Method for correcting immune disorders in covid-19 patients during early period of recovery

Abstract

FIELD: infectious diseases; rehabilitation medicine.SUBSTANCE: used to correct immune disorders in patients in the early recovery period of 4–12 weeks after suffering from the COVID-19 coronavirus infection. The immunomodulatory antioxidant drug sodium aminodihydrophthalazinedione, Galavit® solution is prescribed for intramuscular administration according to the scheme: 10 injections, of which the first 5 injections are administered at 100 mg daily, and the next 5 injections at 100 mg every other day.EFFECT: restoration of disrupted cytokine and free radical homeostasis.1 cl, 2 dwg, 4 tbl, 3 ex

Description

[0001] The invention relates to medicine, namely infectious diseases and rehabilitation medicine, and can be used in the practice of treating immunological disorders in patients after suffering a coronavirus infection caused by the SARS-CoV-2 virus.

[0002] The novel coronavirus infection (COVID-19) pandemic has imposed a significant burden on all of humanity. Despite impressive progress in the diagnosis and treatment of the acute phase of COVID-19, researchers have noted that virus elimination from the body and recovery do not necessarily mark the end of the disease. [Semakin A.V., Fedosenko S.V., Malinovsky V.A., Agaeva S.A., Starovoitova E.A., Kalyuzhin V.V. Quality of life and mental disorders in the post-COVID period (a systematic review). Bulletin of Siberian Medicine. Many patients did not return to their previous state of health and continued to experience symptoms reflecting pathology of various organs and systems. 2023; 22 (4): 188–200. https: / / doi.org / 10.20538 / 1682-0363-2023-4-188-200].

[0003] To describe a wide range of manifestations of acute COVID-19, the World Health Organization proposed the term "post-COVID state" (hereinafter referred to as PCS) [Baimukhambetova D.V., Gorina A.O., Rumyantsev M.A., Shikhaleva A.A., El-Tarawi Ya.A., Bondarenko E.D. et al. Post-COVID state in adults and children. Pulmonology. 2021; 31 (5): 562-570. DOI: 10.18093 / 0869-0189-2021-31-5-562-570].

[0004] Post-COVID syndrome is represented in ICD-10 by code U09.9 "Unspecified post-COVID-19 condition". Symptoms of post-COVID syndrome can be observed for 6 months or more after the new coronavirus infection COVID-19. This is often accompanied by persistent changes in biochemical and immunological parameters [Malkova A.; Kudryavtsev I., Starshinova A. et al. Post COVID-19 Syndrome in Patients with Asymptomatic / Mild Form. Pathogens. 2021;10:1408. DOI:10.3390 / pathogens10111408; Wu J., Tang L., Ma Y. et al. Immunological Profiling of COVID-19 Patients with Pulmonary Sequelae. mBio. 2021;12(5):e0159921. DOI:10.1128 / mBio.01599-21; Nalbandian A., Sehgal K., Gupta A. et al. Post-acute COVID-19 syndrome. Nat. Med. 2021; 27: 601-615. DOI: 0.1038 / s41591-021-01283-z].

[0005] According to published data, the incidence of PCC in different countries ranges from 16% to 76% [Raman B, Bluemke DA, Lüscher TF et al. Long COVID: post-acute sequelae of COVID-19 with a cardiovascular focus. Eur Heart J. 2022 Mar 14;43(11):1157-1172].

[0006] HE Davis et al. note that according to a meta-analysis of the results of observation of 3762 hospitalized patients from 56 countries, which was conducted for 7 months, it was found that with a COVID-19 duration of more than 28 days and a recovery time of more than 35 weeks, patients had 203 different symptoms of PCOS associated with dysfunction of 10 systems and organs. Frequent symptoms of fatigue - 80%, post-exertional malaise - 75%, cognitive dysfunction - 60%. Relapses occurred in 85.9% of patients against the background of and as a result of exercise, physical or mental activity and stress [Davis HE, Assaf GS, McCorkell L et al. Characterizing long COVID in an international cohort: 7 months of symptoms and their impact. EClinicalMedicine. 2021 Aug; 38:101019].

[0007] The manifestations of post-COVID syndrome in the examined patients are characterized by diversity (asthenic syndrome, dry cough, sleep disturbance, hair loss, disturbance of psycho-emotional balance: anxiety, depressive mood, irritability), the duration of the observed symptoms varied from 3 weeks to 6 months or more from the onset of the disease [Skvortsov VV, Tumarenko AV, Skvortsova EM, Shtonda DA Post-COVID syndrome in the practice of a therapist. Vrach, 2022; (4): 19-28 https: / / doi.org / 10.29296 / 25877305-2022-04-03 ].

[0008] The authors of the present invention conducted studies associated with an increase in the activity of the prooxidant system and a deficiency of the antioxidant system and, consequently, a decrease in the values ​​of the ceruloplasmin / malonic dialdehyde index in the acute period of coronavirus infection COVID-19, as well as in the early recovery period [Marzhokhova A.R., Kharaeva Z.F., Marzhokhova M.Yu., Ponezheva Zh.B., Kambachokova Z.A., Blieva L.Z. et al. Some immunological predictors of the development of post-COVID syndrome. Clinical laboratory diagnostics. 2025; 70(4): 243-249 https: / / doi.org / 10.51620 / 0869-2084-2025-70-4-243-249 EDN: VRTSWU; Ploskireva A.A., Marzhokhova A.R., Ponezheva Zh.B., Kharaeva Z.F., Marzhokhova M.Yu., Balagova L.E. et al. Lipid peroxidation indices of biological membranes in patients with COVID-19. Immunopathology, Allergology, Infectology, 2023; 3, 2023, 3: 60-65 DOI: 10.14427 / jipai.2023.3.54].Malondialdehyde (MDA) is considered one of the indicators of activation of the prooxidant system in various pathological conditions. Substances such as ceruloplasmin, superoxide dismutase, catalase, nitrate-nitrites and others act as antioxidants in the body and neutralize the hyperactivity of the prooxidant system, helping to maintain balance [Uskova, Yu.G. Oxidative stress and its correction in hemorrhagic fever with renal syndrome / Yu.G. Uskova, V.F. Pavelkina / / Antibiotics and Chemotherapy. - 2019. - Vol. 64, No. 1-2. - P. 26-33. DOI: 10.24411 / 0235W2990W2019W10005].

[0009] Various viral infections can be accompanied by both a surge and a decline in the activity of antioxidant enzymes at different stages of the disease. With prolonged active radical formation, the protective enzyme systems are depleted, which in some cases manifests itself in extremely low levels of the antioxidant system. Antioxidant deficiency can lead to damage by radicals to the body's own cells and tissues, which is one of the triggers in the etiology of autoimmune diseases and carcinogenesis [Lysenko V.I. Oxidative stress as a nonspecific factor in the pathogenesis of organ damage (a review of the literature and our own research). Med. emergency. 2020; 16 (1): 24-35. doi: 10.22141 / 22240586.16.1.2020.196926].

[0010] Since a universal medical rehabilitation program for patients with post-COVID-19 disorders and post-COVID-19 syndrome cannot be offered due to the lack of any specific symptom or group of signs specific to these conditions, rehabilitation measures for patients with COVID-19 infection should be carried out by a team of medical rehabilitation specialists consisting of the attending physician, a physical therapist, a physiotherapist, a clinical psychologist, and other specialists. These measures are aimed at restoring respiratory function of the bronchopulmonary system, maximizing diaphragmatic breathing, improving bronchial patency, mucociliary clearance, and alveolar ventilation, normalizing ventilation-perfusion relationships, restoring exercise tolerance, psychoemotional stability, and daily activity, as well as drug therapy for organ and system dysfunction.To achieve this goal, the multidisciplinary rehabilitation team will need to pool its efforts and coordinate its actions. This requires assessing the patient's condition and defining rehabilitation goals and objectives [Ivanova G.E., Shmonin A.A., Maltseva M.N., et al. Rehabilitation care during the COVID-19 epidemic at the first, second, and third stages of medical rehabilitation. Physical and Rehabilitation Medicine, Medical Rehabilitation. 2020. Vol. 2. No. 2. pp. 98-117].

[0011] The infectious process in coronavirus infection COVID-19 is associated with an increased level of proinflammatory cytokines, primarily interleukin-6 (IL-6), according to guidelines for the prevention, diagnosis and treatment of a new coronavirus infection, severe and extremely severe patients were administered IL-6 receptor antagonists (tocilizumab or sarilumab, or levilimab) or IL-1 blockers (canakinumab, anakinra), or an IL-6 blocker (olokizumab) [Afrin, LB Covid-19 hyperinflammation and post-Covid-19 illness may be rooted in mast cell activation syndrome / LB Afrin, LB Weinstock, GJ Molderings / / Int J Infect Dis. - 2020. - No. 100. - R. 327-332.- DOI: 10.1016 / j.ijid.2020.09.016; Pathophysiology of Post-COVID syndromes: a new perspective / GE Batiha, HM Al-Kuraishy, ​​AI Al-Gareeb, NN. Welson / / Virol J. - 2022.- Vol. 19, no. 1. - R. 158. - DOI: 10.1186 / s12985-022-01891-2].

[0012] Disadvantages of the described methods: blockade of IL-6 and / or IL-1 receptors inevitably leads to changes in the cytokine status. The nature and severity of the consequences of monoclonal therapy are largely not fully understood. One of the reasons for the development of post-COVID syndrome is the development of multisystem inflammation and dysregulation of the immune status, including after targeted therapy [Post-COVID syndrome. A case series and comprehensive review / JM Anaya, M. Rojas, ML Salinas [et al.] / / Autoimmun Rev. - 2021. - Vol. 20, No. 11. - 102947. - DOI: 10.1016 / j.autrev .2021.102947].

[0013] One of the important links in the development of post-COVID syndrome is the lack of normalization of the cytokine immune system parameters and the processes of lipid peroxidation of biological membranes in the period of early convalescence of the disease (4-12 weeks from the onset). According to the research of the authors of the present invention, in the acute period of coronavirus infection COVID-19 and in the convalescence period from 4 to 12 weeks from the onset of the acute period, most convalescents maintain elevated values ​​of such cytokines as IL-6, IL-8 and IL-23 [Marzhokhova A.R., Kharaeva Z.F., Marzhokhova M.Yu., Ponezheva Zh.B., Kambachokova Z.A., Blieva L.Z. et al. Some immunological predictors of the development of post-COVID syndrome. Clinical laboratory diagnostics. 2025; 70(4): 243-249 https: / / doi.org / 10.51620 / 0869-2084-2025-70-4-243-249 EDN: VRTSWU], and the imbalance of the lipid peroxidation system of biological membranes remains [Ploskireva A.A., Marzhokhova A.R., Ponezheva Zh.B., Kharaeva Z.F., Marzhokhova M.Yu., Balagova L.E. et al. Lipid peroxidation indices of biological membranes in patients with COVID-19. Immunopathology, Allergology, Infectology, 2023; 3, 2023, 3: 60-65 DOI: 10.14427 / jipai.2023.3.54].

[0014] Disadvantages of the method: the rehabilitation measures carried out without restoring the balance of the immune system and lipid peroxidation are insufficient: the condition of patients improves slightly or does not improve at all, in some patients the immune system and the lipid peroxidation system of biological membranes remain unbalanced.

[0015] The objective of the claimed invention is to increase the clinical effectiveness of correcting immunological disorders in patients in the early recovery period of 4-12 weeks after suffering from COVID-19 coronavirus infection due to the pathogenetic regulatory effect on the cytokine and free radical balance of the body.

[0016] The claimed invention was developed within the framework of the research work “Clinical and immunopathological features of the course of coronavirus infection COVID-19 at different periods of the infectious process”, conducted at the Department of Infectious Diseases of the Medical Academy of the Federal State Budgetary Educational Institution of Higher Education “Kabardino-Balkarian State University named after Kh.M. Berbekov” (Russia, Kabardino-Balkarian Republic, Nalchik).

[0017] It is known that the pathogenesis of PCOS is based on the development of a multisystem inflammatory syndrome, which, among other things, is characterized by an imbalance in immune responses, the lipid peroxidation system, etc. Researchers are faced with the question of choosing drugs with immunomodulatory, antioxidant and anti-inflammatory effects.

[0018] Pharmacological agents called antioxidants are used to restore reduced levels of protective enzymes. An important therapeutic effect of antioxidants is their anti-inflammatory and antihypoxic effects. The therapeutic effect of antioxidants is due not only to the replenishment of reducing equivalents (e.g., SH groups) and detoxification of the body, but also to their action at the level of gene transcription. Reactive oxygen species, along with bacterial and viral antigens, cytokines, and calcium channel blockers, stimulate a group of nuclear factor proteins responsible for the transcription of genes involved in inflammation and encoding the synthesis of so-called acute phase reactants. They block the activation of nuclear factor, thereby stopping the transcription of genes responsible for the implementation of the inflammatory response [Nikitina O.A. Activity of lipid peroxidation-antioxidant defense reactions in patients with HIV infection (review). Acta biomedica scientifica.2020; 5(6): 124-132. doi: 10.29413 / ABS.2020-5.6.14].

[0019] In connection with the above, it is proposed to include in the complex therapy of patients with post-COVID syndrome the antioxidant drug sodium aminodihydrophthalazinedione - Galavit® manufactured by Selvim LLC (Russia), which has been on the market since 1997, is presented in 3 forms: injections, rectal suppositories and tablets.

[0020] There is a large evidence base for the effectiveness of Galavit® for the treatment of various infectious diseases of viral etiology - acute respiratory viral infections, influenza, herpes infection, papillomavirus infections (including respiratory), chronic tonsillitis, etc. [Sologub T.V., Osinovets O.Yu. Immunomodulators in the complex therapy of acute respiratory viral infections: the possibilities of using Galavit / Russian Medical Journal. 2013. No. 3. P. 144-146; Svistushkin V.M., Nikiforova G.N., Leonova M.V., Pokoziy I.Yu. Possibilities of using the immunomodulator Galavit in patients with chronic tonsillitis / / Journal "Doctor" - 2016. - No. 8. -P. 20-25].

[0021] A method of using Galavit® is known, showing a positive effect of using this drug in the acute phase of the new coronavirus infection COVID-19 [Kolesov S.V., Gorbatyuk D.S., Panteleev A.A., et al. Prevention of moderate and severe forms of COVID-19 with sodium aminodihydrophthalazinedione (Galavit®) in medical personnel of the "red zone". Immunology. 2020; 6 (41): 527-39. DOI: 10.33029 / 0206-4952-2020-41-6-527-539 20; Svistunov A.A., Khorobrykh T.V., Makhnach G.K., et al. Experience in using immunomodulators for the prevention of coronavirus infection (COVID-19) in medical personnel and complications of pneumonia in patients with COVID-19. Therapy. 2020; 7:156-64. DOI:10.18565 / therapy.2020.7.156-164].

[0022] The objective is achieved by correcting immunological disorders following SARS-CoV-2 coronavirus infection using the immunomodulatory antioxidant drug Galavit® (sodium aminodihydrophthalazinedione). The following regimen is used: 10 injections total – 5 injections of 100 mg intramuscularly daily, then 100 mg every other day. The total treatment duration is 2 weeks.

[0023] Galavit® is extremely effective in treating post-COVID syndrome (PCS) that develops after the acute phase of the novel coronavirus infection (COVID-19). It exhibits a broad spectrum of immunomodulatory activity, as well as anti-inflammatory and antioxidant effects, affecting several components of PCS simultaneously. The drug's mechanism of action is related to its ability to selectively regulate (decreasing or increasing, depending on baseline values) the functional and metabolic activity of innate and adaptive immune cells (macrophages, natural killer cells, neutrophils, etc.).By enhancing the phagocytic activity of macrophages and monocytes, the bactericidal activity of neutrophils, and the cytotoxic activity of NK cells when it is initially deficient, the drug increases the body's nonspecific resistance to infectious diseases of viral, bacterial, and fungal etiology, promotes more rapid elimination of the pathogen from the body, and reduces the frequency, severity, and duration of infections. The anti-inflammatory effect is achieved through reversible (6-8 hours) inhibition of the production of proinflammatory cytokines (IL-1, IL-6, TNF-α) by hyperactivated monocytes / macrophages. Galavit® stimulates the production of endogenous interferons (IFN-α, IFN-γ); normalizes antibody formation, and increases the functional activity of antibodies.Galavit® has an antioxidant effect due to the direct inactivation of a number of radical compounds, regulation of the activity of antioxidant enzyme systems, blocking the production of reactive oxygen species, which leads to a decrease in the level of oxidative stress and protects tissues from the damaging effects of radicals [Svistunov A.A., Khorobrykh T.V., Makhnach G.K., et al. Experience in using immunomodulators for the prevention of coronavirus infection (COVID-19) in medical personnel and complications of pneumonia in COVID-19 patients. Therapy. 2020; 7:156-64. DOI: 10.18565 / therapy.2020.7.156-164; Tsvetov V.M., Kiselev Yu.Yu., Mirzaev K.B., Sychev D.A. The possibility of using a drug containing sodium aminodihydrophthalazinedione in patients with COVID-19, including for the treatment of cytokine storm. Quality Clinical Practice. 2020; S4:4-7. DOI:10.37489 / 2588-0519-2020-S4-4-7].

[0024] To test the effectiveness of the method, 90 convalescents who had survived the acute phase of COVID-19 coronavirus infection in moderate to severe forms (52 women and 38 men aged 32 to 61 years - 52 ± 1.1 years) were examined. They were treated in the rehabilitation department of City Clinical Hospital No. 1 of the Ministry of Health of the Kabardino-Balkarian Republic with a diagnosis of "U09.9 - post-COVID-19 condition". Concomitant diseases: chronic cholecystitis (9%), gastritis (8.8%), pyelonephritis outside of exacerbation (7.8%), hypertension (23%), compensated diabetes mellitus (12.2%). Written voluntary informed consent was obtained from all patients to participate in the study, publish the examination and treatment results.All observed convalescents were divided into two groups: 45 convalescents (Group 1) received conventional combination therapy, while 45 convalescents (Group 2) received Galavit (sodium aminodihydrophthalazinedione) as an immunomodulatory and antioxidant therapy in addition to combination therapy. The course of treatment with sodium aminodihydrophthalazinedione consisted of 10 injections of the drug: 5 injections of 100 mg intramuscularly daily, then 100 mg every other day. The total treatment duration was two weeks. Thirty conditionally healthy donors with no history of COVID-19 were observed for comparison. The groups of patients and healthy donors (control group) were similar in gender and age.

[0025] Statistical analysis of the results was performed using licensed IBM SPSS Statistics 21.0 and the Microsoft Excel 2013 statistical module. Parametric and nonparametric statistical methods were used, including the Student's t-test and Mann-Whitney U-test. Quantitative data are presented as Me (Q1, Q3), where Me is the median, and Q1 and Q3 are the lower and upper quartiles, respectively. Differences between indicators were considered statistically significant at p < 0.05.

[0026] To assess the cytokine status and lipid peroxidation of biological membranes in patients in the observation group, the levels of cytokines IL-6, IL-8, and IL-23 were determined, as well as the ceruloplasmin / malonic dialdehyde (CMI) index as an indicator of lipid peroxidation. Patients were examined before and after administration of Galavit® (sodium aminodihydrophthalazinedione).

[0027] To determine the interleukins (IL-6, IL-8, IL-23) levels, a solid-phase enzyme-linked immunosorbent assay (Vector Best, Russia) was used. Malondialdehyde levels were assessed by the "color reaction" with thiobarbituric acid according to the method of Ushiama M. (1978). To determine the ceruloplasmin level, the method of Ravin (1956) was used, which is based on the oxidation of p-phenylenediamine with the participation of ceruloplasmin.

[0028] Clinical example 1.

[0029] Extract from the case history No. 39** / 232*** of the rehabilitation department of City Clinical Hospital No. 1 in Nalchik. Full name: Patient B., age: born in 1963. Date of admission: 02 / 08 / 2025. Date of discharge: 02 / 26 / 2025.

[0030] Diagnosis: Primary: Condition after bilateral polysegmental pneumonia associated with coronavirus infection COVID-19. DN I; secondary: Atherosclerosis of the aorta, coronary cerebral arteries. Arterial hypertension stage 2, risk of cardiovascular disease 3. Diabetes mellitus type 2. Admitted with complaints of shortness of breath with minor exertion, chest pain, periodic dry cough, headaches, severe general weakness, decreased ability to work, rapid heartbeat, pain in the hip and knee joints, stiffness in the morning, fatigue, anxiety, irritability, tearfulness, memory impairment, poor sleep, dry mouth, dizziness.

[0031] Medical history: In December 2024, he contracted COVID-19 in a severe form. He was treated at the State Budgetary Healthcare Institution "Center for the Prevention and Control of AIDS and Infections."

[0032] KBR Ministry of Health with a diagnosis of COVID-19 coronavirus infection (virus identified), severe course. Community-acquired bilateral viral pneumonia. PP 84% DN 3rd stage.

[0033] After treatment in the infectious diseases department, the above-mentioned complaints persisted, leading to hospitalization for further rehabilitation treatment in the rehabilitation department of Nalchik City Clinical Hospital No. 1. Upon admission, the patient was examined by a multidisciplinary team. A diagnosis was made, and an examination and treatment plan were prescribed.

[0034] General: The patient is in a moderate condition. Conscious and answers questions correctly. He has a normal build and is moderately nourished. Height is 170 cm, weight is 94 cm. The skin is normal in color and moisture. Visible mucous membranes are pink. The musculoskeletal system is normal, but painful with movement. Body temperature is 36.6°C.

[0035] Nasal breathing is free. Percussion reveals clear pulmonary sounds. Auscultation reveals weakened breath sounds in the lungs, no wheezing. Respiratory rate is 19 bpm, SPO2 is 94-95%. Heart sounds are muffled, rhythm is regular. Heart rate is 71 bpm. Blood pressure is 150 / 90 mmHg. The abdomen is soft, painless on palpation, and participates evenly in the act of respiration. The liver is at the edge of the costal arch, the edge is smooth and painless. Stool is regular. Tingling symptom (-) on both sides. Urination is b / b, frequent.

[0036] Rehabilitation Routing Scale Score 3b. (Moderate impairment of functioning and limitation of life activities)

[0037] MMRC Dyspnea Scale Score 1-2b. (Mild-moderate. Shortness of breath when walking quickly on level ground or climbing a gentle hill. Shortness of breath causes walking on level ground to be slower than for people of the same age, or stops breathing when walking at a normal pace.)

[0038] Examination results (at post): Complete blood count: erythrocytes - 4.9x10 12 / l, Hb - 150 g / l, CP - 0.90, thrombus - 267000, lake - 9.0x10 9 / l, e - 1, p - 4, s - 58, l - 35, m -2 . ESR - 4 mm / h, hematocrit - 44.7% UAN: - color - s / yellow, pl. - complete, reactive - acidic, specific weight - 1033 m / m, protein - not detected, flat - single, leukocytes - 4-5 field of view, erythrocytes - negative. Blood biochemistry (post-natal): total protein - 72.0 g / l, creatinine - 95 μmol / l, urea - 7.2 mmol / l, uric acid - 145 μmol / l, ALT - 77.4 U / l, AST - 56.9 U / l, CRP - negative, cholesterol - 3.9 mmol / l, blood sugar - 3.8 mmol / l, alkaline phosphatase - 69 U / l, total bilirubin - 7.7 μmol / l, Ca - 2.02 mmol / l, coagulogram: PTI - 96%, INR - 1.04, fibrinogen 255 mg%, APTT - 32.0, blood sugar 12 mmol / l.

[0039] Received the following treatment: S.Spironaloctone 50, 1 tablet in the morning, Sol.Meldonium 100 mg / ml - 5 ml + Sol. Natrium chloride 0.9% - 100.0; Sol. Vinpocetinum 5.0 mg / ml +Sol. Sodium chloride 0.9% - 100.0; Sol. Omeprazole 20 mg, 1 tablet in the morning. Physiotherapy. Magnet on the knee joints, CaCl electrophoresis on the chest. Physical therapy. Therapeutic exercises, breathing exercises. Exercises on an exercise bike. Chest muscle massage.

[0040] Against the background of this therapy, the patient received a course of treatment with sodium aminodihydrophthalazinedione (Galavit®), which included 10 injections of the drug: 5 at 100 mg intramuscularly daily, then 100 mg every other day.

[0041] As a result of treatment with Galavit®, the patient noted an improvement in his general condition: shortness of breath and dry cough disappeared, weakness, headaches, palpitations, hip and knee pain, fatigue, irritability, and dizziness decreased. At discharge, the Rehabilitation Routing Scale score was 0 points; the mMRC dyspnea scale score was 0 points. Upon examination of the patient after a course of Galavit®, it was found that cytokine and lipid peroxidation system parameters had returned to normal (Table 1).

[0042] Table 1. Immunological parameters and LPO parameters in patient B. before and after treatment with Galavit®

[0043] The indicators studied IL-6 IL-8 IL-23 ICM Before treatment with Galavit 27.5 pg / ml 32.0 pg / ml 42 pg / ml 114.4 units After treatment with Galavit 7.0 pg / ml 7.4 pg / ml 23.0 pg / ml 323.2 units,

[0044] Patient B. suffered a severe case of COVID-19. After hospital treatment, his condition improved but did not recover. He remained in stage 1 respiratory failure, and many parameters had not returned to normal. Therefore, for follow-up treatment and further rehabilitation, he was hospitalized in the rehabilitation department, where he was examined by a multidisciplinary team, and treatment measures were determined. As a result of rehabilitation measures, including the immunomodulator and antioxidant Galavit®, the patient's condition improved, his biochemical and immunological parameters returned to normal, and he was discharged in satisfactory condition.

[0045] Clinical example 2.

[0046] Extract from the case history #36** / 241*** of the rehabilitation department of Nalchik City Clinical Hospital #1. Full name: Patient E., age: born in 1959. Date of admission: 12 / 01 / 2020. Date of discharge: 29 / 01 / 2020. Diagnosis: Condition after bilateral polysegmental pneumonia associated with coronavirus infection COVID-19, DN I, moderate severity. SOP: Arthrosis of the knee joints. Admitted with complaints of: shortness of breath with minor exertion, chest pain, headaches, severe general weakness, rapid heartbeat, pain in the hip and knee joints, stiffness in the morning, fatigue.

[0047] Medical history: In December 2025, she was treated at the State Budgetary Healthcare Institution "Center for the Prevention and Control of AIDS and Infections" of the Kabardino-Balkarian Ministry of Health with a diagnosis of severe COVID-19 coronavirus infection (virus identified). Community-acquired bilateral viral pneumonia, PP 44% DN stage 1.

[0048] After the therapy, the above complaints persisted, and therefore, after being discharged from the hospital 2 weeks later, she was hospitalized for further rehabilitation treatment in the rehabilitation department of City Clinical Hospital No. 1 in Nalchik.

[0049] Objective status: In a moderate condition. Conscious, answers questions correctly. Regular build, moderate nutrition. Height - 174 cm, weight - 87. Skin is of normal color and moisture. Visible mucous membranes are pink. The musculoskeletal system is normal, painful with movement. Body temperature - 36.6 degrees.

[0050] Ob-no. The chest is of normal shape. Both halves of the chest participate equally in the act of respiration. Nasal breathing is free. Percussion reveals clear pulmonary sounds. Auscultation reveals weakened breath sounds in the lungs, no wheezing. Respiratory rate is 19 bpm, SPO2 is 94%.

[0051] Heart sounds are muffled, rhythm is regular. Heart rate is 71 beats per minute. Blood pressure is 130 / 90 mmHg. The tongue is moist. The tonsils are not enlarged. The abdomen is soft, painless on palpation. Urination is normal.

[0052] Rehabilitation Routing Scale Score 3b. (Moderate impairment of functioning and limitation of life activities)

[0053] MMRC Dyspnea Scale score 1-2b (mild-moderate). According to the patient: I get out of breath when I walk quickly on level ground or climb a gentle hill. Because of shortness of breath, I walk more slowly on level ground than people of the same age, or I stop breathing when I walk on level ground at my usual pace.

[0054] Examination results. Complete blood count (CBC) (upon admission): erythrocytes - 4.3x10 12 / l, Hb - 130 g / l, cp 0.90, thrombus - 138000, lake - 3.4x10 9 / l, e - 1, p - 1, s - 59, l - 36, m -3. ESR - 25 mm / h, hematocrit - 38.7%. UAN (22.07.21): color - s / yellow, phosphorus - complete, reactivity - acidic, specific weight - 1012 m / m, protein - not detected, flat - 2-3, leukocytes - 3-4 field of view, erythrocytes - negative.

[0055] Biochemical blood test (on const.): total protein - 65.0 g / l, albumin -35.8 g / l, creatinine - 79.8 μmol / l, urea - 6.9 mmol / l, uric acid - 246.3 μmol / l, ALT -57.8 U / l, AST - 50.2 U / l, CRP - negative, blood sugar - 4.3 mmol / l, total bilirubin - 16.4 μmol / l, D-dimer - 23.4, coagulogram, PTI - 79%, INR - 1.28, fibrinogen 166 mg%, APTT-25.6.

[0056] The patient received drug treatment (Phenzitat 0.5 mg 1 / 2 at night; Omeprazole 20 mg; Sol. Cytoflavin 10.0 + Sol. Sodium chloride 0.9% - 200.0; Magnesium sulfatis 25% 5.0 + Sol. Sodium chloride 0.9% - 100.0; S. spironolactone 50, 1 tablet in the morning$ S. Platyphyllini hydrotartas 2.0 i / m; Xefocami 3.0 i / m), physiotherapy (magnet on the knee joints, CaCl electrophoresis on the chest), exercise therapy (therapeutic exercises, breathing exercises, exercise bike), massage of the chest muscles.

[0057] Against the background of this therapy, the patient received a course of treatment with sodium aminodihydrophthalazinedione (Galavit®), which included 10 injections of the drug: 5 of 100 mg intramuscularly daily, then 100 mg every other day.

[0058] As a result of treatment with Galavit®, the patient noted an improvement in his general condition: decreased shortness of breath, weakness, and hip and knee pain, no cough, and improved sleep. At discharge, the Rehabilitation Routing Scale score was 0b; the mMRC dyspnea scale score was 0b.

[0059] Immunological parameters were assessed before and after a course of Galavit®. Cytokine and lipid peroxidation parameters were found to have returned to normal (Table 2).

[0060] Table 2. Immunological parameters and LPO parameters in patient E. before and after treatment with Galavit®

[0061] The indicators studied IL-6 IL-8 IL-23 ICM Before treatment with Galavit 35.4 pg / ml 29.0 pg / ml 37.0 pg / ml 138.4 units After treatment with Galavit 7.3 pg / ml 7.8 pg / ml 23.0 pg / ml 323.2 units,

[0062] These data indicate that upon admission to the rehabilitation department, IL-6, IL-8, and IL-23 levels were elevated, while ICM levels were below normal. Following treatment, including the immunomodulatory and antioxidant drug Galavit®, these parameters returned to normal, paralleling the patient's improvement.

[0063] Clinical example 3.

[0064] Extract from the case history #65** / 196*** of the rehabilitation department of City Clinical Hospital #1 Full name: patient M., born in 1975. Date of admission: 02 / 10 / 2025. Date of discharge: 02 / 27 / 25. Main diagnosis: Condition after coronavirus infection COVID-19. Discharge: Bilateral polysegmental pneumonia. DN 1 st. Organic emotionally labile asthenic disorder. Subspecialty: Diabetes mellitus type 2. Morbid obesity. Chronic acalculous cholecystitis. Fatty hepatosis.

[0065] Upon admission, the patient complained of shortness of breath during physical exertion, chest discomfort, headaches, severe general weakness, malaise, decreased ability to work, insomnia, dizziness, numbness and heaviness in the lower extremities, muscle pain, memory loss, anxiety, and hair loss.

[0066] Medical history: She was treated at the State Budgetary Healthcare Institution "Center for the Prevention and Control of AIDS and Infections" of the Ministry of Health of the Kabardino-Balkarian Republic in January 2025 with a diagnosis of moderate COVID-19 coronavirus infection (virus identified). Bilateral polysegmental pneumonia. PP 20%.

[0067] Upon discharge from the hospital, shortness of breath with minimal physical exertion, difficulty breathing, weakness and numbness in the lower extremities, dizziness, muscle pain, joint pain, fatigue, memory impairment, and irritability persisted. Due to worsening shortness of breath, severe asthenic syndrome, and general weakness, the patient was hospitalized for further rehabilitation treatment in the rehabilitation department of City Clinical Hospital No. 1.

[0068] About. The patient's general condition is moderate. Conscious. Contact is available. She answers questions adequately. She is asthenic. Emotionally and autonomically labile. The skin is pale. Body temperature = 36.6°C. There is harsh breathing in the lungs, no wheezing. Respiratory rate is 20 per minute. SpO2 in air is 94%. Heart sounds are muffled, rhythmic. Pulse is 79 per minute. Blood pressure is 125 / 80 mmHg. The abdomen is soft, painless. The liver is at the edge of the costal arch. The spleen is not palpable. The stool is formed, without pathological impurities. The percussion symptom is negative on both sides. Urination is free, painless.

[0069] Rehabilitation Routing Scale score 1b. (Absence of manifestations of functional impairment and limitation of life activities in the presence of disease symptoms).

[0070] mMRC Dyspnea Scale Score 1b. (Shortness of breath when walking quickly on level ground or climbing a gentle hill).

[0071] The patient was examined: CBC (upon admission): erythrocytes - 5.5x10 12 / l, Hb - 130 g / l, cp 0.90, thrombus - 257000, lake - 7.5x10 9 / l, e - 1, p - 1, s - 59, l - 36, m -3 ESR - 13 mm / h, urine analysis - normal. Blood biochemistry (constant): all parameters are within normal limits.

[0072] Conducted drug treatment: meldonium 5.0 intravenously by drip, proinin 5 ml intravenously by drip, omeprazole 20 mg 1 tablet 2 times a day, xefocam 8 mg 1 tablet 2 times a day, amitriptyline 1 / 2 at night, phenibut 250 mg 1 / 2 at night. Received physical therapy: therapeutic exercises, breathing exercises, exercise bike training, neck / shoulder massage, magnet on the left hip joint, reflexology, hyperbaric oxygenation.

[0073] Against the background of this therapy, the patient received a course of treatment with sodium aminodihydrophthalazinedione (Galavit®), which included 10 injections of the drug: 5 of 100 mg intramuscularly daily, then 100 mg every other day.

[0074] As a result of treatment with the immunomodulator and antioxidant Galavit®, the patient noted an improvement in her general condition: decreased shortness of breath, weakness, and hip and knee pain, no cough, and improved sleep. At discharge, her Rehabilitation Routing Scale score was 0 points; her mMRC dyspnea score was 0 points.

[0075] Immunological parameters were assessed before and after a course of Galavit. Cytokine and lipid peroxidation parameters were found to have returned to normal (Table 3).

[0076] Table 3. Immunological parameters and LPO parameters in patient M. before and after treatment with Galavit®

[0077] The indicators studied IL-6 IL-8 IL-23 ICM Before treatment with Galavit 27.3 pg / ml 21.0 pg / ml 31.0 pg / ml 156.4 units After treatment with Galavit 7.1 pg / ml 7.3 pg / ml 22.0 pg / ml 331.7 units,

[0078] The data provided indicate that upon the patient's admission to the rehabilitation department, IL-6, IL-8, and IL-23 levels were elevated, while ICM was below normal. Following treatment, including the immunomodulatory and antioxidant drug Galavit®, and parallel improvement in the patient's condition, these parameters returned to normal. The patient was discharged in satisfactory condition.

[0079] Results.

[0080] To evaluate the clinical efficacy of the immunomodulatory drug Galavit, the symptoms of patients in 2 groups were compared (Table 4). Surveys after 2 weeks of taking sodium minodihydrophthalazinedione showed that patients receiving this drug reported improved overall well-being, a surge of energy, improved appetite and sleep, a statistically significant decrease in complaints of fatigue, weakness, and shortness of breath, as well as a reduction in the number of complaints of chest pain, cough, headache, dizziness, and joint and muscle pain (Table 4).

[0081] In patients who did not receive the immunomodulatory drug, all clinical symptoms remained at the same level (Table 4).

[0082] Table 4. Comparison of symptoms in patients of 2 observation groups

[0083] Symptoms Observation Groups (number of patients) 1 group n (%) 2 group n (%) P between gr.1 and gr.2 Fatigue, weakness Start of observation, 45 (100%) 43 (96%) 42 (93%) 0,65 After 15 days, 45 (100%) 37 (82%) 24 (53)% < 0,001* p in one group between observation periods 0,04 < 0,001* Dyspnea Start of observation, 45 (100%) 34 (76%) 32 (71%) 0,63 After 15 days, 45 (100%) 30 (67%) 17 (38%) 0,01* p in one group between observation periods 0,35 0,001* Chest pain Start of observation, 45 (100%) 14 (31%) 13 (29%) 0,82 After 15 days, 45 (100%) 11 (24%) 5 (11%) 0,01* p in one group between observation periods 0,48 0,04* Cough Start of observation, 45 (100%) 16 (36%) 15 (33%) 0,82 After 15 days, 45 (100%) 13 (29%) 5 (11,1%) 0,04* p in one group between observation periods 0,50 0,049* Headache Start of observation, 45 (100%) 15 (33%) 13 (20%) 0,65 After 15 days, 45 (100%) 16 (36%) 4 (8,9%) 0,03* p in one group between observation periods 0,82 0,02* Dizziness Start of observation, 45 (100%) 13 (29%) 14 (21%) 0,82 After 15 days, 45 (100%) 9 (20%) 6 (13,3%) 0,58 p in one group between observation periods 0,33 0,04* Joint and muscle pain Start of observation, 45 (100%) 24 (53%) 25 (56%) 0,83 After 15 days, 45 (100%) 22 (49%) 14 (32%) 0,04* p in one group between observation periods 0,67 0,02* Note: * - statistically significant differences at p<0.05

[0084] When studying the cytokine status of convalescents in the compared groups, it turned out that upon admission to the rehabilitation department, the average IL-6 level was significantly higher than normal for all patients: in patients of the 1st group 28.0 [24.4; 35.80] pg / ml, p<0.001, and in the second 29.0 [25.2: 38.3] pg / ml, p<0.001, p1>0.05. After 2 weeks, the IL-6 level in patients receiving the immunomodulator returned to normal values ​​faster (7.25 [6.2; 8.7] pg / ml), p>0.05, than in patients who did not receive this drug (19.0 [12.6; 23.9] pg / ml), p<0.001, where p is the reliability of the differences to the indicator in healthy individuals, and p1 is the difference to the indicator in patients who did not take the drug (Fig. 1).

[0085] Fig. 1 shows the level of IL-6, IL-8, IL-23 depending on the therapy of convalescents from COVID-19 coronavirus infection with Galavit®.

[0086] The IL-8 level in patients upon admission to the rehabilitation department was, on average, higher than that in healthy subjects and showed no differences between the comparison groups: 36.55 [33.5; 39.1] pg / ml, p<0.05 versus 37.0 [33.4; 38.2] pg / ml, p<0.05, p1>0.05. In the group of patients who received Galavit® as part of combination therapy, the IL-8 level returned to normal values ​​on average faster than in the comparison group 9.1 [5.6; 9.9] pg / ml, p>0.05, p1>0.05, while in those who did not receive it, this indicator remained significantly higher -15.6 [13.0; 20.8] pg / ml, p<0.001 (Fig. 1).

[0087] The IL-23 level on admission in patients of both comparison groups was significantly lower than in healthy subjects and did not differ between the groups: 41 [38; 47] pg / ml, p <0.001 versus 40 [37; 48] pg / ml, p <0.001, p1>0.05.

[0088] The IL-23 level in the group of patients who received Galavit® in combination therapy returned to normal values ​​faster in the period of 4-12 weeks from the onset of the disease (Fig. 1). In patients receiving Galavit®, the IL-23 level after a course of treatment with this drug returned to normal - 25 [21; 30], p> 0.05, p1 < 0.001. (Fig. 1), and in the group who did not receive this drug 33 [27; 38], p < 0.05.

[0089] For a more complete assessment of the balance of the body's pro- and antioxidant systems, the ceruloplasmin / malondialdehyde index (CMI) was studied. In patients of both groups, this indicator was significantly lower than in healthy individuals and did not differ between the groups: 98.5 [65.7: 130.62] units, p<0.001 versus 94.7 [67.5: 127] units, p<0.001, p1>0.05 (Fig. 2).

[0090] Fig. 2 shows the level of ICM depending on the therapy of convalescents from COVID-19 coronavirus infection with Galavit®.

[0091] In patients who received a course of immunomodulator in combination therapy in the period of 4-12 weeks from the onset of the disease, the level of ICM returned to normal faster (Fig. 2). Thus, after a course of this drug in the group of patients who received this drug, ICM was 311.2 [250.7: 335.0] units, p> 0.05, p1 < 0.001, whereas in the group of patients who did not take this drug, ICM remained significantly lower than in healthy people - 118.9 [91.87: 165.5] units, p < 0.001 (Fig. 2).

[0092] Technical result: the use of an immunomodulatory antioxidant drug, aminodihydrophthalazinedione sodium - Galavit® according to a regimen of 10 injections, 5 daily at 100 mg, then 5 every other day at 100 mg, which ensures the restoration of impaired cytokine and free radical homeostasis, which is not achievable using only standard rehabilitation therapy.

Claims

A method for correcting immune disorders in patients in the early recovery period of 4-12 weeks after suffering from COVID-19 coronavirus infection, characterized in that, in order to normalize the cytokine balance indicators and the lipid peroxidation system of biological membranes, an immunomodulatory antioxidant drug, sodium aminodihydrophthalazinedione - Galavit®, is prescribed in the dosage form of a solution for intramuscular administration according to a regimen of 10 injections, of which the first 5 injections are administered at 100 mg daily, and the subsequent 5 injections - at 100 mg every other day.

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