Complementary Therapies in Medicine 23 (2015) 789–793

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A randomized controlled trial of coenzyme Q10 for fatigue in the late-onset sequelae of poliomyelitis Margaret M. Peel a , Marie Cooke a,∗ , Helen J. Lewis-Peel a , Rodney A. Lea b , Wendy Moyle a a NHMRC Centre for Research Excellence in Nursing Interventions, Menzies Health Institute Queensland, Centre for Health Practice Innovation, Griffith University, Queensland, Australia b Institute of Health and Biomedical Innovation, Queensland University of Technology, Queensland, Australia

a r t i c l e

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Article history: Received 22 January 2015 Received in revised form 15 July 2015 Accepted 6 September 2015 Available online 9 September 2015 Keywords: Randomized controlled trial Post-poliomyelitis syndrome Fatigue Coenzyme Q10

a b s t r a c t Objective: To determine if coenzyme Q10 alleviates fatigue in the late-onset sequelae of poliomyelitis. Design: Parallel-group, randomized, placebo-controlled trial. Background setting: Coenzyme Q10 has been shown to boost muscle energy metabolism in post-polio subjects but it does not promote muscle strength, endurance or function in polio survivors with postpoliomyelitis syndrome. However, the collective increased energy metabolism might contribute to a reduction in post-polio fatigue. Participants: Polio survivors from the Australian post-polio networks in Queensland and New South Wales who attribute a moderate to high level of fatigue to their diagnosed late-onset sequelae of poliomyelitis. Those with fatigue-associated comorbidities of diabetes, anaemia, hypothyroidism and fibromyalgia were excluded. Method: Participants were assigned (1:1), with stratification of those who use energy-saving mobility aids, to receive 100 mg coenzyme Q10 or matching placebo daily for 60 days. Participants and investigators were blinded to group allocation. Fatigue was assessed by the Multidimensional Assessment of Fatigue as the primary outcome and the Fatigue Severity Scale as secondary outcome. Results: Of 103 participants, 54 were assigned to receive coenzyme Q10 and 49 to receive the placebo. The difference in the mean score reductions between the two groups was not statistically significant for either fatigue measure. Oral supplementation with coenzyme Q10 was safe and well-tolerated. Conclusion: A daily dose of 100 mg coenzyme Q10 for 60 days does not alleviate the fatigue of the late-onset sequelae of poliomyelitis. The registration number for the clinical trial is ACTRN 12612000552886. © 2015 Elsevier Ltd. All rights reserved.

1. Introduction Along with new and increasing muscle weakness and fatigability, joint and muscle pain, excessive and unaccustomed general fatigue is a major symptom of the late-onset sequelae of poliomyelitis (LOSP), including post-poliomyelitis syndrome (PPS). Cold intolerance, pulmonary dysfunction, sleep disorders, speech and swallowing difficulties, and muscle atrophy, twitching and cramping are other symptoms that may occur.1 These symptoms typically develop after several decades of stable physical functioning following the initial recovery phase from acute poliomyelitis infection. Of these, fatigue has been reported as the

∗ Corresponding author. E-mail address: m.cooke@griffith.edu.au (M. Cooke). http://dx.doi.org/10.1016/j.ctim.2015.09.002 0965-2299/© 2015 Elsevier Ltd. All rights reserved.

major disabling symptom and a persistent problem in polio survivors with LOSP.2,3 The fatigue is multidimensional comprising general, physical, and mental fatigue.4 However, vitality (or the absence of general fatigue) in PPS depends on physiological rather than psychological parameters.5 Although the fatigue does not affect cognitive functioning6 or significantly impair mental health,7 it does negatively impact physical and psychosocial functioning in polio survivors with LOSP.7 Coenzyme Q10 (CoQ10 ), or ubiquinone, is an essential cofactor in oxidative phosphorylation which takes place in the mitochondria of cells with the production of ATP that provides energy for metabolic processes. A pilot study, published in 1997, showed that a daily dose of 100 mg CoQ10 boosted the skeletal muscle energy metabolism in subjects with PPS, as measured by nuclear magnetic resonance, to a significantly greater extent than it did in age-matched, healthy controls after 3 months and progressively by 6 months.8 A follow-up

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pilot study, published in 2008, showed that CoQ10 supplementation during a resistance training program conferred no additional benefit on muscle strength, endurance or function in PPS subjects as compared to the resistance training program alone in control PPS subjects.9 Because of the enhanced muscle energy metabolism, we initiated a parallel-group, randomized, double-blind, placebocontrolled trial to determine whether daily oral supplementation by 100 mg of CoQ10 for 60 days can alleviate the fatigue of LOSP. 2. Method 2.1. Design and participants Trial participants were recruited from the Queensland and New South Wales post-polio networks. The post-polio networks are support groups for polio survivors with LOSP that has been diagnosed by practitioners in neurology or rehabilitation medicine with recognized expertise in this specialty. Eligible participants are those who attribute a moderate to high level of fatigue primarily to LOSP and who are not already taking CoQ10. Exclusion criteria are a diagnosis of diabetes, anaemia, hypothyroidism, and fibromyalgia which are other major medical causes of fatigue. In addition, treatment with warfarin (Coumadin® or Marevan® ) or dabigatran (Pradaxa® ) is contraindicated for CoQ10 supplementation because of potential interactions.10,11 In the first phase of recruitment, two members of the research team made presentations to the Queensland post-polio networks, with the exception of one network in Far North Queensland. The presentations covered the principles of randomized controlled trials, the purpose of the proposed trial and the need for participants to experience a moderate to high level of fatigue that they attribute to LOSP. The first mail-out included a research project information sheet and the consent form. In addition to conforming to the eligibility criteria, participants were asked to sign an agreement to give a blood sample for the determination of CoQ10 plasma concentrations within 24 h of taking the last capsule, later changed to within 6 h of taking any one of the last five capsules. Participants were also asked to make no significant change to their diet or exercise program that might affect their energy levels for the duration of the trial. On receipt of the signed consent form, each participant was contacted by phone to check their eligibility. A form for the collection of demographic and clinical characteristics was posted to those whose eligibility was confirmed. The form included a question on whether power wheelchairs or mobility scooters were used as the sole or major means of mobility. The energy cost of walking in ambulatory polio survivors with lower limb paralysis, with or without walking aids, is significantly higher, by an average of about 40%, than that for age- and sex-matched, healthy subjects.12 This energy demand would contribute to fatigue. Two self-administered questionnaires were included for the assessment of fatigue at baseline. These were the multidimensional assessment of fatigue, MAF13 and the fatigue severity scale, FSS.14 2.2. Randomization and masking An independent, automated web-based service at the Griffith University Clinical Trials Coordination Centre (CTCC) randomly assigned participants to receive CoQ10 or placebo capsules on a 1:1 basis according to a computer-generated sequence for block sizes of four or six, with stratified assignment of those who use energy-saving power wheelchairs or mobility scooters as their sole or major means of mobility. World Health Limited, who donated the CoQ10 capsules and provided the placebo capsules, labelled the capsule containers with identical labels for the CoQ10 and placebo

groups except for an individual number which was different on each label (‘3000’–‘3110’). These container numbers aligned to the randomisation matrix sequence provided by CTCC for either the CoQ10 or placebo capsules. As participants were enrolled and randomized, we assigned the allocated container numbers to them. A novel colloidal formulation with enhanced enteral absorption and bioavailability was used as delivery system for the CoQ10 .15 The placebo was a non-soy, non-nut, vegetable oil in matching soft gel capsules. Participants and investigators were blinded to group allocation for the duration of the study. 2.3. Procedures After phone contact with each participant, we posted the capsules in insulated packages by express post for delivery on the next business day. This procedure minimized exposure of the capsules to high ambient temperatures since CoQ10 should be maintained below 30◦ Celsius. Each participant was contacted again by telephone to confirm receipt and to ask their starting date for taking the capsules. The packages included a diary for recording daily intake of a capsule, with breakfast, and a business-size card that warned against continuing to take the capsules should treatment with warfarin or dabigatran be instituted. About 10 days before the end of the 60-day period of taking capsules, we posted each participant a Request Form for the collection of a blood sample at a pathology collection centre for the determination of plasma CoQ10 concentrations. All samples were submitted for analysis to a Department of Chemical Pathology at a Queensland tertiary hospital. This mail-out also included the final fatigue questionnaires and a questionnaire that actively surveyed the responses that participants may have experienced to oral ingestion of the capsules. 2.4. Assessment of fatigue The primary outcome was fatigue reduction as assessed by the MAF (© Basia Belza 1993; e-mail contact for permission to use is [email protected]). The MAF is a multidimensional measure that addresses degree and severity, distress caused, interference with the activities of daily living, as well as the daily pattern and timing of the fatigue.13 The secondary outcome was fatigue reduction as assessed by the FSS, a unidimensional measure that focuses on the impact of fatigue on the activities of daily living.14 Our choice of these fatigue measures was based on the recommendations of Whitehead16 who reported that the MAF and FSS instruments were among only six of 22 fatigue measures that had robust psychometric properties and among only four that demonstrated the ability to detect changes in fatigue over time or after intervention. The MAF is a 16-item questionnaire that yields a global fatigue index (GFI) ranging from 1 (no fatigue) to 50 (severe fatigue).13 Most of the questions (numbers 4–14) are directed to the degree to which fatigue interferes with the activities of daily living. The MAF has not been used previously for the measurement of fatigue in PPS but it is a revision of the multidimensional Piper Fatigue Scale, which has been validated as a reliable measure of fatigue in post-polio patients.17 The MAF has also been validated for the assessment of multidimensional fatigue in a wide range of other populations and was reported as the only multidimensional measure that is capable of detecting change, provided that change is not small.16 The FSS comprises nine items in a seven-point scale with higher scores in the range of 1–7 indicating higher levels of fatigue.14 Vasconcelos et al.18 compared the applicability and validity of the FSS, visual analog scale and the fatigue impact scale for the measurement of fatigue in PPS and concluded that the FSS was the strongest predictor of severe fatigue and most closely agreed with the intensity of self-reported fatigue in PPS. Since then, Rasch

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analysis has confirmed the validity of eight of the nine items of the FSS (the exception being item 1 on motivation) as a measure of the severity and impact of physical symptoms of fatigue in polio survivors.19 The FSS was originally described as capable of detecting clinically predicted changes in fatigue over time14 ; but the FSS, like the MAF, is insensitive to small changes in fatigue.20 Pearson’s correlation coefficient (r) between the MAF and the FSS is 0.74, p ≤ 0.05.16 2.5. Analysis of plasma samples for CoQ10 levels Total CoQ10 concentrations in the plasma samples were determined by high-performance liquid chromatography (HPLC) with the Alliance HPLC system (Waters Corporation, 34 Maple Street, Milford, Massachusetts, 01757, USA). The CoQ10 was extracted in a mixture of propan-1-ol and hexane, evaporated to dryness, and then reconstituted in a mobile phase of propan-1-ol and acetonitrile. The detector measured absorbance at 275 nm in the ultraviolet range of wavelengths. Results in units of ␮mol/L were calculated and compared with those of internal standards integrated by Empower Software. 2.6. Sample size and statistical analysis The sample size for the MAF was calculated on a conservative assumption that we would observe a SD of 12 units in the MAF outcome and an average difference of 10 units. This assumption was based on the positive findings for a significant reduction in fatigue by treatment of rheumatoid arthritis as reported by Kaltwasser et al.21 For an alpha level of 0.05, we have 97.5% power to find a between-group difference of 10 units or greater if we have 45 participants to each group.22 To allow for 10% dropout, we aimed to recruit at least 50 participants for each group. Prior to undertaking the statistical analyses, we performed a multiple imputation analysis to replace missing at random data for the outcome variables of the MAF and FSS. Means and SDs were calculated for baseline quantitative variables and counts and percentages for categorical variables. The effect of CoQ10 supplementation on the outcome variables of the MAF and FSS was tested by repeated measures analysis of variance (ANOVA). Participants were retained in their original assigned groups for analysis (intention to treat). All statistics were assessed for significance at the alpha level of 0.05. 2.7. Ethical approval and registration Ethical approval for the clinical trial was granted by the Griffith University Human Research Ethics Committee (GUHREC) on receipt of a completed Australian national ethics application form, along with the trial documentation. We subsequently reported adverse events to GUHREC who monitored the safety of the trial. The volunteer subjects provided written informed consent for participation in the trial and for the collection, use and storage of their personal information. The trial was registered with the Australian New Zealand Trial Registry, ACTRN 12612000552886. 3. Results We enrolled 60 participants from Queensland from October 17, 2012, and 43 from New South Wales from April 8, and from July10, 2013. As shown in Fig. 1, 54 of the 103 who responded to the 535 invitations to participate were randomly assigned to receive the active CoQ10 intervention while 49 were assigned to placebo. Table 1 shows that the two groups are well balanced for baseline demographics, clinical characteristics and fatigue scores, and the

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Table 1 Baseline demographics, clinical characteristics and fatigue scores. Coenzyme Q10 (n = 52) Age (years) 69.9 (8.4) Men 15 (28%) Acute poliomyelitis infection 7.8 (6.3) Age at onset 2.1 (1.2) Muscle weakness Stable period after initial maximal recovery from acute poliomyelitis 1.0 (1.0) Muscle weakness Use of walking aids 21 (39%) Use of wheelchairs 2 (4%) Late-onset sequelae of poliomyelitis 48.1 (13.7) Age at onset (years) 25 (46%) Use of walking aids 7 (13%) Use of ventilatory support Need for power wheelchairs 9 (17%) or mobility scooters 33.6 (6.3) MAF score 5.7 (1.1) FSS score

Placebo (n = 49) 69.8 (8.2) 17 (35%) 5.1 (4.7) 2.2 (1.5) 0.9 (0.8) 20 (41%) 3 (6%) 50.4 (13.6) 28 (57%) 5 (10%) 5 (10%) 31.8 (6.1) 5.3 (1.0)

Data are mean (SD) or number (per cent); muscle weakness scored as 1 for each limb, respiratory and other muscle groups, modified from.4 MAF: Multidimensional assessment of fatigue; FSS: fatigue severity scale.

MAF and FSS scores are consistent with a moderate to high level of fatigue.3,13 Table 2 shows the results of the repeated measures ANOVA for the outcome variables of the MAF and FSS at baseline and after 60 days of CoQ10 supplementation. The mean MAF score reductions between the CoQ10 and placebo groups is not statistically significant (F = 0.86, p = 0.36) and neither is the mean FSS score reductions between the two groups (F = 0.11, p = 0.74). Plasma CoQ10 concentrations were determined for 46 of the 48 participants who completed the trial in the CoQ10 group (96%) and for 44 of the 47 participants who completed the trial in the placebo group (94%). The reference range for plasma CoQ10 levels for the relevant age group of >43 years is 0.57 to 1.95 ␮mol/L.23 The mean (SD) of the CoQ10 levels for the 23 participants in the CoQ10 group who presented for blood collection within 24 h of taking the last capsule (an unknown number of whom presented within 6 h) was 2.0 (0.88) ␮mol/L. The mean (SD) of the 23 participants in the CoQ10 group who presented within 6 h of taking a capsule was 2.5 (1.3) ␮mol/L. For the combined results of the CoQ10 group, the mean (SD) was 2.3 (1.0) ␮mol/L (95% CI 2.0–2.6). The mean (SD) for the 44 participants who completed the trial in the placebo group was 1.0 (0.4) ␮mol/L (95% CI 0.9–1.1). The 1.3 ␮mol/L difference between the means of the CoQ10 and placebo groups equates to a 56% change in plasma CoQ10 concentrations, which exceeds the 46.1% for a 99% significant change.23 Seven adverse events were reported from participants in the CoQ10 group and four from the placebo group. Five participants withdrew from the CoQ10 group, one each with respiratory symptoms, kidney dysfunction, insomnia, nausea with mild diarrhoea and an outbreak of pimples, and behavioural problems with psychiatric symptoms. Two withdrew from the placebo group, one because of constipation and the other because of balance problems. The other two adverse events reported from the CoQ10 group were facial palsy and liver dysfunction. Back pain and a blood clot in the leg at the end of the course of capsules were reported by two participants in the placebo group. 4. Discussion The outcome of the randomized, double-blind, placebocontrolled trial is that 100 mg CoQ10 for 60 days does not alleviate the fatigue of LOSP. The findings were non-significant despite the novel formulation of the CoQ10 delivery system that enhanced

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535 invitations issued

432 did not meet eligibility criteria or chose to participate 103 randomly allocated

54 allocated to CoQ10

49 allocated to placebo

5 withdrew due to 2 withdrew due to adverse events adverse events 1 non-compliant

48 completed study

47 completed study

54 analysed for fatigue

49 analysed for fatigue

Fig. 1. Flow chart for trial.

Table 2 Outcome measures for fatigue at baseline and after the 60-day trial. Coenzyme Q10 (n = 54)

MAF FSS

Placebo (n = 49)

Baseline

Final

Change over trial

Baseline

Final

Change over trial

33.6 (0.8) 5.7 (0.2)

28.1 (1.3) 5.3 (0.2)

−5.5 −0.4

31.8 (0.9) 5.5 (0.2)

27.6 (1.4) 5.1 (0.2)

−4.2 −0.3

Difference (95% CI)

F-test

p-Value

−1.3 (−1.2 to −1.3) −0.1 (−0.1 to −0.1)

0.86 0.11

0.36 0.74

Data are means (SEM) unless otherwise indicated; analysis by intention-to-treat repeated measures ANOVA. FSS: Fatigue severity scale; MAF: multidimensional assessment of fatigue.

enteral absorption and bioavailability15 and the use of the MAF and FSS measures that are capable of detecting changes in fatigue over time or after intervention,14,16 although neither is sensitive to small changes.16,20 Several therapeutic drugs have been investigated for the alleviation of fatigue in PPS in randomized, double-blind, placebo-controlled trials (RCTs). These include amantadine,24 pyridostigmine, an anticholinesterase that is capable of improving neuromuscular transmission, twice,25,26 and modafinil, the stimulant that promotes wakefulness, also twice.27,28 None of these therapeutic agents proved effective, and most reported a strong placebo effect. RCTs on the administration of intravenous immunoglobulin to reduce proinflammatory cytokines have also failed to relieve fatigue in PPS.29,30 CoQ10 has an excellent safety record with an observed safety level (OSL), based on data from various clinical trials, of 1200 mg/day/person.31 CoQ10 supplementation is not associated with serious adverse events, even when taken for long periods of time. A 6-year, long-term study of 143 patients with heart failure given 100 mg CoQ10 daily as adjunct therapy showed no definitive evidence of CoQ10 intolerance or toxicity.31 Each of the seven adverse events reported from the CoQ10 group in our study was unique; and, therefore, unlikely to be attributable to CoQ10 supplementation. Based on the reported elimination half-life of about 33 h for CoQ10 ,32 we initially asked participants to present for the collection of blood samples for plasma CoQ10 determinations within 24 h of taking the last capsule. However, this led to a potential difficulty in the interpretation of results because of individual variation in baseline concentrations of plasma CoQ10 which means that a significant change in CoQ10 levels for an individual may occur within the reference range.23 The remaining participants were asked to present for blood collection within 6 h of taking any one of the last five capsules, according to their convenience. The maximum

plasma concentration of CoQ10 in the colloidal formulation that we used occurs 4 h after oral ingestion and plasma levels are still significantly elevated at 8 h.15 The difference between the plasma CoQ10 levels for the CoQ10 group and the placebo group was highly significant indicating a high level of compliance.23 We chose a daily dose of 100 mg of CoQ10 because that was the dose that, over a period of three to 6 months, promoted muscle energy metabolism in post-polio subjects to a significantly greater extent than it did in normal, age-matched controls.8 A daily intake of 100 mg of CoQ10 has also been used commonly as adjunct therapy in cardiovascular diseases.31 Moreover, we used a CoQ10 delivery system that enhanced enteral absorption and bioavailability.15 Nonetheless, the daily dose of 100 mg CoQ10 might not have been sufficient to reach therapeutic levels in some individuals. Further, since muscle metabolism in the post-polio subjects taking 100 mg CoQ10 daily increased between three and 6 months,8 the 60-day period of supplementation might also have been inadequate. Such inadequacies in the dose and duration of oral supplementation by CoQ10 in the current study might account for the non-significant finding. Our study has limitations. We did not account for the contribution of depression to fatigue,4 although one participant with symptoms consistent with depression did withdraw from the trial. This is probably not a major shortcoming because, while MAF scores can reflect fatigue due to depression,13 FSS scores are ‘largely independent of self-reported depressive symptoms’.14 We also had to rely on a history of diagnosed comorbidity as an exclusion criterion. Of the 535 invitations sent to members of the post-polio networks to participate in the trial, 432 did not accept the invitation. Although some would have chosen not to participate, it is reasonable to conclude that many did not meet the eligibility criteria because of comorbidities. That a large number may have comorbidities is unsurprising since the prevalence of diabetes, deficiency anaemia and hypothyroidism is significantly higher in paralytic polio sur-

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vivors than it is in an age- and sex-matched general population.33 In addition, fibromyalgia, with symptoms similar to PPS, is frequently diagnosed in a post-polio clinic.34 Ischaemic stroke has also been shown to be significantly more prevalent in polio survivors than it is in an age- and sex-matched control group.35 Those who have suffered from stroke would not comply with the inclusion criteria because of their ongoing treatment with warfarin or dabigatran which can interact with CoQ10 .10,11 The eligibility of all 103 polio survivors with LOSP who did accept the invitation to participate was checked by telephone on receipt of their consent forms. Since the increase in muscle energy metabolism in post-polio subjects by CoQ10 8 did not translate to improved muscle strength, endurance or function in polio survivors with PPS,9 it was considered that the collective effect of the enhanced energy metabolism might contribute to a reduction in general fatigue but the findings of the RCT show that oral supplementation by 100 mg of CoQ10 for 60 days does not alleviate a moderate to high level of fatigue in polio survivors with LOSP. Future research that investigates the alleviation of the fatigue of LOSP by a higher daily dose of CoQ over a longer period of time is suggested.

9.

10.

11.

12.

13. 14.

15.

16.

17.

Conflict of interest 18.

None. 19.

Funding 20.

The clinical trial was funded by the Cancer and Polio Research Fund (United Kingdom) but the funding source had no involvement in the study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the article for publication. Acknowledgements

21.

22.

23. 24.

We thank Health World Limited of Northgate Queensland for the donation of the coenzyme Q10 capsules and CPX Printing of Kelvin Grove Queensland for printing services. World Health Limited had no influence on the interpretation of data or the final conclusions drawn. We also thank Spinal Injuries Australia (Queensland) and Polio NSW for their role in recruitment. We gratefully acknowledge the technical assistance of Ruth Cantrill and Niall Higgins. References 1. Gonzalez H, Olsson T, Borg K. Management of postpolio syndrome. Lancet Neurol. 2010;9:634–642. 2. Nollet F, Beelen A, Prins MH, et al. Disability and functional assessment in former polio patients with and without postpolio syndrome. Arch Phys Med Rehabil. 1999;80:136–143. 3. Tersteeg IM, Koopman FS, Stolwijk-Swüste JM, Beelen A, Nollet F. A 5-year longitudinal study of fatigue in patients with late-onset sequelae of poliomyelitis. Arch Phys Med Rehabil. 2011;92:899–904. 4. Trojan DA, Arnold DL, Shapiro S, et al. Fatigue in post-poliomyelitis syndrome: association with disease-related, behavioral, and psychosocial factors. PM R. 2009;1:442–449. ´˚ Sunnerhagen KS, Borg K. Vitality among Swedish 5. Östlund G, Wahlin A, patients with post-polio: a physiological phenomenon. J Rehabil Med. 2008;40:709–714. ´˚ Cognitive functioning in post-polio patients with 6. Östlund G, Borg K, Wahlin A. and without general fatigue. J Rehabil Med. 2005;37:147–151. 7. On AY, Oncu J, Atamaz F, Durmaz B. Impact of post-polio-related fatigue on quality of life. J Rehabil Med. 2006;38:329–332. 8. Mizuno M, Quistorff B, Theorell H, Theorell M, Chance B. Effects of oral supplementation of coenzyme Q10 on 31 P NMR detected skeletal muscle

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A randomized controlled trial of coenzyme Q10 for fatigue in the late-onset sequelae of poliomyelitis.

To determine if coenzyme Q(10) alleviates fatigue in the late-onset sequelae of poliomyelitis...
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