People with vascular cognitive impairment (VCI) constitute a clinically heterogeneous group, but previous symptomatic drug trials in VCI did not take this clinical heterogeneity into account. Executive dysfunction and memory impairment are the cognitive domains that are most frequently impaired in VCI, and these impairments are likely to reflect vascular damage to specific neurotransmitter systems, which opens the possibility for targeted symptomatic treatment directed at specific neurotransmitters.Here we describe the design of the "Symptomatic Treatment of Vascular Cognitive Impairment" (STREAM-VCI) trial. In this proof-of-concept study, we investigate whether people with VCI with executive dysfunction due to vascular damage to the monoaminergic neurotransmitter system differentially respond to a monoaminergic challenge, whereas people with VCI with memory dysfunction associated with vascular damage to the cholinergic system will in turn respond to a cholinergic challenge.The STREAM-VCI is a single center, double blind, three-way cross-over trial among 30 people with VCI, in which subjects received a single dose of galantamine, methylphenidate, or placebo on separate occasions. The most important inclusion criteria were a diagnosis of VCI with a Mini-Mental State Examination score of ≥16 and a Clinical Dementia Rating of 0.5-1.0. For each person, the challenges consisted of a single 16 mg dose of galantamine, 10 mg of methylphenidate, and placebo, in random order on three separate visits. Change in performance in executive functioning and memory was assessed directly after the challenge using standardized neuropsychological tests. We will correlate a positive response to the cholinergic and monoaminergic treatment with differences in structural and functional connectivity at baseline using structural magnetic resonance imaging (MRI), diffusion tension MRI, and resting-state functional MRI.The protocol of this study is approved by the Medical Ethics Committee of VU University Medical Center and the competent authority. The first participant was enrolled in April 2014. In September 2017, enrolment for the study was completed. We expect to publish the results in 2018.STREAM-VCI is the first study to investigate the association of a response to a cholinergic and monoaminergic treatment with structural and functional connectivity of the monoaminergic and/or cholinergic systems on MRI. We aim to predict on an individual basis which individuals show a positive response to a cholinergic and/or monoaminergic challenge in people with VCI. This may be instrumental in moving in the direction of individually-tailored pharmacological interventions based on MRI measures in people with VCI.ClinicalTrials.gov NCT02098824; https://clinicaltrials.gov/ct2/show/NCT02098824 (Archived by WebCite at http://www.webcitation.org/6xhO7Ya1q).
To systematically study the pharmacodynamics of a CNS drug early in the development process, we developed and validated a battery of drug-sensitive CNS tests, which we call NeuroCart. Using this test battery, data-intensive phase 1 studies in healthy subjects can be performed to demonstrate the specific, time- and dose-dependent, neurophysiological and/or neuropsychological effects of a compound, thereby confirming whether the test compound reaches its intended target in the CNS – or does not reach its intended target. We use this test battery to demonstrate that a compound passes the blood–brain barrier.
Chronic pain and sleep impairments are often closely associated. Sleep deprivation results in increased pain perception and lower pain thresholds. We recently developed a new method to study nociceptive processing by simultaneous tracking of nociceptive detection thresholds (NDTs) and evoked potentials (EPs) in response to intra-epidermal electric stimuli. In this work, we study whether we can use this method to assess impaired nociceptive processing after sleep deprivation in a cross-over study on 24 subjects.
Investigating 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. The standard tests in the battery are saccadic eye movement, smooth pursuit eye movement, the Bowdle visual analog scale (VAS), the Bond and Lader VAS, body sway, adaptive tracking, visual verbal learning, and quantitative electroencephalography (qEEG). However, the test battery is adaptive in nature, meaning that it can be composed and adjusted with tests fit to investigate specific drug classes, or even specific receptors. Showing effects of new cholinergic drugs designed to have a pro-cognitive outcome has been difficult. The pharmacological challenge model is a tool for early proof-of-pharmacology. Here, a marketed drug is used to induce temporary and reversible disease-like symptoms in healthy subjects, via a pharmacological mechanism related to the disease that is targeted as indication for the new compound. The test battery was implemented to investigate the potential of the nicotinic receptor antagonist mecamylamine to be used as a challenge model for cholinergic dysfunction, as seen in neurodegenerative disorders. A worsening of scores in a dose dependent manner on the visual verbal learning test (VVLT; a test for learning and memory abilities) and the adaptive tracking test (a measure of visuomotor control and arousal), in particular, showed that the test battery is sensitive to showing acute pharmacodynamic effect after administration of anti-cholinergic drugs.
The development of a new medicine is a risky and costly undertaking that requires careful planning. This planning is largely applied to the operational aspects of the development and less so to the scientific objectives and methodology. The drugs that will be developed in the future will increasingly affect pathophysiological pathways that have been largely unexplored. Such drug prototypes cannot be immediately introduced in large clinical trials. The effects of the drug on normal physiology, pathophysiology, and eventually the desired clinical effects will need to be evaluated in a structured approach, based on the definition of drug development as providing answers to important questions by appropriate clinical studies. This review describes the selection process for biomarkers that are fit-for-purpose for the stage of drug development in which they are used. This structured and practical approach is widely applicable and particularly useful for the early stages of innovative drug development.
A mutation in the GBA1 gene is the most common genetic risk factor for developing Parkinson's disease. GBA1 encodes the lysosomal enzyme glucosylceramidase beta (glucocerebrosidase, GCase) and mutations decrease enzyme activity. LTI-291 is an allosteric modulator of GCase, enhancing its activity. These first-in-human studies evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple ascending doses of LTI-291 in healthy volunteers.In the single ascending dose (SAD) study, 40 healthy volunteers were randomly assigned to LTI-291 (n = 8 per dose level) or placebo (n = 2 per dose level). Single doses of 3, 10, 30 and 90 mg LTI-291 were investigated. In the multiple ascending dose (MAD) study, 40 healthy middle-aged or elderly volunteers were randomly assigned to LTI-291 (n = 8 per dose level) or placebo (n = 2 per dose level). Fourteen consecutive daily doses of 3, 10, 30 and 60 mg LTI-291 or placebo were administered. In both the SAD and MAD studies, glycosphingolipid levels were measured and a test battery of neurocognitive tasks was performed.LTI-291 was generally well tolerated and no deaths or treatment-related SAEs occurred and no subject withdrew from a study due to AEs. Cmax , AUC0-24 and AUC0-inf increased in a dose proportional manner. The median half-life was 28.0 hours after multiple dosing. No dose-dependent glycosphingolipid changes occurred. No neurocognitive adverse effects were detected.These first-in-human studies demonstrated that LTI-291 was well tolerated when given orally once daily for 14 consecutive days. This supports the continued clinical development and the exploration of LTI-291 effects in a GBA1-mutated Parkinson population.
Human evoked pain models can be used to determine the efficacy of new and existing analgesics and to aid in the identification of new targets. Aspects of neuropathic pain can be simulated by inducing hyperalgesia resulting from provoked sensitization. The present literature review aimed to provide insight into the sensitivity of different hyperalgesia and allodynia models of pharmacological treatment.A literature search was performed to identify randomized, double-blind, placebo-controlled studies that included human hyperalgesia pain models and investigated the pharmacodynamic effects of different classes of drugs.Three hyperalgesia models [ultraviolet B (UVB) irradiation, capsaicin and thermode burn] have been used extensively. Assessment of hyperalgesia/allodynia and pharmacological effect are measured using challenge tests, which generally comprise thermal (heat/cold) or mechanical stimulation (pin-prick, stroking or impact). The UVB model was sensitive to the antihyperalgesic effects of nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids. The capsaicin model was partially sensitive to opioids. The burn model did not detect any antihyperalgesic effects when NSAIDs or local anaesthetics were administered but responded to the effects of N-methyl D-aspartate (NMDA) receptor antagonists by moderately reducing mechanical hyperalgesia.Based on pharmacological sensitivity, the UVB model adequately reflects inflammatory pain and was sensitive to NSAIDs and opioids. Findings from the capsaicin and burn models raised questions about the translatability of these models to the treatment of neuropathic pain. There is a need for a reproducible and predictive model of neuropathic pain, either in healthy subjects or in patients.
A battery of pain models can be used in clinical trials to investigate the efficacy and to establish the concentration-effect relationship of novel analgesics. This study quantified the pharmacokinetics (PK) of pregabalin after a single oral dose of 300 mg and the pharmacodynamics (PD) on the pain tolerance threshold (PTT) of the cold pressor, electrical stimulation, the pressure pain model, and on the pain detection threshold of a contact heat pain model. The PK were best described using a one-compartment model with lag time, linear absorption, and linear elimination. The PTT of the cold pressor showed a negative linear decrease over time without pregabalin. A linear drug effect was identified on the PTT of the cold pressor test and an on/off effect for the electrical stimulation PTT. No PK/PD relationship could be identified on the pressure pain and heat pain test. Citation.
