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Effects of Coenzyme Q10 in Early Parkinson Disease
Evidence of Slowing of the Functional Decline
Clifford W. Shults, MD;
David Oakes, PhD;
Karl Kieburtz, MD;
M. Flint Beal, MD;
Richard Haas, MB Chir;
Sandy Plumb, BS;
Jorge L. Juncos, MD;
John Nutt, MD;
Ira Shoulson, MD;
Julie Carter, RN, MS, ANP;
Katie Kompoliti, MD;
Joel S Perlmutter, MD;
Stephen Reich, MD;
Matthew Stern, MD;
Ray L. Watts, MD;
Roger Kurlan, MD;
Eric Molho, MD;
Madaline Harrison, MD;
Mark Lew, MD;
and the Parkinson Study Group
Arch Neurol. 2002;59:1541-1550.
ABSTRACT
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Background Parkinson disease (PD) is a degenerative neurological disorder for which
no treatment has been shown to slow the progression.
Objective To determine whether a range of dosages of coenzyme Q10 is
safe and well tolerated and could slow the functional decline in PD.
Design Multicenter, randomized, parallel-group, placebo-controlled, double-blind,
dosage-ranging trial.
Setting Academic movement disorders clinics.
Patients Eighty subjects with early PD who did not require treatment for their
disability.
Interventions Random assignment to placebo or coenzyme Q10 at dosages of
300, 600, or 1200 mg/d.
Main Outcome Measure The subjects underwent evaluation with the Unified Parkinson Disease
Rating Scale (UPDRS) at the screening, baseline, and 1-, 4-, 8-, 12-, and
16-month visits. They were followed up for 16 months or until disability requiring
treatment with levodopa had developed. The primary response variable was the
change in the total score on the UPDRS from baseline to the last visit.
Results The adjusted mean total UPDRS changes were +11.99 for the placebo group,
+8.81 for the 300-mg/d group, +10.82 for the 600-mg/d group, and +6.69 for
the 1200-mg/d group. The P value for the primary
analysis, a test for a linear trend between the dosage and the mean change
in the total UPDRS score, was .09, which met our prespecified criteria for
a positive trend for the trial. A prespecified, secondary analysis was the
comparison of each treatment group with the placebo group, and the difference
between the 1200-mg/d and placebo groups was significant (P = .04).
Conclusions Coenzyme Q10 was safe and well tolerated at dosages of up
to 1200 mg/d. Less disability developed in subjects assigned to coenzyme Q10 than in those assigned to placebo, and the benefit was greatest in
subjects receiving the highest dosage. Coenzyme Q10 appears to
slow the progressive deterioration of function in PD, but these results need
to be confirmed in a larger study.
INTRODUCTION
PARKINSON DISEASE (PD) is a degenerative neurological disorder that
is characterized by resting tremor, slowness of movement, and muscular rigidity.
Parkinson disease affects approximately 1% of Americans older than 65 years.1 The cardinal pathological features of PD are loss
of dopaminergic neurons in the substantia nigra pars compacta and the presence
of Lewy bodies in neurons in the substantia nigra and extranigral regions
of the brain.2-3
The causes of PD are not fully understood,4
but genetic abnormalities and environmental factors have been associated with
PD.5-6 Recognition that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
(MPTP) can cause parkinsonism through the inhibition of complex I in the mitochondrial
electron transport chain stimulated studies of mitochondrial function in PD.7-8 Schapira et al9
and Turner and Schapira10 reported a selective
decrease in complex I activity in the postmortem substantia nigra in patients
with PD. Parker et al11 first reported and
others confirmed12-14
a decrease in complex I activity in platelets from patients with PD.
The likelihood that a reduction in complex I activity plays a role in
the pathogenesis of PD was strengthened by the demonstration that patients
with early, untreated PD have reduced activity of complex I and II/III in
mitochondria isolated from platelets and that treatment with levodopa and
selegiline hydrochloride does not affect mitochondrial function.15-16
The possibility that a systemic insult to the mitochondria could preferentially
injure nigral dopaminergic neurons has been supported by the demonstration
that systemic administration of rotenone, which inhibits complex I but is
not selectively taken up into dopaminergic neurons, causes preferential injury
to the nigral dopaminergic neurons in rats.17
Coenzyme Q10 is the electron acceptor for complexes I and
II and also a potent antioxidant. Shults et al18
demonstrated reduced levels of coenzyme Q10 in the mitochondria
isolated from platelets of patients with PD, and the serum level of coenzyme
Q10 in patients with parkinsonism has been reported to be significantly
lower than that in age-comparable patients with stroke.19
Beal et al20 demonstrated that oral supplementation
with coenzyme Q10 reduced the loss of dopamine and dopaminergic
axons in the striatum in 1-year-old mice treated with MPTP. Matthews et al21 found that oral supplementation with coenzyme Q10 in rats resulted in significant increases in the concentration of
coenzyme Q10 in mitochondria in the cerebral cortex. In a pilot
study, Shults et al22 demonstrated that oral
consumption of coenzyme Q10 at dosages of 400, 600, or 800 mg/d
by patients with PD was well tolerated and resulted in significant elevations
of plasma levels of coenzyme Q10. On the basis of this work, we
undertook a dosage-ranging study to evaluate the safety and tolerability of
high dosages of coenzyme Q10 in patients with early PD and the
ability of coenzyme Q10 to reduce the rate of functional decline
in such patients.
METHODS
ORGANIZATION
This multicenter study was organized by the University of California–San
Diego in conjunction with the Parkinson Study Group; the Clinical Trials Coordination
Center and the Department of Biostatistics at the University of Rochester,
Rochester, NY; the Department of Neurology and Neuroscience at the Weill Medical
College of Cornell University, New York, NY; and the enrolling sites. The
National Institute of Neurological Disorders and Stroke sponsored the trial.
Coenzyme Q10 and matching placebo were supplied by Vitaline Corp,
Ashland, Ore. Ten investigators at 10 Parkinson Study Group sites in the United
States were responsible for the recruitment, enrollment, and follow-up of
subjects. The institutional review board at each site reviewed and approved
the protocol. The principal investigator and the Steering Committee guided
the trial. The Safety Monitoring Committee, established by the Steering Committee,
and the Performance and Safety Monitoring Board, constituted by the National
Institute of Neurological Disorders and Stroke, independently and periodically
reviewed enrollment, premature terminations, end points, adverse events, and
laboratory results.
RECRUITMENT, ENROLLMENT, AND RANDOMIZATION
Eighty subjects with early PD were enrolled in the study at 10 sites.
Inclusion criteria required the presence of all 3 cardinal features of PD
(resting tremor, bradykinesia, and rigidity), which had to be asymmetrical.
The diagnosis of PD must have been made within the previous 5 years in men
or in women 30 years or older. Women must have been postmenopausal for at
least 2 years or surgically sterile or using a reliable form of contraception
for at least 2 months before screening and must have agreed to continue its
use for the duration of participation in the study.
Exclusion criteria included the following:
- The use of any medication for PD for 60 days before
the baseline visit.
- Parkinsonism due to drugs.
- The use of antioxidants such as selegiline, vitamin E, and ascorbic
acid (vitamin C) within 60 days of the baseline visit, and previous use of
coenzyme Q10 within 120 days of the baseline visit. There was no
limitation on the use of antioxidants before pretrial discontinuation of therapy.
Patients were asked to take a standard daily multivitamin without minerals
but no other supplemental vitamins.
- The use of drugs known to interfere with mitochondrial activity.
- The use of methylphenidate hydrochloride, cinnarizine, reserpine,
amphetamines, or monoamine oxidase-A inhibitors within 6 months before the
baseline visit.
- An unstable dosage of drugs active in the central
nervous system (eg, anxiolytics, hypnotics, benzodiazepines, and antidepressants)
during the 60 days before the baseline visit.
- The use of appetite suppressants within 60 days
before the baseline visit.
- Diseases with features of PD (eg, progressive supranuclear
palsy, essential tremor, multiple system atrophy, striatonigral degeneration,
olivopontocerebellar atrophy, and postencephalitic parkinsonism).
- A history of active epilepsy.
- The presence of dementia as evidenced by a Mini-Mental
State Examination score of less than 24.23
- The presence of depression as indicated by a score
on the Hamilton Depression Rating Scale of greater than 10.24
- A history of stroke.
- Disability sufficient to require treatment with
dopaminergic drugs, as determined by the enrolling investigator.
- A modified Hoehn and Yahr Scale score of greater
than 2.5.25
- The presence of other serious illnesses.
- Participation in other drug studies or the use of other investigational
drugs within 30 days before screening.
- A history of electroconvulsive therapy.
- A history of brain surgery for PD.
- A history of structural brain disease.
- A tremor score on the Unified Parkinson's Disease
Rating Scale (UPDRS) of 3 or greater.25
At the screening visit, after the nature, purpose, and potential risks
and benefits of the study were explained to the subject, written informed
consent was obtained. The subject underwent evaluation with a medical history,
physical examination, and a battery of clinical assessments of PD (the UPDRS,25 the Hoehn and Yahr Scale,25
the Schwab and England Scale,25 and a timed
tapping task). Previous studies have established good interrater reliability
for the UPDRS.26-28
For the timed tapping task, the subject alternately touched 2 counters, separated
by 20 cm, with the index finger of 1 hand as many times as possible during
1 minute. Subjects performed 2 trials with each hand.
Screening laboratory studies included electrocardiography, a chemistry
panel (levels of albumin, alkaline phosphatase, aspartate transaminase, alanine
transaminase, bicarbonate, serum urea nitrogen, calcium, chloride, creatinine,
glucose, lactate dehydrogenase, phosphorous, potassium, sodium, total bilirubin,
total creatine kinase, total protein, and uric acid), complete blood cell
count, and urinalysis.
The baseline visit occurred within 1 month of the screening visit. In
addition to the clinical assessments of PD, a blood sample (approximately
110 mL) was obtained to determine complex I activity in platelets and levels
of coenzyme Q10 in plasma.22 On
completion of the baseline visit, each patient was randomly assigned to receive
coenzyme Q10 at a dosage of 300, 600, or 1200 mg/d or matching
placebo in a 1:1:1:1 allocation using a computer-generated randomization plan
that included stratification by the investigator and blocking (with a block
size of 8) to ensure that each investigator had approximately the same number
of subjects assigned to each treatment group. Subjects, enrolling investigators,
enrolling coordinators, and other personnel involved in the care of the patients
and the acquisition and analysis of data were masked to treatment assignment
until completion of the study.
Participants underwent reevaluation at 1, 4, 8, 12, and 16 months (±7
days) after the baseline visit using the battery of clinical examinations,
and the enrolling investigator determined whether sufficient disability had
developed to require treatment with levodopa. Each subject was followed up
for 16 months or until the investigator determined that the patient needed
treatment with levodopa. A blood sample was again drawn at the final visit
for evaluation of platelet mitochondrial function and plasma levels of coenzyme
Q10. Safety laboratory studies (chemistry panel, complete blood
cell count, and urinalysis) were performed at the 1-, 4-, and 8-month and
final visits.
INTERVENTION
Each patient was randomly assigned to receive coenzyme Q10 at a dosage of 300, 600, or 1200 mg/d or matching placebo. The study medication
was taken 4 times each day, with breakfast, lunch, and dinner and at bedtime.
The wafers with active study drug contained 300 mg of coenzyme Q10 and 300 IU of vitamin E as a lipophilic carrier. Matching placebo wafers also
contained 300 IU of vitamin E each.
OUTCOMES, STATISTICAL METHODS, AND SAMPLE SIZE
Safety and Tolerability
All adverse events (using World Health Organization terminology) and
abnormal laboratory values were analyzed by treatment group and severity.
Only new events not present at the screening or the baseline visit were counted.
The Cochran-Armitage exact test for trend (1-tailed) was used to compare treatment
groups with regard to the proportion of subjects experiencing a particular
adverse event or an abnormal laboratory value.29
We used 1-tailed tests because the finding of poorer tolerability in the placebo
group would have been highly unlikely and of no interest. Compliance, as measured
by pill counts, was summarized descriptively by treatment group.
Efficacy and Trial Design
The primary response variable was the change in the total score on the
UPDRS from the baseline to the last visit. The last visit was that at which
the investigator judged that disability requiring levodopa therapy had developed,
the last visit before a premature termination, or the 16-month visit. At each
visit, the investigator was asked to assess whether the subject had reached
disability sufficient to require therapy with levodopa using a form that asked
a series of questions regarding occupation, gait, balance, finances, domestic
responsibility, and activities of daily living. The series of questions was
based on our previous experience with this end point.30
The decision was the responsibility of the enrolling investigator. The choice
of initial antiparkinsonian therapy was also the responsibility of the enrolling
investigator and could include levodopa, dopaminergic agonists, selegiline,
amantadine hydrochloride, and anticholinergic drugs.
The primary statistical analyses were performed according to the intention-to-treat
principle.31 According to the prespecified
primary analysis plan, the mean change in the total UPDRS score was determined
for each treatment group (300-, 600-, and 1200-mg/d and placebo) and tested
for a linear trend between the dosage and mean change in the UPDRS using analysis
of covariance. Analyses were adjusted for the baseline score and investigator.
This analysis allows identification of a beneficial response when there is
a clear dose-response effect and when the effects at all of the dosages tested
are equivalent.32 Because this dosage-ranging
study was designed to detect a trend toward efficacy, not to demonstrate efficacy
per se, we specified use of a less stringent criterion than usual for declaring
statistical significance, namely a 1-sided P value
of .10. However, we present our efficacy data using 2-sided P values.
Sample Size
Based on these suppositions and our previous experience,30
the study was projected to have 73% power to detect an effect of coenzyme
Q10 corresponding to a difference of 6 points in total UPDRS score
between the placebo group and the highest active-dosage group.
We also explored other analyses. As specified, we performed analyses
comparing all combined active-dosage groups against the placebo group and
each active-dosage group against the placebo group using analysis of covariance.
For these secondary analyses, we did not adjust for multiple comparisons.
We examined the area under the curve, ie, accumulated changes in total UPDRS
score during the total duration of the study, and the trajectories of these
curves to assess whether the effect of coenzyme Q10 on total UPDRS
score was more consistent with predominantly short-term effects on symptoms
or long-term effects on disease progression. Time to disability sufficient
to require treatment with levodopa was analyzed using the method of Kaplan
and Meier and the Cox proportional hazards regression model stratified by
investigator.33
Plasma Level of Coenzyme Q10
Subjects were asked to not take study medication after the last dose
on the day before follow-up visits to obtain a plasma level representative
of a steady state. The samples were kept at each site at –80°C until
shipped on dry ice to the laboratory at Weill Medical College of Cornell University.
Assays for plasma levels of coenzyme Q10 were performed by means
of techniques previously described with modification.18
The values from 1 subject, who was assigned to receive coenzyme Q10 at a dosage of 600 mg/d, appeared to represent a reversal of the baseline
and final visits and were not included in the analysis.
Comparisons of plasma levels at the final visit among patients treated
with coenzyme Q10 and placebo were made using analysis of covariance,
adjusting for the baseline value as a covariate.
Mitochondrial Assays
At the baseline and final visits, venous blood was collected into two
50-mL syringes containing 5 mL of anticoagulant sodium citrate solution. The
samples were transferred at room temperature to the Mitochondrial Research
Laboratory at the University of California–San Diego by overnight courier.
Complex I and citrate synthetase activities were measured by means of well-established
techniques.22 The Mitochondrial Research Laboratory,
University of California–San Diego, also performed the assay for complex
I/III using the rotenone-sensitive reduced form of nicotinamide adenine dincleotide
(NADH) cytochrome-c reductase. The electron transport
activities were normalized to that of citrate synthetase to correct for any
differences in mitochondrial mass. Comparisons of complex I and complex I/III
activity at the baseline and final visits among patients treated with coenzyme
Q10 and placebo were made using analysis of covariance, adjusting
for the baseline value and investigator as covariates.
All statistical analyses were performed using SAS software (Version
8; SAS Institute Inc, Cary, NC).
RESULTS
SUBJECTS ENROLLED
Eighty subjects were enrolled from May 24, 1999, through February 17,
2000 (Figure 1). At the baseline
visit, the groups were well matched for sex, age, severity of PD (the UPDRS
and Hoehn and Yahr Scale scores and the timed tapping score), disability (the
Schwab and England Scale score) and intellectual function (the Mini-Mental
State Examination score) (Table 1).
The characteristics of our subjects were very similar to those in previous
studies enrolling subjects who did not have disability sufficient to require
levodopa therapy.30, 34 Three subjects
prematurely terminated or were lost to follow-up from the study before the
investigator determined that they had reached the point that their disability
warranted use of levodopa (Figure 1).
Increased tremor, lower-back pain, and increased nocturia developed in 1 subject
who was receiving 1200 mg/d of coenzyme Q10 and who prematurely
terminated. This subject was noncompliant, and the investigator did not believe
that the symptoms were related to the study drug. This subject was lost to
follow-up.
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Figure 1. Patient flowchart.
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Table 1. Baseline Characteristics*
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TOLERABILITY AND SAFETY
Coenzyme Q10 was well tolerated; no dosage reductions were
needed in any of the treatment groups. The percentages of subjects receiving
coenzyme Q10 who reported any adverse event (19 subjects [90%]
for the 300-mg/d group; 12 [60%] for the 600-mg/d group; and 21 [91%] for
the 1200-mg/d group) were not significantly different from that in the placebo
group (13 subjects [81%]) (P = .51, Cochran-Armitage
exact test for trend). Most adverse events were mild. Eighteen adverse events
were experienced by 4 (5%) or more subjects (Table 2). When mild adverse events were excluded, 3 were experienced
by at least 4 subjects, including viral infection, pharyngitis, and sinusitis.
The differences among the treatment groups were not significant, and no significant
trend by dosage was found in the number of subjects experiencing an adverse
event.
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Table 2. Adverse Events Reported by at Least 4 Subjects
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Analysis of 84 possible high or low laboratory results revealed a nominally
significant or marginally significant trend by dosage in 4, including high
carbon dioxide levels (P = .01), high mean corpuscular
hemoglobin concentration (P = .08), and high sodium
(P = .06) and uric acid levels (P = .08). The ongoing evaluation of abnormal laboratory results during
the study and the review at the completion of the study did not reveal these
to be clinically significant.
Analysis of the data for weight, sitting and standing blood pressure,
and heart rate did not show any significant differences among the treatment
groups (data not shown).
EFFICACY
The adjusted mean changes in the total UPDRS score from the baseline
to the final visit (positive values indicate worsening) were +11.99 for the
placebo group, +8.81 for the 300-mg/d group, +10.82 for the 600-mg/d group,
and +6.69 for the 1200-mg/d group (Table
3). Our primary analysis was a test for a trend between dosage and
the mean change in the UPDRS score, and P = .09 (2-sided)
was significant according to our prespecified criteria. The difference in
the change in the total UPDRS score between the placebo group and the 1200-mg/d
group was 5.30 (95% confidence interval, 0.21-10.39). A prespecified secondary
analysis was comparison of each active treatment group with the placebo group.
The difference was significant for the 1200-mg/d group (P = .04) but not for the 300- (P = .22) or
the 600-mg/d (P = .66) groups.
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Table 3. Adjusted Mean Change From Baseline*
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The reduction in the worsening of the total UPDRS score was the result
of slowed decline in all 3 components of the UPDRS, ie, mental (part I), activities
of daily living (part II), and motor (part III), with the greatest effect
in part II (Table 3). The greatest
reduction was seen at the highest dosage (1200 mg/d). Results for the placebo
vs the combined drug groups were similar (data not shown).
We also found a reduction in the worsening on the Schwab and England
Scale, as assessed by the examiner (P = .04) but
not by the patient (P = .81). The discrepancy between
the results, as determined by the examiners and the patients, appeared to
be primarily due to discordance between 1 subject, who was assigned to the
1200 mg/day treatment group, and the examiner. Coenzyme Q10 did
not have a significant effect on the scores for the Hoehn and Yahr Scale or
the timed tapping task.
Examination of data at the month-1 visit indicated that coenzyme Q10 did not have a significant effect on the total UPDRS score at that
point (Table 4). However, at the
1-month visit, we noted benefit on part II of the UPDRS, particularly at the
highest dosage.
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Table 4. Adjusted Mean Change From Baseline to 1 Month*
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Figure 2 shows the course
of the total UPDRS scores across the 16 months of the study with the last
observation carried forward. By the 8-month visit, the scores had clearly
separated and established a pattern of the 300- and 600-mg/d groups being
similar, with lower scores than those of the placebo group, and with the scores
for the 1200-mg/d group being substantially lower than those of the other
groups. This pattern persisted until the end of the study and was the result
of similar changes in all 3 components of the UPDRS (Figure 3).
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Figure 2. Unified Parkinson's Disease Rating
Scale (UPDRS) scores. The scores for the total UPDRS (last observation carried
forward) are expressed as mean (SEM). Higher scores indicate more severe features
of Parkinson disease. Results of a test for a linear trend between the dosage
and the mean change in the total UPDRS score indicated a trend for coenzyme
Q10 to reduce the increasing disability over time
(P = .09). The score change for the 1200-mg/d
coenzyme Q10 group was significantly different from that of the placebo
group (P = .04).
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Figure 3. The 3 parts of the Unified Parkinson's
Disease Rating Scale (UPDRS). The pattern of attenuation of the worsening
of the total UPDRS score by coenzyme Q10 was also seen in each
of the 3 parts of the UPDRS (mental [part I; A], activities of daily living
[ADL] [part II; B], and motor [part III; C], last observation carried forward).
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Analyses of the area under the curve using the total UPDRS actual visit
data showed similar, but not as significant, results (data not shown). Examination
of the time until the subject was considered to need treatment with levodopa
disclosed no significant effect of coenzyme Q10 on this measure
(P = .43) (Figure
4).
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Figure 4. Percentage of patients who required
levodopa by the time until the investigator considered that the subject needed
treatment with levodopa.
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PLASMA LEVELS OF COENZYME Q10
All groups receiving coenzyme Q10 had highly significant
increases in the mean plasma level of coenzyme Q10 from baseline
to the last visit (Figure 5) (P<.001), and the mean plasma levels of
coenzyme Q10 were significantly different among the 3 groups receiving active
drug (P<.05), with the exception of the 300- and
600-mg/d groups (P = .15). All subjects received
1200 IU of vitamin E daily, and in each treatment group the plasma level of
vitamin E increased slightly more than 2-fold (data not shown).
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Figure 5. Plasma coenzyme
Q10 levels. In all groups treated with coenzyme Q10, the plasma level
at the last visit was significantly different from that at the baseline visit
(P<.001), and the plasma levels of coenzyme Q10 in the 3
groups receiving active drug were significantly different
from each other (P<.05), with the exception of
the 300- and 600-mg/d groups (P = .15). Samples (numbers
of patients) available from the baseline/final visits were 13/14 for the placebo
group, 19/19 for the 300-mg/d group, 16/17 for the 600-mg/d group, and 22/18
for the 1200-mg/d group.
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MITOCHONDRIAL ASSAYS
Results of the assay of the activity of complex I normalized to the
activity of citrate synthetase did not indicate a significant effect of coenzyme
Q10 (P = .73). In this assay, the activity
of complex I did not depend on endogenous coenzyme Q10, as an excess
of exogenous coenzyme Q1 was added
(Figure 6A). We also determined the activity of the electron transport
chain from NADH to cytochrome-c reductase (complexes
I and III), which did depend on the endogenous coenzyme Q10, and
found a significant increase in the activity of the electron transport chain
with treatment with coenzyme Q10 (P = .04)
(Figure 6B).
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Figure 6. Mitochondrial activity. Assays
were normalized to citrate synthetase to correct for differences in mitochondrial
mass. A, Complex I activity, which is not dependent on endogenous coenzyme
Q10, did not differ among the treatment groups. B, The assay of
the reduced form of nicotinamide adenine dincleotide (NADH) to cytochrome-c reductase, which is dependent on the endogenous level
of coenzyme Q10, showed a significant trend for treatment with
coenzyme Q10. Samples (numbers of patients) available from the
baseline/final visits were 12/14 for the placebo group, 18/21 for the 300-mg/d
group, 19/17 for the 600-mg/d group, and 20/21 for the 1200-mg/d group for
the complex I/citrate synthetase; and 12/14 for the placebo group, 19/21 for
the 300-mg/d group, 19/17 for the 600-mg/d group, and 20/20 for the 1200-mg/d
group for NADH to cytochrome-c reductase.
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COMMENT
Our dosage-ranging study found that coenzyme Q10 was safe
and well tolerated at the dosages of 300 to 1200 mg/d and that the 1200-mg/d
dosage was associated with significant slowing of the worsening of PD as measured
by the total UPDRS score. The benefit was seen in all 3 of the components
of the UPDRS, but the effect was greatest in part II (activities of daily
living). Consistent with the effect on part II, we found a significant effect
on the Schwab and England Scale score as judged by the examiner.
The effect of coenzyme Q10 on our primary response variable,
change in total UPDRS score, was not paralleled by the time to disability
requiring treatment with levodopa. However, the group treated with 1200 mg/d
tended to reach this end point more slowly until the end of the study. We
were not surprised by this discrepancy. Analysis of the Deprenyl and Tocopherol
Antioxidative Therapy of Parkinsonism (DATATOP) Study30
suggested that the time to levodopa treatment would be a less informative
measure than the change in total UPDRS score in a 16-month study (D.O., unpublished
data, 1994), thus prompting exploration of the current trial design for phase
2 trials.
The mechanism(s) through which coenzyme Q10 exerted its beneficial
effect cannot be determined from our clinical trial, but our data are consistent
with an effect on mitochondrial function. The assay of NADH to cytochrome-c reductase activity, which relies on endogenous coenzyme
Q10, demonstrated a significant increase in activity in subjects
taking 1200 mg/d of coenzyme Q10. Although the results of our study
of mitochondrial activity in platelets do not prove that a similar benefit
occurred in the brain, the results are consistent with this possibility. Our
data are consistent with the hypothesis that mitochondrial dysfunction plays
a role in the pathogenesis of PD and that treatments targeted at mitochondria
might ameliorate the functional decline in PD.
Coenzyme Q10 was unlikely to exert its effect through an increase
in the level of nigrostriatal dopamine. In preclinical studies, supplementation
of the diet of 1-year-old mice with coenzyme Q10 (200 mg/kg per
day) for 5 weeks did not affect striatal levels of dopamine or its metabolites.20
Investigators have previously described improvement after supplemental
coenzyme Q10 treatment in small case series in which the patients
appeared to have an inherited deficiency of coenzyme Q10.35-38 Similarly,
oral coenzyme Q10 treatment (600 mg/d) for 3 months in patients
with Friedreich ataxia improved bioenergetics in cardiac and skeletal muscle,
but after 6 months of treatment, neurological function was not improved.39
The effect of coenzyme Q10 in other diseases, particularly
neurological disorders, has been inconsistent. There have been numerous reports
of the benefits of coenzyme Q10 in patients with heart disease,
but the studies were often not controlled.40
A recent prospective, randomized, double-blinded, placebo-controlled trial
of coenzyme Q10 in congestive heart failure did not show benefit,
but the dosage (200 mg/d) may not have been adequate.41
Previous studies in a variety of muscular disorders have had inconsistent
results.42-45
The dosages used (30-300 mg/d) may have been inadequate, and heterogeneous
neurological disorders were often studied together in these trials. In the
present study, the strict inclusion criteria maximized the likelihood that
the subjects had idiopathic PD.46
Consistent with our findings of a reduction in the functional decline
in PD are the results of a trial in which patients with early Huntington disease
received coenzyme Q10 (600 mg/d), remacemide hydrochloride (600
mg/d), a combination of remacemide and coenzyme Q10, or placebo.47 The decline in total functional capacity was not
significantly altered by any of the treatments, but subjects receiving coenzyme
Q10 (with or without remacemide treatment) showed 13% less decline
in total functional capacity than did the subjects who did not receive coenzyme
Q10 (P = .15). Previous studies in patients
with Huntington disease showed that coenzyme Q10 significantly
lowered increased lactate levels in the cerebral cortex, demonstrating that
it exerts biological effects in the brain.48
Results of our study, in which the greatest benefit was found at a dosage
of 1200 mg/d, the study of Huntington disease, in which an intriguing trend
toward benefit at a dosage of 600 mg/d was observed, and the congestive heart
failure study, in which no benefit was seen at a dosage of 200 mg/d, indicate
that the dosage of coenzyme Q10 may be crucial. The beneficial
trend in our trial was driven by the effect seen at the highest dosage of
coenzyme Q10 (1200 mg/d). The plasma levels of coenzyme Q10 in
the groups receiving 300 and 600 mg/d were relatively close, as
were the total UPDRS scores in both groups. The plasma and presumably brain
levels of coenzyme Q10 may be a significant determinant of the
effectiveness of the treatment.
To our knowledge, our study is the first trial to systematically explore
the safety and efficacy of high dosages of coenzyme Q10. Our data
suggest that in treatment of neurological disorders in which evidence of complex
I or II dysfunction are found, such as PD and Huntington disease, dosages
much higher than those previously used may be required. The benefit was greatest
in the group receiving the highest dosage, 1200 mg/d. It is conceivable that
a greater effect could be seen at even higher dosages of coenzyme Q10.
Future studies of coenzyme Q10 in PD and other
disorders will need to explore the effect of dosages of 1200 mg/d and higher.
CONCLUSIONS
In our study, coenzyme Q10 treatment at high dosages was
safe and well tolerated and reduced the worsening of PD, as reflected in the
total UPDRS score. It would be premature to recommend the use of coenzyme
Q10 for the treatment of PD. Our results need to be confirmed in
a larger, phase 3 study, and the appropriate dosage and the magnitude of effect
need to be better defined.
AUTHOR INFORMATION
Accepted for publication June 5, 2002.
Author contributions: Study concept and design (Drs Shults, Oakes, Kieburtz, Beal, Haas, Nutt, Shoulson, and
Watts); acquisition of data (Drs Shults, Beal, Haas,
Kompoliti, Perlmutter, Reich, Stern, Watts, Kurlan, Molho, Harrison, and Lew
and Mss Plumb and Carter); analysis and interpretation of data (Drs Shults, Oakes, Kieburtz, Beal, Haas, Juncos, Shoulson, and
Molho and Ms Plumb); drafting of the manuscript (Drs Shults, Oakes, and Shoulson); critical revision of the manuscript
for important intellectual content (Drs Shults, Oakes, Kieburtz,
Beal, Haas, Juncos, Nutt, Shoulson, Kompoliti, Perlmutter, Reich, Stern, Watts,
Kurlan, Molho, Harrison, and Lew and Mss Plumb and Carter); statistical
expertise (Dr Oakes); obtained funding (Drs Shults, Oakes, Kieburtz, and Shoulson); administrative, technical,
and material support (Drs Shults, Kieburtz, Beal, Haas,
Shoulson, Perlmutter, Watts, Kurlan, and Harrison and Ms Plumb); and
study supervision (Drs Shults, Oakes, Beal, Juncos, Perlmutter,
and Stern and Ms Plumb).
This study was supported by grant R01 NS36714 from the National Institutes
of Health, Bethesda, Md (Dr Shults). The coenzyme Q10 and placebo
used in the study were formulated into wafers and packaged without charge
by Vitaline Corp, Ashland, Ore.
We thank the National Institute of Neurological Disorders and Stroke
for support of the study, particularly Eugene Oliver, PhD (Program Director
for the study), and the National Institute of Neurological Disorders and Stroke–Constituted
Performance and Safety Monitoring Board (E. Clarke Haley, MD; David Eidelberg,
MD; Constantine Gatsonis, PhD; and Walter Rocca, MD, MPH). Dr Shults especially
thanks Stephanie Shanks, Riak Akuei and Myra Kosak for administrative oversight
of the study and Aileen Shinaman, JD, Parkinson Study Group Executive Director,
for her support during the study. We also acknowledge the contribution of
Thuy Le, PhD, for mitochondrial assays and Beverly Lorenzo and Linda Metakis
for assays of coenzyme Q10 levels.
| Parkinson Study Group
Steering Committee
Clifford W. Shults, MD (principal investigator, University of California–San
Diego and Veterans Affairs San Diego Healthcare System); David Oakes, PhD
(chief biostatistician, University of Rochester, Rochester, NY); Karl Kieburtz,
MD (director, Clinical Trials Coordination Center, University of Rochester);
M. Flint Beal, MD (director, Neurochemistry Laboratory, Weill Medical College
of Cornell University, New York, NY); Richard Haas, MB Chir (director, Mitochondrial
Research Laboratory, University of California–San Diego); Sandy Plumb,
BS (chief study coordinator, University of Rochester); Jorge L. Juncos, MD
(Emory University, Atlanta, Ga); John Nutt, MD (Oregon Health and Science
University, Portland); and Ira Shoulson, MD (University of Rochester).
Scientific Advisory Committee
Chris Goetz, MD (chair, Rush Presbyterian/St Luke's Medical Center,
Chicago, Ill), and Walter Koroshetz, MD (Massachusetts General Hospital, Boston).
Investigators
Julie Carter, RN, MS, ANP (Oregon Health and Science University); Katie
Kompoliti, MD (Rush Presbyterian/St Luke's Medical Center); Joel S. Perlmutter,
MD (Washington University, St Louis, Mo); Stephen Reich, MD (The Johns Hopkins
University, Baltimore, Md); Matthew Stern, MD (University of Pennsylvania,
Philadelphia); Ray L. Watts, MD (Emory University); Roger Kurlan, MD (University
of Rochester); Eric Molho, MD (Albany Medical College, Albany, NY); Madaline
Harrison, MD (University of Virginia, Charlottesville); and Mark Lew, MD (University
of Southern California, Los Angeles).
Coordinators
Barbara Alexander-Brown, BS, CRA (Oregon Health and Science University);
Kim Janko, RN, BSN (Rush Presbyterian/St Luke's Medical Center); Lori McGee-Minnich,
RN, BSN (Washington University); Becky Dunlop, RN, BSN (The Johns Hopkins
University); Sue Reichwein, BASW (University of Pennsylvania); Colleen Peach,
RN, MSN (Emory University); Nancy Pearson, RN, MSN (University of Rochester);
Sharon Evans, RN (Albany Medical College); Elke Rost-Ruffner, RN, BSN (University
of Virginia); and Connie Kawai, RN (University of Southern California).
Clinical Trials Coordination Center
Giovanni Schiffito, MD, Elaine Julian-Baros, Karen Hodgeman, Connie
Orme, BA, Larry Preston, BPS, and Karen Rothenburgh (University of Rochester);
Lin Zhang, MD (University of California–Davis).
Biostatistics Center
Janice Bausch, BA, and Shirley Eberly, MS (University of Rochester).
Pharmacy Center
Steven Bean, RPh (University of Rochester).
Safety Monitoring Committee
Pierre Tariot, MD, and Jack Hall, PhD (University of Rochester); Robert
Rodnitzky, MD (The University of Iowa, Iowa City).
|
|
Corresponding author and reprints: Clifford W. Shults, MD, Department
of Neurosciences, Mail Code 0662, University of California–San Diego,
9500 Gilman Dr, La Jolla, CA 92093-0662 (e-mail: cshults{at}ucsd.edu).
From the Department of Neurosciences, University of California–San
Diego, La Jolla (Drs Shults and Haas); Veterans Affairs San Diego Healthcare
System, San Diego (Dr Shults); Departments of Biostatistics (Dr Oakes) and
Neurology (Drs Kieburtz, Shoulson, and Kurlan and Ms Plumb), University of
Rochester School of Medicine and Dentistry, Rochester, NY; Department of Neurology
and Neuroscience, Weill Medical College of Cornell University, New York, NY
(Dr Beal); Department of Neurology and Wesley Woods Center, Emory University,
Atlanta, Ga (Drs Juncos and Watts); Parkinson's Disease Research, Education
and Clinical Center–Veterans Affairs Medical Center (Dr Nutt) and Oregon
Health and Science University (Dr Nutt and Ms Carter), Portland; and the Departments
of Neurology, Rush Presbyterian/St. Luke's Medical Center, Chicago, Ill (Dr
Kompoliti), Washington University, St. Louis, Mo (Dr Perlmutter), The Johns
Hopkins University, Baltimore, Md (Dr Reich), University of Pennsylvania and
Parkinson's Disease Research, Education and Clinical Center–Veterans
Affairs Medical Center, Philadelphia (Dr Stern), Albany Medical College, Albany,
NY (Dr Molho), University of Virginia, Charlottesville (Dr Harrison), and
University of Southern California, Los Angeles (Dr Lew). Dr Shults and Mr
Meese are coinventors in a pending patent application. The application is
jointly owned by Enzymatic Therapy, Inc, Green Bay, Wis (owner of Vitaline
Corp, Ashland, Ore), and The Regents of the University of California.
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Neuroprotection in PD--A role for dopamine agonists?
Schapira
Neurology 2003;61:S34-42.
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Coenzyme Q10 in Early Parkinson Disease
Hunter
Arch Neurol 2003;60:1170-1170.
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The Effect of Coenzyme Q10 Therapy in Parkinson Disease Could Be Symptomatic
Horstink and van Engelen
Arch Neurol 2003;60:1170-1172.
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The Saccharomyces cerevisiae COQ6 Gene Encodes a Mitochondrial Flavin-dependent Monooxygenase Required for Coenzyme Q Biosynthesis
Gin et al.
J. Biol. Chem. 2003;278:25308-25316.
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Coenzyme Q Induces Nigral Mitochondrial Uncoupling and Prevents Dopamine Cell Loss in a Primate Model of Parkinson's Disease
Horvath et al.
Endocrinology 2003;144:2757-2760.
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Neuroprotective agents for clinical trials in Parkinson's disease: A systematic assessment
Ravina et al.
Neurology 2003;60:1234-1240.
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Objective measures for the progression of Parkinson's disease
Snow
J. Neurol. Neurosurg. Psychiatry 2003;74:287-288.
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Beneficial Effect of High-Dose Coenzyme Q10 in Early PD?
JWatch General 2002;2002:7-7.
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Diet supplements and gene therapy tried for Parkinson's disease
Hopkins Tanne
BMJ 2002;325:851-851.
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Mitochondrial Abnormalities and Oxidative Imbalance in Neurodegenerative Disease
Ogawa et al.
Sci Aging Knowl Environ 2002;2002:pe16-16.
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Mitochondrial Therapy for Parkinson Disease
Rosenberg
Arch Neurol 2002;59:1523-1523.
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Practice Parameter: neuroprotective strategies and alternative therapies for Parkinson disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology.
Suchowersky et al.
Neurology 2006;66:976-982.
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