Publications in Scientific Journals

Abstract
Preclinical and clinical studies of medical preparations (rengalin, ergoferon) containing release-active (P-A) antibodies to histamine confirmed their ability to provide anti-inflammatory and anti-allergic effect. The mechanism of action of release-active antibodies to histamine is based upon their influence on histamine-dependent activation of histamine receptors. It is shown that P-A antibodies to histamine can effectively eliminate associated allergic infections and inflammatory reactions

Abstract
To optimize selection of antiviral agents for children in routine practice of ARVI management, a double-center, prospective, open-label, randomized study of efficacy and tolerability of schemes including Ergoferon, Cagocel, Arbidol in children > 3 years was performed throughout two epidemic seasons (fall 201 2 spring 2014). In total 1 52 children with ARVI symptoms lasting for no more than 48 hours were randomized into 3 groups, i.e. Ergoferon (group E, n = 67), Cagocel (group C, n = 40), Arbidol (group A, n = 45). At visits 2 and 3 proportion of children with normalized body temperature (primary criterion) and intensity of intoxication and catarrhal syndrome were evaluated. At visit 3 the following parameters were measured: efficacy index (efficacy and tolerability assessment by the doctor using CGI scale) and evaluation of safety and tolerability of the study drug by parents/representatives of the child; incidence of medical product prescriptions was recorded, i.e. the total number of prescriptions per group, incidence and duration of administration of individual groups of agents. 

To analyze and evaluate the data obtained, conventional methods of parametric and non-parametric statistics were applied. Groups C and A were not statistically different in baseline characteristics and throughout efficacy criteria assessment. A new group 2 (n=85) was generated out of these groups for further analysis. At visit 2 group 1 and group 2 showed normalization in morning and evening body temperature in 76% and 79% in group 1, respectively, vs. 73% and 79% in group 2 (χ 2, p > 0.05). 1 00% subjects in group 1 and 98% in group 2 did not have intoxication signs, or the rank value of mild intoxication did not exceed 1 (mild). Proportion of subjects with mild catarrhal syndrome at rank 2-3 in group 1 vs. baseline reduced from 15% to 3%, in group 2 from 18% to 8%. At visit 3, 94% subjects in group 1 and 95% in group 2 did not show clinical intoxication signs. Almost every one in three children in both groups had catarrhal signs completely resolved by the end of the treatment, in 70% and 65% cases in groups 1 and 2 severity of catarrhal syndrome did not exceed rank 1 (χ 2, p > 0.05). No adverse effects associated with the study scheme components have been reported during the study. 

Efficacy and tolerability evaluation by the doctors using CGI in group 1 was 3.37 ± 0.65 (M ± SD, 95% CI 3.22-3.53) vs. 3.23 ± 0.77 (M ± SD, 95%CI 3.08 3.39) in group 2 (Т-test, p = 0.38). In group 1 maximum rating (4 scores) was assigned by the doctors in 46%, minimum one (2 scores) in 9%, while in group 2 the equivalent proportions were 40% and 1 6%, respectively (p = 0.44 for maximum score and p = 0.17 for minimum score). Therapeutic efficacy evaluation by parents in group 1 was 3.73 ± 0.57 (M ± SD, 95% CI 3.59-3.87) vs. 3.35 ± 0.72 (M ± SD, 95%CI 3.20-3.50) in group 2; Т-test, p = 0.04. According to frequency assessment, positive scoring (4-5 scores) was more prevalent among parents in group 1: 71% vs. 44% (group 2), χ 2 test, p = 0.001, minimum scoring (2 scores) was less common in group 1: 1.5% vs. 12% (group 2), χ 2 test, p = 0.02. Evaluation of therapeutic tolerability by parents in group 1 (4.04 ± 0.53, 95%CI 3.91 -4.18) was higher as compared to group 2 (3.82 ± 0.53, 95%CI 3.71 -3.93); Т-test, p = 0.01. Maximum scoring (5 scores) was obtained in group 1 in 1 6% cases, in group 2 6% (χ 2 test, p = 0.03). Analysis of additional drug prescriptions revealed that 3.6 ± 1.2 prescriptions have been made on average in group 1 vs. 5.0 ± 1.2 in group 2 (Т-test, р = 0.01 ). Proportion of children receiving more than 5 drugs was 1 8% in group 1 vs. 32% in group 2 (χ 2 test, p = 0.05). Seven drugs were given to 3% children in group 1 and 1 2% in group 2 (exact Fisher's test, p = 0.067). Duration of therapy with H1 -histamine blockers in group 1 was 5 days (Me: 5.0 (5.0; 6.0) vs. 8.5 days (Me: 8.5 (7.5; 10.0) in group 2 (U-test, р = 0.006). 

Therefore, comparable clinical efficacy and tolerability of anti-ARVI therapeutic schemes were revealed in children using Ergoferon, Cagocel and Arbidol. At that Ergoferon group showed higher therapeutic quality scoring (efficacy and tolerability), both according to the doctors (CGI scale) and parents. Reduced number of prescriptions and duration of drug therapy in Ergoferon group for ARVI management were revealed. 

Abstract
Acute respiratory viral infections (ARVI) along with influenza are the most common diseases both in adult and pediatric practices. Nowadays there are a lot of different medications to cure this condition, but it’s still urgent to find some new drugs, which have a universal antiviral activity and also have proved effectiveness and safety, especially in case of treating patients with different allergic pathologies. The aim of the study was to evaluate the practical use of the drug based on release-active antibodies to interferone-γ,CD4+receptor and histamine (Ergoferon) in ambulatory practice, including cases of late-start treatment and cases with allergic status of patients. Data of pediatric and adult patients who were ambulatory observed with influenza/ARVI diagnosis and used Ergoferon were included into the research. The physician set duration and scheme of the therapy. The received results were estimated retrospectively. The research was carried out with general practitioners from Azerbaijan, Armenia, Georgia, Kazakhstan, Kyrgyzstan, Mongolia, Tajikistan and Uzbekistan; period of observation - epidemiological season 2016-2017. 8411 patients (6005 infants, 2069 adults, 337 without specifications of the age) took part in the research. 706 patients had such allergy manifestations as allergic rhinitis/sinusitis, atopic dermatitis/eczema, bronchial asthma. The duration of the disease before the resolution of all the symptoms was on average 4.84±1.53 days; patients who started treatment from the first day of disease the duration was 4.79±1.44 days (АNOVA, factor «the day of the start of therapy» χ2=31.15, p <0.001). Although the early-start treatment is important, the difference between the duration of all symptoms of the disease in both groups was only 0.39 day (9.4 hours). Therefore the conclusion has been made that Ergoferon has combined antiviral, anti-inflammatory and antihistamine effect only in case of prompt relief of ARVI and influenza symptoms in different terms of the beginning of the therapy independently of the age of patients, and including patients with an allergic status.

Abstract
A prospective, two-center, open-label, randomised clinical trial assessing the efficacy and tolerability of treatment strategies involving the administration of Ergoferon and Kagocel in paediatric outpatients aged over 3 years was carried out. The study was conducted with the objective of obtaining a comprehensive evaluation of drug-based therapy options used in routine paediatric practice to treat acute respiratory infections (ARI) during the 2012-2013 epidemic season. A total of 90 ARI-diagnosed child-age patients able to initiate treatment within 48 hours of infection onset entered the trial. Nine participants were excluded from final analysis due to protocol violation. The patients were randomised into 2 groups (Ergoferon (group 1): 41 subjects and Kagocel (group 2): 40 subjects) with similar distribution of sex, age, baseline clinical data, and time of treatment initiation. 

The study involved clinical assessment including daily body temperature monitoring (morning/evening measurements) and three PCR assays of nasal swabs. At visits 2 and 3, the number of patients achieving normal body temperature (primary endpoint) was estimated and severity of intoxication and catarrhal syndromes and individual symptoms as well as the rate of virus elimination were evaluated. In addition, visit 3 included the assessment of the volume and cost of treatment in conjunction with clinical benefit and treatment safety/tolerability (as judged by the physicians and parents). By the end of the first day of treatment, the number of children with body temperature of above 38 С was significantly decreased as compared to the morning baseline (p=0.008) and respective values in group 2 (p=0.02). At visit 2 (treatment day 4), the state of 80% of patients in either group was assessed as satisfactory and over 70%, respectively, could maintain normal body temperature throughout the day. Total intoxication scores were reduced by 7-10 points and were less than 9 in 100% of patients. The overall scores of catarrhal symptoms were 2.5-3 points lower than the base- line levels and were less or equal to 9 in 80-90% of children in either group. By visit 3, 'satisfactory' health assessments were reported for 95% of patients in respective groups. Signs of catarrh were completely resolved in 37% of participants in group 1 and 15% in group 2 (p=0.03). At the same point, 66% of patients in group 1 and 55% in group 2 were observed to have no (or isolated or negligible) signs of infection which did not require continuation of treatment (p>0.05). 

The percentage of children achieving recovery was 3 times greater in group 1 than in group 2 (p=0.01). No bacterial complications were presented by any of the study subjects. The severity of individual symptoms of catarrh varied significantly between the groups as observed at visits 2 and 3. At visit 2, 92% of subjects in group 1 had no or only minor (requiring no drug intervention) obstruction breathing through the nose and 26.8% reported no nasal blockage (p=0.04), while the latter was observed to persist in 60% of children in group 2 (p<0.001). By the time of visit 2, the number of patients attaining complete resolution of serous nasal discharge was increased by more than 2.5 in group 1 - up to 31.7% (p=0.01), while this number in group 2 was 17.5% and did not significantly differ from the baseline level (visit 1, p=0.4). There were also differences in cough pattern changes between the groups, i.e. the dry cough was converted into a productive cough in 44% of subjects in group 1 vs. 20% in group 2 (p=0.06). As reported at visit 3, the number of patients having no difficulty breathing nasally was 88% in group 1 vs. 38% in group 2 (p=0.008). The percentage of children exhibiting complete resolution of cough as observed at visit 3 was 2 times higher in group 1 then in group 2 (respectively, 24% vs.12%; p>0.05). No adverse events related to medications used as part of the treatments administered were reported during the study. The mean CGI scores (overall safety and efficacy index) were similar between the groups: 3.5+0.6 in group 1 vs. 3.3+0.6 in group 2 (p=0.25). The percent of maximum scores was 51% and 38% in groups 1 and 2, respectively. Mean efficacy scores in patient groups were 3.9+0.6 and 3.6+0.6, respectively (p=0,036), with respective tolerability ratings represented by scores of 4.3+0.7 and 3.8+0.5 (p=0,002). The mean number of drugs prescribed was 4.7+1.0 in group 1 vs. 6.0+1.3 in group 2 (p<0.001). The percent of cases where not more than 4 medications were administered to a subject and the number of occasions when a child was prescribed to receive 6 drugs or over varied significantly between the groups and were 46% vs.10% and 27% vs. 70%, respectively (p<0.001). Similarly, there were differences in the duration of treatment with drugs belonging to distinct pharmacological groups: 6.0+1.4 vs.8.8+1.5 days (p<0.05) for antihistamines; 6.1+2.0 vs. 7.1+2.4 days (p=0.15) for decongestants; 6.0+1.1 vs.7.1+2.4 days (p=0.07) for mucolytics; and 6.9+1.4 vs. 8.4+2.3 days (p=0.04) for locally-acting anti-inflammatory and antiseptic agents, as reported for group 1 vs. group 2, respectively. The mean treatment cost per ARI case was 1353+320.2 rubles in group 1 compared to 1768+491.0 rubles in group 2 (p=0.008). Swab specimens from 76 children (41 subjects from group1 and 35 from group 2) were tested using PCR. Baseline specimens were mostly positive for rhinoviruses, influenza A(H3N2) virus, and parainfluenza virus types 2 and 3. By visit 2, virus elimination was demonstrated for 46% of cases in group 1 and 23% in group 2 (p<0.03). By the time of visit 3, the tests were indicative of virus removal for 66% of children in group 1 and 49% in group 2. 

Thus the antiviral drugs used as part of combination treatment of ARIs were shown to enable fast recovery and prevent the development of bacterial complications, proving to be well-tolerated. Patients in the Ergoferon group demonstrated faster resolution of ARI symptoms and shorter elimination of respiratory viruses, had less need for additional medications, and required 23% less spending on treatment, resulting in a greater number of favorable assessments of Ergoferon by both the physicians and parents.

Abstract
A randomized double-blind controlled study was carried out to evaluate changes in the clinical presentation of acute obstructive bronchitis in preschool children using antiviral, anti-inflammatory therapy. The study enrolled 54 subjects (aged 3-6 years old) hospitalized with verified diagnosis of acute obstructive bronchitis. Their parents had given their informed consent for participation. Group 1 (n=26) received etiotropic therapy with the drug having complex antiviral, anti-inflammatory and antihistamine effect (Ergoferon), group 2 (n=28) received placebo. Meanwhile all children received complex therapy of ARI. To evaluate therapeutic efficacy the following parameters were compared: time to elimination of the clinical manifestations of the disease; extent of alleviation of the key symptoms, incidence of wheezing episodes and complications.
Results. According to PCR, rhinoviruses prevailed in both groups in oropharyngeal swabs (31% in group 1 and 57% in group 2); furthermore, RNA of influenza B virus, respiratory syncytial virus, parainfluenza virus types 2 and 4 and metapneumovirus were also detected; 3 children in each group simultaneously had RNA of various viruses; no differences between the groups were observed. In group 1 average duration of increased body temperature (morning measurement) was 1.6 (1.4-1.9)±0.6 days, respectively, and all children reached normal values of morning and evening body temperature by the end of 3-day therapy. In group 2 morning body temperature reached normal values on types 2.7 (2.1-3.3)±1.2 days, respectively ( U-test, P=0.002), while complete normalization in all children took place on day 6 of the follow-up. Area under curve for daily body temperature was statistically lower in group 1: 514.3 (513.8-514.9)±1.4 (°С x days) vs. 516.3 (515.1-517.5)±2.5(°C x days) in group 2 (U-test, P=0.002). Intoxication in group 1 was eliminated within 2.8 (2.5-3.1)±0.80 days on average, in group 2 within 4.5 (4.1-4.8)±0.96 days (P<0.001). Intensity of catarrhal symptoms (nasal congestion, rhinitis, cough) resolved faster in group 1 (P<0.05). Average elimination term for catarrhal symptoms was 6.0 (5.7-6.3)±0.8 days vs. 9.0 days for groups 1 and 2 (P<0.001), respectively. Wheezing resolved within 4.1 (4.0-4.2)±0.3 days on average in group 1 and within 6.9 (6.7-7.0)±0.4 days in group 2 (P<0.001). Despite the treatment, eight children in group 2 showed moderate reinforcement of wheezing within the first 3-4 days of therapy, 3 of them had body temperature increased to subfebrile values requiring antibacterial treatment. Neither of children in group 1 had any bacterial complications or reinforced wheezing. All children from group 1 had complete recovery on day 8. Neither of subjects recovered completely on day 9 in group 2. Average recovery term in group 1 was 6.0 (5.76.3)±0.8 days vs. 9.0 days in group 2 (P<0.001). No adverse effects associated with the medicinal products were recorded during the study. Average rating of therapeutic efficacy by the investigator using CGI scale was 3.7 (3.5-3.8)±0.49 scores in group 1 vs. 2.6 (2.3-2.9)±0.69 scores in group 2 (P<0.005). Rating of wheezing therapy efficacy was similar: 3.7 (3.43.9)±0.57 and 2.2 (1.7-2.7)±1.29 for groups 1 and 2, respectively. Safety of the products according to CGI scale reached maximum in both groups. Parents' rating of the treatment in group 1 was 50% higher as compared to group 2: 3.6 (3.43.8)±0.57 scores and 2.5 (1.8-2.9)±1.31 scores (P<0.005).
Conclusion. Ergoferon in complex therapy of acute obstructive bronchitis in preschool children ensures rapid therapeutic effect including elimination of wheezing symptoms, prevention of bacterial complications, wheezing progression and is well tolerated by the subjects. 

Abstract
A multi-center double blind placebo-controlled randomized clinical study assessed the efficacy and safety of the drug Ergoferon. The clinical study, carried out in 8 medical centers of the Russian Federation, included patients aged from 18 to 60 years with the body temperature >37.8°C, who had at least one catarrhal symptom (cough, rhinitis, sore throat) and one intoxication symptom (chillness/sweating, malaise, weakness, headache) in the period of seasonal morbidity, and who referred to doctors within 48 hours from the moment of manifestation of the first symptoms of acute respiratory viral infection. The results obtained are indicative of the safety and efficacy of the drug of study in treatment of acute respiratory viral infection in adult patients, the use of the drug ensures effective antiviral defence, shortens the duration of the fever period and promotes faster arrest of the main clinical symptoms of acute respiratory viral infection.

Abstract
The pediatric dosage form of Egroferon — a drug indicated for the treatment of influenza and acute respiratory infections (ARIs) — is developed taking in account the broad range of pathogens (most of which are viruses), and age-dependent features of immune system reactions (absence of specific immunity and immunological memory, relative «immaturity» of immune reactions, reduced interferon production by immunocompetent cells, etc.). Ergoferon interferes with the non-specific mechanisms of antiviral defence that ensure eliciting of an immune response, regardless of the virus type (the interferon system and CD4+cells), and influences virus-induced histamine release and histamine-mediated inflammatory reactions. Used over four years in clinical practice, the drug has shown a high efficacy and safety profile for the treatment of influenza and ARIs in adult patients. The purpose of the multi-center, randomized, double-blind, placebo-controlled study was to evaluate the clinical efficacy and safety of a new ergoferon liquid dosage form in the treatment of ARIs in children. The publication contains the results of the fist study stage completed as per the study plan and data from the interim analysis.
METHODS. The screening involved a total of 162 subjects, aged 3 to 17 years (average, 8.2+3.9 years), that had presented to 13 research centers based in Russia with common signs and symptoms of ARI (body temperature >38.0°C, as measured with a digital infrared temporal artery thermometer; symptom severity score >4) during seasonal morbidity. Ergoferon was administered in 82 subjects receiving the therapeutic regimen of the drug for 5 days; 80 children received placebo. The subjects were monitored for 6 days. Treatment efficacy was assessed on the basis of morning, evening and total daily ARI symptom scores, including scoring estimates of fever, general symptoms and symptoms affecting the nose, throat and chest. Along with this, calculations were performed to obtain the Total Index (TI) of ARI; illness severity was evaluated using a mathematical «area under the curve» model.
RESULTS. Starting from Day 2, the percentage of convalescents was observed to increase — from 6% (morning) and 14% (evening) to 20% and 29% on Day 3, respectively, and 58% and 61% on Day 4. The results suggested a substantially higher efficacy of Ergoferon as compared to placebo treatment (the Cochran-Mantel-Haenszel Xtest: χ2=21.7; p<0.0001). Ergoferon had a marked effect on fever and other signs of intoxication. In Ergoferon group, the percentage of non-fever subjects, with the endpoint defined at <37.2°С, was 43% on Day 2, as estimated in the morning and the evening (vs 25% and 19% in the placebo group, respectively; χ2=10.6; p=0.012), and 83% in the morning and 84% in the evening on Day 3 (vs 60% and 54% in the placebo group, respectively; χ2=16,7; p=0,001). The Generalized Linear Model (GENMOD) procedure confirmed the significance of differences between the Ergoferon and placebo groups according to the following parameters: 1) Ergoferon was significantly more effective in reducing body temperature (to lower values) than the placebo; 2) Ergoferon had an earlier effect on fever (main marker of viremia), as compared to placebo; 3) The significant Ergoferon' s superiority over placebo was also evident by the morning and evening measurements throughout the five-day therapy. The TI was observed to significantly decrease starting from Day 2 of Ergoferon administration: from 13.0+4.5 to 7.9+4.8 on Day 2 and 4.5+2.9 on Day 3 (based on the patient's diary data); from 14.3+4.2 to 4.9+3.0 on Day 3 (based on the doctor's assessment). The severity of ARI-related intoxication signs was reduced most significantly, in particular as indicated by the results of doctor's objective examination on Day 3 (GENMOD: factor «Treatment» - χ2=147.8; p<0.0001; factor «Day of administration» - χ2=6.1; p=0.013; Tukey-Kramer post hoc analysis: z=-3.09; p=0.024). The average fever duration in ergoferon-treated subjects was 1.9+0.8 days (p<0.0001). The overall duration of ARI was much shorter in Ergoferon group than in the group of placebo (p=0.021). The «area under the curve» measure of TI in Ergoferon group was significantly lower as compared to Placebo group, both according to the patient's diary records (21.9+10.9 TIxDays vs 28.0+13.0 TIxDays; p<0.002) and the doctor's examination (12.4+4.7 vs 14.2+5.2 TIxDays; p=0.023). Ergoferon treatment was associated with a lower frequency of using antipyretics χ2=4.1; p=0.043), particularly on the first day of illness. The monitoring of adverse events as well as the haematology, biochemistry and urinalysis findings were indicative of Ergoferon's safety. No signs of drug incompatibility were observed as a result of ergoferon administration in combination with antipyretics, decongestants, expectorants, inhaled corticosteroids, cromoglicic acid derivatives, leukotriene receptor antagonists, short-acting beta2 agonists and topical anti-septics. There were also no cases of bacterial complications, worsening of illness severity, or acute exacerbations of coexisting allergy or chronic ENT pathology. The children demonstrated good drug tolerance and 100% treatment compliance.
CONCLUSIONS. Ergoferon liquid dosage form is an efficacious and safe treatment for ARIs in children. The study results demonstrated the drug's efficacy against the major syndromes associated and caused by viremia — fever and general intoxication. The early onset of the drug's effect was shown to result in a shorter time to convalescence and reduced ARI severity, particularly during the initial days of illness.

Abstract
OBJECTIVES: Ergoferon is an antiviral complex drug containing released-active forms of antibodies to interferon gamma, CD4, and histamine. Its efficacy and safety in the treatment of acute respiratory viral infections has been reported previously. The aim of this study was to compare Ergoferon with oseltamivir.
METHODS: A multicenter, open-label, randomized controlled trial of patients aged 18 to 65 years, who had tested positive for influenza A or B antigens, was performed. A total of 156 patients were enrolled as the intention-to-treat population; these patients were assigned randomly to receive either Ergoferon or oseltamivir (n=78 in each group).
RESULTS: The percentage of patients achieving a normal body temperature (≤37.0°С) following 5 days of treatment did not differ significantly between the groups. The mean duration of fever in the Ergoferon and oseltamivir groups was 2.1±1.5 days and 2.3±1.6 days, respectively (p=0.01). The average time to the resolution of influenza symptoms was approximately 3 days, with no significant between-group difference. Total quality of life scores were similar in the two groups following 5 days of drug administration. The incidence of adverse events did not differ significantly between the groups, nor were there any serious adverse events.
CONCLUSIONS: Ergoferon and oseltamivir were equally effective and safe in adult outpatients with seasonal influenza A or B virus infection.
CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifierNCT01804946.

Author translation
Abstract
Lower respiratory tract viral infections are one of the main causes of morbidity and mortality among pediatric, elderly and immunocompromised patients. RSV (respiratory syncytial virus) is the most common cause of bronchitis, bronchiolitis, and pneumonia in new-born babies. Nearly a million RSV-associated fatal cases are recorded every year worldwide. Most of the existing anti-RSV agents lack efficacy, or are expensive, or tend to produce complications. Ergoferon is a combination of polyclonal antibodies to IFNγ, CD4 receptor and histamine in the released-active form. This study aimed to establish if Ergoferon is able to affect RSV infectivity. The results showed that the infectivity of the virus was reduced 2-fold following pre-incubation of the test preparation with virus stock. This effect might be due to the product’s action on RSV-G and RSV-F virus proteins, which are essential for entry of virion into the target cells.

Abstract
Antiviral activity of Ergoferon was studied in vitro on an experimental model of rotavirus infection in MA-104 cell line. In infected cells treated with Ergoferon, rotavirus titer was shown to decrease by 83 and 90% in comparison with cells treated with solvent used for Ergoferon preparation (p<0.05) and distilled water (p<0.05), respectively. These findings demonstrate high anti-rotavirus activity of Ergoferon.

Summary
For evaluation of effects of release-active antibodies to CD4 on cultured lymphocytes from human peripheral blood, we measured intracellular content of lck-kinase cell-based ELISA. In cells treated with release-active antibodies to CD4, the content of intracellular lck-kinase significantly (p<0.01) decreased in comparison with the control (purified water processed in a similar way). Phytohemagglutinin had no effect on the concentration of lck-kinase in cells. The decrease in the content of CD4-associated lck protein suggests that the preparation enhanced intracellular coupling of lck-kinase with T-cell receptor and potentiated T-cell immune response.