Main directions and prospects for the creation of medicines. A person’s life path as a problem in psychology - Loginova N.A. (1985) Quantity, names, cost, safety of drugs

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Loginova Natalya Anatolevna- Doctor of Psychology, Professor of the Department of Developmental Psychology and Differential Psychology at St. Petersburg State University. Sphere of scientific interests: history of the St. Petersburg psychological school, theory of individual mental development; personality as a subject of life's path.

In 2001, the Cambridge Biographical Center awarded N.A. Loginova for scientific achievements in the “Woman of the Year” category. In 2007 she was awarded a prize from the Faculty of Psychology of St. Petersburg State University. B.G. Ananyev for scientific publications on the history of Russian psychology, the St. Petersburg psychological school, the creativity of B.G. Ananyeva. In 2008 she was awarded the prize named after. S.L. Rubinstein of the Russian Academy of Science for a cycle of scientific research on the history and methodology of Russian psychology.

Publications

1. + - Biographical method in the light of the ideas of B.G. ANANYEVA

   Each scientific method has its own advantages, but also limitations. The methods do not compete, but complement each other. Such friendly, coordination relations of methods are reflected in the classification of B.G. Ananyeva. Among the empirical methods, on a par with well-developed and generally accepted ones, such as experimental, observational, B.G. Ananyev introduced the biographical method, almost forgotten in science. B.G. Ananyev was the first at the present stage of development of psychology to pay special attention to this method in connection with the development of the theory of individuality and individual mental development, in connection with the design of complex human studies. Thanks to him, the biographical method is now, as we see it, experiencing a rebirth. B.G. Ananyev defined the essence of the biographical method, pointing to its specific subject - the path of life. “The biographical method is the collection and analysis of data about the life path of a person as an individual and subject of activity (analysis of human documentation, testimonies of contemporaries, products of the person’s activity, etc.)”

   Http://www.voppy.ru/issues/1986/865/865104.htm

2. + - A person’s life path as a problem in psychology

   Life path is “the history of the formation and development of an individual in a certain society, a contemporary of a certain era, a peer of a certain generation.” The historical nature of a person requires the psychologist to study or at least take into account the historical circumstances of her life. In psychology, a person’s biography has always served as a rich source of knowledge about personality, but, more importantly, it itself is the subject of psychological study. “The position that development is the main way of existence of an individual at all stages of his individual path puts forward for psychology one of the most relevant and least studied tasks of psychological research into the holistic life path of an individual.” The relationship between biographical events and moments in the natural life cycle of an individual; phases, periodization of life; crises of personality development; types of biographies; age-related characteristics of a person’s inner world; the role of spiritual factors in the regulation of social life; age dynamics of creative productivity; overall life course performance; satisfaction with life, etc. - this is not a complete list of questions concerning the very nature of life’s path. The first systematic study of the patterns of life path was undertaken by S. Bühler

   // Questions of psychology 1985

   Http://www.socd.univ.kiev.ua/PUBLICAT/PSY/LOGINOVA/index.htm http://www.voppy.ru/issues/1985/851/851103.htm

3. + - Charlotte Bühler - representative of humanistic psychology

   Psychological science in capitalist countries is characterized by heterogeneity of directions, one of the reasons for which is the lack of a unified methodological basis. Positivism and pragmatism act as such in most cases, and in the post-war period also existentialism. A peculiar reworking of the existentialist worldview occurred in certain circles of psychologists in a number of capitalist countries, especially the USA and Germany. Psychologists-personologists, gravitating toward the personalism of V. Stern and the “understanding” psychology of V. Dilthey and E. Spranger, recognized themselves as a certain movement based on the philosophy of existentialism. As one of the leading psychologists of this direction, A. Maslow, notes, existentialism acted as an integrator of many personological theories that arose independently in psychology. One of the newly formed directions, the so-called humanistic psychology, is in the closest relationship with existential psychology (often these two branches of psychological personology are not distinguished even by their representatives). At the center of humanistic and existential psychology is the problem of human individuality, which is understood as something spiritual, primarily given. Psychologists with an existentialist orientation focus on the ethical themes of choice and responsibility, a person’s aspiration for the future, and the phenomena of authenticity and creative potential of the individual. Unlike philosophical existentialism and its direct descendants in psychology, humanistic psychologists have their own optimistic view of man and his destiny. They believe in altruism and the creative powers of man, in the possibility of a happy life, a life with meaning on the paths of self-actualization. The main research pathos of humanistic psychology is to study the whole personality, and not individual substructures, in order to find specifically human forms of life activity and motives of behavior. Humanistic psychologists highly value methods based on introspection, which, in their opinion, provide direct insight into the subjective world of the individual. They proclaim the study of a person’s life path, i.e., the biographical method, as the main one in humanistic psychology

In modern psychological science, such phenomena as character, life orientation (the meaning of life, life philosophy, “life line”), talent and life experience can be combined in the concept of “a person’s life path.” We call the problems associated with its study biographical. They are closely intertwined with the socio-historical processes of the era. “A person is a person only insofar as he has his own history,” wrote S.L. Rubinstein.

In Soviet psychology, S.L. was the first to address the topic of life path. Rubinstein, B.G. Ananyev. ON THE. Rybnikov took the initiative to develop research on the genetic psychology of personality (20s). For B.G. Ananyev's problem of life's path became relevant in the early 30s. in connection with research on characterology conducted by him at the Psychoneurological Institute. V.M. Bekhterev in Leningrad. S.L. Rubinstein paid attention to psychological issues of biography, theoretically considering issues of self-awareness in “Fundamentals of General Psychology.” Subsequently, various aspects of a person’s life path and life activity were developed in the works of Soviet scientists devoted to the nature of man and his development.

Life path is “the history of the formation and development of an individual in a certain society, a contemporary of a certain era, a peer of a certain generation.” The historical nature of a person requires the psychologist to study or at least take into account the historical circumstances of her life. In psychology, a person’s biography has always served as a rich source of knowledge about personality, but, more importantly, it itself is subject psychological study.

“The position that development is the main way of existence of an individual at all stages of his individual path puts forward for psychology one of the most relevant and least studied tasks of psychological research into the holistic life path of an individual.” The relationship between biographical events and moments in the natural life cycle of an individual; phases, periodization of life; crises of personality development; types of biographies; age-related characteristics of a person’s inner world; the role of spiritual factors in the regulation of social life; age dynamics of creative productivity; overall life course performance; satisfaction with life, etc. - this is not a complete list of questions concerning the very nature of life’s path.

The first systematic study of the patterns of life path was undertaken by S. Bühler and her colleagues at the Vienna Psychological Institute in the 20-30s. . Based on a large amount of empirical material, she established that, despite individual uniqueness, there are patterns (“regularities”) in the timing of the onset of life optima, depending on the ratio of spiritual, “mental,” and biological, “vital” tendencies. Various types of personality development in life were also discovered. S. Bühler developed an idealistic concept of human development as a process of gradual formation and change in the spiritual target structures of self-consciousness. The ideas and empirical research of S. Bühler contributed to the formation of humanistic psychology in the West.

Existentialist, neo-Freudian models of life development were comprehensively and deeply subjected to critical analysis in Soviet science. This criticism is carried out from the perspective of Marxist methodological principles and is constructive in nature. Soviet psychology defined a fundamentally different strategy for developing problems of individual personality development. This strategy was first outlined most fully and programmatically by B.G. Ananyev. He substantiated the project of science about the holistic development of man in a single life cycle. This science, according to Ananyev - ontopsychology, should combine age-related psychophysiology, which studies the ontogenesis of psychophysiological functions of the brain, and genetic personology, aimed at studying the actual personal evolution in the process of life. The subject of ontopsychology is the relationships, interdependencies of ontogenesis and life path, which determine the main patterns of holistic individual human development.

In this integrity, however, B.G. Ananyev clearly distinguished two interacting, but still special forms. Firstly, ontogenesis - the development of the individual and his brain, psychophysiological functions. Ontogenesis is programmed genetically and occurs in biological life time. Secondly, the life path, which is built according to social projects in historical time, is dated by historical and biographical events.

Ontogenesis with a sequence of phases (birth, maturity and maturation, aging and death) acts as an objective factor in the life path. “The history of the individual and the subject of activity unfolds in the real space and time of ontogenesis and, to a certain extent, is determined by it...”. Objective, social and subjective, personal regulation of life, life path planning cannot occur without taking into account the natural life span, the degree of maturity of the body and brain, and age-related health restrictions. The very possibility of subjective regulation of life activity does not arise immediately, but gradually, as the brain and its functions mature, and at the same time as intelligence, self-awareness, and character develop in the processes of socialization. Before becoming a subject, a person exists as an object of many social influences. The objective determination of the life path - partly by ontogeny and to a large extent by social circumstances - is not canceled even when a person becomes a subject in full. The relationship between subjective and objective regulators of life's path is an important issue in biographical research, the intersection of psychology and ethics. The psychological aspect of the answer to this question lies in the study of the mechanisms of subjective regulation by a person of his life and thus his own development. These mechanisms actualize the existing structures of self-awareness, character, life orientation, and talent.

To the extent that a person himself organizes and directs the events of his life’s path, builds his own development environment, and selectively relates to those events that do not depend on his will (for example, socio-historical macro-events of our time), he is subject of life activity. The principle of life activity developed by K.A. Abulkhanova-Slavskaya, , specifies in relation to the individual the more general principle of the unity of consciousness and activity. According to the way consciousness is formed and manifested in activity, integral, “apex” personality structures - character and talent, life orientation and life experience - are formed and manifested as its subjective regulators.

The concept of life activity reflects the active role of a person in his own destiny. The degree of this activity may vary depending on the maturity of the character and its originality. On this basis, it is possible to distinguish between levels of life activity and associated personality types. (At the same time, one cannot abstract from the socio-historical meaning of the values ​​for which the individual lives and fights.) At one pole is a life subordinate to circumstances, a patterned fulfillment of social roles, so to speak, a life of automatism. At the other pole is life creativity, when life activity, embodied in specific forms of social behavior and activity, is directed by the subject in accordance with fundamental relationships and attitudes, when life activity is adequate to character and is self-expression. Truly creative self-expression must be based on the right reflection circumstances and consequences of one’s own behavior, reflecting the objective laws of reality.

Life creativity occurs in social behavior (actions), in communication, work and cognition. The life path of a creative personality is full of events - events of the environment, behavior, inner life. This eventfulness affects the nature and completeness of memories. Memories can be used to judge personality type.

The unity of consciousness and activity is, in biographical terms, the unity of internal and external life. In the broadest sense of the word, the concept of inner life covers all phenomena of mental activity. Inner life should be considered as a psychological component of the life path. It not only reflects real events, but is itself a subjective reality - life. Indeed, a spiritual biography can be no less meaningful and significant than an objective picture of life. Sometimes in biography it comes to the fore. For example, Kant's biographers draw attention to the contrast between the dramatic history of the philosopher's thought and the monotony of his private life. A.V. Gulyga writes in this regard: “Kant has no other biography than the history of his teaching... The most exciting events in it are thoughts.”

The “cell” of inner life is experience. In “Fundamentals of General Psychology” S.L. Rubinstein noted the universal nature of this phenomenon and considered it a personal, subjective aspect of consciousness as a whole. “Experience,” notes S.L. Rubinstein, is primarily a mental fact, a piece of an individual’s own life in his flesh and blood, a specific manifestation of his individual life. It becomes an experience in a narrower, specific sense of the word as the individual becomes a person and his experience acquires a personal character... A person’s experiences are the subjective side of his real life, the subjective aspect of the individual’s life path.” In this second sense of the word, experiences can be called biographical experiences. In fact, their subject is biographical events reflected in the processes of memory, thinking, and imagination. Through them, life activity is regulated, and, finally, they themselves can become life events.

Experiences exist in the form of emotionally charged processes, for example mnemonic, which in personal-biographical terms act as processes of historical memory - memories. Like any biographical experience, memory is included in the life activity of the individual. In connection with life activity, memory has been studied much less than in connection with more private types of activity, say, with learning. The laws of imprinting, preservation, forgetting and reproduction in the system of historical memory have their own specificity, determined by the vital significance of the recorded events. Thus, in contrast to simple forms of memory, in memories there are images that are extremely durable, extremely durable due to the uniqueness of events. Moreover, what is important is not so much the emotional coloring of the image, but its content and vital significance. “The unpleasant persists especially long and lastingly because it is constantly experienced not as a known suffering, but as a known “life lesson.” The pleasant is preserved as a certain moment of moving life forward." This is a long-standing assumption of B.G. Ananyev was confirmed in the experiments of P.V. Simonova. “Memories of faces, meetings, life episodes, which were not at all associated in the anamnesis with any out-of-the-ordinary experiences, sometimes caused exceptionally strong and persistent, objectively recorded shifts that could not be extinguished by repeated reproduction. A more thorough analysis of this... category of cases showed that the emotional coloring of memories depends not on the strength of the emotions experienced at the moment of the event itself, but on relevance these memories for the subject at the moment."

Not only the preservation, but also the forgetting of biographical facts is determined by their vital significance, as S. Freud drew attention to. Forgetting as the involuntary displacement of an image from consciousness is real. But something else is also possible, when a person stores an event in his memory, but deliberately avoids reproducing it, not wanting to cause himself mental pain or disturb his conscience. Memories sometimes require courage.

Memories, embodied in emotionally charged ideas, are part of the actual structure of the personality, forming the mental “fabric” of its self-awareness. By summarizing memories, the life experience of an individual is formed. “Thanks to memory, the unity of our consciousness reflects the unity of our personality, passing through the entire process of its development and restructuring. The unity of personal self-awareness is associated with memory. Any personality disorder, reaching in its extreme forms to the point of its collapse, is therefore always associated with amnesia, a memory disorder, and, moreover, precisely this, its “historical” aspect.” Memories are crucial for a person to understand his own life, master his experience, and regulate his life activities on this basis.

Inner life can also be carried out in the processes of imagination. For different people, an imaginary life - in dreams, hopes, foresights - has different meanings. Sometimes it almost completely replaces real life. Escaping reality into the realm of memories or dreams has the meaning of “protection.” However, this style of internal life demobilizes a person and reduces the level of his social activity. It is optimal when a rich inner life is commensurate with real life, otherwise it itself will eventually become exhausted. “In order to survive, you must first of all live. The nature of human experiences, their depth and truthfulness—the correspondence with life—depends on the fullness and strength of life, on the social existence of a person.”

Experiences undoubtedly also have a mental component. “Thinking processes are involved in solving life and moral problems that involve making a choice and constructing” a strategy of behavior. The point of view of a person's life as a chain of tasks that are typical for a certain age or that arise when faced with various circumstances implies the inclusion of intelligence in the structure of personality. Determining a line of behavior or even a line of one’s entire life is a creative task addressed largely to the intellect.

It can be seen that the functioning of thinking when solving life problems is in many ways similar to mental activity in a problem situation that has no biographical significance at all. In both cases there is a preparatory phase, a moment of insight and a subsequent comprehensive justification for the decision. Moreover, even a random impression can play the role of a “hint”. The brightness and unforgettableness of moments of insight, when the discovery of truth in its moral and vital meaning occurs, testifies to the fact that these moments entered the spiritual biography of a person and became events.

The phenomenon of spiritual events was very expressively described by the writer Vera Ketlinskaya in her autobiographical novel “Hello, Youth!” She writes: “In the spring, three events took place, seemingly not major ones, but only epoch-making events play a role in our mental life! I still feel those three incidents as turning points.” In particular, V. Ketlinskaya recalls the impression of Beethoven’s Ninth Symphony, the sounds of which strengthened her thoughts about a rebellious life. “That exciting, ineradicably cheerful melody arose... and again sparkled - like a premonition that was not entirely clear to me - the moment of awareness of my fate.” A specific impression (here aesthetic) caused experiences that have a biographical meaning (“awareness of fate”). It was not the music itself, but the experiences arising under its influence that formed the essence of the event. Aesthetic experience here contributed to determining the life direction of the individual, and therefore it indirectly influenced the course of life, and therefore became an event in it.

Psychologists have to study and understand the special qualities of all mental processes as experiences. In the flow of inner life, memory becomes a memory, imagination - a dream, thinking - a means of comprehending the essence of life's tasks, inner speech - the voice of conscience (B.G. Ananyev persistently drew attention to this ethical function of speech back in the 40s) In this, biographical meaning, a person’s mind acquires a new quality: “The ability, developed in the course of life in some people, to comprehend life in the grand scheme of things and recognize what is truly significant in it, the ability not only to find means to solve randomly emerging problems, but also to identify the tasks themselves and the purpose of life is to truly know Where in life to go and For what,- this is something infinitely superior to all learning, even if it has a large stock of special knowledge, this is a precious and rare property - wisdom" .

The experiences of strong, talented people rise to the level of passions in the best sense of the word, i.e. to passions inspired by noble ideas (pathos). Great deeds mature in the boiling of such passions - this is evidenced by the biographies of outstanding scientists, writers, and revolutionaries. More than once doubts have been expressed about the possibility of a scientific, psychological study of deeply personal experiences, especially passions - these phenomena are attributed entirely to the department of art and fiction. For example, P.V. Simonov strongly insists on this. He makes pessimistic conclusions regarding the scientific independence of the psychologist. “The subjective side of the inner world of the individual,” he writes, “is not ... the subject of science in general. Retreating from the related disciplines that are pursuing him - neurophysiology, ethology, anthropology, sociology, etc., the psychologist at a certain moment finds himself in a territory where he feels inaccessible to representatives of these branches of knowledge.

With relief, he looks around and discovers that he is in the territory of... art." Real difficulties in understanding the depths of personality should not, however, be perceived as the fundamental powerlessness of science in this area. Biographical studies in psychology testify in favor of science. Without addressing the full-blooded inner life with its passions, scientific psychology still looks incomplete, “cut off at the most interesting place.”

Experiences are a dynamic effect of the entire personality structure, which is most integrally represented in character and talent (B.G. Ananyev). The dynamics of inner life in its biographical meaning are permeated with ideological motives; it bears the stamp of the worldview and life philosophy of the individual. In experiences, the value aspect of self-awareness is revealed, the personality’s relationships are actualized, including towards oneself, generalized in reflexive character traits - self-love, self-esteem, honor. Reflexive properties, “although... are the most recent and dependent on all the others, complete character structure and provide it integrity. They are most intimately connected with the goals of life and activity, value orientations, attitudes, performing the function of self-regulation and control of development, contributing to the formation and stabilization of the unity of the individual.”

Reflexive character traits are stable properties of self-awareness, which in personal-biographical terms acts as awareness of oneself as a subject of life's path, responsible for one's own destiny - unique, inimitable, unique. Self-awareness correlates, on the one hand, the life plans and potentials of the individual, and on the other, real achievements in creativity, career, and personal life. A mature person understands the logical nature of his path, builds a concept of life, linking the past with the present and future. Self-awareness is impossible without knowledge of one’s own existence, the contingent and the necessary in it, the actual and the potential, the actual and the possible. The depth and adequacy of this knowledge are largely determined by a person’s intelligence and, if you like, talent.

Character is the integration of personality properties, genetically related to its tendencies. The system of potencies is integrated into the structure of abilities, and moreover, into talent (see). The psychology of talent is something more than the psychology of abilities. It's not just a matter of different levels of these potentials. Talent is the unity of abilities based on the worldview and life orientation of the individual. Talent is the effect of individualizing abilities, merging them with character. Following B.G. Ananyev, we believe that in the concept of “talent” it is not so much the level of abilities and its components that is important, but rather their originality, compliance with inclinations, awareness and self-regulation. Character and talent in relation to the path of life act as its subjective factors, regulators of the life process and social life. However, they themselves are primarily a product of biographical development. The fate of a talented individual, the possibility of his flourishing, the individual characteristics of the structure of talent, the area of ​​application of creative forces depend on historical time, on the class affiliation of the individual, on the circumstances of the social environment of development. The history of creative activity is inseparable from the civil and personal destiny of a person. That is why psychological studies of talent and characterology studies necessarily turn to biographical material.

Being dependent on biography, talent, in turn, leaves its mark on the fate of the individual. Awareness of one's talent reinforces self-esteem, promotes responsibility for its implementation and development, and encourages a person to live in accordance with his calling. Thus, talent acts as a kind of imperative of life. Moreover, a person is aware of the social function of his talent, his responsibility to solve urgent problems of social life and thereby respond to the demands of our time. In other words, a person realizes not only his potentials and calling, but also his social, historical mission - purpose. This happens not only with great people, but with every conscious subject with a sense of social responsibility and a sense of history. Everyone makes their contribution to the historical process, and everyone is to some extent irreplaceable.

Talent, being an imperative of life, also serves as its instrument. In literary criticism, the correct idea has been expressed that talent in creative life is no less valuable than in special types of activity. So, in the new book by Yu.M. Lotman about Pushkin, the poet’s life is considered as a work of genius. “Pushkin entered Russian culture not only as a Poet, but also as a brilliant master of life, a man who was given the unheard-of gift of being happy even in the most tragic circumstances.” The creativity of life, the self-worth worthy of the years lived, is the main thesis of G. Vinokur’s old work “Biography and Culture”.

So, the multilateral connections between the personality structure, represented by talent and character, and the life path determine the place of these integral formations in the circle of biographical problems: they are the result of the life path and its regulators, moreover, they are the basis of life creativity.

The study of biographical phenomena has not only theoretical, but also practical significance. By understanding the patterns of life activity and life path, a person can better imagine the optimal option for his own development and determine his life path. Understanding the role of the individual in planning and implementing one’s life path contributes to a more responsible attitude towards it, the desire to set serious life goals and achieve their implementation.

Loginova N.V. Polozov G.I.

INTRODUCTION TO PHARMACEUTICAL

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L69 Introduction to pharmaceutical chemistry: Textbook. allowance /

Í. V. Loginova, G. I. Polozov. – Mn.: BSU, 2003. – 250 p. ISBN 985-445-823-7.

 The manual examines the basic provisions and rules for quality control of medicines in the process of their development and production, sets out general principles for assessing the quality of dosage forms and requirements for their storage conditions, and also provides data on research in the field of development of new medicines and trends in the development of the pharmaceutical industry. Includes a section on basic physical and chemical aspects of preparative pharmaceutical chemistry. The manual can serve as a modern addition to textbooks on pharmaceutical chemistry.

For students of chemical and pharmaceutical specialties of higher educational institutions.

PREFACE

The course in pharmaceutical chemistry belongs to the main courses in the complex of chemical and biomedical disciplines designed to provide training for chemists in the field of drug discovery and research. It is based on students’ knowledge of the basics of inorganic, organic, analytical chemistry, biochemistry and other disciplines. The course is traditionally divided into general pharmaceutical chemistry, pharmaceutical chemistry of inorganic and organic drugs. Accordingly, his program consists of three parts.

An idea of ​​the subject, problems, prospects and directions of development of pharmaceutical chemistry is given in the first part of the course (see Appendix 1). In addition, the basic provisions and rules for monitoring the quality of medicines during their development and production are considered, general principles for assessing the quality of dosage forms and requirements for their storage conditions are outlined, and the physical and chemical processes occurring during the storage of medicines are characterized, and ways to increase their stability are indicated. Attention is drawn to the features of using modern methods of separation, purification and determination of the structure of medicinal substances.

è medical materials, familiarity with the use of standard techniques described in the State Pharmacopoeia, but

è studying the features of the chemical processes of their production, sinceThe educational process is aimed primarily at training specialists in the field of synthesis and analysis of medicinal substances. In this regard, the course program contains a section devoted to the basic physical and chemical aspects of preparative pharmaceutical chemistry. It discusses the general principles of using solvents to obtain medicines, modern ideas about the laws of

formation of the solid phase in solution, physicochemical aspects of obtaining polymorphic modifications of medicinal substances and the pharmaceutical significance of polymorphism, as well as physicochemical principles of the use of combinations of components in medicinal products and problems of incompatibility of medicinal substances.

Educational literature on pharmaceutical chemistry (textbooks, manuals for laboratory and practical exercises, manuals containing information on various issues of the program, reference books) do not fully satisfy the needs of students of the Faculty of Chemistry studying this discipline. Textbooks often lack information on some issues of the program of a given course, and the form and sequence of presentation of the material do not correspond to the current program. They do not sufficiently reflect the content of those sections or issues of the program that take into account the professional orientation of students specializing in “Chemistry of Drugs”. Finally, since the main textbooks in this discipline were published and reprinted in the 1980s or early 1990s, they lack information about new scientific advances.

In this regard, for the effective conduct of the educational process, there is an urgent need for manuals that supplement textbooks on pharmaceutical chemistry with information on various sections of the program, taking into account the characteristics of the above specialization, as well as modern information on the state of research in the field of development of new drugs and trends in the development of the pharmaceutical industry . This manual can serve as a modern addition to textbooks on general pharmaceutical chemistry.

In addition, a manual of this type will significantly reduce the classroom load of students by shifting the center of gravity from classroom studies to independent work, which is important for the implementation of a multi-level system of university education. Using this manual and focusing on the program (see page 1), students can master those sections of the course that were omitted or shortened in lectures. For independent work, basic and additional literature is provided, and scientific literature in English is also offered as additional literature. Along with textbooks on pharmaceutical chemistry, the list of references includes reference publications that contain extensive information about medicines and can significantly complement textbooks when studying this course.

Since the training course examines problems in the border areas of various sciences, the manual provides a dictionary that contains the basic terms and concepts of pharmacology and medicine (Fig. 2) necessary for the study of pharmaceutical chemistry. In the manual, the authors used primarily the definitions of the World Health Organization (WHO), included in pharmacological textbooks and reference publications.

The authors express deep gratitude to the chief researcher of the Institute of Bioorganic Chemistry of the National Academy of Sciences of Belarus, Doctor of Chemical Sciences M. A. Kisel, and the Department of Pharmacology of Minsk State Medical University (head of the department, Doctor of Medical Sciences, Professor B. V. Dubovik) for reviewing the manuscript and useful advice.

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Pharmaceutical chemistry (PC) studies the sources and methods of obtaining natural and synthetic medicinal compounds, studies their structure, physical and chemical properties, as well as the relationship between the chemical structure of a substance and its biological and pharmacological activity (“structure - function”). Pharmaceutical chemistry is developing methods for controlling the quality of medicines, the conditions for their storage and transportation in order to increase their stability and shelf life.

For PH, as for any other scientific discipline, the terminology used is of great importance. The exchange of information, results of scientific and practical activities in this area is often difficult due to the simultaneous use of old and new terms. One of the attempts to solve this problem was made back in 1980 through the introduction of a Terminological Dictionary. It includes terms and reveals the semantic content of the basic concepts of PC and clinical pharmacology. In this system, one of the main concepts is medicine(LS). However, the complex and multifactorial path of searching and developing drugs necessitated the introduction of the term pharmacological agent, preceding the drug.

Pharmacological agent– a substance (or mixture of substances) of natural or synthetic origin with established pharmacological activity, which is the object of clinical trials. It receives the name “medicine” only after clinical trials with positive results and after approval for use by the relevant committees of the Ministry of Health.

Medicine– a pharmacological agent approved for use by an authorized government agency for the treatment, prevention or diagnosis of human and animal diseases. In this regard, it is not recommended to use the previously used terms “medicine”, “therapeutic agent”, “medicine”, etc. The definition of drugs given in the TSB (T. 14. P. 278) is also incorrect: “Medicine”

VA are substances used to treat and prevent diseases.” Among the most important classes of drugs are antibiotics, vitamins, alkaloids, hormonal drugs of steroid and polypeptide nature, etc.

Medicines are not only numerous, but also heterogeneous. They can be in different states of aggregation (liquid, solid, gaseous), have a mineral or organic nature, plant or animal origin. These include medicinal substances and medicinal plant materials.

Medicinal substance(DM) is an individual chemical compound obtained synthetically or isolated from medicinal raw materials and used as a drug. It should be emphasized that drugs include only synthetic compounds or objects of natural origin subjected to special processing. Some types of raw materials become drugs after basic processing. Thus, many plants are crushed after drying. But the bulk of the raw materials require complex processing.

Various methods of use, numerous quality requirements, the need to prolong the action of drugs and other factors have led to the fact that for practical use they began to be given a variety of forms. Dosage form(LF) - a state convenient for the use of a drug, specially given to it to achieve the necessary therapeutic effect (tablets, powders, capsules, dragees, pills, solutions, ointments, gels, aerosols, etc.).

A medicine in the form of a specific dosage form, ready for use, is called medicine(LP). For a drug to become a drug, it needs to be given specific physical properties and included in certain mixtures. The drug is active substance(active ingredient) with the addition of various components and auxiliary substances (solvent, other drugs, dyes, adsorbents, flavoring additives, etc.). It should be easy to use and consistent with the therapeutic purpose. For example, atropine sulfate is a drug, and atropine solution in ampoules is a drug.

The following drugs are distinguished: galenic; neogalenic (or novogalenic), which, unlike the Galenaceae, are biologically standardized (see more about them in the next section); prolonged action, or durable (having a longer therapeutic effect); radioactive, and radiopharmaceutical (containing radioactive isotopes of elements for diagnostics and radiation therapy); standard – âåùå-

products with accurately measured physical, chemical, biological parameters, intended for assessing the bioequivalence of drugs.

Any drugs whose quality is regulated by the State Pharmacopoeia are called official (from the Latin officina - pharmacy). A typical example of such drugs are preparations manufactured in factories or pharmacies according to prescriptions approved by the Pharmacopoeial Committee. They are obtained by mixing several types of plant materials in certain proportions. They are intended for preparing infusions, decoctions, etc.

Among the drugs, it should be noted plant juices (plantain, Kalanchoe, aloe, etc.) and fruit purees, produced without extracting the active principles. They, in fact, correspond to the means that Hippocrates (IV century BC) used in his practice

í. BC), which is why they are often called " Hippocratic." A medicinal product that does not contain active components

product, but having the same shape, weight, color, taste, is called a placebo (from the Latin placebo - I will like it or placet - it seems) and is widely used in clinical trials as a control when studying the effectiveness of new drugs. This placebo function was first proposed by G. Peffer in 1945. The greatest placebo effect was achieved for headache and seasickness (58%), the smallest for hypertension (18.4%) and angina pectoris (12%). The use of this “dummy” for the psychotherapeutic effect, which ensures abstinence from treatment, requires appropriate permission from the competent authorities. It is not yet clear how a placebo causes the body to heal itself. Some psychologists believe that the placebo effect is based on the Pavlovian conditioned reflex, which a person develops imperceptibly throughout his life. However, according to pharmaceutical experts, placebos are unlikely to easily find a place among officially recognized treatment methods.

The action of the drug is reduced to transforming the pathological situation that has arisen as a result of the disease into normal. For reasons of medical ethics, medications that increase functional performance: psychostimulants, anabolic steroids, sexual stimulants, etc., are not considered drugs.

Among the drugs used for the prevention of diseases or dysfunctions, the following can be distinguished: prophylactic agents: vaccines, serums, antimalarial drugs, immunomodulators, antioxidants, hormones, vitamins and microelements, enzyme and immune diagnostic agents, etc.

people: contraceptives, tranquilizers, sleeping pills, tonics, digestive stimulants, etc.

In medical practice, combined multifunctional drugs are of great importance, as they make it possible to treat complex pathologies, for example, those associated with infectious processes, vitamin deficiency, and reduced body resistance. They may include antibiotics, cationic antiseptics or sulfonamides, natural and synthetic vitamins, stimulants of reparative processes, etc. as antimicrobial agents.

There are certain requirements for medicinal products, according to which it must combine three mandatory qualities: specificity, effectiveness and harmlessness. Ideally, each disease should have its own drug that protects a person from this disease, or heals it, or facilitates its course, while remaining completely safe for the body. Naturally, it is difficult, most likely impossible, to find such a drug, so a constant search for new and improvement of known drugs is carried out. The search is often difficult due to the lack of suitable animal models of this disease or the lack of effectiveness of drugs in relation to humans.

In addition to drugs, products of the pharmaceutical industry are parapharmaceuticals. These include related products: synthetic and natural polymers for medical purposes, dressings and suture materials, adsorbents, fillers, biologically active food additives (BAA), food and coloring additives, medicinal cosmetics.

One can get an idea of ​​the specificity of pharmaceutical chemistry and its place among such life sciences as pharmacology, biological chemistry, bioorganic chemistry, and medicinal chemistry based on definitions taken from the relevant textbooks.

Biological chemistry– the science of the structure of chemical substances that make up living matter, their transformation and the physicochemical processes that underlie life activity.

Bioorganic chemistry studies the structure and biological functions of the most important components of living matter, primarily biopolymers and low-molecular bioregulators, focusing on elucidating the patterns of the relationship between structure and biological action.

Based on the above definitions, it can be concluded that both biological and bioorganic chemistry are important for

understanding the mechanism of action of drugs, but in no way pretend to solve the problem of their creation and study of properties.

The situation is different with definitions of the subject of research in such scientific fields as pharmacology and pharmaceutical chemistry.

Pharmacology (from the Greek pharmakon - medicine and logos - study) is the science of the interaction of drugs with the body and ways of finding new drugs. The main branches of pharmacology are pharmacodynamicsè pharmacokinetics.

Pharmaceutical chemistry – a science that, based on the general laws of chemical sciences, studies methods of production, structure, physical and chemical properties of drugs, as well as the relationship between their chemical structure and effect on the body, methods of quality control of drugs and changes that occur during their storage.

It is obvious that FH occupies a key position in pharmacy, which studies the issues of searching, obtaining, researching, manufacturing, certification, storage and dispensing of drugs and other substances used for therapeutic and prophylactic purposes. Pharmacy also includes such medical and biological sciences as pharmacognosy (the study of drugs of plant and animal origin), pharmacology, toxicology, production technology of drugs and pharmaceuticals, organization and economics of pharmacy, marketing, etc.

Pharmaceutical chemistry can be considered as a connecting discipline in the entire complex of biomedical and chemical sciences. Based on the general laws of chemical sciences, it allows one to successfully solve many problems of biology and medicine. Therefore, it is natural that PC is closely connected with many areas of clinical medicine, for example, with surgery, virology, oncology, psychiatry, etc. Apparently, there is not a single area of ​​practical medicine in which drugs are not used.

On the other hand, further development and success of PC is impossible without the widespread use of physics, mathematics, and chemistry: these are physical and mathematical methods for studying drugs and the products of their transformation in the body, computer approaches to the search and analysis of new, more effective and safe drugs, new synthetic methods etc.

Thus, Physics is in close contact with many scientific disciplines, which, as is known, is the key to the successful development of any science.

In the 1990s, it developed rapidly medicinal chemistry, which emerged as an independent science by the 1970s. The subject of medicinal chemistry is the discovery, development

botka and identification of physiologically active substances, identifying the relationship between chemical structure and physiological activity and, finally, solving the inverse problem: designing the necessary structures that have a given property (drug design). The main emphasis is on drugs, but the interests of medicinal chemistry are not limited to this, but also include biologically active substances (BAS). The subject of medicinal chemistry is also the study, identification and synthesis of metabolic products of drugs and related compounds.

It should be noted that currently there are two scientific disciplines called “medical chemistry” in Russian. Medicinal chemistry, corresponding to the foreign term medical chemistry, is a branch of medicine, since one of the main subjects of its research is the biochemistry of pathological conditions and the development of various analytical methods used for diagnostic purposes. Medicinal chemistry, corresponding to the foreign term medicinal chemistry (from the word medicine - medicine), is an interdisciplinary science that is at the intersection of organic and inorganic chemistry with biochemistry, bioorganic and bioinorganic chemistry and pharmacology.

In foreign literature, there is sometimes a point of view on medicinal chemistry as a new field of science that replaced PC and was so named because the discoverers of drugs were often pharmacists. However, in the CIS countries, pharmaceutical chemistry exists as an independent discipline. In addition, these areas of science have their own systems of concepts and definitions, which is also characteristic of independent disciplines. Terminological confusion due to the fact that two different disciplines have the same name in Russian (“medical chemistry”) can significantly complicate the targeted development of a discipline equivalent to “medicinal chemistry.”

BRIEF HISTORICAL SKETCH OF THE DEVELOPMENT OF PHARMACEUTICAL CHEMISTRY

Pharmacy originated in ancient times and had a huge influence on the formation of medicine, chemistry and other sciences. In those days, naturally, a purely empirical approach to drugs, based on centuries-old observations, dominated. As a source of drugs, ready-made plant or animal raw materials were used for application to wounds and oral administration. Often treat-

The meeting was accompanied by prayers, ritual actions, and dancing. Over the course of thousands of years, many plants, minerals, and animal tissues were tested for the production of powders, decoctions, ointments, infusions, etc. The ancient Roman physician Claudius Galen (2nd century) believed that the plant, in addition to the main mass-ballast, also contains “ active principle" (according to modern definition, biologically active substance), which has an increased affinity for moisture. Therefore, he recommended that before preparing drugs, medicinal plants should first be dried and then placed in water. Unlike the bulk of the plant (fiber, protein), these highly active chemical compounds, with rare exceptions, are highly soluble in water and are more efficiently extracted from dried plant materials. The preparation of infusions and decoctions is, in fact, an invention of Galen. He described more than 300 drugs in the form of decoctions and infusions obtained from natural compounds of plant and animal origin. Many of herbal remedies have not lost their significance even today, although now they are prepared somewhat differently, and such changes are scientifically justified.

Application idea chemicals for the treatment of diseases was developed only in the Middle Ages. The initiators of this idea were alchemists who used derivatives mercury, arsenic, antimony, copper, zinc, iron etc. However, drugs of this kind often turned out to be toxic and, when taken in large doses, could cause more harm to the patient than the disease itself. During the period of alchemy (IV–XVI centuries), much attention was paid to the search for the “philosopher’s stone” as an eternal elixir of youth and a panacea for all diseases, as well as a means of transforming base metals into gold and silver. Despite utopian ideas, alchemists accumulated enormous experimental material for the development of chemistry and chemical engineering. Methods for obtaining and purifying substances were developed (distillation, sublimation, precipitation, filtration, crystallization, etc.); important chemicals were obtained (inorganic and organic acids, alcohol, various salts). It is impossible not to mention the name of the outstanding Tajik scientist-encyclopedist of the 10th–11th centuries. Avicenna, who is rightfully considered the founder of pharmacy. In five volumes of the “Canon of Medical Science”, he summarized the achievements of Greek, Indian and Arab medicine, described about 1000 drugs of plant, animal and mineral origin, many of which are used in modern medicine.

In the Renaissance (XV-XVI centuries), alchemy was replaced by iatrochemistry (medicinal chemistry), which sought to put chemistry on the

service to medicine. Its founder, the Swiss physician and chemist Philipp Aureolus Theophrastus Bombastus von Hohenheim, known under the pseudonym Paracelsus, considered the goal of chemistry to be the protection of health with the help of drugs. He was the first to express the idea that all processes in the body are complex chemical transformations; studied the effect on the body of many substances of mineral and plant origin, improved a number of instruments for analysis. Paracelsus considered himself an opponent of Galen in the field of medical theory, as well as in the practical field of obtaining new pharmaceutical preparations. Unlike Galen, he believed that in order to extract the active principles of medicinal plants, more intensive and repeated processing of raw materials with various solvents is necessary. As a result of this processing, an extract is obtained - essence, but only the fifth extract - “quintessence" (from the Latin quinta - fifth) contains the desired drug. Extracts and tinctures, the method of preparation of which was invented by Paracelsus, are still obtained by re-extracting the active principles in special devices. ( Currently, galenic drugs include not only infusions and decoctions, but also tinctures, dry and liquid extracts, syrups, poultices, lotions, ointments, liniments and others, prepared by aqueous or non-aqueous extraction of active principles without separation or with partial separation of accompanying ballast substances.) Paracelsus is rightfully considered the founder of PC and pharmaceutical analysis. In 100 years of atrochemistry, science has been enriched with more facts and discoveries than alchemy in 1000 years.

FH received further development in the 17th–18th centuries. At this time, M.V. Lomonosov defined the place of chemistry in medicine as follows: “...A physician cannot be perfect without a sufficient knowledge of chemistry; from almost chemistry alone one must rely on the additions and corrections of medical science...” Many biologically active substances of natural origin were isolated in their pure form and comprehensively studied: alkaloids, glycosides, vitamins. During the 18th century. Only 10 new drugs were created, and over the last decade of the 19th century. - 15.

In the 19th century Methods of chemical analysis were significantly improved, which gave rise to the search in known plants for active ingredients responsible for medicinal properties (quinine, morphine, etc. were isolated). In the second half of the 19th century. Thanks to the creation of the structural theory, as well as the research of many organic chemists, the rapid development of organic chemistry began, which significantly affected the field of drug synthesis: purely synthetic drugs appeared, for example: chloral, used since 1869 as a sedative and sedative; salici-

lic acid, used as an anesthetic. By the end of the 19th century. the synthesis of drugs has already acquired an industrial scale. In 1888, Bayer's company released the effective antipyretic drug phenacetin, and in 1899, the well-known anti-inflammatory drug aspirin.

 end of the 19th century received neogalenic drugs, in which, unlike galenic drugs, the active principles were retained, but ballast substances were completely removed.

It is important to emphasize that by this time the structural identification of compounds such as fats, proteins and carbohydrates had already been carried out, i.e. compounds whose molecules are the main targets of drug action.

Russian doctor D. L. Romanovsky in 1891 outlined basic principle of chemotherapy: an ideal medicine is a substance that causes the least harm to the patient, but at the same time destroys the cause of the disease as much as possible.

The further development of FH is associated with the names of P. Ehrlich,

À. Bayer, A. Fleming (penicillin, 1928), G. Domagk (sulfonamides, 1935) and many others.

 1910 German scientist P. Ehrlich synthesized salvarsan (the first effective remedy against syphilis). This led to the emergence chemotherapy concepts: not just the ability to use chemicals to treat pathologies (diseases), but the need to modify the structures of the proposed medicinal compounds in order to most effectively affect the affected organ. P. Ehrlich also developed receptor theory and structural changes in biologically active substances that occur upon interaction with the receptor: “ Corpora non actunt, nisi fixata", that is, in order to act on the body, the molecule of the substance must be associated with some of its receptors. This theory, as well as the concept of chemotherapy, became the starting points in the targeted search for drugs in PC, and later in modern medicinal chemistry.

 In attempts to reproduce and improve natural substances, chemists have created many thousands of their analogues since the end of the 19th century. before the beginning 70s of the XX century: barbiturates were synthesized as hypnotics, organomercury compounds, Having diuretic properties, sulfonamides are the first effective antibacterial drugs.

In the late 1930s, H. W. Flory and E. Chain resumed work on penicillin, discovered by A. Fleming in 1928, and in 1944, Z. A. Waksman isolated streptomycin. Thus the era of antibiotics was opened.

In pre-revolutionary Russia, systematic research in the field of PH was almost not carried out; the need for medicinal products was met by supplies from Germany. After 1917, during the three pre-war five-year plans, a large chemical-pharmaceutical industry and domestic schools of chemists were created, which had a huge impact on the development of pharmacy. Enough to name names

À. E. Favorsky, N. D. Zelinsky, S. S. Nametkin, I. L. Knunyants, V. M. Rodionov, A. P. Orekhov, M. M. Shemyakin,

À. B. Arbuzov, M. I. Kabachnik, N. K. Kochetkov and others. During the Second World War there was a need for counter-

vomalarial drugs replacing quinine, since its delivery from Indonesia has ceased. This circumstance became a powerful incentive for the synthesis of new drugs. 16 thousand compounds were studied and only in the 7618th experiment chloroquine was obtained,

à then primaquine.

50–60s of the XX century. many psychotropic drugs were created: strong tranquilizers (chlorpromazine, meprobamate), chlordiazepoxide(the first representative of the benzodiazepine class),

à also antidepressants (eg imipramine), which made it possible to treat depression, schizophrenia and other nervous disorders. In the same years, compounds were synthesized that have a hypotensive effect and are used to treat cardiovascular diseases: reserpine and methyldopa.

We emphasize that in the work on the creation of these drugs, purposeful design was not carried out, but the “trial and error” method was used, when organic chemists rather arbitrarily replaced some chemical groups with others. However, gradually, based on the results obtained, an understanding emerged of how the research should be conducted in order to create a drug. The progress of organic, bioorganic and bioinorganic chemistry has stimulated the development of PC and other related disciplines, opening up the possibility of developing fundamentally new effective drugs.

The use of computer methods in organic and pharmaceutical chemistry has led to the development of methods for calculating the structure of molecules: geometry and conformations, charges and electron density maps, energy of molecular orbitals, etc. Thus, it has become possible to quantitatively describe the structural features of even very complex biomolecules. Thus, back in the 70s, a methodological basis was created for the emergence and use of rational approaches to the synthesis of physiologically active substances (drug design - structural concepts for constructing drugs).

PHARMACEUTICAL CHEMISTRY AND INDUSTRY IN THE REPUBLIC OF BELARUS

Providing the population with medicines is an important social problem for any country, and for the Republic of Belarus, taking into account the consequences of the Chernobyl accident, it becomes especially acute. The collapse of the USSR and the centralized supply system negatively affected the state of pharmacy in the Republic of Belarus. The republic faces the task of forming a civilized pharmaceutical market that will be able to provide the population with access to highly effective and safe drugs, both in price and in their range. In the meantime, drugs are in short supply, they are used irrationally, and prices are often too high. The need for imported drugs is satisfied by 20–25%, and for domestic drugs by 30–35%.

The production of drugs is carried out by the Belbiopharm concern, to which Belmedpreparaty JSC, Borisov, Nesvizh and Skidelsky pharmaceutical plants, etc. are subordinate. The construction of new plants, technical re-equipment of existing production facilities and the creation of new joint ventures are envisaged. The pharmaceutical industry of the Republic of Belarus cooperates with many pharmaceutical enterprises in Russia, Ukraine, the Baltic states and with 85 leading pharmaceutical companies from far abroad. Due to the lack of domestic production of many drugs, the republic is forced to purchase them abroad, about a hundred items only for foreign currency. Thus, if the situation does not change, the Republic of Belarus will be forced to invest not in its own production, but in the development of the pharmaceutical industry of foreign countries.

The total capacity of the drug market for the Republic of Belarus is about $200 million, and the share of state budgetary funding accounts for more than 65%. In 1990, enterprises of the Republic of Belarus produced 96, and in the second half of the 1990s - about 300 drugs. Domestic drugs account for about 25% of all receipts; their quality is constantly improving. In 1996, the re-registration of foreign drugs was completed, and since 1997, only registered drugs are allowed for use. By the end of the 1990s, more than 1,700 foreign and more than 300 drugs produced in the Republic of Belarus were registered.

For the development of the pharmaceutical industry in the Republic of Belarus, WHO offers an option that has been tested by some countries of the former socialist community. According to

In this option, the manufacturer should focus on generic (already known) drugs. There is a republican list of 274 vital generic drugs that can be reproduced. To achieve this, three stages are proposed for creating the pharmaceutical industry:

packaging of drugs (the company brings the finished product and organizes its packaging in the Republic of Belarus, which gives a price gain of 10–30%);

after gaining experience in packaging, the premises are expanded, additional equipment is installed, the substance is imported and mixing, tableting or production of solutions is established;

mastering the synthesis of the substance and establishing a full cycle of drug production; Since the chemical base is well developed in the Republic of Belarus, there are favorable conditions for creating such a cycle.

The largest manufacturer of drugs in the Republic of Belarus is JSC Belmedpreparaty. It has been known on the pharmaceutical market for about 70 years; During this time, the range of drugs increased from 36 to 180 items. In 1994, the Scientific and Pharmaceutical Center was created, which is equipped with modern equipment, has experimental, technological and production areas where drugs are produced for in-depth biomedical and clinical trials. The main areas of work of the center:

introduction into production of generic drugs that were not previously produced in the Republic of Belarus and are included in the list of vital drugs;

creation and organization of production of branded (original) drugs based on own scientific developments and proposals of scientists from Belarus and Russia.

Thanks to these works, the niche will be filled in the near future antineoplastic Medicines through the development of technologies for the production of cytarabine, mercaptopurine, thioguanine, cyclophosphamide, doxorubicin, cisplatin, anti-tuberculosis, immunomodulatoryè cardiotropic drugs. New “biotechnological generation” drugs have been developed using microbiological synthesis. A series of unique plasma-substituting solutions based on radiation-modified polysaccharides: neorondex and rondferrin. Pilot industrial production of a number of drugs of polyunsaturated fatty acids of microbiological origin (áèåí, dermaref) with antiallergic activity and the ability to stimulate reparative processes has been organized.

Significant advances have been made in the technology for obtaining the substance and ready-made insulin dosage forms, which now meet the requirements of international standards.

Work is intensively underway to create synthetic antibiotics based on fluoroquinolones and antiviral drugs based on nucleic acids. Of particular interest is the work on the creation of drugs for the treatment of acquired immunodeficiency syndrome (AIDS).

Work on the creation of technologies for the production of enzyme and antienzyme drugs is of great importance. Microbiological synthesis of alpha-amylase, protease, xylonase, cellulase, and ovamine was carried out.

One of the leading enterprises in the country is the republican unitary enterprise Borisov Medical Preparations Plant. It mastered more than 200 drug production technologies, in particular original drugs based on modified cellulose, which were developed in collaboration with the Research Institute of Physico-Chemical Problems of the Belarusian State University. These include polycapran (hemostatic), film with lincomycin(antimicrobial drug), drug "Lincocel" (wound healing drug), etc.

The achievements of pharmaceutical science and industry in the Republic of Belarus are evidenced by a number of created drugs that have no foreign analogues (neorondex, rondferrin, ovomin, ronasan, áèåí, etc.). The production of the anti-leukemia drug cytarabine has been established, and pilot batches of cladribine have been obtained; Zamcyt (against AIDS) and Hephal (used in gastroenterology) are being introduced into production.

WORLD PHARMACEUTICAL MARKET

According to some data, the pharmaceutical industry is in 3rd-4th place in terms of profitability. The special place of the pharmaceutical industry among the spheres of entrepreneurial activity is determined by the fact that health is always the primary concern of both each individual and society as a whole. The demand for effective and safe drugs is constantly growing.

By the beginning of the 1990s, the annual production of drugs amounted to more than 300 thousand tons, among them about 500 main ones can be distinguished, and the production of some is truly impressive. Thus, the amount of acetylsalicylic acid reaches 50 thousand tons per year, so much

ascorbic acid, paracetamol - about 30 thousand tons, -lactam antibiotics - about 16 thousand tons, sulfonamides - 8 thousand tons are produced. At the same time, the need for some drugs is tens of kilograms or even less than one kilogram (for example, peptide hormones, interferons, etc.). Accordingly, the cost of drugs varies widely: from 10 dollars/kg for aspirin to 1000 dollars/g or more for anti-AIDS drugs and highly active peptide hormones. The value of global pharmaceutical products is expected to exceed $400 billion by 2003. It is generally accepted that highly developed countries such as the USA, Germany, France, Great Britain, Japan, etc. play a leading role in the production of pharmaceutical products.

The functioning of pharmaceutical companies is determined by two main interrelated factors:

social necessity;

economic expediency.

Social necessity is directly related to the fact that currently the mortality rate from infectious diseases in the world is 33% of the total mortality rate. According to WHO, the incidence of malaria reaches 500 million cases annually (mortality is about 2 million people per year), acute respiratory diseases claim the lives of at least 4 million, tuberculosis – about 3 million people per year. Viral hepatitis is becoming a global health problem: at least 350 million people are chronic carriers of the hepatitis B virus, and 100 million are chronic carriers of the hepatitis C virus.

A serious problem arose due to the emergence of previously unknown diseases. Thus, according to WHO estimates, from 1975 to 1996, more than three dozen new diseases were registered (for example, Ebola fever, Hanta virus pulmonary syndrome, new cholera strain 0139, etc.).

No less alarming is the problem of mutation of viruses and microflora. In this process, resistance to drugs used in medical practice is developed, which is indirectly reflected in the annual renewal of the pharmaceutical market nomenclature by 1–2%. Thus, in 1963, cases of pneumonia that were not amenable to treatment with drugs of the tetracycline group were first described. Later, the causative agents of this disease became resistant to erythromycin and lincomycin, and now multi-resistant strains have spread everywhere in Europe and the USA.

Unfortunately, society’s desire to overcome the situation associated with changes in the structure of population morbidity, the emergence of new diseases and the general deterioration of the epidemiological situation in the world is limited by financial resources.

Therefore, the question arises about the economic feasibility of the functioning of pharmaceutical companies. On the one hand, there is an objective increase in the cost of research and experimental work, due to the need to use increasingly advanced and expensive equipment and to expand specific samples (per successful drug) of the substances under study. On the other hand, society, fearing the mistakes of manufacturers, limits the development of the pharmaceutical industry to various standards, the implementation of which leads to an increase in the cost of development and production of new drugs.

According to the US Pharmaceutical Manufacturers Association, from 1977 to 1987, research and development (R&D) spending in the US pharmaceutical industry increased by 321%, compared with the average increase of 188% in other industries. The steady increase in costs for such work is one of the main trends in the modern pharmaceutical industry. According to leading economists, it is the availability of financial resources that allow conducting fundamental scientific research that distinguishes from the total mass of pharmaceutical companies a group of leaders (20–30 companies) that are able to annually introduce one or two new drugs to the world pharmaceutical market (based on one company).

The increasingly stringent system of state control over drug safety is another factor determining the significant increase in the cost of new drugs. Thus, in the USA, the strict requirements of the standards of the Federal Pharmaceutical Administration (FDA - Food and Drug Administration) are one of the significant reasons limiting the entry of a number of fundamentally new drugs into the American and world markets. The combination of the above factors determines the phenomenon of declining net profits for some leading pharmaceutical companies.

It is possible that the creation of a new drug will be impossible not because of a lack of knowledge and skills, but because of a lack of financial resources. This takes into account the costs of the pharmaceutical industry and its own source of R&D funding (expert estimates put the research costs for creating a new drug at $200 million or more, and the total costs of bringing a drug to market at $500 million). It should be especially emphasized that, among other industries, the pharmaceutical industry finances R&D costs from its own resources.

The pharmaceutical industry is undergoing significant changes

tions due to an increase in the cost of research and development, a shortening of the period of patent-protected sales and the availability of generic drugs. Their share in the pharmaceutical markets of developed countries currently ranges from 30 to 50%. One of the first reactions of the pharmaceutical industry to the interest in generic drugs was to improve research and development and reduce the time to bring new products to market. Thus, leading pharmaceutical companies have reduced the time to develop a new product from 10–12 to 8–9 years and expect to reach the level of 5–6 years. Nevertheless, the research sector is faced with the urgent task of finding new, cheaper ways to create drugs.

An undoubted factor for commercial success in the pharmaceutical industry is the development of new concepts for creating drugs. Their implementation is an extremely rare event and, as a rule, is possible only due to fundamental changes in the scientific, production and sales sectors of the pharmaceutical market. However, statistics from recent years indicate that an ever-increasing volume of company profits comes from new drugs. Thus, from 1976 to 1981, for firms operating in the American market, new products accounted for up to 22% of profits and 28% of sales volumes, from 1982 to 1987, 31 and 37%, respectively, and from 1988 to 1993. – 44 and 49%.

A typical example of underestimating the potential of a new approach to drug development is the history of the creation and introduction of antibiotics (penicillin) into medical practice, when a new concept, rejected in Europe, was brilliantly implemented by US pharmaceutical companies. This was one of the main reasons for the loss of leading positions by Old World companies in many areas of the pharmaceutical business.

To the main economic stages developments in the global pharmaceutical industry include the following:

formation of new knowledge about drugs;

development of new technology for obtaining drugs;

creation of drugs capable of curing previously incurable diseases or significantly superior in effectiveness to those known on the market;

market expansion;

the emergence of new financial opportunities for pharmaceutical companies;

bringing the industry as a whole to a new qualitative level. This important stage in the separation of pharmacy from the chemical industry

riya into a separate industrial sector of the economy began with

40–50s of the XX century. and was accompanied by a sharp increase in production and sales of pharmaceutical products. The emergence of the pharmaceutical industry was due to the widespread use chemical synthesis to receive drugs. And the next, no less important stage in the development of the pharmaceutical industry was the introduction of biotechnology. Antibiotics, serums, vaccines, and enzymes were created on their basis. From a macroeconomic point of view, the use of biotechnology has placed the pharmaceutical industry among the most important sectors of the economy. By the end of the 20th century. There were about 400 biotech companies in Europe, a third of the number in the United States. More than half of pharmaceutical companies were created after 1985. According to experts, the volume of global sales of biological products is growing faster than the sale of traditional synthetic drugs. Thus, in the first half of the 90s, the growth rate of sales of biological products was estimated at 42% (more than 8% per year).

Appearance genetic engineering contributed to the creation of highly productive strains of producing microorganisms, as well as new generations of antibiotics, amino acids and vitamins. It should be noted that the implementation genetic engineering technology will require a transformation of public consciousness and the development of new ethical standards.

A more distant prospect is gene therapy, which involves the use of drugs that act at the level of genetic changes in cells. However, problems associated with a high level of risk in the development of genetically engineered products do not allow us to confidently predict the use of this concept as a basis for overcoming the crisis of innovation in the period from 2000 to 2005. These problems include the small percentage of developed products reaching the third phase clinical trials, imperfections in the relevant legislation, ethical issues, as well as investor mistrust.

One of the latest advances in technology in the pharmaceutical market is the creation optically pure chiral LW. This approach has proven to be very effective pharmacologically and commercially. If at the end of the 1980s, global sales of chiral drugs amounted to 10–15 billion dollars, then already in 1994 the market for drugs based on pure enantiomers reached 45 billion dollars, and at the beginning of the 21st century, according to forecasts, it could reach 70 billion dollars. However, the ability to use this approach is limited by the list of substances with optically active molecules, as well as some technological problems. Thus, with conventional separation methods (diastereoisomeric, enzymatic) a large amount of

moves; The frequently used asymmetric synthesis also does not yet meet industrial economic requirements.

A number of experts put forward the hypothesis of using the principles combinatorial chemistry as a key technology that allows obtaining and optimizing drugs for subsequent biological screening(see below for more details). The number of alliances between leading manufacturing firms and companies specializing in the field of combinatorial chemistry indicates the significant potential of this approach. To date, the basic principle of combinatorial chemistry has largely been implemented - the creation of computer “chemical libraries”. However, the practical success of such a strategy remains quite modest due to the high complexity of computer modeling of real receptors and the conditions of their interaction with molecules.

In Fig. 1 schematically reflects the features of the development of scientific and technological views in the field of drug creation.

Prehistoric		Use of natural resources in treatment
sky times				(plants, animals, minerals)
Middle Ages		Isolation of active components from natural raw materials
			Laboratory chemical methods
		Isolation of natural							Synthesis of compounds
		ral biological							and isolation of pharmacological
		ski active							gically effective
									components
		Industrial technologies for drug production
				Creation							Receipt
				drugs for wasps
											new forms
	chemical			new plant-
											famous
				leg and stomach
											drugs
				new raw materials
											Chiral
											medicinal
											ny substances

Res. 1. Main directions of development of scientific and technological developments in the field of drug creation

Attempts by the management of leading companies to maintain sustainable economic performance in the face of a critical increase in R&D costs and increased competition with companies producing generic drugs very eloquently reflect the process of active mergers of pharmaceutical companies, which is very typical for 1985–1997. Vertical and horizontal consolidation in the pharmaceutical industry leads to a sharp increase in the share of the global pharmaceutical market controlled by the 10 leading companies: in the 80s - about 35%, in the 90s - more than 40%, and the forecast for the first decade of the 21st century. is 50–60%. The merger strategy achieved its goals: at the end of the 20th century. The production growth rate of the global pharmaceutical industry was 15–20% per year, and the average profit level was 18–30%.

What could be the forecast regarding the possibility of the emergence of new concepts for creating drugs? Expert analysis of the situation on the global pharmaceutical market and scientific publications suggests that the fastest growing sectors of the pharmaceutical industry will be biotechnological enterprises and companies producing chiral drugs. However, as already noted, the basic concepts for creating new drugs that underlie these approaches do not cover the lack of innovation, which, with the aggravation of tensions in the epidemiological sphere, further exacerbates the need to search for fundamentally new approaches to creating drugs.

MAIN CLASSIFICATIONS OF MEDICINES

There are quite a few types of drug classification. By nature of the action they can be divided into three categories:

pharmacodynamic drugs that act in a corrective manner on the course of disturbed physiological processes;

diagnostic tools designed to recognize the disease, as well as monitor it during treatment.

This approach reflects effects of drugs on a particular physiological system : central nervous system (CNS), blood system,cardiovascularsystem, psyche

è etc. In each of these divisions, drugs are usually grouped according to their chemical structure.

More convenient for practical clinicians nosological(from the Greek nosos - disease) classification in which the distribution of drugs into groups is carried out depending on pharmacotherapeutic action for the treatment of certain diseases

(cardiovascular, psychotropic, gastrointestinal, etc.). At the same time, drugs with different chemical structures fall into one group. This classification is used in some drug reference books, in particular in M.D. Mashkovsky, as well as in textbooks on pharmacology. The chemical classification of drugs has been adopted in the pharmaceutical industry, since it mainly allows for the distribution of drugs into groups according to their chemical nature and structure, although such a division is often difficult and largely arbitrary. Chemical classification is often used when considering material in textbooks on chemical chemicals, as well as in scientific and applied works to solve the following problems:

research on methods for obtaining drugs;

establishing a connection between structure and pharmacological action;

to develop methods for pharmaceutical analysis based on the chemical and physical properties of drugs.

In this system, all drugs are divided into inorganic and organic, although in this way it is not possible to avoid a conditional approach. For example, there are many drugs containing metal atoms, complex compounds and simply mixtures of inorganic

è organic compounds (many salts, compound drugs, etc.). Note that organic drugs, as well as organic compounds in general,

units, much more (about 90%) than inorganic ones, which does not mean that inorganic drugs are unpromising.

Organic drugs are divided into derivatives of aliphatic, alicyclic, aromatic and heterocyclic series, and then - accordingly according to classes: saturated and unsaturated hydrocarbons, halogenated derivatives, alcohols, aldehydes, ketones, acids and their numerous derivatives, etc. Heterocyclic drugs are systematized according to the type of main heterocycle. Of course, such a division does not always allow a clear classification of many drugs that contain various functional groups and/or heterocycles.

Natural biologically active substances, which often have a complex chemical structure, are usually considered separately and the following classes are distinguished among them: terpenes, alkaloids, hormones, vitamins, many antibiotics, etc. These are organic compounds that participate in regulation any functions of the body and have a specific effect.

The above characteristics do not exclude the role of steric and chiral factors, point symmetry groups of molecules and conformational parameters. All these factors influence not only the complementarity of the drug to the corresponding target, but can also play a decisive role in determining the type of activity.

Classification inorganic drugs carried out in accordance with the position of elements in the periodic table of D.I. Mendeleev and according to the main classes of compounds (salts, oxides, hydroxides, complex compounds). When assessing the possibilities and limitations of the classification to characterize the relationship between the chemical structure and pharmacological action of drugs, it is necessary to pay attention to the following circumstance: although in each group of the periodic table drugs of various pharmacotherapeutic groups are represented, in some cases drugs of a certain action may predominate.

Since the above classifications are not without some drawbacks, the FH uses mixed classifications, in which various features are taken into account simultaneously. One variant of this approach is the classification proposed by P. J. Sadler. It relates primarily to the biological activity of metal complexes and their use in PC. Currently, metal complexes are an intensively developed area of ​​chemistry, which is of great practical importance for medicine. The basic principle of Sadler's classification is the division of drugs into three main groups by mechanism of action, since it is in the mechanism of action of the drug that the “structure-function” relationship is most fully realized. This approach takes into account both the chemical and pharmacological side of the problem.

The first group of compounds includes those that can (and should) remain associated with the metal when it reaches the corresponding target in the body. For this group of LPs it is essential that the substance used remained completely or partially unchanged at the target compared to the initial state.

In the second group compounds, metal ions are usually kinetically labile, and the nature of the initial ligands is less important for the manifestation of activity at the target (although ligands can have a great influence on the absorption and distribution of the drug).

The function of the ligand in this group is transport : the ligand promotes the delivery of the drug to the target, but has virtually no effect (or very little effect) on the biological activity of the metal in relation to the target.

In the third group, one of the functions of a metal can be delivery of a biologically active ligand to the target. Such active ligands may include organic drugs, agents that target metals in the active site of various enzymes, etc.

It should be noted that Sadler’s classification is not rigid: some drugs can be placed in more than one class, while others have not yet found an appropriate place in it due to the lack of information about the mechanism of their action. In addition, it is not comprehensive enough, since it mainly deals with metal complexes.

The positive characteristics of Sadler's classification include an attempt to consider from a unified perspective the effect of inorganic and organic drugs in the body, since therapy can become more sophisticated due to their more frequent combination. It is also important that the question of the form in which the active principle of a drug can exist after its introduction into the body does not disappear from consideration, and is also taken into account organotropyËÑ.

 Recently, a systemic valeological approach has been gradually introduced into healthcare practice ( valeology from lat. valeo - to be healthy and Greek. logos – word, teaching). Thus, the term “valeopharmacology” is already widely known, denoting one of the branches of pharmacology. Valeopharmacology studies pharmaceutical and parapharmaceutical agents used to achieve and maintain human health under the influence of changing factors of the external and internal environment. However, the classification of valeopharmacological medicinal products (VPMD) has not yet been developed, which complicates the development of valeopharmacology as a science and its implementation in pharmaceutical marketing practice.

The traditional pharmacotherapeutic classification of drugs is focused on a group of the population (36%) with specific medical indications for the use of drugs, and is unacceptable for the rest (64%) of potential drug users. The problem of VFLS classification cannot be solved by isolated classification principles: by mechanism of action, organotropy, chemical structure, origin. The VFLS classification is based on principles that emerged as a result of the integration of Western and Eastern concepts of health. The main principle is expediency, the secondary principle is the direction of action. Organotropy, origin, mechanism of action are taken into account to a lesser extent.

All pharmaceutical and parapharmaceutical products are divided into four groups:

adaptogens – means for preserving sufficient adaptive reserves of a healthy person; these include multivitamins, antiseptics, minerals, emergency infection prevention products, family planning products, vaccines and toxoids, personal hygiene products, etc.; the use of these drugs is advisable for people with any health condition;

protectors - means for protecting and optimizing the intense adaptive capabilities of a person who is in a pre-nosological state or exposed to extreme influences; these include angioprotectors, enteroprotectors, dermatoprotectors, membrane stabilizers, antihypoxants, etc.;

correctors - means that increase the reduced reserves of human adaptation and are capable of correcting “borderline” disturbances in the functioning of organs and systems; these include antioxidants, behavior correctors, nootropics, hematopoiesis correctors, neuromodulators, enterosorbents, immunocorrectors, gastrointestinal tract function correctors, endocrine system function correctors, etc.;

pharmacotherapeutic agents – means for the treatment of patients with a certain nosology and symptoms (with manifestations of maladjustment).

Unlike pharmacotherapeutic agents, adaptogens, protectors and correctors make up the arsenal of VFLS, the purpose of which is to preserve and strengthen health, and not to treat diseases.

QUANTITY, NAMES, COST, SAFETY OF MEDICINES

The number of drugs amounts to many hundreds of thousands and is constantly increasing, but by the end of the 90s, about 5,000 drugs were used in the world. It should be borne in mind that many of them are being discontinued because they are becoming obsolete and are being replaced by new, more effective and safe ones.

Pharmacopoeias of different countries (i.e., official guidelines for pharmacists, containing a description of the properties, methods of preparation, storage, quality control, dosages, therapeutic prescriptions) number from 2 to 15 thousand drugs. On the one hand, such an abundance of drugs in terms of therapeutic possibilities makes the doctor’s work easier, but on the other hand, the variety of drugs used in

treatment of even one disease (taking into account their effectiveness, side effects, compatibility with other drugs) significantly complicates the work of doctors. Therefore, back in 1977, WHO proposed to consider only about 200 drugs as essential, which are effective, fairly safe, have a pronounced known therapeutic effect and can be produced on a mass scale at reasonable prices, since they are not protected by patent law. Since then, this list has been revised several times and minor changes have been made to it (about 300 drugs).

The reference book “Essential Medicines” contains about 450 drugs; The “Register of Medicines of Russia” in 1998 included about 4.5 thousand drugs, and the “List of Medicines Vital for the Population of the Republic of Belarus” indicated 274 drugs (the complete list of human diseases, i.e. nosological units, is about 10 thousand). Such lists allow the pharmaceutical industry to develop plans for the most complete and expedient provision of medicines to the population, and doctors to more clearly navigate the possibilities of treating certain diseases.

Among the most used drugs, the first place is occupied by cardiotropic drugs for the treatment of diseases of the cardiovascular system (18%); followed by bactericidal agents and drugs against infections (17%), among which the leading place belongs to systemic antibiotics. The following active substances can be mentioned: acetylsalicylic acid, ascorbic acid, ampicillin, chloramphenicol, digoxin, erythromycin, nitroglycerin, heparin, tetracycline, vitamins, bisacodyl, furosemide, diazepam, reserpine, ibuprofen and many others.

Every year, pharmaceutical companies synthesize tens of thousands of new chemical compounds that are tested for biological activity in many ways. These include up to 100 types and more specific activities (antitumor, antibacterial, antiviral, anticonvulsant, radioprotective, analgesic, nootropic, etc.). On average, only one out of 10 thousand compounds selected for testing reaches the consumer in the form of a drug. Ideally, such verification is required for any newly synthesized chemical compound (about 500 thousand per year). According to estimates made in 2000, the creation of a modern original drug and its introduction to the market abroad takes 8–15 years and costs $300–800 million; However, there is always a risk of drugs being withdrawn from production due to some unaccounted for or remote effects. The usual duration of operation of most drugs in Western markets is one and a half years, although there are “long-lived” drugs (for example, aspirin has been known since 1899).

MAIN DIRECTIONS AND PROSPECTS FOR DRUG CREATION

SOURCES OF OBTAINING MEDICINES

All medicines can be divided into three groups:

completely synthetic (most of them, about 80%);

natural compounds;

semi-synthetic, i.e. obtained from natural substances.

In Fig. 2 schematically shows the traditional sources of obtaining new drugs.

Vegetable					Animals		Synthetic chemicals
materials							chemical compounds
Extracts			Individual chemical compounds		Bioregulators and metabolic intermediates		Products of “non-target” chemical synthesis		Targeted synthesis products

Bacterial

products

Study of pharmacological activity and development of dosage forms

MEDICINES

Res. 2. Traditional sources of obtaining new drugs

The numerical superiority of synthetic drugs, of course, does not mean that other groups of drugs are unimportant or unpromising, since the latter include classes of compounds such as alkaloids, cardiac glycosides, polysaccharides, many vitamins and antibiotics, etc.

Most natural and semi-synthetic drugs have a very complex chemical structure, and their complete chemical synthesis is currently difficult or impossible. Many antibiotics, natural amino acids, steroid compounds, peptide hormones, including insulin, interferons, antibodies, etc. are now obtained through microbiological synthesis. Recently, this path has been extremely relevant and has good prospects.

It should be noted that it is more economical to obtain synthetically many important drugs that were previously traditionally isolated from natural sources (amino acids, chloramphenicol, caffeine, dopamine, prostaglandins, almost all vitamins, etc.).

The sources of inorganic drugs are mineral raw materials: waters of lakes, seas, underground sources, minerals, ores, chemical industry products.

For the synthesis of synthetic organic drugs, products from the processing of oil, gas, coal, oil shale, peat, wood, plant and animal raw materials are used. For example, such important products as methanol, acetone, acetic acid, phenols, furfural, glucose, ethyl alcohol, etc. are produced only from wood.

Plant raw materials are very promising for obtaining drugs: leaves, buds, bark, roots, fruits of various plants. This is how many essential and fatty oils, resins, proteins, carbohydrates, glycosides and others are synthesized, which are either used directly as drugs or as raw materials for their production. It was from the medicinal plants known in folk medicine that many fundamentally new classes of drugs used for wound healing, treatment of cardiovascular diseases, mental disorders, cancer, etc. were first isolated and subsequently acquired enormous importance.

Interest in plants as a source of biologically active substances arose a long time ago. Extensive information about medicinal plants has been collected over thousands of years. In the ancient papyri of Egypt, a description of about 70 plants was found, including datura, opium, mint, aloe, castor and camphor oils, which are still used today. Hippocrates also described 230 medicinal plants, and Dioscorides increased their number to 500. In the book “Pharmacognosy in

medicine,” which was written by Abu Raikhan Biruni, a contemporary of Ibn Sina (Avicenna), already lists 750 species. In the second half of the 19th century. About 3,500 plants were used in different regions of Russia. In 1898, botanist G. L. Dragendorf had information about 12 thousand medicinal plants. Unfortunately, there are still few plants that have been comprehensively studied in accordance with the requirements of modern science. Their research is a very difficult task, since each plant is a complex mixture of components. Nevertheless, about 30% of drugs used in medicine are obtained from medicinal raw materials.

Research into hydrobionts, in particular marine organisms, has great prospects for the production of drugs for various purposes: vitamins, prostaglandins, polyenoic acids, iodine and bromine drugs, antioxidants, etc. For example, the companion of the spotted yellow coral Eleutherobin, discovered off the coast of Australia, is capable of stop the growth of malignant tumors and destroy metastases, and a composition made from yellow soft coral has been shown to have high antimetastasis activity in some cancers. Another discovery - Pseudopterogorgia elizabethae - is more active than the known hydrocortisone and can help in the treatment of psoriasis and arthritis.

Analysis of the chemical nature of the sources of drug production is an important stage in the informed choice of rational synthesis conditions. It allows you to evaluate possible impurities and select methods for purifying a substance: for example, impurities of copper, silver, lead in bismuth compounds, copper impurities in iron compounds, copper and aluminum impurities in zinc compounds, etc.

The role of chemistry in the creation of new drugs is enormous. A chemist who wishes to become a pharmacochemist must have certain knowledge in the fields of biology, physiology, biochemistry, immunology, pharmacology and, of course, pharmaceutical chemistry.

MAIN DIRECTIONS AND STAGES OF DRUG SEARCH

One of the main areas of PH is the search and implementation of new, more effective and safe drugs. Creation of highly effective drugs and their introduction into clinical practice in the 60–70s of the 20th century. became possible thanks to the successful completion of work on the study of extracts of natural products of the plant world, animal tissues, the isolation of modifications of individual biologically active substances and the use of their medicinal properties identified during general screening (systematic testing of various substances for activity).

The creation of a new drug requires significant funds and hard work of many scientists and practitioners. Of the total costs of creating a drug and releasing it to the market, about 40% falls on the invention process, which amounts to about $200 million. This huge amount also includes the costs of unsuccessful attempts. It has been established that only one out of three drugs turns out to be quite successful in terms of cost recovery and only one out of fifty becomes a “giant” with a billion-dollar turnover.

 In solving the problem of rational search and design of biologically active substances, two main directions can be distinguished - the search for new drugs and the improvement of known drugs.

 practice of pharmaceutical and medicinal chemistry using

There are several main approaches to the search for new drugs.

1. Fundamental research into the biochemical causes of diseases. This path is the most difficult and time-consuming, especially

that our knowledge about the biochemical processes during the functioning of the human body under normal conditions and in pathology is in most cases very limited. However, almost all problems can be solved in this way - deep study and understanding of the nature of diseases at the molecular level. In this case you can correct pathology by influencing various regulatory mechanisms - enzymes, hormones, neurotransmitters. The drug search strategy significantly depends on the initial data about already known drugs, targets of their action, etc. These data are necessary for the search for compounds with high and selective bioactivity and are conditionally divided into four main categories:

the structures of the receptor and ligand are known;

the structure of the receptor is known, but the structure of the ligand is unknown;

the structure of the ligand is known, but the structure of the receptor is unknown;

the structures of the receptor and ligand are unknown.

The concept “receptor” is used in a broad sense to refer to any macromolecule that is the target of a drug in the body, and the concept “ligand” is used to refer to any endogenous compound that interacts with this receptor.

When studying metabolic products and their chemical derivatives based on known drugs, it becomes possible to evaluate the mechanism of biotransformation. Sometimes metabolites turn out to be more active than the original molecules or have a different nature of action, which can initiate the creation of a new drug. These studies are complemented by the study of side effects on the body of drugs that are used in practice or undergo

tests.

2. Isolation from natural sources as a model of a compound inherent in the body (endogenous) or having some effect on it, synthesis of analogues of such a compound (including research and analysis of people's data

Noah and traditional medicine). A study of the drugs that have the greatest success in the pharmaceutical market shows that about 50% of them are obtained from natural substances or are directly natural compounds. However, screening of natural substances is not the main way in the process of drug invention and, according to experts, purchases of natural substances amount on average to no more than 10% of the estimate for creating a collection of compounds. Currently, the largest collection of data on isolated and characterized natural substances includes about 100 thousand compounds, while the real world contains tens of millions of substances. This indicates that isolating a natural substance and establishing its structure requires a long time and significant

material costs.

3. Obtaining chemically modified structures - analogues of known drugs, the effect of which has been proven. This method

improvement of existing drugs has been developed better than other methods, since By making changes to the molecular structure of a drug, it is often possible to eliminate side effects, increase activity and selectivity of action. The basic idea of ​​chemical modification is that compounds with similar structures have similar effects.. By systematically varying the structure of the molecule, a compound with the desired properties can be obtained. The difficulty is that the number of possible changes, even for small molecules, is extremely large, and the researcher needs to sort through many options. It is well known that the character of the action

The viability of a drug is determined not only by the similarity of structure. It consists of the electronic, steric and transport properties of the compound. Structural changes affect each of these factors differently, so that structural similarities are often unclear.

4. Screening of chemical compounds and natural substances.

Screening in the creation of drugs was first used at the beginning of the 20th century. P. Ehrlich to obtain antisyphilitic drugs based on organic arsenic compounds.

The first stage of searching and designing drugs, as a rule, consists of identifying and synthesizing new biologically active substances, usually called basic connections, and in foreign pharmaceutical literature – leading compounds(lead-compound). The leader compound is a kind of structural prototype of the future drug, on the basis of which the drug is created in the future.

In the history of the creation of drugs, there are quite numerous examples when the leading compound was found by chance. Thus, nitroglycerin was discovered, which led to the synthesis of many esters of aliphatic alcohols with nitric acid, and penicillin, on the basis of which its numerous analogues and derivatives were synthesized.

However, usually the initial search involves systematic testing (screening) of various substances for activity. There are two types of it:

study of a large number of compounds in one biological test;

study of several compounds with original structures in many biological tests.

These methods are labor intensive and expensive, severely limiting the testing of a very large potential set of substances. When screening, the term hit-compound is sometimes used, which means “hitting the target,” i.e., identifying a compound with physiological activity. Then compounds with a similar structure are tested, from which the leader compound is selected.

The lead compound can not only be obtained by organic synthesis, but also isolated from natural sources. An example of a lead compound found through systematic screening of natural compounds is taxol, an effective anticancer agent.

In modern PC there are several strategies for directed search for a leader compound. With the development of computer and robotics, the so-called total, total

ny or continuous screening(High Throughput Screening, HTS), which is a mass biological testing of chemical compounds, i.e. testing for the biological activity of all new compounds, regardless of their structure and purpose (for example, as a pesticide or plastic stabilizer). In many chemical and pharmaceutical centers, a substance is tested for 30–70 or more types of specific activity in vitro and in vivo. These tests discard compounds that are inactive, inactive, toxic, prohibitively expensive, or difficult to synthesize.

If a therapeutic effect is detected, the substance is subjected to further in-depth testing. Synthesis of related compounds (analogs) is also carried out to find the most active and safe compound in a given series. The blanket screening method is typically used for radiolabeled ligand displacement and enzyme inhibition tests. Among the successes of the continuous screening method, one can note the production of lovastatin, which has become the leading compound for a new generation of drugs that lower blood cholesterol levels.

The development of continuous screening methods gave rise to a new direction in organic synthesis - synthesis " combinatorial libraries" The latter are a mixture of a large (often very large) number of compounds obtained by the same method using a series of similar reactions and having a controlled composition. This mixture is subjected to total screening, after which those structures of the mixture that exhibit biological activity are identified. At the end of the 1980s, problems in combinatorial chemistry were reflected only in journals. Since then, an entire industry has grown that not only produces large numbers of compounds using this method to enrich compound collections, but also supplies pharmaceutical companies with reagents and equips them with automated process equipment so that they can create compound libraries themselves. Compound collection quality characterized by the following parameters:

number of connections;

chemical diversity, determined by molecular skeletons and functional groups;

the degree of overlap of this collection with other compounds that can be obtained from external sources;

the number of compounds that can interact with proteins;

the number of compounds that are not likely to interact with proteins;

the number of compounds similar (according to some criterion) to known drugs;

the number of compounds that are not similar to known drugs;

the number of molecular skeletons, in relation to which the rapid development of resistance of microorganisms is unlikely;

the number of molecular skeletons or groups that do not cause unwanted side effects;

degree of purity, polarity, stability of compounds;

cost of connections;

the opportunity to pass the test and create a drug prototype. Since the number of connections in the collection is currently

time usually exceeds a million, the cost of continuous screening remains high if it is intended to be carried out each time for the entire collection. Nowadays, the quality of a collection means greater demands on the compounds purchased or the ability to select those compounds that will be screened for the required properties.

The issue of compound stability is directly related to the problem of selection quality, since some companies store their collections of compounds frozen in cassettes, and in order to select an individual compound from the collection, it is necessary to thaw the entire cassette. During the defrosting-freezing process, the possibility of moisture entering cannot be excluded, which can lead to the decomposition of easily hydrolyzed substances. According to expert assessments of the quality of existing collections, about 30% of the compounds in them have already decomposed or their real structure does not correspond to the chemical formula in the database.

A targeted search for a leading compound is often carried out among already known drugs released onto the market. It is obvious that in this case the generated structures, as a rule, are quite similar to their prototype (the so-called therapeutic copies). However, the use of this approach has its own specifics: if the leading compound is a known drug that has a fairly pronounced side effect, during the further development of the drug, special attention will be paid to this property. For example, in the 1980s it was shown that antiadrenergic Drugs (-adrenergic blockers), in particular atenolol, also have a hypotensive effect. Therefore, a similar structure was used as a lead compound for the development of antihypertensive drugs.

drugs that would not have β-blocker activity. This led to the creation of cromakalim, the first compound that acts exclusively on the activation of potassium channels, which is responsible for its antihypertensive activity.

By the early 1970s, a real possibility arose of consciously designing lead compounds based on information obtained through the achievements of bioorganic and bioinorganic chemistry, molecular biology (especially thanks to the establishment of the structures of some receptors and enzymes by X-ray diffraction analysis).

Targeted design is especially effective when the structures of the receptor and ligand are known. In this case, you can use methods computer modeling(see more details below) to achieve the following goals: combining the cavity of the receptor or enzyme and hypothetical molecules and ensuring both maximum alignment of the size of the molecule with the size of the cavity, and maximum mutual binding by taking into account hydrogen bonds, electrostatic attraction, lipophilic interactions, etc. The corresponding structural database can also be searched for a suitable 3D molecular fragment. If the substrate of a receptor or enzyme is a peptide molecule, then by analogy it is possible to construct a non-peptide molecule (peptidomimetic) that would act as an inhibitor of this enzyme. A classic example is to use N-succinyl-L-proline as a lead compound for the creation of an antihypertensive drug based on knowledge of the mechanism of the enzymatic reaction of converting angiotensin I into angiotensin II (the latter increases blood pressure by constricting blood vessels). In 1975, an artificial converting enzyme inhibitor was synthesized based on the above compound -

captopril

As noted above, during drug design optimization consists of creating a synthetic modification of the structure of the leader compound in order to increase its activity and selectivity, as well as reduce toxicity. Approaches used at this stage of drug design include changes to the structure of the molecule, resulting in a better match between the molecule and its target in the body, such as an enzyme or receptor. Such approaches often also include the synthesis of structural analogues of the lead compound. Because the number of possible analogues is so large, rational approaches are now widely used to predict which substituents should be used. The main methods on

This stage of development includes computer modeling and QSAR (Quantitative Structure – Activity Relationship, or “quantitative structure-activity relationship”). QSAR is a mathematical tool that allows you to correlate the structures of chemical compounds with their biological activity (see more details below).

An important stage in the development of a drug is to improve its pharmaceutical and pharmacokinetic properties in such a way as to make the drug convenient for clinical use (for example, increase its solubility in water or chemical stability, prolong its action, etc.). This problem is often solved by structural modification and even special synthesis of new structures, and the following approaches are implemented:

Creation bioisosteric compounds(bioisostere is a chemical group that can replace another chemical group, slightly changing the three-dimensional molecular structure and biological activity of the compound);

creation of pro-drugs (pro-drugs) - compounds that do not have pronounced biological activity, but are capable of being converted into active compounds either through an enzymatic reaction or chemically (without the participation of a protein catalyst);

creation of “soft drugs” (soft drugs) - compounds whose pharmacological effect is localized in a specific place; their distribution in other places leads to rapid destruction or inactivation (for example, this strategic technique was used to create drugs against glaucoma);

Creation " double medications"(twin drugs) - biologically active substances containing two pharmacoactive groups combined covalently into one molecule (this definition excludes the combination of two drugs into one salt molecule); double drugs can be identical or non-identical, i.e. have the same or different groups as components, respectively.

It should be especially noted that the latter type of modification allows for the implementation of a variety of combinations that significantly improve the activity and pharmacokinetic properties of the drug. For example, if an enzyme is known that destroys a drug in the body, then it is possible to construct a binary molecule containing in its structure both a fragment of this drug and a fragment of the inhibitor molecule of this enzyme. When this molecule is broken down in the body, inhibition of the enzyme will lead to a prolongation of the action of this drug.

Each of the above types of modifications leads to

actually to the creation new chemical structure. Therefore, it must be taken into account that a new chemical compound may have less activity or a different pharmacological profile, and therefore this part of the research is closely related to the QSAR stage.

At one of the testing stages on experimental animals being checked acute and chronic toxicity of substances: animals are regularly administered certain doses over several months (up to 6 or more) and then signs of side effects of the compound are carefully looked for. At the same time, the functions of all body systems, biochemical blood parameters are determined, and a pathohistological study of the organs of experimental animals is carried out after the end of drug administration. This study makes it possible to judge whether the drug disrupts the functions of organs and tissues of the body with long-term administration, i.e., whether long-term therapy with this compound is safe. The pharmacologist also determines other possible toxic effects of the drug: its effect on reproductive function(ability to produce offspring); embryotoxic effect(the ability to influence the embryo); teratogenic effect(the ability to cause fetal deformities); mutagenic effect. Using special tests, the effect of a drug on immunity, the possibility of its carcinogenic effect, allergenic activity, etc. are studied.

Screening is increasingly performed by in vitro biochemical assays, measuring receptor affinity or determining enzyme inhibitory potency. To study the activity of antibiotics or antiseptics, their effect on the growth and development of cell culture samples, strains of microorganisms or individual organs is studied. Such approaches have certain advantages:

make it possible to exclude laboratory tests on animals

require a small amount of substance (a few milligrams);

provide the possibility of automated and standard testing.

Similarly, plant extracts and fermentation products can be examined, which are first subjected to only rough purification, and when an active principle is detected, a more thorough purification, isolation and determination of the chemical structure of the active substance is carried out.

Connections

similar

and extracts

connections

genomics

Biotechnological

Prototypes

companies

medications

drug candidate

Lipinski)

Library

virtual

connections

connections

pharmacology,

metabolism

Res. 3. Main directions and stages of searching for new drugs

New areas of their search are beginning to emerge, for example, those associated with the development of stereopharmacology.

Today there is no longer any doubt that humanity is in the process of rethinking the concept of drug treatment. Current direction in the evolution of drugs and treatment methods

	Synthesis of regulators and metabolites
	energy and plastic metabolism
	Synthesis of phytotherapeutic drugs
	Synthesis in the ranks of known medicinal
Chemical
directed	Synthesis of connections with programmable
	properties (computer drug design)
	Synthesis of modifications in a series of polymorphic
	medicinal substances
	Stereoselective synthesis of eutomers
	and the most active conformers
	medicinal substances
	Selection of the most active producers
Biological	medicinal substances
	Genetic engineering method of creation
(biotechnology)	active producers of medicinal

Res. 4. Main strategic directions of chemical and biological synthesis of drugs

characterized by a transition from gross influence to fine regulation. This reflects not only the desire of pharmacists to follow the Hippocratic principle of “do no harm,” but also corresponds to the reality of today, the main problem of which is not only environmental pollution of the environment, but also the contamination of the human body with foreign chemical compounds - xenobiotics. It is known that about 10 thousand biologically alien chemical compounds enter the human body with food alone. Contamination of the internal environment of a sick person with synthetic xenobiotics takes on a health-threatening nature, if we keep in mind that there are over 16 thousand medicinal substances, more than 300 thousand dosage forms in circulation on the pharmaceutical market, and there is an obvious tendency towards their growth. Despite the legalized control over the mutagenic, carcinogenic, allergenic, teratogenic activity of newly developed drugs, the problem of environmental safety has sharply worsened. An analysis of achievements in pharmaceutical chemistry and pharmacology indicates that in the field of research for new drugs, the direction associated with the chemical and biotechnological synthesis of drugs is coming to the fore.

tabolites and endogenous bioregulators of metabolic processes. The possibilities of obtaining new drugs by identifying the biological activity of xenobiotics are considered to be largely exhausted. The main idea of ​​a new direction in medicine called orthopharmacology, was formulated back in the 1980s in the works of L. Pauling and his followers: “Fight diseases by changing the concentrations of substances that are contained in the body itself and are vital for it.”

At the present stage of scientific development, when the essence of metabolic reactions at the molecular level has been studied in sufficient detail and the possibilities of their correction in pathological conditions have been identified, endogenous regulators of metabolism (enzymes, prostaglandins, neuropeptides, etc.) and drugs such as metabolites are of increasing interest for pharmacotherapy. There are two main areas for the use of endogenous bioregulators and metabolites in clinical practice:

replacement therapy - administration of a biosubstrate in case of its deficiency;

regulation (stimulation, inhibition) of metabolism in case of metabolic disorders.

In addition, energy metabolism metabolites with high affinity for certain tissues can be used for selective drug delivery or to reduce its toxicity.

Orthopharmacological agents also include specific endogenous regulators such as endothelium, calmodulin modulators, calcitonin and other compounds of this type.

Treatment of various diseases with substances contained

â the body and its vital needs, Apparently, it will allow in the future to avoid unwanted side effects, which are almost always caused by potent drugs (synthetic drugs and plant extracts). It should also be emphasized the importance for modern pharmacology of a systematic study of the therapeutic capabilities of bioregulators and metabolic intermediates due to the fact that they are natural factors in the adaptation of metabolism to extreme situations and pathological influences.

Against the backdrop of the search and development of fundamentally new drugs, it continues to remain relevant modernization of the most valuable drugs

The substances of many drugs are presented in polymorphic crystalline forms, which may be associated with fluctuations in their biological activity. For example, in the series of steroids, sulfonamides and barbiturates, polymorphism is observed in 67, 40 and

Medicinal substances

Eutomers

Active conformers of polymorphic drugs

Prodrugs with selective activation

LV combinations

Long-acting dosage form

LF providing directed transport

Res. 5. Promising options for modernization of LP

63% of samples. In addition, 74–88% of drugs are racemic mixtures of enantiomers. As noted above, the practice of the pharmaceutical industry has examples of creating “new from the known”: when using various polymorphic modifications of the same chemical substance for the production of drugs, as well as stereoselective synthesis of chiral drugs (separation of molecules by optical activity) and technologies for structural modification of drugs based on conformational polymorphism. The latter are called LUK technologies. They are based on the selection of conditions under which stabilization of high-energy conformations of biologically active substances occurs due to the association and solvation of molecules. These modifications are characterized not only by a new crystalline and conformational structure and physicochemical properties, but also by significantly improved biological characteristics. It is believed that LUK technologies make it possible to obtain known drugs in a state in which they are easily biologically adapted to the body, and thereby bring drugs closer to natural regulators of metabolism. One of the most important applied aspects of the new set of technologies is a significant reduction in time (up to 50%) and material costs (3–5 times) for the development of original, patent-protected drugs, which represents one of the most pressing problems for the global pharmaceutical industry.

The variety of factors influencing the pharmacological effect of drugs greatly complicates the search. Since there is not yet a general model or theory for predicting the biological activity of a drug based on its chemical structure, or calculating physicochemical properties based on data on the elemental composition of the substance and the relative arrangement of atoms, the search and