Safety, Pharmacokinetics, and Pharmacodynamics of a First-in-Class ClC-1 Inhibitor to Enhance Muscle Excitability: Phase I Randomized Controlled Trial.

NMD670 is a first-in-class inhibitor of skeletal muscle-specific chloride channel ClC-1, developed to improve muscle weakness and fatigue in neuromuscular diseases. Preclinical studies show that ClC-1 inhibition enhances muscle excitability, improving muscle contractility and strength. We describe the first-in-human, randomized, double-blind, placebo-controlled study, which evaluated the safety, pharmacokinetics, and pharmacodynamics of single and multiple doses of NMD670 in healthy male and female subjects.

TMS and EEG Pharmacodynamic Effects of a Selective Sphingosine-1-Phosphate Subtype 1 Receptor Agonist on Cortical Excitability in Healthy Subjects.

Current anti-epileptic drugs lack efficacy, cause many side effects and one third of all patients are treatment-resistant. Drugs targeting the sphingosine-1-phosphate receptor show potential anti-convulsant effects in animal models and decrease cortical excitability in patients with multiple sclerosis, but available compounds alter lymphocyte trafficking and cause immunosuppression, limiting their clinical anti-epileptic potential. TRV045 is a selective sphingosine-1-phosphate subtype 1 receptor agonist without effects on lymphocyte trafficking, demonstrating efficacy in animal models of epilepsy, with the potential to target abnormal cortical excitability.

Open-Label Interventional Study in Healthy Volunteers to Evaluate NO-Mediated Vasodilation by Dermal Allyl Isothiocyanate Challenge and Whole-Body Heat Stress.

Dermal allyl isothiocyanate (AITC) administration and whole-body heat stress (WBHS) are two challenge models that are used to evaluate physiological mechanisms of vasodilation and pharmacological activity in humans. Their exact vasodilatory mechanisms in humans are not fully elucidated but are likely to be nitric oxide (NO)-mediated. This study aimed to evaluate whether there is overlap in the vasodilatory pathways of dermal AITC application and WBHS by combining the challenges.

The interactive walkway provides fit-for-purpose fall-risk biomarkers in the elderly: Comparison of zolpidem and suvorexant.

Dynamic balance assessments such as walking adaptability may yield a more realistic prediction of drug-induced falls compared with postural stability measurements, as falls often result from limited gait adjustments when walking. The Interactive Walkway (IWW) measures walking adaptability but sensitivity to medication effects is unknown. If proven sensitive and specific, IWW could serve as a biomarker for targeted fall-risk assessments in early clinical drug development.

Target engagement and immunogenicity of an active immunotherapeutic targeting pathological α-synuclein: a phase 1 placebo-controlled trial.

Investigational therapeutics that target toxic species of α-synuclein (αSyn) aim to slow down or halt disease progression in patients with Parkinson's disease (PD). Here this 44-week, randomized, placebo-controlled, double-blind, single-center phase 1 study investigated safety, tolerability and immunogenicity of UB-312, an active immunotherapeutic targeting pathological αSyn, in patients with PD. The primary outcome measures were adverse event frequency and change in anti-αSyn antibody titers in blood and cerebrospinal fluid (CSF).

Effects of the phosphodiesterase 2 inhibitor BI 474121 on central nervous system cyclic guanosine monophosphate concentrations: Translational studies.

Aims: Phosphodiesterase 2 (PDE2) regulates intracellular cyclic adenosine monophosphate and guanosine monophosphate (cAMP/cGMP) levels, which contribute to processes crucial for learning and memory. BI 474121, a potent and selective PDE2 inhibitor, is in development for treating cognitive impairment associated with schizophrenia.

Methods: The effects of BI 474121 on cGMP concentrations were first assessed in rat cerebrospinal fluid (CSF) to demonstrate central nervous system (CNS) and functional target engagement.

Clinical trial evaluating apomorphine oromucosal solution in Parkinson's disease patients.

Apomorphine, used to treat OFF episodes in patients with Parkinson's disease (PD), is typically administered via subcutaneous injections. Administration of an oromucosal solution could offer a non-invasive and user-friendly alternative. This two-part clinical study evaluated the safety, tolerability, pharmacokinetics (PK), and dose proportionality of a novel apomorphine hydrochloride oromucosal solution, as well as its relative bioavailability to subcutaneous apomorphine injection and apomorphine sublingual film.

A smartphone- and wearable-based biomarker for the estimation of unipolar depression severity.

Drug development for mood disorders can greatly benefit from the development of robust, reliable, and objective biomarkers. The incorporation of smartphones and wearable devices in clinical trials provide a unique opportunity to monitor behavior in a non-invasive manner. The objective of this study is to identify the correlations between remotely monitored self-reported assessments and objectively measured activities with depression severity assessments often applied in clinical trials.

Neurocognitive Effect of Biased µ-Opioid Receptor Agonist Oliceridine, a Utility Function Analysis and Comparison with Morphine.

Background: Oliceridine (Olinvyk) is a μ-opioid receptor agonist that in contrast to conventional opioids preferentially engages the G-protein-coupled signaling pathway. This study was designed to determine the utility function of oliceridine versus morphine based on neurocognitive tests and cold pressor test.

Methods: The study had a randomized, double-blind, placebo-controlled, partial block three-way crossover design.

Randomized placebo-controlled crossover study to assess tolerability and pharmacodynamics of zagociguat, a soluble guanylyl cyclase stimulator, in healthy elderly.

Aims: Dysfunction of nitric oxide-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate signalling is implicated in the pathophysiology of cognitive impairment. Zagociguat is a central nervous system (CNS) penetrant sGC stimulator designed to amplify nitric oxide-cyclic guanosine monophosphate signalling in the CNS. This article describes a phase 1b study evaluating the safety and pharmacodynamic effects of zagociguat.

Machine Learning Techniques for Developing Remotely Monitored Central Nervous System Biomarkers Using Wearable Sensors: A Narrative Literature Review.

Background: Central nervous system (CNS) disorders benefit from ongoing monitoring to assess disease progression and treatment efficacy. Mobile health (mHealth) technologies offer a means for the remote and continuous symptom monitoring of patients. Machine Learning (ML) techniques can process and engineer mHealth data into a precise and multidimensional biomarker of disease activity.

A Phase 1B Trial in GBA1-Associated Parkinson's Disease of BIA-28-6156, a Glucocerebrosidase Activator.

Background: Loss-of-function mutations in the GBA1 gene are one of the most common genetic risk factors for onset of Parkinson's disease and subsequent progression (GBA-PD). GBA1 encodes the lysosomal enzyme glucocerebrosidase (GCase), a promising target for a possible first disease-modifying therapy. LTI-291 is an allosteric activator of GCase, which increases the activity of normal and mutant forms of GCase.

A leucine-rich repeat kinase 2 (LRRK2) pathway biomarker characterization study in patients with Parkinson's disease with and without LRRK2 mutations and healthy controls.

Increased leucine-rich repeat kinase 2 (LRRK2) kinase activity is an established risk factor for Parkinson's disease (PD), and several LRRK2 kinase inhibitors are in clinical development as potential novel disease-modifying therapeutics. This biomarker characterization study explored within- and between-subject variability of multiple LRRK2 pathway biomarkers (total LRRK2 [tLRRK2], phosphorylation of the serine 935 (Ser935) residue on LRRK2 [pS935], phosphorylation of Rab10 [pRab10], and total Rab10 [tRab10]) in different biological sources (whole blood, peripheral blood mononuclear cells [PBMCs], neutrophils) as candidate human target engagement and pharmacodynamic biomarkers for implementation in phase I/II pharmacological studies of LRRK2 inhibitors. PD patients with a LRRK2 mutation (n = 6), idiopathic PD patients (n = 6), and healthy matched control subjects (n = 10) were recruited for repeated blood and cerebrospinal fluid (CSF) sampling split over 2 days.

First-in-human trial to assess safety, tolerability, pharmacokinetics, and pharmacodynamics of zagociguat (CY6463), a CNS-penetrant soluble guanylyl cyclase stimulator.

Soluble guanylate cyclase (sGC) and its product, cyclic guanosine monophosphate, play a role in learning and memory formation. Zagociguat (CY6463) is a novel stimulator of sGC being developed for the treatment of neurodegenerative disease. Single zagociguat doses of 0.

Cognitive performance in healthy clinical trial participants and patients with the NeuroCart, a neurodegenerative disease measured with an automated neuropsychological and neurophysiological test battery.

Background: The prevalence of neurodegenerative diseases increases significantly with increasing age. Neurodegeneration is the progressive loss of function of neurons that eventually leads to cell death, which in turn leads to cognitive disfunction. Cognitive performance can therefore also be considered age dependent.

Smartphone and Wearable Sensors for the Estimation of Facioscapulohumeral Muscular Dystrophy Disease Severity: Cross-sectional Study.

Background: Facioscapulohumeral muscular dystrophy (FSHD) is a progressive neuromuscular disease. Its slow and variable progression makes the development of new treatments highly dependent on validated biomarkers that can quantify disease progression and response to drug interventions.

Objective: We aimed to build a tool that estimates FSHD clinical severity based on behavioral features captured using smartphone and remote sensor data.

A Biomarker Study in Patients with GBA1-Parkinson's Disease and Healthy Controls.

Background: Molecules related to glucocerebrosidase (GCase) are potential biomarkers for development of compounds targeting GBA1-associated Parkinson's disease (GBA-PD).

Objectives: Assessing variability of various glycosphingolipids (GSLs) in plasma, peripheral blood mononuclear cells (PBMCs), and cerebrospinal fluid (CSF) across GBA-PD, idiopathic PD (iPD), and healthy volunteers (HVs).

Methods: Data from five studies were combined.

LRRK2 Inhibition by BIIB122 in Healthy Participants and Patients with Parkinson's Disease.

Background: Leucine-rich repeat kinase 2 (LRRK2) inhibition is a promising therapeutic approach for the treatment of Parkinson's disease (PD).

Objective: The aim of this study was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of the potent, selective, CNS-penetrant LRRK2 inhibitor BIIB122 (DNL151) in healthy participants and patients with PD.

Methods: Two randomized, double-blind, placebo-controlled studies were completed.

Fit for purpose of on-the-road driving and simulated driving: A randomised crossover study using the effect of sleep deprivation.

Introduction: Drivers should be aware of possible impairing effects of alcohol, medicinal substance, or fatigue on driving performance. Such effects are assessed in clinical trials, including a driving task or related psychomotor tasks. However, a choice between predicting tasks must be made.

Mitochondrial function, grip strength, and activity are related to recovery of mobility after a total knee arthroplasty.

Low muscle quality and a sedentary lifestyle are indicators for a slow recovery after a total knee arthroplasty (TKA). Mitochondrial function is an important part of muscle quality and a key driver of sarcopenia. However, it is not known whether it relates to recovery.

A Placebo-Controlled Study to Assess the Sensitivity of Finger Tapping to Medication Effects in Parkinson's Disease.

Background: Movement Disorder Society-Unified Parkinson's Rating Scale Part III (MDS-UPDRS III) is the gold standard for assessing medication effects in patients with Parkinson's disease (PD). However, short and rater-independent measurements would be ideal for future trials.

Objectives: To assess the ability of 3 different finger tapping tasks to detect levodopa/carbidopa-induced changes over time and to determine their correlation and compare their discriminatory power with MDS-UPDRS III.

Decreased integrity of the monoaminergic tract is associated with a positive response to MPH in patients with vascular cognitive impairment - proof of principle study STREAM-VCI.

Background: Patients with vascular cognitive impairment (VCI) are very heterogeneous in both symptoms and type of cerebrovascular pathology. This might be an important reason why there is no symptomatic treatment available for VCI patients. In this study, we investigated in patients with VCI, whether there was an association between a positive response to methylphenidate and galantamine and the type of cerebrovascular disease, structural damage to specific neurotransmitter systems, cerebral perfusion, and presence of co-morbid Alzheimer (AD) pathology.