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Titolo:
Metrifonate - A review of its use in Alzheimer's disease
Autore:
Ormrod, D; Spencer, C;
Indirizzi:
Adis Int Ltd, Auckland 10, New Zealand Adis Int Ltd Auckland New Zealand10 s Int Ltd, Auckland 10, New Zealand
Titolo Testata:
CNS DRUGS
fascicolo: 6, volume: 13, anno: 2000,
pagine: 443 - 467
SICI:
1172-7047(200006)13:6<443:M-AROI>2.0.ZU;2-S
Fonte:
ISI
Lingua:
ENG
Soggetto:
TRANSFORMATION PRODUCT DICHLORVOS; PLACEBO-CONTROLLED TRIAL; MOLECULAR-FORMS; DOUBLE-BLIND; CHOLINESTERASE-INHIBITORS; HUMAN-BRAIN; AGED RATS; ACETYLCHOLINESTERASE INHIBITOR; HEALTHY-VOLUNTEERS; RENAL IMPAIRMENT;
Keywords:
metrifonate; Alzheimer's disease; pharmacodynamics; pharmacokinetics; therapeutic use;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
85
Recensione:
Indirizzi per estratti:
Indirizzo: Ormrod, D Adis Int Ltd, 41 Centorian Dr,Private Bag 65901, Auckland 10, New Zealand Adis Int Ltd 41 Centorian Dr,Private Bag 65901 Auckland New Zealand 10
Citazione:
D. Ormrod e C. Spencer, "Metrifonate - A review of its use in Alzheimer's disease", CNS DRUGS, 13(6), 2000, pp. 443-467

Abstract

Acetylcholinesterase (AChE) inhibitors are currently rile most promising drugs available for the treatment of Alzheimer's disease (AD). Their efficacy is bused on the cholinergic hypothesis of AD which links reduced levels of cerebral acetylcholine (ACh) with declining cognitive function in affected individuals. AChE inhibitors are believed to work by increasing the levelof ACh in the synaptic cleft hy binding to local AChE and preventing the hydrolysis of ACh. Metrifonate differs from other AChE inhibitors in that it is a prodrug which is non-enzymatically converted in vivo to the active moiety 2,2-dichlorovinyl dimethylphosphate (DDVP). DDVP administered alone has a very short plasma elimination half-life. but small amounts released from metrifonate aresufficient to inhibit AChE activity in vivo. DDVP is an irreversible inhibitor of AChE and activity is maintained for several weeks. Metrifonate has been used as an anthelmintic since 1962 and has been under investigation asa treatment for the symptoms of AD since 1990. Randomised. placebo-controlled clinical trials, using a variety of dose regimens, have demonstrated that metrifonate produces a significant, but modest, improvement in the 3 domains of AD: cognition. behaviour and function. However, it should be noted that with some assessment instruments in some trials, the 'improvement' wasactually a reduction in the rate of worsening of symptoms compared with placebo. Weekly and daily schedules, with and without loading doses, have been evaluated and the research supports a fixed daily dose of 40 to 50mg, administered to supply approximately 0.65 mg/kg. In studies of up to 6 months' duration, metrifonate was well tolerated, and adverse events were mild and predominantly gastrointestinal. In clinical practice it is likely that metrifonate will be administered fur several years and long term monitoring of adverse events will be important to further define the drug's tolerability profile. Muscle weakness occurred in a dose-related fashion in approximate to 20 of 3000 patients taking part in long term trials, and in some patients respiratory support was required. The mechanism of muscle weakness is not well defined and requires further investigation. Conclusions: Clinical data support the use of metrifonate in patients withAD. However. the improvement?, noted are modest and to date there is no evidence that metrifonate is more effective than other currently approved AChE inhibitors. The unique pharmacokinetic/pharmacodynamic profile of metrifonate may endow the agent with some advantages over other therapies, but this ha:, yet to be evaluated in comparative trials. Moreover, long term studies evaluating the effects of metrifonate on maintenance of independence arerequired. While the clinical future of metrifonate is uncertain, it is oneof a small group of drugs that have been shown to improve the outlook of patients with AD.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 05/04/20 alle ore 07:00:52