Medicinal disease in the problem of side effects of drugs: the current state

In the XX century. Side effects of drugs and drug disease continue to be the most urgent medical and social problems.

According to WHO, side effects of drugs currently occupy the 5th place in the world after cardiovascular, oncological, pulmonary diseases and injuries.

[1], [2], [3], [4], [5], [6], [7]

Causes of a medicinal disease

The reason for the annual steady increase in the incidence of side effects of drugs and drug disease are:

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

On the pharmaceutical boom speak the figures of use in the pharmaceutical market of Ukraine more than 7 thousand medicines in 15 thousand medicinal 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 cash, in kind and in dollar equivalent.

Of all the manifestations of side effects of drugs, according to the Ukrainian Center for the Study of PID, 73% are allergic reactions, 21% - side effects associated with the pharmacological action of drugs, and 6% - other manifestations. In dermatovenerology, among the most frequently reported manifestations of side effects of drugs are:

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

Despite the prescription of the problems of side effects of drugs and drug disease, there still remains a lot of unresolved and controversial: the absence of official statistics, the absence of a unified view of their terminology and classification, the lack of correspondence of the domestic terminology of true allergic reactions to the terminology medicine ICD-10- revision, diagnosis of side effects of drugs and drug disease, and in particular, the advisability of setting skin tests with drugs before the operation ativnost intervention and the start of antibiotic therapy, drug therapy questions disease.

Currently, the official statistics are only the tip of the iceberg, since it is practically not maintained.

There is no universally recognized classification of adverse drug reactions. The main approaches (etiological and clinico-descriptive) that were previously used in the compilation of classifications, in this case were not applicable, since it is known that the same drug can cause a different clinical picture and vice versa. Therefore, the pathogenetic principle is most often the basis for the current classifications of side effects of drugs. To modern representations the classification in which in allocate most corresponds:

• pharmacological side effect;
• toxic side effect;
• a side effect caused by a violation of the immune system;
• pseudoallergic reactions to drugs;
• carcinogenic action;
• mutagenic action;
• teratogenic effect;
• a side effect caused by massive bacteriolysis or a change in the ecology of microbes (the Yarisch-Gerxheimer reaction, candidomycosis, dysbacteriosis);
• drug addiction (drug addiction and substance abuse, tolerance, withdrawal syndrome, psychogenic reactions and psychophobia).

In clinical practice, of all kinds of side effects of pharmacotherapy, the most widespread reactions are caused by a violation of the body's immune system, the so-called true allergic reactions. However, the question of their terminology still remains controversial. If EA Arkin (1901), EM Tareyev (1955), E. Ya. Severova (1968), G. Mazhrakov, P. Popkhristov (1973), NM Gracheva (1978) manifestations of true allergic reactions to medicines called "drug disease", treating it as an analogue of "serum sickness", then other researchers - drug allergies, toxemia. Meanwhile, according to many years of clinical observations and experimental studies conducted by our institute, there are reasons 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 backdrop of any pathological process and repeated administration mediotherapeutic doses of medications, due not so much to the pharmacological characteristics of the drug as to the characteristics of the immune system the patient and his constitutionally-genetic predisposition. The results of the studies show that with the development of drug disease, all body systems are involved in the pathological process, despite the fact that clinically the disease can occur with the primary lesion of one of them, most often the skin. That is why the drug disease, along with clinicians of all specialties, is of particular interest primarily for dermatologists.

At the heart of the development of the drug disease are immunological mechanisms that fully correspond to the patterns of any other allergic reactions to the antigen. Therefore, during the drug disease, as well as during any allergic process, three stages are distinguished: immunological, pathochemical and pathophysiological (or stage of clinical manifestations). The peculiarities of the medicinal disease appear only in the immunological stage and consist in the fact that at this stage the drug from the hapten becomes a full-fledged antigen into which the r-lymphocytes begin to produce large amounts of antibodies and sensitized lymphocytes. The more the antigen enters the body, the higher the concentration of antibodies and sensitized lymphocytes. Morphologically and functionally, the sensitized cells do not differ from normal cells, and the sensitized person is practically healthy until the organism does not re-allergen and antigen-antibody reactions occur, accompanied by massive release of mediators and pathophysiological disorders.

The development of the allergic process in drug disease, as a rule, proceeds 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 for high affinity for the Fc fragment of IgE. In turn, the binding of a specific allergen to IgE forms a signal passed through the receptors and includes a biochemical activation mechanism of both membrane phospholipids with inositol-triphosphate and diacyl-glycerol production and phosphokinase, followed by phosphorylation of various cytoplasmic proteins. These processes alter the ratio of cAMP to cGMP and lead to an increase in the content of cytosolic calcium, which facilitates the movement of basophil granules to the cell surface. The membranes of the granules and the membrane of the cells merge, and the contents of the granules are ejected into the extracellular space. In the process of degranulation of the basophils of peripheral blood and mast cells, which coincides with the pathochemical stage of the allergic reaction, mediators (histamine, bradykinin, serotonin), as well as various cytokines, are distinguished in large amounts. Depending on the location of antigen-antibody complexes (IgE-mast cells or peripheral blood basophils), a variety of clinical manifestations of drug disease may develop on one or another shock organ.

Unlike the drug disease in pseudoallergic reactions, there is no immunological stage, and therefore the pathochemical and pathophysiological stages of them take place without the involvement of allergic IgE antibodies with excessive release of mediators, which occurs nonspecifically. In the pathogenesis of this excess nonspecific release of mediators with pseudoallergia, three groups of mechanisms participate: histamine; violation of activation of the complement system; metabolic disorders of arachidonic acid. In each case, the leading role is assigned to one of these mechanisms. Despite the differences in the pathogenesis of the drug disease and pseudoallergic reactions, release of the same mediators occurs in the pathochemical stage in one and the other cases, which causes the same clinical symptoms and makes their differential diagnosis extremely difficult.

With drug disease, in addition to changes in immune homeostasis, neuroendocrine regulation, processes of lipid peroxidation and antioxidant protection are violated. In recent years, the role of the peripheral element of the erythron has been studied in the pathogenesis of the drug disease, which has made it possible to reveal the increase in the heterogeneity of the population of circulating erythrocytes with the predominance of their macro forms, the change in the barrier functions of erythrocyte membranes, the redistribution of potassium-sodium gradients between plasma and red blood cells, manifested by the loss of excess potassium and the increase in the entrance to cells of sodium ions and indicating a violation of the ion transport function of erythrocytes. At the same time, the dependence of the parameters characterizing the physicochemical properties of erythrocytes on the clinical symptoms of the drug disease was revealed. Analysis of these studies indicates that red blood cells are a sensitive part of the peripheral erythron system in the mechanisms of the development of drug disease and therefore their morphometric indices, as well as the functional state of their membranes, can be included in the algorithm for examining patients. These data were the basis for the development of biophysical methods for the rapid diagnosis of drug disease based on measurement of erythrocyte absorption levels of ultrasound, as well as estimating the rate of erythrocyte sedimentation in the presence of presumed drug allergens, which favorably differ from traditional immunological tests, because they are more sensitive and allow diagnostics for 20-30 minutes.

In the pathogenesis of the drug disease, the role of the syndrome of endogenous intoxication is established, as evidenced by the high level of peptides of the average molecules, and also by their chromatographic analysis, the appearance of fraction A with subfractions of Al, A2, A3, absent in practically healthy people. The structure of genes that control the mechanisms of the pharmacological reaction and responsible for the synthesis of immunoglobulins E and the development of sensitization is changing. Moreover, favorable conditions for the development of sensitization arise predominantly in individuals with a specific phenotype of enzyme systems, for example, with reduced activity of liver acetyltransferase or the enzyme of glucose-6-phosphate dehydrogenase of erythrocytes, so now, as never before, the study of the pathogenesis of the drug phenotype - external manifestations of the genotype , ie, the totality of traits in individuals who have a tendency to develop allergic reactions to drugs.

The variety of immunological types in drug disease is expressed by the polymorphism of clinical manifestations - generalized (multi-systemic) lesions (anaphylactic shock and anaphylactoid conditions, serum sickness and serum-like diseases, lymphadenopathy, drug fever)

• with a predominant skin lesion:
• often found (by the type of urticaria and Quincke's edema, pink hair loss Zhibera, eczema, various exanthemes),
• less common (type of multiforme exudative erythema, blistering rashes, reminiscent of Dühring's dermatitis, vasculitis, dermatomyositis), rarely found (Lyell's syndrome, Stevens-Johnson syndrome);
• with the primary lesion of individual organs (lungs, heart, liver, kidneys, gastrointestinal tract);
• with the predominant involvement of hematopoietic organs (thrombocytopenia, eosinophilia, hemolytic anemia, agranulocytosis);
• with the primary lesion of the nervous system (encephalomyelitis, peripheral neuritis).

However, there is still no single view on the clinical classification of a drug disease.

The absence of the term in ICD-10, which unites the manifestations of true allergic reactions to medicines, testifies, first, to the discrepancy between international and our terminology, and secondly, does not actually allow us to make statistics and forces us to study the prevalence of the side effects of pharmacotherapy, mainly in terms of availability.

[8], [9], [10], [11], [12]

Diagnosis of drug disease

With a characteristic allergic history and typical clinical manifestations of the diagnosis, the drug disease does not cause difficulties. The diagnosis is confirmed quickly and easily, when there is a temporary connection between taking medications and developing the allergic process, the cycle of the process and a fairly rapid remission after the abolition of a poorly tolerated medication. Meanwhile, the difficulties of differential diagnosis of a medicinal disease and the underlying disease are frequent, for the complication of which it is often accepted, since the skin symptoms of the drug disease are very similar to the clinic of many true dermatoses, some infectious diseases, and also toxic and pseudoallergic reactions.

In view of the foregoing, phased diagnostics of the medicinal disease is applied:

• assessment of allergological history and clinical criteria of the disease;
• assessment of the results of clinical and laboratory examination;
• evaluation of a specific immunological examination to identify the etiological factor of the allergic process;
• differential diagnosis between true and pseudoallergic reactions to medications;
• differential diagnosis of drug disease and toxic reactions;
• differential diagnosis of drug disease and certain infectious diseases (measles, scarlet fever, rubella, chicken pox, secondary early fresh and recurrent syphilis);
• differential diagnosis of drug disease and true dermatoses;
• differential diagnosis of drug disease and psychogenic reactions (psychophobia).

Diagnosis of true and pseudoallergic reactions is based primarily on subjective criteria for their differences (with pseudoallergia according to the allergological history, there is no period of sensitization, the duration of pseudoallergic reactions is short-lived, and there are no repeated reactions when using chemically similar drugs). From the objective differential diagnostic criteria, one can rely only on the results of test tube specific immunological tests, which, when pseudoallergic reactions to medications are usually negative.

On the toxic side effect of drugs show:

• drug overdose; cumulation of drugs in connection with the violation of elimination due to liver and kidney insufficiency; ascertainment of fermentopathy, in which there is a slowing of the metabolism of therapeutic doses of drugs.
• On psychophobia is evidence of a positive intradermal test with a physiological solution.
• Most of all discussions arise when the etiological diagnosis of a drug disease.
• As a rule, the etiologic diagnosis of drug disease is carried out with the help of:
• provocative samples (sublingual test, nasal test, skin tests);
• specific immunological and biophysical tests.

Of provocative samples, relatively rarely put sublingual, nasal and conjunctival samples, which, however, the cases of development of allergic complications are not described. Traditionally, the phased staging of drip, application, scarification and intradermal tests has been widely used, the diagnostic value of which has remained controversial for several decades. Along with opponents of the use of skin tests for the purposes of prognosis and diagnosis of drug disease, even those that are guided by their formulation, recognize their inexpediency associated with the danger to the life of the patient and low informativeness due to the development of false positive and false negative reactions. Meanwhile, in recent years, a draft of a new order to improve the diagnosis of a medicinal disease has been published, in which the emphasis of diagnostics continues to be made on skin tests.

The most common causes of false positive reactions of skin tests are: increased sensitivity of the capillaries of the skin to mechanical irritation; nonspecific irritant effect of allergens due to improper preparation (allergen must be isotonic and have a neutral reaction); difficulty in the dosage of the administered allergen; sensitivity to preservatives (phenol, glycerin, merthiolate); metaallergic reactions (positive reactions in a certain season of the year with allergens, to which patients at other times of the year do not respond); presence of common allergenic groupings between some allergens; use for dilution of medicines of non-standardized solutions.

From the causes of false negative reactions, the following are known: lack of the necessary drug allergen; loss by the drug of allergenic properties due to its long and improper storage or in the process of breeding, since there are still no standardized medicinal allergens; absence or decrease in the sensitivity of the patient's skin, caused by:

• absence of skin-sensitizing antibodies;
• early stage of development of hypersensitivity;
• depletion of the antibody stock in the period or after the exacerbation of the disease;
• decreased skin reactivity associated with impaired blood supply, edema, dehydration, the influence of ultraviolet radiation, advanced age;
• Admission to patients immediately before testing antihistamines.

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

For the formulation of skin tests, in addition to their low information content and relative diagnostic value, there are many other contraindications, of which the main are: an acute period of any allergic disease; a history of anaphylactic shock, Lyell's syndrome, Stevens-Johnson syndrome; acute intercurrent infection 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 illness; tuberculosis and the circulation of tuberculin samples; thyrotoxicosis; severe form of diabetes mellitus; pregnancy, breast-feeding, the first 2-3 days of the menstrual cycle; age up to three years; period of treatment with antihistamines, membrane stabilizers, hormones, bronchospasmolytic.

One of the important moments limiting the use of skin tests is the inability to use them to predict the development of side effects not mediated by immunoglobulin E. It is difficult to formulate skin tests the unfitness for them of insoluble drugs, as well as the duration of their implementation with a phased formulation, especially when you consider that a trial in any modification, you can put only 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, that is, in the list of mandatory methods for examining patients with acute toxic-allergic reactions to medicines 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 in the past but also in recent years, including in the legislative documents of Ukraine, skin tests continue to be recommended both for the purpose of etiologic diagnosis of a drug disease and for the purpose of predicting it before treatment, especially before the injection antibiotic therapy. So, according to the order of the Ministry of Health and the Medical Academy of Ukraine of 02.04.2002 № 127 "On organizational measures for the introduction of modern technologies for diagnosis and treatment of allergic diseases" and attached to it Annex 2 in the form of Instructions on the procedure for diagnosing drug allergy in all medical- prophylactic establishments when appointing patients with treatment with injection antibiotics and anesthetics, it is necessary to prescribe skin tests to prevent complications of pharmacotherapy. According to the instructions, the antibiotic is diluted with a certified solution so that 1 ml contains 1000 units of the corresponding antibiotic. The dermal sample is placed in the forearm area, after first wiping the skin with a 70% solution of ethyl alcohol and receding 10 cm from the elbow bend, with an interval of 2 cm between the samples, simultaneously with not more than 3-4 drugs, and in parallel with the positive 0.01% histamine solution) and negative (dilution fluid) by controls. It is recommended to put mainly prik-test, which, in contrast to the scarification test, is more unified, specific, aesthetic, economical, less dangerous and traumatic. In order to further increase the informative value of skin testing, a rotational prick test is shown, the essence of which is that after a skin prick, a special lancet is fixed to 3 seconds, and then it is rotated 180 degrees to one side and 180 degrees to another. The reaction is taken into account after 20 minutes (if there is a negative reaction, there is no hyperemia, if there is a doubtful reaction, hyperemia is 1-2 mm, with a positive reaction 3-7 mm, positive reaction 8-12 mm, with a hyperergic reaction 13 mm and more).

In the Instruction on the procedure for the diagnosis of drug allergy, in addition to the discussion of the very question of the eligibility of using for this purpose skin tests with medicinal products, there are many other controversial points regarding the technology of their formulation. So, according to the instructions, a skin provocative test can be set in case of an allergic reaction by the reactive type, while the development of the reaction by the cytotoxic and immunocomplex types shows laboratory tests, and when the reaction develops for delayed-type hypersensitivity - laboratory tests and application tests. However, as clinical observations show, before the injection of antibiotic therapy, it is simply impossible to predict the type of allergic reaction in a patient with an unhealthy allergic anamnesis, if this reaction develops, it is simply impossible.

No less contradictory is the indication of the possibility of conducting skin testing simultaneously with 3-4 medications, since there are conflicting opinions on this score, according to which one day you can put a skin test with only one medicine.

The possibility of implementing the postulate of the instruction that skin testing with medicines should be conducted under the supervision of an allergist doctor or doctors who have undergone special allergological training, including activities to provide resuscitation assistance to patients with anaphylaxis, is questionable. There are only a limited number of such specialists in Ukraine, represented only by the doctors of the city and regional allergological offices and hospitals, and consequently, unprepared medical workers will prescribe, according to normative documents, skin tests with medicinal preparations in all medical and preventive institutions. In fact, the normative document on the organization of an allergic-logical service in Ukraine does not have an economic basis for its implementation, since, taking into account the economic situation in the country, it is also impossible to train specialists competent in allergology issues for all medical institutions, these facilities are instrumented and standardized drug sets for screening.

Taking into account all the shortcomings and contraindications to skin tests, as well as the annual growth of allergic and pseudoallergic reactions to medications, it is questionable whether they should be given with antibiotics before the injection of antibiotic therapy, both in patients with advanced dermatoses with complicated pyoderma course, and in patients with infections, sexually transmitted infections in the acute or subacute period of their disease. Meanwhile, despite all the contraindications and danger of skin tests, as well as their low informative content, legislative documents concerning dermatovenereological service continue to insist on the expediency of their setting before the start of antibiotic therapy, as evidenced by the draft of the new order on improvement published by the Ministry of Health and the National Academy of Sciences of Ukraine diagnosis of drug disease, in which the emphasis is still directed to skin tests.

From our point of view, since the formulation of skin tests with medications has many contraindications and limitations, and is also dangerous for the life of patients and is often fraught with the possibility of obtaining false-positive and false-negative results, then 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 contradictory because of their shortcomings: the duration of the exercise; absence of standardized diagnostic medicinal allergens; difficulties in acquiring the necessary material base (vivarium, radioimmune laboratory, luminescent microscope, enzyme immunoassay, test systems, etc.). In addition, it should be borne in mind that there are still no standardized diagnostic drug allergens, which means that it is necessary to work with allergens characterized by different physico-chemical parameters, for which it is not always possible to select the optimal concentrations, as well as their solvents. Therefore, in recent years, biophysical methods for express diagnostics of drug disease have begun to be developed that allow performing etiological diagnostics within 20-30 min, while almost all specific immunological tests require a long time to perform.

Of these biophysical methods of aetiological express diagnostics of medicinal disease, developed at the Institute of Dermatology and Venereology of the National Academy of Medical Sciences of Ukraine, the following should be noted, based on the assessment:

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

Along with this, the institute developed diagnostic devices for aetiological express diagnostics by estimating the erythrocyte sedimentation rate (in conjunction with the National Technical University of Radio Electronics); the level of absorption of ultrasound by erythrocytes pre-incubated with the presumed drug allergen (jointly with the Kharkov TG Shevchenko Instrument-Making Plant).

The automated information systems (AIS) developed in cooperation with the Kharkov National Polytechnic University and the Kharkov Institute of Radio Electronics, which allow to: allocate risk groups, are of great help in the early diagnosis of drug disease; to determine quantitatively the degree of risk of the incidence of allergic dermatoses for each examinee separately; to assess the psychoemotional state of workers and employees of enterprises; to conduct automated selection of applicants for work; keep records of production-related and occupational allergic diseases; conduct an analysis of the effectiveness of preventive measures; give recommendations on the choice of an individual prophylactic complex, depending on the state of immune homeostasis and adaptive-compensatory capabilities of the body.

[13], [14], [15], [16]

Treatment of drug disease

Treatment of drug disease is difficult because of frequent polysensitization, even for corticosteroids and antihistamines. It is built on the basis of data on pathogenetic mechanisms and taking into account the state of the individual. Treatment of drug disease is carried out in two stages. At the first stage of treatment, measures are taken to remove the patient from an acute condition, in which the most effective way is to remove the medicine from the body and the environment to which the patient is sensitized, as well as to exclude further admission, which is not always realistic. The main drugs for acute manifestations of drug disease in modern conditions still remain corticosteroid funds. An important place in therapy is occupied by antihistamines and measures aimed at normalizing the water-electrolyte-protein balance by introducing detoxification solutions (isotonic solution, rheopolyglucin, hemodez) and diuretics (lasix, furosemide, etc.). Meanwhile, the lack of modern injectable hyposensitizing drugs makes it difficult to perform intensive therapy for patients with anaphylactic shock.

An important place in the treatment of drug disease with acute clinical manifestations is taken 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 basis. Special attention deserves creams advantan, elokom, tselestoderm V, and for infection - celostoderm with garamycin, diprogen.

The second stage of treatment begins in the stage of remission, during which the whole complex of measures is carried out, aimed at changing the reactivity of the patient and warning him of the onset of relapses. In the case of polysensitization to medicines, which is often combined with food, bacterial, pollen, sun and cold allergy, non-specific therapy is shown, using traditional desensitizing agents (corticosteroid and antihistamines, calcium, sodium, etc.). Among the antihistamines, the second (claritin, semprex, histalong) or third (telfast, histafen, xizal) generation, which have a high affinity and binding strength to HI receptors, is advantageous, which, together with the absence of a sedative effect, allows the use of the drugs once in for a day, for a long time without substituting for another alternative antihistamine. For patients with a recurrent drug disease in the history of the drug of choice, antihistamines of the third generation of telfast, histafen, xizal, which are devoid of side effects of second-generation drugs - effects on the central nervous and cardiovascular systems, have become the drug of choice.

Successfully used enterosorption (activated charcoal, sorbogel, polyphepan, enterodez, etc.).

Proceeding from the data on the neurohumoral regulation of immunogenesis processes, adrenoblocking action drugs are used - domestic adrenoblockers - pyrroxane and butiroxane, acting selectively on adrenergic neurons concentrated in the hypothalamus.

Taking into account the mechanisms of the development of the medicinal disease, the role of the autonomic nervous system is effectively the appointment of a quaterone (daily dose of 0.04-0.06 g), which acts normalizing in the dysfunction of the autonomic nervous system due to blockade of the H-cholinergic receptors of the vegetative nodes. Effective antioxidant drugs (vitamins A, E, C, etc.), acupuncture and its variety - qigong therapy. The use of other non-pharmacological and physiotherapeutic methods of treatment, such as electrosleep, microwave therapy on the adrenal gland area, magnetotherapy, ultrasound therapy, DMV therapy, drug electrophoresis, psychotherapy, hypnosis, climatotherapy, hypothermia, etc., has been expanded.

From the new methods of treatment of drug disease developed at the Institute, it should be noted:

• a complex-sequential method consisting in the sequential action of a complex of medicines on various levels of the organism's integration, beginning with the higher parts of the central nervous system and ending with the immunogenesis organs;
• a method of treating patients with allergic dermatoses with a burdened allergological anamnesis, which includes the appointment of ultrasound to the site of the projection of the adrenal glands, which is characterized by the addition of an alternating magnetic field of 1-2 W / cm2 per day to the iron for 10 minutes, the ultrasound is administered every other day using a 4 cm diameter radiator, a labile technique, a pulsed mode, an intensity of 0.4 W / cm2, a procedure duration of 5 minutes from each side to the onset clinical remission;
• a method of treating patients with allergies to medicines, including the appointment of a complex of pharmacological agents and physiotherapeutic influences, which is distinguished by the fact that with true allergy the immunological conflict is normalized by the appointment of magnetotherapy by transcerebral technique and ultrasound to the thymus projection site, which alternate every other day with microwave therapy to the cervical sympathetic section nodes and ultrasound to the segment of the projection of the spleen, and with pseudoallergies, correct the cortico-hypothalamic-pituitary interrelation elations and liver function assignment magnetotherapy on collar zone and ultrasound liver projection portion histamine levels - antihistamines, levels of unsaturated fatty acids - calcium antagonists, and the activity of the complement - inhibitors of proteolysis, repeating the regimen to the onset of clinical remission;
• a method of treating patients with allergic dermatoses with a burdened allergological anamnesis, including the appointment of ultrasound to the area of the projection of the adrenal glands, which is characterized by the addition of an additional incubation with laser radiation for 15 minutes at a laser power of 5 to 15 W alternating these procedures every other day, and also an alternating magnetic field of intensity 1-2 W for 10 min in a constant mode until the onset of clinical remission is assigned to the foraminous gland daily;
• a method of treating dermatoses with a burdened allergological anamnesis, including pharmacological agents, which is characterized by the addition of electrosonphoresis with pyrroxane (with concomitant hypertensive disease) or butyroxane (with concomitant hypotension and normal pressure) every other day, and on unoccupied days - microwave therapy for projection adrenal glands;
• a method of therapy of dermatoses with a burdened allergological anamnesis, including pharmacological agents, which is characterized by the addition of prescribing high-frequency electrotherapy to the projection of the adrenal glands, alternating with the electrosphere, while in the days of electrosurgery, an additional phonophoresis of tocopherol acetate is prescribed for the projection of the liver;
• a method for the therapy of dermatoses with a burdened allergological anamnesis, including pharmacological agents, which is characterized by the addition of prescribing local hypothermia alternating with low-temperature effects on 3-4 BATs of general and segmental-reflex action, while the temperature of exposure during the course of therapy is reduced from +20 up to -5 degrees Celsius, and the period of exposure is increased from 1 to 10 minutes.

With regard to the use of new technologies in the treatment of drug disease with polysensibilization in the stage of its remission, then the applicator of resonant correction of the information-exchange loads of "AERES" can be considered as a means of choice if the organism is considered to be the body that perceives and transmits a continuous flow of information, the result of an information malfunction.

Considering the medical disease as the disruption of protective adaptive mechanisms and the disruption of adaptation (disadaptation), which is accompanied by structural and functional changes at all levels, and above all, by disorders of the neuroendocrinal and immune systems, which are the pathogenetic basis of the disease development, in recent years interest in the problem of immunotherapy, that is, the appointment of patients with a complex of drugs that actively affect the immune reactivity of the organism, depending on the detected violations in this or that animal ie immunity.

If we consider a medical disease as a chronic relapsing process and the associated stress caused by a disruption in adaptation, then it entails the appearance of physical and psychological shifts with the development of symptoms characteristic of the chronic fatigue syndrome with asthenic symptoms that reduce the quality of life of patients and require rehabilitation measures, at which the advantage is advisable to be given to non-drug methods or their combination with hyposensitizing agents.

Summarizing all the above, it should be noted that, along with successes on the problem of drug disease, there are still many unresolved issues. Thus, the issue of working with the international medical statistical classification of diseases of the 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 regions, makes it difficult to carry out preventive, anti-relapse, and rehabilitation measures among patients and at-risk groups. Difficulties in the differential diagnosis of drug disease and true dermatoses (urticaria, vasculitis, eczema, etc.), certain infectious diseases (scarlet fever, measles, rubella, scabies, recurrent syphilis, etc.), psychogenic and pseudoallergic reactions to medications create a situation , in which it is difficult for a practical doctor to make a correct diagnosis, and therefore patients with a drug disease are often registered under other diagnoses. The situation is exacerbated by the fact that even if on the basis of the data of an allergological history and clinic there is a suspicion about the development of a medicinal disease in the patient, most of the doctors can not confirm their clinical diagnosis with the results of specific immunological tests because many medical institutions are not engaged in etiological diagnostics.

From the discussion questions, one can point out the lack of a unified view of the terminology and classification of the medicinal disease, as well as whether it is appropriate or not to have skin tests with medications before surgery and initiation of antibiotic therapy. The consensus of dermatologists and allergists on the management of patients with drug disease and other allergic dermatoses is also discussed. It is known that the functional responsibility of allergists is the detection of the etiological factor of allergies and their treatment mainly by specific allergens. However, long-term observations show that the specific treatment of drug disease and allergic dermatoses is not practically applied at present. Specific diagnostics to identify a drug that is responsible for the development of an allergic condition is important, but still ancillary. Leading in the diagnosis of drug disease, along with data from an allergic medical history, is the clinic. Therefore, for patients with a drug disease with predominantly cutaneous manifestations that are most often recorded, the leading specialist is a dermatologist, since only he is able to conduct differential diagnosis of clinical manifestations reminiscent of any true dermatosis. An allergist, even if qualified, but not knowledgeable in dermatology, can misinterpret the clinical manifestations and accept a skin or infectious disease as a medical disease.

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