Oxygen Free Radicals and Aging: Part II

by Emmanuel C. Opara, Ph.D.

In case you missed Part I of this three-part series, we reviewed the major theories of aging, including: the rate of living theory; the somatic mutation theory; the neuroendocrine theory; the glycation theory; the crosslinking theory; and the free radical theory. The free radical theory of aging, which holds that aging is due to damage to DNA and molecular membranes by highly reactive molecules known as free radicals, is especially appealing for many reasons. First, it provides a unifying mechanism for the different theories; second, it can be experimentally verified; third, it suggests a number of parameters that can be evaluated to determine the progress of aging and the success of anti-aging therapies; and finally, it is a mechanism that can be altered by appropriate antioxidant therapies. Sources of free radicals were also discussed, which included both exogenous (outside the body) and endogenous (inside the body) sources. Some of these exogenous sources include air pollution and cigarette smoke. It’s obvious that it’s impossible to avoid contact with these reactive molecules.

Fortunately, the body is naturally equipped with antioxidant defense systems to detoxify these dangerous agents. Unfortunately, the body’s defense system becomes less effective as we get older, leading to the accumulation of oxidative damage and the development of chronic degenerative diseases like arthritis, hypertension, atherosclerosis, diabetes, cancer and diseases of the central nervous system such as stroke, Alzheimer’s disease and Parkinson’s disease. Depletion of antioxidants can thus lead to a variety of chronic diseases. The relationship between oxidative damage and aging is a double-edged sword. On one hand, oxidative damage to DNA, lipids, proteins and other macromolecules appears to be a major contributing factor to aging,1 while at the same time, this oxidative damage accumulates with aging, despite attempts by an individual’s cellular machinery to repair it.7,8

For example, blood levels of glutathione, the major cellular antioxidant in the body, decline with age.1,2 Low glutathione levels are associated with a higher incidence of diseases in the elderly.3 In fact, blood glutathione concentrations may become recognized not only as a predictor of susceptibility to disease, but also as a marker of biological age.

Oxidation and Disease Progression
In this article, we’re going to discuss the specific contributions that damaging free radical reactions make in promoting the onset and progression of the chronic degenerative diseases of aging. We’ll discuss the role of free radicals (oxidants) in the development of each of these diseases, and provide a strong rationale for using antioxidant supplements for disease prevention and treatment. Indeed, a great deal of evidence regarding the role of free radicals in aging and its related diseases has been derived from studies in which antioxidant supplements have been used to successfully treat or prevent these diseases. Many of these studies will be reviewed in Part III of this series.

Cancer
Free radicals are involved in both the process of aging and the development of cancer.4 They attack many cellular targets including membranes, proteins and nucleic acids,5 and cause structural damage to the cellular DNA. These structural changes manifest as point mutations and chromosomal alterations in cancer-related genes.5 Consequently, elderly people are predisposed to the development of cancer. Fortunately, certain antioxidant supplements like vitamins C and E, can prevent much oxidative damage to DNA and thus reduce the ability of the oxidants to induce cancer.7

Cardiovascular Disease
One of the most significant discoveries in modern cardiovascular disease research was the discovery of how free radical activity contributes to cardiovascular disease.4,7 These discoveries were made using two different approaches. One approach, using epidemiological studies, showed that cardiovascular disease is associated with low plasma concentrations of antioxidant vitamins.7 The other approach, using experimental studies, provided strong evidence that free radicals oxidize low density lipoprotein (LDL) – the bad form of cholesterol. The modified LDL molecules are then easily taken up by white blood cells called macrophages (phagocytes) to form foam cells and plaques in the cardiovascular wall,4,7 causing a hardening and narrowing of the blood vessels which impairs blood flow and deprives the heart of oxygen and nutrients. Also, what is known as reperfusion (reoxygenation) injury is caused by inadequate supplies of intracellular antioxidants! Reperfusion injury is the damage to cells which occurs following restoration of the blood and oxygen supply to the heart after a period of ischemia (inadequate blood supply). Antioxidants are able to prevent or reduce the severity of this type of tissue damage.4

Diseases of the Central Nervous System
Oxidative damage has been implicated in brain aging as well as several degenerative diseases of the central nervous system (CNS). A number of mechanisms have been identified which explain the causative role played by free radicals in the neurodegenerative diseases. First, oxidants may activate an enzyme of nerve cells (poly ADP-ribose synthetase) and cause an increase in the intracellular calcium ion concentrations, which is injurious to neurons.12 Second, reoxygenation of brain cells following a period of ischemia contributes to oxidant injury of the CNS, as already mentioned in the case of cardiovascular disease. Third, certain areas of the brain, e.g., the globus, pallidus and substantia nigra often contain high amounts of iron. Excess iron enhances oxidative reactions and consequent injury to the neurons.12 It is therefore not surprising that antioxidant supplements have been successfully used to improve the functioning of the brain both in people who are aging normally, as well as patients suffering from neurodegenerative diseases such as stroke and Alzheimer’s and Parkinson’s diseases.

I. Strokes
Free radical-produced damage due to ischemia-reperfusion in the brain has been implicated as a major cause of strokes.12 Antioxidant supplements appear to be of benefit in the prevention and reduction of strokes.12,13 And, to top it off, recent clinical studies indicate that surgical therapy (i.e., carotid endarterectory) is actually worse than no therapy in many cases.

II. Alzheimer’s Disease
Alzheimer’s disease (AD) is the tragic brain-robbing disease of aging. It can be recognized by the progressive loss of memory and other aspects of cognitive functioning. Its characteristic pathological features include tangles of nerve fibers, senile plaques (which contain aluminum, iron, and calcium) and the loss of brain cells.9 Oxidative damage has been implicated in AD, for a number of reasons. First, the brain has the highest oxygen consumption rate of any organ in the body, high concentrations of easily-oxidizable lipids, and a relative deficiency of antioxidant enzymes (compared to other tissues).9 Second, iron, which plays an important role in free radical generation, has been found in high concentrations in the brain in AD.9 Third, antioxidant supplementation often improves memory performance in aged individuals.10

III. Parkinson’s Disease
The hallmark of Parkinson’s disease is degeneration of a portion of the brain called the substantia nigra – the portion of the brain that produces the stimulatory neurotransmitters epinephrine (adrenaline) and norepinephrine (noradrenaline). There are two mechanisms that have been proposed as possible causes of this neuronal damage.11 The first is that increased production of oxidants causes damage to this vital portion of the brain (the substantia nigra) through iron-dependent free radical reactions. It has been shown that the iron content of the substantia nigra is often elevated, while ferritin, the iron-binding protein is often decreased in Parkinson’s disease. Again, the resulting increase in free iron ions enhances iron-dependent lipid peroxidation and damage to nerve cells.12 A second mechanism is impaired neuronal mitochondrial function, which leads to failure of energy production and adverse changes in the metabolism of nerve cells.

There are several mutually supporting links between these two mechanisms.11 As previously noted, mitochondria are a critical target for damage by free radicals.4,7,11 Also, mitochondrial damage may cause a further increase in generation of free radicals.11 Another link between the two mechanisms (i.e., oxidative damage to mitochondria vs. free-radical induced damage to neuronal metabolism) is glutathione. Patients with Parkinson’s disease tend to have low levels of this powerful intra-cellular antioxidant in their brains, resulting in higher levels of free radical activity.11 These two mechanisms both contribute to neuronal damage through alterations in glutathione levels.11

A variety of antioxidant vitamins and drugs are helpful for patients with this disease, especially Vitamin E and deprenyl I believe that one of the most beneficial nutrients for Parkinson’s disease is N-acetyl cysteine (NAC). NAC boosts glutathione production, and should be of tremendous benefit to Parkinson’s patients, in doses ranging from 600-1200 mg per day.

Inflammatory Diseases
Arthritis and inflammatory diseases of the large intestine, such as ulcerative colitis and Crohn’s disease, are conditions in which oxidative damage has also been implicated.4,14 While there is agreement that free radicals play a role in the pathogenesis of inflammatory disease, the mechanism(s) involved is still a matter of intense research. One plausible mechanism of oxidant mediated injury involves tissue protein oxidation, otherwise referred to as protein carbonylation. It has been proposed that inflammatory bowel disease (IBD) may arise from the oxidation of proteins in the intestinal mucosa cells which thereby disrupt the critical enzyme systems that are important for the maintenance of mucosal integrity or ion transport, both of which are impaired in IBD.15 Antioxidant supplements have helped many people who suffer from a variety of inflammatory diseases.4,7,15

Diabetes
Diabetes is a multi-systemic disease caused by a defect in glucose metabolism. Abnormally high blood sugar levels are a major clinical feature of the disease, which is usually followed by accelerated onset and progression of atherosclerosis and other diseases. In type 2 diabetes, oxidative damage has been implicated in both the development of the disease as well as its many complications. Oxidants inhibit glucose metabolism in the glycolytic pathway and at the level of oxidative phosphorylation, thereby causing a sugar overload in the blood. The medical term for high blood sugar levels is hyperglycemia. Increased blood sugar levels cause auto-oxidation of glucose and glycation of proteins which have been implicated in the development of diabetic complications.16 It is therefore not surprising that antioxidant supplements – particularly vitamins C and E, and lipoic acid – have been found to be beneficial to patients suffering from diabetes.16 This subject was covered extensively in previous reviews by this author (see Nutritional News volume 10: 6 and 7, 1997).

Vision

I. Cataracts
Oxidative damage to the lens of the eye, which collects and focuses light on the retina, plays a major role in the formation of cataracts.7,17 With age, the constituents of the lens are damaged by oxidants causing opaque precipitations that are referred to as senile cataracts.17 A variety of antioxidant supplements have been shown to provide protection against the development of cataracts7,17 – especially, lipoic acid – a key player in the prevention of cataracts.

II. Macular Degeneration
Macular degeneration is a leading cause of blindness in the elderly. It is one condition which ophthalmologists used to stand by and helplessly watch as their patients’ vision failed. Now, they are finding that combinations of antioxidant and carotenoids have demonstrated the ability to halt or delay the progression of this dreaded condition.
Many studies have been performed with multi-nutrient protocols to treat ARMD and cataracts. For example, Dr. E.N. Crary of Smyrna, Georgia published a study in 1987 in the Southern Medical Journal titled “Antioxidant Treatment of Macular Degeneration of the Aging and Macular Edema in Diabetic Retinopathy.” In this study, Dr. Crary used 250 mcg of selenium, 15,000 units of beta carotene, 500 mg of vitamin C and 400 units of vitamin E for a period of 7 to 12 years. He treated over 500 patients and found that the treatments either halted or improved degenerative macular changes in 60% of the patients with age-related macular degeneration.

Summary
It is apparent, as outlined above, that free radical (oxidative) damage plays a significant role in the process of aging as well as in the development of a broad spectrum of age-associated diseases. Specific supplements and their dosages for preventing and minimizing the effects of these diseases will be reviewed in part III of this series.

References:

1. Lang CA, Naryshkin S, Schneider DL, Mills BJ, Lindeman RD. Low blood glutathione levels in healthy aging adults. J Lab Clin Med 120: 720-725, 1992.
2. Vina J, Sastre J, Anton V, Bruseghini L, Esteras A, Aseni M. Effect of Aging on glutathione metabolism. Protection by antioxidants. In: Free Radicals and Aging. Emerit I and Chance B (eds.), 136-144, 1992.
3. Julius M, Lang CA, Gleiberman L, Harburg E, DiFranceisco W, Schork A. Glutathione and morbidity in a community-based sample of elderly. J Clin Epidemiol 47: 1021-1026, 1994.
4. Cross CE, Halliwell B, Borish ET, Pryor WA, Ames BN, Saul RL, McCord JM, Harman D. Oxygen Radicals and Human Disease. Ann Int Med 107: 526-545, 1987.
5. Cerutti P, Ghosh R, Oya Y, Amstad P. The role of the cellular antioxidant defense in oxidant carcinogenesis. Environmental Health Perspectives 102 (suppl 10): 123-130, 1994.
6. Block G. A role for antioxidants in reducing cancer risk. Nutrition Reviews 50: 207-213, 1992.
7. Ames BN, Shingenaga MK, Hagen TM. Oxidants, antioxidants and the degenerative diseases of aging. Proc Natl Acad Sci (USA) 90: 7915-7922, 1993.
8. Gilchrist BA, Bohr VA. Aging processes, DNA damage, and repair. FASEB J 11: 322- 330, 1997.
9. Lovell MA, Ehmann WD, Butler SM, Markesbery WR. Elevated thiobarbituric acid- reactive substances and antioxidant enzyme activity in the brain in Alzheimer’s disease. Neurology 45: 1594-1601, 1995.
10. Perrig WJ, Perrig P, Stahelin H. The relation between antioxidants and memory performance in the old and very old. J Am Geriatr Soc 45: 718-724, 1997.
11. Di Monte DA, Chan P, Sandy MS. Glutathione in Parkinson’s disease: a link between oxidative stress and mitochondrial damage. Ann Neurol 32: S111-S115, 1992.
12. Halliwell B. Oxidants and the central nervous system: some fundamental questions. Acta Neurol Scand 126: 23-33, 1989.
13. Mobarhan S. Micronutrient supplementation trials and the reduction of cancer and cerebrovascular incidence and mortality. Nutrition Reviews 52: 102-105, 1994.
14. Ruan EA, Simbasiva R, Burdick S, Stryker SJ, Telford GL, Otterson MF, Opara EC, Koch TR. Glutathione levels in chronic inflammatory disorders of the human colon. Nutrition Research 17: 463-473, 1997.
15. Otamiri T, Sjodahl R. Oxygen radicals: their role in selected gastrointestinal disorders. Dig Dis 9: 133-141, 1991.
16. Paolisso G, Giugliano D. Oxidative stress and insulin action: is there a relationship? Diabetologia 39: 357-363, 1996.
17. Taylor A. Effect of photooxidation on the eye lens and role of nutrients in delaying cataract. In: Free Radicals and Aging. Emerit I and Chance B (eds.), 266-279, 1992.

Natural Protection and Recovery From Stress

by Ward Dean, MD

As the consequences of our current national trauma unfold in the days and months ahead, each of us must confront the anxiety and stress of facing an unpredictable future. Chronic anxiety and long-term post-traumatic stresses have a devastating effect on mental, psychological and physical health.

The Father of Stress

Eastern researchers have a long history of searching for solutions to stress-related problems. In Russia, after years of scientific investigation, Soviet scientists were inspired by the groundbreaking work of Dr. Hans Selye, a Canadian professor and leading pioneer in stress research. Internationally acknowledged as ‘the father of stress,’ Dr. Selye authored more than 1,700 scholarly papers and 39 books which had a profound influence on Soviet scientists doing stress research for the Russian military, sports and space programs.

General Adaptation Syndrome

Among the most memorable of Selye’s contributions was his concept of the General Adaptation Syndrome (GAS). First described in 1936, the GAS involves three progressive stages:

Alarm: The alarm reaction is the first stage, characterized by surprise and anxiety when exposed to a new situation. The body reacts by producing epinephrine and norepinephrine, the ‘flight or fight’ hormones. Additionally, the adrenal cortex is stimulated to produce additional cortisol and related hormones.

Resistance: In this stage, the body learns to efficiently cope with stress. Ideally, this stage continues until the stressful situation is resolved, leading to a rapid return to the resting state. Unfortunately, our capacity for resistance is limited and highly individualized (i.e. what is stimulating to one person may be devastating to another) and worsen with age. (Fig. 1). Just as a chain breaks at its weakest link, exhaustion of our adaptive capacity can result in stress-induced disease.

Exhaustion: In the presence of long-term exposure to the same stressor, we enter the third stage of GAS — exhaustion, characterized by the depletion of energy reserves and loss of adaptational ability, leading to fatigue or other symptoms or diseases.

This third stage is also sometimes referred to as adrenal maladaptation, or hyperadaptosis (Dilman and Dean, 1992). Chronically elevated cortisol levels can result in the signs and symptoms resembling Cushing’s Syndrome. (Fig. 2) Adrenal dysfunction may be manifested by (1) an excess or inadequacy of cortisol, DHEA, ACTH and/or CRF; (2) relative imbalances of these hormones and releasing factors, and (3) loss of sensitivity of the hypothalamus and pituitary to the normal, inhibiting effects of these hormones.

Symptoms of patients suffering from adrenal maladaptation syndrome include:

• Fatigue

• Nervousness

• Severe PMS

• Salt craving

• Depression

• Inability to concentrate

• Carbohydrate craving

• Allergies (hay fever, asthma)

• Anxiety

• Headache

• Alcohol intolerance

• Muscular pain and tenderness

• Joint pains and tenderness (arthritis)

• Weakness

• Poor memory

• Palpitation

• Abdominal discomfort

• Alternate diarrhea and constipation

• Obesity

• Poor wound healing

• Glucose intolerance

• Moon face

• Purple striae

• Loss of bone density

Dr. Nicholai Lazarev

Selye’s ideas of the General Adaptation Syndrome (GAS) were readily accepted by leading Russian researchers, including Dr. Nicholai Lazarev, a pioneer in the then-emerging fields of toxicology and preventive medicine. Shortly after graduating medical school Lazarev discovered that different industrial chemicals, even in mild concentrations and small dosages, cause similar alarm reactions. When exposure is prolonged, the body adapts by altering its physiological response (resistance). This adaptive reaction tends to gradually disturb homeostasis, which is damaging to health.

Lazarev found that Selye’s publication on stress confirmed his own findings. Selye proved that a variety of stressors — not just chemicals — can cause non-specific stress reactions. Selye’s work was so influential, in fact, that Lazarev changed the direction of his work. He began looking not only for substances that could improve humans’ general resistance to toxins, but could also correct the general adaptation reaction to all kinds of stressors, including both mental and physical stress.

WWII Research

From the beginning of the second World War, Lazarev’s efforts shifted to finding substances that could help Soviet soldiers overcome fatigue and improve their performance on the battlefield. With the soldiers as unknowing guinea pigs for amphetamines and other stimulants, Lazarev learned that many drugs were very effective in improving performance in response to great challenges in extreme situations for very short terms. However, he realized that the stimulants were harmful when used for prolonged periods. When WWII ended, Lazarev switched his focus to natural alternatives.

Traditional Herbs

Lazarev was especially intrigued by a group of herbs that ancient medical traditions referred to as ‘elite’ or ‘kingly.’ In traditional Chinese medicine these herbs were classified as effective for increasing physical and mental capacity, reducing fatigue, improving resistance to disease, and promoting life extension. In China, soldiers used these herbs before battle. In Siberia, hunters used the herbs before long and dangerous journeys. In 1948, Lazarev and his protege, Dr. Israel Brekhman, undertook the challenge of researching the utility and effectiveness of this group of plants that Lazarev named ‘adaptogens.’

The group first focused their efforts on ginseng, but quickly encountered problems with low availability, high cost, and wide fluctuations in effectiveness among different groups of subjects. This prompted Brekhman and his team to next focus their efforts on herbs adapted to growing in harsh environments based on the assumption that unique substances in these herbs enabled them to adapt and survive through millions of years of natural cataclysmic changes.

Eventually Brekhman’s group identified a group of herbs that fit the profile of an adaptogenic compound that is defined as: 1) an herb that is absolutely safe and possesses no side effects, even when used for long periods of time; 2) exhibits broad and nonspecific positive effects on the body; and 3) one that has a normalizing effect that keeps the body in balance while maintaining homeostasis and normalizing all functions.

Among the adaptogens discovered by Brekhman’s team are:

• Eleutherococcus (Siberian Ginseng)

Brekhman and his colleagues were particularly impressed with their studies of Eleutherococcus, commonly known as Siberian Ginseng, which they found had even greater anti-fatigue properties than the better-known Panax ginseng. Their studies soon led to a massive testing program with clinical trials conducted across the USSR on factory workers, long distance truck drivers, sailors on long voyages, and military personnel under severe stress. The stress studies revealed that Eleutherococcus helps to improve stamina, increases oxygen uptake, enhances physical energy and performance, and reduces high blood pressure.

Eleutherococcus was also found to enhance immune function, and incidence of cases during an influenza epidemic dropped by two-thirds. Additionally, 107 patients receiving anti-cancer drugs for gastric cancer showed evidence of a 50% reduction in impaired immunity, and a 50% decrease in drug dosage.

In 1962, Eleutherococcus, the prototype adaptogen, was declared an official herbal medicine by the USSR Minister of Health and was included in the National Drug Guide, the pharmacopoeia of the USSR. Eleutherococcus was soon widely available, and patients, athletes, cosmonauts, and soldiers used it regularly as a restorative. The Soviet government realized that this new class of natural remedy could give the Soviets an advantage in many areas, including sports, the arts, space, military, and medicine.

• Schisandra

Schisandra is an herb widely used in ancient and modern China to treat a number of conditions. It is a powerful antioxidant and anabolic agent. Schisandra also promotes glycogenesis, the process that converts carbohydrates into glycogen. Glycogen is stored in the liver and muscles until needed and then converted into glucose. This process helps spark the energy necessary to revitalize ‘stressed out’ cells.

Research also indicates that Schisandra stimulates the central nervous system, possibly by increasing dopamine and its metabolites in the striatum and hypothalamus. Dopamine — a catecholamine synthesized by the adrenal glands — is an immediate precursor in the synthesis of norepinephrine, which plays a pivotal role in helping the hypothalamus-pituitary-adrenal axis adjust to stress.

• Rhaponticum Carthinoides

Rhaponticum carthinoides is an adaptogenic herb that helps prevent the catabolic state seen in stress. Components of Rhaponticum carthinoides have demonstrated anabolic properties in clinical studies. Under conditions of daily aerobic and anaerobic training, patients who consumed a number of saponins isolated from Rhaponticum for three weeks lost fat and gained muscle mass. Similar results were achieved in animal experiments in which rats fed phytiexdizone-exdisterone (a component of Rhaponticum) for 7 days gained body weight. The amount of protein increased in the animals’ livers, hearts, and kidneys, along with the weights of each of these organs.

• Tribulus Terrestris

In one study, healthy males who took 750 milligrams of Tribulus terrestris daily for five days experienced a 72% increase in luteinizing hormone (LH) and a 40% increase in testosterone. Produced by the adrenal cortex in both males and females, testosterone is an important anabolic, anti-stress hormone. It accelerates growth in tissues, stimulates blood flow and affects many metabolic activities.

• Manchurian Thorn Tree (Aralia Manchurica)

In any condition characterized by adrenal dysfunction, it is extremely important to stabilize blood sugar — whether it is too high or too low — thereby alleviating a major metabolic stress on the body. Studies have shown that adaptogens help achieve extra stamina and energy by enhancing utilization of glucose. In oral glucose tolerance tests in rats, Aralia extracts have acted as hypoglycemic agents. Clinicians have found that Aralia can complement the adrenal-protective actions of other powerful adaptogens such as Eleutherococcus.

Conclusion

The mechanism by which adaptogens achieve their stress-protecting, normalizing action is well researched. Adaptogens act to restore hypothalamic and peripheral receptor sensitivity to the effects of cortisol and other adrenal hormones. In this way, adaptogens enable the body to mount an appropriate stress response with lower amounts of cortisol than would otherwise be required, and help the adrenals return to normal more quickly.

Clinicians have noticed that adaptogens like Siberian Ginseng (Eleutherococcus sinensis), Manchurian Thorn Tree, Schisandra, Rhaponticum carthinoides, Hawthorn extract, Adjuga turkistanica, and Tribulus terrestris act synergistically — that is that they work better in combination than when used separately. They have also learned that certain combinations were more effective at certain times, such as before or after physical challenge, when they often enhanced the body’s recovery process.

References

1. Tintera, John W. The hypoadrenal state and its management. New York State Journal of Medicine, 55: 13, July 1, 1955, 1-35.

2. Selye, Hans. Stress Without Distress. Signet, New York, 1974.

3. Dilman, Vladimir, and Dean, Ward. The Neuroendocrine Theory of Aging and Degenerative Disease, The Center for Bio-Gerontology, Pensacola, Florida, 1992.

4. Gubchenko, P.P. and N.K. Fruentov. ‘Comparative Study of the Effectiveness of Eleutherococcus and Other Plant Adaptogens as Remedies for Increasing the Work Capacity of Flight Personnel.’ New Data on Eleutherococcus: Proceedings of the 2nd International Symposium on Eleutherococcus (Moscow, 1984). Vladivostok. Far East Academy of Sciences of the USSR, 1986, 240.

5. Asano, K., T. Takakhsi, K.H. Kugo, M. Kuboyama. The Influence of Eleutherococcus on Muscle Work Capacity in Humans.’ New Data on Eleutherococcus: Proceedings of the 2nd International Symposium on Eleutherococcus (Moscow, 1984). Vladivostok. Far East Academy of Sciences of the USSR, 1986, 166.

6. Schezin, A.K., V.I. Zinkovich, and L.K. Galanova. ‘Eleutherococcus in Prevention of Influenza, Hypertonia and Ischemia in Drivers of the Bolzhsky Automobile Factory.’ New Data on Eleutherococcus: Proceedings of the 1st International Symposium on Eleutherococcus (Hamburg, 1980). Vladivostok. Far East Academy of Sciences of the USSR, 1981, 93.

7. Brekhman, I.I., I.V. Dardymov. New Substances of Plant Origin which Increase Nonspecific Resistance. Annual Review of Pharmacology, v.9.1969,

8. Kurkin, V.A. and G.G. Zapesochnaya. ‘Chemical Composition and Pharmacological Properties of Rhodiola Rosea. Khimiko-Garmatsevtichesky Zhurnal (Chemical Pharmaceutical Journal), 20(10). 1986. 1231-1244.

9. Wahlstrom, Mikael. Adaptogens: Nature’s Key to Well-Being. Goteborg; Skandinavisk Bok, 1987.

10. Lenard L. Adaptogens and Human Stress Responses. Vitamin Research News. September 1999. Available at www.vrp.com.

11. Liu GT. Pharmacological actions and clinical use of fructus schizandrae. Chin Med J (Engl). 1989; 102(10):740-9.

12. Zhang L, Niu X. [Effects of schizandrol A on monoamine neurotransmitters in the central nervous system]. Chung Kuo I Hsueh Ko Hsueh Yuan Hsueh Pao. 1991; 13(1):13-6.

13. Boza JJ, Moennoz D, Vuichoud J, Jarret AR, Gaudard-de-Weck D, et al. Food deprivation and refeeding influence growth, nutrient retention and functional recovery of rats. J Nutr. 1999; 129(7):1340-6.

14. Dragan I, Stroescu V, Stoian I, Georgescu E, Baloescu R. Studies regarding the efficiency of Supro isolated soy protein in Olympic athletes. Rev Roum Physiol. 1992; 29(3-4):63-70.

15. Syrov VN, Kurmukov AG. [Anabolic activity of phytoecdysone-ecdysterone isolated from Rhaponticum carthamoides (Willd.) Iljin]. Farmakol Toksikol. 1976; 39(6):690-3.

16. Yoshikawa M, Murakami T, Harada E, Murakami N, Yamahara J, Matsuda H. Bioactive saponins and glycosides. VII. On the hypoglycemic principles from the root cortex of Aralia elata Seem.: structure related hypoglycemic activity of oleanolic acid oligoglycoside. Chem Pharm Bull (Tokyo). 1996;44(10):1923-7.

17. Jeffries, William McK. Safe Uses of Cortisone. Charles C. Thomas, Springfield, 1981.

Over 60 years ago the FDA approved a little known product, thimerosal, to be used as a preservative. Today many people question whether this product is responsible for the current epidemic of children diagnosed with learning disabilities and autism.

Thimerosal
Current thinking suggests that exposure to mercury comes primarily from environmental and dietary sources, dental amalgams and rare catastrophic events. Recently, however, another common and pervasive source of mercury exposure has been identified–thimerosal. Thimerosal was first approved as an additive by FDA in the 1930s. It has been utilized as a preservative to prevent bacterial contamination in a number of blood and biological products, including vaccines, immune globulins, and over-the-counter eye and nose drops. The danger that thimerosal presents is that it contains 49.5% ethyl mercury by weight. Mercury is a potent human toxin that has long been the source of many serious health problems. Mercury is especially toxic to the rapidly developing fetal and infant brain. While acceptable levels for exposure are published by Federal Agencies, mercury is a poison at any level.

Chemically, thimerosal is a water soluble, cream colored crystalline powder. In the human body thimerosal is metabolized to ethylmercury and thiosalicylate. The literature on thimerosal metabolism and excretion is old, and toxicological information is limited. Therefore, it has been assumed that the toxicity of ethylmercury is equivalent to that of methylmercury until further information is available. In the past there have been case reports of toxicity and death following inadvertent massive exposures.

FDA’s Discovery

The 1997 FDA Modernization Act required the FDA to compile a list of drugs and foods that contain intentionally introduced mercury compounds, and to provide a quantitative and qualitative analysis of the mercury compounds on the list. Although FDA’s mission is to ensure purity, safety, potency and efficacy of individual products, such analysis had never been a required part of the permitting process. In its review, which took two years to complete, the FDA discovered that infants who receive thimerosal-containing vaccines at several visits may be exposed to mercury in amounts higher than recommended by Federal guidelines for total lifetime mercury exposure.

Infant vaccines that routinely contained thimerosal were DPT, Hep.B and HiB. Following the CDC recommended vaccine schedule, infants were exposed to up to 187.5 mcg of ethyl mercury, depending on the vaccine manufacturer. Total exposure through 18 months could be as high as 237.5 mcg. (Table 1.) The dose thought to be allowable by EPA is 0.1 mcg per kilogram per day. If an average 5 kg infant received all thimerosal-containing vaccines at his 2 month visit, the exposure that day would be 62.5 mcg ethyl mercury, an exposure that is 125 times above the EPA’s guideline.

In its analysis, the FDA multiplied EPA’s daily exposure levels of 0.1 mcg per kilogram by 180 days, even though the exposures had occurred on only 4 days during this time period. It is perplexing that the FDA chose to average an infant’s total exposure to mercury over the first six months of life, as though children were being exposed on a daily basis, and reported that amounts were only slightly above one of the Federal guidelines. According to toxicologists, because of the inherent pharmokinetics of mercury and its long half-life in the body, it is not possible to legitimately calculate the effect of a large injected bolus dose as though it were a small amount administered over a longer period of time. This method of analysis fraudulently minimizes the levels of exposure. If one were to look at the mercury in thimerosal from a daily dose perspective, not one vaccine containing thimerosal would be able to meet EPA’s guidelines for safe exposure. That’s like claiming that taking 4 Tylenol a day at 6-hour intervals for a month is an “equivalent dose” to taking 120 Tylenol in one day.

At the same time the FDA findings were released, The American Academy of Pediatrics published An Interim Report to Physicians on Thimerosal in Vaccines. In this document, the AAP and Public Health Service agreed that the use of thimerosal-containing vaccines should be reduced or eliminated, stating that any potential risk was of concern. While the document discussed much of the uncertainty regarding the potential effect of mercury exposure in vaccines, it clearly stated that there was no evidence of harm having occurred from this exposure. The Academy also recommended, “Infants and children who have received thimerosal-containing vaccines do not need to have blood, urine, or hair tested for mercury, since the concentrations would be quite low and would not require treatment.” If no testing for mercury was recommended, then how could one know, for a fact, that there is “no evidence of harm”?(1)

Historical Perspective

It is interesting to note that thimerosal was introduced only a few short years before Dr. Leo Kanner described a new mental disorder which differed “markedly and uniquely from anything reported” before. In its early history autism was diagnosed more frequently in affluent families, but became more evenly distributed socioeconomically by the 1970s. This apparent widening in demographics paralleled the increasing availability of vaccines to all children through federally sponsored programs. It has been during this same time period–the 1980s, and especially the 1990s–that we have witnessed a tremendous increase in the occurrence of the spectrum of autism disorders. (Table 2.)

In the late 1980s and early 1990s the vaccine schedule was amended to include both Hepatitis B and HiB vaccines. Each vaccine is administered to infants 3 times during the first six-months of life. Their addition to the vaccine schedule potentially tripled an infant’s exposure to mercury if they received all thimerosal-containing vaccines. An additional concern is that these vaccine exposures are occurring on top of prenatal exposures from thimerosal-containing immune globulin preparations administered to RH- mothers during pregnancy, and in addition to dietary, dental and environmental exposures.

Current Investigations

Recent information from large epidemiological studies conducted in mercury-exposed populations suggests that intermittent large exposures may pose a higher risk than small daily exposures. In one study, lower scores on memory, attention, language and motor function tests were found years later in children who had been exposed prenatally to intermittent bolus doses of methyl mercury from dietary exposure at levels that had been previously thought to be safe.(2)

In a recent investigation, mercury levels were obtained before and after exposure to 12.5 mcg of ethyl mercury in hepatitis B vaccine in 15 preterm and 5 term infants.(3) There were no differences between the preterm and term infants with respect to mean pre-vaccination levels, although post immunization mercury levels were significantly increased in both groups of infants. Post vaccination levels in preterm infants were 3 times higher than those of term infants, a difference that was statistically significant. Of interest, one preterm infant developed a post vaccinal mercury level of 23.6 mcg/L, which falls within the range known to result in neurodevelopmental dysfunction.(4)

At the June 21, 2000 Advisory Committee for Immunization Practices meeting held in Atlanta, Georgia, Dr. Thomas Verstraeten of the National Immunization Program presented a review of vaccine safety datalink information on thimerosal-containing vaccines. Over 400,000 children participate in the vaccine safety datalink program. From this database, 100,000 eligible children’s charts were reviewed to determine exposure to thimerosal-containing vaccines and specific neurodevelopmental outcomes. Key findings were statistically significant associations between cumulative exposure to thimerosal-containing vaccines.

A recent report in the Weekly Epidemiology Record, January 2000, reviewed the use of thimerosal as a vaccine preservative. The report stated that “this safety assessment cannot currently exclude the possibility of subtle neurodevelopmental abnormalities in infants from a cumulative exposure to thimerosal in vaccines.”(5)

What Next?

There are many unknowns with respect to thimerosal. These include: a paucity of data on the metabolism, excretion and toxicity of ethyl mercury, the levels of risk to the fetus from maternal exposures and to the infant from exposure occurring during critical windows of neurological development, and the effect of large intermittent bolus exposures to ethyl mercury verses daily low dose oral exposures to methyl mercury. Current investigations are underway from both governmental and private agencies in an effort to address these concerns.

Many questions concerning mercury exposure from thimerosal in vaccines remain unanswered, and there is little consensus as to how best to proceed to diagnose, or effectively treat elevated mercury levels in children. The effectiveness of chelating agents in crossing the blood brain barrier has become a topic of scrutiny, as well as the ability to treat a long-standing exposure which occurred during a critical time in development.

At a recent Defeat Autism Now (DAN) Conference a number of physicians who specialize in the treatment of children with autism and developmental disorders reported many children with elevated mercury levels had remarkable improvement in behavior, speech and cognition when treated with a program to reduce oxidative stress and metal body burden.

What to do

Despite this information, the FDA has only “encouraged” vaccine manufacturers to reduce or eliminate thimerosal. Dr. Neal Halsey at the Institute for Vaccine Safety, Johns Hopkins, summed up this issue best in a recent article on thimerosal published in the Hepatitis Control Report, Summer 1999 issue. “We can say there is no evidence of harm (from thimerosal), but the truth is no one has looked.”(6) Until more research is available, it would be prudent to use thimerosal-free vaccines. [Or avoid vaccines altogether–WD]

Currently, there are still 30 thimerosal-containing vaccine products on the market. The general public, as well as physicians and health professionals, need to be aware that thimerosal-free vaccines exist. Parents research the safest car seats and toys for their children, but do not realize that they also need to research vaccines as well. Thimerosal has been eliminated from latex paints, merthiolate and many other over-the-counter products because of serious toxic effects in infants from these products. Although FDA has only focused on thimerosal in infant vaccines at this time, all vaccines that contain this product should be scrutinized.

Additional Information

For additional information on mercury and autism: www.safeminds.org or http://tlredwood.home.mindspring.com

To a review paper on Autism and Mercury: www.canfoundation.org/newcansite/sciwatch/invest.html

For vaccine products and thimerosal content: www.immunize.org/news.d/thimtabl.htm

For additional information on vaccines go to www.909shot.com

References:

1. American Academy of Pediatrics. Thimerosal in vaccines-An interim report to clinicians. Available at http://www.aap.org/new/thimpublic.html.

2. Grandjean P, Weihe P, White, RF, Debes F. Cognitive performance of children prenatally exposed to “safe” levels of methylmercury. Environ Res. 1998; 77: 165-172.

3. Stajich, G, Loez, G, Harry W, Sexson W. Iatrogenic exposure to mercury after hepatitis B vaccination in preterm infants. J. of Peds. 2000; 136 (5); 679-681.

4. Grandjean P. Weihe P, Nielse, J. Methylmercury: Significance of interuterine and postnatal exposures. Clin. Chem. 1994: 40 (7) 1395-1400.

5. Thimerosal as a vaccine preservative. Wkly Epi Rec. 2000; Jan 14; 75 (2): 12-16.

6. Uproar over a little-known preservative, thimerosal, jostles U.S. hepatitis B vaccination policy. Hep. Control Rep. Summer, 1999. Vol. 4, No.2.

Shared Symptoms of Mercury Exposure and Autism

Mercury toxicity is cumulative, resulting in delayed neurotoxicity which can manifest months after exposure. Many children with autism experience normal development and then regress.

Susceptibility to mercury also appears to have a genetic component–boys are more affected than girls by a ratio of approximately 4 to 1. Autism and ADD/ ADHD also occurs more frequently in boys than girls.

Although the major toxicity of mercury compounds is expressed in the central nervous system, the immune and gastrointestinal systems are also commonly affected. The same abnormalities in these systems have been found in children with autism.

Other shared symptoms of mercury exposure and autism include:

√ Speech and hearing deficits, including difficulty speaking and understanding speech.

√ Sensory disturbances, including numbness in the mouth, hands and feet, sensitivity to loud noises, aversion to touch and over or under response to pain.

√ Cognitive impairment and difficulty dealing with abstract ideas and complex commands, social withdrawal, anxiety and obsessive-compulsive behaviors.

√ Disruption of serotonin, dopamine, glutamate and acetylcholine neurotransmitters.

√ Damage to Purkinje cells and granule layer of the cerebellum in the brain, as well as the amygdala and hippocampus, while other areas are spared.

√ Pervasive and widespread dysfunction of enzymes, transport mechanisms and structural proteins.

√ Damage to the immune system triggering autoimmune processes, including shifts in the Th2 lymphocytes.

√ Increased susceptibility to certain virus strains, which may be related to a decrease in NK cell function.

√ Gastrointestinal disturbances and inhibit digestive enzymes and peptides. Many children with autism develop gastrointestinal problems and have difficulty digesting dairy and wheat products.

Nutritional Support for Mercury Detoxification
DMSA

DMSA (2,3-Dimercaptosuccinic Acid) is a sulfhydryl-containing substance with a long history of use as an orally administered agent for toxic heavy metal poisoning. Extensive clinical research since the 1950s demonstrates that DMSA accelerates elimination of mercury from the brain and effectively removes mercury from the blood, liver and kidneys. DMSA has also been approved for use in the U.S. for the treatment of lead intoxication in children.(1,2,3,4)

EDTA

While DMSA is the nutritional agent of choice for systemic mercury detoxification, EDTA (Ethylene-Dia-mine-Tetra-acetic Acid) is well-documented for its ability to safely remove many heavy metal toxins, including mercury.(5) EDTA, the active ingredient in VRP’s Oral ChelatoRx, is known to remove mercury from cell surfaces and the blood, but not from within cells, whereas DMSA is very effective in removing intracellular mercury and lead, especially from the brain. Evidence suggests that EDTA is less effective at removing mercury when used alone, but use in combination with DMSA may speed up the process of removal.

MINERALS

Since use of DMSA and EDTA may result in the depletion of certain elements, it is highly recommended that when using either or both of these formulas one also supplement with a potent vitamin and mineral formula, such as VRP’s Advanced Essential Minerals or Essential Minerals. Minerals should be taken with meals and not with the chelating agents formula(s).

References:

1. Klaassen CD. Heavy Metals and Heavy-Metal Antagonists; Chapter 69; pp. 1615-1637; in Goodman and Gilman’s The Pharmacological Basis of Therapeutics (6th Ed.); 1980.

2. Aposhian HV. DMSA and DMPS – Water Soluble Antidotes for Heavy Metal Poisoning. Ann. Rev. Pharmacol. Toxicol.; 23: 193-215; 1983.

3. Pangborn JB. Mechanisms of Detoxification and Procedures for Detoxification. Doctor’s Data, Inc., and Bionostics, Inc., Chicago, IL., (708) 231-3649.

4. Ziff MF, Ziff S and Hanson M. Dental Mercury Detox. BioProbe, Inc., 1997.)

5. Gordon, GF. EDTA safe in treating patients with mercury toxicity. Townsend Letter, Feb/Mar 1997.

First Mercury Poisoning Vaccine Lawsuit Filed in US

A Texas law firm has filed the first known civil case involving the use of thimerosal-containing vaccines. The case, Counter, et al v. Abbott Laboratories, et al, (Cause No. GN 100866, 200th District Court – Travis County, Texas) was filed by Waters & Kraus, LLP, a Dallas, Texas-based law firm. The suit alleges that the mercury-based preservative thimerosal, used recently in more than 30 childhood vaccines, has caused mercury poisoning in many children

The symptoms of mercury poisoning are, in many cases, identical to the symptoms of autism, although the suit does not allege that all persons suffering from the symptoms of autism do so as a result of mercury poisoning. However, many children suffering from mercury poisoning have been previously diagnosed with autism due to the similarity of symptoms.

Children have been exposed to cumulative levels of mercury from the vaccines that exceed threshold safety levels that have been established by the United States Environmental Protection Agency.

In many instances, children carry unmistakable evidence of mercury poisoning and the symptoms of mercury poisoning were first manifested after receiving vaccines tainted by thimerosal. In many cases, children exhibited normal neurological and other developmental patterns until such time as the cumulative dose of mercury caused irreparable damage to both the neurological and the general developmental process.

Waters & Kraus anticipates that a significant number of individual cases against the vaccine industry will be filed in the near future.

The information in this article is not intended to provide personal medical advice, which should be obtained from a medical professional, and has not been approved by the U.S. FDA.

Copyright 2001 by Vitamin Research Products, Inc. (VRP) The use of information found in Vitamin Research News for commercial purposes is prohibited without written permission from VRP.
by Lyn Redwood, RN, MSN, CRNP

Turning Back Cancer’s Clock
Kimberly Pryor

The statistics are staggering. Last year in the United States, 563,100 people were expected to die of cancer-more than 1,500 people a day. Cancer is the second leading cause of death in the United States, exceeded only by heart disease. These statistics translate into a very real threat to us all.

For the past two decades, scientists have looked upon fiber almost as a panacea in the battle against cancer, particularly colon, mammary and prostate cancer. The nightly news has bombarded viewers with the latest research outlining fiber’s protective role. Even the marketing divisions of cereal and oatmeal manufacturers jumped on the bandwagon, touting the fiber versus cancer studies in their advertisements. However, recent research reveals that scientists may have been led astray when it comes to the cancer-inhibiting benefits of dietary fiber. As new studies unfold, researchers are beginning to realize that there is an additional substance in dietary fiber that adds to its powerful effects against cancer. This heretofore little-known substance is a component of fiber called inositol
hexaphosphate, also known as InsP6, IP6 or phytic acid.

IP6 occurs in foods that are rich in fiber-especially cereals and wheat bran, along with corn, soy beans, nuts (especially peanuts), oats, seeds and rice. IP6 has traditionally been considered an antinutrient due to its ability to interfere with the body’s absorption of minerals such as iron, calcium and zinc. However, scientists have recently discovered that IP6 is a powerful antioxidant and chemopreventive agent.

Researchers initially overlooked IP6 because it was obscured by its dietary carrier-fiber. Fiber is an important part of the anticancer arsenal. Scientists estimate that up to 70% of all cancer is attributed to diet.4 The typical low fiber Western diet has been linked to the development of colon, prostate and mammary cancers.

For example, in the U.S., the rates of prostate cancer and postmenopausal breast cancer are 26 and 10 times higher than in China, respectively-a difference possibly due to the fact that Americans consume almost three times less cereal than the Chinese.7 In addition, one study of 37 countries found a link between high intake of cereal grains and low rates of colon cancer;8 and researchers at the George Washington University Medical Center discovered that wheat bran alone, or wheat bran plus
psyllium, inhibits earlier phases of carcinogenesis.9

These studies are in contrast to other studies, however, which found no direct link between fiber consumption and colon cancer. For example, Danes have a much higher incidence of colorectal cancer than Finns, although both groups consume approximately equal amounts of dietary fiber. This variance between studies suggests that fiber isn’t the sole factor responsible for the inhibition of
carcinogenesis. Researchers are beginning to suspect that IP6 may be even more potent in preventing cancer than the fiber in wheat bran. Scientists determined that although both Scandinavian populations consume equal amounts of fiber, the lower-risk Finns consume food items with 20-40% more phytic acid (IP6) than the higher-risk Danes.

IP6’s Role
IP6-along with its lower phosphorylated forms, especially IP5-is present in virtually all mammalian cells.12 It is an offspring of the nutrient inositol, and consists of a
myo-inositol ring and six symmetrically distributed phosphate parts.

Scientists have confirmed IP6’s existence within cells, but its primary purpose is still unknown. Although IP6 has been called one of nature’s most powerful antioxidants, its role appears to be far more extensive. It has been suggested that IP6 can regulate heart rate and blood pressure, and may also serve as a neurotransmitter.

Because IP6 is a highly charged molecule, scientists formerly thought it could not be transported inside the cell, and believed that absorption by organisms was impossible. The fact that IP6 might work intracellularly was also discounted. However, preliminary work began to indicate otherwise. In vitro studies show that malignant cells almost imwww.ely begin accumulating IP6
intracellularly. Scientists also found that IP6 is absorbed through the stomach and upper small intestine within one hour after administration.

When cells accumulate IP6, something remarkable happens. Unlike most other anticancer agents, IP6 turns back the clock on the malignant cells, forcing them to revert to a non-cancerous state. This phenomenon has been observed in HT-29 human colon carcinoma cells. Malignant and premalignant cells of the colon and other epithelial cells express the tumor marker
D-galactose-ß-[1 ‘3]-N-acetyl-D-galactosamine; this marker is absent on normal cells. Following IP6 treatment of malignant cells, the tumor marker was significantly suppressed, and in most cells the marker was completely absent. IP6 also caused a decreased rate of cell proliferation.17-18

Proposed Anticancer Mechanisms
IP6 exerts its effects on the body by controlling cell division. IP6 reduces the rate of cellular proliferation, both in vivo and in vitro, and has exhibited an ability to reduce DNA synthesis. Scientists have suggested that one way IP6 may exert this cellular control is by interfering with mineral absorption, since iron and other minerals are important in gene regulation.22 Studies have shown a possible link between excess iron and an increased risk of cancer in animals and humans, particularly colon cancer.23 IP6 has been shown to interfere with iron absorption and reverse iron-dependent augmentation of colorectal
tumorigenesis. IP6 also suppresses iron-catalyzed oxygen generation, and almost totally inhibits iron-catalyzed lipid peroxidation.

A concern in this regard, of course, is the possibility that IP6 may deplete the body’s mineral stores. In numerous studies, researchers have noted no significant differences in the level of serum or bone minerals in rats, even after lengthy treatment with IP6 and inositol.26

AbulKalam Shamsuddin, MD, PhD, has extensively studied IP6. In a 1997 Life Sciences’ article, Shamsuddin stated that “Certainly, its [IP6’s] hypothetical harm connected to chelation is far less than that of other compounds of similar usage (eg. cancer chemotherapeutic and chemopreventive agents) and are far outweighed by the plethora of benefits.”

The questions that arise in regard to IP6’s ability to chelate minerals suggests that other anticancer actions are at play. These actions include:

Boosting natural defense mechanisms. Natural killer (NK) cells defend the body against tumor initiation. Studies have shown that mice with carcinogen-induced tumors, when treated with IP6, demonstrate augmented NK activity over the untreated controls.27

Inhibiting carcinogenesis through the “lower IPs.” Scientists believe that IP6’s actions may be www.ed through lower forms of the molecule. One study by Shamsuddin showed that after IP6 treatment of K-562 human erythroleukemia cells, there was a 41% increase in intracellular IP3 and a 26% decrease in IP2. This alteration in the cellular inositol phosphate pool may indicate that the evolution from IP6 to lower forms of the molecule is a crucial step in the inhibition of carcinogenesis.28

Blocking PI-3 Kinase.PI-3 Kinase is an enzyme necessary for tumor promotion; a normal cell requires PI-3 Kinase to become cancerous. Researchers have found that IP6 is a profound inhibitor of PI-3 kinase.29-30

Altering cellular communication necessary for tumor growth.Proteins called fibroblast growth factors (FGF) initiate conversations between cells. Each FGF possesses a transmitter and receiver. As these cellular conversations occur, sugar molecules called heparan sulfates intercede to modulate the messages, flowing back and forth via the FGF system. It is through this process that a very specific type of heparan sulfate works in different tissues to maintain proper function and control cell division. Fibroblast growth factors have been implicated in tumor cell growth, as certain cancer cell lines have been shown to express FGF binding sites. IP6 mimics one specific part of the long heparan sulfate chain, thereby interfering with the functioning of the entire heparan sulfate molecule, suppressing DNA synthesis and cell division induced by FGFs.31-32

Stimulating the p53 gene.If the tumor suppressor gene p53 is not functioning, cancer cells become more resistant to chemotherapeutic agents. IP6 has been shown to up-regulate the expression of p53.33

Colon Cancer

In 1988, Shamsuddin reported in the journal Carcinogenesis the stunning effect IP6 had on large intestinal cancer in rats. Researchers fed 1% sodium inositol hexaphosphate (Na-IP6) to one group of animals one week prior to inducing cancer, and to another group two weeks after the last dose of a carcinogen was administered. Rats who took the IP6-laced drinking water prior to carcinogen treatment exhibited a 35% decrease in large intestinal cancer compared to the control carcinogen group. The group fed IP6 after receiving the carcinogen showed a similar reduction.34

In 1989, Shamsuddin and colleagues fed rats 2% IP6 in drinking water five months after induction of
carcinogenesis. Compared to untreated rats, animals on IP6 had 27% fewer tumors and the tumors were approximately two-thirds smaller in size. This suggests that IP6 may be important in both the treatment and prevention of cancer.35

Phytic acid (IP6) was also effective at reducing the incidence of colon tumors in conjunction with a high risk, high fat diet. The incidence of colon tumors in carcinogen-treated rats plummeted from up to 70% in the control groups to 30% in the groups fed a high risk diet
(HRD) plus phytic acid.36

Pretlow and colleagues (1994) demonstrated that IP6 is an even more powerful chemopreventive agent than selenium in halting the development of colon carcinogenesis.37

Breast Cancer
Diets high in fat and iron have been linked to an increased risk of mammary cancer. In clinical studies, IP6 has mitigated the dangerous consequences of a high fat diet. Dietary administration of phytic acid (2%) in conjunction with carcinogens and a HRD led to a significant reduction in the incidence of mammary tumors in rats compared to those consuming only the
HRD. Twenty-one weeks after administration of the carcinogens and the HRD, the incidence of mammary tumors in the HRD plus phytic acid group was reduced by up to 50%.38-39

IP6 has been shown to inhibit carcinogenesis in all types of mammary cancer cells-those that require estrogen for growth and those whose growth is independent of the female sex hormone. It accomplishes this by inhibiting DNA synthesis and cell growth, and inducing differentiation of the cancer cell lines.40-42

Other Cancers
In vivo and in vitro studies have shown that IP6 has a protective effect against lung, liver, prostate and skin cancers.

Prostate Cancer
– Shamsuddin noticed a significant dose-dependent growth inhibition in human prostate cancer cells in vitro. As early as three hours after treatment and continuing up to 48 hours, IP6 suppressed DNA synthesis in prostate cancer cells.43

Hepatocellular Carcinoma
– Patients suffering from Hepatocellular carcinoma (HCC), a common liver cancer, usually have an extremely poor prognosis. Studies indicate that IP6 may be an important treatment for this disease. In the first of two experiments, Shamsuddin and colleagues compared the in vitro effects of IP6 on HepG2, a human liver cancer cell line. Compared to other cancer cell lines, HepG2 cells were extremely sensitive to IP6, experiencing a dose-dependent, 50% inhibition of cell growth. IP6 also weakened HepG2’s ability to form colonies. The sequel to the experiment demonstrated that IP6 can regress pre-existing human liver cancer cells transplanted in mice back to their normal, non-cancerous state. In addition, the tumor weight in IP6-treated mice was 86% to 1180% less than that in control mice.44-45

Lung Cancer and Asbestos-Induced Fibrosis
– Scientists have also received positive results with IP6 in regards to lung cancer and asbestos-induced fibrosis and carcinoma. Studies have shown that fibrosarcoma cells in mice treated with IP6 resulted in a significant inhibition of tumor and size as well as improvement of survival over the untreated controls. Similar treatment with IP6 of mice with experimental lung metastasis resulted in a significant reduction in the number of metastatic lung colonies. Due to its antioxidant properties and its ability to chelate iron, IP6 diminishes the asbestos-induced oxidative damage that results in inflammation and fibrosis in the lungs of exposed animals, from six to 30-fold less than in control groups.46-47

Skin Cancer
– In a pilot study of mouse skin
carcinogenesis, Zarkovic and colleagues reported that IP6 prevented skin papillomas when given during cancer initiation. After initiation however, IP6 exerted little effect. In regards to skin cancer, scientists are calling for more studies to determine IP6’s effectiveness in patients who have already been diagnosed with the disease.48

Rhabdomyosarcoma
– IP6 has suppressed the growth of
rhabdomyosarcoma, the most common soft tissue sarcoma in children. Cell line growth was reduced by 50% in vitro in a dose-dependent fashion. After two weeks, IP6 treated mice experienced 25-fold smaller tumors and a 49-fold reduction in tumor size after five weeks.49

Kidney Stones, Platelet Aggregation, Heart Attacks and HIV
A multifaceted nutrient, IP6 has been shown to benefit a number of other conditions. Researchers at the Harvard Medical School and Massachusetts General Hospital in Boston successfully used pure Na-InsP6 to treat idiopathic
hypercalciuria, which is associated with a high incidence of kidney stones.50

Other research points to IP6’s usefulness in preventing platelet aggregation-a prime cause of heart attacks and strokes. In one study, IP6 inhibited platelet aggregation by 45% in an in vivo animal model. An in vitro study by the same researchers, stickiness was induced in human whole blood taken from healthy volunteers. IP6 reduced clotting by 50%, or eliminated it altogether.51

Other research points to IP6’s role in controlling the damage inflicted upon the myocardium (heart muscle) during heart attacks. After a heart attack, doctors reperfuse (fill) the heart area with oxygenated blood. This poses its own set of risks, because the oxygen can churn out free radicals, damaging the blood vessels and heart muscle. Researchers successfully used IP6 to protect the heart muscle from superoxide damage during reperfusion.52-53

As more studies unfold, additional properties of IP6 have been revealed. Otake and colleagues demonstrated that IP6 inhibited the cell destruction induced by HIV as well as the HIV specific antigen expression. IP6’s ability to boost natural killer cells could have future implications for AIDS sufferers.54

Synergistic Effect
In his book, IP6: Nature’s Revolutionary Cancer Fighter, Shamsuddin, calls IP6 combined with inositol, “an anticancer cocktail.” IP6 combined with inositol exerts an even more powerful suppression of cell proliferation and colorectal cancer than with either agent alone. This potent “cocktail” has also been used to suppress carcinogenesis in mammary and metastatic tumor models. Other studies point to the synergistic effect of green tea and phytic acid. When scientists combined these two substances, they had a significant impact on precancerous lesions in rats.55

Dietary IP6 Less Effective
When administered in the diet, IP6 binds with proteins, forming insoluble complexes that are less readily metabolized and absorbed. Because IP6 is particularly abundant in the bran part of certain mature seeds such as wheat, one group of scientists investigated whether a high-fiber bran diet containing high IP6 inhibits rat mammary carcinogenesis induced by 7,12-dimethylbenz[a]anthracene
(DMBA). Rats were fed a diet containing, 5%, 10% or 20% Kelloggs’ All Bran; another group received 0.4% IP6 in drinking water equivalent to that in 20% bran. The fifth group served as the control. After 29 weeks, compared with the carcinogen control, tumor incidence was reduced by 16.7%, 14.6% and 11.4% in rats fed 5%, 10% and 20% bran, respectively, not an insignificant amount. However, rats fed 0.4% IP6 in drinking water had a whopping 33.5% reduction in tumor incidence and nearly 50% fewer tumors.

Researchers stated: “Thus, IP6, an active substance responsible for cereal’s beneficial anticancer effect, is clearly more effective than 20% bran in the diet. …Intake of IP6 may be a more pragmatic approach than gorging enormous quantities of fiber for cancer prophylaxis.”56-57

Safety of IP6
The majority of clinical studies have confirmed the safety of IP6. Shamsuddin and colleagues witnessed no adverse effects on body weight, serum mineral content or any pathological changes of consequence after administering IP6 to F344 or female
Sprague-Dawley rats for 40 weeks. The safety of IP6 has also been confirmed in human studies. Researchers at Harvard Medical School and Massachusetts General Hospital administered pure Na-InsP6 orally to 35 patients at a dose of 8.8 grams (!) per day in divided doses for an average of 24 months. The patients showed no signs of any toxic reactions. Furthermore, researchers have noted that the cell division rate of healthy animals receiving IP6 shows no deviation from the normal.58-60

Conclusion
There is admittedly a dearth of human clinical studies confirming the potential cancer-fighting effects of IP6. Nevertheless, there are certainly ample theoretical reasons why it should be effective, as well as a number of in vitro and in vivo studies that document its ability to normalize cancer cells and reduce tumors in experimental animals. Furthermore, there are animal and human studies confirming the absolute safety of IP6. Consequently, in view of the evidence for potentially great benefit and total lack of toxicity, rather than wait years for further human double-blind placebo controlled studies to be performed, we believe that IP6 should be considered an absolutely essential element in any broad spectrum nutritional cancer preventive or therapeutic program.

References
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2. Shamsuddin AM, Baten A, Lalwani ND. Effects of inositol hexaphosphate on growth and differentiation in K-562 erythroleukemia cell line. Cancer Lett. 1992; 64:195-202.

3. Shamsuddin AM, Yang GY. Inositol hexaphosphate inhibits growth and induces differentiation of PC-3 human prostate cancer cells. Carcinogenesis. 1995; 16(8):1975-1979.

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8. Irving D, Drasar BS. Fibre and Cancer of the Colon. Br J Cancer. 1973; 28:462-463.

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10. Englyst HN, Bingham SA, Wiggins HS, Southgate DAT, Seppanen R, et al. Nonstarch Polysaccharide Consumption in Four Scandinavian Populations. Nutr Cancer. 1982; 4:50-60.

11. Graf E, Eaton JW. Dietary Suppression of Colonic Cancer: Fiber or Phytate? Cancer. 1985. 56:717-18.

12. Szwergold BS, Graham RA, Brown TR. Observation of inositol pentakis- and hexakis-phosphates in mammalian tissues by 31P NMR. Biochem Biophys Res Commun. 1987; 264:874-81.

13. Huisamen B, Lochner A. Inositolpolyphosphates and their binding proteins-a short review. Mol Cell Biochem. 1996; 157(1-2):229-32.

14. Graf E and Empson KL. Phytic acid: a natural antioxidant. J Biol Chem. 1987; 262:11647-50.

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22. O’Halloran TV. Science. 1993; 261:715-25.

23. Weinberg ED. Association of iron with colorectal cancer. Biometals. 1994; 7(3):211-6.

24. Porres JM, Stahl CH, Cheng WH, et al. Dietary intrinsic phytate protects colon from lipid peroxidation in pigs with a moderately high dietary iron intake. Proc Soc Exp Biol Med. 1999; 221(1):80-6.

25. Graf E, Eaton JW. Suppression of colonic cancer by dietary phytic acid. Nutr Cancer. 1993; 19(1):11-9.

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27. Baten A, Ullah A, Tomazic VJ, Shamsuddin AM. Inositol-phosphate-induced enhancement of natural killer cell activity correlates with tumor suppression. Carcinogenesis. 1989. 10:1595-98.

28. Shamsuddin AM, Ullah A and Chakravarthy A. Carcinogenesis. 1989; 10:1461-63.

29. Huang C, Ma W, Hecht SS, Dong Z. Inositol Hexaphosphate Inhibits Cell Transformation and Activator Protein 1 Activation by Targeting Phosphatidylinositol-3′
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30. Dong Z. Personal communication. 1999.

31. Morrison RS, Shi E, Kan M, Yamaguchi F, McKeehan W, Rudnicka-Nawrot M, Palczewski K. Inositolhexakisphosphate (InsP6): an antagonist of fibroblast growth factor receptor binding and activity. In Vitro Cell Dev Biol Anim. 1994; 30A(11):783-9.

32. McKeehan W. Personal communication. 1999.

33. Saied IT, Shamsuddin AM. Up-Regulation of the Tumor Suppressor Gene p53 and WAF1 gene expression by IP6 in HT-29 Human Colon Carcinoma Cell Line.Anticancer Res. 1998; 18(3A):1479-84.

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• Quality air – clean, fresh, sea

FACTORS THAT ENCOURAGE AGGLUTINATION:

Conversely, there are a number of factors that can encourage agglutination such as:

• Insufficient hydration
• Lack of antioxidants
• Excess free radical activity
• Stress (physical or mental)
• Toxins (from air, food, water, environment, drugs, alcohol, dentistry, medical intervention)
• Electromagnetic Radiation
• Insufficient intake or poor conversion of EFAs (particularly O-3)
• Adverse ratio of Omega-6 to Omega-3 HUFAs (specifically EPA & DHA)
• Trans-fats from damaged / processed foods
• Excess saturated or monounsaturated fatty acids
• Imbalance or lack of electrolytes (esp. magnesium)
• Diet that causes increased acidity in the patient (depends on their MT)
• Allergy (inflammatory response)
• Lectins (proteins found in all grains, legumes, dairy and nightshade family plants)

HOW ESSENTIAL FATTY ACIDS AFFECT ZETA POTENTIAL
Phospholipid enzymes surround blood cells, as well as all other cells and their organelles in the body. They also encapsulate and transport triglycerides and cholesterol in the blood.

Phospholipids carry a negative electrical charge on their surfaces. This is due to the fatty acids incorporated in their molecular structure. The more double bonds there are within the fatty acid components of the membrane, the more fluid the structures are and the stronger their negative charge (Udo Erasmus, 1993, Fats that Heal Fats that Kill).

In effect, this negative charge forms a force-field around any particles in the blood surrounded by phospholipids. The stronger the negative charge, the more they repel one another. If the negative charge is reduced the effect will lessen, allowing the constituents of blood to get closer together and begin to aggregate.

Saturated fats have no double bonds and therefore no charge, whilst the long-chain polyunsaturated fatty acids with the most double bonds (Omega-3s: EPA and DHA) carry the strongest negative charge. This fact illustrates the importance of ensuring an adequate intake of essential fatty acids. They directly influence Zeta Potential and that affects the delicate balance of dispersion versus flocculation in the blood.

There is evidence to indicate that the ideal intake of Omega-6 and Omega-3 EFAs should be in a ratio of 1:1. It is important to understand here that most people have a very high intake of Omega-6 EFAs. They are present in all vegetable oils, grains and animal fats, and the foods made from them, which includes the convenience products that form the bulk of many people’s diets. In comparison the best sources of Omega-3s (flaxseed and oily fish) are not consumed very often.

Furthermore O-6s generally have pro-inflammatory effects, and are used to make eicosanoids and prostaglandins that are involved in clotting processes, whilst O-3s are anti-inflammatory and have a thinning effect on the blood.

To redress the imbalance, many nutritionists recommend flaxseed oil supplements but apparently do not realise that often it is of little benefit. Research and practise indicates that large sectors of the populace are not able to convert ALA to the longer chain EPA and DHA that actually produce the anti-inflammatory effects. This applies especially to the chronically ill and those with a genetic adaptation to a diet high in oily fish (ie those with ancestors from temperate and colder climates), as both groups tend to produce insufficient Desaturase enzymes, vital for the conversion. The process is also inhibited by a diet high in carbohydrate and trans-fatty acids, found in most processed foods.

Therefore, to improve the balance between O-6s and O-3s and affect the blood picture positively, supplements of high-quality, concentrated fish-oil are advised, together with natural, full-spectrum vitamin E to protect the oil from free radical attack.

CAUTION: Anyone on blood thinning / anti-coagulation drugs (e.g. Warfarin, aspirin) must consult their GPs and / or Specialists before taking fish oil or vitamin E as these supplements will affect clotting time.

IN SUMMARY
LIVE BLOOD MICROSCOPY is a tool that allows us to directly view the blood and determine how Zeta Potential and other factors are affecting it. It enables us to visually monitor and evaluate a patient’s response to therapeutic measures. Most importantly, it gives patients a window to see into their body, which they sometimes find shocking but often highly motivating.
Understanding the basic concept of Zeta Potential, and utilising that knowledge in conjunction with the powerful medium of visual medicine afforded by the microscope, will enable medical and complementary practitioners to solve many common health problems relatively quickly and inexpensively.

Always bear in mind that neither drugs nor supplements cure disease. The body repairs itself, given the raw materials to do so. Don’t underestimate the importance of the holistic approach. It addresses the underlying cause of disease, rather than isolated symptoms.

There is so much we don’t know, but we do know that nature supplies us with all we need for healthy bodies. A natural, organic diet, pure drinking water, fresh air, sunlight, quality sleep and limited exposure to processed, fake, synthetic foods and drink and commonplace toxins will go a long way towards improving the blood picture. If you add to that basic prescription nothing more than Omega-3 EFAs and a wide range of antioxidants, many patients’ health issues will recede.

Dr George J Georgiou
Holistic Medicine PractitionerDr Georgiou has been an active clinician for 30 years, and Director Founder of the Da Vinci Holistic Health Centre and the Da Vinci College of Holistic Medicine in Larnaca, Cyprus.