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Pyritinol; The Immune-Enhancing, Anti-Arthritis Nootropic
by James South MA to
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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. This is surprisinglfor 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 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 (H2O2), and hydroxyl radical
(HR). Superoxide radical’s 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 neutralise 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 SOR into oxygen and H2O2. H2O2
is less cell-damaging than superoxide radicals, but it is still injurious
if it accumulates in cells.
Although H2O2 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 H2O2 is shown
by the fact that our cells possess two completely different enzymes - catalase
and glutathione peroxidase - to ensure neutralization of H2O2.
H2O2 uncontrolled can damage cell membranes and
structures, as well as promote inflammation.
The brain is particularly vulnerable to
damage by H2O2. (6C) Unfortunately, under conditions all
too common in our cells, superoxide radicals and H2O2 "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 HR. HR 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 HR induced by our toxic modern
diet, environment and lifestyles). HR’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 (BCM) is impaired in a variety of dementias [e.g. Alzheimer’s,
stroke, metabolic, or drug toxicity dementias] and … the degree of reduction
in BCM is correlated with the severity of the dementias ...." (8)
Pyritinol is good for optimal BCM, and what is good for BCM 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 WBC’s 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 SOR, H2O2, 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 SOR and H2O2,
this generates huge quantities of inflammatory, tissue-damaging hydroxyl
radicals. Yet Pyritinol is a powerful quencher of HR’s. Thus Pyritinol is able
to reduce HR-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 WBC 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 (LC). (11) "In humans, the number of neurons in the [LC]
declines with advancing age. Degeneration appears to advance slightly faster in
males than females. The [LC] 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 LC -
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
phosphatidylserine 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.
DISCLAIMER; ALL INFORMATION IS EDUCATIONAL AND SHOULD NOT REPLACE THE ADVICE OF YOUR PHYSICIAN.
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.
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