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The Pharmacology of Actoprotectors: Practical Application for Improvement of Mental and Physical Performance

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Investigations into a new class of pharmacologically active substances for improvement of physical and mental effi ciency in humans, namely actoprotectors, were carried out under Professor Vladimir Vinogradov at the Military Medical Acad-emy (then Leningrad, USSR; now, St. Petersburg, Russia)'s Department of Pharmacology throughout the 1970s. This work resulted in the development of the fi rst and most com-monly used actoprotector, bemitil (chemical structure: 2-eth-ylbenzimidazole hydrobromide, (Fig. 1A); English-language literature: "bemithil", "bemithyl" or "bemethyl"; also known as "bemactor" and "metaprot" in later publications). This achieve-ment earned Professor Vinogradov and his research team the State Prize of the USSR. Other actoprotectors subsequently were formulated as well, the most important of which, from the practical point of view, being bromantane (Oliynyk et al., 2010) (Fig. 1B). The fi rst recipients of bemitil were Soviet cosmonaughts. Bemitil also was successfully employed in preparing the athletes of the USSR's national team for the 1980 Olympic Games held in Moscow. Later, throughout the 1990s, it was used as a basic medicinal agent in almost all of the corps of the Soviet and then Russian armies. Notably, its administra-tion made it possible to increase soldiers' endurance over long marches; in the Air Forces, Missile Troops, and Army Air Defense, it enhanced work capacity and stability to hypoxia; and in the Navy, it reinforced stability to hypoxia and, where Actoprotectors are preparations that enhance body stability against physical loads without increasing oxygen consumption or heat production. Or, in short, actoprotectors are synthetic adaptogens with a signifi cant capacity to improve physical performance. This paper explores the history of actoprotectors' development, their pharmacological properties, mechanism of action, and practical application to the improvement of mental and physical performance. A brief summary of the clinico-pharmacological characteris-tics of the main representatives of this class (bemitil and bromantane) is provided. Some other synthesized compounds, and even natural ones such as ginseng, also are regarded as potential actoprotectors, and these are treated herein as well. Actoprotectors, owing to their wide-ranging pharmacological activities, high effi ciency and safety, can be applied under either normal or extreme conditions.
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444
Investigations into a new class of pharmacologically active
substances for improvement of physical and mental ef ciency
in humans, namely actoprotectors, were carried out under
Professor Vladimir Vinogradov at the Military Medical Acad-
emy (then Leningrad, USSR; now, St. Petersburg, Russia)’s
Department of Pharmacology throughout the 1970s. This
work resulted in the development of the rst and most com-
monly used actoprotector, bemitil (chemical structure: 2-eth-
ylbenzimidazole hydrobromide, (Fig. 1A); English-language
literature: “bemithil”, “bemithyl” or “bemethyl”; also known as
“bemactor” and “metaprot” in later publications). This achieve-
ment earned Professor Vinogradov and his research team the
State Prize of the USSR. Other actoprotectors subsequently
were formulated as well, the most important of which, from
the practical point of view, being bromantane (Oliynyk et al.,
2010) (Fig. 1B).
The rst recipients of bemitil were Soviet cosmonaughts.
Bemitil also was successfully employed in preparing the
athletes of the USSR’s national team for the 1980 Olympic
Games held in Moscow. Later, throughout the 1990s, it was
used as a basic medicinal agent in almost all of the corps of
the Soviet and then Russian armies. Notably, its administra-
tion made it possible to increase soldiers’ endurance over
long marches; in the Air Forces, Missile Troops, and Army Air
Defense, it enhanced work capacity and stability to hypoxia;
and in the Navy, it reinforced stability to hypoxia and, where
Actoprotectors are preparations that enhance body stability against physical loads without increasing oxygen consumption or heat
production. Or, in short, actoprotectors are synthetic adaptogens with a signi cant capacity to improve physical performance. This
paper explores the history of actoprotectors’ development, their pharmacological properties, mechanism of action, and practical
application to the improvement of mental and physical performance. A brief summary of the clinico-pharmacological characteris-
tics of the main representatives of this class (bemitil and bromantane) is provided. Some other synthesized compounds, and even
natural ones such as ginseng, also are regarded as potential actoprotectors, and these are treated herein as well. Actoprotectors,
owing to their wide-ranging pharmacological activities, high ef ciency and safety, can be applied under either normal or extreme
conditions.
Key Words: Actoprotector, Bemitil, Bromantane, Mental work capacity, Asthenia
http://dx.doi.org/10.4062/biomolther.2012.20.5.444
Copyright © 2012 The Korean Society of Applied Pharmacology
*
Corresponding Author
E-mail: skoh@ewha.ac.kr
Tel: +82-2-2650-5749, Fax: +82-2-2650-5850
Received
Aug 22, 2012
Revised
Sep 14, 2012 Accepted
Sep 15, 2012
pISSN: 1976-9148 eISSN: 2005-4483
Open AccessOpen Access
The Pharmacology of Actoprotectors: Practical Application for
Improvement of Mental and Physical Performance
Sergiy Oliynyk and Seikwan Oh*
Department of Neuroscience and TIDRC, School of Medicine, Ewha Womans University, Seoul 158-710, Republic of Korea
Abstract
applicable, high temperatures. The latter property, in fact, had
determined its wide use by the “limited contingent” of Soviet
troops in Afghanistan. Bemitil enabled soldiers, including Spe-
cial Forces, to effectively perform combat missions under both
hypoxic and high-temperature conditions. Bemitil’s effective-
ness for various types of activities was shown also in its en-
hancement of the physical and mental capacities of rescue
and other workers deployed in the wakes of the Chernobyl
catastrophe (1986), the earthquakes in Armenia (1988), and
the railway accidents in Bashkiria (1989) (USSR, 1989; Sha-
banov, 2009a; Oliynyk et al., 2010). Bromantane also was em-
ployed in the Soviet and Russian armies, to shorten recovery
times after strong physical exertion, though not as widely as
bemitil.
After the disintegration of the USSR in 1991, the of cial
manufacture and clinical use of bemitil was discontinued. How-
ever, owing to its wide-ranging pharmacological activity, high
ef ciency, and safety, its initial sports and military medicine
applications have been extended widely to other branches of
practical medicine. As for bromantane, its production contin-
ued after 1991, though its applications were limited, primarily,
to sports medicine (Sizoi et al., 1998; Oliynyk et al., 2010).
Nowadays, bemitil is manufactured in Ukraine (commercial
name: Antihot) and is widely used in preparing Ukrainian na-
tional sport teams for international competitions. Bromantane
is manufactured in Russia (commercial name: Ladasten);
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Biomol Ther 20(5), 444-455 (2012)
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445
Oliynyk and Oh. Pharmacology of Actoprotectors
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Fig. 1. Chemical structures of most common actoprotectors, (A)
bemitil (2-ethylthiobenzimidazole hydrobromide), (B) bromantane
(N-(2-adamantil)-N-(para-bromophenyl)-amine).
Fig. 2. Chemical structures of three synthetic benzimidazole-derivative adaptogens: (A) dibazol (2-benzyl-benzimidazole), (B) levamisole
((-)-2,3,5,6-tetrahydro-6-phenylimidazo[2,1-b]thiazole hydrochloride), (C) afobazol (5-ethoxy-2-[2-(morpholino)-ethylthio]benzimidazole).
should be regarded as synthetic adaptogens having a strong
positive in uence on physical work capacity. This means that
for pharmacological classi cation convenience, some syn-
thetic adaptogens that signi cantly enhance physical perfor-
mance can be termed “actoprotectors” but that other synthetic
adaptogens cannot. For example, benzimidazole derivatives
dibazol (bendazol), levamisole and afobazol (Fig. 2), in the
literature, have been considered to be adaptogens. Dibazol’s
adaptogenic action was rst realized in the context of immune-
mechanism-enabled adaptation to dif cult environmental con-
ditions (Rusin, 1962a, 1962b, 1963a, 1963b, 1963c, 1967;
Ratnikov and Nesterenko, 1984; Novikov and Bortnovskii,
1985; Udintsev et al., 1991; Sidorova and Kiikova, 2000);
levamisole’s adaptogenic activity also is connected primar-
ily with adaptive immune system changes (Voskanian et al.,
1986; Alvarez-Pellitero et al., 2006; Chen et al., 2008; Fabrizi
et al., 2010); afobazol has neuroprotective properties estab-
lished, in vitro, by survival of HT-22 neurons in a model of
oxidative stress and glutamate toxicity (Zenina et al., 2005),
and its adaptogenic action is realized through central nervous
system adaptation (Uyanaev and Fisenko, 2006; Litvintsev et
al., 2007; Bogdan et al., 2011). As re ects their adaptogenic
properties, benzimidazole derivatives are related to bemitil,
but their in uence on physical work capacity is either absent
or minimal. In light of this fact, they cannot be referenced as
actoprotectors. A concise de nition of actoprotectors, in our
opinion, is as follows: “synthetic adaptogens with a signi cant
capacity to increase physical performance”.
Bobkov et al. (1993) provided further characteristics of ac-
toprotector action:
1. These agents have minimal pharmacological activity,
which explains why the mechanism of their action is dif cult to
correlate with their in uence on some concrete types of phar-
macological receptors;
2. The ef cacy of these drugs for rapid recovery is maximal
only when they are administered immediately after exposure
to extreme conditions;
3. The strongest effect of actoprotectors is observed in per-
sons with low or middle resistance to extreme conditions, and
they are almost absent in persons with high resistance;
4. The phenomena of resistance to extreme conditions are
determined not by one concrete biochemical process, but by
a complex of them, primarily the speed of their changes in the
body as a response to extreme conditions;
5. The most optimal agents for resistance enhancement
are agents that decrease entropy by transferring to a lower
functional level the “fastest” parameters of reactivity: oxygen
consumption, body temperature, heart rate;
6. Actoprotectors’ principal ef cacy is independent of ex-
treme conditions (physical load, stress, hypoxia, ischemia, hy-
peremia, gravitation overload etc.), which fact suggests their
in uence on the basic mechanisms of resistance;
since 1997, anti-doping regulations have prohibited its use in
sports, though it has recently been utilized in the treatment of
patients with asthenic and restless-asthenic frustration (Sizoi
et al., 1998; Akilov et al., 2007; Oliynyk et al., 2010).
DEFINITION AND CLASSIFICATION OF ACTOPRO-
TECTORS
Actoprotectors are preparations that enhance body stability
against physical loads without increasing oxygen consump-
tion or heat production. Actoprotectors comprehend metabolic
drugs of a non-consumptive class of action, which to greater
or lesser extents can possess antihypoxic activity. They differ
from antihypoxants, however, in that they primarily (directly)
stimulate protein synthesis and increase working capacity.
Moreover, under hypoxic conditions, they exert an antihypoxic
in uence that can become stronger as a result of mitochondri-
on-decreased ability to oxidize substrates under higher physi-
cal loads, but they do not function in this way in other etiolo-
gies (Oliynyk et al., 2010).
The principal difference between actoprotectors and psy-
chostimulants (e.g. caffeine, sydnocarb, phenamine, methyl-
phenidate, moda nil, adra nil, armoda nil) is that actoprotec-
tors are agents of non-exhaustive action. With actoprotectors,
there is no increase in oxygen consumption or heat produc-
tion; and, unlike nootropic agents – actoprotectors increase
not only mental (intellectual) but also, and primarily, physical
work capacity.
The distinction between actoprotectors and adaptogens
is not straightforward. Their respective characteristics show
many similarities and even identities. Vinogradov and Kriv-
oruchko contended that the separation of actoprotectors as
a new class of pharmacological compound was not justi ed
theoretically, that is, that this classi cation was the result of the
practical requirements of military medicine (2001). According
to Okovitij, agents in the actoprotector class can reasonably
be referred to as synthetic adaptogens, and their strong ac-
toprotective effect can be regarded as a component of their
adaptogenic action (Okovityi, 2003).
Our own opinion is that actoprotectors, most logically,
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Biomol Ther 20(5), 444-455 (2012)
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7. Administration of actoprotectors (for example bemitil) can
modify speci c effects of many pathogenic chemotherapeutic
and somatic direction’s drugs. This fact is a strong theoretical
basis for co-administration of actoprotectors and pathogenic
therapy agents.
Actoprotectors can be classi ed into three groups based
on their chemical compositions (Oliynyk et al., 2010) (Fig. 3):
1. Benzimidazole derivatives (bemitil, ethomersol, etc.);
2. Adamantane derivatives (bromantane, chlodantan, ade-
mol);
3. Compounds that belong to other chemical classes (thia-
zoloindole derivatives, 3-hydroxypyridine derivatives, nicotinic
acid derivatives, 1-oxa-4-aza-2-silacyclanes, ginseng, chito-
sans, etc.).
The classic reference actoprotector is bemitil, the chemical
structure of which is 2-ethylthiobenzimidazole hydrobromide
(see Fig. 1A). Nowadays, just two compounds among all ac-
toprotectors are permitted for medical administration: bemitil
(commercial name: Antihot; certi ed in Ukraine as a dietary
supplement) and bromantane (commercial name: Ladasten;
certi ed in Russia as a drug).
The clinical uses of benzimidazole and adamantane acto-
protectors are similar, but their pharmacokinetics and mech-
anisms of action are different. Actoprotectors can be widely
used for recovery of work capacity, not only by healthy people
but also by asthenic patients af icted with various diseases.
BEMITIL AS REFERENCE ACTOPROTECTOR
As noted above, bemitil, the main representative of the
benzimidazole class of derivatives, is the classic reference
actoprotector. This substance, as are most of the other de-
rivatives of imidazole, is fully absorbed in the alimentary tube,
where absorption is accelerated by carbohydrate-saturated
food. Bemitil penetrates the blood-brain barrier. A polymodal
characteristic of the distribution of pharmacokinetic parame-
ters has been revealed in studies on healthy volunteers. After
biotransformation of the agent and its metabolites in the liver,
they are removed by urine (Boĭko et al., 1986, 1987a, 1987b,
1991; Sergeeva and Gulyaeva, 2006; Kibal'chich et al., 2011).
In course administration, the effect of bemitil increases in the
rst 3-5 days, and thereafter is maintained at the attained level
(USSR, 1989).
Experimental research has established that single and
course administration of bemitil effectively increases the phys-
ical work capacity of animals and accelerates rehabilitation af-
ter exertion under exhaustive loads (Dubovik and Bogomazov,
1987; Syrov et al., 2008). Analyses of such data demonstrates
the essential differences between the actions of actoprotec-
tors and psychostimulants: the psychostimulant sydnocarb
increases work capacity according to all criteria (+10)-(+20%);
the same time bemitil decreases start intensity of work, does
not change volume of the work until the moment of intensity's
decreasing for 50% of control level, but signi cantly increases
maximal volume of the performed work (+33%) and resistance
of mice for tiredness (+60%). Thus, the maximum stimulative
effect of bemitil is observed in the considerable tiredness
phase (Dubovik and Bogomazov, 1987). Signi cantly, the in-
crease of physical work capacity and acceleration of rehabilita-
tion has been observed not only under normal conditions, but
also under extreme ones (hypoxia, over-heating, etc.; Spasov
et al., 1990). The high ef cacy of bemitil under the indicated
conditions differs substantially from psychostimulants (phena-
mine, sydnocarb): in the latter case, the positive in uence on
work capacity (under normal conditions) diminishes or even
Fig. 3. Current classi cation of actoprotectors.
447
Oliynyk and Oh. Pharmacology of Actoprotectors
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becomes a negative effect under hypoxia or over-heating, due
to increases in heat production, heat exhaustion, and oxygen
consumption (Oliynyk et al., 2010).
Numerous clinical studies have con rmed bemitil's positive
normal-conditions in uence on the physical work capacity of
healthy people and patients with asthenic disorders (Boĭko et
al., 1986; Aleksandrovskiĭ et al., 1988; Makarov et al., 1997);
its in uence on helathy people under extreme conditions also
has been documented: for example, high altitudes (Shahnaz-
arov and Makhnovskii, 1991; Oliynyk and Shevchenko, 2009),
heating microclimate (Pastushenkov and Badyshtov, 1995)
and its combination with hypoxia (Sedov et al., 1991, 1993),
and various factors related to long-duration voyages (Novikov,
1991) and space ight (Bobkov and Epishkin, 1988). Our study
on high-performance athletes con rmed the positive effects of
bemitil on the process and results of training (Oliynyk, 2009).
In summary, the positive in uence of bemitil on mental as
well as physical work capacity under both normal and extreme
conditions (hypoxia, hot or cold temperatures) has been es-
tablished. Speci cally, bemitil improves reaction time, the
capacity for instruction, and all intellectual processes. It also
has an expressed antiasthenic effect, accelerating recovery
processes after episodes of high exertion. However, bemitil
does not cause psychomotor agitation (Bobkov and Epishkin,
1988; USSR, 1989).
A primary analysis of bemitil's effect under heavy physical
loads demonstrated its in uence on carbohydrates and en-
ergy metabolism: slight decreases of glycogen and creatine
phosphate content in the liver and muscles and of glucose in
the blood, lower accumulation of lactates in the tissues and
blood, and lower increases in heat production and oxygen
consumption were observed. After the period of exertion end-
ed, rehabilitation of the factors under study was accelerated,
and indeed, some of them showed super compensation.
It has been established that the therapeutic effect of bemitil
is a function of its complex mechanism entailing cell genome
activation, optimization of mitochondrial oxidation, oxidative
stress reduction, and stimulation of cellular immune response
(Shabanov, 2009b; Oliynyk et al., 2010).
Basically, bemitil (and other benzimidazole actoprotectors)
is similar to purine bases in its chemical structure (Fig. 4).
Smirnov supposed that this structural similarity explains the
in uence of bemitil on the cell genome, the amplifying expres-
sion of RNA and proteins, particularly enzymes of gluconeo-
genesis and oxidative phosphorylation, as a central link in be-
mitil’s mechanism of action (Smirnov, 1993). This activation is
rst expressed in organs (i.e. the liver, kidneys, and alimentary
tube) having short-lived, renewable proteins. Administration of
protein synthesis inhibitor actinomycin D eliminates the pro-
tective effect of bemitil under normal and hypoxic (Zarubina
and Mironova, 2002a) conditions. Probably bemitil does not
induce synthesis of RNA and proteins by itself, but causes a
positive modulating action on naturally developing processes
of protein synthesis. In any case, the concrete mechanisms of
bemitil-induced RNA and protein expression remain unknown.
Bemitil primarily encourages anaerobic energy production,
ATP formation, and resynthesis of glucoses from the prod-
ucts of carbohydrates decay (lactate and pyruvate) and from
glycerol and amino acids, which mostly occurs in the liver
and kidneys. Bemitil promotes the utilization of lactates (one
of the main factors in work capacity reduction) under exces-
sive physical loads which process is conjugated with the Cori
and glucose-alanine cycles (Fig. 5). In these cycles, bemitil
neutralizes and eliminates not only lactate but also the nitro-
geneous products of decay (ammonia, etc.) (Oliynyk et al.,
2010).
As was noted above, the mechanisms of glucose resyn-
thesis from catabolism products are realized through gluco-
neogenesis processes; in this regard, the fact that the most
articulated protein synthesis' activating effect of bemitil in or-
gans with short-lived proteins permits the assumption that the
in uence on these organs (liver and kidneys) is the key link in
the mechanism by which physical work capacity is increased
under bemitil administration. The gluconeogenesis process,
which takes place mainly in the liver and to a lesser extent in
the cortex of the kidneys, consists of glucose resynthesis from
the products of its disintegration (lactate and pyruvate) as well
as from amino acids and the products of their degradation.
The importance of gluconeogenesis processes under physical
loads is that they entail utilization of lactate and resynthesis
of consumed carbohydrates as necessary sources of energy
(Rennie and Tipton, 2000; Fournier et al., 2002; De Feo et al.,
2003). The importance of gluconeogenesis as a key link in the
mechansm of action of bemitil was con rmed by experiments
involving administration of the gluconeogenesis inhibitor tryp-
tophan.
Enhancement of the synthesis of mitochondrial enzymes
and the structural proteins of mitochondria effects an increase
in energy production and maintenance of a high degree of
contingency between oxidation and phosphorylation. Mainte-
nance of a high level of ATP synthesis under oxygen de cien-
cy conditions promotes apparent antihypoxic and antiischemic
activity.
Another important aspect of the action of bemitil is its posi-
tive in uence on oxidative balance. Bemitil has no direct an-
tiradical properties (Plotnikov et al., 1992); its antioxidant ac-
tion is known through induction of protein synthesis, including
antioxidant enzymes (SOD, catalase, glutathione metabolism
enzymes, etc). The utility of bemitil and ethomersol in inhib-
iting of free radical accumulation has been demonstrated in
numerous experimental and clinical studies under various
physiological and pathological conditions (Lobzin et al., 1992;
Oliynyk et al., 2009). Evidence of this is the diminishment
of the preventive effect of bemitil on the glutathione system
under hypoxic conditions and actinomicyn D administration
(Zarubina and Mironova, 2002a). Additional information on
the antioxidant action of bemitil can be found in Zarubina and
Mironova (2002b).
The antioxidant properties of bemitil (and other actoprotec-
tors) were instrumental to the discovery of their pharmacologi-
cal activity. Numerous studies conducted in laboratories world-
wide have ascertained that both long- and short-intensive
physical loads cause oxygen stress (Marzatico et al., 1997;
Kostka, 1999; Selamoglu et al., 2000; Bloomer and Goldfarb,
2004; Bloomer et al., 2005; Bloomer and Smith, 2009; Fisher-
Wellman and Bloomer, 2009). The increase in the level of free
radical processes under maximal and submaximal physical
loads is explained by the activation of the sympathoadrenal
system in response to muscular work. The essence of this
mechanism lies in the following: the active forms of oxygen
capable of initiating free radical responses can be generated
both in catecholamine biosynthesis and in their decay, that is,
when adrenaline oxidizes to adrenochrome (Bors et al., 1978;
Diliberto and Allen, 1981). Additionally, the in ow through af-
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Biomol Ther 20(5), 444-455 (2012)
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ferent and efferent nerves increases physical loads, and nerve
pulse advancement is attended by free radical formation (Kol's
et al., 1966). However, the mechanisms of oxidative stress
have some peculiar features that accord with the nature of
physical loads. Speci cally, intensive physical loading in the
aerobic energy-supply zone supports a peak tension in the
work of muscular and cardiac mitochondria, and meanwhile,
the danger of the “out ow” of oxygen-active forms from the
electrical transporting link grows (Zozulia, 1997). The signi -
cant role in the mechanisms of oxidative stress development
is played by acidosis, which is caused by an excess level of
lactate under physical loads of submaximal power in the an-
aerobic energy supply zone.
In this respect, the concept of the importance of antioxi-
dant properties to the realization of the total pharmacological
activity of benzimidazole actoprotectors (bemitil, ethomersol)
(Gromova et al., 1998) has a sound and seemingly very logi-
cal theoretical basis. This cencept, furthermore, accords with
well known data on the properties of reference antioxidants
ionol (dibunol) and vitamin E that increase tolerance for physi-
cal loads (Dillard et al., 1978; Meerson et al., 1983; Krasikov,
1988). Indeed, bemitil (as well as other actoprotectors – etho-
mersol, bromantan etc.) can decrease oxidative stress, which
can be especially important as one of the mechanisms that
protects against oxidative damage to cells and tissues under
physical loads, and, accordingly, promotes acceleration of re-
covery processes.
Bemitil's positive in uence on the immune system is also
related to expression of immune system proteins. Contrasting-
ly, adaption to high altitudes and hypoxia as well as memory
improvement, by bemitil, are related mainly to protein synthe-
sis activation in the brain. Obviously, reinforcement of protein
synthesis is one of the primary aspects of the mechanism of
adaptive action as it affects the central nervous system, which
effects includemental and physical work capacity enhance-
ment under extreme conditions. However, it is necessary to
admit, again, that the speci c mechanisms of bemitil-induced
protein expression remain unknown.
Bemitil also has antimutagenic properties, closely related
to its antioxidant activity, that have been determined in numer-
ous experimental studies. Thorough research on the genetic
activity of bemitil has shown that it fails to induce recessive,
age-related lethal mutations in drosophila, dominant lethal
mutations in germ mammalian cells, and chromosomal dam-
age in murine bone marrow cells and human peripheral blood
cell cultures. Experiments on mice have demonstrated that
therapeutic doses of bemitil cause a two-fold decrease in the
level of aberrant cells induced by alkylating agents photrin and
phopurin (Seredenin et al., 1986). In cultures of lymphocytes
from 12 healthy donors and 12 patients with nettle-rash, the
anticlastogenic effect of bemitil on the induction of chromo-
somal aberrations by photrin and dioxidine was investigated.
Statistically signi cant protective effects of bemitil were dem-
onstrated in cells of healthy donors after treatment with photrin
or dioxidine, and after modi cation of the clastogenic action of
photrin in lymphocytes of nettle-rash patients (Arutyunyan et
al., 1994). In another study, intraperitoneal administration of
the dust of chrysotile-asbestos and zeolites to C57BL/6 mice,
in doses of 50 mg/kg, was found to elevate cell counts and to
effect chromosomal aberrations in peritoneal uid and bone
marrow cells, as dependent on dust-exposure time. It was re-
vealed that ascorbic acid, rutin, chemically modi ed avonoid
of Scutellaria baicalensis Georgy, and drugs such as bemitil
and ethomersol over a broad concentration range (107-103
M) decreased or completely reduced the clustogenic action
of zeolites and chrysotile-asbestos on cultured human whole
blood. The ability of bemitil (1.8-19 mg/kg), unlike the others,
to prevent the mutagenic effect of chrysotile-asbestos was
con rmed by the recorded chromosomal aberrations in the
cells of peritoneal uid and bone marrow in mice (Daugel'-
Dauge et al., 1995).
Bemitil, as well as the other well-studied actoprotectors,
has no serious side effects. Bemitil and the other imidazole
derivatives can cause dyspeptic disturbances (nausea, par-
ticularly on an empty stomach, though seldomly; vomiting; a
general sense of discomfort in the region of the stomach and/
or liver), psychoactivation effects (affective irritability, shorten-
Fig. 4. Chemical structures of the purine bases adenine (A) and
guanine (B) in comparison with bemitil (C).
Fig. 5. Common circuitry of Cori cycle and glucose-alanine cycles.
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Oliynyk and Oh. Pharmacology of Actoprotectors
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ing of sleep quality and length), headache, and hyperemia of
the face. Allergic reactions connected with the presence of
bromide cannot be excluded. Bemitil is contraindicated un-
der hypoglycemia and barbiturate administration conditions
(USSR, 1989; Oliynyk et al., 2010).
Thus, bemitil is a pharmacological agent of metabolic, non-
exhaustive action, which comprises cell genome activation
and expression of RNA and proteins, including enzymes and
other proteins associated with the immune system. Also oc-
curring is expression of gluconeogenesis enzymes synthesis,
which facilitates lactate utilization and carbohydrate resynthe-
sis, which leads in turn to increased physical working capac-
ity. The enhancement of the synthesis of the mitochondrial
enzymes and structural proteins of the mitochondria makes
possible an increase in energy production and the mainte-
nance of a high degree contingency between oxidation and
phosphorylation. Maintenance of high-level ATP synthesis
under oxygen de ciency promotes apparent antihypoxic and
antiischemic activity. As an indirect-action antioxidant, bemitil
enhances biosynthesis of antioxidant enzymes. The antimu-
tagenic properties of bemitil might be important to genomic
protection against mutagenic factors of chemical, physical or
biological origin. Finally, bemitil increases an organism's sta-
bility against the in uence of extreme conditions (heavy physi-
cal loads, stresses, hypoxia, hyper- and hypothermia, etc.).
OTHER ACTOPROTECTORS
As was mentioned above, among the actoprotectors, and
excluding bemitil, recently only bromantane has been permit-
ted for practical administration; the other compounds are or
were at the stage of clinical (ethomersol, chlodantan, ademol)
or pre-clinical (all other compounds) study.
Bromantane
Morozov et al. supposed that benzoylaminoadamantanes,
adamantane derivatives of para-chlorophenoxyacetic acid,
and other structurally close compounds increase the resistance
of the human body with respect to extreme environmental fac-
tors rather than act as direct stimulants of the physical working
capacity under normal conditions. Nonetheless, several com-
pounds, including N-(2-adamantyl)-N-(para-bromophenyl)-
amine (bromantane) (Fig. 1B) and N-(2-adamantyl)-N-(para-
chlorobenzoyl) amine (ADK-910, chlodantane) (Fig. 6a), can
increase physical performance; accordingly, in the literature,
they are regarded as actoprotectors (Morozov and Ivanova,
2001).
Bromantane, upon oral induction, is quickly but not fully ab-
sorbed from the gastrointestinal tract into the blood (bioavail-
ability: 42%). It is quickly, and in large quantities, distributed
over the tissues and organs, and is slowly eliminated from the
body. Bromantane is highly lipophilic, is distributed into the lip-
ids of brain and fat tissue and, nally, is deposited in adipose
tissue. The speed of bromantane absorption from the gastro-
intestinal tract is much higher in women, so the half-life is re-
spectively lower than in men. The time to achievement of the
maximum concentration of blood bromantane is 2.75 hours
in women, and 4.0 hours in men. The drug is metabolized in
the liver, but its elimination occurs mostly through the adre-
nal gland. Bromantane metabolism is characterized mainly
by hydroxylation in the 6th position of the adamantan cycle. All
of the determined metabolites can be found in urine, even in
two weeks after administration of bromantane (this last fact is
important for doping control) (Burnat et al., 1997; Sizoi et al.,
1998; Oliynyk et al., 2010).
In terms of its pharmacological action, bromantane shows
an antiasthenic effect, increases resistance to overheating,
and, thereby, contributes to the restoration of working capac-
ity after physical loads. This compound, which possesses
combined stimulative and anxiolytic effects, increases physi-
cal and intellectual working capacity; inhibits the development
of fatigue processes; accelerates restoration under common
conditions and conditions complicated by hypoxia and hyper-
thermia; promotes improvement of mnemic processes (learn-
ing); improves the coordination of movements; increases body
temperature; has a neuropsychoactivation effect (therefore it
is sometimes referred to as a psychomotor stimulator); reveals
antagonism to the sedative action of tranquilizers; displays a
positive inotropic action without affecting the heart chrono-
tropic function or systemic arterial pressure, and produces
immunomodulation activity (USSR, 1989; Sedov et al., 1999;
Morozov et al., 1999, 2001; Oliynyk et al., 2010).
Whereas bromantane lacks hypno-sedative and neuromus-
cular relaxant properties, it does not possess any addictive
potential. At its application, it does not, unlike typical psycho-
stimulants, develop the phenomena of hyperstimulation.
It was determined that bromantane has a positive in uence
on the indices of psychophysiological conditions: range and
stability of attention, complex sensomotor reaction, and the
parameters of successful operator activity (Viatleva et al.,
2000).
The mechanism of bromantane action is based on the facil-
ity to increase the activity of the lower centers of the central
nervous system (the hypothalamus nuclei, the reticular nuclei
of the operculum, the hippocampus). It does not exert any ex-
pressed action on noradrenergic mediators, but implements
the activation properties through the dopaminergic system.
Bromantane strengthens GABA-ergic mediation, reducing
gene expression, supervising synthesis of GABA-transport-
ers, and functioning as a return capture mediator. A potential-
ity for central serotonin holding effects is also assumed.
A de nite role in the implementation of the bromantane
pharmacological effect is played by its antiradical and mem-
brane protective properties: bromantane increases immunity
even after a single dose (increases the level of B-cells and
circulating immune complex in the blood-stream), and it is
more powerful than another synthetic adaptogen, levamizol,
in terms of its effect on immunity (Morozov et al., 1999, 2001).
Bromantane stimulates synthesis of cytochrome P-450 and
thus facilitates detoxifying liver functions and reduces the hyp-
notic action of thiopental sodium (but at the same time, does
not weaken the anxiolytic effect of benzodiazepines).
Bromantane administration in therapeutic doses is char-
acterized by the almost full absence of side effects including
manifestations of withdrawal syndrome and hyperstimulation
(Morozov et al., 1999). In animal experiments, toxic reactions
were observed only after high doses of bromantane adminis-
tration (>600 mg/kg). Lower doses (30-300 mg/kg) stimulated,
and higher doses (600-9,600 mg/kg) suppressed behavioral
activity. Spontaneous motor activity was increased after single
treatment of bromantane in doses of 30-300 mg/kg, was not
changed after treatment in doses of 600 mg/kg, but was in-
hibited after treatment in doses above 600 mg/kg. The drug
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Biomol Ther 20(5), 444-455 (2012)
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reduced the pain sensitivity threshold in doses of 300-600 mg/
kg, and elevated it, along with tactile sensitivity and reaction to
knock, in doses above 600 mg/kg (Iezhitsa et al., 2002).
Additional and more detailed information on the pharmaco-
logical properties of bromantane is available in a foundational
book, some review articles (Morozov et al., 1999; Morozov
and Ivanova, 2001), and numerous clinical and experimental
studies rst and foremost from the laboratories of I.S. Morozov
and S.B. Seredenin.
Chlodantane
This compound, also known as ADK-910, can be character-
ized as an adaptogen of the estrogen activity type. Chlodan-
tane, exhibiting a broader activity spectrum than bromantan,
is an adaptogen that is capable of protecting the organism
against hypoxia, low and high temperatures, toxic chemicals,
and other extreme factors. Its effect, in contrast to the action
of well-known adaptogens, is manifested after only a single
administration.
Although the mechanisms of chlodantane’s adaptogen ac-
tivity have not been studied in detail, one of the most important
contributions is the increase in the stability of cell membranes
with respect to unfavorable factors. This is achieved, in partic-
ular, by decreasing the rate of overactivating lipid peroxidation
(LPO) processes. Chlodantane also produces an immunos-
timulant action, which is more pronounced than the analogous
effect of bromantane (Morozov and Ivanova, 2001). All of the
data on chlodantane’s pharmacological properties have been
derived from animal or cell culture experiments; no clinical re-
search has been conducted. The most detailed information is
available in the book by I.S. Morozov et al. (2001).
Ademol
Another adamantan-derivative actoprotector, ademol (1-ad-
amantylaethyloxy-3-morpholino-2-propanol hydrochloride) (Fig.
6B), was developed in Ukraine at the Institute of Organic
Chemistry of National Academy of Sciences in the 1990s. It
is the only actoprotector not primarily developed in Russia
or connected to Soviet military or space programs. Ademol
has been studied clinically, though not as an actoprotector;
rather, the focus has been its uterotonic properties. Subse-
quently, ademol’s capacity to enhance memorization was es-
tablished, and it was studied as an actoprotector and, later,
as a nootropic agent at the Department of Pharmacology of
Vinnitsa National Medical University. Ademol is now registered
in Ukraine as a uterotonic drug; however, its manufacture has
ceased, and it is no longer on the market.
Experimental studies on the actoprotective activity of ade-
mol have shown that it is more effective than bemitil in terms
of increasing the endurance of experimental animals (in swim-
ming tests) under normal conditions; under extreme conditions
(hypo- and hyperthermia, hypoxia), it is comparable to bemitil.
The mechanism of ademol’s actoprotective action is related
to the stimulation of DNA and RNA synthesis in the liver as
well as normalization of ATP content in the muscles and its
antioxidant properties; indeed, in many ways, this mechanism
is similar to bemitil’s.
Ethomersol
Like bemitil, ethomersol (in the English-language literature:
“ethomerzol”, “tomerzol” or “tomersol”), according to its chemi-
cal structure, is a benzimidazole derivative (5-ethoxy-2ethyl-
thiobenzimidazole hydrochloride) (Fig. 6C) and has similar
pharmacological properties. Like bemitil too, ethomersol was
formulated in the former USSR for military medicine purposes.
Bemitil, despite its numerous positive characteristics, carries
some drawbacks, among which is low water solubility. Only
in its parenteral forms can it be truly effective for extreme-
condition treatment in military medicine contexts such as mili-
tary toxicology, military surgery, and resuscitation practice. Of
course, in these cases, the focus was not on bemitil’s acto-
protective activity but rather on its properties as an effective
regeneration and reparation aid.
Owing to that low water solubility drawback of bemitil, it
could not be developed in injectable (intravenous or intramus-
cular) forms. Thus, in the latter half of the 1980s, ethomersol
was developed as a water-soluble analog in order to enable
further development in forms suitable for parenteral admin-
istration. The manufacturing technology necessary for those
purposes was pioneered by Ukrainian pharmaceutics in Khar-
kov.
Clinical studies on ethomersol were conducted in 1990-91
at the toxicological clinic of the Military Medical Academy, spe-
ci cally on patients suffering intoxication by phosphoorganic
compounds (insecticides). Notwithstanding their generally
positive results, these clinical studies uncovered new prob-
lems: the ethomersol solutions elicited a strong acid reac-
tion (pH ~3), and caused many post-injection complications.
The most common of these complications after intravenous
administration were phlebitis and acute pain; after intramus-
cular administration, the reactions were aseptic in ammation,
sometimes with subsequent necrosis, and acute pain. After
the fall of the Soviet Union in 1991, clinical studies on ethom-
ersol were interrupted; over the following 20 years, only a few
animal experiments were completed.
As was already emphasized, ethomersol shares many
commonalities with bemitil. Its positive in uence on the energy
production processes was shown in experimental studies on
brain ischemia and craniocerebral trauma models (Kosolapov
et al., 1996; Zarubina and Shabanov, 2005). Ethomersol in-
Fig. 6. Chemical structures of three compounds with actoprotector activity, (A) chlodantane (N-(2-adamantyl)-N-(para-chlorobenzoyl)
amine); (B) ademol (1- adamantylaethyloxy-3-morpholino-2-propanol hydrochloride); (C) ethomersol (5-ethoxy-2ethylthiobenzimidazole hy-
drochloride).
451
Oliynyk and Oh. Pharmacology of Actoprotectors
www.biomolther.org
terrupts the decrease of NAD-dependent breathing and the
uncoupling of oxidative phosphorylation. It also shows anti-
oxidant properties (it decreases lipid peroxidation products in
tissues) in brain ischemia (Vaizova et al., 1994; Mironova et
al., 2003).
Ethomersol shows properties of a central action vasodila-
tor in blocking the potential-dependent and particularly the
receptor-dependent calcium channels. The positive in uence
of ethomersol on the rheological properties of blood also has
been established. It blocks the calcium channels of thrombo-
cyte membranes and interrupts their activation under throm-
bocyte aggregation inductor action, which consequently limits
the development of thrombosis processes (Plotnikova et al.,
1992b).
Ethomersol prevents the decrease of the erythrocyte ca-
pacity for deformation, possibly because of the improvement
of the microviscosity of erythrocyte membranes. It induces
the reduction of haemoglobin's af nity to oxygen and, conse-
quently, increases the quantity of oxygen delivery to tissues
(Plotnikova et al., 1991a, 1991b, 1992a).
Animal experiments have established that ethomersol also
has hepatoprotective properties, which are indirectly related
to its immunomodulant activity (Okovityi and Gaivoronskaia,
2002). Ethomersol is demonstrably capable of accelerating
the process of liver regeneration following partial hepatecto-
my. The drug produces a rapid gain in liver mass, increases
nucleic acid and glycogen contents, and improves the func-
tional state, as manifested by a decrease in the blood biliru-
bin and a reduction in hexenal sleep duration. Ethomersole,
moreover, produces a positive effect on liver morphology and
the intracellular regeneration process (Gaivoronskaia et al.,
2000).
Thiazoloindole derivatives
Most of the thiazoloindole-derivative compounds were
synthesized and studied by Professor Vera Marysheva at the
Military Medical Academy in post-USSR Russia. A series of
12 such compounds belonging to this class possessing an-
tihypoxic activity were studied in order to reveal their acto-
protective properties under normal and extreme conditions in
rats and mice. Five of the compounds were shown to protect
animals from exhaustive loads 1 hour and 24 hours after ad-
ministration; four produced the same effect under acute hy-
percapnic hypoxia conditions. By contrast, under the condi-
tions of acute hemic hypoxia, none of the compounds affected
physical endurance (Gavreev et al., 2010).
3-Hydroxypyridine derivatives
Experiments with mice have shown that most of the 15
new 3-hydroxypyridine-derivative compounds possess anti-
oxidant, actoprotective, and antihypoxic properties. Based on
the results of treadmill and swimming tests, the actoprotec-
tive action of IBKhF-1, 11 and 14 greatly surpassed those of
bemitil and bromantane under ordinary conditions. The inhibi-
tor of gluconeogenesis tryptophan cancelled the stimulative
action of IBKhF-1, 2 and 11 in the treadmill exercise. Gluco-
neogenesis activation, accordingly, can be considered to be
one of the major components of the actoprotective action of
15 compounds. IBKhF-1, 11 and 14 also bested bemytil and
bromantane under the extreme conditions of hyperthermic
running and of swimming with acute hypoxia combined with
hypercapnia. IBKhF-2 and 14, additionally, were better than
amtisol (the standard antihypoxic agent) and bemitil against
acute hypoxia in a pressure chamber, and IBKhF-4 and 14
excelled against them in a thermal chamber (Dormidonova et
al., 2000; Iasnetsov et al., 2011).
Six- and seven-membered 1-oxa-4-aza-2-silacyclanes
This is a new class of compounds synthesized and studied
at Russian State Medical University. Generally, the biological
activity of eight 1-oxa-4-aza-2-silacyclanes with the OSiCH(2)
N fragment, including 6-membered 2-sila-5-morpholinones (1-
3), 4-acyl-2-silamorpholines (4-6), and 7-membered deriva-
tives of salicylic acid (7, 8), were studied. Compounds 1 and
3-6 showed a certain antihypoxic action. Compounds 2 (40
mg/kg), 4 (20 mg/kg), 6 (40 mg/kg), 7 (20 mg/kg) and 8 (40
mg/kg) reduced the physical performance of intact animals.
Compound 1 (20 mg/kg) in uenced physical performance in
a moderate-positive way under the condition of chlorophos
poisoning. Compounds 5-8 displayed protective properties
against chlorophos poisoning at the dose of LD50, and com-
pounds 2, 4, 5, 7, at the LD100 dose. The in uence of com-
pounds 1 and 2 on the emotional behavior of mice also was
studied (Kurochka et al., 1998).
Chitosan
This compound differs from the other natural-origin adato-
gens in its strong actoprotective action established in animal
experiments (Khasina et al., 2005). However, we consider
those results to be only preliminary ones, due to the fact that
the actoprotective activity of chitosan was not compared with
a reference actoprotector bemitil (or, at least, bromantane).
Panax ginseng
Panax ginseng C.A. Meyer is a perennial plant grown in
China, Korea, Japan, and Russia. The dried roots and extract
of this plant are used in some traditional medicines to treat a
variety of conditions, including asthenia and neuroses of var-
ied genesis. The main active ingredients of ginseng are gin-
senosides. Ginsenosides are a special group of triterpenoid
saponins that can be classi ed into two groups according to
the skeleton of their aglycones, namely, the dammarane- and
oleanane types: the Rb1 group (characterized by the pres-
ence of protopanaxadiol: Rb1, Rb2, Rc and Rd) and the Rg1
group (protopanaxatriol: Rg1, Re, Rf, and Rg2). Ginsenosides
are found almost exclusively in Panax species (ginseng), and
to the present date, more than 150 naturally occurring ginsen-
osides have been isolated from the roots, leaves/stems, fruits,
and/or ower heads of ginseng. Ginsenosides have been the
focus of a great deal of research as, indeed, they are believed
to be the main forces behind the many and glowing claims of
ginseng’s ef cacy. These steroid-like phytochemicals are ben-
e cial in countering the negative in uences of stress. The gly-
cosides act on the adrenal glands, helping to prevent adrenal
hypertrophy and excess corticosteroid production in response
to stress. Ginsenosides increase protein synthesis and the ac-
tivity of neurotransmitters in the brain; they stimulate the for-
mation of blood vessels and improve blood circulation in the
brain, thereby improving memory and cognitive abilities. Gin-
seng also is used in the treatment of diabetes, migraine, infec-
tions, and cancer, as well as for radiation and chemotherapy
protection, to aid in sleep, and to stimulate the appetite (Attele
et al., 1999; Choi, 2008; Christensen, 2009).
The results of several animal experiments (Grandhi et al.,
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http://dx.doi.org/10.4062/biomolther.2012.20.5.444
1994; Wang and Lee, 1998) and human studies (Voces et al.,
1999; Ziemba et al., 1999; Kim et al., 2005; Liang et al., 2005;
Yeh et al., 2011) attest to the fact that ginseng (administrated
as an extract) can signi cantly increase physical work capac-
ity; such data, in fact, allow ginseng to be referred to as an ac-
toprotector of natural origin. Nonetheless, the results of other
studies (Morris et al., 1996; Engels and Wirth, 1997; Allen et
al., 1998; Engels et al., 2001; Jung et al., 2004; Kulaputana
et al., 2007; Ping et al., 2011) show no signi cant in uence
on physical performance, effectively refuting the more positive
conclusions on its actoprotective properties.
It seems logical that such controversies are connected to
the relevant studies’ different doses and course durations, as
well as the varying qualities and compositions of the ginseng
supplements utilized therein. Such a conclusion permits con-
tinuance of the idea that ginseng is a potential actoprotector,
at least until further investigation of its in uence on physical
work capacity, endurance and restoration under exhaustive
physical loads (compared with the reference actoprotector be-
mitil) has been conducted. So, as we see, perhaps the benz-
imidazole and adamantane derivatives are not alone in pos-
sessing actoprotective properties. The recently undertaken
pharmacological studies on other perspective compounds are
only the beginning.
CONCLUSIONS
Actoprotectors are preparations that enhance body stability
against physical loads without increasing oxygen consump-
tion or heat production. Or, in short, actoprotectors can be
considered to be synthetic adaptogens that have a signi cant
capacity to improve physical performance. The main repre-
sentatives of this class are benzimidazole-derivative bemitil
and adamantine-derivative bromantane. Nowadays, bemitil is
manufactured in Ukraine and is widely used in the training of
Ukrainian national sport teams. Bromantane is manufactured
in Russia, and is employed mainly in the treatment of patients
with asthenic and restless-asthenic frustration. Some other
synthesized (new benzimidazole and adamantine derivatives,
as well as thiazoindole, 3-hydroxypyridine derivatives, etc.)
and even natural (including ginseng, chitosan) compounds
are regarded as potential actoproptectors as well.
The reference actoprotector is bemitil. The mechanism
of its pharmacological action is complex and has yet to be
fully studied; however, is is established that this compound
primarily (directly) stimulates protein synthesis. Other effects
of bemitil (increasing physical and operator working capac-
ity, antioxidation, antihypoxia, antimutagenic action, etc.) have
been determined by proteins synthesized de novo in different
organs.
All of the thoroughly studied actoprotectors have no seri-
ous side effects. Bemitil can cause dyspeptic disturbances
(nausea, particularly on an empty stomach, though seldomly;
vomiting; a general sense of discomfort in the region of the
stomach and/or liver), psychoactivation effects (affective irrita-
bility, shortening of sleep quality and length), headache, and
hyperemia of the face. Bromantane is characterized by the
almost full absence of side effects including manifestations
of withdrawal syndrome and hyperstimulation (Oliynyk et al.,
2010).
Actoprotectors initially were developed in the former Soviet
Union for space, sports and military medicine applications,
speci cally for the purpose of increasing physical and opera-
tor work capacity under normal and extreme (hypoxia, hyper-
thermia) conditions; later, actoprotectors, owing to their wide-
ranging pharmacological activity, high ef ciency and safety,
were found to offer a wider utility in other branches of practi-
cal medicine. Nowadays, bemitil is successfully employed in
infectology, neurology, hepatology, cardiology, pulmonology,
obstetrics and gynaecology, urology, dermatology, toxicology
and other branches of clinical medicine. It is recommended for
the rehabilitation of patients suffering a variety of diseases,
not only as a symptomatic aid (for decrease of asthenic symp-
toms), but as a pathogenetic one as well.
ACKNOWLEDGMENTS
This work was supported by a Korea Research Foundation
grant (MRC, 2010-0029355) funded by the Korean Govern-
ment (MEST).
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... These investigations resulted from the development of the first and the most commonly used actoprotector, bemitil (chemical structure 2-ethylbenzimidazole hydrobromide) (Fig. 1). Later, other actoprotectors were created, such as bromantane [1,2]. ...
... It has been established that the therapeutic effect of actoprotectors (bemitil, as an example) is a function of its complex mechanism entailing cell genome activation, optimization of mitochondrial oxidation, oxidative stress reduction, and stimulation of cellular immune response [1,2]. ...
... Moreover, the preparations exert an antihypoxic effect under hypoxic conditions, which may advance as a result of mitochondrion-decreased ability to oxidize substrates under higher physical loads. However, this is not the case in hypoxic conditions of other etiology [1,2]. ...
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Actoprotectors are preparations that increase the mental performance and enhance body stability against physical loads without increasing oxygen consumption. Actoprotectors are regarded as a subclass of adaptogens that hold a significant capacity to increase physical performance. The focus of this article is studying adaptogen herbs of genus Panax (P. ginseng in particular) and their capabilities as actoprotectors. Some animal experiments and human studies about actoprotective properties of genus Panax attest that P. ginseng (administered as an extract) significantly increased the physical and intellectual work capacities, and the data provided suggests that ginseng is a natural source of actoprotectors. Preparations of ginseng can be regarded as potential actoprotectors which give way to further research of its influence on physical and mental work capacity, endurance and restoration after exhaustive physical loads while compared with reference actoprotectors.
... Such a complex character of the pharmacological activity of 4-hydroxy-3,5-di-tertbutyl cinnamic acid makes it possible to classify this compound as an actoprotective agent (Voronkov et al. 2017). It is known that actoprotectors are compounds of various origins that normalize physical and mental performance under conditions of adverse effects of a destabilizing factor on the human body (Oliynyk and Oh 2012). The important aspects of the mechanism of action of actoprotectors is the normalization of energy production and the optimization of cellular metabolism. ...
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... Закусова (Москва). Спектр фармакологической активности препарата включает психостимулирующие, анксиолитические, нейропротективные, иммуномодулирующие [14][15][16] и актопротекторные [17][18][19] эффекты. В многоцентровых клинических исследованиях продемонстрирована высокая эффективность и безопасность препарата при лечении широкого спектра астенических расстройств, включая неврастению и соматическую астению [9,20]. ...
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