 |
|
Evaluation of Dyskinesias in a Pilot, Randomized, Placebo-Controlled Trial of Remacemide in Advanced Parkinson Disease
Parkinson Study Group
Arch Neurol. 2001;58:1660-1668.
ABSTRACT
| |
Context Long-term levodopa therapy for Parkinson disease commonly results in
motor complications including "on-off" fluctuations and dyskinesias, but it
is still unclear how best to assess treatment effects on dyskinesias in clinical
trials.
Objective To compare several methods of rating levodopa-induced dyskinesias to
evaluate the effect of remacemide hydrochloride treatment in patients with
advanced Parkinson disease.
Design Two-week multicenter randomized, double-blind, placebo-controlled, parallel-group
study.
Setting Five academic sites of the Parkinson Study Group.
Patients Thirty-nine subjects at least 30 years old with idiopathic Parkinson
disease and disabling dyskinesias.
Interventions Randomly received daily doses of 150 mg, 300 mg, or 600 mg of remacemide
hydrochloride or matching placebo for 2 weeks.
Main Outcome Measures The dyskinesia rating scales used were the Modified Goetz Dyskinesia
Rating scale (MGDRS), a newly created Lang-Fahn Activities of Daily Living
Dyskinesia scale (LFADLDS), and diary dyskinesia ratings.
Results Patient and investigator diaries showed excellent agreement in dyskinesia
ratings. The MGDRS score correlated with clinic diary ratings of the percentage
of "on" time with dyskinesias, and the LFADLDS score correlated with home
and clinic diary assessments of percentage of on time with severe dyskinesias.
The MGDRS score did not correlate highly with the LFADLDS score. This pilot
study also validated previous results demonstrating the safety and tolerability
of remacemide treatment for advanced Parkinson disease but did not result
in any demonstrable improvement or worsening in dyskinesia measures.
Conclusions Diaries may provide a valid means of evaluating dyskinesias in clinical
trials for Parkinson disease, but there remain other aspects of dyskinesias,
as assessed by the MGDRS and LFADLDS, that are not reflected in diary ratings.
INTRODUCTION
WITHIN 5 years of diagnosis approximately half of the patients with
Parkinson disease (PD) treated with levodopa develop motor complications,
including "on-off" fluctuations and dyskinesias.1
Dyskinesias often exhibit a dose-dependent relationship with dopaminergic
therapy, diminishing with dosage decreases and worsening with increases.2 The pathophysiological origins of these phenomena
have not been definitively established; however, the mechanism underlying
the development of dyskinesias may be distinct from that of levodopa's antiparkinsonian
properties.3, 4, 5, 6, 7, 8
Systemic administration of N-methyl D-aspartate
(NMDA) antagonists can ameliorate levodopa-induced dyskinesias without a reduction
in antiparkinsonian response in both primates and rodents.6, 9, 10
Oh and colleagues11 have reported that intermittent
stimulation of normally functioning dopaminergic receptors activates intraneuronal
signaling pathways in striatal spiny neurons that alters the phosphorylation
state of coexpressed NMDA glutamate receptors. This causes an increased sensitivity
of these glutamatergic receptors to cortical input to the striatum and consequent
motor fluctuations and dyskinesias.11, 12
Thus, NMDA antagonists may reduce or prevent the development of these motor
complications.
Remacemide hydrochloride is a noncompetitive NMDA channel antagonist
with antiparkinsonian efficacy in rodent and primate models of PD when used
in combination with levodopa, but not when administered alone.13
It is safe and well tolerated in patients with PD, and preliminary studies
indicate that it may improve motor fluctuations in levodopa-treated patients.14, 15 Whether it has a significant effect
on dyskinesias has not yet been established, but it has been suggested that
an NMDA antagonist effect accounts for the efficacy of amantadine hydrochloride
treatment in improving levodopa-induced dyskinesias.16
We planned this preliminary multicenter randomized, double-blind, placebo-controlled,
parallel-group study to evaluate the effects of 3 different dosages of remacemide
in patients with PD who have disabling dyskinesias. Since no standard criterion
for the evaluation of dyskinesia severity within a clinical trial exists and
the problem is multifaceted, we used several methods of assessment to determine
which might be best suited for future studies. These included the Modified
Goetz Dyskinesia Rating scale (MGDRS),17 the
newly developed Lang-Fahn Activities of Daily Living Dyskinesia scale (LFADLDS)
(Table 1), and dyskinesia diary
rating cards (Figure 1).
|
|
|
|
Table 1. Lang-Fahn Activities of Daily Living Dyskinesia Scale
|
|
|
|
|
|
|
Figure 1. An example of the dyskinesia diary
rating card. The definitions of the various states are as follows: "on" with severe dyskinesias; troublesome or disabling: dyskinesias
make activities somewhat difficult or very difficult. Take feeding for example.
The patient can eat independently, but may do so sloppily with spilling of
food, or may be even more severe—not being able to eat because of dyskinesias. "On" state with mild dyskinesias; not a problem: Dyskinesias
are noticeable but do not interfere with activities. "On"
state with no dyskinesias and normal motor functions: Close to the
way the patient was before developing parkinsonism. Partial
"off" state or mild off state: Slower than at patient's best and can
still function fairly well. Some patients call this a "partial off" or a "partial
on"state. For these patients, this state is clearly not as bad an off as off
can get. Full "off" state: This is equivalent to
the patient's typical full off state. Asleep: This
means that the patient is sleeping. NOTE: Although the decision as to which
state you are in may be difficult, please do not leave any half-hour period
blank. This decision must be made by you, NOT by any other person. You should
rate each period based on your condition in the last few minutes of that period.
Do not write any extra information on the diary. Only one X should be in each
box for each half-hour period.
|
|
|
PATIENTS AND METHODS
PATIENTS
Thirty-nine patients with idiopathic PD were enrolled from 5 sites of
the Parkinson Study Group (Figure 2).
Subjects were aged 30 years or older and had disabling dyskinesias that were
defined by their presence historically greater than 25% of the average waking
day (ie, score  2 on the Unified Parkinson's Disease Rating Scale [UPDRS],
part IV [complications of therapy], item 32 [What proportion of the waking
day are dyskinesias present?]) and interference with activities of daily living
to at least a moderate extent (ie, score 2 on the UPDRS, part IV, item
33 [How disabling are the dyskinesias?], and a score of 2 or more on at least
2 of the 5 items in the LFADLDS [Table 1]). Subjects were treated with stable optimized dosages of levodopa
for at least 2 to 4 weeks prior to enrollment, and could be taking stable
dosages of selegiline hydrochloride, dopamine agonists, or catechol O-methyltransferase inhibitors. Patients were excluded
if they were taking medications that could potentially alter parkinsonism,
affect dyskinesias, or interfere with the metabolism or mechanism of action
of the study medication, or if there was evidence of significant depression,
dementia, psychosis, or other serious medical conditions.
|
|
|
|
Figure 2. Study flowsheet.
|
|
|
PROCEDURES
After informed consent was obtained, screening medical and laboratory
evaluations were performed with the patient in the "on" state (ie, with good
function). Clinical assessments included the modified Hoehn and Yahr scale,
UPDRS parts I to IV (ie, mentation, activities of daily living [ADL], motor
function, and complications of therapy, respectively), Clinical Global Impressions
scale, Schwab and England ADL scale, Mini-Mental State Examination, and the
Beck Depression Inventory. Measures of dyskinesia severity were also obtained
(described in the "Dyskinesia Outcome Measures" subsection of the "Patients
and Methods" section), and the home dyskinesia diaries were introduced. To
ensure reliable and accurate completion of these diaries by each patient,
extensive instructions were given, an instructional videotape classifying
dyskinesia severity was shown, and a training and practice scoring session
was done with the investigator. During this session, the patient had to be
seen in both "full off" and "on with severe dyskinesias" states (adjusting
the dosage and timing of antiparkinsonian medications, if necessary, to do
so), and complete agreement between the patient and the investigator on the
classification of all observed clinical states had to be achieved. Patients
were then given home dyskinesia diaries to fill out on each of 3 consecutive
days immediately prior to the baseline visit.
Within 14 days, qualified patients returned for baseline evaluation
and the 3-day home diaries were reviewed. At this time, pretreatment clinical
assessments were also performed during an observation period of 6 hours. Patients
were instructed to take their usual doses of antiparkinsonian medications
with a low-protein breakfast prior to arrival at the clinic and to report
to the research center for the study visit at a fixed time (9 AM). All antiparkinsonian
medications were given on a predefined schedule identical to the patient's
schedule at home, and a standardized lunch was provided at a set hour.
At the end of the baseline visit, subjects were randomly assigned to
receive remacemide hydrochloride, 150 mg/d, 300 mg/d, or 600 mg/d, or matching
placebo, in 2 divided doses 12 hours (±2 hours) apart. The computer-generated
randomization plan included stratification by center and blocking to ensure
approximate balance among the treatment groups within each center. Sites telephoned
the Parkinson Study Group Coordination Center, Rochester, NY, to enroll patients,
and patient identification numbers were assigned through an interactive computer
module. Patients were then instructed to fill out another set of 3 home diaries
immediately prior to the next visit.
Administration of medication was initiated on the evening of the baseline
visit and titrated up to the assigned dosage over 5 days. This intervention
continued for a total of 2 weeks. If a patient developed intolerance to the
medication, a change from the twice daily regimen to a 4 times daily regimen,
without changing the total daily dosage, was recommended.
Patients were reevaluated after 2 weeks during another 6-hour observation
period with identical clinical assessments. At this visit, home dyskinesia
diaries were also collected, medication compliance was checked, occurrence
of adverse events was reviewed, and safety evaluation measures were obtained.
DYSKINESIA OUTCOME MEASURES
The primary objective of the study was to evaluate the relationships
among several measures of dyskinesia severity. Evaluation of dyskinesias was
done using the MGDRS, the LFADLDS, and dyskinesia diary rating cards at each
study visit.
The MGDRS is a revision of a scale introduced by Obeso,18
and adapted by the Core Assessment Program for Intracerebral Transplantations.19 An investigator describes the phenomenology, severity,
and functional disability associated with a patient's dyskinesias and rates
these dyskinesias on the basis of direct observation of the patient as he
or she performs specific tasks.17 In this study,
the MGDRS was scored every 30 minutes over the 6-hour observation period (for
a total of 13 assessments) at each visit. The investigator watched the patient
walk, drink from a cup, put on a coat, and button clothing. Specific definitions
for the severity rating codes (range, 0-4 for each task) were provided for
reproducibility of results. A higher score indicates more severe impairment.
Scores were averaged over the 13 assessments completed during that visit.
The LFADLDS is modified from the ADL section of the UPDRS (part II)
and requires the patient to respond to questions assessing how dyskinesias,
at maximal severity, influence his or her ability to write, eat, dress, attend
to hygiene, and walk. It was scored at every visit, retrospectively assessing
how the patient's worst dyskinesias affected ADL over the previous few days.
Specific definitions for the severity rating codes (range, 0-4 for each task)
were provided for reproducibility of results. A higher score indicates more
severe impairment (Table 1).
The dyskinesia diary rating card can be completed by either an investigator
or the patient. It requires notation of whether the patient is on state without
dyskinesias, on state with mild dyskinesias, on state with severe dyskinesias,
partially "off state" (ie, with poor function), fully off state, or asleep
(Figure 1). Diary entries are made
every 30 minutes throughout the day, or over a specified period. Diary-derived
outcome variables include the percentage of time during waking hours that
the patient spent in the on state, on state with dyskinesias, and on state
with severe dyskinesias. The dyskinesia diaries were completed by each patient
at home on 3 consecutive days immediately prior to each study visit (home
diaries). The same rating cards were also simultaneously but independently
scored every 30 minutes by the investigator and the patient during the 6-hour
observation periods at the baseline and week 2 visits (clinic diaries).
STATISTICAL ANALYSIS
The degree of agreement between the investigator and the patient with
regard to clinic diary ratings of dyskinesia measures (percentage of on-state
time with dyskinesias or percentage of on-state time with severe dyskinesias)
was assessed using intraclass correlation coefficients. These were estimated
using a 2-way random effects analysis of variance model.20
The degrees of association among the various dyskinesia measures were quantified
using Spearman rank correlation coefficients. These analyses were performed
separately using data from the baseline and week 2 visits.
Changes from baseline to week 2 in the clinical assessments and dyskinesia
measures were compared among the treatment groups using an analysis of covariance
model with treatment group as the independent variable of interest, investigator
as a stratification factor, and the baseline value of the outcome variable
as a covariate. Using this model, the adjusted mean responses in the active
treatment groups were compared separately with that in the placebo group using
2-tailed t tests. The significance level used for
each test was .017, after Bonferroni correction for multiple group comparisons.
Confidence intervals for each of the treatment effects were also computed
using these models, including a Bonferroni-adjusted confidence coefficient
of 98.3%. All statistical analyses were performed according to the intention-to-treat
principle.
RESULTS
SUBJECT CHARACTERISTICS
Baseline characteristics of the 4 treatment groups are given in Table 2. Overall, patients' ages averaged
(±SD) 64.3 ± 8.4 years and they had a diagnosis of PD for 13.3
± 5.8 years (mean ± SD). Patients spent 75.4% ± 16.1%
(mean ± SD) of the waking day in the on state on average, including
59.5% ± 19.9% (mean ± SD) of the waking day with dyskinesias
and 28.5% ± 25.7% (mean ± SD) with severe dyskinesias, according
to the home diary. Some characteristics were not evenly distributed among
the groups as a natural consequence of randomization. In particular, subjects
in the 600–mg/d treatment group tended to be younger and have less severe
PD than patients in the other 2 groups.
|
|
|
|
Table 2. Baseline Characteristics*
|
|
|
INTERRATER RELIABILITY OF DYSKINESIA DIARY MEASURES
Near-perfect agreement was noted between the independent patient and
investigator assessments of the percentage of on-state time with dyskinesias
(intraclass correlation coefficients = 0.89 and 0.91 at baseline and at week
2, respectively) and the percentage of on-state time with severe dyskinesias
(intraclass correlation coefficients = 0.99 and 0.98 at baseline and at week
2, respectively). Table 3 describes
the overall excellent agreement between patients and investigators on all
of the diary classifications using data from all of the half-hour periods
(average, 12.3 per subject) during the baseline visit.
|
|
|
|
Table 3. Agreements Between Subject and Investigator Dyskinesia Diary
Ratings at Baseline*
|
|
|
ASSOCIATIONS AMONG THE DYSKINESIA MEASURES
Spearman correlation coefficients describing the associations among
the dyskinesia measures at the baseline and week 2 visits are provided in Table 4. Moderate to high correlations
were observed between the home diary ratings and the clinic diary ratings.
For the percentage of on-state time with dyskinesias, the correlations with
home diary ratings at baseline were 0.47 for patient clinic ratings and 0.44
for investigator clinic ratings. These were similar to the correlations observed
at the week 2 visit of 0.52 and 0.50, respectively. For the percentage of
on-state time with severe dyskinesias, the correlations were 0.65 for both
patient and investigator clinic ratings at baseline, and 0.78 and 0.77, respectively,
at week 2.
|
|
|
|
Table 4. Correlations Among Dyskinesia Measures
|
|
|
Moderate correlations were seen between the MGDRS score and the home
and clinic diary ratings of the percentage of on-state time with dyskinesias
at the baseline and week 2 visits (Table
4). The associations were notably better between the MGDRS score
and the clinic diary ratings compared with the home diary ratings. At week
2, moderate correlations were also observed between the MGDRS score and the
clinic diary ratings of the percentage of on-state time with severe dyskinesias
(Table 4).
Moderate correlations were demonstrated between the LFADLDS score and
the home and clinic diary ratings of the percentage of on-state time with
severe dyskinesias at the baseline and week 2 visits (Table 3). Only a weak correlation was observed with the home diary
ratings of the percentage of on-state time with dyskinesias. The MGDRS and
LFADLDS scores did not correlate with each other at baseline and correlated
weakly at the week 2 visit (Table 4).
TOLERABILITY AND SAFETY
All 39 patients tolerated their assigned treatments for 2 weeks without
adjustments in total daily dosage. Adverse events were similar to those seen
in previous studies of remacemide treatment in patients with PD, the most
common being dizziness and gastrointestinal discomfort (Table 5). These occurred in a dose-dependent fashion, with 4 patients
each complaining of dizziness and gastrointestinal discomfort at the remacemide
hydrochloride dose of 600 mg/d. No serious adverse events, changes in vital
signs, or significant abnormal laboratory test results were noted, although
prolonged QT intervals were seen in 2 patients (remacemide hydrochloride,
150 mg/d [n = 1], remacemide hydrochloride, 300 mg/d [n = 1]). Medication
compliance was greater than 90% in all 4 treatment arms.
|
|
|
|
Table 5. Reported Adverse Events
|
|
|
EFFICACY
There were no significant differences between the placebo-treated and
remacemide-treated groups for any of the dyskinesia measures (Table 6). Statistically significant improvements in the UPDRS motor
score (P = .01) and the UPDRS ADL score (P = .004) in the off state were seen in patients receiving 150 mg/d
of remacemide hydrochloride after adjustment for multiple comparisons. Trends
toward increased percentage of on-state time in the home diaries (P = .04) and improved UPDRS ADL score in the off state (P = .04) were seen in patients receiving 300 mg/d of remacemide hydrochloride.
Lastly, a trend toward improved UPDRS ADL score in the on state (P = .04) was seen in patients receiving 600 mg/d of remacemide hydrochloride
(Table 6).
|
|
|
|
Table 6. Treatment Effects (TEs) on Changes From Baseline to Week 2
Visit*
|
|
|
COMMENT
While there are standardized methods to assess changes in a patient's
motor function and overall impairment from PD, there are none that satisfactorily
assess treatment effects on dyskinesias.21
The UPDRS, the most widely used scale in the evaluation of PD, includes extensive
assessments of motor and functional capacity.22
For evaluation of dyskinesias, however, it requests only a rough estimation
of their duration (in 25% increments), association with pain, and resulting
effect on function (ie, nil, mild, moderate, or severe effect). The Abnormal
Involuntary Movement Scale, originally designed for studies of tardive dyskinesias,
does not specifically reflect the disabilities, phenomenology, or distribution
of involvement associated with dyskinesias in patients with PD.4, 17, 23
Another scale, introduced by Fahn24 and used
by Kurlan et al25 rated motor function on a
continuum extending from akinesia to hyperkinesia, reporting these as being
on opposite ends of the spectrum, and implying that these 2 phenomena are
mutually exclusive.26
We found consistently excellent agreement between the patient and investigator
assessments using the clinic dyskinesia diary rating cards. Moderate to high
correlations were also seen between clinic diary and home diary assessments.
These validated the use of patient diaries in the documentation of the patient's
functional state and motor fluctuations throughout the day in the home.
The LFADLDS score showed moderate agreement with home and clinic diary
assessments of the percentage of on time with severe dyskinesias at the baseline
and week 2 visits. This corroborated the usefulness of the scale in evaluating
a patient's worst dyskinesias as these effect ADL, a measure for which this
scale was specifically designed.
The MGDRS score showed better agreement with the home and clinic diary
evaluations of the percentage of on-state time with dyskinesias. It did not
correlate with diary assessments of the percentage of on-state time with severe
dyskinesias until the week 2 visit. In addition, not surprisingly, associations
with clinic diary ratings were consistently better than with home diary ratings.
This emphasizes that the MGDRS score more accurately reflects a patient's
status during the observation period, and only less so how the patient fares
at home. Furthermore, the MGDRS is intrinsically a labor-intensive and time-consuming
procedure, and because in practice only a limited number of assessments can
be performed over any given period, it may not capture a representative sample
of a patient's daily dyskinesias. The observation that it was only at the
week 2 visit that more significant correlations were seen between this scale
and both the percentage of on-state time with dyskinesias and percentage of
on-state time with severe dyskinesias also suggests that there may be a learning
curve for the investigators in the use of the MGDRS over time.
The MGDRS score did not correlate with the LFADLDS score at baseline,
and the correlation was weak at the week 2 visit. Again, the week 2 results
suggest that, indeed, there may be a change over time in the investigators'
use of the scale, albeit that only a weak correlation was seen. The poor correlation
between the historical information from the LFADLDS and clinical observation
data from the MGDRS suggests that the dyskinesias evaluated in the office
may not always be a reliable representation of the most severe dyskinesias
experienced at home. This finding further reiterates the usefulness of a historical
disability scale such as the LFADLDS in evaluation of dyskinesias.
Overall, we found that with proper training, dyskinesia diaries designed
to assess the frequency of dyskinesias are a reliable measure of a patient's
day-to-day state and may be a more convenient, less labor-intensive method
of evaluating dyskinesias than an investigator-based assessment. Although
they may not document the entire spectrum of frequency, severity, phenomenology,
anatomical distribution, and functional impairment associated with a patient's
dyskinesias, aspects that may be more accurately and individually assessed
by other scales such as the MGDRS or the LFADLDS, they still provide a practical
and reliable measure with potential utility for evaluating dyskinesias in
clinical trials for PD.
In this study, we confirmed that remacemide hydrochloride is safe and
well tolerated over a 2-week period at dosages up to 600 mg/d in patients
with PD and dyskinesias who are treated with levodopa. There was improvement
in parkinsonian impairment on some secondary outcome variables (eg, motor
UPDRS scores, the percentage of on-state time, and UPDRS ADL scores in the
on and off states), although others (eg, Clinical Global Impressions scale
scores and Schwab and England ADL scores) failed to show any significant differences.
We observed no significant improvement or worsening in dyskinesias with remacemide
treatment as evaluated by the various scales used. However, this was a small
pilot trial, and the 98.3% confidence intervals for the estimated treatment
effects were wide. Thus, larger trials are required to establish the effects
of remacemide treatment on dyskinesias and parkinsonian impairment.
AUTHOR INFORMATION
Accepted for publication July 23, 2001.
The Parkinson Study Group
Steering Committee
Principal Investigator: Ira Shoulson, MD, Rochester,
NY. Co-principal Investigators: Anthony Lang, MD,
Toronto, Ontario, and Stanley Fahn, MD, New York, NY. Chief
Biostatistician: Michael McDermott, PhD, Rochester. Director, Clinical Trials Coordination Center: Karl Kieburtz, MD, Rochester. Medical Director: Steven Schwid, MD, Rochester. Project Coordinator: Elise Kayson, MS, RNC, Rochester. Steering Committee Members: Thomas Chase, MD, Bethesda, Md; Timothy
Greenamyre, MD, Atlanta, Ga; and John Penney, MD, Boston, Mass.
Investigators and Coordinators
Columbia-Presbyterian Medical Center, New York, NY: Steven Frucht, MD; Hal Winfield, RN. Rush-Presbyterian–St
Luke's Medical Center, Chicago, Ill: Christopher Goetz, MD; Lucia Blasucci,
RN. Oregon Health Sciences University, Portland:
John Nutt, MD; Julie Carter, RN, ANP; Sam Morehouse. University
of Saskatchewan, Saskatoon: Ali Rajput, MD; Marianne Ewanishin, RN. Toronto Hospital, Western Division, Toronto: Lisa Johnston,
RN, BSCN.
Parkinson Study Group Biostatistics and Coordination
Centers
University of Rochester: Cindy Casaceli, MBA;
Denni Day, RN, MSPH; Karen Hodgeman; Nirupama Laroia, MD; Joy Antonelle de
Marcaida, MD*; Constance Orme; Arthur Watts; Rajeshwari Natarajan, PhD; Peng
Huang, PhD.
Safety Monitoring Committee
University of Rochester: Pierre Tariot, MD,
Chair; Christopher Cox, PhD, Carl Leventhal, MD.
*Dr de Marcaida is now with the Department of Neurology, Hartford Hospital,
Hartford, Conn.
This article was corrected 10/24/2001.
This study was supported in part by Astra Pharmaceuticals, Wayne, Pa;
by grant M01-RR00044 to the General Clinical Research Centers at the University
of Rochester, from the National Institutes of Health, Bethesda, Md; and by
a National Parkinson Foundation Center of Excellence at the University of
Rochester.
Corresponding author: J. Antonelle de Marcaida, MD, Department of
Neurology, Hartford Hospital, 80 Seymour St, Hartford, CT 06102 (e-mail: jdemarc{at}harthosp.org).
REFERENCES
| |
1. Miyawaki E, Lyons K, Pahwa R, et al. Motor complications of chronic levodopa therapy in Parkinson's disease. Clin Neuropharmacol. 1997;20:523-530.
ISI
| PUBMED
2. Quinn NP. Classification of fluctuations in patients with Parkinson's disease
[review]. Neurology. 1998;51(suppl 2):S25-S29.
3. Fabbrini G, Mouradian MM, Juncos JL, Schlegel J, Mohr E, Chase TN. Motor fluctuations in Parkinson's disease: central pathophysiological
mechanisms, part I. Ann Neurol. 1988;24:366-371.
FULL TEXT
|
ISI
| PUBMED
4. Mouradian MM, Juncos JL, Fabbrini G, Schlegel J, Bartko JJ, Chase TN. Motor fluctuations in Parkinson's disease: central pathophysiological
mechanisms, part II. Ann Neurol. 1988;24:372-378.
FULL TEXT
|
ISI
| PUBMED
5. Mouradian MM, Heuser IJ, Baronti F, Fabbrini G, Juncos JL, Chase TN. Pathogenesis of dyskinesias in Parkinson's disease. Ann Neurol. 1989;25:523-526.
FULL TEXT
|
ISI
| PUBMED
6. Papa SM, Chase TN. Levodopa-induced dyskinesias improved by a glutamate antagonist in
parkinsonian monkeys. Ann Neurol. 1996;39:574-578.
FULL TEXT
|
ISI
| PUBMED
7. Chase TN, Engber TM, Mouradian MM. Contribution of dopaminergic and glutamatergic mechanisms to the pathogenesis
of motor response complications in Parkinson's disease [review]. Adv Neurol. 1996;69:497-501.
ISI
| PUBMED
8. Verhagen Metman L, Locatelli ER, Bravi D, Mouradian MM, Chase TN. Apomorphine responses in Parkinson's disease and the pathogenesis of
motor complications. Neurology. 1997;48:369-372.
FREE FULL TEXT
9. Papa SM, Engber TM, Kask AM, Chase TN. Motor fluctuations in levodopa-treated parkinsonian rats: relation
to lesion extent and treatment duration. Brain Res. 1994;662:69-74.
FULL TEXT
|
ISI
| PUBMED
10. Engber TM, Papa SM, Boldry RC, Chase TN. NMDA receptor blockade reverses motor response alterations induced
by levodopa. Neuroreport. 1994;5:2586-2588.
PUBMED
11. Oh JD, Vaughan CL, Chase TN. Effect of dopamine denervation and dopamine agonist administration
on serine phosphorylation of striatal NMDA receptor subunits. Brain Res. 1999;821:433-442.
FULL TEXT
|
ISI
| PUBMED
12. Oh JD, Russell DS, Vaughan CL, Chase TN, Russell D. Enhanced tyrosine phosphorylation of striatal NMDA receptor subunits:
effects of dopaminergic denervation and L-DOPA administration. Brain Res. 1998;813:150-159.
FULL TEXT
|
ISI
| PUBMED
13. Greenamyre JT, Eller RV, Zhang Z, Ovadia A, Kurlan R, Gash DM. Antiparkinsonian effects of remacemide hydrochloride, a glutamate antagonist,
in rodent and primate models of Parkinson's disease. Ann Neurol. 1994;35:655-661.
FULL TEXT
| PUBMED
14. Parkinson Study Group. A multicenter randomized controlled trial of remacemide hydrochloride
as monotherapy for Parkinson's disease. Neurology. 2000;54:1583-1588.
FREE FULL TEXT
15. Parkinson Study Group. A randomized controlled trial of remacemide for motor fluctuations
in Parkinson's disease. Neurology. 2001;56:455-462.
FREE FULL TEXT
16. Verhagen Metman L, Del Dotto P, van den Munckhof P, Fang J, Mouradian MM, Chase TN. Amantadine as treatment for dyskinesias and motor fluctuations in Parkinson's
disease. Neurology. 1998;50:1323-1326.
FREE FULL TEXT
17. Goetz CG, Stebbins GT, Shale HM, et al. Utility of an objective dykinesia rating scale for Parkinson's disease:
inter-and intratater reliability assessment. Mov Disord. 1994;9:390-394.
FULL TEXT
|
ISI
| PUBMED
18. Langston JW, Widner H, Goetz CG, et al. Core Assessment Program for Intracerebral Transplantations (CAPIT). In: Lindvall O, Bjorklund A, Widner H, eds. Intracerebral
Transplantation in Movement Disorders. Amsterdam, the Netherlands:
Elsevier Science Publishers; 1991:227-241.
19. CAPIT committee, Langston JW, Widner H, Goetz CG, et al. Core Assessment Program for Intracerebral Transplantations (CAPIT). Mov Disord. 1992;7:2-13.
ISI
| PUBMED
20. Fleiss JL. The Design and Analysis of Clinical Experiments. New York, NY: John Wiley & Sons Inc; 1986.
21. Nutt J. A Unified Dyskinesias Rating Scale for l-dopa–induced dyskinesias? Mov Disord. 1999;14(suppl 1):74-80.
22. Fahn S, Elton RL for the members of the UPDRS Development Committee. Unified Parkinson's Disease Rating Scale. In: Fahn S, Marsden CD, Calne DB, eds. Recent Developments
in Parkinson's Disease. London, England: Macmillan Publishing Co Inc;
1987:153-163.
23. Guy W. ECDEU Assessment Manual for Psychopharmacology. Washington, DC: US Government Printing Office; 1976.
24. Fahn S. "On-off" phenomenon with levodopa therapy in parkinsonism: clinical
and pharmacologic correlations and the effect of intramuscular pyridoxine. Neurology. 1974;24:431-441.
FREE FULL TEXT
25. Kurlan R, Rubin AJ, Miller C, Rivera-Calimlim L, Clarke A, Shoulson I. Duodenal delivery of levodopa for on-off fluctuations in parkinsonism:
preliminary observations. Ann Neurol. 1986;20:262-265.
FULL TEXT
|
ISI
| PUBMED
26. Nutt JG. Levodopa-induced dyskinesia: review, observations, and speculations. Neurology. 1990;40:340-345.
FREE FULL TEXT
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
Use and interpretation of on/off diaries in Parkinson's disease
Reimer et al.
J. Neurol. Neurosurg. Psychiatry 2004;75:396-400.
ABSTRACT
| FULL TEXT
Measuring motor complications in clinical trials for early Parkinson's disease
Marras and Lang
J. Neurol. Neurosurg. Psychiatry 2003;74:143-146.
FULL TEXT
|
