological characterization of the selective orexin-1 receptor antagonist JNJ-61393215 in healthy volunteers.

Background: Up to 40% of patients suffering from anxiety disorders do not benefit from currently available pharmacological treatments. Overactivity of the orexin-1 receptor (OX1R) has been implicated in anxiety- and panic-related states.

Aim & Methods: We investigated the pharmacokinetics and characterized the pharmacodynamic (PD) profile of the OX1R antagonist JNJ-61393215 using a battery of central nervous system assessments investigating relevant functional domains such as alertness, attention, (visuo)motor coordination, balance, subjective effects and resting-state electroencephalography in a single ascending dose placebo-controlled study in doses from 1 to 90 mg inclusive, assessing PD up to 10 h after dosing, safety and pharmacokinetic in 48 healthy male subjects.

Pharmacological profile of ALKS 7119, an investigational compound evaluated for the treatment of neuropsychiatric disorders, in healthy volunteers.

Aims: 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.

Simultaneous measurement of intra-epidermal electric detection thresholds and evoked potentials for observation of nociceptive processing following sleep deprivation.

Sleep deprivation has been shown to increase pain intensity and decrease pain thresholds in healthy subjects. In chronic pain patients, sleep impairment often worsens the perceived pain intensity. This increased pain perception is the result of altered nociceptive processing.

Population pharmacokinetics of clonazepam in saliva and plasma: Steps towards noninvasive pharmacokinetic studies in vulnerable populations.

Aim: Traditional studies focusing on the relationship between pharmacokinetics (PK) and pharmacodynamics necessitate blood draws, which are too invasive for children or other vulnerable populations. A potential solution is to use noninvasive sampling matrices, such as saliva. The aim of this study was to develop a population PK model describing the relationship between plasma and saliva clonazepam kinetics and assess whether the model can be used to determine trough plasma concentrations based on saliva samples.

Finding Suitable Clinical Endpoints for a Potential Treatment of a Rare Genetic Disease: the Case of ARID1B.

There is a lack of reliable, repeatable, and non-invasive clinical endpoints when investigating treatments for intellectual disability (ID). The aim of this study is to explore a novel approach towards developing new endpoints for neurodevelopmental disorders, in this case for ARID1B-related ID. In this study, twelve subjects with ARID1B-related ID and twelve age-matched controls were included in this observational case-control study.

Pharmacokinetics of intravenous and inhaled salbutamol and tobramycin: An exploratory study to investigate the potential of exhaled breath condensate as a matrix for pharmacokinetic analysis.

Concentrations of drugs acting in the lungs are difficult to measure, resulting in relatively unknown local pharmacokinetics. The aim of this study is to assess the potential of exhaled breath condensate (EBC) as a matrix for pharmacokinetic analysis of inhaled and intravenous medication. A 4-way crossover study was conducted in 12 volunteers with tobramycin and salbutamol intravenously and via inhalation.

Glutathione-PEGylated liposomal methylprednisolone in comparison to free methylprednisolone: slow release characteristics and prolonged lymphocyte depression in a first-in-human study.

Aims: Intravenous high-dose free methylprednisolone (MP) hemisuccinate is the primary treatment for an acute relapse in relapsing-remitting multiple sclerosis. However, it is inconvenient and its side effects are undesirable. Both dose and dosing frequency can be reduced by incorporating free MP in glutathione-PEGylated liposomes, creating a slow-release formulation with reduced toxicity and prolonged peripheral efficacy.

Sputum RNA signature in allergic asthmatics following allergen bronchoprovocation test.

Background: Inhaled allergen challenge is a validated disease model of allergic asthma offering useful pharmacodynamic assessment of pharmacotherapeutic effects in a limited number of subjects.

Objectives: To evaluate whether an RNA signature can be identified from induced sputum following an inhaled allergen challenge, whether a RNA signature could be modulated by limited doses of inhaled fluticasone, and whether these gene expression profiles would correlate with the clinical endpoints measured in this study.

Methods: Thirteen non-smoking, allergic subjects with mild-to-moderate asthma participated in a randomised, placebo-controlled, 2-period cross-over study following a single-blind placebo run-in period.

NS11821, a partial subtype-selective GABAA agonist, elicits selective effects on the central nervous system in randomized controlled trial with healthy subjects.

NS11821 is a partial GABAA agonist with relatively dominant α2,3 and α5 subtype efficacy but negligible α1 agonism. This first-in-human study was performed in healthy male subjects using a single-dose, parallel, double blind, placebo-controlled, randomized, dose-escalation study design. In total six cohorts (N=48) were enrolled.

Kinetics of TH2 biomarkers in sputum of asthmatics following inhaled allergen.

Background: Allergen-induced late airway response offers important pharmacodynamic targets, including T helper 2 (TH2) biomarkers. However, detection of inflammatory markers has been limited in dithiothreitol-processed sputum.

Objectives: To test whether allergen-induced TH2 inflammatory markers can be reproducibly quantified by sensitive detection techniques in ultracentrifuged sputum and the effect of fluticasone (FP) on these endpoints.

Reproducibility of biomarkers in induced sputum and in serum from chronic smokers.

Rationale: Soluble inflammatory markers obtained from non-invasive airway sampling such as induced sputum may be useful biomarkers for targeted pharmaceutical interventions. However, before these soluble markers can be used as potential targets, their variability and reproducibility need to be established in distinct study populations.

Objective: This study aimed to assess the reproducibility of biomarkers obtained from induced sputum and serum in chronic smokers and non-smokers.

The perception and pharmacokinetics of a 20-mg dose of escitalopram orodispersible tablets in a relative bioavailability study in healthy men.

Background: Rapidly dissolving oral (orodispersible) drug formulations have been developed to overcome problems related to swallowing.

Objective: The aim of this study was to compare the bioavailability of orodispersible and conventional immediate-release (IR) escitalopram tablets.

Methods: This was a randomized, open-label, 3-way crossover trial in which healthy men received single doses of orodispersible escitalopram formulations (2 ×10 mg and 1 × 20 mg) and conventional (2 × 10 mg) oral escitalopram tablets.

Sputum induction with hypertonic saline reduces fractional exhaled nitric oxide in chronic smokers and non-smokers.

Background: Nitric oxide (NO) measurements in exhaled air and hypertonic saline-induced sputum are commonly used biomarker sampling methods of the lower airways. Both sampling methods have been validated in asthmatic patients and healthy controls, however, data from chronic smokers are scarce.

Objectives: To evaluate the reproducibility and differences in fractional exhaled NO (FeNO) values in asymptomatic chronic smokers and healthy, non-smoking controls.