scholarly journals Dementia Management Act and Death Toll by Dementia Drug

2021 ◽  
Author(s):  
Jong-hoon Lee
Keyword(s):  
Nmda Receptor ◽  
South Korea ◽  
Acetylcholinesterase Inhibitors ◽  
Medical Data ◽  
Nmda Receptor Antagonists ◽  
Receptor Antagonists ◽  
Death Toll ◽  
Dementia Patients ◽  
Psychotropic Medicines ◽  
All Cause Mortality

Abstract The Dementia Management Act (DMA) came into effect on August 4, 2011, in South Korea. Medical data on the correlation between Alzheimer's disease (AD) and anti-AD drug (AAD) groups were observed from 2010 to 2019. This study investigated the increase and decrease in deaths and AAD used to treat AD. It is known that psychotropic medicines should not be administered for dementia patients because they increase all-cause mortality. This study demonstrated that acetylcholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists increase the death toll when used to treat dementia.

scholarly journals Dementia Management Act and Death Toll by Dementia Drug

2021 ◽  
Author(s):  
Jong-hoon Lee
Keyword(s):  
Nmda Receptor ◽  
South Korea ◽  
Receptor Antagonist ◽  
Acetylcholinesterase Inhibitors ◽  
Nmda Receptor Antagonist ◽  
Medical Data ◽  
Death Toll ◽  
Dementia Patients ◽  
Psychotropic Medicines ◽  
All Cause Mortality

Abstract The Dementia Management Act (DMA) came into effect on August 04, 2011, in South Korea. Medical data on the correlation between Alzheimer's disease (AD) and anti-AD drug (AAD) groups were observed from 2010 to 2019. This study investigated the increase and decrease in deaths and AAD used to treat AD. It is known that psychotropic medicines should not be administered for dementia patients because they increase all-cause mortality. This study demonstrated that acetylcholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonist also increase the death toll when used to treat dementia.

scholarly journals Dementia Management Act and Death Toll by Dementia Drug

2021 ◽  
Author(s):  
Jong-hoon Lee
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
South Korea ◽  
Acetylcholinesterase Inhibitors ◽  
Medical Data ◽  
Death Toll ◽  
Dementia Patients ◽  
Psychotropic Medicines ◽  
All Cause Mortality

Abstract The Dementia Management Act (DMA) came into effect on August 04 2011, South Korea. Medical data on the correlation between Alzheimer's disease (AD) and anti-AD drugs (AAD) groups were observed from 2010 to 2019. This study investigated the increase and decrease of deaths and AAD used to treat AD. It is known that psychotropic medicines should not be administered for dementia patients because they increase all-cause mortality. This study demonstrated that acetylcholinesterase inhibitors also increase the death toll when used to treat dementia.

scholarly journals Safety of Cholinesterase Inhibitors and NMDA Receptors Antagonists for the Treatment of Patients with Dementia

2019 ◽  
Vol 7 (4) ◽  
pp. 190-199
Author(s):  
A. P. Pereverzev ◽  
O. D. Ostroumova ◽  
O. N. Tkacheva ◽  
Y. V. Kotovskaya
Keyword(s):  
Nmda Receptor ◽  
Nmda Receptors ◽  
Adverse Drug Reactions ◽  
Cholinesterase Inhibitors ◽  
Acetylcholinesterase Inhibitors ◽  
Competitive Inhibitor ◽  
Nmda Receptor Antagonists ◽  
Drug Reactions ◽  
Receptor Antagonists ◽  
Increased Risk

For the treatment of dementia and Alzheimer’s disease, acetylcholinesterase inhibitors (donepezil, rivastigmine, galantamine) and/or the non-competitive inhibitor of N-methyl-D-aspartate receptors (NMDA receptors) memantine are currently used. The administration of these drugs can help temporarily improve or stabilize memory impairments and other cognitive functions, regress behavioral disorders, reduce the patient’s dependence on others, but at the same time can lead to the development of adverse drug reactions. The aim of this study was to analyze the information on the safety of acetylcholinesterase inhibitors (donepezil, rivastigmine, galantamine) and the non-competitive inhibitor of NMDA receptors used to treat dementia. It was shown that stimulation of cholinergic receptors can lead to adverse drug reactions as contraction and narrowing of the pupil (miosis), an increase in lens curvature, accommodation spasm (visual impairment and an increased risk of falls), a decrease in heart rate (bradycardia) and inhibition of conduction of impulses through the conducting system heart, increased tone of the bronchi, gastrointestinal tract, gall and bladder, decreased tone of the sphincters of the digestive tract and bladder, increased secretion of exocrine and glands of the stomach, agitation, confusion. Blockade of NMDA receptors due to impairment of glutamate metabolism in the central nervous system may be the cause of neurotoxicity of NMDA receptor antagonists, and also causes dizziness, feeling of tiredness, hallucinations, drowsiness, and confusion. In case of development of adverse reactions, if possible, it is necessary to stop using the drug or reduce its dose, in case of an overdose or other need, prescribe symptomatic therapy. Information on the safety of cholinesterase inhibitors and NMDA receptor antagonists presented in the article is of practical importance for healthcare professionals, as it allows them to assess the possible risks associated with the use of drugs of these groups more accurately. In addition, the information can be used to optimize and individualize the pharmacotherapy regimens for patients with dementia, including the development of domestic protocols for the deprescribing of drugs (evidence-based practice of withdrawal, replacement or gradual dose reduction) in the elderly. 

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 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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