[Skip to Content]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 54.159.197.114. Please contact the publisher to request reinstatement.
Sign In
Individual Sign In
Create an Account
Institutional Sign In
OpenAthens Shibboleth
[Skip to Content Landing]
Download PDF
Figure 1.
Patient enrollment in the study.

Patient enrollment in the study.

Figure 2.
Daily dosages of budipine and placebo and decrease of the Columbia University Rating Scale (CURS) sum score during the trial.

Daily dosages of budipine and placebo and decrease of the Columbia University Rating Scale (CURS) sum score during the trial.

Table 1. 
Demographic Data of the Participants Who Finished the Study*
Demographic Data of the Participants Who Finished the Study*
Table 2. 
Total Point Reduction of the CURS Score After 16 Weeks*
Total Point Reduction of the CURS Score After 16 Weeks*
1.
Braak  HBraak  EYilmazer  DSchultz  Cde Vos  RAJansen  EN Nigral and extranigral pathology in Parkinson's disease. J Neural Transm Suppl.1995;46:15-31.
2.
Foley  PRiederer  P Pathogenesis and preclinical course of Parkinson's disease. J Neural Transm Suppl.1999;56:31-74.
3.
Jackisch  RKruchen  ASauermann  WHertting  GFeuerstein  TJ The antiparkinsonian drugs budipine and biperiden are use-dependent (uncompetitive) NMDA receptor antagonists. Eur J Pharmacol.1994;264:207-211.
4.
Klockgether  TJacobsen  PLöschmann  PATurski  L The antiparkinsonian agent budipine is an N-methyl-D-aspartate antagonist. J Neural Transm Park Dis Dement Sect.1993;5:101-106.
5.
Klockgether  TWüllner  USteinbach  JPPetersen  VTurski  LLöschmann  PA Effects of the antiparkinsonian drug budipine on central neurotransmitter systems. Eur J Pharmacol.1996;301:67-73.
6.
Kornhuber  JHerr  BThome  JRiederer  P The antiparkinsonian drug budipine binds to NMDA and sigma receptors in postmortem human brain tissue. J Neural Transm Suppl.1995;46:131-137.
7.
Przuntek  HRuss  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.
9.
Jellinger  KBliesath  H Adjuvant treatment of Parkinson's disease with budipine: a double-blind trial versus placebo. J Neurol.1987;234:280-282.
10.
Spieker  SLöschmann  PJentgens  CBoose  AKlockgether  TDichgans  J Tremorlytic activity of budipine: a quantitative study with long-term tremor recordings. Clin Neuropharmacol.1995;18:266-272.
11.
Spieker  SLöschmann  PAKlockgether  T The NMDA antagonist budipine can alleviate levodopa-induced motor fluctuations. Mov Disord.1999;14:517-519.
12.
Spieker  SBreit  SKlockgether  TDichgans  J Tremorlytic activity of budipine in Parkinson's disease. J Neural Transm Suppl.1999;56:165-172.
13.
Przuntek  HMüller  T Clinical efficacy of budipine in Parkinson's disease. J Neural Transm Suppl.1999;56:75-82.
14.
Hughes  AJDaniel  SEKilford  LLees  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.
15.
Marttila  RJRinne  UK Disability and progression in Parkinson's disease. Acta Neurol Scand.1977;56:159-169.
16.
Masur  H Skalen und Scores in der Neurologie: Quantifizierung neurologischer Defizite in Forschung und Praxis.  Stuttgart, Germany: Georg Thieme Verlag; 1995.
Original Contribution
May 2002

Budipine Provides Additional Benefit in Patients With Parkinson Disease Receiving a Stable Optimum Dopaminergic Drug Regimen

Author Affiliations

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.

Arch Neurol. 2002;59(5):803-806. doi:10.1001/archneur.59.5.803
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.

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.37 Eltze8 provides a review. Previous clinical trials912 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).

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.

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).

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.

Back to top
Article 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@ruhr-uni-bochum.de).

References
1.
Braak  HBraak  EYilmazer  DSchultz  Cde Vos  RAJansen  EN Nigral and extranigral pathology in Parkinson's disease. J Neural Transm Suppl.1995;46:15-31.
2.
Foley  PRiederer  P Pathogenesis and preclinical course of Parkinson's disease. J Neural Transm Suppl.1999;56:31-74.
3.
Jackisch  RKruchen  ASauermann  WHertting  GFeuerstein  TJ The antiparkinsonian drugs budipine and biperiden are use-dependent (uncompetitive) NMDA receptor antagonists. Eur J Pharmacol.1994;264:207-211.
4.
Klockgether  TJacobsen  PLöschmann  PATurski  L The antiparkinsonian agent budipine is an N-methyl-D-aspartate antagonist. J Neural Transm Park Dis Dement Sect.1993;5:101-106.
5.
Klockgether  TWüllner  USteinbach  JPPetersen  VTurski  LLöschmann  PA Effects of the antiparkinsonian drug budipine on central neurotransmitter systems. Eur J Pharmacol.1996;301:67-73.
6.
Kornhuber  JHerr  BThome  JRiederer  P The antiparkinsonian drug budipine binds to NMDA and sigma receptors in postmortem human brain tissue. J Neural Transm Suppl.1995;46:131-137.
7.
Przuntek  HRuss  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.
9.
Jellinger  KBliesath  H Adjuvant treatment of Parkinson's disease with budipine: a double-blind trial versus placebo. J Neurol.1987;234:280-282.
10.
Spieker  SLöschmann  PJentgens  CBoose  AKlockgether  TDichgans  J Tremorlytic activity of budipine: a quantitative study with long-term tremor recordings. Clin Neuropharmacol.1995;18:266-272.
11.
Spieker  SLöschmann  PAKlockgether  T The NMDA antagonist budipine can alleviate levodopa-induced motor fluctuations. Mov Disord.1999;14:517-519.
12.
Spieker  SBreit  SKlockgether  TDichgans  J Tremorlytic activity of budipine in Parkinson's disease. J Neural Transm Suppl.1999;56:165-172.
13.
Przuntek  HMüller  T Clinical efficacy of budipine in Parkinson's disease. J Neural Transm Suppl.1999;56:75-82.
14.
Hughes  AJDaniel  SEKilford  LLees  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.
15.
Marttila  RJRinne  UK Disability and progression in Parkinson's disease. Acta Neurol Scand.1977;56:159-169.
16.
Masur  H Skalen und Scores in der Neurologie: Quantifizierung neurologischer Defizite in Forschung und Praxis.  Stuttgart, Germany: Georg Thieme Verlag; 1995.
×