Results Support Cardax Clinical Program
Recent studies continue to support astaxanthin’s broad potential
in chronic inflammatory disease, adding to more than 1,000
peer-reviewed papers published on astaxanthin. Selected
publications from January 2013 to April 2014 include (i) a thorough
review of astaxanthin and its applications, (ii) human studies in
cognitive decline, cardiovascular oxidation, and ocular
dysfunction, and (iii) animal and mechanistic studies addressing
brain health and cognitive decline related pathology,
osteoarthritis and joint health, metabolism, cardiovascular health,
and related diseases, eye and retinal health, skin protection and
health, lung function and health, and kidney function and health
(see highlights below).
These studies support the rationale of the Cardax, Inc.
(“Cardax” or the “Company”) (OTCQB: CDXI) clinical program, which
will seek to prove astaxanthin’s safety and efficacy in major
disease areas with common underlying mechanisms related to
inflammation and oxidative stress. Assuming adequate additional
funding and/or strategic partnership, the Company plans to conduct
a suite of approximately three to five low-risk, high-value human
proof-of-concept (“POC”) clinical trials in such disease areas.
These human clinical trials would not only advance the Cardax
pharmaceutical development program, but could also demonstrate
human POC for potential partners and help catalyze nutraceutical
sales through the Company’s strategic alliance with BASF, under
which Cardax will receive tiered royalties on future BASF
astaxanthin nutraceutical sales.
Astaxanthin review:
Ambati, R.R. et al. reviews
the sources, extraction, stability, biological activities, and
commercial applications of astaxanthin.
Human trials utilizing astaxanthin:
Hashimoto, H. et al.
evaluated the influence of astaxanthin on oxidative stress in the
human eye. Patients (N=35 total) requiring bilateral cataract
surgery underwent surgery on one side before and the other side
after intake of astaxanthin (6 mg/day for 2 weeks). Aqueous humor
was evaluated after each surgery. Astaxanthin significantly reduced
total hydroperoxides and significantly increased superoxide
scavenging capacity. This effect was more dramatic in diabetic
patients and in total supports the capacity for astaxanthin to
reduce oxidative stress in the human eye.
In a double-blind, placebo-controlled human study, Baralic, I. et al. evaluated the capacity
of astaxanthin (4 mg/day for 90 days) to increase paraoxonase
(PON1) activity and oxidative stress in young, healthy soccer
athletes (N=40 total). PON1 activity has an inhibitory effect on
atherosclerosis formation and protects LDL and HDL lipoprotein
particles from harmful oxidative damage. Decreased PON1 has been
correlated with oxidative stress and cardiovascular risk in humans.
Here, astaxanthin significantly increased PON1 activity over the
placebo group most likely resulting from elevated protection of
PON1 oxidation via astaxanthin-induced increase of sulfhydryl
groups.
To evaluate the effect of astaxanthin (in combination with
Bacopa monnieri extract, phosphatdylserine and vitamin E) in
patients with mild cognitive impairment (MCI), Zanotta, D. et al. treated 104 patients for
60 days in a prospective cohort, noncomparative, multicenter trial.
Here, the astaxanthin-containing phytotherapeutic compound
significantly improved Alzheimer’s Disease Assessment
Scale-cognitive subscale scores (ADAS-cog) and clock drawing test
scores with memory tasks demonstrating the greatest improvement.
This study supports the potential for astaxanthin as well as other
antioxidants in the treatment of MCI.
Astaxanthin addressing brain health and cognitive decline
related pathology:
Wu, W. et al. utilized a rat
model of brain aging to evaluate astaxanthin potential to alleviate
aging associated pathology. Here, astaxanthin significantly
restored antioxidant marker levels (GSH, SOD, TAC) and decreased
oxidative stress markers (MDA, 8-OHdG, protein carbonylation).
Astaxanthin also decreased inflammatory effectors including COX-2,
ameliorated histological pathology and restored neurotrophic factor
BNDF levels supporting the potential for astaxanthin to ameliorate
aspects of aging pathology.
Ye, Q. et al. evaluated
astaxanthin potential as a neuroprotective in a cell model of
Parkinson’s Disease. Astaxanthin increased cell viability following
induction of cell damage (MPP) and decreased proteins involved in
mediating cell dysfunction (Sp1, NR1). This study supports the
capacity for astaxanthin to increase neural cell survival and
regulate pathways that respond to oxidative stress by inducing
neural cell death.
Early brain injury (EBI) refers to the acute injuries to the
whole brain within 72 hours following aneurysmal subarachnoid
hemorrhage (SAH) and is the primary cause of death in patients with
SAH. Zhang, X.S. et al. used
two animal models of SAH (rats and rabbits) to evaluate the
capacity of injected or orally delivered astaxanthin to ameliorate
oxidative stress and associated pathology in early brain injury
following SAH. Astaxanthin intracerebroventricular injection
post-SAH in rats significantly attenuated EBI (measured as brain
edema, blood-brain barrier disruption, neural cell apoptosis and
neurological dysfunction). Likewise, oral astaxanthin
administration 3 hours post SAH was also neuroprotective in both
rat and rabbit models.
Astaxanthin addressing osteoarthritis and joint
health:
Chen, W. P. et al. recently
investigated the potential for astaxanthin to alter expression of
matrix metalloproteinases (MMPs) in human chondrocytes. MMPs are
pathologically upregulated in inflammatory diseases such as
osteoarthritis and are critically responsible for degradation of
joint matrix structure leading to more severe joint dysfunction.
Astaxanthin treatment of human joint cells significantly reduced
MMP expression levels (MMP-1, 3, 13) following inflammatory
induction of MMP upregulation (IL-1). This study supports the
influence of astaxanthin on decreasing inflammatory signaling,
particularly pathways leading to OA-related pathology.
To further assess astaxanthin influence on joint health,
Kimble, L.L. et al. treated a
human chondrosarcoma cell line with astaxanthin and measured
various markers of inflammation induced by interleukin 1-
treatment. In addition to significantly decreasing induced
oxidative stress and maintaining activity of the antioxidant GPx,
astaxanthin treatment significantly prevented IL-1-induced
upregulation of several inflammatory mediators critical to
arthritis pathology including; MMP-13, IL-6, TNF-, and PGE2.
Additionally, astaxanthin treatment significantly inhibited NF-B
pathway activation and attenuated AP-1 activation. Similarly to
Chen et al. (above), here, treatment of an arthritis-relevant cell
type underscores the significant capacity of astaxanthin to
diminish pathways of inflammation and attenuate levels of many
inflammatory mediators intrinsic to arthritis pathogenesis.
Astaxanthin addressing metabolism, cardiovascular health and
related diseases:
Liu, P.H. et al.
investigated the effect of astaxanthin on lipid metabolism in both
sedentary and exercising mice (N=8/group). Here, astaxanthin (0.02%
w/w for 2 weeks) reduced plasma fatty acids by 17% in sedentary
mice and significantly by 21% in exercising mice. Astaxanthin
increased intracellular pH levels indicating increased fat
utilization in contrast to carbohydrate metabolism during exercise.
Importantly, astaxanthin administration also significantly
increased PGC-1 (peroxisome proliferator-activated
receptor-coactivator-1) levels. PGC-1 is a master controller of
mitochondrial biogenesis and aerobic metabolism and directly
upregulates critical mitochondrial genes also confirmed induced by
astaxanthin in this study (FNDC5, Cytochrome C).
Aoi, W. et al. published an
important review of oxidative stress during exercise and described
the resulting effects on mitochondrial function. Here, studies are
reviewed that support the significance of astaxanthin in
mitochondria function (see Liu et al. above) as astaxanthin
decreases oxidative stress-driven modification of the metabolic
regulatory protein carnitine palmitoyltransferase-1 (CPT-1) and its
interaction with FAT/CD36 as a limiting step to fat metabolism
during exercise.
Park, J.S. et al.
investigated the influence of astaxanthin (0, 20 mg/day for 16
weeks) on mitochondrial function in dogs (N=14/group). Dogs treated
with astaxanthin exhibited greater mitochondrial function observed
as increased mitochondrial mass, ATP production and cytochrome c
oxidoreductase activity. Ratios of reduced to oxidized glutathione
levels increased indicating restoration of antioxidant function.
This study supports the capacity for astaxanthin to increase
mitochondrial function in vivo in support of Aoi et al. and Liu et
al. as described above.
Bhuvaneswari S. et al.
evaluated the effects of astaxanthin (2 mg/kg/day for 45 days) on
cellular stress and inflammation in mice on a high fat diet
(N=6/group). This diet induces oxidative stress, fatty liver,
inflammation and endoplasmic reticulum stress (ERS plays a role in
many diseases incuding insulin resistance). Here, astaxanthin was
shown to significantly reduce oxidative stress, fatty liver
content, proteins induced by ERS and inflammatory pathway
activation (JNK and NFB) supporting the important
anti-inflammatory role of astaxanthin in modulation of diseases
related to ERS and inflammation including cardiovascular disease,
liver disease, diabetes, etc.
Xu, J. et al. treated rats
(N=10/group) on a high fat diet with astaxanthin in flaxseed oil
(0, 50, 100, 200 mg astaxanthin/kg/day) for 10 weeks and evaluated
oxidative stress, lipids and inflammatory markers. Astaxanthin
treatments resulted in significant reductions in lipid measures
including; triglycerides, total cholesterol and LDL-C. Inflammatory
markers IL-6 and C reactive protein (CRP) were also significantly
reduced. Measures of antioxidant capacity significantly increased
with astaxanthin treatment (SOD, catalase, glutathione, GPx, TAC)
and oxidative stress significantly decreased (TBARS). This study
supports the role of astaxanthin in restoring lipid profiles and
reducing inflammation in metabolic disease.
Ishiki, M. et al. evaluated
the capacity of astaxanthin to alter insulin-related signaling in
rat muscle cells. Astaxanthin treatment significantly increased
insulin-induced responsive pathways leading to enhanced activation
of IRS-1 and AKT, increased translocation of GLUT4 glucose
transporter, increased glucose uptake as well as decreased
activation of JNK pathways and inhibitory IRS-1 phosphorylation.
This study mechanistically supports previously published studies
utilizing animal models to demonstrate the potential for
astaxanthin to ameliorate insulin resistance and related diabetic
pathophysiology.
Astaxanthin addressing eye and retinal health:
Otsuka, T. et al.
investigated the influence of astaxanthin (100 mg/kg administered 8
times over 3 days) in a mouse model of retinal cell death resulting
from intense light exposure (N=10-18/group). Astaxanthin
significantly reduced rod/cone dysfunction (ERG measures) and
protected against rod/cone cell death (histological and apoptosis
measures). In support, astaxanthin also protected cone cells from
light-induced death and lowered the resulting oxidative stress in
cell culture.
Dong, L.-Y. et al. utilized
a mouse model of diabetic disease and retinopathy to evaluate
astaxanthin capacity to diminish retinal ganglion cell death
(RGC)(N=8/group). Astaxanthin treatment (25, 50 mg/kg/day for 8
weeks) significantly reduced RGC cell death and decreased markers
of oxidative stress including MDA, SOA and 8-OHdg and increased
MnSOD antioxidant levels supporting the potential for astaxanthin
to influence oxidative stress associated with diabetic retinal
disease.
Li, Z. et al. treated a
human cell type (RPE) lost in age-related macular degeneration with
astaxanthin and noted that astaxanthin protected the cells against
death and decreased oxidative stress following induction with
hydrogen peroxide (ROS). Additionally, they deduced the astaxanthin
mechanism of action for protection was activation of the
insulin-responsive signaling pathway PI3K/AKT which in turn
activates an antioxidant protection system (Nrf2).
In support of Li et al. observations (above), Saw, C. L. L. et al. observed activation of
Nrf2-pathway antioxidant response elements (ARE) in cells treated
with astaxanthin. Downstream genes activated by the Nrf2-ARE axis
included heme oxygenase 1 (HO-1) and several other important
protective antioxidant functions.
Astaxanthin addressing skin protection and health:
Rao, A.R. et al. evaluated
the potential for astaxanthin to inhibit or attenuate skin cancer
development in a rat model of chemical-induced skin carcinogenesis.
Rats (N=6/group) treated with astaxanthin (0.1, 0.2 mg/kg/day for
60 days) showed significant reductions in skin tumor frequency as
high as 96%. Normalization of tyrosinase and antioxidant levels was
also observed. This study supports astaxanthin in skin protection
and chemoprevention.
Astaxanthin addressing lung function and health:
Wang, M. et al. utilized a
chemically-induced rat model of lung fibrosis to evaluate the
potential of astaxanthin to ameliorate lung disease pathology.
Astaxanthin was administered (24 days at 0, 0.5, 1, 2 mg
astaxanthin/kg/day or dexamethasone 1mg/kg/day)(N=10/group) and was
found superior to dexamethasone in significantly ameliorating the
induced lung fibrosis, decreasing edema and thickness in the
pulmonary alveoli and increasing gas exchange. This study supports
the potential for astaxanthin to ameliorate lung pathophysiology in
vivo.
Astaxanthin addressing kidney function and health:
Colistin methanesulfonate (CMS) is one of the few remaining
therapeutic options for treatment of life-threatening infections
caused by multi-drug resistant pathogens but often induces serious
nephrotoxicity. Ghlissi, Z. et
al. investigated the ability of astaxanthin to
ameliorate renal toxicity from CMS in a rat model (N=6/group).
Astaxanthin treatment (20 mg/kg/day for 7 days) significantly
histopathological damage and restored pathological biochemical
parameters including MDA, SOD, catalase, GPx, GSH to more
physiological levels. This study supports the potential for
astaxanthin to reduce renal toxicity.
Citations Listed
(alphabetical)
Ambati, R.R., Phang, S-M, Ravi, S and Aswathanarayana, R.G.
Marine Drugs 12:128-152, 2014. “Astaxanthin: Sources, Extraction,
Stability, Biological Activities and Its Commercial Applications-A
Review“
Aoi, W., Naito, Y. and Yoshikawa, T. Lipid Hydroperoxide-Derived
Modification of Biomolecules, Subcellular Biochemistry 77, Chapter
15, Springer Science+Business, 2014. “Potential role of oxidative
protein modification in energy metabolism in exercise”
Baralic, I., Djordjevic, B., Dikic, N., Kotur-Stevuljevic, J.,
Spasic, S., Jelic-Ivanovic, Z., Radivojevic, N., Andjelkovic, M.
and Pejic, S. Phytotherapy Research 27:1536-1542, 2013. “Effect of
astaxanthin supplementation on paraoxonase 1 activities and
oxidative stress status in young soccer players”
Bhuvaneswari, S., Yogalakshmi, B., Sreeja, S. and Anuradha, C.V.
Cell Stress and Chaperones 19:183-191, 2014. “Astaxanthin reduces
hepatic endoplasmic reticulum stress and nuclear factor-B-mediated
inflammation in high fructose and high fat diet-fed mice”
Chen, W.-P., Xiong, Y., Shi, Y.-X., Hu, P.-F., Bao, J.-P. and
Wu, L.-D. International Immunopharmacology 19(1):174-177, 2014.
“Astaxanthin reduces matrix metalloproteinase expression in human
chondrocytes”
Dong, L.-Y., Jin, J., Lu, G. and Kang, X.-L. Marine Drugs
11:960-974, 2013. “Astaxanthin attenuates the apoptosis of retinal
ganglion cells in db/db mice by inhibition of oxidative stress”
Ghlissi, Z., Hakim, A., Sila, A., Mnif, H., Zeghal, K., Rebai,
T., Bougatef, Al and Sahnoun, Z. Environmental Toxicology and
Pharmacology 37:960-966, 2014. “Evaluation of efficacy of natural
astaxanthin and vitamin E in prevention of colistin-induced
nephrotoxicity in the rat model”
Hashimoto, H., Arai, K., Hayashi, S., Okamoto, H., Takahashi,
J., Chikuda, M. and Obara, Y. Journal of Clinical Biochemical
Nutrition 53(1):1-7, 2013. “Effects of astaxanthin on antioxidation
in human aqueous humor”
Ishiki, M., Nishidda, Y., Ishibashi, H., Wada, T., Fujisaka, S.,
Takikawa, A., Urakaze, M., Sasaoka, T., usui, I. and Tobe, K.
Endocrinology 154(8):2600-2612, 2013. “Impact of divergent effects
of astaxanthin on insulin signaling in L6 cells”
Kimble, L.L., Mathison, B.D. and Chew, B.P. American Journal of
Advanced Food Science and Technology 2:37-51, 2013. “Astaxanthin
mediates inflammation biomarkers associated with arthritis in human
chondrosarcoma cells induced with interleukin-1”
Li, Z., Dong, X., Liu, H., Chen, X., Shi, H., Fan, Y., Hou, D.
and Zhang, X. Molecular Vision 19:1656-1666, 2014. “Astaxanthin
protects ARPE-19 cells from oxidative stress via upregulation of
Nrf2-regulated phase II enzymes through activation of PI3K/Akt”
Liu, P.H., Aoi, W., Takami, M., Terajima, H., Tanimura, Y.,
Naito, Y., Itoh, Y. and Yoshiawa, T. Journal of Clinical
Biochemical Nutrition 54(2):86-89, 2-14. “The astaxanthin-induced
improvement in lipid metabolism during exercise is mediated by a
PGC-1 increase in skeletal muscle”
Otsuka, T., Shimazawa, M., Nakanishi, T., Ohno, Y., Inoue, Y.,
Tsuruma, k., Ishibashi, T. and Hara, H. Journal of Pharmacological
Science 123:209-218, 2013. “The protective effects of a dietary
carotenoid, astaxanthin, against light-induced retinal damage”
Park, J.S., Mathison, B.D., Hayet, M.G., Zhang, J., Reinhart,
G.A. and Chew, B.P. Journal of Animal Science 91:268-275, 2013.
“Astaxanthin modulates age-associated mitochondrial dysfunction in
healthy dogs”
Rao, A.R., Sindhuja, H.N., Dharmesh, S.M., Sankar, K.U., Sarada,
R. and Ravishankar, G.A. Journal of Agricultural and Food Chemistry
61:1842-3851, 2013. “Effective inhibition of skin cancer,
tyrosinase, and antioxidative properties by astaxanthin and
astaxanthin esters from the green alga Haematococcus pluvialis”
Saw, C.L.L., Yang, A.Y., Guo, Y. and Kong, A.-N.T. Food and
Chemical Toxicology 62:869-875, 2013. “Astaxanthin and omega-3
fatty acids individually and in combination protect against
oxidative stress via the Nrf2-ARE pathway”
Wang, M., Zhang, J., Song, X., Liu, W., Zhang, L., Wang, X. and
Lv, C. Food and Chemical Toxicology 56:450-458, 2013. “Astaxanthin
ameliorates lung fibrosis in vivo and in vitro by preventing
transdifferentiation, inhibiting proliferation, and promoting
apoptosis of activated cells”
Wu, W., Wang, X., Xiang, Q., Meng, X., Peng, Y., Du, N., Liu,
Z., Sun, Q., Wang, C. and Liu, X. Food & Function 5:158-166,
2014. “Astaxanthin alleviates brain aging in rats by attenuating
oxidative stress an increasing BDNF levels”
Xu, J., Gao, H., Zhang, L., Chen, C., Yang, W., Deng, Q., Huang,
Q. and Huang, F. Lipids in Health and Disease 13:63, 2014. “A
combination of flaxseed oil and astaxanthin alleviates
atherosclerosis risk factors in high fat diet fed rats”
Ye, Q., Zhang, X., Huang, B., Zhu, Y. and Chen, X. Marine Drugs
11:1019-1034, 2013. “Astaxanthin suppresses MPP+-induced oxidative
damage in PC12 cells through a Sp1/NR1 signaling pathway”
Zanotta, D., Puricelli, S. and Bonoldi, G. Neuropsychiatric
Disease and Treatment 10:225-229, 2014. “Cognitive effects of a
dietary supplement made from extract of Bacopa monnieri,
astaxanthin, phosphatidylserine, and vitamin E in subjects with
mild cognitive impairment: a noncomparative, exploratory clinical
study”
Zhang, X.-S., Zhang, X., Zhou, M.-L., Zhou, X.-M., Li, N., Li,
W., Cong, Z.-X., Sun, Q., Zhuang, Z., Wang, C.-X. and Shi, J.-X.
Journal of Neurosurgery April 11, 2014 (ahead of print).
“Amelioration of oxidative stress and protection against early
brain injury by astaxanthin after experimental subarachnoid
hemorrhage”
About Cardax
Cardax is a development stage life sciences company that devotes
substantially all of its efforts to developing nutraceutical and
pharmaceutical products that provide the anti-inflammatory benefits
of steroids or NSAIDS, but with exceptional safety profiles, as
conferred by U.S. Food and Drug Administration (“FDA”) Generally
Recognized as Safe (“GRAS”) designation at certain doses. Cardax is
preparing proprietary nature-identical products and related
derivatives by total synthesis to provide scalable, pure, and
economical therapies for diseases where inflammation and oxidative
stress are strongly implicated, including, but not limited to,
osteoarthritis, rheumatoid arthritis, dyslipidemia, metabolic
disease, diabetes, cardiovascular disease, hepatitis, cognitive
decline, macular degeneration, and prostate disease. The initial
primary focus of Cardax is its astaxanthin technologies.
Astaxanthin is a powerful and safe naturally occurring
anti-inflammatory and anti-oxidant without the adverse side effects
typical of anti-inflammatory treatments using steroids or NSAIDS,
including immune system suppression, liver damage, cardiovascular
disease risk, and gastrointestinal bleeding.
Safe Harbor
This release may contain certain forward-looking statements
regarding our prospective performance and strategies within the
meaning of Section 27A of the Securities Act of 1933, as amended,
and Section 21E of the Securities Exchange Act of 1934, as amended.
We intend such forward-looking statements to be covered by the safe
harbor provisions for forward-looking statements contained in the
Private Securities Litigation Reform Act of 1995, and are including
this statement for purposes of said safe harbor provisions.
Forward-looking statements, which are based on certain
assumptions and describe future plans, strategies, and expectations
of our company, are generally identified by use of words
“anticipate,” “believe,” “estimate,” “expect,” “intend,” “plan,”
“project,” “seek,” “strive,” “try,” or future or conditional verbs
such as “could,” “may,” “should,” “will,” “would,” or similar
expressions. Our ability to predict results or the actual effects
of our plans or strategies is inherently uncertain. Accordingly,
actual results may differ materially from anticipated results. Some
of the factors that could cause our actual results to differ from
our expectations or beliefs include, without limitation, the risks
discussed from time to time in our filings with the Securities and
Exchange Commission.
Readers are cautioned not to place undue reliance on these
forward-looking statements, which speak only as of the date of this
release. Except as required by applicable law or regulation, we
undertake no obligation to update these forward-looking statements
to reflect events or circumstances that occur after the date on
which such statements were made.
CardaxJanice Kam, 808-457-1400press@cardaxpharma.com
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