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.
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 radio mitigators 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.
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.
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.
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.
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).
- Antioxidants, especially Tocotrienol was observed to exhibit radio-protective property by lowering inflammation and oxidative stress as shown in Fig. 2.
- Angiogenesis is the process of formation of blood vessels in cancer cells. Tocotrienol promotes cancer cell death to a very great extent.
- Apoptosis is the programmed cell death which leads to the death of cancer cells. Tocotrienol induces apoptosis in cancer cells.
- Anti-Tumor effects on cancer have been observed by all kinds of Tocotrienols isoforms.
- 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.
- 400-600 mg/day.
- Substances that complement Tocotrienol for radiation include Iodine, Selenium etcetera
Why Tocotrienol and Not Tocopherol?
- 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.
- 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.
- 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.
- Tocotrienols: Latest Cancer Research in Vitamin E by Barrie Tan, Ph.D., and Anne M.Trias, MS.
- Tocotrienols: The Promising Analogues of Vitamin E for Cancer Therapeutics https://doi.org/10.1016/j.phrs.2018.02.017
- Gamma-Tocotrienol as a promising countermeasure for acute radiation syndrome.
- To read studies in detail, follow the references and links given.
- The dosages given must not be taken as the advice of a medical practitioner. Consult your physician for the optimum dosage to be consumed.