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Inhibitori katehol‐O‐metiltransferaze naspram aktivnih komparatora za komplikacije kod Parkinsonove bolesti uzrokovane levodopom

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Abstract

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Background

As Parkinson's disease progresses the control of the symptoms often requires the addition of other drugs to levodopa. The principle aim of COMT inhibitor therapy is to increase the duration of effect of the levodopa dose and thus reduce the time patients spend in the relatively immobile 'off' phase.

Objectives

To compare the efficacy and safety of adjuvant COMT inhibitor therapy versus active comparators in patients with Parkinson's disease, already established on levodopa and suffering from motor complications.

Search methods

Electronic searches of the Cochrane Controlled Trials Register (The Cochrane Library Issue 1, 2003), MEDLINE (1966‐2003), EMBASE (1974‐2003), were conducted. Grey literature was hand searched and the reference lists of identified studies and reviews examined. The manufacturers of COMT inhibitors were contacted.

Selection criteria

Randomised controlled trials of adjuvant COMT inhibitor therapy versus an active comparator in patients with a clinical diagnosis of idiopathic Parkinson's disease and long‐term complications of levodopa therapy.

Data collection and analysis

Data was abstracted independently by the authors and differences settled by discussion. The outcome measures used included Parkinson's disease rating scales, levodopa dosage, 'off' time measurements and the frequency of withdrawals and adverse events.

Main results

Two trials were found that examined the efficacy of a COMT inhibitor against an active comparator (n = 349). Koller 1998 compared the efficacy of tolcapone versus pergolide (n = 203) over 12 weeks and TSG 1999 compared the efficacy of tolcapone versus bromocriptine (n = 146) over 8 weeks. No trials were found that compared entacapone with active comparators.

Tolcapone produced similar benefits to bromocriptine in 'off' time reduction, motor impairment and disability ratings over three months of therapy. Tolcapone produced a greater reduction in levodopa dosage than bromocriptine. Tolcapone produced similar benefits to pergolide in levodopa dose reduction, motor impairment and disability ratings, and in generic health‐related quality of life scales over the first two months of therapy. Tolcapone produced a greater improvement in the disease‐specific quality of life scale PDQ‐39 than pergolide. Nausea, constipation and orthostatic complaints were greater with agonist therapy, but otherwise the frequency of adverse events and withdrawals from treatment were similar with the two classes of adjuvant medication. One patient had significantly elevated liver enzymes whilst on tolcapone, but otherwise the frequency of adverse events and withdrawals from treatment were similar.

Authors' conclusions

The two trials comparing tolcapone with the dopamine agonists bromocriptine and pergolide were underpowered to detect clinically relevant differences between them. This is based on medium‐term evidence. No evidence was found comparing entacapone with active comparators. Further larger and longer‐term trials are required to compare tolcapone with entacapone and COMT inhibitor therapy with alternative adjuvant classes of drug in later Parkinson's disease such as dopamine agonists and monoamine oxidase inhibitors.

Laički sažetak

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Nema dovoljno dostupnih podataka o koristima inhibitora KOMT‐a tolkapona u usporedbi s agonistima dopamina bromokriptinom i pergolidom u ublažavanju simptoma kasne Parkinsonove bolesti.

S napredovanjem Parkinsonove bolesti za kontrolu je simptoma uz levodopu često potreban dodatak drugih lijekova. Glavni cilj terapije inhibitorom katehol‐o‐metil transferaze (KOMT) je povećati trajanje učinka svake doze levodope i time smanjiti vrijeme koje pacijenti provedu u relativno nepokretnoj "off" fazi. Međutim, u ovom se stadiju bolesti također mogu koristiti i drugi lijekovi kao što su agonisti dopamina. Ovaj Cochrane sustavni pregled je pokazao da je inhibitor KOMT‐a tolkapon kao dodatak liječenju levodopom imao sličnu razinu koristi kao dva agonista dopamina, bromokriptin i pergolid. U srednje dugom razdoblju nije bilo značajne razlike u djelotvornosti između dodavanja tolkapona i dodavanja bromokriptina ili pergolida. Tolkapon je rjeđe od ovih agonista uzrokovao mučninu, ali je uz tolkapon bilo pojedinih dokaza abnormalnosti funkcije jetre. Praćenje lijeka nakon stavljanja na tržište otkrilo je tri slučaja smrtonosne toksičnosti jetre u bolesnika liječenih tolkaponom. Kao rezultat toga, tolkapon je u nekim zemaljama povučen a u drugima su određena stroga ograničenja za njegovu primjenu.

Nisu pronađeni dokazi usporedbe entakapona s drugim lijekovima koji su dodatak liječenju kod Parkinsonove bolesti.