Simultaneous MAO-B and COMT inhibition in L-Dopa-treated patients with Parkinson's disease.
The effect of selegiline (L-deprenyl) on plasma catecholamines, clinical response, and drug tolerability was studied in 13 patients with Parkinson's disease (PD) treated with L-Dopa/benserazide and entacapone, a peripheral catechol-O-methyltransferase (COMT) inhibitor, in a placebo-controlled double-blind study. An L-Dopa test was performed on 3 study days. The first study day was with L-Dopa/benserazide only (control), the second after 14 days of treatment with 200 mg entacapone taken concomitantly with L-Dopa/benserazide in combination with either selegiline (10 mg daily) or placebo. After a 2-week washout period, selegiline and placebo treatments were switched, and the third study day was after 14 days of treatment. During the study days, clinical response was evaluated at 30-min intervals for 6 h, by using the motor score of the Unified Parkinson's Disease Rating Scale (UPDRS). In addition, repeated blood pressure measurements were made, and plasma samples were taken for analysis of L-Dopa, 3-O-methyldopa (3-OMD), dihydroxyphenyl acetic acid (DOPAC), homovanillic acid (HVA), dopamine, noradrenaline, and 3-methoxy-4-hydroxyphenylethylene glycol (MHPG). Monoamine oxidase B (MAO-B) and COMT enzyme activities were measured from platelets and erythrocytes, respectively. Entacapone improved the clinical response to L-Dopa during both selegiline and placebo (p < 0.001) treatments. The improvement was more marked during combined selegiline and entacapone treatment than with entacapone alone (p < 0.01). Entacapone significantly increased plasma L-Dopa and DOPAC levels and decreased plasma 3-OMD and MHPG levels both with selegiline and placebo. Selegiline partially inhibited the entacapone-induced increase of plasma DOPAC. Plasma dopamine and noradrenaline levels did not change. Entacapone decreased erythrocyte COMT activity by > 35% (p < 0.001), and platelet MAO-B activity was almost completely inhibited by selegiline (p < 0.001). One patient withdrew because of diarrhea, dizziness, and loss of sleep when receiving selegiline treatment. Otherwise no differences in adverse events, mean daily blood pressures, or other safety parameters were observed between selegiline and placebo treatments. Our results suggest that entacapone can be safely administered together with L-Dopa and selegiline in patients with PD, although further studies with larger number of patients and longer treatment periods are necessary to confirm this finding.
Lyytinen
J
J
Department of Neurology, University of Helsinki, Finland.
Kaakkola
S
S
Ahtila
S
S
Tuomainen
P
P
Teräväinen
H
H
D000368:Aged; D000704:Analysis of Variance; D000978:Antiparkinson Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001545:Benserazide; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols / Q000494:pharmacology / Q000627:therapeutic use*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007980:Levodopa / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D009043:Motor Activity / Q000187:drug effects; D009570:Nitriles; D010300:Parkinson Disease / Q000097:blood / Q000188:drug therapy*; D012642:Selegiline / Q000494:pharmacology / Q000627:therapeutic use*
D000978:Antiparkinson Agents; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols; D004791:Enzyme Inhibitors; D008996:Monoamine Oxidase Inhibitors; D009570:Nitriles; D012642:Selegiline; D007980:Levodopa; C071192:entacapone; D001545:Benserazide