NEW PHARMACOTHERAPY FOR PARKINSONS-DISEASE

OBJECTIVE: To summarize the development, pharmacology, pharmacokinetic s, efficacy, and safety of five investigational antiparkinsonian drugs that are in or have recently completed Phase III trials: three dopami ne agonists, pramipexole, ropinirole, and cabergoline; and two catecho l-O-methyltransferase (COMT) inhibitors, entacapone and tolcapone. The pathophysiology and the role of dopamine in Parkinson's disease are a lso reviewed. DATA SOURCES: A MEDLINE search of relevant English-langu age literature, clinical studies, abstracts, and review articles perta ining to Parkinson's disease was conducted. Manual searches of 1996/19 97 meeting abstracts published by the American Academy of Neurology an d the Movement Disorders Society were also performed. Manufacturers pr ovided unpublished Phase III trial efficacy and pharmacokinetic data. STUDY SELECTION AND DATA EXTRACTION: Clinical trial investigations sel ected for inclusion were limited to human subjects. Interim analyses a fter 6 months for long-term clinical trial studies in progress were in cluded. Pharmacokinetic data from animals were cited if human data wer e unavailable. Statistical analyses for all studies were evaluated. DA TA SYNTHESIS: By selectively targeting D-2 receptors, the newer dopami ne agonists (i.e., cabergoline, pramipexole, ropinirole) may delay the introduction of levodopa and thus the occurrence of levodopa-induced dyskinesias. In addition, they are efficacious as adjunctive therapies in patients with advanced Parkinson's disease, Unlike the currently a vailable dopamine agonists, pramipexole and ropinirole are non-ergot d erivatives and do not cause skin inflammation, paresthesias, pulmonary infiltrates, or pleural effusion. The COMT inhibitors, tolcapone and entacapone, improve the pharmacokinetics of levodopa by preventing its peripheral catabolism and increasing the concentration of brain dopam ine; thus, these agents may reduce the incidence of ''wearing-off'' ef fects associated with the short half-life of levodopa and the progress ion of Parkinson's disease. CONCLUSIONS: Interim 6-month analyses of p ramipexole, ropinirole, and cabergoline for symptomatic treatment of e arly Parkinson's disease have shown these drugs to be efficacious and relatively well-tolerated when used as monotherapy, Their role in dela ying the development of motor fluctuations and delaying the addition o f levodopa is the subject of long-term clinical studies, In advanced s tages of Parkinson's disease, these medications were also efficacious; however, the main adverse effects included dyskinesias, somnolence, a nd hallucinations, The COMT inhibitors, entacapone and tolcapone, have also demonstrated efficacy in improving on-time in patients with stab le disease, Tolcapone has also demonstrated efficacy in patients with motor fluctuations. Both drugs are relatively well-tolerated, with the exception of dyskinesias that require reduction of the levodopa dosag e and occasional diarrhea.