Example of Table Blog layout (FAQ section)

VITAMIN C - THE MASTER NUTRIENT

The New Super C

Many of us harbour stereotyped notions about the process of scientific discovery, images fostered and reinforced by an all-too-often theatrical and melodramatic media. We conjur up extreme visions ranging from the diabolical, mad scientist, so obsessed with research that no time is left even for eating or other "normal" activities, to the opposite boring image of the spectacled, white-coated brilliant automaton, incapable of speaking phrases apart from complex equations and Einsteinian theories, devoid of all feeling.

These far-fetched beliefs about scientists and their work would be quickly replaced by a more authentic picture by spending time in any university laboratory - biology, chemistry, physics, and noticing the characteristics and quirks possessed by the researchers working on their respective projects.

Scientific research and discovery is about solving problems and puzzles. When the problem has been solved, the results of any discoveries then become part of a manufacturing or production process, which ought to be methodical and reproducible. However, like writing a book, designing a building, painting or sculpting, scientific discovery is often helped along by other, non-logical factors, such as luck, serendipity, talent, hard work, frustration, failure and persistence, the all-too- familiar societal attributes which shape the landscape of human endeavours.

Those who have studied chemistry may have heard the story about Kekule, who, falling asleep in front of the fire, dreamed about tails of fire chasing each other in a circle; thus was conceived the theory of resonance forstructures such as the benzene ring. We have already heard in an earlier chapter how Szent-Györgyi isolated Vitamin C without originally intending to so do. In a logical world, one might think that companies might set out to develop a better product than those existing on the market. However, all too often, the most highly original products develop from extremely unlikely sources - ideas conceived while waiting at a bus stop, scribbles on serviettes while restaurant dining, or simply looking for one thing and unintentially finding another. The incredibly wasteful volumes of time, money and person power which have been expended upon Vitamin C research using tiny antisorbutic doses have produced fairly uninspiring therapeutic results. On the other hand, the dramatic therapeutic successes of Vitamin C to date, including the discovery of the metabolites of Ester-CR ascorbate, have been due to inspiration, creativity, hard work and serendipity.

The story of Ester-CR ascorbate started with a small company called Inter-Cal Corporation in Prescott, Arizona, which purchased, during 1981, a new process for the manufacture of Calcium Ascorbate. This process, in contrast to other methods of ascorbate production(184), does not use solvents such as alcohol or acetone to precipitate the calcium ascorbate. Instead, the entire process is carried out in water, and the calcium ascorbate was recovered by oven drying the mixture. Problems encountered early on in obtaining uniform consistency prompted Messrs. Gerald Elders and Dick Markham to engage analytical experts to help obtain a more consistent product. Thus started the engagement, over the next several years, (1983-87) of several noted experts encompassing the diverse fields of analytical (Drs. Williard Peterson and Howard Jordi) and organic (Dr. Seth Rose) chemistry, nutrition (Dr. Jeffrey Bland) and biochemistry (Dr. Anthony Verlangieri).

Extensive analyses of the ascorbate product revealed anomalies in its properties from that of calcium ascorbate; analytical investigations, discussions and voluminous scientific correspondence amongst the collaborating individuals prompted a working definition of this product as a "polyascorbate", ie. calcium ascorbate plus other components, or else a polymerized form of calcium ascorbate. The name Ester-CR, which is, chemically speaking, a misnomer, was prompted by the deduction that the product was a polymer of calcium ascorbate in an ester linkage (an ester is a specific type of functional group).

Subsequent research, which is now pointing the way to a novel, exciting facet of Vitamin C research, has revealed that Ester-CR ascorbate is actually a mixture of calcium ascorbate (80.2%), dehydroascorbic acid (5-8%), a mixture of aldonic acids (metabolites) (5-6%), unreacted calcium carbonate (5%) and water. The initial discovery that metabolites are actually a constituent of Ester-CR ascorbate is a classic scientific serendipity story, retold to me in 1989 by Dr. Seth Rose, organic chemist who actually identified a metabolite as part of Ester-CR back in 1986.

Dr. Howard Jordi, using the technique of High Pressure Liquid Chromatography (HPLC), had enriched a fraction of Ester-CR ascorbate, which he presumed was the high molecular weight "polyascorbate" fraction. Dr. Seth Rose isolated the exclusion volume of the sample, which he hypothesized was the active fraction of the presumed polymeric polyascorbate and subjected this sample to analysis by Nuclear Magnetic Resonance (NMR) spectroscopy. Frustrated by not being able, no matter how long he tried, to fit the NMR results with a polymeric polyascorbate structure, he recounted how he started to doodle on a scrap piece of paper, what the proposed structure of the NMR analysis would be, without prejudice or reference to his preconceived hypotheses. He realized that the 4 carbon structure he had drawn actually represented a metabolite product, an aldonic acid, of Vitamin C (see Fig. 3, Ch.2). Then, in accordance with standard scientific procedure, he then had to prepare authentic aldonic acids, match them with the substances identified from Howard Jordi's fraction and then look for these substances in Ester-CR ascorbate. As usual, the inspiration occurred in a flash - the rigorous proof entailed long, hard and tedious work.

Since those early days, considerable research, on cells, animals and humans, has been initiated with metabolite substances of Vitamin C(37,67,207) . This is definitely an area of research which will rewrite our current biochemical understanding of Vitamin C metabolism, which could still be termed, despite the thousands of published papers, "primitive".

ESTER-CR ASCORBATE: Superior Absorption and Retention
________________________________________________

It is somewhat unique that a new patent has been issued to a novel form of Vitamin C. Yet, because of the unique properties of Ester-CR ascorbate, the Commissioner of Patents and Trademarks of the United States issued Patent Number 4,822,816 to this substance as of April 18, 1989(146). World-wide patents have been applied for and are expected to be issued in the near future. The patent relates to "...an improved form of Vitamin C......improved methods for establishing Vitamin C levels in the human body.....methods for improving the human body tolerance to Vitamin C.....more effectively absorbed and retained in the human body ...... metabolites of ascorbic acid.....corresponding to three specific aldonic acids: L-threonic acid, L-xylonic acid and L-lyxonic acid.....".

The clinical data from both animal and human studies demonstrate that Ester-CR ascorbate, this mixture of calcium ascorbate with natural metabolites, is, in fact, absorbed at a higher rate and excreted at a lower rate than both ascorbic acid and calcium ascorbate(37,226-9,241).

Studies performed by Dr. Verlangieri's group comparing the absorption in rats of Ester-CR ascorbate relative to ascorbic acid(225), and calcium ascorbate(228) had the following results:

1. Ester-CR was absorbed within 20 minutes; ascorbic acid, only after 40 minutes(225);

2. The absorption rate was 0.073 ug/min for Ester-CR as compared to 0.033 ug/min for ascorbic acid, or more than double. (See Fig. 6). The statistical significance of this value is extremely high (P=0.0001)(225). The absorption rate of Ester-CR was also double that of calcium ascorbate, 0.04 ug/min compared to 0.02 ug/min(228).

3.Blood plasma concentrations of Vitamin C were higher in Ester-CR-treated animals at 20, 40 and 80 minutes(225);

4. The excretion rate of Ester-CR was slower than for ascorbic acid, as measured by the appearance of ascorbic acid in the urine. It took twice as long, 208 min., as opposed to 104 min. for ascorbic acid to appear in the urine of the Ester-CR-treated rats. This result, demonstrating longer retention of Ester-CR, was highly statistically significant (P=0.0009)(225);

5. In experiments designed to assess the effects of metabolites upon Vitamin C absorption, the absorption of calcium ascorbate, "spiked" with metabolite calcium threonate, exceeded that of plain calcium ascorbate, and equalled or slightly exceeded that of Ester-CR:

Compound (226) Absorption Rate (227)
________________________________

Another Ascorbate 0.04 ug/min 0.035 ug/min
Ester-CR 0.05 ug/min 0.046 ug/min
Calcium Ascorbate + Metabolite 0.05 ug/min 0.048 ug/min

6. Studies investigating the uptake of radioactively labelled ascorbic acid into mouse fibroblast cells in culture(229) showed that the metabolite calcium threonate increased the uptake of ascorbic acid 1.86 fold compared with control Ringer's solution. This result was also shown to be statistically significant using the Student T-test (alpha =0.05).

7. A human clinical study conducted by Dr. Jonathan Wright of the meridian Valley Clinical Laboratory(241) with 12 subjects, showed Ester-CR to produce higher ascorbate levels, longer retention times and slower excretion rates compared to ascorbic acid. An improved and enlarged study is currently being planned to further establish the pharmaco-kinetics of Ester-CR ascorbate in human subjects.

Fig. 6 Faster Absorption of Ester-CR Compared to Ascorbic Acid(225)

The Future of Metabolites and Ester-CR Ascorbate
________________________________________________

The above clinical evidence documents the potentiating effects of metabolites upon the absorption and retention of Vitamin C. In fact, simply "spiking" an ordinary calcium ascorbate with a metabolite makes it behave as though it were Ester-CR ascorbate(226-7), which is a mixture of Vitamin C with metabolites. And, as we have seen in Chapter 3, metabolites may have a role in Vitamin C's inhibitory effect upon HIV infection. The biochemical and pharmacological basis for the effects of metabolites upon Vitamin C action may open an entirely new research vista, investigating the molecular mechanisms of these rather small and simple molecules called "metabolites".

How far have we actually come in our knowledge and understanding of what Vitamin C is and how it works? Although this may seem an impertinent question to ask, in light of the voluminous stacks of research published on the subject, it is important to bear in mind that the essential definition of Vitamin C, (vitamin or essential nutrient), its therapeutic role in treating illness, and optimal human nutritional requirements are all issues considered controversial amongst some members of the medical and orthomolecular professions(122,138,140,150). This is apart from considerations of the efficacy of its various forms, and indeed the biochemical and pharmacological mode of action of Vitamin C's metabolites(107), which until very recently, had been formulae confined to schematics of metabolic pathways of Vitamin C. The "discovery" of the modulating roles of metabolites and their biochemical isolation will almost certainly rewrite all our textbooks on the subject of Vitamin C's many physiological and hormonal roles in the body.

Today, some 250 years after citrus fruit was identified as a preventative against scurvy, and some 60 years following the actual isolation of Vitamin C(202), it is vital to review progress made in our understanding of what Vitamin C is and how it works(138). Table 7 below reviews some of the major fundamental processes identified to date in which Vitamin C is intimately and essentially involved and/or required.

Table 7. Functional Metabolic Roles of Vitamin C

Process Functions
______________

Collagen synthesis Creation, maintenance of structural (52,54,166,200) integrity of skin, muscle, bone, gums, all connective tissues, wound healing

Hormone & Neurotransmitter Neurochemical and endocrine functions in synthesis(68,72,89,101, pituitary, pancreas, gonads, thyroid, 136,137,139) hypothalamus; production & protection of c-AMP and c-GMP

Antioxidant, Vitamin E Neutralize extracellularly reactive regenerator(7,33,65,101,112, oxidants, protection against free radical 161,182) and lipid peroxidation damage

Sugar metabolism modulator Interaction with insulin and glucose in (167,221,223) regulation of sugar homeostasis

Fat metabolism regulator Regulation of cholesterol levels, fatty acid (82,83-8,109,135,) metabolism, prostaglandin synthesis, synthesis of L-carnitine

Modulator of Oxygen-hemoglobin Regulates blood oxygen levels
dissociation curve(138)

Immune modulation Lymphocyte blastogenesis, antibody (30,62,108,166,208,242) production, interferon synthesis, leukocyte phagocytosis

Anti-Viral Activityin AIDS,Immune, free radical, metabolite? action.cancer (43,60,97,158,166)

Modulator of Drug Metabolism Free radical, metabolite? action.
(24-27,173,192,210,245)

How Does Vitamin C Work?
________________________

When we view the above table, and recall that Vitamin C is involved in hundreds of metabolic reactions in the bodies, the reasons behind Vitamin C's wide-ranging therapeutic actions become clearer and less "miraculous".

As an essential nutrient, required for the synthesis of other vital nutrients such as collagen and L-carnitine, as a free radical scavenger which protects against membrane and cellular damage from toxic oxygen species, as an immune enhancer, strengthening our resistance to attack by other organisms, and as an integral part of our metabolic lives with sugar and fat metabolism, as well as neuroendocrinal synthesis, it is no wonder that Vitamin C accomplishes such all-pervasive therapeutic effects when administered in optimal doses.

Some of these functions are accomplished through Vitamin C's outstanding capacity to be both an electron donor and acceptor, which accounts for its multi-varied participation in numerous biochemical hydroxylations, anti-oxidant, and free radical scavenger regenerating abilities. This antioxidant role is doubtless the reason for the high concentration of Vitamin C in neutrophils which use "super oxide" to destroy foreign invaders. These toxic oxygen species are neutralized by free radical scavengers such as Vitamin C.

The requirement for Vitamin C in so many metabolic processes really speaks of its ubiquity prior to the hypothesized evolutionary accident which prevented humans from synthesizing our own Vitamin C.

In reviewing the sorry state of our environment, the magnitude of stresses prevalent in our daily lives, the poor nutritional quality of our food and the excesses in our diets, it is clear from many epidemiological studies that perhaps a majority of people suffer from deficiencies of Vitamin C and doubtless other nutrients as well. In light of such cellular deficiencies of Vitamin C, it is not surprising that small doses may simply not be adequate enough to "boost" the systems depleted of this nutrient.

To illustrate how stress to our immune system can deplete body stores of Vitamin C, we can turn to some remarkable research conducted by MIT biologist Susumu Tonegawa, who was awarded the Nobel Prize in 1987 for his unravelling of the complex process whereby B-cells, the body's antibody-producing cells can generate millions or billions of different antibodies, not by using a separate gene for each antibody, but by shuffling and combining different portions of about 1000 genes. Early in 1990, researchers at the Whitehead Institute announced that the discovery of the "recombination activating gene" (RAG-1) necessarily for this "putting together" process. The process of antibody production requires Vitamins A, C and zinc. Hence, in the face of continuous stress to our immune system, requiring the production of antibodies, we are using up valuable Vitamin C and other nutrients.

The recent announcement of new Recommended Daily Allowances (RDAs) by the U.S. National Research Council, unchanged for non-smokers, at 60 mg, and increased to 100 mg per day for smokers, prompted vigorous protest from a number of leading nutritional authorities. In Dr. Verlangieri's words "....the NRC has chosen to ignore the worldwide studies that show that vitamin C plays a role in many conditions that include degenerative tissue diseases, cataract formation, periodontal disease, immunological diseases, wound healing, anemia, atherosclerosis and free radical scavenging......." Why the medical and scientific research establishment continue to view Vitamin C as a vitamin required in exceedingly small doses merely to prevent death from scurvy, despite such clinical and research evidence documenting Vitamin C's therapeutic potency at high doses, defies the understanding of the author, and underscores the importance of improving communication between the various health professions.

The Possible Functions of Vitamin C Metabolites
_____________________________________

Thus far, based upon experiments described in Chapters 3, 8 and 10, the known effects of metabolites upon Vitamin C utilization are to:

1. Increase the rate of absorption of Vitamin C.

2. Increase the amount of time that Vitamin C is retained in the body, prior to excretion.

3. Increase the delivery of Vitamin C to tissues, to enable it to achieve its therapeutic effects. This would presumably occur during the "extra" time Vitamin C is circulating within the body.
4. Enhance Vitamin C's antiviral effects, as postulated with the AIDS virus and in cancer patients. This activity is as yet only speculatively attributed to the action of metabolites.

Metabolites and Vitamin C's Ability to Modulate Metabolism
______________________________________________

The above effects of metabolites upon Vitamin C metabolism bear a strong resemblance to the way that Vitamin C can exert a potentiating effect upon drugs and other substances including insulin (see Chapter 6). Even as far back as 1941, Richards et al(173) described how Vitamin C deficiency decreased drug (pentobarbital) oxidation and prolonged sleeping times in scorbutic guinea pigs, which could be reversed by supplementation. Also Vitamin C enhances the ability of young animals to eliminate caffeine, another drug(25,210). Since Vitamin C increases the rate of conversion of dopamine to norepinephrine(140), and thence modulates neuroendocrine levels in many endocrine tissues (pituitary, pancreas, gonads, thyroid, hypothalamus), it is clear how Vitamin C and possibly its metabolites could modulate the utilization of many metabolic compounds and drugs.

It is clear from experiments described in Chapter 10, that metabolites added to calcium ascorbate actually potentiated its absorption and retention time, equalling or exceeding the action of Ester-CR ascorbate which contains natural metabolites(226-7). Also, as discussed in Chapter 3, PROLONGED exposure of HIV-infected cells to ascorbic acid resulted in the 99% inhibition of reverse transcriptase activity and other HIV parameters. This result, despite the result that Vitamin C had no DIRECT effect upon HIV(97).

These pioneering experiments may point the way to how metabolites work. It is possible that the these modulating effects of metabolites may be due to:

1. Structural (stereospecific) qualities of metabolites which interact with membranes in certain ways to enhance action of Vitamin C;

2. The oxidation of Vitamin C which gives rise to metabolites and perhaps exerts anti-viral effects;

3. Either or both the above and as yet to be discovered mechanisms of metabolites.

Questions Which Need Answers Regarding Metabolites
__________________________________________

It would appear that, despite considerable clinical experience with Vitamin C, we are still at a very primitive level of understanding about its mode of action, or that of its metabolites. Certain basic questions which, if addressed, could shed light and advance our knowledge of this multi-faceted nutrient:

1. Definition, classification and nomenclature of metabolites. In the metabolic pathway of Vitamin C, which molecules are considered metabolites. Is dehydroascorbic acid a metabolite? Diketogulonic acid, etc?;

2. More precise metabolic scheme for Vitamin C, including the fate of metabolites during absorption, retention and elimination from the body;

3. Is it Vitamin C itself, its metabolites or the combination of the two, which exert the many therapeutic properties discussed throughout this book;

4. How does Vitamin C exert its anti-viral and anti-cancer effects, and what is the role of metabolites?