The subject is unstable molecules in your body.  A bit of reading.

Do look up "Jacques Masquelier" on your search engine to find out more.

Jack

<<<Oligomeric Proanthocyanidin Complexes: History, Structure, and
Phytopharmaceutical Applications


Anne Marie Fine, CPA, ND Candidate 2000
Abstract
Considerable recent research has explored therapeutic applications of
oligomeric proanthocyanidin complexes (OPCs), naturally occurring plant
metabolites widely available in fruits, vegetables, nuts, seeds,
flowers, and bark. OPCs are primarily known for their antioxidant
activity. However, these compounds have also been reported to
demonstrate antibacterial, antiviral, anticarcinogenic,
anti-inflammatory, anti-allergic, and vasodilatory actions. In addition,
they have been found to inhibit lipid peroxidation, platelet
aggregation, capillary permeability and fragility, and to affect enzyme
systems including phospholipase A2, cyclooxygenase, and lipoxygenase.
Based on these reported findings, OPCs may be a useful component in the
treatment of a number of conditions. (Altern Med Rev 2000;5(2):144-151)

Introduction
In 1534, a French explorer, Jacques Cartier, led a winter expedition up
the St. Lawrence River in New York. The group soon found themselves
trapped by ice and forced to survive on salted meat and hard biscuits.
The crew began to show signs and symptoms of scurvy, long before anyone
knew what caused it. Due to a chance meeting with a Native American, who
showed them how to make a tea from the bark and needles of pine trees,
the men survived1
Professor Jacques Masquelier, of the University of Bordeaux, France,
read the book eventually written by Cartier, became intrigued with the
story and postulated that the pine bark must contain vitamin C as well
as flavonoids having ascorbate-like effects. Thus began an exhaustive
study of these compounds which Masquelier named pycnogenols, a term no
longer used in the scientific community today except as a trademark for
OPCs derived from French maritime pine bark. Today they are known as
oligomeric proanthocyanidin complexes (OPCs) or procyanidolic oligomers
(PCOs). Professor Masquelier confirmed the structure, effects, and lack
of toxicity of these proanthocyanidins.1
Masquelier went on to patent the method of extracting OPCs from pine
bark in 1951, and from grape seeds in 1970 (which research has supported
as the preferential source).1

Molecular Structure
Proanthocyanidins are naturally occurring plant metabolites widely
available in fruits, vegetables, nuts, seeds, flowers, and bark.2 Other
plant sources of proanthocyanidins include wine, cranberries, and the
leaves of bilberry, birch, ginkgo, and hawthorne. Also known as
procyanidins, these substances are the main precursors of the
blue-violet and red pigments in plants.
These compounds are part of a specific group of polyphenolic compounds -
the flavonoids (Table 1).3 Flavonoids are further categorized by
subgroups. Proanthocyanidins belong to the category known as condensed
tannins, one of the two main categories of plant tannins (Table 2).3
Tannins are highly hydroxylated structures that can form insoluble
complexes with carbohydrates and protein, a measure of their
astringency, based on their ability to cause precipitation of salivary
proteins.3 The polyphenolics, including proantho-cyanidins, form a
considerable portion of the tannins found in wine, and in particular
contribute heavily to the color and flavor of red wines.
Proanthocyanidins are high-molecular-weight polymers comprised of the
monomeric unit flavan-3-ol ( (+)catechin and (-) epicatechin). Oxidative
condensation occurs between carbon C-4 of the heterocycle and carbons
C-6 or C-8 of the attached A and B rings (Figure 1).3 The procyanidins
B1-B4, characterized by the C4-C8 linkage, are the most common dimers,
occasionally accompanied by corresponding C4-C6 linked isomers (B5-B8)
(Figure 2).4
At a symposium entitled "Free Radicals in Biotechnology and Medicine"
held in London in 1990, it was reported that esterification of
(-)-epicatechin and procyanidin B2 by gallic acid increases their free
radical scavenging ability. Information was also introduced revealing
the dimeric proanthocyanidins having the C4-C8 linkage have greater free
radical scavenging activity than the C4-C6 linkage, and that these
gallate esters are only found in the grape seed extract form.
Grape seed extract contains OPCs made up of dimers or trimers of
(+)-catechin and (-)-epicatechin.4-6 The procyanidin dimers are
comprised of procyanidins B1, B2, B3, B4, B5, B6, B7, and B8. There are
six procyanidin trimers which include procyanidin C1 and C2.
Furthermore, several gallolyl procyanidins, which are most commonly the
gallate esters of the dimeric procyanidins, and some free gallic acid
are present.4,5Tetramers or greater of these flavonols would be known as
polymeric proanthocyanidins and the astringency of the molecule would
increase accordingly. Therefore, oligomeric proanthocyanidins are less
astringent, bind less strongly to proteins, and are more soluble and
mobile in the body.5
Biological Properties
The biological properties of flavonoids, including proanthocyanidins,
have been extensively reviewed.2,7-9 In addition to their free radical
scavenging and antioxidant activity,1,8,10,11 proanthocyanidins have
been reported to have antibacterial, antiviral, anticarcinogenic,
anti-inflammatory, anti-allergic, and vasodilatory actions.2,12
Proanthocyanidins have also been shown to inhibit lipid peroxidation,
platelet aggregation, capillary permeability and fragility, and to
affect enzyme systems including phospholipase A2, cyclooxygenase, and
lipoxygenase.1,2,12,13
The free radical scavenging abilities of proanthocyanidins have been
well documented and command the most attention.1,2,12,14 In vivo studies
have shown grape seed proanthocyanidin extract is a better free radical
scavenger and inhibitor of oxidative tissue damage than vitamin C,
vitamin E succinate, vitamin C and vitamin E succinate combined, and
beta carotene.12 Moreover, in vitro experimental results have
demonstrated proanthocyanidins have specificity for the hydroxyl
radical1,2 in addition to having the ability to non-competitively
inhibit the activity of xanthine oxidase, a major generator of free
radicals,1,9,14 elastase, collagenase, hyaluronidase, and
beta-glucuronidase.9
OPCs have also demonstrated preferential binding to areas characterized
by a high content of glycosaminoglycans (epidermis, capillary wall,
gastrointestinal mucosa, etc.). This feature makes them useful for
decreasing vascular permeability and enhancing capillary strength,
vascular function, and peripheral circulation.113
Therapeutic Applications
Free radical damage has been strongly associated with virtually every
chronic degenerative disease, including cardiovascular disease,
arthritis, and cancer. Free radicals are highly reactive and cause
tissue damage by reacting with polyunsaturated fatty acids found in
cellular membranes, nucleotides in DNA, and sulfhydryl bonds in
proteins. Free radicals may originate endogenously through normal
metabolism and exogenously from polluted air, solvent-laden water,
pesticide-laced food, or radiation exposure.
Clearly, due to their antioxidant activity, the therapeutic potential of
proanthocyanidins is quite broad. In Europe, proanthocyanidins are used
mainly for the treatment of vascular disorders such as venous
insufficiency, varicose veins, and microvascular problems including
capillary fragility and retinopathies.1 In fact, proanthocyanidins are
the active ingredient in a proprietary pharmaceutical product sold in
France (Endotelon) used primarily for microcirculatory disorders. The
main features of proanthocyanidins that comprise the rationale for use
in vascular disorders have been demonstrated experimentally:1
- Specificity for the hydroxyl free radical
- Traps lipid peroxides and free radicals
- Markedly delays the onset of lipid peroxidation
- Chelates to free iron molecules, so as to inhibit iron-induced lipid
peroxidation
- Non-competitively inhibiting xanthine oxidase, a major generator of
free radicals
- Inhibits hyaluronidase, elastase and collagenase, which can degrade
connective tissue structures and lead to increased permeability
Proanthocyanidins have garnered recent attention in helping to explain
the "French Paradox," the observation in France that high intake of
dietary fats does not necessarily lead to high rates of atherosclerosis
and coronary heart disease. When this paradox first came to light,
research focused on the consumption of alcohol in the form of red wine
as the preventive factor, but these results were equivocal.8 Further
research revealed that phenolic substances in red wine, including
proanthocyanidins, had potent antioxidant properties, reducing the
oxidation of human LDL in vitro, as well as inhibiting cyclooxygenase
and lipoxygenase of platelets and macrophages in vivo, further reducing
thrombotic predisposition.8
The 1998 Tufts University, "Dietary Antioxidant and Human Health
Conference," highlighted the results of new research on
proanthocyanidins and has been the most comprehensive scientific review
of polyphenols in the United States to date. At this conference, Dr.
Morazzoni, scientific director of Indena S.p.A., reviewed
epidemiological studies that suggested grape polyphenols, present in red
wine among other sources, could prevent the development of chronic
vascular disease such as atherosclerosis. His conclusion was, "Grape
procyanidins are a viable and clinically-proven, bio-active antioxidant
for the prevention of cardiovascular diseases."
Dr. Kendall, from the University of Birmingham in England, also
introduced results from his clinical research using standardized grape
seed extract. His study demonstrated measurable changes in serum
antioxidant activity in the patients receiving the extract, leading him
to conclude antioxidants may play a role in sudden death prevention,
referring to the fact that for many patients with coronary artery
disease, sudden death may be the first and only indication of the
disease.15
Other noteworthy research in this area, almost exclusively conducted in
Europe, includes:
1. Oral administration of procyanidins from grape seed produced a
hypo-cholesterolemic effect in a high-cholesterol animal feed model.
Specifically it prevented an increase in total and LDL plasma
cholesterol and a decrease in HDL.16
2. In a different hypercholesterolemic model, OPCs significantly lowered
the amounts of cholesterol bound to aortic elastin compared to
controls.17
3. Oral administration of OPCs in an experimental model effectively
increased natural killer cell cytotoxicity and modulated ex vivo levels
of interleukin-1, interleukin-6, and interleukin-10 in
immune-compromised animals.18
4. OPCs from grape seed demonstrated in vitro antimutagenic activity.19
5. In a double-blind study, 71 patients with peripheral venous
insufficiency received 300 mg OPCs from grape seed per day. A
significant reduction in functional symptomatology was observed in 75
percent of the treated patients compared to 41 percent of the patients
given a placebo.20 6. Measurements confirmed that a single
administration of 150 mg OPCs increased venous tone in patients with
widespread varicose veins.21
7. In a double-blind clinical trial, a group of elderly patients with
either spontaneous or drug-induced low capillary resistance were treated
with 100-150 mg OPCs from grape seed extract per day or placebo.
Fifty-three percent of patients in the treated group demonstrated
noticeable improvement in capillary resistance after approximately two
weeks. All patients in this group reached the maximum attainable result
after three weeks.22
8. In an open trial, 147 retinopathy patients received 100 mg OPCs from
grape seed per day. The OPCs successfully treated exudations secondary
to hypoxia of a diabetic, inflammatory, and arteriosclerotic nature.23
9. In a placebo-controlled clinical trial of 63 female breast cancer
patients, post-surgical edema of the upper extremities was tested using
300 mg per day OPCs in the treated group for six months. At six months
the OPC-treated group's functional score was significantly improved. In
particular, there was a disappearance of pain in 59 percent of the
treated patients compared to 13 percent taking the placebo.24
Conclusion
Oligomeric proanthocyanidin complexes are primarily known for their free
radical scavenging and antioxidant activity. However, these compounds
have also been reported to demonstrate antibacterial, antiviral,
anticarcinogenic, anti-inflammatory, anti-allergic and vasodilatory
actions. In addition, OPCs have been reported to inhibit lipid
peroxidation, platelet aggregation, capillary permeability and
fragility, and to affect enzyme systems including phospholipase A2,
cyclooxygenase, and lipoxygenase. These varied biological activities
have resulted in the phytopharmaceutical application of OPCs in
reduction of edema, increased peripheral circulation, improvement in
vision, treatment of diabetic retinopathy, prevention of cardiovascular
disease, treatment of hypercholesterolemia, stabilization of connective
tissue tone, reduced adverse allergic and inflammatory responses, and
enhanced immune function and wound healing. Additional clinical research
is warranted.
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