OBJECTIVES: Decision-analytic models assessing the value of emerging Alzheimer's disease (AD) treatments are challenged by limited evidence on short-term trial outcomes and uncertainty in extrapolating long-term patient-relevant outcomes. To improve understanding and foster transparency and credibility in modeling methods, we cross-compared AD decision models in a hypothetical context of disease-modifying treatment for mild cognitive impairment (MCI) due to AD. METHODS: A benchmark scenario (US setting) was used with target population MCI due to AD and a set of synthetically generated hypothetical trial efficacy estimates. Treatment costs were excluded. Model predictions (10-year horizon) were assessed and discussed during a 2-day workshop. RESULTS: Nine modeling groups provided model predictions. Implementation of treatment effectiveness varied across models based on trial efficacy outcome selection (clinical dementia rating - sum of boxes, clinical dementia rating - global, mini-mental state examination, functional activities questionnaire) and analysis method (observed severity transitions, change from baseline, progression hazard ratio, or calibration to these). Predicted mean time in MCI ranged from 2.6 to 5.2 years for control strategy and from 0.1 to 1.0 years for difference between intervention and control strategies. Predicted quality-adjusted life-year gains ranged from 0.0 to 0.6 and incremental costs (excluding treatment costs) from -US$66 897 to US$11 896. CONCLUSIONS: Trial data can be implemented in different ways across health-economic models leading to large variation in model predictions. We recommend (1) addressing the choice of outcome measure and treatment effectiveness assumptions in sensitivity analysis, (2) a standardized reporting table for model predictions, and (3) exploring the use of registries for future AD treatments measuring long-term disease progression to reduce uncertainty of extrapolating short-term trial results by health-economic models.
- MeSH
- Alzheimerova nemoc * ekonomika farmakoterapie MeSH
- analýza nákladů a výnosů * MeSH
- ekonomické modely MeSH
- kognitivní dysfunkce * ekonomika MeSH
- kvalitativně upravené roky života MeSH
- lidé MeSH
- metody pro podporu rozhodování MeSH
- progrese nemoci MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
Berberine (BBR), a small molecule protoberberine isoquinoline alkaloid, is easy to cross the blood-brain barrier and is a potential drug for neurodegenerative diseases. Here, we explored the role and molecular mechanism of BBR in Alzheimer's disease (AD) progression. Weighted gene co-expression network analysis (WGCNA) was conducted to determine AD pathology-associated gene modules and differentially expressed genes (DEGs) were also identified. GO and KEGG analyses were performed for gene function and signaling pathway annotation. Cell counting kit-8 (CCK8) assay was applied to analyze cell viability. Immunofluorescence (IF) staining assay was conducted to measure the levels of polarization markers. The production of inflammatory cytokines was analyzed by enzyme-linked immunosorbent assay (ELISA). Reactive oxygen species (ROS) level and mitochondrial membrane potential (MMP) were detected using a ROS detection kit and a MMP Detection Kit (JC-1), respectively. AD pathology-associated DEGs were applied for GO function annotation and KEGG enrichment analysis, and the results uncovered that AD pathology was related to immune and inflammation. Lipopolysaccharide (LPS) exposure induced the M1 phenotype of microglia, and BBR suppressed LPS-induced M1 polarization and induced microglia toward M2 polarization. Through co-culture of microglia and neuronal cells, we found that BBR exerted a neuro-protective role by attenuating the injury of LPS-induced HMC3 on SH-SY5Y cells. Mechanically, BBR switched the M1/M2 phenotypes of microglia by activating PI3K-AKT signaling. In summary, BBR protected neuronal cells from activated microglia-mediated neuro-inflammation by switching the M1/M2 polarization in LPS-induced microglia via activating PI3K-AKT signaling. Key words Alzheimer's Disease, Berberine, Microglia polarization, Neuroinflammation, PI3K-AKT signaling.
- MeSH
- Alzheimerova nemoc * metabolismus farmakoterapie patologie MeSH
- berberin * farmakologie terapeutické užití MeSH
- fosfatidylinositol-3-kinasy * metabolismus MeSH
- lidé MeSH
- mikroglie * účinky léků metabolismus MeSH
- myši MeSH
- neuroprotektivní látky * farmakologie MeSH
- polarita buněk účinky léků MeSH
- protoonkogenní proteiny c-akt * metabolismus MeSH
- signální transdukce * účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Alzheimer's disease (AD) is the most common form of dementia. Characterized by progressive neurodegeneration, AD typically begins with mild cognitive decline escalating to severe impairment in communication and responsiveness. It primarily affects cerebral regions responsible for cognition, memory, and language processing, significantly impeding the functional independence of patients. With nearly 50 million dementia cases worldwide, a number expected to triple by 2050, the need for effective treatments is more urgent than ever. Recent insights into the association between obesity, type 2 diabetes mellitus, and neurodegenerative disorders have led to the development of promising treatments involving antidiabetic and anti-obesity agents. One such novel promising candidate for addressing AD pathology is a lipidized analogue of anorexigenic peptide called prolactin-releasing peptide (palm11-PrRP31). Interestingly, anorexigenic and orexigenic peptides have opposite effects on food intake regulation, however, both types exhibit neuroprotective properties. Recent studies have also identified ghrelin, an orexigenic peptide, as a potential neuroprotective agent. Hence, we employed both anorexigenic and orexigenic compounds to investigate the common mechanisms underpinning their neuroprotective effects in a triple transgenic mouse model of AD (3xTg-AD mouse model) combining amyloid-beta (Aβ) pathology and Tau pathology, two hallmarks of AD. We treated 3xTg-AD mice for 4 months with two stable lipidized anorexigenic peptide analogues - palm11-PrRP31, and liraglutide, a glucagon-like peptide 1 (GLP-1) analogue - as well as Dpr3-ghrelin, a stable analogue of the orexigenic peptide ghrelin, and using the method of immunohistochemistry and western blot demonstrate the effects of these compounds on the development of AD-like pathology in the brain. Palm11-PrRP31, Dpr3-ghrelin, and liraglutide reduced intraneuronal deposits of Aβ plaque load in the hippocampi and amygdalae of 3xTg-AD mice. Palm11-PrRP31 and Dpr3-ghrelin reduced microgliosis in the hippocampi, amygdalae, and cortices of 3xTg-AD mice. Palm11-PrRP31 and liraglutide reduced astrocytosis in the amygdalae of 3xTg-AD mice. We propose that these peptides are involved in reducing inflammation, a common mechanism underlying their therapeutic effects. This is the first study to demonstrate improvements in AD pathology following the administration of both orexigenic and anorexigenic compounds, highlighting the therapeutic potential of food intake-regulating peptides in neurodegenerative disorders.
- MeSH
- Alzheimerova nemoc * farmakoterapie metabolismus patologie MeSH
- amyloidní beta-protein metabolismus MeSH
- amyloidový prekurzorový protein beta genetika metabolismus MeSH
- ghrelin farmakologie analogy a deriváty terapeutické užití metabolismus MeSH
- hormon uvolňující prolaktin * analogy a deriváty farmakologie MeSH
- lidé MeSH
- liraglutid farmakologie terapeutické užití MeSH
- modely nemocí na zvířatech * MeSH
- myši inbrední C57BL MeSH
- myši transgenní * MeSH
- myši MeSH
- neuroprotektivní látky farmakologie terapeutické užití MeSH
- neurozánětlivé nemoci farmakoterapie metabolismus MeSH
- presenilin-1 genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Biomarkers are the most significant diagnosis tools tending towards unique approaches and solutions for the prevention and cure of Alzheimer's Disease (AD). The current report provides a clear perception of the concept of various biomarkers and their prominent features through analysis to provide a possible solution for the inhibition of events in AD. Scientists around the world truly believe that crucial hallmarks can serve as critical tools in the early diagnosis, cure, and prevention, as well as the future of medicine. The awareness and understanding of such biomarkers would provide solutions to the puzzled mechanism of this neuronal disorder. Some of the argued biomarkers in the present article are still in an experimental phase as they need to undergo specific clinical trials before they can be considered for treatment.
- MeSH
- Alzheimerova nemoc * farmakoterapie diagnóza metabolismus MeSH
- amyloidní beta-protein metabolismus antagonisté a inhibitory MeSH
- biologické markery * analýza metabolismus MeSH
- lidé MeSH
- proteiny tau metabolismus antagonisté a inhibitory MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- MeSH
- Alzheimerova nemoc farmakoterapie patofyziologie MeSH
- bipolární porucha farmakoterapie patofyziologie MeSH
- centrální nervový systém * fyziologie MeSH
- deprese farmakoterapie patofyziologie MeSH
- klinická studie jako téma MeSH
- kyselina arachidonová fyziologie MeSH
- kyseliny dokosahexaenové farmakologie fyziologie terapeutické užití MeSH
- lidé MeSH
- mozek embryologie růst a vývoj MeSH
- nenasycené mastné kyseliny * farmakologie fyziologie terapeutické užití MeSH
- neurodegenerativní nemoci farmakoterapie klasifikace patofyziologie MeSH
- novorozenec MeSH
- Parkinsonova nemoc farmakoterapie patofyziologie MeSH
- schizofrenie farmakoterapie patofyziologie MeSH
- Check Tag
- lidé MeSH
- novorozenec MeSH
- Publikační typ
- přehledy MeSH
- Klíčová slova
- lecanemab,
- MeSH
- Alzheimerova nemoc * farmakoterapie MeSH
- demence * etiologie prevence a kontrola MeSH
- humanizované monoklonální protilátky farmakologie terapeutické užití MeSH
- lidé MeSH
- rizikové faktory MeSH
- schvalování léčiv MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- novinové články MeSH
- zprávy MeSH
- Klíčová slova
- EGb 761,
- MeSH
- Alzheimerova nemoc farmakoterapie MeSH
- cholinesterasové inhibitory farmakologie terapeutické užití MeSH
- demence farmakoterapie MeSH
- extrakt z ginkgo * terapeutické užití MeSH
- kognitivní dysfunkce * farmakoterapie MeSH
- kombinovaná farmakoterapie * MeSH
- lidé MeSH
- memantin farmakologie terapeutické užití MeSH
- nootropní látky terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Klíčová slova
- valiltramiprosat,
- MeSH
- Alzheimerova nemoc * farmakoterapie MeSH
- amyloidní beta-protein účinky léků MeSH
- klinické zkoušky, fáze II jako téma MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- novinové články MeSH
- zprávy MeSH
Článek upozorňuje na závažnost problematiky syndromu demence a jeho nejčastější příčiny Alzheimerovy nemoci. Představuje současné možnosti nejen farmakoterapie, ale i podpory pacientů a jejich rodinných příslušníků. Podrobněji se zabývá dosud nejvýznamnějším směrem vývoje nových léčiv pro farmakoterapii Alzheimerovy nemoci, antiamyloidovou terapii a diskutuje její efekt, ale i úskalí a bariéry, které jsou v současné době zvažovány v procesu schvalování těchto léčiv a jejich uvedení do praxe. Tyto léky představují významnou naději pro pacienty i jejich blízké a jsou i potvrzením, že progresi Alzheimerovy nemoci (a výhledově i dalších neurodegenerativních onemocnění vedoucích k demenci) je možné významně zpomalit či zastavit. Indikační spektrum těchto léků je zatím relativně úzké a ani v budoucnu z nich nebudou moci profitovat všichni pacienti. Proto je důležité dostatečně využívat možností dostupné symptomatické léčby farmakologické i nefarmakologické.
The article highlights the importance of dementia syndrome and its most common cause, Alzheimer's disease. It presents current options for not only pharmacotherapy but also support for patients and their family members. It delves into the most significant current development in new treatments for Alzheimer's disease, anti-amyloid therapy, discussing its effects, challenges, and the barriers currently considered in the approval process and practical implementation of these drugs. These medications offer significant hope for patients and their loved ones, demonstrating that it is possible to substantially slow or even halt the progression of Alzheimer's disease (and potentially other neurodegenerative diseases leading to dementia). However, the indications for these drugs are currently quite narrow, and not all patients will benefit from them even in the future. Therefore, it is crucial to fully utilize available symptomatic treatments, both pharmacological and non-pharmacological.
- Klíčová slova
- antiamyloidová léčba,
- MeSH
- Alzheimerova nemoc * diagnóza farmakoterapie MeSH
- amyloid antagonisté a inhibitory MeSH
- časná diagnóza MeSH
- demence diagnóza farmakoterapie klasifikace MeSH
- farmakoterapie * klasifikace metody MeSH
- kvalita života MeSH
- lidé MeSH
- memantin farmakologie terapeutické užití MeSH
- nootropní látky farmakologie klasifikace terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
A family of new compounds with sulfonamide and amide functional groups as potential Alzheimer's disease drugs were prepared by multistep synthesis. Thermal stability measurements recorded the initial decomposition in the range of 200-220°C, close above the melting point. The final compounds were tested for their ability to inhibit acetylcholinesterase and butyrylcholinesterase, and the in vitro dissolution behavior of selected compounds was studied through both lipophilic and hydrophilic matrix tablets. All nine tested derivatives were even more active in inhibiting acetylcholinesterase than the clinically used rivastigmine. Regression analysis of the obtained dissolution profiles was performed, and the effects of the pH and the release mechanism were determined. Some substances showed remarkable biological activity and became a subject of interest for further extensive study.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- Alzheimerova nemoc * farmakoterapie MeSH
- butyrylcholinesterasa * metabolismus MeSH
- cholinesterasové inhibitory * farmakologie chemická syntéza chemie MeSH
- koncentrace vodíkových iontů MeSH
- lidé MeSH
- molekulární struktura MeSH
- rivastigmin farmakologie chemická syntéza chemie MeSH
- rozpustnost MeSH
- sulfonamidy * farmakologie chemie chemická syntéza MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
