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,
with 1% each of lecithin
and guar gum. 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?
