Richard Morrill

The History of
Coenzyme Q10 Research
Quality of Life Served in a Softgel Capsule

Forlaget Ny Videnskab
 Richard Morrill

The History of
Coenzyme Q10
Research
 Richard Morrill: The History of Coenzyme Q10 Research
© 2019: Forlaget Ny Videnskab
Under copyright laws, reproduction of the contents of this book,
whole or in part, is prohibited without permission from the publisher.
This prohibition applies to any reproduction whether it is by
printing, duplicating, photocopying, audio recording, etc.
Print: Schweitzer A/S, Denmark
ISBN 978-87-7776-185-0
Forlaget Ny Videnskab

2
Table of content
The History of Coenzyme Q10 Research......................................1

Introduction: Quality of Life Served in a Soft-Gel Capsule..........4

Coenzyme Q10: The Essential Bio-Nutrient................................5

Coenzyme Q10 Researchers.........................................................7

1970s: Coenzyme Q10

for the Treatment of Heart Failure in Japan................................15

1980s: Dr. Folkers Collaborates with

Heart Failure Researchers ..........................................................19

The Coenzyme Q10 Situation by 1990......................................27

Looking Ahead to the 21st Century: The Guidelines..................45

The Second Decade of the 21st Century.....................................62

References..................................................................................80

3
Introduction:
Quality of Life Served
in a Soft-Gel Capsule
When American scientists discovered Coenzyme Q10 for the very
first time back in 1957, they knew that they were on to something,
but they had no idea that their discovery would eventually add a whole
new dimension to medical science. What they had found was the key
to discovering a hitherto unknown factor in the body's energy pro-
duction – energy that the body uses to stay alive and healthy and to
optimize all of its functions. They had uncovered the biochemical
formula for quality of life and put it into capsules.

Coenzyme Q10 is a natural, vitamin-like compound that all cells need

in order to make energy. Nature has designed us humans in such a
way that levels of this energy-providing nutrient peak in our twenties
and decrease from that point onward. What the discovery of Coenzyme
Q10 has enabled us to do is to prevent a drop in energy from taking
place. Figuratively speaking, we can keep our batteries fully charged
throughout life.

So far, Coenzyme Q10 research has yielded a Nobel Prize in biochem-

istry in 1978, when the British scientist Peter Mitchell mapped out
exactly how the nutrient works inside the cell. Most recently, a ground-
breaking study that was published in one of the world’s leading car-
diology journals showed that when heart failure patients take Coenzyme
Q10, their mortality rate drops substantially and their heart muscle
gets more power.

This review will show you the way past some of the most important
milestones of what many scientists consider the largest step forward
in the history of medicine.

4
Coenzyme Q10: The
Essential Bio-Nutrient
Over the past 25 – 30 years, researchers in the bio-medical communi-
ty have built up an extensive knowledge base about the absorption,
safety, and health effects of Coenzyme Q10. Coenzyme Q10 is a
substance that is both synthesized in the body and absorbed from food
sources. Moreover, the use of statin medications inhibits the body’s
production of Coenzyme Q10. It is very difficult if not impossible
to compensate in the diet alone for the Coenzyme Q10 deficits caused
by increasing age and statin medications.

The cumulative research results show that Coenzyme Q10, when

taken as a dietary supplement or as a medicine, is safe and well-toler-
ated. It is necessary for the cellular production of ATP (adenosine
triphosphate) molecules, the basic source of energy in the body. It is
necessary as an antioxidant to neutralize harmful free radicals. It is
necessary to protect the smooth functioning of the endothelium, the
inner lining of the blood vessels and lymph vessels.

Research results now show that adjuvant treatment with Coenzyme

Q10 improves symptoms and survival in patients with chronic heart
failure [64,70], reduces the number and severity of complications
following heart surgery [39,55], and helps to lower high blood pressure
[2,78].

In this history of Coenzyme Q10 research, the following

abbreviations are used:
kg: kilogram mg: milligram
mcg: microgram mL: milliliter
L: liter

5
Coenzyme Q10: A Substance with Many Names
There are many histories that can be written about the discovery and
development of the redox chemical substance that is known by many
names:

• Coenzyme Q10
• Ubiquinone = oxidized Coenzyme Q10
• Ubiquinol (QH) = reduced Coenzyme Q10
• Q or Q10 or CoQ10
• Ubidecarenone
• Myoqinon
• Bio-Quinone Q10
• v2,3-Dimethoxy-5-methyl-6-decaprenyl-1,4-benzoquinone

There are many important people, scientists and biomedical research-

ers and medical doctors, who can and should be emphasized and
celebrated in any history of Coenzyme Q10.

Illustration of the Coenzyme Q10 molecule showing the

quinone head and a part of the long isoprenoid tail –
Coenzyme Q10 is found in the mitochondria of all healthy
cells in the body except in the red blood cells – Coenzyme
Q10 affects everyone positively, and it has no toxic effects at
all.

6
Coenzyme Q10
Researchers
In this particular history of Coenzyme Q10 research, we have chosen
to tell Coenzyme Q10’s story with an emphasis on two very important
men in the story worldwide, Dr. Karl Folkers and Dr. Svend Aage
Mortensen, and, then, with lesser emphasis on the two men, Sven
Moesgaard and Eli Wallin, behind the founding and managing of the
Danish company Pharma Nord, the producer of the Bio-Quinone
Q10 and Myoqinon preparations.

The lives and careers of the two sets of men intersected for many years
and were interwoven around a mutual commitment to the development
of a well-absorbed nutritional supplement and adjuvant medical
therapy drug from the substance Coenzyme Q10.

The first of the two prominent men in the history of Coenzyme Q10
research was the American research chemist and visionary Dr. Karl
August Folkers. Dr. Folkers was a researcher who seemed able to
visualize in his mind the pathways of biochemical reactions whenev-
er he looked at the chemical formulas and structures of naturally
occurring substances. He foresaw more clearly than anyone the po-
tential benefits of Coenzyme Q10 supplementation in patients suf-
fering from heart disease and cancer.

Using his knowledge of chemistry and biology, Dr. Folkers could see
the potential health effects of Coenzyme Q10. He could imagine great
break-throughs if only the funding for biomedical research could be
secured. In the words of Sven Moesgaard, Dr. Folkers was the chem-
ist who dared build Coenzyme Q10 castles in the air.

Visualizing Coenzyme Q10 at the Cellular Level

What Dr. Folkers visualized better than anyone else was the biochem-
ical activity of the substance Coenzyme Q10 in the mitochondria of
human cells. Dr. Folkers knew that the mitochondria are the site in
the cells in which the synthesis of adenosine triphosphate (ATP) takes

7
 Sven Moesgaard of Pharma Nord and Dr. Karl Folkers
(right) – In front of the Tycho Brahe Planetarium,
Copenhagen 1992.

place. ATP is the carrier of chemical energy in the cells. At the same
time, Dr. Folkers knew that the mitochondria are a major producer
of harmful free radicals in the body and need antioxidant protection.

Dr. Folkers could see that Coenzyme Q10, a redox substance known
as ubiquinone in its oxidized form and as ubiquinol in its reduced
form, was an essential bio-nutrient. The ubiquinone form is a com-
ponent of the electron transport chain in the process of aerobic cellu-
lar respiration that produces and transfers chemical energy in the form
of ATP. The ubiquinol form is a powerful antioxidant that can quench
reactive oxygen species.

Dr. Svend Aage Mortensen, 1942 - 2015

The second of the two eminent men in the history of Coenzyme Q10
research was the Danish cardiologist and researcher Dr. Svend Aage
Mortensen. Dr. Mortensen developed the rationale for and designed
and led the multi-center Q-Symbio study that was completed and
published in 2014.

Q-Symbio met the gold standard for a test of Coenzyme Q10 as an

adjunctive treatment of chronic heart failure [70]. It was a randomized,
double-blind, placebo-controlled clinical trial with emphasis on the

8
heart failure patients’ disease symptoms, bio-markers, and long-term
outcomes (hospitalization rates and mortality rates, in particular).

Heart failure is often referred to as congestive heart failure or chronic

heart failure. The condition is increasingly prevalent, and it has a
generally poor prognosis. It is the medical condition that occurs
whenever the heart muscle, in its contractions, is not able to pump
out a sufficient volume of blood to meet the body’s needs for oxygen
and nutrients. Typical symptoms include shortness of breath, early
onset of fatigue, swelling in the legs and possibly chest pain. Common
causes of heart failure are coronary artery disease, high blood pressure,
atrial fibrillation, leaky heart valves, and infection and inflammation
as well as unknown causes.

From Dr. Mortensen’s perspective, a very plausible cause of heart

failure is the energy starvation of the heart muscle cells. Whenever the
concentration of Coenzyme Q10 in the heart muscle cells is abnor-
mally low, the heart muscle will be starved for energy. Dr. Mortensen
suspected dysfunction of the bioenergetics process in the heart muscle
cells, a condition in which the mitochondria of the heart muscle cells
lack an adequate supply of Coenzyme Q10 and fail to synthesize
enough ATP. Dr. Mortensen was determined to provide clinical research
evidence for the plausibility of this explanation of the cause of heart
failure.

Dr. Mortensen was, in the words of his fellow Coenzyme Q10 re-
searcher, Sven Moesgaard, the man who built a good solid foundation
under the Coenzyme Q10 castles in the air that Dr. Folkers had built.
More than any one other researcher, Dr. Mortensen provided the
rationale and the empirical evidence for adding Coenzyme Q10
supplementation as an adjuvant treatment to the guidelines for the
standard treatment of chronic heart failure.

The conventional treatment of chronic heart failure is designed most-

ly to block neurohormonal responses in patients. In the words of Dr.
Mortensen, conventional heart failure therapies block rather than
enhance cellular processes. What adjuvant treatment with Coenzyme
Q10 adds to the treatment regimen is support and enhancement of
the cellular bioenergetics of the failing heart.

9
 Dr. Karl Folkers and Dr. Svend Aage Mortensen (right).

Who Was Dr. Karl Folkers?

Dr. Folkers was such a capable chemist and biochemist that, when
Dr. Folkers died, Professor William Shive, himself a prominent chem-
ist, wrote the biographical memoir of Dr. Folkers that was published
by the National Academy Press [81]. Dr. Shive emphasized not only
Dr. Folkers’ contributions to research science but also his assistance
to and collaboration with many other researchers.

It was a big part of Dr. Folkers’ dream to see Coenzyme Q10 become
a component of medical education and of clinical practice. His major
research interests were first, last, and always the biochemical study of
disease conditions and the use of nutritional supplements to promote
health and well-being. Initially, Dr. Folkers seems to have thought
that the substance Coenzyme Q10 was a vitamin, Vitamin Q, as it
were.

Coenzyme Q10:
Vitamin-like and Essential but Not a Vitamin
In speculating that Coenzyme Q10 would prove to be a vitamin,
Dr. Folkers thought, at first, that Coenzyme Q10 was another one of
those organic compounds that are essential for human growth and

10
development but which the body is unable to synthesize. Very soon,
he realized that yes, the human body does synthesize Coenzyme Q10.
However, further research revealed that the body’s production of the
substance peaks in a person’s 20s and then decreases with increasing
age [42].

The bio-synthesis of Coenzyme Q10 continues to decrease to the

extent that a 65-year-old man’s synthesis of Coenzyme Q10 is likely
to be half or less than a 25-year-old man’s synthesis of the substance
is. Moreover, Dr. Folkers realized and could demonstrate early on that
the statin medications used to inhibit the bio-synthesis of cholesterol
were also inhibiting the bio-synthesis of Coenzyme Q10. He could
envision the conditions for and the consequences of Coenzyme Q10
deficiency.

By 1990, he was able to publish the results of three studies that

demonstrated that the statin medication lovastatin, while successful
at lowering patients’ cholesterol levels, was also inducing Coenzyme
Q10 deficiencies in patients.

Dr. Folkers in the Early Years at Merck:

B Vitamins and Antibiotics
Dr. Folkers joined the American pharmaceutical company Merck
(later Merck, Sharp and Dohme) as a research chemist in 1934 and
did research there, with ever increasing responsibility, until 1963. He
and his research team first did groundbreakning work on the structure
and synthesis of vitamin B6 followed by similar research on other B
vitamins, pantothenic acid and biotin.

Dr. Folkers next got deeply involved in the isolation and structure
determination of the antibiotic streptomycin. Then, in the work for
which he became especially well-acclaimed, he and his research team
determined the chemical structure of vitamin B12 and made its com-
mercial preparation possible.

The Mevalonate Pathway

While still at Merck, Dr. Folkers and his research team succeeded in
the discovery, isolation, and synthesis of mevalonic acid, which is the

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 HMG CoA
HMG CoA
STATINS Reductase

Mevalonic acid

Squalene

Dolichol Cholesterol Coenzyme Q10

(protein synthesis) (hormones, antioxidants) (energy, antioxidant)

A simplified illustration of the mevalonate pathway

producing the building blocks used to make isoprenoids. It
is also seen why statins inhibit the body’s production of
CoQ10.

biochemical precursor of the substances produced in the body in the

mevalonate pathway, namely cholesterol, ubiquinone and dolichol.
The work of the Merck team led directly to the development of ap-
proaches to limiting the biosynthesis of cholesterol. Later, it was Dr.
Folkers’ understanding of the production of cholesterol and Coenzyme
Q10 in the same biological pathway that would make him realize that
cholesterol inhibiting drugs also inhibit Coenzyme Q10 production.

Dr. Folkers and the Work on Coenzyme Q10 at Merck

While Dr. Folkers was at Merck, making his reputation in the struc-
tural determination of natural substances, British and American re-
searchers, working independently of one another, isolated a yellow
fat-soluble quinone substance from animal tissue. In 1955, Dr. Fes-
tenstein and his colleagues, working in the Liverpool laboratory of
Dr. R. A. Morton, isolated the substance. Because it seemed to be
ubiquitous in animal tissue, Professor Morton called it ubiquinone.

12
 Dr. Fred Crane at the London CoQ10 Symposium 2002.

In 1957, unaware of the British discovery and seeking to understand

the role of the electron transport system in the production of ATP,
Dr. Fred Crane and colleagues, working in the lab of Dr. David Green
at the University of Wisconsin, isolated the yellow fat-soluble substance
that they found in the mitochondria of extracts of beef heart tissue.
They called the substance Coenzyme Q based on its role as a Coenzyme
in the electron transfer chain.

Dr. Crane Takes Samples of Coenzyme Q10 to Dr. Folkers

Dr. Crane, knowing of Dr. Folkers’ skills in the laboratory, took
samples of the recently isolated substance to Merck in New Jersey
where Dr. Folkers and his team were able, in 1958, to determine the
structure of Coenzyme Q10. The Q in the name stands for the cyclic
organic arrangement of the quinone head, and the 10 in the name
stands for the number of isoprenoid units in the tail of the substance.

Dr. Folkers and the Role of Coenzyme Q10 in Heart Failure

In 1963, Dr. Folkers resigned from Merck and accepted a position as
president and chief executive officer at the Stanford Research Institute.
At Stanford, in the time that he could spare from his executive duties,
Dr. Folkers continued to do some Coenzyme Q10 research. Then, in

13
1968, he moved to Austin, Texas, to take the position of director of
the Institute of Biomedical Research where he would have more time
and resources for research into the clinical effects of Coenzyme Q10.

In Austin, Dr. Folkers could finally concentrate his research focus on

the medical applications of Coenzyme Q10 supplementation. Dr.
Folkers and his fellow researchers became more and more convinced
of the efficacy of supplementation with Coenzyme Q10 in a variety
of diseases:

• Cardiomyopathy (disease of the heart muscle)

• Hypertension
• Muscular dystrophy
• Periodontal disease

Orange Coenzyme Q10 crystals – A proper Coenzyme Q10

preparation needs to have the raw material dissolved in oils
in a way that inhibits the re-crystallization of the Q10
molecules at body temperature.

14
1970s:
Coenzyme Q10 for the
Treatment of Heart
Failure in Japan
At some time in the early 1970s, Dr. Folkers took samples of Coenzyme
Q10 to a biochemical meeting in Japan. There, he met a cardiologist,
Dr. Yuichi Yamamura, whom he convinced to supplement heart
failure patients with Coenzyme Q10. Dr. Yamamura became the first
cardiologist to treat heart failure patients with Coenzyme Q10.

Initially, Dr. Folkers delivered Coenzyme Q10 that was extracted from
fish livers in a small extraction plant that he had in Galveston, Texas.
The Coenzyme Q10 that was extracted from fish livers obtained from
the fishing industry in Galveston was purified and used in research
studies in Japan and in the USA. For a time in the 1970s, Dr. Folkers
was supplying all of the Coenzyme Q10 used for research in the USA.
Dr. Folkers was, at that time, also investigating methods to extract
Coenzyme Q10 from tobacco plants and methods to produce Coen-
zyme Q10 by a bacterial process (Pseudomonus arius). [information
provided by Dr. William Judy]
Already in 1974, in recognition of the link between lower blood and
tissue levels of Coenzyme Q10 and congestive heart failure, Japan
approved the use of Coenzyme Q10 for the medical treatment of heart
failure. Coenzyme Q10 was known to be safe and without any signif-
icant adverse effects. In 1977, the Kaneka Corporation in Japan began
producing and distributing yeast-fermented Coenzyme Q10.

1970s: Deficiency of Coenzyme Q10

in Human Heart Disease
By the 1970s, Dr. Folkers and his team of researchers, which includ-
ed the Italian researcher Gian Paolo Littarru, had solid evidence that

15
patients with heart disease and patients undergoing heart surgery had
blood and tissue Coenzyme Q10 levels significantly below normal
levels [21]. The evidence came from tissue biopsy samples from more
than 100 cardiac surgery patients and from blood samples from more
than 1000 cardiac patients.

Left to right, Dr. Fred Crane, Dr. Karl Folkers, Dr. Gian
Paolo Littarru at the Ancona CoQ10 Symposium 1996

1978: Dr. Peter Mitchell and the Nobel Prize for Chemistry
For his work done throughout the 1970s, the British chemist Dr.
Peter Mitchell was awarded the Nobel Prize for Chemistry in 1978.
The Royal Swedish Academy of Sciences honored Dr. Mitchell for his
explanation of the role of Coenzyme Q10 in the biological transfer
of energy in the cells through the movement of electrons to the elec-
tron transport chain in the inner mitochondrial membranes and
through the movement of hydrogen ions (protons) across the inner
membranes of the mitochondria.

Dr. Mitchell’s theoretical work on chemiosmosis as an explanation of

the generation of ATP provided valuable underpinnings for the clin-
ical work of Dr. Folkers and the cardiologists with whom Dr. Folkers
collaborated. It also made the significance of the clinical research more
apparent.

16
 His Majesty King Carl Gustaf of Sweden presents the 1978
Nobel Prize in Chemistry to Dr. Peter Mitchell (left).

Who Was Dr. Svend Aage Mortensen?

Dr. Svend Aage Mortensen – known as SAM to his colleagues and
friends – was a very capable and yet very modest man whose passion-
ate interest was the care and welfare of heart disease patients. His
education and training in cardiology was extensive, indeed, but chron-
ic heart failure and chronic diseases of the heart muscle (cardiomyo-
pathy) were his primary focus. His colleagues, in their memorial to
him in the Danish medical journal Ugeskrift for Læger say that he was
the best colleague and mentor that one could hope for.

Dr. Mortensen finished his medical education in 1974. His first

posting as a cardiologist was to Helsingor in northern Zealand where
he introduced the practice of acute pacemaker surgery. Then, in 1978,
he was assigned to Rigshospitalet (later named Copenhagen Univer-
sity Hospital) in Copenhagen, and he remained in The Heart Center
in Copenhagen until his unexpected death from complications fol-
lowing heart valve surgery in 2015.

During a study tour to London, Dr. Mortensen learned to conduct

heart tissue biopsies. His use of the technique and its application
provided the data for his subsequent Doctor of Science dissertation,
which he defended in 1989.

17
On a study tour to Stanford University, Dr. Mortensen learned to do
heart transplantation. In 1990, he was involved in the establishment
of a heart transplantation program in Copenhagen, and, from the
start, he was the medical officer in charge of the program.

From the early 1980s to 2015, Dr. Mortensen’s research efforts were
concentrated on understanding the role of Coenzyme Q10 in the
prevention and treatment of chronic heart disease. Fortunately, before
his untimely death, Dr. Mortensen was able to complete and publish
the results of the Q-Symbio study of the effect of Coenzyme Q10
supplementation on the morbidity and mortality of chronic heart
failure patients. More about the Q-Symbio study later in this history
of Coenzyme Q10.

18
1980s:
Dr. Folkers
Collaborates
with Heart Failure
Researchers
In the early 1980s, Dr. Folkers began to work with two cardiologists
and a post-doctoral research fellow to test the effects of Coenzyme
Q10 supplementation of heart disease patients. These three research-
ers were pioneers in the adjuvant treatment of heart disease with
Coenzyme Q10:

• Dr. Svend Aage Mortensen of Copenhagen, Denmark

• Dr. Per Langsjoen of Temple, Texas
• Dr. William Judy of Indianapolis, Indiana

Dr. Svend Aage

Mortensen, Danish
cardiologist and
Coenzyme Q10 researcher,
leader of the Q-Symbio
study of Coenzyme Q10
adjuvant treatment and
chronic heart failure.

1980s: Folkers and Mortensen:

Low Heart Muscle Tissue Levels of Coenzyme Q10
In 1984 and 1985, Dr. Mortensen and Dr. Folkers were able to
demonstrate that the heart muscle tissue levels of Coenzyme Q10 in
patients in the New York Heart Association classes III and IV were

19
lower than the levels of heart muscle Coenzyme Q10 in patients in
the NYHA classes I and II. With their tissue data, Dr. Folkers and Dr.
Mortensen were beginning to establish a biochemical rationale for the
adjuvant treatment of heart failure patients with Coenzyme Q10
supplements [22].

Briefly, the New York Heart Association classes, widely used in the
diagnosis of heart failure patients, describe patients as follows:

• Class I: feeling capable of ordinary physical exertion but

showing signs of early fatigue and shortness of breath
at higher levels of exertion
• Class II: feeling comfortable at rest but showing signs of early
fatigue and shortness of breath and discomfort at
ordinary levels of physical activity
• Class III: feeling fatigue, heart palpitation,
or shortness of breath during light activity
• Class IV: feeling fatigue, heart palpitation,
or shortness of breath even while at rest

1980s: Folkers and Mortensen:

Supplementation of Heart Disease Patients
with Coenzyme Q10 in Open-label Studies
Dr. Mortensen and Dr. Folkers started slowly, testing the effects of
Coenzyme Q10 supplementation in heart disease patients in open-la-
bel trials, studies in which both the researchers and the patients knew
who was getting the active substance and when he was getting it [66].
The researchers gave 100 milligrams of Coenzyme Q10 daily to patients
with advanced heart failure. All of the patients had been showing an
unsatisfactory response to the conventional medical treatment using
diuretics and digitalis.

The researchers followed the progress of the patients receiving the

Coenzyme Q10 supplementation for seven months. When the patients
were on the Coenzyme Q10, their symptoms – early fatigue and
shortness of breath – improved. When the Coenzyme Q10 treatments
were discontinued, the patients suffered relapses. This study provided
some of the first empirical evidence of the effectiveness of Coenzyme
Q10 as an adjuvant therapeutic agent in advanced cases of heart
failure.

20
The Management of Chronic Heart Failure
(Folkers and Mortensen)
By 1990, Dr. Mortensen and Dr. Folkers had amassed enough clinical
evidence from blood samples, heart biopsy tissue samples, and meas-
urements of cardiac function that they could publish a list of clinical
benefits of Coenzyme Q10 supplementation of heart failure patients
with corresponding biochemical correlates, all of which suggested, in
their words, a scientific breakthrough in the management of chronic
heart failure [65].

• They had seen the significant inverse association between the

level of blood and tissues concentrations of Coenzyme Q10
and the severity of heart failure.
• They had seen significant improvement in the symptoms and
survival of heart failure patients treated with 100 milligrams
of Coenzyme Q10 daily.
• They had seen relapses whenever the administration of
Coenzyme Q10 to heart failure patients was discontinued.

1985: Langsjoen and Folkers: Double-blind Study of the

Effect of Coenzyme Q10 on Cardiomyopathy
In 1985, Dr. Per Langsjoen of Tyler, Texas, and Dr. Folkers published
the results of double-blind studies showing statistically significant
beneficial effects of supplementation with Coenzyme Q10 [47,48].
The researchers enrolled 19 of Dr. Langsjoen’s class III and class IV
heart failure patients in a placebo-controlled, double-blind, cross-over
study. All of the 19 patients had low or borderline concentrations of
Coenzyme Q10 in their blood. All of the patients showed a statisti-
cally significant increase in their blood CoQ10 levels during the pe-
riod of supplementation with the active substance (and not in the
period with the placebo substance).
One group of patients received first Coenzyme Q10 for 12 weeks and,
then, after a washout period, placebo for 12 weeks. The other group
received first placebo for 12 weeks, and, then, after a washout period,
Coenzyme Q10 for 12 weeks. The researchers monitored the blood
levels of Coenzyme Q10 and aspects of cardiac function at points 0,
4, 16, and 28 weeks.
In these patients, who would normally have been expected to die
within two years’ time while on conventional heart disease medications,

21
the researchers measured significant improvements in various aspects
of cardiac function and patient well-being associated with the con-
comitant increases in blood Coenzyme Q10 levels during the periods
of active treatment. In particular, the researchers recorded significant
improvements in the following parameters:

• stroke volume (the amount of blood pumped out in a single

contraction of the heart)
• ejection fraction (the percentage of the blood being pumped out
of the heart as it contracts)

Dr. Langsjoen and Folkers attributed the significant improvement to

the role of Coenzyme Q10 in the bioenergetics in the heart muscle
cells. Coincidentally, 1985, the year of the publication of the dou-
ble-blind study results by Dr. Per Langsjoen and Dr. Folkers was the
year that Dr. Langsjoen’s son Dr. Peter H. Langsjoen began his career
in cardiology.

1988: Langsjoen and Folkers:

Blood Coenzyme Q10 Levels of 2.5mg/L or Higher
to Improve Symptoms in Heart Failure
Dr. Langsjoen and Dr. Folkers compiled the data from 115 heart
failure patients. 88 of the patients completed the course of therapy
with Coenzyme Q10 [49]. The patients were monitored for the fol-
lowing parameters: ejection fraction, cardiac output, and NYHA
functional classification. Nearly 80% of the patients showed significant
improvements in two of the three parameters.

The patients with the lowest baseline ejection fractions showed the
highest increases, but also those patients with higher baseline ejection
fractions showed increases with the Coenzyme Q10 therapy.

There were also significant improvements in NYHA classifications: 17

of 21 patients in class IV, 52 of 62 patients in class III, and 4 of 5
patients in class II improved their status to a lower functional class.

Dr. Langsjoen concluded that the patients’ clinical responses to ther-

apy with Coenzyme Q10 appeared to be best when the supplemen-
tation raised the blood Coenzyme Q10 levels to approximately 2.5
micrograms/mL (2.5 mg/L) or higher.

22
 Dr. Peter H. Langsjoen, a cardiologist much concerned
about the effect of statin medications on his patients.

1990: Langsjoen and Folkers: Six-year Clinical Study

of Coenzyme Q10 Supplementation
In 1990, Dr. Langsjoen (father), Dr. Langsjoen (son), and Dr. Folkers
published a six-year clinical study of successful therapy of cardiomy-
opathy with Coenzyme Q10 supplementation in 143 heart failure
patients in NYHA classes III and IV [50].

Langsjoen and Littarru: Concerns About the Relationship

Between Statin Medications and Atherosclerosis and
Heart Failure
Already in 1990, Dr. Folkers and the elder Dr. Langsjoen had published
research results showing that the use of the statin medication lovasta-
tin decreases Coenzyme Q10 levels in humans [23]. Later, in 2007,
together with Dr. Gian Paolo Littarru, the younger Dr. Langsjoen
published a warning about a possible causal connection between the
use of statin medications and the stimulation of atherosclerosis and
heart failure [57]. More on this topic later in this history.

23
1980s: Judy and Folkers: Independent Confirmation of the
Folkers/Mortensen and the Folkers/Langsjoen Results
In the same period of the 1980s, Dr. William V. Judy was monitoring
the progress of heart failure patients at Methodist Hospital and at
St. Vincent Hospital in Indianapolis, Indiana.

Dr. Judy reported significant improvement in heart failure symptoms

and survival in studies involving 34 patients with NYHA class IV
heart failure and involving 180 patients with NYHA class III and IV
heart failure when the administration of Coenzyme Q10 was added
to the conventional regimen of heart failure medication [38]. More-
over, Dr. Judy observed and reported on the same sort of clinical relapse
and worsening of the congestive heart failure that Dr. Mortensen had
reported whenever the administration of Coenzyme Q10 was discon-
tinued.

Dr. Judy reported improvement in cardiac function in patients treat-

ed with Coenzyme Q10 as compared with patients receiving placebo:

• improved cardiac index (heart output as it relates to body size)

• improved left ventricular ejection fraction (% of blood pumped)
• reduced left ventricular end-diastolic volume (volume of blood
in the chamber at end-load)

Dr. William V. Judy,

former Indiana
University professor
of physiology and
bio-physics, Coenzyme
Q10 researcher, and
founder of SIBR
Research Institute.

24
1986: Dr. Folkers Awarded the Priestley Medal
In 1986, the American Chemical Society honored Dr. Folkers with a
Priestley Medal, the highest honor that the ACS can confer on a
chemist. By that time, Dr. Folkers was the world’s leading Coenzyme
Q10 researcher. He and his cardiologist collaborators had established
a biochemical rationale for the administration of Coenzyme Q10 to
heart failure patients.

1990: Dr. Folkers Awarded the National Medal of Science

In 1990, then, President George H. W. Bush awarded Dr. Folkers the
National Medal of Science in recognition of Dr. Folkers’ contributions
to the advancement of knowledge in chemistry.

President George H. W. Bush congratulates Dr. Karl

Folkers on being awarded the National Medal of Science for
chemistry.

25
Explanations for
Coenzyme Q10 Deficiency in Heart Muscle Cells
Dr. Folkers and the cardiologists thought that the possible explanations
for the Coenzyme Q10 deficiency in the heart muscle cells leading to
the development and worsening of heart failure might be the follow-
ing reasons:

• Decreased bio-synthesis of Coenzyme Q10 with increasing age

• Increased demand for Coenzyme Q10 caused by various
neurohormonal responses
• Inhibition of Coenzyme Q10 bio-synthesis caused by drug
interactions
• Low intakes of Coenzyme Q10 from food
• “Steal phenomenon” – alterations in blood flow patterns causing
oxidative stress of such magnitude in the failing heart that the
available Coenzyme Q10 is used more and more as an
antioxidant

26
The Coenzyme Q10
Situation by 1990
In 1990, then, Coenzyme Q10 became available as a dietary supple-
ment in the United States and in Europe. Until that time, Coenzyme
Q10 had been available as a prescription medical drug in Japan and
as a research drug in the United States and Europe.

By the time that the 1990s rolled around, Dr. Folkers himself and Dr.
Littarru and Drs. Mortensen, Langsjoen, and Judy were convinced of
the need for the inclusion of adjunctive treatment with Coenzyme
Q10 in the guidelines for the treatment of chronic heart failure patients.
They thought that their clinical trial data represented a break-through.

Adequate tissue concentrations of Coenzyme Q10 are necessary for

the proper bio-energetic functioning of the heart muscle. The medical
community, however, wanted more clinical trial evidence before it was
willing to consider changing the guidelines for the treatment of
chronic heart failure.

Further Considerations: Coenzyme Q10 As an Antioxidant

By the 1990s, Dr. Folkers was well aware of the antioxidant activity
of the Coenzyme Q10 molecule. Already in 1977, the Swedish re-
searcher Dr. Lars Ernster had published work on the importance of
Coenzyme Q10 as an antioxidant and scavenger of harmful free
radicals [18].
Dr. Folkers hypothesized that the antioxidant form of Coenzyme Q10
might enhance the effectiveness of chemotherapy drugs. He also
thought that antioxidants such as Coenzyme Q10 might be useful in
suppressing the activity of certain tumor-associated cytokines that
otherwise help to maintain the growth of tumors.

Moreover, as Coenzyme Q10 was known to be a very safe and afforda-

ble oral supplement, Dr. Folkers saw no reason why it should not be
added, experimentally, to anti-tumor medication regimens. Hodges,

27
Hertz, Lockwood, and Lister present a more complete explanation of
Dr. Folkers’ thinking in their 1999 BioFactors review article [31].

1992: Stocker: Coenzyme Q10 As a Potent Antioxidant

Dr. Roland Stocker and research associates in Australia demonstrated
that oral supplementation with Coenzyme Q10 in the ubiquinone
form increases the concentration of Coenzyme Q10 in its reduced
form, ubiquinol, in the plasma and in all lipoproteins [63].

Supplementation with Coenzyme Q10 thereby increases the resistance

of the low-density lipoproteins to harmful radical oxidation.

Dr. Stocker showed that a single oral dose of 100 milligrams or 200
milligrams of Coenzyme Q10 in the form of ubiquinone increased
the total Coenzyme Q10 content in plasma by 80% or 150%, respec-
tively, within 6 hours [63]. Longer-term supplementation (100 mil-
ligrams Coenzyme Q10 three times a day) resulted in a fourfold increase
of ubiquinol in the plasma and the LDL.

To test the role of Coenzyme Q10 as an antioxidant, Dr. Stocker and

his colleagues induced oxidation of the low-density lipoproteins using
a mild, steady flow of aqueous peroxyl radicals, which resulted imme-
diately in a very slow formation of lipid hydroperoxides. In each case,
the rate of the induced lipid oxidation increased noticeably whenever
80%-90% of the ubiquinol had disappeared. Dr. Stocker noted that
the amount of the dose of aqueous peroxyl radicals needed to reach
the breaking point in the lipid oxidation was proportional to the
amount of ubiquinol already incorporated in the low-density lipopro-
teins (Mohr).
The significance of this early work by Dr. Stocker to cardiovascular
disease is the belief that oxidative modification of low-density lipo-
proteins is a crucial step in the development of atherosclerosis (the
build-up of plaques of fatty materials on the inner walls of the arteries).
In addition to improving the bioenergetics of the heart muscle, sup-
plementation with Coenzyme Q10 can reduce the extent of damaging
oxidative modification of the low-density lipoproteins.

28
1993: The Morisco Multi-center Heart Failure Study
There were also encouraging results from Italy. Italian researchers
published the results of a randomized, double-blind, placebo-controlled
study of 641 patients classified as NYHA class III or IV [64]. The
researchers believed that mitochondrial dysfunction and energy star-
vation in the heart muscle are what cause congestive heart failure. They
tested the hypothesis that Coenzyme Q10 adjunctive treatment could
ameliorate the symptoms of heart failure.

The Italian patients received two milligrams of Coenzyme Q10 per

kilogram of body weight per day for a year. That meant that an aver-
age 160-pound man received about 150 milligrams of Coenzyme Q10
per day. The researchers found that Coenzyme Q10 supplementation,
when added to conventional therapy, resulted in significantly fewer
cases of pulmonary edema and cardiac asthma, significantly fewer
serious complications, and significantly fewer hospitalizations. In many
respects, the results of the Morisco study foretold the results of the
Q-Symbio study.

1993: The Baggio Multi-center Heart Failure Study

The results of the largest clinical trial to date – the Italian multi-center
study enrolling 2664 heart failure patients in NYHA classes II and III
in an open-label study conducted in 173 Italian heart centers – were
also published in 1993 [8]. To the conventional treatment with digi-
talis, diuretics, and vasodilators, the researchers added a daily dose of
Coenzyme Q10 in the range from 50-150 milligrams. Most patients
(78%) received 100 mg/day.

The Italian researchers regarded heart failure as a condition of energy

depletion in the heart muscle, and they tested the clinical efficacy of
Coenzyme Q10 adjunctive treatment in heart failure. They evaluated
clinical parameters upon patients’ entry into the study and then again
after three months. At the end of the study, three out of every four
patients showed improvement in one or more of the following symp-
toms:

• Cyanosis (a sign of insufficient oxygen in the blood)

• Edema (excessive accumulation of fluid in body cavities)
• Pulmonary rales (rattling sounds caused by lung congestion)

29
• Jugular reflux (a sign of distension of the jugular vein)
• Palpitations (irregular heart beat)
• Perspiring
• Vertigo (loss of balance)

54% of the patients showed an improvement in at least three symptoms;

the researchers regarded this to be a sign of improved quality of life.

In addition, five out of every eight patients showed an improvement

in arrhythmia. Less than one percent of the participants in the three-
month-long study experienced any side effects, and not all of those
side effects – nausea, gastrointestinal disturbance, rash – could be
linked to the Coenzyme Q10 treatment.

Mid-1990s:
Dr. Folkers Ready to Move on to Cancer Research
At some point in the mid-1990s, Dr. Folkers decided that he was
sufficiently convinced by the available evidence. Coenzyme Q10
supplementation added on to conventional medical therapy does
significantly improve the cardiac function and the quality of life and
survival of heart failure patients. Dr. Folkers was ready, he said, to
move on to research involving Coenzyme Q10 and cancer patients.

Dr. Folkers’ thinking on the subject of Coenzyme Q10 and the treat-
ment of cancer was that, first of all, adequate supplies of Coenzyme
Q10 are necessary for normal cell respiration and functioning. Abnor-
mally low levels of Coenzyme Q10 in the cells could conceivably
disrupt the normal functioning of the cells, could result in abnormal
patterns of cell division, and could possibly result in the development
of tumors.

Wanting to Build on the Research of Dr. Emilie Bliznakov

In the back of his mind, Dr. Folkers was remembering the animal
studies done by another of his early collaborators, Dr. Emile Bliznak-
ov. Using laboratory mice for whom Coenzyme Q9 is the predominant
Coenzyme Q, Dr. Bliznakov had shown a number of thought-provok-
ing results:

30
 Left to right: Sven Moesgaard, Dr. Karl Folkers and Dr.
Knud Lockwood, the authors of the ANICA (Antioxidant
Nutritional Intervention in CAncer) breast cancer study.

• Administration of small dosages of Coenzyme Q10, ranging

from 150 to 750 micrograms, to laboratory mice improved
phagocyte activity and increased antibody counts in the mice.
Phagocytes are the immune system cells that engulf and absorb
harmful foreign microorganisms before they can hurt the cells
and tissues.

• Administration of Coenzyme Q10 to the mice delayed the onset

of tumor growth, limited the growth of tumors, and reduced
mortality when Dr. Bliznakov induced tumor growth by
injecting a carcinogen.

• Administration of Coenzyme Q10 reduced the mortality rate in

laboratory mice infected with leukemia virus.

Basically, Dr. Bliznakov had demonstrated, in animals, that there is a

positive association between aging and depressed Coenzyme Q10
levels and depressed immune response and that Coenzyme Q10 sup-
plementation boosts immune response.

1990s: Swedish and American Human Cancer Studies

Studies of human cancer patients in both Sweden and the United
States had revealed abnormally low levels of blood Coenzyme Q10

31
concentrations in patients suffering from breast, lung, and pancreas
cancer. Dr. Folkers was impatient to initiate augmentative Coenzyme
Q10 treatment to cancer patients.

1990s: The Folkers and Lockwood Breast Cancer Study

During a five-year period in the 1990s, in close collaboration with
Dr. Folkers and Sven Moesgaard, the Danish doctor Knud Lockwood
treated 32 women with breast cancer with a therapeutic formulation
that included 390 milligrams of Coenzyme Q10 daily – a high level
at that time – and various antioxidant vitamins and minerals and
omega-3 and omega-6 fatty acids [58,59]. Eli Wallin and Sven Moes-
gaard of Pharma Nord provided the Coenzyme Q10 and the other
antioxidants and polyunsaturated fatty acids used in the breast cancer
study.

1990s: Partial and Complete Remissions

and Extended Survival
Dr. Lockwood treated the 32 high-risk breast cancer patients whose
cancer had spread to their lymph nodes with the antioxidant nutri-
tional supplementation added on to the conventional protocol of
breast cancer therapy such as Tamoxifen [59].

Left to right: Dr. Josef Mainz, Dr. Magnus Nylander,

Sven Moesgaard, Dr. Svend Aage Mortensen.

32
The results of the Coenzyme Q10 and antioxidant adjunctive treatment
can be summarized in the following way:

• No patients died during the study period when the expected

number of deaths was four.
• No patients showed any signs of additional distant tumors.
• The patients’ quality of life was improved; the patients did not
lose weight, and they reduced their use of pain medications.
• Six patients showed partial or complete remission.

Need for Randomized Controlled Trial

of Coenzyme Q10 and Cancer
The ANICA breast cancer study was an open-label trial without a
proper control group. Its sample size was small. Dr. Folkers was de-
termined to find funding for a randomized controlled trial of adjunc-
tive Coenzyme Q10 treatment for cancer patients. Such a clinical
trial would have focused not only on remission and survival but also
on quality of life and the lessening of the adverse side effects of an-
ti-cancer drugs. It would have tested the use of even higher daily
dosages of Coenzyme Q10.

Coenzyme Q10 and Prostate Cancer

The last cancer management study that Dr. Folkers participated in
was a study of the effect of the treatment of prostate cancer with
Coenzyme Q10. He did a series of three open-label prostate cancer
studies in collaboration with Dr. William Judy. The use of Coenzyme
Q10 was positively associated with stopping the growth and the spread
of prostate cancer. After about 120 days of Coenzyme Q10 supple-
mentation with a dosage of 600 mg/day, plasma PSAs and prostate
mass decreased significantly. The younger patients appeared to be more
responsive than the older patients. In 1998, Dr. Judy presented the
results of the prostate cancer studies at the American College for
Advancement in Medicine (ACAM) meeting in Fort Lauderdale,
Florida.

Dr. Folkers was so excited by the results of the ANICA study and the
prostate cancer studies that he went to Denmark, Sweden, and Finland
to find the funding to continue these studies. With much assistance

33
from Sven Moesgaard and the Swedish researcher Magnus Nylander,
Dr. Folkers spent the final year of his life in 1997 trying to set up
cancer research protocols in Denmark, Sweden, and the United States.

Cardio-toxicity of
Cancer Drugs and the Role of Coenzyme Q10
As early as the 1980s, Japanese researchers had seen toxic effects of
the cancer drug Adriamycin (doxorubicin) on the heart muscle. They
had noticed that patients taking an adjuvant Coenzyme Q10 therapy
suffered less damage to the heart muscle.

In 1984, Dr. Judy and Dr. Folkers and a team of researchers did a
study in which they investigated the effects of Coenzyme Q10 ad-
junctive treatment in lung cancer patients who were being treated
with Adriamycin [40]. The treatment group received the Adriamycin
plus Coenzyme Q10. The control group received Adriamycin and a
placebo.

The Coenzyme Q10 treatment group was able to take twice as much
Adriamycin with little or no evidence of cardio-toxicity. The control
group had a significant loss in cardiac ejection fraction and significant
left ventricular dysfunction. Participants in the control group, the
group not being supplemented with Coenzyme Q10, had to stop
taking Adriamycin because of worsening heart failure.

1990: Pharma Nord Enters the History of Coenzyme Q10

Dr. Mortensen was not the only person in Denmark whom Dr. Folk-
ers was urging to do more and better research. He was also pushing
Sven Moesgaard of Pharma Nord to do research into the absorption,
the bio-availability, and the health effects of Pharma Nord’s Bio-Qui-
none Q10 product.

In the city of Vejle, Denmark, Eli Wallin and Sven Moesgaard had
established the firm that they called Pharma Nord. Their first product,
launched in 1984, was the Bio-Selenium and Zinc preparation, con-
sisting of 100 micrograms of organic selenium and 15 milligrams of
zinc.

34
 Left to right: Eli Wallin, Karl Folkers and Sven Moesgaard.
At Pharma Nord, Eli Wallin serves as Administrative and
Financial Director, and Sven Moesgaard serves as Research
and Technical Director.

Selenium was an important nutritional supplement in northern Europe,

which has generally selenium-poor soils and selenium-poor foods.
Selenium is a co-factor in several important antioxidant enzymes, it
regulates thyroid function, and it may help to reduce the risk of var-
ious cancers. Zinc is also a component in many enzyme activities and
helps to strengthen the immune system.

Moreover, there seems to be an important synergistic relationship

between Coenzyme Q10 and selenium in the body. Selenium defi-
ciencies can inhibit the cells from getting optimal concentrations of
Coenzyme Q10, and, adequate concentrations of Coenzyme Q10
must be available for the cells to benefit from optimal selenium func-
tion [5].

1990s: Pharma Nord’s Bio-Quinone Q10

The crystalline Coenzyme Q10 in raw material form will not com-
pletely dissociate to single molecules in a lipid at body temperature.
The crystalline Coenzyme Q10 raw material will completely dissoci-
ate to single Coenzyme Q10 molecules in a lipid only at a temperature

35
of 11 degrees centigrade (approximately 50 degrees Fahrenheit) above
body temperature. Because humans cannot absorb Coenzyme Q10
crystals and cannot live with a body temperature of 48 degrees centi-
grade, producers of Coenzyme Q10 capsules must necessarily use a
heat treatment on the Coenzyme Q10 raw material to dissolve the
crystalline raw material.

Realizing the central importance of Coenzyme Q10 in the process of

cellular bioenergetics and in the antioxidant protection of the cells,
the directors of Pharma Nord began to experiment to find the best
way to take the yeast-fermented Coenzyme Q10 raw material and
dissolve it in oils to make it more easily absorbed. Coenzyme Q10 is,
after all, a highly fat-soluble substance, its crystals need a higher tem-
perature than body temperature to dissolve, and the absorption cells
in the small intestine cannot absorb crystals. The formulation of the
Coenzyme Q10 preparation is not easy to get right.

Eli Wallin and Sven Moesgaard wanted to sell only those products
that they themselves wanted to take, and they had no interest in
taking a nutritional supplement with a poor absorption rate. So, they
knew that they had their work cut out for them. Even before they
could think about doing studies of the health effects of Bio-Quinone,
they needed to do absorption and bio-availability studies.

Sven Moesgaard and Eli Wallin of Pharma Nord – making

products that they themselves wanted to take based on solid
research results.

36
1990s: Coenzyme Q10 Absorption
and Bioavailability Studies
The concept of absorption in the context of the oral supplement
Coenzyme Q10 refers to the amount of Coenzyme Q10 that passes
from the mouth to the stomach to the small intestine and through the
absorption cells of the small intestine into the lymph and then into
the blood. Typically, after absorption, the ingested Coenzyme Q10
passes slowly through the lymph and reaches a peak concentration in
the blood between 5 and 8 hours later. It is only from a single-dose
study that the percentage of the ingested dose can be used to calculate
the percentage of the dose that has been absorbed.

Bioavailability is generally defined as the degree to which or the rate

at which a substance is absorbed or becomes available at the site in the
body where it exerts its physiological activity. The concept of bioavail-
ability refers to the accumulation (storage) of the Coenzyme Q10 in
the blood over time. Bioavailability is typically measured at 7, 14, 21,
and 30 days over an interval of extended supplementation with a set
daily dosage.

Absorption of Coenzyme Q10 is in no way close to 100 % of the

ingested dose. The crystalline (dry powder) Coenzyme Q10 forms
generally have an absorption of less than one percent. Dry powder
Coenzyme Q10 suspended in oils generally has an absorption between
1.5 and 3.0 percent. The crystal-free Coenzyme Q10 products gener-
ally have an absorption at Cmax of 5 to 8 percent.

By contrast, injected substances (not Coenzyme Q10) will have 100

percent bioavailability. However, the nutritional supplement Coenzyme
Q10 is taken orally. As such, it will not have the 100 percent bioavail-
ability. Oral Coenzyme Q10, because of the difficulties involved in its
absorption, falls far short of 100 percent bioavailability.

1990s: Bioavailability of Pharma Nord's Bio-Quinone Q10

In 1994, Dr. Folkers and Sven Moesgaard published the results of a
one-year bioavailability study of Bio-Quinone Q10 [25]. The research-
ers gave 21 healthy participants 30 milligrams of Coenzyme Q10 three
times a day for nine months. There then followed a withdrawal period
of three months. The researchers took blood samples from the partic-

37
ipants before the start of the supplementation, after three months and
nine months of supplementation, and, again, three months after the
withdrawal of supplementation.

The supplementation with Bio-Quinone Q10 increased the mean

blood Coenzyme Q10 concentration from about 1 mg/L before
supplementation to about 2 mg/L after three and nine months of
supplementation. The mean blood Coenzyme Q10 levels dropped
back down to the pretreatment levels after withdrawal. The increase
in the blood Coenzyme Q10 concentration was statistically significant.

In a second study published in 1994, Sven Moesgaard and Danish

researcher Malene Weis and Dr. Mortensen and a team of researchers
investigated the bioavailability of four different Coenzyme Q10
preparations in a randomized, four-way, cross-over study [90]. Their
results showed that the soybean oil formulation used at the time in
Pharma Nord’s Bio-Quinone Q10 preparation yielded a bioavailabil-
ity superior to that achieved by three different formulations.

Then, in 1997, Danish researchers investigated the absorption of di-

etary Coenzyme Q10 ingested either as a single 30-milligram dose of

Sven Moesgaard and Dr. Karl Folkers (right) – Dr. Folkers

met frequently with Sven Moesgaard and constantly urged
him to do more research on the absorption and effects of
Coenzyme Q10.

38
Bio-Quinone Q10 or as a meal of cooked pork heart containing 30
milligrams of Coenzyme Q10 [89]. Both methods significantly raised
the serum Coenzyme Q10 levels in the study participants. There was
no significant difference between the increases in absorption of the
two methods.

1990s: Pharma Nord Researching Coenzyme Q10

from the Beginning
The point of listing and summarizing the above early absorption and
bioavailability studies is to show that Pharma Nord is a company that
has been around from the beginning and has been willing to do the
research. In this, the influence of Dr. Folkers and Dr. Mortensen on
Eli Wallin and Sven Moesgaard can be seen very clearly.

1990s: Pharma Nord Research on the Effects

of Coenzyme Q10
Pushed by Dr. Folkers, Pharma Nord did more research on the effects
of Coenzyme Q10 supplementation than any other producer. In the
1990s alone, under the guidance of Sven Moesgaard, the company
achieved research results that are relevant even today:

• Demonstrated that patients diagnosed with type-1 diabetes can

take Coenzyme Q10 without risk of hypoglycemic episodes
(Henriksen) [29].
• Demonstrated that Coenzyme Q10 supplementation is well
tolerated by senior type-2 diabetes patients and that their
glycemic control is not affected by the supplementation
(Eriksson) [19].
• Demonstrated that supplementation with 100 milligrams of
Coenzyme Q10 twice daily improves left ventricular
performance in patients diagnosed with chronic heart failure
(Munkholm) [73].
• Demonstrated that supplementation with 100 milligrams of
Coenzyme Q10 daily significantly reduces the extent of gingival
bleeding in patients diagnosed with periodontitis (Nylander)
[74].
• Demonstrated that Coenzyme Q10 supplementation can reduce
gingival inflammation (Denny) [15].

39
• Demonstrated that supplementation with 90 milligrams of
Coenzyme Q10 daily significantly improves measured indexes of
physical performance in top-level cross-country skiers (Ylikoski)
[91].
• Demonstrated that supplementation with Coenzyme Q10 may
be beneficial in improving sperm motility (Lewin) [56].
• Demonstrated evidence that 90 milligrams of Coenzyme Q10
supplementation daily has an antioxidative effect in the blood
where there are many lipids vulnerable to peroxidation (Weber)
[88].
• Demonstrated that supplementation with Coenzyme Q10 may
protect the heart from ischemia/reperfusion injury (Yokoyama)
[92].
• Demonstrated that supplementation with Coenzyme Q10
improves the quality of life of breast cancer patients (no more
loss of weight, reduced use of pain medications, no additional
metastases) (Lockwood) [58,59].
• Demonstrated that daily supplementation with 100 milligrams
of Coenzyme Q10 and 100 micrograms of selenium benefits
acute myocardial infarction patients (Kuklinski) [46].

Dr. Bodo Kuklinski, Director

of the Diagnostic and
Therapeutic Center for
Environmental Medicine,
Rostock, Germany – one of the
first researchers to use
Coenzyme Q10 and selenium
supplements to treat heart
disease patients.

1994: Energy and Defense by Dr. Gian Paolo Littarru

In 1994, Dr. Littarru, a professor of biochemistry at the University of
Ancona Medical College in Ancona, Italy, published a book entitled
Energy and Defense. The book’s subtitle was Facts and Perspectives on
Coenzyme Q10 in Biology and Medicine. The word Energy in the
title refers to the bioenergetics role of Coenzyme Q10 in the cells, and

40
 For many years, Dr. Littarru has
been a professor teaching
biochemistry to medical
students. Until recently, he has
served as the chairman of the
International Coenzyme Q10
Association. His primary
research interest has always
been biomedical research on
Coenzyme Q10.

the word Defense in the title refers to the antioxidant role of Coenzyme
Q10 in quenching harmful free radicals and protecting the body from
oxidative damage.

In his introduction, Dr. Littarru remembered and paid tribute to the

pioneers in Coenzyme Q10 research: Dr. R. A. Morton, Dr. Fred
Crane, Dr. Karl Folkers, Dr. Peter Mitchell, Dr. Yuichi Yamamura,
and Dr. Per Langsjoen. Dr. Svend Aage Mortensen wrote the text on
the inside of the book jacket.

1997: Statins Lower Serum Coenzyme Q10 Concentrations

Dr. Mortensen and a team of researchers enrolled 45 hypercholester-
olemia patients in a randomized, double-blind study [69]. The patients
were treated with increasing dosages of either lovastatin (20-80 mg/
day) or pravastatin (10-40 mg/day) over a period of 18 weeks.

The researchers measured serum levels of Coenzyme Q10 and choles-

terol at baseline and at the end of the study.

They found significant cholesterol-dose-related declines in the serum

concentrations of Coenzyme Q10 in both the pravastatin group and
the lovastatin group. Dr. Mortensen concluded that the cholesterol
inhibiting statin medications are safe and effective in the short run;
however, he also noted that there is a need to monitor patients to see
if the lowering of Coenzyme Q10 becomes increasingly important
during long-term use of statin medications.

41
1997: Soja og Mortensen: The First Meta-analysis of
Coenzyme Q10 and Heart Failure Research
In 1997, one of Dr. Mortensen’s graduate students at Copenhagen
University published a meta-analysis of the treatment of congestive
heart failure with Coenzyme Q10 in eight clinical trials conducted in
the period from 1984 to 1994 [87]. The results of the meta-analysis
showed that adjunctive treatment of heart failure patients with Co-
enzyme Q10 significantly improved the following parameters:

• stroke volume
• cardiac output
• ejection fraction
• cardiac index
• end diastolic volume index
• systolic time intervals
• total work capacity

The beneficial effects of Coenzyme Q10 as an adjunctive treatment

of heart failure were beginning to be well-documented.

1997: The Death of Dr. Folkers

On December 9, 1997, having recently flown back to the United
States from Sweden, Dr. Folkers died of a heart attack caused by a
blood clot. In Sweden, he had been trying to set up clinical studies of
the efficacy of Coenzyme Q10 in the treatment of cancer patients.

For many years, Dr. Folkers had served as the editor of the proceedings
of the International Symposium on Coenzyme Q published by Else-
vier, Inc. in Amsterdam. The symposium proceedings were published
under the title Biomedical and Clinical Aspects of Coenzyme Q, upon
Dr. Folkers’ death, Dr. Gian Paolo Littarru took over as editor of the
symposium proceedings.

1997: The Founding of the International

Coenzyme Q10 Association
Also in 1997, Dr. Gian Paolo Littarru, Dr. Svend Aage Mortensen, and
Sven Moesgaard were the driving force behind the founding of the
nonprofit organization, The International Coenzyme Q10 Association.

42
Article 3 of the Statutes of the Association states that the purpose of
the Association is to promote basic and applied research on the bio-
medical aspects of Coenzyme Q10 in order to diffuse knowledge on
basic biochemistry and genetics, and on the preventive and/or thera-
peutic effects of Coenzyme Q10.

During the period October 11 – 15, 2015, the International Coenzyme

Q10 Association held its 8th international conference. The conference,
organized by Professor Dr. Giorgio Lenaz, Dr. Maria Luisa Genova,
Professor Dr. Anna Ida Falasca and Professor Dr. Placido Navas, was
held at the University of Bologna in Italy. Dr. Placido Navas, Profes-
sor of Cell Biology at the Universidad Pablo de Olavide-CSIC in
Sevilla, Spain, is the present president of the Coenzyme Q10 Associ-
ation (www.icqa.org).

Three years later, June 21 - 24, 2018, the Coenzyme Q10 Association
held its 9th international conference at Columbia University in New
York. Researchers from around the world – 62 in all – presented their
research projects related to Coenzyme Q10. It was agreed
that the next international conference,
most likely to be held in Am-
sterdam in 2021, and a small-
er in-between conference to be
held at the Karolinska Institute
in Stockholm in 2020, will have
Coenzyme Q10's impact on di-
abetes as the theme.

For many years, Pharma Nord’s Myoqinon preparation has

been the preparation selected by International Coenzyme
Q10 Association members for use in research studies. The
dietary supplement edition of Myoqinon is Bio-Quinone
Active CoQ10 GOLD. The quality of those two preparations
is identical.

43
1998: Coenzyme Q10 in Patients
with Acute Myocardial Infarction
As the 20th century drew to a close, Singh and Chopra reported on
the results of a randomized, double-blind, placebo-controlled trial of
Coenzyme Q10 in patients with acute myocardial infarction [85]. For
28 days, the researchers gave 73 patients 120 mg/day and gave 71
patients a placebo preparation.

The Coenzyme Q10 treatment yielded significant improvements in

angina pectoris, total arrhythmias, and left ventricular function.
Moreover, the Coenzyme Q10 treatment was associated with signifi-
cantly lower cardiac events such as cardiac death and nonfatal second
heart attacks. There was a greater reduction in lipid peroxides, indi-
cators of oxidative stress, in the treatment group than in the placebo
group. The study results indicate that supplementation with Coenzyme
Q10 can provide protective benefits in patients with acute myocardi-
al infarctions if the Coenzyme Q10 is administered within 3 days of
the onset of symptoms.

44
Looking Ahead
to the 21st Century:
The Guidelines
As he looked forward to the 21st century, Dr. Mortensen’s goal was
to convince the American College of Cardiology and the American
Heart Association of the need to amend the guidelines for the treatment
of heart failure to include adjuvant treatment with Coenzyme Q10
[1]. He thought that energy starvation of the heart muscle cells is a
dominant feature of the heart failure condition.

The link between a deficiency of Coenzyme Q10 in blood and tissue

and the severity of heart failure had been established. Coenzyme Q10
was a logical adjunct treatment for heart failure patients. It had only
very seldom side effects, which, if they occurred, were mild. Several
randomized controlled trials enrolling altogether more than 1000
heart failure patients had shown that Coenzyme Q10 adjuvant treat-
ment positively affects clinical parameters, lowers NYHA class, improves
exercise capacity, and reduces the need for hospitalization [68].

The Beginning of the 21st Century:

Coenzyme Q10 Research
The 21st century in Coenzyme Q10 research started slowly. The real-
ly big randomized controlled trials, the KiSel-10 study [3] and the
Q-Symbio study [70], were still in the planning stage. But there were
some interesting results, nonetheless, in the first years of the 2000s.

2002: Engelsen: Coenzyme Q10 Safe for Warfarin Patients

One question that remained to be answered was the question of
whether Coenzyme Q10 is safe to use in patients taking the anti-co-
agulant Coumadin (warfarin). Engelsen and a team of Danish re-
searchers tested the effect of a daily dosage of 100 milligrams of Co-
enzyme Q10 for four weeks on 24 patients who were on long-term

45
warfarin medication [17]. The patients’ international normalized ratio
(INR) remained stable throughout the treatment period. The mean
dosage of the warfarin treatment did not change during the treatment
period; 36.5 mg/week (29.1-45.8). The researchers concluded that
Coenzyme Q10 does not influence the clinical effect of warfarin.

A couple of years later, Dr. Zhou and colleagues at the National Uni-
versity of Singapore (2005) reported research results in rats that indi-
cated that supplementation with Coenzyme Q10 did not have an
effect on the absorption and distribution of warfarin but did produce
a significant increase in the total serum clearance of warfarin [93].

As a matter of caution, patients taking an anti-coagulant should

consult with the prescribing physician before taking Coenzyme Q10
supplements. The Coenzyme Q10 could make hitting anticoagulation
targets more difficult, and that is difficult enough as it is.

2003: Mortensen: Preparing for

the Multinational Q-Symbio Clinical Trial
Dr. Mortensen began to prepare the bio-chemical rationale and the
design and the end-points for a multinational clinical trial: the Q-SYM-
BIO clinical trial, a study with focus on the SYMptoms, BIomarker
status, and long-term Outcomes (notably hospitalizations and mor-
tality) of supplementation with Coenzyme Q10 [68,70].

2003: Dr. Mortensen's Review of the Existing

Double-blind Studies
The first thing Dr. Mortensen did was review the existing 13 well-de-
signed studies, the randomized, double-blind, placebo-controlled
studies [68].

• Taken together, the studies comprised the results from over

1000 patients with heart failure.
• All of the studies had a cross-over design or a parallel groups
design.
• All of the studies but one used between 100 and 200 milligrams
of Coenzyme Q10 per day.
• None of the studies reported any significant side effects.

46
• Ten of the 13 studies showed positive effects of adjunctive
treatment of heart failure patients with Coenzyme Q10:
improvements in symptoms, exercise capacity, and quality of
life.
• Three of the 13 studies had neutral outcomes.
• The improvement in exercise capacity associated with Coenzyme
Q10 treatment had the same order of magnitude as the
improvement in exercise capacity associated with the use of ACE
inhibitors in heart failure patients.

2003: Alehagen: The First Senior Participants

Enrolled in the KiSel-10 Study
Dr. Urban Alehagen and researchers at the University Hospital, Linkop-
ing, Sweden, began enrolling senior Swedish citizens in the KiSel-10
clinical trial [3]. KiSel-10 was a study of the effect of a combined
intervention with selenium (SelenoPrecise® 200 micrograms/day) and
Coenzyme Q10 (Bio-Quinone Q10 100 milligrams twice a day) on
cardiovascular mortality and cardiac function in the senior population
in the Kinda municipality in southeastern Sweden.

Ki in the study name KiSel-10

stands for the Kinda
municipality in Sweden,
Sel stands for the organic
SelenoPrecise® selenium,
and 10 stands for
the Myoqinon
Q10 in vegetable
oil.

Myoqinon is the pharmaceutical edition of Bio-Quinone

GOLD. It is registered in some EU countries and is used in
scientific studies. SelenoPrecise® is also registered in the EU,
both in a pharmaceutical edition and as a dietary
supplement.

47
The researchers enrolled seniors aged 70 – 88 years who could be
expected to fulfill a study period of five years. The researchers enrolled
443 participants but excluded any senior individuals who met any of
the following exclusion criteria:
• Recent heart attack (within four weeks).
• Any cardiovascular operative procedure planned within the next
four weeks.
• Inability to consent to participate in the study or to understand
the consequences of participation.
• Any evidence of a serious disease that would reduce the chance
of survival or make it impossible to complete the full five-year
study period.
• Long and difficult transport to the primary health center.
• Drug or alcohol abuse.

The following considerations motivated the researchers:

• Many Northern Europeans have low serum selenium levels.
• Selenium is used by the cells to build approximately 25 different
enzyme systems in the body.
• The cells need the presence of Coenzyme Q10 to produce
selenium-containing enzymes.
• A combined intervention of the two supplements would increase
serum concentrations in seniors sufficiently to have a significant
effect on mortality and cardiac function.

The intervention period for each enrolled participant was to be 4 years.

Blood samples and cardiac natriuretic peptide levels were analyzed at
the beginning, at every six months, and at the end of the study. Echo-
cardiograms were analyzed at the start and at the end of the study. The
study ended in February, 2010.

The KiSel-10 study had a gold standard design: it was a randomized,

double-blind, placebo-controlled clinical trial. The results of the KiSel-10
study were reported in several medical journal articles in the period 2013
– 2015. Long-term supplementation of seniors with SelenoPrecise® and
Bio-Quinone Q10 resulted in significantly lower mortality rates, signif-
icantly lower cardiac natriuretic peptide levels, significantly better cardi-
ac scores on echocardiograms, and significantly lower numbers of hos-
pitalizations in the active treatment group as compared with the placebo
group. More about the results of the KiSel-10 study later in this history.

48
2003: Rosenfeldt:
Systematic Review of Coenzyme Q10 Studies
At the same time that Dr. Mortensen was writing the biochemical
rationale for the Q-Symbio study, Dr. Franklin L. Rosenfeldt of the
Cardiac Surgical Research Unit, Alfred Hospital and Baker Institute,
Melbourne, Victoria, Australia, was doing a systematic review of the
effect of Coenzyme Q10 on cardiovascular disease, hypertension, and
exercise performance [78].

• Coenzyme Q10 in Physical Exercise. Dr. Rosenfeldt identified

11 studies; six showed some modest improvement in exercise
capacity with Coenzyme Q10 supplementation while five
showed no effect.
• Coenzyme Q10 in Hypertension. Dr. Rosenfeldt identified eight
published trials of Coenzyme Q10 in hypertension. In the eight
studies, the mean reduction in systolic blood pressure was 16
mm Hg. The mean reduction in diastolic blood pressure was 10
mm Hg. Coenzyme Q10 had a role as an adjunctive treatment to
conventional treatments in hypertension.
• Coenzyme Q10 in Heart Failure. Dr. Rosenfeldt did a meta-
analysis of nine randomized trials. In those nine trials, there were
non-significant trends towards increased ejection fraction and
reduced mortality.

Dr. Franklin L. Rosenfeldt,

Baker Heart Research
Institute, Alfred Hospital,
Monash University,
Australia, has been
accumulating laboratory
and clinical evidence of the
efficacy of Coenzyme Q10
treatment
of various cardiovascular
disorders for many years.
Dr. Rosenfeldt was one of
primary researchers in the
Q-Symbio study.

49
2003: Rosenfeldt:
Coenzyme Q10 and Class II and III Heart Failure
Dr. Rosenfeldt and his colleagues reported on their own three-month
randomized, double-blind, placebo-controlled pilot study of Coenzyme
Q10 therapy in 35 patients with NYHA class II and class III heart
failure. [43]. The intervention with Coenzyme Q10 yielded a threefold
increase in the blood Coenzyme Q10 levels in the treated group; there
was no increase in the placebo group. The patients treated with Co-
enzyme Q10 showed a statistically significant improvement of one-half
NYHA functional class, compared with patients in the placebo group.
They also showed significant improvement in their Specific Activities
Scale class and in their C-min walk-test distances. The researchers
noted a positive correlation between increases in serum Coenzyme
Q10 concentrations and increases in exercise time [43].

2003: Zita, Mortensen and Moesgaard:

Raising Serum Coenzyme Q10 Levels
Dr. Mortensen knew that he would need to raise patients’ serum
Coenzyme Q10 concentrations to the level of about 2.5 mg/L in
order to achieve a clinical effect [94]. That is the level needed in serum
to have a sufficiently high concentration for the Coenzyme Q10 to
leave the blood and enter the tissue.

Together with Dr. Zita of the Medical Faculty Hospital in Prague,

Czech Republic, and Sven Moesgaard of Pharma Nord, Dr. Mortensen
arranged to test the effect of supplementation with 30 and 100 mil-
ligrams of Coenzyme Q10 (Pharma Nord’s Bio Quinone Q10) in
healthy male volunteers.

At baseline, the median serum CoQ10 concentration in the volunteers

was 1.26 mg/L of serum, and concentration levels ranged from 0.82
(10th percentile) to 1.83 (90th percentile).

After two months of supplementation in a randomized, double-blind,

placebo-controlled study, the patients’ median increases in serum
CoQ10 concentration were 0.55 mg/L for the 30-milligram dosage
and 1.36 mg/L for the 100-milligram dosage.

50
The increases in the two Coenzyme Q10 treatment groups were sig-
nificantly different from the slight decrease of 0.23 mg/L in the pla-
cebo group. Moreover, the supplementation-caused changes in serum
Coenzyme Q10 concentrations were found to be independent of
differences in baseline serum levels, age, or body weight.

In summary, supplementation with 30 milligrams per day brought

the median serum Coenzyme Q10 level up to 1.81 mg/L, and 100
milligrams per day brought the median serum CoQ10 level up to 2.62
mg/L. Clearly, a daily dosage of 100 milligrams or more per day was
indicated for future clinical trials.

2004: Balercia and Littarru: Increasing Sperm Motility

A team of Italian Coenzyme Q10 researchers enrolled 22 patients
diagnosed with reduced sperm motility (mean age 31 years) in a
6-month-long open, uncontrolled pilot study [9].

They gave the patients Bio-Quinone Q10 200 mg/day (100 milligrams
twice daily for 6 months) and recorded significantly increased Coen-
zyme Q10 levels in the patients’ plasma and in sperm cells. They
documented a significant increase in sperm cell motility as well.

They proposed that supplementation with Q10 be considered as a

treatment option in cases of asthenozoospermia (reduced sperm mo-
tility).

2004 Berman:
Coenzyme Q10 for Heart Transplant Patients
Dr. Berman and colleagues at the Rabin Medical Center in Petah
Tikva, Israel, enrolled 32 end-stage heart failure patients who were
waiting for heart transplants in a randomized, double-blind, place-
bo-controlled study [10]. The patients received 60 milligrams of
Coenzyme Q10 or placebo per day in addition to their regular med-
ications. 27 patients completed the three-month program, and the
patients in the Coenzyme Q10 treatment group showed significant
improvements in the six-minute walk test as well as significant de-
creases in difficulty of breathing, in NYHA class, in the need to urinate
at night, and in fatigue. Supplementation with Coenzyme Q10 im-

51
proved functional status, symptoms, and quality of life in end-stage
heart failure patients.

2005: Langsjoen: Use of Coenzyme Q10 and Dis­con­

ti­nuation of Statin Medications in Cardiology Clinic
Patients
The American cardiologist Dr. Peter H. Langsjoen of Tyler, Texas,
evaluated 50 consecutive new cardiology clinic patients who had already
been on statin drug therapy for an average of 28 months for possible
adverse statin effects (muscle pain, fatigue, difficulty breathing, mem-
ory loss, and peripheral neuropathy)[51].

Dr. Langsjoen then discontinued the 50 patients’ statin therapy because

of the adverse side effects of the statin medications, and he started
them on supplemental Coenzyme Q10 at an average of 240 mg/day.
He followed the patients for an average of 22 months with 84% of
the patients followed for more than 12 months.

In the follow-up period, Dr. Langsjoen saw a drop in the prevalence

of the symptoms that the patients reported on their initial visits. Fatigue
decreased from 84% to 16%, muscle pain decreased from 64% to 6%,
difficulty breathing decreased from 58% to 12%, memory loss decreased
from 8% to 4%, and peripheral neuropathy decreased from 10% to
2%.

Heart function in the patients for whom the statin drug therapy had
been discontinued either improved or remained stable in the majori-
ty of patients. There were no adverse consequences from the discon-
tinuation of the statin drug therapy.

2005: Singh, Moesgaard, Littarru:

Raising Serum CoQ10 Levels
Still looking to improve the uptake of Coenzyme Q10, Dr. Singh of
the Halberg Hospital and Research Institute in Moradabad, India,
conducted a randomized, double-blind, placebo-controlled clinical
trial for 20 days [86]. The researchers enrolled 60 healthy men, aged
18-55 years, and tested various dosages and dose strategies using
Pharma Nord’s Myoqinon 100 mg (same raw material and same

52
formulation as in Bio-Quinone Q10) capsule and, for comparison
purposes, crystalline 100 mg Q10 powder capsules or placebo capsules.

The Singh team of researchers found the following

results:
• The patient compliance (checked by capsule counting)
was above 90%.
• The side effects of taking Q10 supplements were negligible.
• The Q10 dissolved in oil (Myoqinon) was more effective than the
same amount of crystal powder Q10 in raising serum Q10 levels.
• A divided dose strategy of Myoqinon 100 milligrams twice a day
(with breakfast and dinner) improved absorption by nearly 45%
compared to a single dose of 200 milligrams of Myoqinon once
a day (with dinner).
• Supplementation with 200 milligrams of Myoqinon Q10 for 20
days resulted in significantly reduced levels of malondialdehyde,
a biological marker for oxidative stress.

2005: Safety of Coenzyme Q10

Singh, Moesgaard, Littarru, et al summarized the studies of relatively
high daily dosages of Coenzyme Q10 [86].

• Langsjoen (1994): doses ranging from 75 to 600 mg/day (mean

242 mg/day) with 424 cardiovascular disease patients with no .
apparent side effects except for one case of nausea [52].
• The Huntington’s Disease Study group (2001): doses ranging
from 600 mg/day to 1200 mg/day for up to 30 months with no
adverse effects [32].
• Shults et al (2002): doses ranging from 400 mg/day to 800 mg/
day with no adverse effects reported and doses up to 1,200 mg/
day for as many as 16 months with no significant side effects
[82].
• Shults and Beal (2004): daily dosages of 1,200, 1,800, 2,400,
and 3,000 mg/day together with a stable dosage of vitamin E
(alpha-tocopherol) 1200 IU/day in 17 patients with Parkinson’s
disease in an open-label study with the only side effects
seemingly unrelated to the Coenzyme Q10 administration. The
patients’ plasma Coenzyme Q10 levels reached a plateau at the
2400 mg/day dosage level [84].

53
A year later, Ikematsu (2006) reported doses up to 900 mg/day for
four weeks safe and well tolerated [33].

2006: Observed Daily Safe Upper Limit for Oral CoQ10

The Huntington’s Disease Study Group proposed that dosages of 2,400
mg/day may strike the best balance between tolerability and blood
level achieved [29]. Somewhat later in 2006, Hathcock and Shao
proposed that 1,200 mg/day should be the observed safe upper limit
for Coenzyme Q10 [32].

A safety assessment done by Kaneka researchers Hidaka and Hosoe

(2008) established 12 milligrams of oral Coenzyme Q10 per kilogram
of body weight per day as the acceptable daily intake. The researchers
settled on 1,200 mg per day as a safe upper limit [30]. Thus, a man
weighing 165 pounds (75 kg) could, conceivably, take 900 mg (cal-
culated as 75 kg times 12 mg) of Coenzyme Q10 daily.

Hidaka and Hosoe examined evidence from pharmacokinetic studies

that show that orally ingested CoQ10 does not influence the biosyn-
thesis of Coenzyme Q10 and does not accumulate in plasma or tissues
after the cessation of supplementation [30]. Hidaka and Hosoe con-
cluded that Coenzyme Q10 is highly safe for use as a dietary supple-
ment based on data from preclinical and clinical studies.

2006: Sander:
Second Meta-analysis of CoQ10 and Heart Failure
Dr. Soja and Dr. Mortensen published the first meta-analysis of stud-
ies of Coenzyme Q10 supplementation and heart failure in 1997 [81].
Dr. Stephen Sander of the University of Connecticut’s School of
Pharmacy in Storrs, Connecticut, and his colleagues did a second
meta-analysis of 11 clinical trials to evaluate the impact of CoQ10
therapy on ejection fraction and cardiac output [79].

The pooled data showed a statistically significant 3.7% net improvement

in ejection fraction with an even better improvement noted in patients
who were not receiving angiotensin-converting enzyme inhibitors.
The data also showed a significantly increased cardiac output. The
researchers concluded that supplementation with Coenzyme Q10
enhances systolic function in chronic heart failure.

54
2006-2007:
Coenzyme Q10 in its Reduced Form, Ubiquinol
In 2006, the Kaneka company introduced Coenzyme Q10 in its re-
duced form, ubiquinol, as a commercial product. This move was
puzzling for several reasons:

• The lack of any documented effect for ubiquinol – all of the

studies showing beneficial health effects had been done with the
oxidized form of Coenzyme Q10, the ubiquinone form.
• The known instability of the ubiquinol molecules (a common
characteristic of antioxidants).
• The absence of any physiological explanation for any supposed
superiority of the ubiquinol product.
• The greater cost of producing the ubiquinol raw material and
finished products.
• The knowledge that the ubiquinol in supplements is converted
to ubiquinone in the stomach and the small intestine prior to
absorption.
• The knowledge that the ubiquinone that enters the absorption
cells in the small intestine is converted to ubiquinol as it passes
into the lymph – it is not necessary to ingest ubiquinol in order
to get ubiquinol in the blood.

2007: Dr. Judy on Coenzyme Q10 Facts and Fabrications

In 2007, Dr. William Judy of the SIBR Research Institute, himself
the holder of a Ph.D. in human physiology and bio-physics, addressed
many of the marketing claims for the newly introduced ubiquinol
product [41]. Dr. Judy was concerned that some of the marketing
claims for ubiquinol supplements were factual but not functionally
important and that other marketing claims for ubiquinol supplements
were more fabrication than fact.

Dr. Judy made the following points about Coenzyme Q10 supplements
[41]:

• The body cannot absorb Coenzyme Q10 crystals; only single

Coenzyme Q10 molecules can be absorbed.

55
• The important thing is to produce Coenzyme Q10 supplements
that have the raw material dissolved in vegetable oils in such a
way that the Coenzyme Q10 does not re-form into crystals at
body temperature or room temperature.
• The melting point of Coenzyme Q10 is approximately 10
degrees centigrade higher than body temperature, and a body
temperature of 47 degrees centigrade is incompatible with life.
• Coenzyme Q10 cannot be made into water-soluble molecules
and continue to be Coenzyme Q10. The two hydrogen ions on
the polar head of the ubiquinol molecule may make it slightly
more water-soluble than the ubiquinone molecule, but the
ubiquinol molecule continues to be far more lipid-soluble than
water-soluble because of the larger non-polar tail of the
molecule.
• Ubiquinol (reduced Coenzyme Q10) is highly unstable and is
converted to ubiquinone in the stomach before it ever reaches
the absorption cells in the small intestine. In fact, the ubiquinol
in some products is converted to ubiquinone inside the softgel
prior to ingestion.
• Coenzyme Q10, whether ingested in the form of ubiquinone or
ubiquinol, leaves the stomach in the form of ubiquinone. In the
absorption cells in the small intestine, and in the distal lymph,
almost all of the ubiquinone being absorbed is converted to
ubiquinol.
• The absorbed Coenzyme Q10 is transported from the absorption
cells to the lymph and from the lymph to the venous blood.
• Coenzyme Q10 concentrations peak in the lymph 2 - 3 hours
after ingestion and in the blood 5 – 8 hours after ingestion.
• 90 – 95% of the Coenzyme Q10 in the circulating blood is in
the form of ubiquinol, regardless of the form in which it was
ingested.
• The energy producing form of Coenzyme Q10 is the ubiquinone
form. Because the body does not need to produce energy in the
lymph and in the blood, it is not surprising that the Coenzyme
Q10 is in the form of ubiquinol, which is the form of Coenzyme
Q10 that provides antioxidant protection against the
peroxidation of the lipids being transported in the blood.
• Coenzyme Q10 accumulates in the blood and becomes
bioavailable to the cells. It is stored in the cell membranes and in
the membranes of cellular organelles.

56
• There is no solid evidence that the absorption or resultant bio-
availability of the best-formulated Coenzyme Q10 in the
ubiquinol form is greater than the absorption and bioavailability
of the best-formulated ubiquinone forms. In fact, the best-
formulated ubiquinone supplements may yield a somewhat
better absorption and bioavailability.
• Many of the claims for the superiority of the ubiquinol form are
the result of comparisons of differing formulations of the two
products. The question is whether the absorption of CoQ10
should be measured from CoQ10 concentrations in the blood or
from CoQ10 concentrations in the distal lymph, which is
adjacent to the absorption cells.
• In the inner membranes of the mitochondria, the ubiquinol is
rapidly converted to ubiquinone. In the mitochondria, there is a
great demand for the ubiquinone form of Coenzyme Q10 to
serve as a carrier of electrons and protons in the process of
producing ATP molecules. The conversion of Coenzyme Q10
from ubiquinol to ubiquinone and back again creates the
Q-cycle described by Dr. Peter Mitchell in the work for which
he received the Nobel Prize in chemistry in 1978 (see above).
• The body cannot store ATP, so it must be continuously
produced. Ubiquinone, the oxidized form of Coenzyme Q10, is
a major co-factor in the cellular process of energy synthesis
(ATP). Ubiquinol cannot replace ubiquinone in this process
because the ubiquinol is not an electron acceptor.
• What ubiquinol can do is regenerate ubiquinone and Vitamin C
and Vitamin E in the body. Ubiquinol is also a powerful
antioxidant that protects the body against toxic oxidative
reactions.

2007: Dr. Judy's Conclusion

Dr. Judy stated, with respect to the new ubiquinol products, that
consumers of Coenzyme Q10 supplements should take certain factors
into consideration. Among these factors, he listed the following prob-
lems facing ubiquinol products: a lack of a documented superior ab-
sorption, the known instability in the stomach, the absence of clinical
trials documenting health effects, and the higher cost of the ubiquinol
products.

57
Relative CoQ10 Content after
Ubiquinol
Relative CoQ10Ingestion
Content after Ubiquinol Ingestion
% CoQ10
100

80

60

40

20

0
Stomach Small Intestine Distal Proximal Blood Plasma
Lymph Duct Lymph Duct

Ubiquinone Ubiquinol

CoQ10 as CoQ10
Location
ubiquinol as ubiquinone
Stomach 100% 0%
Small intestine   2% 98%
Distal lymph duct   4% 96%
Proximal lymph duct 96% 4%
Blood plasma 96% 4%

The above-pictured graph shows Dr. Judy‘s and Dr. Stogsdill’s meas-
urements of the percentages of ubiquinol and ubiquinone during the
transfer of ingested ubiquinol in large animals from the stomach to
the blood. Following the ingestion of ubiquinol, the CoQ10 begins
to be converted to ubiquinone in the stomach because of the high
hydrogen ion concentration. In the small intestine, the CoQ10 is
almost entirely in the form of ubiquinone. In the distal lymph duct,
the CoQ10 is, initially, in the ubiquinone form. The absorbed ubiqui-
none then begins to be converted to ubiquinol. By the time that the
CoQ10 has passed from the lymph to the blood, the total ubiquinol
percentage is 96%, and the ubiquinone percentage is 4%. These data

58
show the redox conversion of ubiquinol to ubiquinone in the stomach
and small intestine and the conversion from ubiquinone to ubiquinol
in the lymph ducts on the way to the systemic circulation. Dr. Judy
presented these data to the membership of the International Coenzyme
Q10 Association at the association’s 8th international conference held
in Bologna, Italy, in October of 2015.

2008: Molyneux: Low Plasma Coenzyme Q10

Is an Independent Predictor
Dr. Sarah L. Molyneux of the Canterbury Health Laboratories in
Christchurch, New Zealand, tested the hypothesis that low plasma
Coenzyme Q10 concentrations predict increased incidence of all-cause
mortality in chronic heart failure patients. She and her colleagues
examined the plasma samples and case histories of 236 heart failure
patients admitted to hospital [63].

They found that low plasma Coenzyme Q10 levels predicted mortal-
ity independent of other factors such as age, gender, previous heart
attack, cardiac natriuretic peptide levels, and renal disease. According
to Dr. Molyneux’ calculations, the optimal value for the prediction of
mortality was ≤ 0.73 micromol/L, which is equivalent to ≤ 0.63 mg/L.

Dr. Svend Aage Mortensen has pointed out that, in the Molyneux
study, the association between the low CoQ10 concentrations and
mortality in heart failure patients is even stronger than the association
between N-terminal pro–B-type natriuretic peptide levels and mor-
tality in heart failure patients [69]. NT-proBNP is a marker for atrial
and ventricular distension caused by increased pressure inside the
heart.

Given that such a relationship exists between plasma Coenzyme Q10

levels and chronic heart failure outcomes, it is important to monitor
heart failure patient plasma levels and to use oral supplementation to
increase plasma concentrations to levels that enable the transfer of the
Coenzyme Q10 from the blood to the tissues.

Dr. William Judy of SIBR Research Institute says that a plasma con-
centration of 2.5 micrograms per milliliter is typically needed for the
Coenzyme Q10 to go into the tissues.

59
Dr. Stephen Sinatra has extrapolated from the research results of
Dr. Peter Langsjoen that a blood Coenzyme Q10 level of 2.5 - 2.9
micrograms per milliliter is needed for optimal improvement of class
III and IV heart failure patients [84].

2008: Adarsh:
Coenzyme Q10 and Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy is a disease in which a portion of the
heart muscle becomes thicker, and the thickening of the muscle makes
the pumping of blood more difficult. Dr. Kumar Adarsh of the Gov-
ernment Medical College in Amritsar, India, recruited 46 patients
with hypertrophic cardiomyopathy and added 200 milligrams of
Coenzyme Q10 to their conventional medications [2]. He then matched
the 46 patients, by age and sex and disease condition, with 41 similar
patients who received only the conventional medications.

All of the patients were classified as NYHA class II or higher. Dr.

Adarsh then observed the patients for an average of 14 months (range:
from 9 months to 27 months).

In the treatment group that received the Coenzyme Q10 supplemen-

tation, Dr. Adarsh observed significant improvement in quality of life
on the six-minute walk test, in NYHA functional class, in diastolic
function, and in mitral regurgitation. Diastolic pressure is the blood
pressure measured when the heart is resting (as opposed to systolic
pressure when the heart is contracting). Mitral regurgitation refers to
a heart valve condition in which the blood leaks backwards through
the mitral valve when the heart contracts.

Dr. Adarsh and his colleagues concluded that supplementation with

Coenzyme Q10 is a safe, effective, and beneficial adjuvant therapy for
diastolic heart failure in patients of hypertrophic cardiomyopathy.

2009: Kocharian:
Coenzyme Q10 for Children with Heart Disease
Dr. Kocharian and colleagues found that adding Coenzyme Q10
supplementation to conventional therapy was beneficial for children
under the age of 18 who had been diagnosed with heart failure caused

60
by idiopathic dilated cardiomyopathy (decreased ability of the heart
to pump blood because of an enlarged and weakened left ventricle)
[45].
Dr. Kocharian and the team of researchers did a randomized, dou-
ble-blind, placebo-controlled trial in which 17 children received
Coenzyme Q10 and 21 children received placebo. The children who
received the Coenzyme Q10 started out with a dosage of a dose of 2
milligrams per kilogram of body weight per day in 2 or 3 divided
daily doses for six months. The dosage was then gradually increased
up to a maximum dosage of 10 milligrams per kilogram per day as
long as the children tolerated the increases. The researchers reported
that the Coenzyme Q10 was well tolerated, and there were no adverse
effects.

After six months of supplementation, the children who had received

the Coenzyme Q10 supplements showed significant improvement in
their index scores for cardiac failure and in their diastolic function.

61
The Second Decade
of the 21st Century
In the second decade of the 21st century, the focus of Coenzyme Q10
clinical research was on the efficacy of Coenzyme Q10 adjuvant
treatment of chronic heart failure patients, on the efficacy of combined
Coenzyme Q10 and selenium supplementation of healthy senior
citizens, on the need for Coenzyme Q10 supplementation together
with the taking of statin medications, and on the efficacy of Coenzyme
Q10 supplementation in exercise and fitness training.

2010: McMurray: Coenzyme Q10 in the CORONA Study

In the Controlled Rosuvastatin Multinational Study in Heart Failure
(CORONA) study, Dr. McMurray and colleagues at the Glasgow
Cardiovascular Research Centre, University of Glasgow, in the Unit-
ed Kingdom measured the serum Coenzyme Q10 concentrations in
1,191 patients with ischemic systolic heart failure [60]. They reported
the following results:

• Patients who had lower serum CoQ10 levels were older patients
who had more advanced heart failure.
• There was a significantly higher mortality rate in the lowest
serum CoQ10 tertile compared to the highest serum CoQ10
tertile.
• The use of the statin medication Rosuvastatin did reduce serum
CoQ10 levels.
• Patients in the lowest serum CoQ10 tertile had significantly
lower left ventricular ejection fractions.
• Patients in the lowest serum CoQ10 tertile had higher
natriuretic peptide levels. (Higher B-type natriuretic peptide
levels are an indicator of volume expansion and pressure
overload in the heart.)

Dr. Michael Felker of the Duke Heart Center in Durham, North

Carolina, concluded from the results of the CORONA study that
serum CoQ10 levels might be good indicators of the severity of heart

62
failure even if serum CoQ10 levels are not necessarily useful for prog-
nostic purposes in and of themselves [80].

Dr. Svend Aage Mortensen pointed out that 10 milligrams of Rosu-

vastatin treatment per day in the CORONA study had reduced the
plasma Coenzyme Q10 concentration significantly by 39%. That
reduction had lowered the median Coenzyme Q10 level below the
baseline level of Coenzyme Q10 in the CORONA patients who were
classified in lowest Coenzyme Q10 tertile -- 0.48 microg/mL – a
level that seemed to indicate tissue depletion of Coenzyme Q10.

2010: Rosenfeldt:
Coenzyme Q10 Before and After Heart Surgery
Dr. Rosenfeldt and research colleagues in the Cardiac Surgical Research
Unit at the Alfred Hospital in Melbourne, Australia, enrolled 117
heart surgery patients – scheduled for coronary artery bypass graft
and/or valve surgery – in a randomized, double-blind, placebo-con-
trolled trial [55]. For two months prior to surgery and for one month
following surgery, the patients received either a combination of Co-
enzyme Q10, magnesium, lipoic acid, fatty acids, and selenium or
corresponding placebos.
On average, the heart surgery patients got the combination therapy
for 76 ± 7.5 days. The combination therapy containing Coenzyme
Q10 and selenium significantly reduced plasma troponin levels 24
hours after the heart operations. Troponins are proteins released into
the blood whenever the heart muscle has been damaged. The greater
the damage, the greater the level of troponins in the blood.

The combination therapy containing Coenzyme Q10 and selenium

also significantly shortened the mean length of postoperative hospital
stay by 1.2 days, which resulted in reduced hospital costs for each
heart operation.

The supplements used in the combination metabolic therapy were

relatively inexpensive and were safe. There were no clinically significant
side effects in the active treatment group. [55]

63
2012: Deichmann:
Coenzyme Q10 and Statins and Exercise
In addition to causing reductions in the biosynthesis of Coenzyme
Q10, statin medications have the potential to cause muscle toxicity.
Dr. Richard Deichmann of the Ochsner Medical Center in New
Orleans investigated the possible effect of statin medications on exer-
cise performance in athletes aged 50 years or older [13].

He and his colleagues randomly assigned 20 older athletes who were

taking statin medications to receive 200 milligrams of Coenzyme Q10
or corresponding placebo daily in a six-week double-blind, place-
bo-controlled cross-over trial. Supplementation with Coenzyme Q10
did not significantly improve the athletes’ anaerobic threshold but did
significantly improve change time to anaerobic threshold and did
significantly improve leg strength as measured by quadriceps muscle
extension repetitions.

2012-2013: Lee: Coenzyme Q10 and Statins

Statin medications reduce the biosynthesis of Coenzyme Q10. Coen-
zyme Q10 plays an important role in cellular bio-energetics and as an
antioxidant. Dr. Lee and a team of researchers from the Chung Shan
Medical University in Taichung, Taiwan, investigated whether daily
supplementation with 300 milligrams of Coenzyme Q10 (taken as
150 milligrams twice a day) could enhance antioxidant enzyme activ-
ity and reduce markers of inflammation in coronary artery disease
patients who were taking statin medications [54].

Supplementation significantly increased the plasma Coenzyme Q10

levels and the levels of the antioxidant enzymes superoxide dismutase,
catalase, and glutathione peroxidase.

Supplementation also significantly reduced the levels of the inflam-

matory markers C-reactive protein, tumor necrosis factor-α, and in-
terleukin-6.

Dr. Lee and his colleagues reported on an earlier study in which patients
with coronary artery disease – patients having at least 50% narrowing
of one major coronary artery or receiving coronary angioplasty – re-
ceived 150 milligrams of Coenzyme Q10 daily for 12 weeks [53].

64
The results of the study showed that Coenzyme Q10 supplementation
significantly reduced the levels of malondialdehyde (a marker for
oxidative stress) and significantly increased the levels of the antioxidant
enzymes catalase and superoxide dismutase.

2013: Fedacko and Pella and Littarru: Coenzyme Q10

and Selenium and Patients on Statin Medications
Drs. Jan Fedacko and Daniel Pella of the Pavol Jozef Safarik Univer-
sity in Kosice, Slovakia, and Dr. Gian Paolo Littarru of the Polytech-
nic University of The Marche in Ancona, Italy, carried out a randomized,
double-blind, placebo-controlled clinical trial with 60 statin medica-
tion patients who were suffering from muscle pain, muscle weakness,
tiredness, or muscle cramps [20].

The researchers gave the statin patients either a combination of 200

milligrams/day Coenzyme Q10 capsules (Bio-Quinone Q10 100
milligrams twice daily) and 200 micrograms/day of organic selenium
yeast tablets (SelenoPrecise®), or corresponding placebo capsules and
tablets. The patients continued to take their regular prescribed med-
ications.

The results showed that supplementation of statin-treated patients

with Coenzyme Q10 and selenium diminished the symptoms of
muscle pain and fatigue, which are associated with the taking of statin
medications.

2013: Bogsrud: Statins, Coenzyme Q10 and Selenium,

and Statin-induced Muscle Pain and Fatigue
In a 12-week randomized, double-blind, placebo-controlled study,
Dr. Bogsrud and a team of Norwegian researchers from Alesund
Hospital, Alesund, Norway, found that the administration of the
statin medication atorvastatin reduced significantly the patients’ blood
Coenzyme Q10 levels in both groups [11]. Supplementation with 400
mg/day of Myoqinon then significantly increased CoQ10 levels in the
active treatment group.

65
Atorvastatin did not decrease blood selenium levels in either group.
Supplementation with SelenoPrecise® increased blood selenium levels
in the active treatment group.

After 12 weeks of supplementation that was first begun after the pa-
tients had experienced the pain and fatigue associated with the taking
of atorvastatin, the results from symptom questionnaire scores and
muscle function tests did not show significant differences between the
treatment group and the placebo group. However, four patients in the
placebo group did stop the statin treatment because of unbearable
pain from the statin medication. No patients in the treatment group
stopped the statin treatment. This difference was not statistically
significant but might be clinically significant.

Moreover, atorvastatin’s effect in decreasing CoQ10 concentrations

may have long-term implications for heart muscle function. Because
the taking of statin medications so clearly decreases the patients’ bio-
synthesis of Coenzyme Q10, patients on statin medications need
Coenzyme Q10 supplements to protect the heart muscle function.

2013: Alehagen and the KiSel-10 study in Sweden:

Coenzyme Q10 and Selenium for Seniors
Starting in 2003 and ending in 2010, Dr. Urban Alehagen and col-
leagues at the University Hospital in Linkoping, Sweden, enrolled 443
healthy senior Swedish citizens aged 70 to 88 in a randomized, dou-
ble-blind, placebo-controlled study of the effects of supplementation
with Coenzyme Q10 (Bio-Quinone Q10 100 mg twice daily) and
with organic selenium yeast (SelenoPrecise® 200 micrograms once
daily). They called the study the KiSel-10 study [3].

In 2013, the researchers reported the statistically significant outcomes

of the supplementation [3]:

• Reduction in cardiovascular deaths

• Reduction in levels of NT-proBNP
(a biological marker for heart disease)
• Better cardiac function scores on echocardiograms
• Fewer hospitalizations

66
 Professor Urban
Alehagen, Department
of Cardiology,
Linkoping University
Hospital, lead researcher
on the KiSel-10 study
and one of the primary
researchers on the
Q-Symbio study.

In subsequent journal articles, Dr. Alehagen and his colleagues report-

ed that the combination treatment with selenium and Coenzyme Q10
is positively associated with improvement in bio-markers for inflam-
mation [6] and for oxidative stress [7]. They also reported that the
combination treatment had resulted in fewer days in hospital and in
better quality of life for the participants in the study [35]. Moreover,
the positive health effects of the treatment had persisted ten years
after the start of the four-year treatment period [4].

In a 2015 follow-up article, Drs. Alehagen and Aaseth summarized

what they had learned from the KiSel-10 study results and from their
review of the relevant research literature [5]:

• There is an important interrelationship between Coenzyme Q10

and selenium. Selenium deficiencies can inhibit the cells from
getting optimal concentrations of Coenzyme Q10, and adequate
concentrations of Q10 must be available for the cells to benefit
from optimal selenium function.
• The available literature shows unequivocally that statin
treatment leads to decreases in serum Q10 levels and that statin
treatment leads to the inhibition of the synthesis of some
important selenoproteins.
• The risk of developing heart disease is positively associated with
low serum Q10 levels and low serum selenium levels.
• The clinical results from the KiSel-10 intervention study using
both selenium and Coenzyme Q10 in a senior population were
statistically significant: a reduction in cardiovascular mortality,

67
 an improved cardiac function shown in echocardiograms, and
slower increases in heart muscle wall tension shown in lower
concentrations of the biomarker NT-proBNP.
• Coenzyme Q10 (in its reduced form) is an important
antioxidant, and selenium is an essential component of some
important antioxidant enzymes. Antioxidant protection is
especially important in the prevention of heart disease because
the mitochondrial DNA in the heart muscle cells is especially
susceptible to damage caused by oxidative stress (oxidative stress
= an imbalance between the body’s production of free radicals
and the body’s ability to neutralize the free radicals).
• There is an interrelationship between selenium and Coenzyme
Q10 that can be exploited for therapeutic advantage if both
substances are used together. The combination of selenium and
Coenzyme Q10 supplementation is appropriate as a preventive
measure in middle-aged and seniors at risk for developing heart
disease and as an adjunctive treatment of patients diagnosed
with heart failure.

Follow-up of the participants in the KiSel-10 study for a

period of 10 years after the initiation of the four-year active
treatment showed that the effect on cardiovascular mortality
from four years of supplementation with Bio-Quinone Q10
and SelenoPrecise® persisted well after the end of the
supplementation.

68
2013: Fotino: A Third Meta-analysis of Coenzyme Q10
Adjuvant Treatment of Heart Failure Patients
Dr. Soja did the first meta-analysis of Coenzyme Q10 and heart
failure studies in 1997 [87]. Dr. Sander did the second meta-analysis
in 2006 [79]. In 2013, Dr. Dominica Fotino and researchers from
Tulane University did a third systematic review of randomized con-
trolled trials of CoQ10 supplementation of heart failure patients [26].
Dr. Fotino focused on studies that reported the ejection fraction (EF)
or NYHA functional class of patients as a primary outcome. The re-
searchers pooled data from 13 clinical trials enrolling 935 heart failure
patients.

The pooled data from the 13 studies showed an improvement in left

ventricular ejection fraction of 3.67% in the CoQ10 treatment group
as contrasted with the placebo group [26].

2013: Madmani: Cochrane Review

Dr. Mohammed Eid Madmani of Case Western Reserve University
School of Medicine, Cleveland, Ohio, reviewed the safety and effica-
cy of Coenzyme Q10 adjuvant treatment in heart failure as compared
to placebo in seven randomized controlled trials with 914 participants
[61]. Five of the seven studies reviewed by Dr. Madmani were among
the 13 studies reviewed by Dr. Fotino [26].

The pooled data from the seven studies demonstrated that supplemen-
tation with Coenzyme Q10 increased blood levels significantly with-
out causing any adverse alterations of the patients’ hemodynamic
status and without raising any concerns about other safety issues.
However, the results from the seven studies did not show significant
improvement in left ventricular ejection fraction or exercise.

Both the Fotino meta-analysis and the Madmani review included the
results of the Khatta study published in 2000. The Khatta study results
remain a puzzle [44]. The supplementation with 200 milligrams of
Coenzyme Q10 daily for six months did increase the mean serum
CoQ10 levels from 0.95 +/- 0.62 mg/L to 2.2 +/- 1.2 mg/L. Howev-
er, the CoQ10 supplementation did not significantly change the pa-
tients’ ejection fraction, peak oxygen consumption, and exercise du-
ration.

69
One probable explanation for the unexpected results is non-compliance
by many of the patients in the active treatment group.
In Figure 2 of the Khatta study report, it can be seen that, of the 22
patients who were assigned to the Coenzyme Q10 treatment group,
one patient showed a decline in Coenzyme Q10 concentration, nine
did not increase their CoQ10 levels beyond 1.0 mg/L, five more did
not increase their CoQ10 levels above 1.5 mg/L, and two patients
pushed their CoQ10 levels close to 2.0 mg/L.

Only five patients achieved CoQ10 levels above 2 mg/L, and, of those
five, only three achieved CoQ10 levels above 2.5 mg/L, the level at
which the Coenzyme Q10 is most likely to pass from the blood to the
heart tissue.

As was indicated above, the American cardiologist Dr. Stephen T.

Sinatra has estimated from the results of available studies that the
therapeutic blood levels of Coenzyme Q10 need to be at least 2.5
mg/L to produce a significant response [84]. At the end of the Khat-
ta study, 19 of the 22 patients (86%) in the CoQ10 treatment group
had blood levels lower than 2.5 mg/L, the minimal therapeutically
effective level. The most likely explanation is that there was consider-
able non-compliance in the Khatta study [44].

2013: Fotino and Madmani Reviews Published

Prior to Q-Symbio Study
Both of the 2013 reviews, by Dr. Fotino [26] and by Dr. Madmani
[61], were completed before the publication of the results of the
Q-Symbio study of the effect of Coenzyme Q10 on morbidity and
mortality in chronic heart failure [70]. Both of the 2013 reviews of
the literature have to be viewed as having come too soon. Inclusion
of the Q-Symbio study –with its 420 heart failure patients the biggest
randomized controlled trial of Coenzyme Q10 and heart failure since
the 1993 Morisco study – would have made for different outcomes.

2014: Mortensen: publication of the results of the Q-Symbio

trial in the Journal of the American College of Cardiology
Going into the Q-Symbio study of the morbidity and mortality of
supplementation with Coenzyme Q10 in chronic heart disease [70],

70
Dr. Mortensen already had biochemical data and explanations to draw
on.

I. Coenzyme Q10 plays important roles in the body:

• It is necessary for the production of ATP in the cells.
• It is an antioxidant that counteracts harmful free radicals.
• It promotes cell membrane stability.
• It plays a role regulating certain genes.

II. Low blood and tissue CoenzymeQ10 concentrations have been

shown to be associated with the development and progression of
chronic heart failure.

III. Several factors explain how the heart failure patients came to have
low blood and tissue concentrations of Coenzyme Q10.
• Biosynthesis of Coenzyme Q10 decreases in step with increasing
age, beginning in the early 20s.
• Patients may be getting less Coenzyme Q10 in their food.
• There may be an increased demand for Coenzyme Q10 caused
by the compensatory neuro-hormonal responses to lower cardiac
output.
• Coenzyme Q10 may be used to excess as an antioxidant in heart
tissues subjected to oxidative stress.
• Statin therapy may be inhibiting the body’s synthesis of
Coenzyme Q10.

IV. Conventional pharmaceutical methods of reducing cardiac dys-

function are all intended to block cellular processes. Adjuvant therapy
with Coenzyme Q10, on the other hand, enhances the cellular pro-
cesses of energy production and antioxidation.

V. Randomized controlled trials of Coenzyme Q10 adjuvant therapy

in chronic heart failure, enrolling a total of 988 patients, had shown
patient improvement in such clinical parameters such as New York
Heart Association (NYHA) functional classification, exercise capacity,
and quality of life. Meta-analyses of randomized controlled trials of
Coenzyme Q10 supplementation of heart failure patients showed a
positive effect of the adjuvant treatment on left ventricular ejection
fraction.

71
VI. Plasma samples from 236 heart failure patients showed an inde-
pendent association between low plasma Coenzyme Q10 levels and
increased risk of mortality in chronic heart failure. The strength of the
association between plasma Coenzyme Q10 levels and heart failure
mortality was greater than the strength of the association between
plasma NT-proBNP levels and heart failure mortality (concentrations
of NT-proBNP in the blood are a biological marker for the severity
of heart failure).

The published results of the Q-Symbio clinical trial (2014)

replicate the earlier results in the Morisco trial (1993) and
the Munkholm trial (1999).

2014: Mortensen: Statistically Significant

Results from the Q-Symbio Study
Q-Symbio was a randomized double-blind multicenter clinical trial
of Coenzyme Q10 as an adjunctive treatment of chronic heart failure
with a focus on changes in SYMptoms, BIomarker status (BNP) and
long-term Outcomes such as hospitalizations and quality of life [70].

The researchers enrolled 420 heart failure patients in heart centers in

Europe, Asia, and Australia and randomly assigned the patients to
receive 300 milligrams of Myoqinon (same raw material and formu-
lation as Bio-Quinone Q10) as 100 milligrams three times daily for
two years or corresponding placebo capsules.

72
When the seal had been broken on the coded patient lists, the adjunc-
tive treatment with Coenzyme Q10 was shown to have achieved the
following statistically (and clinically) significant outcomes:

• A reduction in the number of major adverse cardiovascular events

• A reduction in the number of cardiovascular deaths
• A reduction in the all-cause mortality among the heart failure
patients
• Fewer admissions to hospital

2014: Golomb: Coenzyme Q10 Supplementation for

Veterans Diagnosed with Gulf War Illness
Dr. Beatrice Golomb of the University of California, San Diego in La
Jolla, California, carried out a 3.5 month-long randomized, dou-
ble-blind, placebo-controlled clinical trial of 46 Gulf War veterans
who met both the Kansas and the Centers for Disease Control crite-
ria for Gulf War illness [27]. She gave the veterans in the active
treatment group 100 milligrams of Bio-Quinone Q10 per day.

Supplementation with 100 milligrams of Coenzyme Q10 per day was

associated with improvement in physical function and symptoms in
veterans with Gulf War illness. Among males (85% of enrollees), there
were statistically significant benefits from 100 mg/day of Bio-Quinone
Q10 on General Self-Rated Health and on physical function scores.

In 19 of 20 symptoms (sleep problems being the exception), Coenzyme

Q10 supplementation was associated with signs of improvement, with
several of the symptoms showing statistically significant improvement.

2014: Brauner and Brismar:

Coenzyme Q10 and Patients with Diabetes
Drs. Hanna Brauner and Kerstin Brismar and colleagues at the Kar-
olinska Institute in Stockholm, Sweden, tested whether Bio-Quinone
Q10 100 milligrams twice daily for 12 weeks is a beneficial supplement
to patients with diabetes [12]. The researchers’ data suggest that Co-
enzyme Q10 supplementation can boost the immune system in Type
1 diabetics, can reduce diabetes-associated inflammatory processes,
and may help prevent late complications.

73
The researchers observed signs of reduced inflammation, increased
cytokine production capacity, improved NK cell activity, and reduced
hBD2 expression in Type 1 diabetics receiving daily Q10 supplements.
(hBD2 expression is indicative of pro-inflammatory activity).

2014: Del Pozo-Cruz and Navas:

Coenzyme Q10 and Exercise Capacity in Seniors
Drs. Del Pozo-Cruz, Lopez-Lluch, and Navas and researchers in Se-
villa, Spain, reported on the results of a study of how physical activi-
ty in seniors affects endogenous Coenzyme Q10 levels in blood
plasma [14]. Their findings show that seniors with greater exercise
capacity also have lower levels of cholesterol and lipid peroxidation
and higher levels of Coenzyme Q10 in plasma.

In seniors who are more active, the Coenzyme Q10/cholesterol and

Coenzyme Q10/LDL ratios are higher. Obese seniors tend to have
lower plasma Coenzyme Q10 levels and higher lipid peroxidation
levels, as measured by malondialdehyde levels in plasma. The data
show that physical activity can increase the levels of Coenzyme Q10
and lower the levels of lipid peroxidation in plasma in seniors.

2014: Pourmoghaddas:
A Combination of Atorvastatin and Coenzyme Q10
Dr. Masoud Pourmoghaddas of the Isfahan Cardiovascular Research
Institute, Isfahan University of Medical Sciences, in Isfahan, Iran, and
colleagues conducted a randomized, double-blind, placebo-controlled
trial in which they enrolled 62 eligible patients [77]. The patients in
the intervention group received 10 milligrams atorvastatin daily plus
100 milligrams of a Coenzyme Q10 supplement twice daily. The
placebo group patients received 10 milligrams atorvastatin daily and
a placebo. The trial lasted 4 months.
There were significant improvements in ejection fraction and NYHA
functional class in the intervention group as compared with the ator-
vastatin only group. Dr. Pourmoghaddas and his colleagues conclud-
ed that the combination of atorvastatin and Coenzyme Q10 has a
better effect on ejection fraction and NYHA classification than ator-
vastatin alone.

74
2015: Okuyama and Langsjoen: Continuing Concern
About the Effect of Statin Medications on Coenzyme Q10
Levels and Atherosclerosis
Dr. Harumi Okuyama of the Kinjo Gakuin University College of
Pharmacy in Nagoya, Japan, and Dr. Peter H. Langsjoen collaborated
on an article spelling out the possible pharmacological mechanisms
by which the adverse effects of cholesterol-lowering statin medications
might be causing more and worse cases of chronic heart failure and
atherosclerosis [75].

Statin medications inhibit the body’s endogenous production of Co-

enzyme Q10, which is essential for the cellular production of ATP.
Statin medications inhibit the body’s production of vitamin K2, which
is a cofactor for matrix Gla-protein activation, which protects the
arteries from calcification.

Statin medications inhibit the biosynthesis of selenium containing

proteins, e.g. the glutathione peroxidase antioxidant enzyme that helps
suppress peroxidative stress.

Drs. Okuyama and Langsjoen are concerned that the impairment of

Coenzyme Q10 and selenoprotein biosynthesis by statin medications
may be a factor in the development of congestive heart failure and
atherosclerosis. Consequently, they propose that current statin treatment
guidelines be critically reevaluated.

2015: DiNicolantonio: Review of Coenzyme Q10

and Heart Failure Literature
Dr. James J. DiNicolantonio, a cardiovascular research scientist at
Saint Luke's Mid-America Heart Institute in Kansas City, Missouri,
did a systematic literature review [16]. He found that numerous
randomized controlled trials of supplemental CoQ10 in heart failure
showed improvements in functional parameters such as ejection frac-
tion, stroke volume, and cardiac output without side effects. At least
three meta-analyses confirmed those findings. Then the multi-center
randomized controlled Q-Symbio trial showed significantly reduced
major adverse cardiovascular events after 106 weeks of supplementa-
tion with 300 milligrams of Myoqinon (the drug version and same
formulation as the OTC product, Bio-Quinone Q10) taken three
times daily in 100-milligram capsules.

75
Dr. DiNicolantonio’s summation of the Coenzyme Q10 and heart
failure literature: given the excellent tolerance and the affordability
and the documented health benefits of the natural physiological
compound, Coenzyme Q10, adjuvant treatment of heart failure patients
with supplemental Coenzyme Q10 has become an attractive option
for cardiologists in the management of heart failure.

2015: Mortensen:
Call for New Heart Failure Treatment Guidelines
In his letter to the journal JACC Heart Failure, Dr. Mortensen began
by stating that heart failure is a disabling disease that robs its victims
of energy and quality of life [71]. Heart failure is a disease with a poor
prognosis in spite of the advances in medical drug and medical device
treatment options.

Dr. Mortensen then stressed to his readers that supplementation with

Coenzyme Q10 in addition to the conventional heart failure therapy
has been shown to improve symptoms, improve survival, and reduce
hospitalization rates when compared with placebo supplementation
in randomized controlled clinical trials.

He pointed out, furthermore, that there have been no reports of seri-

ous side effects in any of the more than 200 randomized controlled
trials of Coenzyme Q10 supplementation that have been indexed in
the Medline database.

To calls for additional clinical trials of the efficacy of Coenzyme Q10

as an adjuvant treatment in heart failure, Dr. Mortensen responded
by saying that it is very difficult to raise funding for a large-scale trial
of a non-patentable substance like Coenzyme Q10.

Moreover, and more importantly, he raised the question of whether

it would be ethical, given the survival data from the Q-Symbio trial,
for cardiologists to wait for the results of another trial before recom-
mending Coenzyme Q10 supplementation to their heart failure pa-
tients. The further question is whether it is defensible to give half of
the patients in a future clinical trial placebo capsules when it is known
that Coenzyme Q10 supplementation benefits heart failure patients.

76
Already in 2005, the heart failure treatment guidelines promulgated
by the American College of Cardiology and the American Heart As-
sociation acknowledged that supplementation with Coenzyme Q10
might have a positive effect, but the 2013 guidelines stopped short of
recommending Coenzyme Q10 supplementation until more data were
available [1].

Now, the positive data from the Q-Symbio trial and from the meta-
analyses done by Dr. Soja [87], Dr. Sander [79], and Dr. Fotino [26]
provide the necessary documentation for recommending Coenzyme
Q10 as an adjunctive treatment in heart failure.

One of the best aspects of Coenzyme Q10 supplementation is that it

works with the cells to restore a deficiency state – low blood and tissue
Coenzyme Q10 levels are associated with heart failure – and it improves
the bio-energetic processes and antioxidant processes in the heart
muscle tissue.

2016: Felker: Duke University Review of the Status of

Adjuvant Coenzyme Q10 Treatment in Heart Failure
Dr. Michael Felker and his colleagues at the Division of Cardiology,
Duke University School of Medicine, Duke Heart Center in Durham,
North Carolina, published a state-of-the-art review of the Coenzyme
Q10 and heart failure literature [80]. They summarized the literature
about the mechanisms, the clinical data, and the safety profile of
Coenzyme Q10 supplementation in patients with heart failure. They
concluded that supplementation with Coenzyme Q10 may represent
a safe therapeutic option for patients with heart failure.

Numerous small trials with CoQ10 supplementation in heart failure

populations extending back over 30 years have shown adjuvant ther-
apy with Coenzyme Q10 to have beneficial heart health effects such
as improvement in NYHA functional class, in the 6-minute walk, in
stroke index, in cardiac index score, and in ejection fraction. One large
randomized controlled trial, Morisco (1993), showed decreased hos-
pital admissions, decreased episodes of pulmonary edema, and decreased
episodes of cardiac asthma. The second large randomized controlled
trial, Dr. Mortensen’s Q-Symbio trial (2014), demonstrated a reduc-
tion in major adverse cardiovascular events.

77
The current literature suggests that supplementation with Coenzyme
Q10 is relatively safe with few, if any, drug interactions and side effects.
Moreover, it is already widely available as an over-the-counter supple-
ment.

2018: López-Lluch and Navas: Comparative Bioavailability

Study of Various Coenzyme Q10 Formulations
Professors Guillermo López-Lluch and Placido Navas and their col-
leagues at the Pablo de Olavide University in Sevilla, Spain, published
results from a double-blind, cross-over study. The study data demon-
strated that two major factors influence the absorption and bio-avail-
ability of orally ingested Coenzyme Q10 [López-Lluch 2018]:

1. The composition and formulation of the oils in which the

Coenzyme Q10 raw material is dissolved
2. The individual physiological capacity to absorb oral
Coenzyme Q10

The comparative study done in Sevilla highlights the complexity in-

volved in oral Coenzyme Q10 absorption and bio-availability. Indi-
viduals vary in their response to specific formulations and forms of
oral Coenzyme Q10 by age, body mass index, exercise level, gender,
lifestyle, and other unidentified physiological variables.

In the López-Lluch study, the Bio-Quinone Q10 formulation, the

same formulation used in the Q-Symbio study and in the KiSel-10
study, was associated with a significantly better absorption and bio-avail-
ability than was obtained with five other ubiquinone formulations
and one ubiquinol formulation.

The Legacy of Dr. Karl Folkers: Extensive Clinical Research

into the Safety and the Effects of Coenzyme Q10
Dr. Folkers set the standard for clinical research into the safety and
the effects of Coenzyme Q10 supplementation. He assisted and col-
laborated with Dr. Svend Aage Mortensen, Dr. Gian Paolo Littarru,
Dr. Per Langsjoen and Dr. Peter H. Langsjoen, Dr. William V. Judy,
Mr. Sven Moesgaard and numerous other researchers in getting Co-
enzyme Q10 clinical trials designed and carried out.

78
Thanks to the efforts of Dr. Folkers and his followers, we now have
results from two large randomized controlled trials – Morisco (1993)
and Mortensen (2014) – that show significantly improved symptoms
and survival and significantly fewer hospitalizations in heart failure
patients with Coenzyme Q10 added on to conventional treatment
and compared to placebo treatment. In addition, we have the results
of many smaller studies that confirm a positive health effect of Coen-
zyme Q10 supplementation for heart failure patients, e.g. Langsjoen
(1985), Munkholm (1999), Keogh (2003), Berman (2004), Kochar-
ian (2009), Pourmoghaddas (2014).

We have three meta-analyses – Soja (1997), Sander (2006), and Fo-

tino (2013) – and two systematic literature reviews – Rosenfeldt (2003)
and DiNicolantonio (2015) – that show improvements in various
parameters such as NYHA functional class, ejection fraction, stroke
volume, and cardiac output without side effects.

Clinical research results show that statin medication therapy reduces

the body’s bio-synthesis of Coenzyme Q10 and that supplementation
with Coenzyme Q10 is important for patients taking statin medications
– Folkers (1990), Langsjoen (2007), Pourmoghaddas (2014).

American and Australian studies have shown that supplementation

with Coenzyme Q10 prior to and following heart surgery reduces the
number and severity of complications and can reduce the length of
the hospital stay [39,55].

The meta-analyses and systematic literature reviews show that Coen-

zyme Q10 as an adjuvant treatment in chronic heart failure is excep-
tionally safe and well-tolerated.

Last but not least, we have the results of the KiSel-10 study showing
significantly reduced cardiovascular mortality in healthy senior Swed-
ish citizens after four years of combined selenium and Coenzyme Q10
supplementation. Thanks to the clinical research initiated by Dr.
Folkers, we now understand much more about the mechanisms by
which Coenzyme Q10 improves the working of the failing heart.
Coenzyme Q10 supplementation improves the cardiac ATP produc-
tion, serves as a powerful antioxidant, and helps to correct endothe-
lial dysfunction.

79
References
1. ACCF/AHA Task Force Report. (2013). 2013 ACCF/AHA guideline for the
management of heart failure: a report of the American College of Cardiology
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Coenzyme Q10
– a Scientific Milestone

Science is in the middle of unraveling the mysteries of one of the perhaps

most exciting discoveries ever – a vitamin-like compound named Coenzyme
Q10. Originally observed by American scientists back in 1957, this fasci-
nating molecule has been studied closely and found to control cellular
energy turnover in the entire body. It is known that levels of Coenzyme
Q10 decrease naturally as we grow older. The big question is, can we
compensate for this loss, and how will that affect us?

Today, more than five decades later, researchers have come much closer
to answering that question. Countless studies document that Coenzyme
Q10 supplementation can strengthen the heart muscle, help heart failure
patients survive their disease, and even counteract the side effects of certain
types of heart medicine.

In his book “The History of Coenzyme Q10 Research,” Richard Morrill

takes us on an exciting journey through nearly 60 years of groundbreaking
research, while presenting some of the great pioneers who have contribut-
ed to making Coenzyme Q10 one of the most promising health strategies
of modern times.

Richard Morrill, author and

editor of www.q10facts.com

Forlaget Ny Videnskab
ISBN: 87-7776-185-5