RU2105566C1 - Method for carrying out interferon therapy - Google Patents

Abstract

FIELD: medicine. SUBSTANCE: method involves intramuscularly administering recombinant interferon preparation like α-IFN, γ-IFN or their mixture at an initial dose causing body temperature of a given patient to jump by 1.9 ± 0.5 C, when compared to normal body temperature, in 5.2 ± 1.2 h after administering the preparation. Reaferon, Realdiron, Intron A, roferon A are usable as α-IFN preparations. Imukin and others are usable as γ-IFN preparations. The initial dose of mentioned preparations is equal as a rule to 1 million of IU. An IFN preparation is administered once a day in ascending gradient of single doses so that every following dose produces in patient the mentioned pyrogenic response until it vanishes when single dose being equal to 10-50 fold initial dose is administered. Repeated treatment is carried out when indicated, with IFN preparation not used in previous treatment but at least two months after the previous treatment course is accomplished. EFFECT: enhanced effectiveness of treatment. 12 cl, 6 tbl

Description

 The invention relates to medicine, namely to therapy, and can be used to treat various diseases of the immune genesis, for example, viral diseases, including herpes infections, viral hepatitis A, B, C, etc. allergic diseases, including allergic dermatitis, urticaria, bronchial asthma, Quincke edema, etc. rheumatological diseases, including non-specific infectious arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, Reiter and Sjugren syndromes, ankylosing spondylitis, systemic lupus erythematosus, etc. oncological diseases, including laryngeal papillomatosis, uterine fibroids, breast adenomas and pituitary glands, etc. other diseases, including chronic hepatitis of various etiologies, cirrhosis of the liver, peptic ulcer (stomach and duodenal ulcer), ulcerative colitis, Crohn's disease, chronic pancreatitis, latent diabetes mellitus, autoimmune thyroiditis, chronic pyelonephritis, lipoid nephrosis, lipoid sclerosis, lipoid sclerosis, lymphoid cell disease unclear etiology, chronic adnexitis, sclerocystic ovaries, endometriosis, menstrual irregularities, etc.

Currently, more than 30 interferons (IFN) are known. In accordance with the international nomenclature adopted in 1980, human IFNs are divided into three main types: α IFN, by source classified as leukocyte or lymphoblastoid; b IFN (fibroblast) and g IFN or immune (produced by human T-lymphocytes as a result of induction by mitogens or antigens). According to the production technology, IFNs are divided into natural, isolated from mammalian cells, and gene, obtained by recombinant DNA technology. A feature of genetic engineering technology is the possibility of obtaining large quantities of highly purified IFN preparations with a specific activity of 10 ⁶ -10 ⁸ ME / mg, which have a relatively low cost, which makes them widely used in medical practice.

Interest in IFN drugs is determined mainly by their immunomodulatory, antiproliferative and antiviral effects. Moreover, if the antiviral properties of all types of IFN are quite similar, then with respect to immunomodulating and antiproliferative properties, it is noted that they are enhanced in the order g>α> β [1]
The closest to the claimed solution in terms of the essential features is the method of interferon therapy using recombinant IFN, in which treatment regimens (single doses, route of administration, frequency and duration of drug use) are regulated for each specific disease, taking into account the type of IFN drug used. In this case, a single dose (common for all patients with this pathology) is, as a rule, a constant fixed value during the entire course of treatment, and the daily (weekly) dose can either be kept constant during the treatment, or it decreases once during the transition to the final phase of treatment remaining constant (reduced compared to the original) until the end of the course of treatment. So, for example, reaferon (recombinant a ₂ IFN) in acute viral hepatitis B is administered intramuscularly (IM) 1 million ME. 2 times a day for 5 to 6 days, then the dose is reduced to 1 million ME per day and administered for another 5 days. If necessary, the course of treatment can be continued at 1 million ME twice a week for 2 weeks. The course dose is 15 20 (21) million ME. In case of kidney cancer (stage IV), reaferon is used IM 3 million ME daily for 10 days. Repeated courses of treatment (3-9 or more) are carried out with an interval of 3 weeks. The total amount of the drug is from 90 (120) million ME to 270 (300) million ME or more. With hairy cell leukemia, Reaferon is injected IM 3-6 million ME daily for 2 months. With normalization of the hemogram, the daily dose is reduced to 1 2 million ME. Then prescribe maintenance therapy at 3 million ME twice a week for 6-7 weeks. The total amount of the drug is 420-600 million ME or more. With multiple sclerosis, Reaferon is prescribed 1 million ME, with pyramidal syndrome 3 times a day, with cerebellar syndrome 1-2 times a day for 10 days, followed by the introduction of 1 million ME once a week for 5-6 months . The total amount of the drug is 50-60 million ME [2] For malignant lymphomas and Kaposi’s sarcoma, Reaferon is administered IM 3 million ME per day daily for 10 days [3]
Similar treatment regimens for the above diseases are recommended in the case of using the reaferon analog of realdirone. However, the recommended area of application of the latter is somewhat wider than that of reaferon. So, in addition to acute viral hepatitis B, realdiron is prescribed for acute prolonged hepatitis B, chronic active hepatitis B and D without signs of cirrhosis and with signs of liver cirrhosis. Moreover, in acute prolonged and chronic active hepatitis B without signs of cirrhosis and with the exception of delta infection, realdiron is administered IM 1 million ME 2 times a week for 1-2 months. If there is no effect, the treatment is extended to 3-6 months or after the end of treatment, 2-3 similar courses are carried out with an interval of 1-6 months. In chronic active hepatitis D without signs of cirrhosis, realderone is administered IM 500 thousand-1 million ME, 2 times a week for 1 month. A second course of treatment after 1-6 months. In chronic active hepatitis B and D with signs of cirrhosis of the liver, realdiron is administered IM 250-500 thousand ME per day 2 times a week for 1 month. When signs of decompensation appear, conduct similar courses with an interval of at least 2 months. The use of realdiron in juvenile laryngeal papillomatosis is also recommended. The drug is administered at 100-150 thousand ME per kg of body weight, daily for 45-50 days, starting immediately after the surgical removal of tumor tissue. Then at the same dosage three times a week for one month. The second and third courses (daily administration for 45-50 days, then 3 times a week for 1 month) are carried out with an interval of 2-6 months [4]
Treatment regimens based on the principles of the prototype method [2] but differing in specific specific parameters are also used when using IFN preparations such as roferon A (interferon alfa-2a), intron A (interferon alfa-2b), imukin (interferon gamma -1b) . For example, in the case of hairy cell leukemia, roferon A is given at the rate of 3 million ME / m ² per day intramuscularly or subcutaneously for 16-24 weeks. Intron A has a slightly different dosage regimen: the drug is administered at a dose of 2 million ME / m ² intramuscularly or subcutaneously 3 times a week for 1-2 months. In the treatment of Kaposi’s sarcoma in AIDS patients with roferon A, the initial dose of the drug is 36 million ME per day intramuscularly for 8-12 weeks. Maintenance dose of 36 million ME per day 3 times a week. Intron A is recommended to be administered intravenously at 50 million ME / m ² daily for 5 consecutive days, after which a break of at least 9 days is taken, and then 5-day treatment is again carried out with the same dose of the drug. In this mode, the drug can be used for a long time. According to another treatment regimen, intron A in the case of Kaposi’s sarcoma is administered at a dose of 30 million ME / m ² IM or subcutaneously 3 times a week. In the treatment of laryngeal papillomatosis using intron A, the drug is administered subcutaneously 3 times a week (every other day) at 3 million ME / m ² . Treatment may last more than 6 months [5, 6]
There are no recommended treatment regimens for rheumatological diseases using IFN drugs in Russia [2, 3, 4] However, the currently tested interferon therapy options are based, as a rule, on the principles of the prototype method [2] So, reaferon was prescribed 1 in the treatment of rheumatoid arthritis million ME every other day for 1 month, then 1-2 million ME per week for 6 months [7] Gammaferon in the same disease was used at a dose of 1 million ME IM every other day for 20 days, and then 1 million ME once a week for 3 months [8]
The prototype method does not allow to obtain a technical result achieved when using the proposed method. This is due to the following. It is known that the rate of inclusion of the IFN system in the process of antiviral defense of the body determines the course and outcome of the disease. Delayed or reduced production of endogenous IFN can lead to chronic disease or progression of the infection to death [9] Various variants of interferon status disorders have been identified in a number of diseases: with viral and bacterial infections (acute respiratory infections, hepatitis), chronic viral diseases (herpes, hepatitis B) and non-viral nature, allergic diseases (asthma (BA), urticaria), autoimmune diseases (systemic lupus erythematosus (SLE), rheumatoid arthritis (RA)), cancer diseases, etc. [9, 7, 10, 8, 11, 12]
Currently, there is quite conflicting information about the scope and effectiveness of interferon therapy. It is believed, in particular, that a malfunction of the IFN system (including a decrease in the production of α- and γ IFN) can serve as a pathogenetic justification for the use of IFN drugs for therapeutic purposes [9, 7, 8] On the other hand, it is believed that indications for the clinical use of IFN have not been established [13] The regimens currently used in the administration of IFN drugs are mainly empirical in nature [14, 8] and the effectiveness of interferon therapy varies over a wide range of values depending on the type of disease and the severity and the period of its development, the complications of the disease, as well as on the type of IFN, its mode of use, etc. So, in acute hepatitis B, the therapeutic effect of reaferon in the first 5-6 days of jaundice was observed in 75-96% of patients, in about 50% of cases later [15] Interferon is practically ineffective in developing hepatic coma and cholestatic hepatitis [2, 3 , 4] in acute hepatitis B with a fulminant course, as well as in acute hepatitis delta [15, 16] The use of reaferon in chronic active hepatitis B provided a significant improvement in the clinical course in 56.7% of patients [15] and interferon therapy for hepatitis C successful treatment 25-30% are sick [16] When treating herpetic infections with reaferon (herpes simplex, including herpetic keratitis, genital herpes; herpes zoster), a pronounced therapeutic effect was observed in 66-80% of cases [15] There is an indication that IFN drugs are contraindicated in severe forms of allergic diseases [2, 3, 4] Despite the fact that the active production of endogenous IFN indicates, in the opinion of the researchers [9], the inappropriateness of interferon therapy, it has been established that IFN preparations have a positive effect not only on clinical symptoms CV (characterized by a high level of production of endogenous a-IFN [9, 17]), but also by a number of immunological parameters [10] It is noted that when using IFN in the treatment of cancer pathologies, on the one hand, a bright antitumor effect was demonstrated, on the other hand, its use is often turned out to be completely ineffective [12] For example, the therapeutic effect of reaferonotherapy with hairy cell leukemia was observed in all patients. The use of reaferon in the treatment of stage IV kidney cancer provided complete or partial tumor regression in 33% of patients, stabilization of the process in 58% of patients; with Kaposi's sarcoma, complete regression in 40% of patients and a significant improvement in 40% of cases; with reticulosarcomatosis - a significant improvement in 100% of patients in the absence of cases of complete regression, etc. [fifteen]
The question of the appropriateness of IFN monotherapy is still unresolved. At present, the use of IFN in complex therapy is considered more effective (according to the results of clinical trials), which is reflected in the recommended treatment regimens [2, 3, 4]. For example, the results of clinical trials have shown that treatment of patients with multiple sclerosis with reaferon in combination with conventional complex treatment provided a pronounced therapeutic effect in 73.9% of patients in the absence of cases of deterioration, whereas with isolated administration of reaferon, a pronounced effect was noted in 46.7% of patients, deterioration in 6.7% [15] Pipeline currently various options for combined therapy, or (usually) support the view, or do not allow firm conclusions. For example, during combined treatment with addition of natural antioxidants (vitamins E and C) in addition to reaferon in patients with recurrent herpes, improvement was recorded in 65% of cases, while monotherapy with reaferon had practically no effect on the clinical dynamics of the disease [8] With combined therapy RA with reaferon and metatrexate, the number of patients in whose condition improvement was noted was 86%, while with treatment with only reaferon such patients only 55% [7] In contrast, patients with RA who received Only gammaferon, the clinical improvement was observed in 76% of cases, and when using gammaferona with methotrexate in 57% of patients [8] On the other hand, argued that the beneficial effect of γ- IFN preparations in RA remains controversial [19]
The currently recommended and tested interferon therapy regimens (based on the principles of the prototype method) are based to one degree or another on adjusting the state of the IFN system. According to modern concepts, the concept of an IFN system includes genes and their repressors, IFN themselves, specific cellular receptors, and, finally, enzyme systems activated by the interaction of IFN with these receptors, primarily ds-RNA dependent 2 ', 3' oligoadenylate synthetase and protein kinase [ 20] The presence of direct and inverse correlation between the change in immunological reactivity and interferon formation [9] Thus, in the treatment of IFN drugs of various diseases in some cases, a tendency to normalization was observed immunological indicators, and indicators of immunoreactivity correlated with clinical data [8, 7, 11, 10, 21, 22]
The mechanisms of the immunomodulating effects of IFN are associated with the action of IFN on the receptor apparatus of the cell, intracellular processes and, as a consequence, on the individual functions of immunocompetent (ICC) and auxiliary cells (proliferation, differentiation, migration, etc.) [23]
The dependence of the characteristics of the immunomodulating action of regulatory peptides (RP) is known, incl. IFN, from the initial state of the tested KIC. It was established that a greater severity of the effect is observed when exposed to cells characterized by reduced functional activity [11, 23, 24]. Given that the development of immunodeficiency states changes the sensitivity of the target cell to the ligand (usually as a result of changes in density, less often affinity of receptors), it is believed that a change in the state of ICC receptors for RP during the modulation of ligand-receptor interactions is the content of one of the most important compensatory and pathogenetic mechanisms of immunomodulation [24]
However, it is known that the severity and orientation of the immunomodulatory effects of IFN also depends on its type (subtype), concentration, and type of studied KIC [23, 25, 24] It has been established that during interferonogenesis in the body, as a rule, a set of interferons regulated by different genes is formed formed in different cells and differing in properties and quality [1, 23] It is known that recombinant IFNs are cloned subtypes (rather than the sum of the molecular species that make up natural IFNs) and, as a rule, do not possess concomitant cytokine activity [20, 23, 1] It is also known that the effect of any biological response modifiers (which include IFN) largely depends on the initial state of the modified systems, on their safety, lability and functional usefulness [2] Insufficiency or hyperfunction of the IFN system can be associated with both primary defects (at the genetic level) and secondary (acquired) changes, the identification of which is currently a rather difficult task [9] but which nevertheless can require the use of various methods and means for their adjustment. There is also evidence that for a number of diseases (for example, lymphogranulomatosis, ophthalmic herpes, SLE, chronic bronchitis, etc.), the defective IFN system can be combined with the presence of defects in other cytokine systems, in particular in the interleukin system, which can be localized at various stages development of a proliferative response [26]
In the recommended and most currently tested interferon therapy schemes, the principle of individual dosage of the drug is practically not used, although for some diseases there are indications of the possibility of reducing a single dose of IFN in order to reduce or eliminate its side effects [5] However, as noted in [27] fundamental differences in the natural release of a biologically active substance into the bloodstream and any attempt to model this process by the introduction of an exogenous preparation (mismatch of place and time characteristics of the substance’s entry into the bloodstream, the absence of combined biochemical reactions and the distortion of the complex pattern of satellite substances, the presence of impurities in the administered drug, etc.), as well as the diversity and breadth of the spectrum of the functional states of the body (various types of pathologies, individual sensitivity, etc. .) can cause various effects, both adequate and not adequate, to the action of endogenous substances in the body in vivo in a given situation.

 The interaction of the central nervous system (CNS) and the immune system in the process of interferon therapy is currently very little studied and is practically not taken into account when developing optimal schemes for the use of IFN drugs in specific diseases. Available single publications devoted to this problem mainly contain facts confirming the presence of the relationship of the immune system and the central nervous system. For example, researchers [28] found that prolonged use of reaferon in patients with chronic active hepatitis B contributed to the formation of adaptive reactions in these systems, which was reflected in phase changes in the central nervous system and activation of cellular immune factors after a 2-month course of therapy.

 Thus, the recommended [2, 3, 4, 5] and most of the currently tested interferon therapy regimens (both IFN monotherapy and its use in complex regimens) mainly use the peripheral effects of IFN drugs based on modulation of intercellular interaction, excluding the state of the body of a particular patient. In this case, when using only the peripheral effects of a particular recombinant IFN preparation, the effectiveness of its therapeutic effect is limited by the range of biological properties characteristic of IFN of this type and subtype, the possibility and degree of manifestation of which will depend on the severity of the immunodeficiency state (IDS) of the body, in t .h. from the nature, quantity, level of localization of defects in the IFN system and systems of other cytokines. The lack of individual variable dosing of exogenous IFN, taking into account the severity of IDS, makes it difficult to create and virtually eliminates the possibility of maintaining in the brain structures, primarily the hypothalamic, physiologically effective concentration of IFN as an endogenous regulatory signal in this immunopathology, which prevents the implementation of neurohumoral regulation of immune responses adequate to IDS specific patient. In this regard, the use of interferon therapy (based on the principles of the prototype method [2]), which provides, to one degree or another, the management of individual links or stages of the immunogenesis process without taking into account the nervous and humoral effects caused by the central nervous system, does not allow for the correction of the intensity of protective processes as a whole reactions and leads to a relatively low therapeutic efficacy and a relatively long course of treatment.

 The objective of the invention is to create a method of interferon therapy, providing the formation of a new dynamic stereotype of the relationship of the immune system and the central nervous system, simulating the body’s response to the influence of a factor that caused the development of an immunodeficiency state in this particular patient, which makes it possible for the neurohumoral regulation of the immune system to work by creating conditions for functioning units of the immune system in the mode of duplication of the functions of defective units.

The problem is solved in that in the method of interferon therapy by intramuscular injection into the human body of recombinant interferon preparations in doses that vary during the course of treatment, according to the invention, the treatment is carried out in an increasing gradient of single doses of the interferon drug, and initially the drug is administered in a dose that provides an increase compared to with a normal body temperature in each individual patient 5.2 ± 1.2 hours after the administration of the drug at 1.9 ± 0.5 ^o C, then the administration of the drug is repeated once a day in doses that provide the patient with the above pyrogenic effect, until it disappears with the introduction of a single dose, 10-50 times the initial single dose. In this case, it is possible to use preparations of α-IFN, which are used, for example, reaferon or its analog realdiron, roferon A, intron A. The introduction of these drugs in an initial dose of 1 million ME is effective. It is also possible to use preparations of γ-IFN, in particular imukin, which is advisable to introduce in an initial dose of 1 million ME. In addition, it is possible to use a mixture of at least two different IFN preparations, for example a mixture of α- and γ-IFN. According to indications, a repeated course of treatment is carried out with a previously unused IFN preparation, but not earlier than 2 months after the end of the previous course of treatment.

III вариант:

IV вариант:

Автором заявленного решения было также установлено, что параметры пирогенной реакции в ответ на введение рекомбинантного ИФН зависят как от функционального состояния организма больного (вид заболевания, степень выраженности ИДС, индивидуальная чувствительность и т.д.), так и от вида ИФН и режима его дозирования. При этом было выявлено, что терапевтически значительными параметрами (непосредственно влияющими на достижение положительного результата лечения) являются параметры Δt $\genfrac{}{}{0ex}{}{\text{°}}{\text{max}}$ и Δt₂
Для выбора оптимального режима интерферонотерапии было исследовано влияние различных значений терапевтически значимых параметров пирогенной реакции Δt $\genfrac{}{}{0ex}{}{\text{°}}{\text{max}}$ и Δt₂ обеспечиваемых в процессе лечения с помощью различных режимов дозирования препаратов ИФН, на эффективность лечения. Были проанализированы результаты, полученные при лечении препаратами рекомбинантного ИФН (монотерапии) 654 больных с различными заболеваниями иммунного генеза, которые составили 64 группы (от 5 до 30 человек в группе):
группы 1 4, 17 20, 33 36, 49 52 больные с вирусными заболеваниями, в т.ч. (в каждой из групп) с герпетической инфекцией с различной локализацией проявлений на коже и слизистых (60% больных) и с вирусными гепатитами A, B, C (40% больных);
группы 5 8, 21 24, 37 40, 53 56 больные с аллергическими заболеваниями, в т.ч. (в каждой из групп) с аллергическим дерматитом (40% больных), с крапивницей (40% больных), с БА (20% больных;
группы 9 12, 25 28, 41 44. 57 60 больные с ревматологическими заболеваниями, в т.ч. (в каждой из групп) с неспецифическим инфекционным артритом (60% больных) и с РА (40% больных);
группы 13 16, 29 32, 45 48, 61 64 больные с онкологическими заболеваниями, в т. ч. с фибромиомой матки (40,5% больных), с аденомой молочной железы (39,3% больных), с аденомой гипофиза (20,2% больных). Причем в каждой из групп больные с указанными заболеваниями распределялись соответственно, чел. группа 13 3:3:2, группа 14 3:2:1, группы 15, 16, 29 32, 45 48, 61 64 2:2:1.The selection of the optimal parameters of the mode of the claimed method was carried out as follows. The results of preliminary studies of the inventor showed that the pyrogenic reaction developing in patients with diseases of the immune genesis (n 382 people) in response to the administration of recombinant IFN drugs (at the same dosages and modes of administration) can vary in severity and time of manifestation in depending on the values of temperature and time parameters (M ± m) can be attributed to one of 4 options:
I option: the maximum increase in body temperature compared with the norm (36.6 ^o C) Δt $\genfrac{}{}{0ex}{}{\text{°}}{\text{max}}$ = 1.9 ± 0.5 ^° C time from the moment of drug administration to the start of temperature rise Δt ₁ = 3.4 ± 1.1 h time from the time of drug administration to the maximum temperature Δt ₂ = 5.2 ± 1.2 h time to maintain maximum temperature at a constant level (temperature plateau) Δt _max = 2.0 ± 0.6 h time from the moment of drug administration to lower the temperature to the initial level Δt ₃ = 9.2 ± 1.0 h
II option:

III option:

IV option:

The author of the claimed solution also found that the parameters of the pyrogenic reaction in response to the introduction of recombinant IFN depend both on the functional state of the patient’s body (type of disease, severity of IDS, individual sensitivity, etc.), and on the type of IFN and its dosage regimen . It was found that therapeutically significant parameters (directly affecting the achievement of a positive treatment result) are Δt $\genfrac{}{}{0ex}{}{\text{°}}{\text{max}}$ and Δt ₂
To select the optimal interferon therapy regimen, the effect of various values of therapeutically significant parameters of the pyrogenic reaction Δt was studied $\genfrac{}{}{0ex}{}{\text{°}}{\text{max}}$ and Δt ₂ provided during treatment using various dosage regimens of IFN drugs, on the effectiveness of treatment. The results obtained during treatment with recombinant IFN (monotherapy) drugs were analyzed for 654 patients with various diseases of the immune genesis, which comprised 64 groups (from 5 to 30 people in the group):
groups 1 4, 17 20, 33 36, 49 52 patients with viral diseases, including (in each group) with a herpetic infection with different localization of manifestations on the skin and mucous membranes (60% of patients) and with viral hepatitis A, B, C (40% of patients);
groups 5 8, 21 24, 37 40, 53 56 patients with allergic diseases, including (in each group) with allergic dermatitis (40% of patients), with urticaria (40% of patients), with asthma (20% of patients;
groups 9 12, 25 28, 41 44. 57 60 patients with rheumatological diseases, including (in each group) with non-specific infectious arthritis (60% of patients) and with RA (40% of patients);
groups 13 16, 29 32, 45 48, 61 64 patients with oncological diseases, including with uterine fibroids (40.5% of patients), with breast adenoma (39.3% of patients), with pituitary adenoma (20 , 2% of patients). Moreover, in each of the groups, patients with these diseases were distributed accordingly, people. group 13 3: 3: 2, group 14 3: 2: 1, groups 15, 16, 29 32, 45 48, 61 64 2: 2: 1.

 In all patients, before administration of the IFN preparation, a control measurement of body temperature (in the armpit) was performed using a medical thermometer (initial level). After the injection of the drug, the patient's body temperature was measured with an interval of 0.5 h (reference point, the moment of IFN administration), fixing the obtained values, up to a temperature drop to normal.

During treatment, two dosage regimens of IFN preparations were used:
I regimen IFN preparations were administered in an increasing gradient of single doses. At the same time, in groups 1, 2, 5, 6, 9, 10, 13, 14, IFN preparations were administered IM in doses providing for each individual patient an increase in body temperature Δt $\genfrac{}{}{0ex}{}{\text{°}}{\text{max}}$ = 1.9 ± 0.5 ^° C 5.2 ± 1.2 hours after the administration of IFN during the entire course of treatment (sub-mode Ia). In groups 17, 18, 21, 22, 25, 26, 29, 30, the parameters of the pyrogenic reaction during the course of treatment were kept within; Δt $\genfrac{}{}{0ex}{}{\text{°}}{\text{max}}$ = 1.9 ± 0.5 ^° C after 8.3 ± 1.2 hours (sub mode Ib); in groups 33, 34, 37, 38, 41, 42, 45, 46 Δt $\genfrac{}{}{0ex}{}{\text{°}}{\text{max}}$ = 0.8 ± 0.4 ^° C after 5.2 ± 1.2 hours (sub mode Iv); and in groups 49, 50, 53, 54, 57, 58, 61, 62 Δt $\genfrac{}{}{0ex}{}{\text{°}}{\text{max}}$ = 0.8 ± 0.4 ^° C after 8.3 ± 1.2 hours (sub mode Ig);
II regimen IFN preparations were administered in constant single (or daily) doses throughout the course of treatment (treatment regimens are based on the principles of the prototype method [2] The following treatment regimens were used:
in case of viral diseases: for a herpetic infection, the IFN preparation was administered intramuscularly in a single dose of 1 million ME once a day for 10 days; for viral hepatitis, the IFN preparation was administered IM in a single dose of 1 million ME twice a day for 5 days, then 1 million ME once a day for 5 days;
in case of allergic diseases, the IFN preparation was prescribed IM in a single dose of 1 million ME once a day for 10 days;
for rheumatic diseases, the IFN preparation was administered intramuscularly in a single dose of 1 million ME once a day for 14 days;
in case of oncological diseases, IFN preparation was used intramuscularly in a single dose of 1 million ME once a day for 10 days.

 Moreover, depending on the values of the parameters of the pyrogenic reaction that develops in response to the introduction of IFN, the patients were divided into groups belonging to one of 4 options (sub-modes IIa, IIb, IIc and IIg) similar to the distribution of mode I.

 Recombinant preparations α IFN reaferon and realdiron and preparation g IFN imukin were used as IFN preparations (for I and II dosage modes). When using IFN preparations a, reaferon was administered in each group of 50% of patients, and realdiron was administered to the other half of patients.

 The observation results are presented in table. one.

From the data of table 1 it can be seen that when using the 1st and 2nd dosage modes, various variants of the pyrogenic reaction are possible in response to the introduction of IFN. However, in regimen I, the parameters of the pyrogenic reaction in each individual patient can be brought (by varying doses) to preset values and maintained at a given level throughout the course of treatment (10-14 days). In the II dosing regimen, the parameters of the pyrogenic reaction that develops in response to the administration of the drug are uncontrolled values that depend on the individual characteristics of the patient’s body and cannot be maintained during the entire course of treatment, because with the introduction of constant single (daily) doses, the pyrogenic reaction disappears after repeated injections of the drug (2-3 days after the start of treatment). The results presented in table. 1 also indicate that the optimal parameters of the pyrogenic reaction in response to the introduction of IFN are Δt $\genfrac{}{}{0ex}{}{\text{°}}{\text{max}}$ = 1.9 ± 0.5 ^° C and Δt ₂ = 5.2 ± 1.2 h (characteristic for sub-regimes Ia and IIa), which ensure, when using both variable and constant (during the course of treatment), single doses of IFN drugs achieving positive treatment results exceeding similar results for other parameters of the pyrogenic reaction (characteristic for sub modes Ib, Ib, Ig, IIb, IIc, IIg). However, it is dosing of IFN in an increasing dose gradient so as to ensure the maximum rise in body temperature by Δt $\genfrac{}{}{0ex}{}{\text{°}}{\text{max}}$ = 1.9 ± 0.5 ^° C 5.2 ± 1.2 hours after drug administration during the entire course of treatment (10-14 days) (sub-mode Ia) is optimal, because allows to achieve maximum treatment effectiveness (a positive treatment result was achieved on average in 74.8% of patients, varying from 53.3 to 90% of patients depending on the profile of the disease and type of IFN).

The choice of the optimal initial dose of specific preparations of recombinant IFN was carried out by studying the effect of various doses of IFN on the development of a pyrogenic reaction characterized by optimal therapeutically significant parameters (achievement of Δt $\genfrac{}{}{0ex}{}{\text{°}}{\text{max}}$ = 1.9 ± 0.5 ^° C after 5.2 ± 1.2 hours from the time of drug administration) in 105 patients with various diseases of immune origin. All patients were divided into 8 groups (from 5 to 20 people in the group) as follows:
groups 1, 2 patients with viral diseases, including (in each group) with a herpetic infection with different localization of manifestations on the skin and mucous membranes (60% of patients) and with viral hepatitis A, B, C (40% of patients);
groups 3, 4 patients with allergic diseases, including (in each group) with allergic dermatitis (40% of patients), with urticaria (40% of patients), with asthma (20% of patients);
groups 5, 6 patients with rheumatological diseases, including with non-specific infectious arthritis (60% of patients) and with RA (40% of patients);
groups 7. 8 patients with oncological diseases, including with uterine fibroids (40% of patients), with breast adenoma (40% of patients), with pituitary adenoma (20% of patients).

 Patients of each group were injected with IM one of the preparations of α- or γ-IFN in various single doses (0.5 ME, 1 ME, 2 ME) with a weekly interval between injections. In this case, patients of 1, 3, 5 and 7 groups were administered reaferon, and patients of 2, 4, 6 and 8 groups of imukin. The observation results are presented in table. 2.

 From the data table. 2 it follows that the administration of IFN preparations in a single dose of 0.5 million ME provides the development of a pyrogenic reaction, characterized by optimal parameter values, on average in 5.7 patients. A single dose of 1 million ME causes an optimal pyrogenic reaction in an average of 70.5% of patients, varying from 55 to 90% depending on the disease profile and type of IFN. Thus, with an increase in the initial parameter (single dose) by 0.5 million ME there is a qualitative jump in the resulting parameter (the number of patients with a pyrogenic reaction in response to the introduction of IFN) by 64.8%. A further increase in the dose of IFN by 1 million ME leads to an increase in the resulting parameter by only 11.4% (the number of patients with a pyrogenic reaction with a single dose of 2 Million ME averages 81.9%), therefore, the use of a single dose of 2 million ME as an initial dose is not practical. Similar data were also obtained for preparations of α-IFN of realdiron, intron A and roferin A. Thus, a dose of 1 million ME for the indicated preparations of α- and γ-IFN is optimal and is taken as the initial single dose.

 Experimental studies conducted by the author of the proposed method showed that the use of the I dosing regimen (in an increasing dose gradient) allows maintaining a pyrogenic reaction (characterized by predetermined parameters) in response to the administration of the IFN preparation for some finite period. With an increase in the dose of the administered drug over a certain limiting value, which varies depending on the type of pathology and the individual characteristics of the body of each particular patient, the pyrogenic effect (as well as other "side" effects associated with the action of IFN) disappears. To establish the limit value of the final single dose of IFN, 84 patients with various diseases of immune genesis were given IM injections of α- and γ-IFN in an increasing dose gradient (initial single dose of 1 million ME) in such a way as to maintain optimal parameters of the pyrogenic reaction, continuing injections of IFN until the last disappearance of the latter (i.e., the absence of signs of a pyrogenic reaction, not only in response to the introduction of a certain threshold dose of IFN, but also doses exceeding it). Due to the significant individual variability of the limiting values of single doses of IFN, which practically excludes the possibility of expressing the average final single dose of the drug in absolute terms, the relative exponent of the final single dose of the drug relative to the initial one was used to characterize the threshold values indicated.

All patients were divided into 8 groups from 6 to 20 people in each as follows:
groups 1, 2 patients with viral diseases, including (in each group) with a herpes infection with different localization of its manifestations on the skin and mucous membranes (60% of patients) and with viral hepatitis A, B, C (40% of patients);
groups 3, 4 patients with allergic diseases, including (in each group) with allergic dermatitis (40% of patients), with urticaria (40% of patients), with asthma (20% of patients);
groups 5, 6 patients with rheumatological diseases, including (in each group) with non-specific infectious arthritis (60% of patients) and with RA (40% of patients);
groups 7, 8 patients with cancer, including with uterine fibroids (42.9% of patients), with breast adenoma (35.7% of patients), with pituitary adenoma (21.4% of patients). Moreover, in group 7, patients with these diseases were distributed, respectively, people. 3: 3: 2, and in group 8 - 3: 2: 1.

 Patients of groups 1, 3, 5, 7 were injected with α-IFN preparations (50% of patients in each group were administered reaferon, the other half of patients had realdiron), and patients of groups 2, 4, 6, 8, were given γ-IFN (imukin).

 In parallel with the establishment of the maximum single dose of IFN, the relationship between the moment of the disappearance of the pyrogenic reaction with the introduction of this dose and the achievement of a positive treatment result was studied.

 The research results are presented in table. 3.

 Given in the table. 3 data indicate that the optimal condition for obtaining a positive treatment effect in the maximum number of patients (from 60 to 80% with the introduction of drugs α-IFN and from 70 to 83.3% with the introduction of γ-IFN) is the termination of treatment with the achievement of the final single dose of the drug, the ratio of which with respect to the initial single dose is in the range of 10 50 (varying from 10 to 40 for viral and allergic diseases and from 15 to 50 for rheumatological and oncological diseases). From the data table. Figure 3 also shows that the indicated values of the considered indicator were achieved, as a rule, on the 10-14 day of treatment (10 12 day for viral and allergic diseases and 10 14 day for rheumatological and oncological diseases), while correlating with the moment of persistent disappearance of the pyrogenic effect in response to the introduction of IFN, which allowed us to consider the specified period as the optimal duration of the course of treatment.

The achievement of the technical result provided by the invention is due to the following. The proposed method of interferon therapy is based on the assumption that the vast majority of diseases of immune genesis have a viral etiology. Based on this assumption, the author of the invention put forward the concept of a causal role of viral effects on the immune system. Many DNA and RNA-containing viruses: herpes viruses, adenoviruses, hepadnaviruses, hepnadaviruses, caliciviruses, picarnaviruses, para- and orthomyxoviruses, re- and retro-viruses, other viruses that are still poorly understood and unidentified, as well as tumor-associated viruses transformed into oncogenes organism as carriers of foreign information, cause damage to vital parts of the immune system and form immunodeficiency states, autoimmune aggression, cause (or contribute) the development of tumors. The immunopathological processes that developed in this process lead to various clinical manifestations, which in every person are genetically determined in most cases: connective tissue damage, allergic conditions, blood diseases, endocrine disorders, oncological diseases, sluggish inflammatory processes of an autoimmune nature in internal organs, including damage to structures brain, etc. which often defy traditional therapy. As indicated in the review [29] in recent years, it has become apparent that recovery from viral infections is associated not only with the removal of the pathogen and infected cells from the body, but also with the restoration of the impaired regulation of the immune response, as well as with the suppression of immunopathological reactions. At the same time, the point of view is expressed that the nervous and humoral influences due to the central nervous system are perhaps more critical in the mechanisms of regulation of the functions of the immune system in the whole organism than was assumed. Moreover, there is more and more evidence that, apparently, all components or stages of the formation of the immune response can be neurohumorally corrected and the final effect of regulation largely depends on what the regulatory signal is addressed to [30]
Currently, the fact of the interaction of the nervous and immune systems in the process of the body's response to the antigen is considered proven, although researchers have not yet come to a single point of view on the mechanisms of regulation of this interaction. Thus, it has been shown that influences addressed to certain CNS structures alter the microenvironment of lymphoid cells, the number of circulating antibodies, the intensity of cellular immune responses, and the ratio of lymphocytes in subpopulations. In turn, the subcortical structures of the brain respond to the introduction of antigens by a stable reproducible restructuring of neuron activity, the level of excitability and dynamics of bioelectric potentials [24, 30] It is believed that neurodynamic rearrangements in the activity of nerve structures correlate with active processes in the peripheral organs of immunity and ICC. At present, it is believed that the result of the interaction of the immune system and the central nervous system during the implementation of the body's immune response to the appearance of a genetically foreign antigen under normal conditions is a neuroendocrine correction of the body's protective functions and the restructuring of the functional activity of certain brain structures during activation or suppression of the immune system functions. The first of these processes determines the possibility of neurohumoral regulation of the immune system in accordance with the situation of the external and internal environment. The second is associated with the influx into the central nervous system of information about the "immunological situation" in the body, with the processing of this information and the formation of the corresponding efferent signals [24]
Most of the work on the neurophysiological analysis of the interaction of the nervous and immune systems found the participation of the hypothalamus in this process. It is known that the general principle of the functional organization of the hypothalamus provides the possibility of perceiving various information about the state of the internal and external environment coming through the nervous and humoral paths, and the implementation of integrative regulation of the physiological systems of the body. In the hypothalamus as the central formation of the peptidergic system of the brain, neurosecretory (neuroendocrine) cells are concentrated, combining the functions of a neuron and the ability to secrete regulatory peptides. The work of these cells is controlled neurotransmitter, i.e. depends on information coming to the brain via nerve fibers [24] It is assumed that there are hard programs in the hypothalamus that are launched when a certain set of signals coincide [31]
As a result of studying the neural activity of the structures of the hypothalamus caused by the potentials of the slow electrical processes of the brain, it was shown that in vivo the brain enters the process in the first 10 30 minutes after immunization and in this situation a dynamic interaction occurs between the nervous and immune systems. It was experimentally proved that after immunization, a number of structures of the hypothalamus (primarily the posterior hypothalamic and medial preoptic fields) are characterized by a transition to a completely different level of functioning, which has never been noted before immunization. It is suggested that neurodynamic changes in the activity of nerve structures during the implementation of the immune response correspond to active processes in the peripheral organs of the immune system and ICC.

The restructuring of various structures of the hypothalamus in response to the introduction of an antigenic stimulus, apparently, can be both general and specific in nature, depending on the strength characteristics of the stimulus (degree of immunogenicity of the antigen), the quantity and quality of the introduced antigens [24]
It is also known that the hypothalamus plays an important role in providing temperature homeostasis. The regulation of body temperature is carried out, first of all, by the center of thermoregulation, which is localized in the medial preoptic region of the anterior hypothalamus (POPG) near the bottom of the third ventricle and the posterior hypothalamus. The thermoregulation center includes several anatomically and functionally separate units, the main of which are the heat-sensitive region (thermostat), the heat-setting region ("setting point") and two effector regions (heat production and heat transfer). The "setting point" is a conglomerate of neurons in POPG, which determines the body temperature necessary at any given moment. It serves as a reference point for the thermoregulation mechanism, giving a signal about the desired body temperature [32, 33] It has been established that the nerve elements of the anterior hypothalamus (medial preoptic region) have the ability not only to perceive and integrate temperature signals, but also to respond to non-temperature signals, in particular pyrogenic agents. It was shown that the local administration of microdoses of pyrogens such as interleukin-1 (IL-1), α-IFN changed (dose-dependent) the activity of individual neurons of the hypothalamus. It is believed that heat-sensitive nerve cells of this region have chemoreceptive properties [24,34]
The mechanisms of the regulatory effects of the hypothalamus on optimizing the relationship of immune and temperature homeostasis during the implementation of the immune response have been little studied. Nevertheless, a comparison of the dynamics of the index of super slow brain activity after immunization and after the introduction of bacterial (exogenous) pyrogen (Pyrogenal) allowed researchers to conclude that the rearrangements that took place in the structures of the central nervous system under these effects are unequal and irreducible changes that occur after immunization pyrogenic effect, concomitant administration of antigen [24]
The least studied aspect of the interaction of the nervous and immune systems are the methods and channels for transmitting information from the immune system to the brain. Apparently, there is more than one way of transmitting information from the immune system to the central nervous system; the chemical nature of carriers of afferent signals may also be different. According to one option, within the framework of the concept of humoral transmission of signals to the central nervous system, it is assumed that the biologically active factor secreted by the cells of the immune system is carried by the blood stream to the brain and is perceived there by the cells that receive this factor. In another embodiment, the possibility of the perception of such a humoral agent by chemoreceptors of lymphoid organs is postulated, with the subsequent stage of information transfer being carried out through nerve conductors [24, 30]
According to some authors, some of the soluble peptide-protein factors synthesized by ICC under the influence of various antigenic stimuli may be material information carriers. These factors include interleukin, interferons and other lymphokines, thymus hormones, neuropeptides (adrenocorticotropin, thyrotropin, endorphins, enkephalins, etc.) synthesized by various populations of lymphocytes and macrophages [35, 24, 36, 37]
It is assumed that the release of RP when a foreign antigen enters the body or when another stimulating factor acts on the ICC, on the one hand, helps trigger a complex chain of immune reactions, on the other hand, “informs” the neuroendocrine system and the whole body about the processes that occur in the immune system. At the same time, the same RP is capable of performing the functions of both a neuro- and immunomodulator, depending on the department of the body in which an effective concentration of this peptide is achieved. According to the notions currently developing, the immune system functions as a “receptor organ,” capable of receiving signals from the external and internal environment that are inaccessible to other receptor systems of the body [24]
There are a number of studies that indicate that IFN (in particular, α-IFN) can have a direct effect not only on the immune system, but also on the central nervous system [34, 38] In particular, there is evidence of a pronounced (dose-dependent) effect recombinant IFN on the central nervous system when they are introduced into the human body. So, in small doses, IFN causes unpleasant sensations characteristic of viral infections: headache, weakness, muscle pain, etc. With an increase in the dose of IFN, symptoms appear such as loss of ability to concentrate and think, speech disturbances, loss of sense of taste and smell, difficulty in orientation in space and time, visual hallucinations occur, depression, lethargic states and coma are also observed [39, 40 , 41, 24] The indicated central effects of recombinant IFNs are unambiguously attributed to the toxic effect of drugs [42]
To elucidate the mechanisms of IFN action, a number of researchers are currently using a model that provides for the existence of a tetine bioregulation system in the body. According to this model, in living organisms, along with hormonal and kinin bioregulation systems, there is also a third - the tetin system, acting through functional regulatory oligopeptides of products of limited proteolysis of peptide and protein precursors that transmit tete-a-tete information during the interaction of individual cells. It is assumed that additional information can be encoded in the primary structures of functionally active precursor proteins that determines the order of cleavage of the tetins, which sequentially activate individual conjugate immunological or other biochemical reactions. It is believed that the tetine bioregulation system provides information transfer during cell cooperation, for example, the immune system (the interaction of the lymphocyte lymphocyte and macrophage lymphocyte) and the central nervous system (neuron neuron, glia cell neuron), as well as the exchange of information between the nervous and immune systems. Local formation and contact transfer of tetins (via an immuno- or neurosynapse or simply by diffusion from one cell to another) ensures their high local concentrations and selectivity of action. It is believed that the system of regulation of cells by oligopeptide fragments is universal and is essential for the action of cytokines, immunoglobulins, and other regulatory proteins.

 According to the model developed by Chipens et al., The IFN molecule induces biological effects in two ways, acting, first, as a whole unit through active centers located on its surface (for example, while providing some antiviral effects), and secondly, as a precursor of multifunctional oligopeptide bioregulators, which are small active fragments that are formed in the reactions of limited proteolysis of selective enzymatic cleavage of one or more peptide communication.

человека обнаружил свойства модулятора долговременной памяти (типа вазопрессина) и выраженные анальгетические свойства [42, 43, 30, 44] Иммуномодуляторные и нейротропные эффекты проявляют также полярины C концевых участков молекул ИФН. Чипенс и др. рассматривают их в качестве наиболее вероятных медиаторов, переносящих информацию между иммунной системой и ЦНС. С ними также связывают такие центральные эффекты, как галлюцинация, летаргия, кома и т.д. [30, 42, 43, 35]
Начиная со времени первых клинических испытаний ИФН, одним из главных его побочных эффектов считалась лихорадочная реакция [45] Подобная точка зрения принята и в современной терапевтической практике. Хотя считают, что в принципе побочные явления (в т.ч. и лихорадочная реакция) не являются препятствием для продолжения применения препаратов ИФН, однако при резко выраженных побочных реакциях рекомендуется прекращать инъекции препарата [2, 3, 4, 5] У лиц с высокой пирогенной реакцией (39^oC и выше) на введение реаферона (реальдирона) целесообразным считают одновременное применение индометацина [3, 4] Установлено, что пирогенностью обладают все виды ИФН (как природные, так и рекомбинантные) независимо от степени их очистки. При этом наличие пирогенных свойств у высокоочищенных природных и рекомбинантных ИФН доказало, что пирогенность является необъемлемым свойством ИФН, которое не может быть объяснено наличием примеси эндотоксина либо других протеинов, сопутствующих природным ИФН [46, 45, 47]
Имеющиеся в настоящее время сведения о степени выраженности, времени проявления, частоте и длительности пирогенной реакции в ответ на введение препаратов ИФН достаточно разнообразны и в отдельных моментах противоречивы. Отмечают, что частота и выраженность лихорадочной реакции зависит от дозы препарата и способа его введения [48, 46, 47] Кроме того, параметры пирогенной реакции при применении ИФН имеют различные значения при разных заболеваниях. Так, по данным различных исследователей, повышение температуры тела в ответ на введение ИФН варьирует от субфебрильных значений до 39,5^oC и выше как у здоровых доноров, так и при различных видах патологий; количество пациентов с лихорадочной реакцией колеблется от 27,6% (при вирусном гепатите B) до 90-100% (у здоровых добровольцев и при некоторых видах заболеваний); время развития пирогенной реакции составляет от 30 мин до 8 ч после инъекции препарата; длительность от нескольких часов до 12 ч; появление лихорадочной реакции возможно как после начальных доз препарата (вирусные, онкологические заболевания, здоровые добровольцы), так и на первом месяце лечения и позднее (например, при PA) [15, 48, 45, 14, 49, 8, 50, 46, 47] При этом высказано мнение [50] что возможность сопоставления побочных эффектов (в т.ч. параметров лихорадочной реакции) при лечении ИФН разнообразных вирусных и опухолевых заболеваний крайне затруднительна из-за разнообразия самих заболеваний и используемых препаратов ИФН, различия в схемах лечения и дозировке препаратов, продолжительности курса лечения и т.д.A comparative analysis of the primary structures of IFN and other immunologically active proteins showed that the source of tetins can be conserved and C-terminal regions of IFN molecules [42, 43]
Given the profile of the polarities of the peptide chain, 4 main groups of biologically active oligopeptides with different properties are distinguished. Thus, the bioassay data of the synthesized peptides (loop section 122-144, as one of the active regions of potential sources of the tetins of the IFN molecule) indicated their pronounced immunological and neurotropic activity. In particular, it was found that oligopeptides with a mixed arrangement of polar and hydrophobic amino acids of the RIT-LY type are regulators of T-lymphocytes, and amphiphilic segmented oligopeptides of the YFQP type are macrophage regulators. Tetrapeptide sequence 122-125 leukocyte

human has discovered the properties of a long-term memory modulator (such as vasopressin) and pronounced analgesic properties [42, 43, 30, 44] Immunomodulatory and neurotropic effects are also exhibited by polarins C of the terminal regions of IFN molecules. Chipens and others see them as the most likely mediators that carry information between the immune system and the central nervous system. Central effects such as hallucination, lethargy, coma, etc. are also associated with them. [30, 42, 43, 35]
Since the first clinical trials of IFN, a febrile reaction was considered one of its main side effects [45] A similar point of view is accepted in modern therapeutic practice. Although it is believed that, in principle, side effects (including a febrile reaction) are not an obstacle to the continued use of IFN drugs, it is recommended that discontinuation of drug injections with pronounced adverse reactions [2, 3, 4, 5] The simultaneous use of indomethacin is considered appropriate by the pyrogenic reaction (39 ^° C and higher) to the administration of reaferon (realdirone) [3, 4] It has been established that all types of IFNs (both natural and recombinant) have pyrogenicity, regardless of the degree of their purification. Moreover, the presence of pyrogenic properties in highly purified natural and recombinant IFNs proved that pyrogenicity is an integral property of IFN, which cannot be explained by the presence of an admixture of endotoxin or other proteins associated with natural IFN [46, 45, 47]
Currently available information on the severity, manifestation time, frequency and duration of the pyrogenic reaction in response to the administration of IFN drugs is quite diverse and in some instances is contradictory. It is noted that the frequency and severity of the febrile reaction depends on the dose of the drug and the method of its administration [48, 46, 47]. In addition, the parameters of the pyrogenic reaction when using IFN have different meanings for different diseases. So, according to various researchers, an increase in body temperature in response to the introduction of IFN varies from subfebrile values to 39.5 ^o C and higher both in healthy donors and in various types of pathologies; the number of patients with a febrile reaction ranges from 27.6% (with viral hepatitis B) to 90-100% (in healthy volunteers and in certain types of diseases); the development time of the pyrogenic reaction is from 30 minutes to 8 hours after injection of the drug; duration from several hours to 12 hours; the appearance of a febrile reaction is possible both after the initial doses of the drug (viral, oncological diseases, healthy volunteers), and in the first month of treatment and later (for example, with PA) [15, 48, 45, 14, 49, 8, 50, 46, 47] At the same time, an opinion was expressed [50] that the possibility of comparing side effects (including parameters of a febrile reaction) in the treatment of IFN of various viral and tumor diseases is extremely difficult due to the variety of diseases themselves and the used IFN drugs, differences in treatment regimens and dosage of drugs deceitfulness of the course of treatment, etc.

At present, the interpretation of fever as a protective and adaptive reaction of the body, which is closely interconnected with mechanisms to ensure specific resistance of the body, is accepted. The basis of the febrile reaction is a special mechanism of the physiological activity of the thermoregulatory apparatus. Its essence lies in shifting the regulation of temperature homeostasis to a higher than normal level that provides the most favorable conditions for the implementation of certain protective functions. In contrast to the usual adaptive thermoregulatory reactions, the febrile reaction is triggered by non-temperature signals - endogenous pyrogens (EPs), under the influence of which the temperature of the “setting point” of POPG increases. After receiving a pulse from the thermostat about the actual body temperature, the "set point" fine-tunes the centers of heat production and heat transfer in order to bring the actual body temperature to the desired level. Body temperature rises until it reaches the reference temperature of the "set point". In this case, heat production again comes into equilibrium with heat transfer, although at a higher temperature than normal [51, 32]
According to modern concepts, interferons are classified as endogenous pyrogens [33, 27, 45] However, the mechanism of the development of a febrile response in response to the introduction of IFN is still unclear. So, according to the researchers [46], the debatable question is whether IFN acts directly by inducing the synthesis of mediators, such as, for example, prostaglandins. There are numerous data confirming the view that recombinant IFN-α ₂ IFN initiates fever by the same mechanism as other EPs (IL-1, tumor necrosis factor, etc.), i.e. by directly acting on thermosensitive neurons of POPH, the mechanism of which involves the induction of the synthesis of prostaglandins E ₂ (PGE ₂ ) by these cells, as well as other metabolites of arachidonic acid [45, 33] However, the mechanism for transferring the hypothalamic thermoregulatory center to a new level of functioning has not been clearly established. There are several hypotheses, in particular, based on the fact that EPs reach the brain with blood flow. they themselves do not penetrate the blood-brain barrier, but interact with endothelial cells that limit a specific area of POPH, the so-called organum vasculosum laminae terminalis, inducing the synthesis of PGE ₂ or indirectly other neurotransmitters by these cells, which shift the “setting point” of thermoregulation to a higher level [45] Much more complex and less studied is the question of the proposed mechanism of the pyrogenic action of α-IFN. There is evidence that γ-IFN does not directly affect prostaglandin synthesis in hypothalamic sections of a rabbit in vitro [45] It has been suggested that the pyrogenic effect of γ-IFN is mediated by other lymphokines, such as IL-1 or IL-2 [47] However, although there is evidence of in vitro stimulation of γ-IFN production of IL-1, a number of researchers believe that the enhancement of the inducing effect of endoxin is more likely for γ-IFN than direct stimulation of IL-1 synthesis [45, 52] Data confirming the ability of γ- IFN stimulate the production of IL-1 in vito, absent [45] with respect to γ-- IFN are extremely small in number and are very controversial, which complicates any interpretation. So, Dinarello et al. [45] believe that β-IFN, like β-IFN, alone cannot induce the synthesis of IL-1 in vitro. Researchers [52], on the contrary, observed a dose-dependent effect of stimulation of IL-1 secretion by human monocytes under the influence of α-IFN.

 The claimed mode of administration of IFN drugs, based on individual dosing in an increasing dose gradient, allows, according to the author of the invention, to create optimal conditions for the manifestation of not only peripheral, but also central effects of IFN. Considering that normally the early production of IFN in the body is associated with acute viral infection [53], the administration of exogenous IFN can ensure the functioning of INF in the body, in particular, in the structures of the hypothalamus, including as an unconditional signal that mimics an adequate endogenous signal of the immune system the ingestion of the antigen of the virus that caused the development of IDS in this particular patient. At the same time, on the one hand, IFN as an RP will help to launch a cascade of immune responses, on the other hand, it will ensure the transmission of information to the central nervous system. The criterion for the adequacy of the immune response will be not just a change in the functional activity of the central structures, but the transition of certain brain structures, primarily the hypothalamus, to a qualitatively different level of functioning.

 The above literature data allow us to conclude that the development of a febrile reaction can be considered as an external manifestation of one of the components of the complex of radical neurophysiological rearrangements in the activity of central structures (primarily hypothalamic), reflecting the normal functioning of the body's regulatory systems as a holistic reaction in response to the introduction of a foreign agent in an immunogenic dose. With immunopathology, the severity of the pyrogenic reaction of the body, ceteris paribus (in particular, in the absence of central nervous system damage) will depend, incl. from the depth and volume of existing inflammatory and destructive processes of viral etiology (as well as secondary bacterial infection), i.e. will be an integral indicator, including and the functional viability of the immune system. When simulating the stimulating effect of a viral antigen by introducing a regulatory peptide (in particular, IFN), the characteristic parameters of a febrile reaction will be formed as derivatives of a complex set of central and peripheral effects, both potentially possible for a given RP, and appearing at any given moment throughout the course body reactions to the "antigen" depending on the functional viability of the immune system, the degree to which the model matches the real process, the characteristics of dimogo preparation, etc. In addition, it is currently believed [54] that the physiological effects of any RP depend not only on direct action. Sequential modulation of the output of other RPs is a typical process, and secondary RPs, in turn, may include a number of additional physiological mechanisms. These additional mechanisms may appear later than the direct effects of the initiating peptide, as a result of which the general effect of administering the first RP can be longer than the direct effects. In connection with the foregoing, the parameters of a febrile reaction developing in response to the introduction of RP, according to the author of the claimed solution, can vary in a fairly wide range of values not only in different patients with the same disease, but also in each individual patient.

 Based on the above notions of bioregulation by means of limited proteolysis products [43, 42], the author of the proposed method assumes that the functionally active unit affecting the structures of the hypothalamus are polyfunctional regulatory oligopeptides of the tetrine type that have a similar structure and biological properties regardless of species (subtype) IFN. Considering the available information that IFNs obtained by genetic engineering using bacteria are often devoid of C-terminal fragments with a length of 10 to 15 amino acid residues [43, 42] as well as the opinion that the terminal regions of the IFN molecule are not so important for the manifestation of its biological activity [55] it can be assumed that the source of these oligopeptides (apparently belonging to the group with a mixed arrangement of polar and hydrophobic amino acids) are conserved regions of IFN molecules. According to the author of the invention, in accordance with the program incorporated in the IFN molecule, the considered tetine is cleaved in a limited proteolysis reaction and acts on the hypothalamic structures either directly or by modulating the upward afferentation of the autonomic nervous system that innervates the organs of the immune system.

 The action of IFN (or regular oligopeptide) as an unconditional signal, according to the author of the claimed method, can be considered as a special case of the action of the stimulus on the biosystem, described by the general laws of irritation. It is known [33] that in order to generate an active functional response of a biosystem (in this case, an adequate immune response), a necessary condition is a combination of certain physicochemical and functional changes in an irritated object. Excitation arises if these shifts reach a certain critical threshold value, individual for each object. However, in the presence of an immune genesis disease that developed against the background of IDS, the body usually has formed pathological connections (direct and reverse) between the immune system and the central nervous system (pathological stereotype), which affect the value of the threshold of excitation. Thus, in order to obtain an adequate response of the body to imitation of the effect of a viral antigen in the presence of persistent pathological connections, the strength of the stimulus (in this case, the regulatory peptide) must exceed a certain critical value by the available pathological signals. Therefore, the IFN preparation, according to the author of the invention, should be administered in a dose that will allow to achieve in hypothalamic structures, primarily in POPG, an effective concentration of regulatory oligopeptide, necessary and sufficient to ensure the launch of a program involving the transfer of hypothalamic structures (in t. including medial preoptic and posterior hypothalamic fields) to a qualitatively different level of functioning, characteristic of the normal development of an immunological reaction initiated by contact with the antism of viral antigen. At the same time, acting on the thermosensitive neurons of POPG, the specified tetin raises (directly or directly by one of the mechanisms described above) the normal "setting point" of thermoregulation, and the effective concentration of this particular tetin provides, in the opinion of the author of the claimed solution, the launch of a development subprogram corresponding to this signal febrile reactions and given intervals optimal for the occurrence of adequate immune responses of the parameter values. In this regard, the individual selection of doses of IFN, carried out in such a way as to provide certain characteristics of the pyrogenic reaction, allows us to achieve an effective concentration of the regulatory oligopeptide in hypothalamic structures, which is, apparently, a kind of code for launching a comprehensive program of an adequate central and peripheral response of the body. The functioning of this program makes it possible to break the pathological connections between the immune system and the central nervous system and lays the foundation for the formation of a new relationship between these systems that is adequate to the normal immunological response. The achievement (by correcting to IFN) in each individual patient during the treatment of the declared characteristics of the febrile reaction thus signals not only a radical change in the functioning mode of the central structures, but also the beginning of the functioning of a new dynamic relationship between the immune system and the central nervous system, which ensures neurohumoral regulation the immune system in accordance with the state of the internal environment of the patient, which contributes to the achievement of a positive result and treatment.

 The relationship of temperature and immune homeostasis also plays an important role in ensuring a positive treatment outcome in the implementation of the claimed method. The implementation of the principle of biological feedback in the body, on the one hand, leads to the fact that upon reaching the optimal parameters of the pyrogenic reaction, activation of individual parts of the immune system occurs (for example, activation of T-helpers and B-lymphocytes, increased antibody production, induction of EP production by various cells, as well as newly synthesized endogenous pyrogens, etc. [45] In this regard, the creation of optimal temperature conditions for the development of immunological processes in the treatment of the proposed method allows It is possible to achieve not only the mobilization of the required number of ICCs to start the cascade of immune response reactions to mimic the effects of a viral antigen, but also the additional activation of their legal capacity, resulting in a restructuring of the functional properties of the healthy elements of the immune system, allowing them to take on additional functions of defective units. elements of the immune system in a duplication mode contributes to the formation of new direct and feedback links between the immune system and the central nervous system, with Creating the basis for compensation for impaired functions. On the other hand, the intensification of immunological processes, in turn, will have an effect (including multidirectional) on the development processes (including optimization of parameters) and attenuation of the febrile reaction in the patient. For example, based on the above described possibility of prolonging the action of the initiator peptide due to additional effects of secondary RP [54], increased EP synthesis can lead to prolongation of the pyrogenic effect of IFN, optimization of its parameters; on the contrary, the regulation of the production of endogenous pyrogens by endogenous pyrogens according to the type of negative feedback (postulated by the researchers [45] will contribute to the timely attenuation of the febrile reaction, minimizing its negative effects on the body (metabolic disturbances, possible damage to neuronal tissues, etc. [45]) .

 A significant effect in terms of increasing the effectiveness of treatment has a number of peripheral effects of IFN, manifested during the implementation of the claimed method. So, given the incomplete correspondence of the structure of IFN obtained by genetic engineering and natural IFN, according to the author of the invention, recombinant IFNs, when introduced into the body, can have a combined effect as endogenous and as exogenous factors. In particular, acting as an exogenous pyrogen (via induction of IL-1 synthesis), IFN seems to allow duplicating and, possibly, prolonging the pyrogenic effect caused by it as an endogenous pyrogen, which may additionally affect the optimization processes of the parameters of the pyrogenic reaction. In addition, acting as an exogenous factor, IFN allows you to expand the range of ICCs involved in the immune response, which also contributes to the implementation of the principle of interchangeability and replacement of the functions of defective parts of the immune system in the course of treatment by the proposed method and further increases the positive result of treatment.

 In addition, apparently, with the help of IFN introduced in an adequate amount, ICC (microphages, subpopulations of T and B lymphocytes), other tissues of the body are released from viruses and their degradation products, components damaged by their toxic effects of cells, etc. P. During this process, a certain amount of a foreign (or altered) protein is released into the bloodstream, which leads to additional activation of the phagocytic link (for subsequent phagocytosis). Alien and altered intrinsic proteins, appearing in the bloodstream, begin to act as exogenous pyrogens (in addition to IFN), increasing the production of mediators (cytokines) by phagocytic cells, in particular, IL-1, which in turn make an additional contribution to the development of the pyrogenic reaction and affect the optimization of its characteristics, causing an increase in the effectiveness of treatment.

 A single injection of IFN into the patient's body cannot provide the formation of persistent new connections between the immune system and the central nervous system. This is due to and the existence of feedback-blocking mechanisms of a febrile reaction [45] that limit the duration of the pyrogenic effect of IFN. At the same time, the newly acquired ability of the healthy elements of the immune system to function as understudies for defective elements fades and the healthy element returns to its original state. Only as a result of repeated exposure to IFN (in the claimed mode) does an “immune” memory begin to form, characterized in that the developed new functional state of the healthy elements of the immune system does not fade, but, on the contrary, becomes more and more stable. On the basis of this, a new dynamic stereotype of the relationship of the immune system and the central nervous system is formed.

 However, there is evidence of a weakening and (or) disappearance of side effects of IFN, in particular, a pyrogenic reaction, after repeated injections of the drug [48, 15, 14, 8, 46, 50]. These data correlate with the results of the author of the claimed solution, showing that pyrogenic the effect in response to the introduction of IFN disappears after a 2-3-fold injection of the same dose of the drug.

It is known that with repeated injections of bacterial pyrogens, for example lipopolysaccharides (LPS), a state of tolerance, the so-called endotoxin tolerance, develops. The early phase of endotoxin tolerance to the pyrogenic effect of LPS is associated with impaired macrophage ability to produce EP and other endogenous factors in response to LPS administration, and the late phase is due to the appearance of circulating antibodies against the O-polysaccharide part of the LPS molecule, which have a protective effect, including against the pyrogenic effect of LPS. It is also known that repeated administration of very small and very large doses of antigen (including LPS) ensures the development of immunological tolerance, which has a different nature than endotoxin tolerance [56, 57]
Apparently, tolerance to the action of IFN can be divided by analogy with endotoxin tolerance into two phases (early and late), which nevertheless differ in the mechanism of their induction from the corresponding phases of endotoxin tolerance. The development of the early phase of tolerance, manifested, in particular, with respect to the pyrogenic effect of IFN, according to the author of the invention, may be due, first of all, to the inclusion of various central regulatory mechanisms. So, for example, it is known that under the action of a constantly acting stimulus, receptors (including hypothalamic chemoreceptors) adapt, i.e. decrease in their level of excitation [33] Considering that IFN has a common sequence with adrenocorticotropic hormone (ACTH) and β-endorphin [58] and is capable of in vivo exhibiting pharmacological activity as a morphinomimetic [38] as well as available data on the participation of brain peptide hydrolases in central thermoregulation mechanisms [59] it is possible that, by analogy with the development of tolerance to morphine [60], the development of tolerance to the pyrogenic effect of IFN can be caused, for example, by a gradual change in the activity of brain proteolytic enzymes, to the body's response to exposure.

 It is also known that the sensitivity of the receptor adapted to changes in stimulus increases and any stimulus enhancement acts on the adapted receptor as a new stimulus [33] Therefore, with an increase in the subsequent single dose of the administered IFN preparation compared with the previous one, cancellation of the early phase tolerance to IFN can be achieved. According to the law of the force of irritation, the stronger the stimulus, the stronger the response of the object to known limits. However, the reaction of a living system is determined not only by the strength and duration of the stimulus, but also by the rate of growth in time of the force acting on the object, i.e. the gradient. Moreover, according to the law of the gradient, the higher the steepness of the growth of the stimulus in time, the greater the functional response to known limits. Thus, under the action of the stimulus on the living system, mechanisms are turned on that are aimed at stabilizing its state and leading to an increase in the threshold of excitation. These "inactivation" processes are included simultaneously with the "activation", but the rate of their development in time, as a rule, is lower than the latter. The probability of occurrence of excitation under the action of a stimulus with these characteristics will be determined by the initial level of “activation” and “inactivation” processes and the relative rates of their change during irritation [33] Individual dosage of IFN according to the proposed method using a pyrogenic reaction as an criterion of adequacy (with the stated parameters) , developing in response to the introduction of the drug, allows, according to the author of the invention, to create a sufficiently high gradient of stimulus (IFN), p In which the “inactivation" processes in the central (including the hypothalamus) and peripheral structures will lag behind the rate of summation of functional shifts aimed at generating excitation, which will ensure the adequacy of the body's immunological response to imitate the effects of the viral antigen.

 Given that, according to the laws of irritation, the functional response of a biosystem can increase with increasing strength, duration of its action and its growth rate in time only to known limits [33], the patient’s pyrogenic reaction in response to the introduction of IFN in an increasing dose gradient should also occur only during a certain deadline (treatment period). Indeed, it was found that in the course of treatment by the proposed method, with an increase in a single dose of 10-50 times compared with the initial pyrogenic reaction disappears. Due to the fact that the disappearance of the pyrogenic reaction, as a rule, is accompanied by the disappearance of other “side effects of IFN, as well as normalization (in dynamics) of clinical and immunological parameters, it can be assumed that tolerance to IFN (late phase) is integral and may include as components of the condition, phenomenologically similar to immunological tolerance, endotoxin tolerance (late phase), etc. The formation of tolerance to the action of IFN (late phase), according to the author This decision is due to both central and peripheral mechanisms and correlates with the completion of the regulatory program through the creation of optimal conditions for the development of immunological processes (which required the constant exposure to an external exogenous factor - IFN drug), the result of which is a new dynamic stereotype of the relationship of the immune system and CNS, as well as, apparently, with the completion of the body's primary immune response program to the action of a causally significant viral antigen a, which would function under normal conditions, and with the transition of the central and peripheral systems of the body to a regime of autonomous regulation and self-regulation, aimed at eliminating certain damages of a viral or autoimmune nature.

 Thus, as a result of the interconnected work of the extra- and intraimmune mechanisms of regulation and self-regulation provided during the implementation of the claimed method, all the missing endogenous mediators (cytokines) are formed at the proper level, including the entire spectrum of IFN, necessary for an adequate and complete immune response aimed at eliminating the pathological the process in the patient’s body and the correction of IDS. In the process of an adequate immunological response, the pathogen and its own damaged cells are eliminated, hematopoiesis is stimulated with the generation of a healthy cell population, correction of the imbalance of different parts of the immunological reactivity (including the suppression of the hyperreactivity of certain parts of the immune system during autoimmune and allergic pathology), the restoration of damaged tissues organism, regression of tumors, etc. which leads to the achievement of a positive treatment effect.

 It is the relationship between the development of a pyrogenic reaction (characterized by certain parameters) in response to the introduction of IFN and the formation of a new dynamic stereotype of the relationship between the immune system and the central nervous system that mimics the body's response to the effect of viral antigen, which caused the development of IDS in this particular patient, that was not revealed only peripheral, but also central effects of IFN, which made it possible neurohumoral regulation of the immune system. Moreover, from the prior art, according to the applicant, the influence of the transformations prescribed by the invention, characterized by significant features distinctive from the prototype, on the achievement of a technical result is not revealed.

The method is as follows. The patient is injected intramuscularly with a recombinant interferon preparation, for example, β-IFN, α-IFN, or a mixture of them in an initial dose, which provides an increase in comparison with the normal body temperature of this particular patient after 5.2 ± 1.2 hours (i.e., after approximately 4 6.5 h) after administration of the drug at 1.9 ± 0.5 ^o C (i.e., as a rule, up to 38 39 ^o C). Reaferon, realdiron, intron A, roferon A, etc. are used as γ IFN preparations. as drugs α-IFN - for example, imukin. In this case, the initial single dose of these drugs, as a rule, is 1 million ME. Measure the patient’s body temperature and establish the parameters of the pyrogenic reaction in response to the introduction of the drug. Repeated administration of IFN once a day under the control of thermometry, while on the eve of the subsequent administration of the drug, the single dose is adjusted (if necessary) upward so as to maintain the parameters of the pyrogenic reaction within the indicated ranges of values. IFN is administered until the pyrogenic reaction disappears in response to a single dose, 10 50 times the initial dose (for viral and allergic diseases, the final single dose usually exceeds the initial dose by 10 40 times, for rheumatological and oncological diseases, 15 50 times). An additional factor indicating the need to complete the treatment process is the disappearance of negative side effects (pain, signs of local inflammation of various localization, etc.) that occur in the patient during treatment, proceeding in the regime of the so-called "artificial exacerbation". The course of treatment is usually 10 to 14 days. According to indications, a repeated course of treatment is carried out with a previously unused IFN preparation, but not earlier than 2 months after the end of the previous course of treatment.

 The invention is illustrated by the following examples.

 Example 1

 Patient L. 24 years. Diagnosis: acute hepatitis B. He complained of lethargy, chills, muscle and joint pain, loss of appetite, discomfort in the epigastric region, aversion to smoking. For the first time, these complaints appeared 5 days before treatment after intense physical exertion. An objective examination without features. From the anamnesis it is known that the patient’s wife suffered a viral hepatitis 4 months ago and was treated in a city hospital.

Before starting treatment with the claimed method, a preliminary comprehensive laboratory examination was carried out. Survey Results:
Clinical blood test: Hb (hemoglobin) 147 g / l; er (red blood cells) - 4.8 • 10 ¹² / l; Col. pok. (color indicator) 0.92; L (white blood cells) - 5.4 • 10 ³ / l; c (segmented neutrophils) 42% e (eosinophils) - 3% lymph (lymphocytes) 42% mon (monocytes) 13% ESR (erythrocyte sedimentation rate) 3 mm / h.

 Clinical urine analysis: color rich yellow; transparent beats density 1024; pH slightly acidic; glucose and protein not detected; urobilinogen is weakly positive; L unit in p / sp; oxalates are insignificant.

Biochemical parameters: CRP (C-reactive protein) negative; bilirubin: total 20.4 μmol / L, direct 12.0 μmol / L. glucose 4.2 mmol / l; cholesterol 5.1 mmol / l; AST (aspartate aminotransferase) 0.6 μmol / hh. ALT (alanine aminotransferase) 0.85 μmol / hh. thymol test - 4.5 units SH; total protein 72.5 g / l; fractions: albumin 65% γ-2.8% α ₁ -globulin - 7.4% α ₂ -globulin 9.5% β-globulin 15.3% a / g (albumin-globulin coefficient) 1.86; prothrombin index 98%
Immunological examination: T-lymph. total 74% T-helpers 60% T-suppressors 13% RTML ^o with PHA (phytohemagglutinin) 100% RTMLS DNA 1: 9 77% with DNA 1:49 69% JgG 16.5 g / l, JgA 2.7 g / l, JgM 1.3 g / l; CEC - 145 conv. units CH ₅₀ (total complement activity of 50% hemolysis) - 54.2 units. RF (rheumatoid factor) <1: 8;
ELISA: a / t (antibodies) to tbc (tuberculosis) in a serum titer of 1: 300 - negative. a / t to HAV and HCV denied. HBsAg (hepatitis virus surface antigen) is positive. HBsAg Confirmed. (confirmatory test) put. HBeAg ("e" antigen) will put. Anti HBs (antibodies to the surface antigen), Anti HBe (antibodies to the "e" antigen), Anti HBc (antibodies to the nuclear antigen) are denied.

 Thus, a preliminary laboratory examination of the patient revealed the presence of the Australian HBsAg antigen marker of hepatitis B in two test systems, the presence of "e" particles as a factor for virus replication in the prodromal course of viral hepatitis B, the sensitization of the body in RTML to the virus, a slight decrease T-suppressor levels, increased CEC levels. This indicates the onset of viral aggression (prodromal, icteric period before the appearance of cytolysis).

The treatment was carried out by the claimed method using nitron-A. Before the introduction of the drug, the patient made a control measurement of body temperature (in the armpit) using a medical thermometer, which amounted to t _ref. 36.6 ^o C (baseline). Intron A was administered to the patient in an initial single dose of 1 million ME. After the injection of the drug, the temperature was measured at an interval of 1 h (the reference point is the moment of introduction of the intron A), fixing the time when the temperature started to rise, the time to reach the maximum temperature γ- and its value (t _max ), and the time the temperature dropped to normal, after which the measurements were stopped. Subsequently, intron-A injections were repeated once a day under the control of thermometry, while on the eve of the subsequent administration of the drug, the single dose was adjusted (if necessary) upward so as to maintain the parameters of the pyrogenic reaction within the stated ranges of values. The method was carried out according to the following scheme (see table. 7).

 Intron A was administered until the pyrogenic reaction disappeared, which took place on the 10th day of treatment with the introduction of a single dose of the drug, an 18-fold initial dose. The course dose was 92 million NE.

 Against the background of interferon therapy, there were complaints of a flu-like nature, a sharp decrease in appetite and a change in taste sensations, pain and heaviness in the right hypochondrium (especially when the temperature parameters reach a plateau), weakness, sweating. All these negative phenomena (except weakness) passed independently by the end of the course of treatment (their disappearance was correlated with the disappearance of the pyrogenic reaction in response to the introduction of IFN). A week after the end of treatment, health was completely normal.

 After completion of the course of treatment, control complex laboratory examinations of the patient were carried out in dynamics: two weeks (1st examination), one month (2nd examination) and a month and a half (3rd examination) after the cessation of intron-A injection.

The results of the 1st control examination:
Clinical blood test: Hb 135 g / l; er (red blood cells) - 4.2 • 10 ¹² / l; Col. pok. 0.96; L 4.0 • 10 ⁹ / l; n (rod-nuclear neutrophils) 2% with 46% e 2% lymph 41% mon 9% ESR 9 mm / h.

 Clinical urine analysis without pathology.

Biochemical parameters: CRP is negative. bilirubin: total 17.4 μmol / L, direct 8.4 μmol / L; ALT 0.65 μmol / lhh. thymol sample 4.0 units SH; glucose 4.5 mmol / l; cholesterol 4.7 mmol / l; total protein 70.5 g / l; fractions: albumin 61.6% (Δt ₂ ) 1.4% α ₁ -globulin 3.8% α ₂ -globulin-globulin 11.4% β-globulin 22.3% a / g 1.57.

Immunological examination: T-lymph. common 75% T-helpers 63% T-suppressors 11% RTML with PHA 92% RTML with DNA 1: 9 65% with DNA 1:49 43% JgG 17.5 g / l, JgA 3.0 g / l, JgM 1.0 g / l; CEC 170 conv. units CH ₅₀ 44.0 units

 ELISA: HBsAg weakly put. HBeAg is negative. Anti HBc JgM (JgM class antibodies to nuclear antigen) weakly put. Anti HBs JgM (antibodies of the JgM class against a surface antigen) weakly put. a / t to HAV, HCV, tbc - negative.

The results of the 2nd control examination:
Clinical blood test: Hb 135 g / l; er 4.3 • 10 ¹² / l; Col. pok. 0.94; L 4.2 • 10 ⁹ / l; p 1% with 49% e 1% lymph 42% mon 7% ESR 5 mm / h.

 Clinical urine analysis: no pathology.

 Biochemical parameters: without pathology.

Immunological examination: T-lymph. common 75% T-helpers 60% T-suppressors 14% RTML with PHA 81% RTML with DNA 1: 9 78% with DNA 1:49 69% JgG 17.0 g / l, JgA 2.66 g / l, JgM 1.0 g / l; CEC 110 srvc units CH ₅₀ 46.0 units

 ELISA: HBsAg and HBeAg negative. Anti HBs will put. Anti HBs JgM - positive. Anti HBe JgM will put.

The results of the 3rd control examination:
Clinical blood test: Hb 130 g / l; er 4.0 • 10 ¹² / l; Col. pok. 0.98; L 5.2 • 10 ⁹ / l; n 1% with 59% e 1% lymph 32% mon 7% ESR 3 mm / h.

 Clinical urine analysis: straw yellow; beats density 1026; pH sl. sour glucose, no protein detected; microscopic examination of sediment without features.

 Biochemical parameters: without pathology.

Immunological examination: T-lymph. common 77% T-helpers 60% T-suppressors 17% RTML with PHA 60% RTML with DNA 1: 9 and 1:49 ≥ 80% JgG - 16.0 g / l, JgA 2.2 g / l, JgM 0 66 g / l; CEC 80 conv. units CH ₅₀ 55 units

 ELISA: HBsAg negative. Anti HBs JgG, Anti HBe JgG and Anti HBc JgG (antibodies of the JgG class) will put. Anti HBs JgM, Anti HBe JgM and Anti HBc JgM are denied.

 Thus, in the dynamics of the control and immunological examination, elimination of viral hepatitis B antigens was observed (2 weeks after the end of the course of treatment); the formation of immunity through short-term in the JgM class to permanent in the JgG class, which was completed in a month and a half; normalization of immunological parameters (levels of T-suppressors, CEC, lack of sensitization to exogenous DNA), which ended after a month and a half. There was a complete recovery of the patient with consolidation of stable immunity to viral hepatitis B, which lasts more than 2 years.

 Example 2

 Patient U. 61 years old. Diagnosis: urticaria. Quincke's edema. From the anamnesis it is known that laryngeal edema first appeared in 1987 as a reaction to powder medications, which I began to experience increased sensitivity to since 1984, besides that there was an increased sensitivity to plant pollen. She was treated in the allergological departments of specialized hospitals in 1987, 1988 and 1993. (hormone therapy).

 In April 1993 (one month after hormone therapy), a preliminary comprehensive laboratory examination was performed before starting treatment with the claimed method.

Survey Results:
Clinical blood test: Hb 125 g / l; er 3.7 • 10 ¹² / l; L - 6.8 • 10 ⁹ / l; n 7% with 48% e 7% lymph 33% mon 5% ESR 24 mm / h.

Biochemical parameters: CRP positive. sialic acids 2.8 mmol / l; total calcium 2.08 mmol / l; iron 17.9 μmol / l; glucose 4.8 mmol / l; cholesterol 6.4 mmol / l; total protein 66.1 g / l; fractions: albumin 51.8% γ- 4.8% α ₁ -globulin 9.3% α ₂ -globulin-globulin 13.1% β- -globulin 21.0; a / g 1.06;
Immunological examination: T-lymph. common 59% T-helpers 45% T-suppressors 25% RTML with PHA 113% RTML with streptococci 70% RTML with DNA 1: 9 60% with DNA 1: 49 72% RTML with RNA (type I and type II virus) 65% JgG 28.0 g / l, JgA 8.0 g / l, JgM 2.64 g / l; JgE 117 KE / ml; CEC 80 conv. units CH ₅₀ 21.7 units RF <1: 8; ASL 0 (antistreptolysin 0) - 625 units / ml.

 ELISA: a / t to tbc in a serum titer of 1: 300 is negative. CEA (cancer-embryonic antigen) 4.8 ng / ml; CA 19 9 (tumor associated antigen 19 9 pancreatic cancer tumor marker) 1.4 E / ml; AFP (alpha-fetoprotein-oncofetal antigen) 3.1 E / ml.

The results of a preliminary laboratory examination showed that the patient has an increased (compared to normal) leukocyte count and ESR (blood test); elevated levels of CRP, sialic acids, cholesterol, γ-globulin (biochemical parameters). The analysis of immunological parameters revealed a decrease in T-helpers, RTML with PHA, sensitization to DNA, RNA and streptococci; a sharp increase in the level of JgA, JgM, JgG and JgE; reduced CH ₅₀ . This indicates autoimmune aggression of viral etiology, the presence of allergic sensitization of the body.

The treatment of the claimed method using reaferon analogously to example 1. The initial dose of reaferon 1 million ME. Initial temperature (before drug administration) t _ref. 36.7 ^o C. The method was carried out according to the following scheme (see table. 8).

 The duration of treatment is 12 days. The pyrogenic reaction stopped with the introduction of a single dose, a 10-fold initial dose. The total amount of the drug is 58 million ME.

 In the first days of treatment, the patient had complaints of a flu-like nature, during periods when the temperature parameters reached a plateau, there was an increase in swelling in the larynx, swelling of the eyelids, and an increase in rashes on the skin and mucous membranes of the nasal passages. From the 5th to the 9th days of treatment, diarrhea was noted. On the 9th day of treatment, the intensity of discomfort, pain, decreased significantly. On the 12th day of treatment, pastes of the eyelids, a feeling of tightness in the larynx completely disappeared, the activity of the gastrointestinal tract was restored, allergic rashes on the skin and mucous membranes disappeared (which correlated with the disappearance of the pyrogenic reaction to reaferon). General weakness and physical fatigue were observed for another week after the end of the course of treatment, after which the state of health was fully normalized.

 A month after the end of treatment, the patient for the first time in 10 years in the country there was no allergic reaction to pollen of flowering plants.

2 months after the end of the course of treatment, a control complex laboratory examination was performed. Survey Results:
Clinical blood test: Hb 114 g / l; er 3.7 • 10 ¹² / l; L - 4.8 • 10 ⁹ / l; n 3% with 58% e 0% lymph 25% mon 14% ESR 21 mm / h.

Biological indicators: CRP negative; sialic acids 2.1 mmol / l; total calcium 2.25 mmol / l; glucose 4.7 mmol / l; cholesterol 5.9 mmol / l; total protein 68.5 g / l; fractions: albumin 59.3% γ-3.0% α ₁ -globulin - 7.5% α ₂ -globulin globulin 10.7% β-globulin 19.5% a / g 1.47.

Immunological examination: T-lymph. common 80% T-helpers 63% T-suppressors 15% RTML with PHA 90% RTML with streptococci, with DNA, with PHK (virus group)> 80% JgG 17.9 g / l, JgA 6.36 g / l, JgM 0.66 g / l; JgE - 28 KE / ml; CEC 62 srvc units CH ₅₀ 66.4 units

 ELISA: CEA 2.2 ng / ml.

Thus, the results of the control complex examination showed that after the course of treatment the patient had normal leukocyte count, ESR (blood test) decreased; biochemical parameters of CRP, sialic acids, cholesterol, γ-globulin normalized. The positive dynamics of immunological parameters was expressed in the normalization of the content of T-helpers; normalization of RTML with PHA; lack of sensitization to DNA, PHK, streptococci; normalization of JgM, JgG, JgE and a decrease in JgA; normalization of CH ₅₀ .

 With further immunological monitoring (4 months after the end of the piece of treatment), the immune status is within normal limits, including the level of JgE.

 During the observation of the patient for 2 years, there was no allergic reaction to pollen, as well as to drugs.

 Example 3

 Patient P. 39 years. Diagnosis: Sharp's syndrome (systemic lupus erythematosus (SLE), systemic scleroderma (SJS), Syuhren's syndrome). Complaints of morning stiffness, pain in the small joints of the hands, feet, elbow joints, right shoulder joint, weight loss, frequent exacerbations of chronic sinusitis, chronic tracheobronchitis, dry mouth, weakness, fatigue, periodically "feeling of pain" in the eyes.

 From the anamnesis it is known that the patient systematically suffered from acute respiratory infections (ARVI), suffered rheumatism at age 12, tonsillectomy was performed at age 16, and diagnosed with chronic infectious non-specific polyarthritis at age 17. Chronic hypoacid gastritis. From the age of 24, he suffers from chronic bilateral adnexitis, from the age of 30, there are symptoms of colitis, from the age of 31, chronic sinusitis and vasomotor rhinitis. At the age of 35 years, there was a sharp deterioration in overall well-being, annual pneumonia, frequent exacerbations of chronic sinusitis, vaginal candidiasis, exacerbation of chronic colitis. At 37, she was diagnosed with sluggish laryngitis. Chronic tracheobronchitis of viral and bacterial etiology. Overgrowth of the epiglottis. The treatment was ineffective. At 38 years old, consultation in a rheumatic center, diagnosis: rheumatoid arthritis, articular-visceral form, FIS-III, activity of the II degree.

Before starting treatment in the traditional way adopted in the treatment of this disease, a preliminary comprehensive laboratory examination was carried out. Survey Results:
Clinical blood test: Hb 135 g / l; er 4.5 • 10 ¹² / l; platelets 247 • 10 ⁹ / l; L 6.5 • 10 ⁹ / l; n 5% with 70% e 1% lymph 19% mon 5% ESR 15 mm / h.

 Clinical urine analysis without pathology.

Biochemical parameters: CRP ±; sialic acids 2.2 mmol / l; glucose 4.5 mmol / l; cholesterol 4.0 mmol / l; ALT 0.25 mmol / LHh; AST - 0.18 mmol / LHh; ALP (alkaline phosphatase) 48 IU / L; creatinine 100 μmol / l; urea 5.1 mmol / l; uric acid 0.196 mmol / l; thymol sample 3.7 units SH; total protein 83.3 g / l; fractions; albumin 68% γ-globulin 1.7% α ₁ -globulin 5.8% α ₂ -globulin-globulin 7.5, β-globulin 17.0% a / g = 2.12.

 Immunological examination: T-lymph. total 78% T-helpers 55% T-suppressors 10% RTML with PHA 100% RTML with streptococci> 80% RTML with DNA 1: 9 53% with DNA 1:49 71% with RNA (type I and II influenza virus)> 80% JgG 20.0 g / l, A-4.4 g / l; JgM 2.68 g / l; JgE 85 KE / ml.

CEC 165 conv. units CH ₅₀ 30.5 units RF denied. ASL-O - denied. ANF (antinuclear factor) 1: 16 (marginal and cellular luminescence); No LE cells were detected.

 ELISA: a / t (antibodies) to tbc in a serum titer of 1: 300 is weakly positive. NSE (lung cancer tumor marker) 18 E / ml; MCA (breast cancer tumor marker) 14 E / ml; CEA 4.8 ng / ml; CA-19 9 7.0 E / ml; HBsAg is negative. A-HAV - Negative. a / t to Herpes l m. put in the title of 1: 3200.

 On radiographs of the hands, narrowing of the joint spaces, periarticular osteoporosis.

 Thus, the results of a preliminary laboratory examination showed that the patient had elevated CRP, decreased T-helpers, T-suppressors, RTML with phHA, sensitization to DNA, increased levels of JgA, JgG, JgM, CEC, weakly positive ANF. An ELISA revealed sensitization to tuberculosis, an increased titer to a number of tumor markers, and the presence of herpes antigen in high concentration. This indicates the presence of autoimmune aggression of viral etiology, the failure of the antitumor defense of the body.

 The patient underwent traditional therapy with non-steroidal anti-inflammatory drugs (NSAIDs); there was no positive effect. A month later, basic therapy with plaquenil and methindole was prescribed (later bromhexine was added), which was carried out for 3 months. The dynamics showed a decrease in pain, but pains in the joints of the upper extremities continued to bother, sharply expressed weakness continued, dry mouth progressed, the symptoms of "pain" in the eyes intensified, hyperemia of the mucous membranes, dry cough, and colitis. Against the background of the ongoing therapy, the SARS phenomenon joined. With a second consultation in the rheumatic center (during the period of basic therapy), the diagnosis was made: Sharp syndrome (SLE + SJS + Syuhren's syndrome), activity of the II degree.

An intermediate laboratory examination in dynamics (against the background of basic therapy) showed a decrease in ESR to 5 mm / h, an increase in lymphocytes to 33% increase in anemia (Hb 118 g / l, er - 3.7 • 10 ¹² / l); decrease in T-suppressors (from 10% to 5%), CEC 160 conv. units revealed RF 1: 1024, single LE cells in the preparations; there was an increase in the level of tumor markers (NSE up to 28 E / ml, MCA up to 15 E / ml), and / t to tbc in the serum titer of 1: 300 remained positive, the presence of herpes antigen in high concentration was still observed (a / t 1: 3200).

 Thus, the results of clinical and laboratory examination indicated the absence of a positive effect of basic therapy.

After 4 months of treatment with traditional methods, the patient was prescribed a course of reaferonotherapy with the claimed method (monotherapy) with the abolition of basic therapy with plaquenil and NSAIDs. The treatment was carried out analogously to example 1. The initial dose of reaferon 1 million ME. Initial temperature (before drug administration) t _ref. = 37.1 ^o C.

 The method was carried out according to the following scheme (see table. 9).

 Reaferon was administered until the pyrogenic reaction disappeared, which occurred on the 14th day of treatment with the introduction of a single dose of the drug 20 times the initial dose. The course dose was 129 million ME.

 Against the background of reaferonotherapy, complaints of a flu-like nature were noted, severe headaches, pain in the eyes, increased pain in the joints, increased swelling. By the end of treatment, these phenomena disappeared on their own (which correlated with the disappearance of the pyrogenic effect of reaferon). There was also a sharp decrease in appetite, up to a complete aversion to food, severe weakness, dizziness. After the end of the course of treatment, a gradual improvement in health was observed, although weakness and malaise were observed during the week. By the end of the month after the end of the course of treatment, a complete restoration of the functional mobility of the joints, a significant decrease in the dryness of the mucous membranes, and an increase in working capacity were noted.

2 months after the end of the course of treatment, a control complex laboratory examination was performed. Survey Results:
Clinical blood test: Hb 121 g / l; er 3.9 • 10 ¹² / l; L - 5.2 • 10 ⁹ / l; n 5% with 57% e 2% lymph 27% mon 9% ESR 7 mm / h.

Biochemical parameters: CRP negative; sialic acids 2.1 mmol / l; glucose 4.1 mmol / l; cholesterol 4.8 mmol / l; urea 3.7 mmol / l; creatinine 79 μmol / L; uric acid 0.185 mmol / l; total protein 75.0 g / l, fractions: albumin 62% γ-4.0% α ₁ -globulin 7.4% α ₂ -globulin-globulin - 10.2% β-globulin 16.4% a / g 1.63.

Immunological examination: T-lymph. total 73% T-helpers 63% T-suppressors 9% RTML with PHA 85% RTML with streptococci>80; RTML with DNA 1: 9 79% with DNA 1: 49> 80% CEC 105 conv. units CH ₅₀ 37.0 units RF <1: 8; JgG 17.9 g / l; JgA 3.2 g / l; JgM 1.0 g / l; LE cells were not detected.

 ELISA: a / t to tbc in a serum titer of 1: 300 is negative. MCA 5.6 E / ml; NSE - 7.8 E / ml; CEA 2.1 ng / ml; herpes virus antigens not determined. (negative).

 Thus, the results of the control examination showed that there was a normalization of CRP; normalization of T-helpers, T-suppressors at the same level; RTML with PHA approached the upper limit of normal, slight sensitization to DNA; normalization of the level of immunoglobulins; CEC level increased; no antinuclear factor was detected. In ELISA, the lack of sensitization to tbc (antibody titer within normal limits), previously elevated tumor markers within the upper normal range, herpes antigen is not determined. The values of the indicators indicated an incomplete normalization of the immune status of the body, in particular, they did not achieve the elimination of sensitization to DNA.

 Control comprehensive examination 4 months after the end of the course of treatment, the indicators of immune status remained at the same level.

6 months after the end of the first course of treatment due to the deterioration of general well-being, the patient was prescribed a second course of treatment of the claimed method using imukin. The treatment was carried out analogously to example 1. The initial temperature (before drug administration) t _ref. 36.7 ^o C. The initial dose of imukin is 1 million ME. The method was carried out according to the following scheme (see table. 10).

 The duration of the second course of treatment was 11 days. The pyrogenic reaction stopped with the introduction of a single dose of the drug 15 times the initial dose. The total amount of the drug for the second course of treatment is 78 million ME.

 A comparative analysis of two courses of treatment with different types of IFN revealed a similar picture of their effect on the patient. In the course of treatment with imukin, as well as with treatment with reaferon (I course), there was a short-term aggravation of the joints, a decrease in appetite. As the doses of the drug increased, the intensity of pain and flu-like manifestations decreased, and by the 11th day of treatment all negative phenomena (except general weakness) disappeared (which correlated with the disappearance of the pyrogenic effect of the drug). At the end of the second course of treatment, the recovery of good general health, working capacity was faster; joint pain, the patient is not bothered, increased resistance to viral infections.

The results of the control laboratory examination 2 months after the end of the second course of treatment:
Clinical blood test: Hb 130 g / l; er 4.0 • 10 ¹² / l; L - 5.6 • 10 ⁹ / l; n 3% with 53% e 1% lymph 36% mon 7% ESR 7 mm / h.

Immunological examination: T-lymph. common 79% T-helpers 61% T-suppressors 15% RTML with PHA 77% RTML with streptococci, DNA, PHK> 80% JgG 16.5 g / l, JgA 2.6 g / l, JgM 0.9 g / l; CEC 69 conv. units CH ₅₀ - 33.0 units RF <1: 8.

 IFA: a / t to tbc denied. MCA 0.0 E / ml; NSE 1.4 E / ml; CEA 0.5 ng / ml.

 Thus, the results of the control examination showed that there was a normalization of all the determined indicators of the immune status, except for T-suppressors (approached the lower limit of the norm); in ELISA tumor markers within the lower limit of normal.

The results of the control laboratory examination 4 months after the end of the second course of treatment, the indicators of immune status are normal, including T-suppressors
Example 4

 Patient B. 21 years old. Diagnosis: laryngeal papillomatosis. Latent diabetes. From the anamnesis it is known that he suffers from laryngeal papillomatosis from 1 year. Repeatedly operated on this occasion. The patient was regularly observed and treated at the Research Institute of Ear, Throat, Nose and Speech. At the time of examination, before starting treatment with the claimed method, the patient had aphonia, a colloid scar from a tracheostomy (last operation 6 months ago), a repeated growth of papillomas on the vocal cords and mucous membranes of the larynx (according to the examination of an ENT doctor).

Before starting treatment with the claimed method, a preliminary comprehensive laboratory examination was carried out. Survey Results:
Clinical blood test: Hb 115 g / l; er 4.4 • 10 ¹² / l; platelets 488 • 10 ⁹ / l; L 6.3 • 10 ⁹ / l; n 1% with 51% e 6% lymph 38% mon 4% ESR 6 mm / h.

Biochemical parameters: CRP positive. sialic acids 2.1 mmol / l; glucose 6.0 mmol / l; cholesterol 4.8 mmol / l; ALT 0.31 mmol / LHh; total protein 84.6 g / l; fractions: albumin 54.8% γ-1.7% α ₁ -globulin 7.1% α ₂ -globulin-globulin 15.3% β-globulin 21.1% a / g 1.21.

Immunological examination: T-lymph. 70% total T-helpers 35% T-suppressors 2% RTML with PHA 148% RTML with streptococci> 80% RTML with DNA 1: 9> 72% with DNA 1:49> 80% RTML with RNA (influenza virus I t. ) 13% with RNA (influenza virus IV T.) 50% JgG 12.4 g / l, JgA 3.2 g / l, JgM 1.32 g / l, CEC 120 conv. units RF <1: 8; ASL 0 is negative. CH ₅₀ 22.2 units

 ELISA: a / t to tbc in a serum titer of 1: 300 is negative. CEA 2.4 ng / ml.

According to the results of the preliminary examination, the patient revealed an increased content of lymphocytes (blood test), an increased content of CRP, glucose, γ-globulin (biochemical parameters), a decrease in T-helpers, T-suppressors, RTML with PHA, sensitization to DNA, RNA, increased the content of JgA, CEC, a reduced level of CH ₅₀ (immunological parameters). This indicates the presence of an immunodeficiency state of viral etiology.

The patient was treated with reaferon according to the claimed method analogously to example 1. The initial dose of reaferon is 1 million ME. Initial temperature (before drug administration) t _ref. 36.6 ^o C. The method was carried out according to the following scheme (see table. 11).

 The duration of treatment is 14 days. The pyrogenic reaction stopped with the introduction of a single dose of the drug 15 times the initial dose. The total amount of the drug is 111 million ME.

 In the first half of the course of treatment, she complained of a flu-like nature, sometimes against the background of an elevated temperature (especially at maximum values of temperature parameters), tingling in the heart, increased pain and swelling in the larynx, aphonia were noted. In the second half of the treatment, the intensity of the pain decreased. All the main symptoms of the flu-like nature, pain independently stopped by the 14th day of treatment (except for the weakness and malaise that passed a week after the end of treatment), correlating with the disappearance of the pyrogenic effect of reaferon. With the independent rejection of papillomas (the patient "cleared their throat"), the voice began to recover. The process of rejection of papillomas continued for another week after the end of the course of treatment.

The results of the control laboratory examination (2 months after the end of the course of treatment):
Clinical blood test: Hb 110 g / l; er 3.7 • 10 ¹² / l; platelets 250 • 10 ⁹ / l; L 5.0 • 10 ⁹ / l; n 3% with 5% lymph 36% mon 11% ESR 5 mm / h.

Biochemical parameters: CRP is denied; glucose 5.2 mmol / l; cholesterol 4.2 mmol / l; total protein 85.3 g / l, fractions: albumin 64.8% γ-3.1% α ₁ -globulin 6.8% α ₂ -globulin globulin 10.0% β-globulin 15.3% a / g 1.84 .

Immunological examination: T-lymph. total 76% T-helpers 50% T-suppressors 12% RTML with PHA 100% RTML with DNA and RNA (influenza virus)> 80% JgG 14.0 g / l, JgA 4.72 g / l, JgM 1.32 g / l; CEC 60 srvc units CH ₅₀ 24.1 units

The results of the control complex examination indicated the normalization of glucose, CRP; normalization of all globulin fractions, including γ-globulin. Immunological examination showed an increase in helpers and suppressors, a decrease in RTML with PHA, a lack of sensitization to DNA, RNA, normalization of the CEC, and an increase in the level of CH ₅₀ . This indicates a decrease in IDS and the approach of the immune status to normal.

 3 months after the end of the course of treatment by the claimed method, the patient was examined by an ENT specialist at a research institute of the ear, throat, nose and speech.

 Conclusion: "At the time of examination: the vocal folds are movable, the edges are flat, blunt. In the posterior part of the left vocal fold, there is a single papilloma ≈2 mm."

 Remission lasts more than 2 years after the end of the course of treatment. With repeated immunological examinations (after 4 months and 12 months after the end of the course of treatment), further approximation of the immune status indicators is normal.

 Example 5

 Patient V., 42 years old. Diagnosis: pituitary adenoma (according to computed tomography, NMR, optometrist examination). Uterine fibromyoma (according to gynecological examination and ultrasound). Fibroadenomatous changes in the mammary glands with single cysts (according to examination by a mammologist and mammography). From the anamnesis it is known that the patient's mother died of ovarian cancer. In a patient, estradiol was determined for several years at significantly higher concentrations (up to a 10-fold increase in the level compared to the norm).

Before starting treatment with the claimed method, a preliminary comprehensive laboratory examination was carried out. Survey Results:
Clinical blood test: Hb 104 G / l; er 3.7 • 10 ¹² / l; L - 4.7 • 10 ⁹ / l; n 6% with 62% e 3% lymph 22% mon 10% ESR - 16 mm / h.

Biochemical parameters: CRP positive. glucose 3.6 mmol / l; cholesterol 6.6 mmol / l; ALT 0.52 mmol / LHh; total protein 85.0 g / l, fractions: albumin 60.2% γ-3.0% α ₁ -globulin 6.5% α ₂ -globulin globulin 9.0% β-globulin 21.3% a / g 1 , 51.

Immunological examination: T-lymph. common 81% T-helpers 73% T-suppressors 6% RTML with PHA 10.5% RTML with streptococci 50% RTML with DNA 1: 9 50% with DNA 1:49 66% RTML with RNA (influenza A virus) 1: 3200 10% 1: 1280 44% RTML with brain structures 67% JgG 17.9 g / l, JgA 3.32 g / l. JgM 3.6 g / l; CEC 209 conv. units CH ₅₀ 15.2 units RF <1: 8.

 ELISA: ISA 14 E / ml; CA 125 (tumor associated antigen 125 - tumor marker of ovarian cancer) 49 E / ml.

The results of a preliminary examination showed that the blood test is within normal limits; increased CRP and the level of γ-globulin (biochemical parameters); increased T-helpers, reduced T-suppressors, RTML with PHA; sensitization to DNA, RNA, brain structures, streptococci; increased levels of JgA, JgG, JgM, CEC; reduced CH ₅₀ (immunological parameters). In ELISA, tumor markers of breast and ovarian cancer are above the upper limit of normal. This indicates autoimmune disorders of viral etiology and failure of the antitumor defense.

The patient was treated with the claimed method analogously to example 1 using a mixture of reaferon and imukin preparations. The initial dose of reaferon is 1 million ME. The initial dose of imukin is 1 million ME (mixed with 4 million ME reaferon). The initial temperature (before drug administration) t _ex 36.7 ^o C. The method of implementation according to the following scheme (see table. 12).

 The duration of treatment is 11 days. The pyrogenic reaction stopped with the introduction of a single dose of the drug 23 times the initial dose. The total amount of the drug is 108 million ME reaferon and 16 million ME imukin.

 During treatment, exacerbation of headaches, cough, runny nose, decreased appetite, sweating, which disappeared on the 9th 11th day of treatment (correlating with the disappearance of the pyrogenic effect of INF preparations). However, a feeling of fatigue, weakness was noted within 10 days after the end of the course of treatment.

The results of the control laboratory examination (2 months after the end of the course of treatment):
Clinical blood test: Hb 120 g / l; er 4.4 • 10 ¹² / l; L - 6.1 • 10 ⁹ / l; n 1% with 55% e 2% lymph 38% mon 4% ESR 6 mm / h.

Biochemical parameters: CRP neg. glucose 4.6 mmol / l; cholesterol 5.6 mmol / l; ALT 0.26 mmol / LHh; total protein 82.5 g / l; fractions: albumin 66.2% γ-30% α ₁ -globulin 6.5% α ₂ -globulin globulin 9.3% β-globulin 16.0% a / g 1.96.

Immunological examination: T-lymph. common 74% T-helpers 50% T-suppressors 15% RTML with PHA 69% RTML with streptococci, DNA, RNA (influenza A virus), brain structures> 80% JgG 11.2 g / l, JgA 3.7 g / l, JgM 1.6 g / l, CEC 60 conventional units CH ₅ 27.5 units

 ELISA: ISA 8.0 E / ml; CA-125 37.4 E / ml.

The results of the control laboratory examination showed the normalization of CRP and the level of γ-globulin (biochemical parameters); normalization of T-helpers and T-suppressors, RTML with PHA; lack of sensitization to causally significant antigens; normalization of levels of immunoglobulins, CEC, CH ₅₀ V ELISA cause-significant tumor markers within normal limits.

 During the control ultrasound 3 months after the end of the course of treatment, nodes in the mammary glands and uterus were not detected.

 A control laboratory examination 4 months after the end of the course of treatment, immunological parameters and tumor markers are normal.

 Control x-ray examination 7 months after the end of the course of treatment (at the Central Research Institute of Radiology, Central Scientific Research Radiological Radiobiological Institute) on a radiograph of the skull (compared with the radiograph 5 months before the start of treatment), the size of the Turkish saddle is reduced from 13x8 mm to 11x8 mm.

 10 months after the end of the course of treatment, a control computed tomogram was made at the Oncology Research Institute, which revealed the disappearance of the pituitary adenoma, the size of the pituitary gland within normal limits.

 Example 6

 Patient S. 52 years. Diagnosis: chronic persistent hepatitis. Cirrhosis of the liver. Chronic pancreatitis. Concomitant diagnoses: urolithiasis. Chronic pyelonephritis. He complained of increased fatigue, decreased performance, constant pain in the right hypochondrium, periodically occurring attacks of girdle pain, heartburn. From the anamnesis it is known that for the first time pain in the right hypochondrium occurred 10 years ago. A year ago, the pain attacks became permanent and did not stop with emergency help. Ultrasound diagnosed with cholelithiasis. Within a month I was in hospital treatment, during which a cholecystectomy was performed. During the operation, a change in the liver of a cirrhotic nature was noted. In this regard, it was additionally examined: a marker of viral hepatitis B HBsAg, an increased activity of aminotransferases (ALT 1.4 mmol / hh; AST 1.1 mmol / hh), an increased level of thymol test, etc. on the basis of which the diagnosis was made: chronic persistent hepatitis. Cirrhosis of the liver. Within a year after the operation, he actively applied to various medical institutions for further medical assistance. During this period, the presence of HBsAg and an increase in the activity of aminotransferases, alkaline phosphatase, lactate dehydrogenase, amylase, and γ-globulin levels were constantly examined repeatedly; an increase in CA-19-9 level of 265.3 E / ml was revealed.

Before starting treatment with the claimed method, a preliminary comprehensive laboratory examination was carried out. Survey Results:
Clinical blood test: Hb 179 g / l; er 6.0x10 ¹² / l; L - 5.8x10 ⁹ / l; n 4% with 49% e 1% basophils 1% lymph 35% mon - 10% ESR 5 mm / h.

Immunological examination: T-lymph. common 55% T-helpers 43% T-suppressors 1% RTML with PHA 101% RTML with streptococci> 80% RTML with DNA 1: 9 65% with DNA 1: 49 78% RTML with RNA (type I and type II virus) > 80% JgG 18.9 g / l; JgA 3.2 g / l; JgM 3.4 g / l; CEC 245 conv. units CH ₅₀ - 13.4 units RF <1: 8; ASL O is denied.

 IFA: HBsAg will put. Ca-19-9-40.3 E / ml.

The results of an immunological examination showed that T-lymph was reduced. general, T-helpers, T-suppressors, RTML with PHA; sensitization to DNA; increased levels of JgG, JgM, CEC; reduced CH ₅₀ ELISA contains the Australian HBsAg antigen marker of hepatitis B; increased pancreatic cancer marker. This indicates the presence of autoimmune suppression of viral etiology.

The patient was treated with the claimed method analogously to example 1 using roferon A. The initial dose of roferon A is 1 million ME. Initial temperature (before drug administration) t _ref. = 36.6 ^o C. The method was carried out according to the following scheme (see table. 13).

 The duration of treatment is 10 days. The pyrogenic reaction stopped with the introduction of a single dose of the drug 15 times the initial dose. The course dose is 81 million ME of the drug.

 During treatment, flu-like complaints were noted; in the first half of the course of treatment, very intense pain in the right hypochondrium, sometimes - girdle pain; a sharp decrease in appetite, general weakness. In the second half of the course, the pain gradually decreased, weakened.

 The painful sensations and most flu-like manifestations disappeared towards the end of treatment (correlating with the disappearance of the pyrogenic effect of roferon A). Within a month after the course of treatment, the general state of health gradually returned to normal, fatigue disappeared, working capacity improved, appetite returned to normal, heartburn disappeared, and pain in the right hypochondrium ceased to bother. This allowed the patient to move away from a strict diet, which he followed for the past few years.

During the control laboratory examination a month and a half after the end of the course of treatment, the following results were obtained:
Clinical blood test: Hb 155 g / l; er 5.3x10 ¹² / l; L - 5.3x10 ⁹ / l; n 3% with 53% e 1% lymph 37% mon 6% ESR 6 mm / h.

 Clinical urine analysis: straw yellow; beats density 1021; pH is slightly acidic; glucose, total protein not found; L 2-3 p / sp; mucus (+); oxalates (+).

Biochemical parameters: CRP is negative. glucose 4.3 mmol / l; cholesterol 5.0 mmol / l; ALT 0.45 mmol / LHh; AST 0.6 mmol / LHh; ALP (alkaline phosphatase) 43 II / l; total protein 79.0 g / d, fractions: albumin - 57.3% γ-3.9% α ₁ -globulin -8.0% α ₂ -globulin-globulin 11.3% β-globulin 19.5% a / g 1.34.

Immunological examination: T-lymph. total 64% T-helpers 52% T-suppressors 9% RTML with PHA 71% RTML with streptococci, DNA, RNA (type I and II influenza virus)> 80% JgG 17.2 g / l, JgA-3.2 g / l, JgM-2.64 g / l; CEC - 100 conv. units CH ₅₀ 17.4 units

 ELISA: HBsAg- negative. CA-19-9 21.5 E / ml.

Thus, a control laboratory examination showed an increase in T-lymph. general, T-helpers, T-suppressors, normalization of RTML with PHA, lack of sensitization to DNA, normalization of JgG, JgM, CEC levels, increase in CH ₅₀ . In ELISA, the absence of the Australian HBsAg antigen, the pancreatic tumor marker is within normal limits. The survey results indicate the absence of autoimmune disorders and the approach to normal immune status.

 With repeated immunological examinations (4, 6, and 8 months after the end of the course of treatment), a further tendency toward normalization of immunological parameters was observed.

 For a year and a half of observation (after the end of the course of treatment) there are no dietary restrictions, he feels well, and laboratory indicators are within normal limits. Thus, the treatment of the claimed method made it possible to achieve long-term remission (over 1.5 years).

 Example 7

 Patient B. 23 years. Diagnosis: bilateral chronic adnexitis. Menstrual irregularities. From the anamnesis it is known that the diagnosis was made more than 2 years ago, confirmed by repeated ultrasound of the pelvic organs. Conducted multiple courses of antibiotic therapy, nonspecific anti-inflammatory therapy. A preventive course of tubazide was carried out (in the urban TB dispensary).

Before starting treatment with the claimed method, a preliminary laboratory comprehensive examination was carried out. Survey Results:
Clinical blood test: Hb 143 g / l; er 4.8x10 ¹² / l; L - 5.4 x ^{10 9} / L; with 42% e 3% lymph 42% mon 13% ESR 3 mm / h.

Biochemical parameters: CRP positive. sialic acids 2.1 mmol / l; glucose 4.5 mmol / l; cholesterol 4.8 mmol / l; ALT 0.52 mmol / LHh; Alkaline phosphatase - 147, 9 E / l; total protein 78.9 g / l, fractions: albumin 61.2% γ-3.0% α ₁ -globulin - 6.0% α ₂ -globulin-globulin 10.7% β-globulin 19.1% a / g 1.58.

 Indicators of endocrine status: LH (luteinizing hormones), FSH (follicle-stimulating hormones), TSH (thyroid stimulating hormone), prolactin, estradiol, testosterone, progesterone within the normal range of the corresponding levels of the expected mid-menstrual cycle, cortisol 837.7 nmol / L.

Immunological examination: T-lymph. common 80% T-helpers 74% T-suppressors 6% RTML with PHA 62% RTML with DNA 1: 9 75% with DNA 1:49 75% RTML with RNA (influenza virus type AI and II) 75% RTML with head structures brain 75% JgG-17.9 g / l, JgA-3.2 g / l, JgM 1.32 g / l; CEC 325 srvc units ASL-O 1250 ME / ml; RF <1: 8; CH ₅₀ 64.13 units

 ELISA: a / t to tbc in a serum titer of 1: 300 is negative.

 As a result of a laboratory examination, it was found that the content of lymphocytes (blood test) was significantly increased, CRP was increased, and γ-globulin was slightly increased (biochemical parameters); endocrine indicators within normal limits except for cortisol (slightly exceeds the upper limit of normal); increased T-helpers, decreased T-suppressors, sensitization to DNA, RNA, brain structures, the level of CEC (immunological indicators) is sharply increased. This indicates the presence of IDS of viral etiology (acute inflammatory process).

The patient was treated with the claimed method analogously to example 1 using realdiron. The initial dose of realdiron is 1 million ME. Initial temperature t _ref. = 36.6 ^o C. The method was carried out according to the following scheme (see table. 14).

 The duration of treatment is 11 days. The pyrogenic reaction stopped when a single dose of the drug was administered in a 21-fold initial dose. The total amount of the drug is 131 million ME.

 In the first half of the treatment, the complaints were minor, of a general nature - flu-like; from the 4th to the 8th day of treatment (which correlated with the disappearance of the pyrogenic reaction to the administration of the drug). General weakness, malaise, lethargy persisted 6 days after the end of the course of treatment. The menstrual cycle returned to normal immediately after treatment.

During the control laboratory examination 2 months after the end of the course of treatment, the following results were obtained:
Clinical blood test: Hb 135 g / l; er 4.2 • 10 ¹² / l; L - 4.7 • 10 ⁹ / l; n 2% with 58% lymph 34% mon 4% ESR 4 mm / h,
Biochemical parameters: CRP is negative. glucose 4.1 mmol / l; cholesterol 4.6 mmol / l; total protein 75.0 g / l, fractions: albumin 60.5% γ-4.0% α ₁ -globulin 7.0% α ₂ -globulin-globulin 11% β-globulin 17.5% a / g 1 , 48.

Immunological examination: T-lymph. total 76% T-helpers 65% T-suppressors 18% RTML with PHA 60% RTML with DNA, with RNA (influenza virus)> 80% JgG 16.0 g / l, JgA 3.2 g / l, JgG 0, 65 g / l; CEC 80 conventional units ASL-O 625 ME / ml; CH ₅₀ 44.0 units

 The results of the control examination showed the normalization of lymphocytes (blood test); absence of CRP, normalization of γ-globulin (biochemical parameters); normalization of T-helpers, T-suppressors, lack of sensitization to DNA, RNA, brain structures; normalization of the CEC.

 When examined by a gynecologist and an ultrasound scan (4 months after the end of the course of treatment), no visible pathology was detected.

 Repeated control laboratory examination (4 months after the end of the course of treatment) immunological parameters are normal.

The claimed method of interferon therapy was used in the treatment of 501 patients with various diseases of the immune genesis with confirmed (based on data from a comprehensive examination) diagnoses, of which:
86 patients with viral diseases (30 men and 41 women aged 18 to 72 years old, 15 children aged 4 to 12 years old), including with a herpetic infection with different localization of its manifestations on the skin and mucous membranes of 59 people and with viral hepatitis A, B, C in all periods of the course of 27 people (of which: with acute hepatitis A 2 people with acute hepatitis B 5 people with acute hepatitis B with a fulminant course of 2 people with acute hepatitis C - 5 people with chronic persistent hepatitis B 5 people with chronic active hepatitis B 8 people);
72 patients with allergic diseases (22 men and 40 women aged 16 to 78, 10 children aged 4 to 15 years), including with allergic dermatitis, urticaria, Quincke's edema, bronchial asthma;
168 patients with rheumatic diseases (44 men and 113 women aged 25 to 65 years, 11 children aged 4 to 13 years), including with non-specific infectious arthritis (reactive arthritis), with rheumatoid arthritis, with juvenile rheumatoid arthritis, with Reiter's syndrome, Syugren's, with ankylosing spondylitis and with systemic lupus erythematosus;
20 patients with cancer (1 man and 18 women aged 40 to 74 years, 1 child aged 7 years), including with laryngeal papillomatosis, uterine fibroids, breast adenoma, pituitary adenoma;
155 patients with other diseases (36 men and 113 women aged 32 to 78 years, 6 children aged 7 to 15 years), including with chronic active hepatitis of various etiologies, cirrhosis of the liver, peptic ulcer (stomach and duodenal ulcer), ulcerative colitis, Crohn’s disease, chronic pancreatitis, latent diabetes mellitus, autoimmune thyroiditis, chronic pyelonephritis, lipoid nephrosis, diffuse nephrosis, disseminosis, adnexitis, sclerocystic ovaries, endometriosis, menstrual irregularities, patients at risk (a history of intrauterine damage to the fetus, ending miscarriage).

 The treatment was carried out at the clinics of the Military Medical Academy and the St. Petersburg State Pediatric Medical Academy, the Diagnostic Advisory Center N 85 and the district polyclinics at the patients' place of residence.

 A preliminary comprehensive examination included a clinical laboratory examination as traditional to confirm the diagnosis of each specific disease, as well as (according to indications) ultrasound diagnostics (ultrasound), endoscopy, nuclear magnetic resonance (NMR), etc. as well as special studies. In the framework of traditional methods, in addition to clinical examination, the following clinical and biochemical studies were carried out: general analysis of blood, urine; determination of acute phase inflammation proteins, phenotyping of dyslipoproteinemias, determination of cholesterol, glucose, glycosylated hemoglobin, urea, uric acid, creatinine, determination of electrolyte balance, prothrombin index, determination of the activity of organ-specific enzymes, determination of a number of individual blood proteins, as well as (according to indications) the level of necessary hormones (pituitary, thyroid, adrenal glands, pancreas, hormones involved in the regulation of the menstrual cycle). To confirm the viral and (or) autoimmune nature of the pathological process, the patient’s immune status was assessed using special studies: an immunological examination, including the study of cellular and humoral factors of immunity, including determination of T and B lymphocytes; T-helpers; T-suppressors; determination of sensitization to viruses and their metabolic products in the inhibition of leukocyte migration (RTML) with exogenous RNA, DNA; determination of immunoglobulins A, M, G, (JgA, JgM, JgG), as well as the concentration of total and causally significant immunoglobulin E (JgE) to various allergens; circulating immune complexes (CEC); complement system components; cytokine levels; parameters of phagocytic activity, etc. [61, 62] as well as enzyme-linked immunosorbent assay (ELISA) by test systems of the Hoffmann-La Roche concern (Switzerland), including the determination of causally significant tumor markers; verification of viral antigens in the classes JgM and JgG, as well as the degree of formation of immunity to them; detection of sensitization to tuberculosis and other infections. Clinical, biochemical and immunological examinations, ELISA and a number of instrumental examinations were carried out on the basis of the Diagnostic Consultative Center N 86 (St. Petersburg).

 To assess the effectiveness of treatment by the claimed method, the following criteria were used: clinical evaluation of the disappearance of the pathological process - normalization of body temperature, absence of pain, signs of local inflammation, reduction (disappearance) of tumors confirmed by instrumental methods of research; normalization of clinical, biochemical and immunological parameters; in ELISA, a decrease in the titer of tumor markers and elimination of viral antigens.

Static processing of the observation results was carried out using the Student criterion, the Fisher test, the Kerber method and the probit method [63]
The effectiveness of the treatment of patients with various diseases of the immune genesis using the inventive method using various preparations of recombinant IFN (after the first and after two courses of treatment) is presented in table. 4. In the table. 5 and 6 show data on the effectiveness of the treatment of the proposed method when using IFN preparations of various types of γ- and subtypes (alpha 2, alpha 2a, alpha 2b).

 An analysis of the data in Table 4 shows that the use of the claimed method ensures the achievement of a positive treatment effect after 1 course of interferon therapy on average in 77.2% of patients (varying from 50 to 100% depending on the type of disease), and on average in two courses of treatment 99.0% of patients (varying from specific diseases from 99.9 to 100%). Moreover, the use of the proposed method for the treatment of viral, allergic, oncological diseases and diseases classified as "other" ensures the achievement of a positive treatment result in 84.7 88.4% of patients after 1 course of treatment. The effectiveness of the first course of treatment of diseases of the rheumatological profile is characterized by slightly lower results. In approximately 40% of cases, a second course of treatment is required. However, after two courses of interferon therapy, a positive effect in all disease profiles (including rheumatological diseases) is achieved in 98.6 100% of patients.

 From the data in Table 5 it is seen that the effectiveness of the use of various preparations of α- and γ-IFN (reaferon, realdiron, intron A and roferon A) ranged from 70 to 77.8% (the number of patients who achieved a positive treatment effect) while the best results were obtained using intron A (77.8% of patients), reaferon and its analogue realdiron showed approximately the same results (respectively 74.8 and 73.2% of patients).

 From the data table. 6 it follows that the use of the drug α-IFN (imukin) ensures the achievement of a positive treatment effect on average in 85.9% of patients (varying from a disease profile from 64.5% to 92.9% of patients), which exceeds the corresponding results the use of γ-IFN preparations (reaferon, realdiron, intron A and roferon A) by an average of 11.6% (depending on the profile of the disease, the difference varies from 5.6 to 10.7%). The use of a mixture of α-IFN for the treatment of patients with rheumatological diseases ensured a positive treatment result in 63.6% of patients, which indicates a higher therapeutic efficacy of the mixture compared to individual preparations of α- and γ-IFN (the difference is 5.7 %), and its comparability in terms of effectiveness with α-IFN (the difference is 0.9%).

Thus, the use of the claimed method provides an increase in the effectiveness of treatment in comparison with known interferon therapy schemes based on the principles of the prototype method [2] In particular, a comparison of the data in Table 4 with published data [15, 7, 8, 16] shows that the use of the claimed The method allows to increase the effectiveness of the treatment of a number of diseases:
hepatitis B virus; acute forms from 4 15% to 50% depending on the timing, including acute hepatitis B with a fulminant course of 100% chronic forms of 43.4% hepatitis C 70 70%
herpetic infection (with various localization of manifestations on the skin and mucous membranes) from 20 to 34%
rheumatoid arthritis 24 45%
multiple sclerosis by 53.3%, etc.

 Using the proposed method also allows you to expand the scope, in particular the use of IFN drugs for the treatment of bronchial asthma, endometriosis and other nosological forms of diseases in which interferotherapy has not been previously used, as well as to shorten the treatment time.

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Claims (11)

1. The method of interferon therapy by intramuscular injection into the human body of recombinant interferon preparations in doses that vary during the course of treatment, characterized in that the treatment is carried out in an increasing gradient of single doses of the interferon drug, and the drug is initially administered in a dose that provides an increase compared to the normal temperature body each individual patient through 5.2 ± 1.2 hours after dosing on 1.9 ± 0.5 ^o C, then repeated administration of the drug once a day in dosages that will provide the aforementioned minutes pyrogenic effect, before it disappears when administered a single dose of 10 to 50 times the initial dose.  2. The method according to claim 1, characterized in that use preparations of α-interferon.  3. The method according to claim 2, characterized in that reaferon or realdirone is used as α-interferon preparations.  4. The method according to claim 2, characterized in that roferon A. is used as the preparation of α-interferon.  5. The method according to claim 2, characterized in that intron A is used as the preparation of α-interferon.  6. The method according to PP.3 to 5, characterized in that the preparations of α-interferon are administered in an initial single dose of 1 million IU. 7. The method according to claim 1, characterized in that the use of γ-interferon preparations.
8. The method according to claim 7, characterized in that imukin is used as a γ-interferon preparation, which is administered in an initial single dose of 1 million IU.  9. The method according to claim 1, characterized in that a mixture of at least two different interferon preparations is used.  10. The method according to claim 9, characterized in that a mixture of α- and γ-interferons is used.  11. The method according to claim 1, characterized in that, according to the indications, a second course of treatment is carried out, but not earlier than 2 months after the end of the previous course of treatment.  12. The method according to claim 11, characterized in that the second course of treatment is carried out with a previously unused interferon drug.

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