 |
|
Budipine Provides Additional Benefit in Patients With Parkinson Disease Receiving a Stable Optimum Dopaminergic Drug Regimen
Horst Przuntek, MD;
Stefan Bittkau, MD;
Harald Bliesath, MD;
Ulrich Büttner, MD;
Gerd Fuchs, MD;
Joachim Glass, MD;
Harald Haller, MD;
Thomas Klockgether, MD;
Peter Kraus, MD;
Lutz Lachenmayer, MD;
Dieter Müller, MD;
Thomas Müller, MD;
Bernhard Rathay, MD;
Jörg Sgonina, PhD;
Volker Steinijans, PhD;
Elemer Teshmar, MD;
Gudrun Ulm, MD;
Dieter Volc, MD
Arch Neurol. 2002;59:803-806.
ABSTRACT
| |
Background The complex pharmacological profile of the antiparkinsonian drug budipine
influences neurotransmission beyond the dopaminergic system. Previous studies
have demonstrated the therapeutic efficacy of budipine on motor symptoms in
insufficiently treated patients with Parkinson disease.
Objective To demonstrate the efficacy of 20 mg of budipine, 3 times daily, in
addition to a stable, prior, optimum-titrated dopaminergic substitution consisting
of a combination of levodopa and a dopa decarboxylase inhibitor, bromocriptine
mesylate, and optional selegiline hydrochloride in 99 patients with idiopathic
Parkinson disease in a multicenter, double-blind, placebo-controlled trial.
Results Budipine significantly (P<.001) decreased
the Columbia University Rating Scale sum score (median, 15.0; 95% confidence
interval, 11.3-17.0) compared with placebo (median, 4.3; 95% confidence interval,
3.0-7.5) at study end point. Budipine reduced Columbia University Rating Scale
subscores for tremor, rigidity, and akinesia.
Conclusion The additional application of budipine provides further therapeutic
benefit in subjects with Parkinson disease receiving a stable, prior, optimum-titrated
dopaminergic drug regimen because of the hypothetical positive impact of budipine
on altered nondopaminergic neurotransmission in patients with Parkinson disease.
INTRODUCTION
ANTIPARKINSONIAN drug trials have mainly focused on the substitution
of the nigrostriatal dopaminergic deficit and have mainly resulted in improvement
of parkinsonian motor symptoms. But insidious deteriorating neurodegeneration
also affects other neurotransmitter systems and extranigral anatomical structures
in patients with idiopathic Parkinson disease (PD).1
Thus, the neurodegenerative process causes onset of a wide heterogeneous variety
of parkinsonian features, all of which limit quality of life.2
Therefore, compounds with a complex pharmacological profile, which also influences
neurotransmission beyond the dopaminergic system, may hypothetically provide
an additional therapeutic benefit in patients with PD. Budipine represents
such a drug, because it also influences, for instance, GABAergic, norepinephrinergic,
serotoninergic, and cholinergic neurotransmission.3-7
Eltze8 provides a review. Previous clinical
trials9-12
have demonstrated the therapeutic efficacy of budipine on motor symptoms in
subjects with PD who receive an insufficient antiparkinsonian drug regimen.
Przuntek and Müller13 provide a review.
The objective of this multicenter, placebo-controlled, double-blind clinical
trial was to demonstrate the antiparkinsonian efficacy of budipine in addition
to a stable, prior, optimally titrated dopaminergic drug regimen consisting
of a combination of levodopa and a dopa decarboxylase inhibitor, bromocriptine
mesylate, and optional selegiline hydrochloride.
PATIENTS AND METHODS
PATIENTS
We enrolled 99 patients with idiopathic PD, according to the United
Kingdom Brain Bank criteria, into the study (Figure 1).14 They were randomized
to treatment with budipine (n = 49; Hoehn and Yahr stage II [n = 2], III [n
= 17], IV [n = 18], or V [n = 3] [totals reflect patients who completed the
trial]) or placebo (n = 50; Hoehn and Yahr stage II [n = 4], III [n = 16],
IV [n = 20], or V [n = 4] [totals reflect patients who completed the trial])
by chance. Their drug regimen had to consist of a combination of levodopa/a
dopa decarboxylase inhibitor, bromocriptine, and optional selegiline. Their
Columbia University Rating Scale (CURS) score at study enrollment had to be
between 24 and 50.15 Subjects with severe unpredictable
motor fluctuations; clinically relevant cardiac, hepatic, gastrointestinal,
metabolic, renal, allergic, or psychiatric disorders; and/or intake of drugs
that affect the dopaminergic system were not allowed to participate. Eighty-four
patients finished the trial. We excluded 15 individuals (before unblinding)
from the per-protocol analysis because of either premature termination not
related to study medication (5 [10%] of budipine-treated patients and 2 [4%]
of placebo-treated participants) or a major protocol violation (4 [8%] of
budipine-treated individuals and 4 [8%] of placebo-treated subjects). There
were no clinically relevant differences for the demographic data and clinical
characteristics between both groups at baseline (Table 1).
|
|
|
|
Figure 1. Patient enrollment in the study.
|
|
|
|
|
|
|
Table 1. Demographic Data of the Participants Who Finished the Study*
|
|
|
DESIGN
We titrated the preexisting dopaminergic drug regimen to its optimum
efficacy and tolerability (eg, onset of dyskinesia, vivid dreams, and cognitive
deficits) according to the patients' and treating physicians' opinion within
4 weeks. Then, we kept the antiparkinsonian therapy stable for at least 4
weeks. A further 4-week screening period followed. Next, we slowly started
titration of budipine from the initial application of 20 mg/d up to 60 mg/d,
adding 10 mg/wk (Figure 2). Soon
after that, participants took budipine, 20 mg 3 times daily, until the end
of the trial for 11 weeks. We allowed reduction of budipine to 40 mg/d because
of the onset of adverse effects. One blinded investigator determined the score
of the patients. Another blinded independent physician controlled patients'
compliance, safety, and tolerability of budipine.
|
|
|
|
Figure 2. Daily dosages of budipine and
placebo and decrease of the Columbia University Rating Scale (CURS) sum score
during the trial.
|
|
|
STATISTICAL ANALYSIS
We computed differences of the CURS score and its subscores of tremor
(items [grade, 0-4]: arm [score right and left], head, and leg [score right
and left]), rigidity (items [grade, 0-4]: arm [score right and left separately],
neck, and leg [score right and left separately]), and bradykinesia (items
[grade, 0-4]: bradykinesia [combining slowness and poverty of movement in
general], gait disturbance, posture, postural stability, and arising from
a chair [straight-back wooden or metal chair]) between baseline (score: [V-4+ V0]/2) and the end of the trial (score: [V12 + V16]/2) in the budipine- and the placebo-treated groups
(Figure 2).15-16
(V indicates visit; subscript numbers, number of the visit.) Then, we used
the Wilcoxon rank sum test for comparison of both treatment arms. The P value was adjusted to .01 for multiple testing of CURS
and its subscores.
RESULTS
There was a significant distinct reduction of the CURS sum score in
the budipine-treated patients compared with the placebo-treated patients (Table 2 and Figure 2). The improvement of the median CURS score corresponded
to nearly 40% in the budipine-treated group. Columbia University Rating Scale
subscores of tremor, rigidity, and akinesia were significantly more reduced
in the budipine than the placebo-treated subjects (Table 2). Scores for depression and dementia did not significantly
change within and between both groups (P = .12 and
.29, respectively; Wilcoxon rank sum test). Dizziness (n = 4), dry mouth (n
= 4), loss of appetite (n = 3), nervousness (n = 3), and visual dysfunction
(n = 3) were reported adverse effects of the budipine-treated patients, whereas
only 1 participant in the placebo-treated group complained of dizziness. There
were no clinically relevant changes for blood variables, blood pressure, heart
rate, and electrocardiographic results (data not shown).
|
|
|
|
Table 2. Total Point Reduction of the CURS Score After 16 Weeks*
|
|
|
COMMENT
Additional treatment with budipine in doses up to 20 mg 3 times daily
significantly further improved parkinsonian symptoms compared with placebo
in our trial. We confirm the results of another double-blind placebo-controlled
study on the efficacy of budipine, 20 mg administered in the morning. This
study showed a significant decrease of the CURS sum score and amelioration
of rigidity, akinesia, and tremor in 29 patients undergoing levodopa and benserazide
monotherapy. Two dropouts appeared in this earlier study.9
Previous open-label monocenter trials9, 12
described the tremorlytic efficacy of budipine with additionally performed
long-term electromyographic recordings in 20 patients with PD (11 patients
in one trial and 9 in another). Our results also confirm those of earlier
predominantly open-label and retrospective studies on subjects with PD without
a previous stable drug regimen and with an insufficiently titrated dopaminergic
antiparkinsonian drug regimen. Przuntek and Müller13
provide a review. In contrast to those earlier studies, we used a higher dose
of budipine, 20 mg 3 times daily, and titrated with certain selected dopaminergic
drugs to an optimum response. Finally, our participants were enrolled in the
study after receiving a stable dopaminergic drug regimen for 4 weeks. Despite
this complex design, the addition of budipine further reduced parkinsonian
symptoms. Therefore, we hypothesize that budipine, with its complex pharmacological
profile, also influenced altered nondopaminergic systems in a positive manner
and, therefore, caused this additional therapeutic benefit. The adverse effects
of this drug were clear and were much more present. Therefore, the blinding
of the investigators is at least uncertain in some patients. This could have
biased our results to a certain extent, despite the use of 2 different investigators,
one only for scoring and a second for further assessments. Both investigators
were blinded to each other.
In conclusion, our study demonstrates that budipine, 20 mg 3 times daily,
provides an additional therapeutic benefit because of its hypothetic positive
impact on altered nondopaminergic neurotransmission in patients with PD.
AUTHOR INFORMATION
Accepted for publication January 3, 2002.
Author contributions: Study concept and design (Drs Przuntek, Bliesath, Büttner, Fuchs, Kraus, T. Müller,
and Sgonina); acquisition of data (Drs Bittkau, Fuchs,
Glass, Haller, Kraus, Lachenmayer, D. Müller, T. Müller, Rathay,
Sgonina, Teshmar, Ulm, and Volc); analysis and interpretation of data (Drs Przuntek, Bittkau, Bliesath, Klockgether, Kraus, Sgonina,
and Steinijans); drafting of the manuscript (Drs
Przuntek, Bittkau, Bliesath, Kraus, T. Müller, Sgonina, and Steinijans); critical revision of the manuscript for important intellectual content (Drs Przuntek, Bliesath, Büttner, Fuchs, Glass, Haller, Klockgether,
Kraus, Lachenmayer, D. Müller, Rathay, Sgonina, Teshmar, Ulm, and Volc); statistical expertise (Drs Przuntek, Bliesath, T.
Müller, and Steinijans); obtained funding (Drs
Przuntek, Bittkau, Bliesath, Kraus, and Ulm); administrative, technical,
and material support (Drs Przuntek, Büttner, Fuchs,
Glass, Haller, Klockgether, Kraus, D. Müller, Rathay, Sgonina, Ulm, and
Volc); and study supervision (Drs Przuntek, Klockgether,
Kraus, Lachenmayer, T. Müller, and Sgonina).
This study was supported by Byk Gulden Pharmaceuticals, Constance, Germany;
and Lundbeck GmbH & Co, Hamburg, Germany.
Corresponding author and reprints: Horst Przuntek, MD, Department
of Neurology, Ruhr University of Bochum, Gudrunstrass 56, 44791 Bochum, Germany
(e-mail: Horst.Przuntek{at}ruhr-uni-bochum.de).
From the Department of Neurology, Ruhr University of Bochum, Bochum,
Germany (Drs Przuntek, Kraus, and T. Müller); Byk Gulden Pharmaceuticals,
Constance, Germany (Drs Bliesath and Steinijans); the Department of Neurology,
Ludwig Maximilian University of Munich, Munich, Germany (Dr Büttner);
Parkinson Clinic, Wolfach (Dr Fuchs); the Department of Neurology, University
of Bonn, Bonn, Germany (Dr Klockgether); the Department of Neurology, Barmbek
General Hospital (Dr Lachenmayer), the Department of Neurosurgery, University
of Hamburg (Dr D. Müller), and Lundbeck GmbH & Co (Dr Sgonina), Hamburg,
Germany; Paracelsus-Elena Clinic, Kassel, Germany (Dr Ulm); and Josephstadt
Neurological Outpatient Clinic, Vienna, Austria (Dr Volc). Drs Bittkau, Glass,
Haller, Rathay, and Teshmar are in private practice in Germany.
REFERENCES
| |
1. Braak H, Braak E, Yilmazer D, Schultz C, de Vos RA, Jansen EN. Nigral and extranigral pathology in Parkinson's disease. J Neural Transm Suppl. 1995;46:15-31.
PUBMED
2. Foley P, Riederer P. Pathogenesis and preclinical course of Parkinson's disease. J Neural Transm Suppl. 1999;56:31-74.
PUBMED
3. Jackisch R, Kruchen A, Sauermann W, Hertting G, Feuerstein TJ. The antiparkinsonian drugs budipine and biperiden are use-dependent
(uncompetitive) NMDA receptor antagonists. Eur J Pharmacol. 1994;264:207-211.
FULL TEXT
| PUBMED
4. Klockgether T, Jacobsen P, Löschmann PA, Turski L. The antiparkinsonian agent budipine is an N-methyl-D-aspartate
antagonist. J Neural Transm Park Dis Dement Sect. 1993;5:101-106.
FULL TEXT
|
ISI
| PUBMED
5. Klockgether T, Wüllner U, Steinbach JP, Petersen V, Turski L, Löschmann PA. Effects of the antiparkinsonian drug budipine on central neurotransmitter
systems. Eur J Pharmacol. 1996;301:67-73.
PUBMED
6. Kornhuber J, Herr B, Thome J, Riederer P. The antiparkinsonian drug budipine binds to NMDA and sigma receptors
in postmortem human brain tissue. J Neural Transm Suppl. 1995;46:131-137.
PUBMED
7. Przuntek H, Russ H. Budipine and the MPTP binding site [letter]. Lancet. 1985;2:35-36.
8. Eltze M. Multiple mechanisms of action: the pharmacological profile of budipine. J Neural Transm Suppl. 1999;56:83-105.
PUBMED
9. Jellinger K, Bliesath H. Adjuvant treatment of Parkinson's disease with budipine: a double-blind
trial versus placebo. J Neurol. 1987;234:280-282.
PUBMED
10. Spieker S, Löschmann P, Jentgens C, Boose A, Klockgether T, Dichgans J. Tremorlytic activity of budipine: a quantitative study with long-term
tremor recordings. Clin Neuropharmacol. 1995;18:266-272.
PUBMED
11. Spieker S, Löschmann PA, Klockgether T. The NMDA antagonist budipine can alleviate levodopa-induced motor fluctuations. Mov Disord. 1999;14:517-519.
PUBMED
12. Spieker S, Breit S, Klockgether T, Dichgans J. Tremorlytic activity of budipine in Parkinson's disease. J Neural Transm Suppl. 1999;56:165-172.
PUBMED
13. Przuntek H, Müller T. Clinical efficacy of budipine in Parkinson's disease. J Neural Transm Suppl. 1999;56:75-82.
PUBMED
14. Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a
clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry. 1992;55:181-184.
ABSTRACT
15. Marttila RJ, Rinne UK. Disability and progression in Parkinson's disease. Acta Neurol Scand. 1977;56:159-169.
PUBMED
16. Masur H. Skalen und Scores in der Neurologie: Quantifizierung
neurologischer Defizite in Forschung und Praxis. Stuttgart, Germany: Georg Thieme Verlag; 1995.
RELATED ARTICLE
Archives of Neurology Reader's Choice: Continuing Medical Education
Arch Neurol. 2002;59(5):878-880.
FULL TEXT
|
