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The effect of COMT inhibition with entacapone on cardiorespiratory responses to exercise in patients with Parkinson's disease
Parkinsonism & Related Disorders Parkinsonism and Related Disorders 8 (2002) 349±355
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The effect of COMT inhibition with entacapone on cardiorespiratory responses to exercise in patients with Parkinson's disease J. Lyytinen a,*, S. Kaakkola a, A. Gordin b, E.-R. Kultalahti b, H. TeraÈvaÈinen a, A. SovijaÈrvi c a
Department of Neurology, University of Helsinki, P.O. Box 340, 00029 Helsinki, Finland b Orion Research Center, Orion Pharma, Espoo, Finland c Department of Clinical Physiology and Nuclear Medicine, University of Helsinki, Helsinki, Finland Received 14 May 2001; revised 16 August 2001; accepted 6 September 2001
Abstract The inhibition of catechol-O-methyltransferase (COMT) may impair catecholamine clearance resulting in unwanted cardiac and hemodynamic events. We therefore studied the effects of entacapone, an inhibitor of peripheral COMT, on cardiorespiratory and plasma noradrenaline (NA) responses to exercise and on respiratory muscle strength in l-dopa treated patients with Parkinson's disease (PD). A randomized, double-blind, cross-over study with two 1 week treatment periods was performed in 15 PD patients. The test battery included analysis of hemodynamics, gas exchange parameters and plasma NA during a maximal exercise test, assessment of maximal static airway pressures and pre- and post-exercise motor scores of the Uni®ed Parkinson's Disease Rating Scale (UPDRS). The ®rst test was done after withholding l-dopa overnight (`run-in' test, off-phase). The second and third tests were done in on-phase after 1 week treatment with either entacapone 200 mg or placebo given with each dose of l-dopa. No differences in maximal work load, plasma NA, or in cardiorespiratory responses to either maximal or work rate standardized submaximal exercise were observed between entacapone and placebo, except for O2 pulse, which was slightly lower p , 0:05 after entacapone at submaximal exercise level. Maximal airway pressures were similar between the study treatments and run-in. Exercise had no effect on motor UPDRS after either study treatment or during the run-in test. No serious adverse events were observed. The results of this study suggest that entacapone does not change the work capacity, work ef®ciency or respiratory muscle strength in l-dopa treated PD patients with mild to moderate disease severity, and that its use with l-dopa seems to be safe in conditions of maximal physical effort. However, data from the long-term use of COMT inhibitors are needed to con®rm these ®ndings. q 2002 Elsevier Science Ltd. All rights reserved. Keywords: Entacapone; Catechol-O-methyltransferase; Exercise; Gas exchange; Hemodynamics; Parkinson's disease
1. Introduction In addition to the major symptoms of rest tremor, bradykinesia and muscle rigidity, weakness and lack of endurance are commonly experienced by patients with Parkinson's disease (PD). Early fatigue in repetitive tasks, decreased isotonic strength [1], and abnormally low metabolic ef®ciency of breathing [2] and work [3] were demonstrated in PD patients. The pathophysiology behind these ®ndings is most likely diverse, and may include abnormalities in neural control [4], muscles [5] and ventilation [2]. l-dopa therapy was shown to improve ventilatory function [6], and both work endurance and ef®ciency in PD patients without affecting exercise hemodynamics [7]. When challenged by physical effort, the autonomic * Corresponding author. Fax: 1358-9-4717-4003. E-mail address: jukka.lyytinen@helsinki.® (J. Lyytinen).
nervous system (ANS) responds by markedly increasing the release of catecholamines, which are then eliminated both by neuronal re-uptake and enzymatically by monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT). During exercise, the role of elimination pathways may become even more important in PD patients, who use the exogenous catecholamine l-dopa. Dysfunction of the ANS is well documented in PD [8]; it includes impairments in noradrenaline (NA) synthesis, release, uptake and turnover [9], and in systolic blood pressure (BP) responses to exercise [10]. Entacapone, a selective and reversibly acting inhibitor of extracerebral COMT, reduces peripheral degradation of l-dopa and prolongs its plasma half-life [11,12], thereby increasing signi®cantly both l-dopa bioavailability [13] and duration of clinical effect in PD patients with motor ¯uctuations [14±16]. COMT inhibition in PD patients might theoretically
1353-8020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved. PII: S 1353-802 0(01)00050-5
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Table 1 Patient demographics; PD, Parkinson's disease; LD, l-dopa; H&Y, Hoehn and Yahr staging; M, male; F, female Age (years)
Gender
Duration (years) PD
43 56 60 60 56 46 48 60 61 49 69 47 62 65 63 Mean SD Range n a b
56.7 7.9 43±69 15
F M F F M M M M M M M M M F M
H&Y
LD
LD a
Fluctuations
6 8 8 9 1 6 3 2 2 5 6 5 5 6 15
6 8 7 8 1 6 3 1 2 5 6 5 5 6 10
2 6 None None None 4 2 1 1 2 3 5 2 2 3
5.8 3.4 1±15 15
5.3 2.6 1±10 15
2.8 1.5 1±6 12
Daily dose (mg) Other b
2 2 1 2 1 2 2 1 2 2 2 2 2 1 2
500 850 600 700 600 300 400 600 300 800 600 1000 900 300 300
1±2 15
720 160 300±1000 15
Pergolide 1.5 Bromocript 15 Bromocript 30 Bromocript 30 Bromocript 15 Bromocript 20
Includes both standard and controlled-release formulations. Bromocript, bromocriptine; all patients used selegiline 5±10 mg o.d.
impair catecholamine clearance and lead, e.g. to cardiac and hemodynamic adverse events. It is therefore important to study the safety of COMT inhibition under maximal exercise conditions. This was already done in healthy human volunteers, in which entacapone had no effect on submaximal exercise hemodynamics or ECG [17]. No hemodynamic problems were observed after co-administration of entacapone with either the MAO type A (MAO-A) inhibitor moclobemide [18] or the neuronal re-uptake inhibitor imipramine [19] in healthy subjects. In PD patients, entacapone has not changed plasma catecholamine levels at rest [20] or cardiovascular autonomic responses to sympathetic/parasympathetic stimuli [21,22]. The effects of entacapone on cardiorespiratory responses to exercise, and on respiratory muscle strength were not studied previously in PD patients. We thus performed a double-blind, placebo-controlled, cross-over trial to investigate these issues in PD patients after multiple-dose administration of entacapone as an adjunct to l-dopa. 2. Methods The present study was conducted according to the amended Declaration of Helsinki and the study protocol was approved by the Ethics Committee of the Department of Neurology, Helsinki University Central Hospital. Fifteen PD patients, either with or without ¯uctuations in clinical disability, were enrolled. Their demographics are presented in Table 1. Prior to inclusion, the patients received oral and
written information on the study objectives, design, and possible risks and discomforts involved. A written consent was then obtained. As a screening test, ventilatory capacity was assessed by ¯ow-volume spirometry with measurements of direct maximal voluntary ventilation, forced expiratory volume during 1 s and forced vital capacity. A clinical examination, ECG and laboratory safety screening were also performed. None of the patients had clinical or laboratory signs of severe cardiovascular, pulmonary, renal, hepatic or psychiatric illnesses and none used other drugs with presumable effect on cardiorespiratory parameters. The study had a double-blind, randomized, cross-over design, where all patients were allocated to receive 1 week study treatments of either entacapone 200 mg or placebo with each dose of l-dopa. The daily dose of entacapone was 600±1000 mg (3±5 daily doses), depending on the dosing frequency of l-dopa. There were 3 study visits in hospital. On the ®rst visit (run-in) tests were performed in off-phase after withholding l-dopa overnight. On the second and third study visits, each at the end of a 1 week treatment period, the tests were performed in on-phase after administration of study treatments. During the study days, no other antiparkinsonian drugs, smoking, cola drinks or coffee were allowed prior to the tests. The dosages of all antiparkinsonian drugs were to be kept unchanged throughout the study, although clinically indicated adjustments in l-dopa dosage were allowed. On study days the patients arrived at the hospital at 10.45 a.m. after having had a light breakfast at home. On the ®rst visit l-dopa was not allowed until after the exercise test. On
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Table 2 Cardiorespiratory variables determined during a maximal cycle ergometer test Variable
Unit 0
Maximal work load (Wmax/3 ) Minute ventilation (VÇE) Oxygen uptake (VÇO2) Oxygen pulse (O2 pulse) Ventilatory equivalent for O2 Ventilatory equivalent for CO2 Breathing reserve (BR)
Explanation
W
The highest completed work load (W) for the last 3 min period the highest completed work load (W) 1 (exercise duration at highest achieved work load (min)/3 min) £ 40W l/min Breathing frequency (l/min) £ tidal volume (l) BF £ VT l/min Minute ventilation (l/min) £ (fraction of O2 in inspired air 2 fraction of O2 in expired air) VÇE(FIO2 2 FEO2) ml/beat Oxygen uptake (l/min)/heart rate (beats/min) VÇO2/HR ± Minute ventilation (l/min)/oxygen uptake (l/min) VÇE/VÇO2 ± Minute ventilation (l/min)/CO2 output (l/min) VÇE/VÇCO2 % {(Maximal voluntary ventilation (l/min) 2 maximal minute ventilation (l/min))/maximal voluntary ventilation (l/min)} £ 100 {(MVV 2 VÇE)/MVV} £ 100
the second and third visits, the study drugs were administered at 11 a.m. with the patients' individual morning dose of l-dopa. At noon maximal static airway pressures were measured using a resistive mouthpiece equipped with a pressure sensor. Three acceptable ventilatory efforts were obtained for calculation of mean maximal inspiratory and expiratory airway pressures from time-pressure plots. Pre-exercise clinical disability was then evaluated according to the motor score of the Uni®ed Parkinson's Disease Rating Scale (UPDRS) [23], modi®ed by the grading of arm movements [13]. On the second and third visits blood samples were drawn for determination of safety parameters and 3-O-methyldopa (3-OMD) levels. Blood safety parameters were assayed by routine methods. Plasma 3-OMD was determined by high performance liquid chromatography (HPLC) [24]. Before the exercise test, the patients rested supine for 30 min, after which an ECG was recorded and a blood sample for plasma NA assay was drawn. Plasma NA was determined using HPLC [25]. A maximal work conducted exercise test was performed 1.5±2 h after study drug intake, using an electrically braked bicycle ergometer (Bosch) and an incremental work load protocol with a 40 W starting load followed by 40 W increments. The increment duration was 3 min in order to reach steady-state of gas exchange kinetics. Target cycling speed was 60 rpm. Paramagnetic and infrared analyzers were used for continuous measurement of O2 and CO2 partial pressures, respectively, from the expired air, and pneumotachographic spirometry for measurement of breathing frequency, tidal volume and minute ventilation (EOS Jaeger, Erich Jaeger GmbH, WuÈrtzburg, Germany). An automated printout of all gas exchange variables, including O2 uptake, CO2 production and respiratory exchange ratio, was produced at 30 s intervals. Continuous ECG monitoring with ST segment analysis was carried out throughout the exercise test, and tracings were collected at 30 s intervals. BP was measured 2 min after each work load increment using an aneroid manometer. An ear-lobe pulse oximeter detector was used for monitoring of arterial oxygen saturation. The rate of perceived exertion was determined at the end of each workload using Borg's scale [26]. The exercise test was continued to subjective maximum
(19±20 out of 20 in Borg perceived exertion scale) unless clinical criteria for stopping the exercise were met. At peak exercise level, BP and ECG were recorded and a blood sample for the determination of plasma NA was drawn. After exercise, the patients rested supine for 10 min while ECG and BP were registered repeatedly. After this follow-up, post-exercise motor UPDRS and any adverse events that had emerged during exercise were assessed. The patients were then allowed to take their antiparkinsonian medication. A submaximal work load standard was selected individually for each patient in order to compare cardiorespiratory variables at a given work load. This standard was de®ned as the highest workload that a patient was able to complete during every exercise test. The variables determined at the end of this submaximal workload were then compared between study treatments and run-in. Most of the cardiorespiratory variables determined (either measured directly or derived automatically by calculation) are explained in Table 2. In addition, systolic and diastolic BPs and HR at peak exercise and at submaximal workload were determined. The statistical comparisons of main interest were between the study treatments, i.e. between entacapone and placebo. Due to the open status of the run-in test and the possible training effect brought by it, the comparisons between the study treatments and run-in were considered to be of secondary importance. Comparisons of cardiorespiratory, clinical and biochemical variables between study treatments and between treatments and run-in were carried out by using either repeated measures analysis of variance (ANOVA) appropriate for cross-over design (normally distributed variables) or Wilcoxon rank sum and signed rank tests (nonnormally distributed variables). The number of patients with adverse events was compared statistically by using McNemar's test. In all statistical comparisons, a p-value of ,0.05 was considered statistically signi®cant. 3. Results All 15 enrolled patients completed the study. No signi®cant period or carry-over effects were observed in any of the
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Table 3 Work capacity and cardiorespiratory responses at peak exercise (max) during a maximal cycle ergometer test, ®rst in the off-phase after withholding l-dopa overnight (run-in visit), then in on-phase after 1 week treatment with either placebo or entacapone 200 mg administered with each dose of l-dopa in 15 patients with Parkinson's disease; Values expressed as mean ^ SD; HRmax, heart rate; BPmax, blood pressure; Wmax/3 0 , the mean highest completed work load for the last 3 min period; VÇO2max, oxygen uptake; VÇEmax, minute ventilation; BR, breathing reserve; Study treatments vs. run-in: * p , 0.05, ** p , 0.01. There were no signi®cant differences in the variables between the study treatments Variable
Run-in (without l-dopa)
Placebo 1 l-dopa
Entacapone 1 l-dopa
HRmax (beats/min) Systolic BPmax (mmHg) Diastolic BPmax (mmHg) Wmax/3 0 (W) VÇO2max (l/min) VÇEmax (l/min) BR (%)
153:0 ^ 20:5 195:4 ^ 22:7 91:8 ^ 8:4 139:0 ^ 46:2 2:0 ^ 0:5 71:5 ^ 24:3 38:3 ^ 18:2
151:2 ^ 22:1 187:7 ^ 22:2 87:1 ^ 10:5 154:1 ^ 47:6** 2:2 ^ 0:6* 75:0 ^ 21:5 34:3 ^ 14:7
153:1 ^ 23:4 184:8 ^ 24:2 79:2 ^ 12:2* 149:9 ^ 47:9* 2:0 ^ 0:6 73:7 ^ 23:0 35:6 ^ 15:0
statistical analyses. The plasma 3-OMD (mean ^ SD) level was signi®cantly lower p , 0:001 after 1 week of entacapone (1.24 ^ 0.55 mg/ml) than after placebo (2.58 ^ 1.08 mg/ml). This decrease in 3-OMD was observed in every patient while they were on entacapone indicating both good compliance and the ef®cacy of entacapone combined with l-dopa treatment. There were no signi®cant differences in the maximal inspiratory airway pressures either between placebo (12.7 ^ 3.5 kPa) and entacapone (12.9 ^ 3.0 kPa) administered with l-dopa, or between the study treatments and the run-in visit (12.0 ^ 2.6 kPa). Maximal expiratory airway pressures were similar between the study treatments (19.1 ^ 4.8 and 20.8 ^ 4.5 kPa for placebo and entacapone, respectively), and between the study treatments and the run-in visit (19.3 ^ 4.6 kPa). Maximal work load and cardiorespiratory responses at peak exercise are presented in Table 3. There were no statistically signi®cant differences in any of these variables between the study treatments. Diastolic BP at peak exercise level was lower p , 0:05 after entacapone 1 l-dopa than during the run-in visit. Higher maximal work load after both entacapone p , 0:05 and placebo p , 0:01; and a slightly higher maximal O2 uptake after placebo p , 0:05 were achieved than during the run-in visit.
Cardiorespiratory responses at submaximal work load are presented in Table 4. O2 pulse was slightly lower p , 0:05 after entacapone 1 l-dopa than after placebo 1 l-dopa. The differences in other submaximal variables were not signi®cant between the study treatments. Ventilatory equivalent for CO2 was higher p , 0:05 during the runin visit than after placebo 1 l-dopa. Submaximal HR was lower p , 0:05 after placebo 1 l-dopa, and submaximal BPs after both study treatments p , 0:01 2 0:001 than during the run-in visit. Plasma NA (Fig. 1) at rest was 1.9 ^ 0.8 nmol/l during run-in visit, 1.8 ^ 0.8 nmol/l after entacapone and 1.7 ^ 0.7 nmol/l after placebo. At peak exercise, the values increased 10 fold, as expected, to 18.7 ^ 12.7, 21.5 ^ 15.7 and 21.3 ^ 15.7 nmol/l, respectively. The changes in plasma NA due to exercise were not signi®cantly different between the treatments. Pre- and post-exercise scores of the modi®ed motor UPDRS were lower after entacapone 1 l-dopa (13.9 ^ 8.6 and 15.9 ^ 11.5, respectively) and placebo 1 l-dopa (15.8 ^ 6.2 and 16.8 ^ 6.2, respectively) than during the run-in visit (22.7 ^ 12.5 and 24.8 ^ 12.5, respectively). The effect of exercise on motor UPDRS was not statistically signi®cant after either study treatment or during the run-in visit.
Table 4 Cardiorespiratory responses at the end of submaximal work load standard (std), selected for each patient individually as the highest work load that a patient was able to complete during every study visit, during a maximal cycle ergometer test. The ®rst test was done in off-phase after withholding l-dopa overnight (run-in visit). The second and third tests were done in on-phase after 1 week treatment with either placebo or entacapone 200 mg administered with each dose of ldopa in 15 patients with Parkinson's disease; Values expressed as mean ^ SD; HRstd, heart rate; BPstd, blood pressure; VÇO2std, oxygen uptake; VÇO2/HRstd, oxygen pulse; VÇEstd, minute ventilation; VÇE/VÇO2std, ventilatory equivalent for oxygen; VÇE/VÇCO2std, ventilatory equivalent for carbon dioxide; Study treatments vs. run-in: * p , 0.05, ** p , 0.01, *** p , 0.001; Entacapone vs. Placebo: # p , 0.05 Variable
Run-in (without l-dopa)
Placebo 1 l-dopa
Entacapone 1 l-dopa
HRstd (beats/min) Systolic BPstd (mmHg) Diastolic BPstd (mmHg) VÇO2std (l/min) VÇO2/HRstd (ml/beat) VÇEstd (l/min) VÇE/VÇO2std VÇE/VÇCO2std
139:5 ^ 17:3 185:0 ^ 17:8 95:7 ^ 7:8 1:8 ^ 0:5 12:8 ^ 3:2 58:6 ^ 21:3 32:2 ^ 5:5 32:5 ^ 3:6
134:2 ^ 17:7* 167:3 ^ 19:6*** 84:3 ^ 11:1*** 1:8 ^ 0:6 13:7 ^ 4:0 56:3 ^ 18:9 30:8 ^ 4:8 30:8 ^ 3:6*
135:8 ^ 21:0 167:6 ^ 17:6*** 86:1 ^ 11:2** 1:7 ^ 0:6 12:5 ^ 3:7# 54:4 ^ 19:1 32:5 ^ 6:3 32:1 ^ 4:5
J. Lyytinen et al. / Parkinsonism and Related Disorders 8 (2002) 349±355
Fig. 1. Plasma NA levels (nmol/l, mean 1 SEM) at rest and at peak exercise during maximal bicycle exercise test, ®rst in off-phase after withholding ldopa overnight (run-in) and then in on-phase after 1 week treatment with either entacapone 200 mg or placebo administered with each dose of l-dopa in 15 patients with Parkinson's disease.
There were no serious adverse events during the study, and no exercise tests were stopped prematurely for clinical reasons. Chest pain was not reported during exercise, and no signs of exercise hypotension, impaired cerebral perfusion, hypoxia or signi®cant ischemic/arrhythmic ECG changes were observed. During exercise tests, adverse events were reported by six patients during the run-in, by ®ve after entacapone 1 l-dopa and by seven after placebo 1 l-dopa (NS for entacapone vs. placebo). All these events were mild to moderate in severity. Dystonia, fatigue and aggravated parkinsonism were the most common events reported. Adverse events were reported by 12 patients after 1 week ambulatory treatment with entacapone 1 l-dopa and by six after 1 week with placebo 1 l-dopa p , 0:05: All these events were mild to moderate in severity, and of them headache, insomnia and nausea were the most common ones reported. One asymptomatic and transient increase in liver transaminases was observed after 1 week of entacapone 1 l-dopa. This was associated with positive cytomegalovirus serology. Otherwise, no clinically signi®cant changes in blood safety variables were observed. The total daily dose of l-dopa was reduced due to dyskinesia in one patient (from 850 to 450 mg), and due to foot dystonia in another (from 600 to 400 mg) while on entacapone 1 l-dopa treatment. Both events resolved completely after dose reductions. 4. Discussion l-dopa is recognized most often as an improver of the
353
motor symptoms of PD, but it has also improved ventilatory function [6], exercise endurance and metabolic ef®ciency of work [7]. Although the cardiovascular safety of l-dopa is subject to much controversy, it is unlikely to cause orthostatic hypotension [8,27] and it was not associated with cardiac toxicity either during exercise [7] or in PD patients with concurrent heart disease [28]. This was the ®rst controlled trial to study cardiorespiratory capacity and exercise safety in parkinsonian patients after multiple-dose administration of entacapone as an adjunct to l-dopa. Because the assessments during the ®rst study visit (run-in) did set requirements for marked and sustained physical effort after overnight l-dopa withdrawal, mainly patients with relatively mild disease severity (H&Y stage 1±2) were enrolled. The study population included both sedentary and physically active patients. Maximal static airway pressures correlate with the short-term isometric power of respiratory muscles, but do not re¯ect overall ventilatory mechanics, ef®ciency or endurance. When our study patients were in off-phase, their maximal airway pressures were in the normal range, which is in accordance with previous reports [2]. Although l-dopa was reported to improve maximal airway pressures in PD [6], we found no signi®cant change after l-dopa alone or after l-dopa and entacapone. In the present study, Borg's scale, respiratory exchange ratio (CO2 production/O2 uptake) and age-predicted maximal HR ( 205 2 age/2) were used in the evaluation of perceived, metabolic and circulatory maximality of exercise, respectively. All study patients attained scores of 19±20/20 in Borg's scale and respiratory exchange ratios . 1 during each exercise test, indicating that these criteria for exercise maximality were met. However, only six out of 15 patients reached $90% of age-predicted maximal HR on each test; one patient reached it twice, one patient once, while seven did not reach it during any of the tests. Comparable results were reported by Stanley et al. [29] and Canning et al. [30], although reports on normal exercise HR responses in PD were also published [3,10]. Treatment seemed not to in¯uence the HR during exercise in the present study. This is in concordance with previous reports of unchanged HR values between pre- and post l-dopa bicycle exercise testing [7]. The age-predicted maximal HR is considered to have measurement error, inter-subject variability, and to be an inaccurate indicator of exercise maximality [31]. When on l-dopa either with or without entacapone, the patients achieved signi®cantly higher maximal work loads than during the run-in visit. In addition to the l-dopa effect, other factors, such the training effect, could contribute to this ®nding. During the run-in visit, the patients were unfamiliar with the exercise procedure and had to endure marked physical effort in off-phase. In contrast to maximal workload, maximal O2 uptake was not increased by entacapone 1 l-dopa when compared to run-in visit results. Although maximal O2 uptake was higher after placebo 1
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l-dopa than during the run-in visit, the difference was small and in proportion to the correspondingly higher maximal work load after placebo 1 l-dopa. Similar values for maximal minute ventilation indicated that maximal exercise capacities were accompanied by similar ventilatory efforts both after the study treatments and during the run-in visit. Entacapone did not change the rest and peak exercise concentrations of plasma NA, hemodynamics or ECG during maximal exercise. This ®nding is in line with results from previous studies in healthy volunteers [17,18,32] and also with the long-term experience on cardiovascular and hemodynamic safety of entacapone in patients with PD [33]. Unlike entacapone, tolcapone, another COMT inhibitor, has recently been described to increase the plasma levels of NA and other catecholamines in l-dopa treated PD patients [34]. It was noticeable that all our study patients used selegiline and six were on a dopamine agonist co-therapy. There appeared to be no safety problems with the concomitant use of these drugs, as con®rmed by the results of the longterm studies with entacapone [15,16,33]. The confounding effect of work rate on cardiorespiratory parameters was eliminated by comparing them at equal (standardized) work loads, which were principally submaximal for each patient. Regardless of entacapone intake, submaximal BP values were lower after l-dopa than during the run-in visit without l-dopa. This reduction was quite small and could be attributed to the training effect. The O2 uptake was similar at standard work load, irrespective of whether the patients were in off-phase, or in on-phase with entacapone or placebo. This suggests that neither entacapone nor l-dopa enhances the metabolic ef®ciency of work in PD. However, the overnight withdrawal of l-dopa does not necessarily represent a pure off-phase, as the drug is known to have also a long-duration response [35]. Some of the patients also used long-acting dopamine agonists and all had selegiline in their antiparkinsonian regimen. The slight decrease in O2 pulse after entacapone may suggest a more non-uniform distribution of blood ¯ow in working muscles, or some other mechanism leading to a decrease in O2 uptake in the working muscle cells with entacapone. However, the effect, if any, seems to be minor and is considered not to be clinically signi®cant. Maximal O2 uptake values did not differ between the treatment groups. We observed no signi®cant effect of exercise on l-dopa motor response, a ®nding in agreement with previous reports [36]. Physical activity has caused a signi®cant improvement in dyskinesias [36], but our study patients were hardly dyskinetic during the pre-exercise motor assessment and therefore such potential effect was not discernible. Entacapone was well tolerated. Adverse events were in most cases related to increased dopaminergic stimulation, e.g. dyskinesia and dystonia, that was well documented in previous clinical studies [13,15,16]. Such events were effectively controlled by reductions in the l-dopa dosage. The results of the present study with 15 PD patients suggest that the use of entacapone with l-dopa and
selegiline seems to be safe in patients with mild to moderate disease, even during maximal physical effort. These results are in line with other studies, in which larger number of patientsÐsome in the more advanced stages of the diseaseÐhave received long-term treatment with entacapone [15,16,33].
Acknowledgements The study was supported by Orion Pharma, Espoo, Finland, which also provided entacapone and matching placebo preparations. The authors also wish to express their appreciation to the staff of the Laboratory of Clinical Physiology, Helsinki University Central Hospital, for their technical assistance. References [1] Koller W, Kase S. Muscle strength testing in Parkinson's disease. Eur Neurol 1986;25:130±3. [2] Tzelepis GE, McCool FD, Friedman JH, Hoppin FG. Respiratory muscle dysfunction in Parkinson's disease. Am Rev Respir Dis 1988;138:266±71. [3] Protas EJ, Stanley RK, Jankovic J, Macneill B. Cardiovascular and metabolic responses to upper-and lower-extremity exercise in men with idiopathic Parkinson's disease. Phys Ther 1996;76:34±40. [4] Hayashi A, Kagamihara Y, Nakajima Y, Narabayashi H, Okuma Y, Tanaka R. Disorder in reciprocal innervation upon initiation of voluntary movement in patients with Parkinson's disease. Exp Brain Res 1988;70:437±40. [5] Hufschmidt A, Stark K, LuÈcking CH. Contractile properties of lower leg muscles are normal in Parkinson's disease. J Neurol Neurosurg Psychiatr 1991;54:457±60. [6] Vincken WG, Darauay CM, Cosio MG. Reversibility of upper airway obstruction after levodopa therapy in Parkinson's disease. Chest 1989;96:210±2. [7] LeWitt PA, Bharucha A, Chitrit I, et al. Perceived exertion and muscle ef®ciency in Parkinson's disease: l-dopa effects. Clin Neuropharmacol 1994;17:454±9. [8] Goetz CG, Lutge W, Tanner CM. Autonomic dysfunction in Parkinson's disease. Neurology 1986;36:73±5. [9] Goldstein DS, Holmes C, Li S-T, Bruce S, Metman LV, Cannon RO. Cardiac sympathetic denervation in Parkinson's disease. Ann Intern Med 2000;133:338±47. [10] Reuter I, Engelhardt M, Freiwaldt J, Baas H. Exercise test in Parkinson's disease. Clin Auton Res 1999;9:129±34. [11] Kaakkola S, Gordin A, MaÈnnistoÈ PT. General properties and clinical possibilities of new selective inhibitors of catechol-O-methyltransferase. Gen Pharmacol 1994;25:813±24. [12] MaÈnnistoÈ PT, Kaakkola S. Catechol-O-methyltransferase (COMT): biochemistry, molecular biology, pharmacology and clinical ef®cacy of the new selective COMT inhibitors. Pharmacol Rev 1999;51: 593±628. [13] Kaakkola S, TeraÈvaÈinen H, Ahtila S, Rita H, Gordin A. Effect of entacapone, a COMT inhibitor, on clinical disability and levodopa metabolism in parkinsonian patients. Neurology 1994:77±80. [14] Ruottinen HM, Rinne UK. Entacapone prolongs levodopa response in a one month double blind study in parkinsonian patients with levodopa related ¯uctuations. J Neurol Neurosurg Psychiatr 1996; 60:36±40. [15] Parkinson Study Group. Entacapone improves motor ¯uctuations in
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levodopaÐtreated Parkinson's disease patients. Ann Neurol 1997;42:747±55. Ê , Worm-Petersen J. Entacapone Rinne UK, Larsen JP, Siden A enhances the response to levodopa in parkinsonian patients with motor ¯uctuations. Neurology 1998;51:1309±14. Illi A, Sundberg S, Koulu M, Scheinin M, HeinaÈvaara S, Gordin A. COMT inhibition by high-dose entacapone does not affect hemodynamics but changes catecholamine metabolism in healthy volunteers at rest and during exercise. Int J Clin Pharm 1994;32:582±8. Illi A, Sundberg S, Ojala-Karlsson P, Scheinin M, Gordin A. Simultaneous inhibition of catechol-O-methyltransferase and monoamine oxidase A: Effects on hemodynamics and catecholamine metabolism in healthy volunteers. Clin Pharmacol Ther 1996; 59:450±7. Illi A, Sundberg S, Ojala-Karlsson P, Scheinin M, Gordin A. Simultaneous inhibition of catecholamine O-methylation by entacapone and neuronal uptake by imipramine: lack of interactions. Eur J Clin Pharmacol 1996;51:273±6. Lyytinen J, Kaakkola S, Ahtila S, Tuomainen P, TeraÈvaÈinen H. Simultaneous MAO-B and COMT inhibition in l-dopa treated patients with Parkinson's disease. Mov Disord 1997;12:497±505. MyllylaÈ VV, Sotaniemi KA, Illi A, Suominen K, KeraÈnen T. Effect of entacapone, a COMT inhibitor, on the pharmacokinetics of levodopa and on cardiovascular responses in patients with Parkinson's disease. Eur J Clin Pharmacol 1993;45:419±23. Lyytinen J, SovijaÈrvi A, Kaakkola S, Gordin A, TeraÈvaÈinen H. The effect of COMT inhibition with entacapone on cardiovascular autonomic responses in l-dopaÐtreated patients with Parkinson's disease. Clin Neuropharmacol 2001;24:50±7. Members of the UPDRS Development Committee, Fahn S, Elton R. Uni®ed Parkinson's disease rating scale. In: Fahn S, Marsden CD, Calne D, Goldstein M, editors. Recent developments in Parkinson's disease, New Jersey: MacMillan Healthcare Information, 1987. p. 153±63. Wikberg T. Simultaneous determination of levodopa, its main metabolites and carbidopa in plasma by liquid chromatography. J Pharmaceut Biomed 1991;9:167±76.
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[25] Scheinin M, Koulu M, Laurikainen E, Allonen H. Hypokalaemia and other non-bronchial effects of inhaled fenoterol and salbutamol: a placebo-controlled dose-response study in healthy volunteers. Br J Clin Pharmacol 1987;24:645±53. [26] Borg GA. Perceived exertion: a note on history and methods. Med Sci Sports 1973;5:90±3. [27] Haapaniemi TH, Kallio MA, Korpelainen JT, et al. Levodopa, bromocriptine and selegiline modify cardiovascular responses in Parkinson's disease. J Neurol 2000;415:868±74. [28] Hunter KR, Hollman A, Laurence DR, Stern GM. Levodopa in parkinsonian patients with heart disease. Lancet 1971;1:932±4. [29] Stanley RK, Protas EJ, Jankovic J. Exercise performance in those having Parkinson's disease and healthy normals. Med Sci Sports Exerc 1999;31:761±6. [30] Canning CG, Alison JA, Allen NE, Groeller H. Parkinson's disease: an investigation of exercise capacity, respiratory function, and gait. Arch Phys Med Rehab 1997;78:199±207. [31] Myers JN. Principles of exercise testing. In: Myers JN, editor. Essentials of cardiopulmonary exercise testing, Illinois: Human Kinetics1996. p. 37±57. [32] Sundberg S, Scheinin M, Illi A, Akkila J, Gordin A, KeraÈnen T. The effects of the COMT inhibitor entacapone on haemodynamics and peripheral catecholamine metabolism during exercise. Br J Clin Pharmacol 1993;36:451±6. [33] MyllylaÈ VV, Kultalahti E-R, Haapaniemi H, FILOMEN Study Group. Twelve-month safety of entacapone in patients with Parkinson's disease. Eur J Neurol 2001;8:53±60. [34] Rojo A, Fontan A, Mena MA, Herranz A, Casado S, de Yebenes JG. Tolcapone increases plasma catecholamine levels in patients with Parkinson's disease. Parkinsonism Relat Disord 2001;7:93±6. [35] Nutt JG, Holford NHG. The response to levodopa in Parkinson's disease: imposing pharmacological law and order. Ann Neurol 1996;39:561±73. [36] Reuter I, Harder S, Engelhardt M, Baas H. The effect of exercise on pharmacokinetics and pharmacodynamics of levodopa. Mov Disord 2000;15:862±8.
www.elsevier.com/locate/parkreldis
The effect of COMT inhibition with entacapone on cardiorespiratory responses to exercise in patients with Parkinson's disease J. Lyytinen a,*, S. Kaakkola a, A. Gordin b, E.-R. Kultalahti b, H. TeraÈvaÈinen a, A. SovijaÈrvi c a
Department of Neurology, University of Helsinki, P.O. Box 340, 00029 Helsinki, Finland b Orion Research Center, Orion Pharma, Espoo, Finland c Department of Clinical Physiology and Nuclear Medicine, University of Helsinki, Helsinki, Finland Received 14 May 2001; revised 16 August 2001; accepted 6 September 2001
Abstract The inhibition of catechol-O-methyltransferase (COMT) may impair catecholamine clearance resulting in unwanted cardiac and hemodynamic events. We therefore studied the effects of entacapone, an inhibitor of peripheral COMT, on cardiorespiratory and plasma noradrenaline (NA) responses to exercise and on respiratory muscle strength in l-dopa treated patients with Parkinson's disease (PD). A randomized, double-blind, cross-over study with two 1 week treatment periods was performed in 15 PD patients. The test battery included analysis of hemodynamics, gas exchange parameters and plasma NA during a maximal exercise test, assessment of maximal static airway pressures and pre- and post-exercise motor scores of the Uni®ed Parkinson's Disease Rating Scale (UPDRS). The ®rst test was done after withholding l-dopa overnight (`run-in' test, off-phase). The second and third tests were done in on-phase after 1 week treatment with either entacapone 200 mg or placebo given with each dose of l-dopa. No differences in maximal work load, plasma NA, or in cardiorespiratory responses to either maximal or work rate standardized submaximal exercise were observed between entacapone and placebo, except for O2 pulse, which was slightly lower p , 0:05 after entacapone at submaximal exercise level. Maximal airway pressures were similar between the study treatments and run-in. Exercise had no effect on motor UPDRS after either study treatment or during the run-in test. No serious adverse events were observed. The results of this study suggest that entacapone does not change the work capacity, work ef®ciency or respiratory muscle strength in l-dopa treated PD patients with mild to moderate disease severity, and that its use with l-dopa seems to be safe in conditions of maximal physical effort. However, data from the long-term use of COMT inhibitors are needed to con®rm these ®ndings. q 2002 Elsevier Science Ltd. All rights reserved. Keywords: Entacapone; Catechol-O-methyltransferase; Exercise; Gas exchange; Hemodynamics; Parkinson's disease
1. Introduction In addition to the major symptoms of rest tremor, bradykinesia and muscle rigidity, weakness and lack of endurance are commonly experienced by patients with Parkinson's disease (PD). Early fatigue in repetitive tasks, decreased isotonic strength [1], and abnormally low metabolic ef®ciency of breathing [2] and work [3] were demonstrated in PD patients. The pathophysiology behind these ®ndings is most likely diverse, and may include abnormalities in neural control [4], muscles [5] and ventilation [2]. l-dopa therapy was shown to improve ventilatory function [6], and both work endurance and ef®ciency in PD patients without affecting exercise hemodynamics [7]. When challenged by physical effort, the autonomic * Corresponding author. Fax: 1358-9-4717-4003. E-mail address: jukka.lyytinen@helsinki.® (J. Lyytinen).
nervous system (ANS) responds by markedly increasing the release of catecholamines, which are then eliminated both by neuronal re-uptake and enzymatically by monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT). During exercise, the role of elimination pathways may become even more important in PD patients, who use the exogenous catecholamine l-dopa. Dysfunction of the ANS is well documented in PD [8]; it includes impairments in noradrenaline (NA) synthesis, release, uptake and turnover [9], and in systolic blood pressure (BP) responses to exercise [10]. Entacapone, a selective and reversibly acting inhibitor of extracerebral COMT, reduces peripheral degradation of l-dopa and prolongs its plasma half-life [11,12], thereby increasing signi®cantly both l-dopa bioavailability [13] and duration of clinical effect in PD patients with motor ¯uctuations [14±16]. COMT inhibition in PD patients might theoretically
1353-8020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved. PII: S 1353-802 0(01)00050-5
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Table 1 Patient demographics; PD, Parkinson's disease; LD, l-dopa; H&Y, Hoehn and Yahr staging; M, male; F, female Age (years)
Gender
Duration (years) PD
43 56 60 60 56 46 48 60 61 49 69 47 62 65 63 Mean SD Range n a b
56.7 7.9 43±69 15
F M F F M M M M M M M M M F M
H&Y
LD
LD a
Fluctuations
6 8 8 9 1 6 3 2 2 5 6 5 5 6 15
6 8 7 8 1 6 3 1 2 5 6 5 5 6 10
2 6 None None None 4 2 1 1 2 3 5 2 2 3
5.8 3.4 1±15 15
5.3 2.6 1±10 15
2.8 1.5 1±6 12
Daily dose (mg) Other b
2 2 1 2 1 2 2 1 2 2 2 2 2 1 2
500 850 600 700 600 300 400 600 300 800 600 1000 900 300 300
1±2 15
720 160 300±1000 15
Pergolide 1.5 Bromocript 15 Bromocript 30 Bromocript 30 Bromocript 15 Bromocript 20
Includes both standard and controlled-release formulations. Bromocript, bromocriptine; all patients used selegiline 5±10 mg o.d.
impair catecholamine clearance and lead, e.g. to cardiac and hemodynamic adverse events. It is therefore important to study the safety of COMT inhibition under maximal exercise conditions. This was already done in healthy human volunteers, in which entacapone had no effect on submaximal exercise hemodynamics or ECG [17]. No hemodynamic problems were observed after co-administration of entacapone with either the MAO type A (MAO-A) inhibitor moclobemide [18] or the neuronal re-uptake inhibitor imipramine [19] in healthy subjects. In PD patients, entacapone has not changed plasma catecholamine levels at rest [20] or cardiovascular autonomic responses to sympathetic/parasympathetic stimuli [21,22]. The effects of entacapone on cardiorespiratory responses to exercise, and on respiratory muscle strength were not studied previously in PD patients. We thus performed a double-blind, placebo-controlled, cross-over trial to investigate these issues in PD patients after multiple-dose administration of entacapone as an adjunct to l-dopa. 2. Methods The present study was conducted according to the amended Declaration of Helsinki and the study protocol was approved by the Ethics Committee of the Department of Neurology, Helsinki University Central Hospital. Fifteen PD patients, either with or without ¯uctuations in clinical disability, were enrolled. Their demographics are presented in Table 1. Prior to inclusion, the patients received oral and
written information on the study objectives, design, and possible risks and discomforts involved. A written consent was then obtained. As a screening test, ventilatory capacity was assessed by ¯ow-volume spirometry with measurements of direct maximal voluntary ventilation, forced expiratory volume during 1 s and forced vital capacity. A clinical examination, ECG and laboratory safety screening were also performed. None of the patients had clinical or laboratory signs of severe cardiovascular, pulmonary, renal, hepatic or psychiatric illnesses and none used other drugs with presumable effect on cardiorespiratory parameters. The study had a double-blind, randomized, cross-over design, where all patients were allocated to receive 1 week study treatments of either entacapone 200 mg or placebo with each dose of l-dopa. The daily dose of entacapone was 600±1000 mg (3±5 daily doses), depending on the dosing frequency of l-dopa. There were 3 study visits in hospital. On the ®rst visit (run-in) tests were performed in off-phase after withholding l-dopa overnight. On the second and third study visits, each at the end of a 1 week treatment period, the tests were performed in on-phase after administration of study treatments. During the study days, no other antiparkinsonian drugs, smoking, cola drinks or coffee were allowed prior to the tests. The dosages of all antiparkinsonian drugs were to be kept unchanged throughout the study, although clinically indicated adjustments in l-dopa dosage were allowed. On study days the patients arrived at the hospital at 10.45 a.m. after having had a light breakfast at home. On the ®rst visit l-dopa was not allowed until after the exercise test. On
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Table 2 Cardiorespiratory variables determined during a maximal cycle ergometer test Variable
Unit 0
Maximal work load (Wmax/3 ) Minute ventilation (VÇE) Oxygen uptake (VÇO2) Oxygen pulse (O2 pulse) Ventilatory equivalent for O2 Ventilatory equivalent for CO2 Breathing reserve (BR)
Explanation
W
The highest completed work load (W) for the last 3 min period the highest completed work load (W) 1 (exercise duration at highest achieved work load (min)/3 min) £ 40W l/min Breathing frequency (l/min) £ tidal volume (l) BF £ VT l/min Minute ventilation (l/min) £ (fraction of O2 in inspired air 2 fraction of O2 in expired air) VÇE(FIO2 2 FEO2) ml/beat Oxygen uptake (l/min)/heart rate (beats/min) VÇO2/HR ± Minute ventilation (l/min)/oxygen uptake (l/min) VÇE/VÇO2 ± Minute ventilation (l/min)/CO2 output (l/min) VÇE/VÇCO2 % {(Maximal voluntary ventilation (l/min) 2 maximal minute ventilation (l/min))/maximal voluntary ventilation (l/min)} £ 100 {(MVV 2 VÇE)/MVV} £ 100
the second and third visits, the study drugs were administered at 11 a.m. with the patients' individual morning dose of l-dopa. At noon maximal static airway pressures were measured using a resistive mouthpiece equipped with a pressure sensor. Three acceptable ventilatory efforts were obtained for calculation of mean maximal inspiratory and expiratory airway pressures from time-pressure plots. Pre-exercise clinical disability was then evaluated according to the motor score of the Uni®ed Parkinson's Disease Rating Scale (UPDRS) [23], modi®ed by the grading of arm movements [13]. On the second and third visits blood samples were drawn for determination of safety parameters and 3-O-methyldopa (3-OMD) levels. Blood safety parameters were assayed by routine methods. Plasma 3-OMD was determined by high performance liquid chromatography (HPLC) [24]. Before the exercise test, the patients rested supine for 30 min, after which an ECG was recorded and a blood sample for plasma NA assay was drawn. Plasma NA was determined using HPLC [25]. A maximal work conducted exercise test was performed 1.5±2 h after study drug intake, using an electrically braked bicycle ergometer (Bosch) and an incremental work load protocol with a 40 W starting load followed by 40 W increments. The increment duration was 3 min in order to reach steady-state of gas exchange kinetics. Target cycling speed was 60 rpm. Paramagnetic and infrared analyzers were used for continuous measurement of O2 and CO2 partial pressures, respectively, from the expired air, and pneumotachographic spirometry for measurement of breathing frequency, tidal volume and minute ventilation (EOS Jaeger, Erich Jaeger GmbH, WuÈrtzburg, Germany). An automated printout of all gas exchange variables, including O2 uptake, CO2 production and respiratory exchange ratio, was produced at 30 s intervals. Continuous ECG monitoring with ST segment analysis was carried out throughout the exercise test, and tracings were collected at 30 s intervals. BP was measured 2 min after each work load increment using an aneroid manometer. An ear-lobe pulse oximeter detector was used for monitoring of arterial oxygen saturation. The rate of perceived exertion was determined at the end of each workload using Borg's scale [26]. The exercise test was continued to subjective maximum
(19±20 out of 20 in Borg perceived exertion scale) unless clinical criteria for stopping the exercise were met. At peak exercise level, BP and ECG were recorded and a blood sample for the determination of plasma NA was drawn. After exercise, the patients rested supine for 10 min while ECG and BP were registered repeatedly. After this follow-up, post-exercise motor UPDRS and any adverse events that had emerged during exercise were assessed. The patients were then allowed to take their antiparkinsonian medication. A submaximal work load standard was selected individually for each patient in order to compare cardiorespiratory variables at a given work load. This standard was de®ned as the highest workload that a patient was able to complete during every exercise test. The variables determined at the end of this submaximal workload were then compared between study treatments and run-in. Most of the cardiorespiratory variables determined (either measured directly or derived automatically by calculation) are explained in Table 2. In addition, systolic and diastolic BPs and HR at peak exercise and at submaximal workload were determined. The statistical comparisons of main interest were between the study treatments, i.e. between entacapone and placebo. Due to the open status of the run-in test and the possible training effect brought by it, the comparisons between the study treatments and run-in were considered to be of secondary importance. Comparisons of cardiorespiratory, clinical and biochemical variables between study treatments and between treatments and run-in were carried out by using either repeated measures analysis of variance (ANOVA) appropriate for cross-over design (normally distributed variables) or Wilcoxon rank sum and signed rank tests (nonnormally distributed variables). The number of patients with adverse events was compared statistically by using McNemar's test. In all statistical comparisons, a p-value of ,0.05 was considered statistically signi®cant. 3. Results All 15 enrolled patients completed the study. No signi®cant period or carry-over effects were observed in any of the
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Table 3 Work capacity and cardiorespiratory responses at peak exercise (max) during a maximal cycle ergometer test, ®rst in the off-phase after withholding l-dopa overnight (run-in visit), then in on-phase after 1 week treatment with either placebo or entacapone 200 mg administered with each dose of l-dopa in 15 patients with Parkinson's disease; Values expressed as mean ^ SD; HRmax, heart rate; BPmax, blood pressure; Wmax/3 0 , the mean highest completed work load for the last 3 min period; VÇO2max, oxygen uptake; VÇEmax, minute ventilation; BR, breathing reserve; Study treatments vs. run-in: * p , 0.05, ** p , 0.01. There were no signi®cant differences in the variables between the study treatments Variable
Run-in (without l-dopa)
Placebo 1 l-dopa
Entacapone 1 l-dopa
HRmax (beats/min) Systolic BPmax (mmHg) Diastolic BPmax (mmHg) Wmax/3 0 (W) VÇO2max (l/min) VÇEmax (l/min) BR (%)
153:0 ^ 20:5 195:4 ^ 22:7 91:8 ^ 8:4 139:0 ^ 46:2 2:0 ^ 0:5 71:5 ^ 24:3 38:3 ^ 18:2
151:2 ^ 22:1 187:7 ^ 22:2 87:1 ^ 10:5 154:1 ^ 47:6** 2:2 ^ 0:6* 75:0 ^ 21:5 34:3 ^ 14:7
153:1 ^ 23:4 184:8 ^ 24:2 79:2 ^ 12:2* 149:9 ^ 47:9* 2:0 ^ 0:6 73:7 ^ 23:0 35:6 ^ 15:0
statistical analyses. The plasma 3-OMD (mean ^ SD) level was signi®cantly lower p , 0:001 after 1 week of entacapone (1.24 ^ 0.55 mg/ml) than after placebo (2.58 ^ 1.08 mg/ml). This decrease in 3-OMD was observed in every patient while they were on entacapone indicating both good compliance and the ef®cacy of entacapone combined with l-dopa treatment. There were no signi®cant differences in the maximal inspiratory airway pressures either between placebo (12.7 ^ 3.5 kPa) and entacapone (12.9 ^ 3.0 kPa) administered with l-dopa, or between the study treatments and the run-in visit (12.0 ^ 2.6 kPa). Maximal expiratory airway pressures were similar between the study treatments (19.1 ^ 4.8 and 20.8 ^ 4.5 kPa for placebo and entacapone, respectively), and between the study treatments and the run-in visit (19.3 ^ 4.6 kPa). Maximal work load and cardiorespiratory responses at peak exercise are presented in Table 3. There were no statistically signi®cant differences in any of these variables between the study treatments. Diastolic BP at peak exercise level was lower p , 0:05 after entacapone 1 l-dopa than during the run-in visit. Higher maximal work load after both entacapone p , 0:05 and placebo p , 0:01; and a slightly higher maximal O2 uptake after placebo p , 0:05 were achieved than during the run-in visit.
Cardiorespiratory responses at submaximal work load are presented in Table 4. O2 pulse was slightly lower p , 0:05 after entacapone 1 l-dopa than after placebo 1 l-dopa. The differences in other submaximal variables were not signi®cant between the study treatments. Ventilatory equivalent for CO2 was higher p , 0:05 during the runin visit than after placebo 1 l-dopa. Submaximal HR was lower p , 0:05 after placebo 1 l-dopa, and submaximal BPs after both study treatments p , 0:01 2 0:001 than during the run-in visit. Plasma NA (Fig. 1) at rest was 1.9 ^ 0.8 nmol/l during run-in visit, 1.8 ^ 0.8 nmol/l after entacapone and 1.7 ^ 0.7 nmol/l after placebo. At peak exercise, the values increased 10 fold, as expected, to 18.7 ^ 12.7, 21.5 ^ 15.7 and 21.3 ^ 15.7 nmol/l, respectively. The changes in plasma NA due to exercise were not signi®cantly different between the treatments. Pre- and post-exercise scores of the modi®ed motor UPDRS were lower after entacapone 1 l-dopa (13.9 ^ 8.6 and 15.9 ^ 11.5, respectively) and placebo 1 l-dopa (15.8 ^ 6.2 and 16.8 ^ 6.2, respectively) than during the run-in visit (22.7 ^ 12.5 and 24.8 ^ 12.5, respectively). The effect of exercise on motor UPDRS was not statistically signi®cant after either study treatment or during the run-in visit.
Table 4 Cardiorespiratory responses at the end of submaximal work load standard (std), selected for each patient individually as the highest work load that a patient was able to complete during every study visit, during a maximal cycle ergometer test. The ®rst test was done in off-phase after withholding l-dopa overnight (run-in visit). The second and third tests were done in on-phase after 1 week treatment with either placebo or entacapone 200 mg administered with each dose of ldopa in 15 patients with Parkinson's disease; Values expressed as mean ^ SD; HRstd, heart rate; BPstd, blood pressure; VÇO2std, oxygen uptake; VÇO2/HRstd, oxygen pulse; VÇEstd, minute ventilation; VÇE/VÇO2std, ventilatory equivalent for oxygen; VÇE/VÇCO2std, ventilatory equivalent for carbon dioxide; Study treatments vs. run-in: * p , 0.05, ** p , 0.01, *** p , 0.001; Entacapone vs. Placebo: # p , 0.05 Variable
Run-in (without l-dopa)
Placebo 1 l-dopa
Entacapone 1 l-dopa
HRstd (beats/min) Systolic BPstd (mmHg) Diastolic BPstd (mmHg) VÇO2std (l/min) VÇO2/HRstd (ml/beat) VÇEstd (l/min) VÇE/VÇO2std VÇE/VÇCO2std
139:5 ^ 17:3 185:0 ^ 17:8 95:7 ^ 7:8 1:8 ^ 0:5 12:8 ^ 3:2 58:6 ^ 21:3 32:2 ^ 5:5 32:5 ^ 3:6
134:2 ^ 17:7* 167:3 ^ 19:6*** 84:3 ^ 11:1*** 1:8 ^ 0:6 13:7 ^ 4:0 56:3 ^ 18:9 30:8 ^ 4:8 30:8 ^ 3:6*
135:8 ^ 21:0 167:6 ^ 17:6*** 86:1 ^ 11:2** 1:7 ^ 0:6 12:5 ^ 3:7# 54:4 ^ 19:1 32:5 ^ 6:3 32:1 ^ 4:5
J. Lyytinen et al. / Parkinsonism and Related Disorders 8 (2002) 349±355
Fig. 1. Plasma NA levels (nmol/l, mean 1 SEM) at rest and at peak exercise during maximal bicycle exercise test, ®rst in off-phase after withholding ldopa overnight (run-in) and then in on-phase after 1 week treatment with either entacapone 200 mg or placebo administered with each dose of l-dopa in 15 patients with Parkinson's disease.
There were no serious adverse events during the study, and no exercise tests were stopped prematurely for clinical reasons. Chest pain was not reported during exercise, and no signs of exercise hypotension, impaired cerebral perfusion, hypoxia or signi®cant ischemic/arrhythmic ECG changes were observed. During exercise tests, adverse events were reported by six patients during the run-in, by ®ve after entacapone 1 l-dopa and by seven after placebo 1 l-dopa (NS for entacapone vs. placebo). All these events were mild to moderate in severity. Dystonia, fatigue and aggravated parkinsonism were the most common events reported. Adverse events were reported by 12 patients after 1 week ambulatory treatment with entacapone 1 l-dopa and by six after 1 week with placebo 1 l-dopa p , 0:05: All these events were mild to moderate in severity, and of them headache, insomnia and nausea were the most common ones reported. One asymptomatic and transient increase in liver transaminases was observed after 1 week of entacapone 1 l-dopa. This was associated with positive cytomegalovirus serology. Otherwise, no clinically signi®cant changes in blood safety variables were observed. The total daily dose of l-dopa was reduced due to dyskinesia in one patient (from 850 to 450 mg), and due to foot dystonia in another (from 600 to 400 mg) while on entacapone 1 l-dopa treatment. Both events resolved completely after dose reductions. 4. Discussion l-dopa is recognized most often as an improver of the
353
motor symptoms of PD, but it has also improved ventilatory function [6], exercise endurance and metabolic ef®ciency of work [7]. Although the cardiovascular safety of l-dopa is subject to much controversy, it is unlikely to cause orthostatic hypotension [8,27] and it was not associated with cardiac toxicity either during exercise [7] or in PD patients with concurrent heart disease [28]. This was the ®rst controlled trial to study cardiorespiratory capacity and exercise safety in parkinsonian patients after multiple-dose administration of entacapone as an adjunct to l-dopa. Because the assessments during the ®rst study visit (run-in) did set requirements for marked and sustained physical effort after overnight l-dopa withdrawal, mainly patients with relatively mild disease severity (H&Y stage 1±2) were enrolled. The study population included both sedentary and physically active patients. Maximal static airway pressures correlate with the short-term isometric power of respiratory muscles, but do not re¯ect overall ventilatory mechanics, ef®ciency or endurance. When our study patients were in off-phase, their maximal airway pressures were in the normal range, which is in accordance with previous reports [2]. Although l-dopa was reported to improve maximal airway pressures in PD [6], we found no signi®cant change after l-dopa alone or after l-dopa and entacapone. In the present study, Borg's scale, respiratory exchange ratio (CO2 production/O2 uptake) and age-predicted maximal HR ( 205 2 age/2) were used in the evaluation of perceived, metabolic and circulatory maximality of exercise, respectively. All study patients attained scores of 19±20/20 in Borg's scale and respiratory exchange ratios . 1 during each exercise test, indicating that these criteria for exercise maximality were met. However, only six out of 15 patients reached $90% of age-predicted maximal HR on each test; one patient reached it twice, one patient once, while seven did not reach it during any of the tests. Comparable results were reported by Stanley et al. [29] and Canning et al. [30], although reports on normal exercise HR responses in PD were also published [3,10]. Treatment seemed not to in¯uence the HR during exercise in the present study. This is in concordance with previous reports of unchanged HR values between pre- and post l-dopa bicycle exercise testing [7]. The age-predicted maximal HR is considered to have measurement error, inter-subject variability, and to be an inaccurate indicator of exercise maximality [31]. When on l-dopa either with or without entacapone, the patients achieved signi®cantly higher maximal work loads than during the run-in visit. In addition to the l-dopa effect, other factors, such the training effect, could contribute to this ®nding. During the run-in visit, the patients were unfamiliar with the exercise procedure and had to endure marked physical effort in off-phase. In contrast to maximal workload, maximal O2 uptake was not increased by entacapone 1 l-dopa when compared to run-in visit results. Although maximal O2 uptake was higher after placebo 1
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l-dopa than during the run-in visit, the difference was small and in proportion to the correspondingly higher maximal work load after placebo 1 l-dopa. Similar values for maximal minute ventilation indicated that maximal exercise capacities were accompanied by similar ventilatory efforts both after the study treatments and during the run-in visit. Entacapone did not change the rest and peak exercise concentrations of plasma NA, hemodynamics or ECG during maximal exercise. This ®nding is in line with results from previous studies in healthy volunteers [17,18,32] and also with the long-term experience on cardiovascular and hemodynamic safety of entacapone in patients with PD [33]. Unlike entacapone, tolcapone, another COMT inhibitor, has recently been described to increase the plasma levels of NA and other catecholamines in l-dopa treated PD patients [34]. It was noticeable that all our study patients used selegiline and six were on a dopamine agonist co-therapy. There appeared to be no safety problems with the concomitant use of these drugs, as con®rmed by the results of the longterm studies with entacapone [15,16,33]. The confounding effect of work rate on cardiorespiratory parameters was eliminated by comparing them at equal (standardized) work loads, which were principally submaximal for each patient. Regardless of entacapone intake, submaximal BP values were lower after l-dopa than during the run-in visit without l-dopa. This reduction was quite small and could be attributed to the training effect. The O2 uptake was similar at standard work load, irrespective of whether the patients were in off-phase, or in on-phase with entacapone or placebo. This suggests that neither entacapone nor l-dopa enhances the metabolic ef®ciency of work in PD. However, the overnight withdrawal of l-dopa does not necessarily represent a pure off-phase, as the drug is known to have also a long-duration response [35]. Some of the patients also used long-acting dopamine agonists and all had selegiline in their antiparkinsonian regimen. The slight decrease in O2 pulse after entacapone may suggest a more non-uniform distribution of blood ¯ow in working muscles, or some other mechanism leading to a decrease in O2 uptake in the working muscle cells with entacapone. However, the effect, if any, seems to be minor and is considered not to be clinically signi®cant. Maximal O2 uptake values did not differ between the treatment groups. We observed no signi®cant effect of exercise on l-dopa motor response, a ®nding in agreement with previous reports [36]. Physical activity has caused a signi®cant improvement in dyskinesias [36], but our study patients were hardly dyskinetic during the pre-exercise motor assessment and therefore such potential effect was not discernible. Entacapone was well tolerated. Adverse events were in most cases related to increased dopaminergic stimulation, e.g. dyskinesia and dystonia, that was well documented in previous clinical studies [13,15,16]. Such events were effectively controlled by reductions in the l-dopa dosage. The results of the present study with 15 PD patients suggest that the use of entacapone with l-dopa and
selegiline seems to be safe in patients with mild to moderate disease, even during maximal physical effort. These results are in line with other studies, in which larger number of patientsÐsome in the more advanced stages of the diseaseÐhave received long-term treatment with entacapone [15,16,33].
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