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POSSIBILITIES FOR PREVENTING EXACERBATIONS OF CHRONIC
RESPIRATORY DISEASES
Khushvakova Nilufar Jurakulovna
D.M.Sc, Professor, Head of the department of Otorhinolaryngology №1 Samarkand State Medical Institute Uzbekistan Sanginov Mirmuhammad Xolboyevich 2nd year clinical ordinator of the Department of Otorhinolaryngology No. 1 of the
Samarkand State Medical University Turaev Sherali Jurabek ugli 6th year student of the pediatrics faculty of the Samarkand State Medical University
Annotation: Control of virus-induced inflammation of the respiratory tract in patients with chronic bronchopulmonary pathology remains an urgent medical task. Management of the immune response in case of acute respiratory viral infection (ARVI) in such patients seems to be one of the promising areas. This review summarizes the results of observational programs and initiative studies demonstrating the experience of using a drug based on technologically processed antibodies, which has an immune-mediated antiviral and antibacterial effect, in patients in pulmonology practice. The mechanism of action of the drug is associated with the activation of antigen processing and presentation with the participation of molecules of the major histocompatibility complex, which in turn contributes to the formation of an adequate immune response in the infectious process, which determines the possibility of its use in the treatment of ARVI in patients at risk of an unfavorable course of respiratory infection.
Keywords: chronic bronchopulmonary pathology, chronic obstructive pulmonary disease, bronchial asthma, chronic bronchitis, community-acquired pneumonia, antibiotic resistance.
Introduction.
The relevance of improving the set of measures for the prevention, treatment and rehabilitation of patients with chronic respiratory diseases is beyond doubt. Ranking third among the causes of death worldwide, chronic obstructive pulmonary disease (COPD) leads to significant economic losses due to the loss of the working population 1 [1]. There is an increase in the number of patients with bronchial asthma
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(BA), including severe forms, among the young population, which is the reason for the reduction in life expectancy for men by 6.6 years, for women - by 13.5 years [2].
When managing such patients, special attention is paid to controlling exacerbations, the frequency of which correlates with the rate of disease progression and a decrease in the quality of life. One of the leading causes of exacerbation of chronic bronchopulmonary diseases is acute respiratory viral infection (ARVI) [3-5]. It is known that almost every case of ARVI in children suffering from bronchial asthma is accompanied by an exacerbation [4]. According to various authors, from 25 to 38.4% of cases of COPD exacerbations and 75-80% of bronchial asthma exacerbations in adults occur against the background of ARVI, while in patients with moderate or severe COPD, respiratory viruses are identified in the secretions of the upper respiratory tract 11 times more often compared to patients with stable COPD [3-6]. Damage to the respiratory tract epithelium, impaired mucociliary clearance, and suppression of immunity during ARVI favor the growth of pathogenic and opportunistic bacteria and an increased risk of losing control over the disease [7]. It has been noted that bacterial pathogens are detected in 47% of hospitalized patients with COPD, and most often these are Haemophilus influenzae and pneumococcus [6, 8].
Patients with chronic bronchopulmonary pathology, along with elderly people and those with aggravated comorbid background, are at risk of unfavorable course of influenza and pneumonia. This is associated, among other things, with infection and colonization of the respiratory tract of such patients with resistant strains of microorganisms, and, without a doubt, each subsequent exacerbation requiring antimicrobial chemotherapy contributes to this component. On the contrary, rational treatment of ARVI in patients with chronic bronchopulmonary pathology will be accompanied by a smaller number of exacerbations requiring the use of antibiotics
[9].
In this regard, the innovative drug Rafamine deserves attention. It belongs to the class of biological drugs obtained on the basis of gradual technology 3 . The active components of the drug 4 , obtained from a substance of biological origin -antibodies, have a modifying effect on target molecules, changing their spatial structure, properties and the nature of interaction with complementary molecules [11]. The targets affected by the drug are the domains of the major histocompatibility complex (MHC) class I and II, with the participation of which the presentation of foreign antigens by immunocompetent cells is carried out; the CD4 receptor, involved in the process of pathogen recognition, and interferon y (IFNy) - one of the
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key factors of the antiviral immune response, responsible, among other things, for stopping the reproduction of viruses and protecting cells from infection. The drug has an immune-mediated antiviral, antibacterial and anti-inflammatory effect. In particular, it has been shown that the components of the drug have a pronounced antiviral effect comparable to that of oseltamivir [12]. Of interest are the results of a study by the Vibiosfen laboratory (Labege, France), where, when modeling non-lethal SARS-CoV-2 infection in laboratory mice, accompanied by impaired immune response, Rafamine restored the number of blood cells to normal values and reduced the level of C-reactive protein and IL-6, the main inflammatory markers of infection, compared to placebo 5 . The presence of an antibacterial effect of the drug was demonstrated in a model of non-lethal pneumococcal infection caused by Streptococcus pneumoniae: the drug provided a significant reduction in the bacterial load in the lungs of infected mice compared to placebo, comparable in severity to the effect of amoxicillin (AMS) [13]. In another model, when mice were infected with an AMS-resistant strain of Klebsiella pneumoniae BAA-1705, the use of the drug components together with AMS doubled the antibacterial effect of the antibiotic, which indicates the possibility of overcoming antibiotic resistance and increasing the effectiveness of antibacterial therapy (ABT) [14]. In an experimental study of the effect of Rafamine on the gastrointestinal microbiome (a fragment of the cecum of animals) using NGS sequencing and quantitative PCR, it was found that: 1) the drug contributed to the maintenance of the number of normal flora, which, in turn, can provide additional protection by preventing the proliferation of pathogenic bacterial species; 2) the drug did not cause the development of multiresistance: the qualitative and quantitative set of intestinal microbiome genes remained unchanged [15].
The therapeutic efficacy and safety of the drug in the treatment of adults with ARVI were studied in a double-blind, placebo-controlled, randomized clinical trial (RCT), where a reduction in the duration of ARVI (almost by a day) and a decrease in the frequency of bacterial complications were noted [16], which is especially important for patients with chronic bronchopulmonary pathology.
This article summarizes the results of observational programs, initiative studies and examples from personal clinical experience of using the drug Rafamin in patients with pulmonary diseases.
A large-scale observational program involving 14,033 people, conducted under the auspices of the "Alliance of Chemotherapists and Microbiologists", studied the experience of using the drug Rafamin in patients with ARVI in routine outpatient clinical practice [17]. The absence of strict inclusion criteria compared to RCTs made
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it possible to evaluate the efficacy and safety of standard ARVI therapy supplemented with a drug based on technologically processed antibodies, on a large sample of patients represented by the usual contingent of outpatient clinics. Thus, patients over 18 years of age were included, without upper age limit, with characteristic manifestations of ARVI, including those with various concomitant diseases, including those who sought medical attention at a late stage from the onset of the disease (after 3 days or more from the appearance of the first symptoms). It was noted that the prescribed treatment helped eliminate the symptoms of the disease in an average of 4 days, including in patients with a late start of therapy, and made it possible to avoid the development of secondary bacterial complications and the subsequent prescription of antibacterial drugs (ABP) in 99.4% of patients.
Among the program participants, 160 patients had chronic bronchopulmonary diseases, according to medical records. This cohort of participants was selected for additional analysis to assess the frequency of complicated ARVI and the number of exacerbations during therapy [18]. Chronic bronchopulmonary diseases were presented as bronchial asthma in 103 (64.4%), chronic bronchitis (CB) in 34 (21.2%), and COPD in 23 (14.4%) patients, respectively. Patients consulted a doctor mainly on the 2nd-3rd day of illness with complaints of ARVI manifestations, which mainly corresponded to the moderate severity of the disease. At the time of inclusion in the program, patients did not have signs of exacerbation of chronic bronchopulmonary pathology. When conducting PCR diagnostics for SARS-CoV-2, positive results were subsequently obtained in 9 people. All patients received the drug according to the regimen corresponding to the instructions for medical use, 48% of patients took drugs for the treatment of obstructive airway diseases, 13% of participants received antibiotics simultaneously with the start of taking Rafamine (among them 11 patients with asthma, 7 with chronic bronchitis and 3 with COPD).
It was noted that the prescribed therapy contributed to the relief of respiratory infection symptoms in patients with bronchial asthma by an average of 3.6±1.6 days, with COPD - by 4.0±1.3 days, with CB - by 3.5±1.6 days. In most patients (n=156, 97.5%), the acute respiratory viral infection episode ended in complete recovery and did not lead to an exacerbation of chronic bronchopulmonary disease. Only four participants had exacerbations: two patients had an exacerbation of bronchial asthma (one of them with a positive PCR result for SARS-CoV-2), and two more had an exacerbation of CB, which were relieved with bronchodilators and glucocorticosteroids. In case of signs of bacterial infection in the form of purulent sputum, increased number of peripheral blood leukocytes, increased level of C-
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reactive protein, ABT was prescribed, which was required in four patients: one with bronchial asthma, one with chronic bronchitis and two with COPD (who did not initially receive ABT). No cases of hospitalization or death were registered among the examined patients. Doctors noted a favorable safety profile and good tolerability of the drug. The obtained results, indicating, among other things, the possibility of controlling virus-induced inflammation in patients with chronic bronchopulmonary pathology using Rafamine, nevertheless require confirmation in the form of further RCTs with placebo control.
The demonstrated results of clinical observations of the use of Rafamine in pulmonology practice are due to its ability to improve the recognition of viruses and bacteria by the immune system and regulate the launch of T-cell immune responses aimed at the destruction and elimination of both extracellular pathogens and infected cells. It is known that the most important role in immune protection against both viruses and bacteria is played by molecules and receptors that form the so-called immune synapse, which is understood as the contact of cells involved in the detection of an antigen and the launch of a subsequent chain of reactions to destroy it [20]. MHC molecules are directly involved in the work of the immune synapse and can currently be considered as a promising target for the development of drugs for the treatment of various infectious diseases [9]. Rafamine, including through its effect on MHC molecules, helps the immune system to form a full-fledged response to infection by activating both humoral and cellular immunity.
It should be noted that the use of the drug is not recommended for children under 18 years of age, pregnant and breastfeeding women due to insufficient data on the efficacy and safety in these categories of patients; as well as in people with galactose intolerance, lactase deficiency and glucose-galactose malabsorption due to the content of lactose monohydrate. If necessary, it can be combined with other antiviral, symptomatic and antibacterial agents.
Conclusion
From a clinical point of view, it is important that Rafamine, which implements an antiviral and antibacterial effect through the regulation of immune processes in the body, can be widely used in the treatment of ARVI, especially in patients at risk of an unfavorable course of respiratory infection. However, to obtain more convincing data, additional RCTs are required in accordance with the criteria of evidence-based medicine. It should be noted that a number of such studies are already being conducted, and several more RCTs are being prepared for launch. The most promising direction for future research may be the study of the possibility of
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preventing the formation of antibiotic resistance as one of the most pressing problems of modern medicine.
References:
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