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Pyritinol;
Immune-Enhancing, Nootropic
by James South MA
Pyritinol is perhaps the oldest nootropic
drug which is still in use - it has been continuously used and researched in
Europe since it was patented by Merck in 1961. Surprisingly for a drug
whose patent expired in the late 1970’s.
Pyritinol has generated as much published
research in the 1980’s and 1990’s as was generated in the early years of
Pyritinol studies. This seems to be due to the wide range of uses, safety, and
efficacy of Pyritinol. Most of the research on Pyritinol has been published in
British, French, German, Czech, and Swiss journals. Thus the drug is virtually
unknown in America, not to mention ignored by the AMA and FDA.
Pyritinol has been used clinically in a
wide range of disorders. A 1981 report states: "Pyritinol... is widely used
throughout Europe for the treatment of organic psychosyndromes..., cerebral
circulatory disorders..., alcoholism..., dyslexic factors..., behavior and
intellect disorders in children... and post-cerebral infarction [stroke]
states....
In patients suffering from cerebral trauma
it has been reported to be of therapeutic benefit in influencing the immediate
post-operative recovery state and as an aid in rehabilitation...." (1)
Pyritinol has also shown excellent benefit
on the clinical course of victims of traumatic coma (caused by head injury).
Pyritinol has both reduced the normal high death rate in such cases, and has
rapidly returned coma patients to more or less normal waking consciousness, even
when the brain injuries were so severe the patient ultimately died.
(2)
Pyritinol has also been used successfully to treat rheumatoid arthritis
patients. (3)
Pioneer nootropic researcher I.Hindmarch has also noted that
"The clinical properties of Pyritinol have also been demonstrated using
experimentally induced hypoxia [low brain oxygen] where a 68% [decrease] on
psychometric assessments was reduced to 21% by 600 mg and to 12% by 1000 mg of
the drug." (4)
Pyritinol is almost identical to
pyridoxine (vitamin B6), yet it has no B6 activity. (4)
Pyritinol is also known
as pyrithioxine, and pyridoxine disulfide. In the Pyritinol molecule, two
pyridoxine sulfide molecules are linked together by their two sulfur atoms.
One of the keys to understanding
Pyritinol’s wide mode of action was first revealed in 1989. Two Czech
scientists performed sophisticated experiments on 6 nootropic drugs to determine
their free radical-quenching power. Pyritinol proved to be far superior to the
acknowledged antioxidant nootropics, centrophenoxine (Lucidril) and DMAE, while
piracetam and oxiracetam showed no antioxidant effect. Pavlik and Pilar state:
"There is growing evidence that free-radical interactions are implicated in
the pathogenesis of many diseases including radiation injury, atherosclerosis,
arthritis, cancer and aging.... The most dangerous [kind] of oxygen radicals is
the hydroxyl radical that can attack proteins, lipids, nucleic acids and,
actually, almost any molecule of a living cell. If the production of hydroxyl
radical escapes the control mechanisms, then … substantial damage to cell
functions [and structure] may occur.... It was found that Pyritinol exerted a
pronounced scavenger action against hydroxyl radicals which was confirmed by the
electron spin resonance spectroscopic technique in spin trapping
experiments". (5)
It is interesting to note that brain proteins were
protected from hydroxyl radical damage by Pyritinol in these experiments. As
will now be explained, the superior hydroxyl radical antioxidant effect of
Pyritinol is what provides much of the immune, arthritis, and neuroprotective
benefits of Pyritinol.
Three of the most common ‘free
radicals’ that are continuously being produced in human cells are superoxide
radical, hydrogen peroxide, and hydroxyl radical. Superoxide
radicals are
normally produced through white blood cell germ-killing activities, energy
metabolism, and in many disease states. "It is believed that the activity
of superoxide is at least partly.... responsible for aging and most if not all
degenerative diseases". (6A)
Fortunately the body has two different
enzymes - copper-zinc SOD and manganese SOD - to neutralize superoxide
radicals. Unfortunately,
SOD production drops with age: "Lowered levels of SOD... have been found in
elderly persons.... Decreases in all human tissues examined have found in
humans, progressing from ages 1 to 89".
(6B)
SOD converts neutralize superoxide
radicals into oxygen
and hydrogen peroxide. Hydrogen peroxide is less cell-damaging than
neutralize superoxide
radicals, but it is still injurious if it
accumulates in cells.
Although hydrogen peroxide has some uses in the body
(e.g. white blood cells secrete it to kill germs), the body’s need to
continuously rid itself of hydrogen peroxide is shown by the fact that our cells possess two
completely different enzymes - catalase and glutathione peroxidase - to ensure
neutralization of hydrogen peroxide. Hydrogen peroxide uncontrolled can damage cell membranes and
structures, as well as promote inflammation.
The brain is particularly vulnerable to
damage by hydrogen peroxide. (6C) Unfortunately, under conditions all too common in our
cells, neutralize superoxide
radicals and hydrogen peroxide "will react with each other in what is known as the
Haber-Weiss reaction. The product of this reaction is a free radical even more
damaging than superoxide known as the hydroxyl radical...." (6D). And to
make matters worse, human cells have no enzymatic defense against hydroxyl radical.
hydroxyl radical is
normally quenched primarily by cholesterol, Vitamin C or proanthocyanidins, (6E). (Thus, the elevated cholesterol levels found in most modern humans may
actually be a defensive tactic used by the body to quench the excesses of hydroxyl radical
induced by our toxic modern diet, environment and lifestyles). hydroxyl radical’s are so
injurious to cells that when huge uncontrollable numbers of them are generated
in a person exposed to massive levels of X-ray or gamma radiation, the flesh may
literally melt from the bones within hours!
As Pavlik and Pilar note: "There are
some clinical reports that may be viewed as supporting the opinion that
Pyritinol may also have a [hydroxyl] scavenger effect in vivo. Camus [et al]
(1978) and Berry (1986) used Pyritinol successfully, instead of the … more
toxic scavenger penacillamine, for the treatment of some cases of rheumatoid
arthritis. [So did Lemmel et al, reporting in 1993. (3)] The protection of
cartilage and synovial protein against free-radical -induced degradation … may
be an important factor in the treatment of rheumatoid arthritis. The same line
of reasoning may be applied to some cases of stroke or brain trauma ..., where
the generation of hydroxyl free-radicals … is abundant … and where Pyritinol
was successfully used for treatment .... Finally, the potency of Pyritinol to
protect proteins in brain against radical induced polymerization, in conjunction
with recent reports that Pyritinol enhanced cholinergic transmission in brain
..., substantiates its use for the treatment of cognitive disorders". (5)
Increased brain cell energy
Another key benefit of Pyritinol has been
known since the 1960’s: its ability to enhance or normalize glucose transport
through the blood-brain barrier and to increase brain cell energy production
from glucose.(7)
In a placebo-controlled, double-blind study, Hoyer and
colleagues examined 87 patients suffering from various brain disorders. Careful
measurements of cerebral blood flow, oxygen uptake, glucose uptake, and cerebral
metabolic rate were taken. Of the 45 patients receiving Pyritinol, 27 (60%)
suffered from disturbed glucose uptake/cerebral energy metabolism.
"Cerebral uptake of glucose, … which … was reduced to approximately 50%
of the normal value, increased significantly during Pyritinol treatment … and
returned to normal.... The clinical disturbances generally also improved to the
same extent as did the disturbed glucose metabolism". (7)
Enhanced Glucose Transport
Pyritinol’s ability to enhance glucose
transport through the blood-brain barrier when it is low is a highly significant
benefit of Pyritinol. Although the brain is usually less than 2% of total
bodyweight, the brain must produce and use about 20% - 500 calories per day - of
the body’s total energy production. And under normal, non-fasting conditions,
the brain can only ‘burn’ glucose (sugar) for fuel. Unlike virtually all
other body cells, nerve cells cannot use fat as an energy fuel. Brain cells also
cannot store any significant amount of glucose - they are completely dependent
upon a continuous delivery of glucose from the blood, through the blood-brain
barrier. Thus, brain glucose uptake is a major rate-limiting factor for crucial
brain energy production. Low cerebral glucose uptake necessarily translates into
low brain carbohydrate energy metabolism.
And brain energy metabolism is so
important to optimal, healthy brain function that "... brain carbohydrate
metabolism is impaired in a variety of dementias [e.g. Alzheimer’s,
stroke, metabolic, or drug toxicity dementias] and … the degree of reduction
in brain carbohydrate
metabolism is correlated with the severity of the dementias ...." (7) Pyritinol
is good for optimal brain carbohydrate
metabolism , and what is good for brain carbohydrate
metabolism is good for the brain and the
mind!
Effective Immune Enhancer
A surprising effect of Pyritinol was first
reported in 1993: Pyritinol may be an effective immune enhancer through its
stimulation of neutrophil migration. (9)
Neutrophils are a major type of white
blood cell (WBC) - they typically constitute about 60% of the total number of white
blood cells in the blood. Wherever there is a wound, cut, sore, abrasion etc.,
neutrophils are attracted to leave the bloodstream and travel to the site of
injury/infection - the process of chemotaxis. Once at the site of injury,
neutrophils proceed to engulf germs - especially bacteria - that may now be
growing at the injury site. Neutrophils then secrete a powerful mix of free
radicals and oxidants, such as hydrogen peroxide and hypochlorous acid, which destroy
the germs before they can seriously multiply and overwhelm the body. However,
neutrophils sooner or later die "in the line of duty" from their own
germ-killing free radical barrage.
One neutrophil averages 5 to 20 germ kills
before succumbing. The free radicals neutrophils release also typically promote
inflammation at the site of injury, a process that all too easily gets out of
control and proceeds to excess. Excessive inflammation promotes excessive
swelling, tenderness, redness, heat and pain at the injury site. The pus that
forms with cuts and wounds is in large part made up of dead neutrophils.
In a study with rabbit neutrophils,
Elferink and De Koster found that Pyritinol, at levels likely to be achieved in
tissue, through oral doses, strongly promoted neutrophil chemotaxis (migration
to injury site), but did not increase free radical levels or inflammation. (9)
Given the earlier discussion on Pyritinol’s antioxidant effects, this
differential effect of Pyritinol on neutrophil activity (increases migration,
but not free radicals or inflammation) becomes comprehensible. When large
numbers of neutrophils release huge amounts of hydrogen peroxide and hydrogen peroxide, this generates huge
quantities of inflammatory, tissue-damaging hydroxyl radicals. Yet Pyritinol is
a powerful quencher of hydroxyl radicals. Thus Pyritinol is able to reduce hydroxyl
radical-induced
inflammation and tissue damage - the unpleasant side effect that usually
accompanies successful germ-killing by neutrophils.
Immune Defense
Neutrophils comprise the body’s first
line of white
blood cell immune defense - they are normally first to arrive at wound/injury
sites. Yet our modern sugar-rich diet has been shown in multiple studies to
significantly impair neutrophil activity.
When human volunteers were given various
forms and levels of sugar in drinks, the number of germs a neutrophil could kill
before dying from its own free radical release typically dropped 50 - 80%! The
effect began within one hour of sugar intake, peaked at two hours, and was still
significant five hours after sugar ingestion.
(10) Thus a sugar-rich diet
literally enhances neutrophil self-destruction as neutrophils kill germs, yet
Pyritinol enhances neutrophil survival through reducing the hydroxyl radical
excesses that normally lead to neutrophil death.
Another key property of Pyritinol is its
vigilance-enhancing effect. Pyritinol increases nerve activity in the locus
coeruleus. (11)
"In humans, the number of neurons in the locus
coeruleus declines
with advancing age. Degeneration appears to advance slightly faster in males
than females. The locus
coeruleus is a brain area that … is particularly susceptible to
neuronal degeneration in Alzheimer’s disease.... [There are many] studies
indicating a role of this system in control of attention and … learning and
memory". (11)
EEG Power
"Pyritinol has also been shown to
produce a vigilance response, both behaviorally and electrophysiologically (EEG
recordings) in animals and in healthy human volunteers. More recently, using
topographic brain mapping of EEG, it has been shown that 600 mg Pyritinol
resulted in an increase in total (EEG) power and … other changes indicative of
improved vigilance.... Specific studies of the effects of Pyritinol on …
memory using a battery of seven tests … showed that repeated daily doses of
Pyritinol 300mg improved memory performance [which is in part a function of locus
coeruleus -
regulated vigilance] over a wide range of measures in volunteers aged from 16 to
66 years". (4)
Who might benefit?
1. Pyritinol may be useful in various
forms of dementia, organic brain syndrome, head injury, stroke aftermath, coma,
and cerebral circulatory disorders. Vinpocetine, piracetam, oxiracetam, and
phosphatidyl serine may be useful synergists with Pyritinol.
2. Pyritinol may be useful as an
anti-brain aging nootropic drug.
3. Pyritinol may be useful as an aid to
increased focus and concentration, memory, alertness and information processing
in both young and old, normal or mildly brain dysfunctional persons.
4. Pyritinol may be useful in Attention
Deficit Disorder (ADD), hyperkinetic, or mildly retarded children to increase
drive, alertness, concentration and learning ability.
(12, 13)
5. Pyritinol may be useful as part of a
health-optimizing antioxidant program, along with vitamins C and E, selenium,
zinc and lipoic acid.
6. Pyritinol may be useful in the
treatment of rheumatoid arthritis. In a large, double blind yearlong trial
comparing Pyritinol to a standard anti-rheumatoid drug (Auranofin), the response
rate was superior for Pyritinol (78% vs. 59%, at one year). "Every
individual efficacy parameter showed a numerical trend for better results in the
Pyritinol group...." (3)
Pyritinol Side-Effects
Most published studies on Pyritinol report
few if any side effects, with skin rashes and/or gastric upset occasionally
noted. E.g. "In general, the tolerability of the drug was good. Practically
no problems occurred during the trial.... None of the reported symptoms were
rated as serious or persisted over a long period of time". (14) "No
undesirable side-effects were observed". (13) "With the exception of
cutaneous [skin] symptoms ... there were no significant differences in the
incidence of adverse reactions in the drug and placebo group.... No significant
changes were observed in [clinical laboratory] parameters".
(1)
The one major exception to Pyritinol’s
low side-effect profile occurred in the large-scale rheumatoid arthritis trial.
The authors note that Pyritinol side effects "were mostly nuisance events,
which led to stopping therapy [in some cases], but did not constitute a health
risk for the patient and were fully and rapidly reversible." (3) However,
they also note a general trend in the Pyritinol-arthritis literature of about 2%
potentially serious adverse effects involving blood, kidney or liver, which
makes it important for regular monitoring of liver enzymes, urine status and
blood cell status when using Pyritinol to treat rheumatoid arthritis. Therefore,
Pyritinol should be used in rheumatoid arthritis treatment only with the
knowledge and supervision of a physician.
Pyritinol Doses
A wide range of doses have been used in
Pyritinol studies. These have ranged from as low as 100 mg twice daily (12) to
200 mg three time’s daily (14) or 200 mg four times daily.
(15)
For
anti-aging, cognition-enhancing or antioxidant purposes, 100 mg Pyritinol two or
three times daily is generally safe and adequate. Higher doses (400 - 1000 mg
daily) should probably be used only with physician supervision, just to err on
the safe side. Pyritinol may be taken either on empty stomach or after food, as
desired. Persons only prone to insomnia should probably only take Pyritinol
morning and early afternoon. There may be a mutual enhancement of action between
Pyritinol and other nootropic drugs, allowing/requiring lower doses of some or
all the drugs in order to avoid an over-excitation effect.
REFERENCES
1. K.Kitamura (1981) "Therapeutic
Effect of Pyritinol on Sequelae of Head Injuries" J Int Med Res 9, 215-21.
2. G. Dalle Ore et al (1980) "The
Influence of the Administration of Pyritinol on the Clinical Course of Traumatic
Coma", J Neuroserg Sci 24, 1-8.
3. E.-M. Lemmel (1993) "Comparison of
Pyritinol and Auranofin in the Treatment of Rheumatoid Arthritis" Br J
Rheumatol 32, 375-82.
4. I. Hindmarch et al (1990) "Psychpharmacalogical
Effects of Pyritinol in Normal Volunteers" Neuropsychobiol 24, 159-64.
5. A. Pavlik & J. Pilar (1989)
"Protection of Cell Proteins Against Free-Radical Attack by Nootropic
Drugs: Scavenger Effects of Pyritinol Confirmed by Electron Spin Resonance
Spectroscopy" Nueropharmacol 28, 557-61.
6. R. Bradford & H. Allen, Oxidology,
Chula Vista, CA: R.W. Bradford Foundation, 1997. A:p.65 B:p323 C:p.142 D:p.66
E:p.175.
7. S. Hoyer et al (1977) "Effect of
Pyritinol-HCL on Blood Flow and Oxidative Metabolism of the Brain in Patients
with Dementia" Arzneim Forsch/Drug Res 27, 671-74.
8. R. Branconnier (1983) "The
Efficacy of the Cerebral Metabolic Enhancers in the Treatment of Senile
Dementia" Psychopharmacol Bull 1983 Spring;19(2):212-9.
9. J. Elferink & B. de Koster (1993)
"Differential Stimulation of Neutrophil Functions by Pyrithioxine" Int
J Immunopharmac 15, 641-46.
10. R. Huemer & J. Challem, "The
Natural Health Guide to Beating the Supergerms", NY: PocketBooks, 1997.
Pp.124-27.
11. H.-R. Olpe et al (1985) "Locus
Coeruleus as a Target for Psychogeriatric Agents" Ann NY Acad Sci 444,
394-405.
12. G. Logue et al (1974) "The
Effects of Pyrithioxine on the Behavior and Intellectual Functioning of
Learning-Disabled Children" S.Afr Med J 48, 2245-46.
13. D. Lane O’Kelly (1975) "Pyritinol
in the Treatment of Chronic Alcoholics" J Int Med Res 3, 323-27.
14. K. Fischhof et al (1992)
"Therapeutic Efficacy of Pyritinol in Patients with Senile Dementia of the
Alzheimer Type (SDAT) and Multi-Infarct Dementia (MID)" Neuropsychobiol 26,
65-70.
15. A. Cooper & R. Magnus (1980)
"A Placebo-Controlled Study of Pyritinol in
Dementia" Pharmatherapeutica 2, 317-22.
The above article is copyrighted and may
not be copied without the written permission of International Antiaging
Systems, Les Autelets Suite A, Sark GY9 0SF, Channel
Islands, UK.
ALL INFORMATION IS EDUCATIONAL AND SHOULD
NOT REPLACE THE ADVICE OF YOUR PHYSICIAN.
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