RU2562537C2 - Method for prevention of aggravated recurrent rhinosinusitis - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: method for prevention involves the three-week stress-protection therapy, diet therapy, omega 3 fatty acid deficiency therapy, vitamin therapy, probiotic therapy, probiotic-like therapy, antioxidant therapy, and local immunocorrective therapy.

EFFECT: method enables more effective prevention ensured by reducing the microecological imbalance, endotoxinemia, carrier state of viral and bacterial pathogens on the upper airway mucosa and recovery of local immune reactivity, colonisation resistance and nasal mucociliary clearance.

11 tbl

Description

The invention relates to medicine, namely otorhinolaryngology, relates to a method for the prevention of exacerbations of recurrent rhinosinusitis.

Rhinosinusitis is an inflammation of the mucous membrane of the nasal cavity and at least one of the paranasal sinuses [1-3].

Domestic otolaryngologists, depending on the duration of inflammation, distinguish:

- acute rhinosinusitis (the duration of the disease is less than twelve weeks and the complete disappearance of the symptoms of the disease after recovery);

- recurrent rhinosinusitis (from one to four episodes of acute rhinosinusitis per year, periods between exacerbations last at least eight weeks, at this time there are no symptoms of the disease, treatment is not performed);

- chronic rhinosinusitis (the presence of symptoms of the disease over a period of time of more than twelve weeks) [3].

US experts rhinosinusitis is usually divided into four classification groups:

- acute rhinosinusitis (resolution of inflammation within four weeks);

- subacute rhinosinusitis (inflammation lasts four to eight weeks);

- recurrent rhinosinusitis (three or more episodes of acute rhinosinusitis within one year);

- chronic rhinosinusitis (inflammation of the mucous membrane of the nasal cavity and paranasal sinuses, persisting for more than eight weeks) [4].

According to the European position paper on rhinosinusitis and nasal polyps - EPOS 2012:

- acute rhinosinusitis - acute inflammation of the nasal mucosa and sinuses (appearing suddenly and lasting no less than one and a half, but no more than twelve weeks), characterized by the presence of two or more symptoms, of which the obligatory symptom is nasal congestion or discharge (from the nose or the back wall of the pharynx), and additional - pain or pressure in the face, hypo- or anosmia;

- chronic rhinosinusitis - inflammation of the nasal mucosa and sinuses (lasting more than twelve weeks), characterized by the same symptoms as acute rhinosinusitis. The European Guidelines for Rhinosinusitis (EPOS 2012) postulate:

- acute rhinosinusitis is initiated by respiratory viruses;

- chronic rhinosinusitis - inflammation, not infection [5].

The prevalence of rhinosinusitis is extremely high. Inflammatory pathology of the nasal mucosa and paranasal sinuses occupies a leading position in the structure of inflammatory diseases of the upper respiratory tract and affects about 16% of the adult US population during the year [6]. “Rhinosinusitis” is one of the ten most common diagnoses in outpatient practice and it is estimated that up to 15% of the world's adult population suffers from various forms of rhinosinusitis [7]. In the countries of the European Union, the prevalence of only chronic rhinosinusitis is 10.9% of the population [8]. At the end of the twentieth century in Russia, rhinosinusitis was diagnosed in 10 million people annually [9]. Epidemiological studies indicate a permanent increase (for unknown reasons) in the incidence of rhinosinusitis - over the past decade, this indicator has increased almost threefold [10]. In just three years (2006-2009), the incidence of acute rhinosinusitis in the United States increased by 2% (in 2006, the incidence was 11% of the adult population of the country - 26 million cases [11]), and in 2009 - 13 % (29 million cases [12]). The prevalence of chronic rhinosinusitis in the United States is 146: 1000 [11] and this indicator in the age group of the population under 45 significantly exceeds the prevalence of any other chronic diseases [13]. Patients hospitalized for inflammatory pathology of the nasal mucosa and paranasal sinuses account for up to two thirds of the total number of patients in specialized ENT hospitals [15]. Among all clinical forms of rhinosinusitis in children, acute rhinosinusitis prevails (56.4%), the incidence of chronic rhinosinusitis is 18.9%, and subacute and recurrent - 13.2% and 11.5%, respectively [16]. Rhinosinusitis takes the fifth place among the diseases for which antibiotics are prescribed [7]: over seven years, the cost of treating only chronic rhinosinusitis in the USA has increased almost one and a half times - from 6.0 to 8.6 billion dollars a year [6, 17] .

Acute rhinosinusitis is characterized by an increasingly pronounced tendency to relapse with subsequent chronization of the process in the paranasal sinuses [18]. And the understanding that recurring rhinosinusitis sooner or later can be converted into chronic inflammation of the nasal mucosa and paranasal sinuses is becoming more widespread [19]. It has been proved, and it is important to note that antibiotics do not reduce the risk of progression of recurrent rhinosinusitis in its chronic clinical form [20].

Rhinosinusitis most negatively affects the quality of life of patients [21-23], leads to enormous economic costs [17] and is fraught with a number of serious life-threatening complications [24-27]. Although the incidence of rhinosinusogenic intraorbital complications is 0.8%, and intracranial “only” 0.01% of the total number of patients with inflammatory diseases of the nasal mucosa and paranasal sinuses [28], but given the prevalence of this pathology and that of the orbital and intracranial complications of rhinosinusitis, mortality reaches 5% [24] and 25% [29], respectively, it is difficult to underestimate the importance of this aspect of the pathology. In addition, inflammatory diseases of the mucous membrane of the nasal cavity and paranasal sinuses often lead to allergies, the development of bronchopulmonary pathology, and dysfunction of many internal organs and body systems [30-35].

An impressive body of clinical observations and experimental data has been accumulated concerning almost any aspect of the inflammatory pathology of the sinonasal region. Recently, several new hypotheses have been proposed for the etiopathogenesis of rhinosinusitis (fungal, bacterial superantigens, immune barrier, bacterial biofilms) [36–41], but no effective therapeutic strategies have been proposed [5,42–44].

All this indicates that recurrent rhinosinusitis is an urgent problem of modern clinical medicine and healthcare organization [5, 45]. At the same time, prevention tactics have not been defined, there is no republican standard for specialized medical care for recurrent rhinosinusitis [46, 47]. Therefore, topical issues remain in the search for means and methods of pathogenetically substantiated effective prevention of recurrent rhinosinusitis.

Currently, there is no single generally accepted scheme for preventing exacerbations of recurrent rhinosinusitis. However, methods of surgical and therapeutic prevention of exacerbations of recurrent inflammation of the nasal mucosa and paranasal sinuses are known. In particular, surgical interventions have been proposed as methods of preventing exacerbations of recurrent rhinosinusitis: “A method for remodeling the hooked process” [48], “A method for treating chronic recurring sinusitis” [49]. Known methods and conservative therapeutic prevention of exacerbations of recurrent rhinosinusitis by:

- the purpose of the drug Sinupret [50];

- desensitization of the body during course prescriptions of anthelmintic and antiangiotic preparations [51];

- topical endonasal autolymphocytotherapy ("A method for the treatment of chronic recurrent inflammatory diseases of the nasal mucosa and paranasal sinuses using endonasal autolymphocytotherapy" [52]);

- replacement therapy with recombinant IL-1β (Betaleikin) with a genetically determined insufficient level of expression of endogenous IL-1β [53].

The disadvantages of all of these analogue methods are low efficiency (only a reduction in the likelihood of relapse is achieved), the availability of indications for use only in special cases (congenital or acquired anatomical and physiological abnormalities, genetic predisposition, intestinal infestations) and invasiveness of prophylactic procedures (surgical methods of prevention).

The closest in technical essence to the claimed method is a method for the prevention of exacerbations of recurrent rhinosinusitis before autumn and spring outbreaks of acute respiratory viral infections by the course of a combined immunomodulator for intranasal use of IRS19. Topical immunization with IRS19 containing 18 lysed strains of the most common pathogens of respiratory tract infections reduces the level of contamination of the nasal mucosa with pathogenic microorganisms, reduces the severity of inflammation symptoms and helps prevent relapse of rhinosinusitis [54-57].

The disadvantages of the prototype method:

1. The likelihood of adverse reactions to the drug containing many antigenic determinants of bacterial proteins, especially with repeated course prescriptions [58];

2. The short duration of the immunomodulatory effects of the drug (no more than three months) and, as a result, the need to repeat the course of the topical immunomodulator every three to four months [56];

3. The insufficiently high efficiency of monotherapy through the appointment of IRS19 [59].

The purpose of the invention is to increase the effectiveness of prevention of exacerbations of recurrent rhinosinusitis by applying a method that provides a comprehensive corrective effect on the main pathogenetic mechanisms of the formation / maintenance of aberrant pro-inflammatory readiness of the nasal mucosa, paranasal sinuses and allows you to restore eubiosis, local antiviral protection.

This goal is achieved by the fact that in a comprehensive course for three weeks, in the inter-relapse period (the period of absence of inflammation of the nasal mucosa and paranasal sinuses), prescribing drugs of systemic and local action that affect the main pathogenetic mechanisms of recurrent inflammation of the nasal mucosa and paranasal sinuses :

1. Stress-protective therapy. As a stress protector enhancing the effects of mexidol, melatonin and omega-3 polyunsaturated fatty acids, tricyclic antidepressant amitriptyline is prescribed orally twice a day daily at a subtherapeutic dose of 6.25 mg (1/4 tablet).

2. Diet therapy. The main content of diet therapy is the inclusion in the diet of morning and evening servings of oatmeal with a volume of 200-300 ml, each portion is prepared from 100-125 g of oatmeal; the lunch menu includes buckwheat porridge and one raw egg white; monosaccharides, disaccharides and dishes containing them, drinks and products that include phosphodiesterase inhibitors (chocolate, cocoa, coffee, tea) are excluded from the diet; For the preparation of first, second courses, desserts and drinks, only filtered water is used, and the water intended for drinking is also boiled.

3. Therapy to eliminate the deficiency of omega-3 polyunsaturated fatty acids. To eliminate the deficiency of omega-3 polyunsaturated fatty acids, fish oil is prescribed in the form of the drug “Biafishenol” daily three times a day with 5 capsules (each capsule contains 300.0 mg of fish oil) for three weeks.

4. Vitamin therapy. Vitamins B ₁ (thiamine hydrochloride), B ₆ (pyridoxine hydrochloride), B ₁₂ (cyanocobalamin) are prescribed as part of Neuromultivit daily, once per day, after meals, one tablet, each of which contains 100.0 mg of thiamine hydrochloride, 200.0 mg of pyridoxine hydrochloride and 200, mcg of cyanocobalamin; vitamin B _{9 is} prescribed as part of the folic acid daily daily, once a day, before meals, 1/2 tablet (0.5 mg); Vitamin B _{7 is} prescribed as part of the Biotin Complex daily orally once with meals (1 tablet contains 121-150 micrograms of biotin); vitamin A is prescribed as part of the Retinol Acetate preparation during the first week, daily, orally once a day after a meal, one capsule containing 33,000 IU of retinol acetate, and every other day, orally once a day, after a meal, one capsule containing 33,000 ME retinol acetate, over the next two weeks; Vitamin E (α-tocopherol) is prescribed daily as part of the drug Alpha-Tocopherol acetate orally three times a day, one capsule (100.0 mg) for the first week and one capsule (100.0 mg) twice daily orally per day for the next two weeks; Vitamin D ₃ (calcitriol) is prescribed daily as part of the AquaDetrim preparation orally once a day at a dose of 2000 ME (four drops); Vitamin C (ascorbic acid) is prescribed daily as part of the ascorbic acid preparation orally three times a day, in two tablets, each containing 50.0 mg of ascorbic acid, during the first week and in two tablets (total 100.0 mg ascorbic acid) daily orally twice a day for the next two weeks.

5. Probiotic therapy. During probiotic therapy, a third-generation probiotic Bifiform, one capsule three times a day, is prescribed daily, orally after a meal.

6. Therapy with drugs with prebiotic-like activity. To restore eubiosis of the mucous membrane of the upper respiratory tract and the gastrointestinal tract, a 1.67% solution of emoxipin succinate (Mexidol) and 0.25% solution of Ambroxol hydrochloride (Lazolvan) in 0.33 are prescribed intranasally daily three times a day. % novocaine solution in a volume of 3.0 ml in each nasal passage for 8-10 minutes (1 ml of the solution contains 16.7 mg of emoxipin succinate, 2.5 mg of ambroxol hydrochloride and 3.3 mg of novocaine); A three-component solution including emoxipine succinate, ambroxol hydrochloride and novocaine is prepared immediately before use by mixing in a single bottle of 2.0 ml of official 1% ampoule solution of novocaine, 5% ampoule solution of emoxipine succinate (Mexidol) and 0.75% ampoule Ambroxol hydrochloride solution (Lazolvana); the solution instilled into the nasal passages, as it swells along the mucous membrane of the nasal cavity and the posterior wall of the nasopharynx, is recommended to be swallowed. The drug Enterosgel is prescribed daily orally three times a day, two hours after a meal and medications, 15 g each (one tablespoon); calcium glycerophosphate is administered orally three times a day after meals, one tablet containing 0.2 g of the substance.

7. Antioxidant therapy. As antioxidants, in addition to antioxidant vitamins (retinol acetate, α-tocopherol and ascorbic acid) are prescribed: lipoic (thioctic) acid - orally three times daily for three weeks after meals, one tablet (25.0 mg) ; N-acetylcysteine (“ACC” preparation) - daily, for three weeks, orally three times a day, one effervescent tablet (200.0 mg) after dissolution in water; dihydroquercetin - daily orally three times a day, one tablet (25.0 mg) with meals during the first week and one tablet (25.0 mg) twice daily with meals for the next two weeks; melatonin (the drug "Melaxen") - daily for three weeks, orally once a day, one tablet (3 mg of melatonin) thirty minutes before going to bed; selenium (the drug "Selenium-Active") - daily orally once a day with meals, one tablet (50 mcg) for three weeks.

8. Local immunocorrective therapy. To stimulate local immunity of the upper respiratory tract, a multivalent antigenic complex in the form of lozenges is prescribed for three weeks daily, six times a day (every two hours) - the drug "Imudon".

As a theoretical basis of the proposed method for the prevention of exacerbations of recurrent rhinosinusitis, a new vision of the pathogenesis of recurrent inflammation of the nasal mucosa and paranasal sinuses is proposed.

Recurrent rhinosinusitis can be a consequence of a congenital predisposition (genetic or anatomical and physiological). But in most cases, this is a consequence of a violation of the colonization resistance of the nasal mucosa and paranasal sinuses that occurs with microecological imbalance. Microecological imbalance is associated with morphological and functional failure of the epithelial lining of the upper respiratory tract (manifested by impaired barrier function and mucociliary clearance), aberrant expression of mucin glycans, glycans and pectins of the cytoplasmic membrane of epithelial cells, and an decrease in the expression of factors of the anti-bacterial immune system and anti-bacterial dysfunctions. At the same time, the dysbiotic state is a systemic phenomenon that affects all microecological niches of the macroorganism and arises during chronic stress loads (chronic exposure to stressors of a psycho-emotional, physical, chemical, biological nature), inadequate to the needs of the biological system “macroorganism - symbiotic microbial” diet, irrational use of antibacterial funds. The latter (irrational use of antibacterial agents) makes it possible to understand why the prevalence of inflammatory diseases of the nasal mucosa and paranasal sinuses in the second half of the twentieth century acquired the features of a pandemic.

The problem of microecological imbalance is increasingly associated with the problem of chronic stress. Long-term stimulation of the activity of the hypothalamic-pituitary-adrenal stress-implementing system, in particular, manifests itself [60-69]:

- an imbalance of neuro-humoral factors that determine the colonization resistance of epithelial barriers and directly affect the phenotype of microorganisms;

- deficiency of mediators of the stress-limiting system, which determines the pathogenetic weight of the subthreshold under normal conditions stress-inducing stimuli;

- partial replacement of the symbiont microbiome by a non-resident microflora, accompanied by an active rivalry between microorganisms for dominance in microecological niches;

- the formation of circulus vitiosus (vicious circle) of self-maintenance of microecological imbalance due to the stress-inducing nature of the aberrant intestinal microbiome against the background of the failure of the mechanisms of the stress-limiting system.

At the same time, antibiotics, diet errors, upper respiratory tract and periodontal infections can act both as independent etiological factors in the formation of the dysbiotic state of the nasal mucosa, paranasal sinuses and nasopharynx, and as effectors potentiating the effects of chronic stressors.

The stress-associated / antibiotic-induced dysbiotic state of the nasal mucosa and paranasal sinuses, as a local manifestation of systemic microecological imbalance, is a necessary condition and the cause of exacerbations of recurrent rhinosinusitis. Therefore, as an obligate part of the proposed method for the prevention of exacerbations of recurrent rhinosinusitis, measures should be considered to relieve microecological imbalance.

In order to reduce the tone of the hypothalamic-pituitary-adrenal stress-implementing system and normalize mucociliary transport, the administration of a tricyclic antidepressant amitriptyline in a subtherapeutic dose of 6.25 mg (1/4 tablet) twice a day has been shown [70-72]. Significant aspects of the pharmacological activity of amitriptyline also appear to be its ability to block the biological effects of gram-negative bacteria lipopolysaccharide by suppressing TLR-4-dependent signal transduction [73] and inhibit the expression of inducible NO synthase (iNOS), which has a significant pathogenetic role in the genesis of inflammatory respiratory pathology pathways and lungs [74-77].

The role of diet therapy in maintaining eubiosis is undeniable. In order to optimize the vegetation conditions of symbionts, the use of products characterized by a high content of dietary fiber is shown. The most suitable for the restoration of eubiosis can be considered oatmeal and buckwheat. In oat grains, the proportion of dietary fiber is up to 10-12%, which is approximately half represented by the most valuable β-glucans for the human body. In 1997, the US Food and Drug Administration (US FDA) recognized oat bran as the first food product to lower blood cholesterol (apparently due to the normalization of intestinal microbiome) [78]. And the US National Academy of Sciences recommends a daily dose of oat fiber at the level of 25-28 g for healthy young women and men [79]. The recommended dose of dietary fiber is contained in 200-250 g of oatmeal, from which morning and evening portions of oatmeal of equal volumes (200-300 ml) should be prepared for dietary correction of the dysbiotic state. At lunchtime, it is advisable to use porridge from buckwheat as a side dish or an independent dish (portion 200-300 g).

Dietary fibers (a combination of various water-soluble polysaccharides) are not digested (not broken down into monosaccharides) by the endogenous secrets of the human gastrointestinal tract and unchanged reach the colon, where they are metabolized by anaerobic (“herbivorous”) symbiotic microflora to short chain fatty acids. Short chain fatty acids (acetate, propionate, butyrate, valerate) are the main energy substrate for colon mucosa epithelial cells [80], which stimulates proliferation, cell differentiation, and mucin mucus formation.

The effects of short-chain fatty acids are, to a certain extent, mediated by the protein-G-dependent receptors GPR41 and GPR43 (localized on the cytoplasmic membrane of the epithelial cells of the distal small intestine, colon, enteroendocrine and mast cells of the intestinal mucosa [81, 82]) an increase in the level of cytosolic Ca ²⁺ and a corresponding decrease in the content of intracellular cyclic adenosine monophosphate (cAMP) [83]. Therefore, in order to avoid blocking the receptor-dependent effects of short chain fatty acids by inhibiting the activity of phosphodiesterases that provide hydrolytic cleavage of cAMP [84], dietary therapy of microecological imbalance should avoid the use of foods and drinks (chocolate, cocoa, tea, coffee) containing phosphodiesterase inhibitors - caffeine, theophylline, theobromine and methylated xanthines.

Water-soluble β-glucans are able to translocate from the intestinal lumen to the vascular bed and exert a pronounced receptor-mediated immunomodulating effect, block the pro-inflammatory effects of the lipopolysaccharide of gram-negative bacteria [85, 86]. As a specific sensor of β-glucans, the inducible receptor Dectin-1 is expressed on the cytoplasmic membrane of the respiratory tract epithelial cells. Dectin-1 immunocytes, epithelial cells mediate the antifungal, antibacterial and anti-inflammatory effects of β-glucans [87-90].

It is best to take oatmeal β-glucans on a lean stomach, which optimally ensures their intestinal passage. Oral ingestion of β-glucans into the body is also physiologically effective, as well as their parenteral administration [91]. β-glucans are extremely stable and do not lose biological activity during cooking [92], which is manifested in their ability to:

- optimize cholesterol metabolism, modulate the activity of the immune system in a receptor-mediated and dose-dependent manner without the effects of excessive stimulation [85, 93-95] and, therefore, without contraindications in subjects with autoimmune, allergic, fungal and cardiovascular diseases [96, 97];

- block the pro-inflammatory effects of the lipopolysaccharide of gram-negative bacteria [86] and prevent the prophylactic administration of septic conditions [98] and adhesive disease [99];

- specifically bind to the CR3 lectin site (Complement Receptor 3, CR3) and the inducible sensor of β-glucans on the plasma membrane of epithelial cells and immunocytes, enhancing their fungi, bactericidal activity, including protection against tumor cells [88, 89, 100-103];

- improve intestinal motor function [104];

- selectively stimulate the growth of symbiont lactobacilli and bifidobacteria [105-107] and exhibit antioxidant properties [108-110], including protecting mitochondria from free radical damage [111].

In order to prevent (stop) the syndrome of excessive growth of bacteria in the small intestine, simple saccharides (mono- and disaccharides - glucose, fructose, sucrose, etc.) and products containing them (honey, jam, syrups, etc.) are excluded from the diet. ) Avoid the use of any alcoholic beverages and products, which include sweeteners, colorants, flavors and preservatives.

It is advisable to use raw egg white containing a significant amount of iron-binding protein ovotransferrin. Ovotransferrin is able to drastically reduce the level of iron ions in the intestinal environment, which are a “growth factor” for opportunistic and pathogenic microflora, which, naturally, favors the restoration of eubiosis [112, 113].

The water used to prepare the first dishes and drinks must be filtered to remove residual chlorine, iron oxides and other pollutants. After filtration, water intended for drinking is necessarily subjected to boiling [114].

Deficiency of omega-3 (ω-3, n-3) essential polyunsaturated fatty acids (PUFA) due to excessive consumption of animal, vegetable fats with a high content of omega-6 (ω-6, n-6) polyunsaturated fatty acids (ω-6 PUFAs - antagonists of ω-3 PUFAs) and fructose (as part of sucrose) are found in the diet of almost all population groups [115, 116]. Therefore, there is no doubt that the omega-3 PUFA deficiency factor currently occupies a leading position in terms of the degree of negative impact on human health [117-119]. A pronounced inverse correlation between the volume of per capita consumption of seafood (the main source of omega-3 PUFAs), the content of omega-3 polyunsaturated fatty acids in biological tissues and the prevalence of a number of chronic diseases characterized by metabolic and neurotransmitter processes, immune dysfunction and pro-inflammatory mood of the body has been established [ 119-122]. In addition, a diet rich in omega-6 PUFA and deficient in omega-3 PUFA, reduces the body's stress resistance due to stimulation of the activity of the hypothalamic-pituitary-adrenal system (stress-implementing system) [123, 124] and, therefore, contributes to the occurrence of microecological disturbances [125, 126].

Omega-3 PUFAs - eicosapentaenoic (Eicosapentaenoic acid - EPA) and docosahexaenoic (Docosahexaenoic acid - DHA) - are distinguished by a wide range of physiological effects:

- interacting with a specific sensor omega-3 PUFA GPR120 (G Protein-coupled Receptor 120 - GPR120), abundantly expressed in tissues of the colon, lungs, and on the cytoplasmic membrane of adipocytes and active macrophages [127], initiate its conjugation with β-arrestin-1 , which is accompanied by inhibition of TAK-1 kinase activity (Transforming growth factor-β-Activated Kinase-1 - TAK-1) and subsequent blocking of the pro-inflammatory signaling cascades associated with TLR and TNFα receptors, while stimulating anti-inflammatory effects dependent on Nrf12 -signal systems [128, 129];

- eicosapentaenoic and docosahexaenoic acids, modulating the phospholipid composition of the cytoplasmic cell membranes, thereby changing the microdomain organization of integral plasma membrane proteins, including TLR-4 receptors, lowering the sensitivity of these sensors, and therefore block NAD (P) H-oxidase-dependent H ₂ O production and subsequent redox-mediated activation of protein kinase C, necessary for the functioning of the NF-kB-dependent pro-inflammatory signal transduction [130, 131];

- electrophilic metabolites (oxo derivatives) of omega-3 PUFAs - lipoxins (LXs - LXA4, LXB4), resolvines (Rvs - RvE1, RvE2, RvD1, RvD2, RvD3, RvD4), maresin (MaR1), protectin peptides (PD1) - capable of receptor-mediated suppression of the production of pro-inflammatory chemo- and cytokines, block the stimulation and recruitment of neutrophils, inhibit the production of prooxidants (superoxide radical anion, nitric oxide); Nrf2-dependent way to stimulate the expression of antioxidant factors and effectively contribute to the resolution of the inflammatory reaction, including inflammation of the mucous membrane of the upper respiratory tract [132-138];

- omega-3 PUFAs (DHA) inhibit the expression of proinflammatory cytokines by airway epithelial cells [139], stimulate the activity of dual oxidase DUOX2 (DUal OXidase 2 - DUOX2 - generates H ₂ O ₂ as a factor of colonization resistance [140]) and choline phosphotransferase [141]; choline phosphotransferase - a speed-limiting enzyme for the synthesis of the main component of the surfactant - phosphatidylcholine, which exhibits the properties of an anti-inflammatory immunomodulator, a mediator of remodeling of the mucous membrane of the upper respiratory tract and an antiviral, antibacterial factor [142-145], which has the ability to prevent the formation of bacterial biofilms [146];

- omega-3 PUFAs effectively inhibit macrophage apoptosis (induced by Streptococcus pneumoniae as a method of immune evasion) and increase their bactericidal activity against intracellular pathogens [147], apparently due to the stimulation of the autophagy by polyunsaturated fatty acid derivatives [148, 149];

- the omega-3 PUFA derivative - protectin D1 - has a pronounced ability to inhibit the replication of the influenza virus, blocking the export mechanism of viral RNA [150, 151], which is significant in terms of the problem under consideration, since in the vast majority of cases (90-98%) rhinosinusitis is initiated by respiratory viral infection [152, 153]; in addition, the oral administration of omega-3 PUFAs with low doses of aspirin promotes cyclooxygenase-2-dependent conversion of EPA and DHA into protectin D1 and resolvin D [154, 155];

- omega-3 PUFAs have the ability to stimulate the tone of n.vagus, which is accompanied by an increase in the level of extracellular acetylcholine, its interaction with α-7 nicotinic receptors of immunocytes, subsequent inhibition of NF-kB-dependent pro-inflammatory signal transduction and stimulation of STAT3, which is realized by increasing SOCS3 expression ( Suppressor Of Cytokine Signaling 3 - SOCS3), inhibiting the activity of proinflammatory cytokine receptors [156-158]; Incidentally, it is the stimulation of the release of acetylcholine from the terminals of parasympathetic nerve fibers that explains the anti-inflammatory effects of low-frequency ultrasound, which is widely used in inflammatory diseases of the upper respiratory tract [159-161];

- omega-3 essential fatty acids have a pronounced antibacterial activity against non-resident microflora of the upper respiratory tract (Streptococcus mutants, Candida albicans, Fusobacterium nucleatum, Porphyromonas gingivalis) [162], which protein kinase C-epsilon-dependent inhibits ciliary cell and cell ligation from the basement membrane [163], changes the quality of expressed mucin (stimulates the secretion of the gel-forming mucin Muc5n and inhibits the expression of membrane-bound mucin Muc4), which inhibits mucociliary clearance and allows bacterial cells to interact with the cytoplasmic membrane of epithelial cells, that is, in conditions of omega-3 PUFA deficiency, a predisposition to infectious inflammation of the mucous membranes of the upper respiratory tract is created and maintained [164];

- omega-3 PUFAs, altering the expression of a wide range of genes either due to modulation of the phospholipid composition of biological membranes and microdomain organization of cytoplasmic integral sensory proteins [165, 166], or by modulation of the functional state of NF-kB and Nrf2-dependent signal transduction systems [167, 168 ] or by direct interaction with nuclear receptors (transcription factors) PPARs (Peroxisome Proliferator-Activated Receptors - PPARs), LXR (Liver X Receptor-LXR), FXR (Famesoid X Receptor - FXR), RXR (Retinoid X Receptor-RXR) [ 169-176], optimize morpho-function the main state of the epithelial barriers, restore / maintain eubiosis [177, 178].

The prevalence of omega-3 PUFA-deficient conditions among the population that reduce the body's stress resistance, form microecological imbalance, immuno-hormonal dysfunctions, metabolic disorders and pro-inflammatory mood of the body, manifested by the loss of colonization resistance and increased susceptibility to viral and bacterial infections of the upper respiratory tract mucosa , allow us to consider the appointment of omega-3 PUFAs as an obligate element of the proposed profile method tics exacerbations of recurrent rhinosinusitis.

Recent studies have convincingly demonstrated that the time of persistence of probiotic strains of microorganisms in the distal gastrointestinal tract is limited to several days, associated with the expression of specific polypeptides, lectins, glycoproteins with enterocytes [179-182] and, moreover, is determined by the palette decorating the bacterial cell in as adhesion factors of polysaccharides, teichoic acids and proteins (including sortase-dependent and carbohydrate-binding) [183-186]. The variety of profiles exhibited on the cell wall of adhesion molecules even inside each type of symbiont microorganism is very large [187-189]. The presence of a stunningly wide subject-specific variety of spectra of decorating elements located on the plasma membrane of mammalian epithelial cells, and a strain-specific pattern of adhesion molecules on the bacterial cell wall determine the selectivity of their relationships. The biological expediency of such “wastefulness” is to ensure the resistance of multicellular eukaryotes to the effects of various pathogens at the species and individual levels by hindering the interaction of non-resident microorganisms with the structural elements of the plasma membrane of the integumentary tissue cells. Therefore, the goal of probiotic therapy in the prevention of exacerbations of recurrent rhinosinusitis is not to substitute non-resident microorganisms of the aberrant microbiome of the gastrointestinal tract and other microecological niches, including the mucous membrane of the upper respiratory tract, by probiotic bacteria strains, but to create the conditions for the restoration of eubiosis by colonizing various organisms partially preserved and new resident symbiont microflora. And this determines the duration of probiotic therapy, which is several weeks. The effect of probiotic bacterial strains on the human body, contributing to the restoration of eubiosis, is manifested [185, 190-195]:

- general effects (synthesis of nutrients and physiologically active substances, modulating the state of microbiomes of various biotopes, the immune system and neuro-endocrine status);

- changes of a local nature (formation / restoration of the structural and functional usefulness of epithelial barriers, stopping the pro-inflammatory phenotype of cellular elements of integumentary tissues, inducing dynamics of the physicochemical parameters of the biotope environment favorable for the biological system “host-symbiotic microbiome”);

- cellular-humoral effects (optimization of the tone of the stress-realizing and stress-limiting systems, modulation of the expression of immunoglobulins, cytokines, glycoconjugates, the functional state of epithelial cells and cells of the MALT system).

When implementing the proposed method for the prevention of exacerbations of recurrent rhinosinusitis, probiotic therapy should be carried out in a course lasting three weeks, prescribing one of the third-generation probiotic preparations, for example, Bifiform inside, one capsule three times a day.

An important aspect of the proposed method for the prevention of exacerbations of recurrent rhinosinusitis is the inclusion in the list of appointments for the correction of microecological imbalance of pharmacological agents that can stimulate the vegetation of symbiotic microflora, but do not meet the criteria for prebiotics, that is, exhibiting prebiotic-like activity (preparations with prebiotic-like activity - novocaine, emoxipin succinate, ambroxol hydrochloride) [66].

When procaine enters the body’s biological environment, it hydrolyzes relatively quickly, decomposing into para-aminobenzoic acid and diethylaminoethanol [196]. Para-aminobenzoic acid (vitamin B ₁₀ ) is a “growth factor” for representatives of symbiotic microflora [197], which helps to suppress the vegetation of non-resident microorganisms [198]. In addition, being an inducer of interferon, para-aminobenzoic acid is an effective antiviral agent [199] and a stimulator of expression of the polymeric immunoglobulin A receptor (pIgR), which provides sIgA transcytosis through epithelial cells (under conditions of sufficient vitamin A supply to the body), which contributes to an increase in sIgA (as a factor of colonization resistance) on the mucous membranes of the respiratory tract [200-201]. In terms of the problem under consideration, it is significant that in the process of transcytosis, the polymeric form of sIgA neutralizes intracellular pathogens, their toxins and prevents the formation of a bacterial biofilm [202–205], and interferon-gamma stimulates the autophagy process [206, 207], which ultimately can provide effective eradication intracellular pathogens. Novocaine, as a precursor of para-aminobenzoic acid, is also an effective inducer of interferon [208]. INF-γ, in addition to the antiviral and antibacterial (vitamin D-dependent) effects [209-212], also has the property of reducing the hyperresponsiveness of the mucous membrane of the upper respiratory tract [213, 214]. The listed biological effects of novocaine / para-aminobenzoic acid are pathogenetically significant for the prevention of exacerbations of recurrent rhinosinusitis due to the fact that, against the background of chronic inflammatory pathology of the upper respiratory tract, expression of IFN-γ is significantly blocked [215-217] (it should be noted that IFN-γ production γ also suppresses topical corticosteroids [218]) and this supports the persistence of rhinoviruses and promotes the attachment of bacterial infection [219-221].

As a growth promoter of symbiotic microflora and an interferon inducer, it is advisable both to administer a solution of novocaine in a volume of 2.0 ml of a 1% solution three times a day, and its topical use for irrigation of the nasal mucosa and nasopharynx.

Emoxipine succinate (the official drug Mexidol) has long been known and has been successfully used in the treatment of critical conditions [222]. Mexidol has a wide range of pharmacological activity: it is antihypoxic, stress-protective, nootropic, anticonvulsant and anxiolytic agent, effectively inhibiting the processes of free radical oxidation. Also, this drug has an anti-inflammatory effect, improves microcirculation and stimulates reparative and regenerative processes, exhibits a pronounced lipid-lowering effect, reduces the viscosity of the lipid bilayer and increases the fluidity of membranes, which is accompanied by optimization of the conformational state of integral proteins of the cytoplasmic cell membranes [223, 224]. In terms of the problem under consideration, it is also significant that Mexidol stimulates apoptosis of cells with viral inclusion, exhibits pronounced immunomodulating activity during herpetic infections of the oral cavity and therefore begins to enter the “gold standard” for the treatment of periodontal diseases [225, 226]. Such a bright palette of pharmacological effects of Mexidol (emoxipin succinate) is due to the drug’s ability to stimulate succinate oxidase oxidation (a compensatory pathway for ATP synthesis) [227, 228], phosphorylate in biological systems and inhibit serine, metal-dependent proteinases [229, 230], and inhibit free radical stages of prostaglandin synthesis [231, 232], as well as chelation of iron ions, thereby excluding the catalytic production of prooxidants involving cations of this metal ne Yemen valence and its accessibility to non-resident microflora. This is probably why Mexidol was more effective than protease inhibitors in the treatment of acute pancreatitis and the prevention of its complications [233]. It is important that the pharmacological activity of Mexidol is manifested, among other things, by the effects of increasing the activity of superoxide dismutase and Se-dependent glutathione peroxidase, decreasing the activity of inducible NO synthase, preventing hypoxia-mediated release of norepinephrine from synaptic terminals, prolonging the functioning of mitochondria and secretory expression during hypoxia IgA, lysozyme in the oral cavity [234-238].

In inflammatory pathology of the upper respiratory tract, exacerbation is usually associated and initiated, in most cases, by a viral infection [239]. Therefore, in the context of the problem under consideration, an important aspect of the pharmacological activity of emoxipin succinate is the ability of the biotransformation products of this substance to inhibit various proteinases. This, on the one hand, determines (in part) its anti-inflammatory effects, and on the other hand, it can also determine antiviral activity. It is known, for example, that the internalization of enveloped viruses requires preliminary processing of the glycoproteins of the viral particle membrane, which is carried out on the mucous membrane of the respiratory tract by trypsin-like secretory leukoproteinases [240-242]. Naturally, when secretory proteinases are inhibited by phosphorylated derivatives of emoxipin, virulence of enveloped viruses can be reduced, which is manifested in the experiment by suppression of their multicyclic replication [243]. In addition, it is known that the inflammatory reaction provides / supports the presence of free iron cations in the area of inflammation, stimulating the processes of peroxidation and vegetation of pathogenic microflora [244]. Probably, precisely the ability of Mexidol to optimize the vegetative status of the organism [245], antiallergic [246], antiviral and antibacterial manifestations of the pharmacological activity of emoxipin metabolites can be taken as an explanation of its effectiveness as a treatment for chronic pharyngitis [247], repeated tonsillitis [248] ], chronic catarrhal gingivitis [235], acute radiation sickness [249] and pneumonia in acute exogenous poisoning [250].

Based on the notion of the pathogenetic significance of the biological effects induced by Mexidol and phosphorylated derivatives of emoxipin, in blocking the mechanisms of formation / maintenance of inflammation of the mucous membrane of the upper respiratory tract it seems that the use of emoxipin succinate in the prevention of exacerbations of recurrent rhinosinusitis is quite justified.

Of particular importance is the ability of phosphorylated derivatives of 3-hydroxypyridine (emoxipin) to chelate iron ions and inhibit the activity of proteinases due to the fact that, against the background of inflammation of the mucous membrane of the upper respiratory tract, lactoferrin activity is locally suppressed [251, 252] due to its proteolytic degradation under the influence of elastases and cathepsins neutrophils and non-resident microorganisms [253-255].

Lactoferrin is a glycoprotein abundantly expressed by the cellular elements of the mucous membranes, has a pronounced anti-inflammatory, bacteriological / virucidal activity and is able to block the formation of bacterial biofilms [256-259] due to:

- an effective iron-chelating action that maintains the bacteriostatic status of the biological environment of an organism [260, 261];

- the ability to directly bind the lipopolysaccharide and its receptor CD14 [257, 262], block TLR-dependent signal transduction [263, 164];

- inhibition of the formation and lysis of existing bacterial biofilms, direct iron-independent destruction of structural elements of the cell wall of microorganisms and the shell of viral particles [259, 265-267].

In connection with the foregoing, it should be noted that lactoferrin gene expression is regulated by both external and endogenous factors [268]. In particular, bacterial antigens [269] and ligands of the nuclear receptor RAR (Retinoic Acid Receptor - RAR) stimulate the expression of lactoferrin [270]. Long-term administration of retinoic acid has been shown to be very clinically effective in chronic rhinosinusitis [271]. Therefore, the inclusion of vitamin A (retinoic acid - a hydroxylated derivative of retinol) and the topical immunocorrecting agent Imudon, a multivalent antigenic complex in the form of resorption tablets, is quite justified in the list of measures to prevent exacerbations of recurrent rhinosinusitis of vitamin A.

The antiviral effect of novocaine (as an interferon inducer), emoxipin succinate (as a protease inhibitor) in the prevention of exacerbations of recurrent rhinosinusitis is advisable to enhance due to the effects of the mucolytic ambroxol hydrochloride (the official drug "Lazolvan"). Ambroxol - a physiologically active metabolite of bromhexine (the latter, in turn, is a derivative of the natural alkaloid vasicin) - is able to effectively:

- stimulate the synthesis and inhibit the degradation of surfactant [272, 273];

- inhibit secretory leukoproteases and induce the expression of immunoglobulin A [274];

- stimulate mucociliary transport and inhibit the secretion of MUC5AC [275];

- block the adhesion of non-resident microorganisms to the cytoplasmic membrane of cells in the low micromolar concentration range [276];

- increase the sensitivity of the vascular wall to adrenergic (vasoconstrictor) stimulation [277];

- provide a local anesthetic effect due to local blocking of Na ⁺ channels [278, 279];

- inhibit non-enzymatic oxidation [280], induce the activity of alkaline phosphatase, an enzyme of detoxification of the lipopolysaccharide of gram-negative bacteria [272, 281].

The adhesive properties of bacteria are determined by the palette of carbohydrate-binding proteins of the cell wall of microorganisms (including the activity of sortases that catalyze the formation of covalent bonds with peptidoglycans [282, 283]) and depend on the spectrum of glycan decoration of mucin polypeptide chains and protein molecules of the cytoplasmic membrane of epithelial cells [284 -286]. To ensure colonization resistance, indigenous microorganisms affect the spectrum profile of pectins and glycans expressed by epithelial cells [287-290]. At the same time, it is well known that the structure of glycopolymer chains (unlike polypeptides) is not encoded in the eukaryotic genome, but is determined by the pattern of expression and activity of glycosyltransferases involved in the synthesis of polysaccharides. Nevertheless, the qualitative and quantitative characteristics of glycans synthesized in the mammalian organism are species-specific and individual for each organism. That is, the spectrum of expressed glycans is still under tight control. In this regard, one should pay attention to the fact that the phenotype of an individual cell and a multicellular organism as a whole is determined mainly by the extragenomic part of DNA (which does not contain information about the amino acid sequences of polypeptide chains) that controls gene expression [291, 292]. Epigenetic control of gene transcriptional activity, according to modern concepts, includes DNA methylation mechanisms [293-295], various reversible covalent modifications of the chromatin histone structure: phosphorylation, ubiquitination, acetylation, methylation, sumoylation, ADP-ribosylation, glycosylation [296-298] and regulatory effects of non-coding RNAs (miRNAs, piRNAs, esiRNAs, RNA splicing factor, siRNAs, ncRNAs) that block gene expression [299-301]. It is believed that the epigenetic hereditary system is less stable than the genome and more sensitive to various disturbing influences [302-304]. Gradually, an understanding comes that epigenetic reprogramming is a key pathogenetic mechanism of many diseases [305, 306]. And even the biological clock that defines the “biological time”, that is, the age of eukaryotes, is apparently hidden in the epigenome [307].

The formation of ideas about the epigenetic regulation of gene expression, the role of this system in the formation of phenotypic features of the biological system at different stages of its development and organization levels, about the mechanisms that control its functioning, is in its infancy, and therefore no specific means for its correction have been created, but already installed:

- epigenetic changes are recorded and measurable;

- epigenetic lesions are reversible and this potentially provides certain therapeutic possibilities;

- micronutrients capable of exerting synergism and additivity in physiological doses in terms of optimizing the functioning of the epigenome, which suggests their complex use, can significantly affect the body's epigenetic status.

Methionine can become a limiting link in the processes of DNA and histone methylation under conditions of vitamin B ₁₂ deficiency states. Methionine, the main donor of methyl groups in the body, is an essential amino acid synthesized from its demethylated form (homocysteine) with the participation of vitamin B ₁₂ -dependent methionine synthase [308-310]. Vitamin B ₁₂ -dependent epigenetic effects are supplemented and optimized by carotenoids (vitamin A) [311, 312], folates (vitamin B ₉ ), biotin (vitamin B ₇ ) [313-315], and physiological microdoses of selenium [316-319]. The state of the mechanisms of epigenetic control of gene expression is also modulated by micronutrients such as vitamin C (ascorbate) [320, 321], vitamin E (tocopherols) [322], zinc [323, 324], omega-3 polyunsaturated fatty acids [325] and quercetin [ 326].

In terms of the proposed method for the prevention of exacerbations of recurrent rhinosinusitis, it is important to note that the modulating effect of the listed micronutrients on the epigenic is accompanied by optimization of the functioning of the immune system, anti-inflammatory effect, and quercetin has a pronounced antibacterial activity against virtually any non-resident bacteria that cause inflammation of the mucous membrane of the upper respiratory tract [327, 328 ]. It is likely that the antibacterial effects of this flavonoid are associated with a modification of the prokaryotic DNA structure by the genotoxic products of the bacterial metabolism of quercetin, which activate the reparative SOS regulon [329–331], which is inevitably accompanied by the induction of latent phages (prophages) and subsequent lysis of microorganisms [332]. It should be emphasized separately that the antibacterial effects of quercetin can hardly be extended to representatives of the mutualistic symbiont microflora carrying defective prophages that are not able to convert to lytic form [333].

Given the prevalence of selenium deficiency states (up to 80-90% of the population of Russia, which is due to the low content of selenium in soils and agricultural products; Northwest region of Russia, Upper Volga region, Western Siberia, Transbaikalia are especially unfavorable) [334-337] and vitamin B ₁₂ -hypovitaminosis [338, 339], when implementing the proposed method for the prevention of exacerbations of recurrent rhinosinusitis, these factors should be borne in mind. Based on the fact that even without the participation of the specific mechanism of transfer (Castle factor) in the absorption of vitamin B _12, about 1% of the total amount of cyanocobalamin entering the intestine is successfully resorbed, for the prevention of exacerbations of recurrent rhinosinusitis, this vitamin should be prescribed daily at a dose of 100 -200 mcg. The physiological daily requirement of an adult in vitamin B ₁₂ is only 1.0-1.25 μg, therefore, the oral intake of cyanocobalamin in the specified dose can adequately fill the body's request [340]. Other B vitamins, vitamin A and selenium should also be administered orally daily in doses that cover daily requirements.

Recently, it has been established that under physiological conditions in mucin mucus, the ratio of phage particles and non-resident bacteria is extremely large in comparison with the environment. In fact, we are talking about the selective accumulation of bacteriophages of non-resident bacteria due to the specific interaction of Ig-like domains of the capsid protein of phage particles with mucin glycoprotein. Such local (on the surface of the mucous membranes), which plays a protective role, accumulation of bacteriophages is the result of evolutionarily established mutualistic relationships between viruses and multicellular eukaryotes [341, 342]. However, under conditions of microecological imbalance, the pattern of expression of mucin genes under the influence of non-resident microflora, hormonal and immune factors can undergo significant dynamics [343], which will certainly affect both the ability of mucin to accumulate bacteriophages of non-resident bacteria and its ability to inhibit the fixation of pathogens on cytoplasmic membrane of epithelial cells. Therefore, the optimization of the functioning of the epigenome and the epigenetic regulation of the expression of mucin genes by the cellular elements of the mucous membrane of the upper respiratory tract, in particular, is a prerequisite for the restoration of eubiosis of the respiratory tract and, therefore, the success of the prevention of exacerbations of recurrent rhinosinusitis.

For inflammatory diseases of the upper respiratory tract, including rhinosinusitis, intensification of peroxidation processes and a decrease in the effectiveness of antioxidant protection are characteristic, which requires the appointment of an adequate antioxidant correction [344–347]. It is also known that pharmacological correction of the manifestations of oxidative stress is effective only with the combined use of water-, fat-soluble antioxidant vitamins and thiols that restore them [348]. Adhering to this concept, in the prevention of exacerbations of recurrent rhinosinusitis, it is advisable to use: water-soluble ascorbic acid, fat-soluble α-tocopherol, lipoic (thioctic) acid as the thiol that restores them, and amino acid precursor N to replace the pool of endogenous glutathione. Retinol (vitamin A), which potentiates the biological membranes from the damaging effects of prooxidants, in cooperation with α-tocopherol (forming dynamic sensory-conducting complexes in the lipid bilayer of membranes, each of which protects 300-500 molecules of phospholipids [349]) effects of vitamin E [350]. In addition, vitamin A maintains the integrity of the epithelial barriers and optimizes immunoreactivity [351-353], inhibiting lipopolysaccharide-induced bioconversion of arachidonic acid into pro-inflammatory mediators and IL-17 expression, and exhibits anti-inflammatory activity [354-356]. And the spectrum of physiological activity of vitamin E, in addition to canonical antioxidant effects, also includes its ability to regulate (optimize) gene expression both at the transcription level and at the translation stage [357-360]. The antioxidant effects of vitamin E and retinol are enhanced in the presence of selenium. Selenium has a pronounced chelating activity with respect to metal ions of variable valency (1: 1 binding stoichiometry) [361] and contributes to a rapid increase in the activity of superoxide dismutase, glutathione reductase, glutathione peroxidase [362-365].

Lipoic (thioctic) acid is synthesized in the human body in the minimum amount necessary to cover metabolic needs. With age and against the background of pathological conditions (inflammation), the production of lipoic acid decreases [366-367]. Therefore, under conditions of oxidative stress, a deficiency of thioctic acid is formed, which can / must be stopped by the intake of dithiol from external sources [368, 369]. As a reducing dithiol, lipoic acid has a unique complex of antioxidant properties:

- thioctic acid, being tropic to both polar and nonpolar media, easily overcomes biological barriers [370] and effectively inhibits free radical reactions both in the lipid bilayer of biological membranes and in the cytosol of cells [371], inhibits the production of prooxidants in mitochondria, contributing to conservation structural and functional usefulness of these organelles [372];

- antioxidant effects are inherent in both reduced and oxidized forms of lipoic acid (unlike most other antioxidants) [373, 374];

- dihydrolipoic acid, as a reducing agent (ORP - 320 mV [375]), is capable of reducing oxidized glutathione (ORP - 250 mV [375]) and antioxidant vitamins (ORP ascorbate - 282 mV [375]), acting as their synergist [ 376], recycles ascorbic acid more efficiently than reduced glutathione [377];

- under the influence of lipoic acid, as a result of increased imports of cysteine by the cells and stimulation of the expression of γ-glutamylcysteine ligase, the synthesis of glutathione is accelerated [370];

- lipoic acid not only effectively restores various prooxidants, but also inhibits the expression of pro-inflammatory cytokines [378];

- oxidized and reduced forms of lipoic acid effectively chelate metal cations of variable valency, depriving them of their catalytic activity [379];

- alpha lipoic acid is effective and safe as a therapeutic agent in the pharmacological correction of pathological conditions accompanied by intensification of peroxidation processes [380, 381].

Oxidative stress associated with recurrent rhinosinusitis, with each exacerbation, is able to induce mitochondrial dysfunction in epithelial cells in the inflammation zone, which can persist outside of periods of exacerbation [382–384]. Recently, the role of mitochondrial dysfunction in the pathogenesis of inflammatory pathology has become increasingly obvious and significant [385]. Therefore, due to the inaccessibility of the intramitochondrial compartment for canonical antioxidants, when implementing the proposed method for the prevention of exacerbations of recurrent rhinosinusitis, among other antioxidants, it is advisable to use melatonin as a mitochondrial antioxidant. Melatonin is a unique stoichiometric free radical quencher:

- melatonin is synthesized in various organs and tissues of the human body, its level significantly exceeds the concentration of glutathione in epithelial cells [386], the melatonin content in the tissue significantly decreases against the background of inflammation [387];

- unlike antioxidant vitamins, being an amphiphilic compound, melatonin is able to restore free radicals in both polar (cytosol) and nonpolar (lipid bilayer membranes) media and can easily overcome various biological barriers [388, 389];

- melatonin is capable of selectively accumulating in mitochondrial membranes [390, 391], interacting with complexes I, II, III, and IV of the electron transport chain, supporting / restoring the movement of electrons and, therefore, blocking electron leakage (formation of prooxidants) [389, 392, 393], thereby preventing the peroxidation of cardiolipin, a critical phospholipid, which ensures the optimal functioning of complexes of the III and IV electron transfer chains [394, 395]. Under conditions of oxidative stress, melatonin protects mitochondria more effectively than the specially created mitochondrial antioxidants MitoQ and MitoE [396];

- melatonin is twice as effective as α-tocopherol and inhibits lipid peroxidation of biomembranes [397], five times more active than glutathione it neutralizes the hydroxyl radical [398] and protects against free radical damage to DNA especially reliably (by binding, shielding) [399];

- in addition to hydroxyl and peroxyl radicals, melatonin effectively restores the superoxide radical anion, singlet oxygen, hydrogen peroxide and hypochlorite anion [400, 401];

- melatonin and some of its metabolites block excess production of nitric oxide in pathophysiological conditions and, therefore, inhibit the generation of peroxynitrite, having an inhibitory effect on the activity of the mitochondrial isoform of NO synthase, thus preserving the morphological and functional authenticity of mitochondria [402, 403];

- melatonin, when reducing (extinguishing) prooxidants, transmits two electrons at once and subsequently, unlike antioxidant vitamins, it does not transform into free radical derivatives; primary and secondary hydroxy derivatives of melatonin also have pronounced antioxidant properties - up to ten prooxidant molecules can be reduced as a result of oxidative transformations of one melatonin molecule [393, 404];

- receptor-mediated way (via plasma membrane and nuclear receptors of the neurohormone) melatonin (in the pharmacological range of doses) induces the expression of antioxidant enzymes, while the activity of mitochondrial glutathione peroxidase increases most significantly (4-8 times) [405, 406];

- by stimulating the expression of γ-glutamylcysteine synthetase (an enzyme that limits the rate of glutathione synthesis), melatonin increases the volume of glutathione production, ensuring that its concentration in cells is maintained at an optimal level [407, 408];

- inhibiting the expression of inducible cyclooxygenase-2 and iNOS, controlling (reciprocally) the activation and binding of the nuclear transcription factors NF-kB, AP-1 (pro-inflammatory signaling cascades) and Nrf2 (anti-inflammatory transcription factor) to the promoter DNA portions, exhibiting anti-apoptotic effects, has a cytoprotective effect [409-414];

- by controlling / optimizing the tone of the hypothalamic-pituitary-adrenal system, melatonin helps to minimize the adverse effects of stress-inducing factors [415, 416] and to stop the stress-induced dysfunction of the immune system [417];

- optimizingly affecting the functional state of the immune system, melatonin increases the expression of secretory immunoglobulin A [418], supports the barrier function of the mucous membranes, prevents bacterial translocation [419, 420] and has a beneficial effect on inflammatory pathology of the respiratory tract [421].

Given the prevalence of falling asleep and sleeping disorders among patients with inflammatory pathology of the upper respiratory tract [422-424] (which are apparently associated with changes in neuro-mediator processes, neuro-endocrine regulation, cytokine background) and the physiological nature of hypnotic action of melatonin, when implemented of the proposed method for the prevention of exacerbations of recurrent rhinosinusitis, this substance should be prescribed in the form of the drug "Melaxen" daily immediately before going to bed inward at a dose of 3 mg.

In recent years, pleiotropy (the ability of a biologically active compound to realize more than one mechanism of action during the induction of a biological response [425]) of the pharmacological effects of vitamin D ₃ (calcitriol) and, in particular, its receptor-dependent nonclassical role (more and more clearly) has become increasingly apparent ( not related to calcium homeostatization) in the implementation of the protective functions of epithelial barriers [426-431]. Vitamin D ₃ deficiency is associated with a high risk of autoimmune and infectious diseases, including infectious and inflammatory diseases of the upper respiratory tract [427, 431, 432]. Under the direct or receptor-mediated controlling effect of calcitriol, several hundred genes are expressed (about 3% of the genome) [433-435].

New aspects (associated with calcitriol) of the participation of symbiont microorganisms in the implementation of the protective functions of the mucous membranes have been identified [436]. In particular, it was found that epithelial cells in contact with non-resident microorganisms have the potential to dramatically increase the expression of polypeptide defense factors such as cathelicidins and defensin-β-2, which have a broad spectrum of antimicrobial activity, are active against many viruses, fungi, and differ in their ability to neutralize gram lipopolysaccharide negative bacteria [437-439]. Catelicidins, in addition, by stimulating angiogenesis and mitotic activity of cells, contribute to maintaining the structural and functional usefulness of epithelial barriers [440–442]. It should be noted that the cathelicidin LL-37, stimulating the expression of Beclin-1 Atg5 genes, thereby induces the fusion of bacterial phagosomes with lysosomes. Thus, in conditions of sufficient supply of the organism with vitamin D _{3, the} process of microautophagy is stimulated, leading to the elimination of intracellular persistent pathogens [443, 444]. But these protective reactions of epithelial cells are effectively realized only in the presence of an active form of vitamin D ₃ [445, 446]. The conversion of 25-hydroxyvitamin D ₃ to its active form (1α, 25 (OH) ₂ D ₃ ) is catalyzed by 1α-hydroxylase CYP27B1, and the catabolic transformation of 1α, 25 (OH) ₂ D _{3 is} carried out with the participation of monooxygenase CYP24A1 [447]. Expression of these isoforms of cytochrome P-450 (CYP27B1, CYP24A1), a vitamin D ₃ receptor, is controlled by epigenetic regulatory mechanisms [448, 449]. Under physiological conditions, the active form of vitamin D ₃ (1α, 25 (OH) ₂ D ₃ ) autocrine / paracrine is involved in the regulation of proliferation, differentiation, and apoptosis of epithelial cells [447]. The effects of vitamin D _{3 are} synergistically enhanced by vitamins A and B ₉ [446, 450, 451], including in terms of anti-infection resistance of the body [452, 453].

In vivo, the optimal level of enzymes (synthesis and catabolism) of the vitamin D ₃ -dependent regulatory system in epithelial cells is induced only by contact of the resident (symbiont) microorganisms with the corresponding receptors for the recognition of epithelial cells (mutual microflora stimulates the maintenance of the background 1α-hydroxylase activity of cellular elements [epithelial barriers) 438, 454-456]. The immunomodulatory effect of 1,25-dihydroxyvitamin D _{3 is} mediated by its receptor, the interaction of the ligand-receptor complex (in the form of a homodimer or heterodimer) with the retinoid X receptor as a transcription factor for genes with a vitamin D-responsive element, and, in addition, can be carried out by modulating the functional state of signal transduction systems NFAT and NF-kB [457-460]. Under conditions of vitamin D ₃ deficiency, the production of antibacterial peptides by the cellular elements of mucous barriers is suppressed, which, for example, is manifested by a 50-fold increase in the bacterial contamination rate of intestinal wall tissue [461] and the formation of aberrant microbiomes in microecological niches [456, 462].

When using vitamin D ₃ in the prevention of exacerbations of recurrent rhinosinusitis, the weight and antioxidant effects of calcitriol are significant. Vitamin D ₃ , stimulating the gene expression of glucose-6-phosphate dehydrogenase (a key enzyme of the pentose phosphate pathway for glucose oxidation), which ensures the reduction of the pyridine nucleotides [NAD (P) +] in the cytosol of cells, promotes faster reduction of the oxidized forms of water and fat-soluble antioxidants. That is, vitamin D ₃ , by intensifying the process of recycling of antioxidants, increases their relative antiradical capacity, thereby supporting the activity of the system of non-enzymatic quenching of free radical reactions. In addition, 1,25-dihydroxyvitamin D ₃ significantly increases the level of glutathione, the activity of superoxide dismutase and glutathione peroxidases in the cell cytosol [463-465].

Therefore, taking into account the prevalence of D ₃ -hypovitaminosis in the autumn-winter-spring period among the population of temperate latitudes [466-468] and the association of the functional state of epithelial barriers with the availability of calcitriol in the body, oral administration of vitamin D ₃ once daily at a dose of 2000 ME (50 μg) that provides the daily physiological need of the human body [469, 470], it seems quite appropriate and necessary in the prevention of exacerbations of recurrent rhinosinusitis.

Paraoxonases (Paraoxonases: PON1, PON2, PON3) are an evolutionarily ancient family of enzymes [471], characterized by a wide spectrum of substrate specificity [472], which have lactonase activity and are especially effective in hydrolyzing N-acyl homoserin lactones [473-475]. N-acyl homoserinlactones are signal molecules of the “quorum feeling” of intraspecific and interspecific communication of gram-negative bacteria, providing coordination of phenotypic changes in microorganisms, including the expression of virulence factors and the formation of bacterial biofilms [476, 477]. Paraoxonases are synthesized in various mammalian tissues, are secreted abundantly by the salivary glands, are expressed by epithelial cells and are able to induce the destruction of bacterial biofilms [478, 479]. The level of PON1 in the blood decreases under the influence of prooxidants [480, 481], pro-inflammatory cytokines [482], with dysfunction of the thyroid gland [483] and endotoxin of gram-negative microorganisms [484].

Monooxygenases and glucuronyl transferases are involved in the metabolic transformation of N-acyl homoseryl lactones [485], but paraoxonases are the dominant factor in the catabolism of these signaling substances [486]. Therefore, against the background of a decrease in the expression level of paraoxonases, the susceptibility of the organism to the effects of gram-negative bacteria increases [479, 487-489].

In connection with the foregoing, the ability of certain pharmacological agents and food products to stimulate the expression of paraoxonases [490] attracts attention, and quercetin turned out to be the most active inducer of PON1.

Quercetin, a representative of the group of flavonoids, previously designated as vitamin P, has, among other things, pronounced anti-inflammatory, antioxidant and antibacterial effects, the ability to inhibit the activity of aldose reductases (an active participant in the formation / maintenance of the inflammatory reaction [491, 492]), protein kinases, DNA topoisomerases ( inhibition of DNA topoisomerases is manifested by anti-inflammatory phenomena and the effect of DNA protection [493, 494]), block the formation of mitochondrial dysfunction and exert influence of the epigenetic regulation of the expression of several genes (including paraoxonase, cyclooxygenase-2, anti / pro-apoptotic factor) [495-501].

Querecetin’s physiological activity is characterized by its ability to inhibit xanthine oxidoreductase activity (a source of superoxide anion radical) [502, 503], block protein nitration by binding nitrogen dioxide [504], and to chelate copper and iron ions in extracellular fluids and cytosol (excluding the participation of transition metal ions in the catalytic production of prooxidants and their availability for pathogenic microorganisms) [505-507]. In terms of prevention of exacerbations of recurrent rhinosinusitis, the effects of quercetin are especially significant:

- blocking lipopolysaccharide-induced expression of pro-inflammatory cytokines and metalloproteinases MMP9, MMP12 by epithelial cells by stimulating the activity of histone deacetylase Sirt-1, which ensures deacetylation of the H4 gene promoter [508, 509];

- suppression of the expression of corticotropin-releasing factor, manifested by stress-protective phenomena [510, 511];

- inhibition of virus replication (including those causing acute respiratory infections) [512-516].

It is not surprising that with this list of physiological effects, quercetin proved to be an effective means of relieving metabolic syndrome [517, 518], treating periodontal diseases [519, 520], and treating cardiovascular and inflammatory diseases of an infectious nature [521], including chronic non-specific tonsillitis [ 522], chronic rhinosinusitis [523]. Based on the foregoing, it should be assumed that the inclusion in the list of appointments for the prevention of exacerbations of recurrent rhinosinusitis hydrogenated quercetin analog - dihydroquercitin - (inside 25 mg in the form of a tablet two to three times a day with meals) is pathogenetically justified and appropriate.

An important component of the prevention of exacerbations of recurrent rhinosinusitis is antiendotoxin therapy [524-526]. It is endotoxinemia with microecological imbalance that forms a pro-inflammatory (stress-inducing) background, metabolic syndrome, endocrine system dysfunction and impaired barrier functions of the epithelial barriers. Detection of functionally active Toll-like receptor 3 (TLR-3 - a sensor of double-stranded RNA viruses) and Toll-like receptor 4 (TLR-4 - a sensor of lipopolysaccharide) on the cytoplasmic membrane of thyrocytes (thyroid gland epithelial cells) indicates the possible involvement of the thyroid gland in pathogenetic mechanisms of the formation of chronic inflammatory pathology of viral and bacterial etiology [527, 528]. Indeed, the lipopolysaccharide is capable of dramatically changing the functional state of the thyroid gland, lowering the level of thyroid hormones in the tissues. In addition, endotoxin of gram-negative bacteria is a pathogenetically significant factor in the occurrence of autoimmune thyroiditis [529-531]. A similar direction of action, realized through the central part of the hypothalamic-pituitary-thyroid system, is also distinguished by IL-18 induced by lipopolysaccharide [532, 533]. The expression of thyroid hormones and thyroid receptors, the local activity of deiodinases DIO1, DIO2 and DIO3 (lodothyronine Deiodinase types I, II and III - DIO1, DIO2 and DIO3) decreases / modulates in bacterial infections [534, 535]. In turn, the subclinical form of hypothyroidism is manifested by an increased tendency to infection of the upper respiratory tract [536] and may be associated with an infectious and inflammatory pathology of the upper respiratory tract [537, 538].

Thyroid hormones have a significant effect on the functional state of epithelial barriers [539-543]. In particular, the thyroid hormone triiodothyronine (TK) is the main regulatory factor for alkaline phosphatase expression by enterocytes [539, 544]. For a long time, it was difficult to say anything definite regarding the physiological functions of abundantly expressed intestinal alkaline phosphatases (ALPs). And only in recent years it has been established that the superfamily of metal-dependent alkaline phosphatase effectively hydrolyzes phospho-, sulfo- and phosphono-carbohydrate substrates [545, 546]. In particular, it turned out that alkaline phosphatases are enzymes for the detoxification of endotoxin of gram-negative bacteria by dephosphorylation of lipopolysaccharide and, thus, participating in maintaining the tolerance of the macroorganism to the presence of gram-negative commensals [547, 548]. In the case of a decrease in alkaline phosphatase activity, an increase in the concentration of endotoxin and a decrease in the level of phosphate anion [Pi] in the intestinal medium are observed. The latter circumstance of the conditionally pathogenic microflora of the gastrointestinal tract is perceived as a sign of physiological distress of the macroorganism and serves as an inducing signal for the expression of the virulent phenotype (production of toxins, factors that increase the permeability of epithelial barriers, disorganizing immunoreactivity, etc.). Such a transformation of the commensal phenotype is completely prevented or reversed with oral (but not parenteral) administration of phosphates [549–551]. As a means of increasing [Pi] in the intestine, when implementing the proposed method for the prevention of exacerbations of recurrent rhinosinusitis, calcium glycerophosphate should be used (inside, 1 tablet containing 200 mg of the substance, three times a day). Under conditions of sufficient supply of phosphate anion, the commensals of the gastrointestinal tract become relatively less sensitive to the effects of other factors inducing a virulent phenotype [552, 553].

In addition, thyroid hormones regulate the expression of Se-dependent peroxidases (including thyroperoxidases, providing the synthesis of thyroid hormones) and Se-dependent monodeiodinase (deiodinase-1, DIO1), which converts thyroxin (T4) into its active form, triiodothyronine (T3) [554]. In turn, the availability of selenium determines the functional state of the thyroid gland. With selenium deficiency - hyposelenosis - a state of thyroid hormone deficiency (subclinical hypothyroidism syndrome) may develop [555, 556]. Therefore, given the fact that up to 80% of the population of the Russian Federation has selenium deficiency status [336], it is advisable to use physiological daily doses of the trace element selenium in the prevention of exacerbations of recurrent rhinosinusitis (1 tablet of the Selen-Active drug containing 50 μg of selenium once inside in a day).

It is known that chronic stress contributes to the formation of microecological imbalance, and microecological disturbances are characterized by stress-inducing activity [66]. It is also known that chronic stress (regardless of the nature of the stress-inducing factor) is manifested, inter alia, by the suppression of the activity of deiodinase-1 (DIO1) [557-559] and the stimulation of the activity of deiodinase-3 (DIO3), which converts T4 into its reversible form - rT3 [560-562]. Reverse T3 (rT3) is a competitive inhibitor of the receptor-dependent physiological effects of T3 [563-566], which blocks the import of T4 and T3 into cells [567, 568]. The stress-associated increase in the level of cortisol in the blood is accompanied by a reciprocal decrease in the concentration of T3 and an increase in the content of reverse T3 [569-574]. Like cortisol, synthetic glucocorticoids also inhibit the activity of deiodinase-1 and stimulate the activity of deiodinase-3 [575], that is, they induce manifestations of hypothyroidism with all the ensuing consequences regarding anti-infection resistance. Since topical corticosteroids suppress the production of IFN-γ [218] (accompanied by the persistence of rhinoviruses, provokes the attachment of a bacterial infection [219-221]) and, apparently, can contribute to the formation of a local hypothyroid status of tissues, glucocorticoids are not used to prevent exacerbations of recurrent rhinosinusitis reasonable.

An effective way to reduce the endotoxin level of gram-negative bacteria in the intestinal contents, and, therefore, in the blood, is the oral administration of enterosorbents. Among the many enterosorbents, Enterosgel, an organosilicon sorbent used in the form of a hydrogel, attracts attention. In addition to sorption of bacterial toxins, enterosgel selectively stimulates the growth of symbiont microorganisms, inhibits the vegetation of non-resident microflora and promotes the repair of intestinal mucosa [576, 577]. When implementing the proposed method for the prevention of exacerbations of recurrent rhinosinusitis "Enterosgel" should be administered orally three times a day, two hours after eating and medicines, one tablespoon of a course of two to three weeks.

For a comparative assessment of the effectiveness of the prevention of exacerbations of recurrent rhinosinusitis by the claimed method and the prototype method, two groups of patients were formed: the main and control. Criteria for selecting patients in the main and control groups:

- age from 18 to 65 years;

- the duration of the disease from two years;

- lack of polyps in the sino-nasal region;

- lack of congenital and acquired predispositions;

- inter-relapse period, that is, the absence of symptoms of inflammation in the last two to three weeks.

To assess the effect of prevention of exacerbations of recurrent rhinosinusitis by the claimed method and the prototype method on the carriage of pathogens of viral nature, the microbial landscape of the nasopharyngeal mucosa and the microecological status of the intestine, virological and microbiological studies were performed [578-580]. Material was taken for examination from the surface of the nasopharyngeal mucosa before and after the prevention of exacerbations of recurrent rhinosinusitis with a sterile cotton swab, which was then placed in an Amies transport medium for delivery to the laboratory. To carry out bacteriological research of feces at the same time, a material weighing 2-3 grams was taken in a sterile container and delivered to the laboratory. The severity of microbiological disturbances in intestinal dysbiosis was assessed in accordance with the requirements of OST 91500.11.0004-2003 [581].

The inventive method for the prevention of exacerbations of recurrent rhinosinusitis provided a pronounced (complete) reduction in the prevalence of carriage of pathogens of a bacterial nature on the mucous membrane of the nasopharynx (table 1). So, if before the start of prophylaxis, all types of bacterial pathogens were sown in all patients of the main group (in every third person examined as part of the microbial association), then at the end of the prevention of exacerbations of recurrent rhinosinusitis, pathogenic microflora from the nasopharyngeal mucosa was not sown in any case. In contrast to this, as can be seen from table 1, the prevention of exacerbations of recurrent rhinosinusitis by the prototype method had little effect on the carriage of pathogens of a bacterial nature on the mucous membrane of the nasopharynx.

The inventive method for the prevention of exacerbations of recurrent rhinosinusitis is characterized by a pronounced reduction in the carriage of viral pathogens on the mucous membrane of the nasopharynx. As can be seen from table 2, the inventive method provided complete sanitation of the mucous membrane of the nasopharynx from the carrier of acute respiratory viral infections. In contrast, the prevention of exacerbations of recurrent rhinosinusitis by the prototype method did not provide sanitation of the surface of the mucous membrane of the nasopharynx from ARVI carriage.

An important consequence of the prevention of exacerbations of recurrent rhinosinusitis of the claimed method (table 3) should be recognized as the normalization of the colonization of the surface of the nasopharyngeal mucosa by symbiotic microorganisms, that is, the restoration of eubiosis. Prevention of exacerbations of recurrent rhinosinusitis by the prototype method did not lead to the relief of microecological imbalance in this microecological niche (table 3).

As can be seen from table 4, in all patients of the main and control groups, before the onset of prophylaxis of exacerbations of recurrent rhinosinusitis, intestinal dysbiosis of 1 or 2 degrees (mostly 2 degrees) of microbiological disorders was diagnosed. And if under the influence of prevention of exacerbations of recurrent rhinosinusitis by the claimed method, the condition of intestinal eubiosis was restored in almost all patients of the main group (in 95.5%), then the prototype method did not stop the microecological imbalance in the intestine.

For a comparative assessment of the effect on the local immunoreactivity of the prevention of exacerbations of recurrent rhinosinusitis by the claimed method and the prototype method, the immunoglobulins in the oral fluid were quantified by radial diffusion in gel [582], as well as the content of lysozyme according to Bukharin, O.B. and Vasiliev N.V. [583].

As can be seen from tables 5 and 6, under the influence of prevention of exacerbations of recurrent rhinosinusitis by the claimed method, there was a statistically significant increase in the levels of secretory immunoglobulin A (sIgA) and lysozyme in the oral fluid. In contrast, the prevention of exacerbations of recurrent rhinosinusitis by the prototype method did not significantly affect the levels of IgA, sIgA and lysozyme in the oral fluid.

An integral indicator of the severity of microecological imbalance (the degree of microbiological disturbances), dysfunction of the epithelial barriers and the pro-inflammatory background in the body is the level of lipopolysaccharide (endotoxin) of gram-negative microorganisms in the systemic circulation [584-587]. The level of lipopolysaccharide in the blood was determined using the Micro-LAL-test kit [588].

As can be seen from table 7, the level of endotoxin of gram-negative microorganisms in the systemic circulation in all patients with recurrent rhinosinusitis in the inter-relapse period was significantly (p <0.002) higher than the reference norm. Moreover, the prevention of exacerbations of recurrent rhinosinusitis by the claimed method provided a highly reliable (p <0.001) decrease in the concentration of lipopolysaccharide in the blood in all patients of the main group (to the level of physiological norm). In contrast, the prevention of exacerbations of recurrent rhinosinusitis by the prototype method did not significantly affect the severity of endotoxinemia.

Mucociliary clearance of the mucous membrane of the upper respiratory tract is one of the components of the first line of defense of the ciliated epithelium from pathogenic agents [589]. To assess the effectiveness of the prevention of exacerbations of recurrent rhinosinusitis by the claimed method and the prototype method, the transport function of the ciliated epithelium of the nasal mucosa and maxillary sinuses was studied using the saccharin test [590] and the test with an aqueous solution of Lugol [591].

As can be seen from tables 9 and 10, the time of mucociliary transport of the mucous membrane of the nasal cavity and the mucous membrane of the maxillary sinuses in all patients with recurrent rhinosinusitis in the inter-relapse period was significantly increased. And only under the influence of the prevention of exacerbations of recurrent rhinosinusitis by the claimed method (in contrast to the prevention by the prototype method) did this indicator reach the level of the reference norm indicator.

In the process of implementing the proposed method for the prevention of exacerbations of recurrent rhinosinusitis in any patient, no side effects and complications were noted. The dynamics of the frequency of exacerbations of recurrent rhinosinusitis under the influence of prophylaxis by the claimed method and the prototype method is presented in table 11. As can be seen, the vast majority of patients in the main group (90.9%) did not seek medical help for a year, and the remaining patients in this group 9.1%) there was a decrease in the frequency of calls. In contrast, in the prevention of exacerbations of recurrent rhinosinusitis by the prototype method, all patients in the control group applied for medical care during the year.

Thus, the inventive method for the prevention of exacerbations of recurrent rhinosinusitis by course complex administration of systemic and local drugs that have a corrective effect on the main pathogenetic mechanisms of recurrent inflammation of the nasal mucosa and paranasal sinuses is not only more effective in comparison with the prototype method, but also quite simple in performance, well tolerated by patients, does not cause any side effects and for the implementation involves the use of available domestic official drugs. The totality of the data presented proves the possibility of implementing the proposed method (achieve the objectives of the invention). Noteworthy is the vastness of the list of prescriptions needed to implement the proposed method for the prevention of exacerbations of recurrent rhinosinusitis. But this is dictated by necessity. The new concept of the pathogenesis of recurrent inflammation of the mucous membrane of the nasal cavity and paranasal sinuses in terms of preventing exacerbations aims, first of all, to stop microecological imbalance as a systemic phenomenon and to restore the colonization resistance of the epithelial lining of the respiratory tract. And given the multifaceted nature of the problems of restoring microecological well-being and the colonization resistance of body biotopes, we can safely assume that achieving this goal does not have a simple therapeutic solution and involves the integrated use of drugs that affect the main pathogenetic mechanisms of their formation.

The claimed invention meets the criterion of "novelty", since for the first time a method is proposed for the prevention of exacerbations of recurrent rhinosinusitis based on the course, integrated appointment in the inter-relapse period of systemic and local preparations that have a corrective effect on the main pathogenetic mechanisms of recurrent inflammation of the nasal mucosa and paranasal sinuses, through stress-protective therapy, diet therapy, therapy to stop the deficiency of omega-3 polynenes saturated fatty acids, vitamin therapy, probiotic therapy, topical and systemic therapy with prebiotic-like drugs, local immunocorrective therapy, which helps to reduce microecological imbalance, restore colonization resistance of biotopes, stimulate local antiviral defense, vegetation of symbiotic microorganisms and thereby prevent upper respiratory infections .

The claimed invention meets the criterion of “inventive step”, since there are no data (unknown) in known and accessible sources of information (from the prior art) containing descriptions of methods for the prevention of exacerbations of recurrent rhinosinusitis, from which it would be obvious the possibility of achieving a positive effect (purpose of the invention ) - prevention of exacerbations of recurrent rhinosinusitis - through systemic and local course, integrated prescription of drugs and diet therapy, as well as suitability this approach for the prevention of exacerbations of recurrent rhinosinusitis.

Compliance with the criterion of "suitability for use" is proved by the results of clinical studies, which show that the claimed method for the prevention of exacerbations of recurrent rhinosinusitis ensures the achievement of a pronounced clinical effect through the use of official medicines available in the Russian Federation. The inventive method for the prevention of exacerbations of recurrent rhinosinusitis is quite simple to implement and can be carried out as in stationary. as well as outpatient settings.

BIBLIOGRAPHY

1. Scheid D.C., Hamm R.M. Acute bacterial rhino sinusitis in adults: part I. Evaluation. Am. Fam. Physician. 2004; 70 (9): 1685-1692.

2. Masood A., Moumoulidis I., Panesar J. Acute rhinosinusitis in adults: an update on current management. Postgrad. Med. J. 2007; 83 (980): 402-408.

3. Lopatin A.S., Gamov V.P. Acute and chronic rhinosinusitis: etiology, pathogenesis, clinical features, diagnosis and treatment principles. M .: Honey. inform. agency. 2011.76 p.

4. Slavin R.G., Spector S.L., Bernstein I.L. et al. American College of Allergy, Asthma and Immunology; Joint Council of Allergy, Asthma and Immunology. The diagnosis and management of sinusitis: a practice parameter update. J. Allergy Clin. Immunol. 2005; 116 (6): S13-S17.

5. Fokkens W.J., Lund V.J., Mullol J. et al. European position paper on rhinosinusitis and nasal polyps 2012. Rhinol Suppl. 2012; 23 (3): 1-298.

6. Anand V.K. Epidemiology and economic impact of rhinosinusitis. Ann. Otol. Rhinol. Laryngol. Suppl. 2004; 193: 3-5.

7. Lopatin A.S., Svistushkin V.M. Acute rhinosinusitis: etiology, pathogenesis, diagnosis and treatment principles. Clinical recommendations. M. 2009.26 p.

8. Hastan D., Fokkens W. J., Bachert C. et al. Chronic rhinosinusitis in Europe - an underestimated disease. A GA2LEN study. Allergy. 2011; 66 (9): 1216-1223.

9. Struchansky L.S., Kamanin E.I. Antibacterial therapy of infections in otorhinolaryngology. Rus honey. Journal. 1998; 6 (11): 684-693.

10. Piskunov G.Z., Piskunov S.Z. Clinical rhinology. M .: Miklos. 2002.S. 225-233. (390 p.)

11. Summary Health Statistics for U.S. Adults: National Health Interview Survey, 2007. National Center for Health Statistics. Vital Health Stat. 2009; 10 (240).

12. Summary Health Statistics for U.S. Adults: National Health Interview Survey, 2010. National Center for Health Statistics. Vital Health Stat. 2012; 10 (2520.

13. Hamilos D.L., Baroody F.M. (Eds.) Chronic rhinosinusitis: pathogenesis and medical management. N.Y .: Informa Healthcare. 2007. 368 RUR

14. Pikunov G.Z., Piskunov S.Z. On the classification of sinusitis. Grew up. rhinol. 1977; 2:13.

15. Turovsky A.B. Treatment and prevention of recurrent bacterial sinusitis. Diss. ... cand. honey. sciences. M. 2009.209 p.

16. Choi S.H., Nal M.Y., Ahn Y.M. et al. Predisposing factors associated with chronic and recurrent rhinosinusitis in childhood. Allergy Asthma Immunol. Res. 2012; 4 (2): 80-84.

17. Bhattacharyya N. Incremental health care utilization and expenditures for chronic rhinosinusitis in the United States. Ann. Otol. Rhinol. Laryngol. 2011; 120 (7): 423-427.

18. Sakovich A.R. Sinusitis: a clinical and epidemiological analysis. Military medicine: a peer-reviewed scientific and practical journal. 2009; 3: 60-62.

19. Magris A., Paluch-Oles J., Koziol-Montewska M. Microbiology aspects of rhinosinusitis. In: Pecular aspects of rhinosinusitis. Marseglia G.L., Caimmi D.P. (Eds.) 2011.p.27-38.

20. U.S. Department of Health and Human Services. Agency for Healthcare Research and Quality. Acute rhinosinusitis in adults. National Guideline Clearinghouse. (2011). www.guideline.gov/content.aspxid=34408.

21. Lund V.J. Health related quality of life in sinonasal disease. Rhinology. 2001; 39 (4): 182-186.

22. Schaiek P. Rhinosinusitis - its impact on quality of life. In: Peculiar aspects of rhinosinusitis. Marseglia G.L., Caimmi D.P. (Eds.) 2011. www.intechopen. com / download / pdf / 24280.

23. Rudmik L., Smith T.L. Quality of life in patients with chronic rhinosinusitis. Curr. Allergy Asthma Rep. 2011; 11 (3): 247-252.

24. Velasco e Cruz A.A., Demarco R.C., Valera F.C. et al. Orbital complications of acute rhinosinusitis: a new classification. Braz. J. Otorhinolaryngol. 2007; 73 (5): 684-688.

25. Bayonne E., Kania R., Tran P. et al. Intracranial complications of rhinosinusitis. A review, typical imaging data and algorithm of management. Rhinology. 2009; 47 (1): 59-65.

26. Kastner J., Taudy M., Lisy J. et al. Orbital and intracranial complications after acute rhinosinusitis. Rhinology. 2010; 48 (4): 457-461.

27. Gyusan A.O., Kubanova A.A., Uzdenova R.Kh. Rhinosinusogenic orbital complications: prevalence and treatment guidelines. Vestn. otorhinolaryngol. 2010; 4: 46-47.

28. Kuranov N.I. Orbital and intracranial complications of rhinosinusitis. Vestn. otorhinolaryngol. 2001; 4: 46-47.

29. Gois C.R.T., Pereira C.U., D′Avila J.S., Melo V.A. Intracranial complications of rhinosinusitis. Int. Arch. Otorhinolaryngol. 2005; 9 (4): 264-269.

30. Chester A.C. Symptoms of rhinosinusitis in patients with unexplained chronic fatigue or body pain: a pilot study. Arch. Intern. Med. 2003; 163 (15): 1832-1836.

31. Meltzer E.O., Szwarcberg J., Pill M.W. Allergic rhinitis, asthma, and rhinosinusitis: diseases of the integrated airway. J. Manag. Care Pharm. 2004; 10 (4): 310-317.

32. Yang P.C., Liu T., Wang B.Q. et al. Rhinosinusitis derived staphylococcal enterotoxin B possibly associates with pathogenesis of ulcerative colitis. BMC Gastroenterol. 2005; 5: 28. Doi: 10.1186 / 1471-230-5-28.

33. Wasan A., Fernandez E., Jamison R.N. Association of anxiety and depression with reported disease severity in patients undergoing evaluation for chronic rhinosinusitis. Ann. Otol. Rhinol. Laryngol. 2007; 116 (7): 491-497.

34. Bourdin A., Gras D., Vachier I., Chanez P. Upper airway x 1: allergic rhinitis and asthma: united disease through epithelial cells. Torax. 2009; 64 (11): 999-1004.

35. Litvack J.R., Mace J., Smith T.L. Role of depression in outcomes of endoscopic sinus surgery. Otolaryngol. Head Neck Surg. 2011; 144 (3): 446-451.

36. Sasama J., Sherris D.A., Shin D.A. et al. New paradigm for the roles of fungi and eosinophils in chronic rhinosinusitis. Curr. Opin. Otolaryngol. Head Neck Surg. 2005; 13 (1): 2-8.

37. Kato A., Schleimer R.P. Beyond inflammation: airway epithelial cells are at the interface of innate and adaptive immunity. Curr. Opin. Immunol. 2007; 19 (6): 711-720.

38. Backert C., Gevaert P., Zhang N. et al. Role of staphylococcal superantigens in upper airway disease. Curr. Opin. Allergy Clin. Immunol. 2008; 8 (1): 34-38.

39. Tieu D.D., Kern R.C., Schleimer R.P. Alterations in epithelial barrier function and host defense responses in chronic rhinosinusitis. J. Allergy Clin. Immunol. 2009; 124 (1): 37-42.

40. Cohen M., Kofonow J., Nayak J.V. et al. Biofilms in chronic rhinosinusitis: a review. Am. J. Rhinol. Allergy. 2009; 23 (3): 255-260.

41. Tan B.K., Schleimer R.P., Kern R.C. Perspectivies on the etiology of chronic rhinosinusitis. Curr. Opin. Otolaryngol. Head Neck Surg. 2010; 18 (1): 21-26.

42. Turovsky A.B. Treatment and prevention of recurrent bacterial sinusitis. Diss. ... doctor. honey. sciences. 2009. M. 209 p.

43. Cain R.B., Lal D. Update on the management of chronic rhinosinusitis. Infect. Drug. Resist 2013; 6: 1-14.

44. Manes R.P., Batra P.S. Etiology, diagnosis and management of chronic rhinosinusitis. Expert Rev. Antiinfect. Ther. 2013; 11 (1): 25-35.

45. Mikhailov Yu.Kh. Etipatogenetic mechanisms of acute and chronic rhinosinusitis (systematic analysis of the results of clinical studies). Diss. ... doctor. honey. sciences. SPb. 2005.250 s.

46. Order of the Ministry of Health and Social Development of the Russian Federation of November 29, 2004. No. 289 "On approval of the standard of care for patients with sinusitis."

47. Order of the Ministry of Health of Russia dated December 22, 2012. No. 1203Н “On the approval of the standard of specialized medical care for chronic sinusitis”.

48. RF patent 2365347 C1.

49. RF patent 2077276 C1.

50. Tarasova G.D. Possibilities for preventing relapse of chronic rhinosinusitis. Russian honey. Journal. 20074 15 (1): 3-6.

51. Savenko I., Ilyina I. The role of intestinal infestations in the pathogenesis of recurrent bacterial rhinosinusitis in childhood. Laboratory of Hearing and Speech of the Research Center of St. Petersburg named after Academician I.P. Pavlova, www.doclor.ru. Scientific work.

52. RF patent 2403071 C1.

53. Sharipova E.R. Interleukin-1β in the immunopathogenesis of recurrent purulent rhinosinusitis. Abstract. diss. ... cand. honey. sciences. SPb. 2007.24 s.

54. Luchikhin L.A., Polyakova T.S., Mironov A.A. Experience with the use of the drug IRS-19 for the prevention and treatment of inflammatory diseases of the upper respiratory tract. News otorhinolaryngol. 20014 2: 183-184.

55. Luchikhin L.A., Tettsoeva Z.M., Bogdanets S.A. Immunotherapy with IRS-19 in patients with acute and chronic sinusitis. Bulletin of otorhinolaryngol. 2002; 3: 44-46.

56. Suloeva S.V. Clinical and immunological efficacy of a topical immunomodulator of bacterial origin in children and adolescents with HIV infection and children born to HIV-infected women. Diss. ... cand. honey. sciences. Nizhny Novgorod. 2005.172 s.

57. Teterkina M.N., Lopatin A.S. A clinical assessment of the effectiveness of the drug IRS19 in the prevention of exacerbations of chronic / recurrent rhinosinusitis. Russian rhinology. 2007; 3: 22-24.

58. Maciorkowska E., Kaczmarski M., Cudowska B. et al. The assessment of the therapeutic effectiveness of IRS-19 in allergic children with recurrent or chronic respiratory infections. Rocz. Akad. Med. Bialymst. 1995; 40 (3): 619-624.

59. Antoniv V.F., Flimochkina K.V., Elkun G.B. et al. Immunocorrective therapy in the complex treatment of rhinosinusitis. Bulletin of otorhinolaryngol. 2013; 1: 81-84.

60. Hawrelak J.A., Myers S.P. The causes of intestinal dysbiosis: a review. Alternat. Med. Rev. 2004; 9 (2): 180-197.

61. Nesvizhsky Yu.V., Bogdanova EA, Vorobev A.A. Study of the effect of Staphylococcus aureus on rat gastrointestinal microbiocenosis. Bulletin of RAMS. 2006; 9-10: 82-82.

62. Tan L., Psaltis A., Baker L.M. et al. Aberrant mucin glycoprotein patterns of chronic rhinosinusitis patients with bacterial biofilms. Am. J. Rhinol. Allergy. 2010; 24 (5): 319-324.

63. Pedersen A., Zachariae R., Bovbjerg D.H. Influence of psychological stress on upper respiratory infection - a meta-analysis of prospective studies. Psychosom. Med. 2010; 72 (8): 823-832.

64. Lee Y.K., Mazmanian S.K. Has the microbiota played a critical role in the evolution of the adaptive immune system? Science. 2010; 330 (6012): 1768-1773.

65. Ichinohe T., Pang I.K., Kumamoto Y. et al. Microbiota regulates immune defense against respiratory tract influenza A virus infection. Proc. Natl. Acad. Sci. USA 2011; 108 (13): 5354-5359.

66. Microecology: fundamental and applied problems. Ed. N.N. Pluzhnikova, Y.A. Nakatisa, O.G. Hurtsilavy. SPb .: Publishing house of the North-West. honey. university. 2012.304 p.

67. Li N., Li Q., Zhou X.D. et al. Chronic mechanical stress induces mucin 5AC expression in human bronchial epithelial cells through ERK dependent pathways. Mol. Biol. Rep. 2012; 39 (2): 1019-1028.

68. Cohen S., Janicki-Deverts D., Doyle W.J. et al. Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk. Proc. Natl. Acad. Sci. USA 2012; 109 (16): 5995-5999.

69. Belkaid Y., Naik S. Compartmentalized and systemic control of tissue immunity by commensals. Nat. Immunol. 2013; 14 (7): 646-653.

70. Stengel A., Tache Y. Neuroendocrine control of the gut during stress: corticotropin-releasing factor signaling pathways in the spotlight. Annu. Rev. Physiol. 2009; 71: 219-239.

71. Almeida-Reis R., Toledo A.C., Reis F.G. et al. Repeated stress reduces mucociliary clearance in animals with chronic allergic airway inflammation. Respir. Physiol. Neurobiol. 2010; 173 (1): 79-85.

72. Leick E.A., Reis F.G., Honorio-Neves F.A. et al. Effects of repeated stress on distal airway inflammation, remodeling and mechanics in an animal model of chronic airway inflammation. Neuroimmunomodulation. 2012; 19 (1): 1-9.

73. Hutchinson M.R., Loran L.C., Zhang Y. et al. Evidence that tri cyclic small molecules may possess Toll-like receptor and MD-2 activity. Neurosci. 2010; 168 (2): 551-563.

74. Hess A., Bloch W., Rocker J. et al. Detection of nitric oxide synthases in physiological and pathophysiological processes of the nasal mucosa. HNO. 2000; 48 (7): 489-495.

75. Chiba Y., Matsuo K., Sakai H. et al. Increased expression of inducible nitric oxide synthase in nasal mucosae of guinea pigs with induced allergic rhinitis. Am. J. Rhinol. 2006; 20 (3): 336-341.

76. Farghaly H.S., Abdel-Zaher A.O., Mostafa M.G., Kotb H.I. Comparative evaluation of the effect of tricyclic antidepressants on inducible nitric oxide synthase expression in neuropathic pain model. Nitric Oxide. 2012; 27 (2); 88-94.

77. Marques R.H., Reis F.G., Starling C.M. et al. Inducible nitric oxide synthase inhibition attenuates physical stress-induced lung hyper-responsiveness and oxidative stress in animals with lung inflammation. Neuroimmunomodulation. 2012; 19 (3): 158-170.

78. Food and Drug Administration. Food labeling: healthy claims; oats and coronary heart disease: proposed rule. 23/01/1997. Federal Register. 1997; 62 (15): 3584-3601.

79. Lupton J.R., Turner N.D. Dietary fiber and coronary disease: does the evidence support an association. Curr. Atheroscler Rep. 2003; 5 (6); 500-505.

80. Andoh A., Tsujikawa T., Fujiyama Y. Role of dietary fiber and short-chain fatty acids in the colon. Curr. Pharm. Des. 2003; 9 (4): 347-458.

81. Karaki S.I., Mitsui R., Hayashi H. et al. Short-chain fatty acids receptor GPR43 is expressed by enteroendocrine cells and mucosal mast cells in rat intestine. Cell Tissue Res. 2006; 324 (3): 353-360.

82. Tazoe H., Otomo Y., Kaji I. et al. Roles of short-chain fatty acids receptors, GPR41 and GPR43, on colon functions. J. Physiol. Pharmacol 2008; 59 (2): 251-262.

83. Le Poul E., Loison C., Struif S. et al. Functional characterization of human receptors for short-chain fatty acids and their role in polymorphonuclear cell activation. J. Biol. Chem. 2003; 278 (28): 25481-25489.

84. Dayl J.W. Alkylxanthines as research tools. J. Auton. Nerv. Syst. 2000; 8 (1-3): 44-52.

85. Yamada J., Hamuro J., Hatanaka H. et al. Alleviation of seasonal allergy symptoms with superfine beta-1,3-glucan: a randomized study. J. Allergy Clin. hnmunol. 2007; 119 (5): 1119-1126.

86. Sandvik A., Wang Y.Y., Morton M.C. et al. Oral and systemic administration of beta-glucan protects against lipopolysaccharide-induced shock and organ injury in rats. Clin. Exp. Immunol. 2007; 148 (1): 168-177.

87. Tsoni S.V., Brown G. D. Beta-glucans and Dectin-1. Ann. N.Y. Acad. Sci. 2008; 1143: 45-60.

88. Catalli A., Kulka M. Chitin and β-glucan polysaccharides as immunomodulators of airway inflammation and atopic disease. Recent Path. Endocrin. Metabol. Immune Drug Disc. 2010; 4 (3): 175-189.

89. Daou C., Zhang H. Oat beta-glucan: its role in health promotion and prevention of diseases. Comp. Rev. Food Sci. Food safety. 2012; 11 (4): 355-365.

90. Vannucci L., Krizan J., Sima P. et al. Immunostimulatory properties and antitumor activities of glucans. Int. J. Oncol. 2013; 43 (2): 357-364.

91. Rice P.J., Adams E.L., Ozmet-Scelton T. et al. Oral delivery and gastrointestinal absorption of soluble glucans stimulate increased resistance to infectious challenge. J. Pharm. Exp. Ther. 2005; 314 (3): 1079-1086.

92. Beta glucans. http://www.nazdorovye.ru/glucan.html.

93. Babineau T.J., Hackford A., Kenler A. et al. A phase II multicenter, double-blind, randomized, placebo-controlled study of three dosages of an immunomodulators (PGG-glucan) in high-risk surgical patients. Arch. Surg. 1994; 129 (11): 1204-1210.

94. Miura N.N., Ohno N., Aketagawa J. et al. Blood clearance of (1- □ 3) -beta-glucan in MLR lpr / lpr mice. FEMS Immun. Med. Microbiol. 1996; 13 (1): 51-57.

95. Wolever T.M.S., Tosh S.M., Gibbs A.L. et al. Physicochemical properties of oat β-glucan influence its ability to reduce serum LDL cholesterol in humans: a randomized clinical trial. Am. J. Clin. Nutr. 2010; 92 (4): 723-732.

96. Chihara G. Recent progress in immunopharmacology and therapeutic effects of polysaccharides. Dev. Biol. Stand. 1992; 77: 191-197.

97. Beck E. Oats and beta-glucan affecting weight and safety. Cardiovasc. Med. General Pract. 2011; 15: 8.

98. Tzinabos A.O., Gibson F.C., Cisneros R.L., Kasper D.L. Protection against experimental intraabdominal sepsis by two polysaccharide immunomodulators. J. Infect. Dis. 1998; 178 (1): 200-206.

99. Bedirli A., Gokahmetoglu S., Sakrak O. et al. Prevention of intraperitoneal adhesion formation using beta-glucan after ileocolic anastomosis in a rat bacterial peritonitis. Model. Am. J. Surg. 2003; 185 (4): 339-343.

100. Vetvika V., Thornton B.P., Ross G. D. Soluble beta-glucan polysaccharide binding to the lectin site 0f neutrophil or natural killer cell complement receptor 3 (CD116 / CD18) generates a primed state of receptor capable of mediating cytotoxicity of iC3b-opsonized target cells. J. Clin. Invest. 1996; 98 (1): 50-61.

101. Akramiene D., Kondrotas A., Didziapetriene J., Kevelaitis E Effects of β-glucans on the immune system. Medicina. 2007; 43 (8): 597-606.

102. Tsoni S.V., Brown G. D. Beta-glucans and Dectin-1. Ann. N.Y. Acad. Sci. 2008; 1143: 45-60.

103. Vanucci L., Krizan J., Sima P. et al. Immunostimulatory properties and antitumor activities of glucans. Int. J. Oncol. 2013; 43 (2): 357-364.

104. Dongowaki G., Huth M., Gebhardt E., Flamme W. Fiber-rich barley products beneficially affect the intestinal tract of rats. J. Nutr. 2002; 132 (12): 3704-3714.

105. Jaskari J., Kontula P., Siitonen A. et al. Oat beta-glucan and xylan hydrolysates as selective substrates to Bifidobacterium Lactobacillus strains. Appl. Microbiol. Biotechnol. 1998; 49 (2): 175-181.

106. Murphy P., Bello F. D., O′Doherty J.V. et al. Effects of cereal β-glucans and enzyme inclusion on the porcine gastrointestinal microbiota. Anaerobe 2012; 18 (6): 557-565.

107. Murphy P., Bello F. D., O'Doherty J. et al. Analysis of bacterial community shifts in the gastrointestinal tract of pigs fed diets supplemented with β-glucan from Laminaria digitata, Laminaria hyperborean and Saccharomyces cerevisiae. Animal 2013; 7 (7): 1079-1087.

108. Stamenova D., Labaj J., Krizkova L. et al. Protective effects of fungal (1- □ 3) -beta-D-glucan derivatives against oxidative DNA lesions in V79 hamster lung cells. Cancer Lett. 2003; 198 (2): 153-160.

109. Kayali H., Ozdaq M.F., Kahraman S. et al. The antioxidant effect of beta-glucan on oxidative stress status in experimental spinal cord injury in rats. Neurosurg. Rev. 2005; 28 (4): 298-302.

110. Senoglu N., Yuzbasioglu M.F., Aral M. et al. Protective effects of N-acetylcysteine and beta-glucan pretreatment on oxidative stress in cecal ligation and puncture model of sepsis. J. Invest. Surg. 2008; 21 (5): 237-243.

111. Shaki F., Purahmad J. Mitochondrial toxicity of depleted uranium: protection by beta-glucan. Iranian J. Pharm. Res. 2013; 12 (1): 131-140.

112. Corda R., Biddau P., Corrias A., Puxeddu E. Conalbumin in the treatment of acute enteritis in the infant. Int. J. Tissue React. 1983; 5 (1): 117-123.

113. Stevens L. Egg white protein. Comp. Biochem. Physiol. B. 1991; 100 (1): 1-9.

114. Kotanko P., Carter M., Levin N.W. Intestinal bacterial microflora - a potential source of chronic inflammation in patients with chronic kidney disease. Nephrol. Dial Transplant 2006; 21 (8): 2057-2060.

115. Innis S.M. Dietary (n-3) fatty acids and drain development. J. Nutr. 2007; 137 (4): 855-859.

116. Cortes E., Hidalgo M.J., Rizo-Baeza M.M. et al. High ratio of omega 6 / omega 3 ratio children with neuropathies: cause of effect. Nutr. Hop. 2013; 18 (4): 116501170.

117. McNamara R.K. Membrane omega-3 fatty acid deficiency as a preventable risk factor for comorbid coronary heart disease in major depressive disorders. Cardiovasc. Psychiatry Neurology. 2009; ID 362 795.13 p.

118. Itariu B.K., Zeyda M., Leitner L. et al. Treatment with n-3 polyunsaturated fatty acids overcomes the inverse association of vitamin D deficiency with inflammation in severely obese patients: a randomized controlled trial. PLOS ONE. 2013; 8 (1): e54634.

119. Sinopoulos A.P. Dietary omega-3 fatty acid deficiency and high fructose intake in the development of metabolic syndrome, brain metabolic abnormalities, and non-alcoholic fatty liver disease. Nutrients 2013; 5: 2901-2923. Dot: 10.3390 / nu5082901.

120. Lafourcade M., Larrieu T., Mato S. et al. Nutritional omega-3 deficiency abolishes endocannabinoid-mediated neuronal functions. Nat. Neurosci. 2011; 14 (3): 345-350.

121. Kim H.Y., Spector A.A. Synaptamide, endocannabinoid-like derivative of docosahexaenoic acid with cannabinoid-independent function. PLEFA. 2013; 88 (1): 121-125.

122. McNamara R.K., Jandacek P., Rider T. et al. Omega-3 fatty acid deficiency increases constitutive pro-inflammatory cytokine production in rats: relationship with central serotonin turnover. PLEFA. 2010; 93 (4-6): 185-191.

123. Nieminen L.R., Malino K.K., Mehta N. et al. Relationship between omega-3 fatty acids and plasma neuroactive steroids in alcoholism, depression and controls. PLEFA. 2006; 75 (4-5): 309-314.

124. Liu Y., Chen F., Li Q. et al. Fish oil alleviates activation of hypothalamic-pituitary-adrenal axis associated with inhibition of TLR4 and NOD signaling pathways in weaned piglets after a lipopolysaccharide challenge. J. Nutr. 2013;

125. Gosh S., Molcan E., DeCoffe D. et al. Diets rich in n-6 PUFA induce intestinal microbial dysbiosis in aged mice. Br. J. Nutr. 2013; 110 (3): 515-525.

126. Gosh S., DeCoffe D., Brown K. et al. Fish oil attenuates omega-6 polyunsaturated fatty acid-induced dysbiosis and infectious colitis but impair LPS dephosphorylation actively causing sepsis. PLOS ONE. 2013; 8 (2): e55468.

127. Miyauchi S., Hirasawa A., Iga T. et al. Distribution and regulation of protein expression of free fatty acid receptor GPR120. Naunyn Schmidebergs Arch. Pharmacol 2009; 379 (4): 427-434.

128. Harisawa A., Naga T., Katsuma S. et al. Free fatty acid receptors and drug discovery. Biol. Pharm. Bull. 2008; 31 (10): 1847-1851.

129. Yang Y.C., Lii C.K., Wei Y.L. et al. Docosahexaenoic acid inhibition of inflammation is partially via cross-talk between Nrf2 / heme oxygenase 1 and IKK / NF-kB pathways. J. Nutr. Biochem. 2013.24 (1): 204-212.

130. Lee J.Y., Sohn K.H., Rhee S.H., Hwang D. Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like receptor 4. J. Biol. Chem. 2001; 276 (20): 16683-16689.

131. Massaro M., Habib A., Lubrano L. et al. The omega-3 fatty acid docosahexaenoate attenuates endothelial Cyclooxygenase-2 induction through both NADP (H) oxidase and PKC epsilon inhibition. Proc. Natl. Acad. Sci. USA 2006; 103 (41): 15184-15189.

132. Serhan C.N. Resolvins and protectins: novel lipid mediators in anti-inflammation and resolution. Scand. J. Food Nutr. 2006; 50 (52): 68-78.

133. Groeger A., Cippolina C., Cole M.P. et al. Cyclooxygenase-2 generates anti-inflammatory mediators from omega-3 fatty acids. Nat. Chem. Biol. 2010; 6 (6): 433-441.

134. Seki H., Fukunaga K., Arita M. et al. The anti-inflammatory and pro-resolving mediator resolving El protects mice from bacterial pneumonia and acute lung injury. J. Immunol. 2010; 184 (2): 836-843.

135. Cippolina C., Salvatore S., Freeman B.A., Schopfer F.J. Late-breaking abstract: cyclooxygenase- and lipoxygenase-dependent generation of omega-3 electrophilic fatty acid-derivatives with anti-inflammatory properties. Eur. Respir. Soc. Ann. Congress. Amsterdam. 2011; p.763.

136. Das U.N. Lipoxins, resolvins, protectins, maresins and nitrolipids, and their clinical implications with specific reference to cancer: Part I. Clin. Lipidology. 2013; 8 (4): 437-463.

137. Marcon R., Bento A.F., Dutra R.C. et al. Maresin 1, a proresolving lipid mediator derived from omega-3 polyunsaturated fatty acids, exerts protective actions in murine models of colitis. J. Immunol. 2013; 191 (8): 4288-4298.

138. Dalli J., Zhu M., Vlasenko N.A. et al. The novel 13S, 14S-epoxy-maresin is converted by human macrophages to maresin 1 (MaR1), inhibits leukotriene A4 hydrolase (LTA4H), and shifts macrophage phenotype. FASEB J. 2013; 27 (7): 2573-2583.

139. Saedisomeolia A., Wood L.G., Carg M.L. et al. Anti-inflammatory effects of long-chain n-3 PUFA in rhinovirus-infected cultured epithelial cells. Br. J. Nutr. 2009; 101 (4): 533-540.

140. Rajendiran E. The differential effects of omega-6 and omega-3 polyunsaturated fatty acids on intestinal microbial ecology and host redox responses. A thesis ... master of science. The University of British Columbia (Okanagan). 2012.86 p.

141. Mallampalli R.K., Salome R.G., Spector A.A. Regulation of CTP: choline-phosphate cytidylyltransferase by polyunsaturated n-3 fatty acids. Am. J. Physiol. Lung Cell. Mol. Physiol. 1994; 267 (6 Pt1): L641-L648.

142. Hillaire M.L.B., van Eijk M., van Trierum S.E. et al. Assessment of the antiviral properties of recombinant porcine SP-D against various influenza A virus in vitro. Plos one. 2011; 6 (9): e25005.

143. Uhliarova B., Svec M., Calkovska A. Surfactant and its role in the upper respiratory system and Eustachian tube. Acta Medica Martiniana. 2012; 12 (1): 12-21.

144. Bersani I., Kunzmann S., Speer C.P. Immunomodulatory properties of surfactant preparations. Expert Rev. Anti Infect. Ther. 2013; 11 (1): 99-110.

145. Richardson K.E., Xue Z., Huang Y. et al. Physicochemical and antibacterial properties of surfactant mixtures with quatemized chitosan microgels. Carbohydr. Polym. 2013; 93 (2): 709-717.

146. Barlett J., Gakhar L., Penterman J. et al. PLUNG: a multifunctional surfactant of the airways. Biochem. Soc. Trans. 2011; 39 (4): 1012-1016.

147. Saini A., Harjai K., Chhibber S. Inhibitory effect of polyunsaturated fatty acids on apoptosis induced by Streptococcus pneumoniae in alveolar macrophages. Indian J. Med. Res. 2013; 137 (8): 1193-1198.

148. Jing K., Song K.S., Shin S. et al. Docosahexaenoic acid induces autophagy through p53 / AMPK / mTOP signaling and promotes apoptosis in human cancer cells harboring wild-type p53. Autophagy. 2011; 7 (11): 1348-1358.

149. Rovito D., Giordano C., Vizza D. et al. Omega-3 PUFA ethanolamides DHEA and EPEA induce autophagy through PPARγ activation in MCF-7 breast cancer cells. J. Cell. Physiol. 2013; 228 (6): 1314-1322.

150. Morita M., Kuba K., Ichikawa A. et al. The lipid mediator protectin D1 inhibits influenza virus replication and improves severe influenza. Cell. 2013; 153 (1): 112-125.

151. Garcia-Sastre A. Lesions from lipids in the fight against influenza. Cell. 2013.154 (1): 22-23.

152. Gwaltney J.M. J., Wiesinger B.A., Patrie J.T. Acute community-acquired bacterial sinusitis: the value of antimicrobial treatment and the natural history. Clin. Infect. Dis. 2004; 38 (2): 227-233.

153. Aring A.M., Chan M.M. Acute rhinosinusitis in adults. Am. Fam. Physician. 2011; 83 (9): 1057-1063.

154. Spite M., Serhan C.N. Novel lipid mediators promote resolution of acute inflammation impact of aspirin and statins. Circ. Res. 2010; 107 (10): 1170-1184.

155. Serhan C.N., Fredman G., Yang R. et al. Novel proresolving aspirin-triggered DHA pathway. Chem. Biol. 2011; 18 (8): 976-987.

156. Singer P., Shapiro H., Thiella M. et al. Anti-inflammatory properties of omega-3 fatty acids in critical illness: novel mechanisms and an integrative perspective. Intensive Care Med. 2008; 34 (9): 1580-1592.

157. Andersson U., Tracey K.J. Neural reflexes in inflammation and immunity. J. Exp. Med. 2012; 209 (6): 1057-1068.

158. Vukelic M., Qing X., Redecha P. et al. Cholinergic receptor modulate immune complex-induced inflammation in vitro and in vivo. J. Immunol. 2013; 191 (4): 1800-1807.

159. Zhao M., He X., Bi X.Y. et al. Vagal stimulation triggers peripheral vascular protection through the cholinergic anti-inflammatory pathway in a rat model myocardial ischemia / reperfusion. Basic Res. Cardiol. 2013; 108 (3): 345. Doi: 10.1007 / s00395-013-0345-l.

160. Gigliotti J.C., Huang L., Ye H. et al. Ultrasound prevents renal ischemia-reperfusion injury by stimulating the splenic cholinergic anti-inflammatory pathway. J. Am. Soc. Nephrol. 2013; 24 (9): 1451-1460.

161. Hougardy J.M., Sadis C., Le Moine A. Ultrasonic stimulation of the cholinergic anti-inflammatory pathway for renal protection. J. Am. Soc. Nephrol. 2013; 24 (9): 1340-1342.

162. Huang C. B., Ebersole J. L. A novel bioactivity of omega-3 polyunsaturated fatty acids and their ester derivatives. Mol. Oral. Microbiol. 2010; 25 (1): 75-80.

163. Bailey K.L., LeNan T.D., Yanov D.A. et al. Non-typeable Haemophilus influenza decreases cilia beating via protein kinase C epsilon. Respir. Res. 2012; 13: 9. http://respiratory-research.com/content/3/1/49.

164. Tetaert D., Pierre M., Demeyer D. et al. Dietary n-3 fatty acids have suppressive effects on mucin upregulation in mice infected with Pseudomonas aeruginosa. Respir. Res. 2007; 8:39. Doi: 10.1186 / 1465-9921-8-39.

165. Calder P.C. Fatty acids and inflammation: the cutting edge between food and pharma. Eur. J. Pharmacol. 2011; 668 (S.1): S50-S58.

166. Calder P.C. Mechanisms of action of (n-3) fatty acids. J. Nutr. 2012; 142 (3): 592S-599S.

167. Novak T.E., Babcock T.A., Jho D.H. et al. NF-kB inhibition by ω-3 fatty acids modulates LPS-stimulated macrophage TNF-α-transcription. Am. J. Physiol. 2003; 284 (1): L84-L89.

168. Gao L., Wang J., Sekhar K.P. et al. Novel n-3 fatty acid oxidation products activate Nrf2 by destabilizing the association between Keap1 and Cullin3. J. Biol. Chem. 2007; 282 (4): 2529-2537.

169. Clarke S.D., Gasperikova D., Nelson C. et al. Fatty acid regulation of gene expression: a genomic explanation for the benefits of the Mediterranean diet. Ann. N.Y. Acad. Sci. 2002; 967: 283-298.

170. Deckelbaum R.J., Worgall T. S., Seo T. n-3 Fatty acids and gene expression. Am. J. Clin. Nutr. 2006; 83 (6): S1520-S1525.

171. Jump D.B. N-3 polyunsaturated fatty acid regulation of hepatic gene transcription. Curr. Opin. Lipidol. 2008; 19 (3): 242-247.

172. Di Nunzio M., van Deursen D., Verhoeven A.J., Borboni A. n-3 and n-6 Polyunsaturated fatty acids suppress sterol regulatory element binding protein activity and increase flow of non-esterified cholesterol in HepG2 cells. Br. J. Nutr. 2010; 103 (2): 161-167.

173. Zuniga J., Cancino M., Medina F. et al. N3-PUFA supplementation triggers PPAR-α activation and PPAR-α / NF-kB interaction: anti-inflammatory implications in liver ischemia-reperfusion injury. Plos one. 2011; 6 (12): e28502.

174. Schmidt S., Willers J., Stahl F. et al. Regulation of lipid metabolism-related gene expression in whole blood cells of normo- and dyslipidemic men after fish oil supplementation. Lipids Health Dis. 2012; 11: 172. Doi: 10.1186 / 1476-511x-11-172.

175. Schmidt S., Stahl F., Mutz K.O. et al. Transcriptome-based identification of antioxidative gene expression after fish oil supplementation in normo- and dyslipidemic men. Nutr. Metab. 2012; 9 (1): 45.

176. Vanden Heuvel J.P. Nutrigenomics and nutrigenetics of ω-3 polyunsaturated fatty acids. Prog. Mol. Biol. Transl. Sci. 2012; 108: 75-112.

177. Bomba A., Nemcova R., Gancarcikova S. et al. The influence of omega-3 polyunsaturated fatty acids (omega-3 PUFA) on lactobacilli adhesion to intestinal mucosa and on immunity in gnotobiotic piglets. Berl. Munch. Hierarchtl. Wochenschr. 2003; 116 (7-8): 312-316.

178. Kastel R., Bomba A., Vasko L. et al. The effect of probiotics potentiated with polyunsaturated fatty acids on the digestive tract of germ-free piglets. Veterinami Medicina. 2007; 52 (2): 63-68.

179. Mayansky A.N. Dysbiosis: illusions and reality. Pediatrics. 2004; 4: 80-88.

180. Dennou E., Pridmore R. D., Berger B. et al. Identification of genes associated with long-gut-persistence phenotype of the probiotic Lactobacillus johnsonii strain NCC533 using a combination of genomics and transcriptome analysis. J. Bacteriol. 2008; 190 (9): 3161-3168.

181. Saxelin M., Lassig A., Karjalainen H. et al. Persistence of probiotic strains in the gastrointestinal tract when administered as capsules, yoghurt, or cheese. Int. J. Food Microbiol. 2010; doi: 10.1016 / j.ifoodmicro.2010.10.00.009.

182. Remus D.M., Bongers R.S., Meijerink M. et al. Impact of Lactobacillus plantarum sortase on target protein sorting, gastrointestinal persistence, and host immune response modulation. J. Bacteriol. 2013; 195 (3): 502-509.

183. Marraffini L.A., Dedent A.C., Schneewind O. Sortases and the art of anchoring proteins to the envelopes of gram-positive bacteria. Microbiol. Mol. Biol. Rev. 2006; 70 (1): 192-221.

184. Lebeer S., Vanderleyder J., De Keersmaeker S.C. Genes and molecules of Lactobacilli supporting probiotic action. Microbiol. Mol. Biol. Rev. 2008; 72 (4): 728-764.

185. Remus D.M. Molecular analysis of candidate probiotic effector molecules of Lactobacillus plantarum. Thesis ... the degree of doctor at Wageningen University. 2012.188 p.

186. Kim S.W., Suda W., Kim S. et al. Robustness of gut microbiota of healthy adults in response to probiotic intervention revealed by high-throughput pyrosequencing. DNS Res. 2013.20 (3): 241-253.

187. Kleerebezem M., Vaughan E.E. Probiotic and gut Lactobacilli and Bifidobacteria: molecular approach to study diversity and activity. Annu. Rev. Microbiol. 2009; 63: 269-290.

188. Remus D.M., Kleerebezem M., Bron P.A. An intimate tet-a-tet - how probiotic lactobacilli communicate with the host. Eur. J. Pharmacol. 2011; 668 (A.1): S33-S42.

189. Gonzalez-Rodrigues I., Ruiz L., Gueimonde M. et al. Factors involved in the colonization and survival of Bifidobacteria in the gastrointestinal tract. FEMS Microbiol. 2013; 340 (1): 1-10.

190. Ried G., Jass J., Sebulsky M.T. Potential uses of probiotics in clinical practice. Clin. Microbiol. Rev. 2003; 16 (4): 658-672.

191. De Vrese M., Schrezenmeir J. Probiotics, prebiotics, and synbiotics. Adv. Biochem. Eng. Biotechnol. 2008; 11: 1-66.

192. Rauch M., Lynch S.V. Probiotic manipulation of the gastrointestinal microbiota. Gut Microbes. 2010; 1 (5): 335-338.

193. Ohiand C. L., Mac Naughton W.K. Probiotic bacteria and intestinal epithelial barrier function. Gastrointest. Liver Physiol. 2010; 298 (6): G807-G819.

194. Johansen F.E., Kaetzel C. Regulation of the polymeric immunoglobulin receptor and its role in mucosal immunity. Mucosal. Immun. 2011; 4 (6): 598-602.

195. Di Mauro A., Neu J., Riezzo G. et al. Gastrointestinal function development and microbiota. Ital. J. Pediatr. 2013; 39: 15. Doi: 10.1186 / 1824-7288-39-15.

196. Mashkovsky M.D. Medicines M .: New Wave. 2005.1200 s.

197. Efremov V.V., Spirichev V.B., Simakova P.A. Vitamins Big Medical Encyclopedia. 1976.V.4. from 270-275.

198. RF patent 2339389 C2.

199. RF patent 2132681 C1.

200. Loman S., Jansen H.M., Out T.A., Lutter R. Interleukin-4 and interferon-gamma synergistically increase secretory component gene expression, but are additive in stimulating secretory immunoglobulin A release by Calu-3 airway epithelial cells. Immunol. 1999; 96 (4): 537-543.

201.Sarkar J., Gangopadhyay N.N., Moldoveanu Z. et al. Vitamin A is required for regulation of polymeric immunoglobulin receptor (pIgR) expression by interleukin-4 and interferon-gamma in a human intestinal epithelial cells line. J. Nutr. 1998; 128 (7): 1063-1069.

202. Kaetzel C.S. The polymeric immunoglobulin receptor: binding innate and adaptive immune responses at mucosal surfaces. Immunol. Rev. 2005; 206: 83-99.

203. Johansen F.E., Kaetzel C.S. Regulation of the polymeric immunoglobulin receptor and IgA transport: new advances in environmental factors that stimulate pIgR expression and its role in mucosal immunity. Mucosal Immunol. 2011; 4 (6): 598-602.

204. Liu Y., Rhoads J.M. Communication between B-cells and microbiota for maintenance of intestinal homeostasis. Antibodies. 2013; 2: 535-553.

205. Corthesi B. Role of secretory IgA in infection and maintenance of homeostasis. Autoimmun. Rev. 2013; 12 (6): 661-665.

206. Tu S.P., Quante M., Bhagat G. et al. IFN-γ inhibits gastric carcinogenesis by inducing epithelial cell autophagy and T-cell apoptosis. Cancer Res. 2011; 2011; 71 (12): 4247-4259.

207. Matsuzawa T., Kim B.H., Shenoy A.R. et al. IFN-γ elicits macrophage autophagy viap38 MAPK signaling pathway. J. Immunol. 2012; 189 (2): 813-818.

208. RF patent 2116788 C1.

209. Stark G.R., Kerr I.M., Williams B.R. et al. How cells respond to interferons. Annu. Rev. Biochem. 1998; 67: 227-264.

210. Schoenborn J.R., Wilson C. B. Regulation of interferon-gamma during innate and adaptive immune responses. Adv. Immunol. 2007; 96: 41-101.

211. Paun A., Pitha P.M. The IFN family, revisited. Biochemie. 2007; 89 (6-7): 744-753.

212. Fabri M., Stenger S., Shin D.M. et al. Vitamin D is required for IFN-gamma-mediated antimicrobial activity of human macrophages. Sci. Transl. Med. 2011; 3 (104): 104ra102. Doi: 10.1126 / scitranslmed.3003045.

213. Nakajima H., Takatsu K. Role of cytokines in allergic airway inflammation. Int. Arch. Allergy Immunol. 2007; 142 (4): 265-273.

214. Corthesy B. Multi-faceted functions of secretory IgA at mucosal surfaces. Front Immunol. 2013; 4: 185. Doi: 10.3389 / fimmu.2013.00.005. eCollection2013.

215. Dasgupta M.K. Biofilm causes decreased production of interferon-gamma. J. Am. Soc. Nephrol. 1996; 7 (6): 877-882.

216. Jyonouchi H., Sun S., Kelly A., Rimell F.L. Effects of exogenous interferon gamma on proteins with treatment-resistant chronic rhinosinusitis and dysregulated interferon gamma production: a pilot study. Arch. Otolaryngol. Head Neck Surg. 2003; 129 (5); 563-569.

217. Chattoray S.S., Ganesan S., Fans A. et al. Pseudomonas aeruginosa suppresses interferon response to rhinovirus infection in cystic fibrosis but not in normal bronchial epithelial cells. Infect. Immun. 2011; 79 (10): 4131-4145.

218. Van Wauwe J., Aerts F., Walter H., de Boer M. Cytokine production by phytohemagglutinin-stimulated human blood cells: effects of corticosteroids, T cell immunosuppressants and phosphodiesterase IV inhibitors. Inflamm. Res. 1995; 44 (9): 400-405.

219. Passariello C., Schippa S., Conti C. et al. Rhinoviruses promote internalization of staphylococcus aureus into non-fully permissive cultured pneumocytes. Microb. Infect. 2006; 8 (3): 758-766.

220. Sajjan U., Wang Q., Zhao Y. et al. Rhinovirus disrupt the barrier function of polarized airway epithelial cells. Am. J. Respir. Crit. Care Med. 2008; 178 (12): 1271-1281.

221. Comstock A.T., Ganesan S., Chattoraj A. et al. Rhinovirus-induced barrier dysfunction in polarized airway epithelial cells is mediated by NADPH oxidase 1. J. Virol. 2011; 85 (13): 6795-6808.

222. Sadchikov D.V., Kulikova T.N., Lopatin I.V. Mexidol in the treatment of critical conditions. Saratov. 2004.14 p.

223. Voronina T.A. Mexidol. The main effects, mechanism of action, application. http://medi.ru/doc/a070196.htm.

224. Voronina T.A. The main neuropsychotropic effects and mechanism of action. Farmateka. 2009; 6 (475): 28-31.

225. Shumsky A.V. The use of Mexidol in the treatment of herpes oral infections. Dentistry today. 2005; 8: 63.

226. Lemetskaya T.I., Sukhova T.V., Petrovich Yu.A. The effect of Mexidol on the soft tissues of the oral cavity in the conditions of dental pathology. Dentistry 2008; 6: 31-35.

227. Lukyanova L.D., Atabaeva R.E., Shepeleva S.Yu. Bioenergy mechanisms of the antihypoxic action of a succinate-containing derivative of 3-hydroxypyridine. Bull. experiment, biol. honey. 1993; 115 (3) W 259-260.

228. Lukyanova L.D. Bioenergy hypoxia: concept, mechanisms and methods of correction. Bull. experiment, biol. honey. 1997; 124 (9): 245-254.

229. Zolotev N.N., Smirnov L.D., Kuzmin V.I. and others. Derivatives of 3-hydroxypyridine as inhibitors of proteolytic enzymes. Chem.-farm. Journal. 1989; 23 (2): 133-135.

230. Vasiliev I.T., Mumladze RB, Kolesova O.E., Yakushin V.I. Clinical efficacy of Mexidol in the treatment of acute surgical diseases. M. 2004.22 p.

231. Efendiev A.M., Pomoynetsky S.V., Smirnov L.D., Lubatiev A.M. The effect of antioxidants on the synthesis of prostaglandins, prostacyclin and thromboxane in different layers of the kidneys of old rats. Farmakol. toxicol. 1986; 49 (3) W 60-63.

232. Tanashyan M.M., Maksimova M.Yu., Smirnova I.N., Stepanchenko O.A. Antioxidant therapy for cerebrovascular diseases with diabetes mellitus and metabolic syndrome. Difficult patient. 2013; 1: 26-35.

233. Mal S.V. The advantage of antioxidants over protease inhibitors in the treatment of acute pancreatitis and the prevention of its complications. Abstract. diss. ... Dr. med. sciences. Rostov on the Don. 2007.47 p.

234. Klebanov G.I., Lyubitsky O.B., Ilyina S.U. and others. Antioxidant activity of inhibitors of free radical reactions used in dressings for the treatment of wounds. Biol. honey. Pharmac chemistry. 2006; 52 (1) W 69-82.

235. Kazarina L.N., Ellaryan L.K. The influence of Mexidol Dent Asset toothpaste on the state of local oral immunity in chronic catarrhal gingivitis. Dentist practitioner. 2011; 2: 56-58.

236. Shchulkin A.V. The effect of Mexidol on the development of the phenomenon of excitotoxicity of neurons in vitro. Magazine Nevrol. Psychiatrist named after S.S. Korsakova. 2012; 2: 35-39.

237. Vereshchagin B.C. Investigation of some aspects of the mechanism of the antiarrhythmic action of dimephosphone and mexidol. Diss. ... cand. honey. sciences. Kupavna. 2002.134 s.

238. Voronina T.A. Mexidol: Spectrum of pharmacological effects. Medical almanac. 2013; 1: 145-146.

239. Fokkens W., Lund V., Mullol J. EP3OS 2007: European position paper on rhinosinusitis and nasal polyps 2007. A summary for otorhinolaryngologist. Rhinology. 2007; 45 (2): 97-101.

240. Kido H., Okumura Y., Yamada H. et al. Secretory leukoprotease inhibitor and pulmonary surfactant serve as principal defenses against influenza A virus in the airway and chemical agents up-regulating their levels have therapeutic potential. Biol. Chem. 2004; 385 (11): 1029-1034.

241. Abaturov A.E. The role of local protease inhibitors in nonspecific respiratory tract protection. Theoretical medicine. 2011; 4 (3): 117-123.

242. Kido H., Okumura Y., Takahashi E. et al. Role of host cellular proteases in the pathogenesis of influenza and influenza-induced multiple organ failure. Biochim. Biophys. Acta. 2012; 1824 (1): 186-194.

243. Stebaeva L., Nikolaeva I., Peters V., Guskova T. The effect of emoxipin (E) and its structural analogs (SA) on the non-specific cellular immunity factors in experiments. Clin. Microbiol. Infect. 2008; 5 (S3): 410 (Abstract P.1208).

244. Lagan A.L., Melley D.D., Evans T.W., Quilan G.J. Pathogenesis of the systemic inflammatory syndrome and acute lung injury: role of iron mobilization and decompartment-talization. Am. J. Lung Cell Mol. Physiol. 2008; 294 (2): L161-L174.

245. Kuzin VB, Tepaev D.V. The effect of the drug Mexidol on a number of indicators of vegetative status and humoral immunity. Farmateka. 2006; 16: 76-78.

246. Demidova M.A., Shneur S.Ya., Galimskaya E.V., Kovtun A.A. The effect of Noopept and Mexidol on allergic reactions. Pharmacy. 2007; 3: 28-30.

247. RF patent 2281760 C1.

248. Shchipakina S.V. The effect of emoxipin and mexidol on the dynamics of clinical and laboratory parameters with repeated tonsillitis. Diss. ... cand. honey. sciences. Saransk. 2010.135 s.

249. Voronina T.A., Deshevoy Yu.B., Moroz B.B. and others. Acute radiation sickness in an experiment in the context of the use of Mexidol. Pathologist, fiziol. exp therapy. 2007; 3: 22-23.

250. RF patent 2205641 C1.

251. Psaltis A.J., Bruhn M.A., Ooi E.H. et al. Nasal mucosa expression of lactoferrin in patients with chronic rhinosinusitis. Laryngoscope 2007; 117 (11): 2030-2035.

252. Psaltis A.J. The role of bacterial biofilms in chronic rhinosinusitis. A thesis submitted for the degree of doctor philosophy. Adelaide. 2008.200 p.

253. Britigan B.E., Edeker B.L. Pseudomonas and neutrophil products modify transferrin and lactoferrin to create conditions that favor hydroxyl radical formation. J. Clin. Invest. 1991; 88 (4): 1092-1102.

254. Britigan B.E., Hayek M. B., Doebbehing N. B., Fick R. B. J. Transferrin and lactoferrin undergo proteolytic cleavage in the Pseudomonas aeruginosa-infected lungs of patients with cystic fibrosis. Infect. Immun. 1993; 61 (12): 5049-5055.

255. Rogan M.P., Taggart C.C., Greene C.M. et al. Loss of microbicidal activity and increased formation of biofilm due to decreased lactoferrin activity in patients with cystic fibrosis. J. Infect Dis. 2004; 190 (7): 1245-1253.

256. Singh P.K., Tack B.F., McCray P.B.Jr., Welsh M.J. Synergistic and additive killing by antimicrobial factors found in human airway surface liquid. Am. J. Physiol. Lung Cell. Mol. Physiol. 2000; 279 (5): L799-L804.

257. Valenti P., Antonini G. Lactoferrin: an important host defense against microbial and viral attack. Cell. Mol. Life Sci. 2005; 62 (22): 2576-2587.

258. Legrand D., Pierce A., Ellas E. et al. Lactoferrin structure and function. Adv. Exp. Med. Biol. 2008; 606: 163-193.

259. Berlutti F., Pantanella F., Natalizi T. et al. Antiviral properties of lactoferrin - a natural immunity molecule. Molecules 2011; 16 (8): 6992-7018.

260. Baker H.M., Baker E.N. Lactoferrin and iron: structural and dynamics aspects of binding and release. Biometals. 2004; 13 (3): 209-216.

261. Sinha M., Kaushik S., Kaur P. et al. Antimicrobial lactoferrin peptides: the hidden players in the protective function of a multifunctional protein. Int. J. Pept. 2013; 2013: 390230.

262. Munford R.S. Detoxifying endotoxin: time, place and person. J. Endotoxin Res. 2005; 11 (2): 69-84.

263. Puddu P., Lattore D., Carollo M. et al. Bovine lactoferrin counteracts toll-like receptor mediated activation signals in antigen presenting cells. Plos one. 2011; 6 (7): e22504.

264. Legrand D. Lactoferrin, a key molecule in immune and inflammatory process. Biochem. Cell. Biol. 2012; 90 (3): 252-268.

265. Bellamy W., Wakabayashi H., Takase M. et al. Killing of Candida albicans by lactoferrin B, a potent antimicrobial peptide derived from N-terminal region of bovine lactoferrin. Med. Microbiol. Immunol. 1993; 182 (2): 97-105.

266. Qiu J., Hedrixson D.R., Baker E.N. et al. Human milk lactoferrin inactivates two putative colonization factors expressed by Haemophilus influenza. Proc. Natl. Acad. Sci. USA 1998; 95 (21): 12641-12646.

267. Singh P.K. Iron sequestration by human lactoferrin stimulates P.aeruginosa surface motility and blocks biofilm formation. Biometals. 2004; 17 (3): 267-270.

268. Teng C.T. Factors regulating lactoferrin gene expression. Biochem. Cell. Biol. 2006; 84 (3): 263-267.

269. Li Y., Limmon G.V., Imani F., Teng C. Induction of lactoferrin gene expression by innate immune stimuli in mouse mammary epithelial HC-11 cells. Biochemie. 2009; 91 (1): 58-67.

270. Geng K., Li Y., Bezault J., Furmaski P. Induction of lactoferrin expression in murine ES cells by retinoic acid and estrogen. Experiment. Cell Res. 1998; 245 (1): 114-220.

271. Beriat G.K., Yalcinkaya E., Akmansu S.H. et al. Evaluation of the clinical effects of isotretinoin on chronic rhinosinusitis. Kulak Burun Bogaz Ihtis Derg. 2011; 21 (5): 251-256.

272. Beeh K.M., Beier J., Esperester A., Paul L.D. Antiinflammatory properties of ambroxol. Eur. J. Med. Res. 2008; 13 (2): 557-562.

273. Gao X., Huang Y., Han Y. et al. The protective effects of ambroxol in Pseudomonas aeruginosa-induced pneumonia in rats. Arch. Med. Sci. 2011; 7 (3): 405-413.

274. Kido H., Okumura Y., Yamada H. et al. Secretory leukoprotease inhibitor and pulmonary surfactant serve as principal defenses against influenza A virus infection in the air way and chemical agents up-regulating their levels may have therapeutic potential. Biol. Chem. 2004.385 (11): 1029-1034.

275. Seagrave J.C., Albrecht H.H., Hill D.B. et al. Effects of huaifenesin, N-acetylcysteine and ambroxol on MUC5AC and mucociliary transport in primary differentiated human tracheal-bronchial cells. Respir. Res. 2012; 13: 98.

276. Hafez M.M., Aboulwafa M.M., Yassien M.A., Hassouna N.A. Activity of some mucolytics against bacterial adherence to mammalian cells. Appl. Biochem. Biotechnol. 2009; 158 (1); 97-112.

277. Holecyova A., Kriska M. The effect of ambroxol on vascular reactivity in the rabbit. Bratisl. Lek. Listy. 1998; 2: 99-103.

278. Malerba M., Ragnoli B. Ambroxol in the 21 ^st century: pharmacological and clinical update. Exp. Opin. Drug Metab. Toxicol. 2008; 4 (8): 1119-1129.

279. Hama A.T., Plum A.W., Sagen J. Antinociceptive effect of ambroxol with neuropatic spinal cord injury pain. Pharmacol Biochem. Behav. 2010; 97 (2): 249-255.

280. Stetinova V., Herout V., Kvetina J. In vitro and in vivo antioxidant activity of ambroxol. Clin. Exp. Med. 2004; 4 (3): 152-158.

281. Koyama I., Matsunaga T., Harada T. et al. Ambroxol reduces LPS toxicity mediated by induction of alkaline phosphatase in rat lung. Clin. Biochem. 2004; 37 (8): 688-693.

282. Lalioui L., Pellgrini E., Dramis S. et al. The SrtA sortase of Streptococcus agalactiae is required for cell wall anchoring of proteins containing LPXTG motif, for adhesion to epithelial cells, and for colonization of the mouse intestine. Infect. Immun. 2005; 73 (8): 3342-3350.

283. Guiton P.S., Hung C.S., Kline K.A. et al. Contribution of autolysin and sortase A during Enterococcus faecalis DNA-dependent biofilm development. Infect. Immun. 2009; 77 (9): 3626-3638.

284. Hooper L.V., Gordon J.I. Glycans as legislator of host-microbial interactions: spanning the spectrum from symbiosis to pathogenicity. Glycobiology. 2001; 11 (2): R1-R10].

285. Imberty A., Wimmerova M., Mitchell E.P., Gilboa-Garbet N. Structures of the lectins from Pseudomonas aeruginosa: insight into the molecular basis for host glycan recognition. Micr. Infect. 2004; 6 (2): 221-228.

286. Bucior I., Moston K., Engel J.N. Pseudomonas aeruginosa-mediated damage requires distinct receptors at the apical and basolateral surfaces of the polarized epithelium. Infect. Immun. 2010; 78 (3): 939-953.

287. Freitas M., Axellson L.G., Cayuela C. et al. Microbial-host interactions specifically control the glycosylation pattern in intestinal mouse mucosa. Histochem. Cell. Biol. 2002; 118 (2): 149-161.

288. Cash H.L., Whitham C.V., Behrandt C.L., Hooper L.V. Symbiotic bacteria direct expression of an intestinal lectin. Science. 2006; 313 (5790): 1126-1130.

289. Ley R.E., Peterson D.A., Gordon J.I. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell. 2006; 124 (4): 837-848.

290. Bergstrom K.S.B., Xia L. Micin-type O-glycans and their roles in intestinal homeostasis. Glycobiol. 2013; 23 (9); 1026-1037.

291. Jablonka E., Lamb M.E. Evolution in four dimensions: genetic, epigenetic, behavioral and symbolic variations in the history of life. Bradford Books / MIT Press. 2005. P.113-154.

292. Inbar-Feigenberg M., Choufani S., Butcher D.T. et al. Basic concepts of epigenetics. Fertil. Steril. 2013; 99 (3): 607-615.

293. Endam L. M., Filali-Mouhim A., Divoy C. et al. Genome-wide methylation profiling of chronic rhinosinusitis. 2011. www.ichg2011.org/cgi-bin/showdetail.pl?(Abstract).

294. Lim D.H.K., Maher E.R. DNA methylation: a form of epigenetic control of gene expression. Obstetrician Gynaecologist. 2010; 12 (1): 37-42.

295. Seiberling K..A., Church C.A., Herring J.L., Sowers L.C. Epigenetics of chronic rhinosinusitis and the role of the eosinophil. Int. Forum Allergy Rhinology. 2012; 2 (1): 80-84.

296. Van Vliet J., Oates N.A., Whitelaw E. Epigenetic mechanisms in the context of complex disease. Cell. Mol. Life Sci. 2007; 64 (12): 1531-1538.

297. Bayarsaihan D. Epigenetic mechanisms in inflammation. J. Dental Res. 2011; 90 (1): 9-17.

298. Shanmugan M.K., Sethi G. Role of epigenetics in inflammation-associated diseases. Subcell. Biochem. 2012; 61: 627-657.

299. Mattick J.S. The functional genomics ofnoncoding RNA. Science. 2005; 309 (5740): 1527-1528.

300. Kaikkonen M.U., Lam M.T., Glass C.K. Non-coding RNA′s as regulators of gene expression and epigenetics. Cardiovasc. Res. 2011; 90 (3): 430-440.

301. Bierne H., Hamon M., Cossart P. Epigenetics and bacterial infection. Cold Spring Harbor Perspect. Med. 2012. Doi: 10.1101 / cshperspect.a010272.

302. Bombail V., Moggs J.G., Orphandes G. Perturbation of epigenetic status by toxicant. Toxicol. Lett. 2004; 149 (1-3): 51-58.

303. Korkmaz A., Yaren H., Kunak Z.I. et al. Epigenetic perturbation in the pathogenesis of mustard toxicity; hypothesis and preliminary results. Interdisc. Toxicol. 2008; 1 (3-4): 236-241.

304. Johannes F., Colome-Tatche M. Quantitative epigenetics through epigenomic perturbation of isogenic lines. Genetics 2011; 188 (1): 215-227.

305. Schleithoff C., Voelter-Mahknecht S., Dahmke I.N., Mahlknecht U. On the epigenetic of vascular regulation of disease. Clin. Epigenetics. 2012; 4 (1): 7. Doi: 10.1186 / 1868-7083-4-7.

306. Al Akeel P. Role of epigenetic reprogramming of the host genes in bacterial pathogenesis. Saudi J. Biol. Sci. 2013; 20 (4): 305-309.

307. Horvath S. DNA methylation age of human tissues and cell types. Genome Biology. 2013; 14 (10): R115.

308. Lechner K., Fodinger M., Grisold W. et al. Vitamin B12 deficiency. New data on an old theme. Wien Klin. Wochenschr. 2005; 117 (17): 579-591.

309. Schneider E., Pliushch G., Hajj N.B. et al. Spatial, temporal and niterindividual epigenetic variation of functionally important DNA methylation patterns. Oxford J. Life Sci. 2010; 38 (12): 3380-3390.

310. Karapieri K., Gousis C., Papaioannidou P. The role of vitamin B12 in DNA modulation mechanisms. Front Pharmacol Conference-XEMET2010. Doi: 10.3389 / conf.fphar. 2010.60.00140.

311. Kiec-Wilk B., Polus A., Mikolajczyk M., Mathers J.C. Beta-carotene and arachidonic acid induced DNA methylation and the regulation of pro-chemotactic activity of endothelial cells and its progenitors. J. Physiol. Pharmacol 2007; 58 (4): 757-766.

312. Vove W.K., Berletch J.B., Andrews L.G., Tellefsbot T.O. Epigenetic regulation of telomerase in retinoid-induced differentiation of human leukemia cells. Int. J. Oncol. 2008; 32 (3): 625-631.

313. Crider K.S., Yang T.P., Berry R.J., Bailey L.B. Folate and DNA methylation: a review of molecular mechanisms and the evidence for folate′s role. Adv. Nutr. 2012; 3: 21-38.

314. Xue J., Zempleni J. Epigenetic synergies between biotin and folate in the regulation of proinflammatory cytokines and repeats. Scand. J. Immunol. 2013; dot: 10.1111 / sji.12108.

315. Meethal S.V., Hogan K.J., Mayamil C.S., Iskandar B.J. Folate and epigenetic mechanisms in neural tube development and defects. Childs Nerv. Syst. 2013; 29 (9): 1427-1433.

316. Xiang N., Zhao R., Song G., Zhong W. Selenite reactivates silenced genes by modifying DNA methylation and histones in prostate cancer cells. Carcinogenesis. 2008; 29 (11): 2175-2181.

317. Zeng H., Yan L., Cheng W.H., Uthus E.O. Dietary selenomethionine increases axon-specific DNA methylation of the p53 gene in rat liver and colon mucosa. J. Nutr. 2010; 141 (8): 1464-1468.

318. Joseph J., Loscaizo J. Selenistasis: epistatic effects of selenium on cardiovascular phenotype. Nutrients 2013; 5 (2): 340-358.

319. Bermingham E.N., Bassett S.A., Young W. et al. Post0weaning selenium and folate supplementation affects gene and protein expression and global DNA methylation in mice fed high-fat diets. BMC Med. Genomics 2013; 6: 7. Doi: 10.1186 / 1755-8794-6-7.

320. Minor E.A., Court B. L., Young J. I., Wang G. Ascorbate induces ten-eleven translocation (Tet) methylcytosine dioxygenase-mediated generation of 5-hydroxymethyl-cytosine. J. Biol. Chem. 2013; 288 (19): 13669-13674.

321. Blaschke K., Ebata K.T., Karimi M.M. et al. Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells. Nature. 2013; 500 (7461): 222-226.

322. Hyang Y., Khor T.O., Shu L. et al. A γ-tocopherol-rich mixture of tocopherols maintains Nrf2 expression in prostate tumors of TRAMP mice via epigenetic inhibition of CpG methylation. J. Nutr. 2012; doi: 10.3945 / jn.111.153114.

323. Lang C., Murgia C., Leong M. et al. Anti-inflammatory effects of zinc and alterations in zinc transporter mRNA in mouse of allergic inflammation. Am. J. Physiol. Lung Cell. Mol. Physiol. 2007; 292 (2): L577-L584.

324. Wong C.P., Magnusson K.R., But E. Increased inflammatory response in aged mice is associated with age-related zinc deficiency and zinc transporter dysregulation. J. Nutr. Biochem. 2013; 24 (1): 353-359.

325. Lee H.S., Barraza-Villarreal A., Hernandez-Vargas H. et al. Modulation of DNA methylation states and infant immune system by dietary supplementation with ω-3 PUFA during pregnancy in an intervention study. Am. J. Clin. Nutr. 2013; 98 (2): 480-487.

326. Tseng T.M. Quercetin induces FasL-related apoptosis, in pert, through promotion of histone H3 acetylation in human leukemia HL-60 cells. Oncol. Rep. 2011; 25 (2): 583-591.

327. Rigano D., Formisano C., Basile A. et al. Antibacterial activity of flavonoids and phenilpropanoids from Murrabium globosum spp. libanoticum. Phytother. Res. 2007; 21 (4): 395-397.

328. Hirai I., Okuno M., Katsuma R. et al. Characterization of anti-staphylococcal aureus activity of quercetin. 2010; 45 (6): 1250-1254.

329. Czeczot H., Kusztelac J. A study of the genotoxic potential of flavonoids using short-term bacterial assays. Acta Biochem. Pol. 1993; 40 (4): 549-554.

330. Llagostera M., Garrido S., Barbe J. et al. Influence of S9 mix in the induction of SOS system by quercetin. Mutat. Res. 1987.191 (1): 1-4.

331. Tan J., Wang B., Zhu L. DNA binding and oxidative DNA damage induced by a quercetin copper (II) complex: potential mechanisms of its antitumor properties. J. Biol. Inorg. Chem. 2009; 14 (5): 727-739.

332. Selva L., Viana D., Regev-Yochay C. et al. Killing niche competitors by remote-control bacteriophage induction. Proc. Natl. Acad. Sci. USA 2009; 106 (4): 1234-1238.

333. Martin R., Soberon N., Escobedo S., Suarez J.E. Bacteriophage induction versus vaginal homeostasis: role of H (2) O (2) in the selection of Lactobacillus defective prophages. Int. Microbiol. 2009; 12 (2): 131-136.

334. Selenium. Hygienic criteria for the state of the environment. Geneva: WHO. 1989.V. 58. 270 s

335. Golubkina N.A., Skalny A.V., Sokolov Y.A. Selenium in medicine and ecology. M .: KMK Publishing House. 2002.134 s.

336. Baranova T.A. Hygienic and epidemiological examination of the system for the prevention of selenium deficiency in the population of the Omsk region. Diss. ... cand. honey. sciences. Omsk 2008.134 p.

337. Shirshova T.I., Golubkina N.A., Beshley I.V., Matisov N.V. Selenium deficiency and the possibility of reducing it. The accumulating properties of some representatives of the genus Allium L. in relation to selenium. Bulletin of the Komi Scientific Center, Ural Branch of the Russian Academy of Sciences. 2011; 3 (7): 48-54.

338. Oh R.C., Brown D.L. Vitamin D12 deficiency. Am. Fam. Physician. 2003; 67 (5): 979-986.

339. Alien L.H. How common is vitamin D-12 deficiency? Am. J. Clin. Nutr. 2008; 89 (2): 6935-6965.

340. Verhaeverbeke I., Mets T., Mulkens K., Vandewoude M. Normalization of low vitamin B-12 serum levels in older people by oral treatment. J. Am. Geriatr. Soc. 1997; 45 (1): 124-125.

341. Barr J.J., Auro R., Furlan M. et al. Bacteriophage adhering to mucus provide a non-host-derived immunity. Proc. Natl. Acad. Sci. USA 2013; 110 (26): 10771-10776.

342. Meyer J.R. Sticky bacteriophage protect animal cells. Proc. Natl. Acad. Sci. USA 2013; 110 (26): 10475-10476.

343. Thai P., Loukoianov A., Wachi S., Wu R. Regulation of airway mucin gene expression. Annu. Rev. Physiol. 2008; 70: 405-429.

344. Jobsis R. Q., Schellekens S. L., Fakkel-Kroesbergen A. et al. Hydrogen peroxide in breath condensate during a common cold. Mediat. Inflamm. 2001; 10 (6): 351-354.

345. Vanin V.V. The use of local antioxidant therapy in the complex treatment of patients with acute purulent rhinosinusitis. Diss. ... cand. honey. sciences. Novokuznetsk. 2008; 132 p.

346. Chesnokova N.P., Mareev O.V., Kapustina N.Yu. The nature and mechanisms of the development of metabolic disorders in chronic sinusitis. From the time of. high technology. technologies. 2008; 3: 34-37.

347. Braskett M., Riedl M.A. Novel Antioxidant approaches to the treatment of upper airway inflammation. Curr. Opin. Allergy Clin. Immunol. 2010; 10 (1): 34-41.

348. Pluzhnikov N.N., Chizh S.I., Yuzvinkevich L.S. and others. Oxidative stress. Fundamental and applied problems. In: Actual Problems and Prospects for the Development of Military Medicine: Teach, tr. NIIITs (MBZ) GNII VM MO RF. t.2. SPb. 2000.S. 193-223.

349. Pluzhnikov N.N., Bakulina L.S., Legeza V.I. et al. Some aspects of the antiradical protection of biomembranes. In: Actual Problems and Prospects for the Development of Military Medicine: Scientific. tr NIIITs (MBZ) GNII of the Ministry of Defense of the Russian Federation. T. 4. SPb. 2003.S. 123-139.

350. Tesoriere L., Bongiorno A., Pintaudi A.M. et al. Synergistic interactions between vitamin A and vitamin E against lipid peroxidation in phosphatidylcholine liposomes. Arch. Biochem. Biophys.

351. Mukherjee S., Date A., Patravale V. et al. Retinoids in treatment of skin aging: an overview of clinical efficacy and safety. Clin. Interv. Aging. 2006; 1 (4): 327-348.

352. Hall J. A., Grainger J. R., Spencer S. P., Belkaid Y. The role of retinoic acid in tolerance and immunity. Immunity. 2011; 35 (1): 13-22.

353. Tan X., Sande J.L., Pufnock J.S. et al. Retinoic acid as a vaccine adjuvant enhances CD8 + T cell response and mucosal protection from viral challenge. J. Virol. 2011; 85 (16): 8316-8327.

354. Kampmann E., Johann S., van Neerven S. et al. Anti-inflammatory effect of retinoic acid on prostaglandin synthesis in cultured cortical astrocytes. J. Neurochem. 2008; 106 (1): 320-332.

355. Keino H., Watanabe T., Sato Y., Okada A. Anti-inflammatory effect of retinoic acid on experimental autoimmune uveoretinitis. Br. J. Ophtalmol. 2010; 94 (6): 802-807.

356. Kwok S.K., Park M.K., Cho M.L. et al. Retinoic acid attenuates rheumatoid inflammation in mice. J. Immunol. 2012; 189 (2): 1062-1071.

357. Gaedicke S., Zhang X., Schmelzer C. et al. Vitamin E dependent microRNA regulation in rat liver. FEBS Lett. 2008; 582 (23-24): 3542-3546.

358. Rimbach G., Moehring J., Huebbe P., Lodge J.K. Gene-regulatory activity of alpha-tocopherol. Molecules 2010; 15 (3): 1746-1761.

359. Li C., Li R.W., Elsasser T.N. Alpha-tocopherol modulates transcriptional activities that affect essential biological progress in bovine cells. Gene Regul. Syst. 2010; 4 (4): 109-124.

360. Wong M., Lodge J.K. A metabolic investigation of the effects of vitamin E supplementation in humans. Nutr. Metab. 2012; 9 (1): 110.

361. Batt E.E., Zimmerman M.T., Ramoutar R.R. et al. Preventing metal-mediated oxidative DNA damage with selenium compounds. Metallomics 2011; 3 (5): 503-512.

362. Harrison J.H., Conrad H.R. Selenium content and glutathione peroxidase activity in tissues of the dairy cow after short-term feeding. J. Dairy Sci. 1984; 67 (10): 2464-2470.

363. Petrovich Yu.A., Terekhina N.A., Shmagel K.V. The effect of sodium selenite on the activity of glutathione peroxidase and superoxide dismutase in the tissues of the eye with herpetic keratitis. Bull. experiment, biol. honey. 1987; 103 (4): 405-407.

364. Huseynov G.M., Nasibov E.M., Dzhafarov A.I. The participation of selenium in the regulation of lipid peroxidation of biomembranes and the activity of glutathione peroxidase. Biochemistry. 1990; 55 (3): 499-507.

365. Wu X., Huang K., Wei C. Regulation of cellular glutathione peroxidase by different form and concentration of selenium in primary cultured bovine hepatocytes. J. Nutr. Biochem. 2010; 21 (2): 153-161.

366. Ross S.M. Clinical applications of lipoic acid in type II diabetes. Holis. Nutr. Pract. 2006; 20 (6): 305-306.

367. Padmalayam I., Hasham S., Saxena U., Pillarisetti S. Lipoic acid synthase (LASY). A novel role in inflammation, mitochondrial function, and insulin resistance. Diabetes. 2009; 58 (3): 600-608.

368. Maczurek A., Hager K., Kenklies M. et al. Lipoic acid as an anti-inflammatory and neuroprotective treatment for Alzheimer’s disease. Adv. Drug. Deliv. Rev. 2008; 60 (13-14): 1463-1470.

369. Tripathi P., Nair S., Arora N. Supplementation of antioxidants glutathione and α-lipoic acid attenuates oxidative stress and Th2 response in allergic airway inflammation. Indian J. Allergy Asthma Immunol. 2013; 27 (1): 19-26.

370. Biewenga G.P., Haenen G.R., Bast A. The pharmacology of the antioxidant lipoic acid. Gen. Pharmacol 1997; 29 (3): 315-331.

371. Kagan V.E., Shvedova A., Serbinova E. et al. Dihydrolipoic acid - a universal antioxidant both in the membrane and in the aqueous phase. Reduction of peroxyl, ascorbyl and chromanoxyl radicals. Biochem. Pharmacol 1992; 44 (8): 1673-1649.

372. Wang L., Wu C.G., Fang C.Q. et al. The protective effect of α-lipoic acid on mitochondria in the kidney of diabetic rats. Int. J. Clin. Exp. Med. 2013; 6 (2): 90-97.

373. Bast A., Haenen G.R. Lipoic acid: a multifunctional antioxidant. Biofactors. 2003; 17 (1-4): 207-213.

374. Baraboy V.A. Alpha-lipoic acid-dihydrolipoic acid is an active bioantioxidant and bioregulatory system. Ukr. Bioxim. Zhurn. 2005; 72 (3): 20-26.

375. Lee J., Koo N., Min D.B. Reactive oxygen species, aging, and antioxidative nutraceuticals. Compr. Rev. Food Sci. Food safety. 2004; 3 (1): 21-33.

376. Bilska A., Wlodek L. Lipoic acid - the drug of the future? Pharmacol Rep. 2005; 57 (5): 570-577.

377. Suh J.H., Shenvi S.V., Dixon B.M. et al. Decline in transcription activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid. Proc. Natl. Acad. Sci. USA 2004; 101 (10): 3381-3386.

378. Alleva R., Nasole E., Di Donato R. et al. α-Lipoic acid supplementation inhibits oxidative damage, accelerating chronic wound healing in patients undergoing hyperbaric oxygen therapy. Biochem. Biophys. Res. Commun. 2005; 333 (2): 404-410.

379. Sigel H., Prijs B., McCormick DB, Shih JC Stability and structure of binary and ternary complexes of α-lipoate and lipoate derivatives with Mn ^{2 +, Cu 2+, and Zn 2+} in solution. Arch. Biochem. Biophys. 1978; 187 (1): 208-214.

380. Cremer D.R., Rabeler R., Roberts A., Lynch B. Safety evaluation of alpha-lipoic acid (ALA). Regul. Toxicol. Pharmacol 2006; 46 (1): 29-41.

381. Goraca A., Huk-Kolega H., Piechota A. et al. Lipoic acid - biological activity and therapeutic potential. Pharmacol Rep. 2011; 63 (4): 849-858.

382. Reddy P.H. Mitochondrial dysfunction and oxidative stress in asthma: implications for mitochondria-targeted antioxidant therapeutics. Pharmaceuticals 2011; 4 (3): 429-456.

383. Cui H., Kong Y., Zhang H. Oxidative stress, mitochondrial dysfunction, and aging. J. Signal Transd. 2012; doi: 10.1155 / 2012/646354.

384. Hernandez-Aguilera A., Rull A., Rodriguez-Callego E. et al. Mitochondrial dysfunction: a basic mechanism in inflammation-related non-communicable diseases and therapeutic opportunities. Mediators Inflamm. 2013; ID 135698.

385. Plotnikov E.Y., Morosanova M.A., Pevzner I.B. et al. Protective effect of mitochondria-targeted antioxidants in an acute bacterial infection. Proc. Natl. Acad. Sci. USA 2013; 110 (33): E3100-E3108.

386. Tan D.X., Manchester L.C., Terron M.P. et al. One molecule, many derivatives: a never-ending interaction of melatonin with reactive oxygen and nitrogen species? J. Pineal. Res. 2007; 42 (1): 28-42.

387. Lopez Gonzalez M.A., Guerrero J.M., Ceballo Pedraja J.M., Delgado Moreno F. Melatonin in palate tonsils with recurrent acute tonsillitis and tonsillar hypertrophy. Acta Otomnolaringol. Esp. 1998; 49 (8): 625-628.

388. Reiter R.J., Tan D.X., Leon J. et al. When melatonin gets on your nerves: its beneficial effects in experimental model of stroke. Exp. Biol. Med. 2005; 230 (2): 104-117.

389. Hardeland R. Antioxidative protection by melatonin: multiplicity of mechanisms from radical detoxification to radical avoidance. Endocrine. 2005; 27 (2): 119-130.

390. Messner M., Hardeland R., Rodenbeck G., Huether G. Tissue retention and subcellular distribution of continuously infused melatonin in rats under near physiological conditions. J. Pineal Res. 1998; 24 (4): 251-259.

391. Srinivasan V., Spence D.W., Pandi-Perumal S.R. et al. Melatonin in mitochondrial dysfunction and related disorders. Int. J. Alzheimer′s Dis. 2011; 2011: 326320.

392. Lopez A., Garcia J.A., Escames G. et al. Melatonin protects the mitochondria from oxidative damage reducing oxygen consumption, membrane potential, and superoxide anion production. J. Pineal Res. 2009; 46 (2): 188-198.

393. Reiter R.J., Paredes S.D., Korkmaz A. et al. Melatonin combats molecular terrorism at the mitochondrial level. Interdisc. Toxicol. 2008; 1 (2): 137-149.

394. Petrosillo G., Fattoretti P., Matera M. et al. Melatonin prevents age-related mitochondrial dysfunction in rat brain via cardiolipin protection. Rejuvenation Res. 2008; 11 (5): 935-943.

395. Paradies G., Petrosillo G., Paradies V. et al. Melatonin, cardiolipin and mitochondrial bioenergetics in health and disease. J. Pineal Res. 2010; 48 (4): 297-310.

396. Loves D.A., Webster N.R., Murphy M.P., Galley M.F. Antioxidants that protect mitochondria reduce interleukin-6 and oxidative stress, improve mitochondrial function, and reduce biochemical markers of organ dysfunction in a rat model of acute sepsis. Br. L. Anest. 2013; 110 (3): 472-480.

397. Fieri C., Marra M., Moroni F. et al. Melatonin: a peroxyl radical scavenger more effective than vitamin E. Life Sci. 1994; 55 (15): PL271-PL276.

398. Sofic E., Rimpapa Z., Kundorovic Z. et al. Antioxidant capacity of the neurohormone melatonin. J. Neurol. Transm. 2005; 112 (3): 349-358.

399. Qi W., Reiter R.J., Tan D.X. et al. Cromium (III) -induced 8-hydroxydeoxygu-anosine in DNA and its reduction by antioxidants: comparative effects of melatonin, Ascorbate, and vitamin E. Environ. Health Respect 2000; 108 (5): 399-402.

400. Reiter R.J., Tan D.X., Manchester L.C., El-Sawi M. Melatonin reduces oxidant damage and promotes mitochondrial respiration: implications for aging. Annu. N.Y. Acad. Sci. USA 2002; 259: 238-250.

401. Tan D.X., Reiter R.J., Manchester L.C. et al. Chemical and physical properties and potential mechanisms: melatonin as broad spectrum antioxidant and free radical scavenger. Curr. Top Med. Chem. 2002; 2 (2): 181-197.

402. Acuna-Castroviejo D., Escames G., Lopez L.C. et al. Melatonin and nitric oxide: two required antagonists for mitochondrial homeostasis. Endocrine. 2005; 27 (2): 159-168.

403. Escames G., Lopez L.C., Tapias V. et al. Melatonin counteracts inducible mitochondrial nitric oxide synthase-dependent mitochondrial dysfunction in skeletal muscle of septic mice. J. Pineal Res. 2006; 40 (1); 71-78.

404. Rosen J., Than N.N., Koch D. et al. Interactions of melatonin and its metabolites with the ABTS cation radical: extension of the radical scavenger cascade and formation of a novel class of oxidation products, C2-substituted 3-indolinones. J. Pineal Res. 2006; 41 (4): 374-381.

405. Acuna-Castroviejo D., Escames G., Rodriguez M.I., Lopez L.C. Melatonin role in the mitochondrial function. Front Biosci. 2007; 12: 947-963.

406. Rodriguez M.I., Escames G., Lopez L.C. et al. Improved mitochondrial function and increased life span after chronic melatonin treatment in senescent prone mice. Exp. Gerontol. 2008; 43 (8): 479-756.

407. Urata Y., Honma S., Goto S. et al. Melatonin induces gamma-glutamylcysteine synthetase mediated by activator protein-1 in human vascular endothelial cells. Free Radic. Biol. Med. 1999; 27 (7-8): 838-847.

408. Winiarska K., Fraczyk T., Melinska D. et al. Melatonin attenuates diabetes-induced oxidative stress in rabbits. J. Pineal Res. 2006; 40 (2): 168-176.

409. Ross A.W., Barrett P., Mercer J.G., Morgan P.J. Melatonin suppresses the induction of AP-1 transcription factor components in the pars tuberalis of the pituitary. Mol. Cell. Endocrinol. 1996; 123 (1): 71-80.

410. Deng W.G., Tang S.T., Tseng H.P., Wu K.K. Melatonin suppresses macrophage cyclooxygenase-2 and inducible nitric oxide synthase expression by inhibiting p52 acetylation and binding. Blood. 2006; 108 (2): 518-524.

411. Luchetti F., Canonico B., Betti M. et al. Melatonin signaling and cell protection function. FASEB J. 2010; 24 (10): 3603-3624.

412. Murakami Y., Yuhara K., Takada N. et al. Effect of melatonin on cyclooxygenase-2 expression and Nuclear Factor-kappa B activation in RAW264.7 macrophage-like cells stimulated with fimbriae of Porphyromonas gingivalis. In vivo. 2011; 25 (4): 541-647.

413. Kilic U., Kilic E., Tuzcu Z. et al. Melatonin suppresses cisplatin-induced nephrotoxicity via activation of Nrf-2 / Ho-1 pathway. Nutr. Metab. 2013; 10: 7.

414. Haghjooy Javanmard S., Ziaei A., Ziaei S. et al. The effect of preoperative melatonin on nuclear erythroid 2-related factor 2 activation in patients undergoing coronary artery bypass grafting surgery. Oxid. Med. Cell. Longev. 2013; 2013: 676829.

415. Konakchieva R., Mitev Y., Almeida O.F.X., Patchev V.K. Chronic melatonin treatment and the hypothalamo-pituitary-adrenal axis in the rat: attenuation of the secretory response to stress and effects on hypothalamic neuropeptide content and release. Biol. Cell. 1997; 89 (9): 587-596.

416. Sejian V., Srivastava S. Effects of melatonin on adrenal cortical function of Indian goats under thermal stress. Vet. Med. Inter. 2010; ID 348919.

417. Carrillo-Vico A., Lardone P.J., Alvarez-Sanchez N. et al. Melatonin: buffering the immune system. Int. J. Mol. Sci. 2013; 14 (4): 8638-8683.

418. Park S.J., Tokura H. Bright light exposure during the daytime affects circadian rhythms of urinary melatonin and salivary immunoglobulin A. Chronobiol. Intern. 1999; 16 (3): 359-371.

419. Sun X., Shao Y., Jin Y. et al. Melatonin reduces bacterial translocation by preventing damage to the intestinal mucosae in an experimental severe acute pancreatitis rat model. Exp. Therapeut. Med. 2013; doi: 10.3892 / etm.2013.1338.

420. Sommanson A., Saudi W. S. W., Nylander O., Sjoblom M. Melatonin inhibits alcohol-induced increases in duodenal mucosal permeability in rats in vivo. Am. J. Physiol. Gastrointest. Liver Physiol. 2013; 303: G95-G105.

421. Chen C.F., Wang D., Reiter R.J., Yeh D.Y. Oral melatonin attenuates lung inflammation and airway hyper reactivity induced by inhalation of aerosolized pancreatic fluid in rats. J. Pineal Res. 2011; 50 (1): 46-53.

422. Storms W., Yawn B., Fromer L. Therapeutic options for reducing sleep impairment in allergic rhinitis, rhinosinusitis, and nasal polyps. Cur. Med. Opin. 2007; 23 (9): 2135-2146.

423. Craig T.J., Fergusson B.J., Krouse J.H. Sleep impairment in allergic rhinitis, rhinosinusitis, and nasal polyposis. Am. J. Otolaringol. 2008.29 (3): 209-217.

424. Alt J.A., Smith T.L. Chronic rhinosinusitis and sleep: a contemporary review. Int. Forum Allergy Rhinol. 2013; doi: 10.1002 / alr. 21217.

425. Bizunok N.A. Pleiotropic pharmacological effect - a new look at the action of biologically active compounds and drugs. New technologies. 2013; 2: 152-156.

426. Kong J., Zhang Z., Mussch M.W. et al. Novel role of the vitamin D receptor in maintaining the integrity of the intestinal mucosal barrier. Am. J. Physiol. Gastrointest. Liver Physiol. 2007; 294 (1): 20-25.

427. Hughes D.A., Norton R. Vitamin D and respiratory health. Clin. Exp. Immunol. 2009; 158 (1): 20-25.

428. Sun J. Vitamin D and mucosal immune function. Curr. Opin. Gastroenterol. 2010; 26 (6): 591-595.

429. Yin Z., Pintea V., Lin Y. et al. Vitamin D enhances corneal epithelial barrier function. Invest. Ophtalmol. Vis Sci. 2011; 52 (10): 7359-7364.

430. Schwalfenberg G.K. A review of the critical role of vitamin D in the functioning of the immune system and the clinical implications of vitamin D deficiency. Mol. Nutr. Food Res. 2011; 55: 96-108.

431. Sundaram M.E., Coleman L.A. Vitamin D and influenza. Adv. Nutr. 2012; 3 (4): 517-525.

432. Holick M.F., Chen T.C. Vitamin D deficiency: a worldwide problem with health consequences. Am. J. Clin. Nutr. 2008; 87 (4): S1080-S1086.

433. Holick M.F. Vitamin D deficiency. N. Engl. J. Med. 2007; 353 (3): 266-281.

434. Bouillon R., Carmeliet G., Verlinden L. et al. Vitamin D and Human health: lessions from vitamin D receptor null mice. Endocr. Rev. 2008; 29 (6): 726-776.

435. Carlberg C., Seuter S. A genomic perspective on vitamin D signaling. Anticancer Res. 2009; 29 (9): 3485-3493.

436. Zasloff M. Fighting infection with vitamin D. Nat. Med. 2006; 12 (4): 388-390.

437. Zanetti M. Cathelicidins, multifunctional peptides of the innate immunity. J. Leuk. Biol. 2004; 75 (1): 39-48.

438. Liu P.T., Stenger S., Li H. et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science. 2006; 311 (5768): 1770-1773.

439. Pushpanathan M., Gunasekaran P., Rajendhran J. Antimicrobial peptides: versatile biological properties. Int. J. Pept. 2013; 2013: 675391.

440. Tiabringa G.S., Aarbiou J., Ninander D.K. et al. The antimicrobial peptide LL-37 activate innate immunity at the airway surface by translocation of the epithelial growth factor receptor. J. Immunol. 2003; 171 (2): 6690-6696.

441. Otte J.M., Zdebik A.E., Brand S. et al. Effects of the cathelicidin LL-37 on intestinal epithelial barrier integrity. Regul. Pept. 2009; 156 (1-3): 104-117.

442. Doss M., Whithe M.R., Tecle T., Hartshorn K.L. Human defensins and LL-37 in mucosal immunity. J. Leukocyte Biol. 2010; 87 (1): 79-92.

443. Yuk J.M., Shin D.M., Lee H.M. et al. Vitamin D induces autophagy in human monocytes / macrophages via cathelicidin. Cell Host Microbe. 2009; 6 (3): 231-243.

444. Wu S., Sun J. Vitamin D, vitamin D receptor, and macroautophagy in inflammation and infection. Discov. Med. 2011; 11 (59): 325-335.

445. Gombart A.F. The vitamin D-antimicrobial peptide pathway and its role in protection against infection. Future Microbiol. 2009; 4 (9): 1151-1165.

446. Kunisawa J., Kiyono H. Vitamin-mediated regulation of intestinal immunity. Front Immunol. 2013; 4: 189. Doi: 10.3389 / fimmu.2013.00.009.

447. Cross H.S., Kallay E. Regulation of the colonic vitamin D system for prevention tumor progression: an update. Future Oncology. 2009; 5 (4): 493-507.

448. Khorchide M., Lechner D., Cross H.S. Epigenetic regulation of vitamin D hydroxylase expression and activity in normal and malignant human prostate cells. J. Steroid. Biochem. Mol. Biol. 2005; 93 (2-5): 167-172.

449. Essa D., Denzer N., Mahlknecht U. et al. VDR micro RNA expression and epigenetic silencing of vitamin signaling in melanoma cells. J. Steroid. Biochem. Mol. Biol. 2010; 121 (1-2): 110-113.

450. Camagna A., Testa U., Masciulli R. et al. The synergistic effect of simultaneous addition of retinoic acid and vitamin D3 on the in-vitro differentiation of human promyelocytic leukemia cell lines could be efficiently transposed in vivo. Med. Hypothesis. 1998; 50 (3): 253-257.

451. Sha J., Pan J., Ping P. et al. Synergistic effect and mechanisms of vitamin A and vitamin D on inducing of apoptosis of prostate cancer cells. Mol. Biol. Rep. 2013; 40 (4): 2763-2768.

452. Anand P.K., Kaul D., Sharma M. Synergistic action of vitamin D and retinoic acid restricts invasion of macrophages by pathogenic mycobacteria. J. Microbiol. Immunol. Infect. 2008; 41 (1): 17-25.

453. Mawson A.R. Role of fat-soluble vitamins A and D in the pathogenesis of influenza: a new perspective. ISRN Infect. Dis. 2013; 2013. ID 246737.

454. Cannel J.J., Zasloff M., Gardland C. et al. On the epidemiology of influenza. Virology J. 2008; 5 (1): 29-41.

455. Hansdottir S., Monick M.M., Hinde S.L. Respiratory epithelial cells covert inactive vitamin D to its active form: potential effects on host defense. J. Immunol. 2008; 181 (10): 7090-7099.

456. Ooi J.H., Li Y., Rogers C.J., Cantoma M.T. Vitamin D regulates the gut microbiome and protects mice from dextran sodium sulfate-induced colitis. J. Nutr. 2013; 143 (10): 1679-1686.

457. Alroy I., Towers TL, Freedman LP Transcriptional repression of the interleukin-2 gene by vitamin D ₃ : direct inhibition of NFATp / AP-1 complex formation by a nuclear hormone receptor. Mol. Cell. Biol. 1995; 15 (19): 5789-5799.

458. McMahon L., Schwartz K., Yilmaz O. et al. Vitamin D-mediated induction of innate immunity in gingival epithelial cells. Infect. Immun. 2011; 79 (6): 2250-2256.

459. Wu S., Sun J. Vitamin D, vitamin D receptor, and macroautophagy in inflammation and infection. Discov. Med. 2011; 11 (59): 325-335.

460. Chen Y., Zhang J., Ge X. et al. Vitamin D receptor inhibits nuclear factor kB activation by interacting with IkB kinase β protein. J. Biol. Chem. 2013; 288 (27): 1945-19458.

461. Lagishetty V., Misharin A.V., Liu N.Q. et al. Vitamin D deficiency in mice impairs colonic antibacterial activity and predisposes to colitis. Endocrinol. 2010; 151 (6): 2423-2432.

462. Ly N.P., Litonjua A., Gold D.R., Celedon J.C. Gut microbiota, probiotics, and vitamin D: interrelated exposures influencing allergy, asthma, and obesity? J. Allergy Clin. Immunol. 2011; 127 (5): 1087-1094.

463. Nasr L. B., Monet J. D., Lucas P., Bader C. A. Vitamin D3 and glucose-6-phosphate dehydrogenase in rat duodenal epithelial cells. Am. J. Physiol. 1989; 257 (5 Pt1): G760-G765.

464. Sardar S., Chakraborty A., Chatterjee M. Comparative effectiveness of vitamin D3 and dietary vitamin E on lipids and enzymes of the hepatic antioxidant system in Sprague-Dawley rats. Int. J. Vitam. Nutr. Res. 1996; 66 (1): 39-45.

465. Bao B.Y., Ting H.J., Hsu J.W., Lee Y.F. Protective role of 1 alpha, 25-dihydroxy-vitamin D3 against oxidative stress in nonmalignant human prostate epithelial cells. Int. J. Cancer. 2008; 122 (12): 2699-2706.

466. Wejse C., Gomes V.F., Rabna P. et al. Vitamin D as supplementary treatment for tuberculosis: a double-blind, randomized, placebo-controlled trial. Am. J. Crit. Care Med. 2009; 179 (9): 843-850.

467. Wang S. Epidemiology of vitamin D in health and disease. Nutr. Res. Rev. 2009; 22 (2): 188-203.

468. Kennel K.A., Drake M.T., Hurley D. Vitamin D deficiency in adults: when to test and how to treat. Mayo Clin. Proc. 2010; 85 (8): 752-758.

469. Ahmed M.S., Shoker A. Vitamin D metabolites, protective versus toxic properties: molecular and cellular perspectives. Nephr. Rev. 2010; 2: e5.

470. Alshohrani F., Aljohani N. Vitamin D: deficiency, sufficiency and toxicity. Nutrients 2013; 5: 3605-3616.

471. Furlong C.E. Paraoxonases: an historical perspective. In: B. Mackness, M. Mackness, M. Aviram, G. Paragh (Eds.) The Paraoxonases: Their role in disease development and xenobiotic metabolism. Springer, Dordrecht, Netherlands. 2008. P.3-31.

472. Bornscheuer U.T., Kazlauskas R.J. Catalytic promiscuity in biocatalysis: using old enzymes to form new bonds and follow new pathways. Angew. Chem. Int. Ed. Engl. 2004; 43 (45): 6032-6040.

473. Aharini A., Gaidukov L., Yagur S. et al. Directed evolution of mammalian Paraoxonases PON1 and PON3 for bacterial expression and catalytic specialization. Proc. Natl. Acad. Sci. USA 2004; 101 (2): 482-487.

474. Khersonsky O., Tawfik D.S. Structure-reactivity studies of serum paraoxonase POM1 suggest that native activity is lactonase. Biochemistry. 2005; 44 (16): 6371-6382.

475. Khersonsky O., Roodveldt S., Tawfik D.S. Enzyme promiscuity: evolutionary and mechanical aspects. Curr. Opin. Chem. Biol. 2006; 10 (5): 498-508.

476. Parsek M.R., Greenberg E.P. Acyl-homoserine lactone quorum sensing in gram-negative bacteria: a signal mechanism involved in association with higher organisms. Proc. Natl. Acad. Sci. USA 2000; 97 (16): 8789-8793.

477. Estin M.L., Stolz D.A., Zabner J. Paraoxonase 1, quorum sensing, and P. aeruginosa infection: a novel model. Adv. Exp. Med. Biol. 2000; 660: 183-193.

478. Rodriguez-Sanabria F., Rull A., Beltran-Debon R. et al. Tissue distribution and expression of Paraoxonases and chemokines in mouse: the ubiquitous and joint localization suggest a systemic and coordinated role. J. Mol. Histol. 2010; 41 (6): 379-386.

479. Camps J., Pujol I., Ballester F. et al. Paraoxonases as potential antibiofilm agents: their relationship with quorum-sensing signals in gram-negative bacteria. Antimicr. Agents. Chemother. 2011; 55 (4): 1325-1331.

480. Aviram M., Rosenblat M., Billecke S. et al. Human serum Paraoxonase (PON1) is inactivated by oxidized low density lipoprotein and preserved by antioxidants. Free Radio Biol. Med. 1999; 26 (7-8): 892-904.

481. Bayram F., Baskol G., Tanriverdi F. et al. Paraoxonase is reduced in patients with growth hormone deficiency: a novel risk factor for atherosclerosis. J. Res. Med. Sci. 2013; 18 (4): 291-296.

482. Kumon Y., Nakauchi Y., Suehiro T. et al. Proinflammatory cytokines but not acute phase serum amyloid A or C-reactive protein, downregulate Paraoxonase 1 (PON1) expression by HepG2 cells. Amyloid. 2002; 9 (3): 160-164.

483. Azizi F., Raiszadeh F., Solati M. et al. Serum Paraoxonase 1 activity is decreased in thyroid dysfunction. J. Endocrinol. Invest. 2003; 26 (8): 703-709.

484. Feingold K.R., Memon R.A., Moser A.H., Grunfed C. Paraoxonase activity in the serum and hepatic mRNA levels decrease during the acute phase response. Atheroscler 1998; 139 (2): 307-315.

485. Davis A.M., Haines D.C. Defending against infection: quorum quenching by enzymes in human liver microsomes. FASEB J. 2010; 24 (meeting abstracts): Ib209.

486. Teiber J.F., Horke S., Haines D.C. et al. Dominant role of paraoxonases in inactivation of the Pseudomonas aeruginosa quorum-sensing signal N- (3-oxododecanoyl) -L-homoserine lactone. Infect. Immun. 2008; 76 (6): 2512-2519.

487. Stolz D.A., Ozer E.A., Ng C.J. et al. Paraoxonase-2 deficiency enhances Pseudomonas aeruginosa quorum sensing in murine tracheal epithelia. Am. J. Physiol. Lung Cell. Mol. Physiol. 2007; 292 (4): L852-L860.

488. Asian M., Nazligul Y., Horoz M. et al. Serum paraoxonase-1 activity in Helicobacter pylori infected subjects. Atheroscler 2008; 196 (1): 270-274.

489. Manolescu B.N. Paraoxonases as protective agents against N-acyl homoserine lactone-producing pathogenic microorganisms. Maedica. 2013; 8 (1): 49-52.

490. Costa L.G., Giordano G., Furlong C.E. Pharmacological and dietary modulators of paraoxonase 1 (PON1) activity and expression: the hunt goes on. Biochem. Pharmacol 2011; 81 (3): 337-344.

491. Ravindranath T.M., Mong P.Y., Ananthakrishnan R. et al. Novel role for aldose reductase in mediating acute inflammatory responses in the lung. J. Immunol. 2009; 183 (12): 8128-8137.

492. Pandey S., Srivastava S.K., Ramana K.V. A potential therapeutic role for aldose reductase inhibitors in the treatment of endotoxin-related inflammatory diseases. Expert Opin. Invest. Drugs 2012; 21 (3): 329-339.

493. Mizishina Y., Kuramochi K., Ikawa H. et al. Structural analysis of epolactaene derivatives as DNA polymerase inhibitors and anti-inflammatory compounds. Int. J. Mol. Med. 2005; 15 (5): 785-793.

494. Bau J.T., Kurz E.U. Sodium salicylate is a novel catalytic inhibitor of human DNA topoisomerase II alpha. Biochem. Pharmacol 2011; 81 (3): 345-354.

495. Moskaug J.Q., Carlsen H., Myhrstad M., Blomhoff R. Molecular imaging of the biological effects of quercetin and quercetin-rich foods. Mech Ageing Dev. 2004; 125 (4): 315-324.

496. Bischoff S.C. Quercetin potentials in the prevention and therapy of diseases. Curr. Opin. Clin. Nutr. Metab. Care 2008; 11 (6): 733-740.

497. Romero M., Jemenez R., Sanchez M. et al. Quercetin inhibits vascular superoxide production induced by endothelin-1: role of NADPH oxidase, uncoupled eNOS and PKC. Atheroscler 2009; 202 (1): 58-67.

498. Paolillo R., Carratelli C. R., Rizzo A. Effect of resveratrol and quercetin in experimental infection by Salmonella enterica serovar Typhimurium. Int. Immunopharmacol. 2011; 11 (2): 149-156.

499. Carrasco-Pozo S., Mizgier M. L., Speisky H., Gotteland M. Differential protective effects of quercetin, resveratrol, rutin and epigallocatechin against mitochondrial dysfunction induced by indomethacin in Caco-2 cells. Chem. Biol. Interact 2012; 195 (3); 199-205.

500. Boesch-Saadatmandi S., Wagner A.E., Wolffram S., Rimbach G. Effect of quercetin on inflammatory gene expression in mice liver in vivo - role ofredox factor 1, miRNA-122 and miRNA-125b. Pharmacol / Res. 2012; 65 (5): 523-530.

501. Wang B. L., Gao X., Men K. et al. Treating acute cystitis with biodegradable micelle-encapsulated quercetin. Int. J. Nanomedicine. 2012; 7: 2239-2247.

502. Bindoli A., Vakente M., Cavallini L. Inhibitory action of quercetin on xanthine oxidase and xanthine dehydrogenase activity. Pharmacol Res. Commun. 1985; 17 (9): 831-839.

503. Pauf J.H., Hille R. Inhibition studies of bovine xanthine oxidase by luteolin, silibinin, quercetin and circumin. J. Nat. Prod. 2009; 72 (4): 725-731.

504. Hirota S., Takahama U., Ly T.N., Yamauchi R. Quercetin-dependent inhibition of nitration induced by peroxidase / H2O2 / nitrite system in human saliva and characterization of an oxidation product of quercetin formed during the inhibition. J. Agric. Food Chem. 2005; 53 (9); 3265-3272.

505. Mird L., Fernandez M.T., Santos M. et al. Interactions of flavonoids with iron and copper ions: a mechanism for their antioxidant activity. Free Radic. Res. 2002; 36 (11): 1199-1208.

506. Pekal A., Biesaga M., Pyrzinska K. Interaction of flavonoids with copper ions: complexation, oxidation and reactivity towards radicals. Biometals. 2011; 24 (1): 41-49.

507. Baccan M.M., Chiarelli-Neto O., Pereira R.M., Esposito B.P. Quercetin as shuttle for labile iron. J. Inorg. Biochem. 2012; 107 (1): 34-39.

508. Nanua S., Zick S.M., Andrade J.E. et al. Quercetin blocks airway epithelial cells chemokine expression. Am. J. Respir. Cell. Mol. Biol. 2006; 35 (5): 602-610.

509. Ganesan S., Faris A.N., Comstock A.T. et al. Quercetin prevents progression of disease in elastase / LPS-exposed mice by negatively regulating MMP expression. Respir. Res. 2010; 11 (1): 131. Doi: 10.1186 / 1465-9921-11-131.

510. Davis J.M., Murphy E.A., McClellan J.L. et al. Quercetin reduces susceptibility to influenza infection following stressful exercise. Regul. Integr. Compar. Physiol. 2008; 295 (2): R505-R509.

511. Kawabata K., Kawai Y., Terao J. Suppressive effect of quercetin on acute stress-induced hypothalamic-pituitary-adrenal axis response in Wistar rats. J. Nutr. Biochem. 2010; 21 (5): 374-380.

512. Choi H.J., Kim J.H., Lee C.H. et al. Antiviral activity of quercetin 7-rhamnoside against porcine epidemic diarrhea virus. Antiviral. Res. 2009; 81 (1): 77-81.

513. Kim Y., Narayanan S., Chang K.O. Inhibition of influenza virus replication by plant-derived isoquercetin. Antiviral. Res. 2010; 88 (2): 227-235.

514. Uchide N., Toyoda H. Antioxidant therapy as a potential approach to severe influenza-associated complications. 2011; 16: 2032-2052.

515. Johari J., Kianmehr A., Mustafa M.R. et al. Antiviral activity of baicalein and quercetin against Japanese encephalitis virus. Int. J. Mol. Sci. 2012; 13 (12): 16785-16795.

516. Ganesan S., Faris A.N., Comstock A.T. et al. Quercetin inhibits rhinovirus replication in vitro and in vivo. Antiviral. Res. 2012; 94 (3): 258-271.

517. Rivera L., Moron R., Sanchez M. et al. Quercetin ameliorates metabolic syndrome and improves the inflammatory status in obese Zucher rats. Obesity. 2008; 16 (9): 2081-2087.

518. Panchal S.K., Poudyal H., Brown L. Quercetin ameliorates cardiovascular, hepatic, and metabolic changes in diet-induced metabolic syndrome in rats. J. Nutr. 2012; 142 (6): 1026-1032.

519. US Patent application 20100292287. 11/18/2010.

520. Geoghegan F., Wong R.W., Rabie A.B. Inhibitory effect of quercetin on periodontal pathogens in vitro. Phytother. Res. 2010; 24 (6): 817-820.

521. Middleton E.Jr., Kandaswami S., Theoharides T.C. The effects of plant flavonoids on mammalian cells: implication for inflammation, heart disease, and cancer. Pharmacol Rev. 2000; 52 (4): 673-751.

522. Antipenko VV Conservative and surgical treatment of chronic nonspecific tonsillitis. Diss. ... cand. honey. sciences. SPb. 2009.160 s.

523. Helms S., Miller A.L. Natural treatment of chronic rhinosinusitis. Altem Med. Rev. 2006; 11 (3): 196-207.

524. Balabantsev A.G., Pobersky V.V., Bogdanov V.V. Principles of anti-relapse treatment of patients with polypoid rhinosinusitis, taking into account the state of anti-endotoxin immunity. Ross rhinology. 2005; 2: 8-9.

525. Mavzyutov A.R., Murzabaeva R.T., Mavzyutova G.A. and other nature of changes in the level of lipopolysaccharide-binding protein in various infectious processes and dysbiosis. Zhurn. microbiol. epidemiol. immunobiol. 2011; 2: 66-72.

526. Higaki T., Okamo M., Fujiwara T. et al. COX / PGE (2) axis critically regulates effects of LPS on eosinophilia-associated cytokine production in nasal polyps / Clin. Exp. Allergy. 2012; 42 (8); 1217-1226.

527. Yamazaki L., Suzuki K., Yamada E. et al. Suppression of iodide uptake and thyroid hormone synthesis with stimulation of the type I interferon system by double-stranded ribonucleic acid in cultured human thyroid follicles. Endocrinol. 2007; 148 (7): 3226-3235.

528. Nicola J.P., Velez M.L., Lucero A.M. et al. Functional toll-like receptor 4 conferring lipopolysaccharide responsiveness is expressed in thyroid cells. Endocrinol. 2009; 150 (1): 500-508.

529. Okayasu I., Hatakeyama A. A combination of necrosis of autologous thyroid gland and injection of lipopolysaccharide induces autoimmune thyroiditis. Clin. Immunol. mimunopathol. 1984; 31 (3): 344-352.

530. Van der Poll, T., Van Zee, K.J., Endert, E. et al. Interleukin-1 receptor blockade does not affect endotoxin-induced changes in plasma thyroid hormone and thyrotropin concentration in man. J. Clin. Endocrinol. Metab. 1995; 80 (4): 1341-1346.

531. Van der Poll T., Endert E., Coyle S.M. et al. Neutralization of TNF does not influence endotoxin-induced changes in thyroid hormone metabolism in humans. Am. J. Physiol. 1999; 276 (2 Pt2): R357-R362.

532. Boelen A., Kwakkel J., Platvoetter Schiphorst M. et al. Interleukib-18, a proinflammatory cytokine, contributes to pathogenesis of non-thyroid illness mainly via central part of the hypothalamus-pituitary-thyroid axis. Eur. J. Endocrinol. 2004; 151 (4): 497-502.

533. Abu Elhija M., Lunenfeld E., Huleihel M. LPS increases the expression levels of IL-18, ICE and IL-18 R in mouse testes. Am. J. Reprod. Immunol. 2008; 60 (4): 361-371.

534. Biegneux A.R., Moser A.H., Shigenaga J.K. et al. Sick euthyroid syndrome is associated with decreased TR expression and DNA binding in mouse liver. Am. J. Physiol. Endocrinol. Metab. 2003; 284 (1): E228-E236.

535. Boelen A., Kwakkel J., Fliers E. Beyond low plasma T3: local thyroid hormone metabolism during inflammation and infection. Endocrin. Rev. 2011; 32 (5): 670-693.

536. Birring S.S., Patel R. B., Parker D. et al. Airway function and markers of airway inflammation in patients with treated hypothyroidism. Torax. 2005; 60: 249-253.

537. Gazmatov E.G. Features of the treatment of allergic rhinitis and rhinosinusitis associated with pathology of the thyroid gland. Diss. ... cand. honey. sciences. M. 2008.134 s.

538. Gunel S., Basak H.S., Guney E. The relationship between hypothyroidism and rhinitis. Kulak Burun Bodaz Ihtis Derg. 2010; 20 (4): 163-168.

539. Malo M.S., Zhang W., Alhhoury F. et al. Thyroid hormone positively regulates the enterocyte differentiation marker intestinal alkaline phosphatase gene via an atypical response element. Mol. Endocrinol. 2004; 18 (8): 1941-1962.

540. Plateroli M., Kress E., Mori J.I., Samarut J. Thyroid hormone receptor alpha 1 directly controls transcription of beta-catenin gene in intestinal epithelial cells. Mol. Cell. Biol. 2006; 26 (8): 3204-3214.

541. Safer J.D. Thyroid hormone action on skin. Dermatoendocrinol. 2011; 3 (3): 211-215.

542. Wang Z.G. The protective effect of thyroid hormone in rats with obstructive jaundice. Thesis. 2007.

543. Hasebe T., Fu L., Miller T.C. et al. Thyroid hormone-induced cell-cell interactions are required for the development of adult intestinal stem cells. Cell. Biosci. 2013; 3 (1): 18.

544. Hodin R.A., Chamberlain S.M., Upton M.P. Thyroid hormone differentially regulates rat intestinal brush border enzyme gene expression. Gastroenterol. 1992; 103 (5): 1529-1536.

545. Jonas S., Hollfelder F. Mapping catalytic promiscuity in the alkaline phosphatase superfamily. Pure appl. Chem. 2009; 81 (4): 731-742.

546. Duarte F., Amrein B.A., Kamerlin S.C.L. Modeling catalytic promiscuity in the alkaline phosphatase superfamily. Phys. Chem. Chem. Phys. 2013; 15 (27): 11160-11177.

547. Lalles J.P. Intestinal alkaline phosphatase: multiple biological roles in maintenance of intestinal homeostasis and modulation by diet. Nutr. Rev. 2010; 68 (6): 323-332.

548. Vaishnava S., Hooper L.V. Alkaline phosphatase: keeping the peace at the gut epithelial surface. Cell Host Microbe. 2007; 2 (6): 365-367.

549. Long J., Zaborina O., Holbrook C. et al. Depletion of intestinal phosphate after operative injury activates the virulence of Pseudomonas aeruginosa causing lethal gut-derived sepsis. Surgery 2008; 144 (2): 189-197.

550. Zaborin A., Romanowski K., Morozowa I. et al. Intestinal phosphate depletion develops during human critical illness and activates the virulence of key pathogens associated with gut-derived sepsis. Surgical Infection Society Thirtieth Annual Meeting. 2010. Nevada, Las Vegas. sisna.org/abstracts/2010/10.cgi.

551. Romanowski K., Zaborin A., Fernandez H. et al. Prevention of siderophore-mediated gut-derived sepsis due to P. aeruginosa can be achieved without iron provision by maintaining local phosphate abundance: role of pH. BMC Microbiol. 2011; 11: 212.

552. Lamarche M., Wanner B.L., Crepin S., Harel J. The phosphate regulon and bacterial virulence: a regulatory network connecting phosphate homeostasis and pathogenesis. FEMS Microbiol. Rev. 2008; 32 (3): 461-473.

553. Zaborin A., Gerdes S., Hobrook C. et al. Pseudomonas aeruginosa overrides the virulence inducing effect of opioids when it senses an abundance of phosphate. PLOS ONE. 2012; 7 (4): e34883.

554. Mittag J., Behrends T., Hoefig C.S. et al. Thyroid hormones regulate selenoprotein expression and selenium status in mice. PLOS ONE. 2010; 5 (9): el2931.

555. Liu M.L., Xu G., Huang Z.Y. et al. Euthyroid sick syndrome and nutritional status are correlated with hyposelenemia in hemodialysis patients. Int. J. Artif. Organs. 2011; 34 (7): 577-583.

556. Drutel A., Archambeaud F., Caron P. Selenium and the thyroid gland: more good news for clinicians. Clin. Endocrinol. 2013. 78 (2): 155-164.

557. Chopra I.J., Chopra U., Smith S.R. et al. Reciprocal changes in serum concentration of 3.3 ′, 5-triiodothyronine (T3) in systemic illness. J. Clin. Endocrinol. Metab. 1975; 41 (6): 1043-1049.

558. Bianco A.C., Nunes M.T., Hell N.S., Maciel R.M.B. The role of glucocorticoids in the stress-induced reduction of extrathyroidal 3,5,3′-triiodthyronine generation in rats. Endocrinol. 1987; 120 (3): 1033-1038.

559. Reed H.L., Brice D., Shakir K.M. et al. Decreased free fraction of thyroid hormones after prolonged Antarctic residence. J. Appl. Physiol. 1990; 69 (4): 1467-1472.

560. Bianco A.C., Salvatore D., Gereben B. et al. Biochemistry, cellular and molecular biology, and physiological roles of the lodothyronine selenodeiodinases. Endocr. Rev. 2002; 23 (1): 38-89.

561. Peeters R. P., Wouters P. J., Kaptein E. et al. Reduced activation and increased inactivation of thyroid hormones in tissues of critically ill patients. J. Clin. Endocrinol. Metab. 2003; 88 (7): 3202-3211.

562. Peeters R.P., Wouters P.J., van Toor H. et al. Serum 3,3 ′, 5′-triiodthyronine (rT3) and 3,5,3′-triiodthyronine / rT3 are prognostic markers in critically ill patients and are associated with postmortem tissue Deiodinase activities. J. Clin. Endocrinol. Metab. 2005; 90 (8): 4559-4565.

563. Pittman J.A., Tinglei J.O., Nickerson J.F., Hill S.R.Jr. Antimetabolic activity of 3.3 ′, 5′-triiodo-DL-thyronineinman. Metabolism. 1960; 9: 293-295.

564. Sechman A., Niezgoda J., Sobocinski R. The relationship between basal metabolic rate (BMR) and concentration of plasma thyroid hormones in fasting cockerels. Folia Biol. 1989; 37 (1-2): 83-90.

565. Okamoto R., Leibfritz D. Adverse effects of reverse triiodthyronine on cellular metabolism as assessed by 1H and 31P NMR spectroscopy. Res. Exp. Med. 1997; 197 (4): 211-217.

566. Tien E. S., Matsui K., Moore R., Negishi M. The nuclear receptor constitutively active / androstane receptor regulates type 1 deiodinase and thyroid hormone activity in the regenerating mouse liver. J. Pharmacol. Exp. Ther. 2007; 320 (1): 307-313.

567. Visser T.J., Lamberts W.J., Wilson J.H. et al. Serum thyroid hormone concentration during prolonged reduction of dietary intake. Metabolism. 1978; 27 (4): 405-409.

568. Mitchell A.M., Manley S.W., Rowan K.A., Mortimer R.H. Uptake of reverse T3 in the human choriocarcinoma cell line, JAr. Placenta. 1999; 20 (1): 65-70.

569. Nicoloff J.T., Fisher D.A., Appleman M.D. The role of glucocorticoids in the regulation of thyroid function in man. J. Clin. Invest. 1970; 49 (10): 1922-1929.

570. Banos C., Tako J., Salamon F. et al. Effect of ACTH-stimulated glucocorticoid hyper-secretion on the serum concentration of thyroxine-binding globulin, thyroxine, triiodothyronine, reverse triiodothyronine and on the TSH-response to TRH. Acta Med. Acad. Sci. Hung 1979; 36 (4): 381-394.

571. Brabant G., Brabant A., Ranft U. et al. Circadian and pulsatile thyrotropin secretion in euthyroid man under the influence of thyroid hormone and glucocorticoid administration. J. Clin. Endocrinol. Metab. 1987; 65 (1): 83-88.

572. Forhead A.J., Curtis K., Kaptein E. et al. Developmental control of iodothyronine deiodinases by cortisol in the ovine fetus and placenta near term. Endocrinol. 2006; 147 (12); 5988-5994.

573. Cremaschi G.A., Gorelik G., Klecha A.J. et al. Chronic stress influences the immune system through the thyroid axis. Life Sci. 2000; 67 (26): 1323-1329.

574. DeGroot L.J. "Non-thyroidal illness syndrome" is functional central hypothyroidism, and if severe, hormone replacement is appropriate in light of present knowledge. J. Endocrinol. Invest. 2003; 26 (12): 1163-1170.

575. Gupta A.M. Regulation of type 3 iodothyronine deiodinase by glucocorticoids. Boston: Boston University. 2009.88p.

576. Boyarskaya A.M., Osadchaya O.I., Kovalenko O.N. The use of enterosorbent enterosgel in the complex treatment of intestinal dysbiosis in children with burn disease. Honey. inevitable states. 2006; 1 (2): 50-52.

577. Nemtsov V.I. Disorders of the intestinal microflora and metabolic syndrome. Clinical Lab. consultation. 2010; 1 (32): 4-12.

578. Order of the Ministry of Health of the USSR No. 535 of 04/22/1985 on the unification of microbiological (bacteriological) research methods used in clinical diagnostic laboratories of medical institutions.

579. Private Virology: A Guide. Ed. Zhdanova V.M., Gaidamovich S.Ya. M .: Medicine. 1982.Vol. 2. 520 s

580. Medical microbiology. Ch. ed. Pokrovsky V.I., Pozdeev O.K. M .: GEOTAR Medicine. 1999. 1200 s.

581. Order of the Ministry of Health of the Russian Federation dated 09.06.2003 No. 231 On the approval of the industry standard “Protocol for the management of patients. Intestinal dysbiosis. " (OST 91500.11.0004-2003).

582. Mancini G., Carbonara A.O., Heremans J.F. Immunochemical quantitation of antigens by single radial immunodiffusion. Immunochem. 1965; 2 (3): 235-254.

583. Bukharin O.B., Vasiliev N.V. Lysozyme and its role in biology and medicine. Tomsk: Publ. Tomsk University. 1974. 208 p.

584. Vorobyov A.A., Minaev V.I., Bondarenko V.M. et al. Bacterial endotoxinemia in children with intestinal dysbiosis. Zhurn. microbiol. epidemiol. immunobiol. 1999; 3: 67-70.

585. Kagan L.G. Hyperendotoxinemia in case of dysbiosis caused by antibiotic therapy and its correction in geriatric practice. Abstract. diss. ... cand. honey. sciences. M. 2004. 24 p.

586. Garaeva Z.Sh., Safina N.A., Tyurin Yu.A. et al. Intestinal dysbiosis as a cause of systemic endotoxinemia in patients with psoriasis. Vestn. dermatol. venerol. 2007; 1: 23-27.

587. Visegurov Y. Kh. Intestinal endotoxin as a universal factor in the pathogenesis of endogenous inflammatory pathology of the eye and antiendotoxin direction of its treatment. Diss. ... doctors honey. sciences. M. 2007.200 p.

588. RF patent 2169367 C1.

589. Kobylyansky V.I. Mucociliary system. Fundamental and applied aspects. M .: Binom. 2008.416 p.

590. Kozlov B.C., Shilenkova VV, Azatyan A.S., Kramnoy A.I. Mucociliary transport and motor activity of the ciliary apparatus of the nasal mucosa in patients with chronic polypous rhinosinusitis. Bulletin of otorhinolaryngol. 2008; 2: 10-13.

591. Volkov A.G., Bojokov A.R. Can the speed of mucociliary transport of the nasal mucosa serve as an expert test? Basic research. 2007; 12: 382-383.

Table 1 - Carriage of pathogens of a bacterial nature on the mucous membrane of the nasopharynx with recurrent rhinosinusitis in the inter-relapse period before and after the prevention of exacerbations Prevention Method Type of pathogen Carriage of bacteria (pers./%) Remediation (krat) before prevention after prophylaxis The claimed S. aureus 12 / 54.5 - complete way S. pneumoniae 5 / 22.7 - complete (n = 22) H. influenzae 13 / 59.1 - complete Way- S. aureus 14 / 60.9 11 / 47.8 1.27 prototype S. pneumoniae 4 / 17.4 4 / 17.4 - (n = 23) H. influenzae 12 / 52.2 9 / 39.1 1.33

table 2 - Carriage of viral pathogens on the mucous membrane of the nasopharynx with recurrent rhinosinusitis in the inter-relapse period before and after the prevention of exacerbations Prevention Method Carriage of ARVI viruses (person /%) Remediation (krat) before prevention after prophylaxis The inventive method (n = 22) 21 / 95.5 - complete Prototype method (n = 23) 22 / 95.7 16 / 69.6 1.38

Table 3 - Colonization of the mucous membrane of the nasopharynx with symbiont microorganisms in case of recurrent rhinosinusitis in the intercurrent period before and after the prevention of exacerbations Prevention Method Type of bacteria Colonization of the nasopharynx (CFU / ml) before prevention after prophylaxis The claimed Lactobacterium spp (0.1-0.7) · 10 ² (1.0-4.0) · 10 ⁴ method (n = 22) Bifidobacterium spp (0.1-0.5) · 10 ² (0.8-1.5) · 10 ³ Prototype method (n = 23) Lactobacterium spp bifidobacterium spp (0.1-0.7) · 10 ² (0.1-0.6) · 10 ² (0.1-0.9) 10 ² (0.2-0.8) 10 ²

Table 4 - The severity of intestinal dysbiosis (degree of microbiological disorders) with recurrent rhinosinusitis in the inter-relapse period before and after the prevention of exacerbations Prevention Method Study period The nature of microbiological disorders (person /%) 1 degree 2 degrees 3 degrees eubiosis The inventive method before prevention 9 / 40.9 13 / 59.1 - - (n = 22) after prophylaxis ¼, 5 - - 21 / 95.5 Prototype method before prevention 8 / 34.8 15 / 65.2 - - (n = 23) after prophylaxis 10 / 43.5 13 / 56.5 - -

Table 5 - Levels of immunoglobulins in the oral fluid with recurrent rhinosinusitis in the inter-relapse period before and after the prevention of exacerbations Prevention Method Study period IgA level (g / l) SIgA Level (g / l) The inventive method (n = 22) before prevention 0.19 ± 0.03 0.25 ± 0.06 after prophylaxis 0.13 ± 0.04 0.51 ± 0.08 * Prototype method (n = 23) before prevention 0.18 ± 0.02 0.27 ± 0.05 after prophylaxis 0.17 ± 0.03 0.31 ± 0.07 Reference indicators: norms of IgA level - 0.12 ± 0.04 g / l; sIgA level norms - 0.55 ± 0.06 g / l; * - the difference in the group is significant

Table 6 - The level of lysozyme in the oral fluid with recurrent rhinosinusitis in the inter-relapse period before and after the prevention of exacerbations Prevention Method Study period Lysozyme level (mcg / ml) The inventive method before prevention 9.15 ± 0.73 after prophylaxis 14.22 ± 0.87 * Prototype method before prevention 9.30 ± 0.71 after prophylaxis 10.17 ± 0.80 The reference indicator of the norm of lysozyme level is 13.12 ± 0.65 μg / ml; * - the difference in the group is significant

Table 7 - The level of endotoxin in the blood of patients with recurrent rhinosinusitis in the inter-relapse period before and after the prevention of exacerbations Prevention Method Study period Endotoxin Level (EU / ml) The inventive method before prevention 2.47 ± 0.53 after prophylaxis 0.35 ± 0.09 * Prototype method before prevention 2.39 ± 0.62 after prophylaxis 2.55 ± 0.57 The reference indicator of the norm of the endotoxin level is 0.37 ± 0.11 EU / ml

Table 8 - The level of malondialdehyde in the blood plasma of patients with recurrent rhinosinusitis in the inter-relapse period before and after the prevention of exacerbations Prevention Method Malondialdehyde Level (μM / L) before prevention after prophylaxis The inventive method 2.09 ± 0.16 1.25 ± 0.07 * Prototype method 2.07 ± 0.13 1.95 ± 0.12 The reference indicator of the norm of the level of malondialdehyde is 1.3 ± 0.06 μM / L; * - the difference in the group is significant

Table 9 - The state of mucociliary transport of the nasal mucosa in patients with recurrent rhinosinusitis in the inter-relapse period before and after the prevention of exacerbations Prevention Method Mucociliary transport time (min) before prevention after prophylaxis The inventive method 24.7 ± 1.3 12.1 ± 0.7 * Prototype method 23.9 ± 1.4 21.3 ± 1.6 The reference indicator of the norm is 12.5 ± 0.6 min; * - the difference in the group is significant

Table 10 - The state of mucociliary transport of the mucous membrane of the maxillary sinuses in patients with recurrent rhinosinusitis in the inter-relapse period before and after the prevention of exacerbations Prevention Method Mucociliary transport time (min) before prevention after prophylaxis The inventive method 32.2 ± 2.6 16.1 ± 0.8 * Prototype method 33.5 ± 2.4 28.7 ± 2.2 The reference indicator of the norm is 16.9 ± 0.9 min; * - the difference in the group is significant

Table 11 - The dynamics of the frequency of exacerbations of recurrent rhinosinusitis under the influence of prevention by the claimed method and the prototype method Exacerbation rate The number of patients, people (%) Before prevention After prophylaxis without dynamics decrease extinction The inventive method 1-2 times a year 5 (22.7) - - 5 (22.7) 3-4 times a year 14 (63.6) - - 14 (63.6) 5 or more times 3 (13.6) - 2 (9.1) 1 (4,5) Total 22 (100) - 2 (9.1) 20 (90.9) Prototype method 1-2 times a year 6 (26.1) 4 (17.4) 2 (8.7) - 3-4 times a year 15 (65.2) 12 (52.2) 3 (13.0) - 5 or more times 2 (8.7) 2 (8.7) - - Total 23 (100) 18 (78.3) 5 (21.7) -

Claims (1)

A method for the prevention of exacerbations of recurrent rhinosinusitis through course prescribing, during the inter-relapse period, of systemic and local preparations, characterized in that they comprehensively spend three weeks correcting the main pathogenetic mechanisms of recurrent inflammation of the nasal mucosa and paranasal sinuses, including stress-protective therapy, diet therapy, therapy for stopping the deficiency of omega-3 polyunsaturated fatty acids, vitamin therapy, probiotic therapy, topical and systemic therapy with prebiotic-like drugs, antioxidant therapy, and local immunocorrective therapy, while stress-protective therapy is prescribed a tricyclic antidepressant amitriptyline daily at a sub-therapeutic dose of 6.25 mg - 1/4 tablet daily as a stress protector;
when conducting diet therapy, the diet includes morning and evening portions of oatmeal 200-300 ml each, each of which is prepared from 100-125 g of oatmeal, and 200-300 g of buckwheat porridge as an independent dish or side dish are included in the lunch menu and one raw chicken egg protein, monosaccharides, disaccharides and dishes containing them, as well as foods and drinks in the form of chocolate, cocoa, coffee, tea, which include phosphodiesterase inhibitors, for preparing the first, second courses, desserts and drinks, are excluded from the diet I use only filtered water, and for drink - also boiled;
during therapy to eliminate the deficiency of omega-3 polyunsaturated fatty acids, fish oil is prescribed in the form of the drug “Biafischenol” daily three times a day with meals, 5 capsules, each of which contains 300.0 mg of fish oil, for three weeks;
when conducting vitamin therapy appoint:
- vitamins B ₁ , B ₆ , B ₁₂ in the composition of the drug "Neuromultivit" daily orally once a day after meals, one tablet containing 100.0 mg of vitamin B ₁ , 200.0 mg of vitamin B ₆ , 200.0 μg of vitamin B ₁₂ ;
- Vitamin B ₇ as part of the Biotin Complex preparation, orally daily once a day with meals, one tablet containing 121-150 μg of vitamin B ₇ ;
- vitamin B ₉ in the composition of the folic acid daily daily, once a day, before meals, 1/2 tablet, and half a tablet of folic acid contains 0.5 mg of vitamin B ₉ ;
- Vitamin A in the composition of Retinol Acetate during the first week, daily, orally, once a day, after meals, one capsule containing 33000 IU of Retinol acetate, and then orally, once a day, after the meal, one capsule containing one 33,000 IU of retinol acetate;
- vitamin E in the composition of the drug "Alpha-tocopherol acetate" during the first week, daily, orally, three times a day, one capsule containing 100.0 mg of alpha-tocopherol acetate, and then for the next two weeks, daily, orally, twice a day, one capsule containing 100.0 mg of alpha-tocopherol acetate;
- Vitamin D ₃ in the composition of the drug "AquaDetrim" daily orally once a day at a dose of 2000 ME - four drops;
- Vitamin C in the composition of the ascorbic acid preparation during the first week every day three times a day in two tablets, each of which contains 50.0 mg of vitamin C, and then during the next two weeks, twice daily, orally, twice a day dragees, each of which contains 50.0 mg of vitamin C;
during probiotic therapy, a third-generation probiotic of the third generation “Bifiform” is prescribed orally daily after meals, one capsule three times a day for three weeks;
during the treatment with prebiotic-like drugs for three weeks, a 1.67% solution of emoxipin succinate in the form of the drug “Mexidol” and 0.25% solution of ambroxol hydrochloride in the form of the drug “Lazolvan” in a 0.33% solution are prescribed daily three times a day novocaine in a volume of 3.0 ml in each nasal passage for 8-10 minutes, a three-component solution is prepared immediately before use by mixing in a single bottle of 2.0 ml of official 1% ampoule solution of novocaine, 5% ampoule solution of emoxip of succinate in the form of Mexidol preparation and 0.75% ampoule solution of Ambroxol hydrochloride in the form of Lazolvan preparation, moreover, it is recommended to swallow the three-component solution after instillation into the nasal passages and as it flows down the mucous membrane of the nasal cavity and the posterior wall of the nasopharynx. provides topical and systemic effects of substances of a three-component solution; Enterosgel is prescribed daily orally three times a day, two hours after meals and medications, 15 g each - one tablespoon; calcium glycerophosphate is administered orally three times a day after meals, one tablet containing 0.2 g of the substance;
when conducting antioxidant therapy appoint:
- lipoic acid for three weeks daily orally three times a day after meals, one tablet containing 25.0 mg of lipoic acid;
- N-acetylcysteine in the form of “ACC 200” for three weeks, orally daily three times a day after meals, one effervescent tablet containing 200.0 mg of N-acetylcysteine, after preliminary dissolution in water;
- dihydroquercetin during the first week, daily orally three times a day with meals, one tablet containing 25.0 mg of dihydroquercetin, and then for the next two weeks daily, orally twice a day with meals, one tablet containing 25.0 mg dihydroquercetin;
- melatonin in the composition of the drug "Melaxen" for three weeks daily, orally once a day, one tablet containing 3.0 mg of melatonin, thirty minutes before bedtime;
- selenium in the composition of the drug "Selenium-Active" for three weeks daily orally once a day with meals, one tablet containing 50.0 μg of selenium;
when conducting local immunocorrective therapy, the drug "Imudon" is prescribed in the form of tablets for resorption for three weeks daily six times a day every two hours.