By John T.A. Ely
Copyright 2002
Overview

"Unprofitable" modalities (UM) refer to published scientifically proven treatments ignored by mainstream medicine as unpatentable and unprofitable. Commonly, o optimize health, UM simply adjust certain molecules normally in the body to significantly different levels than typical in affluent societies. For recovery of health, the changes can be much larger. Some molecules such as sugar, tryptophan and methionine must be kept below specifiable levels. Misunderstood essential nutrients including coenzyme Q10 (Q10) also called ubiquinone, ascorbic acid (AA), and vitamins A and E (A, E) must be supplemented, in some conditions, to many times the RDA's. Such changes are called orthomolecular (i.e., correct molecular levels for homeostasis). They are pure science, not quackery as supposed by those, unread, who condemn without investigation.

A world-famous physician from Stanford University made a generalization re orthomolecular "megadosing". The last sentence from Cathcart (1981) states: "I anticipate that other essential nutrients will be found being utilized at unsuspectedly rapid rates in disease states. Complications caused by failures in systems dependent upon those nutrients will be found. The magnitude of supplementations necessary to avert those complications will seem extraordinary by standards accepted today."

Mainstream medicine (of which the authors are constructively motivated but dissenting members) has recently received strong criticism cited here from the most respected authorities (Pauling, Relman, Shute, Watson, etc.) which we, sadly, cannot refute. Medicine has been accused of being both the sole judge of its own quality and historically calloused in its slowness to modernize (by elimination of long held erroneous views) at enormous cost in morbidity and mortality (M&M) (Ely, 1999). Today there are still erroneous ideas that cripple medicine in the US and other countries with similar medical systems. These were shown in reveleations by Pauling (1987,p.234; Ch.25; etc.) and Shute (1975,pp.230-242), to have resulted from deliberate deceit on the part of a few. The ensuing rejection of UM, even essential nutrients (usable alone or adjunctive to conventional therapy), has been perpetuated by their low cost and unpatentable nature. This, even though they are less invasive, have less side effects and yield a much longer and higher quality of life. The related change of US medicine from social service to a profit driven exploitation of captive ignorant customers was criticized and lamented by Harvard Medical School professor and former Editor-in-Chief of New England Journal of Medicine, Arnold Relman (1992). Unfortunately, a small number of the UM are essential nutrients without which a human cannot have a long or healthy life, let alone have successful surgery, resist disease, or retain youthful tissue. Nor can one avoid continuous subjection to the outmoded ineffective high cost "treatments of choice" (ToC) that accelerate death. Rejection of these UM causes the exorbitant ToC to cost US annually over 1 million early patient deaths (before age 65) and over US$1 trillion (> 1/6 of the national debt). From infections alone, there are ~200,000 US deaths annually, costing ~US$18 billion. Addressing the Mayo Clinic, T. J. Watson, CEO of IBM, (1973) said the US spends more of its GNP for medical care than any country on earth but is 24th in life expectancy (males)..."and becoming as a nation a massive medical disgrace." These failures of ToC occur primarily because the rejected UM include the essential nutrients without which no treatment, pharmaceutical or otherwise, can succeed. The failures dominate every specialty, cardiology, oncology, etc, and, surprisingly, immunology most of all, as we show below (see "Immunology's Failure").

Rejected methods of great value lie buried and unused in the many millions of pages of recognized medical science research and clinical literature (medlit) published over the past 50 years (currently over 40 million pages per decade). How can it be that countless unused therapies, better than ToC, abound in medlit? There are several factors contributing to these problems. First, society's expectations of clinicians are not humanly possible to fulfill. In addition to the literature size problem, there are: constraints imposed by medical disciplinary boards that forbid departing from ToC; clinical journals gain support from ads of, and are strongly influenced by the pharmaceutical industry; education of physicians in use of pharmaceuticals (which necessarily cost enormous sums to develop) must be actively implemented by the detail persons of the drug industry; etc. It is no wonder that UM lie unread.

Medical Literature (MedLit) Plan

The MedLit Plan is advanced to improve the quality of medical care simultaneous with major reductions in its cost. This requires the addition of long known but ignored UM that can end and reverse five decades of falling efficacy and increasing cost of ToC. Before discussing specific examples of the UM, we list some of the related areas of ignorance (especially re essential nutrients) in mainstream medicine so fundamental it seems preposterous to think they could exist. These include: (1) Q10 whose structure and functions have been known for ~40 years, while the absolute necessity of supplementing Q10 in the aged and ill is ignored by mainstream physicians, most of whom had never heard of it in 1999; (2) the pharmacokinetics of AA in mammals; (3) totally inadequate AA body pools accepted as normal in humans (i.e., non-synthesizing mammals); (4) the profound effects of AA deficiency in disease, other stress, and aging; (5) the striking success reported since 1949 of correcting this deficiency in infections and other disorders; (6) the effects of glycemic (blood glucose, BG) modulation on cell mediated immunity (cmi), cancer, etc (some known for over a century); (7) the hyperglycemic levels accepted as normal in affluent populations; and (8) other essential nutrients, such as A and E, also important for all degenerative and infectious diseases.

Coenzyme Q10. (see also http://faculty.washington.edu/ely) Q10 has been listed for years as an essential nutrient in the Physicians Desk Reference (PDR) (e.g., 1988, 42nd Edition, p.2154). Normal healthy humans have a Q10 average blood level of ~1ppm (1mcg/ml), but obtain only a very small fraction of their Q10 from food. Most (~0.5g/d) is synthesized in all tissues (body pool ~2g), including the liver, by a complex process requiring many nutrients as substrate (Langsjoen, 1995; PDR 1997, p.2769). In the ill or infirm, Q10 is usually <1ppm; a typical daily oral dose is 400 mg which should raise blood levels to 2 to 4 ppm (some people absorb poorly, requiring more). To get 400 mg Q10 from two of the best food sources would require eating ~20 kg peanut butter or ~5 kg of mackerel. Synthesis decreases after age 20 and may fall off rapidly after middle age, accelerating aging itself. Q10 is needed by every cell (and system) in the body for: (1) synthesis of adenosine triphosphate (ATP, molecules for energy); (2) cell membrane fluidity; and (3) protection against free radicals (50 times more antioxidant power than E, but E is still needed for other reasons). Exercise increases catabolism of and need for Q10. In disease or other stress, intake and absorption of the substrate (component) molecules is impaired. This reduces Q10 synthesis, causing further degradation of function due to a Q10 deficiency state in one or more (possibly all) systems in the body. Q10 supplementation is beneficial in the prevention, treatment or cure of heart disease, stroke, cancer, viral diseases including AIDS, etc. Q10 slowed aging markedly, restored youthful thymic response to viruses and tumors, and extended lifespan 50% when given to very old mice (Bliznakov, 1973). Safety and efficacy of Q10 has been demonstrated in numerous very large clinical trials (Langsjoen 1995; Langsjoen and Langsjoen 1999; Ely and Krone 2000). A caveat: in patients with alkalinized stomachs, oral Candida can colonize upper gut (potentially lethal) and candidal growth can be stimulated by Q10 (Krone et al 2001). Before prescribing Q10, their physicians should study Marshall et al (1988).

Aging mutations occur at a very high rate in mitochondria (compared to intranuclear DNA which are stabilized by histones) if ubiquinone, AA, etc are low. In this aging mechanism, low values of ubiquinone permit oxidative damage to the DNA of mitochondria to accumulate, permanently and progressively impairing their ability to function. If, by supplementation, the ubiquinone level is restored to its proper value, the rate of oxidative damage will be lessened, but the impairment remains. Because of its free radical dependence (in contrast to glycation), this process gives increased emphasis to the importance of the theory of aging proposed by Denham Harman in the 1960's (1969; 1981; 2001). Actually, Harman first integrated the theoretical and experimental work by himself and others to predict in 1972 that mitochondrial aging is a principal cause of early death (1972)].

Ascorbic Acid has many functions. Over 20,000 papers on ascorbic acid (AA) published in indexed journals since 1964 are accessible on Pub Med. Many others, including some with most important findings were published earlier, >1200 in 1938-1939 alone. It is commonly called vitamin C although it is not a vitamin The short treatment of AA pharmacokinetics offered here is believed simpler and more physiologically correct on basic concepts than any published before. Lack of this understanding has been pivotal in the clinical failures of modern medicine.

All mammals have the same requirements for AA. Among mammals, only humans, the other primates, the guinea pig and a fruit eating bat are known to have lost (by genetic defect) the ability to synthesize AA. It is most important to appreciate that other features of AA kinetics were not lost. The same high needs exist in these four non-synthesizers that constitute an abnormal group. It is observed that many and possibly all ~4000 other mammals are normal and synthesize AA copiously from glucose in the liver. This is necessary because AA has numerous functions necessary for optimum health requiring its presence continuously at high concentrations throughout the body. These functions and the associated high serum levels, far above the AA renal threshold, ~1.4mg/dL (mg/deciliter, commonly read "mg per centum" and written mg%), are the same in the 4000 normal and the four abnormal mammals. Thus, both groups of mammals have approximately the same daily AA requirements, ~50mg/(kg body weight), to replace urinary and catabolic losses when young, healthy and unstressed. It is possible, with care, to obtain this amount from food (Pauling, 1987,p.99).

Consequences of non-synthesis. In the stress of pain, disease, intoxication, etc., normal mammals respond by increasing AA synthesis in an intensity-dependent way up to several hundred fold, excreting AA "far in excess" of total body stores each day (Lewin, 1976, p.109). Because such amounts of AA could not be obtained from food, even if it could be consumed, it is clear why most mammals still synthesize AA. When a human suffers injury, surgery, intoxication, infection, etc, the AA pool is also rapidly distributed to the sites of use. However, it is depleted with dire consequences because a large concurrent AA synthesis by the liver, for which the rest of the body is still programmed, does not occur. This dangerous fall of AA to scorbutic levels within 12 hours after stress was reported in 31 consecutive heart attack patients (Hume et al, 1982). In such situations, an enlightened physician provides the AA a normal 70kg mammal would have synthesized, perhaps 70g/d or more, saving the patient.

Treating with AA can be simple. For numerous clinical applications, AA dosing is simple, i.e., 10g/d indefinitely (e.g., see chronic hepatitis below). A second example: in a 1976 study, human lymphocyte multiplication rate ~doubled if the donors had taken AA 5g/d for 3 days, tripled after 10g/d, and quadrupled after 18g/d (Pauling, 1987,p.132).

Treating with AA can be complex. There are a number of complications that must be understood for many other disorders. As detailed in Glycemic Control below: (1) when BG is low, intracellular AA becomes high and the hexose monophosphate shunt (HMP) is strongly stimulated because it runs at a rate proportional to intracellular AA (Cooper et al, 1971); and (2) lymphocytes multiply more rapidly and phagocytes ingest and kill more effectively when intracellular AA is high. A classic example of this effect of AA on lymphocyte multiplication is the 1976 study above. Such human white blood cell (wbc) AA systematics are quantified and explained by study of Cooper et al (1971), Denson et al (1961), and Figure 7.2 (Lewin, 1976). Although awkward, correct AA dosing (humanity's only choice) yields impressive medical benefits. However, dosing obviously pales in comparison to the instantaneous effortless response of the AA synthesizer to infectious challenge.

Immunology's failure. The discovery that HMP rate is proportional to intracellular AA should have changed all fields of medicine. Because Cooper et al (1971) used wbc, all immunologists should have immediately changed their thinking on AA. Certainly, some of them read "Infection and Immunity". Even Ely, who is not an immunologist by training, was able to extend the theory and obtain new findings in aging, birth defects, cancer, infectious diseases, etc (some cited here). In 1971, immunologists should have realized explicitly that intracellular AA (as measured by buffy coat (wbc) AA): (1) gives a prompt indication of immune status: and (2) is a universal limiting factor that determines the rate and intensity of cmi response in humans. Yet, nearly 30 years later, in a recent study of six excellent and highly respected immunology texts (Fudenberg, Roitt, Klein, etc) published from 1980 to 1998, none mentioned the HMP-AA need. Ely felt that even his coauthor (Ely et al 1998, 1999; Krone et al, 2001), H. H. Fudenberg, the 4th most frequently cited immunologist in the world for 15 years, had taken part in this oversight, although his book was the only one that mentioned the HMP at all and also reviewed transfer factor. In recent telecons with two of the most famous immunology authors, one a Medicine Nobel Laureate, both agreed these serious omissions must be corrected. Texts in other specialties are equally remiss.

Aging and death. Optimum health certainly includes the maintenance of youthful properties in structural proteins. One of the largest parts of the 50mg/kg AA required for all unstressed mammals is in the hydroxylation reactions necessary to constantly renew the flexible quality of collagen and the elasticity of elastin (blood vessels, lungs, etc.) degraded by "daily wear and tear" (Pauling, 1987,p.92). If the AA intake is the low level necessary to prevent scurvy, the human may avoid scurvy but will not be able to renew structural proteins and will age more rapidly. In a follow-up study of 577 people over age 50 in California, low AA intake predisposed to high mortality. The death rate was more strongly correlated with AA than any other variable including tobacco (Pauling, 1987,p.107).

Disease Prevention and Treatment. The best AA synthesizers are resistant to most viral diseases, tuberculosis (TB), diphtheria, and also do not share the susceptibility to anaphylactic shock, leukemia, and polio-like infection seen in the human and guinea pig. With normal BG and high AA blood levels, humans and guinea pigs also become resistant to these disorders, and, like the normal mammals, spill AA in the urine (dog ~1g/d) as a small price for this protection. The antibiotic properties of AA act directly by bacteriostatic and bactericidal levels in body fluids and indirectly by stimulating wbc.

Fred R. Klenner, MD, Duke 1936, originally a chemist, had many important discoveries in medicine that should be read by everyone (e.g., Klenner, 1949, 1971, 1974). In patients, dosing with amounts that elevate wbc AA sufficiently (50-100 g/d by iv and/or oral)* produces prompt (3-7 day) cures of polio, viral encephalitis, acute hepatitis (all types), etc. A simple dosing method, called "titration to bowel tolerance" (TBT), permits a very sick outpatient to administer AA in exactly the correct oral dose each day (flu, mono, etc) is explained by Cathcart (1980,1981).
* In iv dosing, AA is always sodium ascorbate.

Miscellaneous, Primarily Bacterial. Bacterial infections were studied in the 1930's and 1940's by researchers who published hundreds of papers but used inadequate doses because of their conviction that AA was a vitamin. However, their findings were sufficiently encouraging that it appeared almost certain that the "massive" doses used by Klenner and Cathcart would cure the following infections (some rapidly): diphtheria, dysentery, leprosy, pertussis, pneumonia, TB, typhoid fever, typhus (and other rickettsial diseases). These papers were reviewed by Irwin Stone (1972) who introduced Pauling to AA. Klenner reported serious bacterial infections including diphtheria, hemolytic strep and staph clear within hours following one injection of AA, as sodium ascorbate of course, 0.5 to 0.7 g/kg body weight and "run in through a 20G needle as fast as the patient's cardiovascular system will allow" (1974,p.49). And, he reported (1974,p.62) that "massive daily doses will also cure tuberculosis..." but we have been unable to find how massive (50, 100 g/d?) or for how long (months, year?); this may not be difficult to determine in NZ, using "bowel tolerance." It has been demonstrated by Sirsi (1952) that a bactericidal level in vitro and in body fluids for virulent Mycobacterium tuberculosis is 10 mg%. Humans with sufficient AA intake to maintain the bacteriostatic level for TB (only 1 mg%) do not develop TB. In a 5-year follow-up study of 1100 men originally free of TB, 28 cases developed, all in the group with substandard blood AA levels (Stone, 1972,p.81). Cathcart (1981) has reported that serious uncontrollable infections by antibiotic resistant bacteria (necrotizing fasciitis, etc) can be successfully treated in a week with megadose AA along with the antibiotic, ineffective alone. The necessity of high AA in wbc for cmi has been stressed above.

Miscellaneous, Primarily Viral. In diseases requiring prolonged treatment [i.e., acute hepatitis (week), viral encephalitis (days)] a variety of protocols exist; AA is often given around the clock with intravenous ascorbate (ivc) drip and always with oral. Vitamin E should be given with AA to everyone, preventing hemolysis in Northern Europeans and others except people with genetic lytic tendencies. These should have medical supervision, erythrocyte testing, E, and due caution for multigram AA dosing. Because of total ignorance re AA in mainstream medicine, no one has tried it against the most frightening viruses (hanta, Ebola, etc). Theoretically, it should cure them just as well as polio, except for any that produce latency, and might control most of these. Although it has been reported by Cathcart (1984) that AIDS patients could be stabilized by high level AA („10g/d), no one expects this modality can cure HIV. This has only been done with antigen-specific Transfer Factor, another unprofitable modality.

Prognostic value of the ratio AA/DHA. In optimum health, the ratio exceeds 10. In the sick and moribund, AA/DHA drops below 1. This reverses the redox potential, removing reducing power just when it is needed most, accelerating the ratio's fall and death. In 163 patients studied, Chakrabarti and Bannerjee (1955) found this ratio is prognostic even when the impending death is from a highly lethal disease. Thus, raising AA/DHA above 10, preferably by iv (or intubation) should save the lives and cure the diseases as is reported by Klenner and Cathcart.

Much additional information will be given in Apresi Bulletins and can be found in Cathcart (1980, 1981, 1984) and Klenner (1949, 1971, 1974) most of which are now available on Cathcart's website (www.orthomed.com).

Glycemic Control. Almost 2000 years ago in the time of Galen, it was observed that tumors grew poorly or not at all in underfed (i.e., low BG) animals. In 1972, Ely deduced and related to Linus Pauling a theoretical reason why clinical trials of AA against colds and cancer might fail because of the high BG levels in the affluent nations. The theory is relevant to aging, birth defects, cancer, cardiovascular disease (cvd), infections, etc. It is called the "Glucose Ascorbate Antagonism" (GAA) and is important in the "small" dose range (AA~10g/d or less). It says that certain cell types such as leukocyte and fetal have intracellular AA levels that are "pumped up" largely by insulin ~50 times higher than serum AA levels in the surrounding blood. This occurs if BG is in the low range that was normal until the 1900's and is still seen today where the primitive (unrefined) diet prevails, i.e., 50-90 mg% two hours postprandial (Ely 1996; Chatterjee and Bannerjee, 1979, Table1). The high AA levels in such cells are needed to drive the HMP shunt to supply hydrogen peroxide for phagocytosis and ribose for mitosis. "Modest" BG elevations (~50%, common after western diet meals) competitively inhibit insulin-mediated active transport of AA into these cells, resulting in low intracellular AA levels, low HMP shunt, and cell dysfunction (i.e., leukocytes don't attack tumors or pathogens, fetal cells divide too slowly, etc.); this is the "Antagonism". It has been suggested that low BG may also cause the removal of negatively charged sialic acid (a 9-carbon sugar) from tumors that otherwise repel negatively charged T-cells. A principal cause of cvd is hyperglycemia which reduces AA to scorbutic levels in vascular intimal cells (see pp. 52-55 in Pauling 1987). The GAA theory gives rise naturally to "Aggressive Glycemic Control" (AGC) as a modality that, properly used, appears to have much value against many disorders as stated above.

Some Hypoglycemic Limits. Of course, one doesn't want BG too low because cortisol rises and can damage cmi by its lympholytic effects. Also, humans become unconscious (not necessarily harmful) below 40 mg%. Brain damage is reported to occur below 20 mg%. However, cmi is reported to work well down to ca 10 mg%. Cancer, infections and other diseases (cvd, etc) have much lower incidence with adequate AA and BG 50-90 mg%. In insulin-coma therapy, formerly used in the treatment of psychiatric patients, blood glucose was maintained circa 30 mg%. Incidental to this, remissions from cancer were reported to occur in patients whose incurable malignancies were unknown to the psychiatrist at the time of treatment (Koroljow, 1962). A more practical AGC might maintain BG at 50-60 mg% with insulin or Orinase (a non-halogenated oral hypoglycemic). Trivalent chromium deficiency in US soil and diet causes impaired glucose tolerance, high BG, and disease (Ely, 1996).

Studies in Humans and Animals. In 1978 and 1979, two inoperable stage-4 breast cancer patients with large tumor burdens, worsening rapidly ("one month" prognoses) although already on chemotherapy, elected to use AGC and both became tumor free in six months and were still alive in 1992 (Ely, 1996). With partial support from Fred Hutchinson Cancer Research Center (FHCRC), etc., Ely and co-workers were able to reproduce this result in an animal model showing strong glycemic modulation of tumor tolerance (Santisteban et al, 1985). In 1983, an American Cancer Society UW-FHCRC committee (reviewing applications from new investigators) approved AGC as a research topic and urged Ely to pursue it without delay. The obvious theoretical relevance of GAA to birth defects had already been described (Ely, 1981). As explained above, hyperglycemia (high BG) slows cell division. Thus, high BG in early pregnancy, causes gross malformations (about 60,000 per year in the US!). But, high BG in late pregnancy, when cell division is primarily in the brain, produces reduced brain mass and mental retardation, or other CNS defects. The theory was cited in a lead article by a recognized expert in the field (Cousins, 1983). Motivated by that review and need to test the GAA theory in a non-tumor model, Ely et al showed that hyperglycemia of early pregnancy did induce striking reproductive anomalies in an animal model [mainly fetal resorption in mice (Hamel et al., 1986)].

Other Nutrients.
In both health and disease, all essential nutrients must be adequate. It has long been known that steroid excess, even endogenous cortisol elevation due to stress, depletes vitamin A, depressing immunity. Antibodies cannot be produced if vitamin B5 (pantothenic acid) is deficient. Some essential mineral deficiencies (zinc, selenium, magnesium) suppress cmi. For the numerous benefits of vitamin E as published in leading journals, from 1950 on, by world respected clinicians (ie, Ochsner, Haeger, etc), and its arbitrary insulting rejection by self-appointed "authorities", see revelations by Pauling (1987, p.210), Shute (1975) and Cilento (1973). For example, inter alia, Ochsner found in surgery that E is a safe prophylactic against venous thrombosis without producing a hemorrhagic tendency. It is surprising that E, second only to Q10 among available antioxidants, known for ~50 years could be termed "worthless" by a prominent nutritionist (Shute, 1975, p.77). Although d-alpha tocopherol acetate is a stable form of active E, other forms that are inactive and/or unstable have caused much confusion for 60 years. It is well known that: (1) cholesterol is not a risk factor for cvd unless LDL is oxidized; and (2) this is simply prevented by E (Gey et al., 1991; Esterbauer et al., 1991). In the late 1940's, the Shutes were able to show striking beneficial effects in cvd and other patients by 300 IU E/d. They were also able to conclude that loss of E in food processing to produce the US refined diet was a most probable cause of the appearance and growth of cvd as the largest producer of M&M from ~1916 on. These matters are known to capable students of nutrition. Until recent Q10 stroke findings (Ely et al 1998), Shute's E therapies were the only or best available for cvd, rheumatic fever, stroke, etc.

Acknowledgements

We are grateful to Linus Pauling whose wisdom, courage and stature gave weight to the arguments of those who understand the tragedy of US medicine, identified those responsible, and collected in one volume over 450 references to facilitate the eventual victory of science and truth (Pauling, 1987).