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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 Background: Parkinson disease (PD) is a degenerative
in the total score on the UPDRS from baseline to the last neurological disorder for which no treatment has been Results: The adjusted mean total UPDRS changes were
Objective: To determine whether a range of dosages of
+11.99 for the placebo group, +8.81 for the 300-mg/d coenzyme Q10 is safe and well tolerated and could slow 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 Design: Multicenter, randomized, parallel-group, pla-
change in the total UPDRS score, was .09, which met our cebo-controlled, double-blind, dosage-ranging trial.
prespecified criteria for a positive trend for the trial. Aprespecified, secondary analysis was the comparison of Setting: Academic movement disorders clinics.
each treatment group with the placebo group, and thedifference between the 1200-mg/d and placebo groups Patients: Eighty subjects with early PD who did not re-
quire treatment for their disability.
Conclusions: Coenzyme Q10 was safe and well toler-
Interventions: Random assignment to placebo or co-
ated at dosages of up to 1200 mg/d. Less disability de- enzyme Q10 at dosages of 300, 600, or 1200 mg/d.
veloped in subjects assigned to coenzyme Q10 than in thoseassigned to placebo, and the benefit was greatest in sub- Main Outcome Measure: The subjects underwent
jects receiving the highest dosage. Coenzyme Q10 ap- evaluation with the Unified Parkinson Disease Rating Scale pears to slow the progressive deterioration of function (UPDRS) at the screening, baseline, and 1-, 4-, 8-, 12-, in PD, but these results need to be confirmed in a larger and 16-month visits. They were followed up for 16 months or until disability requiring treatment with levodopa haddeveloped. The primary response variable was the change PARKINSONDISEASE(PD)isa chondrialelectrontransportchainstimu-
lated studies of mitochondrial function in Schapira10 reported a selective decrease in cular rigidity. Parkinson disease affects For editorial comment
see page 1523
65 years.1 The cardinal pathological fea-tures of PD are loss of dopaminergic neu- complex I activity in the postmortem sub- stantia nigra in patients with PD. Parker firmed12-14 a decrease in complex I activ- ity in platelets from patients with PD.
complex I activity plays a role in the patho- ated with PD.5,6 Recognition that 1-methyl- demonstration that patients with early, un- plex I and II/III in mitochondria isolated from platelets and that treatment with le- (REPRINTED) ARCH NEUROL / VOL 59, OCT 2002 2002 American Medical Association. All rights reserved.
vodopa and selegiline hydrochloride does not affect mi- 2 years or surgically sterile or using a reliable form of contra- tochondrial function.15,16 The possibility that a systemic ception for at least 2 months before screening and must have insult to the mitochondria could preferentially injure ni- agreed to continue its use for the duration of participation in gral dopaminergic neurons has been supported by the demonstration that systemic administration of rote- Exclusion criteria included the following: none, which inhibits complex I but is not selectively taken 1. The use of any medication for PD for 60 days before the base- up into dopaminergic neurons, causes preferential in- jury to the nigral dopaminergic neurons in rats.17 Coenzyme Q10 is the electron acceptor for com- 3. The use of antioxidants such as selegiline, vitamin E, and plexes I and II and also a potent antioxidant. Shults et al18 ascorbic acid (vitamin C) within 60 days of the baseline visit, demonstrated reduced levels of coenzyme Q10 in the mi- and previous use of coenzyme Q10 within 120 days of the base- tochondria isolated from platelets of patients with PD, and line visit. There was no limitation on the use of antioxidants the serum level of coenzyme Q10 in patients with parkin- before pretrial discontinuation of therapy. Patients were asked sonism has been reported to be significantly lower than that to take a standard daily multivitamin without minerals but no in age-comparable patients with stroke.19 Beal et al20 dem- onstrated that oral supplementation with coenzyme Q 4. The use of drugs known to interfere with mitochondrial ac- duced the loss of dopamine and dopaminergic axons in the striatum in 1-year-old mice treated with MPTP. Matthews 5. The use of methylphenidate hydrochloride, cinnarizine, re-serpine, amphetamines, or monoamine oxidase-A inhibitors et al21 found that oral supplementation with coenzyme Q10 within 6 months before the baseline visit.
in rats resulted in significant increases in the concentra- 6. An unstable dosage of drugs active in the central nervous tion of coenzyme Q10 in mitochondria in the cerebral cor- system (eg, anxiolytics, hypnotics, benzodiazepines, and anti- tex. In a pilot study, Shults et al22 demonstrated that oral depressants) during the 60 days before the baseline visit.
consumption of coenzyme Q10 at dosages of 400, 600, or 7. The use of appetite suppressants within 60 days before the 800 mg/d by patients with PD was well tolerated and re- sulted in significant elevations of plasma levels of coen- 8. Diseases with features of PD (eg, progressive supranuclear palsy, essential tremor, multiple system atrophy, striatonigral 10. On the basis of this work, we undertook a dosage- ranging study to evaluate the safety and tolerability of high degeneration, olivopontocerebellar atrophy, and postencepha- 10. The presence of dementia as evidenced by a Mini-Mental State Examination score of less than 24.2311. The presence of depression as indicated by a score on the Hamilton Depression Rating Scale of greater than 10.2412. A history of stroke.
ORGANIZATION
13. Disability sufficient to require treatment with dopaminer-gic drugs, as determined by the enrolling investigator.
This multicenter study was organized by the University of Cali- 14. A modified Hoehn and Yahr Scale score of greater than 2.5.25 fornia–San Diego in conjunction with the Parkinson Study 15. The presence of other serious illnesses.
Group; the Clinical Trials Coordination Center and the De- 16. Participation in other drug studies or the use of other in- partment of Biostatistics at the University of Rochester, Roch- vestigational drugs within 30 days before screening.
ester, NY; the Department of Neurology and Neuroscience at 17. A history of electroconvulsive therapy.
the Weill Medical College of Cornell University, New York, NY; 18. A history of brain surgery for PD.
and the enrolling sites. The National Institute of Neurological 19. A history of structural brain disease.
Disorders and Stroke sponsored the trial. Coenzyme Q10 and 20. A tremor score on the Unified Parkinson’s Disease Rating matching placebo were supplied by Vitaline Corp, Ashland, Ore.
Ten investigators at 10 Parkinson Study Group sites in the UnitedStates were responsible for the recruitment, enrollment, and At the screening visit, after the nature, purpose, and poten- follow-up of subjects. The institutional review board at each tial risks and benefits of the study were explained to the subject, site reviewed and approved the protocol. The principal inves- written informed consent was obtained. The subject underwent tigator and the Steering Committee guided the trial. The Safety evaluation with a medical history, physical examination, and a Monitoring Committee, established by the Steering Commit- battery of clinical assessments of PD (the UPDRS,25 the Hoehn tee, and the Performance and Safety Monitoring Board, con- and Yahr Scale,25 the Schwab and England Scale,25 and a timed stituted by the National Institute of Neurological Disorders and tapping task). Previous studies have established good interrater Stroke, independently and periodically reviewed enrollment, reliability for the UPDRS.26-28 For the timed tapping task, the sub- premature terminations, end points, adverse events, and labo- ject 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.
RECRUITMENT, ENROLLMENT,
Screening laboratory studies included electrocardio- AND RANDOMIZATION
graphy, a chemistry panel (levels of albumin, alkaline phos-phatase, aspartate transaminase, alanine transaminase, bicar- Eighty subjects with early PD were enrolled in the study at 10 bonate, serum urea nitrogen, calcium, chloride, creatinine, sites. Inclusion criteria required the presence of all 3 cardinal glucose, lactate dehydrogenase, phosphorous, potassium, so- features of PD (resting tremor, bradykinesia, and rigidity), which dium, total bilirubin, total creatine kinase, total protein, and had to be asymmetrical. The diagnosis of PD must have been uric acid), complete blood cell count, and urinalysis.
made within the previous 5 years in men or in women 30 years The baseline visit occurred within 1 month of the screen- or older. Women must have been postmenopausal for at least ing visit. In addition to the clinical assessments of PD, a blood (REPRINTED) ARCH NEUROL / VOL 59, OCT 2002 2002 American Medical Association. All rights reserved.
sample (approximately 110 mL) was obtained to determine com- nists, selegiline, amantadine hydrochloride, and anticholiner- plex I activity in platelets and levels of coenzyme Q10 in plasma.22 On completion of the baseline visit, each patient was randomly The primary statistical analyses were performed accord- assigned to receive coenzyme Q10 at a dosage of 300, 600, or 1200 ing to the intention-to-treat principle.31 According to the pre- mg/d or matching placebo in a 1:1:1:1 allocation using a computer- specified primary analysis plan, the mean change in the total generated randomization plan that included stratification by the UPDRS score was determined for each treatment group (300-, investigator and blocking (with a block size of 8) to ensure that 600-, and 1200-mg/d and placebo) and tested for a linear trend each investigator had approximately the same number of sub- between the dosage and mean change in the UPDRS using analy- jects assigned to each treatment group. Subjects, enrolling in- sis of covariance. Analyses were adjusted for the baseline score vestigators, enrolling coordinators, and other personnel in- and investigator. This analysis allows identification of a ben- volved in the care of the patients and the acquisition and analysis eficial response when there is a clear dose-response effect and of data were masked to treatment assignment until comple- when the effects at all of the dosages tested are equivalent.32 Because this dosage-ranging study was designed to detect a trend Participants underwent reevaluation at 1, 4, 8, 12, and 16 toward efficacy, not to demonstrate efficacy per se, we speci- months (±7 days) after the baseline visit using the battery of clini- fied use of a less stringent criterion than usual for declaring sta- cal examinations, and the enrolling investigator determined tistical significance, namely a 1-sided P value of .10. However, whether sufficient disability had developed to require treatment we present our efficacy data using 2-sided P values.
with levodopa. Each subject was followed up for 16 months oruntil the investigator determined that the patient needed treat- Sample Size
ment with levodopa. A blood sample was again drawn at the fi-nal visit for evaluation of platelet mitochondrial function and Based on these suppositions and our previous experience,30 the plasma levels of coenzyme Q10. Safety laboratory studies (chem- study was projected to have 73% power to detect an effect of istry panel, complete blood cell count, and urinalysis) were per- coenzyme Q10 corresponding to a difference of 6 points in total formed at the 1-, 4-, and 8-month and final visits.
UPDRS score between the placebo group and the highest active-dosage group.
INTERVENTION
We also explored other analyses. As specified, we per- formed analyses comparing all combined active-dosage groups Each patient was randomly assigned to receive coenzyme Q10 against the placebo group and each active-dosage group against at a dosage of 300, 600, or 1200 mg/d or matching placebo. The the placebo group using analysis of covariance. For these sec- study medication was taken 4 times each day, with breakfast, ondary analyses, we did not adjust for multiple comparisons.
lunch, and dinner and at bedtime. The wafers with active study We examined the area under the curve, ie, accumulated changes drug contained 300 mg of coenzyme Q10 and 300 IU of vita- in total UPDRS score during the total duration of the study, min E as a lipophilic carrier. Matching placebo wafers also con- and the trajectories of these curves to assess whether the effect of coenzyme Q10 on total UPDRS score was more consistent withpredominantly short-term effects on symptoms or long-term OUTCOMES, STATISTICAL METHODS,
effects on disease progression. Time to disability sufficient to AND SAMPLE SIZE
require treatment with levodopa was analyzed using the methodof Kaplan and Meier and the Cox proportional hazards regres- Safety and Tolerability
All adverse events (using World Health Organization termi- Plasma Level of Coenzyme Q10
nology) and abnormal laboratory values were analyzed by treat-ment group and severity. Only new events not present at the Subjects were asked to not take study medication after the last screening or the baseline visit were counted. The Cochran- dose on the day before follow-up visits to obtain a plasma level Armitage exact test for trend (1-tailed) was used to compare representative of a steady state. The samples were kept at each treatment groups with regard to the proportion of subjects ex- site at –80°C until shipped on dry ice to the laboratory at Weill periencing a particular adverse event or an abnormal labora- Medical College of Cornell University. Assays for plasma lev- tory value.29 We used 1-tailed tests because the finding of poorer els of coenzyme Q10 were performed by means of techniques tolerability in the placebo group would have been highly un- previously described with modification.18 The values from 1 sub- likely and of no interest. Compliance, as measured by pill counts, ject, who was assigned to receive coenzyme Q10 at a dosage of was summarized descriptively by treatment group.
600 mg/d, appeared to represent a reversal of the baseline andfinal visits and were not included in the analysis.
Efficacy and Trial Design
Comparisons of plasma levels at the final visit among pa- tients treated with coenzyme Q10 and placebo were made us- The primary response variable was the change in the total score ing analysis of covariance, adjusting for the baseline value as a on the UPDRS from the baseline to the last visit. The last visit was that at which the investigator judged that disability requir-ing levodopa therapy had developed, the last visit before a pre- Mitochondrial Assays
mature termination, or the 16-month visit. At each visit, theinvestigator was asked to assess whether the subject had reached At the baseline and final visits, venous blood was collected into disability sufficient to require therapy with levodopa using a two 50-mL syringes containing 5 mL of anticoagulant sodium form that asked a series of questions regarding occupation, gait, citrate solution. The samples were transferred at room tem- balance, finances, domestic responsibility, and activities of daily perature to the Mitochondrial Research Laboratory at the Uni- living. The series of questions was based on our previous ex- versity of California–San Diego by overnight courier. Com- perience with this end point.30 The decision was the responsi- plex I and citrate synthetase activities were measured by means bility of the enrolling investigator. The choice of initial anti- of well-established techniques.22 The Mitochondrial Research parkinsonian therapy was also the responsibility of the enrolling Laboratory, University of California–San Diego, also per- investigator and could include levodopa, dopaminergic ago- formed the assay for complex I/III using the rotenone- (REPRINTED) ARCH NEUROL / VOL 59, OCT 2002 2002 American Medical Association. All rights reserved.
Patients Undergoing Screening for Study (n = 89) Not Eligible (n = 6)Declined (n = 1)Enrollment Closed (n = 2) Unsatisfactory Response and Lost to Follow-up (n = 1) Additional Subjects Lost to Follow-up (n = 0) Figure 1. Patient flowchart.
Table 1. Baseline Characteristics*
Coenzyme Q10 Groups
Placebo Group
1200 mg/d
P
Schwab and England Scale score for ADL (examiner) Schwab and England Scale score for ADL (subject) *Unless otherwise indicated, data are given as mean (SD). UPDRS indicates Unified Parkinson’s Disease Rating Scale; ADL, activities of daily living.
sensitive reduced form of nicotinamide adenine dincleotide groups were well matched for sex, age, severity of PD (the (NADH) cytochrome-c reductase. The electron transport ac- UPDRS and Hoehn and Yahr Scale scores and the timed tivities were normalized to that of citrate synthetase to correct tapping score), disability (the Schwab and England Scale for any differences in mitochondrial mass. Comparisons of com- score) and intellectual function (the Mini-Mental State plex I and complex I/III activity at the baseline and final visits Examination score) (Table 1). The characteristics of our
among patients treated with coenzyme Q10 and placebo weremade using analysis of covariance, adjusting for the baseline subjects were very similar to those in previous studies value and investigator as covariates.
enrolling subjects who did not have disability sufficient All statistical analyses were performed using SAS soft- to require levodopa therapy.30,34 Three subjects prema- ware (Version 8; SAS Institute Inc, Cary, NC).
turely terminated or were lost to follow-up from the studybefore the investigator determined that they had reached the point that their disability warranted use of levodopa(Figure 1). Increased tremor, lower-back pain, and in- SUBJECTS ENROLLED
creased nocturia developed in 1 subject who was receiv-ing 1200 mg/d of coenzyme Q10 and who prematurely Eighty subjects were enrolled from May 24, 1999, through terminated. This subject was noncompliant, and the February 17, 2000 (Figure 1). At the baseline visit, the
investigator did not believe that the symptoms were (REPRINTED) ARCH NEUROL / VOL 59, OCT 2002 2002 American Medical Association. All rights reserved.
Table 2. Adverse Events Reported by at Least 4 Subjects
Coenzyme Q10 Groups, No. (%)
Adverse Event
Placebo Group, No. (%)
1200 mg/d
P Value*
Reported by at least 4 (5%) of subjects, excluding mild *Determined by the Cochran-Armitage exact test for trend.
related to the study drug. This subject was lost to nificant differences among the treatment groups (data not TOLERABILITY AND SAFETY
EFFICACY
Coenzyme Q10 was well tolerated; no dosage reductions were The adjusted mean changes in the total UPDRS score from needed in any of the treatment groups. The percentages of the baseline to the final visit (positive values indicate wors- subjects receiving coenzyme Q10 who reported any ad- ening) were +11.99 for the placebo group, +8.81 for the verse event (19 subjects [90%] for the 300-mg/d group; 12 300-mg/d group, +10.82 for the 600-mg/d group, and [60%] for the 600-mg/d group; and 21 [91%] for the 1200- +6.69 for the 1200-mg/d group (Table 3). Our primary
mg/d group) were not significantly different from that in analysis was a test for a trend between dosage and the the placebo group (13 subjects [81%]) (P=.51, Cochran- mean change in the UPDRS score, and P = .09 (2-sided) Armitage exact test for trend). Most adverse events were was significant according to our prespecified criteria. The mild. Eighteen adverse events were experienced by 4 (5%) difference in the change in the total UPDRS score be- or more subjects (Table 2). When mild adverse events
tween the placebo group and the 1200-mg/d group was were excluded, 3 were experienced by at least 4 subjects, 5.30 (95% confidence interval, 0.21-10.39). A prespeci- including viral infection, pharyngitis, and sinusitis. The dif- fied secondary analysis was comparison of each active ferences among the treatment groups were not signifi- treatment group with the placebo group. The difference cant, and no significant trend by dosage was found in the was significant for the 1200-mg/d group (P= .04) but not number of subjects experiencing an adverse event.
for the 300- (P = .22) or the 600-mg/d (P = .66) groups.
Analysis of 84 possible high or low laboratory re- The reduction in the worsening of the total UPDRS sults revealed a nominally significant or marginally sig- score was the result of slowed decline in all 3 compo- nificant trend by dosage in 4, including high carbon di- nents of the UPDRS, ie, mental (part I), activities of daily oxide levels (P=.01), high mean corpuscular hemoglobin living (part II), and motor (part III), with the greatest effect concentration (P=.08), and high sodium (P=.06) and uric in part II (Table 3). The greatest reduction was seen at acid levels (P = .08). The ongoing evaluation of abnor- the highest dosage (1200 mg/d). Results for the placebo mal laboratory results during the study and the review vs the combined drug groups were similar (data not at the completion of the study did not reveal these to be We also found a reduction in the worsening on the Analysis of the data for weight, sitting and stand- Schwab and England Scale, as assessed by the examiner ing blood pressure, and heart rate did not show any sig- (P = .04) but not by the patient (P = .81). The discrep- (REPRINTED) ARCH NEUROL / VOL 59, OCT 2002 2002 American Medical Association. All rights reserved.
Table 3. Adjusted Mean Change From Baseline*
Coenzyme Q10 Groups
Placebo Group
1200 mg/d
P
Value†
*Changes are given as the last observation carried forward, and reported as adjusted (least squares) means (95% confidence intervals) from the analysis of covariance. Abbreviations are explained in the first footnote to Table 1.
†Determined by the test for trend, as specified in the analysis plan.
Table 4. Adjusted Mean Change From Baseline to 1 Month*
Coenzyme Q10 Groups
Placebo Group
1200 mg/d
P Value†
*Changes are given as the last observation carried forward and reported as adjusted (least squares) means (95% confidence intervals) from the analysis of covariance. Abbreviations are explained in the first footnote to Table 1.
†Determined by means of the test for trend, as specified in the analysis plan.
ancy between the results, as determined by the examin- ers and the patients, appeared to be primarily due to dis- cordance 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.
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 ofthe 300- and 600-mg/d groups being similar, with lower Figure 2. Unified Parkinson’s Disease Rating Scale (UPDRS) scores. The
scores than those of the placebo group, and with the scores for the total UPDRS (last observation carried forward) are expressedas mean (SEM). Higher scores indicate more severe features of Parkinson scores for the 1200-mg/d group being substantially disease. Results of a test for a linear trend between the dosage and the mean lower than those of the other groups. This pattern per- change in the total UPDRS score indicated a trend for coenzyme Q10 to sisted until the end of the study and was the result of reduce the increasing disability over time (P = .09). The score change for the similar changes in all 3 components of the UPDRS 1200-mg/d coenzyme Q10 group was significantly different from that of theplacebo group (P = .04).
(Figure 3).
(REPRINTED) ARCH NEUROL / VOL 59, OCT 2002 2002 American Medical Association. All rights reserved.
Figure 4. Percentage of patients who required levodopa by the time until the
investigator considered that the subject needed treatment with levodopa.
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 atthe baseline visit (PϽ.001), and the plasma levels of coenzyme Q10 in the 3 groups receiving active drug were significantly different from each other (PϽ.05), with the exception of the 300- and 600-mg/d groups (P=.15).
Samples (numbers of patients) available from the baseline/final visits were13/14 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.
of vitamin E increased slightly more than 2-fold (data not Figure 3. The 3 parts of the Unified Parkinson’s Disease Rating Scale
(UPDRS). The pattern of attenuation of the worsening of the total UPDRSscore 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 MITOCHONDRIAL ASSAYS
III; C], last observation carried forward).
Results of the assay of the activity of complex I normal- Analyses of the area under the curve using the total ized to the activity of citrate synthetase did not indicate a UPDRS actual visit data showed similar, but not as sig- significant effect of coenzyme Q10 (P=.73). In this assay, nificant, results (data not shown). Examination of the time the activity of complex I did not depend on endogenous until the subject was considered to need treatment with coenzyme Q10, as an excess of exogenous coenzyme Q1 was levodopa disclosed no significant effect of coenzyme Q10 added (Figure 6A). We also determined the activity of
on this measure (P = .43) (Figure 4).
the electron transport chain from NADH to cytochrome-creductase (complexes I and III), which did depend on the PLASMA LEVELS OF COENZYME Q10
endogenous coenzyme Q10, and found a significant in-crease in the activity of the electron transport chain with All groups receiving coenzyme Q10 had highly signifi- treatment with coenzyme Q10 (P=.04) (Figure 6B).
cant increases in the mean plasma level of coenzyme Q10
from baseline to the last visit (Figure 5) (PϽ.001), and
the mean plasma levels of coenzyme Q10 were signifi-cantly different among the 3 groups receiving active drug Our dosage-ranging study found that coenzyme Q10 was (PϽ.05), with the exception of the 300- and 600-mg/d safe and well tolerated at the dosages of 300 to 1200 mg/d groups (P = .15). All subjects received 1200 IU of vita- and that the 1200-mg/d dosage was associated with sig- min E daily, and in each treatment group the plasma level nificant slowing of the worsening of PD as measured by (REPRINTED) ARCH NEUROL / VOL 59, OCT 2002 2002 American Medical Association. All rights reserved.
nous coenzyme Q10, demonstrated a significant increase in activity in subjects taking 1200 mg/d of coenzyme Q Although the results of our study of mitochondrial ac- tivity in platelets do not prove that a similar benefit oc-curred in the brain, the results are consistent with thispossibility. Our data are consistent with the hypothesis that mitochondrial dysfunction plays a role in the patho-genesis of PD and that treatments targeted at mitochon-dria 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 pre- clinical 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 me- Investigators have previously described improve- ment after supplemental coenzyme Q10 treatment in smallcase series in which the patients appeared to have an in- herited deficiency of coenzyme Q10.35-38 Similarly, oral co- enzyme Q10 treatment (600 mg/d) for 3 months in pa-tients with Friedreich ataxia improved bioenergetics in cardiac and skeletal muscle, but after 6 months of treat-ment, neurological function was not improved.39 The effect of coenzyme Q10 in other diseases, par- ticularly neurological disorders, has been inconsistent.
There have been numerous reports of the benefits of co- enzyme Q10 in patients with heart disease, but the stud-ies were often not controlled.40 A recent prospective, ran- Figure 6. Mitochondrial activity. Assays were normalized to citrate
domized, double-blinded, placebo-controlled trial of synthetase to correct for differences in mitochondrial mass. A, Complex Iactivity, which is not dependent on endogenous coenzyme Q10, did not differ coenzyme Q10 in congestive heart failure did not show among the treatment groups. B, The assay of the reduced form of benefit, but the dosage (200 mg/d) may not have been nicotinamide adenine dincleotide (NADH) to cytochrome-c reductase, which adequate.41 Previous studies in a variety of muscular dis- is dependent on the endogenous level of coenzyme Q10, showed a significanttrend for treatment with coenzyme Q orders have had inconsistent results.42-45 The dosages used available from the baseline/final visits were 12/14 for the placebo group, (30-300 mg/d) may have been inadequate, and heterog- 18/21 for the 300-mg/d group, 19/17 for the 600-mg/d group, and 20/21 for eneous neurological disorders were often studied to- the 1200-mg/d group for the complex I/citrate synthetase; and 12/14 for the gether in these trials. In the present study, the strict in- placebo group, 19/21 for the 300-mg/d group, 19/17 for the 600-mg/dgroup, and 20/20 for the 1200-mg/d group for NADH to cytochrome-c clusion criteria maximized the likelihood that the subjects Consistent with our findings of a reduction in the func- the total UPDRS score. The benefit was seen in all 3 of the tional decline in PD are the results of a trial in which pa- components of the UPDRS, but the effect was greatest in tients with early Huntington disease received coenzyme Q10 part II (activities of daily living). Consistent with the effect (600 mg/d), remacemide hydrochloride (600 mg/d), a com- on part II, we found a significant effect on the Schwab and bination of remacemide and coenzyme Q10, or placebo.47 England Scale score as judged by the examiner.
The decline in total functional capacity was not signifi- The effect of coenzyme Q10 on our primary re- cantly altered by any of the treatments, but subjects receiv- sponse variable, change in total UPDRS score, was not ing coenzyme Q10 (with or without remacemide treat- paralleled by the time to disability requiring treatment ment) showed 13% less decline in total functional capacity with levodopa. However, the group treated with 1200 than did the subjects who did not receive coenzyme Q10 mg/d tended to reach this end point more slowly until (P=.15). Previous studies in patients with Huntington dis- the end of the study. We were not surprised by this dis- ease showed that coenzyme Q10 significantly lowered in- crepancy. Analysis of the Deprenyl and Tocopherol An- creased lactate levels in the cerebral cortex, demonstrat- tioxidative Therapy of Parkinsonism (DATATOP) Study30 ing that it exerts biological effects in the brain.48 suggested that the time to levodopa treatment would Results of our study, in which the greatest benefit be a less informative measure than the change in total was found at a dosage of 1200 mg/d, the study of Hun- UPDRS score in a 16-month study (D.O., unpublished tington disease, in which an intriguing trend toward ben- data, 1994), thus prompting exploration of the current efit at a dosage of 600 mg/d was observed, and the con- gestive heart failure study, in which no benefit was seen The mechanism(s) through which coenzyme Q10 ex- at a dosage of 200 mg/d, indicate that the dosage of co- erted its beneficial effect cannot be determined from our enzyme Q10 may be crucial. The beneficial trend in our clinical trial, but our data are consistent with an effect trial was driven by the effect seen at the highest dosage on mitochondrial function. The assay of NADH to cyto- of coenzyme Q10 (1200 mg/d). The plasma levels of co- chrome-c reductase activity, which relies on endoge- enzyme Q10 in the groups receiving 300 and 600 mg/d (REPRINTED) ARCH NEUROL / VOL 59, OCT 2002 2002 American Medical Association. All rights reserved.
To our knowledge, our study is the first trial to sys- tematically explore the safety and efficacy of high dos- Steering Committee
ages of coenzyme Q10. Our data suggest that in treat- Clifford W. Shults, MD (principal investigator, Univer- ment of neurological disorders in which evidence of sity of California–San Diego and Veterans Affairs San complex I or II dysfunction are found, such as PD and Diego Healthcare System); David Oakes, PhD (chief bio- Huntington disease, dosages much higher than those pre- statistician, University of Rochester, Rochester, NY); Karl viously used may be required. The benefit was greatest Kieburtz, MD (director, Clinical Trials Coordination Cen- in the group receiving the highest dosage, 1200 mg/d. It ter, University of Rochester); M. Flint Beal, MD (direc-tor, Neurochemistry Laboratory, Weill Medical College is conceivable that a greater effect could be seen at even of Cornell University, New York, NY); Richard Haas, higher dosages of coenzyme Q10. Future studies of coen- MB Chir (director, Mitochondrial Research Laboratory, zyme Q10 in PD and other disorders will need to explore University of California–San Diego); Sandy Plumb, BS the effect of dosages of 1200 mg/d and higher.
(chief study coordinator, University of Rochester); JorgeL. Juncos, MD (Emory University, Atlanta, Ga); John Nutt, MD (Oregon Health and Science University, Portland);and Ira Shoulson, MD (University of Rochester).
In our study, coenzyme Q10 treatment at high dosages Scientific Advisory Committee
was safe and well tolerated and reduced the worsening Chris Goetz, MD (chair, Rush Presbyterian/St Luke’s of PD, as reflected in the total UPDRS score. It would be Medical Center, Chicago, Ill), and Walter Koroshetz, MD premature to recommend the use of coenzyme Q10 for (Massachusetts General Hospital, Boston).
the treatment of PD. Our results need to be confirmed Investigators
in a larger, phase 3 study, and the appropriate dosage and Julie Carter, RN, MS, ANP (Oregon Health and Science Uni- the magnitude of effect need to be better defined.
versity); Katie Kompoliti, MD (Rush Presbyterian/St Luke’sMedical Center); Joel S. Perlmutter, MD (Washington Uni- Accepted for publication June 5, 2002. versity, St Louis, Mo); Stephen Reich, MD (The Johns Hop- From the Department of Neurosciences, University of kins University, Baltimore, Md); Matthew Stern, MD (Uni-versity of Pennsylvania, Philadelphia); Ray L. Watts, MD California–San Diego, La Jolla (Drs Shults and Haas); Vet- (Emory University); Roger Kurlan, MD (University of Roch- erans Affairs San Diego Healthcare System, San Diego (Dr ester); Eric Molho, MD (Albany Medical College, Albany, Shults); Departments of Biostatistics (Dr Oakes) and Neu- NY); Madaline Harrison, MD (University of Virginia, Char- rology (Drs Kieburtz, Shoulson, and Kurlan and Ms Plumb), lottesville); and Mark Lew, MD (University of Southern University of Rochester School of Medicine and Dentistry, Rochester, NY; Department of Neurology and Neurosci- Coordinators
ence, Weill Medical College of Cornell University, New York, Barbara Alexander-Brown, BS, CRA (Oregon Health and NY (Dr Beal); Department of Neurology and Wesley Woods Science University); Kim Janko, RN, BSN (Rush Pres- Center, Emory University, Atlanta, Ga (Drs Juncos and byterian/St Luke’s Medical Center); Lori McGee- Watts); Parkinson’s Disease Research, Education and Clini- Minnich, RN, BSN (Washington University); Becky Dun- cal Center–Veterans Affairs Medical Center (Dr Nutt) and lop, RN, BSN (The Johns Hopkins University); Sue Oregon Health and Science University (Dr Nutt and Ms Reichwein, BASW (University of Pennsylvania); Col- Carter), Portland; and the Departments of Neurology, Rush leen Peach, RN, MSN (Emory University); Nancy Pear- Presbyterian/St. Luke’s Medical Center, Chicago, Ill (Dr son, RN, MSN (University of Rochester); Sharon Evans,RN (Albany Medical College); Elke Rost-Ruffner, RN, Kompoliti), Washington University, St. Louis, Mo (Dr BSN (University of Virginia); and Connie Kawai, RN (Uni- Perlmutter), The Johns Hopkins University, Baltimore, Md (Dr Reich), University of Pennsylvania and Parkinson’s Dis-ease Research, Education and Clinical Center–Veterans Af- Clinical Trials Coordination Center
Giovanni Schiffito, MD, Elaine Julian-Baros, Karen Hodge-
fairs Medical Center, Philadelphia (Dr Stern), Albany Medi- man, Connie Orme, BA, Larry Preston, BPS, and Karen cal College, Albany, NY (Dr Molho), University of Virginia, Rothenburgh (University of Rochester); Lin Zhang, MD Charlottesville (Dr Harrison), and University of Southern California, Los Angeles (Dr Lew). The complete list of the Biostatistics Center
Parkinson Study Group members is listed in the box on this Janice Bausch, BA, and Shirley Eberly, MS (University page. Dr Shults and Mr Meese are coinventors in a pending patent application. The application is jointly owned by En-zymatic Therapy, Inc, Green Bay, Wis (owner of Vitaline Pharmacy Center
Steven Bean, RPh (University of Rochester).
Corp, Ashland, Ore), and The Regents of the University ofCalifornia. Safety Monitoring Committee
Author contributions: Study concept and design (Drs
Pierre Tariot, MD, and Jack Hall, PhD (University of Roch- Shults, Oakes, Kieburtz, Beal, Haas, Nutt, Shoulson, and ester); Robert Rodnitzky, MD (The University of Iowa, IowaCity).
Watts); acquisition of data (Drs Shults, Beal, Haas,Kompoliti, Perlmutter, Reich, Stern, Watts, Kurlan,Molho, Harrison, and Lew and Mss Plumb and Carter); were relatively close, as were the total UPDRS scores in analysis and interpretation of data (Drs Shults, Oakes, both groups. The plasma and presumably brain levels of Kieburtz, Beal, Haas, Juncos, Shoulson, and Molho and coenzyme Q10 may be a significant determinant of the ef- Ms Plumb); drafting of the manuscript (Drs Shults, Oakes, and Shoulson); critical revision of the manuscript for im- (REPRINTED) ARCH NEUROL / VOL 59, OCT 2002 2002 American Medical Association. All rights reserved.
portant intellectual content (Drs Shults, Oakes, Kieburtz, affect platelet mitochondrial function in early parkinsonism. Neurology. 1995; Beal, Haas, Juncos, Nutt, Shoulson, Kompoliti, Perlmut- 17. Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre ter, Reich, Stern, Watts, Kurlan, Molho, Harrison, and JT. Chronic systemic pesticide exposure reproduces features of Parkinson’s dis- Lew and Mss Plumb and Carter); statistical expertise (Dr ease. Nat Neurosci. 2000;3:1301-1306.
18. Shults CW, Haas RH, Passov D, Beal MF. Coenzyme Q Oakes); obtained funding (Drs Shults, Oakes, Kieburtz, activities of complexes I and II/III in mitochondria from parkinsonian and non- and Shoulson); administrative, technical, and material sup- parkinsonian subjects. Ann Neurol. 1997;42:261-264.
port (Drs Shults, Kieburtz, Beal, Haas, Shoulson, Perlmut- 19. Matsubara T, Azuma T, Yoshida S, Yamagami T. Serum coenzyme Q10 level in Parkinson syndrome. In: Folkers K, Littarru GP, Yamagami T, eds. Biomedical ter, Watts, Kurlan, and Harrison and Ms Plumb); and study and Clinical Aspects of Coenzyme Q. New York, NY: Elsevier Science Publish- supervision (Drs Shults, Oakes, Beal, Juncos, Perlmut- 20. Beal MF, Matthews RT, Tieleman A, Shults CW. Coenzyme Q10 attenuates the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced loss of striatal do- This study was supported by grant R01 NS36714 from pamine and dopaminergic axons in aged mice. Brain Res. 1998;783:109-114.
the National Institutes of Health, Bethesda, Md (Dr Shults). 21. Matthews RT, Yang L, Browne S, Baik M, Beal MF. Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective ef- 10 and placebo used in the study were fects. Proc Natl Acad Sci U S A. 1998;95:8892-8897.
formulated into wafers and packaged without charge by 22. Shults CW, Beal MD, Fontaine S, Nakano K, Haas RH. Absorption, tolerability and effects on mitochondrial activity of oral coenzyme Q10 in parkinsonian pa-tients. Neurology. 1998;50:793-795.
We thank the National Institute of Neurological Dis- 23. Folstein MF, Folstein SE, McHugh P. “Mini-Mental State”: a practical method for orders and Stroke for support of the study, particularly Eu- grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975; gene Oliver, PhD (Program Director for the study), and the 24. Hamilton MA. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1988; National Institute of Neurological Disorders and Stroke– Constituted Performance and Safety Monitoring Board (E. 25. Lang AE. Clinical rating scales and videotape analysis. In: Koller WC, Paulson G, Clarke Haley, MD; David Eidelberg, MD; Constantine Gat- eds. Therapy of Movement Disorders. 2nd ed. New York, NY: Marcel Dekker Inc;1995:21-46.
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