Stellenwert der Catechol-O-Methyltransferase -Hemmung in der modernen Parkinson-Therapie

Zusammenfassung

Die älteste, wirksamste und am besten verträgliche Substanz zur Behandlung von Parkinson-Patienten im Rahmen einer dopaminergen Stimulation ist Levodopa (LD). Die kurze Halbwertszeit von LD wird jedoch als Faktor in der Entstehung von motorischen Langzeitkomplikationen angesehen. Aus diesem Grund wird die Therapie mit LD erst spät begonnen. Die zunächst aufgrund pharmakokinetischer und tierexperimenteller Untersuchungen angenommene Verzögerung dieser motorischen Komplikationen unter Kombination aus LD mit Carbidopa (CD) und Entacapon (EN), einem Hemmer der Catechol-O-Methyltransferase (COMT), konnte anhand der STRIDE-PD Studie nicht bestätigt werden. Unter COMT-Hemmung konnte eine bessere Symptomkontrolle mit konsekutiv verbesserter Lebensqualität beobachtet werden. Das Auftreten von motorischen Fluktuationen war jedoch in dieser Gruppe früher beobachtet worden. Weitere kleine, standardisierte Studien beschreiben einen möglichen Einfluss der COMT-Hemmung auf Kognition und Muskelkraft, wobei ergänzende Untersuchungen hierzu ausstehen. Ferner wurden Anhaltspunkte für eine Reduktion der Homozystein-Synthese unter Kombination von COMT-Hemmung und LD-Gabe beschrieben. Neben der 3-fach Kombination LD/CD/EN stehen die COMT-Hemmer Tolcapon (TO) und EN zur Verfügung. Die vorliegenden Sicherheitsdaten von EN im Vergleich zu TO führen aktuell zum Vorzug von EN, auch wenn die Gabe von TO wahrscheinlich eine bessere Wirksamkeit bietet. Die aktuelle Indikation zur COMT-Hemmung unter LD Therapie bei M. Parkinson, bleibt in der Behandlung von „wearing off“ und anderen motorischen Komplikationen wie z. B. Fluktuationen. Neue therapeutische Ansätze bedingt durch ein besseres Verständnis des Enzyms und seiner Funktionen bleiben abzuwarten.

Abstract

Levodopa (LD) is the oldest, most efficacious and best-tolerated drug for dopaminergic substitution of patients with Parkinson’s disease (PD). Its main drawback is its short half-life, which supports the onset of motor complications in the longterm. Therefore therapy is started as late as possible. The at first expected delay of the onset of motor complications under the combination of LD with carbidopa (CD) and the catechol-O-methyltransferase (COMT) inhibitor entacapone (EN) on the basis of pharmacokinetic trials and experimental research to a certain extent, was proved to be wrong in the STRIDE-PD study. Although the control of symptoms and consecutive improved quality of life were better, motor complications under COMT inhibition occurred even earlier. Small studies show a possible influence on cognition and muscle strength, but further research is necessary. There is also an evidence for a reduction in homocysteine synthesis under the combination of COMT inhibition and LD administration. Besides, the triple combination of LD/CD/EN the COMT inhibitors EN and tolcapone (TO) is available for therapy. The safety data of EN compared with TO explain the current preference of EN, even if TO probably offers a better efficacy. The indication for additional COMT inhibition still remains in the treatment of motor complications like “wearing off” and other fluctuations as yet. New therapeutic approaches due to a better understanding of the enzyme and its features are still to be awaited.

Schlüsselwörter

Levodopa - COMT-Hemmung - Metabolismus - Parkinson-Therapie - motorische Komplikationen

Keywords

levodopa - COMT inhibition - metabolism - Parkinson therapy - motor complications

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