AChE Inhibitors and NMDA Receptor Antagonists in Advanced Alzheimer's Disease

2017 ◽  
Vol 32 (9) ◽  
pp. 511-518 ◽  
Author(s):  
Brianna E. Glynn-Servedio ◽  
Trisha Seys Ranola
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Nmda Receptor ◽  
Nmda Receptor Antagonists ◽  
Receptor Antagonists ◽  
Ache Inhibitors

scholarly journals What is the impact of regulatory guidance and expiry of drug patents on dementia drug prescriptions in England: a trend analysis in the Clinical Practice Research Datalink

2017 ◽  
Author(s):  
Venexia M Walker ◽  
Neil M Davies ◽  
Patrick G Kehoe ◽  
Richard M Martin
Keyword(s):  
Nmda Receptor ◽  
Drug Class ◽  
Practice Research ◽  
Clinical Practice Research Datalink ◽  
Nmda Receptor Antagonists ◽  
Receptor Antagonists ◽  
Regulatory Guidance ◽  
Ache Inhibitors ◽  
Patent Expiry ◽  
Nice Guidance

Background: Drugs for dementia have been available in England from 1997. Since their launch, there have been several changes to national guidelines and initiatives that may have influenced prescribing. These include changes in National Institute for health and Care Excellence (NICE) guidance; several government dementia strategies; the addition of dementia to the Quality and Outcomes Framework (QOF); and the expiry of drug patents. Despite this, there has been little research into the effect of these events on prescribing. This paper examines prescribing trends in England using data from the UK Clinical Practice Research Datalink since the launch of drugs for dementia up to 1st January 2016. Methods: We considered the monthly proportion of patients eligible for treatment, with a diagnosis of probable Alzheimer’s disease, receiving their first prescription for each drug class – namely acetylcholinesterase (AChE) inhibitors (donepezil, rivastigmine, galantamine) and N-Methyl-D-aspartate (NMDA) receptor antagonists (memantine). Trend analysis using joinpoint models was then applied to identify up to two trend changes per treatment of interest. Results: The overall trend was for increasing prescriptions in each drug class over the period they were studied. This was indicated by the average monthly percentage change, which was 6.0% (95% CI: -6.4 to 19.9; June 1997 to December 2015) for AChE inhibitors and 15.4% (95% CI: -77.1 to 480.9; January 2003 to December 2015) for NMDA receptor antagonists. Prescriptions of AChE inhibitors increased at the end of 2012, probably in response to the patent expiry of these drugs earlier that year. The Prime Minister’s Dementia Challenge launched in May 2012 may also have contributed to the observed increase. However, neither this strategy nor patent expiry appeared to influence prescriptions of NMDA receptor antagonists. Instead trend changes in this drug class were driven by NICE guidance released in 2011 that allowed access to these drugs outside of clinical trials. Conclusions: Dementia drug prescribing does not always respond to factors such as regulatory guidance, recommendations or patent expiry and, when it does, not necessarily in a predictable way. This suggests that improved communication with clinicians may be needed to improve the cost-effective use of drugs for dementia.

scholarly journals Pursuing the Complexity of Alzheimer’s Disease: Discovery of Fluoren-9-Amines as Selective Butyrylcholinesterase Inhibitors and N-Methyl-d-Aspartate Receptor Antagonists

Biomolecules ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 3
Author(s):  
Jan Konecny ◽  
Anna Misiachna ◽  
Martina Hrabinova ◽  
Lenka Pulkrabkova ◽  
Marketa Benkova ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Nmda Receptor ◽  
In Silico ◽  
Docking Simulation ◽  
Initial Assessment ◽  
Unknown Etiology ◽  
Cholinesterase Inhibition ◽  
Symptomatic Therapy ◽  
Receptor Antagonists

Alzheimer’s disease (AD) is a complex disorder with unknown etiology. Currently, only symptomatic therapy of AD is available, comprising cholinesterase inhibitors and N-methyl-d-aspartate (NMDA) receptor antagonists. Drugs targeting only one pathological condition have generated only limited efficacy. Thus, combining two or more therapeutic interventions into one molecule is believed to provide higher benefit for the treatment of AD. In the presented study, we designed, synthesized, and biologically evaluated 15 novel fluoren-9-amine derivatives. The in silico prediction suggested both the oral availability and permeation through the blood–brain barrier (BBB). An initial assessment of the biological profile included determination of the cholinesterase inhibition and NMDA receptor antagonism at the GluN1/GluN2A and GluN1/GluN2B subunits, along with a low cytotoxicity profile in the CHO-K1 cell line. Interestingly, compounds revealed a selective butyrylcholinesterase (BChE) inhibition pattern with antagonistic activity on the NMDARs. Their interaction with butyrylcholinesterase was elucidated by studying enzyme kinetics for compound 3c in tandem with the in silico docking simulation. The docking study showed the interaction of the tricyclic core of new derivatives with Trp82 within the anionic site of the enzyme in a similar way as the template drug tacrine. From the kinetic analysis, it is apparent that 3c is a competitive inhibitor of BChE.

scholarly journals What is the impact of regulatory guidance and expiry of drug patents on dementia drug prescriptions in England: a trend analysis in the Clinical Practice Research Datalink

2017 ◽  
Author(s):  
Venexia M Walker ◽  
Neil M Davies ◽  
Patrick G Kehoe ◽  
Richard M Martin
Keyword(s):  
Nmda Receptor ◽  
Drug Class ◽  
Practice Research ◽  
Clinical Practice Research Datalink ◽  
Nmda Receptor Antagonists ◽  
Receptor Antagonists ◽  
Regulatory Guidance ◽  
Ache Inhibitors ◽  
Patent Expiry ◽  
Nice Guidance

Background: Drugs for dementia have been available in England from 1997. Since their launch, there have been several changes to national guidelines and initiatives that may have influenced prescribing. These include changes in National Institute for health and Care Excellence (NICE) guidance; several government dementia strategies; the addition of dementia to the Quality and Outcomes Framework (QOF); and the expiry of drug patents. Despite this, there has been little research into the effect of these events on prescribing. This paper examines prescribing trends in England using data from the UK Clinical Practice Research Datalink since the launch of drugs for dementia up to 1st January 2016. Methods: We considered the monthly proportion of patients eligible for treatment, with a diagnosis of probable Alzheimer’s disease, receiving their first prescription for each drug class – namely acetylcholinesterase (AChE) inhibitors (donepezil, rivastigmine, galantamine) and N-Methyl-D-aspartate (NMDA) receptor antagonists (memantine). Trend analysis using joinpoint models was then applied to identify up to two trend changes per treatment of interest. Results: The overall trend was for increasing prescriptions in each drug class over the period they were studied. This was indicated by the average monthly percentage change, which was 6.0% (95% CI: -6.4 to 19.9; June 1997 to December 2015) for AChE inhibitors and 15.4% (95% CI: -77.1 to 480.9; January 2003 to December 2015) for NMDA receptor antagonists. Prescriptions of AChE inhibitors increased at the end of 2012, probably in response to the patent expiry of these drugs earlier that year. The Prime Minister’s Dementia Challenge launched in May 2012 may also have contributed to the observed increase. However, neither this strategy nor patent expiry appeared to influence prescriptions of NMDA receptor antagonists. Instead trend changes in this drug class were driven by NICE guidance released in 2011 that allowed access to these drugs outside of clinical trials. Conclusions: Dementia drug prescribing does not always respond to factors such as regulatory guidance, recommendations or patent expiry and, when it does, not necessarily in a predictable way. This suggests that improved communication with clinicians may be needed to improve the cost-effective use of drugs for dementia.

Use of Both Fluoro-Jade B and Hematoxylin and Eosin to Detect Cell Death in the Juvenile Rat Brain Exposed to NMDA-Receptor Antagonists or GABA-Receptor Agonists in Safety Assessment

2021 ◽  
pp. 019262332110077
Author(s):  
Catherine A. Picut ◽  
Odete R. Mendes ◽  
David S. Weil ◽  
Sarah Davis ◽  
Cynthia Swanson
Keyword(s):  
Cell Death ◽  
Nmda Receptor ◽  
Rat Brain ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Nmda Receptor Antagonists ◽  
Neonatal Rats ◽  
Receptor Antagonists ◽  
Fluoro Jade B ◽  
Hematoxylin And Eosin

Administration of pediatric anesthetics with N-methyl D-aspartate (NMDA)-receptor antagonist and/or γ-aminobutyric acid (GABA) agonist activities may result in neuronal degeneration and/or neuronal cell death in neonatal rats. Evaluating pediatric drug candidates for this potential neurotoxicity is often part of overall preclinical new drug development strategy. This specialized assessment may require dosing neonatal rats at postnatal day 7 at the peak of the brain growth spurt and evaluating brain tissue 24 to 48 hours following dosing. The need to identify methods to aid in the accurate and reproducible detection of lesions associated with this type of neurotoxic profile is paramount for meeting the changing needs of neuropathology assessment and addressing emerging challenges in the neuroscience field. We document the use of Fluoro-Jade B (FJB) staining, to be used in conjunction with standard hematoxylin and eosin staining, to detect acute neurodegeneration and neuronal cell death that can be caused by some NMDA-receptor antagonists and/or GABA agonists in the neonatal rat brain. The FJB staining is simple, specific, and sensitive and can be performed on brain specimens from the same cohort of animals utilized for standard neurotoxicity assessment, thus satisfying animal welfare recommendations with no effect on achievement of scientific and regulatory goals.

scholarly journals Exploitation of Marine Molecules to Manage Alzheimer’s Disease

Marine Drugs ◽  
2021 ◽  
Vol 19 (7) ◽  
pp. 373
Author(s):  
Marisa Silva ◽  
Paula Seijas ◽  
Paz Otero
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Senile Plaques ◽  
Nmda Receptor Antagonists ◽  
Average Life ◽  
Average Life Expectancy ◽  
Large Reservoir ◽  
Drug Candidates ◽  
Neurodegenerative Process ◽  
Main Action

Neurodegenerative diseases are sociosanitary challenges of today, as a result of increased average life expectancy, with Alzheimer’s disease being one of the most prevalent. This pathology is characterized by brain impairment linked to a neurodegenerative process culminating in cognitive decline and behavioral disorders. Though the etiology of this pathology is still unknown, it is usually associated with the appearance of senile plaques and neurofibrillary tangles. The most used prophylaxis relies on anticholinesterase drugs and NMDA receptor antagonists, whose main action is to relieve symptoms and not to treat or prevent the disease. Currently, the scientific community is gathering efforts to disclose new natural compounds effective against Alzheimer’s disease and other neurodegenerative pathologies. Marine natural products have been shown to be promising candidates, and some have been proven to exert a high neuroprotection effect, constituting a large reservoir of potential drugs and nutraceutical agents. The present article attempts to describe the processes of extraction and isolation of bioactive compounds derived from sponges, algae, marine bacteria, invertebrates, crustaceans, and tunicates as drug candidates against AD, with a focus on the success of pharmacological activity in the process of finding new and effective drug compounds.

scholarly journals Structural basis of subunit selectivity for competitive NMDA receptor antagonists with preference for GluN2A over GluN2B subunits

2017 ◽  
Vol 114 (33) ◽  
pp. E6942-E6951 ◽  
Author(s):  
Genevieve E. Lind ◽  
Tung-Chung Mou ◽  
Lucia Tamborini ◽  
Martin G. Pomper ◽  
Carlo De Micheli ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Binding Affinity ◽  
Binding Mode ◽  
Structural Basis ◽  
Nmda Receptor Antagonists ◽  
Receptor Antagonists ◽  
Glutamate Binding ◽  
Subunit Interface ◽  
The Central Nervous System ◽  
Contact Residues

NMDA-type glutamate receptors are ligand-gated ion channels that contribute to excitatory neurotransmission in the central nervous system (CNS). Most NMDA receptors comprise two glycine-binding GluN1 and two glutamate-binding GluN2 subunits (GluN2A–D). We describe highly potent (S)-5-[(R)-2-amino-2-carboxyethyl]-4,5-dihydro-1H-pyrazole-3-carboxylic acid (ACEPC) competitive GluN2 antagonists, of which ST3 has a binding affinity of 52 nM at GluN1/2A and 782 nM at GluN1/2B receptors. This 15-fold preference of ST3 for GluN1/2A over GluN1/2B is improved compared with NVP-AAM077, a widely used GluN2A-selective antagonist, which we show has 11-fold preference for GluN1/2A over GluN1/2B. Crystal structures of the GluN1/2A agonist binding domain (ABD) heterodimer with bound ACEPC antagonists reveal a binding mode in which the ligands occupy a cavity that extends toward the subunit interface between GluN1 and GluN2A ABDs. Mutational analyses show that the GluN2A preference of ST3 is primarily mediated by four nonconserved residues that are not directly contacting the ligand, but positioned within 12 Å of the glutamate binding site. Two of these residues influence the cavity occupied by ST3 in a manner that results in favorable binding to GluN2A, but occludes binding to GluN2B. Thus, we reveal opportunities for the design of subunit-selective competitive NMDA receptor antagonists by identifying a cavity for ligand binding in which variations exist between GluN2A and GluN2B subunits. This structural insight suggests that subunit selectivity of glutamate-site antagonists can be mediated by mechanisms in addition to direct contributions of contact residues to binding affinity.

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