Stages of development of new drugs. Principles for the creation of new drugs
The main tasks of pharmacology are the search and study of the mechanisms of action of new drugs for their subsequent introduction into wide medical practice. The process of creating drugs is quite complicated and includes several interrelated stages. It should be emphasized that in addition to pharmacologists, synthetic chemists, biochemists, biophysicists, morphologists, immunologists, geneticists, toxicologists, process engineers, pharmacists, and clinical pharmacologists are directly involved in the creation and study of drugs. If necessary, other specialists are also involved in their creation. At the first stage of creating drugs, synthetic chemists begin to work, who synthesize new chemical compounds with potential biological activity. Usually, synthetic chemists carry out a targeted synthesis of compounds or modify the chemical structure of already known endogenous (produced in the body) biologically active substances or drugs. Targeted synthesis of medicinal substances implies the creation of biologically active substances with predetermined pharmacological properties. As a rule, such a synthesis is carried out in a series of chemical compounds, in which substances with specific activity were previously identified. For example, it is known that aliphatic phenothiazine derivatives (promazine, chlorpromazine, etc.) belong to the group of drugs effective in the treatment of psychosis. The synthesis of aliphatic derivatives of phenothiazines similar in chemical structure to them suggests that the newly synthesized compounds have antipsychotic activity. Thus, such antipsychotic drugs as alimemazine, levomepromazine, etc. were synthesized and then introduced into wide medical practice. In some cases, synthetic chemists modify the chemical structure of already known drugs. For example, in the 70s. 20th century in Russia, the antiarrhythmic drug moratsizin was synthesized and introduced into wide medical practice, which, according to the leading US cardiologist B. Lown, was recognized as the most promising antiarrhythmic drug of that time. The replacement of the morpholine group in the moracizin molecule by diethylamine made it possible to create a new, original, highly effective antiarrhythmic drug etacizin. It is also possible to create new highly effective drugs by synthesizing exogenous analogs (obtained artificially) of endogenous (existing in the body) biologically active substances. For example, it is well known that the macroergic compound creatine phosphate plays an important role in the transfer of energy in the cell. At present, a synthetic analogue of creatine phosphate has been introduced into clinical practice - the drug Neoton, which is successfully used to treat unstable angina pectoris, acute myocardial infarction, etc. In some cases, not a complete structural analogue of an endogenous biological substance is synthesized, but a chemical compound close to it in structure. In this case, sometimes the molecule of the synthesized analog is modified in such a way as to give it some new properties. For example, the structural analogue of the endogenous biologically active substance norepinephrine, the drug phenylephrine, has a vasoconstrictor effect similar to it, however, unlike norepinephrine, phenylephrine in the body is practically not destroyed by the enzyme catechol-O-methyltransferase, therefore, it acts for a longer time. Another way of targeted synthesis of drugs is also possible - a change in their solubility in fats or water, i.e. changes in lipophilicity or hydrophilicity of drugs. For example, the well-known acetylsalicylic acid is insoluble in water. Attachment to the molecule of acetylsalicylic acid lysine (drug acetylsalicylate lysine) makes this compound easily soluble. Being absorbed into the blood, this drug is hydrolyzed to acetylsalicylic acid and lysine. Many examples of targeted drug synthesis can be cited. Biologically active compounds can also be obtained from microorganisms, plant and animal tissues, i.e. biotechnological way. Biotechnology - a branch of biological science in which various biological processes are used to produce materials, including drugs. For example, the production of natural antibiotics is based on the ability of a number of fungi and bacteria to produce biologically active substances that have a bacteriolytic (causing the death of bacteria) or bacteriostatic (causing the loss of the ability of bacterial cells to reproduce) action. Also, with the help of biotechnology, it is possible to grow a cell culture of medicinal plants, which, in terms of biological activity, are close to natural plants. An important role in the creation of new highly effective drugs belongs to such a direction of biotechnology as Genetic Engineering. Recent discoveries in this area, which have shown that human genes are cloned (cloning is the process of artificially obtaining cells with desired properties, for example, by transferring a human gene into bacteria, after which they begin to produce biologically active substances with desired properties), have made it possible to proceed to a wide industrial the production of hormones, vaccines, interferons and other highly effective drugs with predetermined properties. For example, transplantation of a human gene responsible for the production of insulin in his body to a non-pathogenic microorganism - Escherichia coli (E.coli), made it possible to produce human insulin on an industrial scale. Recently, another direction has appeared in the creation of new highly effective drugs, based on the study of the characteristics of their metabolism (transformation) in the body. For example, it is known that parkinsonism is based on a deficiency of the neurotransmitter dopamine in the extrapyramidal system of the brain. It would be natural to use exogenous dopamine to treat parkinsonism, which would compensate for the lack of endogenous dopamine. Such attempts were made, but it turned out that due to the peculiarities of the chemical structure, exogenous dopamine is not able to penetrate the blood-brain barrier (the barrier between blood and brain tissue). Later, the drug levodopa was synthesized, which, unlike dopamine, easily penetrates the blood-brain barrier into the brain tissue, where it is metabolized (decarboxylated) and converted into dopamine. Another example of such drugs can be some angiotensin-converting enzyme inhibitors (ACE inhibitors) - perindopril, ramipril, enalapril, etc. So, biologically inactive enalapril, being metabolized (hydrolyzed) in the liver, forms a biologically highly active metabolite enalaprilat with hypotensive (lowering blood pressure) action. Such drugs are called prodrugs, or bioprecursors(metabolic precursors). There is another way to create drugs based on the study of their metabolism - the creation of complexes "carrier substance - biologically active substance. For example, it is known that a semi-synthetic antibiotic from the group of penicillins - ampicillin - is poorly absorbed in the gastrointestinal tract (GIT) - no more than 30-40% of the amount of the drug taken. To increase the absorption (bioavailability) of ampicillin, a semi-synthetic penicillin of the III generation was synthesized - bicampicillin, which does not have an antimicrobial effect, but is almost completely absorbed in the intestine (90 - 99%). Once in the blood, bicampicillin is metabolized (hydrolyzed) within 30-45 minutes to ampicillin, which has a pronounced antimicrobial effect. Drugs related to bioprecursors and carrier substances have received the general name - prodrugs. In addition to the study of pharmacologically active chemical compounds obtained by targeted synthesis or modification of the structure of known drugs, it is possible to search for biologically active substances among various classes of chemical compounds or products of plant and animal origin, previously not studied as potential drugs. In this case, using various tests, among these compounds, substances with the maximum biological activity are selected. Such empirical(from Greek. empeiria - experience) approach is called screening pharmacological drugs. Screening (from English. screening) - selection, screening, sorting. In the case when, in the study of compounds, the entire spectrum of their pharmacological activity is evaluated, they speak of full scale screening and in the case of a search for substances with a certain pharmacological activity, for example, anticonvulsants, one speaks of directed screening of medicinal substances. After that, in animal experiments (in vivo) and / or experiments carried out outside the body, for example, in cell culture (in vitro), they are moving to a systematic study of the spectrum and features of the pharmacological activity of newly synthesized or empirically selected compounds. At the same time, the study of the biological activity of the compounds is carried out both on healthy animals and in model experiments. For example, the study of the spectrum of pharmacological activity of substances with antiarrhythmic activity is carried out on models of cardiac arrhythmias, and antihypertensive (lowering blood pressure - blood pressure) compounds - in experiments on spontaneously hypertensive rats (a specially bred line of rats with congenital hypertension - high blood pressure). After revealing high specific activity in the studied compounds, which is not inferior, at least, to the activity of already known (reference) drugs, they proceed to the study of the features of their mechanism of action, i.e., the study of the features of the influence of these compounds on certain biological processes in the body, by means of which their specific pharmacological effect is realized. For example, the local anesthetic (pain-relieving) action of local anesthetics is based on their ability to lower the permeability of nerve fiber membranes for Na + ions and thereby block the conduction of efferent impulses through them, or the effect of b-blockers on the heart muscle is due to their ability to block b 1 -adrenergic receptors, located on the cell membrane of myocardial cells. In addition to pharmacologists themselves, biochemists, morphologists, electrophysiologists, etc. take part in these studies. Upon completion of pharmacological studies and after determining the mechanisms of action of the studied compounds, a new stage begins - the assessment of the toxicity of potential drugs. Toxicity(from Greek. toxicon - poison) - the action of a drug that is harmful to the body, which can be expressed in a disorder of physiological functions and / or a violation of the morphology of organs and tissues up to their death. The toxicity of newly synthesized compounds is studied in special toxicological laboratories, where, in addition to toxicity proper, the mutagenicity, teratogenicity, and oncogenicity of these compounds are determined. Mutagenicity(from lat. mutatio change, Greek genes - generative) - a type of toxicity that characterizes the ability of a substance to cause changes in the genetic spectrum of a cell, leading to the transmission of its altered properties by inheritance. Teratogenicity(from Greek. teras - monster, freak, Greek. genes - generative) - a type of toxicity that characterizes the ability of a substance to have a damaging effect on the fetus. Oncogenicity(from Greek. onkoma - tumor, Greek genes - generative) - a type of toxicity that characterizes the ability of a substance to cause cancer. In parallel with the study of the toxicity of a substance, process engineers develop a dosage form of the substance under study, determine methods for storing the dosage form, and, together with synthetic chemists, develop technical documentation for the industrial production of the substance. Substance(active substance, active principle) - a component of a medicinal product that has its own therapeutic, prophylactic or diagnostic effect. The dosage form (a condition that is convenient for use in clinical practice, in which the desired effect is achieved) is added to the dosage form, also includes excipients (sugar, chalk, solvents, stabilizers, etc.), which do not have pharmacological activity on their own. In cases where, after toxicological studies, the safety of the studied substance for the body has been proven, the results of pharmacological and toxicological studies are summarized, a temporary Pharmacopoeia article is compiled and materials are submitted to the Federal State Institution "Scientific Center for Expertise of Medicinal Products" (FGU "NTsESMP") under the Ministry of Health and Social development of the Russian Federation to obtain permission to conduct phase I clinical trials. Pharmacopoeia article - state standard for drugs, containing a list of indicators and methods for monitoring their quality. Federal State Institution "NTsESMP" is an expert body of the Ministry of Health and Social Development of the Russian Federation, dealing with issues related to the practical use of domestic and foreign medicinal, preventive, diagnostic and physiotherapeutic agents, as well as excipients. The main issue that FGU "NTsESMP" solves is the preparation of recommendations to the Ministry of Health and Social Development of the Russian Federation for the approval of the medical use of new drugs. After the receipt of documents by the Federal State Institution "NTsESMP", all materials of preclinical study of drugs are considered in detail by a special expert council, which includes leading specialists of the country (pharmacologists, toxicologists, clinical pharmacologists, clinicians), and in case of a positive assessment of the submitted materials, a decision is made to conduct Phase I clinical trials. tests. In the case of obtaining permission from the Federal State Institution "NTsESMP", the tested drug is transferred to clinical pharmacologists for conducting phase I clinical trials, which are carried out on a limited number of patients. In some countries, phase I clinical trials are carried out on healthy subjects - volunteers (20 - 80 people). In this case, special attention is paid to the study of the safety and tolerability of single and multiple doses of the test drug and the features of its pharmacokinetics. Phase II clinical trials of a new drug are carried out on patients (200 - 600 people) suffering from a disease for the treatment of which the study drug is supposed to be used. The main goal of Phase II clinical trials is to prove the clinical efficacy of the studied drug. In the event that phase II clinical trials have shown the effectiveness of the drug, they proceed to phase III studies, which are carried out on a larger number (more than 2,000) of patients. The main objective of phase III clinical trials is to determine the efficacy and safety of the studied drug under conditions as close as possible to those in which it will be used in the event of obtaining permission for widespread medical use of the drug. In case of successful completion of this stage of clinical trials, all available documentation is summarized, an appropriate conclusion is made, and the materials are transferred to the Ministry of Health and Social Development of the Russian Federation to obtain final permission for the widespread clinical use of the drug. The last stage (phase IV) of clinical trials is carried out after obtaining permission from the Ministry of Health and Social Development of the Russian Federation for the clinical use of a new drug; Phase IV clinical trials are called post-marketing research. - post-marketing trials). The goal of Phase IV clinical trials is:
- improvement of dosing schemes of the drug;
- comparative analysis of the effectiveness of treatment with the studied drugs and reference drugs used for the pharmacotherapy of this pathology;
- identification of differences between the studied drug and other drugs of this class;
- identification of the features of the interaction of the studied drug with food and / or other drugs;
- identifying the features of the use of the studied drug in patients of different age groups;
- identification of long-term results of treatment, etc.
The development of new drugs includes a series of successive stages.
First stage aimed at search for promising compounds possibly having a medicinal effect. The main routes are outlined above.
Second phase- this is preclinical study of biological activity substances designated for further investigation. Preclinical study of a substance is divided into: pharmacological and toxicological.
Target pharmacological research- determination of not only the therapeutic efficacy of the drug and its effect on the body systems, but also possible adverse reactions associated with pharmacological activity.
At toxicological studies establish the nature and possible damaging effects on the body of experimental animals. Allocate three stages toxicological studies: 1) study of the toxicity of the drug with a single injection; 2) determination of chronic toxicity of a substance upon repeated administration for 1 year or more; 3) establishing the specific effect of the compound (oncogenicity, mutagenicity, effects on the fetus, etc.).
The third stage - clinical trials new medicinal substance. Held assessment of therapeutic or prophylactic efficacy, tolerability, establishing doses and regimens for the use of the drug, as well as comparative characteristics with other drugs. During clinical trials, four phase.
AT phase I determine the tolerability and therapeutic effect of the study drug on limited number of patients (5-10 people), as well as in healthy volunteers.
AT phase II clinical trials are carried out on a group of patients (100-200 people), as well as in the control group. To obtain reliable data, use "double blind" method when neither the patient nor the doctor, but only the head of the trial, knows which drug is being used. Efficacy and tolerability of a new pharmacological drug compared with those of a placebo or a drug of similar action.
aim phase III testing is to obtain additional information about the study pharmacological agent. At the same time, research is being carried out on hundreds or even thousands of patients in both inpatient and outpatient settings. After comprehensive clinical trials, the Pharmacological Committee gives a recommendation for practical use.
Phase IV research studies the effect of a medicinal product in practice in a variety of situations, with particular attention to the collection and analysis of data on the side effects of investigational medicinal products.
Each drug, before being used in practical medicine, must undergo a certain procedure of study and registration, which would guarantee, on the one hand, the effectiveness of the drug in the treatment of this pathology, and on the other hand, its safety.
The drug study is divided into two stages: preclinical and clinical.
At the preclinical stage, the drug substance is created and the drug is tested on animals in order to determine the pharmacological profile of the drug, determine acute and chronic toxicity, teratogenicity (non-inherited defects in offspring), mutagenic (inherited defects in offspring) and carcinogenic effects (tumor cell transformation) . Clinical trials are conducted on volunteers and are divided into three phases. The first phase is carried out on a small number of healthy people and serves to determine the safety of the drug. The second phase is carried out on a limited number of patients (100-300 people). Determine the tolerability of therapeutic doses by a sick person and the expected undesirable effects. The third phase is performed on a large number of patients (at least 1,000-5,000 people). The degree of severity of the therapeutic effect is determined, undesirable effects are clarified. In a study in parallel with the group taking the study drug, a group is recruited that receives a standard comparator drug (positive control) or an inactive drug that mimics the drug under study (placebo control). This is necessary in order to eliminate the element of self-hypnosis in the treatment of this medicine. At the same time, not only the patient himself, but also the doctor and even the head of the study may not know whether the patient is taking a control drug or a new drug. In parallel with the start of sales of a new drug, the pharmaceutical concern organizes the fourth phase of clinical trials (post-marketing studies). The purpose of this phase is to identify rare but potentially dangerous side effects of the drug. Participants in this phase are all practitioners who prescribe the drug and the patient who uses it. If serious deficiencies are found, the medicine may be withdrawn by the concern. In general, the process of developing a new drug takes from 5 to 15 years.
When conducting clinical trials, the intensity of communication and cooperation of specialists in the field of fundamental and clinical pharmacology, toxicology, clinical medicine, genetics, molecular biology, chemistry and biotechnology increased.
Pharmacokinetic and pharmacodynamic parameters began to be determined both at the stage of preclinical pharmacological and toxicological studies, and at the stage of clinical trials. The choice of doses began to be based on an assessment of the concentrations of drugs and their metabolites in the body. The arsenal of toxicology includes research in vitro and experiments on transgenic animals, which made it possible to bring disease models closer to real-life human diseases.
Domestic scientists have made a great contribution to the development of pharmacology. Ivan Petrovich Pavlov (1849 - 1936) headed the experimental laboratory at the clinic of S.P. Botkin (1879 - 1890), headed the department of pharmacology at the Military Medical Academy of St. Petersburg (1890 -1895). Prior to that, in 1890, he was elected head of the department of pharmacology at the Imperial Tomsk University. The activity of I.P. Pavlov as a pharmacologist was distinguished by a wide scientific scope, brilliant experiments and deep physiological analysis.
pharmacological data. Physiological methods created by I. P. Pavlov made it possible to investigate the therapeutic effect of cardiac glycosides (lily of the valley, adonis, hellebore) on the heart and blood circulation, to establish the mechanism of the antipyretic antipyretic effect, to study the effect of alkaloids (pilocarpine, nicotine, atropine, morphine), acids, alkalis and bitterness for digestion.
The ingenious completion of the scientific work of IP Pavlov was the work on the physiology and pharmacology of higher nervous activity. Using the method of conditioned reflexes, the mechanism of action of ethyl alcohol, bromides, and caffeine on the central nervous system was first discovered. In 1904, research by I.P. Pavlov were awarded the Nobel Prize.
Nikolai Pavlovich Kravkov (1865 - 1924) - the generally recognized founder of the modern stage of development of domestic pharmacology, the creator of a large scientific school, head of the department at the Military Medical Academy (1899 - 1924). He opened a new experimental pathological direction in pharmacology, introduced the method of isolated organs into experimental practice, proposed and, together with the surgeon S.P. Fedorov, performed intravenous anesthesia with hedonal in the clinic. N. P. Kravkov is the founder of domestic industrial toxicology, evolutionary and comparative pharmacology, he was the first to study the effect of drugs on the endocrine system. The two-volume guide of N. P. Kravkov "Fundamentals of Pharmacology" was published 14 times. In memory of the outstanding scientist, a prize and a medal have been established for works that have made a significant contribution to the development of pharmacology.
N. P. Kravkov's students Sergey Viktorovich Anichkov (1892 - 1981) and Vasily Vasilyevich Zakusov (1903-1986) conducted fundamental research on synaptotropic drugs and drugs that regulate the functions of the central nervous system.
Progressive trends in pharmacology were created by M. P. Nikolaev (who studied the effect of drugs in diseases of the cardiovascular system), V. I. Skvortsov (studyed the pharmacology of synaptotropic and hypnotic drugs), N. V. Vershinin plants and semi-synthetic levorotatory camphor), A.I. V. Valdman (creator of effective psychotropic drugs), M. D. Mashkovsky (creator of original antidepressants, author of a popular guide to pharmacotherapy for doctors), E. M. Dumenova (created effective drugs for the treatment of epilepsy), A. S. Saratikov (offered for the clinic, camphor preparations, psychostimulants-adaptogens, hepatotropic drugs, inducers of inter feron).
Algorithm for creating a new drug
The development of a new drug usually involves the following steps:
1. idea;
2. laboratory synthesis;
3. bioscreening;
4. clinical trials;
The search for new drugs is developing in the following areas:
I. Chemical synthesis of drugs
A. Directional synthesis:
1) reproduction of nutrients;
2) creation of antimetabolites;
3) modification of molecules of compounds with known biological activity;
4) study of the structure of the substrate with which the drug interacts;
5) combination of structural fragments of two compounds with the required properties;
6) synthesis based on the study of chemical transformations of substances in the body (prodrugs; agents that affect the mechanisms of biotransformation of substances).
B. Empirical way:
1) chance finds; 2) screening.
II. Obtaining preparations from medicinal raw materials and isolation of individual substances:
1) animal origin;
2) vegetable origin;
3) from minerals.
III. Isolation of medicinal substances that are the waste products of fungi and microorganisms; biotechnology (cell and genetic engineering)
Currently, drugs are obtained mainly through chemical synthesis. One of the important ways of targeted synthesis is to reproduce biogenic substances formed in living organisms or their antagonists. For example, epinephrine, norepinephrine, y-aminobutyric acid, prostaglandins, a number of hormones, and other physiologically active compounds were synthesized. One of the most common ways to find new drugs is the chemical modification of compounds with known biological activity. Recently, computer modeling of the interaction of a substance with a substrate such as receptors, enzymes, and so on has been actively used, since the structure of various molecules in the body is well established. Computer modeling of molecules, the use of graphic systems and appropriate statistical methods make it possible to get a fairly complete picture of the three-dimensional structure of pharmacological substances and the distribution of their electronic fields. Such summary information about physiologically active substances and the substrate should facilitate the efficient design of potential ligands with high complementarity and affinity. In addition to directed synthesis, the empirical route for obtaining drugs still retains a certain value. One of the varieties of empirical search is screening (a rather laborious test of the effect of a drug in rats, then in humans).
In the pharmacological study of potential drugs, the pharmacodynamics of substances is studied in detail: their specific activity, duration of effect, mechanism and localization of action. An important aspect of the study is the pharmacokinetics of substances: absorption, distribution and transformation in the body, as well as excretion routes. Special attention is paid to side effects, toxicity with single and long-term use, teratogenicity, carcinogenicity, mutagenicity. It is necessary to compare new substances with known drugs of the same groups. In the pharmacological evaluation of compounds, a variety of physiological, biochemical, biophysical, morphological and other research methods are used.
Of great importance is the study of the effectiveness of substances in appropriate pathological conditions (experimental pharmacotherapy). Thus, the therapeutic effect of antimicrobial substances is tested on animals infected with pathogens of certain infections, antiblastoma drugs - on animals with experimental and spontaneous tumors.
The results of the study of substances promising as drugs are submitted to the Pharmacological Committee of the Ministry of Health of the Russian Federation, which includes experts from various specialties (mainly pharmacologists and clinicians). If the Pharmacological Committee considers the experimental studies carried out to be exhaustive, the proposed compound is transferred to clinics with the necessary experience in the study of medicinal substances.
Clinical trial - a scientific study of the efficacy, safety and tolerability of medical products (including medicines) in humans. There is an international standard "Good Clinical Practice". The National Standard of the Russian Federation GOSTR 52379-2005 "Good Clinical Practice" contains a full synonym for this term - a clinical trial, which, however, is less preferable due to ethical considerations.
The basis for conducting clinical trials (tests) is the document of the international organization "International Conference on Harmonization" (ICG). This document is called "Guideline for Good Clinical Practice" ("Description of the GCP Standard"; Good Clinical Practice translates as "Good Clinical Practice").
In addition to physicians, there are usually other clinical research specialists working in the field of clinical research.
Clinical research must be conducted in accordance with the founding ethical principles of the Declaration of Helsinki, the GCP standard, and applicable regulatory requirements. Prior to the start of a clinical trial, an assessment should be made of the relationship between the foreseeable risk and the expected benefit for the subject and society. At the forefront is the principle of priority of the rights, safety and health of the subject over the interests of science and society. The subject can be included in the study only on the basis of voluntary informed consent (IC), obtained after a detailed acquaintance with the study materials. This consent is certified by the signature of the patient (subject, volunteer).
The clinical trial must be scientifically justified and described in detail and clearly in the study protocol. Assessment of the balance of risks and benefits, as well as review and approval of the protocol of the study and other documentation related to the conduct of clinical trials, are the responsibilities of the Expert Council of the Organization / Independent Ethics Committee (IEC / IEC). Once approved by the IRB/IEC, the clinical trial can proceed.
In most countries, clinical trials of new drugs usually go through 4 phases.
1st phase. It is carried out on a small group of healthy volunteers. Optimum dosages are established that cause the desired effect. Pharmacokinetic studies concerning the absorption of substances, their half-life period, and metabolism are also advisable. It is recommended that such studies be performed by clinical pharmacologists.
2nd phase. It is carried out on a small number of patients (usually up to 100-200) with the disease for which the drug is offered. Pharmacodynamics (including placebo) and pharmacokinetics of substances are studied in detail, and side effects that occur are recorded. This testing phase is recommended to be carried out in specialized clinical centers.
3rd phase. Clinical (randomized controlled) trial on a large contingent of patients (up to several thousand). Efficacy (including "double-blind control") and safety of substances are studied in detail. Special attention is paid to side effects, including allergic reactions, and drug toxicity. Comparison with other drugs of this group is carried out. If the results of the study are positive, the materials are submitted to the official organization, which gives permission for the registration and release of the drug for practical use. In our country, this is the Pharmacological Committee of the Ministry of Health of the Russian Federation, whose decisions are approved by the Minister of Health.
4th phase. Extensive study of the drug on the largest possible number of patients. The most important are data on side effects and toxicity, which require especially long-term, careful and large-scale follow-up. In addition, long-term results of treatment are evaluated. The data obtained are drawn up in the form of a special report, which is sent to the organization that gave permission for the release of the drug. This information is important for the further fate of the drug (its use in wide medical practice).
The quality of drugs produced by the chemical-pharmaceutical industry is usually evaluated using chemical and physico-chemical methods specified in the State Pharmacopoeia. In some cases, if the structure of active substances is unknown or chemical methods are not sensitive enough, biological standardization is resorted to. This refers to the determination of the activity of drugs on biological objects (by the most typical effects).
According to the world-renowned information resource "Wikipedia", in Russia, at present, new drugs are mainly being researched in the field of cancer treatment, the second place is the treatment of diseases of the endocrine system. Thus, in our time, the creation of new drugs is completely controlled by the state and the institutions it manages.
The development of new drugs is carried out by the joint efforts of many branches of science, with the main role played by specialists in the field of chemistry, pharmacology, and pharmacy. The creation of a new drug is a series of successive stages, each of which must meet certain provisions and standards approved by state institutions - the Pharmacopeia Committee, the Pharmacological Committee, the Department of the Ministry of Health of the Russian Federation for the introduction of new drugs.
The process of creating new drugs is carried out in accordance with the international standards GLP (Good Laboratory Practice Good Laboratory Practice), GMP (Good Manufacturing Practice Good Manufacturing Practice) and GCP (Good Clinical Practice Good Clinical Practice).
A sign of compliance of a new drug being developed with these standards is the official approval of the IND (Investigation New Drug) process for their further research.
Obtaining a new active substance (active substance or complex of substances) goes in three main directions.
Ways of creating new medicines I. Chemical synthesis of drugs directed synthesis; empirical path. II. Obtaining preparations from medicinal raw materials and isolation of individual substances: animal origin; vegetable origin; from minerals. III. Isolation of medicinal substances that are the waste products of microorganisms and fungi. Biotechnology.
Chemical synthesis of drugs directed synthesis Reproduction of biogenic substances Adrenaline, norepinephrine, γ-aminobutyric acid, hormones, prostaglandins and other physiologically active compounds. Creation of antimetabolites Synthesis of structural analogs of natural metabolites with the opposite effect. For example, antibacterial agents sulfonamides are similar in structure to para-aminobenzoic acid, which is necessary for the vital activity of microorganisms, and are its antimetabolites:
Chemical synthesis of drugs directed synthesis Chemical modification of compounds with known activity The main task is to create new drugs that compare favorably with the already known ones (more active, less toxic). 1. On the basis of hydrocortisone produced by the adrenal cortex, many much more active glucocorticoids have been synthesized, which have a lesser effect on water-salt metabolism. 2. Hundreds of synthesized sulfonamides are known, of which only a few have been introduced into medical practice. The study of series of compounds is aimed at elucidating the relationship between their structure, physicochemical properties and biological activity. Establishing such regularities makes it possible to carry out the synthesis of new drugs more purposefully. At the same time, it turns out which chemical groups and structural features determine the main effects of the action of substances.
Chemical modification of compounds with known activity: modification of substances of plant origin Tubocurarine (arrow poison curare) and its synthetic analogues Relax skeletal muscles. The distance between two cationic centers (N+ - N+) matters.
Chemical synthesis of drugs directed synthesis Study of the structure of the substrate with which the drug interacts The basis is not a biologically active substance, but the substrate with which it interacts: receptor, enzyme, nucleic acid. The implementation of this approach is based on data on the three-dimensional structure of macromolecules that are the targets of the drug. Modern approach using computer modeling; x-ray diffraction analysis; spectroscopy based on nuclear magnetic resonance; statistical methods; genetic engineering.
Chemical synthesis of drugs directed synthesis Synthesis based on the study of chemical transformations of a substance in the body. Prodrugs. 1. Complexes "substance carrier - active substance" Provide directed transport to target cells and selectivity of action. The active substance is released at the site of action under the influence of enzymes. The function of carriers can be performed by proteins, peptides and other molecules. Carriers can facilitate the passage of biological barriers: Ampicillin is poorly absorbed in the intestine (~ 40%). The prodrug bacampicillin is inactive, but absorbed by 9899%. In serum, under the influence of esterases, active ampicillin is cleaved.
Chemical synthesis of drugs directed synthesis Synthesis based on the study of chemical transformations of a substance in the body. Prodrugs. 2. Bioprecursors These are individual chemicals that are inactive on their own. In the body, other substances are formed from them - metabolites, which exhibit biological activity: prontosil - sulfanilamide L-DOPA - dopamine
Chemical synthesis of drugs directed synthesis Synthesis based on the study of chemical transformations of a substance in the body. Means influencing biotransformation. Based on the knowledge of enzymatic processes that ensure the metabolism of substances, it allows you to create drugs that change the activity of enzymes. Acetylcholinesterase inhibitors (prozerin) enhance and prolong the action of the natural mediator acetylcholine. Inducers of the synthesis of enzymes involved in the processes of detoxification of chemical compounds (phenobarbital).
Chemical synthesis of drugs empirical way Random finds. The decrease in blood sugar levels found with the use of sulfonamides led to the creation of their derivatives with pronounced hypoglycemic properties (butamide). They are widely used in diabetes. By chance, the effect of teturam (antabuse) was discovered, which is used in the manufacture of rubber. It is used in the treatment of alcoholism. Screening. Checking chemical compounds for all types of biological activity. Laborious and inefficient way. However, it is inevitable when studying a new class of chemicals, the properties of which are difficult to predict based on the structure.
Preparations and individual substances from medicinal raw materials Various extracts, tinctures, more or less purified preparations are used. For example, laudanum is a tincture of raw opium.
Preparations and individual substances from medicinal raw materials Individual substances: Digoxin - cardiac glycoside from foxglove Atropine - M-anticholinergic agent from belladonna Salicylic acid - anti-inflammatory substance from willow Colchicine - colchicum alkaloid, used in the treatment of gout.
Stages of drug development Preparation of the drug Animal testing Natural sources Efficacy Selectivity Mechanisms of action Metabolism Safety assessment ~ 2 years Drug substance (active compound) Chemical synthesis ~ 2 years Clinical trials Phase 1 is the drug safe? Phase 2 Is the drug effective? Phase 3 Is the drug effective in double-blind control? Metabolism Safety assessment ~ 4 years Marketing DRUG INTRODUCTION 1 year Phase 4 post-marketing surveillance Advent of Geneticists 17 years after approval Patent expiration
