Peptide bioregulators and their application: from neonatology to gerontology

Peptides - what are they? These are parts of proteins consisting of amino acids connected in chains of different lengths. The size of the connection depends on the number of links. Science knows of peptides containing from 2 to 40 amino acids. They have different purposes and special uses in medicine.

All cells synthesize amino acids, which are then combined into peptide bonds. Peptides can also be formed as a result of exchange between interacting cells.

The uniqueness of the substances under consideration lies in their organ-specific characteristics - these compounds are individual for each organ, and can only be used purposefully. Thus, using pulmonary peptides to treat, for example, the heart is pointless. However, with consistently long courses of administration, it is possible to use amino acids formed as a result of the natural breakdown of specific stable compounds to form other necessary peptides. This explains why there are no overdoses with course doses, and stimulation of specific organs with biopeptides has a good effect on neighboring ones.

All known peptides are organic substances, even those produced by synthesis. Features of the technological production of peptides consist of two stages:

1. Obtaining amino acids;

2. Connecting them into stable chains.

Thus, the recently appeared term is quite justified - biopeptides, which include short peptides (they contain 2-8 amino acids and are obtained by synthesis).

As studies have shown, in “their” organs, peptides trigger restoration and rejuvenating processes that affect life expectancy and human health in general. The productive work of individual elements of any organ predetermines the high-quality functioning of the entire system. At the same time, malfunctions of cells lead to the development of tissue pathologies. In addition to the functions of ensuring organ renewal, scientists have established the important role of peptides in the formation of immune protection of cells from unfavorable external factors.

Such properties are manifested in the effective fight of peptides against the consequences of addictions, toxic and radioactive injuries, rehabilitation after various diseases - infectious, colds, immune and even nervous. By forming long peptide bonds, certain types of biopeptides independently fight pathogenic bacteria, being one of the factors in building the immune defense of the biosystem.

The beneficial effect of peptides on increasing the body’s resistance to adverse environmental factors was noticed by scientists at the beginning of the 20th century, which made it possible to consider the study of these substances of small molecular structure in the light of the development of research not only in the direction of increasing life expectancy, but also with the aim of increasing human adaptive qualities to the environment and to stimulate an increase in resource capacity for endurance.

Peptide bioregulators

Peptides - what are they?

Initially, peptides were isolated from animal organs. This technology has been developed for several decades and received its final design in the hands of St. Petersburg scientists. It was they who, in the 70s of the 20th century, began to obtain tissue-specific peptides capable of restoring cellular metabolism in certain organs and systems to an optimal level - precisely those from which they were isolated. Long-term observations subsequently made it possible to create special-purpose drugs—peptide bioregulators.

They are effective in restoring the protective functions of the body, which in the future provides enormous benefits in the treatment of a wide range of diseases, as well as for regenerating the working capabilities of a number of systems.

These drugs have long been used to restore the immune system at the cellular level, which is important for almost all diseases, including cancer. They are used to regulate the neuroendocrine system, stimulate the prostate gland, in the treatment of neurological diseases, bronchopulmonary and cardiovascular systems, organs of vision and systems responsible for cleansing the body, such as the kidneys and liver.

Diseases

Peptides - what are they? This is the building material of the cell. Their presence in free form in the intercellular and intracellular space provides opportunities for the constant presence of resources for renewal, division and restoration of cellular structures. For many years in developed countries, peptides have been used in the treatment of various diseases of a traumatic, infectious, age-related nature.

For example, every year more and more discoveries are made in the field of peptide research, making it possible to turn on organ renewal mechanisms, prolonging human life and its quality.

What is being treated with peptides now?

• rehabilitation after strokes and heart attacks;
• bronchopulmonary diseases - asthma, bronchitis, COPD, respiratory infections;
• nervous diseases associated with deep damage to the functions of the central peripheral nervous system;
• recovery from mechanical injuries;
• eye diseases associated with age-related pathologies;
• type 2 diabetes mellitus;
• cystitis, prostatitis;
• normalization of the male reproductive system, including reproductive function.

This is not a complete list. But it is sufficient to pay serious attention to the inclusion of peptides in systemic prevention and complex therapy, as irreplaceable nano-elements that stimulate tissue renewal.

How safe are peptides for humans?

Peptides - what kind of substances are they? These are organic compounds that are as close as possible to the human body at the cellular level:

• peptides do not have the ability to intoxicate the body if they accumulate excessively in systems that are targeted by therapy; they quickly decompose into amino acids and are used again by the body, or participate in new acts of synthesis;
• peptides are completely safe, as they are natural elements of the cell;
• peptides are effective in preventing the occurrence of diseases, neutralizing their causes;
• no side effects were identified during clinical trials, therefore peptide bioregulators can be used for absolutely all categories of patients;
• The main contraindications for the use of peptides may be individual intolerance and pregnancy, for which the effect has not been studied.

Practice and results of use

Peptides - what are they? These are drugs widely used in various branches of medicine.

• Clinical studies of regulatory peptides took place in the eighties of the 20th century in the practice of military doctors. An example of their successful use was the treatment of people injured as a result of the Chernobyl accident. The main identified effect is radioprotection, which allows them to be used for the prevention and treatment of radiation injuries.
• Separate studies of the effects of peptides on the body of employees of the Gazprom corporation (2009) made it possible to establish the high effectiveness of the drugs in the treatment and prevention of acute respiratory infections. In general, over the year, the incidence rate decreased by a record 2.3 times, while simultaneously improving the condition of patients with low levels of immunity. More than 9,000 people took part in the studies.
• Peptides were also used in studies conducted with a very eminent group of patients at the Kremlin Hospital. The excellent results achieved as a result of the treatment of a variety of diseases made it possible to resolve the issue of financing the production program under the auspices of the “Health of the Nation”.
• The use of regulatory peptides by athletes is a special topic. Few people know how effective regulatory peptides are in increasing the level of endurance of the body. But the excellent results of Russian sports teams in artistic gymnastics and figure skating give the right to recommend these drugs to all people with high physical and psycho-emotional stress. Moreover, peptides help protect the body from exhaustion caused by excessive loads of any nature.

Clinical pharmacology of Thymogen®. Chapter 1

Introduction

Chapter 1. Mechanisms of peptide regulation of homeostasis (V.V. Malinin, V.G. Morozov)

Chapter 2. Regulatory peptides of the thymus (V.S. Smirnov)

Chapter 3. Thymogen®: structure, chemical synthesis, properties (S.V. Kulikov, V.S. Smirnov)

Chapter 4. Thymogen® in the prevention and complex therapy of infectious diseases (V.S. Smirnov)

Chapter 5. Thymogen® in the treatment of bronchopulmonary diseases (V.S. Smirnov)

Chapter 6. Use of thymogen in complex therapy of internal diseases (V.S. Smirnov, A.E. Sosyukin)

Chapter 7. Thymogen® in dermatology (V.S. Smirnov)

Chapter 8. Use of Thymogen® for the prevention and treatment of radiation injuries (V.I.Legeza, V.S. Smirnov)

Chapter 9. Application of Thymogen® in the complex treatment of mechanical and thermal injuries (V.S. Smirnov)

Chapter 10. Thymogen® in obstetric and gynecological practice (G.V. Dolgov, V.S. Smirnov)

Chapter 11. Features of the use of Thymogen® in pediatrics (V.S. Smirnov)

Conclusion

Chapter 1. MECHANISMS OF PEPTIDE REGULATION OF HOMEOSTASIS

V.V. Malinin, V.G. Morozov

The mechanisms that regulate the constancy of the internal environment (homeostasis) are a complex set of neurohumoral processes that allow the body to maintain viability and stability in the environment. At the same time, the stability of the internal environment is closely related to the level of biological defense of the body.

According to modern concepts, the regulation of homeostasis in multicellular systems is carried out using neuroendocrine, immunological, cellular and molecular mechanisms. The role of nervous and hormonal influences on the processes that allow the body to control the constancy of the internal environment has been most studied (Gorizontov, 1981). The function of the immune system is considered as visceral, ensuring the preservation of the genetic constancy of the cellular composition, i.e. it is one of the homeostatic mechanisms of the whole organism (Korneva, 1993).

The nervous and endocrine systems are known to modulate immune system functions through neurotransmitters, neuropeptides, and hormones, and the immune system interacts with the neuroendocrine system through cytokines, immunopeptides, and other immunotransmitters. The role of endogenous peptides in the formation of compensatory and adaptive reactions of the body in response to stress and disturbances of homeostasis has now been established. The peptide system is considered to be universal in neuroimmunoendocrine interactions (Korneva and Shkhinek, 1988; Fabry et al., 1994).

Despite the multi-level hierarchy, all mechanisms regulating homeostasis perform a single task, namely, coordinating biosynthesis processes in cells by influencing gene expression. Previously, the concept of peptide regulation of homeostasis was developed, which makes it possible to explain some mechanisms of biological regulation (bioregulation) at the molecular and cellular level, and also opens the way for the development of new treatments for diseases (Morozov, Khavinson, 1981a, 1981b, 1983, 1996; Kuznik et al. ., 1998). According to this concept, any information entering the body is controlled by a system of peptide bioregulators called cytomedins. This term is usually used to designate low-molecular peptides of para- and autocrine nature that perform the functions of intra- and intercellular messengers. The action of this system is aimed at maintaining a high degree of stability of the functioning of the genome, managing homeostasis and the protective functions of the body. In this case, information about the state of the environment can induce certain changes in the system of peptide regulation of homeostasis, which are necessary for the regulation of processes that support optimal cell functioning.

It has been established that cytomedins are complexes of peptides of uncertain composition with a molecular weight of 1000-10000 Da. They, like regulatory peptides, participate in the transfer of information between groups of cells, regulate their activity and have a multifunctional effect in the body. Unlike regulatory peptides, cytomedins have a tissue-specific effect. The organotropy of cytomedins can be explained by a certain set of short peptides, the point of application of which is the cells that produce this type of cytomedins.

When studying the mechanism of action of cytomedins, it was found that these factors are directly involved in the processes of tissue-specific regulation of gene expression and biosynthesis. As a result, the rate of accumulation of pathological changes in cells (DNA damage, mutations, malignant transformation, etc.) decreases and the activity of reparative processes aimed at restoring cellular homeostasis increases.

Violation of cytomedine regulation reduces the resistance of cells and tissues of the body to destabilizing factors of both the external and internal environment. This may be one of the reasons for the development of diseases, involution of organs and tissues, as well as accelerated aging. Subsequent work confirmed that the peptidergic regulation system includes a wide range of tissue-specific peptides that maintain homeostasis (Ivanov et al., 1997; Karelin et al., 1998).

Currently, cytomedins have been isolated from almost all cells, tissues and biological fluids of the body. According to physicochemical studies, these peptide complexes differ from each other in composition, molecular weight and electrochemical properties of the components. A number of new drugs have been developed based on cytomedins. The use of these drugs in conditions of disturbed cellular homeostasis makes it possible to restore the functional activity of various physiological systems of the body (Morozov, Khavinson, 1996).

When assessing the role of peptides in the mechanisms of regulation of homeostasis, the importance of the concept of a regulatory peptide cascade should be emphasized (Ashmarin, Obukhova, 1986). According to this concept, after the exogenous administration of a peptide or its endogenous release, other peptides are released, for which the original peptide serves as an inducer. The next unique feature of peptide regulation of homeostasis is the processing of polypeptides, which allows, by activating peptidases, to form in the right place and at the right time the required number of short peptide fragments that have higher biological activity than the original compounds.

Intensive research of regulatory peptides over the past 2-3 decades has led to a radical revision of ideas about the mechanisms of regulation of physiological functions, the principles of coordination of homeostasis processes and adaptation of the body's functional systems to the environment.

It turned out that the presence of a whole molecule is not necessary to influence physiological processes. Moreover, in some cases, fragments consisting of only 3-4 amino acid residues were more effective than native compounds. These data served as a prerequisite for the formation of the idea that the regulation and coordination of body functions can be carried out through the processing of polypeptides, when, depending on the needs of the body, fragments are split off from sufficiently long polypeptide chains that have varying degrees of activity, specificity and direction of action on certain physiological systems. Processing regulation has a significantly greater degree of flexibility, allowing, in a short time, by activating the appropriate peptidases, to form the required regulators in the right place from a ready-made precursor. In addition, the processing mechanism contains a specific program for the sequence of switching on the regulators. The processing type of regulation is most characteristic of peptide compounds with a linear structure, which opens up wide possibilities for changing the conformation of the molecule upon elimination of at least one amino acid residue from any end. In addition, with such detachment, other properties of the molecule can significantly change, for example, the degree of its hydrophobicity, which determines the ability to pass through cell membranes and histohematic barriers, etc. (Eroshenko et al., 1991).

As is known, the vast majority of regulatory peptides have polyfunctionality. In other words, one compound provides regulation of various, often physiologically dissimilar functions. In this regard, many physiological functions are under the control of a number of regulatory peptides.

More and more evidence suggests that regulatory oligopeptides are involved in the processes of growth, development and regeneration. Many of them are well-studied structures that regulate various physiological functions of the body (Zamyatnin, 1988). It is assumed that at the level of oligopeptides there is a unified system of regulation of both embryonic development, growth and regeneration, and the functioning of the formed organism. Apparently, during the process of morphogenesis, most (if not all) functionally active oligopeptides take part in the emergence of new forms and structures during individual development. At the same time, the conventionality of dividing oligopeptides into neuro-, endocrine- or immunoactive and at the same time into morphogenetically active factors becomes obvious (Zamyatnin, 1992).

It is known that the interaction of a ligand with a receptor is realized on the basis of their structural correspondence (Govyrin, Zhorov, 1994). For an oligopeptide, this means the presence of a certain set of properties of the molecule, which, based on the application of the principles of system analysis and elements of information theory, was proposed to be called a signature (Chipens, 1980). Obviously, this concept also includes information about the amino acid sequence. As noted by G.I. Chipens, each peptide molecule has an infinite number of properties that are manifested and determined only in the process of interaction with other molecules as a result of intra- and intermolecular interactions under the conditions of a given environment.

The analysis of the primary structures of proteins and peptides was based on three principles of information theory - signatures, ambiguity and equivocation (Chipens, 1980; Quastler, 1965). According to the signature principle, the interaction and complex formation of molecules is determined by sets of properties (signatures) of the active regions of their electronic structures (signature carriers). Since a molecule can have multiple signatures, this leads to uncertainty about the biological effects that it can induce (the principle of ambiguous information theory). In certain situations, molecules with different chemical structures can have the same signatures and perform the same functions (the principle of equivocation, or the uncertainty of the cause of the effect). Based on the principles of signatures and equivocation, ideas about equifunctional, i.e. unidirectionally acting amino acid residues. Depending on the signature, amino acid residues of very different chemical structures can act unidirectionally (Chipens et al., 1990).

Thus, based on the concepts of signatures, as well as the principles of equivocation (several structures ® one signature ® one function) and ambiguity (one structure ® several signatures ® several functions), we can try to give a general description of the functional features of endogenous regulatory oligopeptides, which will help understand why structurally different molecules are able to cause close, almost identical reactions, or why one molecular structure is involved in different physiological processes? Obviously, based on the principle of ambiguity, the inconsistency of existing concepts and terms can be explained by the presence of several signatures in one oligopeptide molecule, which allows it to interact with several types of receptors.

The identification of two types of functionally significant groups—positively charged and cyclic (R+ and cyc)—allows us to consider one of the signature properties as the relative arrangement of these groups in the primary structure of the oligopeptide. Based on this, it is possible to imagine a significant number of structures containing the same arrangement of R+ and cyc radicals, while these radicals themselves in different molecules will belong to amino acid residues of different types. Well-known examples of this type among R+ radicals are the mutual substitutions of Arg and Lys residues in members of the same oligopeptide family. Moreover, numerous possible substitutions of other amino acid residues while maintaining the location of R+ and cyc can also lead to the same signature with a different primary structure. Examples include data comparing the primary structures of different oligopeptides or families obtained as a result of classification, including substitution of amino acid residues close in radicals in a quasi-conservative region. Apparently, this is where the principle of equivocation manifests itself (Zamyatnin, 1991).

The basis of the principle of ambiguity is the high conformational mobility of oligopeptides, as a result of which one molecule takes on different conformations (has several signatures), and this ensures spatial correspondence with receptors of various types.

Based on studies of the physicochemical characteristics of endogenous oligopeptides, it has been suggested that the spectrum of functional activity of these substances is mainly determined by two types of radicals that form the signature, and the composition of the radicals determines the polyfunctionality of the oligopeptides. At the same time, their unique distribution along the molecular chain (sequence) determines the specificity of action. These two types of radicals could, in principle, form the basis of a molecular physiological code. These findings can be used to predict the functional properties of oligopeptides based on structural considerations. In addition, the discovery of a limited number of functionally significant groups will apparently make it possible to narrow the search for new highly active compounds of a peptide nature (Zamyatnin, 1990).

A characteristic feature of regulatory oligopeptides was their low content of amino acid residues with negatively charged side radicals (Asp and Glu). At the same time, the content of residues with a positive charge is significantly higher only for Arg. The amino acid residues Pro, Phe, Tyr, Trp and Cys are quite common. Most of these molecules contain a cyclic chemical group (and Cys is usually involved in the formation of molecular macrocycles). From the above it follows that regulatory oligopeptides with a given spectrum of functional activity contain predominantly positively charged and cyclic radicals.

Comparison of amino acid sequences of peptide drugs isolated from various organs and tissues of mammals does not allow identifying homologous regions in them. If we compare the total amino acid composition, we can note the high content of amino acids with side amino and carboxyl groups, i.e., the high dipolarity of these macromolecules. It can be assumed that it is highly basic side groups, such as those of tuftsin, that ensure the selective interaction of these peptides with cell surface receptors, which, as a rule, contain carboxyl groups of glutamic, aspartic and sialic acids. In other words, the selective affinity interaction of regulatory peptides with the cell membrane is based on ion-ion and ion-dipole interactions of the peptide with the carboxyl groups of the membrane (Demin et al., 1994).

The intracellular target for endogenous biologically active peptides is probably a biochemical complex that carries out protein synthesis in the cell. The first experimental data have been obtained proving the feasibility of introducing the concept of essential amino acids as a metabolic feature of each organ (tissue). This suggests that changes in the intracellular concentration of these amino acids (their special combination in the form of di- and tripeptides) play an important role in the regulation of ribosomal protein synthesis. Speaking about the unique features of the metabolism of some organs, we mean the fact that some cells, for example, cardiomyocytes, synthesize new protein compounds mainly from amino acids, released only during the catabolism of their own proteins. From the incoming blood, cardiomyocytes utilize only two amino acids - Asp and Glu. This position suggests a solution to the issue of essential amino acids in the composition of peptides that are highly tropic for the myocardium (Kozhemyaki, 1992).

The problem of the biogenesis of regulatory oligopeptides from protein precursors near cellular receptors is fundamental for studying the mechanism of action of growth transforming factors, neuroactive peptides and proteins, protein hormones, etc.

As with most physiologically active substances, the effect of regulatory peptides is determined by interaction with specific receptors. Calculations show that in some cases the effects associated with peptides cannot be explained in terms of ligand-receptor interactions. Hence the assumption arose about their modulating influence, which boils down to a change in the characteristics of excitable cell membranes (receptors), facilitating the implementation of the effect of the main mediator (Gomazkov, 1992).

Regulatory peptides and enzymes associated with their function should be considered as a complex adaptive system of the body, organizing the implementation of adaptive reactions at all levels of its integration. Perhaps the diverse effects of one peptide are explained not by its direct action, but by modulation of the effects of nervous and humoral regulation.

Of particular interest is the study of endocytosis processes (and not only ligand-receptor complexes). Separate sections of the surface membranes of cells are continuously drawn inward and come off, forming intracellular vesicles containing substances that were in the external environment or were adsorbed on the cell surface. Therefore, we can assume the possibility of peptides and proteins entering cells without the presence of receptors specific to them on the cell surface.

Based on the biochemical universality of all cells, it can be assumed that the mechanisms of activation and inhibition of their activity are the same, despite differences in the structure and origin of bioregulators.

The results obtained indicate that short peptides, including those containing only polar amino acids, can exhibit pronounced specific biological activity, depending on the chemical structure of the compound. Moreover, this activity manifests itself in low concentrations, characteristic of natural regulatory peptides.

Data indicating the high biological activity of oligopeptides are in good agreement with their extremely low natural content, i.e., concentrations less than 10-5 M (Ashmarin, Obukhova, 1985). Based on the concept of the existence of a peptide continuum - the functional continuity of regulatory peptides - a change in the concentration of any peptide compound in the body can stimulate or inhibit the formation of other peptides. As a result, primary effects can develop over time in the form of chain or cascade effects. Apparently, the initial stages of cascade regulation begin with single molecules at concentrations less than 10-20 M (in accordance with Avogadro's number), which are not yet available for determination.

Recently, there has been an increasing interest among researchers in the paradoxical effects of ultra-low doses (10-18-10-14 M) of biologically active substances. These effects are observed for a variety of groups of substances - hormones and regulatory peptides, as well as some substances of a non-peptide nature.

The results of experiments with concentrations of substances of 10-19 M and below are quite contradictory, and the explanation of effects at concentrations below 10-19 M requires the use of such concepts as “activated” water, “memory of molecules” (Zamyatnin, 1992).

One of the features of the action of ultra-low doses of peptides is the presence of a distinct effect, despite the fact that in many cases the experimental object contains a significantly higher endogenous concentration of the same substance. It is assumed that the effects of ultra-low doses are associated with adaptation phenomena, since the cell can respond not to the value of the effective concentration, but to changes in the concentration of the substance in small and ultra-low doses (Sazanov, Zaitsev, 1992). Strengthening the signal is possible not only by changing the concentrations of secondary messengers, but also by activating the synthesis of proteins involved in signal transmission (Reibman et al., 1991). It is assumed that to achieve an effect, it is enough that the “fastest” molecules of the active substance from the general distribution reach the cells, and not all molecules (Burlakova et al., 1990).

There are several main systems necessary to realize the effects of ultra-low concentrations (doses) of endogenous and exogenous substances: a) cascade systems that amplify the signal; b) collecting, “catching” systems; c) storage devices and transporters of signal molecules; d) superaffinity receptors (Ashmarin et al., 1996).

The physico-chemical basis of the phenomenon of the body’s high sensitivity to so-called low-intensity factors, including ultra-low doses of biologically active substances, consists of the processes of vibration of biomolecules, the transition of one type of energy to another, resonance interaction effects and some other mechanisms. At the same time, from a cybernetic point of view, it is possible to transfer a complex system to a different level of response (for example, exiting a pathological state) through information influences on it, which are basically in the nature of weak signals (Podkolzin et al., 1994).

As noted, peptide regulation communicates between the nervous, endocrine, immune and, apparently, other systems involved in maintaining homeostasis. The polyfunctionality of peptides and the cascade mechanism for the implementation of biological effects determine the processes that occur in the body both after the exogenous administration of the peptide and after its endogenous formation.

One example of peptide regulation of cell functions is thymomimetic regulation (Morozov et al., 2000). The proposed concept is based on ideas about the role of peptides with thymomimetic properties in the regulation of the processes of proliferation and differentiation of T-lymphocytes. The thymus is the central organ in whose cells peptide thymomimetics are formed. However, under certain conditions, such peptides can be produced by other cells during processing, which allows the body to carry out thymomimetic regulation in various tissues, regardless of the thymus. The thymus, possibly with the help of peptides produced by its cells, has a regulatory effect on the proteolytic processes occurring in the cells of the body. At the same time, in different tissues, depending on conditions, the rate of formation of peptides with immunomodulatory and, in particular, thymomimetic properties can change. It is likely that under stress (damage), the redistribution of T-lymphocytes in tissues, as well as the rate of subsequent restoration of the structure and function of damaged tissues, are associated with the intensity of the formation of peptide thymomimetics.

Thus, peptide bioregulation is a new scientific direction associated with the study of molecular and cellular mechanisms that control homeostasis, the development of methods and means for restoring the physiological functions of the body in order to prevent and treat diseases. Further development of this direction will make it possible to take a new approach to the study of the functions of the body in health and disease, as well as to explain the mechanisms of regulation of homeostasis at the level of cells and macromolecules.

Introduction

Chapter 1. Mechanisms of peptide regulation of homeostasis (V.V. Malinin, V.G. Morozov)

Chapter 2. Regulatory peptides of the thymus (V.S. Smirnov)

Chapter 3. Thymogen®: structure, chemical synthesis, properties (S.V. Kulikov, V.S. Smirnov)

Chapter 4. Thymogen® in the prevention and complex therapy of infectious diseases (V.S. Smirnov)

Chapter 5. Thymogen® in the treatment of bronchopulmonary diseases (V.S. Smirnov)

Chapter 6. Use of thymogen in complex therapy of internal diseases (V.S. Smirnov, A.E. Sosyukin)

Chapter 7. Thymogen® in dermatology (V.S. Smirnov)

Chapter 8. Use of Thymogen® for the prevention and treatment of radiation injuries (V.I.Legeza, V.S. Smirnov)

Chapter 9. Application of Thymogen® in the complex treatment of mechanical and thermal injuries (V.S. Smirnov)

Chapter 10. Thymogen® in obstetric and gynecological practice (G.V. Dolgov, V.S. Smirnov)

Chapter 11. Features of the use of Thymogen® in pediatrics (V.S. Smirnov)

Conclusion

What exactly are peptides useful for?

Among the substances necessary for the body, stable chains of amino acids play a special role. After all, they are building materials for cells, and renewal processes in the body occur constantly. Due to the wear and tear of a number of organs, which is largely due to the fault of technogenic human activity that disrupts and rapidly changes the environment, the synthesis of amino acids and their combination into chains seriously slows down with age. What are these peptides? These are those compounds that are obtained by combining amino acids by joining them to each other.

Old age comes gradually - by reducing the activity of individual organs in the production of material that renews them. This is so noticeable that it even manifests itself in the form of changes in the skin - they wrinkle, sag, lose elasticity, become dry and lifeless. We cannot see what is happening to our organs at this time, and we do not have the opportunity to compare the heart of a 20-year-old boy and a 40-year-old man. But there are differences and they are very significant.

Old age spares no one. And it can especially affect people who are exposed to stress, whose lives involve heavy physical exertion, or who live and work in difficult climatic and environmental conditions. This is the answer to the question why athletes do not live long. They simply wear out their body prematurely.

This does not mean that sport is harmful. This means that when doing it, you need to be especially careful about nutrition issues. It must include all the elements necessary for the full passage of intracellular reactions. As a rule, even people belonging to the elite parts of bourgeois societies do not have ideal nutrition. Although the representatives of this environment have it much better than any other ordinary person.

Unlike vitamins, coenzymes, and other organic and inorganic elements that supply the body with reagents that improve the passage of biochemical reactions, peptides are ready-made parts of cells. They themselves are food.

Semax

(Semax, CAS 80714-61-0) belongs to the group of neuropeptides and is used as a nootropic drug. The molecule of this peptide includes seven amino acid residues: Met-Glu-His-Phe-Pro-Gly-Pro (MEHFPGP), which is reflected in the name - from the abbreviation. "seven amino acids"

The drug Semax was developed and obtained by Russian scientists under the leadership of academician. I.P. Ashmarin (Institute of Molecular Genetics of the Russian Academy of Sciences, formerly the Research Institute of Molecular Genetics of the USSR Academy of Sciences) [3]. Research on the drug has been conducted since 1982 for more than ten years. In the 1980s–90s. preclinical experiments on animals were carried out many times; in 1990–1994 – phase I clinical trials and in 1994–1996. – phase II, and then the peptide entered medical practice [4]. On the territory of the Russian Federation, Semax in the form of nasal drops is registered as a medicinal product belonging to the pharmacotherapeutic group of nootropic drugs, according to the anatomical therapeutic chemical classification - “other psychostimulants and nootropic drugs” (code N06BX), and is included in the “Vital and Essential Medicines” drugs" [5]. Semax is prescribed as part of complex therapy in the acute period of moderate and severe ischemic stroke [6]. In addition, Semax is prescribed by practicing doctors for the treatment of hereditary degenerative diseases (Parkinson's disease, Alzheimer's disease, Huntington's chorea) and chronic cerebral circulatory failure caused by cerebral atherosclerosis [7].

Semax (30 mg)

Semax is characterized by a unique mechanism of neurospecific effects on the central nervous system. However, its exact description is still not given, although some evidence is known that Semax acts on melanocortin receptors. Thus, it was reported that the peptide acts as an antagonist of α-melanocyte-stimulating hormone (α-MSH) in relation to melanocortin receptors MC4 and MC5 [8-10]. The drug affects the activation and expression of brain-derived neurotrophic factor (BDNF), which promotes neuronal development, and trkB, a receptor that increases the survival of neurons [11].

Semax in its structure is a synthetic analogue of corticotropin, which has antihypoxic, antioxidant, neuroprotective and psychostimulating effects, but, unlike natural closely related compounds, does not exhibit hormonal activity [12]. Semax shows virtually no toxicity in various regimens of use, and has an effect similar in effectiveness to piracetam (nootropil) when used in a dose ~6 thousand times less than the latter [7]. Let us note that the term “nootropics” (Greek nους – mind + τροπή – desire, affinity) or “smart drugs” (English: “smart medicines”) is usually used to designate a variety of drugs that act on cognitive functions and correct cognitive disorders [13].

Semax peptide is a synthetic analogue of a fragment of adrenocorticotropic hormone, namely the ACTH4-10 fragment. In humans and rodents, ACTH stimulates cognitive functions [11] and controls the production of glucocorticoids, adrenal hormones - cortisone, cortisol, corticosterone, regulates the level of androgens, estrogens, progesterone [14]. The bioavailability of Semax is high, especially when administered intranasally - it penetrates the blood-brain barrier (GERD) in four minutes, and the effects last for about a day with a single dose of 15-50 mcg/kg: cerebral circulation, attention and short-term memory improve, resistance to hypoxia increases) [11, 15, 16]. This is explained by the gradual degradation of the peptide, since the half-life products retain biological activity; a significant part of the biological effects of the drug is retained in its degradation products. The longest-living tripeptide is Pro-Gly-Pro, which is especially resistant to proteolysis [15]. Thus, Semax can be considered as a stabilized peptide ACTH4-7 + Pro-Gly-Pro.

Currently, research into the biological activity and new possible applications of Semax continues. The drug became the basis for the development of a series of analogues. One of these drugs was Selank (Selank, CAS 129954-34-3),

Tuftsin, Selank and analogues. Immunity, anti-stress, libido

nootropic peptide Thr-Lys-Pro-Arg-Pro-Gly-Pro, developed under the guidance of academician. N.F. Myasoedov at the Institute of Molecular Genetics of the Russian Academy of Sciences [17], but is a synthetically modified short fragment of the heavy chain of immunoglobulin IgG, extended and stabilized, like Semax, by introducing the Pro-Gly-Pro sequence. In addition, Semax derivatives, for example, Acetyl Semax, are in the early stages of research [18].

Semax and its analogues. N-Acetyl-Semax and Semax-Amide

Youth elixir

Biopeptides are a real storehouse of health and youth. If the body stops producing them, it begins to gradually shut down the organs and death occurs. It turns out that even people leading an absolutely healthy lifestyle are not immune from early death caused by age-related diseases.

Today, diseases that signal the onset of old age include: cardiovascular diseases, disorders of the endocrine system, decreased production of certain functional hormones, type 2 diabetes mellitus, pulmonary diseases caused by long-term intoxication by bad habits and poor working conditions.

And all these diseases are not a death sentence if organs that are beginning to “give up” are “fed.” Any health problems make themselves felt first as temporary, then frequent, and then permanent ailments.

People over 40 know this from the example of age-related changes in the skin or a gradual decrease in vision sharpness.

But what prevents, if not preventing such symptoms, then at least slowing down the aging process, thereby prolonging life and delaying or postponing “age-related” diseases indefinitely?

Biopeptides are a real elixir of youth and longevity, which is available to everyone and can be taken as simply and easily as vitamins and other biological supplements.

The whole truth about hormone replacement therapy

Murzaeva Irina Yurievna

Endocrinologist, Preventive Medicine Doctor

September 28, 2014

I take the liberty to describe the benefits and fears of prescribing hormone replacement therapy (HRT). I assure you - it will be interesting!

Menopause, according to modern science, is not health, it is a disease. Its characteristic specific manifestations are vasomotor instability (hot flashes), psychological and psychosomatic disorders (depression, anxiety, etc.), urogenital symptoms - dry mucous membranes, painful urination and nocturia - “night trips to the toilet”. Long-term effects: CVD (cardiovascular disease), osteoporosis (low bone density and fractures), osteoarthritis and Alzheimer's disease (dementia). As well as diabetes and obesity.

HRT in women is more complex and multifaceted than in men. If a man needs only testosterone for replacement, then a woman needs estrogens, progesterone, testosterone, and sometimes thyroxine.

HRT uses smaller doses of hormones than hormonal contraceptives. HRT drugs do not have contraceptive properties.

All the materials below are based on the results of a large-scale clinical study of HRT in women: Womens Health Initiative (WHI) and published in 2012 in the consensus on hormone replacement therapy of the Research Institute of Obstetrics and Gynecology. IN AND. Kulakova (Moscow).

So, the main postulates of HRT.

1. You can start taking HRT for another 10 years after the cessation of your menstrual cycle (taking into account contraindications!). This period is called the “window of therapeutic opportunity.” Over 60 years of age, HRT is not usually prescribed. How long is HRT prescribed? – “As much as needed” To do this, in each specific case, you need to decide on the purpose of using HRT in order to determine the timing of HRT. The maximum period for using HRT: “last day of life – last pill.”
2. The main indications for HRT are vasomotor symptoms of menopause (these are menopausal manifestations: hot flashes), and urogenital disorders (dyspariunia - discomfort during sexual intercourse, dry mucous membranes, discomfort during urination, etc.)
3. With the right choice of HRT, there is no evidence of an increase in the incidence of breast and pelvic cancer ; the risk may increase with a duration of therapy of more than 15 years! HRT can also be used after treatment of stage 1 endometrial cancer, melanoma, and ovarian cystadenomas.
4. When the uterus is removed (surgical menopause), HRT is given as estrogen monotherapy.
5. When HRT is started on time, the risk of cardiovascular diseases and metabolic disorders is reduced. That is, during hormone replacement therapy, normal metabolism of fats (and carbohydrates) is maintained, and this prevents the development of atherosclerosis and diabetes mellitus, since the deficiency of sex hormones in postmenopause aggravates existing ones and sometimes provokes the onset of metabolic disorders.
6. The risk of thrombosis increases when using HRT with a BMI (body mass index) = more than 25, that is, if you are overweight!!! Conclusion: excess weight is always harmful.
7. The risk of thrombosis is higher in women who smoke. (especially when smoking more than 1/2 packs per day).
8. It is advisable to use metabolically neutral gestagens in HRT (this information is more for doctors)
9. Transdermal forms (external, that is, gels) are preferable for HRT ; they exist in Russia!
10. Psycho-emotional disorders often prevail in menopause (which does not allow one to discern a psychogenic disease behind their “mask”). Therefore, HRT can be given for 1 month for trial therapy for the purpose of differential diagnosis with psychogenic diseases (endogenous depression, etc.).
11. In the presence of untreated arterial hypertension, HRT is possible only after stabilization of blood pressure.
12. Prescription of HRT is possible only after normalization of hypertriglyceridemia** (triglycerides are the second, after cholesterol, “harmful” fats that trigger the process of atherosclerosis. But transdermal (in the form of gels) HRT is possible against the background of elevated triglyceride levels).
13. In 5% of women, menopausal symptoms persist for 25 years after the cessation of the menstrual cycle. HRT is especially important for them to maintain normal well-being.
14. HRT is not a method of treating osteoporosis, it is a method of prevention (it should be noted that it is a cheaper method of prevention than the cost of treating osteoporosis itself).
15. Weight gain often accompanies menopause , sometimes an additional + 25 kg or more, this is caused by a deficiency of sex hormones and related disorders (insulin resistance, impaired carbohydrate tolerance, decreased insulin production by the pancreas, increased production of cholesterol and triglycerides by the liver). This is collectively called menopausal metabolic syndrome. Timely prescribed HRT is a way to prevent menopausal metabolic syndrome (provided that it did not exist before, before menopause!)
16. Based on the type of menopausal symptoms, it is possible to determine which hormones a woman lacks in her body, even before taking blood for a hormonal analysis. According to these signs, menopausal disorders in women are divided into 3 types: a) type 1 - only estrogen deficiency: weight is stable, no abdominal obesity (at the abdominal level), no decreased libido, no depression and urinary disorders and decreased muscle mass, but there is menopausal hot flashes, dry mucous membranes (+dysparium), and asymptomatic osteoporosis; b) type 2 (only androgen-deficient, depressive) if a woman has a sharp increase in weight in the abdominal area - abdominal obesity, increasing weakness and loss of muscle mass, nocturia - “night urge to go to the toilet”, sexual disorders, depression, but no hot flashes and osteoporosis according to densitometry (this is an isolated lack of “male” hormones); c) type 3, mixed, estrogen-androgen deficiency: if all the previously listed disorders are expressed - hot flashes and urogenital disorders are pronounced (dysparunia, dry mucous membranes, etc.), a sharp increase in weight, loss of muscle mass, depression, weakness - then there is not enough both estrogen and testosterone, both of which are required for HRT. It cannot be said that any of these types is more favorable than the other. **Classification based on materials from Apetov S.S.
17. The question of the possible use of HRT in the complex treatment of stress urinary incontinence in menopause should be decided individually.
18. HRT is used to prevent cartilage degradation and, in some cases, to treat osteoarthritis. An increase in the incidence of osteoarthritis with multiple joint lesions in women after menopause indicates the involvement of female sex hormones in maintaining the homeostasis of articular cartilage and intervertebral discs.
19. Estrogen therapy has been shown to be beneficial for cognitive function (memory and attention).
20. Treatment with HRT prevents the development of depression and anxiety , which often occurs with menopause in women predisposed to it (but the effect of this therapy occurs provided that HRT therapy is started in the first years of menopause, or better yet, premenopause).
21. I no longer write about the benefits of HRT for a woman’s sexual function, aesthetic (cosmetological) aspects - prevention of “sagging” of the skin of the face and neck, prevention of worsening wrinkles, gray hair, tooth loss (from periodontal disease), etc.

Contraindications to HRT:

Main 3:

1. History of breast cancer, current or suspected; If there is a hereditary history of breast cancer, a woman needs to undergo a genetic test for the gene for this cancer! And if the risk of cancer is high, HRT is no longer discussed.
2. History or current history of venous thromboembolism (deep vein thrombosis, pulmonary embolism) and current or history of arterial thromboembolic disease (eg, angina pectoris, myocardial infarction, stroke).
3. Liver diseases in the acute stage.

Additional:

• estrogen-dependent malignant tumors, for example, endometrial cancer or if this pathology is suspected;
• bleeding from the genital tract of unknown etiology;
• untreated endometrial hyperplasia;
• uncompensated arterial hypertension;
• allergy to active substances or to any of the components of the drug;
• cutaneous porphyria;
• dysregulated type 2 diabetes mellitus

Examinations before prescribing HRT:

• Taking an anamnesis (to identify risk factors for HRT): examination, height, weight, BMI, abdominal circumference, blood pressure.
• Gynecological examination, collection of smears for oncocytology, ultrasound of the pelvic organs.
• Mammography
• Lipidogram, blood sugar, or sugar curve with 75 g of glucose, insulin with calculation of the HOMA index
• Additionally (optional):
• analysis for FSH, estradiol, TSH, prolactin, total testosterone, 25-OH-vitamin D, ALT, AST, creatinine, coagulogram, CA-125
• Densitometry (for osteoporosis), ECG.
• Individually – Doppler ultrasound of veins and arteries

About the drugs used in HRT.

In women 42-52 years old with a combination of regular cycles with cycle delays (as a phenomenon of premenopause), who need contraception, who do not smoke!!!, you can use contraception instead of HRT - Jess, Logest, Lindinet, Mercilon or Regulon / or use an intrauterine system — Mirena (in the absence of contraindications).

Then they switch to HRT in a cyclic mode (with menstrual bleeding), and when the cycle stops, they switch to a continuous regimen of therapy.

Cutaneous etrogens (gels):

Divigel 0.5 and 1 g 0.1%, Estrogel

Combined E/G drugs for cyclic therapy: Femoston 2/10, 1/10, Climinorm, Divina, Trisequence

Combined E/G preparations for continuous use: Femoston 1/2.5 conti, Femoston 1/5, Angelique, Klmodien, Indivina, Pauzogest, Klimara, Proginova, Pauzogest, Ovestin

Tibolone

Gestagens: Duphaston, Utrozhestan

Androgens: Androgel, Omnadren-250

Alternative treatments include

herbal preparations: phytoestrogens and phytohormones. Data on the long-term safety and effectiveness of this therapy are insufficient.

In some cases, a one-time combination of hormonal HRT and phytoestrogens is possible. (for example, with insufficient relief of hot flashes by one type of HRT).

Women receiving HRT should visit their doctor at least once a year. The first visit is scheduled 3 months after the start of HRT. The doctor will prescribe the necessary examinations for monitoring HRT, taking into account the characteristics of your health!

Important! Message from the site administration about questions on the blog:

Dear readers! By creating this blog, we set ourselves the goal of giving people information on endocrine problems, diagnostic methods and treatment. And also on related issues: nutrition, physical activity, lifestyle. Its main function is educational.

Within the framework of the blog, in answering questions, we cannot provide full-fledged medical consultations; this is due to both the lack of information about the patient and the doctor’s time spent in order to study each case. Only general answers are possible in the blog. But we understand that not everywhere it is possible to consult with an endocrinologist at your place of residence; sometimes it is important to get another medical opinion. For such situations, when a deeper dive and study of medical documents is needed, at our center we have a format for paid correspondence consultations on medical documentation.

How to do it? Our center’s price list includes a correspondence consultation on medical documentation, costing 1,200 rubles. you can send scans of medical documents, a video recording, a detailed description, everything that you consider necessary regarding your problem and questions to which you want answers. The doctor will see if the information provided can give a full conclusion and recommendations. If yes, we will send the details, you will pay, and the doctor will send a report. If, based on the documents provided, it is impossible to give an answer that could be considered as a doctor’s consultation, we will send a letter stating that in this case, absentee recommendations or conclusions are impossible, and, of course, we will not take payment.

Sincerely, Administration of the Medical

Biopeptides - effect

When used in the complex therapy of senile diseases, biopeptides or short peptides, in addition to the targeted renewal of the organ affected by pathological changes, create the following effects:

• breaking down into amino acids, in case of an exceeded dose, they form new peptides necessary for other organs;
• stimulate self-healing processes of organs and systems;
• increase immunity;
• promote weight loss and decrease appetite, as they are structural units of the protein synthesis process;
• reduce blood pressure by dissolving cholesterol plaques and improving vascular elasticity;
• normalize all metabolic processes - both at the level of organs and tissues, and at the cellular level.

How to live long

The popular theory that 80% of the human body’s resource depends on hereditary factors has long been shattered by scientific research. The 21st century has become the first in which life expectancy is steadily increasing, especially in highly developed countries that have provided great opportunities for this.

What factors influence life expectancy?

1. Diagnosis of age-related diseases as early as possible.
2. Availability of effective therapeutic methods available to the population.
3. Nutritious and healthy nutrition.
4. High environmental safety indicators of residential areas.
5. Lack of stress caused by the uncertainty of life - lack of work, comfort and personal life, security of life.
6. Consumption of replacement elements necessary for the body.

Peptides

What are peptides?

Peptides are short chains of amino acids that are building materials for the human body. Peptides trigger gene expression and also give the body an accentuated signal to restore a specific organ.
Peptides are chains containing from two to one hundred amino acids. These amino acids have not yet reached the same size as protein, which is much larger in composition. Peptides can be short (up to 10 amino acids) or long (more than 10). They carry both construction and signaling functions. They can be integrated into the functioning of organs, or they can trigger gene expression and give instructions to intracellular DNA so that it synthesizes this or that protein.

Our genes are the recipe for all the proteins in the body; they are assembled inside the cell by reading information from the cell’s RNA.

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How do peptides work?

Peptides , when entering the body, give a signal that it is necessary to begin the process of restoration of a particular organ. For example, vascular peptides , if given to a patient in tablet form, will enter the bloodstream and provide signal information for the body to restore the vascular wall. In the same way, peptides activate the restoration of certain organs.

Khavinson peptides

What is special about Khavinson peptides and why are they the most popular?

Khavinson was the first to analyze peptide preparations for specific organs and systems, after which he launched the production of peptides using his patented technology. The peculiarity of Khavinson peptides is that they are short and consist of two to five amino acids. But at the same time they do not affect the function of the organ, i.e. not on a separate biochemical part, but affect the entire organ and its structure.

Peptide complexes

What is it and what is it for?

Peptide complexes affect various groups of organs in the body. They were developed because most often it is not just one organ that hurts, but there is damage to a number of organs (stomach, pancreas, gall bladder). There is multiple organ damage, so peptide complexes include several drugs at the same time in order to recover faster. Let's talk in more detail about what they are:

Vascular peptides

Vascular peptides restore vascular endothelium. They are used for circulatory disorders, for inflammatory vascular diseases, including can be used in rehabilitation after coronavirus infection and for diabetic polyneuropathy. Their task is to restore the vessel wall. They can also be prescribed for difficult-to-heal wounds of the extremities, during postoperative processes. Can be used to strengthen blood vessels in the post-infarction and post-stroke period.

Pineal Peptides

The peculiarity of the pineal gland is that it synthesizes melatonin. Melatonin is the father of all neurohormones; without melatonin, everything else in the body is poorly synthesized. Therefore, by increasing the synthesis of melatonin, we can achieve a good anti-aging effect. This is the only peptide that has been studied in gerontological terms. Based on Khavinson's research, systemic repair of the pineal gland can prolong a person's life by about 35%.

Thymus peptides

The thymus is the thymus gland, i.e. immune organ. In the modern health paradigm, it ranks second after the intestines. By restoring the functions of the thymus with the help of peptide drugs , we increase the immune status of a person. For secondary immunodeficiencies, this will be a very effective drug that has no analogues. Natural immune stimulation helps for people who are often sick.

Peptides for men and women.

With the help of peptide drugs you can directly influence male libido. Peptide therapy increases testosterone synthesis and improves potency and desire. Most often, Khavinson peptide complexes are used for these purposes. In some cases, synthetic American drugs are used for intravenous injections and invasive administration.

There are also peptides for women , which are aimed at normalizing all functions of the reproductive system, they normalize the cycle, increase libido and fertility. There are peptides that can be used during menopause to help you recover faster after menopause.

Peptide therapy at the Medintercom clinic

Peptide therapy can be administered in several ways: intravenous injections, infusion therapy and oral administration. At the Medintercom clinic we use all options, depending on the needs and condition of the patient.

For IV drips , we use synthetic peptides, since they are sterile and start working faster (turn on faster), unlike organic ones, but they have a shorter period of action.

Organic peptides (tablets) are more “dirty”, which is why they cannot be injected into IVs. They take longer to turn on, but have a longer period of action.

Therefore, it is better to start therapy with synthetic peptides, and only after that undergo therapy in tablet form. You can also combine droppers with peptides and oral administration to achieve the best effect.

peptide therapy program is selected individually and based on the patient’s requests and general medical history.

Indications and contraindications

There are no contraindications, only allergies to substances (cellulose, lactose). There can be no overdose. Any excess you gain will be broken down into amino acids by your body and used to build another protein.

Are peptides addictive?

Not addictive. Peptides are proteins and are completely natural.

Are peptides hormones?

Khavinson's peptides are not hormones. American long-chain peptides are also not full-fledged hormones. They may be a fragment of growth hormone. They may speed up fat metabolism, but they won't speed up bone growth.

Are peptides doping?

Yes, they are doping. Some peptides are officially prohibited for use in professional athletes. Many international peptides are prohibited. Khavinson's peptides are not doping.

What can you combine peptides with?

The course of peptide therapy is prescribed by the chief physician of the Medintercom clinic, Gleb Gennadievich Kuzminov, during a consultation. During the initial appointment, the doctor will collect an anamnesis and conduct an examination, and, based on the patient’s anamnesis and tests, recommend a specific treatment and diet plan. Depending on the general condition of the patient, peptides can be used in parallel with courses of hydrogen therapy, infusion therapy and MDM therapy . They are added to some IVs and are easily combined with vitamins. The more comprehensive the approach, the faster we will achieve clinical results.

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Substitution elements

It is impossible to prevent old age, but it is quite possible to delay it. And this will be helped by substances, the synthesis of which in the body decreases with age, but which can be artificially “infused.” Such a brilliant idea was proposed back in the mid-twentieth century by research scientists in industries responsible for improving the quality of life and increasing its duration.

Add to your diet what the body needs and what it does not produce on its own.

What do they add?

• hormones;
• coenzymes;
• peptides;
• vitamins.

There are quite a few substances that are not produced by the body on its own, but are extremely necessary for the quality of metabolic processes. This includes vitamins.

But vitamins are compounds with large molecules and when they enter the esophagus they are used as catalyzers or, when broken down, form smaller substances - enzymes involved in cell metabolism.

Peptides are synthesized strictly by organic structures. They can be produced by synthesis outside the body, but their biological origin is organic. Peptides are extremely necessary. Their presence in cells stimulates the processes of renewal and restoration, without which cells become damaged, age, lack reproductive functions and are subject to slow death.

Meanwhile, by adding peptides to a regular diet, a person can extend the resources of his body.

Material and methods

The study included 498 people (498 eyes) with POAG. All patients were randomly divided into three groups, comparable by age, gender and general somatic status. Each group included approximately equal numbers of patients with initial (I), advanced (II) and advanced (III) stages of the disease (Table 1) . Retinalamine (manufactured in the Russian Federation) was used as a neuroprotective drug.

Table 1. Distribution of patients by stages of POAG
According to the developers of the drug, the mechanism of the neuroprotective effect of retinalamine is based on the regulation of intracellular protein synthesis in retinal cells, preservation of the pigment epithelium, activation of reparative processes and functional interaction of cells, correction of metabolism, prevention of oxidative stress and excitotoxicity; preventing cell death (apoptosis). Specific actions of retinalamine: stimulation of photoreceptors and cellular elements of the retina, improvement of the functional interaction of the pigment epithelium and outer segments of photoreceptors, acceleration of the restoration of light sensitivity of the retina, stimulation of reparative processes in the retina.

Recommended methods of administration: parabulbar (performed by an ophthalmologist), intramuscularly. The contents of the bottle (5 mg) are dissolved in 0.5-1 ml of water for injection, isotonic sodium chloride solution or 0.5% novocaine solution and administered daily for 10 days.

The criteria for inclusion of patients in the study were stable normalization of IOP levels achieved through medication or surgery, the absence of macular pathology, and refractive errors of no more than 3 diopters. The difference between the groups was only in the method of drug administration. The distribution of patients according to this criterion is presented in Table. 2 .
Table 2 Distribution of patients into groups depending on the method of drug administration.
The total dose of the drug per course was 50 mg. Before treatment, all patients underwent visometry with optimal correction of ametropia and tonometry (according to Maklakov, weight 10 g). The state of visual functions was assessed using computer perimetry data. Static perimetry was performed using a Humphrey Visual Field Analyzer II (HFA II) 750i (Germany). Depending on the initial visual acuity and the degree of visual impairment, a screening or threshold research program was used. When assessing the central visual field, all patients underwent correction of near visual acuity. Screening was carried out according to the FF-120 Screening program using a three-zone strategy. The threshold program for studying the visual field included the use of tests Central 30-2 when studying the central visual field (within 30° from the point of fixation of the gaze) and Peripheral 60-4 when assessing the peripheral visual field (from 30 to 60°). At the same time, we analyzed the threshold foveal photosensitivity, the sum of decibels (dB) of threshold values ​​in each quadrant, across the entire field of view, the indicators of mean deviation (MD) and pattern standard deviation (PSD), calculated automatically by the device taking into account its own database data. In addition, contrast sensitivity (on-off activity of the cone system) was studied. Parameters were monitored 3 and 6 months after the course of neuroprotective therapy. These terms were the most informative for assessing the results and their sustainability.

The future of peptides

The excellent ability of short peptides to penetrate cell walls, due to their extremely small size, has made them particularly effective in a number of medical fields. But cosmetologists were the first to notice their valuable qualities and rapid inclusion in rejuvenation processes. A number of modern treatments use peptides in skin care. Unlike all known procedures, peptide procedures do not just improve the condition of the skin, they restore its youth by launching self-renewal mechanisms.

It is important to understand that the use of peptides in cosmetics and procedures is not enough and not as necessary as using them to renew the body as a whole. After all, you cannot look young if you have sick and aging internal systems. No matter how beautiful the face looks, the gait, manners, posture and general condition will reveal an old man in a person.

Scientists have proven that the most effective peptide effect on the body is oral therapy. This means that after the age of forty, a person simply needs complex peptide bioregulation to maintain himself in good shape.

In the first decade of the new century, a group of scientists from the University of Zurich published an article entitled “Treatment of acute pancreatitis from the perspective of evidence-based medicine. A look at the established paradigm" [1]. It analyzed data obtained by various scientific groups in a large number of clinical trials, carried out in accordance with the rules adopted in evidence-based medicine, on the results of treatment of pancreatitis. An assessment of the effectiveness of the most commonly used drugs for the treatment of acute pancreatitis (AP) was presented: gabexylate mesylate, lexipafant, aprotinin (contrical, trasylol), octreotide (somatostatin analogue). The findings of the meta-analyses turned out to be quite unexpected: none of these drugs can be regarded as an effective medicine for the treatment of pancreatitis due to their insufficiently proven effectiveness.

The findings of this work forced scientists to reconsider the importance of antisecretory and antiprotease drugs in the treatment of AP. And if in the countries of Western Europe and the USA they have practically abandoned the use of these drugs, in Russia they are still often prescribed by doctors to relieve the symptoms of O.P. Probably the most commonly prescribed of these agents is sandostatin (octreotide). Octreotide (OC) is a synthetic analogue of the octapeptide somatostatin (SS). SS was isolated from the sheep hypothalamus in 1973. Somewhat later, it was identified in the central nervous system and peripheral nervous system (NS), localized in D-cells of the autonomous NS of the pancreas (PG), in the stomach and duodenum. Two molecular forms of natural SS have been identified: S-14 and S-28. The first form is interpreted as a neuropeptide, the second as a circulating hormone. SS inhibits the release, but not the synthesis, of growth hormone. In the gastrointestinal tract (GIT), it inhibits the secretion of most intestinal hormones, along with this it significantly inhibits gastric secretion, the secretion of pancreatic enzymes and bicarbonates, and reduces blood flow in the abdominal organs [2, 3].

In 1982, the Swiss created a long-acting synthetic analogue of SS, which was called sandostatin (OK). This medicinal compound retained numerous effects of CC, mainly of an inhibitory nature regarding hormones of the digestive system, gastric and digestive secretions. The mechanism of action of OCs is based on inhibition of adenylate cyclase and a subsequent decrease in cAMP in the cell. The inhibitory effect of OC on gastric G-cells led to inhibition of the production of the hormone gastrin, which affected the insufficient production of pepsin and hydrochloric acid secretion. A decrease in the concentration of another hormone (motilin) ​​led to a decrease in the motor activity of the gastrointestinal tract.

In the 80-90s of the 20th century, one of the leading factors in the development of AP was considered to be the activation of pancreatic enzymes, ultimately leading to “self-digestion” of the gland. Inhibition of pancreatic secretion and enzyme systems by prescribing CC or OCs looked promising. This was facilitated by the first positive results of clinical observations of the effects of SS on the pancreas of patients with AP [4]. Later, numerous clinical studies failed to confirm the effectiveness of SS in the treatment of AP [5, 6].

Almost the same situation arose with the use of OCs in the treatment of patients with O.P. Initially, encouraging articles appeared on the effectiveness of OCs in relieving attacks of pancreatitis, but as the results of studies conducted according to the rules of evidence-based medicine accumulated, the number of negative reviews about OCs as an effective remedy increased. An example is the work of S. Heinrich et al. [1]. This meta-analysis combined four clinical studies. Its results indicated that OK does not reduce the number of surgical interventions in patients with AP (23.3% versus 16.3%; p=

0.09), does not reduce the incidence of sepsis, does not reduce mortality, as well as the total number of complications (70.6% versus 63.2%;
p =
0.2). In addition, no difference was found for any route of drug administration (subcutaneous or intravenous). As a result, the authors do not recommend that patients with severe AP be prescribed OCs. In other works of the same period of time, the number of negative reviews about the possibility of using the peptide drug OC in AP was constantly increasing, which led to a situation where the medical standards of Great Britain and the International Association of Pancreatologists did not recommend the use of OC and SS in AP [7–9]. Thus, the idea of ​​using powerful antisecretory and antienzyme agents (and primarily CC and OC) in the treatment of AP has not been confirmed in the clinical practice of gastroenterologists and abdominal surgeons. At the same time, OK and SS are used in modern surgery; they effectively stop bleeding from varicose veins of the esophagus and stomach in patients with cirrhosis of the liver, and are used to prevent relapses in secreting endocrine tumors of the pancreas (glucagonomas, VIPomas, carcinoid tumors, gastrinomas, Zollinger-Ellison syndrome) can be used in the treatment of acromegaly.

In this situation, in the late 80s - early 90s, the peptide drug dalargin began to be widely used in our country for the treatment of AP. Dalargin is a synthetic analogue of leucine-enkephalin (Tyr-D-Ala-Gly-Phe-Ley-Arg). Being a synthetic opioid neuropeptide, it practically does not penetrate the blood-brain barrier and does not cause addiction, physical dependence or tolerance [3, 10]. The pharmacological action of the opioid is primarily due to interaction with delta receptors and, to a lesser extent, with mu receptors. Dalargin is primarily an active regulator of the body's homeostasis and has the ability to influence various biological systems. In experimental studies on a model of cystiamine duodenal ulcers in rats, it was shown that dalargin has a powerful reparative effect on ulcerative lesions [11]. The established activity was confirmed by stimulation of the marker enzyme of regeneration processes, ornithine decarbonylase (ODC), in the duodenal mucosa. The pronounced ability of the hexapeptide to activate the processes of regeneration and tissue growth, along with the identified moderate antisecretory effects on gastric and pancreatic secretion, and improvement of blood microcirculation in the damaged area, determined the potential of the drug in the treatment of a number of gastroenterological diseases [12]. As a medicine, dalargin is currently used to treat peptic ulcer disease (PU), pancreatitis, including AP, and pancreatic necrosis.

Already in the first works of surgeons, convincing data were obtained on the ability of dalargin (5 mg/day) to limit or stop the progressive course of destruction of the exocrine parenchyma of the pancreas (it was confirmed by histological and electron microscopic methods) in 56 patients with various forms of AP and developing pancreatic necrosis [13, 14 ]. In a study by R.H. Vasilyeva et al. [15] tested various doses and routes of administration of the peptide for combined gastroenterological diseases (for example, PU and AP). Dalargin was highly effective in the treatment of concomitant diseases of the pancreaticoduodenal zone. Based on the results of studies conducted in the surgery clinic, it was proposed to prescribe hexapeptide therapy to all patients at the pre- and postoperative stage of treatment, which led to accelerated healing of complicated gastroduodenal ulcers, prevention of the transition of edema to pancreatic necrosis, and inhibition of the enzyme secretory function of the pancreas. When comparing the therapeutic activity of dalargin and other drugs used in the treatment of ulcer, the peptide drug was superior in its activity to all other antiulcer drugs (proton pump inhibitors were not used in the work). In the treatment of pancreatic diseases, the hexapeptide was superior in activity to cytostatics, protease inhibitors, ribonuclease, pantriptin, CC, calcitonin, and glucagon. The therapeutic effectiveness of dalargin was assessed by the authors as a result of the systemic effect of the peptide on the digestive organs.

Dalargin was successfully used in the treatment of chronic pancreatitis (CP) that developed after gastric resection in patients with ulcerative disease—postgastroresection pancreatitis (PGRP) [15]. Hexapeptide was used in 25 patients with PHRP at a dose of 1 mg intramuscularly 2 times a day, and in 25 patients receiving traditional therapy. The results of the study showed that dalargin faster and in a greater number of cases (84%) reduced the intensity of epigastric pain and improved overall well-being than in the control group (pain relief in 72% of patients). The authors noted in patients of the main group a positive dynamics of changes in the functional state of the pancreas, which persisted throughout the year, and, according to long-term observations, was more effective than standard therapy. In addition, during the studies, pronounced antioxidant activity of the hexapeptide was recorded, which is regarded as one of the pathogenetic mechanisms of action of the peptide drug [15]. There are other works in which dalargin was widely used in the treatment and prevention of postoperative pancreatitis (PP) with positive results [16].

Based on the analysis of the condition of 1164 patients who underwent radical duodenoplasty due to gastroduodenal ulcerative lesions, measures to prevent PP were developed at all stages of patient management [17, 18]. Alternate use of dalargin and OCs against the background of standard therapy significantly (10-12 times) reduced the incidence of postoperative complications. The given prophylactic regimen for prescribing peptide drugs is now quite often successfully used by abdominal surgeons. Only one clinical and economic observation is known, which provides data on the insufficient preventive effectiveness of the combination of dalargin with 5-fluorouracil and contrical in relation to OC and OC depot in patients with PP after surgery for gastric cancer [19].

Dalargin has been used for many years in the treatment of CP of various origins. An example is our study, in which dalargin was used in doses of 2 and 3 mg intravenously (in 200 ml of saline) 2 times a day for 5 days against the background of standard therapy in 38 patients with the edematous stage of alcoholic CP [20]. During treatment, the pain intensity was relieved (by the 5th day in 90% of patients), the level of enzymeemia, ESR and leukocytosis decreased. Ultrasound data of the pancreas indicated a positive dynamics in the size of the gland due to a decrease in its swelling; in 14 patients, it was possible to achieve a reduction in the size of the gland to normal sizes. The advisability of using dalargin in the treatment of alcoholic CP is indicated by O.N. Minushkin and L.V. Maslovsky [21]. In their opinion, dalargin should be used for mild and moderate cases (edematous form) of alcoholic CP, as well as for CP with elements of dystrophy and endocrine dysfunction. For alcoholic CP, the authors recommend prescribing O.K. along with dalargin. There are opinions of other authors [22] that the combination of dalargin and somatostatin analogues (SS and OK) is the most promising when using these drugs in the treatment of pancreatic diseases.

In 2007, a pharmacological composition consisting of dalargin and OC in the form of a solution was patented, intended for the treatment of AP [23]. This composition was tested in the treatment of experimental cold-induced moderate-to-severe AP in rats. In this combination, dalargin was used in amounts of 0.8 and 0.9 mg/kg, OK - 0.1 mg/kg; as a control there were groups of animals that received only a solution of NaCl, dalargin or OK. The main criterion for assessing the effectiveness of the composition was animal mortality, which was assessed on days 1, 5, 10 and 15. In addition, morphological changes in the pancreas, the activity of glandular enzymes and the production of lipid peroxidation were assessed. The combination of dalargin and OC in severe pancreatic lesions caused a summation of the effects of the drugs and had a clear therapeutic effect, expressed in a decrease in rat mortality to 4%. During the experiment, a more favorable effect on the course of AP was noted already by the 5-10th day of using a combination of peptide agents and restoration of acinar parenchyma by the 15th day without residual effects of sclerosis and inflammation. The positive therapeutic effect of the composition and its pharmacological properties are determined by its two peptide agents that act synergistically. The preservation of the bioregulatory properties inherent in the peptide system and the peptide components themselves may contribute to the compensatory capabilities of the new compound in case of damage to the pancreas [12, 14]. Less significant private mechanisms can also lead to a positive overall effect, for example, the pronounced reparative abilities of the hexapeptide dalargin can prevail in this combination of agents and contribute to the rapid regeneration of animal tissues [11].

The combination of dalargin and OK formed the basis for the development of a new drug in the form of a solution for intravenous and infusion administration, called Daloktin P.V. Currently, pharmacologists have begun to use the principles of synergy of active substances when creating new medicines. Synergism refers to the simultaneous action in the same direction of two or more compounds, which provides greater overall effectiveness than either of them alone. In this case, for optimization and convenience of selection of treatment regimens, the new drug is presented in two dosages with correlation in the content of active ingredients dalargin and OK per 1 ml of solution, namely 2 mg + 0.05 mg, respectively. A new drug with pancreatic activity is intended for the treatment of AP, exacerbation of CP, and prevention of pancreatic necrosis. The new drug was extensively studied in preclinical studies on two animal species, including studies of various types of toxicity, pharmacokinetics and routes of administration, and was classified as class 6 “relatively harmless substances”, which determines the possibility of continuing research in clinical settings. Note that both OCs and especially dalargin are characterized by an almost complete absence of side effects when used for therapeutic purposes. Currently, clinical trials of the drug Daloktin P are being conducted in the treatment of pancreatic diseases.

To summarize, we can say that the idea of ​​using peptide medicinal compounds in the treatment of pancreatic diseases has not been exhausted. And if specialists have a certain skepticism regarding OK, then information about the positive therapeutic capabilities of dalargin for various pancreatitis deserves the closest attention. In the latter case, it is necessary to carry out new scientific work, carried out at the level of evidence-based medicine, and transfer research to the meta-analysis mode. As for the recently created drug Daloktin P, we can assume that, taking into account the theoretical premises and experimental data indicating its pancreatotropic activity, there is every reason to expect a new drug for the treatment of pancreatic diseases to appear in the arsenal of gastroenterologists, and the results of a full cycle of clinical trials will provide an objective assessment of the new peptide drug Daloktin P.

The author declares no conflict of interest.

The author declare no conflicts of interest.

Information about authors

Bulgakov Sergei Alexandrovich

- Doctor of Medical Sciences, Prof. Federal State Budgetary Educational Institution of Higher Education "Russian National Research Medical University named after. N.I. Pirogov" Ministry of Health of Russia, Moscow Russia; e-mail; https://orcid.org/0000-0002-9004-9400

Regulatory peptides - a therapeutic approach

What are peptides and how to take them? Taking care of your skin without quality nutrition and necessary physical activity is ineffective. A culture of caring about one’s health and the availability of resources in the body for constant renewal is part of beauty, and the most important one.

An excellent means of preventing aging for men and women are peptide complexes created by specialists at TD Peptide Bio. They include several peptide bioregulators, which are essential for maintaining rejuvenation processes.

It is necessary to take such complexes two or three times a year, and it is best to do this already on the threshold of the forty-year mark. We draw the attention of our patients to the fact that the complexes will not relieve you of chronic diseases that require serious drug therapy, as they are a preventative measure. However, when used in combination with basic medications, they will significantly improve the body’s vital signs and allow tissue renewal processes to begin.

You can take such complexes-sets (“Beauty and Youth” for women and “Strength and Health” for men) both simultaneously with prescribed drug therapy, and during periods of remission and rehabilitation after crises. The interaction with all drugs is excellent - after all, peptides, in comparison with other drugs and dietary supplements, act at the cellular level, and not at the organ level.

Peptides do not cure and this is important to understand. As a rule, to obtain a serious effect from their use, it is necessary to take several courses, or take them in very large doses, about which you should consult with specialists.

However, patients who are regular consumers of peptide bioregulators note their high effectiveness both in the prevention and in the complex treatment of diseases of various etiologies.

Dalargin

(Dalargin, Tageflar, CAS 81733-79-1) is a synthetic regulatory hexapeptide of the formula Tyr-D-Ala-Gly-Phe-Leu-Arg (YAGFLR), which is registered as a medicine in Russia (P N001319/01-231209); pharmacotherapeutic group – drugs for the treatment of peptic ulcers. Dalargin is interesting in that it is an analogue of two natural enkephalins - methionine-enkephalin (Tyr-Gly-Gly-Phe-Met-COOH = YGGFM) and leucine-enkephalin (Tyr-Gly-Gly-Phe-Leu = YGGFL), in which the glycine residue in the second position is replaced by D-alanine, and the C-terminal amino acid is replaced by arginine, which is reflected in the name of the drug (Dalargin from D-Ala, Arg). The introduction of D-amino acids is a well-known approach aimed at increasing biological activity and increasing the resistance of peptide molecules to degradation in biological environments [1]. The replacement of the C-terminal part of the structure with a highly polar arginine was carried out to obtain a peripheral effect and hinder the penetration of the peptide through GERD [19].

Dalargin (10 mg)

The therapeutic effect of Dalargin, an agonist of delta-opioid receptors, is due to its affinity for enkephalins. Due to this, these peptides are characterized by the presence of an analgesic effect, which, due to their low stability to proteolysis, is observed only when directly introduced into the brain, and reduce the motor activity of the gastrointestinal tract. Endogenous ligands for opioid receptors were identified in 1974, which greatly stimulated the study of neuropeptides and their analogues. In the 1980s, the production and initial testing of Dalargin were first carried out in the laboratory of peptide synthesis of the All-Russian Scientific Research Center of the USSR Academy of Medical Sciences under the guidance of prof. M.I. Titova [19]. Thus, the history of the drug Dalargin goes back more than 35 years.

Dalargin promotes the healing of duodenal and gastric ulcers, suppresses the increase in foci of necrosis, moderately reduces the secretion and acidity of gastric juice, as well as hyperenzymemia. The drug exhibits a weak hypotensive effect. Dalargin is prescribed for exacerbations of duodenal and gastric ulcers, pancreatic necrosis and pancreatitis [21].

In addition, in studies of the immunological status of laboratory animals, as a result of activation of the body's opioid systems using the method of transcranial electrical stimulation and the administration of Dalargin, the modulating effect of opioid peptides on the immune system of animals was shown: B- and T-lymphocytes, phagocytic activity of lymphocytes, phagocytic index , bactericidal and lysozyme activity of blood serum [22]. Since opioid peptides are rapidly degraded by endopeptidases, the authors suggest that Dalargin acts as a trigger, activating the body's defense mechanisms. The results obtained by the researchers confirm the assumption of the immunomodulatory properties of endopioid peptide analogues.

Dalargin may promote a synergistic effect when administered in combination with certain peptides. It was found that intraperitoneal injections of Gly-His-Lys, dalargin and thymogen (0.5, 1.2 and 0.5 μg/kg, respectively) over a ten-day experiment into rats with bone fractures led to a decrease in the blood concentration of malondialdehyde , as well as increased catalase activity and increased reparative activity. The combination of peptides was more potent than any of the peptides tested administered alone. The synergistic effect of peptides was proposed by the authors to stimulate reparative osteogenesis [23]. Dalargin was tested in a rat model of wound healing as a means to accelerate damage repair. Three days after wounding, an increase in granulation was observed at dalargin concentrations of 10 μg/ml and 50 μg/ml (oral administration). Improvements were observed already at a dalargin concentration of 5 μg/ml. This confirmed the stimulating effect on wound healing [24].

It was recently reported that Dalargin, due to its wound-healing and immunostimulating properties, can be used in the treatment of coronavirus infection COVID-19 , namely, the treatment of severe pneumonia accompanied by respiratory failure [25]. As a result of preliminary tests on an animal model of total alveolitis and interstitial pulmonary edema, it was shown that the use of Dalargin reduced the release of cytokines by 4 times (preventing a dangerous, potentially lethal reaction of the immune system, the so-called “cytokine storm”) and significantly increased it to 70–100 % survival of animals with acute respiratory distress syndrome versus 100% mortality in the control group in 72 hours. It is indicated that various schemes for the administration of Dalargin were used, but the details of the experiment were not disclosed.

As a result of studying the amino acid composition of various cytomedins (Greek κύτος - ​cell + Lat. medium - ​intermediary)) of the pineal and thymus glands, a series of biologically active short peptides was obtained: vilon (Lys-Glu), thymogen and epithalon [26]. It turned out that such small synthetic molecules demonstrate even greater pharmacological activity at lower concentrations than their natural predecessors, and are characterized by tissue specificity, but do not show immunogenicity and species specificity [27].

Release form

TD Peptide Bio preparations are produced in cardboard boxes of 60 capsules. The standard package contains four blisters. For preventive use, one package is enough. However, many general practitioners consider such doses to be too small and unlikely to have a visible effect. Therefore, as a rule, the course of administration is indicated for a longer period and includes increased doses.

This must be taken into account by everyone who expects a miracle from peptide bioregulation.

Miracle is life. And peptides are parts of its biological form. In fact, these are the elements from which cells are formed. By supplying peptides to the body, a person helps his body recover, using ready-made forms and without wasting effort on their synthesis, which is complicated by age-related changes.

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Carrying out the procedure

The procedure should be followed in a course.

On average, signal peptides live for 3-5 days. Therefore, the cell is “awakened” with some regularity. The number of procedures is from 3 to 7. At the first stage, at least once a week. Then you can do it less often.

There are no seasonal indications for peptide therapy. The procedure can be done after heavy sun exposure and before tanning. Injections are administered at different depths with incremental distances of 0.5-0.7 mm. This frequency is close to the mesotherapeutic effect. Therefore, there are practically no external consequences.

For some patients the procedure is a little painful

- a burning sensation may be felt. Then application anesthesia is acceptable. But you need to understand that any anesthetic conceals the effect of the drug by up to 30%.

Effect

The first effect patients notice is skin conditioning. Softening occurs, tightness goes away, the skin becomes silky. This is noticeable not only on aging skin, but also in young patients and on the skin of smokers.

Peptide injections should not be considered as an alternative to mesotherapy, but rather as an addition to it. These are biocomplementary drugs that act as skin protectors.

Peptide therapy is indicated for recovery after plastic surgery, laser skin resurfacing, and thread lifting procedures. It shortens rehabilitation time, limits the inflammatory process, reduces the severity of the scar, removes post-traumatic pigmentation, and improves skin texture.

To date, many peptide-containing cosmetic creams have been created. But you need to understand that injection procedures affect precisely those layers of the dermis that give the greatest effect. The use of creams has only a superficial effect.