Modern life is often so eventful that almost exhausts people. Approximately 40% of patients of general practitioners complaint of general overfatigue, empty feeling and chronic fatigue sense. These states are manifestations of asthenic syndrome where conventional therapeutic methods (i.e., rest, exercises, vitamins and nootropics) do not always provide significant effect. Traditionally, there was no available specific therapy of asthenic syndrome. Prof. Sergei Borisovich SEREDENIN (Director of V.V. Zakusov Scientific Research Institute for Pharmacology of Russian Academy of Medical Sciences, member of Russian Academy of Medical Sciences, one of the drug developers) agreed to talk us about invention history and properties of Ladasten (Bromantane).
– Why did you take on development of an antiasthenic drug?
– We worked on the creation of an entire group of new-generation psychotropic drugs for a long time. Way back in the 80s we realised that existing benzodiazepine tranquillizers have several limitations and present psychostimulants are practically forbidden. Despite variety of immunostimulating agents, they have no other properties. Thus, we develop new drugs with advanced mechanisms of action to avoid all the disadvantages of current medications. So we have achieved some success. Developed in our institute, Ladasten does not have negative effects of psychostimulants and tranquillisers. Moreover, it provides high antiasthenic activity.
– What is Ladasten like?
– Ladasten is an adamantane derivative which was invented in our institute quite a long ago (in the 70s). The primary idea was to create a drug with actoprotective properties. Actoprotectors are substances to provide increased working capacity in extreme conditions. For the first time, the drug was synthesised under the guidance of Prof. B.M. Pyatin. Later the study was continued by Prof. I.S. Morozov. It was shown that the medication (formerly named as bromantane) has psychostimulant and immunostimulating properties. That’s why, it was involved in various pharmacological experiments at once. When it was described as a psychostimulant and compared with sydnocarb (i.e. common representative of this product group), it was found that general stimulating properties of Ladasten are significantly lower than those of sydnocarb. So further studies of this drug were stopped.
Studies of its psychostimulant properties in terms of pharmacogenetics put new life into the medication. In the 80s we developed a model which allowed to detect genetic differences in responses of the most standardised inbred mice to emotional stresses (for example, transition from darkness to luminous area). It has been found that one group of mice provided very good responses to standard psychostimulants (such as amphetamine and sydnocarb) but another group of animals were irresponsive. As for bromontane (Ladasten), stimulation in behavior was observed in both groups. This fact was quite hard to explain. After investigation of this issue we realised that nonstress stimulation is observed only in animals responding to conventional psychostimulants. On the contrary, nonstress stimulation is not induced in irresponsive animals. This fact led us to a firm conclusion that Ladasten-induced stimulation in behaviour is performed by 2 ways. In fact, this drug provides anxiolytic (antianxiety) action to prevent phobic reaction along with mild psychostimulant action. It was very compelling because we synthesised the world’s first compound with psychostimulant and antianxiety actions. Immunostimulating properties were also demonstrated earlier.
– Why does Ladasten provide so unique properties?
– We conducted repudiatory biochemical and neurochemical studies even involving a French company to perform a comprehensive receptor analysis. We failed to detect a Ladasten-induced receptor. Thus, we studied various intracellular processes and mentioned that secondary signal molecule system plays a great role in drug effect. The next stage included pharmacogenomic studies. We explored Ladesten influence on expression of 1,116 genes. As a result, altered activity of 16 genes was detected. All the detected genes are related to nervous cell functioning. Observed pharmacological effects were entirely explained by altered activity of 2 genes among those mentioned above. Hence, Ladasten increases tyrosine hydroxylase gene expression. It is a key enzyme providing synthesis of catecholamine. This means that Ladasten increases this enzyme level due to enhanced tyrosine hydroxylase gene activity resulting in increased dopamine synthesis. Its mild psychostimulant action is explained well by this fact. Administration of a common psychostimulant causes strong psychostimulant effect followed by extreme exhaustion. Ladasten provides lower psychostimulant effect without exhaustion. Common psychostimulants affect dopamine release from storage vesicles and interact with reverse dopamine transporter in synaptic trough. On the contrary, Ladasten increases synthesis of neurotransmitters associated with mental stimulation. Therefore, this means entirely new mechanism of action.
According to analysis of other genes, Ladasten decreases expression of GABA transporter gene. This leads to increased GABA level in synaptic trough consequently explaining anxiolytic (antianxiety) drug effect because GABA is a main inhibitory neurotransmitter of human central nervous system.
Therefore, pharmacogenomic studies showed that pharmacological effects are directly associated with observed changes in expression of genes. According to recent unique representations, Ladasten regulates activity of nerve cell genome. Our studies are still ongoing. It has already been found that Ladasten increases expression of tyrosine hydroxylase gene causing demethylation of its promoter site. Transcription factor associated with this effect was also detected.
Therefore, we have sufficient understanding of Ladasten-induced cellular changes. This fact confirms our conviction that we have managed to create the world’s first drug providing simultaneous antianxiety and psychostimulant actions. It is evident that such a drug fully corresponds with purposes of therapy of asthenic disorders.
– What adverse events may be caused by Ladasten?
– This issue was studied as deep as well. According to Ladasten toxicity assessment, this drug is low toxic. It does not provide local irritative, allergizing, mutagenic or teratogenic properties. Furthermore, Ladasten does not have negative effect on reproductive function of rats, as well as growth and development of their offspring. Also, there were no effects potentially associated with abnormal addiction to the drug. Due to well-known pharmacokinetics, dosing regimen is based on half-life of Ladasten.
All the adverse events observed during clinical trials were possibly/probably related to Ladasten therapy. These mild events did not have significant influence on therapeutic efficacy.
Ladasten was synthesised and used in clinical practice according to all the essential requirements to preclinical and clinical studies.
– What clinical trials were conducted to study this drug?
– Asthenic states are associated with decreased working capacity, anxiety and immune disorders. Whereas Ladasten has a beneficial effect on all the asthenic manifestations, we describe this drug as an antiasthenic one. We performed number of clinical trials concerning efficacy and safety of Ladasten use for treatment of asthenic disorders. These studies entirely confirmed pharmacological data on antiasthenic properties of Ladasten.
Psychostimulant action of Ladasten was manifested in significant improvement or total recovery of decreased physical and mental activity in patients with various asthenic disorders. The drug is effective against somatogenic asthenia, as well as neurasthenia. Ladasten increases quality of life in patients with asthenic and asthenoneurotic disorders; also, it results in enhanced adaptive resources. Favorable tolerability range is 50-200 mg/day. That’s why, the medication may be used to treat various somatic diseases.