Klaassen ES

References (5)

Title : Safety and Pharmacokinetics of HTL0018318, a Novel M(1) Receptor Agonist, Given in Combination with Donepezil at Steady State: A Randomized Trial in Healthy Elderly Subjects - Bakker_2021_Drugs.R.D__
Author(s) : Bakker C , van der Aart J , Labots G , Liptrot J , Cross DM , Klaassen ES , Dickinson S , Tasker T , Groeneveld GJ
Ref : Drugs R D , : , 2021
Abstract : INTRODUCTION: HTL0018318 is a selective muscarinic M(1) receptor partial agonist under development for the symptomatic treatment of dementias, including Alzheimer's disease. Clinically, HTL0018318 would likely be used alone or in conjunction with cholinesterase inhibitors (e.g. donepezil). OBJECTIVE: We investigated the safety, tolerability, and pharmacokinetics of HTL0018318 given alone and in combination with donepezil. METHODS: This was a randomized, double-blind, placebo-controlled trial in 42 (to deliver 36 with combination treatment) healthy elderly subjects investigating the effects of oral HTL0018318 15 and 25 mg given alone and combined with donepezil 10 mg at steady state on adverse events (AEs), vital signs, saliva production, sleep quality, pulmonary function, subjective feelings, and pharmacokinetics. RESULTS: AEs were reported by lower percentages of subjects after HTL0018318 alone than after donepezil alone. There was no increase in the percentage of subjects reporting AEs after co-administration than after donepezil alone. Supine systolic blood pressure was 1.6 mmHg (95% confidence interval [CI] -3.1 to -0.1) lower after HTL0018318 alone than after combination treatment. This was comparable with results from placebo alone: 1.7 mmHg (95% CI -3.2 to 0.2) lower than with combination treatment. Supine pulse rate was 3.3 bpm (95% CI 1.5-5.1) higher after HTL0018318 alone than with co-administration. HTL0018318 and donepezil did not meaningfully affect each other's pharmacokinetics. CONCLUSION: HTL0018318 was well tolerated when given alone and in combination with donepezil. HTL0018318 and donepezil do not demonstrate pharmacokinetic or pharmacodynamic interactions, indicating that HTL0018318 can be safely administered in combination with donepezil. CLINICAL TRIAL REGISTRATION: Netherlands Trial register identifier NL5915, registered on 28 October 2016.
ESTHER : Bakker_2021_Drugs.R.D__
PubMedSearch : Bakker_2021_Drugs.R.D__
PubMedID: 34164794

Title : Safety, pharmacokinetics, and pharmacodynamics of Gln-1062, a prodrug of galantamine - Bakker_2020_Alzheimers.Dement.(N.Y)_6_e12093
Author(s) : Bakker C , van der Aart J , Hart EP , Klaassen ES , Bergmann KR , van Esdonk MJ , Kay DG , Groeneveld GJ
Ref : Alzheimers Dement (N Y) , 6 :e12093 , 2020
Abstract : INTRODUCTION: Gln-1062 (MEMOGAIN) is an intranasally administered lipophilic prodrug of galantamine. Based on high brain-to-blood concentrations observed in pre-clinical studies, Gln-1062 is expected to have superior cognitive efficacy compared to oral galantamine. METHODS: Forty-eight healthy elderly subjects were randomized 12:4 to Gln-1062 (5.5, 11, or 22 mg, b.i.d., for 7 days) or placebo. Safety, tolerability, pharmacokinetics, and pharmacodynamics were assessed repeatedly. Pharmacokinetics were compared with 16 mg oral galantamine. RESULTS: Gln-1062 up to 22 mg, b.i.d., was well tolerated. Gln-1062 plasma concentrations increased immediately following dosing (median T(max) of 0.5 hour [range 0.5-1.0]). C(max) and AUC(0-last) increased in a dose-linear manner over all three dose levels. Gln-1062 was rapidly cleaved into galantamine. Gln-1062 significantly improved adaptive tracking (sustained attention) with 1.95% (95% confidence interval [CI] 0.630-3.279, P = 0.0055) compared to placebo after correction for individual baseline performance. DISCUSSION: Gln-1062 was considered to be safe and caused fewer gastrointestinal side effects than oral galantamine. Gln-1062 behaved pharmacokinetically as expected and improved performance on cognitive tests.
ESTHER : Bakker_2020_Alzheimers.Dement.(N.Y)_6_e12093
PubMedSearch : Bakker_2020_Alzheimers.Dement.(N.Y)_6_e12093
PubMedID: 33083515

Title : Cholinergic and serotonergic modulation of resting state functional brain connectivity in Alzheimer's disease - Klaassens_2019_Neuroimage_199_143
Author(s) : Klaassens BL , van Gerven JMA , Klaassen ES , van der Grond J , Rombouts S
Ref : Neuroimage , 199 :143 , 2019
Abstract : 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. Connectivity maps of ten functional networks were extracted using a dual regression method and drug vs. placebo effects were compared between groups with a multivariate analysis with signals coming from cerebrospinal fluid and white matter as covariates at the subject level, and baseline and heart rate measurements as confound regressors in the higher-level analysis (at p<0.05, corrected). A galantamine induced difference between groups was observed for the cerebellar network. Connectivity within the cerebellar network and between this network and the thalamus decreased after galantamine vs. placebo in AD patients, but not in controls. For citalopram, voxelwise network connectivity did not show significant groupxtreatment interaction effects. However, we found default mode network connectivity with the precuneus and posterior cingulate cortex to be increased in AD patients, which could not be detected within the control group. Further, in contrast to the AD patients, control subjects showed a consistent reduction in mean connectivity with all networks after administration of citalopram. Since AD has previously been characterized by reduced connectivity between the default mode network and the precuneus and posterior cingulate cortex, the effects of citalopram on the default mode network suggest a restoring potential of selective serotonin reuptake inhibitors in AD. The results of this study also confirm a change in cerebellar connections in AD, which is possibly related to cholinergic decline.
ESTHER : Klaassens_2019_Neuroimage_199_143
PubMedSearch : Klaassens_2019_Neuroimage_199_143
PubMedID: 31112788

Title : Serotonergic and cholinergic modulation of functional brain connectivity: A comparison between young and older adults - Klaassens_2018_Neuroimage_169_312
Author(s) : Klaassens BL , van Gerven JMA , Klaassen ES , van der Grond J , Rombouts S
Ref : Neuroimage , 169 :312 , 2018
Abstract : 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 (30mg) and the acetylcholinesterase inhibitor galantamine (8mg) was measured in 12 young and 17 older volunteers during a randomized, double blind, placebo-controlled, crossover study. A powerful dataset consisting of 522 RS-fMRI scans was obtained by acquiring multiple scans per subject before and after drug administration. Groupxtreatment interaction effects on voxelwise connectivity with ten functional networks were investigated (p<.05, FWE-corrected) using a non-parametric multivariate analysis technique with cerebrospinal fluid, white matter, heart rate and baseline measurements as covariates. Both groups showed a decrease in sensorimotor network connectivity after citalopram administration. The comparable findings after citalopram intake are possibly due to relatively similar serotonergic systems in the young and older subjects. Galantamine altered connectivity between the occipital visual network and regions that are implicated in learning and memory in the young subjects. The lack of a cholinergic response in the elderly might relate to the well-known association between cognitive and cholinergic deterioration at older age.
ESTHER : Klaassens_2018_Neuroimage_169_312
PubMedSearch : Klaassens_2018_Neuroimage_169_312
PubMedID: 29258890

Title : First in human study with a prodrug of galantamine: Improved benefit-risk ratio? - Baakman_2016_Alzheimers.Dement.(N.Y)_2_13
Author(s) : Baakman AC , t Hart E , Kay DG , Stevens J , Klaassen ES , Maelicke A , Groeneveld GJ
Ref : Alzheimers Dement (N Y) , 2 :13 , 2016
Abstract : INTRODUCTION: Gln-1062 (Memogain) is a pharmacologically inactive prodrug of galantamine. Owing to its lipophilic nature, it preferentially enters the brain, where it is cleaved into active galantamine. Gln-1062 is expected to have fewer peripheral side effects than other cholinesterase inhibitors, with improved effectiveness.
METHODS: This was a double-blind, comparator and placebo-controlled, sequential cohort, single ascending dose study in 58 healthy subjects with Gln-1062 in doses of 5.5, 11, 22, 33, and 44 mg, compared with oral galantamine 16 mg and donepezil 10 mg. Safety, tolerability, pharmacokinetics, and pharmacodynamics were assessed.
RESULTS: Gln-1062 doses up to 33 mg were well tolerated and induced a dose-dependent increase in the plasma concentrations of Gln-1062 and galantamine. Gln-1062 had a dose-dependent positive effect on verbal memory and attention, mainly in the first hours after drug administration. DISCUSSION: Gln-1062 was better tolerated than galantamine in doses with the same molarity and led to improved effects in cognitive tests. This is most likely caused by the more favorable distribution ratio between peripheral and central cholinesterase inhibition. These results give reason for further exploration of this compound.
ESTHER : Baakman_2016_Alzheimers.Dement.(N.Y)_2_13
PubMedSearch : Baakman_2016_Alzheimers.Dement.(N.Y)_2_13
PubMedID: 29067291