Evidence that the clinical effects of cholinesterase inhibitors are related to potency and targeting of action.
Notice bibliographique
Résumé
Since degenerative alterations associated with cholinergic changes in the brains of demented patients occur in specific regions, optimal efficacy may be achieved by targeting the actions of potent cholinesterase inhibitors in relevant regions. When evaluating the activities of these agents, only cerebrospinal fluid (CSF)-based studies in demented patients provide reliable data. Preclinical or healthy volunteer studies of cholinesterase inhibitory activity using plasma or erythrocytes as an enzyme source are inconclusive due to differences between enzymes, their relative activities, and the profiles of their isoforms from different sources, with additional changes during disease progression. Tacrine and rivastigmine inhibit both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in the CSF of Alzheimer's disease patients. Both enzymes are involved in the breakdown of acetylcholine (ACh) in the brain and dual inhibition may lead to greater, broader efficacy, as well as a greater potential for disease modification. However, potent and rapid elevation in levels of ACh may also induce more acute tolerability problems, such as nausea and vomiting. Only rivastigmine appears to show brain region-selectivity, particularly for regions involved in attention and behaviour and that are known to degenerate during the progression of various dementia types. This selectivity is due to preferential inhibition of the G1 form of AChE and, probably, also BuChE. Cholinesterase inhibitors that lack preferential selectivity for particular isoforms may provide less targeted actions. This may explain the relatively higher incidences of certain peripheral side effects observed during maintenance treatment with some of these drugs. All cholinesterase inhibitors interact via ACh, additionally available due to enzyme inhibition, with nicotinic and muscarinic receptors (nAChRs and mAChRs). Allosteric modulation of a presynaptic nAChR has been shown in vitro with many of these agents, and it has been proposed, but not demonstrated, that this may result in an increased release and potentiation of ACh in the brain. The clinical relevance of this mechanism is unknown. The rapidly reversible actions of donepezil, tacrine and galantamine may lead to tolerance due to their ability to upregulate target enzyme activities; however upregulation is not seen with the slowly reversible (pseudo-irreversible) inhibitor rivastigmine. Available clinical data support the hypothesis that potent, slowly reversible inhibitors of AChE and BuChE targeted to the G1 isoforms may lead to greater, broader and more sustained benefits. However, further investigation of the cholinesterase inhibitors to elucidate more definitely the clinical consequences of their differing pharmacological properties is required.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,004 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».