Drug sickness in the problem of adverse drug reactions: current status

In the 20th century, side effects of drugs and drug-induced disease continue to be the most pressing medical and social problems.

According to WHO, drug side effects currently rank 5th in the world after cardiovascular, oncological, pulmonary diseases and injuries.

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Causes of drug-induced illness

The reasons for the annual steady increase in cases of adverse drug reactions and drug-induced illness are:

• violation of the ecology of the environment;
• the presence of pesticides, preservatives, antibiotics and hormonal agents in food products;
• duration of a course of treatment with medicinal products (MP) for many diseases;
• polypharmacy (against the background of stress, urbanization, chemicalization of industry, agriculture and everyday life);
• self-medication;
• irresponsibility of state policy in matters of selling medicines (without prescriptions);
• pharmacological boom (growth in the production of branded drugs, generics, dietary supplements).

The pharmaceutical boom is evidenced by the figures of use on the pharmaceutical market of Ukraine of more than 7 thousand drugs in 15 thousand dosage forms, produced by 76 countries of the world. These data are confirmed by the volumes of pharmacy sales of drugs of domestic and foreign production in monetary, physical terms and dollar equivalent.

Of all the manifestations of side effects of drugs, according to the Ukrainian Center for the Study of PDLS, 73% are allergic reactions, 21% are side effects associated with the pharmacological action of drugs, and 6% are other manifestations. In dermatovenereology, the most frequently recorded manifestations of side effects of drugs include:

• true allergic reactions (drug and serum sickness) - 1-30%;
• toxic-allergic reactions - 19%;
• pseudo-allergic reactions - 50-84%;
• pharmacophobia - no data.

Despite the long history of the problems of side effects of drugs and drug-induced illness, there are still many unresolved and debatable issues: the lack of official statistics, the lack of a unified view on their terminology and classification, the lack of compliance of the domestic terminology of true allergic reactions to drugs with the terminology of the ICD-10th revision, issues of diagnosing side effects of drugs and drug-induced illness, and in particular, the advisability of performing skin tests with drugs before surgery and the start of antibiotic therapy, issues of therapy for drug-induced illness.

At present, official statistics are only the tip of the iceberg, since they are practically not kept.

There is no generally accepted classification of adverse drug reactions. The main approaches (etiological and clinical-descriptive), which were previously used in compiling classifications, were not applicable in this case, since it is known that the same drug can cause different clinical pictures and vice versa. Therefore, the pathogenetic principle is most often used as the basis for currently existing classifications of adverse drug reactions. The classification that best suits modern concepts is the one that distinguishes:

• pharmacological side effect;
• toxic side effect;
• side effect caused by a disorder of the immune system;
• pseudo-allergic reactions to drugs;
• carcinogenic effect;
• mutagenic effect;
• teratogenic effect;
• side effects caused by massive bacteriolysis or changes in the ecology of microbes (Jarisch-Herxheimer reaction, candidiasis, dysbacteriosis);
• drug addiction (drug addiction and substance abuse, tolerance, withdrawal syndrome, psychogenic reactions and psychophobia).

In clinical practice, of all the types of side effects of pharmacotherapy, the most widespread are reactions caused by a disorder of the body's immune system, the so-called true allergic reactions. However, the question of their terminology is still debatable. If E. A. Arkin (1901), E. M. Tareyev (1955), E. Ya. Severova (1968), G. Majdrakov, P. Popkhristov (1973), N. M. Gracheva (1978) called manifestations of true allergic reactions to medications "drug disease", considering it an analogue of "serum sickness", then other researchers - drug allergy, toxicodermia. Meanwhile, according to long-term clinical observations and experimental studies conducted by our institute, there are grounds to consider true allergic reactions to drugs not as a symptom or syndrome, but as an independent multifactorial disease - as a second disease developing against the background of any pathological process and repeated administration of average therapeutic doses of drugs, caused not so much by the pharmacological characteristics of the drug as by the characteristics of the patient's immune system and his constitutional and genetic predisposition. The results of the studies indicate that with the development of drug disease, all body systems are involved in the pathological process, despite the fact that clinically the disease can proceed with predominant damage to one of them, most often the skin. That is why drug disease, along with clinicians of all specialties, is of particular interest primarily to dermatologists.

The development of drug-induced disease is based on immunological mechanisms that fully correspond to the patterns of any other allergic reactions to an antigen. Therefore, in the course of drug-induced disease, as in the course of any allergic process, three stages are distinguished: immunological, pathochemical and pathophysiological (or the stage of clinical manifestations). The features of drug-induced disease are manifested only in the immunological stage and consist in the fact that at this stage the drug turns from a hapten into a full-fledged antigen, to which p-lymphocytes begin to produce antibodies and sensitized lymphocytes in large quantities. The more antigen enters the body, the higher the concentration of antibodies and sensitized lymphocytes becomes. In morphological and functional terms, sensitized cells do not differ from normal ones, and a sensitized person is practically healthy until the allergen enters his body again and antigen-antibody reactions occur, accompanied by a massive release of mediators and pathophysiological disorders.

The development of the allergic process in drug-induced disease usually occurs according to four types of allergic reactions. In this case, IgE-dependent degranulation is initiated only by specific allergens, which already in the body bind to IgE molecules fixed on the surface of basophils and mast cells due to a special receptor of high affinity to the Fc fragment of IgE. In turn, the binding of a specific allergen to IgE forms a signal transmitted through receptors and including a biochemical mechanism of activation of both membrane phospholipids with the production of inositol triphosphate and diacylglycerol, and phosphokinase with subsequent phosphorylation of various cytoplasmic proteins. These processes change the ratio of cAMP and cGMP and lead to an increase in the content of cytosolic calcium, which promotes the movement of basophil granules to the cell surface. The membranes of the granules and the cell membrane merge, and the contents of the granules are released into the extracellular space. During the process of degranulation of peripheral blood basophils and mast cells, coinciding with the pathochemical stage of the allergic reaction, mediators (histamine, bradykinin, serotonin) and various cytokines are released in large quantities. Depending on the localization of antigen-antibody complexes (IgE-mast cells or peripheral blood basophils) on a particular shock organ, various clinical manifestations of drug disease may develop.

Unlike drug-induced disease, pseudoallergic reactions have no immunological stage, and therefore their pathochemical and pathophysiological stages occur without the participation of allergic IgE antibodies with excessive release of mediators, which occurs in a non-specific way. Three groups of mechanisms participate in the pathogenesis of this excessive non-specific release of mediators in pseudoallergy: histamine; disorders of activation of the complement system; disorders of arachidonic acid metabolism. In each specific case, the leading role is given to one of these mechanisms. Despite the differences in the pathogenesis of drug-induced disease and pseudoallergic reactions, in the pathochemical stage in both cases, the same mediators are released, which causes the same clinical symptoms and makes their differential diagnosis extremely difficult.

In drug-induced disease, in addition to changes in immune homeostasis, the following are disrupted: neuroendocrine regulation, lipid peroxidation processes and antioxidant protection. In recent years, the role of the peripheral link of the erythron has been studied in the pathogenesis of drug-induced disease, which made it possible to identify an increase in the heterogeneity of the population of circulating erythrocytes with a predominance of their macroforms, a change in the barrier functions of erythrocyte membranes, a redistribution of potassium-sodium gradients between plasma and erythrocytes, manifested by the loss of excess potassium and an increase in the entry of sodium ions into cells and indicating a violation of the ion-transport function of erythrocytes. At the same time, a dependence of the indicators characterizing the physicochemical properties of erythrocytes on the clinical symptoms of drug-induced disease was revealed. Analysis of these studies indicates that erythrocytes are a sensitive link in the peripheral system of the erythron in the mechanisms of drug-induced disease development and, therefore, their morphometric indicators, as well as the functional state of their membranes, can be included in the algorithm for examining patients. These data formed the basis for the development of biophysical methods for express diagnostics of drug-induced disease based on measuring the levels of ultrasound absorption by erythrocytes, as well as assessing the rate of erythrocyte sedimentation in the presence of suspected drug allergens, which compare favorably with traditional immunological tests, as they are more sensitive and allow diagnostics to be carried out in 20-30 minutes.

The role of endogenous intoxication syndrome has been established in the pathogenesis of drug-induced disease, as evidenced by the high level of medium-molecule peptides, as well as the appearance of fraction A with subfractions Al, A2, A3, absent in practically healthy people, during their chromatographic analysis. The structure of genes that control the mechanisms of pharmacological response and are responsible for the synthesis of immunoglobulins E and the development of sensitization changes. At the same time, favorable conditions for the development of sensitization occur mainly in individuals with a special phenotype of enzyme systems, for example, with reduced activity of liver acetyltransferase or the enzyme glucose-6-phosphate dehydrogenase of erythrocytes, therefore, now, more than ever, it is extremely important to study the phenotype in the pathogenesis of drug-induced disease - external manifestations of the genotype, i.e. a set of signs in individuals who are prone to developing allergic reactions to drugs.

The diversity of immunological types in drug-induced disease is expressed by the polymorphism of clinical manifestations - generalized (multisystemic) lesions (anaphylactic shock and anaphylactoid conditions, serum sickness and serum-like diseases, lymphadenopathies, drug fever)

• with predominant skin lesions:
• frequently encountered (such as urticaria and Quincke's edema; Gibert's pityriasis rosea, eczema, various exanthemas),
• less common (such as erythema multiforme exudative; vesicular rashes resembling Duhring's dermatitis; vasculitis; dermatomyositis), rare (Lyell's syndrome; Stevens-Johnson syndrome);
• with predominant damage to individual organs (lungs, heart, liver, kidneys, gastrointestinal tract);
• with predominant damage to the hematopoietic organs (thrombocytopenia, eosinophilia, hemolytic anemia, agranulocytosis);
• with predominant damage to the nervous system (encephalomyelitis, peripheral neuritis).

However, there is still no unified view on the clinical classification of drug-induced disease.

The absence in ICD-10 of a term that unites manifestations of true allergic reactions to drugs indicates, firstly, a discrepancy between international and our terminology, and secondly, it does not actually allow for statistics and forces us to study the prevalence of side effects of pharmacotherapy mainly by the number of requests.

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Diagnosis of drug-induced disease

With a characteristic allergological anamnesis and typical clinical manifestations, the diagnosis of drug-induced disease does not cause difficulties. The diagnosis is confirmed quickly and easily when there is a temporary connection between taking medications and the development of an allergic process, the cyclical nature of the process and its fairly rapid remission after the withdrawal of the poorly tolerated drug. Meanwhile, difficulties in differential diagnosis of drug-induced disease and the underlying disease, for the complication of which it is often taken, are not uncommon, since the skin symptoms of drug-induced disease have a great similarity with the clinical picture of many true dermatoses, some infectious diseases, as well as toxic and pseudo-allergic reactions.

Taking into account the above, a step-by-step diagnosis of drug-induced disease is used:

• evaluation of allergy history data and clinical criteria for drug-induced illness;
• evaluation of the results of clinical and laboratory examination;
• assessment of specific immunological examination in order to identify the etiological factor of the allergic process;
• differential diagnosis between true and pseudo-allergic reactions to drugs;
• differential diagnosis of drug-induced illness and toxic reactions;
• differential diagnostics of drug-induced disease and some infectious diseases (measles, scarlet fever, rubella, chickenpox, secondary early fresh and recurrent syphilis);
• differential diagnosis of drug-induced disease and true dermatoses;
• differential diagnosis of drug-induced illness and psychogenic reactions (psychophobias).

The diagnosis of true and pseudo-allergic reactions is based primarily on subjective criteria of their differences (in pseudo-allergy, according to the allergological anamnesis, there is no sensitization period; the duration of pseudo-allergic reactions is short-lived; there are no repeated reactions when using chemically similar drugs). Of the objective differential diagnostic criteria, one can only rely on the results of test-tube specific immunological tests, which, in pseudo-allergic reactions to drugs, are usually negative.

Toxic side effects of drugs are indicated by:

• drug overdose; drug accumulation due to impaired elimination caused by liver and kidney failure; detection of enzymopathies, which are characterized by a slowdown in the metabolism of therapeutic doses of drugs.
• A positive intradermal test with saline solution indicates psychophobia.
• The most controversy arises when establishing the etiological diagnosis of drug-induced disease.
• As a rule, etiological diagnosis of drug-induced disease is carried out using:
• provocative tests (sublingual test, nasal test, skin tests);
• specific immunological and biophysical tests.

Of the provocative tests, the sublingual, nasal and conjunctival tests are comparatively rarely performed, although cases of allergic complications have not been described. Traditionally, the step-by-step staging of drop, application, scarification and intradermal tests is more widely used, the diagnostic value of which has remained debatable for several decades. Along with opponents of the use of skin tests for the purpose of prognostication and diagnostics of drug disease, even those who rely on their staging admit their inexpediency, associated with the danger to the patient's life and low information content due to the development of false positive and false negative reactions. Meanwhile, in recent years, a draft of a new order on improving the diagnostics of drug disease has been issued, in which the emphasis of diagnostics continues to be placed on skin tests.

The most common causes of false-positive reactions of skin tests are: increased sensitivity of skin capillaries to mechanical irritation; non-specific irritant action of allergens due to their improper preparation (the allergen should be isotonic and have a neutral reaction); difficulty in dosing the administered allergen; sensitivity to preservatives (phenol, glycerin, thimerosal); metallergic reactions (positive reactions in a certain season of the year with allergens to which patients do not react at other times of the year); the presence of common allergenic groups between some allergens; the use of non-standardized solutions for diluting drugs.

The following are known causes of false negative reactions: absence of the necessary medicinal allergen; loss of allergenic properties of the medicinal product due to its long-term and improper storage or during the dilution process, since there are still no standardized medicinal allergens; absence or decreased sensitivity of the patient's skin caused by:

• absence of skin-sensitizing antibodies;
• early stage of development of hypersensitivity;
• depletion of antibody reserves during or after an exacerbation of the disease;
• decreased skin reactivity associated with impaired blood supply, swelling, dehydration, exposure to ultraviolet radiation, and old age;
• taken by the patient immediately before testing antihistamines.

An important factor limiting the use of skin tests with drugs is their relative diagnostic value, since the registration of their positive results to a certain extent indicates the presence of an allergy, and negative ones in no way indicate the absence of an allergic condition in the patient. This fact can be explained by the fact that, firstly, most drugs are haptens - incomplete allergens that become complete only when they bind to blood serum albumins. That is why it is not always possible to recreate a reaction on the skin adequate to that occurring in the patient's body. Secondly, almost all drugs undergo a number of metabolic transformations in the body, and sensitization develops, as a rule, not to the drug itself, but to its metabolites, which can also be stated as a negative reaction to the drug being tested.

In addition to their low information content and relative diagnostic value, there are many other contraindications for skin tests, the main ones being: acute phase of any allergic disease; history of anaphylactic shock, Lyell's syndrome, Stevens-Johnson syndrome; acute intercurrent infectious diseases; exacerbation of concomitant chronic diseases; decompensated conditions in diseases of the heart, liver, kidneys; blood diseases, oncological, systemic and autoimmune diseases; convulsive syndrome, nervous and mental diseases; tuberculosis and tuberculin test conversion; thyrotoxicosis; severe diabetes mellitus; pregnancy, breastfeeding, first 2-3 days of the menstrual cycle; age under three years; period of treatment with antihistamines, membrane stabilizers, hormones, bronchodilators.

One of the important points limiting the use of skin tests is the impossibility of predicting the development of side effects not mediated by immunoglobulin E. The implementation of skin tests is complicated by the unsuitability of insoluble drugs for them, as well as the duration of their implementation when staged, especially considering that the test in any modification can only be done with one drug per day, and its diagnostic value is limited to a short period of time. Obviously, taking into account all the shortcomings of skin tests with drugs, they were not included in the diagnostic standards, i.e. in the list of mandatory methods for examining patients with acute toxic-allergic reactions to drugs, recommended by the Institute of Immunology of the Ministry of Health of the Russian Federation and the Russian Association of Allergists and Clinical Immunologists. Meanwhile, in numerous publications not only of the past but also of the recent years, including in the legislative documents of Ukraine, skin tests continue to be recommended both for the purpose of establishing an etiological diagnosis of a drug disease and for the purpose of predicting it before starting treatment, especially before administering injection antibiotic therapy. Thus, according to the order of the Ministry of Health and the Academy of Medical Sciences of Ukraine dated 02.04.2002 No. 127 "On organizational measures for the implementation of modern technologies for the diagnosis and treatment of allergic diseases" and the appendix No. 2 attached to it in the form of Instructions on the procedure for conducting diagnostics of drug allergy in all medical and preventive institutions, when prescribing treatment to patients using injectable antibiotics and anesthetics, mandatory skin tests are regulated to prevent complications of pharmacotherapy. According to the instructions, the antibiotic is diluted with a certified solution so that 1 ml contains 1000 U of the corresponding antibiotic. The skin test is performed on the forearm, after wiping the skin with a 70% ethyl alcohol solution and stepping back 10 cm from the elbow bend, with an interval of 2 cm between tests, and simultaneously with no more than 3-4 medicinal preparations, as well as in parallel with positive (0.01% histamine solution) and negative (dilution liquid) controls. It is recommended to perform mainly a prick test, which, unlike a scarification test, is more unified, specific, aesthetic, economical, less dangerous and traumatic. In order to further increase the information content of skin testing, it is recommended to perform a rotational prick test, the essence of which is that after pricking the skin, a special lancet is fixed for up to 3 seconds, and then it is freely rotated 180 degrees in one direction and 180 degrees in the other. The reaction is recorded after 20 minutes (with a negative reaction - no hyperemia, with a questionable reaction - hyperemia 1-2 mm, with a positive reaction - 3-7 mm, with a positive reaction - 8-12 mm,in case of hyperergic reaction - 13 mm or more).

In the Instructions on the procedure for conducting diagnostics of drug allergies, in addition to the debatable nature of the question of the legitimacy of using skin tests with drugs for this purpose, there are many other controversial points regarding the technology of their implementation. Thus, according to the instructions, a skin provocation test can be performed in the case of an allergic reaction of the reagin type, while in the case of a reaction of the cytotoxic and immune complex types, laboratory tests are indicated, and in the case of a reaction of delayed hypersensitivity - laboratory tests and application tests. However, as clinical observations show, before starting injection antibiotic therapy, it is simply impossible to predict in advance the type of allergic reaction in a patient with an unburdened allergological anamnesis, if this reaction suddenly develops.

No less controversial is the indication about the possibility of conducting skin testing simultaneously with 3-4 medications, since there are opposing opinions on this matter, according to which a skin test can only be done with one medication on the same day.

It is doubtful whether it is possible to implement the instruction postulate that skin testing with drugs should be carried out under the supervision of an allergist or doctors who have undergone special allergological training, including measures to provide resuscitation care to patients with anaphylaxis. There are a limited number of such specialists in Ukraine, represented only by doctors of city and regional allergological offices and hospitals, and therefore, skin tests with drugs in all medical and preventive institutions, according to regulatory documents, will be carried out, as it was before, by untrained medical workers. In fact, the regulatory document on the organization of the allergological service in Ukraine does not have an economic basis for its implementation, since, given the economic situation in the country, it is currently as unrealistic to train specialists competent in allergology for all medical institutions, as it is to provide these institutions with instruments and standardized drug kits for screening diagnostics.

Taking into account all the shortcomings and contraindications of skin tests, as well as the annual increase in allergic and pseudoallergic reactions to drugs, the advisability of their use with antibiotics before the start of injection antibiotic therapy is questionable, both in patients with common dermatoses with complicated pyoderma, and in patients with sexually transmitted infections, in the acute or subacute period of their disease. Meanwhile, despite all the contraindications and dangers of skin tests, as well as their low information content, legislative documents concerning the dermatovenereological service continue to insist on the advisability of their use before the start of antibiotic therapy, as evidenced by the draft new order published by the Ministry of Health and the National Academy of Medical Sciences of Ukraine on improving the diagnosis of drug disease, in which the emphasis is still on skin tests.

In our opinion, since skin tests with drugs have many contraindications and limitations, and are also dangerous to the life of patients and often fraught with the possibility of obtaining false positive and false negative results, it is more expedient to use specific immunological tests when conducting etiological diagnostics. The attitude to them, as well as to skin tests, is no less controversial due to their shortcomings: duration of implementation; lack of standardized diagnostic drug allergens; difficulties in acquiring the necessary material base (vivarium, radioimmune laboratory, fluorescent microscope, enzyme immunoassay analyzer, test systems, etc.). In addition, it should be taken into account that there are still no standardized diagnostic drug allergens, as a result of which it is necessary to work with allergens characterized by various physicochemical parameters, for which it is not always possible to select optimal concentrations, as well as their solvents. Therefore, in recent years, biophysical methods for rapid diagnostics of drug-induced disease have been developed, allowing etiological diagnostics to be carried out within 20-30 minutes, while almost all specific immunological tests require a long time to perform.

Of such biophysical methods of etiological express diagnostics of drug-induced disease, developed at the State Institution “Institute of Dermatology and Venereology of the National Academy of Medical Sciences of Ukraine”, the following should be noted, based on the assessment:

• maximum intensity of ultra-weak luminescence of blood serum pre-incubated with a suspected drug allergen and induced by hydrogen peroxide;
• the rate of onset of erythrocyte hemolysis in the presence of suspected drug allergens;
• erythrocyte sedimentation rate in the presence of suspected drug allergens;
• the level of ultrasound absorption in erythrocytes pre-incubated with a suspected drug allergen.

In addition, the institute has developed diagnostic devices for etiological express diagnostics by assessing: the erythrocyte sedimentation rate (in collaboration with the National Technical University of Radio Electronics); the level of ultrasound absorption by erythrocytes pre-incubated with a suspected drug allergen (in collaboration with the T. G. Shevchenko Kharkov Instrument-Making Plant).

Automated information systems (AIS), developed jointly with the Kharkiv National Polytechnic University and the Kharkiv Institute of Radio Electronics, provide great assistance in the early diagnosis of drug-induced disease. They allow: identifying risk groups; quantifying the degree of risk of allergodermatoses for each individual examined; assessing the psychoemotional state of workers and employees of enterprises; conducting automated professional selection of applicants for employment; keeping records of work-related and occupational allergic diseases; analyzing the effectiveness of preventive measures; giving recommendations on the choice of an individual preventive complex depending on the state of immune homeostasis and the adaptive and compensatory capabilities of the body.

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Treatment of drug-induced disease

Treatment of drug-induced bronchitis is difficult due to frequent polysensitization even to corticosteroids and antihistamines. It is based on data on pathogenetic mechanisms and taking into account the individual's condition. Treatment of drug-induced bronchitis is carried out in two stages. At the first stage of treatment, measures are taken to bring the patient out of the acute condition, in which the most effective method is to remove the drug to which the patient is sensitized from the body and the environment, as well as to exclude its further use, which is not always feasible. The main drugs for acute manifestations of drug-induced bronchitis in modern conditions continue to be corticosteroids. An important place in therapy is occupied by antihistamines and measures aimed at normalizing the water-electrolyte-protein balance by introducing detoxifying solutions (isotonic solution, rheopolyglucin, hemodez) and diuretics (lasix, furosemide, etc.). Meanwhile, the lack of modern injectable hyposensitizing drugs creates difficulties in providing intensive therapy to patients with anaphylactic shock.

An important place in the treatment of drug disease with acute clinical manifestations is occupied by external therapy. In addition to lotions, corticosteroid ointments and creams are widely used, the effectiveness of which depends not only on the active corticosteroid, but also on its base. Advantan, Elokom, Celestoderm B creams deserve special attention, and in case of infection - Celestoderm with Garamicin, Diprogent.

The second stage of treatment begins at the stage of remission, during which a full range of measures is carried out aimed at changing the patient's reactivity and preventing future relapses. In case of polysensitization to medications, which is often combined with food, bacterial, pollen, solar and cold allergies, non-specific therapy is indicated, which uses traditional desensitizing agents (corticosteroids and antihistamines, calcium, sodium, etc.). Of the antihistamines, preference is given to second-generation (claritin, semprex, histalong) or third-generation (telfast, histafen, xyzal) drugs, which have high affinity and binding strength to HI receptors, which, along with the absence of a sedative effect, allows the use of drugs once a day, for a long time without replacing them with another alternative antihistamine. For patients with a history of recurrent drug-induced disease, the drug of choice is currently the third-generation antihistamines Telfast, Gistafen, Xyzal, which are free of the side effects of second-generation drugs - effects on the central nervous and cardiovascular systems.

Enterosorption (activated carbon, sorbogel, polyphepan, enterodesis, etc.) is successfully used.

Based on data on neurohumoral regulation of immunogenesis processes, drugs with adrenergic blocking action are used - domestic adrenergic blockers - pyrroxane and butyroxane, which act selectively on adrenergic neurons concentrated in the hypothalamus.

Taking into account the role of the autonomic nervous system in the mechanisms of drug-induced disease development, it is effective to prescribe kvateron (daily dose 0.04-0.06 g), which has a normalizing effect on autonomic nervous system dysfunction due to the blockade of H-cholinergic receptors of the autonomic ganglia. Antioxidant drugs (vitamins A, E, C, etc.), acupuncture and its variety - qigong therapy are effective. A wider use of other non-drug and physiotherapeutic methods of treatment has been shown, such as electrosleep, microwave therapy on the adrenal glands, magnetotherapy, ultrasound therapy, UHF therapy, drug electrophoresis, psychotherapy, hypnosis, climatotherapy, hypothermia, etc.

Among the new methods of treating drug-induced disease developed at the institute, the following should be noted:

• a complex-sequential method, consisting of the sequential effect of a complex of medications on various levels of integration of the body, starting with the higher parts of the central nervous system and ending with the organs of immunogenesis;
• a method of treating patients with allergic dermatoses with a complicated allergological anamnesis, which includes the administration of ultrasound to the projection area of the adrenal glands, which is distinguished by the fact that an alternating magnetic field with an intensity of 1-2 W/cm2 is additionally administered daily to the thymus gland for 10 minutes, in a constant mode, while ultrasound is administered every other day, using an emitter with a diameter of 4 cm, a labile technique, a pulse mode, an intensity of 0.4 W/cm2, the duration of the procedure is 5 minutes on each side until clinical remission occurs;
• a method of treating patients with allergies to medications, including the prescription of a complex of pharmacological agents and physiotherapeutic influences, which is distinguished by the fact that in case of true allergy, the immunological conflict is normalized by prescribing magnetic therapy using the transcerebral method and ultrasound to the thymus projection area, which are alternated every other day with microwave therapy to the area of the cervical sympathetic nodes and ultrasound to the area of the spleen projection, and in case of pseudoallergy, the cortico-hypothalamic-pituitary relationships and liver function are corrected by prescribing magnetic therapy to the collar zone and ultrasound to the area of the liver projection, the histamine level - with antihistamines, the level of unsaturated fatty acids - with calcium antagonists, and the activity of complement - with proteolysis inhibitors, repeating the treatment regimens until clinical remission occurs;
• a method of treating patients with allergic dermatoses with a complicated allergological anamnesis, including the administration of ultrasound to the projection area of the adrenal glands, which is distinguished by the fact that supracubital laser irradiation is additionally carried out for 15 minutes at a laser power of 5 to 15 W, alternating these procedures every other day, and an alternating magnetic field with an intensity of 1-2 W is also administered to the thymus gland daily for 10 minutes in a constant mode until clinical remission occurs;
• a method of treating dermatoses with a complicated allergological anamnesis, including pharmacological agents, which is distinguished by the fact that electrosonphoresis with pyrroxane (with concomitant hypertension) or butyroxane (with concomitant hypotension and normal blood pressure) is additionally prescribed every other day, and on unoccupied days - microwave therapy on the projection of the adrenal glands;
• a method of treating dermatoses with a complicated allergological anamnesis, including pharmacological agents, which is distinguished by the fact that high-frequency electrotherapy is additionally prescribed on the projection of the adrenal glands, which is alternated with electrosleep, while on the days of electrosleep, ultrasound phonophoresis of tocopherol acetate is additionally prescribed on the projection of the liver;
• a method of treating dermatoses with a burdened allergic anamnesis, including pharmacological agents, which is distinguished by the fact that local hypothermia is additionally prescribed, alternating with low-temperature effects on 3-4 BAPs of general and segmental-reflex action, while the temperature of exposure during the course of therapy is reduced from + 20 to - 5 degrees Celsius, and the period of exposure is increased from 1 to 10 minutes.

As for the use of new technologies in the treatment of drug-induced polysensitization disease in the remission stage, the applicator of resonance correction of information-exchange loads "AIRES" can be considered as the means of choice, if the body is considered an organ that perceives and transmits a continuous flow of information, and drug-induced disease is the result of an information failure.

Considering drug-induced disease as a breakdown of protective and adaptive mechanisms and a violation of adaptation (maladaptation), which is accompanied by structural and functional changes at all levels, and above all by disorders of the neuroendocrine and immune systems, which are the pathogenetic basis for the development of the disease, in recent years there has been an increased interest in the problem of immunotherapy, i.e., prescribing to patients a complex of drugs that actively affect the immune reactivity of the body depending on the identified disorders in one or another link of the immune system.

If we consider drug-induced illness as a chronic recurrent process and the associated stress caused by a violation of adaptation, then it entails the emergence of physical and psychological changes with the development of signs characteristic of chronic fatigue syndrome with asthenic symptoms, reducing the quality of life of patients and requiring rehabilitation measures, during which it is advisable to give preference to non-drug methods or their combination with hyposensitizing agents.

Summarizing all the above, it should be noted that, along with the successes in the problem of drug disease, there are still many unresolved issues. Thus, the issue of working with the International Medical Statistical Classification of Diseases, Tenth Revision (ICD-10) remains open. There are no official statistics on the prevalence of drug disease, which makes it impossible to analyze its dynamics by region, complicates the implementation of preventive, anti-relapse, and rehabilitation measures among patients and risk groups. Difficulties in differential diagnosis of drug disease and true dermatoses (urticaria, vasculitis, eczema, etc.), some infectious diseases (scarlet fever, measles, rubella, scabies, recurrent syphilis, etc.), psychogenic and pseudo-allergic reactions to medications create a situation in which it is difficult for a practicing physician to make a correct diagnosis, in connection with which patients with drug disease are often registered under other diagnoses. The situation is aggravated by the fact that even if, based on the allergological anamnesis and clinical data, there is a suspicion that the patient is developing a drug-induced disease, most doctors cannot confirm their clinical diagnosis with the results of specific immunological tests due to the fact that many medical institutions simply do not engage in etiological diagnostics.

Among the controversial issues, one can point out the lack of a unified view on the terminology and classification of drug-induced disease, as well as the advisability or lack thereof of skin tests with drugs before surgery and the start of antibiotic therapy. No less controversial are the issues of consensus among dermatologists and allergists on the management of patients with drug-induced disease and other allergic dermatoses. It is known that the functional responsibility of allergists is to identify the etiologic factor of allergies and treat them mainly with specific allergens. However, long-term observations show that specific treatment of drug-induced disease and allergic dermatoses is currently practically not used. Specific diagnostics to identify the drug responsible for the development of an allergic condition is important, but still auxiliary. The leading role in diagnosing drug-induced disease, along with the data of the allergological anamnesis, is the clinical picture. Therefore, for patients with drug-induced disease with predominantly cutaneous manifestations, which are registered most often, the leading specialist is a dermatologist, since only he is able to conduct differential diagnostics of clinical manifestations resembling any true dermatosis. An allergist, even a qualified one, but not having knowledge of dermatology, can incorrectly interpret clinical manifestations and take a skin or infectious disease for a drug-induced disease.

Prof. E. N. Soloshenko. Drug-induced disease in the problem of side effects of drugs: current state // International Medical Journal - No. 3 - 2012