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Titolo:
Pharmacodynamic-tolerability relationships of cholinesterase inhibitors for Alzheimer's disease
Autore:
Imbimbo, BP;
Indirizzi:
Chiesi Farmaceut, Dept Res & Dev, I-43100 Parma, Italy Chiesi Farmaceut Parma Italy I-43100 ept Res & Dev, I-43100 Parma, Italy
Titolo Testata:
CNS DRUGS
fascicolo: 5, volume: 15, anno: 2001,
pagine: 375 - 390
SICI:
1172-7047(2001)15:5<375:PROCIF>2.0.ZU;2-S
Fonte:
ISI
Lingua:
ENG
Soggetto:
PLACEBO-CONTROLLED TRIAL; RANDOMIZED CONTROLLED TRIAL; DOUBLE-BLIND; ACETYLCHOLINESTERASE INHIBITION; CLINICAL PHARMACOKINETICS; CHOLINERGIC NEURONS; CONTROLLED-RELEASE; GLOBAL FUNCTION; SELECTIVE LOSS; METRIFONATE;
Tipo documento:
Review
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
88
Recensione:
Indirizzi per estratti:
Indirizzo: Imbimbo, BP Chiesi Farmaceut, Dept Res & Dev, Via Palermo 26-A, I-43100 Parma, Italy Chiesi Farmaceut Via Palermo 26-A Parma Italy I-43100 , Italy
Citazione:
B.P. Imbimbo, "Pharmacodynamic-tolerability relationships of cholinesterase inhibitors for Alzheimer's disease", CNS DRUGS, 15(5), 2001, pp. 375-390

Abstract

According to the cholinergic hypothesis, the impairment of cognitive function and the behavioural disturbances that affect patients with Alzheimer's disease are mainly due to cortical deficiencies in cholinergic transmission. Numerous cholinesterase inhibitors have been investigated for treatment of this disease, the rationale being to support the cholinergic system by blocking the degradation of acetylcholine released from presynaptic neurons. These drugs can be classified as reversible (tacrine, donepezil and galantamine), pseudo-reversible (physostigmine, eptastigmine and rivastigmine) or irreversible (metrifonate) enzyme inhibitors. This article reviews efficacy and tolerability results from 6-month placebo-controlled studies of 7 cholinesterase inhibitors: tacrine (80 to 160 mg/day), donepezil (5 to 10 mg/day), rivastigmine (1 to 12 mg/day), metrifonate (30 to 80 mg/day), eptastigrmine (30 to 60 mg/day), physostigmine (30 to 36 mg/day) and galantamine (8 to 32 mg/day). All these agents have demonstrated a statistically significant, although modest, effect versus placebo onthe cognitive and global performance of patients with Alzheimer's disease. Dramatic clinical response has been seen in only 3 to 5% of patients. There are no major differences in terms of efficacy between the different drugs. The mean difference between drug and placebo effects on standardised psychometric scales is about 2 to 4 points on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog; a 70-point cognitive scale) and 0.2 to 0.5 points on the Clinician's Interview-Based Impression of Changewith Caregiver Input (CIBIC-Plus; a 7-point global scare), or 5 to 14% of the average value of the scales. The most common adverse effects observed after administration of cholinesterase inhibitors are nausea, vomiting, diarrhoea, dizziness, asthenia and anorexia, all symptoms linked to cholinergic overstimulation. These effects are dose related and largely depend on the degree of cholinesterase inhibition. Also important is the rate of onset of cholinesterase inhibition, which depends on the kinetics of enzyme inhibition, the presence and rate of titration, and the pharmacodynamic peak-to-trough fluctuations. A model predicting the incidence of nausea bared on acetylcholinesterase inhibition and the half-life of acetylcholinesterase recovery is proposed. In conclusion, cholinesterase inhibitors arts the only pharmacological agents proved to be effective for the treatment of Alzheimer's disease in large, long term, double-blind, placebo-controlled trials. While the efficacy of different cholinesterase inhibitors is similar, their tolerability profiles differ. For example, the incidence of nausea (in excess of that seen with placebo) at cognitively effective dosages ranges from 1 % with eptastigmine 60 mg/day to 53 % with physostigmine 30 mg/day. Differences in tolerability profile may be due to the extent of peripheral acetylcholinesterase inhibition needed to reach clinical efficacy. Other contributing pharmacodynamic factors are the rate of onset of and fluctuations in acetylcholinesterase inhibition at steady state.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 19/01/20 alle ore 08:58:31