Você está na página 1de 11

Review Articles

Coenzyme Q10 (Ubiquinone) : Implications in Clinical Practice


Deepak Langade*, Pratibha Tarapure#, Abhay Jagtap**, Preeti Arora***,
Sanjeev Anand***

INTRODUCTION
Coenzyme Q10 (CoQ10) is a lipophilic compound naturally found throughout the
body. It is an endogenously synthesized provitamin that serves as a lipid soluble
electron carrier in the mitochondrial electron transport.1 The alternative names
ubidecarenone and ubiquinone, meaning ubiquitous quinone, allude to the presence of
CoQ10 in all cells.2 The cellular effects of CoQ10 may be important in patients with
cardiac diseases especially coronary artery disease and congestive cardiac failure. It has
been used as an adjunctive therapy for various cardiovascular conditions and in some
countries it is available as over-the-counter nutritional supplement.

Coenzyme-Q exists in several forms and can be found in microorganisms, plants and mammals
including humans. Co-enzymes q6, q7, q8 are found in yeast and bacteria whereas co enzyme
q9 is found in rats and mice. CoQ10 is prevalent in humans, with high endogenous
concentration found in the heart, liver, kidney and pancreas. Current CoQ10 supplements are
manufactured by the fermentation of beets and sugarcane.
It can be synthesized in the body therefore CoQ10 is not considered to be an essential
nutrient. It is present in foods such as beef, poultry and broccoli.3 Other sources of
CoQ10 are soy oil, fish oils, peanuts, sardines and mackerel. Dietary intake of CoQ10
is 2-5 mg per day, which is always inadequate to provide levels in the body required to
be beneficial in pathological states. The total body content of CoQ10 is 0.4 to 1.5 gm..

Chemistry
Chemically CoQ10 is 2, 3 dimethoxy - 5 methyl - 6 decaprenyl benzoquinones. It is a
naturally occurring fat-soluble quinone ubiquitous in eukaryotic cells. (Fig. 1).

Synthesis
CoQ10 is synthesized in almost all tissues in the body from the amino acid Tyrosine. The
biosynthesis of the compound is multifold, with the isoprenyl side chain deriving from
mevolonate, the benzoquinone ring structure from tyrosine, and condensation of these
structures through polyprenyl transferase enzyme activity.4 The primary regulation of CoQ10
biosynthesis is the 3 hydroxy-methyl glutaryl coenzyme a, (HMG-COA) reductase reaction that
is similar in cholesterol synthesis. (Fig. 2).

History
CoQ10 was first isolated from beef heart
mitochondria by Dr. Frederick Crane of
University of Wisconsin, USA in 1957,
Professor Morton introduced the name
ubiquinone, meaning the ubiquitous
quinone.1 In 1958, professor Karl Folkers
and coworkers determined the precise
chemical tructure of CoQ10 as 2, 3,
dimethoxy-5 methyl-6 decaprenyl
benzoquinones synthesized and were the
first to produce it by fermentation.

In 1960, professor Yamamura of Japan


became the first in the world to use
coenzyme q7 a related Compound in the
treatment of human diseases viz.
congestive heart failure.

In 1978, Peter Mitchell received the Noble


prize for his contribution to the
understanding of biological energy transfer
through the formulation of the
chemiosmotic theory, which includes the
vital proton motive role of CoQ10 in
energy transfer systems.
Mechanism of Action

CoQ10 is a lipid soluble benzoquinone with a 10-isoprenyl unit side chain, is


structurally similar to vitamin-K5. It is an essential component in the synthesis of ATP
and exhibits both anti-oxidants and membrane stabilizing property. CoQ10 acts as a
redox link between flavoproteins and cytochromes that are needed for oxidative
phosphorylation and synthesis of ATP. It serves as an electron transport carrier during
the processes of respiration and oxidative phosphorylation. Thus, it is involved in the
manufacture of ATP. CoQ10 directly regulates NADH and succinate dehyrogenase,
enabling reversible reactions between these enzymes in the mitochondrial electron
transport chain. CoQ10 must be reduced to ubiquinol to wield its anti-oxidative
function, and supplementation with CoQ10 may inhibit lipid oxidizability.

Coenzyme-Q participates in the electron transport inside the mitochondria of the cell,
thus either hydrogen ions or electrons are gained or lost by CoQ10. It serves as an
electron acceptor for one group of enzymes and as an electron donor to the next group
of enzymes in the electron transport chain. It helps transport electron from complex-i to
complex-ii and from complex-ii to complex-iii. The [H]+ accumulated in the
intermembrane space of mitochondria is driven back into the mitochondria matrix via
ATP syntheses (complex-v) with formation of ATP.

Other mechanisms of action may include stabilization of calcium dependent slow


channels, inhibition of intracellular phospholipases, and alteration of prostaglandin
metabolism.5

Physiological role of CoQ10


I. CoQ10 as Energizer
CoQ10 participates in the electron transport inside the mitochondria of the cell, thus
either H+ or e- are gained or lost by CoQ10. It serves as an electron acceptor for one
group of enzymes and as an electron donor to the next group of enzymes in the electron
transport chain.

ATP synthase is like a turbine where higher concentrations of H+ leads to more energy
trapping and ATP formation and vice-versa. CoQ10 is the important coenzyme
responsible for taking up electrons and pushing H+ into the intermembrane space.

Thus, CoQ10 is an essential component in the ATP synthesis in the mitochondria and
high concentrations of CoQ10 can increase the total utilization of energy released by
the metabolic processes in the body; whereas deficiency of which may lead to loss of
energy generated during the metabolic processes in the form of heat.

It is a central rate-limiting constituent of the mitochondrial respiratory chain, which


generates most of the ATP within the cell. Thus CoQ10 acts as an energizer where it
improves the efficiency of the cells to utilize all available energy from its sources.
II. Antioxidant effects of CoQ10
It is well known that free radicals cause oxidative damage in various chronic disease
states like atherosclerotic heart disease, hypertension, congestive heart failure, diabetes
mellitus, ischaemia reperfusion injury, dyslipidaemia and many other conditions.

Free radicals are the substances, which have one or more unpaired electrons. These
unpaired electrons can easily react with cell components to cause free radicals injury or
oxidative damage. The unutilized oxygen in the body can lead to the formation of free
oxygen radicals viz. Suproxide anion (O2-), Hydroxyl radicals (OH-).

Various drugs, chemicals, pesticides, industrial pollutants, tobacco smoke, sunlight and
ionizing radiation can generate free radicals; whereas in the body they are being
constantly formed in the lysosomes, peroxisomes, endoplasmic reticulum, plasma
membrane and the cytoplasm. Free radicals bring about modulation of inflammatory
process by regulating prostaglandin synthesis.

Free radicals have high propensity to damage cellular DNA leading to activation of
carcinogenesis. They also lead to fatty acid peroxidation and damage to the cell
architecture and function. They also damage the various cellular metabolic processes
and interfere with ion channels located on the cells.

CoQ10 acts as an antioxidant by decreasing formation of free radicals. It improves the


transport of electrons (e-) and protons (H+) and thus prevents the formation of
superoxide radicals that would otherwise form from the released O2. It itself is a strong
directly acting endogenous antioxidant. It acts as a substrate for free radicals and
accepts the free electrons from free radicals; gets converted to reduced CoQ
(Ubiquinol), thus rendering free radicals into harmless compounds. Reduced CoQ10
then gives up electrons and gets reactivated again for further activity. CoQ10 is found
to regenerate the oxidized Vitamin-E thus converting it into a strong antioxidant.

III. Other possible roles of CoQ


It may be involved in maintenance of cell membrane integrity of RBCs and maintains
optimum blood viscosity. It stabilizes the calcium channels and may promote apoptosis
in malignant cells and may improve the immune status of patients.

Pharmacokinetics

Absorption
In animal studies CoQ10 has an oral bioavailability of 2-3%. With high doses of
dietary CoQ10, the blood concentration in both rats and humans can be increased about
2 to 4-fold. Following ingestion of 100 mg of CoQ10,peak plasma levels occur
between 5 and 10 hours. Tmax is approximately 6.5 hours, which indicates slow
absorpiton from the GI tract possibly due to the high molecular weight and low water
solubility of CoQ10.2 Uptake of dietary CoQ10 in the liver does not affect the
synthesis of endogenous CoQ10.
Distribution
The mean plasma levels after a single 100 mg oral dose of CoQ10 in human subjects is
1.004 0.37 mg/ml. In humans, CoQ10 is found in relatively high concentrations in
the heart, liver, kidney, and pancreas.6 The plasma half-life of CoQ10 in different
tissues varies between 49-125 hours.7 Following absorption from the GI tract, CoQ10
is taken up by chylomicrons. The major portion of an exogenous dose of CoQ10 is
deposited in the liver and packaged into VLDL lipoprotein.

Metabolism and Excretion


It is assumed that metabolism and excretion of exogenous CoQ10 is analogous to
endogenously produced CoQ10. The excretion of CoQ10 predominantly occurs via the
biliary tract.

Role in pathological conditions


Role in CHF
Coenzyme Q10 supplementation as an adjunct to CHF standard therapy is reported to
have positive outcomes, especially in patients with deficient levels of the provitamin.
Heart failure often is characterized by an energy depletion status that has been
associated with low endogenous CoQ10 levels. The possible usefulness of the CoQ10
in the treatment of CHF may be related to its ability to increase ATP synthesis and
enhancement of myocardial contractility.5

As with other muscle types, cardiac muscle fibres require calcium for contraction and
relaxation, and more energy is required for relaxation. These cells rely heavily on fat
sources of energy and hence contain more mitochondria. Since energy synthesis (ATP
Synthesis) from fats requires a higher oxygen concentration, mitochondria function in
the cardiac myocytes can be significantly impaired in deficiency of CoQ10. Therefore,
administration of CoQ10 increases the energy synthesis in the mitochondria and
significantly improves the cardiac function (contraction and relaxation), decreases end
diastolic ventricular pressure and improves the ejection fraction in CHF.

Thus, therapy with CoQ10 may be considered to be an efficacious aid in the traditional
treatment of chronic congestive heart failure along with other agents used in CHF.
CoQ10 administration has shown to reduce the signs and symptoms of CHF like
oedema, pulmonary rales, cyanosis, hepatomegaly and breathlessness on exertion.

CoQ10 is also useful in patients with hypertension, cardiac transplantation, cardiac


bypass surgery, cardiomyopathies and ischaemic heart disease. In patients of
dyslipidaemia who are on statins, which decrease cholesterol synthesis by HMG-CoA
reductase inhibition, there is an apparent deficiency of CoQ10 and concurrent CoQ10
administration in such patients significantly improves the cellular function and reduces
the complications of dyslipidaemia. CoQ10 also reduces the ischaemia-reperfusion
injury seen in patients recovering from myocardial ischaemia. Its antioxidant properties
contribute to prevention of lipid peroxidation, which alleviates the oxidative stress
inherent in CHF. Patients with severe CHF, i.e. NYHA class III and IV tend to have
lower levels of endogenous CoQ10 than that of patients with NYHA class-I CHF or
healthy subjects.5 Thus, patients with severe diseases may be more likely to attain a
favourable clinical response to CoQ10 supplementation.

Studies reported clinical benefits from short-term (1-4 wks) and long-term (3 months -
6 yrs) therapy with oral CoQ10 supplements, 50-100 mg/day, added to conventional
therapy in patients with severe CHF (NYHA class III and IV).4,5,8-11 Two large
multicenter, open-label studies evaluated the efficacy and safety of CoQ10 as adjuvant
therapy in CHF. The two studies examined a total of more than 4000 patients with
varying severity of CHF (i.e. patients with NYHA class II and III and class III and IV
CHF) who experienced clinical improvement in signs and symptoms such as cyanosis,
oedema, pulmonary rales, dyspnoea, and palpitations.12,13

Role in angina
The mechanism for improved exercise tolerance in patients with stable angina may be
due to ischaemic myocardial protection by CoQ10, allowing tissue to reach higher
levels of energy expenditure.5 Possible activities of the coenzyme in the maintenance
of oxidative phosphorylation, enhancement of ATP synthesis, or reduction of free
radicals formation create distinctions between the anti-anginal effects of CoQ10 and
the effects of other agents such as nitrates, calcium channel blockers, or b-adrenergic
blockers. The ability of exogenous CoQ10 to protect the ischaemic myocardium and
reduce or delay signs and symptoms of angina is suggested by six small randomized,
double-blind, placebo-controlled studies involving patients with stable angina
pectoris.14,15-19 All of these studies determined that CoQ10 dosages of 60-600
mg/day significantly prolonged exercise duration, reduced exercise-induced ischaemic
ST-segment depression, and delayed the onset of stable angina pectoris when compared
with placebo.

Role in hypertension
These effect of CoQ10 to decrease blood pressure is attributed to the correction of
endogenous pro-vitamin deficiency.20,21 In a study of hypertensive rats, a deficiency
in the activity of succinate de-hydrogenase CoQ10 reductase in leucocytes was found.
Deficient activity of this enzyme can result in decreased levels of CoQ10.22 Having
identified same deficiency in human subject with chronic hypertension, investigators
conducted a pilot study in which they concluded that increased succinate
dehydrogenase CoQ10 reductase activity and subsequent increased CoQ10 level lead to
decreases in systolic and diastolic blood pressures.20,23 Statistically significant
decreases in systolic and diastolic blood pressure were observed with CoQ10 dosages
ranging from 30-360 mg/day in patients with hypertension but these results are not
consistent among the trials.20,21,24-29

Male infertility
Three important parameters in infertility are count, morphology and motility of sperm
cells. The sperm count and morphology may be adversely affected due to damage by
free radicals. The reduced sperm motility is the consequence of decrease in energy
production ATP. CoQ10 has been found to be useful in idiopathic asthenozoospermia,
which is loss or decrease of sperm motility in semen. In Jan 2004 a study was
conducted to evaluate role of CoQ10 in male infertility. In this study subjects with
history of primary infertility received 200 mg twice daily of CoQ10 for 6 months. At
the end of study period CoQ10 levels in seminal plasma and phosphatidylcholine
increased significantly. Motility of sperm cells also increased from 9.13% to 16.34%.

Testicular tissue and sperm viability are particularly vulnerable to peroxidation injury
produced by free radicals and reactive oxygen species. Increased lipid peroxidation of
sperm leads to its damage and thereby causing infertility. The reasons why sperms are
vulnerable to damaging effects of these are: wide surface of the sperm membranes,
poor cytoplasmic defense mechanisms, lack of protection in the female genital tract
once the sperms are ejaculated. Whenever there is oligoasthenozoospermia, the
available sperm also have a high chance of being damaged by free radicals.

Asthenospermia and ATP


The main concentration of mitochondria in the sperm is in its midpiece. The sperm
motility is directly dictated by its ability to generate ATP, which in turn is dependent on
CoQ10 production. The motility of sperm requires a high-energy expenditure, and
hence optimal mitochondrial ATP generation plays an important role in sperm
motility.30

Just before ovulation, the quantity of water and mucus increases in the living cells of
the cervix in female. The water and salt interact with the glycoproteins present in
mucus to form crystal. This is called ferning and, as a result of the latter channels is
formed in mucus, which only allows sperms, which are normal, and possess adequate
motility, to navigate successfully so as to reach the ovum for fertilization in the optimal
69 minutes of time. CoQ10 encourages better sperm viability due to proving protection
against the damaging effects of reactive oxygen species, and also by enhancing sperm
motility. The CoQ10 concentration in serum is usually 0.081-1.066 mmol, and good
correlation has been demonstrated between these levels and sperm motility/count.31
Due to its lipophillic nature. CoQ10 increases the membrane integrity of sperm and
increases defense mechanism of the sperm. Because of its antioxidant and free radical
scavenging activity, CoQ10 prevents the sperm from free radical induced damage.

After administration, CoQ10 gets incorporated in the sperm mitochondria during the
process of spermatogenesis. Since the complete process of spermatogenesis requires a
long time CoQ10 should be administered at least for a period of 10 to 12 weeks

Side-effects
In therapeutic dosages, CoQ10 has proved to be relatively devoid of major side effects.
The most common adverse effects are nausea, epigastric pain, diarrhoea, heartburn, and
appetite-suppression. However, the prevalence of these adverse effects was less than
1% in reported studies.3,5 Gastrointestinal effects of CoQ10 may be lessened with a
dosage reduction or may subside with continued therapy. Asymptomatic elevations in
serum lactate dehydrogenase and hepatic enzymes were observed and may occur with
oral dosages of CoQ10 in excess of 300 mg/day; however, cases of serious
hepatotoxicity have not been reported.6,35 Clinical relapse was noted on withdrawal of
CoQ10, whereas reinstatement of therapy resulted in improvement.36-37 In one
withdrawal study, subsequent onset of fatigue and dyspnoea indicating clinical relapse
occurred in 88% of 16 patients, yet 75% improved and regained their clinical status
with resumption of CoQ10.36

Drug interactions
A drug interaction may occur between HMG-CoA reductase inhibitors and CoQ10
because the coenzyme is a byproduct of the cholesterol biosynthetic pathway. Use of
HMG-CoA reductase inhibitors (statins i.e. simvastatin, pravastatin, lovastatin) may
result in the diminution of CoQ10 blood levels due to interruption of synthesis.38-41
Other antilipidaemic agents such as cholestyramine of fibrate derivatives do not appear
to affect CoQ10 concentrations.40

The oral antidiabetic agents (i.e., acetohexamide, glyburide, phenformin, and


tolazamide) may inhibit enzymes (e.g., NADH and succinate dehydrogenase) resulting
in reductions in serum CoQ10 levels.42

CoQ10 is structurally related to vitamin-K and subsequently possesses procoagulant


effects. The potentially critical interaction can result as a diminished response to
warfarin therapy. Several reports describe decreases in international normalized ratio
(INR) after the addition of CoQ10 in patients previously stabilized with warfarin
therapy.43 The concomitant use of warfarin and CoQ10 should be avoided due to the
risk of thrombotic complications.

Also, reduced insulin requirements were observed in patients with diabetes who were
taking CoQ10 because it exerts favourable effects on ATP, which in turn acts as a
chemical energy carrier in the biosynthesis of insulin.42

CoQ10 supplementation in patients with hepatic insufficiency or biliary obstruction


may increase serum CoQ10 levels because this molecule is metabolized in liver and
excreted primarily through the biliary tract.35

Safety profile of CoQ10 during pregnancy and lactation has not been established, and
interactions between CoQ10 and food, herbs, or other dietary supplements are not
known.

Conclusions
CoQ10 administered orally has favourable actions in various cardiovascular conditions
and appears to be safe and well tolerated in the adult population. A conservative
approach to CoQ10 therapy is to support its use as adjuvant treatment for CHF, angina
or hypertension. Its favourable effects on ejection fraction, exercise tolerance, cardiac
output, and stroke volume were demonstrated in CHF. These clinically significant
effects may benefit patients with NYHA class II, III and IV CHF who are using CoQ10
as an adjuvant to traditional heart failure therapy. Patients with angina may see
prolonged exercise duration and reduced exercise-induced ST-segment depression with
CoQ10. CoQ10 may possibly find a place in the therapy of parkinsonism,
dyslipidaemia, migraine, male infertility, and atherosclerosis in near future.

Acknowledgement
The authors wish to thank the Dean, Dr. ME Yeolekar, for granting us permission to
publish this report.

References
1. Folkers K. Heart failure is a dominant deficiency of coenzyme Q10 and challenges
for future clinical research on CoQ10. Clin Invest 1993; 71 (suppl 8) : S51-4.
2. Overvad K, Diamant B, Holm L, et al. Coenzyme Q10 in health and disease. Eur J
Clin Nutr 1999; 53 : 764-70.
3. Jellin JM, Batz F, Hitchens K. Coenzyme Q10. Pharmacists letter/prescribers
letter: natural medicines comprehensive database. Stockton, CA: Therapeutic
Research Center, 1999 : 172-3.
4. Mortensen SA. Perspectives on therapy of cardiovascular diseases with coenyme
Q10 (ubiquinone). Clin Invest 1993; 71 : 116-3.
5. Greenberg S, Frishman WH. Co-enzyme Q10: a new drug for cardiovascular
disease. J Clin Pharmacol 1990; 30 : 596-608.
6. Schardt F, Welzel D, Scheiss W, et al. Effect of coenzyme Q10 on ischemia-
induced ST-segment depression: a double-blind, placebo-controlled crossover
study. In: Folkers K, Yamamura Y, eds. Biomedical and clinical aspects of
coenzyme Q, Amsterdam: Elsevier Science Publishers BV, 1986; 5 : 358-94.
7. Weber C, Bysted A, Holmer H. Intestinal absorption of coenzyme Q10
administered in a meal or as capsules to healthy subjects. Nutr Res 1997; 17 : 941-
5.
8. Mortensen SA, Vadhanavikit S, Baandrug U, et al. Long-term coenzyme Q10
therapy: a major advance in the management of resistant myocardial failure. Drugs
Exp Clin Res 1985; 11 : 581-93.
9. Langsjoen PH, Vadhanavikit S, Folkers K. Response of patients in classes II and
IV of cardiomyopathy to therapy in blind and crossover trial with coenzyme Q10.
Proc Natl Acad Sci USA 1985; 82 : 4240-4.
10. Langsjoen PH, Folkers K, Lyson K, et al. Effective and safe therapy with
coenzyme Q10 for cardiomyopathy. Klin Wochenschr 1988; 66 : 583-90.
11. Ishiyama T, Morita Y, Toyama S, et al. A clinical study of the effect of coenzyme
Q10 on congestive heart failure. Jap Heart J 1976; 17 : 32-42.
12. Baggio E, Gandini R, Plancher AC, et al. Italian multicenter study on the safety
and efficacy of coenzyme Q10 as adjunctive therapy in heart failure. Mol Aspects
Med 1994; 15 (suppl) : S287-94.
13. Lampertico M, Comis S. Italian multicenter study on the efficacy and safety of
coenzyme Q10 as adjuvant therapy in heart failure. Clin Invest 1993; 71 (supple 8)
: S129-33.
14. Serra G, Lissoni F, Piemonti C, et al. Evaluation of coenzyme Q10 in patients with
moderate heart failure and chronic stable effort angina. In: Folkers K, Littaru GP,
Yamagami T, eds. Biomedical and clinical aspects of coenzyme Q, vol. 6.
Amsterdam: Elsevier Science Publishers. 1991 : 327-38.
15. Yamagami T, Takagi M, Akagami H, et al. Effect of coenzyme Q10 on essential
hypertension: a double-blind controlled study. In: Folkers K, Yamamura Y, eds.
Biomedical and clinical aspects of coenzyme Q, Amsterdam: Elsevier Science
Publishers BV, 1986; 5 : 337-43.
16. Kamikawa T, Kobayashi A, Yamashita T, et al. Effects of coenzyme Q10 on
exercise tolerance in chronic stable angina pectoris. Am J Cardiol 1985; 56 : 247-
51.
17. Schardt F, Welzel D, Scheiss W, et al. Effect of coenzyme Q10 on ischemia-
induced ST-segment depression: a double-blind, placebo-controlled crossover
study. In: Folkers K, Yamamura Y, eds. Biomedical and clinical aspects of
coenzyme Q, Amsterdam: Elsevier Science Publishers BV, 1986; 5 : 358-94.
18. Mazzola C, Guffanti EE, Vaccarella A, et al. Non-invasive assessment of
coenzyme Q10 in patients with chronic stable effort angina and moderate heart
failure. Curr Ther Res 1987; 41 : 923-32.
19. Wilson MF, Frishman WH, Giles T, et al. Coenzyme Q10 therapy and exercise
duration in stable angina. In: Folkers K, Littaru GP, Yamagami T, eds. Biomedical
and clinical aspects of coenzyme Q, Amsterdam: Elsevier Science Publishers,
1991; 6 : 339-48.
20. Yamagami T, Shibata N, Folkers K. Bioenergetics in clinical medicine: studies on
coenzyme Q10 and essential hypertension. Res Commun Chem Pathol Pharmacol
1975; 11 : 273-88.
21. amagami T, Shibata N, Folkers K. Bioenergetics in clinical medicine VIII.
Administration of coenzyme Q10 to patients with essential hypertension. Res
Commun Chem Pathol Pharmacol 1976; 14 : 721-7
22 Iwamoto Y, Yamaguchi T, Folkers K, et al. Deficiency of coenzyme Q10 in
hypertensive rats and reduction of deficiency by treatment with coenzyme Q10.
Biochem Biophs Res Commun 1974; 58 : 743-8.
23. Yamagami T, Iwamoto Y, Folkers K, et al. Deficiency of activity of succinate
dehydrogenase-coenzyme Q10 reductase in leukocytes from patients with essential
hypertension. Int J Vitam Nutr Res 1974; 44 : 404-14.
24. Folkers K, Drzewoski J, Richardson PC, et al. Bioenergetics in clinical medicine.
XVI. Reduction of hypertension in patients by therapy with coenzyme Q10. Res
Commun Chem Pathol Pharmacol 1981; 31 : 129-40.
25 Yamagami T, Shibata N, Folkers K. Bioenergetics in clinical medicine. VIII.
Administration of coenzyme Q10 to patients with essential hypertension. Res
Commun Chem Pathol Pharmacol 1976; 14 : 721-7.
26. Digiesi V, Cantini F, Brodbeck B. Effect of coenzyme Q10 on essential arterial
hypertension. Curr Ther Res 1990; 47 : 841-5.
27. Digiesi V, Cantini F, Oradei A, et al. Coenzyme Q10 in essential hypertension. Mol
Aspects Med 1994; 15 (suppl) : S257-63.
28. Langsjoen P, Langsjoen P, Willis R, et al. Treatment of essential hypertension with
coenzyme Q10. Mol Aspects Med 1994; 15 (suppl) : S262-72.
29. Singh RB, Niaz MA, Rastogi SS, et al. Effect of hydrosoluble coenzyme Q10 on
blood pressure and insulin resistance in hypertensive patients with coronary artery
disease. J Hum Hypertens 1999; 13 : 203-8.
30. Tanimura J. Studies on arginine in human semen. Part III. The influences of
several drugs on male infertility. Bull Osaka Med School 1967; 13 : 90-100.
31. Lewin A, Lavon H. The effect of coenzyme Q10 on sperm motility and function.
Mol Aspects Med 1997; 18 Suppl : S213-9.
32 Shults CW, et al. Effects of coenzyme Q10 in early Parkinson disease. Arch Neurol
2002; 59 : 1541-50.
33. Lockwood K, et al. Partial and complete regression of breast cancer in patients in
relation to dosage of coenzyme Q10. Biochem Biophs Res Comm 1994; 199 :
1504-8.
34. Chopra RK, Goldman R, Sinatra ST, et al. Relative bioavailability of coenzyme
Q10 formulations in human subjects. Int J Vitam Nutr Res 1998; 68 : 109-13.
35. Micromedex. Healthcare series. Ubidecarenone. Englewood, CO: Micromedex,
Inc.
36 Mortensen SA, Vadhanavikit S, Muratsu K, et al. Coenzyme Q10: clinical benefits
with biochemical correlates suggesting a scientific breakthrough in the
management of chronic heart failure. Int J Tissue Reac 1990; XII(3) : 155-62.
37. Mortensen SA, Vadhanavikit S, Baandrug U, et al. Long-term coenzyme Q10
therapy: a major advance in the management of resistant myocardial failure. Drugs
Exp Clin Res 1985; 11 : 581-93.
38. Watts GF, Bastelluccio C, Rice-Evans C, et al. Plasma coenzyme Q (ubiquinone)
concentrations in patients treated with simvastatin. J Clin Pathol 1993; 46 : 1055-7.
39. Bargossi AM, Grossi G, Fiorella PL, et al. Exogenous CoQ10 supplementation
prevents plasma ubiquinone reduction induced by HMG-CoA reductase inhibitors.
Mol Aspects Med 1994; 15 (suppl) : S187-93.
40. Ghirlanda B, Oradei A, Manto A, et al. Evidence of plasma CoQ10 reductase
inhibitors: a double blind, placebo-controlled study. J Clin Pharmacol 1993; 33 :
226-9.
41. Mortensen SA, Leth A, Agner E, et al. Dose-related decrease of serum coenzyme
Q10 during treatment with HMG-CoA reductase inhibitors. Mol Aspects Med
1997; 18 (suppl) : S137-44.
42. Kishi T, Kishi H, Watanabe T, et al. Bioenergetics in clinical medicine. Xi. Studies
on coenzyme Q and diabetes mellitus. J Med 1976; 7 : 307-21.
43. Spigset O. Reduced effect of warfarin caused by ubidecarenone. Lancet 1994;
344 : 1372-3.

Você também pode gostar