Parkinsonism &

Related Disorders

Parkinsonism and Related Disorders 8 (2002) 349355

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. Teravainen a, A. Sovijarvi 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 Unied 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 efciency 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 conrm these ndings. q 2002 Elsevier Science
Ltd. All rights reserved.
Keywords: Entacapone; Catechol-O-methyltransferase; Exercise; Gas exchange; Hemodynamics; Parkinson's disease

1. Introduction nervous system (ANS) responds by markedly increasing

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 efciency 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 ventila-
tion [2]. l-dopa therapy was shown to improve ventilatory
function [6], and both work endurance and efciency 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).
1353-8020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S 1353-802 0(01)00050-5
the release of catecholamines, which are then eliminated
both by neuronal re-uptake and enzymatically by monoa-
mine 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 turn-
over [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 signicantly both l-dopa bioavailability [13]
and duration of clinical effect in PD patients with motor
uctuations [1416].
COMT inhibition in PD patients might theoretically
350 J. Lyytinen et al. / Parkinsonism and Related Disorders 8 (2002) 349355

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) H&Y Daily dose (mg)

PD LD Fluctuations LD a Other b

43 F 6 6 2 2 500 Pergolide 1.5

56 M 8 8 6 2 850
60 F 8 7 None 1 600 Bromocript 15
60 F 9 8 None 2 700
56 M 1 1 None 1 600
46 M 6 6 4 2 300 Bromocript 30
48 M 3 3 2 2 400 Bromocript 30
60 M 2 1 1 1 600
61 M 2 2 1 2 300 Bromocript 15
49 M 5 5 2 2 800 Bromocript 20
69 M 6 6 3 2 600
47 M 5 5 5 2 1000
62 M 5 5 2 2 900
65 F 6 6 2 1 300
63 M 15 10 3 2 300
Mean 56.7 5.8 5.3 2.8 720
SD 7.9 3.4 2.6 1.5 160
Range 4369 115 110 16 12 3001000
n 15 15 15 12 15 15
a
Includes both standard and controlled-release formulations.
b
Bromocript, bromocriptine; all patients used selegiline 510 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-administra-
tion 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 cate-
cholamine 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 inves-
tigate these issues in PD patients after multiple-dose admin-
istration 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 measure-
ments 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 enta-
capone was 6001000 mg (35 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 adminis-
tration 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 antiparkinso-
nian 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
 J. Lyytinen et al. / Parkinsonism and Related Disorders 8 (2002) 349355 351

Table 2
Cardiorespiratory variables determined during a maximal cycle ergometer test

Variable Unit Explanation

0
Maximal work load (Wmax/3 )
Minute ventilation (VE)
Oxygen uptake (VO2)
Oxygen pulse (O2 pulse)
Ventilatory equivalent for O2
Ventilatory equivalent for CO2
Breathing reserve (BR)
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) VE(FIO2 2 FEO2)
ml/beat Oxygen uptake (l/min)/heart rate (beats/min) VO2/HR
Minute ventilation (l/min)/oxygen uptake (l/min) VE/VO2
Minute ventilation (l/min)/CO2 output (l/min) VE/VCO2
% {(Maximal voluntary ventilation (l/min) 2 maximal minute ventilation (l/min))/maximal voluntary ventilation
(l/min)} 100 {(MVV 2 VE)/MVV} 100

the second and third visits, the study drugs were adminis-
tered 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 accord-
ing to the motor score of the Unied Parkinson's Disease
Rating Scale (UPDRS) [23], modied 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
1.52 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 incre-
ments. 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 pres-
sures, respectively, from the expired air, and pneumotacho-
graphic spirometry for measurement of breathing
frequency, tidal volume and minute ventilation (EOS
Jaeger, Erich Jaeger GmbH, Wurtzburg, 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 satura-
tion. 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
(1920 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 antiparkinson-
ian medication.
A submaximal work load standard was selected individu-
ally for each patient in order to compare cardiorespiratory
variables at a given work load. This standard was dened 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 vari-
ables) or Wilcoxon rank sum and signed rank tests (non-
normally 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 signicant.
3. Results
All 15 enrolled patients completed the study. No signi-
cant period or carry-over effects were observed in any of the
352 J. Lyytinen et al. / Parkinsonism and Related Disorders 8 (2002) 349355

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; VO2max, oxygen uptake; VEmax, minute ventilation; BR, breathing reserve; Study treatments vs. run-in: * p , 0.05, ** p , 0.01. There were no
signicant 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) 153:0 ^ 20:5 151:2 ^ 22:1 153:1 ^ 23:4

Systolic BPmax (mmHg) 195:4 ^ 22:7 187:7 ^ 22:2 184:8 ^ 24:2
Diastolic BPmax (mmHg) 91:8 ^ 8:4 87:1 ^ 10:5 79:2 ^ 12:2*
Wmax/3 0 (W) 139:0 ^ 46:2 154:1 ^ 47:6** 149:9 ^ 47:9*
VO2max (l/min) 2:0 ^ 0:5 2:2 ^ 0:6* 2:0 ^ 0:6
VEmax (l/min) 71:5 ^ 24:3 75:0 ^ 21:5 73:7 ^ 23:0
BR (%) 38:3 ^ 18:2 34:3 ^ 14:7 35:6 ^ 15:0

statistical analyses. The plasma 3-OMD (mean ^ SD) Cardiorespiratory responses at submaximal work load are
level was signicantly lower p , 0:001 after 1 week of presented in Table 4. O2 pulse was slightly lower p , 0:05
entacapone (1.24 ^ 0.55 mg/ml) than after placebo after entacapone 1 l-dopa than after placebo 1 l-dopa.
(2.58 ^ 1.08 mg/ml). This decrease in 3-OMD was The differences in other submaximal variables were not
observed in every patient while they were on entacapone signicant between the study treatments. Ventilatory
indicating both good compliance and the efcacy of equivalent for CO2 was higher p , 0:05 during the run-
entacapone combined with l-dopa treatment. in visit than after placebo 1 l-dopa. Submaximal HR was
There were no signicant differences in the maximal lower p , 0:05 after placebo 1 l-dopa, and submaximal
inspiratory airway pressures either between placebo BPs after both study treatments p , 0:01 2 0:001 than
(12.7 ^ 3.5 kPa) and entacapone (12.9 ^ 3.0 kPa) adminis- during the run-in visit.
tered with l-dopa, or between the study treatments and the Plasma NA (Fig. 1) at rest was 1.9 ^ 0.8 nmol/l during
run-in visit (12.0 ^ 2.6 kPa). Maximal expiratory airway run-in visit, 1.8 ^ 0.8 nmol/l after entacapone and
pressures were similar between the study treatments 1.7 ^ 0.7 nmol/l after placebo. At peak exercise, the values
(19.1 ^ 4.8 and 20.8 ^ 4.5 kPa for placebo and entacapone, increased 10 fold, as expected, to 18.7 ^ 12.7, 21.5 ^ 15.7
respectively), and between the study treatments and the and 21.3 ^ 15.7 nmol/l, respectively. The changes in
run-in visit (19.3 ^ 4.6 kPa). plasma NA due to exercise were not signicantly different
Maximal work load and cardiorespiratory responses at between the treatments.
peak exercise are presented in Table 3. There were no statis- Pre- and post-exercise scores of the modied motor
tically signicant differences in any of these variables UPDRS were lower after entacapone 1 l-dopa
between the study treatments. Diastolic BP at peak exercise (13.9 ^ 8.6 and 15.9 ^ 11.5, respectively) and placebo 1
level was lower p , 0:05 after entacapone 1 l-dopa than l-dopa (15.8 ^ 6.2 and 16.8 ^ 6.2, respectively) than
during the run-in visit. Higher maximal work load after both during the run-in visit (22.7 ^ 12.5 and 24.8 ^ 12.5, respec-
entacapone p , 0:05 and placebo p , 0:01; and a tively). The effect of exercise on motor UPDRS was not
slightly higher maximal O2 uptake after placebo p , statistically signicant after either study treatment or during
0:05 were achieved than during the run-in visit. 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 l-
dopa in 15 patients with Parkinson's disease; Values expressed as mean ^ SD; HRstd, heart rate; BPstd, blood pressure; VO2std, oxygen uptake; VO2/HRstd,
oxygen pulse; VEstd, minute ventilation; VE/VO2std, ventilatory equivalent for oxygen; VE/VCO2std, 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) 139:5 ^ 17:3 134:2 ^ 17:7* 135:8 ^ 21:0

Systolic BPstd (mmHg) 185:0 ^ 17:8 167:3 ^ 19:6*** 167:6 ^ 17:6***
Diastolic BPstd (mmHg) 95:7 ^ 7:8 84:3 ^ 11:1*** 86:1 ^ 11:2**
VO2std (l/min) 1:8 ^ 0:5 1:8 ^ 0:6 1:7 ^ 0:6
VO2/HRstd (ml/beat) 12:8 ^ 3:2 13:7 ^ 4:0 12:5 ^ 3:7#
VEstd (l/min) 58:6 ^ 21:3 56:3 ^ 18:9 54:4 ^ 19:1
VE/VO2std 32:2 ^ 5:5 30:8 ^ 4:8 32:5 ^ 6:3
VE/VCO2std 32:5 ^ 3:6 30:8 ^ 3:6* 32:1 ^ 4:5
 J. Lyytinen et al. / Parkinsonism and Related Disorders 8 (2002) 349355
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 l-
dopa 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 signicant 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 head-
ache, 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 signicant 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 efciency of
work [7]. Although the cardiovascular safety of l-dopa is
subject to much controversy, it is unlikely to cause ortho-
static 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 cardio-
respiratory 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 with-
drawal, mainly patients with relatively mild disease severity
(H&Y stage 12) 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 reect overall ventilatory mechanics, efciency 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 signicant 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 maxi-
mal HR ( 205 2 age/2) were used in the evaluation of
perceived, metabolic and circulatory maximality of exer-
cise, respectively. All study patients attained scores of
1920/20 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 maxi-
mal 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 inuence 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 signicantly 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
354 J. Lyytinen et al. / Parkinsonism and Related Disorders 8 (2002) 349355
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 maxi-
mal 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 conrmed by the results of the long-
term 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 submax-
imal 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 enta-
capone nor l-dopa enhances the metabolic efciency 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 consid-
ered not to be clinically signicant. Maximal O2 uptake
values did not differ between the treatment groups.
We observed no signicant effect of exercise on l-dopa
motor response, a nding in agreement with previous
reports [36]. Physical activity has caused a signicant
improvement in dyskinesias [36], but our study patients
were hardly dyskinetic during the pre-exercise motor assess-
ment 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
patientssome in the more advanced stages of the
diseasehave 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.
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