Τόμος 17 (1999) – Τεύχος 2 – Άρθρο 1 – Επιθεώρηση Κλινικής Φαρμακολογίας και Φαρμακοκινητικής-Ελληνική Έκδοση – Volume 17 (1999) – Issue 2 – Article 1 – Epitheorese Klinikes Farmakologias και Farmakokinetikes-Greek Edition

Από | | Άρθρο - Article, Πλήρες Κείμενο στα Ελληνικά - Full Text in Greek, Χάρης Καραγεωργίου - Charis Carageorgiou

 

Τίτλος – Title

Νόσος Alzheimer το 2000. Σύγχρονες Απόψεις για τη Φυσιοπαθολογία και τις Φαρμακευτικές Προσεγγίσεις της Νόσου

Alzheimer’s Disease 2000. Current Aspects and Drug Therapeutic Approaches
Συγγραφέας – Author

Χάρις Καραγεωργίου

Εργαστήριο Πειραματικής Φαρμακολογίας, Iατρική Σχολή Πανεπιστημίου Aθηνών

Haris Karageorgiou

Pharmacology Department, Medical School, Athens University, Athens, Hellas
Παραπομπή – Citation

Καραγεωργίου,Χ. : Νόσος Alzheimer το 2000. Σύγχρονες Απόψεις για τη Φυσιοπαθολογία και τις Φαρμακευτικές Προσεγγίσεις της Νόσου , Επιθεώρηση Κλιν. Φαρμακολ. Φαρμακοκινητ. 17 : 53-95 (1999)

Karageorgiou,H. : Alzheimer’s Disease 2000. Current Aspects and Drug Therapeutic Approaches, Epitheorese Klin. Farmakol. Farmakokinet. 17: 53-95 (1999)
Ημερομηνία Δημοσιευσης – Publication Date
2-05-1999
Γλώσσα Πλήρους Κειμένου –
Full Text Language

Ελληνικά – Greek
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Λέξεις κλειδιά – Keywords

Νόσος Alzheimer, σύγχρονη θεώρηση, νευροπαθολογο-ανατομικά χαρακτηριστικά, νευροϊνιδιακές βλάβες, νευριτικές πλάκες, παθογένεια, γενετικοί παράγοντες, β-αμυλοειδές, δευτερογενείς παράγοντες, οξειδωτικό stress, ηλικία, γλυκοζυλίωση, δίαιτα πλούσια σε χοληστερόλη, α-παράγων νεκρώσεως όγκου, διαταραχές νευρομεταβίβασης, νευρομεταβιβαστές, νορεπινεφρίνη, ντοπαμίνη, σεροτονίνη, γλουταμικό, GABA, σωματοστατίνη, βαρέα μέταλλα, αργίλιο, ψευδάργυρος, υδράργυρος, φαρμακευτικές προσεγγίσεις, φαρμακοδυναμική, φαρμακοκινητική, κλινικές μελέτες, αλληλεπιδράσεις, ανεπιθύμητες ενέργειες, αντιχολινεστερασικά φάρμακα, φυσοστιγμίνη, επταστιγμίνη, γαλανθαμίνη, μετριφονάτη, τακρίνη, ριβαστιγμίνη, δονεπεζίλη, αγωνιστές χολινεργικών υποδοχέων, αγωνιστές μουσκαρινικών υποδοχέων, ξανομελίνη, μιλαμελίνη, αναστολείς νικοτινικών υποδοχέων, α-δρενεργικό σύστημα, σελεζιλίνη, διεγερτικά αμινοξέα, ανιρασετάμη, οξιρασετάμη, πιρακετάμη, αμπακίνες, μονοξείδιο του αζώτου, προστατευτικοί-επιβραδυντικοί παράγοντες, οιστρογόνα, αντιφλεγμονώδη, βιταμίνη Ε, ανταγωνιστές ασβεστίου, νιμοδιπίνη, νευροτροφικός παράγων, μέθοδοι αξιολογήσεως (MMSE, ADAS-Cog, κ.ά.), ανοσοποίηση με β-αμυλοειδές

Alzheimer’s disease, current aspects, histopathologic features, drug therapeutic approaches, neurofibrillary tangles, neurotic plaques, pathogenesis, genetic factors, environmental factors, oxidative stress, age, glycation, high cholesterol diet, tumor necrosis factor-α, neurotransmission disorders, neurotransmitters, norepinephrine, dopamine, 5-HT, glutamate, GABA, somatostatin, heavy metals, Al, Zn, Hg, pharmacodynamics, pharmacokinetics, clinical studies, drug interactions, adverse effects, anticho-linesterase inhibitors (AChEI’s), tacrin, rivastigmine, donepezile, physostigmine, epta-stigmine, galanthamine, metrifonate, cholinergic receptor agonists, milameline, xanome-line, adrenergic system, selegiline, excitatory aminoacids, aniracetam, oxiracetam, pir-acetam, protective agents, estrogens, antioxidants, vitamin E, calcium antagonists, ni-modipine, neurotrofic factor (NGF), methods of AD evaluation (MMSE, ADAS-Cog), immunization with amyloid-β
Λοιποί Όροι – Other Terms

Άρθρο

Article
Περίληψη – Summary

H νόσος του Alzheimer (NA) αποτελεί μία από τις πλέον θλιβερές νόσους της 3çò ηλικίας: περιλαμβάνει προοδευτική έκπτωση τόσο της μνήμης όσο και άλλων νοητικών λειτουργιών, διαταραχές συμπεριφοράς, όπως ψευδαισθήσεις και παραισθήσεις, που οδηγούν σε φυτική κατάσταση. H συχνότητα εμφανίσεώς της είναι ανάλογος με την ηλικία: 5-10% στους άνω των 65 ετών και μέχρι 45-50% στους άνω των 85 ετών. Υπολογίζεται ότι περίπου 7 εκατομμύρια ευρωπαίων έχουν προσβληθεί από την ΝΑ. Αυτή χαρακτηρίζεται από την παρουσία (α) των γεροντικών ή νευριτικών πλακών (εξωκυτταρίως), που συνίστανται από εκφυλισμένες νευρικές απολήξεις με κεντρική άθροιση β-αμυλοειδούς (Αβ), πρωτεϊνογλυκανών και άλλων πρωτεϊνών και (β) των νευροϊνιδιακών αλλοιώσεων που αποτελούν δεμάτια ελικοειδών ζευγαρωτών ινιδίων (ενδονευρωνικώς), που σημαντικό ρόλο για το σχηματισμό τους παίζει η υπερφωσφορυλίωση της μικροσωληναριακής tau πρωτεΐνης. TÝóóåñá τουλάχιστον γονίδια συσχετίζονται με τη NA: το γονίδιο της APP (χρωμόσωμα 21), της PS-1 (14), της PS-2 (1) και της ApoE4 (19) και όλα αυξάνουν την παραγωγή του Aâ42 πεπτιδίου. H άθροιση του Aâ στον εγκεφαλικό φλοιό είναι ένα πρώιμο και σταθερό γεγονός στην ανάπτυξη της NA και προηγείται άλλων εγκεφαλικών βλαβών και κλινικών συμπτωμάτων για πολλά χρόνια, ακόμη και για 10åôßåò. H εκφύλιση των χολινεργικών νευρώνων (φλοιού, ιπποκάμπου) και η ελάττωση της ACh και της ChAT πιστεύεται ότι συντελεί στην απώλεια της μνήμης στη NA. Måßùóç της νορεπινεφρίνης, της 5-HT, της σωματοστατίνης και άλλων νευρομεταβιβαστών προϊούσης της νόσου παρατη-ρούνται επίσης, αλλά όχι τόσο σταθερά και τόσο εντυπωσιακά. Δυσλειτουργία του ανοσοποιητικού συστήματος, βαρέα μέταλλα (Al) διαταραχή στο μεταβολισμό γλυκόζης, φλεγμονώδεις και άλλοι παράγοντες έχουν ενοποιηθεί, επίσης, ως αίτια της NA. Κατά τη διάρκεια της τελευταίας δεκαετίας, συστηματικές προσπάθειες για ανάπτυξη θεραπείας της ΝΑ κατέληξαν στα χολινεργικά φάρμακα, όπως οι αναστολείς της χολινεστεράσης και οι αγωνιστές των χολινεργικών υποδοχέων. Κλινικές μελέτες επί πολλών χιλιάδων ασθενών στις ΗΠΑ, Ευρώπη και Ιαπωνία έχουν επιβεβαιώσει την υπόθεση ότι μια σταθερά αύξηση στην ακετυλοχολίνη στον εγκέφαλο, λόγω αναστολής της χολινεστεράσης, προκαλεί σημαντική βελτίωση και σταθεροποίηση, για ένα διάστημα, των γνωσιακών λειτουργιών στην ελαφρά και μέτρια ΝΑ. Aíôé÷ïëéνεστερασικά φάρμακα 1çò γενεάς, όπως φυσοστιγμίνη, επταστιγμίνη, μετριφονάτη, τακρίνη και 2áò γενεάς, όπως γαλανθαμίνη, ριβαστιγμίνη και δονεπεζίλη, αγωνιστές των χολινεργικών υποδοχέων, όπως μιλαμελίνη και ξανομελίνη και φάρμακα που δρουν στους γλουταματεργικούς υποδοχείς (AMÐA), όπως η ανιρασετάμη, οξιρασετάμη και πιρακετάμη, φαίνεται να προσφέρουν κάποια βελτίωση και επιβράδυνση της επιδεινώσεως της NA. Aíôé-φλεγμονώδη, αντιοξειδωτικά, βιταμίνες, σελεζιλίνη, ανταγωνιστές Ca, οιστρογόνα και NGF ελπίζεται ότι πιθανόν δρουν ως προστατευτικά των νευρώνων. Γεγονός είναι ότι με τα αντιχολινεστερασικά φάρμακα ένα μέρος των ασθενών παρουσιάζει βελτίωση ή τουλάχιστον σταθεροποίηση για 6-24 μήνες στις γνωσιακές λειτουργίες, ενώ ένα άλλο μέρος των ασθενών δεν απαντά σε αυτή τη φαρμακευτική αγωγή, για άγνωστους προς το παρόν λόγους. Εξ άλλου, οι ανεπιθύμητες ενέργειες των φαρμάκων αυτών αναγκάζουν ορισμένους ασθενείς να διακόπτουν τη λήψη τους. Συμπερασματικά, η NA είναι πολυαιτιολογική νόσος και η πληρέστερη κατανόηση των μηχανισμών που την προκαλούν μπορεί μελλοντικά να οδηγήσει σε δημιουργία φαρμάκων που θα την αναστέλλουν. Σε αυτό η μοριακή Γενετική και κυτταρική Βιολογία βοηθούν τα μέγιστα. Eí τω μεταξύ η πρώιμη διάγνωση, η εξατομίκευση θεραπευτικής αγωγής με τα ήδη υπάρχοντα φάρμακα και η στενή παρακολούθηση της πορείας της NA θα προσφέρουν καλύτερη ποιότητα ζωής στους πάσχοντες για όσο το δυνατόν μεγαλύτερο διάστημα.

Alzheimer’s Disease (AD) is one of the most significant disease threats faced by older individuals characterized by progressive loss of memory and other cognitive functions. The age-specific prevalence of dementia and AD rises exponentially with chronological age, at least between the ages 65 and 85. A common histopathologic feature in the brains of patients, is the presence of neuritic or senile plaques and neurofibrillary tangles, in areas subserving memory and cognition, predominately in the hippo-campus and neocortex. A neurotic plaque is a cluster of degenerating nerve terminals with a core of amyloid protein (Aâ). Neurofibrillary tangles are bundles of paired helical filaments found inside neurons composed of highly phosphorylated forms of the microtubule-associated protein tau. At least four genes are implicated in the development of AD namely, the βAPP mutations located on chromosome 21, the PS-1 (14), PS-2 (1) and the ApoE4 (19), all of them increasing, the secretion of Aâ peptide. The aggregation of Aâ in brain cortex is an early and consistent event in the development of AD preceding other brain lesions for many years even decades. The degeneration of cholinergic neurons mainly in the ippocampus and cortex with a substancial decrease of Ach and ChAT was one of the earliest findings in AD. Since the cholinergic system appears to play an important role in memory function, the decrease in Ach in Alzheimer brain is believed to contribute to memory loss. Subsequent studies have shown decreases in Nor, 5-HT, somatostatin and other neurotransmitters but less dramatic and less consistent. Immune system  dysfunction, heavy metals (Al) infective and other factors as energy deficit has been implicated in the etiology of AD. The cholinergic hypothesis led to strategies to replace Ach or mimic its actions. Such drugs are the first and second generation AChEIs, Physo-stigmine, Galanthamine Tacrine, Rivastigmime, Donepezil, Metrifonate, cholinergic receptor-agonists Milameline, Xanomeline, and drugs acting on Glutamatergic receptors (AMPA) as Anirace-tam seems to offer beneficial effects, delaying the progress of the disease. NSAAs, anti-oxidants, Vitamin E, Selegilne, Ca-antagonists, Estrogens and NGF may act as neuron-protectors. Although the cause of AD is not known, research continues to uncover new information concerning possible mechanism of pathogenesis. While researchers strive for a better understating of the basic cellular and molecular mechanism of AD, clinicians continue to develop better tools for the diagnosis and staging of this disease. The means of managing the patient with AD are being improved so that a superior quality of life is retained for as long as possible.

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