Damier_edit.qxp 20/2/09 9:04 am Page 38
Age-related Neurodegenerative Disease Parkinson’s Disease
Figure 1: Metabolism of Levodopa – Levodopa–Carbidopa–
Safety data demonstrate that concomitant entacapone with levodopa–
Entacapone Increases the Availability of Dopamine in the Brain
DDCI is well tolerated. The majority of the safety data have been
derived from analysis of the adverse events reported in: the four main
A
Peripheral Brain phase III, double-blind, placebo-controlled efficacy studies;
7–10
DDC
NOMESAFE, a three-year open-label extension of the NOMECOMT
L-DOPA L-DOPA Dopamine
study with up to five years of follow-up;
11
the long-term phase III
COMT DDC
safety study FILOMEN;
12,13
and post-marketing surveillance studies
representing over one million patient-years of exposure.
3-OMD Dopamine
Blood–brain barrier
Two categories of side effects can be determined: dopaminergic
adverse events, which include dyskinesias, nausea and vomiting, and
B
Peripheral Brain non-dopaminergic events, which include urine discolouration,
Entacapone Carbidopa
diarrhoea, abdominal pain and constipation. A retrospective analysis of
DDC
pooled data from the four comparative phase III studies
7–10
and the
L-DOPA L-DOPA Dopamine
FILOMEN safety study
12,13
showed that approximately 30% of patients
COMT DDC
administered levodopa–DDCI and entacapone developed dyskinesias
as an adverse event. However, the number of patients who dropped
3-OMD Dopamine
out of trials as a result of an increase in dyskinesias was only 1–2%.
Blood–brain barrier
Approximately 10% of patients reported urine discolouration.
Diarrhoea occurred in 10% of patients, but resulted in withdrawal of
COMT = catechol-omethyl transferase; 3-OMD = 3-omethylevodopa; DDC = dopa
decarboxylase; L-DOPA = levodopa.
study medication in only 2.5–3% of cases (see Table 1).
Figure 2: Entacapone Leads to a Less Pulsatile Plasma Levodopa
Profile by Avoiding Deep Troughs
In the NOMESAFE study,
11
all patients received open-label levodopa–
DDCI and entacapone. Over three years, levodopa–DDCI and
500 STALEVO (TID) entacapone were found to maintain a good tolerability profile. The
Conventional levodopa (TID)
mean duration of benefit self-reported by patients from first morning
400
***
**
dose with levodopa–DDCI and entacapone increased from a mean of
**
**
300
*** 2.1 hours at baseline to 2.8 hours at three months and remained
mean±SEM)
***
*** significantly above baseline at three years (p<0.001 in all cases). The
200
***
*
NOMESAFE study also indicated no significant deterioration in UPDRS
(hg/ml; **
Plasma level of levodopa
100
scores with levodopa–DDCI and entacapone, demonstrating
1st trough 2nd trough
0
preservation of patient function at three years compared with
0 30 60 90 120 150 180 210 240 270 300 330 360 390 420 450
baseline. There were no significant changes in mean UPDRS I scores,
Drug intake Time (minutes)
while mean UPDRS II (ADL) and III (motor) scores improved significantly
(p<0.05) from 10.5 to 9.8 during the first 12 months and from 28.4 at
Source: Muller et al., J Neural Transm, 2006;113(10):1441.
*p<0.05; **p<0.01; ***p<0.001; TID = three times daily.
baseline to 26.9 at month three, respectively. By month 36, both
UPDRS II and III scores were similar to baseline.
Figure 3: Effect of Entacapone on Motor Fluctuations
These data on the efficacy and safety of COMT inhibition in the
‘On’-time
a
8
‘Off’-time
b
p<0.001 p<0.001 *p<0.05
treatment of patients experiencing re-emergence of symptoms due to
2.0
1.5
7
wearing-off were given a level A status by the joint European Federation
1.0 6
of Neurological Societies (EFNS), the Movement Disorder Society–
0.5
’
-time (hours)
’
-time (hours)
Improvement
0.0
Change in daily European Section (MDS-ES) 2006 guidelines
14
and the quality standards
Change in daily
‘
on
5
‘
on Improvement
*
-0.5
4
B2 4 8 16 24 subcommittee of the American Academy of Neurology (AAN).
15
Time (weeks)
Withdrawal
Time (months)
Motor scores
a,c
ADL scores
b
-4.0
p<0.05 -1.5 p<0.05 Current Therapeutic Options to Reduce Motor Fluctuations
-1.2
-3.0
-1.0
Several therapeutic options can be considered in a patient treated
c
ore
c
ore -0.8
-2.0
-0.6
-0.4
with conventional levodopa and suffering from motor fluctuations.
Improvement
-0.2
(motor) s
-1.0
Improvement (motor) s
0
The first strategy is to increase the levodopa dose frequency. This
Change in UPDRS III Change in UPDRS III -0.2
-0.0
-0.4
choice has the advantage of not introducing a new drug, but renders
Levodopa/DDCI and placebo Levodopa/DDCI and entacapone*
the daily treatment more cumbersome because while drug intake at
each meal is easy to organise, the added pill burden required to
Sources: a. Rinne et al., Neurology, 1998;51(5):1309; b. Poewe et al., Acta Neurol Scand,
2002;105:245; c. Stalevo US prescribing information.
increase drug intake every three hours is more complicated. Another
*Levodopa–carbidopa–entacapone is available as Stalevo
®
.
option is to use a sustained-release form of levodopa,
16,17
although
such a strategy has a limited effect in reducing motor fluctuations.
18
treated with levodopa–DDCI and entacapone by -1.1 points and From a practical point of view, the sustained-release form appears to
deteriorated with levodopa–DDCI plus placebo by 0.2 points; again, the be beneficial as a late-evening dose for improving night and early-
difference between the groups was statistically significant (p<0.05). morning akinesia.
19
38 EUROPEAN NEUROLOGICAL REVIEW
Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68  |  Page 69  |  Page 70  |  Page 71  |  Page 72  |  Page 73  |  Page 74  |  Page 75  |  Page 76  |  Page 77  |  Page 78  |  Page 79  |  Page 80  |  Page 81  |  Page 82  |  Page 83  |  Page 84  |  Page 85  |  Page 86  |  Page 87  |  Page 88  |  Page 89  |  Page 90  |  Page 91  |  Page 92  |  Page 93  |  Page 94  |  Page 95  |  Page 96  |  Page 97  |  Page 98  |  Page 99  |  Page 100  |  Page 101  |  Page 102  |  Page 103  |  Page 104  |  Page 105  |  Page 106  |  Page 107  |  Page 108  |  Page 109  |  Page 110  |  Page 111  |  Page 112  |  Page 113  |  Page 114  |  Page 115  |  Page 116  |  Page 117  |  Page 118  |  Page 119  |  Page 120  |  Page 121  |  Page 122  |  Page 123  |  Page 124