3. ABOUT THE CREATION OF NEW DRUGS
3. ABOUT THE CREATION OF NEW DRUGS
The progress of pharmacology is characterized by the continuous search and creation of new, more active and safer drugs. Their path from a chemical compound to a drug is shown in Scheme 1.1.
Recently, fundamental research has become increasingly important in obtaining new drugs. They concern not only chemical (theoretical chemistry, physical chemistry, etc.), but also purely biological problems. The advances in molecular biology, molecular genetics, and molecular pharmacology began to significantly affect such an applied aspect of pharmacology as the creation of new drugs. Indeed, the discovery of many endogenous ligands, secondary transmitters, presynaptic receptors, neuromodulators, the isolation of individual receptors, the development of methods for studying the function of ion channels and the binding of substances to receptors, advances in genetic engineering, etc. - all this played a decisive role in determining the most promising directions for the design of new drugs.
The great importance of pharmacodynamic research for solving applied problems modern pharmacology obvious. Thus, the discovery of the mechanism of action of non-steroidal anti-inflammatory drugs has fundamentally changed the ways of searching for and evaluating such drugs. A new direction in pharmacology is associated with the isolation, extensive research and implementation of prostaglandins in medical practice. The discovery of the prostacyclin-thromboxane system was a serious scientific basis for a targeted search and practical application of antiplatelet agents. The release of enkephalins and endorphins stimulated research on the synthesis and study of opioid peptides with different spectrum of receptor action. The establishment of the role of the proton pump in the secretion of hydrochloric acid in the stomach led to the creation of previously unknown drugs - proton pump inhibitors. The discovery of endothelial relaxing factor (NO) allowed
Scheme 1.1.The sequence of creation and implementation of medicines.
Note. Ministry of Health of the Russian Federation - Ministry of Health of the Russian Federation.
explain the mechanism of the vasodilating action of m-cholinomimetics. These works also contributed to the elucidation of the mechanism of the vasodilating effect of nitroglycerin and sodium nitroprusside, which is important for further searches for new physiologically active compounds. The study of the mechanisms of fibrinolysis made it possible to create a valuable selectively acting fibrinolytic - a tissue activator of profibrinolysin. There are many such examples.
The creation of drugs usually begins with research by chemists and pharmacologists, whose creative collaboration is the basis for the "design" of new drugs.
The search for new drugs is developing in the following directions.
I. Chemical synthesis of drugs A. Directed synthesis:
1) reproduction of nutrients;
2) creation of antimetabolites;
3) modification of molecules of compounds with known biological activity;
4) studying the structure of the substrate with which it interacts medicine;
5) a combination of fragments of structures of two compounds with the required properties;
6) synthesis based on the study of chemical transformations of substances in the body (prodrugs; agents affecting the mechanisms of biotransformation of substances).
B. Empirical way:
1) accidental finds;
2) screening.
II. Obtaining drugs from medicinal raw materials and isolating individual substances:
1) animal origin;
2) vegetable origin;
3) from minerals.
III.Isolation of medicinal substances that are products of the vital activity of fungi and microorganisms; biotechnology (cellular and genetic engineering)
As already noted, currently, drugs are obtained mainly through chemical synthesis. One of the important ways of directed synthesis is reproduction of nutrients, formed in living organisms. For example, epinephrine, norepinephrine, γ-aminobutyric acid, prostaglandins, a number of hormones, and other physiologically active compounds were synthesized.
Search for antimetabolites (antagonists of natural metabolites) has also led to the development of new drugs. The principle of creating antimetabolites is the synthesis of structural analogs of natural metabolites, which have the opposite effect of metabolites. For example, antibacterial agents sulfonamides are similar in structure to para-aminobenzoic acid (see below), which is necessary for the vital activity of microorganisms, and are its antimetabolites. By changing the structure of the fragments of the acetylcholine molecule, it is also possible to obtain its antagonists. Below
shows the structure of acetylcholine and its antagonist - the ganglion blocker hygronium. In both cases, there is a clear structural analogy in each of the pairs of compounds.
One of the most common ways to find new drugs is chemical modification of compounds with known biological activity. The main task of such research is to create new drugs (more active, less toxic) that differ favorably from those already known. The starting compounds can be natural substances of plant (Fig. I.8) and animal origin, as well as synthetic substances. Thus, on the basis of hydrocortisone produced by the adrenal cortex, many significantly more active glucocorticoids have been synthesized, which have a lesser effect on water-salt metabolism than their prototype. There are hundreds of synthesized sulfonamides, barbiturates and other compounds, of which only individual substances, the structure of which provides the necessary pharmacotherapeutic properties, have been introduced into medical practice. Similar studies of the series of compounds are also aimed at solving one of the main problems of pharmacology - the elucidation of the relationship between the chemical structure of substances, their physicochemical properties and biological activity. The establishment of such regularities allows the synthesis of drugs in a more targeted manner. In this case, it is important to find out which chemical groups and structural features determine the main effects of the action of the substances under study.
In recent years, new approaches to the creation of drugs have been outlined. The basis is not taken a biologically active substance, as was done earlier, but the substrate with which it interacts (receptor, enzyme, etc.). Such studies require the most detailed data on the three-dimensional structure of those macromolecules that are the main “target” for the drug. Currently, there is a bank of such data, including a significant number of enzymes and nucleic acids. A number of factors have contributed to the progress in this direction. First of all, X-ray structural analysis was improved, and spectroscopy based on nuclear magnetic resonance was developed. The latter method opened up fundamentally new possibilities, since it made it possible to establish the three-dimensional structure of substances in solution, i.e. in a non-crystalline state. An essential point was the fact that with the help of genetic engineering it was possible to obtain a sufficient number of substrates for detailed chemical and physicochemical research.
Using the available data on the properties of many macromolecules, it is possible to simulate their structure with the help of computers. This gives a clear idea of the geometry not only of the entire molecule, but also of its active centers interacting with ligands. The features of the surface topography are investigated.
Rice. I.8.(I-IV) Obtaining preparations from plant raw materials and creating their synthetic substitutes (by the example of curariform agents).
I.Initially, from a number of plants in South America, the Indians isolated arrow poison - curare, which causes paralysis skeletal muscle.
a, b - plants from which curare is obtained;v - dried pumpkin pots with curare and Indian hunting implements;G - hunting with curare. In long tubes (blowguns) the Indians placed small, light arrows with curare-oiled points; with an energetic exhalation, the hunter sent an arrow to the target; from the point where the arrow hit, the curare was absorbed, muscle paralysis set in, and the animal became the prey of hunters.
II.In 1935, the chemical structure of one of the main alkaloids of curare, tubocurarine, was established.
III.In medicine, purified curare containing a mixture of alkaloids (preparations of curarin, intocostrin) began to be used in 1942. Then they began to use a solution of the alkaloid tubocurarine chloride (the drug is also known as "tubarin"). Tubocurarine chloride is used to relax skeletal muscles during surgical operations.
IV.Later, many synthetic curariform drugs were obtained. When creating them, we proceeded from the structure of tubocurarine chloride, which has 2 cationic centers (N + - N +) located at a certain distance from each other.
substrate, the nature of its structural elements and possible types of interatomic interactions with endogenous substances or xenobiotics. On the other hand, computer modeling of molecules, the use of graphic systems and the corresponding 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 substrate should facilitate the efficient construction of potential ligands with high complementarity and affinity. Until now, such opportunities could only be dreamed of, now it is becoming a reality.
Genetic engineering opens up additional possibilities for investigating the significance of individual components of the receptor for their specific binding to agonists or antagonists. These methods make it possible to create complexes with individual receptor subunits, substrates without putative ligand binding sites, protein structures with a disturbed composition or sequence of amino acids, etc.
There is no doubt that we are on the verge of fundamental changes in the tactics of creating new drugs.
The possibility of creating new drugs attracts attention based on the study of their chemical transformations in the body. This research is developing in two directions. The first direction is associated with the creation of so-called prodrugs. They are either “carrier-active substance” complexes or are bioprecursors.
When creating complexes "substance-carrier-active substance", directed transport is most often meant. The "carrier substance" usually combines with the active substance through covalent bonds. The active compound is released under the influence of appropriate enzymes at the site of action of the substance. Desirably, the carrier is recognized by the "target" cell. In this case, you can achieve significant selectivity of action.
Proteins, peptides, and other compounds can function as carriers. So, for example, you can get monoclonal antibodies to specific antigens of the epithelium of the mammary glands. Such antibodies-carriers in combination with anti-blastoma agents, obviously, can be tested in the treatment of disseminated breast cancer. Among peptide hormones, β-melanotropin, which is recognized by malignant melanoma cells, is of interest as a carrier. Glycoproteins can interact quite selectively with hepatocytes and some hepatoma cells.
Selective expansion of renal vessels is observed with the use of γ-glutamyl-DOPA, which undergoes metabolic transformations in the kidneys, leading to the release of dopamine.
Sometimes "carrier substances" are used to transport drugs across biological membranes. So, it is known that ampicillin is poorly absorbed from the intestine (about 40%). Its esterified lipophilic prodrug - bacampicillin - is absorbed from the digestive tract by 98-99%. Bacampicillin itself is inactive; antimicrobial activity is manifested only in the cleavage of ampicillin by esterases in the blood serum.
Lipophilic compounds are commonly used to facilitate passage through biological barriers. In addition to the example already given, we can mention the cetyl ester of γ-aminobutyric acid (GABA), which, unlike GABA, easily penetrates into the brain tissue. The pharmacologically inert epinephrine dipivaline ether passes well through the cornea. In the tissues of the eye, it undergoes enzymatic hydrolysis, which leads to the local formation of adrenaline. In this regard, the dipivaline ester of epinephrine, called dipivefrine, has been shown to be effective in the treatment of glaucoma.
Another type of prodrug is called bioprecursors (or metabolic precursors). In contrast to the "substance-carrier-active substance" complex, based on the temporary connection of both components, the bioprecursor is a new chemical substance. In the body, another compound is formed from it - a metabolite, which is the active substance. Examples of the formation of active metabolites in the body are well known (prontosyl-sulfanilamide, imipramine-desmethylimipramine, L-DOPA-dopamine, etc.). The same principle was used to synthesize pro-2-PAM, which unlike 2-PAM It penetrates well into the central nervous system, where the active reactivator of acetylcholinesterase 2-PAM is released.
In addition to increasing the selectivity of action, increasing lipophilicity and, accordingly, bioavailability, prodrugs can be used
to create water-soluble drugs (for parenteral administration), as well as to eliminate unwanted organoleptic and physicochemical properties.
The second direction, based on the study of biotransformation of substances, provides for the study of the mechanisms of their chemical transformations. Knowledge of the enzymatic processes that ensure the metabolism of substances makes it possible to create drugs that change the activity of enzymes. For example, acetylcholinesterase inhibitors (proserin and other anticholinesterase agents) have been synthesized, which enhance and prolong the action of the natural mediator acetylcholine. Also obtained are inhibitors of the MAO enzyme involved in the inactivation of norepinephrine, dopamine, serotonin (these include the antidepressant nialamide, etc.). Substances are known that induce (enhance) the synthesis of enzymes involved in the detoxification of chemical compounds (for example, phenobarbital).
In addition to directed synthesis, the empirical route of obtaining drugs still retains a certain value. A number of drugs were introduced into medical practice as a result of accidental finds. Thus, a decrease in blood sugar levels found when using sulfonamides led to the synthesis of their derivatives with pronounced hypoglycemic properties. Now they are widely used in the treatment of diabetes mellitus (butamide and similar drugs). The effect of teturam (antabuse), used in the treatment of alcoholism, was also discovered by chance in connection with its use in industrial production in the manufacture of rubber.
One of the varieties of empirical search is screening 1... In this case, any chemical compounds that may be intended for non-medical purposes are tested for biological activity using a variety of techniques. Screening is a very laborious and ineffective way of empirical search for drugs. However, sometimes it is inevitable, especially if a new class of chemical compounds is being investigated, the properties of which, based on their structure, are difficult to predict.
In the arsenal of drugs, in addition to synthetic drugs, a significant place is occupied by preparations and individual substances from medicinal raw materials(of vegetable, animal origin and from minerals; Table I.2). In this way, many widely used medicines have been obtained, not only in the form of more or less purified preparations (galenic, novogalenic, organic preparations), but also in the form of individual chemical compounds (alkaloids 2, glycosides 3). So, the alkaloids morphine, codeine, papaverine are isolated from opium, reserpine from rauwolfia serpentine, from digitalis - cardiac glycosides digitoxin, digoxin, from a number of endocrine glands - hormones.
1 From the English. to screen- sift.
2 Alkaloids are nitrogenous organic compounds found mainly in plants. Free alkaloids are bases [hence the name of alkaloids: al-qili(Arabic) - alkali, eidos(Greek) - view]. In plants, they are usually found in the form of salts. Many alkaloids have high biological activity (morphine, atropine, pilocarpine, nicotine, etc.).
3 Glycosides are a group of organic compounds of plant origin that decompose when enzymes or acids act on sugar, or glycone (from the Greek. glykys- sweet), and the non-sugar part, or aglycone. A number of glycosides are used as medicines (strophanthin, digoxin, etc.).
Table I.2.Natural preparations
Some medicinal substances are waste products of fungi and microorganisms.
The successful development of this path has led to the creation of a modern biotechnology, which laid the foundation for the creation of a new generation of medicines. The pharmaceutical industry is already undergoing big changes, and radical changes are expected in the near future. This is due to the rapid development of biotechnology. In principle, biotechnology has been known for a long time. Already in the 40s of the twentieth century. began to obtain penicillin by fermentation from the culture of certain types of mold fungus penicillium. This technology has also been used in the biosynthesis of other antibiotics. However, in the mid-70s, there was a sharp leap in the development of biotechnology. This is due to two major discoveries: the development of hybridoma technology (cell engineering) and the method of recombinant DNA (genetic engineering), which determined the progress of modern biotechnology.
Biotechnology is a multidiscipline in the development of which molecular biology plays an important role, including molecular genetics, immunology, various fields of chemistry and a number of technical disciplines. The main content of biotechnology is the use of biological systems and processes in industry. Usually, microorganisms, cell cultures, plant and animal tissues are used to obtain the necessary compounds.
Dozens of new drugs have been created on the basis of biotechnology. Thus, human insulin is obtained; a growth hormone; interferons; interleukin-2; growth factors that regulate hematopoiesis - erythropoietin, filgrastim, molgramostim; the anticoagulant lepirudin (a recombinant variant of hirudin); fibrinolytic urokinase; tissue activator of profibrinolysin alteplase; the anti-leukemic drug L-asparaginase and many others.
Of great interest are also monoclonal antibodies that can be used in the treatment of tumors (for example, the drug of this group, trastuzumab, is effective in breast cancer, and rituximab - in lymphogranulomatosis). The antiplatelet abciximab also belongs to the group of monoclonal antibodies. In addition, monoclonal antibodies are used as antidotes, in particular for intoxication with digoxin and other cardiac glycosides. One of these antidotes is available under the name Digoxin immune fab (Digibind).
It is quite obvious that the role and prospects of biotechnology in relation to the creation of new generations of drugs are very great.
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 the routes of excretion. 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.
It is of great importance to study the effectiveness of substances in the corresponding pathological conditions (experimental pharmacotherapy). So, 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. In addition, it is desirable to have information about the features of the action of substances against the background of those pathological conditions in which they can be used (for example, in atherosclerosis, myocardial infarction, inflammation). This direction, as already noted, has received the name "pathological pharmacology". Unfortunately, existing experimental models rarely fully match what is observed in the clinic. Nevertheless, to some extent, they imitate the conditions in which drugs are prescribed, and thereby bring experimental pharmacology closer to practical medicine.
The results of the study of substances that are 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 that have the necessary experience in the study of medicinal substances. This is a very important stage, as clinicians have a decisive say in evaluating new drugs. A large role in these studies is assigned to clinical pharmacologists, whose main task is the clinical study of the pharmacokinetics and pharmacodynamics of drugs, including new drugs, and the development on this basis of the most effective and harmless methods of their use.
At clinical trial new drugs should be based on a number of principles (Table I.3). First of all, they need to be investigated on a significant contingent of patients. In many countries, this is often preceded by a test on healthy subjects (volunteers). It is very important that each new substance is compared with well-known drugs in the same group (for example,
Table I.3.Principles of clinical research of new drugs (their pharmacotherapeutic efficacy, side and toxic effects)
opioid analgesics - with morphine, cardiac glycosides - with strophanthin and digitalis glycosides). A new drug must necessarily differ from the existing ones for the better.
In clinical trials of substances, it is necessary to use objective methods to quantify the observed effects. Comprehensive study using large set adequate methods is another of the requirements for clinical trials of pharmacological substances.
In cases where the element of suggestion (suggestion) can play a significant role in the effectiveness of substances, placebo 1 is used - dosage forms that are appearance, smell, taste and other properties imitate the drug taken, but do not contain a medicinal substance (they consist only of indifferent form-forming substances). In "blind control", the drug and placebo are alternated in an unknown sequence for the patient. Only the attending physician knows when the patient is taking a placebo. In case of "double blind control" a third person is informed about this (the head of the department or another doctor). This principle of the study of substances makes it possible to evaluate their effect especially objectively, since in a number of pathological conditions (for example, with some pain), a placebo can have a positive effect in a significant part of patients.
The reliability of the data obtained by different methods must be confirmed statistically.
Compliance with ethical principles is an important element of clinical research of new drugs. For example, patients need consent to be included in a specific study program for a new drug. Do not test on children, pregnant women, patients with mental illness... Placebo is excluded if the disease is life threatening. However, solving these issues is not always easy, since in the interests of patients sometimes it is necessary to take a certain risk. To solve these problems, there are special ethical committees that are
1 From lat. placeo- I will like it.
consider relevant aspects when conducting trials of new drugs.
In most countries, clinical trials of new drugs usually go through 4 phases.
1st phase.Conducted on a small group of healthy volunteers. Optimal dosages are established that produce the desired effect. Pharmacokinetic studies concerning the absorption of substances, their half-life, and metabolism are also advisable. It is recommended that such studies be performed by clinical pharmacologists.
2nd phase.Held on not a large number patients (usually up to 100-200) with a disease for the treatment of which this drug is proposed. Pharmacodynamics (including placebo) and pharmacokinetics of substances are studied in detail, the arising side effects... This phase of approbation is recommended to be carried out in specialized clinical centers.
3rd phase.Clinical (randomized 1 controlled) trial on a large contingent of patients (up to several thousand). The efficacy (including double-blind control) and the safety of the substances are being studied in detail. Special attention is paid to side effects, including allergic reactions, and drug toxicity. A comparison is made with other drugs in this group. 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.
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STATE EDUCATIONAL INSTITUTION
HIGHER PROFESSIONAL EDUCATION
NOVOSIBIRSK STATE MEDICAL UNIVERSITY
FEDERAL HEALTH AGENCY
AND SOCIAL DEVELOPMENT OF THE RUSSIAN FEDERATION
(GOU VPO NGMU ROSZDRAVA)
Department of Pharmaceutical Chemistry
TOURSOVWORK
in pharmaceutical chemistry
on the topic: "Creation and testing of new drugs"
Completed: 4-year correspondence student
departments of the Faculty of Pharmacy
(abbreviated form of training based on VHO)
Diana Kundenko
Checked by: L.V. Pashkova
Novosibirsk 2012
1. Stages of the process of creating a new drug. Stability and shelf life of medicines
2. Clinical Trials of Medicines (GCP). GCP stages
3. Quantitative analysis mixtures without preliminary separation of the components of physical chemical methods
4. Quality control system in the conditions of chemical and pharmaceutical plants and factories
5. The main tasks and features of biopharmaceutical analysis
6. Types of state standards. Requirements of general standards for dosage forms
7. Hydrochloric acid: physical properties, authenticity, quantification, application, storage
8. Oxygen: physical properties, authenticity, good quality, quantification, application, storage
9. Bismuth nitrate basic: physical properties, identity test, quantification, application, storage
10. Preparations of magnesium compounds used in medical practice: physical properties, authenticity, quantification, application, storage
11. Preparations of iron and its compounds: physical properties, authenticity, quantification, application, storage
12. Pharmacopoeial radioactive preparations: authenticity, establishment of radiochemical composition, specific activity
1. Stages of the process of creating a new drug. Stability and shelf life of medicines
The creation of drugs is a long-term process that includes several main stages - from forecasting to implementation in a pharmacy.
The creation of a new drug is a series of sequential stages, each of which must meet certain regulations and standards approved by state institutions, the Pharmacopoeial Committee, the Pharmacological Committee, the Office of the Ministry of Health of the Russian Federation for the introduction of new drugs.
The development of a new drug includes the following stages:
1) The idea of creating a new LP. It usually arises as a result of the joint work of scientists of two specialties: pharmacologists and synthetic chemists. Already at this stage, a preliminary selection of synthesized compounds is carried out, which, according to experts, can be potentially biologically active substances.
2) Synthesis of preselected structures. At this stage, selection is also carried out, as a result of which substances, etc., are not subjected to further research.
3) Pharmacological screening and preclinical testing. The main stage, during which unpromising substances synthesized at the previous stage are eliminated.
4) Clinical check. It is performed only for promising biologically active substances that have passed all stages of pharmacological screening.
5) Development of a technology for the production of a new drug and a more rational DF.
6) Preparation of regulatory documents, including quality control methods for both the medicinal product itself and its medicinal product.
7) The introduction of drugs into industrial production and the development of all stage production in the factory.
Obtaining a new active substance (active substance or complex of substances) proceeds in three main directions.
Empirical route: screening, chance finds;
Directed synthesis: reproduction of the structure of endogenous substances, chemical modification of known molecules;
Purposeful synthesis (rational design of a chemical compound), based on the understanding of the relationship "chemical structure, pharmacological action".
The empirical path (from the Greek empeiria - experience) of creating medicinal substances is based on the "trial and error" method, in which pharmacologists take a number of chemical compounds and determine the presence of or lack of certain pharmacological activity. So, the presence of antimicrobial activity is determined on microorganisms; antispasmodic activity - on isolated smooth muscle organs (ex vivo); hypoglycemic activity by the ability to lower the blood sugar level of the test animals (in vivo). Then, among the studied chemical compounds, the most active are selected and the degree of their pharmacological activity and toxicity is compared with existing drugs that are used as a standard. This way of selecting active substances is called drug screening (from the English screen - to sift out, sort). A number of drugs have been introduced into medical practice as a result of accidental finds. Thus, the antimicrobial effect of an azo dye with a sulfanilamide side chain (red streptocide) was revealed, as a result of which a whole group of chemotherapeutic agents, sulfonamides, appeared.
Another way to create medicinal substances is to obtain compounds with a certain type of pharmacological activity. It is called the directed synthesis of medicinal substances.
The first stage of this synthesis is to reproduce the substances formed in living organisms. This is how adrenaline, norepinephrine, a number of hormones, prostaglandins, and vitamins were synthesized.
Chemical modification of known molecules makes it possible to create medicinal substances with a more pronounced pharmacological effect and fewer side effects. Thus, a change in the chemical structure of carbonic anhydrase inhibitors led to the creation of thiazide diuretics, which have a stronger diuretic effect.
The introduction of additional radicals and fluorine into the nalidixic acid molecule made it possible to obtain a new group of fluoroquinolone antimicrobial agents with an extended spectrum of antimicrobial action.
Purposeful synthesis of medicinal substances implies the creation of substances with predetermined pharmacological properties. The synthesis of new structures with the expected activity is most often carried out in the class of chemical compounds where substances with a certain direction of action have already been found. An example is the creation of histamine H2 receptor blockers. It was known that histamine is a potent stimulant of the secretion of hydrochloric acid in the stomach and that antihistamines (used for allergic reactions) do not reverse this effect. On this basis, it was concluded that there are subtypes of histamine receptors that perform different functions, and these subtypes of receptors are blocked by substances of different chemical structures. It has been hypothesized that the modification of the histamine molecule can lead to the creation of selective antagonists of histamine receptors in the stomach. As a result of the rational design of the histamine molecule in the mid 70s of the XX century, the antiulcer agent cimetidine appeared - the first blocker of H2 histamine receptors. Isolation of medicinal substances from tissues and organs of animals, plants and minerals
In this way, medicinal substances or complexes of substances are isolated: hormones; galenic, novogalenic drugs, organopreparations and minerals. Isolation of medicinal substances, which are the waste products of fungi and microorganisms, by biotechnology methods (cellular and genetic engineering). Biotechnology is engaged in the isolation of medicinal substances, which are the metabolic products of fungi and microorganisms.
Biotechnology uses biological systems and biological processes on an industrial scale. Microorganisms, cell cultures, plant and animal tissue cultures are commonly used.
Semi-synthetic antibiotics are obtained using biotechnological methods. The production of human insulin on an industrial scale by genetic engineering is of great interest. Biotechnological methods have been developed for the production of somatostatin, follicle-stimulating hormone, thyroxine, steroid hormones... After obtaining a new active substance and determining its main pharmacological properties, it undergoes a number of preclinical studies.
Various drugs have different terms suitability. The shelf life is the period during which the medicinal product must fully meet all the requirements of the relevant State quality standard. The stability (resistance) of a medicinal substance (LP) and its quality are closely related. The stability criterion is the preservation of the drug quality. A decrease in the quantitative content of a pharmacologically active substance in a drug confirms its instability. This process is characterized by the rate constant of drug decomposition. A decrease in the quantitative content should not be accompanied by the formation of toxic products or a change in the physicochemical properties of drugs. As a rule, a 10% decrease in the amount of drugs should not occur within 3-4 years in finished dosage forms and within 3 months in drugs prepared in a pharmacy.
The shelf life of drugs is understood as the period of time during which they must fully maintain their therapeutic activity, harmlessness and, in terms of the level of qualitative and quantitative characteristics, comply with the requirements of the State Pharmacopoeia or FS, in accordance with which they were released and stored under the conditions stipulated by these articles.
After the expiration date, the medicinal product cannot be used without re-quality control and a corresponding change. the deadline suitability.
The processes occurring during the storage of drugs can lead to a change in their chemical composition or physical properties (formation of sediment, change in color or state of aggregation). These processes lead to a gradual loss of pharmacological activity or to the formation of impurities that change the direction of the pharmacological action.
The shelf life of drugs depends on the physical, chemical and biological processes taking place in them. These processes are greatly influenced by temperature, humidity, light, pH of the environment, air composition and other factors.
Physical processes occurring during drug storage include: absorption and loss of water; a change in the phase state, for example, melting, evaporation or sublimation, delamination, coarsening of particles of the dispersed phase, etc. essential oils) the drug content in the dosage form may change.
Chemical processes take place in the form of hydrolysis, oxidation-reduction, racemization, and the formation of high-molecular compounds. Biological processes cause changes in drugs under the influence of the vital activity of microorganisms, which leads to a decrease in drug stability and human infection.
Medicines are most often contaminated with saprophytes, which are widespread in environment... Saprophytes are able to decompose organic matter: proteins, lipids, carbohydrates. Yeast and filamentous fungi destroy alkaloids, antipyrine, glycosides, glucose, and various vitamins.
The shelf life of drugs can be sharply reduced due to the poor quality of the packaging. For example, when storing solutions for injections in vials or ampoules from low-quality glass, sodium and potassium silicate transitions from glass to solution. This leads to an increase in the pH of the medium and the formation of so-called "sparkles" (particles of broken glass). With an increase in pH, salts of alkaloids and synthetic nitrogen-containing bases decompose with a decrease or loss of the therapeutic effect and the formation of toxic products. Alkaline solutions catalyze oxidation processes ascorbic acid, chlorpromazine, ergotal, vicasol, vitamins, antibiotics, glycosides. In addition, the alkalinity of the glass also contributes to the development of microflora.
The shelf life of drugs can be increased by stabilization.
Two methods of drug stabilization are used - physical and chemical.
Physical stabilization methods, as a rule, are based on the protection of medicinal substances from the adverse effects of the external environment. V last years a number of physical methods for increasing the resistance of drugs during their preparation and storage have been proposed. For example, freeze drying of thermolabile substances is used. Thus, an aqueous solution of benzylpenicillin retains its activity for 1 - 2 days, while a dehydrated drug is active for 2 - 3 years. Ampulation of solutions can be carried out in a stream of inert gases. It is possible to apply protective coatings on solid heterogeneous systems (tablets, dragees, granules), as well as microencapsulation.
However, physical stabilization methods are not always effective. Therefore, methods of chemical stabilization are more often used, based on the introduction of special excipients - stabilizers into drugs. Stabilizers ensure the stability of physicochemical, microbiological properties, biological activity of drugs over a certain period of storage. Chemical stabilization is of particular importance for drugs undergoing different types sterilization, especially thermal. Thus, stabilization of drugs is a complex problem, including the study of the resistance of drugs in the form of true solutions or dispersed systems to chemical transformations and microbial contamination.
2. Clinical Trials of Medicines (GCP). GCP stages
The process of creating new medicines is carried out in accordance with international standards GLP (Good Laboratory Practice Good Laboratory Practice), GMP (Good Manufacturing Practice Good Manufacturing Practice) and GCP (Good Clinical Practice Good Clinical Practice).
Clinical trials of drugs include the systematic study of an investigational drug in humans in order to verify its therapeutic effect or detect an adverse reaction, as well as the study of absorption, distribution, metabolism and excretion from the body to determine its effectiveness and safety.
Clinical trials of a drug are a necessary step in the development of any new drug, or the expansion of indications for the use of a drug already known to physicians. At the initial stages of drug development, chemical, physical, biological, microbiological, pharmacological, toxicological and other studies are carried out on tissues (in vitro) or on laboratory animals. These are the so-called preclinical studies, the purpose of which is to obtain scientific evaluations and evidence of the effectiveness and safety of drugs. However, these studies cannot provide reliable information on how the studied drugs will act in humans, since the organism of laboratory animals differs from humans both in pharmacokinetic characteristics and in the response of organs and systems to drugs. Therefore, it is necessary to conduct clinical trials of drugs in humans.
Clinical study (trial) of a medicinal product - it is a systematic study of a medicinal product through its use in a person (patient or healthy volunteer) in order to assess its safety and efficacy, as well as to identify or confirm its clinical, pharmacological, pharmacodynamic properties, assess absorption, distribution, metabolism, excretion and interaction with other medicinal products means. The decision to start a clinical trial is made by the customer, who is responsible for organizing, monitoring and funding the trial. The responsibility for the practical conduct of the study rests with the researcher. As a rule, the sponsor is pharmaceutical companies that develop medicinal products, but the researcher can also act as a sponsor if the research is initiated on his initiative and he is fully responsible for its conduct.
Clinical research must be conducted in accordance with the fundamental ethical principles of the Declaration of Helsinki, the Good Clinical Practice (GCP) Rules and applicable regulatory requirements. Prior to the initiation of a clinical trial, an assessment should be made of the ratio of the foreseeable risk to the expected benefit to 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 (IS) obtained after detailed acquaintance with the research materials. Patients (volunteers) participating in the testing of a new drug should receive information about the nature and possible consequences of the tests, the expected efficacy of the drug, the degree of risk, conclude a life and health insurance contract in the manner prescribed by law, and during the tests be under constant supervision of qualified personnel. In the event of a threat to the patient's health or life, as well as at the request of the patient or his legal representative, the head of clinical trials is obliged to suspend the trials. In addition, clinical trials are suspended in the absence or insufficient effectiveness of a drug, as well as violation of ethical standards.
The first stage of clinical trials of drugs is carried out on 30-50 volunteers. The next stage is extended trials on the basis of 2 - 5 clinics with the involvement of a large number (several thousand) patients. In this case, individual cards of patients with detailed description the results of various studies - blood tests, urine tests, ultrasound, etc.
Each drug goes through 4 phases (stages) of clinical trials.
Phase I. The first experience of using a new active substance in humans. Most often, research begins in volunteers (adult healthy men). The main goal of research is to decide whether to continue working on a new drug and, if possible, to establish the doses that will be used in patients during phase II clinical trials. During this phase, researchers obtain preliminary data on the safety of the new drug and describe its pharmacokinetics and pharmacodynamics in humans for the first time. Sometimes it is impossible to conduct phase I studies in healthy volunteers due to the toxicity of this drug (treatment of cancer, AIDS). In this case, non-therapeutic studies are carried out with the participation of patients with this pathology in specialized institutions.
Phase II. Usually this is the first experience of use in patients with a disease for the treatment of which the drug is supposed to be used. The second phase is divided into IIa and IIb. Phase IIa is a therapeutic pilot study, as the results obtained in these studies provide optimal planning for subsequent studies. Phase IIb is a larger study in patients with a disease that is the primary indication for a new drug. The main goal is to prove the effectiveness and safety of the drug. The results of these studies (pivotal trial) serve as the basis for planning Phase III studies.
Phase III. Multicenter trials involving large (and, if possible, diverse) patient groups (on average 1000-3000 people). The main goal is to obtain additional data on the safety and efficacy of various forms of the drug, on the nature of the most frequent adverse reactions, etc. Most often, clinical trials in this phase are double-blind, controlled, randomized, and the research conditions are as close as possible to the usual real routine medical practice. The data obtained in phase III clinical trials are the basis for the creation of instructions for the use of the drug and for the decision on its registration by the Pharmacological Committee. A recommendation for clinical use in medical practice is considered justified if the new drug:
More effective than known drugs of similar action;
Has better tolerance than known drugs (with the same effectiveness);
Effective in cases where treatment with known drugs is unsuccessful;
More profitable economically, has a simpler treatment method or a more convenient dosage form;
In combination therapy, it increases the effectiveness of existing drugs without increasing their toxicity.
Phase IV. Studies are carried out after the start of the sale of the drug in order to obtain more detailed information about long-term use in different groups of patients and with different risk factors, etc. and thus more fully assess the strategy of drug use. A large number of patients take part in the study, this makes it possible to identify previously unknown and rare adverse events.
If a drug is going to be used for a new indication that has not yet been registered, then additional studies are carried out for this, starting with phase II. Most often, in practice, an open study is carried out, in which the doctor and the patient know the method of treatment (the study drug or the reference drug).
When tested by a simple blind method, the patient does not know what drug he is taking (it may be a placebo), and when using the double-blind method, neither the patient nor the doctor is aware of this, but only the head of the trial (in a modern clinical trial of a new drug, four parties: research sponsor (most often it is a pharmaceutical manufacturing company), monitor - contractual research organization, researcher, patient). In addition, triple blind studies are possible, when neither the doctor, nor the patient, nor those who organize the study and process its data, do not know the prescribed treatment for a particular patient.
If doctors know which patient is being treated by which remedy, they may inadvertently assess the treatment based on their preferences or explanations. The use of blind methods increases the reliability of clinical trial results by eliminating the influence of subjective factors. If the patient knows that he is receiving a promising new drug, then the effect of the treatment may be related to his calming down, satisfaction that the most desirable treatment possible has been achieved.
Placebo (Latin placere - to like, to be appreciated) means a drug that obviously does not have any healing properties. The Big Encyclopedic Dictionary defines a placebo as “a dosage form containing neutral substances. Used to study the role of suggestion in therapeutic effect of any medicinal substance as a control in the study of the effectiveness of new medicinal products ”. quality medicinal product pharmaceutical
Negative placebo effects are called nocebos. If the patient knows what side effects the drug has, then in 77% of cases they occur when he takes a placebo. Belief in this or that effect can lead to the appearance of side effects. According to the commentary by the World Medical Association on Article 29 of the Declaration of Helsinki , "... the use of a placebo is justified if it does not lead to an increase in the risk of causing serious or irreversible damage to health ...", that is, if the patient is not left without effective treatment.
There is a term "full blinded studies", when all parties to the study do not have information about the type of treatment in a particular patient until the analysis of the results obtained is completed.
Randomized controlled trials serve as the quality standard for research on treatment efficacy. For the study, patients are first selected from a large number of people with the studied condition. Then these patients are randomly divided into two groups, comparable in terms of the main prognostic signs. Groups are generated randomly (randomization) using tables random numbers in which every digit or every combination of digits has an equal probability of being selected. This means that patients in one group will, on average, have the same characteristics as patients in another. In addition, prior to randomization, it should be ensured that disease characteristics known to strongly influence outcome occur with equal frequency in the treatment and control groups. To do this, you must first distribute patients into subgroups with the same prognosis and only then randomize them separately in each subgroup - stratified randomization. The experimental group (treatment group) undergoes an intervention that is expected to be beneficial. The control group (comparison group) is in exactly the same conditions as the first, except that its patients are not undergoing the study intervention.
3. Quantitative analysis of mixtures without preliminary separation of components by physicochemical methods
Physicochemical methods are becoming increasingly important for the purpose of objective identification and quantitative determination of medicinal substances. The most accessible for use in pharmaceutical analysis are photometric methods, in particular, spectrophotometry in the IR and UV regions, photometry in the visible region of the spectrum and their various modifications. These methods are included in the State Pharmacopoeia, in the International Pharmacopoeia and national pharmacopoeias of many countries, as well as in other regulatory documents. Pharmacopoeial monographs, which are state standards containing a list of indicators and methods used to control the quality of a medicinal product.
Physicochemical methods of analysis have a number of advantages over classical chemical methods. They are based on the use of both physical and chemical properties of substances and in most cases are characterized by rapidity, selectivity, high sensitivity, the possibility of unification and automation.
The inclusion of the developed methods in regulatory documents is preceded by extensive research in the field of pharmaceutical analysis. The number of completed and published works on the use of photometric methods is enormous.
To establish the authenticity of medicinal substances, pharmacopoeias use, along with other physical and chemical methods, IR spectroscopy - a method that provides the most objective identification. The IR spectra of the tested medicinal substances are compared either with the spectrum of a standard sample obtained under the same conditions, or with the attached spectrum recorded earlier for this medicinal substance.
Along with IR spectroscopy, the analysis of medicinal substances uses different options UV spectrophotometry of organic compounds. In the first works in this direction, the state was generalized and the prospects for using this method were outlined. Approaches to the use of UV spectrophotometry in drug standardization have been formulated, different ways analysis. In the authenticity test methods presented in the pharmacopoeias and other regulatory documents, identification is usually carried out according to the generally accepted parameters of UV spectra - the wavelengths of the maxima and minima of light absorption and the specific absorption index. For this purpose, one can also use such parameters as the position and half-width of the absorption band, the asymmetry factor, the integral intensity, and the oscillator strength. When these parameters are controlled, the specificity of the qualitative analysis increases.
In some cases, the visible region of the spectrum is used for the photometric determination of medicinal substances. The analysis is based on carrying out color reactions with subsequent measurement of optical density on spectrophotometers and photocolorimeters.
In pharmaceutical analysis, UV and visible spectrophotometry is often combined with separation methods (thin layer and other types of chromatography).
As is known, differential methods of photometric measurements carried out using a reference solution containing a certain amount of a standard sample of a test substance have increased accuracy. This technique leads to an expansion of the working area of the scale of the device, allows you to increase the concentration of the analyzed solutions and, ultimately, increases the accuracy of the determination.
4. Quality control system in the conditions of chemical and pharmaceutical plants and factories
The manufacturer of medicinal products must organize production in such a way that medicinal products are guaranteed to meet their intended purpose and requirements for them and do not pose a risk to consumers due to violation of safety, quality or efficacy conditions. Managers and all employees of the enterprise are responsible for meeting these requirements.
To achieve this goal, a quality assurance system must be created at the manufacturing enterprise, which includes the organization of work in accordance with GMP, quality control and a risk analysis system.
Quality control includes sampling, testing (analysis) and the preparation of relevant documentation.
The purpose of quality control is to prevent the use or sale of materials or products that do not meet quality requirements. Quality control activities are not limited to laboratory work, but also include research, testing and participation in any decisions regarding product quality. The fundamental principle quality control is its independence from production units.
Basic requirements for quality control:
Availability of the necessary premises and equipment, trained personnel, approved methods for sampling, verification and testing of raw materials and packaging materials, intermediate, on packaged and finished products;
Testing by certified methods;
Drawing up protocols confirming the actual carrying out of all necessary sampling, inspections and tests, as well as registering any deviations and investigations in full;
Preservation enough samples of raw materials and products for possible verification if necessary. Product samples should be kept in their final packaging, excluding large packages.
Each manufacturer must have a quality control department, independent of other departments.
Adequate microbiological purity is regulated for medicinal products. Microbial contamination can occur at different stages of production. Therefore, tests for microbiological purity are carried out at all stages of drug preparation. The main sources of microbial contamination are raw materials, water, equipment, the air of industrial premises, packaging of finished products, and personnel. To quantify the content of microorganisms in the air, use different methods sampling: filtration, sedimentation in liquids, sedimentation on solid media. Sterility tests are carried out to assess microbiological purity.
When determining the sterility of drugs with a pronounced antibacterial effect, bacteriostatic, fungistatic properties, as well as drugs containing preservatives or poured into containers of more than 100 ml, the membrane filtration method is used.
When controlling the sterility of dosage forms of β-lactam antibiotics, it is possible to use as an alternative method of direct inoculation with the use of the enzyme penicillinase in an amount sufficient to completely inactivate the tested antibiotic.
The application of the membrane filtration method is based on the passage of drugs through a polymer membrane. In this case, microorganisms remain on the surface of the membrane. Then the membrane is placed in an appropriate nutrient medium and the formation of colonies is observed during incubation.
For counting viable microorganisms, membranes of cellulose ethers (nitrocellulose, cellulose acetate and mixed cellulose ethers) with a pore size of 0.45 μm are usually used.
The technique for conducting tests for the microbiological purity of drugs using the membrane filtration method is given in the supplement to the FS "Test for microbiological purity" dated December 28, 1995.
The quality of medicines can be guaranteed with confidence if at all stages of the life cycle of medicines, all the rules of handling are strictly observed, in particular, preclinical and clinical trials, production, wholesale and retail sales of pharmaceutical products.
5. The main tasks and features of biopharmaceutical analysis
Biopharmaceutical analysis is a promising new direction in pharmaceutical chemistry. The task of biopharmaceutical analysis is to develop methods for the isolation, purification, identification and quantitative determination of drugs and their metabolites in biological fluids such as urine, saliva, blood, plasma or blood serum, etc. .e. to study the issues of absorption, transport and excretion of medicinal substances, its bioavailability, metabolic processes. All this makes it possible to prevent possible toxic effects of drugs, develop optimal regimens of pharmacotherapy and control the treatment process. It is especially important to determine the concentration of a medicinal substance in biological fluids when, along with a therapeutic effect, they exhibit toxicity. It is also necessary to control the content of medicinal substances in biological fluids of patients suffering from gastrointestinal diseases and diseases of the liver and kidneys. With such diseases, absorption processes change, metabolic processes are disrupted, and the excretion of drugs from the body slows down.
Biological fluids are very difficult objects to analyze. They are multicomponent mixtures containing a large number of inorganic and organic compounds of various chemical structures: trace elements, amino acids, polypeptides, proteins, enzymes, etc. Their concentration ranges from 10 mg / ml to several nanograms. Even in such a relatively simple physiological fluid as urine, several hundred organic compounds have been identified. Any biological object is a very dynamic system. Its condition and chemical composition depend on individual characteristics organism, the impact of environmental factors (composition of food, physical and mental stress, etc.). All this further complicates the performance of biopharmaceutical analysis, since against the background of so many complex software chemical structure organic substances need to determine often very low concentrations of drugs. Drugs introduced into biological fluids in the process of biological transformation form metabolites, the amount of which is often several dozen. Isolating these substances from complex mixtures, separating them into individual components and establishing their chemical composition is an extremely difficult task.
Thus, the following features of biopharmaceutical analysis can be distinguished:
1. The objects of research are multicomponent mixtures of compounds.
2. The amounts of the determined substances, as a rule, are calculated in micrograms and even nanograms.
3. The investigated medicinal substances and their metabolites are found in an environment consisting of a large number of natural compounds (proteins, enzymes, etc.).
4. The conditions for the isolation, purification and analysis of the investigated substances depend on the type of biological fluid being examined.
In addition to the theoretical value that research in the field of biopharmaceutical analysis has for the study of newly created medicinal substances, the practical role of this branch of knowledge is also undoubted.
Therefore, biopharmaceutical analysis is a kind of tool necessary for conducting not only biopharmaceutical, but also pharmacokinetic research.
6. Types of state standards. Requirements of general standards for dosage forms
Product quality standardization refers to the process of setting and applying standards. A standard is a reference or sample taken as a reference for comparing other similar objects with it. The standard as a normative document establishes a set of norms or requirements for the object of standardization. The application of standards contributes to the improvement of product quality.
In the Russian Federation, the following categories of normative documents ND have been established: State standards (GOST), industry standards (OST), republican standards (RST) and technical specifications (TU). The standards for drugs are FS, TU, which regulate their quality, as well as production regulations that regulate their technology. FS - regulatory documents that define a set of quality standards and methods for their determination. These documents ensure the same effectiveness and safety of drugs, as well as the consistency and uniformity of their production regardless of the batch. The main document regulating the quality of drugs produced in our country is the State Pharmacopoeia (GF). Industry standards (OSTs) are regulatory documents that reflect additional technical requirements for the production, control, storage, labeling, packaging, transportation of drugs.
Since June 2000, the industry standard “Rules for organizing production and quality control of drugs” has been introduced in Russia. This is a standard identical to the international GMP rules.
In addition to the specified standard, which ensures the production of high-quality drugs, a standard has been introduced that normalizes the quality of drugs, governs the procedure for creating new and improving the current regulatory documentation for drugs. It was approved by the Ministry of Health of the Russian Federation on November 1, 2001 (Order No. 388), registered by the Ministry of Justice of the Russian Federation on November 16, 2001, and is an industry standard OST 91500.05.001-00 “Quality Standards for Medicines. Basic Provisions ". The previously existing standard OST 42-506-96 has lost its validity. The purpose of creating an industry standard is to establish categories and a unified procedure for the development, presentation, design, examination, agreement, designation and approval of drug quality standards. The requirements of this standard are mandatory for development organizations, drug manufacturers, organizations and institutions that carry out expertise of quality standards for domestic drugs, regardless of departmental affiliation, legal status and forms of ownership.
In the newly approved OST, the categories of drug quality standards have been changed. A drug quality standard is a regulatory document (ND) containing a list of standardized indicators and quality control methods for drugs. It must ensure the development of an effective and safe drug.
The new OST provides for two categories of quality standards:
State quality standards for medicines (GSKLS), which include: General Pharmacopoeia Monograph (OFS) and Pharmacopoeia Monograph (FS);
Quality standard (SKLS); pharmacopoeial monograph of the enterprise (FSP).
The OFS contains the main General requirements to the dosage form or description of standard methods of drug control. The OFS includes a list of standardized indicators and test methods for a specific DF or a description of the methods for analyzing drugs, requirements for reagents, titrated solutions, indicators.
The FS contains a mandatory list of indicators and methods of quality control of a medicinal product (taking into account its LF) that meet the requirements of leading foreign pharmacopoeias.
Drug treatment is inextricably linked to the dosage form. Due to the fact that the effectiveness of treatment depends on the dosage form, the following general requirements are imposed on it:
Compliance with the therapeutic purpose, the bioavailability of the drug in the given dosage form and the corresponding pharmacokinetics;
Uniform distribution of medicinal substances in the mass of auxiliary ingredients and hence the accuracy of dosing;
Stability during shelf life;
Compliance with the norms of microbial contamination, if necessary, preservation;
Ease of reception, the ability to correct unpleasant taste;
Compactness.
OFS and FS are developed and revised after 5 years by the Scientific Center for Expertise and State Control of Medicines, and for immunobiological preparations - by the National MIBP Control Body.
OFS and FS constitute the State Pharmacopoeia (GF), which is published by the Ministry of Health of the Russian Federation and is subject to reprint every 5 years. The State Pharmacopoeia is a collection of state quality standards for drugs, which has a legislative character.
7. Hydrochloric acid: physical properties, authenticity, quantification, application, storage
Diluted hydrochloric acid (Acidum hydrochloridum dilutum) is a colorless transparent acidic liquid. density, solution density 1.038-1.039 g / cm3, volume fraction 8.2-8.4%
Hydrochloric acid (Acidum hydrochloridum) is a colorless transparent volatile liquid with a peculiar odor. Density 1.122-1.124 g / cm3, volume fraction 24.8-25.2%.
Hydrochloric acid drugs are mixed with water and ethanol in all proportions. They differ only in the content of hydrogen chloride and, accordingly, in density.
The chloride ion can be detected with the help of silver nitrate by the formation of a precipitate of silver chloride, insoluble in water and in nitric acid solution, but soluble in ammonia solution:
HCl + H2O-> AgClv + HNO3
AgCl + 2NH3 * H2O-> 2Cl + 2H2O
Another method for detecting chloride ion is based on the separation free chlorine when heating drugs with manganese dioxide:
4HCl + MnO2-> Cl2? + MnCl2 + 2H2O
Chlorine is detected by smell.
Determine the content of hydrogen chloride in medicinal preparations of hydrochloric acid by acid-base titration, titrating with sodium hydroxide solution in the presence of methyl orange indicator:
HCl + NaOH-> NaCl + H2O
Purity tests. Hydrochloric acid may contain impurities of heavy metals, mainly in the form of iron (II) and iron (III) salts. These impurities can get into the drug from the material of the apparatus in which the acid is produced. The presence of iron salts can be detected by the following reactions:
FeCl3 + K4> KFeFe (CN) 6v + 3KCl
FeCl2 + K3> KFeFe (CN) 6v + 2KCl
It can be seen from the last two reactions that the composition of the formed precipitates is identical. This has been established relatively recently. Previously, it was believed that two individual compounds are formed - Prussian blue and Turnbule blue.
If hydrogen chloride is produced by the reaction between hydrogen and chlorine, chlorine may be detected as an impurity. Its determination in solution is carried out by adding potassium iodide in the presence of chloroform, which acquires a violet color as a result of the concentration of released iodine in it:
Cl2 + 2KI> I2 + 2 KCl
Upon receipt of hydrogen chloride by the reaction:
2NaCl (TB) + H2SO4 (CONC)> Na2SO4 (TB) + 2 HCl ^
In drugs, impurities of sulfites and sulfates are possible. An admixture of sulfurous acid can be detected by adding iodine and starch solution. In this case, iodine is reduced: H2SO3 + I2 + H2O> H2SO4 + 2HI and the blue color of the iodine-starch complex disappears.
When the barium chloride solution is added, a white precipitate of barium sulfate is formed:
H2SO4 + BaCl2> BaSO4 + HCl
If hydrochloric acid has been produced using sulfuric acid, arsenic may also be present as a highly undesirable impurity.
Quantitation. The concentration of hydrochloric acid can be determined by two methods:
1). by neutralization method (titration with alkali for methyl orange - pharmacopoeial method):
HCl + NaOH> NaCl + H2O
2) argentometric method for chloride ion:
HCl + AgNO3> AgClv + HNO3
Hydrochloric acid was previously used as a drug for insufficient acidity of gastric juice. Assign inside 2-4 times a day with meals, 10-15 drops (for? -1/2 glass of water).
Titrated solutions of hydrochloric acid with a molar concentration of 0.01 - 1 mol / l are used in pharmaceutical analysis. Storage: in closed containers made of glass or other inert material at temperatures below 30 ° C.
Apply diluted hydrochloric acid in case of insufficient acidity of gastric juice. Assign orally 2-4 times a day with meals, 10-15 drops (for? -1/2 glass of water) If it is prescribed without indicating the concentration, diluted hydrochloric acid is always released; 6% acid solution is used in the treatment of scabies according to Demyanovich.
Storage conditions:
List B. In a dry place. In flasks with ground-in corks. For medical purposes, diluted hydrochloric acid is used.
8. Oxygen: physical properties, authenticity, good quality, quantification, application, storage
Oxygen - Oxygenium. A simple substance oxygen consists of non-polar molecules O2 (dioxygen) with a y, p-bond, a stable allotropic form of the element's existence in a free form.
Colorless gas, light blue in liquid state, blue in solid state.
Air constituent: 20.94% by volume, 23.13% by mass. Oxygen boils off from liquid air after nitrogen N2.
Supports combustion in air
Slightly soluble in water (31 ml / 1 L of H2O at 20 ° C), but slightly better than N2.
The authenticity of oxygen is determined by introducing a smoldering torch into the gas stream, which flares up and burns with a bright flame.
It is necessary to occasionally bring a smoldering torch to the opening of the gas outlet tube, and as soon as it starts to flash, the tube should be lifted, then lower it into the crystallizer with water and bring it under the cylinder. The incoming oxygen fills the cylinder, displacing the water.
A smoldering torch is introduced into one of the cylinders with N2O, it flares up and burns with a bright flame.
To distinguish oxygen from another gaseous preparation, nitrous oxide (dinitrogen oxide), equal volumes of oxygen and nitrogen oxide are mixed. The gas mixture turns orange-red due to the formation of nitrogen dioxide: 2NO + O2-> 2NO2
Nitrous oxide does not give this reaction. During industrial production, oxygen can be contaminated by impurities of other gases.
Evaluation for purity: in all tests for purity, the admixture of other gases is established by passing a certain amount of oxygen (at a rate of 4 l / h) through 100 ml of the reagent solution.
Oxygen must be neutral. The presence of gaseous impurities of an acidic and basic nature is established colorimetric method(color change of methyl red indicator solution)
Impurity of carbon (II) is detected by passing oxygen through ammonia solution silver nitrate. Darkening indicates the reduction of silver to carbon monoxide:
CO + 2 [Ag (NH3) 2] NO3 + 2H2O -> 2Agv + (NH4) CO3 + 2NH4NO3
The presence of an impurity of carbon dioxide is established by the formation of opalescence when oxygen is passed through a barium hydroxide solution:
CO2 + Ba (OH) 2 -> BaCO3v + H2O
The absence of impurities of ozone and other oxidizing substances is established by passing oxygen through a solution of potassium iodide, to which a starch solution and a drop of glacial acetic acid have been added. The solution should remain colorless. The appearance of a blue color indicates the presence of an admixture of ozone:
2KI + O3 + H2O -> I2 + 2KOH + O2?
Quantitation. All methods for the quantitative determination of oxygen are based on the interaction with easily oxidizable substances. Copper can be used for this. Oxygen is passed through a solution containing a mixture of solutions of ammonium chloride and ammonia (ammonia buffer solution, pH = 9.25 ± 1). Pieces of copper wire with a diameter of about 1 mm are also placed there. Copper is oxidized by oxygen:
The resulting copper (II) oxide reacts with ammonia to form bright blue copper (II) ammonia:
CuO + 2 NH3 + 2 NH4CI> Cl2 + H2O
Application. In medicine, oxygen is used for the preparation of oxygen water and air baths, for inhalation by patients - "medical gas". For general anesthesia in the form of inhalation anesthesia, a mixture of oxygen and low-toxic cyclopropane is used.
Oxygen is used for diseases accompanied by oxygen deficiency (hypoxia). Oxygen inhalation is used for respiratory diseases (pneumonia, pulmonary edema), of cardio-vascular system(heart failure, coronary insufficiency), poisoning with carbon monoxide (II), hydrocyanic acid, asphyxiant substances (chlorine C12, phosgene SOS12). A mixture of 40-60% oxygen and air is prescribed for inhalation at a rate of 4-5 l / min. They also use carbogen - a mixture of 95% oxygen and 5% carbon dioxide.
In hyperbaric oxygenation, oxygen is used at a pressure of 1.2-2 atm in special pressure chambers. It has been established that this method is highly effective in surgery, intensive care of serious diseases, and in case of poisoning. At the same time, oxygen saturation of tissues and hemodynamics improves. Usually one session is performed a day (40-60 minutes), the duration of treatment is 8-10 sessions.
The method of enteral oxygen therapy is also used by introducing oxygen foam into the stomach, used in the form of an oxygen cocktail. The cocktail is prepared by passing oxygen under slight pressure through the protein of a chicken egg, to which add rosehip infusion, glucose, vitamins B and C, infusions medicinal plants... Fruit juices, bread kvass concentrate can be used as a foaming agent. The cocktail is used to improve metabolic processes in the complex therapy of cardiovascular diseases.
Storage. In pharmacies, oxygen is stored in blue cylinders with a volume of 27-50 liters, containing 4-7.5 m3 of gas under a pressure of 100-150 atm. Do not lubricate the cylinder reducer thread with grease or organic oils (possible spontaneous combustion). Only talc ("soapstone" is a mineral belonging to layered silicates) serves as a lubricant. Oxygen is dispensed from pharmacies in special pillows equipped with a funnel-shaped mouthpiece for inhalation.
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In the female body, there are small amounts of male hormones androgens, which are responsible for normalization menstrual cycle and hair growth in intimate areas. With a high production of the hormone in women, bald patches begin to appear in the temples, and vegetation in other parts of the body also increases. Antiandrogenic drugs for women are designed to combat this process, which we will consider below.
With androgenic alopecia, special medications are prescribed
"Androkur"
This drug has a tablet form. Its main purpose is to block androgen receptors. For female representatives, it has the following indications for use:
Androkur leads to a weakening of the effect of androgen on the female body
- the appearance of hair on the face and body;
- seborrhea;
- acne disease.
"Androkur" leads to a weakening of the influence of androgen on the female body, and also helps to eliminate pathological changes in the form of increased vegetation.
The dosage and duration of the course of drug treatment should be determined strictly by the doctor. The drug is prohibited for use in persons suffering from the following pathologies:
- prolonged depression;
- thrombosis;
- hepatic pathologies;
- diabetes.
Taking the drug is also contraindicated during pregnancy and breastfeeding the female.
Among the side effects that are observed while taking the drug, allergic reactions accompanied by a rash, pain in the abdomen, a feeling of nausea, and an apathetic state should be distinguished. Since the medication can lead to a decrease in concentration, during the period of treatment they should refrain from driving, as well as engaging in activities that require a quick reaction and concentration.
"Vizanna"
Visanne should only be prescribed by a doctor.
The medication has indications for use such as endometriosis. It is also prescribed in the event of increased vegetation on the body, which is caused by the production of large quantities of androgens in the female body.
This is a rather serious drug with a large list of contraindications, therefore, it is not used without a doctor's prescription. "Visanne" is contraindicated in the presence of such pathologies as pathologies of the cardiovascular system, liver, internal bleeding, jaundice. Also, the drug is not prescribed in the presence of diabetes mellitus, thrombophlebitis, lactase deficiency.
Usually the drug is taken once a day with an equal amount of time interval between doses. The duration of treatment should be determined strictly by the doctor.
The drug can lead to complications such as vaginal bleeding, headaches, and depression.
"Marvelon"
Marvelon has a large list of contraindications and side effects
This medication belongs to contraceptives, which can be used in therapy in women with the appearance of increased vegetation against the background of hyperproduction of androgens in the body. The duration and dosage of the medication should be determined exclusively by a specialist.
Marvelon has a large list of contraindications and side effects. The drug should not be taken in the following cases:
- vaginal bleeding;
- diabetes;
- frequent, severe headaches;
- severe hepatic pathologies;
- pancreatitis;
- nicotine addiction in persons over 35 years old;
- lack of lactase;
- pathology of the cardiovascular system.
Against the background of taking the drug, it is possible to develop such negative phenomena as the development of pathologies of the gastrointestinal tract, the appearance of autoimmune diseases, in particular lupus erythematosus, the development of depressive conditions, etc.
It is worth considering that the medication is incompatible with many groups of drugs, therefore, before you start taking it, you should carefully read the instructions for use.
"Diana 35"
Diane 35 suppresses the increased production of androgens in a woman's body
This drug suppresses the increased production of androgens in a woman's body, thereby eliminating the pathological process that leads to the appearance of excess vegetation in unwanted places. A drug is also prescribed for this type of dermatitis, such as seborrhea of the scalp.
Under the influence of the drug, the production of the sebaceous glands by the body decreases, the hair follicles become stronger, which prevents premature loss of curls. Also, the drug helps to eliminate increased hairiness faces. Long-term therapy for several months is required to obtain the result. How much exactly to take the medicine should be decided directly by the doctor.
The medication cannot be used in therapy in patients suffering from different kinds thrombosis, diabetes mellitus, jaundice, liver pathologies and vaginal bleeding.
Among the adverse reactions provoked by the drug, the development of migraine, decreased libido, and allergic rashes should be distinguished. After discontinuation of the drug, adverse events usually disappear.
"Janine"
Janine refers to contraceptives
The drug belongs to contraceptives, the use of which is permissible with increased vegetation in the female against the background of increased production of male hormones by the body.
The drug is taken for several weeks. When the medication should be discontinued, the doctor must decide. It is recommended to use pills at regular intervals for a better therapeutic effect.
"Zhanin" has a lot of contraindications, including various thrombosis, liver pathologies, the period after childbirth. Also, the drug should not be taken to a certain group of diabetics, as well as to patients suffering from migraines. If there is bleeding, the product should also not be used.
"Janine" is incompatible with many medicines, so before taking it, you should carefully read the instructions.
Among the side effects that the drug can provoke are vaginitis, cystitis, anemia, weight loss, etc.
"Logest"
Logest is prescribed only by a doctor
This medication acts as an oral contraceptive prescribed for women with increased vegetation on the body and baldness on the head.
The dosage and duration of therapy are determined purely by a specialist. The first positive results should not be expected quickly. The effectiveness of therapy occurs after a few months.
For any type of thrombosis, as well as in the presence of pathologies such as diabetes mellitus, tumors, liver pathologies, severe headaches and vaginal bleeding, the drug is not prescribed. If the dosage is exceeded, there is a high risk of uterine bleeding.
The drug has poor compatibility with antibiotics of the tetracyclines and penicillins groups. Also, the drug is not recommended to be used simultaneously with medicines that contain carbamazepine and phenobarbital.
In some cases, the drug can form such undesirable reactions as the occurrence of migraines, apathy, decreased libido, body weight, allergies, etc.
"Spironolactone"
Spironolactone is indicated for severe acne and seborrhea.
An antiadrogen group medication is prescribed for severe types of acne and seborrhea. It is also used to reduce vegetation on unwanted areas of the body. It helps to normalize the sebaceous glands and strengthens the hair follicles.
The drug also belongs to strong diuretics, therefore it is often prescribed during pregnancy in the presence of severe edema.
The drug is prohibited for use in liver failure, diabetes mellitus, thrombophlebitis.
Usually, the medication is prescribed for three times a day. The duration of therapy will depend largely on the severity of the pathological process.
Long-term use of the drug can lead to the development of gastritis, bleeding in the organs of the gastrointestinal tract, drowsiness, etc.
"Spironolactone" can reduce concentration, for this reason, during treatment, it is prohibited to drive vehicles.
"Cyproterone Teva"
Cyproterone Teva is one of the most effective drugs
Antiandrogenic medication is one of the most effective drugs in this category, which is prescribed to women with androgenic alopecia.
Prescribe a medication for oral administration once a day. Treatment begins at the onset of menstruation. When results appear, the dosage is halved at the discretion of the physician.
In the presence of such pathologies as kidney failure, hepatic pathologies, diabetes mellitus, thromboembolism and the presence of chronic depression, "Cyproterone Teva" is not prescribed. If the prescribed dose is exceeded, the drug can lead to intoxication of the body, which requires symptomatic treatment.
Androgens are male sex hormones, which are also present in small quantities in women. They regulate the menstrual cycle, hair growth, and other processes in the body. If these hormones are produced in excess, this is manifested by a number of unpleasant symptoms: excessive vegetation on the body, alopecia, acne.
To combat hyperandrogenism, antiandrogenic drugs are widely used. Only a doctor can prescribe such funds, taking into account the results of the diagnosis, the reasons for the increase in the level of androgens and other factors.
Functions of androgens
Androgens are a group of male steroid hormones that are responsible for the functionality of the reproductive system. These include androsterone, testosterone, androstenediol. They are also present in small quantities in women. Their synthesis occurs in the ovaries, adrenal cortex.
It is androgens that are responsible for hair growth in intimate places, the normal course of menstrual cycles. Androgens are regulators of the functionality of the fat and sweat glands. If they are produced in excess in the female body, this immediately affects the condition of the hair and skin. Alopecia may develop.
As a result of hyperandrogenism, a woman has characteristic male gender characteristics:
- - increased hairiness on the face, chest and other parts of the body;
- oily seborrhea;
- skin rashes, acne;
- male obesity;
- disruptions of the menstrual cycle;
- alopecia;
- infertility.
Reasons for the failure of hormone synthesis
Disruptions in the synthesis of androgens in women, their excess level in the body may be associated with the following factors:
- androgen producing tumors;
- alpha reductase hyperactivity;
- uncontrolled intake of certain medications.
Review and characteristics of antiandrogenic drugs
If a woman has symptoms increased level androgens, it is necessary to carefully examine and find out the causes of this condition. To reduce the concentration of hormones in the complex therapy, antiandrogenic drugs are prescribed. Their main task is to suppress the excessive synthesis of androgens, to prevent them from accumulating in large quantities in the body. The mechanism of action of antiandrogens is different. It is possible to suppress the effect of hormones by inhibiting the activity of the enzyme 5a-reductase, blocking androgen receptors, and increasing the level of globulin. Consider the most effective antiandrogenic agents that are used in manifestations.
Androkur
A drug based on cyproterone acetate. It is produced in the form of powder for injection and tablets. Cyproterone is structurally a progestogen, but with mild progestogenic properties. Androkur is often prescribed for the treatment of alopecia in women against the background of hyperandrogenism, elimination of acne, seborrhea. The active substance of the drug replaces androgens in the receptors of hair follicles. Since taking the drug can have a number of side effects, only a specialist should prescribe it, carefully selecting the dosage and determining the duration of treatment. Androkur should be taken with caution after operations to remove tumor formations. The remedy is contraindicated for liver diseases, Rotor syndrome, for pregnant and lactating women.
A warning! It is forbidden to take oral contraceptives simultaneously with Cyproterone preparations. Their combination significantly increases the risk of thromboembolism. Do not combine medication with alcohol.
Byzanne
Non-steroidal antiandrogenic agent with anticancer action in the form of tablets. The active substance is bicalutamide. Byzanne is often used in the complex treatment of endometriosis and other disorders in the female reproductive system. The tablets should be taken 1 time per day, preferably at the same hour. The course of treatment is usually at least six months. It is forbidden to take the drug for diabetes mellitus, severe liver diseases, malignant tumors, alcoholism.
Spironolactone
An antiandrogenic agent widely used in the complex treatment of severe forms of acne. The active component of the drug is a mineralocorticoid with diuretic and antihypertensive effects. Spirolonolactone regulates the sebaceous glands, helps to reduce skin rashes. The drug is also effective for menstrual irregularities, polycystic ovaries, alopecia in women.
Long-term uncontrolled intake of Spironolactone can stimulate the development of breast tumors. The drug is contraindicated in diabetes mellitus, liver failure, 1 trimester of pregnancy. Take with caution in women with thrombophlebitis.
Marvelon
A drug that is a contraceptive with an antiandrogenic effect. 1 tablet contains 0.15 mg desogestrol, 0.03 mg ethinylestradiol. Start taking the drug from 1 day of menstruation and continue for 21 days. You can continue taking it after a week's break.
Marvelon can only be taken as directed by a doctor. There are a number of contraindications for using the product:
- diabetes;
- hepatic and renal failure;
- lactase deficiency;
- heart diseases.
Janine
The antiandrogenic effect of this contraceptive is provided due to the active component dienogest, it acts like a natural one. Janine not only protects against unwanted pregnancy, but also suppresses the synthesis of androgens in the ovaries, excludes squeezing from interaction with DES, affects the synthesis of and.
Janine is not prescribed for pregnant, lactating women, as well as for liver diseases, thrombosis, diabetes, vaginal bleeding. Before using the drug, you need to conduct a pregnancy test.
How to use for diabetes mellitus? Read useful information.
The causes of pain and burning in the mammary gland, as well as the treatment of discomfort, are described on the page.
Go to the address and read the instructions for use of Mastodinon for the treatment of mastopathy.
Logest
An oral contraceptive based on gestodene, a substance with an antiandrogenic effect. The drug is effective not only as a barrier against pregnancy, it well eliminates the symptoms of hyperandrogenism. Logest stabilizes the menstrual cycle, reduces skin rashes. Prescribe a remedy for women over 15 years old. It is rarely used during menopause. The drug is contraindicated for thrombophlebitis, liver failure, uterine bleeding, neurological migraines.
Yarina
The active ingredients are drospirenone and ethinylestradiol. The drug blocks skin receptors for androgens. It is recommended to take Yarina to patients over 30 years old to normalize the menstrual cycle, eliminate acne. The drug is also used to combat obesity. A visible therapeutic effect is observed after 3 months of using the agent.
Oral contraceptives also have antiandrogenic effects:
- Diane-35,
- Jazz,
- Three Mercy,
- Belara and others.
Any possibility of using such funds should be agreed with the gynecologist. Otherwise, uncontrolled intake of hormonal drugs is fraught with various disorders and complications of the woman's condition.
Hyperandrogenism in women is a condition that may indicate various disorders in the body. Before taking antiandrogenic drugs, it is necessary to undergo a thorough examination, to find out the reasons high level androgens in the blood. Since such funds affect the hormonal background of a woman, only a specialist should deal with their appointment. Only strict adherence to the doctor's prescriptions will allow you to cope with the problem and avoid unwanted consequences.
See also diane, nilutamide, proscar, serpen, flutamide.
Cyproterone
Synonyms: Androkur, Androkurdepo, Cyproietorone acetate.
Pharmachologic effect. It has an antiandrogenic (opposite to the action of male sex hormones) effect due to the blockade of androgen receptors (male sex hormones). Cyproterone is similar in chemical structure to the male sex hormone testosterone and other natural androgens, has the ability to competitively bind to tissue receptors of these hormones in target organs, which include the testes, prostate gland, etc. In this regard, the drug reduces or eliminates the effects androgens, including those associated with excess production of male sex hormones. Possesses progestogenic activity (gestagen-like action: gestagens - female sex hormones produced by the corpus luteum of the ovary and the adrenal cortex, cause changes in the endometrium / inner layer of the uterus /, preparing it for implantation / implantation / fertilized egg, ensure the normal flow of pregnancy, uterus especially a pregnant woman, stimulate the development of the lactic divisions of the mammary glands), has a contraceptive (contraceptive) effect in women.
Indications for use. In men: control of sexual desire in case of sexual deviations. In women: severe androgenization phenomena (appearance of masculine features). In children: idiopathic (unknown origin) precocious puberty.
Method of administration and dosage. Men with pathologically altered sexual behavior and increased sex drive are prescribed 1 tablet 2 times a day, less often 2 tablets 2 times a day or temporarily 2 tablets 3 times a day. Cyproterone-depot is injected intramuscularly in 3 ml (1 ampoule) every 10-14 days. If necessary, the dose of the drug can be increased to 6 ml (2 ampoules) every 10-14 days. At this dosage, it is preferable to administer 3 ml (1 ampoule) to each buttock. If a satisfactory therapeutic effect is achieved, the dose of the drug can be reduced, with a simultaneous and gradual increase in the time intervals between injections. The course of treatment usually lasts several months. If necessary, drug treatment is combined with psychotherapeutic measures.
For women, the drug is prescribed only orally in combination with the drug Diane-35. For children, the drug is prescribed only internally according to special schemes.
With the simultaneous use of alcohol, it is possible to reduce the effect of controlling sexual desire. During the period of treatment, careful monitoring of the function of the liver, adrenal cortex and blood picture is necessary; in patients with diabetes mellitus - control of blood glucose levels. In women, pregnancy should be excluded before starting therapy. In children receiving high doses of the drug, at high intensity loads, it may be necessary to substitute glucocorticoids due to latent adrenal insufficiency.
Side effect. Change in body weight, anxiety, depression (depression), fatigue, deterioration in the ability to concentrate. In men: suppression of spermatogenesis (the process of formation of male germ cells - sperm), gynecomastia (enlargement of the mammary glands). In women: depression (with combination therapy), a feeling of tension in the chest. In children: a negative effect on the hypothalamus, leading to suppression of the adrenal cortex (when using the drug in high doses). In some cases, when using high doses of the drug - severe liver dysfunction.
Contraindications Diseases (including tumors, if they are not caused by metastases / spread of cancer to other tissues and organs due to the transfer of cancer cells with blood or lymph from the primary focus / carcinoma of the prostate), Dubin-Johnson syndrome ( hereditary disease liver, characterized by a moderate increase in the level of bilirubin in the blood) and Rotor (hereditary liver disease, characterized by a moderate increase in the level of bound bilirubin in the blood); cachexia (extreme exhaustion) - if it is not associated with prostate carcinoma; severe forms of depression; thromboembolism (blockage of a vessel by a blood clot), including a history (medical history); severe diabetes mellitus with vascular lesions; sickle cell anemia (hereditary disease characterized by increased breakdown of sickle-shaped erythrocytes and the presence of functionally defective hemoglobin / oxygen carrier /); pregnancy; lactation period; idiopathic (of unknown origin) jaundice (yellowing of the skin and mucous membranes) of pregnant women or severe itching and herpes (a viral disease characterized by a rash on the skin and / or mucous membranes of grouped vesicles) of pregnant women in history.
Release form. Tablets of 0.05 g of cyproterone acetate in a package of 20 and 50 pieces. Solution for injection (1 ml - 0.1 g of cyproterone acetate) in ampoules of 3 ml in a package of 3 pieces.
Storage conditions. List B. In a dry place.