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Dr Robert Cathcart MD – Vitamin C, the Nontoxic, Nonrate-Limited Antioxidant Free Radical Scavenger


Vitamin C, the Non-Rate Limited Free Radical Scavanger

Medical Hypotheses, 18:61-77, 1985.

Copyright (C), 1994 and prior years, Dr. Robert F. Cathcart, M.D. Allergy, Environmental, and Orthomolecular Medicine

Abstract
Introduction
Table I – Usual Bowel Tolerance Doses (4)
Effect of Ascorbate Detoxification Dramatic in Selected Group
The Rate Limitations of Antioxidant Free Radical Scavengers, a Cause of Many Pathologic Processes
Example of a Rate Limited, Antioxidant Free Radical Scavenging Pathway
Free Radical Suppression of the Immune System, Common to Most Infectious Diseases, Neutralized by Ascorbate
Ascorbate in AIDS
Ascorbate, a Non Rate Limited, Antioxidant Free Radical Scavenger
Effective Reducing Redox Potential at a High Tissue Threshold
Wide Spectrum Benefits From Ascorbate Match Expectations For a Non Rate Limited, Antioxidant Free Radical Scavenger
Glucose 6 Phosphate Dehydrogenase (G-6-PD) Deficiencies
Other Possible Difficulties
Oxalate Kidney Stones
Anascorbemia and Acute Induced Scurvy
Sudden Infant Death Syndrome
Conclusions
Acknowledgements
References

Abstract

The amount of oral ascorbic acid that a patient can tolerate without diarrhea,
increases somewhat proportionately to the "toxicity" of his disease. Clinically,
in a disease ameliorated by ascorbate, there is a suppression of symptoms only with very
high doses and approximately to that extent which a
nonrate-limited,_antioxidant_free_radical_scavenger, might be expected to affect that
disease process if all harmful free radicals and highly reactive oxidizing substances were
quenched. In most pathologic processes, the rate at which free radicals and highly
reactive oxidants are produced, exceeds the rate at which the ordinary rate-limited
antioxidant free radical scavenging mechanisms can quench those free radicals and
oxidants. When ascorbate acts as a scavenger, dehydroascorbate is formed; but if the
ascorbate/dehydroascorbate (AA/DHA) ratio is kept high (the redox potential kept reducing)
until the unstable dehydro- ascorbate undergoes hydrolysis or can be reduced back to
ascorbate, the dehydroascorbate will do no harm. Since even at very high doses, ascorbate
is virtually nontoxic, it may be given in the enormous doses necessary to quench almost
all unwanted free radicals and oxidants. The wide spectrum of infectious diseases
ameliorated by massive doses of ascorbate indicates some common pathologic processes in
these diseases.

Introduction

Based on my experience with over 11,000 patients during the past 14 years, it has been
my consistent observation that the amount of ascorbic acid dissolved in water which a
patient, tolerant to ascorbic acid, can ingest orally without producing diarrhea,
increases considerably somewhat proportionately with the "toxicity" of his
illness. A person who can tolerate orally 10 to 15 grams of ascorbic acid per 24 hours
when well, might be able to tolerate 30 to 60 grams per 24 hours if he has a mild cold,
100 grams with a severe cold, 150 grams with influenza, and 200 grams per 24 hours with
mononucleosis or viral pneumonia. The clinical symptoms of these diseases and other
conditions previously described, are markedly ameliorated only as bowel_tolerance dose
levels (the amount that almost, but not quite, causes diarrhea) are approached (1-6).

Table I – Usual Bowel Tolerance Doses

(4)

                                   GRAMS PER         NUMBER OF DOSES 

    
CONDITION                          24 HOURS          PER 24 HOURS
      normal                       4 -  15              4 -  6 
      mild cold                   30 -  60              6 - 10 
      severe cold                 60 - 100+             8 - 15 
      influenza                  100 - 150              8 - 20 
      ECHO, coxsackievirus       100 - 150              8 - 20 
      mononucleosis              150 - 200+            12 - 25 
      viral pneumonia            100 - 200+            12 - 25 
      hay fever, asthma           15 -  50              4 -  8 
      environmental and 
       food allergy              0.5 -  50              4 -  8 
      burn, injury, surgery       25 - 150+             6 - 20 
      anxiety, exercise and 
       other mild stresses        15 -  25              4 -  6 
      cancer                      15 - 100              4 - 15 
      ankylosing spondylitis      15 - 100              4 - 15 
      Reiter's syndrome           15 -  60              4 - 10 
      acute anterior uveitis      30 - 100              4 - 15 
      rheumatoid arthritis        15 - 100              4 - 15 
      bacterial infections        30 - 200+            10 - 25 
      infectious hepatitis        30 - 100              6 - 15 
      candidiasis                 15 - 200+             6 - 25 


There was a remarkable lack of systemic difficulties in these patients that could be
directly related to the massive doses of ascorbate. The majority of these patients, ill
with some acute or chronic disease, were able to take massive doses of ascorbic acid
orally without difficulties. Minor complaints about ascorbic acid such as it causing gas,
diarrhea, or acid stomach, while common in well persons even at low doses, were rare in
very sick patients. Low or moderate doses (doses substantially below bowel tolerance)
usually had no noticeable immediate beneficial effects, but high doses (doses just below
the amount that would produce diarrhea in a patient tolerant to ascorbate) would have the
effect of markedly suppressing symptoms as the high dose levels were reached. This sudden
effect is often quite dramatic clinically and is not usually obtained even partially at
lower doses. It is as if a threshold were reached at which point the ascorbate becomes
very effective.

Mixtures of mineral ascorbates (calcium, magnesium, potassium, zinc, and sometimes
sodium) are used in certain circumstances to increase bowel tolerance for even more
clinical effectiveness but do not clearly demonstrate the increasing bowel tolerance
phenomenon being discussed here.

Knowledge of the known vitamin functions of ascorbate would not have allowed one to
predict these beneficial results. The lack of serious difficulties with these massive
doses is surprising.

Effect of Ascorbate Detoxification Dramatic in Selected Group

Part of the unexpected benefit at the high dose levels is frequently a feeling of
well-being. This feeling of well-being, especially with the more toxic conditions, is
despite the gas and diarrhea sometimes produced. If the malaise from the basic disease is
great (e.g. mononucleosis, acute hepatitis, viral pneumonia, etc.), the obvious benefit
from ascorbic acid is usually so great that the patient usually cares little about the
minor gastrointestinal disturbances. Lowering dose levels too soon before bowel tolerance
decreases, results in the return of the malaise and other acute symptoms of the disease.
The_clinical_sensation_experienced_with_the_massive
doses_of_ascorbate_is_one_of_"detox- ification"_as_a_threshold_is_reached. By
raising and lowering the doses, the symptoms of "toxicity" can be readily turned
off and on rapidly by some skilled patients.

I cannot emphasize enough that in "selected" patients (selected only by
excellent tolerance to ascorbic acid, good understanding of the principles of determining
the flexible bowel tolerance doses, and the willingness to follow directions in fine
detail), this effect is invariable, dramatic, and unmistakable. The patient most likely to
experience this effect is the psychologically stable, not suggestible, practical, not
liking to be sick patient, with a "cast iron stomach." Children and teenagers,
much as they may hate the taste of ascorbic acid in water, make particularly good patients
once they experience the ameliorating effects of these massive doses. Infants, upon
receiving very large intramuscular or intravenous injections, frequently
"detoxify" in minutes to the astonishment and marked relief of their parents.

These feelings of well-being experienced by tolerant patients from the ingestion of
massive doses of ascorbic acid are definite clinical indications that no acidosis or other
acute toxic metabolic effect is resulting. Massive intravenous doses of sodium ascorbate
are even more impressive than oral ascorbic acid, because the beneficial effects are even
more dramatic and gastrointestinal gas and diarrhea are not produced. Patients who
ordinarily would be relatively incapacitated, can usually remain functional and sometimes
even participate in athletics if frequent and massive ascorbate doses are maintained.

Patients must be encouraged to take these massive doses. Patients taking Vitamin C on
their own, seldom take doses high enough to discover this effect. I do not want to give
the impression that this method is easy to use; the mechanics of taking these doses can be
very difficult for many patients. Nevertheless, when properly instructed, the majority of
patients are able to achieve these effects. If a patient is relatively intolerant to oral
ascorbate only because of gastrointestinal complaints, and if his disease is one that
usually responds to oral ascorbate in tolerant patients, and if the severity of the
condition warrants the inconvenience and expense, then intravenous ascorbate is indicated.

Such effects of these large doses of ascorbate cannot be readily explained from its
known vitamin functions. The spectrum of diseases affected by massive doses of ascorbate
is a wonder in itself, but also gives some hint at the probable mechanisms involved. The
sudden detoxifying effect experienced clinically only at the very high threshold doses,
suggests that ascorbate is participating in chemical reactions where a critical
concentration of ascorbate is necessary, or where a certain ratio between ascorbate and
certain other reactants must be achieved. The concept that free radicals and other highly
reactive oxidants are a frequent factor in pathologic processes (7,8) and that ascorbate
is an antioxidant free radical scavenger, could explain much of this.

The Rate Limitations of Antioxidant Free Radical Scavengers, a Cause of Many Pathologic Processes

Chemical reactions involving free radicals and highly reactive oxidants are necessary
in the normal metabolism of cells. Metabolic processes utilizing oxygen (aerobic
metabolism) which release energy are important examples. Ordinarily, these reactions occur
in conjunction with appropriate enzymes or in the proper places within the cells. While it
has been documented that potentially harmful reactants leak from their normal cellular
confines and are potentially toxic (9), these rates of leakage are usually low enough for
the natural antioxidant, free radical scavenging mechanisms to handle. One of the causes
of natural aging may be that some (albeit small) portion of stray free radicals inevitably
escape quenching (10). While the human body does contain many free radical scavenging
mechanisms for the purpose of mopping up free radicals, I hypothesize that in_pathologic
processes_these_rate-limited,_mechanisms_are_acutely_inadequate_t o_neutralize
the_volume_of_free_radicals_produced. A threshold is reached where these additional free
radicals produced, initiate an inflammatory cascade, can cause immune suppression, and can
result in degenerative diseases.

Example of a Rate Limited, Antioxidant Free Radical Scavenging Pathway

In general free radical scavenging occurs through complex metabolic pathways involving
many steps which are rate-limited. Deficiencies of nutrients, vitamins and minerals, which
make up the enzymes and coenzymes of these systems can slow down or halt certain pathways.

It is apposite to describe one of these rate-limited, free radical scavenging
mechanisms, to give the impression of its complexity and why it is rate-limited. The
example chosen involves the glutathione pathway which is possibly one of the most
important pathways.

When, for example, a superoxide radical must be destroyed, superoxide dismutase can
catalyze its conversion to O2 and H2O2 (11). Ascorbate, nonenzamatically, also converts
superoxide to H202 but is oxidized in the process to the ascorbate free radical and
dehydroascorbate. The ascorbate free radical and the dehydroascorbate are reduced back to
ascorbate either by NADH (catalyzed by semidehydroascorbate reductase and forming NAD) or
reduced glutathione (GSH) (catalyzed by dehydroascorbate reductase and forming oxidized
glutathione (GSSG)) (12). Some of the peroxide can be converted to oxygen and water by
catalase but most will be destroyed by a glutathione-requiring enzyme system. GSH
(catalyzed by glutathione peroxidase) reduces the peroxide to water but in the process is
oxidized to GSSG. The resulting GSSG is reduced by NAD(P)H (catalyzed by glutathione
reductase). The resulting NAD is reduced back to NADH by way of the Krebs cycle or
resulting NADP is reduced back to NADPH by the hexose monophosphate (HMP) pathway. It is
thought that commonly the rate-limiting step in the last series of reactions is that
catalyzed by glutathione peroxidase and its cofactor selenium, but other substances which
could limit all this are the vitamin E, Vitamin C, vitamin B2, vitamin B3, cysteine, etc.
Note: the ascorbate used in this example is as in the Vitamin C sense; the small amount
available is oxidized to dehydroascorbate and then must be reduced back to ascorbate by
the pathway described, to be reused as ascorbate. One can easily see how this mechanism
and similar mechanisms could be overwhelmed by a toxic pathogen liberating free radicals
or by an inflammatory cascade regardless of its cause.

Free Radical Suppression of the Immune System, Common to Most Infectious Diseases, Neutralized by Ascorbate

I further hypothesize that the pathogens of most acute infectious diseases depend upon
free radical toxicity to defend themselves against immediate destruction by the immune
system. If a pathogen produces free radicals at a rate sufficient to exceed the rate at
which the host can produce free radical scavengers to protect the immune system, the
pathogen will be free to invade and multiply. The more toxic pathogens produce more free
radical toxins than just necessary to suppress the immune system. The spill over of free
radicals reaches a threshold where an inflammatory cascade in the tissues affected, is
initiated.

Neutrophils liberate free radicals and highly reactive oxidants both intracellularly
and extracellularly in their attempt to destroy pathogens, in the process termed the
respiratory burst (13-18). The respiratory burst consumes NADPH which must be continually
restored if the respiratory burst is to be maintained. Restoration of NADPH supplies is
accomplished by way of the HMP pathway, by various rate-limited enzymatic mechanisms.

I suggest that if rate-limited enzymatic processes or the limited availability of the
antioxidant free radical scavenging mechanisms of the leukocytes, superoxide dismutase
(18), catalase (20), glutathione peroxidase, and glutathione (21-23), fall short of being
able to contain and direct free radicals and reactive oxidants toward the pathogen, that
failure causes the free radicals to backfire, damage the host itself, and initiate an
inflammatory cascade.

If a critical tissue concentration of free radical scavenger could protect the immune
system from the free radicals produced by the pathogen, and would assist the leukocytes in
modulating their own free radical generation, the immune system might be expected to
prevail and destroy the pathogen rapidly by direct phagocytosis. If such a scavenger were
found to be effective in large numbers of infectious diseases, it could imply that there
was a common mechanism of free radical suppression of the immune system operative in all
these diseases. Until such a free radical scavenger were recognized to exist, the
commonality of such a mechanism to all these diseases might be overlooked. I hypothesize
that ascorbate is, in fact, such a free radical scavenger when used in the doses being
discussed. Its effectiveness in a wide spectrum of infectious diseases is evidence of the
common mechanism many pathogens have of sup- pressing the immune system.

By neutralizing virtually all unwanted free radicals and toxic oxidants, massive doses
of ascorbate can be made to protect the immune system to such a degree that early in acute
viral diseases, the immune system can usually destroy the pathogen within hours. When used
later in the course of an acute viral disease where the pathogen has established itself
intracellularly in significant numbers of cells, massive doses of ascorbate can protect
the immune system, suppress most symptoms, and prevent secondary complications until the
immune system destroys the pathogen by secondary means such as with antibodies.

I have found that massive doses of ascorbate work synergistically with appropriate
antibiotics when used against acute bacterial diseases, and broaden the spectrum of the
antibiotics considerably. I have not been able to explore thoroughly the extent to which
ascorbate can be used alone in bacterial diseases, but I have had some serendipitous
clinical evidence that certain bacteria do very poorly in the face of massive doses of
ascorbate even where antibiotics were not used.

Conditions involving indolent bacterial infections such as chronic bronchitis,
sinusitis, otitis media, tonsillitis, osteomyelitis, nonspecific urethritis, etc., are
frequently cured by massive doses of ascorbate.
I_hypothesize_that_probably_induced_localized_scurvy_plays_a_deci sive_part_in
a_pathologic_equilibrium_set_up_between_the_chronically_infected_ tissue_and_the pathogen.
When the induced scurvy is eliminated by driving tissue levels of ascorbate up above a
certain threshold, the immune system usually rapidly eliminates the infection and the
affected areas heal.

Where allergies in combination with infections play a major role, massive doses of
ascorbate are helpful but continuing maintenance doses will be required. In this
situation, continuing blockade of the allergically-induced inflammatory cascade must be
maintained.

With recurrent herpes virus infections, very high maintenance doses of ascorbate seem
to prevent some attacks, and bowel tolerance doses will shorten and reduce the severity of
attacks. A topically applied ascorbate paste (ascorbic acid or sodium ascorbate and water)
(24) appears to be particularly effective on herpes simplex.

In chronic hepatitis, ascorbate may not cure the condition; nevertheless, massive doses of ascorbate will
usually ameliorate the condition; and I have evidence that shedding of the virus may stop.
I have not determined whether the patient will resume shedding of the virus if large doses
of ascorbate are discontinued. In conditions where a virus has become well established
intracellularly, there are some limitations on the ability of ascorbate to assist the
immune system.

Ascorbate in AIDS

More recently, I have found ascorbate useful in the management of the acquired immune
deficiency syndrome (AIDS). The AIDS patient who has already suffered a marked suppression
of helper T-cells, presents a clinical problem of management similar to a bubble baby. If,
in addition to the other measures described in my previous reports (24,25), the patient
takes bowel tolerance doses of ascorbic acid orally almost every hour (intra- venously in
emergencies), he may remain clinically well despite the continuing severe suppression of
the helper T-cells. All this must be started before multiple infections riddle the
patient’s body with excessive sources of free radicals. There have been suggestive
anecdotal cases which indicate that in the prodromal period, before the destruction of the
helper T-cells, there might be avoidance of the development of the AID syndrome by this
program. Confirmation of this possibility awaits long- term laboratory follow-up. There is
evidence that a retroviral infection in cats, the feline leukemia virus, can be cured in
the prodromal stage with large oral doses of ascorbate used in combination with other
nutrients (26).

Ascorbate, a Non Rate Limited, Antioxidant Free Radical Scavenger

It is my hypothesis that what makes ascorbate truly unique is that very large amounts
can act as a nonrate-limited antioxidant free radical scavenger.

Clinically, ascorbate is virtually nontoxic (27,28,4). But as ascorbate acts as an
antioxidant free radical scavenger in the body, it is oxidized to dehydroascorbate. There
are animal experiments that indicate that dehydroascorbate is toxic (29-31). However,
dehydroascorbate is not administered directly to humans as it was in the animal
experiments. Whatever dehydro- ascorbate comes to exist in the human body, comes by way of
the oxidation of ascorbate, as the ascorbate is utilized to reduce free radicals or other
reactive oxidizing substances. The potential of the dehydroascorbate to do damage should
be less than the harmful potential of the substances it reduces to become dehydroascorbate
(the oxidizing redox potential has been diminished). Therefore a patient should not be
expected to be more toxic from the dehydroascorbate formed than he was from the original
disease unless there is some peculiar specific sensitiv- ity to dehydroascorbate (see
discussion of G-6-PD deficiencies below).

Used in the doses I suggest, there is an even more important mechanism which prevents
toxicity from dehydroascor- bate. I take advantage of a combination of the facts that even
in enormous doses, ascorbate is not clinically toxic, and that dehydroascorbate is only
toxic when there is a low AA/DHA ratio.

Effective Reducing Redox Potential at a High Tissue Threshold

Several (32-36) have hypothesized and reviewed many of the biochemical advantages of
large doses of ascorbate. Of particular interest are Lewin’s calculations and hypotheses
(34) that high tissue concentrations of ascorbate to dehydroascorbate can directly reduce
various substances (e.g. the disulfides). I doubt that tissue levels of ascorbate achieved
with doses much below bowel tolerance are sufficient to significantly accomplish these
reductions under pathological circumstances. Clinically however, something very dramatic
happens as bowel tolerance is approached. I hypothesize that as a certain threshold ratio
of ascorbate to dehydroascorbate is reached, certain direct reductions of substances such
as oxidized glutathione and adreno- chrome by ascorbate begin. When a patient is sick or
experiencing much stress, the amounts of these substances which can potentially and
beneficially be reduced, increases greatly. If ascorbate is not available to reduce these
substances, those that escape reduction to nontoxic derivatives by the rate-limited,
antioxidant free radical scavenging mechanisms, damage the patient and cause symptoms.
Under these circumstances, when made available, large amounts of ascorbate are utilized
for these direct reducing purposes. These ascorbate reductions are not rate-limited, and
therefore quench the harmful oxidants and free radicals almost instantly.

When the potential need for ascorbate for these purposes is satisfied, the blood level
of ascorbate rises and retards the absorption of ascorbate from the gut. Soon, sufficient
amounts of ascorbate reach the rectum to produce diarrhea.

Based on clinical evidence, I hypothesize that ascorbate can maintain this reducing
redox potential under very adverse circumstances, but that the doses necessary to do this
are enormous by any other standards. This antioxidant free radical scavenging effect of
enormous doses of ascorbate seems not particularly contingent upon other nutrients.
However, vitamin functions of lower doses of Vitamin C are frequently potentiated by and
work in conjunction with vitamin A, zinc, selenium, bioflavonoids, and other nutrients
which play roles in various defense mechanisms.

Chayen has discussed the significance of redox couples and has emphasized that whether
a reaction will proceed left to right, or in reverse, depends upon the ratio of the
oxidized to the reduced members of a redox couple. He suggests designing "redox
drugs" as a possible way of treating imbalances of oxidation-reduction potentials of
critical intracellular systems (37).

Wide Spectrum Benefits From Ascorbate Match Expectations For a Non Rate Limited, Antioxidant Free Radical Scavenger

I would anticipate that if it were possible to eliminate the vast majority of stray
free radicals and highly reactant oxidative substances, the usual inflammatory cascade
would not occur following injury or surgery. Pain, complications, and recovery times would
be reduced. In conditions resulting from combinations of mechanical derangements,
nutritional deficien- cies, immune dysregulations, hemorrhage with release of free radical
generating iron and copper atoms, and then secondary inflammatory cascades (e.g.
degenerative disc disease, degenera- tive arthritis, rheumatoid arthritis, ankylosing
spondylitis, blunt trauma of the spine, etc.), therapeutic effects could be expected
proportional to what might result from blocking of the free radicals and the inflammatory
cascade. Reversal of the mechanical and nonfree radical injury could not be expected,
although certain healing mechanisms might be enhanced.

Toxic substances, whose mechanisms of action involve free radical generation, e.g.
toxic poisons such as snake bites and spider bites, certain drugs, such as barbiturates,
chemotherapeutic agents, narcotics, and powerful oxidizing pollutant chemicals, might be
neutralized. Conditions triggered by allergic reactions and perpetuated by the
inflammatory cascade might be expected to be partially alleviated. Psychological symptoms
resulting from oxidative products such as adrenochrome and noradrenochrome (38), would be
expected to be ameliorated to a degree.

Tumors invading the body or holding off the immune system by way of free radical
toxicity might be expected to respond to varying degrees. As an increasing number of human
cancers are recognized as probably being caused and possibly maintained by infectious
organisms (e.g. Kaposi’s lesions by the CMV (39), some adult T-cell lymphomas by the HTLV
(40), certain cervical and vaginal cancers by the papilloma virus (41,42)), it should not
be surprising if such tumors would respond in various degrees to ascorbate. Since any
treatment of cancers by a physician with nutritional substances is incredibly a felony in
California in 1984, it may be practical to recognize early that a tumor caused by a virus
should no longer be considered a cancer (e.g. Kaposi’s lesions).

If, to these diseases, we add conditions benefitted which could be caused or aggravated
by actual dietary deficiency of Vitamin C, or from an acute induced deficiency of vitamin
C, there is a very close approximation to the clinical spectrum of disease conditions
which in the experience of those actually using such doses (4,26-28,32,33,43,44), appear
to be beneficially affected. In a rough way, these conditions are ameliorated to the
degree that one might anticipate if this ideal mechanism of being able to quench all stray
free radicals and highly reactant oxidative substances, were actually accomplished.

Glucose 6 Phosphate Dehydrogenase (G-6-PD) Deficiencies

There is fear that ascorbate given in large amounts to patients with G-6-PD
deficiencies would cause hemolysis (45,46). In a case where a black man with G-6-PD
deficiency who sustained a burn of one hand was given 80 grams of ascorbic acid
intravenously on each of 2 consecutive days, the patient subsequently suffered hemolysis,
renal failure, a stroke, coma, and then death (46). There are available for intravenous
use, solutions of actual ascorbic acid rather than sodium ascorbate; ascorbic acid, in my
opinion, should never be used in any large amount intravenously. It must be buffered to
reduce the acidity. There are also preparations labelled Vitamin C that contain
preservatives which also should never be used. It was not clear from the article what
preparations had been used.

The sequence of reactions whereby certain drugs cause hemolysis with G-6-PD deficiency
is poorly understood. It appears that G-6-PD deficient cells lack a mechanism to
regenerate reduced glutathione (GSH) from oxidized glutathione (GSSG) and that this lack
may result in several biochemical alterations, the final result being hemolysis of the red
cells. The maintenance of glutathione in the reduced state (GSH) is probably the most
important function of the HMP pathway. It may be that the hemolysis caused by certain
drugs is initiated by the drug forming either free radicals or hydrogen peroxide. When
peroxides are reduced back to water, GSH is oxidized to GSSG, a reaction catalyzed by
glutathione peroxidase. Ordinarily the GSSG is reduced back to GSH by NADPH, a reduction
catalyzed by glutathione reductase. The resulting oxidized NADP is reduced back to NADPH
in the first step of the HMP pathway, as glucose-6- phosphate is oxidized to
6-phosphogluconolactone. This critical reaction is catalyzed by G-6-PD. G-6-PD deficient
cells may be expected to accumulate peroxides which could then oxidize other red cell
components (see review in 47).

As discussed previously, if the AA/DHA redox potential is kept reducing enough by high
enough concentrations of ascorbate, it should directly reduce the GSSG to GSH. I
hypothesize that this mechanism should compensate for the lack of G-6-PD; but I would
offer some words of caution. I have no clinical experience with this condition. It is
apparent, however, that in the case reported that the redox potential was not kept
consistently on the reducing side throughout the course of treatment and that there might
have been variables not appreciated at the time which were very important.

With the increasing millions of persons taking large doses of Vitamin C, it is
inevitable that individuals with G-6-PD deficiencies will take these doses. Serendipitous
data should be collected. I would appreciate receiving any well documented case histories.

It is important to understand that G-6-PD deficiencies have a wide range of clinical
severities. Severe deficiencies are rare and found in Mediterranean and Asian groups.
Blacks have a milder form but with higher frequency of occurrence. There is substantial
decrease in the activity of G-6-PD with aging. The possibilities exist that in certain
individuals with various degrees and forms of G-6-PD deficiencies that: 1) Vitamin C has
no deleterious effect; 2) Vitamin C has a peculiar effect on that person such that any
significant amount causes hemolysis; 3) Vitamin C in low or moderate amounts will produce
hemolysis, while massive amounts maintaining a continuing reduced redox potential will not
cause hemolysis and will prevent the hemolysis from other causes. (This last possibility
will not be determined unless those administering the ascorbate are very aggressive and do
not let up the doses until whatever was the cause for which the ascorbate was given in the
first place, is completely passed.)

As the immense value of ascorbate in the doses I am describing becomes entirely
apparent in normal people, the theoretical possibility of preventing hemolysis in G-6-PD
deficient persons subjected to pathologic oxidative stress, which would result in massive
hemolysis of blood cells anyway, may be recognized. Meanwhile,
I_advise_that_large_doses_of_ascorbate not_be_given_G-6-PD_deficient_patients. I suggest
the possibility that all this may apply to G-6-PD deficiency only to stimulate the
collection of data and to suggest research on the subject.

Calabrese has suggested that megadoses of ascorbic acid might pose a hemolytic risk to
persons with sickle cell trait and sickle cell anemia because their erythrocytes possess
more copper than normal persons and that ascorbic acid markedly enhances copper induced
hemolysis (48). Again I suggest that it is possible that if ascorbate is given in large
enough amounts during a sickle cell crisis, it may keep the redox potential of the various
problem systems reducing. Vitamin E might futher facilitate beneficial effects (49).

Other Possible Difficulties

One might remain unnecessarily cautious in the use of ascorbate because of my
qualification about "tolerant" patients. Any real problems have been rare. I
cannot recall any patient who has been damaged by large doses of ascorbate (other than the
topical effect of the acid on tooth enamel). Some preexisting gastrointestinal tract
difficulties, such as peptic ulcer or colitis, may have been aggravated by topical
effects, but advice on these is difficult to give because more frequently the same
conditions may be benefitted. All these topical difficulties are circumvented by using
intravenous ascorbate.

A high percentage of persons with food and/or chemical sensitivities may have nuisance
difficulties with Vitamin C. However, attempts to have these sensitive patients take
ascorbate should be made because great benefits can often be obtained, particularly from
calcium, magnesium, and potassium ascorbate, in many of these patients. Frequently, after
the administration of selenium, ascorbate is better tolerated by chemically allergic
patients. Levine has suggested that chemically allergic patients frequently benefit from
selenium because selenium augments the glutathione peroxidase activity (8). I have had
some clinical evidence that certain chemically allergic patients who force through
nuisance problems of low doses of ascorbate, can derive benefits from consistently taken
large doses. It may be that chemically allergic persons accumulate dehydroascorbate more
readily than others because of a deficiency of glutathione per- oxidase. I had one
chemically allergic patient who responded well to intravenous ascorbate until an hour
after it was discon- tinued. She then developed a severe headache that lasted several
hours. In retrospect, it seems possible that the intravenous ascorbate was able to
maintain a reducing redox potential, which then returned to the oxidizing side after the
intravenous ascorbate was discontinued.

True allergic reactions seem always traceable to substances from which the ascorbate is
made, or chemicals used in its manufacture, and not to the ascorbate itself.

Oxalate Kidney Stones

Oxalate kidney stones have been suggested as a theoretical problem, in that oxalate is
one of the breakdown products of ascorbate (50). In my experience clinically, ascorbate in
these doses not only does not cause kidney stones but seems to prevent stones in patients
who have had them previously. The slight increase in the acidity of the urine from
ascorbate (51,52), and the slight diuresis (53) solubilizes calcium salts. I think that
high concentrations of ascorbate, by being bacteriostatic in the urine, should prevent
many of the niduses of infection around which oxalate stones frequently form. The
increased ascorbate concentration complexes Ca++ and thereby decreases the amount of Ca++
available to complex with oxalate (34). Here again is the paradoxical situation where with
small doses of Vitamin C, it is possible that where most of the nutrient is oxidized to
dehydro- ascorbate and then some to oxalic acid, it is theoretically possible that there
could be a slight increase in tendency to form stones. However, I find it difficult to
believe that if this were the case, that this tendency would not have been noticed with
the millions taking small doses of Vitamin C. I hypothesize that by using the bowel
tolerance method of determining the dosages of ascorbate to be taken, that no matter how
much dehydroascorbate is formed and hence oxalic acid, the spill of ascorbate in the urine
will be kept very high and should prevent oxalate stones.

Anascorbemia and Acute Induced Scurvy

I suggest that the enormous draw on ascorbate for free radical scavenging purposes, can
exhaust the Vitamin C available for known housekeeping functions of the vitamin. I term
this condition acute_induced_scurvy. This deficiency starts in the tissues directly
involved in the disease; then blood levels of Vitamin C drop (anascorbemia); and then
tissues distant from the primary focus of the disease become involved. Secondary
complications occur which can be averted by fully satisfying the increased need for
ascorbate (4).

A very important part of these very large doses of ascorbate being able to assist the
immune system against pathogens is likely that serum levels and leukocyte levels of
ascorbate are raised enough to drive ascorbate into the depths of infected tissues. The
amount of ascorbate needed to satisfy the enormous potential utilization of ascorbate as
an antioxidant free radical scavenger in the depths of the diseased tissues is provided.
The shut down of Vitamin C dependent housekeeping functions of affected cells and the shut
down of Vitamin C dependent immune system functions are prevented.

Sudden Infant Death Syndrome

I think that many crib deaths are caused by this acute induced scurvy even before it is
evident that the infant is sick with some infectious disease. Kalokerinos (28) has
demonstrated the value of Vitamin C in preventing crib deaths. I have seen enormous
increases in bowel tolerance to ascorbate in adults several hours before there was any
outward sign of their getting sick. It is easy to imagine certain vital centers in an
infant failing when suddenly deprived of Vitamin C by the ascorbate being used up for
acute free radical scavenging purposes. For_many_reasons, it is unfortunate that
the free radical scavenger ascorbate is the same substance as Vitamin C.
Infants
tolerate ascorbate well. In addition to substantial maintenance doses of Vitamin C, even
infants should be given large doses of ascorbate when ill. Amounts should be given
sufficient to relieve fever, irritability, and other outward signs of toxicity (4).

Conclusions

While it is not denied that there could be very rare serious complications associated
with the use of massive doses of ascorbate, fear of this possibility should not retard use
of the substance in patients with normal metabolism. In my experience, the margin of
safety (therapeutic index or selectivity) for massive doses of ascorbate as related to
significant complica- tions is greater than aspirin, antihistamines, antibiotics, all pain
medications, muscle relaxants, tranquilizers, sedatives, diuretics, etc. Not only is the
margin of safety of ascorbate extremely favorable but when used with most of these drugs,
the combination frequently acts synergistically and has a margin of safety greater than
with the drug alone. While ascorbate may block the effects of some sedatives and
narcotics, massive doses of ascorbate frequently alleviate the need for those substances.

Clinically, ascorbate in the very large doses described is very effective and safe as
part of the treatment of a wide variety of conditions, especially infectious diseases. It
is my hypothesis that this clinical effectiveness when a critical threshold is reached, as
indicated by bowel intolerance to ascorbic acid in the form of diarrhea, occurs both
because massive doses of ascorbate can act as a nonrate-limited, antioxidant free radical
scavenger and because acute induced scurvy is avoided. When high enough tissue levels are
reached in tissues directly affected by the disease processes, the redox potential of the
AA/DHA system in those tissues is kept reducing; substances such as oxidized glutathione
are directly reduced; and stray free radicals are rapidly quenched.

This effect of ascorbate is rate-limited only by the lack of courage of those
administering ascorbate or the tolerance of the patient taking it. I hope to increase that
courage by pointing out the observed lack of toxicity clinically and the theoretical
reasons for that lack of toxicity.

This effect, when understood, opens up a wide range of opportunities to understand
certain pathological processes. It is especially important in the case of infectious
diseases because of the probable common mechanism of free radical toxicity that many
pathogens have of suppressing the immune system. The increasing bowel tolerance to
ascorbic acid can be used as a fairly accurate measure of the "toxicity" and
activity of certain disease processes.

In toxic conditions, the use of ascorbate by the body for these scavenging purposes,
results in such a localized and systemic deficiency of Vitamin C that there is not enough
of the nutrient remaining for Vitamin C dependent housekeeping functions. I call this
condition acute_induced scurvy. This condition can be induced by any stress and is
responsible for a high percentage of the secondary complications of many diseases. The
magnitude of this scavenging drain on ascorbate is enormous as revealed by the increasing
bowel tolerance to ascorbic acid somewhat proportional to the toxicity of the disease
process. Only the doses discussed can fully satisfy this need.

I think that most crib deaths are due to acute induced scurvy.

I have hypothesized here that massive doses of ascorbate may paradoxically be of
benefit in G-6-PD deficiency, but have urged caution until more data is obtained.
Ascorbate, when used with care, can be of great benefit in chemically allergic patients.

Rinse ascorbic acid and carbonated ascorbates off the teeth as prolonged exposure may
cause damage to the enamel.

Acknowledgements

Partly supported by the Burton Goldberg Foundation. The author appreciates the comments
of Stephen A. Levine and Parris M. Kidd.

References

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Content (C) 1995 and prior years,  Robert F. Cathcart., M.D.

IMPORTANT:  Information provided is intended for educational purposes and is not intended to be medical advice nor offered as a prescription, diagnosis or treatment for any disease, illness, infirmity or physical condition. Always consult your own medical provider about your health and medical questions before making any health related decision. These statements have not been evaluated by the Food & Drug Administration.