Coenzima Q10 o ubichinone Ubiquinone (coenzyme q(10)) and mitochondria in oxidative stress of Parkinson's disease. Ebadi ! "ovitra#on$ P!

%harma %! et a&. 'io& %i$na&s (ece#t )001*10+)),-)./.

Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease affecting approximately1 of the population older than !0 years" #here is a $orld$ide increase in disease prevalence due to the increasing age of human populations" A definitive neuropathological diagnosis of Parkinson's disease re%uires loss of dopaminergic neurons in the substantia nigra and related brain stem nuclei& and the presence of 'e$y bodies in remaining nerve cells" #he contribution of genetic factors to the pathogenesis of Parkinson's disease is increasingly being recognized" A point mutation $hich is sufficient to cause a rare autosomal dominant form of the disorder has been recently identified in the alpha(synuclein gene on chromosome ) in the much more common sporadic& or *idiopathic' form of Parkinson's disease& and a defect of complex + of the mitochondrial respiratory chain $as confirmed at the biochemical level" ,isease specificity of this defect has been demonstrated for the parkinsonian substantia nigra" #hese findings and the observation that the neurotoxin 1(methyl()(phenyl(1&-&.& /(tetrahydropyridine 01P#P2& $hich causes a Parkinson(like syndrome in humans& acts via inhibition of complex + have triggered research interest in the mitochondrial genetics of Parkinson's disease" 3xidative phosphorylation consists of five protein(lipid enzyme complexes located in the mitochondrial inner membrane that contain flavins 0415& 4A,2& %uinoid compounds 0coenzyme Q0102& CoQ01022 and transition metal compounds 0iron(sulfur clusters& hemes& protein(bound copper2" #hese enzymes are designated complex + 05A,67ubi%uinone oxidoreductase& 8C 1"/" !".2& complex ++ 0succinate7ubi%uinone oxidoreductase& 8C 1"."!"12& complex +++ 0ubi%uinol7ferrocytochrome c oxidoreductase& 8C 1"10"-"-2& complex +9 0ferrocytochrome c7oxygen oxidoreductase or cytochrome c oxidase& 8C 1":"."12& and complex 9 0A#P synthase& 8C ."/"1".)2" A defect in mitochondrial oxidative phosphorylation& in terms of a reduction in the activity of 5A,6 CoQ reductase 0complex +2 has been reported in the striatum of patients $ith Parkinson's disease" #he reduction in the activity of complex + is found in the substantia nigra& but not in other areas of the brain& such as globus pallidus or cerebral cortex" #herefore& the specificity of mitochondrial impairment may play a role in the degeneration of nigrostriatal dopaminergic neurons" #his vie$ is supported by the fact that 1P#P generating 1(methyl()(phenylpyridine 01PP0;22 destroys dopaminergic neurons in the substantia nigra" Although the serum levels of CoQ0102 is normal in patients $ith Parkinson's disease& CoQ0102 is able to attenuate the 1P#P(induced loss of striatal dopaminergic neurons"

0oenzyme 110 conc%erum &eve&s of coenzyme 110 in #atients 2ith mu&ti#&e sc&erosis. de 'ustos 3! 4imenez-4imenez 34! o&ina 45! et a&. 5cta 6euro& %cand )000*101+)07-)11.

#o elucidate $hether serum coenzyme Q10 levels are related $ith the risk for multiple sclerosis 01<2 or are a marker for the activity of the disease& $e compared serum levels of coenzyme Q10 and the coenzyme Q10=cholesterol ratio& in .1 patients $ith 1< 0during exacerbations2 and 1: matched controls using a high performance li%uid chromatography techni%ue" #he mean serum coenzyme Q10 levels and the coenzyme Q10=cholesterol ratio did not differ significantly bet$een the - study groups" #he values did not correlate $ith age& age at onset& and duration of the disease"

#hese results suggest that serum coenzyme Q10 concentrations are unrelated $ith the risk for 1< and are not a useful marker of activity of the disease"

8he effect of coenzyme 110 in #atients 2ith con$estive heart fai&ure. 9hatta ! 5&exander '%! 9richten 0 ! et a&. 5nn :ntern ed )000*1/)+;/;-;,0.

>AC?@A3B5,7 Coenzyme Q10 is commonly used to treat congestive heart failure on the basis of data from several unblinded& subCective studies" 4e$ randomized& blinded& controlled studies have evaluated obCective measures of cardiac performance" 3>D8C#+987 #o determine the effect of coenzyme Q10 on peak oxygen consumption& exercise duration& and eCection fraction" ,8<+@57 Aandomized& double(blind& controlled trial" <8##+5@7 Bniversity and 9eterans Affairs hospitals" PA#+85#<7 !! patients $ho had congestive heart failure $ith 5e$ Eork 6eart Association class +++ and +9 symptoms& eCection fraction less than )0 & and peak oxygen consumption less than 1F"0 m'=kg per minute 0or G!0 of predicted2 during standard therapy $ere randomly assigned" 4orty( six patients completed the study" +5#8A985#+357 Coenzyme Q10& -00 mg=d& or placebo" 18A<BA8185#<7 'eft ventricular eCection fraction 0measured by radionuclide ventriculography2 and peak oxygen consumption and exercise duration 0measured by a graded exercise evaluation using the 5aughton protocol2 $ith continuous metabolic monitoring" A8<B'#<7 Although the mean 0;=(<,2 serum concentration of coenzyme Q10 increased from 0":!;=(0"/- microg=m' to -"-;=(1"- microg=m' in patients $ho received active treatment& eCection fraction& peak oxygen consumption& and exercise duration remained unchanged in both the coenzyme Q10 and placebo groups" C35C'B<+357 Coenzyme Q10 does not affect eCection fraction& peak oxygen consumption& or exercise duration in patients $ith congestive heart failure receiving standard medical therapy" entrations and antioxidant status in tissues of breast cancer #atients. Portaka& <! <zkaya <! Erden :na& ! et a&. 0&in 'iochem )000*//+)=7-)>,.

3>D8C#+98<7 An increasing amount of experimental and epidemiological evidence implicates the involvement of oxygen derived radicals in the pathogenesis of cancer development" 3xygen derived radicals are able to cause damage to membranes& mitochondria& and macromolecules including proteins& lipids and ,5A" Accumulation of ,5A damages has been suggested to contribute to carcinogenesis" +t $ould& therefore& be advantageous to pinpoint the effects of oxygen derived radicals in cancer development" ,8<+@5 A5, 18#63,<7 +n the present study& $e investigated the relationship bet$een oxidative stress and breast cancer development in tissue level" >reast cancer is the most common malignant disease in Hestern $omen" #$enty(one breast cancer patients& $ho under$ent radical mastectomy and diagnosed $ith infiltrative ductal carcinoma& $ere used in the study" He determined coenzyme Q10 0Q2 concentrations& antioxidant enzyme activities 0mitochondrial and total superoxide dismutase 0<3,2& glutathione peroxidase 0@<6(Px2& catalase2& and malondialdehyde 01,A2 levels in tumor and surrounding tumor(free tissues" A8<B'#<7 Q concentrations in tumor tissues significantly decreased as compared to the surrounding normal tissues 0p G 0"0012" 6igher 1,A levels $ere observed in tumor tissues than noncancerous tissues 0p G 0"0012" #he activities of 1n<3,& total <3,& @<6(Px and catalase in tumor tissues significantly increased 0p G 0"0012 compared to the controls" C35C'B<+35<7 #hese findings may support that reactive oxygen species increased in malignant cells& and may cause overexpression of antioxidant enzymes and the consumption of coenzyme Q10" +ncreased antioxidant enzyme activities may be related $ith the susceptibility of cells to carcinogenic agents and the response of

tumor cells to the chemotherapeutic agents" Administration of coenzyme Q10 by nutrition may induce the protective effect of coenzyme Q10 on breast tissue"

?oes $astrointestina& 0andida a&bicans #revent ubiquinone absor#tion@ 9rone 05! E&mer "A! E&y 48! et a&. ed By#otheses )001*.=+.=0-.=).

Bbi%uinones 0coenzyme Qs 0CoQ22 are essential for oxidative phosphorylation in yeasts and humans& although the isomers present in each are different" #he human coenzyme Q& CoQ10& is administered orally for the treatment of heart disease and other disorders" <ome patients& ho$ever& re%uire much higher doses than others to attain a therapeutic CoQ10 blood level" He propose that one possible explanation for this variability is Candida colonization of the @+ tract" 1any common medical treatments including antibiotics and anti(hyperchlorhydric agents increase the risk of @+ tract Candida colonization" <ubse%uent uptake and utilization of supplemental CoQ10 by the yeast could diminish availability for the human subCect" ,ata from one patient and an in vitro pilot study using t$o pathogenic strains of C" albicans support this hypothesis" +f C" albicans in the @+ tract can hinder availability and interfere $ith therapeutic effects of CoQ10& it could be of clinical significance for large numbers of patients

8he (o&e of 0oenzyme 110 in 0&inica&

by 5&an (. "aby! 5'%8(508 ?

edicine+ Part :

#his revie$ discusses the potential role of coenzyme Q10 in the treatment of ac%uired immunodeficiency syndrome 0A+,<2& cancer& periodontal disease& gastric ulceration& obesity& muscular dystrophy& and allergy" #he effect of coenzyme Q10 0CoQ102 on immune function and physical performance is also revie$ed" Controlled trials have demonstrated a beneficial effect of CoQ10 in the treatment of periodontal disease" Promising 0although anecdotal2 clinical results have been reported for cases of cancer& A+,<& and muscular dystrophy" CoQ10 is of theoretical value as a treatment for gastric ulceration and allergiesI ho$ever& CoQ10 treatment of these conditions has not been tested in humans" #here is limited evidence that CoQ10 may enhance immune function and improve physical performance in certain circumstances" #he value of CoQ10 as a treatment for obesity remains speculative" 0Alt 1ed Aev 1::/I1711(1F"2

8he (o&e of 0oenzyme 110 in 0&inica& edicine+

Part ::. 0ardiovascu&ar ?isease! By#ertension! ?iabetes e&&itus and :nferti&ity

by 5&an (. "aby! 5bstract #his revie$ discusses the role of coenzyme Q10 0CoQ102 in cardiovascular disease& hypertension& diabetes mellitus& and infertility" ,eficiencies of CoQ10 have been documented in patients $ith heart disease" Administration of CoQ10 has been sho$n to prolong survival and improve %uality of life in patients $ith cardiomyopathy" +n patients $ith congestive heart failure& CoQ10 ameliorated symptoms& reduced the number of hospitalizations and appeared to increase the survival rate" #reatment $ith CoQ10 may also reduce the number of anginal attacks in patients $ith stable angina pectoris" CoQ10 has been sho$n to prevent adriamycin cardiotoxicity and to reduce the incidence of postoperative cardiac dysfunction in patients undergoing heart surgery" <everal studies indicate that CoQ10 may also have a role in the treatment of essential hypertension" #his nutrient may be of value for patients $ith diabetes mellitus or male infertility& but additional studies are needed in these areas" CoQ10 status may be adversely affected by treatment $ith certain cholesterol(lo$ering drugs& beta blockers& tricyclic antidepressants& and phenothiazines" 0Alt 1ed Aev 1::/I10.271/J(1F!"2 Part + of this t$o(part article revie$ed the relationship bet$een coenzyme Q10 0CoQ102 and immune function& periodontal disease& gastric ulceration& obesity& physical performance& allergy& and muscular dystrophy" Part ++ discusses the effect of CoQ10 on cardiovascular disease& hypertension& diabetes mellitus& and infertility& as $ell as revie$ing drug interactions $ith CoQ10" 0ardiovascu&ar ?isease - "enera& 5s#ects 8nhancing myocardial function is an important& though fre%uently overlooked component of the overall prevention and treatment of cardiovascular disease" CoQ10 plays a key role in energy production& and is therefore essential for all energy(dependent processes& including heart(muscle contraction" CoQ10 deficiency has been documented in patients $ith various types of cardiovascular disease" +t is not clear $hether a decline in CoQ10 levels is a primary cause or a conse%uence of heart disease" 6o$ever& given the fundamental involvement of CoQ10 in myocardial function& it is not unlikely that CoQ10 deficiency $ould exacerbate heart disease and that correction of such a deficiency $ould have therapeutic value" +n addition& CoQ10 has been sho$n to be a potent antioxidant" +n one study& ubi%uinol( 10& the reduced form of CoQ10& protected human lo$ density lipoproteins 0','2 more efficiently against lipid peroxidation than did vitamin 8"1 <ince oxidation of ',' is .?.

believed to be an initiating factor in the development of atherosclerosis& CoQ10 appears to be a preventive factor" 0o110 ?eficiency in 0ardiac ?isease Circulating levels of CoQ10 $ere significantly lo$er in patients $ith ischemic heart disease- and in those $ith dilated cardiomyopathy 0mostly 5e$ Eork 6eart Association K5E6AL functional class +++ or +92 than in healthy controls". +n another study& CoQ10 levels in myocardial tissue 0estimated by enzymatic methods2 $ere lo$ in approximately F! of patients undergoing cardiac surgery" Concentrations of CoQ10 declined progressively in both blood and myocardial tissue $ith increasing severity of heart disease") 1yocardial deficiencies of CoQ10 $ere also found in the maCority of patients $ith aortic stenosis or insufficiency& mitral stenosis or insufficiency& diabetic cardiomyopathy& tetralogy of 4allot& atrial septal defects and ventricular septal defects"! +n patients $ith cardiomyopathy and myocardial deficiency of CoQ10& oral administration of 100 mg=day of CoQ10 for -(J months resulted in an increase in myocardial CoQ10 levels ranging from -0(J! "/ #hese findings suggest that CoQ10 deficiency is common in patients $ith various types of cardiovascular disease& and that oral administration of CoQ10 can increase tissue levels of this nutrient" 8reatment of 0ardiomyo#athy +n one study& 1-/ patients $ith dilated cardiomyopathy 0:J of $hom $ere in 5E6A functional class +++ or +92 received 100 mg=day of CoQ10 for periods of up to // months" After / months of treatment& the mean eCection fraction increased from )1 to !: 0p G 0"0012& and remained stable thereafter $ith continued treatment" After - years& J) of the patients $ere still alive and at !"! years& !- $ere alive"F #hese survival rates are considerably better than the published survival statistics of patients given conventional therapy 0i"e"& -(year survival rate of !0 for symptomatic cardiomyopathy and 1(year survival rate of !0 for decompensated cardiomyopathy2" +n another study& JJ patients $ith cardiomyopathy received 100 mg=day of CoQ10 for periods of 1(-) months" <ignificant improvements in at least t$o of three cardiac parameters 0eCection fraction& cardiac output and 5E6A class2 $ere seen in F!(J! of the patients" Approximately J0 of the patients improved to a lo$er 0i"e"& more favorable2 5E6A functional class"J +n a double(blind& crossover trial& 1: patients $ith cardiomyopathy 05E6A classes +++ and +92 received 100 mg=day of CoQ10 or a placebo& each for 1- $eeks" Compared $ith placebo& CoQ10 treatment significantly increased cardiac stroke volume and eCection fraction" 8ighteen patients reported subCective improvement in tolerance for physical activity $hile taking CoQ10": 0on$estive Beart 3ai&ure

#he potential of CoQ10 as a treatment for congestive heart failure 0C642 $as suggested as early as 1:/F by Dapanese researchers"10 +n 1:F/& these same investigators administered .0 mg=day of CoQ10 to 1F patients $ith C64" All of the patients improved& and : 0!. 2 became asymptomatic after ) $eeks of treatment"11 +n an open trial of .) patients $ith refractory 5E6A class +9 C64& administration of 100 mg=day of CoQ10 resulted in sustained improvement in cardiac function in -J cases 0J- 2" #he survival rate after t$o years $as /- & compared $ith an expected t$o(year survival rate of less than -! for similar patients"1+n another study& 1- patients $ith advanced C64 $ho had failed to respond ade%uately to digitalis and diuretics received 100 mg=day of coenzyme Q10 for F months" #$o( thirds of the patients sho$ed definite clinical improvement after a mean treatment period of .0 days" +n these patients& dyspnea at rest disappeared and energy level and tolerance for activity increased" 3bCective improvements included decreased hepatic congestion& reductions in heart rate and heart volume& and a decline in systolic time intervals 0suggesting improved myocardial performance2" Hithdra$al of coenzyme Q10 $as follo$ed by severe clinical relapse& $ith subse%uent improvement upon resumption of treatment"1. +n a large multicenter trial of 1&11. C64 patients& !0(1!0 mg=day of CoQ10 $as given for . months 0FJ of the patients received 100 mg=day2" #he proportion of patients $ith improvements in clinical signs and symptoms $ere as follo$s7 s$eating& J-") I Cugular reflux& J1"! I cyanosis& J1 I pulmonary rales& FJ") I edema& F/": I palpitations& F!"F I vertigo& F. I arrhythmia& /- I insomnia& /0"- I dyspnea& !)"- I nocturia& !0"F I and enlargement of the liver area& ):". "1) #he results of these uncontrolled studies $ere confirmed more recently in a double(blind trial" <ome /)1 patients $ith C64 05E6A classes +++ or +92 $ere randomly assigned to receive placebo or CoQ10 0- mg=kg=day2 for one year" Conventional therapy $as continued in both groups" #he number of patients re%uiring hospitalization during the study for $orsening heart failure $as .J less in the CoQ10 group than in the placebo group 0p G 0"0012" 8pisodes of pulmonary edema $ere reduced by about /0 in the CoQ10 group& compared $ith the placebo group 0p G 0"0012"1! 5n$ina #$elve patients $ith stable angina pectoris $ere randomly assigned to receive 1!0 mg=day of CoQ10 or a placebo& each for ) $eeks& in a double(blind crossover trial" CoQ10 treatment significantly increased exercise tolerance on a treadmill 0time before onset of chest pain2& and significantly increased the time until <#(segment depression occurred" Compared $ith placebo& there $as a !. reduction in the fre%uency of anginal episodes and a !) reduction in the number of nitroglycerin tablets needed during CoQ10 treatmentI ho$ever& these differences $ere not statistically significant"1/

#hese results suggest that CoQ10 is a safe and effective treatment for angina pectoris" Although the amelioration of anginal attacks $as not statistically significant& the magnitude of the effect $as large" +t $ould therefore be $orth$hile to perform a similar study $ith a larger number of patients" 5rrhythmias #$enty(seven patients $ith ventricular premature beats 09P>'s2 and no evidence of organic heart disease received a placebo for .() $eeks& follo$ed by /0 mg=day of coenzyme Q10 for )(! $eeks" #he reduction in 9P>'s $as significantly greater after CoQ10 than after placebo" #he beneficial effect of CoQ10 $as seen primarily in diabetics& in $hom the mean reduction in 9P> fre%uency $as J!"F " A significant reduction in 9P>'s also occurred in 1 011 2 of : other$ise healthy patients and in ) 0./ 2 of 11 patients $ith hypertension"1F Prevention of 5driamycin 8oxicity #he clinical value of adriamycin as anti(cancer agent is limited by its toxicity& $hich includes cardiomyopathy and irreversible heart failure" Adriamycin(induced cardiotoxicity is believed to be caused& at least in part& by a reduction in CoQ10 levels and by inhibition of CoQ10(dependent enzymes" +n rats treated $ith adriamycin& administration of CoQ10 restored the levels of this nutrient to normal and prevented adriamycin(induced morphologic changes in the heart"1J #reatment $ith CoQ10 also prevented adriamycin(induced cardiotoxicity in rabbits"1: Cancer patients receiving adriamycin had lo$er myocardial levels of coenzyme Q10 than did controls" #he magnitude of CoQ10 depletion $as directly related to the severity of cardiac impairment"-0 #o determine the effect of CoQ10 supplementation on adriamycin cardiotoxicity& F patients receiving adriamycin $ere also given 100 mg=day of CoQ10& beginning .(! days before adriamycin $as started" Another F patients 0control group2 received adriamycin $ithout CoQ10" Cardiac function deteriorated significantly in the control group& $hereas patients given CoQ10 had little or no cardiotoxicity& even though the cumulative dose of adriamycin in the CoQ10 group $as !0 greater than that in the control group"-1 ,espite the small number of patients in this study& the results are highly encouraging" <ince administration of CoQ10 does not appear to affect the antitumor activity of adriamycin&-- CoQ10 prophylaxis seems appropriate for all patients receiving adriamycin" Protection ?urin$ 0ardiac %ur$ery Postoperative lo$ cardiac output is a maCor cause of early death follo$ing cardiac surgery" 4ifty patients undergoing cardiac surgery for ac%uired valvular lesions $ere randomly assigned to receive .0(/0 mg=day of CoQ10 for / days prior to surgery or to a control group that did not receive CoQ10" Postoperatively& a state of severe lo$(cardiac output developed in )J of the patients in the control group& compared $ith only 1-

of those in the CoQ10 group" #hese results suggest that preoperative administration of CoQ10 increases the tolerance of the heart to ischemia during aortic cross(clamping"-. itra& Ca&ve Pro&a#se Cardiac performance $as evaluated using an isometric hand grip test in 1:) children $ith symptomatic mitral valve prolapse" Prior to treatment& all patients had an abnormal hand(grip test" <ixteen children received - mg=kg=day of CoQ10 or a placebo for / $eeks& in a single(blind trial" 6and grip strength became normal in F children receiving CoQ10 and in none of the placebo(treated patients"-) 5ote that the relevance of this study to the treatment of mitral valve prolapse in adults is %uestionable& and hand grip may not be a reliable test of cardiac function" 4urthermore& impaired cardiac function is not typical of mitral valve prolapse in adults and the symptoms associated $ith this condition do not appear to be caused by diminished cardiac function" Hhile the symptoms associated $ith mitral valve prolapse may respond to magnesium supplementation&-! the role of CoQ10 in the treatment of this disorder is unclear" By#ertension 8nzymatic assays revealed a deficiency of CoQ10 in .: of !: patients $ith essential hypertension& compared $ith only / of healthy controls" +n animal models of hypertension& including spontaneously hypertensive rats& uninephrectomized rats treated $ith saline and deoxycorticosterone& and experimentally hypertensive dogs& orally administered CoQ10 significantly lo$ered blood pressure"-/(-: #$enty(six patients $ith essential hypertension received coenzyme Q10& !0 mg t$ice a day" After 10 $eeks of treatment& mean systolic blood pressure decreased from 1/)"! to 1)/"F mm 6g and mean diastolic blood pressure decreased from :J"1 to J/"1 mm 6g 0p G 0"0012" #he fall in blood pressure $as associated $ith a significant reduction in peripheral resistance& but there $ere no changes in plasma renin activity& serum and urinary sodium and potassium& and urinary aldosterone" #hese results suggest that treatment $ith CoQ10 decreases blood pressure in patients $ith essential hypertension& possibly because of a reduction in peripheral resistance".0 +n another study& 10: patients $ith essential hypertension received coenzyme Q10 0average dose& --! mg=day2 in addition to their usual antihypertensive regimen" #he dosage of CoQ10 $as adCusted according to clinical response and blood CoQ10 levels 0the aim $as to attain blood levels greater than -"0 mcg=ml2" #he need for antihypertensive medication declined gradually and& after a mean treatment period of )") months& about half of the patients $ere able to discontinue bet$een one and three drugs".1 <imilar results have been reported by others".+t should be noted that the effect of CoQ10 on blood pressure $as usually not seen until after )(1- $eeks of therapy" #hat observation is consistent $ith the delayed increase in

enzyme activity that results from administration of CoQ10" #hus& CoQ10 is not a typical antihypertensive drugI rather& it seems to correct some metabolic abnormality that is involved in the pathogenesis of hypertension" ?iabetes e&&itus

,iabetes mellitus is a multifactorial disease that is associated $ith a number of different metabolic abnormalities" #he electron transport chain& of $hich CoQ10 is a component& plays a maCor role in carbohydrate metabolism" A deficiency of CoQ10 might therefore have an adverse effect on glucose tolerance" ,ecreased levels of CoQ10 0measured as total CoQ2 $ere found in rats $ith experimentally(induced diabetes" Administration of CoQF 0an analog of CoQ102 partially corrected abnormal glucose metabolism in alloxan(diabetic rats" 0>efore CoQ10 became commercially available& some therapeutic trials $ere done $ith CoQF" #hese t$o compounds are considered to be nutritionally e%uivalent"2 #hirty(nine diabetics received 1-0 mg=day of CoQF for -(1J $eeks" 4asting blood sugar levels fell by at least .0 in .1 of the patients and the concentration of ketone bodies declined by at least .0 in !: of the patients" 3ne patient $ho $as poorly controlled on /0 units=day of insulin sho$ed a marked fall in fasting blood sugar and ketone bodies after receiving CoQF".. a&e :nferti&ity >ecause sperm production and function are highly energy(dependent processes& CoQ10 deficiency could presumably be a contributing factor to infertility in men" +n one study& administration of 10 mg=day of CoQF resulted in a significant increase in sperm count and motility in a group of infertile men".) Additional research is needed to determine $hether CoQ10 therapy has a role in the treatment of infertility" ?ru$ :nteractions Cholesterol(lo$ering drugs such as lovastatin and pravastatin inhibit the enzyme .( hydroxy(.(methylglutaryl061@2(CoA reductase& $hich is re%uired for biosynthesis of both cholesterol and CoQ10" #hus& administration of these drugs might compromise CoQ10 status by decreasing its synthesis" <upplementation of the diet of rats $ith lovastatin 0)00 mg=kg of diet2 for ) $eeks reduced the concentration of CoQ10 in the heart& liver& and blood".! +n another study& administration of lovastatin to ! patients receiving CoQ10 for heart failure $as follo$ed by a reduction in blood levels of CoQ10 and a significant deterioration of clinical status" <ome of these patients improved after the dosage of CoQ10 $as increased or the lovastatin $as discontinued"./ #hese results suggest that people $ho have lo$ CoQ10 levels and suboptimal cardiac function might develop clinically significant CoQ10 depletion after taking an 61@( CoA reductase inhibitor" Although individuals $ith high CoQ10 levels and good cardiac

function can probably tolerate these drugs better& a case can be made that all patients being treated $ith 61@(CoA reductase inhibitors should also receive CoQ10 prophylactically" #he beta blockers propranolol and metaprolol have been sho$n to inhibit CoQ10( dependent enzymes".F #he antihypertensive effect of these drugs might therefore be compromised in the long run by the development of CoQ10 deficiency" +n one study& administration of /0 mg=day of CoQ10 reduced the incidence of drug(induced malaise in patients receiving propranolol".J A number of phenothiazines and tricyclic antidepressants have also been sho$n to inhibit CoQ10(dependent enzymes" +t is therefore possible that CoQ10 deficiency may be a contributing factor to the cardiac side effects that are fre%uently seen $ith these drugs" +n t$o clinical studies& supplementation $ith CoQ10 improved electrocardiographic changes in patients on psychotropic drugs".: (eferences 1" <tocker A& >o$ry 9H& 4rei >" Bbi%uinol(10 protects human lo$ density lipoprotein more efficiently against lipid peroxidation than does alpha(tocopherol" Proc 5atl Acad <ci 1::1IJJ71/)/(1/!0" -" 6anaki E& <ugiyama <& 3za$a #& 3hno 1" Aatio of lo$(density lipoprotein cholesterol to ubi%uinone as a coronary risk factor" 5 8ngl D 1ed 1::1I.-!7J1)(J1!" ." 'angsCoen P6& 'angsCoen P6& 4olkers ?" 'ong(term efficacy and safety of coenzyme Q10 therapy for idiopathic dilated cardiomyopathy" Am D Cardiol 1::0I/!7!-1(!-." )" 'ittarru @P& 6o '& 4olkers ?" ,eficiency of coenzyme Q10 in human heart disease" Part +" +nt D 9itam 5utr Aes 1:F-I)-7-:1(.0!" !" 4olkers ?& 'ittarru @P& 6o '& Aunge #1& 6avanonda <& Cooley ," 8vidence for a deficiency of coenzyme Q10 in human heart disease" +nt D 9itam 5utr Aes 1:F0I)07.J0( .:0" /" 4olkers ?& 9adhanavikit <& 1ortensen <A" >iochemical rationale and myocardial tissue data on the effective therapy of cardiomyopathy $ith coenzyme Q10" Proc 5atl Acad <ci 1:J!IJ-7:01(:0)" F" 'angsCoen P6& 'angsCoen P6& 4olkers ?" 'ong(term efficacy and safety of coenzyme Q10 therapy for idiopathic dilated cardiomyopathy" Am D Cardiol 1::0I/!7!-1(!-." J" 'angsCoen P6& 4olkers ?& 'yson ?& 1uratsu ?& 'yson #& et al" 8ffective and safe therapy $ith coenzyme Q10 for cardiomyopathy" ?lin Hochenschr 1:JJI//7!J.(!:0" :" 'angsCoen P6& 9adhanavikit <& 4olkers ?" 8ffective treatment $ith coenzyme Q10 of patients $ith chronic myocardial disease" ,rugs 8xptl Clin Aes 1:J!I117!FF(!F:"

10" Eamamura E& +shiyama #& Eamagami #& 1orita E& +shio <& ?ashi$amura <& et" al" Clinical use of coenzyme(Q for treatment of cardiovascular disease" Dpn Circ D 1:/FI.171/J" 0+n this study& CoQF $as usedI ho$ever& this compound is apparently converted by the body into CoQ10"2 11" +shiyama #& 1orita E& #oyama <& Eamagami #& #sukamoto 5& Hada 5& et" al" A clinical study of the effect of coenzyme Q on congestive heart failure" Dpn 6eart D 1:F/I1F7.-()-" 1-" Anonymous" Coenzyme aids cardiomyopathy" 1ed Horld 5e$s 1:J!I0J=1-277/:" 1." 1ortensen <A& 9adhanavikit <& >aandrup B& 4olkers ?" 'ong(term coenzyme Q10 therapy7 a maCor advance in the management of resistant myocardial failure" ,rugs 8xptl Clin Aes 1:J!I117!J1(!:." 1)" >aggio 8& @andini A& Plancher AC& Passeri 1& Carmosino @& et al" +talian multicenter study on the safety and efficacy of coenzyme Q10 as adCunctive therapy in heart failure 0interim analysis2" Clin +nvest 1::.IF17<1)!(<1):" 1!" 1orisco C& #rimarco >& Condorelli 1" 8ffect of coenzyme Q10 in patients $ith congestive heart failure7 a long(term multicenter randomized study" Clin +nvest 1::.IF17<1.)(<1./" 1/" ?amika$a #& ?obayashi A& Eamashita #& 6ayashi 6& Eamazaki 5" 8ffects of coenzyme Q10 on exercise tolerance in chronic stable angina pectoris" Am D Cardiol 1:J!I!/7-)F(-!1" 1F" 4uCioka #& <akamoto E& 1imura @" Clinical study of cardiac arrhythmias using a -)( hour continuous electrocardiographic recorder 0!th report2 ( antiarrhythmic action of coenzyme Q10 in diabetics" #ohoku D 8xp 1ed 1:J.I1)10<uppl27)!.()/." 1J" 3gura A& #oyama 6& <himada #& 1urakami 1" #he role of ubi%uinone 0coenzyme Q102 in preventing adriamycin(induced mitochondrial disorders in rat heart" D Appl >iochem 1:F:I17.-!(..!" 1:" ,omae 5& <a$ada 6& 1atsuyama 8& ?onishi #& Bchino 6" Cardiomyopathy and other chronic toxic effects induced in rabbits by doxorubicin and possible prevention by coenzyme Q10" Cancer #reat Aep 1:J1I/!7F:(:1" -0" ?arlsson D& 4olkers ?& Astrum 6& Dansson 8& Perno$ >& et al" 8ffect of adriamycin on heart and skeletal muscle coenzyme Q 0CoQ102 in man" +n 4olkers ? and Eamamura E 0eds"2" >iomedical and Clinical Aspects of Coenzyme Q& volume !& 8lsevier& 1:J/" -1" Dudy H9& 6all D6& ,ugan H& #oth P,& 4olkers ?" Coenzyme Q10 reduction of adriamycin cardiotoxicity" +n 4olkers ?& Eamamura E 0eds"2" >iomedical and Clinical Aspects of Coenzyme Q& vol" )& 8lsevier Publ"& 1:J)& pp" -.1(-)1"

--" Cortes 8P& @upta 1& Chou C& Amin 9C& 4olkers ?" Adriamycin cardiotoxicity7 early detection by systolic time interval and possible prevention by coenzyme Q10" Cancer #reat Aep 1:FJI/-7JJF(J:1" -." #anaka D& #ominaga A& Eoshitoshi 1& 1atsui ?& ?omori 1& <ese A& et" al" Coenzyme Q107 the prophylactic effect on lo$ cardiac output follo$ing cardiac valve replacement" Ann #horac <urg 1:J-I..71)!(1!1" -)" 3da #& 6amamoto ?" 8ffect of coenzyme Q10 on the stress(induced decrease of cardiac performance in pediatric patients $ith mitral valve prolapse" Dpn Circ D 1:J)I)J71.JF" -!" @aby AA" 1agnesium" ?eats Publishing& 5e$ Canaan& 1::)" -/" Eamagami #& +$amoto E& 4olkers ?& >lom%vist C@" Aeduction by coenzyme Q10 of hypertension induced by deoxycorticosterone and saline in rats" +nt D 9itam 5utr Aes 1:F)I))7)JF():/" -F" @arashi #& 5akaCima E& #anaka 1& 3htake <" 8ffect of coenzyme Q10 on experimental hypertension in rats and dogs" D Pharmacol 8xp #her 1:F)I1J:71):(1!/" -J" +$amoto E& Eamagami #& 4olkers ?& >lom%vist C@" ,eficiency of coenzyme Q10 in hypertensive rats and reduction of deficiency by treatment $ith coenzyme Q10" >iochem >iophys Aes Commun 1:F)I!J7F).(F)J" -:" 3kamoto 6& ?a$aguchi 6& #ogashi 6& 1inami 1& <aito 6& et al" 8ffect of coenzyme Q10 on structural alterations in the renal membrane of stroke(prone spontaneously hypertensive rats" >iochem 1ed 1etabol >iol 1::1I)!7-1/(--/" .0" ,igiesi 9& Cantini 4& 3radei A& >isi @& @uarino @C& et al" Coenzyme Q10 in essential hypertension" 1olec Aspects 1ed 1::)I1!0<uppl27<-!F(<-/." .1" 'angsCoen P& 'angsCoen P& Hillis A& 4olkers ?" #reatment of essential hypertension $ith coenzyme Q10" 1olec Aspects 1ed 1::)I1!0<uppl27<-/!(<-F-" .-" ,igiesi 9& Cantini 4& >rodbeck >" 8ffect of coenzyme Q10 on essential hypertension" Curr #her Aes 1::0I)F7J)1(J)!" .." <higeta E& +zumi ?& Abe 6" 8ffect of coenzyme QF treatment on blood sugar and ketone bodies of diabetics" D 9itaminol 1://I1-7-:.(-:J" .)" #animura D" <tudies on arginine in human semen" Part +++" #he influences of several drugs on male infertility" >ull 3saka 1ed <chool 1:/FI1-7:0(100" .!" Hillis AA& 4olkers ?& #ucker D'& Ee C(Q& Mia '(D& et al" 'ovastatin decreases coenzyme Q levels in rats" Proc 5atl Acad <ci 1::0IJF7J:-J(J:.0"

./" 4olkers ?& 'angsCoen P& Hillis A& Aichardson P& Mia '(D& et al" 'ovastatin decreases coenzyme Q levels in humans" Proc 5atl Acad <ci 1::0IJF7J:.1(J:.)" .F" ?ishi #& ?ishi 6& 4olkers ?" +nhibition of cardiac CoQ10(enzymes by clinically used drugs and possible prevention" +n7 4olkers ?& Eamamura E 0eds"2" >iomedical and Clinical Aspects of Coenzyme Q& 9ol" 1& 8lsevier=5orth(6olland >iomedical Press& Amsterdam& 1:FF& pp" )F(/-" .J" 6amada 1& ?azatani E& 3chi #& +to #& ?okubu #" Correlation bet$een serum CoQ10 level and myocardial contractility in hypertensive patients" +n7 4olkers ?& Eamamura E 0eds"2" >iomedical and Clinical Aspects of Coenzyme Q& 9ol" )& 8lsevier <cience Publishers& Amsterdam& 1:J)& pp" -/.(-F0" .:" ?ishi #& 1akino ?& 3kamoto #& ?ishi 6& 4olkers ?" +nhibition of myocardial respiration by psychotherapeutic drugs and prevention by coenzyme Q" +n7 Eamamura E& 4olkers ?& +to E 0eds"2" >iomedical and Clinical Aspects of Coenzyme Q& 9ol" -& 8lsevier=5orth(6olland >iomedical Press& Amsterdam& 1:J0& pp" 1.:(1!)"