A PILOT EVALUATION OF THE TOLERABILITY, SAFETY, AND EFFICACY OF TOLCAPONE ALONE AND IN COMBINATION WITH ORAL SELEGILINE IN UNTREATED PARKINSONS-DISEASE PATIENTS

Tolcapone is a potent, reversible catechol-O-methyltransferase (COMT) inhibitor with both peripheral and central activity. It has been demon strated to improve motor function and allow levodopa dose reductions i n Parkinson's disease (PD) patients who are experiencing either a stab le response or motor fluctuations while on levodopa/dopa decarboxylase inhibitor therapy. Because shiatal dopamine is metabolized by COMT an d monoamine oxidase (MAO), central COMT inhibition alone or in combina tion with MAO inhibition might provide symptomatic benefit for patient s not receiving levodopa. We conducted a pilot study to evaluate the t olerability, safety, and efficacy of tolcapone alone and in combinatio n with oral selegiline in early untreated PD patients. Patients were r andomized to receive 200 mg tolcapone three times a day or placebo for the 8 weeks of the study. Open-label oral selegiline (5 mg in the mor ning and midday) was administered to all patients during the second 4 weeks of the study. There was no difference between treatment groups a ccording to the investigator's assessment of tolerability at week 4. N inety-five percent of tolcapone-treated patients and 98% of placebo-tr eated patients experienced excellent or good tolerability during the f irst 4 weeks (95% confidence interval [CI]: -10.3, 5.7; p = 0.57). A d ecrease in tolerability occurred in the tolcapone group during the sec ond 4 weeks of the study following the addition of selegiline. The mos t commonly reported side effects were diarrhea (31% tolcapone, 7% plac ebo), nausea (21% tolcapone, 2% placebo), urine discoloration (12% tol capone, 0% placebo), dizziness (12% tolcapone, 5% placebo), headaches (12% tolcapone, 10% placebo), and abdominal pain (10% tolcapone, 5% pl acebo). We did not identify symptomatic benefit associated with tolcap one alone or in combination with oral selegiline in this group of othe rwise untreated PD patients.