Pathophysiological Basis for the Use of Derinat in Complex Therapy of Hemorrhagic Fever with Renal Syndrome

The dissertation is devoted to the pathophysiological basis for the use of the immunomodulator derinat in complex therapy of hemorrhagic fever with renal syndrome (HFRS), an acute viral zoonotic disease endemic to the Middle Volga region. The research is dedicated to the study of patterns of lipid peroxidation processes, the level of endogenous intoxication, the state of antioxidant protection, and cellular and humoral components of the immune system in HFRS patients. The study compares indicators of clinical, laboratory, and biochemical blood analyses during basic therapy and with the additional inclusion of derinat in complex treatment. The obtained data indicate the ability of derinat to reduce the degree of endogenous intoxication, correct free radical lipid oxidation reactions, and restore antioxidant protection of the organism, as well as to exert a positive effect on non-specific and specific immunity. The results of the study make it possible to substantiate the feasibility of including derinat in complex therapy of HFRS in order to increase treatment efficacy, alleviate symptoms, and prevent the development of complications.

Relevance of the Problem. At the present time, viral infections remain one of the most urgent medical and socio-economic problems. Among them is hemorrhagic fever with renal syndrome (HFRS) — an acute viral disease of zoonotic nature, endemic to the Middle Volga region, caused by representatives of the genus Hantavirus. In humans, HFRS manifests as a clinically overt infection with signs of acute renal failure (ARF) and hemorrhagic syndrome (Alekseev O. A. et al., 1998; Efratova E. S., 1998; Pimenov L. T. et al., 2003).

At the present time, HFRS has acquired wide spread and represents an important problem for the healthcare systems of many countries (Onishchenko G. G., 2000; Morozov V. G. et al., 2002; Figurnov V. A., Marunich N. A., 2003). The relevance of studying HFRS is determined by the high level of morbidity in many regions of Russia, including the Republic of Mordovia, the severity of complications developing in the course of the infectious process, as well as prolonged periods of temporary disability and long-lasting polyorganic disorders in convalescents (Tkachenko E. A., 2000; Merkulov A. V., Nafteev A. A., 2002; Utenkova E. O. et al., 2004).

Within the territory of the Republic of Mordovia, an actively functioning natural focus of HFRS exists. Morbidity of this fever since 1964 and to the present day has a pronounced tendency toward growth (the average increment rate is +6.4%). Such a situation is associated both with the improvement of the quality and efficacy of clinical and laboratory diagnosis and with the activation of natural foci of this disease in the territory of the republic (Chumakov M. E., 2003, 2004). Among patients, individuals of young working age predominate. The disease is characterized by a severe course. Moreover, the process of restoration of impaired functions of various organs and systems is prolonged and does not always lead to complete recovery (Sidelnikov L. N., 1993; Sirotin B. Z., Klebanov Yu. A., 1996; Pimenov L. T., Vasil'ev M. Yu., 2004).

In connection with the vasotropism of the virus, the pathophysiological basis of HFRS are changes in the vascular wall (Roshupkin V. I., Suzdal'tsev A. A., 1995; Ibragimova L. A., 2001; Kim G. et al., 1998). The development of the disease is determined by the characteristics of the response reactions in the form of immunopathological processes, changes in the coagulation system, and endocrine disturbances. A cardinal role in this is attributed to immune reactions causing secondary changes in organs, most pronounced in the kidneys (Sirotin B. Z., Klebanov Yu. A., 1996; Babushkina F. A., 2002; Hlaed D., Arnautovia A., Vessenjak-Hirian J., 2000). In this disease, disturbances of the mechanisms of cellular and humoral components of the immune response are also observed (Asеinova R. Z., 2000; Mirsaeva G. Kh. et al., 2000; Lee N. Wang, Charles Calisher, 1998).

In the pathogenesis of HFRS, a significant role is played by the activation of lipid peroxidation (LPO) processes and the reduction of antioxidant protection (AP) of the organism (Fazlyeva R. M. et al., 1995; Matveev S. B. et al., 2005; Silberberg L., 1995). The excessive formation of final and intermediate products of LPO reactions exerts a cytotoxic, membrane-destructive, and immunosuppressive effect, contributing to the destruction and destabilization of phospholipid membranes of cells and subcellular organelles, which leads to the development of endogenous intoxication and disturbances in immune status. Consequently, pharmacological correction of endotoxemia and immune indicators may be realized through the management of LPO processes (Golikov P. P. et al., 2000; Boyarinov G. A. et al., 2002; Piksin I. N. et al., 2002). This testifies to the advisability of including in the complex treatment of HFRS agents with immunocorrective and antioxidant properties.

In the problem of HFRS, the most relevant aspect is the treatment of patients, the success of which depends on timely primary diagnosis, early hospitalization, and correctly chosen therapy. At the present stage, therapeutic measures for HFRS are limited. Etiotropic therapy is effective in the first five days of the disease; however, within these time frames, patients rarely seek medical assistance (Lescheva G. G., Kustarnikov G. K., 1998; Shutov A. M., Savinova G. A., 2002). The recognition of the significant role of the immune and antioxidant systems in the development of the pathological process in HFRS served as the basis for the search and application of medicinal preparations with immunocorrective and antioxidant action. It is known that the immunomodulatory and antioxidant properties of derinat are due to the ability to remove various oxygen radicals from the organism, to restore and activate the restructuring of immune capacity (Vlasov A. P. et al., 2002; Zhabko A. N. et al., 2005; Klyuchnikov S. O., 2005).

Thus, the study of the intensity of lipid peroxidation processes and the state of the antioxidant system, the investigation of non-specific and specific components of cellular and humoral immunity, and the level of endogenous intoxication under conditions of immunocorrective and antioxidant therapy is advisable. Obtaining positive results would make it possible to substantiate the use of immunomodulators and antioxidants in the practice of HFRS treatment. Having information on the immunocorrective and antioxidant properties of derinat, we decided to use it in the complex therapy of HFRS. Information on the use of this drug in HFRS is not available in the accessible literature.

Based on the above, the goal and objectives of the study were determined.

Goal of the Work. On the basis of the investigation of indicators of endotoxemia, antioxidant, and immune protection, to provide the pathophysiological basis for the use of derinat in the complex treatment of hemorrhagic fever with renal syndrome.

Objectives of the Research:

1. To investigate the processes of lipid peroxidation, the level of endogenous intoxication in HFRS patients at the onset of the disease and during the period of early convalescence against the background of basic therapy.

2. To identify the influence of derinat on the characteristics of lipid peroxidation processes, antioxidant protection, and the level of endogenous intoxication in HFRS patients.

3. To determine the state of the immune status of HFRS patients during early and late convalescence under conventional treatment and to establish the possibility of its correction under conditions of additional use of derinat.

4. To assess the influence of derinat on the dynamics of the clinical course and outcome of the disease in HFRS patients.

Scientific Novelty. 1. The dynamics of the activity of the antioxidant protection enzyme catalase and the intermediate product of lipid peroxidation — malondialdehyde (MDA) — in plasma blood and erythrocytes during spontaneous and iron-induced lipid peroxidation in HFRS patients against the background of basic treatment and the inclusion of derinat into it have been studied.

2. The advisability of determining erythrocyte adsorptive capacity for the additional assessment of the degree of severity of endogenous intoxication in HFRS has been established.

3. The high efficacy of derinat in the complex treatment of HFRS aimed at preventing the development of complications, correcting free radical oxidation, and compensating for immune deficiency has been demonstrated.

Practical Significance

1. The advisability of using derinat as part of combined therapy of HFRS has been proven, which makes it possible to reduce the level of endotoxemia, correct lipid peroxidation reactions, and restore the antioxidant protection of the organism. An important property of derinat is also its positive influence on both non-specific and specific cellular and humoral immunity in HFRS patients.

2. The results obtained make it possible to pathophysiologically substantiate the possibility of including derinat in the complex therapy of HFRS patients in order to increase the efficacy of treatment, which is expressed in the earlier alleviation of disease symptoms, the shortening of disease periods, the duration of hospital stay, and the prevention of the development of complications.

Propositions to be Defended

1. The use of derinat in the complex treatment of HFRS patients leads to the suppression of lipid peroxidation processes, the degree of expression of endogenous intoxication, and the optimization of antioxidant protection.

2. The additional use of derinat in conjunction with basic therapy in HFRS positively influences the cellular and humoral components of immune protection, increases the efficacy of treatment, and reduces the risk of developing complications.

Presentation of the Work. The materials of the dissertation were reported at meetings of the Republic of Mordovia Society of Infectious Disease Specialists (Saransk, 2003–2004); annual scientific-practical conferences of the State Educational Institution of Higher Professional Education "Mordovian State University named after N.P. Ogarev" ("Ogarev Readings," 2003–2004); conferences of young scientists of the State Educational Institution of Higher Professional Education "Mordovian State University named after N.P. Ogarev" (Saransk, 2003–2004); II Volga Regional Scientific-Practical Conference "The Use of the Domestic Immunomodulator 'Derinat' in Various Fields of Medicine" (Saransk, 2004); regional scientific-practical conference dedicated to the memory of Academician N.N. Burdoenko "Actual Issues of Modern Clinical Medicine" (Penza, 2004); XI scientific-practical conference for young scientists and applicants "Actual Issues of Diagnosis, Treatment, and Rehabilitation of Patients" (Penza, 2004); scientific-technical conference dedicated to the 80th anniversary of the sanitary enlightenment service of the Republic of Tatarstan "Organization and Experience of Hygienic Education of the Population of the RT" (Kazan, 2004); scientific-practical conference "Key Issues in the Fight Against Infection" (St. Petersburg, 2004); All-Russian Scientific-Practical Conference "Actual Problems of Disinfection and Epidemiology in the Medical Industry" (Kazan, 2005).

Publications and Implementation. The dissertation research was conducted from 2002 to 2005 in accordance with the plan of scientific research of the department on the problem "Immune Reactivity of the Organism in Norm and under Certain Types of Pathology." The studies were carried out in the therapeutic-diagnostic departments of the municipal healthcare institution — the infectious clinical hospital of Saransk (chief physician — V. V. Smirnov), which serves as the clinical base of the department of infectious diseases of the State Educational Institution of Higher Professional Education "Mordovian State University named after N.P. Ogarev" (head of the department — D. Med. Sci., Prof. V. M. Mamykin), as well as in the laboratory of clinical immunology of the Republican Center for Clinical Immunology and in the Central Scientific-Research Laboratory of the Medical Faculty.

Based on the materials of the dissertation, 12 scientific works have been published. Immunocorrective therapy, included in the basic treatment of hemorrhagic fever with renal syndrome through the use of derinat, has been introduced into the practice of the therapeutic-diagnostic department of the municipal healthcare institution — the infectious clinical hospital of Saransk. Theoretical and practical aspects developed in the dissertation research have been introduced into the educational and scientific process of the department of infectious diseases of the Medical Faculty of the State Educational Institution of Higher Professional Education "Mordovian State University named after N.P. Ogarev."

Structure and Volume of the Dissertation. The dissertation consists of an introduction, a literature review, and 4 chapters of original research, discussion, conclusions, practical recommendations, and a reference list comprising 249 domestic and 53 foreign sources. The work is presented on 146 pages of computer text, illustrated by 17 tables and 15 figures.