Otolaryngology–Head and Neck Surgery (2007) 136, 72-77

ORIGINAL RESEARCH

A pilot clinical trial of the effects of coenzyme Q10

on chronic tinnitus aurium

Martin Khan, MD, Johann Gross, MD, PhD, Heidemarie Haupt, MSc Eng,Annett Jainz, Msc Eng, Petra Niklowitz, MD, Hans Scherer, MD, PhD,Frank-Peter Schmidt, MD, Burghard F. Klapp, MD, PhD,

Anett Reisshauer, MD, and Birgit Mazurek, MD, Berlin, Germany

OBJECTIVE: To determine the short-term effects of coenzymeQ10 (CoQ10) on the antioxidative status and tinnitus expression inpatients with chronic tinnitus aurium.STUDY DESIGN: A 16-week prospective nonrandomizedclinical trial (n � 20). Tinnitus and Short Form-36 Question-naires (TQ/SF-36) were evaluated together with the plasmaconcentrations of CoQ10, malondialdehyde, and the total antiox-idant status.RESULTS: The mean plasma CoQ10 concentration rose underexternal CoQ10 supply and remained elevated after medicationstopped without overall effects on the tinnitus score. However, ina subgroup of 7 patients with low initial plasma CoQ10 concen-tration and significant increase in the plasma CoQ10 level, a cleardecrease in the TQ score was observed.CONCLUSION: In patients with a low plasma CoQ10 concen-tration, CoQ10 supply may decrease the tinnitus expression.SIGNIFICANCE: This is the first study to examine the effect ofCoQ10 in chronic tinnitus aurium.© 2007 American Academy of Otolaryngology–Head and NeckSurgery Foundation. All rights reserved.

Coenzyme Q10 (CoQ10) has been used to treat a varietyof disorders. It is predominantly administered in the

adjunctive treatment of chronic heart failure, but efficacyhas also been suggested for hypertension, muscular dystro-phy, and neurodegenerative diseases.

CoQ10 is a 2,3-dimethoxy,5-methyl,6-polyisoprene para-

From the Departments of Otorhinolaryngology (Drs Khan, Gross,Scherer, and Mazurek and Ms Haupt); Internal Medicine: Division Psy-chosomatics and Psychotherapy (Dr Klapp); and Physical Medicine andRehabilitation (Dr Reisshauer); Charité-University Medicine Berlin; theInstitute of Medical Diagnostics (Dr Schmidt and Ms Jainz); Berlin; andVestische Kinderklinik Datteln (Dr Niklowitz); University Witten/Herd-

ecke, Datteln, Germany.

0194-5998/$32.00 © 2007 American Academy of Otolaryngology–Head and Necdoi:10.1016/j.otohns.2006.07.010

benzoquinone and is located in all membranes throughoutthe cell. The highest concentrations are found in the heart,the liver, the kidneys, and the pancreas. It is an endog-enously synthesized substance involved in a variety of es-sential processes. The influence on the mitochondrial elec-tron transport chain is well recognized. However, it alsoappears to have membrane-stabilizing properties and to actas an antioxidant in conjunction with vitamin E.1

Under normal conditions, cells may regulate their CoQ10content independently of the latter’s external supply. How-ever, where CoQ10 deficiency occurs, a higher CoQ10content of cell membranes could be expected after externalCoQ10 supply.2 In age-related degenerative and neurode-generative diseases like Parkinson’s disease, a low level ofthe antioxidant CoQ10 is believed to contribute to oxidativedamage caused by reactive oxygen species (ROS) produc-tion.3

The amount of free radicals is determined by the balanceof many different factors, whereas the source of ROS for-mation is mainly constituted by mitochondria during elec-tron transport in the oxidative phosphorylation chain. Mi-tochondria are thought to play a crucial role in the agingprocess not only due to their role as main intracellulargenerators of ROS, but also because they are targets of ROSattack.4

In patients with Parkinson’s disease, the administration

This work was sponsored by MSE Pharmazeutika GmbH, Bad Hom-burg, Germany.

Reprint requests: Birgit Mazurek, MD, Department of Otorhinolaryn-gology, Tinnitus Centre, Charité-University Medicine Berlin CCM, Schu-mannstrasse 20/21, 10117 Berlin, Germany.

E-mail address: birgit.mazurek@charite.de.

k Surgery Foundation. All rights reserved.

73Khan et al A pilot clinical trial of the effects of coenzyme Q10 . . .

of CoQ10 showed a moderate beneficial effect.5 CoQ10 isalso known to have a protective function against ischemiclesions produced by mitochondrial toxins.6

That psychological stress is linked to tinnitus has beenconfirmed in many studies.7 Tinnitus as a disturbing anduncontrollable symptom acts like a chronic stressor and,thereby, interferes with T-Helfer 1 (TH1)/T-Helfer 2 (TH2)cytokines. In chronic stress, a shift from TH2 cells to TH1cells was observed. This was determined in changes under-gone by immunological markers, ie, tumor necrosis factor �(TNF �) represents the TH1 cytokines and interleukin (IL)6 and 10 represent TH2 cytokines. In association with psy-chological stress and major depressive disorders, elevatedTNF � levels and decreased levels of IL6 were detected.This could be linked with an altered function of reactiveoxygen intermediates. Several studies8,9 have documentedan increase in oxidative damage in stress conditions.

Preventing ROS formation may be one mechanism todecrease oxidative stress conditions.4 Antioxidative phar-maceuticals have an effect on ROS formation and couldtherefore protect cells from oxidative stress.10 However, theuse of CoQ10 is still speculative and large-scale clinicaltrials of antioxidants showed inconsistent results. In patientswith chronic tinnitus, CoQ10 may cause an improvement ofthe physical and mental condition because of its antioxida-tive properties.

The aim of this study was to examine the effect ofNanoquinone, a CoQ10 drug, on the tinnitus expression.Therefore, patients were treated with Nanoquinone for 12weeks and assessed on the basis of the tinnitus questionnaire(TQ) and the short form 36 (SF-36) to determine the tinnitusexpression.

MATERIALS AND METHODS

Test PersonsTwenty patients from the Tinnitus Center of the CharitéDepartment of Otorhinolaryngology were included (6 fe-males, 14 males). Their ages ranged between 21 and 77years, with an average of 54 � 16 years. Any underlyingretro cochlear pathology was excluded by a full scale ofmedical and audiological examinations.

The patients received 100 mg Nanoquinone (Sanomit,MSE Pharmazeutika GmbH, Bad Homburg, Germany)3 times daily over a period of 12 weeks. The dosage of 300mg/d is considered to be effective in patients.2

Inclusion criteria were the following: minimum age of 18years, tinnitus persistence of at least 3 months, and informedconsent. Test persons were excluded by the following cri-teria: atypical tinnitus, medication induced tinnitus, fluctu-ating disease, participation in other clinical studies withinthe previous 30 days, intake of magnesium, and calciumand/or vitamins 2 months before and after the study.

Fifteen patients had bilateral tinnitus and 5 patients hadunilateral tinnitus. The mean tinnitus frequency measured in

the affected ears was 6 kHz and the mean (� standard

deviation [SD]) tinnitus loudness amounted to 44 � 24 dBSPL (sound pressure level). The patients had a mean hearingloss of 24.4 � 12.0 dB SPL measured by pure tone audio-gram (500 Hz, 2 kHz, and 4 kHz).

Patients were psychologically assessed before the ther-apy and after 4 and 12 weeks of the therapy including theTQ according to Goebel and Hiller11 and the SF-36 accord-ing to Ware and Sherbourne.12 The TQ is a standard ques-tionnaire to investigate the psychological parameters in per-sons with tinnitus. The TQ is a 52-item self-rating scalea n d w a s established and published by Goebel and Hiller.11

The main TQ score is calculated according to Hiller andGoebel.13 Briefly, the main TQ score is ranked from 0 to 84points. Because of the small number of patients involvedand for a clearer evaluation, 2 groups of the main TQ scorewere built: group I, 0 to 46 points with compensated tinnitusand group II, 47 to 84 points with decompensated tinnitus.The TQ differentiates between several dimensions: emo-tional distress (12 items with a score range of 0 to 24points), cognitive distress (8 items with a score range of 0 to16 points), intrusiveness (8 items with a score range of 0 to16 points), auditory perceptional difficulties (7 items with ascore range of 0 to 14 points), sleep disturbances (4 itemswith a score range of 0 to 8 points), and somatic complaints(3 items with a score range of 0 to 6 points).13

The SF-36 health survey score was chosen for its well-established acceptance as a valid, reliable measure of per-ception of physical and mental health across a large range ofdisease entities.12 The SF-36 assesses 36 items of physicaland mental health across several individual domains andproduces both a physical and a mental component score.Scores range from 0 to 100, with higher scores indicatinghigher levels of functioning and associated quality of life.

The study was approved by the Human Ethics Commit-tee of the Charité-University Medicine Berlin and was con-ducted with the informed consent of the patients.

Blood Sample AnalysisLevels of CoQ10, malondialdehyde (MDA), and total anti-oxidative status (TAS) in plasma were determined beforetherapy, during the therapy (4 weeks), and 4 weeks after theend of the medication (16 weeks). Lithium heparin andEDTA (ethylendiamine tetra-acetic acid) tubes were usedfor this purpose. The plasma component was separated (cen-trifugation at 3000 � g for 10 minutes), and 1 mL aliquotswere stored at –84°C until analysis. The total amount ofCoQ10 was determined by high performance liquid chro-matography (HPLC).2 The MDA levels in plasma were alsodetermined by HPLC with the use of a kit of fluorometricdetection supplied by Chromsystems (Munich, Germany).The total antioxidant status in plasma was determined withthe Randox assay (Crumlin, Antrim, UK).

Statistical AnalysisMeans � SD or standard errors of the mean (SEM) were

calculated for all parameters measured. Plasma levels of

74 Otolaryngology–Head and Neck Surgery, Vol 136, No 1, January 2007

CoQ10, MDA, and TAS analyzed at different times werecompared with the Wilcoxon matched pairs test. Indepen-dent samples were compared with the Mann-WhitneyU-test. The scores of the TQ and its dimensions counted atdifferent times were compared between responders and non-responders with ANOVA with repeated measurements fol-lowed by contrast analysis to test individual means. Allstatistical tests and graphics were made using Statistica 7.1(StatSoft). P � 0.05 was the criterion for significance.

RESULTS

The initial TQ score of the patients amounted to 36.7 �17.0. Thirteen patients had chronic compensated tinnitusand 7 patients had a decompensation at the beginning of thetherapy. The SF-36 resulted in 48.4 � 9.8 scores for themental health status and 49.6 � 11.4 scores for the physicalhealth status assessed at initial visit of the 20 patients.Demographic factors such as age, gender, body mass index,tinnitus side, or loudness showed no statistical influence ontinnitus annoyance (Mann-Whitney U-test). Blood pressureand pulse did not change under the therapy. No adverseside-effects were noted.

The mean plasma concentration of CoQ10 significantlyincreased under the supplement of Nanoquinone from 1.4 to6.8 �mol/L as measured 4 weeks after the onset of the therapy(Fig 1) and was still elevated 4 weeks after the end of externalCoQ10 supply (2.1 �mol/L). The oxidized plasma CoQ10level slightly increased. The plasma concentration of MDAincreased during the whole observation period, but re-mained within normal concentration ranges (�0.21 �mol/L).The initial TAS value amounted to 1.48 � 0.14 mmol/L(mean � SD) and did not show any changes.

Under therapy with Nanoquinone, no significant changeswere found in the overall TQ score and in the dimensions of

Figure 1 CoQ10 content and content of malondialdehyde(MDA) in plasma of all patients (n � 20) at initial visit (T0), 4weeks after Nanoquinone (T1) and 4 weeks after Nanoquinonewas stopped (T3). Given are the means � SEM (*/**P � 0.01/

0.0001 vs initial value, Wilcoxon test).

emotional and cognitive distress, intrusiveness, auditory per-ceptional difficulties, sleep disturbances, and somatic com-plaints (data not shown). The general health status SF-36showed no significant changes either. No statistical differ-ences were determined between patients with decompen-sated or compensated tinnitus (data not shown).

In a subgroup of 7 patients, a significant reduction of theTQ scores from 38 to 24 was observed over the 12-weekperiod of medication with Nanoquinone (Fig 2). Moreover,ANOVA revealed a significant interaction effect betweenthese responders and the nonresponders (P � 0.001). Inaddition, the responders also had a significant reductionin all dimensions of the TQ score compared with theirinitial values except for the dimension of emotional distress(Fig 3). The interaction effects were also found to be sig-nificant between the 2 groups except for the emotionaldistress. To determine factors that contribute to these ef-fects, we compared the SF-36 scores and the initial audio-logical parameters of both groups. The SF-36 of the 13nonresponders resulted in 49 � 10 (mean � SD) scores forthe mental health status and 51 � 10 for the physical healthstatus at initial visit. The scores of the 7 responders weresimilar and amounted to a mean value of 48 for the mentaland physical health status. No changes in the SF-36 mentaland physical health status scores were observed in the 2groups during the whole observation period. The initialaudiologic parameters also did not show any differencesbetween responders and nonresponders (Table 1). Yet, inthe responders, the initial CoQ10 level was significantlylower (1.12 � 0.28 �mol/L) than in nonresponders (1.59 �0.52 �mol/L, mean � SD; P � 0.05, Mann-WhitneyU-test). Moreover, the increase of the CoQ10 level fromweek 0 to week 16 was significantly higher in responders

Figure 2 TQ score of the responders (n � 7) and nonre-sponders (n � 13) counted at initial visit (T0), 4 weeks (T1) and12 weeks (T2) with Nanoquinone. Given are the means � SEM.The asterisks indicate significance vs initial value (*/**P � 0.05/0.0001, ANOVA).

than in nonresponders (Table 2). The changes in oxidized

ect be

75Khan et al A pilot clinical trial of the effects of coenzyme Q10 . . .

CoQ10, MDA, and TAS were not significant between these2 groups.

DISCUSSION

The present work resulted in 2 major findings: 1) in patientswith low CoQ10 ground level, tinnitus expression signifi-cantly decreased after Q10 application, and 2) overall, nooxidative stress indicators were observed in patients withchronic tinnitus.

In all patients, the CoQ10 level significantly increasedunder external CoQ10 supply and was still elevated 4 weeksafter the treatment.

Figure 3 Scores of the 6 TQ dimensions of responders (n � 7)and 12 weeks (T2) following Nanoquinone. Given are the means0.05/0.001). The P values show significance of the interaction eff

Table 1

Audiologic parameters of responders and nonrespond

Group

Hearing loss,dB SPL

Right Left

Nonresponders (n � 13) 24 � 12 29 � 14Responders (n � 7) 21 � 11 21 � 14

The MDA and the TAS did not change when comparedwith their normal values (reference range of MDA: �0.21�mol/L, reference range of TAS: 1.30 to 1.77 mmol/L).Because MDA and TAS are indicators of oxidative stress,the missing effect of CoQ10 on these criteria seems unex-pected. However, MDA and TAS may be regarded as globalcriteria of oxidative stress that indicate severe oxidativeprocesses in the body.

Several studies showed alterations of single serum pa-rameters associated with oxidative stress in diverse diseases.The serum MDA level is suggested to be a reliable andsensitive marker for the reperfusion in patients with isch-emic stroke.14 However, in patients with Parkinson’s dis-

onresponders (n � 13) counted at initial visit (T0), 4 weeks (T1),M. The asterisks indicate significance vs initial value (*/**P �

tween the 2 groups (ANOVA).

easured at initial visit (mean � SD)

Tinnitus frequency,kHz

Tinnitus loudness,db SPL

Right Left Right Left

.5 � 3.1 6.1 � 3.2 44 � 23 48 � 25

.6 � 1.5 5.7 � 2.6 41 � 21 39 � 30

and n� SE

ers m

56

76 Otolaryngology–Head and Neck Surgery, Vol 136, No 1, January 2007

ease, where oxidative stress is believed to be causative,serum levels of the lipid peroxidation product, MDA, andantioxidants such as Vitamin E remained unchanged whencompared with normal subjects.3 On the other hand, globalcriteria of oxidative stress may not reflect specific oxidativestress in regions of the brain and can probably not be usedto monitor such oxidative stress. Therefore, up to now, nogold standard exists to define the oxidative damage in pa-tients, and biomarkers reflecting oxidative stress of specificregions of the body are still searched.15

Growing evidence suggests that tinnitus correlates withchanges in spontaneous neural activity, especially in thedorsal cochlear nucleus (DCN).16 Shifts of the input balancefrom the cochlea are supposed to be mainly responsible forthe hyperactivity in the DCN leading in chronic state to areorganization of the auditory cortex.16,17 Tinnitus as a phe-nomenon of the interaction between the auditory system andthe central nervous system can itself act as a stressor and maytherefore lead to psychological stress that causes oxidativestress.7 Yet, little is known about the oxidative status inpatients with tinnitus. The normal initial plasma concentra-tions of MDA and TAS and the missing effects of CoQ10on their concentrations indicate that, in the selected patients,severe general oxidative stress does not exist. In addition,CoQ10 exerts its effects mainly in cellular and mitochondrialmembranes. The determination of CoQ10 in plasma providesonly limited information about oxidative defense mechanism.2

Overall, besides the increase of CoQ10 concentration inplasma, no changes in the scores of the TQ and the SF-36could be determined in the present study. However, in 7 pa-tients, the main TQ score decreased significantly. In addition,the TQ scores of all dimensions of the responders decreasedsignificantly except for the emotional distress dimension. Re-sults of the SF-36 tests and of the initial audiological data pointout that no changes of the cochlear function and the generalhealth occur in these 2 groups. The SF-36 is a standardized andinternational validated questionnaire to evaluate the generalhealth status in patients with chronic disease. Our data showedonly a poor correlation between the TQ and the SF-36 score,which is in agreement with an earlier publication.18

The responders had a lower initial CoQ10 level with ahigher CoQ10 increase compared with nonresponders indi-cating that CoQ10 application may be associated with the

Table 2

Changes of CoQ10, oxidized CoQ10 (percent of CoQ10

nonresponders between initial values and values at w

2 groups was performed by the Mann-Whitney U-test.

Group � CoQ10 (�mol/L) � oxidiz

Nonresponders (n � 13) 0.27 � 0.17Responders (n � 7) 1.38 � 0.68

P � 0.05

improvement of the tinnitus symptoms.

CoQ10 is mainly involved in 2 intracellular mechanisms.It is an essential cofactor of the electron transport chain aswell as a potent free radical scavenger in lipid and mito-chondrial membranes.1 A deficiency of CoQ10 is caused bygenetic or acquired reasons. CoQ10 deficiency in the brainis under discussion to cause neurodegenerative diseases.The main reason may be a CoQ10 deficiency at the mito-chondrial respiratory chain.19 In accordance with these sug-gestions, a double-blind study showed a moderate beneficialeffect of oral CoQ10 supplementation in patients with Par-kinson’s disease.20 In addition, the administration of water-miscible CoQ10 in mice and rats achieved a significantaugmentation of the CoQ10 content in the brain.20

Though no prior study of CoQ10 in chronic tinnitusexists, this study was designed as a pilot study to analyze theeffect of CoQ10 on tinnitus. The study design and thenumber of patients included were kept small because of costconstraints. Therefore, no placebo group and no controlgroup were included. The dosage of 300 mg/d was used onthe basis of an earlier publication.2 In the future, a multi-center, double-blind controlled study with focus on theresponder group should include a placebo and a controlgroup who receive different doses of CoQ10.

In conclusion, our data demonstrated an increase of CoQ10levels after application of CoQ10. Overall, no improvement oftinnitus was observed. However, patients with a low CoQ10level before treatment and with a significant increase in theCoQ10 level afterward showed a decrease of the total tinnitusscore and of all its dimensions, except for the emotional dis-tress. Although the small patient numbers preclude definitivecomment on clinical response, these data together with dataof beneficial effects of oral CoQ10 supplementation in pa-tients with neurodegenerative diseases indicate that CoQ10may be a potentially useful agent for the treatment of pa-tients with a CoQ10 deficiency. However, placebo-controlledrandomized studies are necessary to provide evidence.

We thank Dr G. Gamel for technical support.

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