BEMITHYL: ITS MECHANISM AND ITS EFFECTS

STEMC stemc at interlog.com
Mon Aug 12 21:48:44 EST 1996



BEMITHYL:  ITS MECHANISM AND ITS EFFECTS

BACKGROUND.    Bemithyl was developed under a classified program
at the Military Medical Academy in St. Petersburg, Russia.  
Its first intended recepients were Russian astronaughts. Later, it
was widely used in Soviet Spetsnaz Forces, to improve the soldiers'
capacity for withstanding physical exertion, as well as for tank 
crews (hypoxy and carbon dioxide), flight crews, etc. Later, civil, 
medical applications were developed.

It has been established that the therapeutic effect of Bemithyl
is caused by its complex mechanism of activating the cell genome, 
optimizing the mitochondrial oxidation, reducing the peroxide 
oxidation of lipids and the stimulating the fabric and the cellular 
immune reactions. 
 
The principle mechanisms of Bemithyl's action was discovered as
it was used as a means to increase and rehabilitate work capacity.  
Bemithyl and its analogs came to represent a new pharmacological 
class of acto protectors (from Latin "aktus" - motion).  This class is
designed to sustain motion activity and work capacity of humans in 
complicated environmental conditions. First acto protectors, including
Bemithyl were synthesized and studied at the Department of Pharmacology of
the Military Medical Academy in St.Petersburg in the 1970's under the 
guidance of Professor V.M. Vinogradov. 

Experimental research established, that even with a single application 
of Bemithyl, it substantially increases physical work capacity of animals 
and accelerates rehabilitation after terminal exertions. 
This last affect is articulated particularly acutely in complications
of hypoxy, over-heating, etc.  In multiple dosages, the effect of Bemithyl 
increases in the first 3-5 days, and then is steadily maintained at the
achieved level.  A primary analysis of the preparation's effect
at physical exertions demonstrated Bemithyl's influence upon carbohydrates 
and energy metabolism:  at standard exertion a smaller lowering of glycogen 
and creatine phosphate content in the body, of glucose in the blood, lower 
accumulation of lactate in the body, lower increase in heat production and 
oxygen consumption were observed.  After the exertion was removed, the
rehabilitation of the factors under study was accelerated and some of them
showed super compensation.  

This data, as well as structural similarity of Bemithyl, which is
a derivative of benzamidazole, with neurine foundations of nucleic acids 
serve to suggest a hypothesis of cell genome activation, with a resulting 
increase of RNA and of protein as a main link in Bemithyl's action mechanism.
It was believed, that the preparation increased formation of ferment proteins,
which assure favourable metabolic and functional changes during physical 
activity and after such.  One of the proofs of this hypothesis were the
results of experiments using aktinomicin D -- highly selective
inhibitor of RNA synthesis.  This inhibitor completely removed deposited 
effect of Bemithyl upon work capacity as well as upon functional metabolic
shifts under exertion.  In subsequent experiments, the estimate
of inclusion of Sc methamine into the fabric of various body parts confirmed 
the activation of protein synthesis by Bemithyl.  This activation
articulated most of all in the body parts with short lifespan,
constantly renewable proteins (liver, kidneys, gastric track).  With body 
parts with more long living proteins (skeletal muscles, heart, brain), the
activating effect of Bemithyl would increase and became noticeable when 
protein synthesis was induced under the influence of some other factors, 
for example an increase in the functional activity of this body part.  
Probably, Bemithyl does not by itself induce synthesis of RNA and of protein, 
but causes positive modulating action upon naturally developing processes 
of protein synthesis.

The most articulated activating effect of this preparation in
body parts with short living proteins -- liver and kidneys -- allowed to 
assume, that the influence upon these body parts, in particular constitutes a
key link in the mechanism of  increasing physical work capacity using
Bemithyl.  Modern conception of short living, fast renewable proteins 
plays a decisive role in the adaptive reactions of organisms:  its primary
reinforcing  synthesis may  assist in redevelopment of very early
signs of adaptation, and their fastest reduction in body tissues at 
extreme impacts should serve as starting factor of the adaptation.  

Based on our assumption, among proteins, actively synthesized in
the liver and kidney and under the influence of Bemithyl, the main role 
in supporting physical work capacity is played by gluconeogenesis
ferments.  The gluconeogenesis process, taking place mainly in
the liver and in kidney linings, consist, as is known, of re - synthesis 
of glucose from the product of its disintegration -- lactate and pyruvate, as
well as glycerine and certain amino acids, mainly alanine in the liver
and glutamine in the kidneys.  The part of gluconeogenesis during physical
activity consists in utilization of the lactic acid being produced --
one of the main factors, reducing work capacity, and in re-synthesis
of the consumed carbohydrates - very important source during muscle 
exertions, the supply of which in the body is quite limited.  Moreover,
gluconeogenesis, working closely with gluco-alanincylce and
glutamine exchange, resists the formation of lactate and amio acids in the 
muscles and participates in utilization and the exhaust of nitrite products
of disintegration.  

Experimental testing has shown activation of gluconeogenesis by
Bemithyl during physical exertion and after it.  This activation certainly 
is carried by a reinforcement of synthesis of the appropriate ferments,
because aktinomicin D blocked the action of Bemithyl upon
gluconeogenesis.  Tryptophan, selected inhibitor of gluconeogenesis, 
prevented positive influence of Bemithyl upon work capacity, as well as
its influence upon the indicators of carbohydrate exchange.

The main role, that the activation of the synthesis of
gluconeogenic ferments plays in the mechanism of
increasing work capacity using Bemithyl received a more serious
proof in the experiments that used
exogenic RNA method, which was suggested to analyze complexities
of various pharmacological
preparations.  This method is based on the fact, that RNA
from tissues and organs, in which some
process has taken place, that is caused by the activation of
protein synthesis at transcription level.  It
may reproduce this process in these organs and tissues.  The
method of exogenic RNA allows to
segregate the component, which is caused by the stimulation of protein
synthesis in a particular organ or tissue,
from complex reactions of body to pharmacological preparations. 
Subsequent transfer and specific
reproduction of component in the appropriate organ or tissue of the
animal - recipient, allowed to study in the pure
form and to estimate the functional significance for the bodies
as a whole.  The method of exogenic RNA is not new, but it was 
previously used for analysis of complex biological phenomena, especially
upon the entire body.  Based on the results of the RNA
experiments where liver and kidneys of
animals - donors, that received Bemithyl, reproduced in the recipients
activating influence of the preparation
upon work capacity as well as upon gluconeogenesis.  At simultaneous
application of the indicated RNA
from liver and kidney this reconstruction was complete.  RNA from
other organs of animals, that received
Bemithyl, and from all the studied organs of the unaffected
controls, including a liver and kidneys, did
not cause a noticeable effect.  Therefore the connection between the
activation by Bemithyl of gluconeogenesis and the increase in 
physical work capacity is without a doubt. 
This key link of the mechanism's action
is characteristic for other active protectors -- derivatives of
the benzamidazole, and what is described
by us earlier.

An important effect of Bemithyl is also its favourable influence
upon mitochondrial oxidation at
extreme and impairing impacts upon the cell, in particular at hypoxies. 
The influence upon mitochondria, that
was studied in great detail also with etomerizole -- very close by
structure and pharmacological properties
analog of Bemithyl -- is in the weakening of the slow down of the
above - dependent breathing and of
activity of succinate dehydrogenase, the reduction in the
separation between oxidation and
phosphorylation, prevention of deep low energy shift.  Based
on some preliminary data we received, the optimizing action of 
Bemithyl and its analogs upon the functions of mitochondria may be caused
by the activation of the mitochondrial protein synthesis.

An important property of both Bemithyl and  etomerzole is
presence of anti-oxidation activity. 
And the conditions characterized by the increase in the peroxide
oxidation of lipids (POL), active protectors reduce formation of
hydro-peroxides of lipids, of dien conjugates, malon dialdigide.  They
do not posses, on the other hand, a direct anti-radical property.  
It is possible to assume, that here also
the effect of Bemithyl and its analog may be explained by the primary
activation of protein synthesis, that brings an increase in the formation
of the anti-oxidant ferments. In any case, typical for Bemithyl is an
increase in the activity of these ferments, particularly super
oxide dismutase cys, and the conditions
extreme for human body.  

Optimizing effect upon mitochondrial functions, carbohydrate
exchange and suppression of POL by
Bemithyl is at the foundation of the characteristic for Bemithyl
economizing action, that was confirmed
in human experiments; Bemithyl reduces at various exertions upon
body, the increase in the oxygen consumption, heat exhaust, 
body temperature, products of metabolism, frequency of heart
contractions, the usage of energy resources.  Thanks to this effect of
the preparation, as the authors observed the work capacity of the tested 
patients in physical or operator's activity in complex
conditions increased, for example at high altitude hypoxy and over-heating. 
High efficiency of Bemithyl and other acto-protectors in the indicated 
conditions differs substantially from psycho-motor stimulators
(phenamine, sydnocarb), the positive influence of which upon work capacity
(in normal conditions) reduces of even reverses into a negative on during 
hypoxy and over-heating because of the modilizing, exhausting type
of action upon the body, an increase in heat production heat
exhaust and oxygen consumption.

A non- specific reinforcement by Bemithyl of a naturally induced
reaction of protein synthesis determines
a possibility to use this preparation as a means to activate
various adaption processes.  Bemithyl in a serial
application accelerates and increases processes of adaption to
heavy physical  exertion, high altitude
hypoxy, over-heating, as well as encourages development and
increase of stability to cross out
adaption to hypoxy and  physical exertions.

Using a method of exogen RNA, it was established, that the
activation by Bemithyl of adaption to high
altitude, hypoxy is caused mainly by an increase in protein
synthesis in the brain.  This should
appear logical considering high sensitivity of CNS to oxygen deficiency. 
Activation of protein synthesis in the
brain explains also improvement by Bemithyl and its analogs of
memory processes.  Obviously,
reinforcement of protein synthesis is part of a number of leading
links of acto-protector action
mechanism upon CNS, including increasing work capacity at mental and
operating activity in complicated
conditions. 

Positive effects of Bemithyl in different types of activities
allowed to practically use the preparation to
increase the work capacity of participants of liquidation
consequences of the Chernobyl catastrophe,
earthquakes in Armenia, and railway accidents in Bashkiria.  

Optimizing the influence upon key metabolic processes and
important functions of the body, increase
and rehabilitation of work capacity, potential ability to activate
reparative processes thanks to
reinforcement of protein synthesis -- all these became a reason to 
study and to use Bemithyl in clinical practice, first
of all, as an anti-asthenic and rehabilitation preparation with a
broad range of action.  

Preparation clearly reduces asthenic impairment after
cerebral-brain traumas, encephalites, meningitis
TC's, intoxications (by insecticides with anti-cholinesterase
action and others), as well as at
athera-sclerosis of the brain vessels, neurasthenia, different
somatic diseases.  The influence of
Bemithyl most of the patients experience reduction in weakness and quick
exhaustion, appearance of feeling of
fitness, improvement in attention, memory and mood, increase in physical
and mental work capacity. 
Anti-asthenic effect of the preparation begins to articulate
itself already after the first administration of
the preparation and becomes clearly visible at 3rd - 5th day of the
treatment.  When compared on the basis
of speed of development and articulation of this effect, Bemithyl
exceeds isotrops pyracetam and
pyriditole. 

Indication  of Bemithyl with a background of traditional therapy
accelerates reparative processes in
the liver, rehabilitation of patients with viral hepatitis A,
liquidation of aesthenic effects and rehabilitation
of work capacity (Smirnov - see this publication).

In instances of acute electro-radiation, Bemithyl also
accelerates liquidation of aesthenic anomalies
and rehabilitation of work capacity.  More over, it assures a faster
normalization of blood creation and creation, as well as increasing 
the effect of lithium carbonate as blood building stimulator. 
Application of Bemithyl in the cases of radiation is recommended also because
the preparation demonstrated anti-mutagen and immuno-stimulating activity.

Bemithyl activates humoral, as well as cell immuno reactions,
stimulates non-specific resistance of the
body, mainly macrophages functions.  Its action could be
demonstrated very strongly in conditions,
caused by significant suppression of the immune system.  It is probably
connected, like its other effects, to the
increase in the protein-synthetic processes.  In judging efficacy
and the picture of its normalizing effect
upon defensive reactions, Bemithyl in most cases exceeds a well
known immuno-stimulator
levamizole. 
Bemithyl plays positive influence upon various primary and
secondary myopathies with progressive
muscular dystrophies (V.S. Lobsin, V.P. Pustozerov, in the
compendium).  It effectively prevents
development of the neurosensor deafness for persons working in
the conditions of intensive noise (L.A.
Glaznikov, et al, in the present compendium).  Use of Bemithyl in
epileptic patients was also studied.

It is obvious, that the data presented does not cover all the
possible applications of Bemithyl, based on
its mechanism.  It is reasonable to see further broadening of
applications for the pharmacology of a
heathy person, as well as in medical practice.

For further information regarding Bemithyl, including
availablity, please contact STEMC (Toronto, Canada) 416-250-0442
E-mail: stemc at interlog.com





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