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A Randomized, Double-blind, Placebo-Controlled Trial of Subcutaneously Injected Apomorphine for Parkinsonian Off-State Events
Richard B. Dewey, Jr, MD;
J. Thomas Hutton, MD, PhD;
Peter A. LeWitt, MD;
Stewart A. Factor, DO
Arch Neurol. 2001;58:1385-1392.
ABSTRACT
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Objective To assess the safety and efficacy of subcutaneous apomorphine hydrochloride
administration for off-state (poor motor function) periods in patients with
Parkinson disease with motor fluctuations under both inpatient titration and
outpatient therapeutic conditions.
Patients and Methods Twenty-nine patients had advanced Parkinson disease with 2 hours or
more off time despite aggressive oral therapy. Patients randomly received
titrated doses of subcutaneous apomorphine hydrochloride (2-10 mg, n = 20)
or pH-matched vehicle placebo (n = 9) during an inpatient and 1-month outpatient
phase. A change in the United Parkinson Disease Rating Scale motor score 20
minutes after inpatient dosing during a practically defined off-state event
and the percentage of injections successfully aborting off-state events were
the primary inpatient and outpatient efficacy factors.
Results The average (SEM) levodopa equivalent dose of apomorphine hydrochloride
was 5.4 ± 0.5 mg and the mean placebo dose was 1.0 mL. Mean inpatient
United Parkinson Disease Rating Scale motor scores were reduced by 23.9 and
0.1 points (62% and 1%) by apomorphine treatment and placebo, respectively
(P<.001). The mean percentage of outpatient injections
resulting in successful abortion of off-state events was 95% for apomorphine
and 23% for placebo (P<.001). Inpatient response
was significantly correlated with and predictive of outpatient efficacy (P<.001). The levodopa dose was not predictive of the
apomorphine dose requirement. Frequent adverse events included dyskinesia,
yawning, and injection site reactions.
Conclusion Apomorphine by intermittent subcutaneous injection is effective and
safe for outpatient use to reverse off-state events that occur despite optimized
oral therapy.
INTRODUCTION
MOTOR fluctations are common in patients with advanced Parkinson disease
(PD) whose symptoms are managed with oral levodopa and represent some of the
most disabling complications of the disorder. The transition from good motor
(on-state) function to that of poor motor (off-state) function occurs when
brain levodopa levels fall below the threshold needed to adequately stimulate
striatal dopamine receptors. Since the progression of PD is typically accompanied
by progressive shortening of the clinical effect from each dose of levodopa,1 off states often occur unless strategies are used
that can provide a more continuous stimulation of dopamine receptors. A number
of such strategies have been developed including the use of dopamine agonists,
catechol O-methyl transferase inhibitors, and controlled-release
formulations of levodopa. While these strategies are often helpful, some patients
continue to suffer from episodic, often unpredictable, off states.
There are no agents available in the United States that can provide
a rapid reversal of an individual off state. This "rescue" property is highly
desirable since off states can be very disabling to some patients precipitating
immobility, panic attacks, pain, screaming, or drenching sweats.2, 3, 4
Apomorphine is a direct-acting dopamine agonist with strong D1 and D2 dopamine receptor–stimulating properties that
is administered by a parenteral route (intravenously, rectally, subcutaneously,
sublingually, or intranasally). It has similar efficacy to levodopa with a
substantially more rapid time to onset.5 While
an extensive literature exists for apomorphine therapy for PD, only a few
studies have been conducted as randomized, placebo-controlled trials using
subcutaneous injections of apomorphine to abort off-state events.6, 7, 8, 9, 10, 11, 12, 13, 14, 15
To our knowledge, only a single study has been previously published evaluating
the drug in both inpatient and outpatient settings; in the outpatient setting,
all patients received active drug without a placebo comparator.7
To date there have been no published studies attempting to correlate inpatient
efficacy measures with outpatient results. The present study was performed
to (1) establish the efficacy and safety of subcutaneous apomorphine injections
in a therapeutic setting, and (2) establish whether inpatient efficacy measures
accurately predict outpatient responses when both assessments are performed
in a placebo-controlled, double-blind fashion.
PATIENTS AND METHODS
PATIENT SELECTION
This prospective randomized trial was approved by institutional review
boards of each of the 4 participating US sites, and all patients provided
written informed consent. Enrollment was limited to patients with advanced
idiopathic PD suffering from motor fluctuations. At least 2 hours of off time
per day despite an optimized oral drug regimen, including levodopa and an
oral dopamine agonist, was required. Exclusion criteria included atypical
parkinsonism, psychosis, dementia, drug or alcohol dependency, previous stereotactic
brain surgery for PD, unstable medical illnesses, or previous exposure to
apomorphine. A significant improvement in the United Parkinson Disease Rating
Scale (UPDRS) motor score (part III) after administration of oral levodopa
was required (an expected UPDRS motor score improvement of  30% response
was defined by protocol, but a single patient with a levodopa response of
24% was allowed to randomize).
GENERAL STUDY DESIGN
The study was a prospective, randomized, double-blind, placebo-controlled,
parallel group trial involving 2 phases. Phase 1 consisted of inpatient observation
of upwardly titrated doses given to reverse a practically defined off state
achieved by withholding antiparkinsonian drugs overnight. Phase 2 involved
a 1-month period of outpatient observation of drug effectiveness when administered
by patients or caregivers as needed for reversal of spontaneous off-state
events (wearing-off or on-off). Prior to the inpatient phase, patients were
observed for at least 14 days as outpatients to establish the number of off
hours present per day at baseline. On the first day of the inpatient phase,
all patients were tested under unblinded conditions for their response to
their typical morning dose of oral levodopa (levodopa challenge).
TREATMENTS STUDIED
Apomorphine hydrochloride, 10 mg/mL (Bertek Pharmaceuticals Inc, a subsidiary
of Mylan Laboratories Inc, Pittsburgh, Pa), was compared with its pH 3.5–matched
vehicle placebo. The study drug was packaged in sealed glass ampules, and
at the time of use, was drawn up into a 1-mL insulin syringe. Upward titration
of apomorphine hydrochloride or placebo was begun at 0.2 mL with 0.2-mL increments
to a maximum of 1.0 mL (2-10 mg active) per dose. Titration was terminated
at 1.0 mL or on demonstration of a UPDRS motor score reduction of at least
90% of that recorded during the levodopa challenge. If a dose of apomorphine
or placebo had not generated a levodopa-equivalent response, a second or third
dose could be tested on a single day at intervals of not less than 2 hours.
During the 4-week outpatient phase, patients continued either active
apomorphine or placebo injections as previously randomized in addition to
their regular oral PD medications at the same baseline dosage and frequency.
Patients or caregivers could draw up several doses of the study drug into
syringes at the start of each day that were carried with them wherever they
went. The initial outpatient dose of apomorphine or placebo was the highest
dose achieved during titration, with the option to adjust the dose once after
2 weeks. Outpatient doses were allowed up to 5 times daily as needed to reverse
off-state events. Outpatient injections were not administered if the off-state
event occurred within 1 hour of the last dose of oral medication or within
15 minutes of the next scheduled dose of oral drug. Trimethobenzamide hydrochloride,
250 mg thrice daily, initiated at least 3 days prior to the first possible
dose of apomorphine, was used to minimize the risk of nausea.16
INPATIENT EVALUATION
After overnight PD medication withdrawal, patients were evaluated in
the practically defined off state using the UPDRS motor score as the primary
outcome measure supplemented with the hand tapping score,5
the Webster step-seconds score,17 and the dyskinesia
score.18 Motor assessments were conducted prior
to dosing and were repeated when a clinical on state occurred or within 60
minutes after the levodopa challenge and 15 to 20 minutes after study drug
injection. The primary efficacy factor was the predose to postdose change
in UPDRS motor score assessed at the highest titration dose achieved.
OUTPATIENT EVALUATION
During the 4-week outpatient phase, patients completed daily diaries.
For each injection, patients recorded whether the off-state event was aborted,
the latency to perceived response, and the presence and severity of dyskinesia
and nausea and/or vomiting. Also recorded were the total awake time, time
off, time on, time on with dyskinesias, time of meals, and time of oral medication
ingestion.
SAFETY EVALUATION
Dyskinesia was specifically recorded by the investigator when seen following
levodopa challenge or injected study drug during the inpatient phase, and
by the patient (via diary entry) when occurring following study drug injection
in the outpatient phase. In addition, an adverse event of dyskinesia was reported
for patients developing more severe dyskinesias than prior to study. All other
adverse events were queried using open-ended questions. Routine clinical laboratory
tests, electrocardiograms, and physical examinations were also conducted at
study enrollment and exit.
POWER ANALYSIS
A 2:1 preponderance of active drug to placebo assignment was designed.
Sample size estimation assumed postdosing UPDRS motor scores of (mean ±
SEM) 27.0 ± 12.0 for placebo-treated subjects and 10.0 ± 12.0
for apomorphine-treated subjects. A sample size of 8 patients receiving placebo
and 16 patients receiving apomorphine would support a .05 level of statistical
significance with 87% power. A 10% to 20% dropout was expected.
MEASURES FOR CONTROLLING BIAS
Treatment assignments were randomly and blindly assigned. Using identical-appearing
ampules, medications were independently packaged to support randomized assignment
in the order of patient presentation. All treatment assignments were concealed
until the last patient completed the study and until documentation of all
decisions regarding patient qualification for analysis. With striking differences
in inpatient outcome, it is impossible to assure that blinding was functionally
maintained after the first dose of drug, but no aspect other than drug effect
could provide any basis for a correct guess of drug identity.
STATISTICAL METHODS
The primary measure of inpatient drug effectiveness was the comparison
of predose to postdose change in UPDRS motor raw scores between the highest
doses of apomorphine and the highest doses of placebo. The primary measure
of outpatient drug effectiveness was the percentage of off-state events aborted.
Two inpatient efficacy factors (change in UPDRS motor score and change
in hand tapping score) were suitable for parametric testing using analysis
of variance (ANCOVA). All other secondary inpatient efficacy measures and
all outpatient measures were tested using nonparametric tests (Wilcoxon rank
sum test,  2 test, or others where noted).  Level was
.05. Except where noted, means are presented as mean ± SEM.
Correlation between inpatient response to study injection (percentage
of UPDRS motor score change) and levodopa dose (single morning dose and total
daily dose) was executed by linear regression (levodopa controlled-release
doses multiplied by 0.75 for pooling with immediate-release doses). Correlation
between inpatient response (percentage of UPDRS motor score change) and outpatient
response (percentage of off-state events aborted) was a categorical analysis
with the 67th percentile demarcating the 2:1 equivalent for median success.
Comparison of the efficacy of first vs last daily outpatient doses was tested
for active doses only using a t test. All tests other
than change in UPDRS motor raw score were declared to be secondary or exploratory;
no correction for test multiplicity was imposed.
Intent-to-treat (ITT) assumptions were applied. Patients who failed
to progress through the complete titration were analyzed at the highest dose
achieved. For outpatient factors, analyses were determined on the basis of
available observations with no adjustment or imputation for missing observations.
RESULTS
STUDY POPULATION
Thirty-two patients were enrolled in the study, 29 qualified for ITT
inpatient analysis (20 apomorphine-treated patients and 9 placebo-treated
patients) and 26 qualified for ITT outpatient analysis (18 apomorphine-treated
patients and 8 placebo-treated patients). Two patients dropped out prior to
inpatient dosing because of failure to demonstrate a significant response
to the levodopa challenge, and 1 patient dropped out after signing the consent
form but prior to any inpatient dosing. Three patients tested under inpatient
conditions failed to progress to the outpatient evaluation. One placebo-treated
patient discontinued participation in the study because of a lack of effect
after the third level of inpatient dosing and 1 apomorphine-treated patient
discontinued participation in the study because of adverse events (nausea
and vomiting) during dose titration. One additional apomorphine-treated patient
began outpatient dosing, discontinued participation in the study because of
chest pain during the first week of treatment, and did not keep at least 1
outpatient evaluation visit. A flowchart of the study is shown in Figure 1.
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Figure 1. Patient disposition flowchart.
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The baseline demographics of the safety-ITT population are shown by
treatment assignment in Table 1.
There were no statistically significant differences between groups at baseline.
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Table 1. Baseline Characteristics of the 2 Treatment Groups*
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INPATIENT PHASE
The distribution of levodopa-equivalent doses of the injected study
drug (or maximum dose achieved if not therapeutically equivalent to levodopa)
is shown by treatment group in Figure 2. The distribution of doses was significantly different between the apomorphine-treated
and placebo-treated groups (P<.001, Mantel-Haenszel 2 test) and was bell shaped for the apomorphine-treated group with an
average dose of 5.4 ± 0.5 mg. The only placebo dose less than the maximum
of 1 mL was a placebo-treated patient who terminated the trial after the 0.6-mL
injection because of a lack of effect.
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Figure 2. Distribution of the therapeutically
equivalent dose (or maximum dose achieved) by treatment group. One placebo-treated
patient dropped out after receiving the 0.6-mL dose, declaring a lack of effect.
The average (±SEM) apomorphine hydrochloride dose was 5.4 ±
0.5 mg. The distribution was statistically significantly different between
the groups (P<.001, Mantel-Haenszel 2 test).
For the active apomorphine group, milligrams are 10 times the milliliter values.
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Table 2 lists the UPDRS
motor score along with associated dyskinesia scores measured in response to
oral levodopa (60-minute assessment) and blinded study drug injection (20-minute
assessment). The change in UPDRS motor scores was not significantly different
following oral levodopa (P = .29, ANCOVA primary
analysis) but was significantly different following the study drug injection.
Apomorphine treatment resulted in a change of 23.9 UPDRS points (62% improvement)
while placebo produced essentially no change in UPDRS motor score (P<.001, ANCOVA primary analysis). There was no difference between
the 2 groups in dyskinesias following levodopa challenge, but in the group
receiving active apomorphine, dyskinesias similar to those seen with levodopa
treatment were preferentially seen (P = .001). Table 3 shows similar results for the secondary
efficacy measures.
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Table 2. Primary Efficacy Parameter: UPDRS Motor Score Change at Maximum
Dose Tested With Associated Dyskinesia Scores*
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Table 3. Secondary Inpatient Efficacy Parameters: Hand Tapping Scores
and Webster Step-Second Scores*
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OUTPATIENT PHASE
At the 2-week point of the outpatient phase, doses were increased by
2 mg in 5 apomorphine-treated patients to improve efficacy (from 2, 4, 6,
8, and 8 mg) and reduced from 6 to 4 mg to control nausea in one patient assigned
to apomorphine treatment. In 1 of the patients whose dose increased from 8
to 10 mg, subsequent dose reduction to 5 mg was required because of resultant
confusion. Patient experiences during the outpatient phase (as recorded in
diaries) are given in Table 4.
With up to 5 doses per day allowed as needed, patients elected to inject an
average of 2.5 doses per day. Apomorphine treatment aborted 95% of the off-state
events for which it was used compared with 23% for placebo (P<.001, primary outpatient analysis). Exploratory analysis of first
daily dose vs last daily dose demonstrated no significant difference in outpatient
efficacy under these conditions of use. From a baseline of 6 hours of off
time per day, apomorphine-treated patients demonstrated a 2-hour reduction
in off time while placebo-treated patients demonstrated no reduction (P = .02). This reduction in off time was seen without a
reduction in the number of discrete off-state events suffered per day.
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Table 4. Outpatient Diary Parametersa
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CORRELATION ANALYSES
Figure 3 shows a scatterplot
for the regression of apomorphine dose on oral levodopa dose (that single
morning dose that produced the effect to which apomorphine responses were
matched). Despite a response ratio of 96%, the morning levodopa dose was not
predictive of required apomorphine dose (R2 = 0.05, P = .35, slope = 0.006, and intercept
= 4.0). Total daily levodopa dose also was not predictive of apomorphine dose
(R2 = 0.05, P
= .32, slope = 0.002, and intercept = 4.2).
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Figure 3. Regression analysis of therapeutically
equivalent single doses of apomorphine hydrochloride and oral levodopa. The
regression equation is: apomorphine dose in milligrams = 0.0062 (levodopa
AM dose+4.0 mg); R2 = 0.05, P = .35.
The regression equation for the ampomorphine dose vs the total daily levodopa
dose (not plotted) is: apomorphine dose in milligrams = 0.0015 (levodopa daily
dose+4.2 mg); R2 = 0.05, P = .32. The
20 data points are reflected with 3 superimposed outcomes.
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Figure 4 shows a scatterplot
with contingency table for the correlation between inpatient and outpatient
efficacy results. Outpatient outcome was characterized by the invariant grouping
of results about 2 distinct values (100% or 0% successful abortion of off-state
events). The 67th percentile for success (2:1 randomization) was a 35% reduction
in UPDRS motor score and reversal of at least 80% of outpatient off-state
events. In 22 of 26 patients, inpatient and outpatient results were concordant
(P<.001, Fisher exact test).
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Figure 4. Correlation of inpatient vs outpatient
response. Linear regression of outpatient-inpatient response on inpatient
response shows a statistically significant correlation, R2 = 0.54, P<.001. Categorical analysis is more appropriate
since outpatient scores cluster around a single score of 100% relief. With
a 2:1 preponderance of apomorphine, the 67th percentile is selected to categorize
responses as successful or not. The Fisher exact test of the resulting contingency
table is statistically significant at P<.001. UPDRS indicates
United Parkinson Disease Rating Scale.
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Table 5 summarizes the response
to apomorphine at doses less than levodopa equivalent. The 2-mg dose of apomorphine
hydrochloride, (optimal for 3 of the 20 patients) was statistically distinct
from placebo (32% improvement apomorphine vs 6.3% change placebo, P = .02). The levodopa-equivalent dose of apomorphine hydrochloride
produced a 62% improvement in UPDRS motor score while 2 mg below the levodopa-equivalent
dose (or 2 mg in 3 patients titrated to only 2 mg) still provided 42% improvement
in UPDRS motor score (P<.001 ANCOVA, apomorphine-treated
vs placebo-treated patients).
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Table 5. Apomorphine Dose Response*
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ADVERSE EFFECTS
Adverse events (mostly mild in severity) occurred in 85% of apomorphine-treated
patients and in 89% of placebo-treated patients (Table 6). A single serious adverse event (chest pain, myocardial
infarction ruled out) occurred in a patient assigned to the placebo study
drug. Similar events, without hospitalization, occurred in 3 apomorphine-treated
patients. Injection site complaints (including bruising, pain, skin reaction,
and nodule development) were common. Yawning was reported by 40% of the apomorphine-treated
group but none of the placebo-treated group (P =
.03). Thirty-five percent of the apomorphine-treated patients (and no placebo-treated
patients) experienced drowsiness or somnolence (P
= .07). Dyskinesias were reported as an adverse event by 35% of the apomorphine-treated
group and 11% of the placebo-treated group. Nausea or vomiting occurred in
30% of the apomorphine-treated patients and 11% of the placebo-treated patients.
In 1 apomorphine-treated patient, nausea with vomiting at the 6-mg dose (given
during the inpatient phase) was severe and resulted in discontinuation from
the study. Outpatient nausea was usually mild to moderate in severity and
was generally reported as an isolated event (nausea was not seen in 96% of
all apomorphine-treated patients who received outpatient injections).
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Table 6. Adverse Events Experienced by 2 or More Patients
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Uric acid demonstrated statistically significant change from the mean
baseline value (+0.27 mg/dL for apomorphine, -0.34 mg/dL for placebo, P = .02) but was never outside the normal range. There
were no statistically significant changes in other safety measures (blood
test results, electrocardiograms, or physical examination findings).
COMMENT
This study was conducted in patients with significant residual off time
despite aggressive attempts to control symptoms using both levodopa and oral
dopamine agonists. In this setting, outpatient subcutaneous injections represent
a reasonable therapeutic option for acutely reversing individual off events.
This is the first clinical trial to evaluate both inpatient and outpatient
use under placebo-controlled conditions, and it established the predictive
nature of inpatient test responses on outpatient therapeutic responses to
injected apomorphine.
Our study showed that subcutaneous apomorphine injections effectively
reverse off-state events that occur in advanced PD. Outpatients or caregivers
demonstrated the capacity to prepare apomorphine from glass ampules and inject
it. While we did not use formal quality of life measures, most patients assigned
to active drug were pleased with the effects. Patients randomized to apomorphine
treatment had reduced total off time that was not derived from lessening the
number of off-state events, but from shortening the duration of individual
off states. Although within-day tolerance has been previously demonstrated
following intravenous infusions of apomorphine,19
this phenomenon was not observed with the subcutaneous injections used in
our study.
Since levodopa dosage was not predictive of apomorphine dose requirements,
individual titration is required to establish the correct dose. Under inpatient
observation, the average dose required to produce effects equivalent in magnitude
to oral levodopa was 5.4 mg, while the average final outpatient dose was 5.8
mg. At levodopa-equivalent doses, dyskinesias were equal in magnitude to those
produced by levodopa, but these were mild and generally nondisabling. The
only adverse event that was significantly more common in the apomorphine-treated
group was yawning. This adverse effect has been reported in patients treated
with apomorphine in other studies20 but is
rare with levodopa and the oral dopamine agonists.21
A review of the Physicians Desk Reference revealed
that of the oral dopamine agonists and levodopa preparations available in
the United States, yawning is a listed adverse effect only for ropinirole
hydrochloride occurring in 3% of patients. The 40% incidence of yawning associated
with apomorphine in our study represents more than a 10-fold increase compared
with ropinirole. Studies of apomorphine-induced yawning in rats have indicated
that stimulation of D2 dopamine receptors on paraventricular neurons
of the hypothalamus leads to increased nitric oxide synthase activity and
yawning behavior.22 Why levodopa, which produces
a similar degree of antiparkinsonian efficacy, is associated with a much lower
incidence of yawning is unknown.
Our data show that domperidone is not needed to support the use of apomorphine
in patients selected and treated according to our protocol. Clinically significant
nausea and vomiting was as rare in our study (only 4% of injections of active
drug caused nausea) as has been previously reported in European studies of
apomorphine combined with domperidone.20, 23
Our data suggest that trimethobenzamide is an adequate replacement for domperidone
therapy. Alternatively, it is possible that down-regulation of dopamine receptors
in the area postrema had already occurred because of chronic exposure to long-acting
oral dopamine agonists and that this patient group actually does not require
an antinauseant.
We conclude that subcutaneously injected apomorphine rapidly and reliably
reversed off-state events in patients with advanced PD in whom conventional
antiparkinsonian medications had been optimized. We believe that this study
confirms previous work and serves as proof of the clinical effectiveness of
subcutaneous apomorphine injections when used to reverse off events.
AUTHOR INFORMATION
Accepted for publication May 14, 2001.
This study was supported by Bertek Pharmaceuticals Inc, Division of
Mylan Laboratories Inc.
We thank the following coinvestigators, study coordinators, and data
analysis personnel for their contributions to this project. Coinvestigators: Ben Williams, MD, PhD; Bhupesh Dihenia, MD; and Eric Molho, MD. Study Coordinators: Jennifer Stanford, RN; Janice Stewart, RN, BSN,
CCRC; Angela Bednarz, RN, BSN; Merena Tindall, RN; Diane Brown, RN; Sharon
Evans, LPN; and Kathie Mistura, RN. Data Management, Statistical, and
Editorial Support Staff: Marlene R. Pope, BS; Brenda E. VanLunen, MS;
Jeffrey P. Smith, PhD, and Patrick D. McGrath, PhD.
From the Department of Neurology, University of Texas Southwestern
Medical Center, Dallas (Dr Dewey); Neurology Research and Education Center,
Covenant Medical Center, Lubbock, Tex (Dr Hutton); Clinical Neuroscience Center,
Southfield, Mich (Dr LeWitt); and the Department of Neurology, Albany Medical
College, Albany, NY (Dr Factor).
Corresponding author: Richard B. Dewey, Jr, MD, University of Texas
Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9036.
REFERENCES
| |
1. Hughes AJ, Frankel JP, Kempster PA, Stern GM, Lees AJ. Motor response to levodopa in patients with parkinsonian motor fluctuations:
a follow-up study over three years. J Neurol Neurosurg Psychiatry. 1994;57:430-434.
FREE FULL TEXT
2. Quinn NP. Classification of fluctuations in patients with Parkinson's disease
[review]. Neurology. 1998;51(suppl 2):S25-S29.
3. Sage JI, Mark MH. Drenching sweats as an off phenomenon in Parkinson's disease: treatment
and relation to plasma levodopa profile. Ann Neurol. 1995;37:120-122.
FULL TEXT
|
ISI
| PUBMED
4. Steiger MJ, Quinn NP, Toone B, Marsden CD. Off-period screaming accompanying motor fluctuations in Parkinson's
disease. Mov Disord. 1991;6:89-90.
FULL TEXT
|
ISI
| PUBMED
5. Dewey RB Jr, Maraganore DM, Ahlskog JE, Matsumoto JY. Intranasal apomorphine rescue therapy for parkinsonian "off" periods. Clin Neuropharmacol. 1996;19:193-201.
ISI
| PUBMED
6. Cotzias GC, Lawrence WH, Papavasiliou PS, Duby SE, Ginos JZ, Mena I. Apomorphine and parkinsonism. Trans Am Neurol Assoc. 1972;97:156-159.
7. Ostergaard L, Werdelin L, Odin P, et al. Pen injected apomorphine against off phenomena in late Parkinson's
disease: a double-blind, placebo-controlled study. J Neurol Neurosurg Psychiatry. 1995;58:681-687.
FREE FULL TEXT
8. Cotzias GC, Papavasiliou PS, Fehling C, Kaufman B, Mena I. Similarities between neurologic effects of L-dopa and of apomorphine. N Engl J Med. 1970;282:31-33.
9. Duby SE, Cotzias GC, Papavasiliou PS, Lawrence WH. Injected apomorphine and orally administered levodopa in parkinsonism. Arch Neurol. 1972;27:474-480.
ISI
| PUBMED
10. Merello M, Pikielny R, Cammarota A, Leiguarda R. Comparison of subcutaneous apomorphine versus dispersible madopar latency
and effect duration in Parkinson's disease patients: a double-blind single-dose
study. Clin Neuropharmacol. 1997;20:165-167.
ISI
| PUBMED
11. Sohn YH, Metman LV, Bravi D, et al. Levodopa peak response time reflects severity of dopamine neuron loss
in Parkinson's disease. Neurology. 1994;44:755-757.
FREE FULL TEXT
12. van Laar T, Neef C, Danhof M, Roon KI, Roos RA. A new sublingual formulation of apomorphine in the treatment of patients
with Parkinson's disease. Mov Disord. 1996;11:633-638.
FULL TEXT
|
ISI
| PUBMED
13. van Laar T, Jansen EN, Essink AW, Neef C, Oosterloo S, Roos RA. A double-blind study of the efficacy of apomorphine and its assessment
in "off"-periods in Parkinson's disease. Clin Neurol Neurosurg. 1993;95:231-235.
FULL TEXT
|
ISI
| PUBMED
14. 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
15. Hardie RJ, Lees AJ, Stern GM. On-off fluctuations in Parkinson's disease: a clinical and neuropharmacological
study. Brain. 1984;107:487-506.
FREE FULL TEXT
16. Dewey RB Jr, Maraganore DM, Ahlskog JE, Matsumoto JY. A double-blind, placebo-controlled study of intranasal apomorphine
spray as a rescue agent for off-states in Parkinson's disease. Mov Disord. 1998;13:782-787.
FULL TEXT
|
ISI
| PUBMED
17. Webster DD. Critical analysis of the disability in Parkinson's disease. Mod Treat. 1968;5:257-282.
ISI
| PUBMED
18. Goetz CG, Stebbins GT, Shale HM, et al. Utility of an objective dyskinesia rating scale for Parkinson's disease:
inter- and intrarater reliability assessment. Mov Disord. 1994;9:390-394.
FULL TEXT
|
ISI
| PUBMED
19. Gancher ST, Woodward WR, Nutt JG. Apomorphine tolerance in Parkinson's disease: lack of a dose effect. Clin Neuropharmacol. 1996;19:59-64.
ISI
| PUBMED
20. Frankel JP, Lees AJ, Kempster PA, Stern GM. Subcutaneous apomorphine in the treatment of Parkinson's disease. J Neurol Neurosurg Psychiatry. 1990;53:96-101.
FREE FULL TEXT
21. Goren JL, Friedman JH. Yawning as an aura for an L-dopa–induced "on" in Parkinson's
disease. Neurology. 1998;50:823.
22. Melis MR, Succu S, Argiolas A. Dopamine agonists increase nitric oxide production in the paraventricular
nucleus of the hypothalamus: correlation with penile erection and yawning. Eur J Neurosci. 1996;8:2056-2063.
FULL TEXT
|
ISI
| PUBMED
23. Stibe CM, Lees AJ, Kempster PA, Stern GM. Subcutaneous apomorphine in parkinsonian on-off oscillations. Lancet. 1988;1:403-406.
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| PUBMED
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