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Age and Ageing May 2024An updated time-trend analysis of anti-dementia drugs (ADDs) is lacking. The aim of this study is to assess the incident rate (IR) of ADD in individuals with dementia...
BACKGROUND
An updated time-trend analysis of anti-dementia drugs (ADDs) is lacking. The aim of this study is to assess the incident rate (IR) of ADD in individuals with dementia using real-world data.
SETTING
Primary care data (country/database) from the UK/CPRD-GOLD (2007-20), Spain/SIDIAP (2010-20) and the Netherlands/IPCI (2008-20), standardised to a common data model.
METHODS
Cohort study. Participants: dementia patients ≥40 years old with ≥1 year of previous data. Follow-up: until the end of the study period, transfer out of the catchment area, death or incident prescription of rivastigmine, galantamine, donepezil or memantine. Other variables: age/sex, type of dementia, comorbidities. Statistics: overall and yearly age/sex IR, with 95% confidence interval, per 100,000 person-years (IR per 105 PY (95%CI)).
RESULTS
We identified a total of (incident anti-dementia users/dementia patients) 41,024/110,642 in UK/CPRD-GOLD, 51,667/134,927 in Spain/SIDIAP and 2,088/17,559 in the Netherlands/IPCI.In the UK, IR (per 105 PY (95%CI)) of ADD decreased from 2007 (30,829 (28,891-32,862)) to 2010 (17,793 (17,083-18,524)), then increased up to 2019 (31,601 (30,483 to 32,749)) and decrease in 2020 (24,067 (23,021-25,148)). In Spain, IR (per 105 PY (95%CI)) of ADD decreased by 72% from 2010 (51,003 (49,199-52,855)) to 2020 (14,571 (14,109-15,043)). In the Netherlands, IR (per 105 PY (95%CI)) of ADD decreased by 77% from 2009 (21,151 (14,967-29,031)) to 2020 (4763 (4176-5409)). Subjects aged ≥65-79 years and men (in the UK and the Netherlands) initiated more frequently an ADD.
CONCLUSIONS
Treatment of dementia remains highly heterogeneous. Further consensus in the pharmacological management of patients living with dementia is urgently needed.
Topics: Humans; Male; Female; Dementia; Aged; Aged, 80 and over; Middle Aged; Netherlands; Databases, Factual; Time Factors; Nootropic Agents; Spain; United Kingdom; Practice Patterns, Physicians'; Age Factors; Drug Utilization
PubMed: 38783756
DOI: 10.1093/ageing/afae106 -
BMC Public Health Jan 2024The South Korean government has been actively involved in plans to combat dementia, implementing a series of national strategies and plans since 2008. In July 2014,... (Observational Study)
Observational Study
Changes in dementia treatment patterns associated with changes in the National Policy in South Korea among patients with newly diagnosed Alzheimer's disease between 2011 and 2017: results from the multicenter, retrospective CAPTAIN study.
BACKGROUND
The South Korean government has been actively involved in plans to combat dementia, implementing a series of national strategies and plans since 2008. In July 2014, eligibility for mandatory long-term care insurance (LTCI) was extended to people with dementia enabling access to appropriate long-term care including the cognitive function training program and home nursing service. This study aimed to investigate changes in treatment patterns for Alzheimer's disease (AD) between July 2011 and June 2017 which spanned the 2014 revision.
METHODS
This multicenter, retrospective, observational study of patients with newly diagnosed AD analyzed electronic medical records from 17 general hospitals across South Korea. Based on their time of AD diagnosis, subjects were categorized into Cohort 1 (1 July 2011 to 30 June 2014) and Cohort 2 (1 July 2014 to 30 June 2017).
RESULTS
Subjects (N=3,997) divided into Cohorts 1 (n=1,998) and 2 (n=1,999), were mostly female (66.4%) with a mean age of 84.4 years. Cohort 1 subjects were significantly older (P<0.0001) and had a lower number of comorbidities (P=0.002) compared with Cohort 2. Mean Mini-Mental State Examination (MMSE) scores in Cohorts 1 and 2 at the time of AD diagnosis or start of initial treatment were 16.9 and 17.1, respectively (P=0.2790). At 1 year, mean MMSE scores in Cohorts 1 and 2 increased to 17.9 and 17.4, respectively (P=0.1524). Donepezil was the most frequently administered medication overall (75.0%), with comparable rates between cohorts. Rates of medication persistence were ≥98% for acetylcholinesterase inhibitor or memantine therapy. Discontinuation and switch treatment rates were significantly lower (49.7% vs. 58.0%; P<0.0001), and mean duration of initial treatment significantly longer, in Cohort 2 vs. 1 (349.3 vs. 300.2 days; P<0.0001).
CONCLUSIONS
Comparison of cohorts before and after revision of the national LTCI system for dementia patients found no significant difference in mean MMSE scores at the time of AD diagnosis or start of initial treatment. The reduction in the proportion of patients who discontinued or changed their initial treatment, and the significant increase in mean duration of treatment, were observed following revision of the LTCI policy which enabled increased patient access to long-term care.
Topics: Humans; Female; Aged, 80 and over; Male; Alzheimer Disease; Retrospective Studies; Acetylcholinesterase; Donepezil; Cholinesterase Inhibitors
PubMed: 38216922
DOI: 10.1186/s12889-024-17671-2 -
International Journal of Alzheimer's... 2024Alzheimer's disease (AD) is a "progressive, neurodegenerative disease that occurs when nerve cells in the brain die." There are only 4 drugs approved by the United...
Alzheimer's disease (AD) is a "progressive, neurodegenerative disease that occurs when nerve cells in the brain die." There are only 4 drugs approved by the United States Food and Drug Administration (FDA). Three (donepezil, rivastigmine, and galantamine) out of these four drugs are anticholinesterase inhibitors, while the fourth one memantine is an N-methyl-D-aspartate (NMDA) receptor inhibitor. Currently, two immunotherapy drugs that target amyloid protein (donanemab and lecanemab) are being considered for the treatment of Alzheimer's disease at an early stage. All these drug molecules are still not the complete answer to the treatment of Alzheimer's disease. A recent report from the Office of National Statistics showed that AD is the leading cause of death in 2022. Therefore, there is an urgency to develop more drugs that can treat AD. Based on this urgency, we aim to investigate how bioactive and already approved drugs could be repurposed for inhibiting the anticholinesterase enzyme using computational studies. To achieve this, the data science tool-Python coding was compiled on Jupyter Notebook to mine bioactive compounds from the ChEMBL database. The most bioactive compounds obtained were further investigated using Molecular Operating Environment (MOE) software to carry out molecular docking and ligand analysis, and this was followed by molecular dynamics simulation production at 35 ns using GROMACS 2022.4 on Archer 2 machine. The molecular dynamic analysis was carried out using HeroMDanalysis software. Data mining of the ChEMBL database was carried out for lipase inhibitors, and this gave CHEMBL-ID 1240685, a peptide molecule, the most active compound at the time of data mining. Further literature studies gave Zoladex an FDA-approved drug for the treatment of breast cancer as another compound of interest. The studies were carried out against the anticholinesterase enzyme using two FDA-approved drugs donepezil and galantamine as a template for comparing the activities of the repurposed drugs. A very useful receptor for this study was PDB-1DX6, a cocrystallized galantamine inhibitor of acetylcholinesterase enzyme. The molecular docking analysis (using ligand interactions) and molecular dynamic analysis (root mean square deviation (RMSD) and root mean square fluctuation (RMSF)) showed that the two peptide molecules CHEMBL-1240685 and Zoladex gave the best binding energy and stability when compared to the FDA-approved drugs (donepezil and galantamine). Finally, further literature studies revealed that Zoladex affects memory reduction; therefore, it was dropped as a possible repurposed drug. Our research showed that CHEMBL-1240685 is a potential compound that could be investigated for the inhibition of anticholinesterase enzyme and might be another drug molecule that could be used to treat Alzheimer's disease.
PubMed: 38371416
DOI: 10.1155/2024/2988685 -
European Journal of Medicinal Chemistry Mar 2024Neurodegenerative disorders of the central nervous system (CNS) such as Alzheimer's and Parkinson's diseases, afflict millions globally, posing a significant public...
Neurodegenerative disorders of the central nervous system (CNS) such as Alzheimer's and Parkinson's diseases, afflict millions globally, posing a significant public health challenge. Despite extensive research, a critical hurdle in effectively treating neurodegenerative diseases is the lack of neuroprotective drugs that can halt or reverse the underlying disease processes. In this work, we took advantage of the neuroprotective properties of the neuropeptide glycyl-l-prolyl-l-glutamic acid (Glypromate) for the development of new peptidomimetics using l-pipecolic acid as a proline surrogate and exploring their chemical conjugation with relevant active pharmaceutical ingredients (API) via a peptide bond. Together with prolyl-based Glypromate conjugates, a total of 36 conjugates were toxicologically and biologically evaluated. In this series, the results obtained showed that a constrained ring (l-proline) at the central position of the peptide motif accounts for enhanced toxicological profiles and biological effects using undifferentiated and differentiated human neuroblastoma SH-SY5Y cells. Additionally, it was shown that biased biological responses are API-dependent. Conjugation with (R)-1-aminoindane led to a 38-43% reduction of protein aggregation induced by Aβ (10 μM), denoting a 3.2-3.6-fold improvement in comparison with the parent neuropeptide, with no significative difference between functionalization at α and γ-carboxyl ends. On the other hand, the best-performing neuroprotective conjugate against the toxicity elicited by 6-hydroxydopamine (6-OHDA, 125 μM) was obtained by conjugation with memantine at the α-carboxyl end, resulting in a 2.3-fold improvement of the neuroprotection capacity in comparison with Glypromate neuropeptide. Altogether, the chemical strategy explored in this work shows that the neuroprotective capacity of Glypromate can be modified and fine-tuned, opening a new avenue for the development of biased neurotherapeutics for CNS-related disorders.
Topics: Humans; Neuroprotection; Cell Line, Tumor; Neuroblastoma; Neuroprotective Agents; Oxidopamine; Oligopeptides; Neurodegenerative Diseases; Neuropeptides; Apoptosis
PubMed: 38306884
DOI: 10.1016/j.ejmech.2024.116174 -
Magyar Onkologia Mar 2024In patients with poor performance status (KPS<50), ineligibility for effective systemic treatment and multiple brain metastases (BM) best supportive care is the...
In patients with poor performance status (KPS<50), ineligibility for effective systemic treatment and multiple brain metastases (BM) best supportive care is the preferred treatment over whole brain radiotherapy (WBRT). WBRT should be considered for the treatment of non-limited number (>4) brain metastases, depending on the patient's life expectancy, neurological symptoms, size, number and location of brain metastases, indication, type and availability of systemic therapy. In these patients if life expectancy is >4 months without small cell histology and without hippocampal lesions, hippocampal sparing WBRT with or without memantine is recommended. Simultaneous integrated boost for the BM is a logical and supportable concept. Prophylactic cranial irradiation (PCI) is still recommended in small cell lung cancer patients with complete remission. Hippocampal sparing WBRT needs further validation in this indication.
Topics: Humans; Brain Neoplasms; Brain; Treatment Outcome; Cranial Irradiation; Radiosurgery; Lung Neoplasms
PubMed: 38484376
DOI: No ID Found -
Cureus Apr 2024Malignant catatonia is a rare, life-threatening variant of catatonia requiring prompt treatment. Malignant catatonia is characterized by typical catatonia symptoms of...
Malignant catatonia is a rare, life-threatening variant of catatonia requiring prompt treatment. Malignant catatonia is characterized by typical catatonia symptoms of psychomotor, neurologic, and behavioral changes complicated by autonomic instability, with an estimated mortality rate of 50% or more when untreated. Electroconvulsive therapy (ECT) is considered the definitive and most effective treatment for malignant catatonia, with minimal literature on the efficacy of pharmacological interventions alone. Timely access to life-saving ECT may be limited in some hospitals due to restrictive laws on the use of ECT when the patient is incapacitated or due to lack of treatment availability. This case report describes the successful pharmacologic treatment of a patient with malignant catatonia where ECT was unobtainable due to legal restrictions and lack of access to treatment. The patient was initially commenced on lorazepam but continued to deteriorate, subsequently developing complications of aspiration pneumonia and colitis. The patient's malignant catatonia resolved with a combination of lorazepam, memantine, and a one-time dose of dantrolene. This complex case highlights the challenges of treating malignant catatonia in under-resourced systems or jurisdictions with restrictive ECT laws and adds additional data on the successful use of pharmacologic interventions for malignant catatonia where ECT is impractical or delayed.
PubMed: 38737995
DOI: 10.7759/cureus.58071 -
Research Square May 2024Preclinical methods are needed for screening potential Alzheimer's disease (AD) therapeutics that recapitulate phenotypes found in the Mild Cognitive Impairment (MCI)...
Preclinical methods are needed for screening potential Alzheimer's disease (AD) therapeutics that recapitulate phenotypes found in the Mild Cognitive Impairment (MCI) stage or even before this stage of the disease. This would require a phenotypic system that reproduces cognitive deficits without significant neuronal cell death to mimic the clinical manifestations of AD during these stages. A potential functional parameter to be monitored is long-term potentiation (LTP), which is a correlate of learning and memory, that would be one of the first functions effected by AD onset. Mature human iPSC-derived cortical neurons and primary astrocytes were co-cultured on microelectrode arrays (MEA) where surface chemistry was utilized to create circuit patterns connecting two adjacent electrodes to model LTP function. LTP maintenance was significantly reduced in the presence of Amyloid-Beta 42 (Aβ42) oligomers compared to the controls, however, co-treatment with AD therapeutics (Donepezil, Memantine, Rolipram and Saracatinib) corrected Aβ42 induced LTP impairment. The results presented here illustrate the significance of the system as a validated platform that can be utilized to model and study MCI AD pathology, and potentially for the pre-MCI phase before the occurrence of significant cell death. It also has the potential to become an ideal platform for high content therapeutic screening for other neurodegenerative diseases.
PubMed: 38826367
DOI: 10.21203/rs.3.rs-4313679/v1 -
Neuropsychopharmacology Reports Jun 2024Behavioral psychological symptoms of dementia (BPSD) are sometimes difficult to treat due to severe psychiatric symptoms such as delusions of poisoning and violent...
AIM
Behavioral psychological symptoms of dementia (BPSD) are sometimes difficult to treat due to severe psychiatric symptoms such as delusions of poisoning and violent behavior. Moreover, in cases of parental neglect, the management of these psychiatric symptoms becomes more difficult. Therefore, home-visiting doctors sometimes have to manage patients with BPSD and severe psychiatric symptoms, and a new approach is needed. In this case report, the effect of blonanserin transdermal patch on these patients is to be highlighted.
METHODS
The patient is a 91-year-old woman diagnosed with Alzheimer's disease. She had severe BPSD such as delusion of robbery and violent behavior, and refused oral medications including memantine and yokukansan. Then she was treated with blonanserin transdermal patch (20 mg/day). The severity of psychiatric symptoms of BPSD was assessed over time using the Neuropsychiatric Inventory (NPI) score. Moreover, the patient's cognitive function was also assessed over time by Mini-Mental State Examination (MMSE).
RESULTS
After the introduction of blonanserin patch, the patient's psychiatric symptoms were stabilized markedly, and both NPI and MMSE scores improved. The patient was able to stay at home calmly and was mentally well stabilized to the extent that she did not require hospitalization. No apparent side effects were admitted.
CONCLUSIONS
The blonanserin transdermal patch may be able to manage BPSD at home and is effective in patients who refuse oral medications. Home-visiting doctors may consider the use of blonanserin patches at home for patients with severe BPSD, manifesting as delusions of poisoning and refusing oral drugs.
Topics: Humans; Female; Piperidines; Aged, 80 and over; Transdermal Patch; Piperazines; Alzheimer Disease; Dementia; Treatment Outcome; Antipsychotic Agents
PubMed: 38558544
DOI: 10.1002/npr2.12434 -
Indian Journal of Psychological Medicine May 2024
PubMed: 38699773
DOI: 10.1177/02537176231181512 -
Analytical Science Advances Feb 2024In the development of bioanalytical methods, stabilizing drug molecules in biological matrices is crucial for ensuring reliable exposure data in pharmacokinetic and...
In the development of bioanalytical methods, stabilizing drug molecules in biological matrices is crucial for ensuring reliable exposure data in pharmacokinetic and toxicokinetic sample analyses. This study focuses on the evaluation of stabilizing effects on the synthetic triterpenoid TX101, a cyanoenone triterpenoid Nrf2 activator with known instability in plasma samples. The molecule's unsaturated double bond is susceptible to oxidation, either nonenzymatically via oxygen or enzymatically through cytochrome P450 enzyme-catalyzed epoxidation. The research explores the impact of antioxidants (L-ascorbic acid, sodium metabisulfite, sodium sulfite) and P450 enzyme inhibitors (sodium diethyldithiocarbamate, memantine hydrochloride, 1-aminobenzotriazole) on TX101 stability in rat plasma samples. Results reveal that adding 2.5 mg/mL sodium sulfite or sodium metabisulfite effectively inhibits the nonenzymatic oxidation of TX101 to TX101-epoxide, while L-ascorbic acid shows minimal stabilizing effect. Among P450 enzyme inhibitors, sodium diethyldithiocarbamate and memantine hydrochloride exhibit modest stabilizing effects, likely attributed to their antioxidant activity. The developed High-formance liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) method, incorporating Supported Liquid Extraction for sample cleanup, allows simultaneous monitoring of TX101 and TX101-epoxide. Application of this method in a rat dose-range finding study confirms successful inhibition of TX101-epoxide formation in samples treated with sodium sulfite or sodium metabisulfite. Overall, the study emphasizes the importance of stabilizers in preventing nonenzymatic oxidation reactions during sample storage, providing valuable insights for bioanalytical method development and validation.
PubMed: 38828082
DOI: 10.1002/ansa.202300058