Radiation – Latest Studies
Nuclear and radiological mass – casualty are quite hazardous
risks to deployed military members and civilians. Mishaps, such as the
Fukushima Daiichi Nuclear Power Plant and the Chernobyl Nuclear Power Plant,
lay stress on the need for available and effective therapeutic options to
mitigate and treat the damaging effects of exposure to lethal doses of ionizing
radiation and combined injury. It is possible that an improvised nuclear
device, radiological dispersal device or a dirty bomb can be detonated in a
densely – populated city, inciting not only panic, fear, injury, destruction
and death, but also a series of other medical issues arising from the blast,
radioactive fallout and extreme heat. The large number of individuals affected
by these events would require urgent medical attention and management.
The hazard of ionizing radiation exposure due to nuclear
accidents or terrorist attacks is a matter of great concern. Despite several
years of research, there is a shortage of non-toxic, safe and effective medical
countermeasures for radiological and nuclear emergency or ailments. To date,
the United States Food and Drug Administration (U.S. FDA) has approved only two
growth factors, Neupogen (granulocyte colony – stimulating factor (G-CSF),
filgrastim) and Neulasta (PEGylated G-CSF, pegfilgrastim) for the treatment of
hematopoietic acute radiation syndrome (H-ARS) following the Animal Efficacy
Rule. Promising radioprotective efficacy results of Gamma – Tocotrienol (Eannatto
– DeltaGold) in the mouse model encouraged its further evaluation in the
nonhuman primate (NHP) model. These studies have demonstrated that Gamma –
Tocotrienol (Eannatto – DeltaGold) significantly aided the recovery of
radiation – induced neutropenia and thrombocytopenia compared to the vehicle
controls; these results were particularly significant after exposure to 5.8 or
6.5 Gray (Gy) whole body Gamma – irradiation. The stimulatory effect of Gamma –
Tocotrienol (Eannatto – DeltaGold) on neutrophils and thrombocytes (platelets)
was directly and positively correlated with dose; a 75 mg/kg dose of Gamma –
Tocotrienol was more effective compared to 37.5 mg/kg of Gamma – Tocotrienol. Gamma
– Tocotrienol (Eannatto – DeltaGold)was also effective against 6.5 Gy whole
body γ-irradiation for improving neutrophils and thrombocytes. Moreover, a
single administration of Gamma – Tocotrienol (Eannatto – DeltaGold) without any
supportive care was equivalent, in terms of improving hematopoietic recovery,
to multiple doses of Neupogen and two doses of Neulasta with full supportive
care (including blood products) in the NHP model. Gamma – Tocotrienol (Eannatto
– DeltaGold)may serve as an ultimate radio – protector for use in humans,
particularly for military personnel and first responders. In brief, Gamma –
Tocotrienol (Eannatto – DeltaGold) is a promising radiation countermeasure that
ought to be further developed for United States FDA approval for the ARS
indication.
But why Tocotrienol is so important but unappreciated? Most
research in the past 50 – 60 years has been focused on Tocopherols and 50% of
all the research in last 30 years has been done on Tocotrienols in last 5
years. Half of the Tocotrienol research ever published has been published in
last 10 years as shown in Fig. 1. Each day it is becoming increasingly
understood that Tocotienols (especially Eannatto – DeltaGold) are the right
form of Vitamin E. Well in excess of 100 studies and clinical trials have shown
the surprising benefits of Tocotrienols – without any known side effects.
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Fig. 1: In the graph, as you can see, R & D on
Tocotrienol has increased exponentially over the years in all fields while
research on Tocopherols has decreased. Whether it is cancer, Cardiovascular
diseases (CVD), Diabetes, Anti – Oxidant activities or others, in all fields
research on Tocotrienol has not only gained pace but quant as well.
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Study
In humans, significant acute radiation injury occurs at
radiation doses above 1 Gray (Gy), with conditions getting increasingly severe
with the increase of absorbed radiation dosage. After an exposure in the range
of 1 to 6 Gy, the hematopoietic system in humans gets damaged in a dose –
dependent manner, resulting in hematopoietic acute radiation syndrome (H-ARS),
which is associated with severe damages to the hematopoietic system. The
concentrations of white and red blood cells, platelets, neutrophils,
lymphocytes and other blood cell components drop and the vulnerability to
possibly lethal infections significantly increases. After exposure to 6 to 8
Gy, hematopoietic symptoms still exist, though with them arise additional
symptoms caused by the breakdown of the gut mucosa, resulting in gastrointestinal
syndrome (GI-ARS). Gastrointestinal syndrome includes severe injury to the
gastrointestinal tract and translocation of gut bacteria to peripheral
circulation and also to remote organs, which results in sepsis and ultimately
death of the victim exposed to radiation. H-ARS and GI-ARS are the major
sub-syndromes of ARS. After exposure to even higher radiation doses,
irreversible damage occurs in the nervous and cardiovascular systems which is
also known as neurovascular syndrome, resulting in unconditional and rapid
death. Due to the degree of damage and the rapidity of symptom onset,
neurovascular syndrome has been recognized as untreatable by the clinical and
scientific research community, and therefore, efforts have been focused on
discovering preemptive and mitigating therapy for H-ARS and GI-ARS victims. The
search for suitable radiation countermeasures has been ongoing for several
decades now and has resulted in the identification of various categories of
radiation countermeasures, which can be used as radio – protectors or mitigators.
Several novel approaches, including cell – based therapies, have been
investigated. However, till present, only two radiomitigators for H-ARS and no
radio – protector have been approved by the United States Food and Drug
Administration (U.S. FDA) for the treatment or prevention of ARS. Amifostine
(WR2721) is another radio – protector that has received U.S. FDA approval for
narrowly-defined indications in humans. Amifostine is clinically used for the
reduction of xerostomia (dry mouth) resulting from salivary gland injury in
head and neck cancer patients undergoing radiotherapy and to protect against
renal toxicity as a result of cis-platinum chemotherapy to patients with
advance ovarian cancer, among several other treatment modalities.
Studies indicate that the vitamin E family members
(Tocotrienols and Tocopherols) mostly act through diverse mechanisms and do not
reveal biological attributes that notably overlap or are redundant.
Tocotrienols have clearly different functions in treating disease and
maintaining health and moreover, several studies have shown superior
antioxidant properties of Tocotrienols over Tocopherols. It has been shown that
Delta – Tocotrienol and Gamma – Tocotrienol protect mice against ionizing
radiation injuries. Among these agents, Gamma – Tocotrienol (Eannatto –
DeltaGold) has been most extensively investigated for its radio – protective
efficacy in mice and nonhuman primates (NHPs) at the Armed Forces Radiobiology
Research Institute (AFRRI) and University of Arkansas for Medical Sciences.
Gamma – Tocotrienol (Eannatto – DeltaGold) antioxidant
activity was a compelling reason to evaluate it for its radio – protective
property. Studies have shown that a single subcutaneous administration prior to
whole body irradiation is capable of dramatically decreasing radiation injury
in several organ systems, including the GI, the hematopoietic system and the
vascular system as well. Actually, after a radiation dose that is uniformly
lethal within 14 days, mice receiving a single dose of Gamma – Tocotrienol (Eannatto
– DeltaGold) 24 hours prior to irradiation showed aound 100% long-term survival
as shown in Fig. 2. Comparatively, Gamma – Tocotrienol (Eannatto – DeltaGold)
appeared to be the most promising Tocol tested as a radiation countermeasure to
date.
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Fig. 2: Radio protective property of
subcutaneously-administered Gamma – Tocotrienol (Eannatto – DeltaGold) in
irradiated CD2F1 strain male mice. Two groups of mice were administered
eitherGamma – Tocotrienol (Eannatto – DeltaGold) (200 mg/kg) or vehicle
subcutaneously 24 hours prior to whole body irradiation with 9.2 Gray (Gy)
(dose rate 0.6 Gy/min). Mice were observed for 30 days. Mice treated with GT3
had a significantly higher survivor rate compared to the vehicle control group (n =
16 each group).
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Gamma – Tocotrienol (Eannatto – DeltaGold) has been observed
to significantly enhance mouse survival through mitigating the
radiation-induced injuries of the hematopoietic and GI systems. In the CD2F1
strain mouse model, the Gamma – Tocotrienol (Eannatto – DeltaGold) dose
reduction factor (DRF) has been estimated to be 1.29. Additional studies have shown
that 24 hours prior to irradiation to be the most effective time for
administration. This might be due to the induction of important hematopoietic
cytokines. The optimal dose of Gamma – Tocotrienol (Eannatto – DeltaGold), 200
mg/kg, accelerated hematopoietic recovery and improved peripheral blood
profiles (total white blood cells, platelets, reticulocytes, neutrophils and monocytes).
Colony-forming assays on sorted hematopoietic stem cells have shown that whole
body irradiation reduces the total number of colonies in irradiated mice
compared to the un – irradiated group (naive mice). Irradiated mice treated
with Gamma – Tocotrienol (Eannatto – DeltaGold)had higher numbers of progenitor
colonies, suggesting preservation of the self – renewable capacity of
hematopoietic stem cells. Histopathological evaluation of mouse sternum shows
that Gamma – Tocotrienol (Eannatto – DeltaGold)treated animals have more
myeloid regenerative microfoci, as well as megakaryocytes and had better
cellularity compared to vehicle-treated and irradiated control animals at 7 and
13 days after whole body irradiation. Gamma – Tocotrienol (Eannatto –
DeltaGold) treatment resulted in significantly reduced numbers of
micronucleated erythrocytes, suggesting that Gamma – Tocotrienol (Eannatto –
DeltaGold) protects hematopoietic tissue by preventing persistent DNA damage in
the hematopoietic stem and progenitor cells.
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Fig. 3: The property of Gamma – Tocotrienol (Eannatto –
DeltaGold) administration on sternal cellularity and megakaryocytes in mice exposed
to ionizing radiation. 2 groups of mice were administered subcutaneously the
vehicle or Gamma – Tocotrienol (Eannatto – DeltaGold) (200 mg/kg) 24 h prior to
irradiation. Mice were exposed to 9.2 Gy (0.6 Gy/min) whole body Gamma-radiation.
Sterna from mice were harvested 6 h after irradiation. Cross-sections of sterna
were processed for tissue fixation, and sternal bone marrow cells were stained
(H&E) to score cellularity. Representative areas of cross-sections are
shown (left panels, 100×; right panels are the marked enlarged
area from respective left panels of each photomicrograph at 400× magnification).
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Gamma – Tocotrienol (Eannatto – DeltaGold)has showed the
ability to mitigate GI radiation injury by improving the survival of intestinal
crypt cells, the recovery of the intestinal mucosal surface area, the
acceleration of soluble endothelial function markers, as well as the reduction
of the vascular oxidative stress in a manner independent of HMG-CoA reductase
after irradiation. Gamma – Tocotrienol (Eannatto – DeltaGold)ability to
decrease radiation-induced oxidative stress was reversed by mevalonate. Tocotrienols
accumulate in the small intestine, as well as colon to greater levels than
tocopherols, which may also aid in their ability to reduce GI injury. In fact, Gamma – Tocotrienol (Eannatto –
DeltaGold)concentrates in endothelial cells at concentrations 30- to 50-times
greater than Alpha – Tocopherol.
Gamma – Tocotrienol (Eannatto – DeltaGold) reduces
post-irradiation vascular peroxynitrite production through inhibition of
HMG-CoA reductase. The inhibitors of this kind mediate their efficacy by
endothelial nitric oxide synthase, with tetrahydrobiopterin (BH4) as an
important cofactor. The effects of irradiation on the bioavailability of BH4
have been investigated in mice, as well as those of Gamma – Tocotrienol (Eannatto
– DeltaGold)on BH4 metabolism.
It has been shown that concentrations of BH4 in lung
decreased compared to baseline values 3.5 days post-irradiation; however, the
treatment with Gamma – Tocotrienol (Eannatto – DeltaGold) reversed this effect.
Both Gamma – Tocotrienol (Eannatto – DeltaGold), as well as BH4 supplementation
significantly inhibited the production of vascular peroxynitrite at 3.5 days
post-irradiation and increased bone marrow colony formation. Gamma –
Tocotrienol (Eannatto – DeltaGold) administration modulated apoptosis of
endothelial cells, reduced guanosine triphosphate cyclohydrolase-1 (GTPCH)
feedback regulatory protein, known as GFRP, and resulted in reduced GFRP-GTPCH
binding. These results suggest reduction in the bioavailability of BH4 in the
early post-irradiation period. They also suggest that exogenous administration
of BH4 reduces post-irradiation vascular oxidative stress. Gamma – Tocotrienol (Eannatto
– DeltaGold)GT3 may produce some of its valuable effects on free radical
production after irradiation partly by offsetting the reduction in BH4,
potentially by reducing the expression of GFRP.
Gamma – Tocotrienol (Eannatto – DeltaGold)has also been
shown to up – regulate A20, an anti-inflammatory enzyme and inhibitor of
nuclear factor-κB (NF-κB), which leads to basal activation of NF-κB. Gamma –
Tocotrienol (Eannatto – DeltaGold)treatment increased phosphorylation of
translation initiation factor-2, inhibitor of κBα (IκBα) and Jun amino-terminal
kinase. The basal activation of NF-κB may lead to the up – regulation of
protective enzymes and other proteins, which may result in radioprotection.
Summary
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Studies have been conducted by Armed Forces
Radiobiology and Radiation Institute of America on Tocotrienol. They are
looking for a compound that will protect armed forces from radiation
exposure. When they get exposed to radiation in regions like those in Iran,
North Korea, Pakistan etcetera, in one month, their white blood cells and red
blood cells should be normal in yellow region like you can see in Fig. 4.
With Tocotrienol WBCs, Neutrophils, Blood Platelets, Lymphocytes etcetera
all were able to come back in the yellow region of the graph for
sustainability. If after 30 days they won’t get back to normal then life would
not be sustainable.
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Fig. 4: We can see how the WBC’s, Neutrophil’s, Blood
Platelet’s and Lymphocyte’s count was back to normal by the effect of
Gamma-Tocotrienol and Delta – Tocotrienol and also, how the bone marrow was
protected by their action.
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A Delta – Tocotrienol study was also done
related to the survival of animals in case of radiation exposure as shown in
Fig. 5. It was observed that the chances of survival were increased when the
animals were given Delta – Tocotrienol (Eannatto – DeltaGold).
So why Tocotrienol? |
Fig. 5: The black line in the graph represents the
decreasing survival rate when exposed to radiation without being given
Tocotrienol. In 12-13 days, the survival rate fell below 50% and in 18 days,
all the animals were dead. While the red line with solid squares represents the
survival rate when 150 mg/kg of Delta – Tocotrienol was given to animals and
the survival rate never fell below 80%. The blue line with triangles represents
the survival rate when 400 mg/kg of Gamma – Tocotrienol was given to animals
and it was observed that the survival rate never fell below 90%. The red line
with hollow squares represents the survival rate when 300 mg/kg of Delta –
Tocotrienol was given to animals and it was observed that the survival rate
even when exposed to radiation was 100%!
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Antioxidants, especially Tocotrienol was
observed to exhibit radio-protective property by lowering inflammation and
oxidative stress as shown in Fig. 2.
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Fig. 6: In the study conducted by Dr. Qureshi, he saw that
at 250 mg of Tocotrienols, the endogenous anti-oxidant, TAS (represented with
grey colour) increased, while the C-reactive protein (CRP) dropped by 40%,
oxidized fat (MDA) dropped by 34% and Total Anti-oxidant increased by 22%.
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Angiogenesis is the process of formation of
blood vessels in cancer cells. Tocotrienol promotes cancer cell death to a very
great extent.
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Fig. 7: In a study, it was observed in mice cells, that
Delta - Tocotrienol inhibited the formation of blood vessels in cancer cells
(Anti – Angiogenesis) while Tocopherol completely failed on such grounds.
Delta-Tocotrienol was also observed to induce apoptosis in the mice cancer
cells.
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Apoptosis is the programmed cell death which
leads to the death of cancer cells. Tocotrienol induces apoptosis in cancer
cells.
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Anti-Tumor effects on cancer have been observed
by all kinds of Tocotrienols isoforms.
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Cancer stem cell death has been observed by the
action of Tocotrienols especially Delta – Tocotrienols (DeltaGold – Eannatto).
Even after chemotherapies, radiation and surgeries, there are stem cells of
those cancerous tissues left revolving in your body which can lead to your
cancer coming back. Henceforth, their death is very necessary and Tocotrienols
have been observed to kill cancer stem cells.
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Fig. 8: About 1% of cancer cells are Cancer Stem Cells (CSC)
which keep circulating in your body even after nailing the cancer through
chemo. It has been observed that Gamma – Tocotrienol and Delta – Tocotrienol,
both specifically target CSC.
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Dosage
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400-600 mg/day.
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Substances that complement Tocotrienol for
radiation include Iodine, Selenium etcetera
Why Tocotrienol and Not Tocopherol?
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Tocopherol, the enemy of Tocotrienol: Earlier,
in a breast cancer clinical study a mixture of Tocotrienol and Tocopherol was
used but then Tocopherol was replaced by Gamma-Tocotrienol because it witnessed
interference of Tocopherol in the functioning of Tocotrienol! Tocopherol has
been observed to attenuate cancer inhibition, inhibits absorption, reduces
adipose storage, and compromises cholesterol and triglyceride reduction.
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Tocotrienol, the protector of State: Tocotrienol
has more mobility than Tocopherol due to its small structure so it can cover a
larger area targeting more number of breast cancer cells.
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Small structure and less molecular weight: The
higher anti-oxidant activity of Tocotrienols is due to their small structure
and less molecular weight which assist in their integration of the cell, unlike
Tocopherols.
· Absorption: As compared to Tocopherols,
Tocotrienols absorb better in the body and Tocopherols have been observed to
prevent absorption of Tocotrienols.
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Fig. 9: The 2nd pie chart represents Palm Tocotrienol rich
fraction with 32% Alpha – Tocopherol which was given to people and when the
Alpha – Tocopherol was removed then it was represented by the 1st pie chart
with 0.3% Alpha – Tocopherol which was then given to people. In the graph, the
hollow bar represents the Tocotrienol with Tocopherol which reduced the
concentrations of Alpha, Gamma and Delta Tocotrienol in the body but when
Tocopherol was removed from the dosage (Solid grey bars in graph), the concentrations
of Alpha, Gamma and Delta – Tocotrienol significantly increased.
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References:
·
Tocotrienols: Latest Cancer Research in Vitamin
E by Barrie Tan, Ph.D., and Anne M.Trias, MS.
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Tocotrienols: The Promising Analogues of Vitamin
Efor Cancer Therapeuticshttps://doi.org/10.1016/j.phrs.2018.02.017
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Gamma-Tocotrienol as a promising countermeasure
for acute radiation syndrome.
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