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Catechol-O-Methyltransferase Inhibitor, on the Motor Response to Acute Treatment with Levodopa in Patients with Parkinson's Disease

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Catechol-O-Methyltransferase Inhibitor, on the Motor Response to Acute Treatment with Levodopa in Patients with Parkinson's Disease 18616ournal ofNeurology, Neurosurgery, and Psychiatry 1994;57:186-189 Effect of entacapone, a peripherally acting J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.57.2.186 on 1 February 1994. Downloaded from catechol-O-methyltransferase inhibitor, on the motor response to acute treatment with levodopa in patients with Parkinson's disease Marcelo Merello, Andrew J Lees, Roy Webster, Michael Bovingdon, Ariel Gordin Abstract treatment.7-'0 The oral bioavailability of lev- Catechol-O-methyltransferase (COMT) odopa is low due to first pass metabolism inhibitors may be useful in the treatment which is at least partly due to the high activity of Parkinson's disease by improving the of COMT in the gut and liver." 12 The com- bioavailability of levodopa and by pro- bination of a peripheral COMT inhibitor longing its effects. Entacapone (OR-611), with levodopa/DCI therapy might therefore a novel COMT inhibitor, which does not produce a smoother and more prolonged cross the blood brain barrier, was motor response in patients with Parkinson's assessed in 12 patients with Parkinson's disease."3 14 As early as in 1971 Ericsson'5 disease and motor fluctuations in a reported beneficial effects with a COMT randomised, double-blind, cross-over, inhibitor with concomitant reduction in single dose study. The magnitude and levodopa-induced dyskinesias. More recently, duration of the therapeutic response to a a new generation of COMT inhibitors have single dose of 200 mg levodopa/50 mg been developed, which are much more potent carbidopa was evaluated after concomi- and specific."'3 1620 Fluorodopa positron tant placebo, or 200 or 800 mg enta- emission tomography (PET) studies in mon- capone. A significant increase in the keys and patients with Parkinson's disease duration of the motor response to lev- have also shown that peripheral COMT odopa was seen when 200 mg entacapone inhibitors increase striatal fluorodopa was given with levodopa/carbidopa. uptake.21-23 Plasma levodopa concentrations were Entacapone (OR-611) is a highly selective increased with both doses of the COMT and potent nitrocatechol-structured COMT inhibitor. The latency to onset of motor inhibitor that penetrates the brain poorly, act- response did not differ significantly ing mainly in the gut. In animal models of between active drug and placebo. Parkinson's disease, entacapone potentiated Entacapone may prove useful in prolong- and prolonged the therapeutic effect of levo- ing the duration of the benefit obtained dopa in a dose-dependent manner.2425 from individual doses oflevodopa. We have studied the motor response and pharmacokinetics of levodopa in 12 patients (7 Neurol Neurosurg Psychiatry 1994;57:186-189) with Parkinson's disease and severe motor http://jnnp.bmj.com/ fluctuations after acute levodopa challenge alone or in combination with two different Catechol-O-methyltransferase (COMT) is an entacapone doses. important enzyme involved in the peripheral and central metabolism of dopamine.1 In the Departnent of central nervous system it is believed to exert Materials and methods Neurology in Twelve from the of on October 2, 2021 by guest. Protected copyright. M Merello its major action the synaptic cleft. patients Department A J Lees When decarboxylation of levodopa is Neurology, University College and Middlesex Department of blocked by peripheral dopa decarboxylase Hospitals, London treated with levodopa (I 1 Pharmacology, inhibitors (DCIs), 0-methylation becomes men and one woman, mean age 58 5 (range University College and the most prominent pathway of levodopa 46-71) years), mean duration of disease 14-7 Middlesex Hospitals School ofMedicine, catabolism2 and leads to the accumulation of (range 8-24) years), mean daily levodopa London, UK 3-0-methyldopa. It has been suggested that dose 1183 (range 300-4250) mg agreed to R Webster 3-0-methyldopa may impair the transport of participate. The patients were informed about M Bovingdon levodopa across the blood brain barrier and the objectives and design of the study, and Research Center, compete with levodopa for decarboxylation informed consent was obtained. The study Orion Pharmaceutica, Espoo, Finland within the brain.'-5 It has also been proposed was approved by the Ethics Committee of the A Gordin that accumulation of 3-0-methyldopa may be Faculty of Clinical Sciences, University Correspondence to: a causal factor in the development of motor College School of Medicine, London. Dr Andrew J Lees, All the United Department of Neurology, fluctuations in Parkinson's disease.6 This the- patients fulfilled Kingdom Middlesex Hospital, ory, however, has been challenged. The Parkinson's Disease Brain Bank clinical Mortimer Street, London for Parkinson's WIP 8AA, UK. plasma concentrations of 3-0-methyldopa diagnostic criteria idiopathic Received 20 January 1993 causing a deleterious effect on the clinical disease26 and had a clear response to an acute and in revised form response to levodopa in parkinsonian patients challenge with levodopa. Patients with secon- 26 April 1993 and are 17 May 1993. much higher than those found during dary parkinsonism, severe dementia, unstable Accepted 21 May 1993 long term levodopa decarboxylase inhibitor cardiac, renal, pulmonary, or gastrointestinal Entacapone and the motor response to levodopa in Parkinson's disease 187 disease, and women of childbearing age were the Wilcoxon rank test. Statistical analysis of J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.57.2.186 on 1 February 1994. Downloaded from excluded. Those patients receiving drugs for the plasma concentrations was carried out treating parkinsonism other than levodopa with analysis of variance and the Newman- continued on these unchanged throughout Keuls test. the study. The magnitude and duration of the thera- peutic response of a single dose of 200 mg Results levodopa in combination with 50 mg car- CLINICAL RESPONSE bidopa (two tablets of Sinemet plus, Merck, The latency to peak motor response was not Sharp, and Dohme were evaluated after con- significantly different between the three trial comitant administration of placebo, or 200 or days, but the duration of effect when enta- 800 mg entacapone (Orion Pharmaceutica, capone was administered with levodopa was Espoo, Finland). The pharmacokinetics and increased by a mean of 34 5 minutes (200 metabolism of levodopa were also studied. mg) and 39 minutes (800 mg), respectively, The study followed a double-blind, cross- compared with the placebo day (table). The over design and the order of medication was difference in the duration between the randomised. placebo and 200 mg days was statistically The single doses of levodopa/carbidopa significant (p < 0 05) by paired t test, but sig- and study drugs (entacapone/placebo),were nificance was not quite reached between the given simultaneously at 8.00 am in the fasting placebo and 800 mg day due to a larger varia- state after an overnight drug holiday. tion in response (table). When 200 mg of Clinical scoring was carried out at 15-30 entacapone was used, the overall scores for minute intervals from 7.30 am to noon. If the tapping (p < 0 05), dyskinesias (p < 0 005), drug effect persisted after the noon rating, and global score (p < 0-05) were significantly assessments were continued at 30-minute higher and the walking time significantly intervals until motor scores had returned to lower (p < 0-05) than on the placebo day baseline. The motor function was assessed (figs la and b). The global score with 200 mg by (1) a tapping test-the number of times of entacapone was also higher (p < 0 05) than the patient could alternately tap two labora- with 800 mg, but no statistically significant tory counters 20 cm apart in 30 s with the differences were found between the placebo more severely affected hand; (2) a walking day and the 800 mg day when maximum test-the time required to rise from an arm- values were compared (fig lb). The 800 mg less chair,.walk 6 m, turn, and sit down (cut dose of entacapone gave a higher peak score off time 30 s); (3) a 5-point dyskinesia scale; for dyskinesias than placebo (p < 0 05). The and (4) an overall global score (-4 = severe, maximum tapping score with 200 mg disabling symptoms to 0 = normal to + 4 = entacapone was significantly higher than with severe disabling dyskinesia). The criteria used 800 mg (p< 005; fig la). to assess the duration of response and the Two patients showed a biphasic motor time to "switch off' have been previously response when they received 800 mg enta- described.27 capone (table). Pronounced waning of the Plasma concentrations of levodopa, 3-0- motor response was followed in these patients methyldopa, and the dopamine metabolites by a second spontaneous motor improvement dihydroxyphenyl acetic acid and homovanillic lasting 45 to 60 minutes. These findings are http://jnnp.bmj.com/ acid were measured by high performance liq- not included in the statistics. Patient 6 did uid chromatography (HPLC).25 not "switch on" at all either with placebo or with 800 mg of entacapone. Patient 7 also STATISTICS failed to "switch on" with 800 mg of enta- For each clinical variable, the mean duration capone. These patients are not included in of the difference of the means and the mean the calculation of the latency and duration of of the maximum values for each patient in the motor response to levodopa. By contrast, each treatment sequence were compared by all the patients on 200 mg entacapone on October 2, 2021 by guest. Protected copyright. Table Motor response (time in minutes) Entacapone Placebo 200 mg 800 mg Patient Latency Duration Latency Duration Latency Duration 1 105 120 45 195 30 360 2 105 105 75 120 60 150 3 60 165 60 240 45 105 4 45 165 45 180 60 270 5 45 165 45 225 90 90 6t NR NR 60 60 NR NR 7t 45 90 120 45 NR NR 8 30 150 45 180 75 210 9 75 105 30 60 120 105 10 30 180 45 225 30 210 11 105 30 90 60 105 60 12 60 105 60 150 90 120 Mean (SD) 66 (30-17) 129 (45-39) 54 (17-61) 163-5 (65 36)* 70 5 (30 86) 168 (93 75) *p < 0-01 v placebo.
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