Article Highlights from “The Pharmacology of Actoprotectors: Practical Application for Improvement of Mental and Physical Performance (2012)”

Oliynyk, Sergiy ; Oh, Sei-Kwan ;


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 significant 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 characteristics 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 efficiency and safety, can be applied under either normal or extreme conditions.

Highlights of the full article (from my emphasis):

The basic classification of actoprotectors. (Take this as a pictorial summary of the article)

The first 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 administration 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 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 Special Forces, to effectively perform combat missions under both hypoxic and high-temperature conditions.


Actoprotectors are preparations that enhance body stability against physical loads without increasing oxygen consumption 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 influence that can become stronger as a result of mitochondrion-decreased ability to oxidize substrates under higher physical loads, but they do not function in this way in other etiologies.

The principal difference between actoprotectors and psychostimulants (e.g. caffeine, sydnocarb, phenamine, methylphenidate, modafinil, adrafinil, armodafinil) is that actoprotectors are agents of non-exhaustive action. With actoprotectors, there is no increase in oxygen consumption or heat production; 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. It was contended that the separation of actoprotectors as a new class of pharmacological compound was not justified theoretically, that is, that this classification was the result of the practical requirements of military medicine. Agents in the actoprotector class can reasonably be referred to as synthetic adaptogens, and their strong actoprotective effect can be regarded as a component of their adaptogenic action.


Further characteristics of actoprotector action provided are as follows:

1. These agents have minimal pharmacological activity, which explains why the mechanism of their action is difficult to correlate with their influence on some concrete types of pharmacological receptors;

2. The efficacy 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 persons 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 efficacy is independent of extreme conditions (physical load, stress, hypoxia, ischemia, hyperemia, gravitation overload etc.), which fact suggests their influence on the basic mechanisms of resistance;

7. Administration of actoprotectors (for example bemitil) can modify specific 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.

Current classification of actoprotectors.

1. Benzimidazole derivatives (bemitil, ethomersol, etc.);

2. Adamantane derivatives (bromantane, chlodantan, ademol);

3. Compounds that belong to other chemical classes (thiazoloindole derivatives, 3-hydroxypyridine derivatives, nicotinic acid derivatives, 1-oxa-4-aza-2-silacyclanes, ginseng, chitosans, 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 actoprotectors are permitted for medical administration: bemitil (commercial name: Antihot; certified in Ukraine as a dietary supplement) and bromantane (commercial name: Ladasten; certified in Russia as a drug).

The clinical uses of benzimidazole and adamantane actoprotectors are similar, but their pharmacokinetics and mechanisms of action are different. Actoprotectors can be widely used for recovery of work capacity, not only by healthy people but also by asthenic patients afflicted with various diseases.



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 derivatives 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 parameters 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 first 3–5 days, and thereafter is maintained at the attained level.

Experimental research has established that single and course administration of bemitil effectively increases the physical work capacity of animals and accelerates rehabilitation after exertion under exhaustive loads (Dubovik and Bogomazov, 1987; Syrov et al., 2008). Analyses of such data demonstrates the essential differences between the actions of actoprotectors 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 significantly 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). Significantly, the increase of physical work capacity and acceleration of rehabilitation has been observed not only under normal conditions, but also under extreme ones (hypoxia, over-heating, etc.; Spasov et al., 1990). The high efficacy of bemitil under the indicated conditions differs substantially from psychostimulants (phenamine, sydnocarb): in the latter case, the positive influence on work capacity (under normal conditions) diminishes or even becomes a negative effect under hypoxia or over-heating, due to increases in heat production, heat exhaustion, and oxygen consumption.

Numerous clinical studies have confirmed bemitil’s positive

normal-conditions influence 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 influence on helathy people under extreme conditions also has been documented: for example, high altitudes (Shahnazarov 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 flight (Bobkov and Epishkin, 1988). Our study on high-performance athletes confirmed the positive effects of bemitil on the process and results of training (Oliynyk, 2009).

In summary, the positive influence of bemitil on mental as well as physical work capacity under both normal and extreme conditions (hypoxia, hot or cold temperatures) has been established. Specifically, 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).

A primary analysis of bemitil’s effect under heavy physical loads demonstrated its influence on carbohydrates and energy 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 ended, 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).


Another important aspect of the action of bemitil is its positive influence on oxidative balance. Bemitil has no direct antiradical properties (Plotnikov et al., 1992); its antioxidant action is known through induction of protein synthesis, including antioxidant enzymes (SOD, catalase, glutathione metabolism enzymes, etc). The utility of bemitil and ethomersol in inhibiting 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, 2002).


Bemitil’s positive influence on the immune system is also related to expression of immune system proteins. Contrastingly, adaption to high altitudes and hypoxia as well as memory improvement, by bemitil, are related mainly to protein synthesis 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 enhancement under extreme conditions. However, it is necessary to admit, again, that the specific mechanisms of bemitil-induced protein expression remain unknown.


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, 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 irritability, shortening 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 under hypoglycemia and barbiturate administration conditions.

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 occurring

is expression of gluconeogenesis enzymes synthesis, which facilitates lactate utilization and carbohydrate resynthesis, which leads in turn to increased physical working capacity. The enhancement of the synthesis of the mitochondrial enzymes and structural proteins of the mitochondria makes possible an increase in energy production and the maintenance of a high degree contingency between oxidation and phosphorylation. Maintenance of high-level ATP synthesis under oxygen deficiency promotes apparent antihypoxic and antiischemic activity. As an indirect-action antioxidant, bemitil enhances biosynthesis of antioxidant enzymes. The antimutagenic properties of bemitil might be important to genomic protection against mutagenic factors of chemical, physical or biological origin. Finally, bemitil increases an organism’s stability against the influence of extreme conditions (heavy physical loads, stresses, hypoxia, hyper- and hypothermia, etc.).



Morozov and Ivanova 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 factors rather than act as direct stimulants of the physical working capacity under normal conditions. Nonetheless, several compounds, 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 absorbed from the gastrointestinal tract into the blood (bioavailability: 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 lipids of brain and fat tissue and, finally, is deposited in adipose tissue. The speed of bromantane absorption from the gastrointestinal tract is much higher in women, so the half-life is respectively 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 adrenal 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).

In terms of its pharmacological action, bromantane shows an antiasthenic effect, increases resistance to overheating, and, thereby, contributes to the restoration of working capacity after physical loads. This compound, which possesses combined stimulative and anxiolytic effects, increases physical and intellectual working capacity; inhibits the development of fatigue processes; accelerates restoration under common conditions and conditions complicated by hypoxia and hyperthermia; promotes improvement of mnemic processes (learning); 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 chronotropic function or systemic arterial pressure, and produces immunomodulation activity (Sedov et al., 1999; Morozov et al., 1999).

Whereas bromantane lacks hypno-sedative and neuromuscular relaxant properties, it does not possess any addictive potential. At its application, it does not, unlike typical psychostimulants, develop the phenomena of hyperstimulation.

It was determined that bromantane has a positive influence 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 facility 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 expressed 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-transporters, and functioning as a return capture mediator. A potentiality for central serotonin holding effects is also assumed.

A definite role in the implementation of the bromantane pharmacological effect is played by its antiradical and membrane 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).

Bromantane stimulates synthesis of cytochrome P-450 and thus facilitates detoxifying liver functions and reduces the hypnotic action of thiopental sodium (but at the same time, does not weaken the anxiolytic effect of benzodiazepines).

Bromantane administration in therapeutic doses is characterized 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 administration (>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 inhibited after treatment in doses above 600 mg/kg. The drug 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 pharmacological 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 first and foremost from the laboratories of I.S. Morozov and S.B. Seredenin.


This compound, also known as ADK-910, can be characterized as an adaptogen of the estrogen activity type. Chlodantane, 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 activity 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 particular, by decreasing the rate of overactivating lipid peroxidation (LPO) processes. Chlodantane also produces an immunostimulant 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 research has been conducted.


Another adamantan-derivative actoprotector, ademol (1-adamantylaethyloxy-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. Subsequently, ademol’s capacity to enhance memorization was established, 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 ademol have shown that it is more effective than bemitil in terms of increasing the endurance of experimental animals (in swimming 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.


Actoprotectors are preparations that enhance body stability against physical loads without increasing oxygen consumption or heat production. Or, in short, actoprotectors can be considered to be synthetic adaptogens that have a significant capacity to improve physical performance. The main representatives 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 capacity, antioxidation, antihypoxia, antimutagenic action, etc.) have been determined by proteins synthesized de novo in different organs.

All of the thoroughly studied actoprotectors have no serious 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 irritability, 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.

Actoprotectors initially were developed in the former Soviet Union for space, sports and military medicine applications, specifically for the purpose of increasing physical and operator work capacity under normal and extreme (hypoxia, hyperthermia) conditions; later, actoprotectors, owing to their wide-ranging pharmacological activity, high efficiency and safety, were found to offer a wider utility in other branches of practical 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 symptoms), but as a pathogenetic one as well.

Additional Reading:

  1. [The neuro- and psychophysiological effects of bromantane].”

2. “[Adamantane derivatives enhancing body’s resistance to emergencies].”

3. “[Ladasten, the new drug with psychostimulant and anxiolytic actions in treatment of neurasthenia (results of the comparative clinical study with placebo)].”

4. “[The mechanisms of the neurotropic action of bromantan].”

5. “[The effect of bromantane on the dopamin- and serotoninergic systems of the rat brain]”

6. “[A quantitative pharmaco-electroencephalographic analysis of the action of bromantane].”

7. “[Effect of actoprotectors on the work capacity of operators during modeling of various factors of space flight].”

8. “[Effectiveness of bemitil in recurrent erysipelas].”

9. “[Antihypoxic and antioxidative properties of bemitil].”

10. “[The effect of bemitil on conditioned-reflex memory in normal rats and under stress exposures].”

11. “[Use of the new psychotropic preparation bemitil in treating asthenic disorders (clinico-pharmacological research)].”

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