[The effect of etiopathogenetic therapy of COVID-19 on the severity of the disease: results of a multicenter double-blind placebo-controlled randomized trial].

AIM: The search for etiopathogenetic agents to prevent the development of severe and extremely severe COVID-19 remains relevant. A placebo-controlled randomized clinical trial was conducted to evaluate the efficacy and safety of the antibody-based biological drug (Raphamin). MATERIALS AND METHODS: 785 outpatients 18-75 y.o. with laboratory confirmed mild COVID-19 were included within 24 hours from the disease onset. 771 patients were randomized to the group Raphamin (n=382) and the Placebo group (n=389). The study drug/placebo was prescribed for 5 days. The rate of progression to a more severe degree of COVID-19 by day 28 as well as the time to sustained clinical recovery and the frequency of hospitalization were evaluated. Safety was assessed taking into account adverse events, vital signs and laboratory parameters. RESULTS: The number of cases of progression to a more severe degree of COVID-19 in participants receiving Raphamin was 59 (15.5%) [52 (14.6%)] versus placebo - 89 (22.9%) [85 (23.7%)], ITT and [PP] analysis data are presented. The odds ratio between groups was OR=0.6157 [OR=0.5494], 95% confidence interval 0.4276-0.8866 [0.3750-0.8048], which meant a reduction in the chance of progression to a more severe degree by 38.4% [45.1%] or 1.48 [1.62] times; p=0.0088 [p=0.0019]. The time to sustained recovery in the Raphamin group was 4.5±2.4 [4.6±2.4] days, versus placebo - 5.8±4.7 [6.0±4.8] days; p=0.0025 [p=0.0036]. No adverse events with a certain relationship were registered. CONCLUSION: Raphamin reduces the risk of progression to a more severe degree of the COVID-19 and significantly shortens the duration of clinical symptoms.

[Non-specific prevention of COVID-19 during vaccination against a new coronavirus infection: results of a multicenter, double-blind, placebo-controlled, randomized clinical trial].

BACKGROUND: A multicenter, double-blind, placebo-controlled, randomized clinical trial (RCT) of the phase III efficacy and safety of Ergoferon® for the non-specific prevention of COVID-19 during vaccination against a new coronavirus infection was conducted (permission of the Ministry of Health of the Russian Federation №559 dated 22.09.2021; ClinicalTrials.gov Identifier: NCT05069649). AIM: To evaluate the efficacy and safety of the use of Ergoferon for the non-specific prevention of COVID-19 during vaccination against a new coronavirus infection. MATERIALS AND METHODS: From October 2021 to April 2022, 1,057 patients aged 18 to 92 years who received component I of the "Gam-COVID-Vac" vaccine were included. After screening, 1,050 patients were randomized into 2 groups: 526 people received Ergoferon according to the prophylactic scheme - 1 tablet per administration 2 times a day for 3 weeks, the drug is not allowed during the meal and should be kept in the mouth without swallowing, until completely dissolved; 524 patients received a placebo according to the Ergoferon® scheme. The total duration of participation in the study was 5 weeks + 3 days. The primary endpoint is the number of RT-PCR - confirmed cases of SARS-CoV-2 infection, regardless of the presence of symptoms during participation in the study. An additional criterion of effectiveness is the proportion of those hospitalized with COVID-19. The safety assessment included consideration of the presence and nature of adverse events (AEs), their severity, relationship with the drug intake, and outcome. Statistical data processing was carried out using SAS 9.4 with the calculation of the exact Fisher test, χ2 test, Cochrane-Mantel-Hensel test, Wilcoxon test and other parameters. RESULTS: The ITT (Intention-to-treat) and PP [Per Protocol] efficacy analysis included data from 1,050 [970] patients: 526 [489] people - Ergoferon® group and 524 [481] people - Placebo group. The primary endpoint - the number of laboratory-confirmed cases of SARS-CoV-2 infections was 3 times less compared to placebo - 7 (1.43%) vs 22 (4.57%), respectively (p=0.0046; [p=0.0041]). Taking Ergoferon® reduces the risk of SARS-CoV-2 infection by more than 3 times in vaccinated patients during 5 weeks of the vaccination and post-vaccination periods (p=0.0046 [p=0.0041]). Of the COVID-19 patients in the Ergoferon® group (1.33%) nobody was hospitalized. According to the Post hoc analysis, Ergoferon® reduces the risk of COVID-19 disease by 4 times in the period between the components I and II of the "Gam-COVID-Vac" vaccine (p=0.0066 [p=0.006]). The frequency of AEs in both groups did not differ. There were no registered AEs associated with the drug with a reliable degree. There was a high level of patient compliance and good tolerability. CONCLUSION: Ergoferon is an effective and safe drug for the prevention of COVID-19 in people vaccinated against a new coronavirus infection.

[Cytochemical activity of cells of the lymphocytic-macrophageal system in patients with chronic acquired toxoplasmosis].

The peripheral blood lymphocytic activities of acid phosphatase (AP) and acid nonspecific esterase (ANE) (alpha-naphthylacetate esterase) were determined in 45 patients with chronic acquired toxoplasmosis on an exacerbation. There was a considerable increase in the activity of AP in the white blood cells, which being more pronounced in the monocytes. The activity of ANE was moderately enhanced in the lymphocytes. The determination of the leukocytic activities of AP and ANE may be used as additional tests in the diagnosis of an exacerbation of chronic acquired toxoplasmosis and in the evaluation of the efficiency of the treatment performed.

[Clinical significance of the activity of nitric oxide synthase in patients with leptospirosis].

Endotoxin-induced activation of inducible nitric oxide (NO) synthase (iNOS) becomes one of the triggers of the systemic response syndrome (SIRS). Determination of the activity of iNOS reflects the level of NO accumulation and may serve as a prognostically significant test of the severity of a pathological process. A procedure for determining the monocytic activity of iNOS has been developed on the basis of a histochemical reaction to NADPH-diaphorase. iNOS activity was determined in a group of healthy individuals and in 17 patients with leptospirosis. iNOS activity was decreased or absent (mean 0.56 +/- 0.085 c.u.) in patients with a very severe course of the disease and in those with protracted early convalescence. The increased activity of iNOS during early convalescence testifies to the incompleteness of an infectious process.

[Serum nitric oxide as an additional criterion for evaluating the course of leptospirosis].

The blood level of nitric oxide (NO) was studied during an infectious process in 107 patients with leptospirosis. The content of NO was estimated from the level of the final stable nitrogen cycle metabolite--nitrite was estimated by the Griss reaction. Infectious toxic shock (57%), disseminated intravascular coagulation syndrome (31%), respiratory distress syndrome (36%), and acute renal and hepatic failure (76%) were observed in the examinees. A combination of 3-4 of the above abnormalities was noted in 49% of the patients. There were elevated blood nitrite levels at the onset of the disease in patients with leptospirosis with signs of infectious toxic shock (15.3+/-2.79 micromol/l). In patients with a poor or complicated rehabilitative period, the high levels of nitrite were retained or its concentration repeatedly increased at weeks 3-4 of the disease. It has been shown that the measurements of blood nitrite levels may be used as an additional diagnostic criterion for evaluating the course of leptospirosis.

[Outcome and tendency of late convalescence in icterohemorrhagic leptospirosis]. / Iskhody i techenie otdalennoi rekonvalestsentsii pri ikterogemorragicheskom leptospiroze.

To elucidate the time of onset and duration of complications of icterohemorrhagic leptospirosis (IL), a clinical course of early and late convalescence was analysed in 170 patients who were followed up for 1.5-9 years. It was found that affection of hepatobiliary, urinary, cardiovascular and nervous systems persisted for a year after the acute disease in 65.3, 67.6, 31.8 and 13.5% patients, respectively. The organ of vision was affected for 1 year in 7.1% patients. A total of 86% patients retained the above disorders in early convalescence (for a year). In early convalescence the author observed development of such diseases as chronic hepatitis, a latent stage of chronic renal failure, myocardiac myocardiodystrophy. Nervous and ocular complications manifested both in early and late convalescence (4-18 months). The complications combined in 66.0% cases, renal dysfunction + hepatic dysfunction being most frequent. Endogenic infection foci activated within 6 months after IL. In 19.4% patients, the pathological process prolonged up to 1.5 years. In 5.3% patients it can last for several years. It is concluded that IL patients should be followed up for 1.5 years, combined pattern of organ affection typical for IL should be taken into account.

[Bone marrow hematopoiesis in leptospirosis and its role in anemia pathogenesis]. / Kostno-mozgovoe krovetvorenie pri leptospiroze i ego rol' v patogeneze anemii.

Sternal biopsy was made for and the dynamics of medullary hemopoiesis was examined in 20 patients with leptospirosis caused by L. icterohaemorragiae, L. canicola and L. gebdomadis. A severe icteric disease form complicated on day 10.75 +/- 1.26 by anemia was observed in all patients. A moderate activation of erythropoiesis, irritation of the lymphomonocytic sprout as well as oppression of the basophile and neutrophile series were the characteristic features of myelograms at the acute illness stage. Leptospirosis did not affect the functional ability of the bone marrow and no oppressive myelotoxic action as produced by Leptospira was observed. Anemia in patients with leptospirosis is predominantly of the hyperregenerative nature with the normoblastic hemopoiesis type.

[The role glucose-6-phosphate dehydrogenase in pathogenesis of anemia in leptospirosis]. / Rol' gliukozo-6-fosfatdegidrogenzy v patogeneze anemii pri leptospiroze.

The activity of glucose-6-phosphate dehydrogenase (G-6-PDG) of plasma and erythrocytes, levels of erythrocytes, hemoglobin, free hemoglobin and reticulocytes in different periods of illness were assessed in 30 men with severe icteric leptospirosis and anemia. Elevation of plasma G-6-PDG activity, levels of free hemoglobin (FH) and reticulocytes were found. Hemolysis was more pronounced at the height of the disease. One of the causes of hemolysis in severe leptospiral jaundice may be deficiency of erythrocytic G-6-PDG which is inheritable male disease. Low G-6-PDG activity of erythrocytes on the second week of the illness preceded anemia in 83.3% cases which could be a prognostic criterion of developing anemic syndrome. Combined treatment of leptospirosis with administration of tocopherol acetate resulted in a significant fall of plasma FH and G-6-PDG, of severity and duration of anemia versus the control group.

[Hematological parameters in characterization of anemia in leptospirosis]. / Gematologicheskie parametry v kharakteristike anemii pri leptospiroze.

Blood samples from 46 patients with leptospirosis were analyzed on a Cobas Vega (ABX, France) device over the course of disease. Hemoglobin content, erythrocyte count, mean volume of erythrocytes, mean content and mean concentration of hemoglobin in an erythrocyte, anisocytosis index, reticulocyte count, and content of free hemoglobin (FH) were analyzed. Anemia (normocytic normochromic hyperregeneratory) is a typical manifestation of leptospirosis during the second week of disease. The leading pathogenetic mechanism of anemia associated with leptospirosis is erythrocyte hemolysis, whose intensity during the acute period depends on the severity of intoxication and extracorporeal methods of detoxication. Persistence of anemia during convalescent period is due to involvement of the kidneys (nephrotic nephritis).

[The importance of myoglobin in the pathogenesis of leptospirosis]. / Znachenie mioglobina v patogeneze leptospiroza.

Measurements were made of serum and urine myoglobin in 48 patients with leptospiral jaundice (LJ) and 56 patients with various acute infections. At the height of LJ blood myoglobin level reached 28.96 +/- 4.3 micrograms/l (normal concentration 0.315 +/- 0.002 microgram/l). Compared to acute pneumonia, acute viral hepatitis, tonsillitis, erysipelas, diphtheria, health values, the ratio of serum myoglobin to urine myoglobin in leptospirosis made up 45.25 against 5.4, 4.8, 6.8, 3.7, 1.8 and 1.3, respectively. A relationship was found between concentrations of myoglobin, bilirubin, creatinine in the blood and leptospirosis severity. Elevation of serum myoglobin as a manifestation of specific myositis is pathognomic for leptospirosis and contributes to the onset of acute renal failure and disturbance of bilirubin metabolism. Quantitation of blood myoglobin may be helpful as an additional test for leptospirosis severity.

[Relationship between cytochemical activity of leukocytes and autorosette formation phenomenon and its clinical significance in patients with leptospirosis]. / Vzaimosviaz' tsitokhimicheskoi aktivnosti leikotsitov s fenomenom autorozetkoobrazovaniia i ego klinicheskoe znachenie u bol'nykh leptospirozom.

The content of autorosettes in the peripheral blood forming from red cells round neutrophils and monocytes was found increased during the acute period of icterohemorrhagic leptospirosis. Autorosette-forming cells are characterized by a high activity of alkaline and acid phosphatases and low NBT-test values. The content of autorosettes directly correlates with the disease severity, bilirubin level, and presence of anemia. Assessment of autorosette-forming cells in patients with leptospirosis may be used as an additional test for evaluating the severity of intoxication, disease course, and for predicting the complications and disease outcome.

[Adhesive intercellular interactions]. / Adgezivnye mezhkletochnye vzaimodeistviia.

The process of intercellular interactions during morphogenesis, inflammation and malignant growth are considered from the point of view of possible intercellular contacts provided by cell adhesion molecules. The system analysis of different cell adhesion molecules classes? their structure and influence on functional cell activity is performed. Clinical importance of expression disturbances of cell adhesion molecules at various pathological processes is considered.

[Leukocyte chromatin anisotropy in patients with leptospirosis]. / Anizotropiia khromatina leikotsitov u bol'nykh leptospirozom.

Chromatin anisotropy is measured and its correlation with the cytochemical activity of leukocytes estimated in 19 patients with icterohemorrhagic leptospirosis. Leukocyte and neutrophil nuclei chromatin anisotropy increases during the acute period of leptospirosis, indicating an increase of cuchromatization and transcription activity. Neutrophil nuclei euchromatization is observed in patients with all forms of leptospirosis irrespective of the disease severity. Lymphocyte nuclei euchromatization is observed only in the patients with a favorable course but not in those with the severe course of the disease. Correlations between neutrophil and lymphocyte nuclei euchromatization and cytochemical activity of lymphocytes and monocytes are detected. The optic anisotropic effect is proposed to be used as an extra diagnostic criterion of leptospirosis severity.

[Study of acid lability of DNA in patients with leptospirosis]. / Izuchenie kislotolabil'nosti DNK u bol'nykh leptospirozom.

Measurements of DNA and study of chromatin status in blood cell nuclei help solve numerous basic problems of biology and medicine. Acid lability of DNA was assessed in 5 patients with grave icterohemorrhagic leptospirosis. The distribution of fluorescence peaks on the curve of neutrophil DNA hydrolysis in patients with grave leptospirosis indicates that functionally low-active acid-resistant DNA fraction predominates in their chromatin. Assessment of acid lability of DNA is proposed to be used for assessing the severity of the pathological process.

[Prognostic significance of the NBT test in patients with ichterohaemorrhagic leptospirosis]. / Prognosticheskoe znachenie NST-testa u bol'nykh ikterogemorragicheskim leptospirozom.

The values of spontaneous NBT test significantly rise at the peak of leptospirosis in patients with an uncomplicated course of the disease (p < 0.05). Low values of the spontaneous NBT test with stimulation with Staphylococcus in patients with grave leptospirosis predict the development of life-threatening complications. Leptospirosis vaccine reduced the elevated values of the NBT in leptospirosis. The depressing effect of leptospirosis vaccine is indicative of a high risk of development of late complications.

[Modifications of cytochemical methods of detecting alkaline and acid phosphatase activities of leukocytes]. / Modifikatsii tsitokhimicheskikh metodik vyiavleniia aktivnosti shchelochnoi i kisloi fosfataz leikotsitov.

Wide use of the detection of the leukocytic alkaline and acid phosphatase (AIP and AP) activities by the azo coupling method has necessitated the development of rational modifications of the routine methods. When staining just few smears, it is recommended that the neutrophilic AIP activity be detected by applying the incubation medium onto the filter paper covering the blood smear; such a modification, used for the staining of 1-6 blood smears, reduces the reagent consumption by 5-6 times and is time-saving. The modification of the method for the detection of the leukocytic AP activity involves the use of the diazole blue O stain manufactured in this country; the acetate-veronal buffer (containing sodium diethylbarbital) is replaced by citrate buffer, pH 6.4. The leukocytic AIP and AP activities, determined in the blood smears stained according to the suggested and routine methods, coincide (p greater than 0.05).