’ Natural Astaxanthin:
`King of the Carotenoids
`
`By Bob capeni
`with Dr. Gerald Cysewski
`
`
`
`Natural Astaxanthin concentrated in Haematocoocus micmalgae
`
`Pubiished by Cyanotech Corporation
`© Copyright 2007 by Cyanotech Corporation
`Second printing 2008
`Third printing 2009
`Fourth printing 2011
`All rights reserved.
`
`ISBN-13: 978—0—9792353-0-6
`
`ISBN—10: 0—9792353—0—8
`
`
`
`UNIVERSITY EXHIBIT 26
`Cyanotech v. University
`IPR2013-00401
`
`

`

`Table of Contents
`
`Introduction ......- .......................................... vi
`
`I
`
`”King of the Carotenoids” ................................. 1
`Other Carotenoids .................................... 4
`
`What is Astaxanthin‘? ................................. 7
`
`|| World’s Strongest Antioxidant ............................ 11
`Free Radicals ....................................... 12
`
`Causes of Free Radical Production ..................... 14
`
`Antioxidants: A Daily Regimen ........................ 16
`Nature’s Ultimate Antioxidant: Astaxanthin!
`............ 17
`
`Natural versus Synthetic Astaxanthin ................... 19
`Antioxidant for the Brain, Eyes and Central
`
`Nervous System ................................. 20
`Never a “Pro-Oxidant” ................................ 21
`
`III
`
`Safe, Natural Anti-Inflammatory ........................... 23
`What Exactly is Inflammation? ........................ 24
`Mechanism of Action ................................ 26
`
`“Silent” Inflammation and C-Reactive Protein ............ 29
`
`Tennis Elbow (Tendonitis) ............................ 32
`Carpal Tunnel Syndrome (Repetitive Stress Injury) ........ 33
`Rheumatoid Arthritis ................................. 35
`
`Joint Soreness after Exercise ......................... 36
`
`1V Healthy Eyes, Healthy Brain .............................. 37
`
`V
`
`Internal Beauty Pill? Sunscreen in a Pill? .................. 44
`
`VI The Athlete’s Secret Weapon ............................. 51
`
`VII Other Medical Research ................................. 61
`
`Immune System Support ............................. 61
`Cardiovascular Benefits
`............................. 64
`
`iv
`
`5
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`

`

`W U
`
`lcers, Gastric Injury, Stomach Cancer ................. 68
`Detoxification ....................................... 69
`
`Cancer Prevention and Tumor Reduction ................ 70
`
`Help for Diabetics ................................... 74
`Trying to Have a Baby? Give your Husband Natural
`Astaxanthin! ..................................... 75
`
`Additional Research ................................. 76
`
`VIII Love Your Pet? Give it Natural Astaxanthin ................. 78
`
`Uses of Astaxanthin in Aquaculture .................... 78
`A Wonderful Reward for Man’s Best Friend .............. 82
`
`Any Animal Will Benefit from Natural Astaxanthin ........ 84
`
`IX Other Vital Information ................................... 87
`
`Safety ............................................. 87
`Stability ........................................... 89
`Delivery Methods .................................... 90
`Dosage and Bioavailability ............................ 92
`Other Commercial Applications ........................ 94
`Natural Astaxanthin as a Food Color ............. 94
`
`Cosmetic Applications ......................... 95
`Other Ideas ................................... 96
`
`Differences between Cyanotech’s Technology and
`Other Manufacturers .............................. 97
`
`Natural versus Synthetic and Phaffia-Derived
`Astaxanthin .................................... 101
`
`Synthetic Astaxanthin ......................... 102
`Phaffia-Derived Astaxanthin .................... 105
`
`Natural Astaxanthin from Salmon
`
`.............. 106
`
`Unique Measurement Challenges ..................... 107
`
`X Testimonials ..................' ........................ 110
`
`TestimOnials from the USA ........................... 110
`
`Testimonials from Around the World ................... 124
`
`References ............................................... 133
`
`Order Form ............................................... 141
`
`6 About the Authors ......................................... 142V
`
`

`

`to Synthetic
`fled” molecule, and makes Natural. Astaxanthin far superior
`Astaxanthin as an antioxidant and in many other ways, which we’ll explore later.
`Another critical difference is that
`the Natural Astaxanthin tested
`(BioAstin® from Cyanotech Corporation in Hawaii)
`is extracted from
`Haematococcus Pluvialis microalgae. When the microalgae hyperaccumulates
`Astaxanthin as a survival mechanism due to environmental stress, it also produces
`small quantities of other supporting carotenoids. The resulting complex is bro-
`ken down as follows:
`
`nee _
`astaxanthm mm”
`5% 4% eanthaxanthin
`i 5% heta carotene
`:
`"
`60/
`
`
`
`
`Distribution of naturally occurring
`carotenoids in Astaxanthin from
`
`Haematocaccus micmalgae.
`
`The additional carotenoids beta carotene, canthaxanthin and lutein work in
`synergy to make Natural Astaxanthin a more effective antioxidant than Synthetic
`Astaxanthin. At the same time, they lead to much more efficacy in treating vari-
`ous health conditions and ensuring Natural Astaxanthin’s many health benefits.
`We’ll discuss the difference between Natural Astaxanthin and synthetic
`
`Astaxanthin in more detail in Chapter 9.
`
`Antioxidant for the Brain, Eyes; and (Senna!
`Newton‘s System
`
`Many antioxidants and even carotenoids that are closely related to Natural
`Astaxanthin cannot cross the blood-brain barrier and get into the brain, the eyes
`and the central nervous system. Even beta carotene, the most well known of all
`carotenoids cannot do this. Neither can some other well known carotenoids such
`
`20
`
`

`

`M W
`
`orld’s Strongest Antioxidant
`
`as lyccpene. But Astaxanthin can! This is vital for antioxidants because scien—
`tists currently theorize that diseases and injuries of the eye and central nervous
`system are caused by the increased generation and presence of singlet oxygen
`and other free radicals (superoxide, hydroxyl, hydrogen peroxide, etc.) or by
`decreased free radical removal ability. Such diseases include age-related macu—
`lar degeneration (the leading cause of blindness in the United States), retinal arte—
`rial and venous occlusion, glaucoma, diabetic retinopathy and injuries resulting
`from trauma and inflammation. An antioxidant that can reach the inner eye by
`crossing the blood-brain and blood-retinal barriers would protect the eye 1from
`these damaging conditions.
`Although Astaxanthin is not normally found in the eye, Dr. Mark Tso was
`the first to prove that Astaxanthin could cross the blood-brain and blood-retinal
`barriers by feeding Astaxanthin to rats and finding it in their eyes. He then proved
`it protected the eye from light-induced damage, photoreceptor cell damage, gan—
`glion cell damage, neuronal damage and inflammatory damage (Tso, ct a1, 1996).
`Astaxanthin may be the absolute best protection for the eyes among any supple-
`ments, although researchers are just beginning to find out about this now.
`
`Never a “Pro—Qxidant”
`
`There is a potential for some wonderful antioxidants, under certain condi-
`tions, to become “pro-oxidants” and actually have a negative effect by causing
`oxidation in the body. Some of the better—known carotenoid antioxidants that can
`become pro—oxidants are beta carotene, lycopene and zeaxanthin (Martin, et al,
`1999). Even such familiar antioxidants as Vitamin C, Vitamin E and zinc can
`become pro—oxidants. This is another important factor separating Astaxanthin
`from other antioxidants—nit never becomes a pro-oxidant (Beutner, et a1, 2000).
`This is one more reason that Astaxanthin is clearly a superior antioxidant to oth-
`ers.
`
`A famous study of beta carotene on smokers was done in Finland in the
`1990’s. In this study, it was found that smokers who took synthetic beta carotene
`supplements actually had a higher incidence of cancer than those taking a place-
`bo.
`The challenge with beta-carotene is that it relies on other antioxidants,
`specifically vitamin C, to properly protect cells from free radicals.
`(Try to think
`of a free radical as a hot potato that needs to be passed from one antioxidant to
`another until it cools off.)
`The people in this study were very heavy smokers (three packs per day)
`21
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`

`

`CHAPTER 4
`
`M
`
`Other carotenoids have begun to attain a certain level of fame for having
`beneficial properties for the eyes. There is no doubt that lutein and zeaxanthin
`are wonderful products to support and protect the eyes, and there is credible evi-
`dence that they can help prevent age related macular degeneration and other
`degenerative conditions. But due to Natural Astaxanthin’s superior antioxidant
`and anti—inflammatory properties, indications are that it will prove to be superior
`to all other nutraceuticals for eye and brain health.
`As we briefly discussed in Chapter 2, many antioxidants and even
`carotenoids that are closely related to Natural Astaxanthin cannot cross the blood-
`brain barrier. This means that they can’t do anything to help the brain, the eyes
`or the central nervous system, and we all know how vital these organs are. Beta
`carotene and lycopene are just two of the well known carotenoids without this
`capability.
`There is substantial evidence that most diseases associated with the eyes
`and brain are the result of oxidation and/or inflammation. Free radicals and sin—
`glet oxygen wreak havoc in your head over time, and the consequences, if left
`unchecked, manifest in such horrible diseases as blindness caused by macular
`degeneration or dementia caused by Alzheimer’s. It is essential that people take
`antioxidants that can cross the blood—brain and bleed-retinal barriers as they get
`older to protect these vital organs. And it’s not just macular degeneration and
`Alzheimer’s to be concerned with, but a whole list of potential problems associ—
`ated with oxidation and inflammation in the brain and eyes. Below is a list of
`some of the many detrimental. conditions that can develop:
`
`- Glaucoma
`
`- Cataract
`
`- Retinal arterial occlusion
`
`- Venous occlusion
`
`- Diabetic retinopathy
`- Age—related macular degeneration
`
`37
`
`

`

`- Injuries resulting from trauma
`- Inflammatory injuries
`- Alzheimer’s disease
`
`- Parkinson’s disease
`
`- Huntington’s disease
`- Amyotrophic lateral sclerosis (Lou Gehrig’s disease)
`- Senility
`0 Other forms of age-related dementia
`
`Scientists believe that something may cause people’s internal antioxidant
`defense system to malfunction or wear out as we age. Our bodies may lose the
`ability to produce high levels of the antioxidants that are normally produced inter-
`nally such as superoxide dismutase, catalase and glutathione peroxidase. Also, as
`was pointed out in Chapter 2, our bodies are now subjected to unprecedented lev-
`els of oxidation caused by environmental factors such as pollution, contaminants,
`processed food and the high levels of stress in modern life. All of these lead to
`an assault on our Vital organs as we age, including of course, our brains and eyes.
`The eye, in particular, is now subjected to much higher levels of oxidation
`than our ancestors experienced. The depletion of the ozone layer is causing more
`intense sunlight than ever before, which directly affects the eyes and skin.
`Excessive exposure to sunlight and to the highly oxygenated environment causes
`free radicals to generate in the eye. A condition called “ischemia” which is a type
`of blockage that deprives the eye of nutrition and oxygen is a common cause of
`increased oxidation in the eye. Another cause of increaSed oxidation in the eye
`happens when the ischemic blockages are removed. The reoxygenation of the tis-
`sue after blockage is called “reperfusion,” and the end result is another attack on
`the eye’s normal oxidative balance. EVen normal. enzymatic processes canse
`increased generation of free radicals and singlet oxygen such as hydrogen perox-
`ide, superoxide and hydroxyl in the eyes.
`Free radicals and singlet oxygen oxidize the polyunsaturated fatty acids in
`the retina which leads to functional impairment of the retinal cell membranes,
`causing temporary and permanent damage to the retinal cells. Once the retina is
`damaged, it cannot be replaced. Antioxidants that can reach the inner eye by
`crossing the blood-brain and blood—retinal barriers are essential because they pro—
`tect the eye from these damaging conditions.
`The carotenoids lutein and zeaxanthin are normally found in the eyes.
`Astaxanthin is not. We Spoke very briefly about groundbreaking work done by
`
`38
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`

`% H
`
`ealthy Eyes, Healthy Brain
`
`Dr. Mark Tso of the University of Illinois in Chapter 2. Dr. Tso was the first per—
`son to prove that Astaxanthin can cross the blood-brain and blood-retinal bar-
`riers. He took laboratory rats and tested their eyes for Astaxanthin. As expect-
`ed, he did not find any present. Then he fed the rats Astaxanthin and retested, this
`time finding Astaxanthin present in the retina. He proved that Astaxanthin could
`cross first the blood-brain barrier and get into the brain, and then once in the brain
`it could reach the retina and the macula by crossing through the blood—retinal bar-
`rier.
`
`_
`
`Through an extensive series
`.
`'; of tests, Dr. Tso went on to prove
`
`'
`
`
`
`that Astaxanthin has many protective
`- properties once it reaches the eyes.
`5' Among the many benefits that Dr.
`3 Tso found include Astaxanthin’s
`
`'
`'
`
`ability to protect the eye from:
`
`. Light-induced damage
`- Photoreceptor cell damage
`
`- Ganglion cell damage
`- Neuronal damage
`
`-
`
`Inflammatory damage
`
`Just as with Astaxanthin’s
`
`The blood—brain barrier: Astaxamhin can cross
`through to protect the brain.
`
`anti-inflammatory properties which are a very diverse group of pathways that
`combat inflammation, the eye-protective properties of Astaxanthin are similar:
`Astaxanthin protects the eyes through various pathways rather than through just
`one (Tso, et a1, 1996). We see a pattern emerging in which Astaxanthin attacks
`different problems in a multitude of ways. Perhaps someday researchers will dis-
`cover that, similar to the case with single pathway anti—inflammatories like Vioxx
`which have dangerous side effects, this multiple pathway “shotgun” approach to
`eye health is also the safest and most natural.
`Since Dr. Tso’s groundbreaking work, other scientists have found further
`benefits for the eyes when using Natural Astaxanthin. For example, eye fatigue
`is a serious problem in many of today’s occupations. Working for long periods at
`visual display terminals reportedly induces various visual problems such as eye
`strain, blurring and diplopia (a disorder of vision in which two images of. a sin-
`gle object are seen because of unequal action of the eye muscles — also called
`
`39
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`

`

`In a double blind study performed in Japan, after four weeks of
`double vision).
`stipplementation with 5 mg of Astaxanthin per day (extracted from
`Haematococcus algae meal) the authors reported a 46% reduction in the number
`of eye strain subjects. They also found higher accommodation amplitude (the
`adjustment in the lens of the eye that allows it to focus) in subjects who used visu-
`al display terminals. The mechanism
`of action is still not understood, but
`
`it’s most likely due to Astaxanthin’s
`potent antioxidant properties (Nagaki,
`et al, 2002). Additional research in
`
`the area of eye fatigue has been car-
`ried out.
`In fact, there are now nine
`
`different positive human clinical stud—
`ies that have been published in the
`area of eye fatigue.
`Two different dosage levels
`
`
`
`The eye’s retina contains the macula. Once dam-
`aged, the mum camarbg rgplawd‘
`
`were tested for eye fatigue by a group
`led by Dr. Nakamura in 2004. They
`found positive effects at 4 mg per day’
`but found a better result at 12 mg per
`day (Nakamura, et a1, 2004).
`Another group of Japanese researchers found similar results in another
`human clinical study. This double blind study was done to evaluate Astaxanthin’s
`effect on eye fatigue and visual accommodation. Forty subjects were divided into
`placebo and treatment groups, with the treatment group receiving 6 mg of
`Astaxanthin for four weeks. The results were that three separate visual parame—
`ters were found to have statistically significant benefits from Astaxanthin supple—
`mentation. This research established an optimum daily dose for eye fatigue at 6
`
`mg per day (Nitta, et ai, 2005).
`Additional studies have validated this work, showing that 6 mg per day of
`Natural Astaxanthin supplementation for four weeks can reduce eye soreness,
`dryness, tiredness and blurred vision (Shiratori, et a1, 2005 and Nagaki, et a1,
`2006).
`
`Astaxanthin may work in a preventive role for eye fatigue as compared to
`the curative role that has already been established. The other studies referenced
`above all centered on the use of Astaxanthin to cure eye fatigue. A clinical study
`was done on subjects whose eyes were healthy, with no signs of fatigue or strain.
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`

`Healthy Eyes, Healthy Brain
`
`Both the treatment and the placebo groups were subjected to heavy visual stim—
`
`uli to induce eye fatigue, and it was found that the treatment group recovered
`
`more quickly. This clearly indicates that Natural Astaxanthin may serve to pre-
`vent eye fatigue from occurring in healthy people (Takahashi and Kajita,
`2005).
`
`It is very important to have sufficient blood flow to the eyes and the reti-
`na. A human clinical study examined the ability of Astaxanthin to improve reti-
`nal capillary blood flow. Eighteen subjects were given 6 mg per day of Natural
`
`Astaxanthin and another eighteen people were given a placebo. After four weeks
`it was found that the treatment group had improved retinal capillary blood flow
`as compared to the placebo group (Yasunori, N, 2005).
`The mechanisms of action thought to enable Astaxanthin to reduce or pre-
`vent eye fatigue are diverse. Of course, Astaxanthin’s role as an antioxidant and
`anti-inflammatory must play a part. A study conducted at
`the Hokkaido
`University Graduate School of Medicine determined that Astaxanthin inhibited
`inflammation in the eye by blocking nitric oxide synthase (Ohgami, et a1, 2003).
`Astaxanthin was also found to have potent antioxidant effects in the prevention of
`cataracts in rats” eyes (Wu, et a], 2002).
`In addition, the increased blood flow to
`the retina surely plays a part. The final, yet very significant mechanism is
`
`improved accommodation amplitude. By enabling the lens to more easily adjust,
`the ability of the eye to focus is improved.
`Another, very different type of human study on Natural Astaxanthin’s
`effects on the eyes has also yielded positive results. This study was done in Japan
`
`with subjects comprised of twenty year old men. The treatment group was given
`6 mg of Natural Astaxanthin per day for four weeks. Different visual parameters
`were measured, with statistically significant improvement found in two different
`parameters for visual acuity (the ability to see detail). The greatest enhanCc-
`ment was seen in depth perception which improved by 46% in the group sup—
`
`plementing with Natural Astaxanthin (Sawaki, et a1, 2002).
`Of course, along with the human clinical trials, there are also pre—clinica].
`animal studies and in-vitro experiments on Astaxanthin and eye health. One such
`study took the lens from the eyes of pigs and tested the ability of Astaxanthin to
`protect them from induced oxidative damage. This experiment found that
`Astaxanthin was capable of protecting the lens proteins from oxidative dam—
`age. In fact, Astaxanthin performed better than the antioxidant glutathione which
`is produced by the pig’s own body (Wu, et a1, 2006).
`A study done in rats was very helpful in that it measured the effect of
`
`41
`
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`

`Astaxanthin on three important inflammatory markers in the uvea (the middle
`layer of the eye including the iris). Inflammation in the uvea was induced, after
`which nitric oxide, tumor necrosis factor alpha and prostaglandin E-2 were meas-
`ured. The rats that had been injected with Astaxanthin had lower levels of all
`three inflammatory markers. The researchers concluded that Astaxanthin is
`effective in reduoing ocular inflammation (Suzuki, et a1, 2006). A previous
`study done on inflammation of the eye of rats yielded similar results, but also
`demonstrated that the effects of Astaxanthin worked in a dose-dependent fashion.
`Additionally,
`this study proved these anti—inflammatory mechanisms in-vitro
`(Ohgami, et a1, 2003).
`Less research has been done in direct relation to Astaxanthin’s effects on
`
`the brain than the extensive work we’ve cited concerning the eyes, but what has
`been done is very promising. A series of tests on rodents at the International
`Research Center for Traditional Medicine in Japan shows great potential.
`In the
`first experiment, blood pressure was reduced by the introduction of Astaxanthin
`to hypertensive rats. Blood pressure is a causative factor for many diseases
`including some associated with the eyes and brain. The researchers went on to
`examine the effects of Astaxanthin on stroke prone rats. They found that after
`five weeks of continuous supplementation, the incidence of stroke was delayed in
`the treated group. Next, they established a possible mechanism for these results
`in-vitro, which they believed to be nitric oxide suppression.
`The same study went on to demonstrate a neuroprotective effect (protec-
`tion of brain function) in ischemic mice. Ischemia is the condition where there
`is a deficient supply of blood to the brain as a result of the obstruction of arterial
`blood flow.
`In the case of these mice, ischemia was induced by blocking the
`carotid artery.
`In humans, this condition can be caused by plaque buildup which
`can block the flow of blood through the carotid artery in the neck, the primary
`source of blood to the brain. This build up of plaque can lead to many different
`maladies including stroke and different types of dementia.
`The ischemic mice were fed Astaxanthin only once—just one hour before
`the ischemia was induced. Remarkable results were seen in the treated group——
`the mice performed better in a maze designed as a learning performance test.
`“The present results suggest that Astaxanthin can attenuate the development of
`hypertension and may help to protect the brain from stroke and ischemic
`insults...ln addition, Astaxanthin showed neuroprotective effects at relatively
`high doses by preventing the ischemia-induced impairment of spatial memory in
`mice. This effect is suggested to be due to the significant antioxidant property of
`
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`m H
`
`ealthy Eyes, Healthy Brain
`
`Astaxanthin on ischemia-induced free radicals and their consequent pathological
`cerebral and neural effects. The current result indicates that Astaxanthin may
`have beneficial effects in improving memory in vascular dementia” (Hussein,
`et al, 2005a). It appears that Astaxanthin actually made these mice with restrict-
`ed blood flow to their brains smarter by improving their memory. The impli-
`cations of this study are extremely exciting, as our aging population sees grow-
`ing numbers of Alzheimer’s patients, stroke sufferers and people afflicted by
`dementia caused by other factors. Further research in humans must be done to
`fully understand the potential benefit, but these pro-clinical experiments indicate
`that Astaxanthin may help sufferers of many brain-related diseases live better
`lives.
`
`A similar study had been done previously and was published in Carotenoid
`Science. This study also demonstrated that Astaxanthin could prevent brain
`damage due to ischemia (Kudo, et a1, 2002). A company in Japan did some fur-
`ther work in this area in a rat model. The company fed rats Astaxanthin twice:
`Twenty four hours before and again one hour before inducing ischemia by
`occluding the rats’ middle arteries. The blood flow stoppage duration was one
`hour, at which point blood flow to the brain was permitted to resume. The rats
`were given one more dose of Astaxanthin after blood flow restarted, and then two
`hours later the rats were sacrificed and their brains were removed. The brains
`were compared to rats from a control group fed olive oil, and it was found that
`the rats fed Astaxanthin had 40% less brain damage than the control group
`
`(Oryza Company, 2006).
`Although the research on Astaxanthin’s effects on the brain is comprised
`exclusively of pre—clinical animal studies so far, it is nevertheless very exciting
`and demonstrates gleat promise for humans. After seeing the extensive work with
`Astaxanthin for eye health in human clinical trials, it stands to reason that simi-
`lar results will be found for brain health as well. This supposition is a logical
`extension of Astaxanthin’s ability to cross the blood—brain and blood—retinal bar—
`1iers——once in the brain and eyes, Astaxanthin’s superior antioxidant properties
`and anti—inflammatory activity are sure to yield great benefits for these vital
`
`organs.
`
`43
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`