Prevention and treatment of acute respiratory infections in children with asthma
Anaferon for children

Study Objective: To assess the efficacy of Anaferon for children, a Russian preparation of anti-interferon gamma antibodies, in preventing and treating repeated acute respiratory viral infections (ARVI) in children with asthma.
Study Design: This was a double-blind, placebo-controlled, randomized clinical study. Materials and Methods: Children, aged 1 to 5, with mild or moderate-to-severe asthma were randomized into the main group (n = 100) or the control group (n = 100). In the main group, children received a standard preventive regimen of Anaferon for children for 3 months and were temporally switched to a standard therapeutic regimen in case of ARVI. In the control group, subjects received the same regimens of placebo. In both groups, pathogenesis-based and symptomatic treatment was additionally used in case of ARVI.
Results: In the main group, 40 children had ARVI and 20 of them had these infections twice (60 ARVI events in total). In the control group, 76 children had ARVI, while 36 had had two events and 10 had had three events (132 ARVI events in total). The mean duration of the first and second ARVI episodes was 5.7 ± 0.4 and 5.2 ± 0.5 days in the main group and 9.4 ± 0.6 and 9.1 ± 0.8 days in the control group. Asthma exacerbations were reported in 20% and 64% of children in the main and control groups, respectively (p < 0.001).
Conclusion: The study showed that, compared to a placebo, preventive and therapeutic treatment with Anaferon for children in patients with asthma reduced the rates of ARVI, including the rates of repeated episodes, and the duration of ARVI episodes. Such treatment also contributed to a reduction in the frequency and duration of virus-induced asthma exacerbations in these patients and, therefore, improved asthma control.

Assessment of efficiency of repeated preventive and medical courses of anaferon for kids for development of rational schemes at ARVI in children
Original title. Оценка эффективности и безопасности повторных профилактических и лечебных курсов Анаферона детского в отношении острых респираторных вирусных инфекций у детей
Anaferon for children
Effectiveness and safety of kolofort use in case of irritable bowel syndrome: results of multicentre double blind placebo-controlled randomized clinical study
Original title. Эффективность и безопасность применения Колофорта при синдроме раздраженного кишечника: итоги многоцентрового двойного слепого плацебо-контролируемого рандомизированного клинического исследования

Author translation
Irritable bowel syndrome (IBS) is a widespread functional disorder which is characterized by regularly repeated pains or discomfort in the abdominal area along with violation of the bowel without identifiable organic causes. Recently it has been shown, the trigger in IBS appearance turns out to be stress causing the emergence of excessive emotions. Under stressful conditions neuropeptides (substance P) activation occurs and contributes the inflammatory changes appearance of the mucous membrane of the colon with minimum character. Continuing attempts to produce the effective therapy scheme of IBS with prolonged action didn’t show the results in any current of disease. Due to the results, problem of search and unbiased assessment of a medication faces difficulties in the complication and the poor knowledge of IBS pathophysiology and high level of placebo effect in the group of patients. A new approach in IBS therapy is the use of medicine Kolofort, made by Materia Medika Holding company on the basis of antibodies to human factor in tumour necrosis α (anti-FTN- α), brain specific protein S-100 (anti-S100) and histamine (anti-H). Combination of the three active components allows to affect central and peripheral links in pathogenesis of bowel functional violations, including visceral hypersensitivity, facilitates the reduction of abdominal severity of pain syndrome and recovery of gastrointestinal tract motility. Preclinical and clinical research, made earlier, showed the effectiveness and safety of Kolofort and its components in treatment of gastrointestinal pathology of inflammatory and functional genesis, along with the cupping of somatoform disfunctions and psychoneurological disorders on the background of somatic and neurologic diseases. Many specialists are interested in the results of multicentre randomized clinical research, made with aim to show the clinical effectiveness and safety of Kolofort when treating patients with IBS under conditions of blind placebo-control.

Comparative efficacy of infectious and post-infectious cough treatment in acute respiratory infections in adults

Cough is one of the most common symptoms of acute respiratory infections (ARI), manifesting and maintaining with participation of all its launchers factors and mechanisms and is a multifactorial problem. 
Objective: To estimate the efficacy of cough treatment in adults with ARI with complex drugs with different mechanisms of action. The study was open-label, comparative, randomized and included outpatients. 
Material and Methods: the study included 60 patients aged 18 to 75 years, with ARI, developed between 7-14th days before the screening visit. The main inclusion criterion was cough, non-productive / unproductive at the time of screening, started not less than 7 days before the screening. Complex preparations. Rengalin® and Stoptussin® were prescribed in accordance with appropriate schemes. The investigator examined the patient at least for 2 times – on the 1st visit, at the time of enrollment, on the 2nd visit (on the 7 th (±1) day of treatment). If the doctor made the decision to continue therapy on the 2nd visit, he appointed the 3d visit ( on 14 th (±1) day of treatment). 
Results: Patients were divided into 2 groups (n=30). Group 1 was treated with Rengalin, Group 2 was treated with Stoptussin. All 60 patients visited the investigator for 2 times. 12 patients (7 – from group 1 and 5 – from group 2) had the 3d visit. Cough syndrome characteristics, clinical severity of ARI, efficacy and safety of the therapy are evaluated for all visits. 
Discussion: Rengalin use in post-infectious cough treatment has significant therapeutic effects independently of the cough nature in shorter terms, without adverse events, including bacterial complications due to combination of antitussive, bronchodilator and anti-inflammatory effects.

Rengalin, a novel drug for treatment of cough in children. Intermediate data on multicentre, comparative randomized clinical trial

Rengalin liquid formulation on the basis of antibodies to bradlkinin histamine and morphine was specially designed for the treatment of cough in children. The three-component combination in therapeutically active against both dry and wet cough due to effect on diverse pathogenetic aspects of the cough reflex. The aim of the multicenter, comparative, randomized clinical trial was to estimate the efficacy and safety of rengalin in the treatment of cough in patients with acute respiratory infection (ARI) of the upper respiratory tract. 
Methods. One hundred forty six patients at the age of 3 to 17 years (the average age of 8.2+3.6 years) from 14 medical centres of Russia were observed. The patients sufferedfrom dry/nonproductive, frequent, sore cough preventing from day-time activity and/or night sleep (>4 by the Cough Severity Scale). The cough duration ranged from 12 hours to 3 days. For 3 days the patients of group 1 (n=71) and group 2 (n=75) were treated with rengalin and sinekod (butamirate) respectively. For the following 4 days the patients (in case of viscid expectoration were treated with ambroxole in the age doses. The results of the Per Protokol Analysis (n=67 rengalin group and n=73 sinekod group) with an account of the Non-Infectiority Design are presented. 
Results. In 3 days the number of the group 1 patients with significant improvement/recovery by the day and night estimates amounted to 90% and 88% respectively (vs. 81% and 88% in the group 2 patients, no night opisodes of cough after 3-days rengalin use being recorded in 52% of the patients vs. 34% in the sinekod group patients (p=0.0003). On the 7 th day of the treatment with rengalin the number of the children with significant improvement of or recovery from day-time cought amounted to 99%and that of the patients with significant improvement of or recovery from night-time cough amounted to 93%, in 90% of them no night-time cough being recorded (p=0.0008). As for the patients of the reference group, the respective values were 93% and 90%, no night-time cough being recorded in 81% of the patients. The time required for development of productive/moist cough during the 3-day treatment course in the patients of both the group was the same (2.9+0.3 days in the patients of group 1 and 2.9+0.4 days in the group 2 patients. Moreover, in 34% of the rengalin dry cough became residual (as rare episode of tussiculation with scantly exudation). After 3-day course of the rengalin therapy, 66% of the patients was treated with ambroxole (versus 95% in sinecod group (p<0.0001) based on comparative analysis and χ2=17.7, p>0.0001 by the results of the frequency analysis). The total duration of cough in the patients of groups 1 and 2 was 6.5±0.8 and 6.7±0.7 days respectively (the comparability truth, p=0.0001). The severity of the day-time cough by the area under the curve estimates for 7 days of the treatment in the rengalin group patients was equel to 14.3+5.6 numbers - days and that of the patients of the sinekod® group was equal to 15.9±6.1 numbers - days. The severity of the night-time cough was equal to 4.2+2.7 number - days respectively. In 2 patients (3%) treated with sinekod® signs of ARI generalization was observed after the 3-day treatment (p>0.0001). The research physicians-investigators (CGI-EL Scale) the combination of the anti- and protussive activities in one drug to be efficient and absolutely safe for the chilgren. The therapeutic efficacy in the patients of the rengalin group was higher in 3 days (2.1±0.5 numbers) and even in 7 days (2.7±0.5 numbers). The results value in the patients of the sinekod® group being 1.8±0.4 and 2.5±0.6 numbers (one-way ANOVA for repeated estimates ANOVA: Visit - F 1/138=146, p<0.0001, TREATMENT - F 1/138=9.0, p=0.003). The factor of the side effects in the patients of the rengalin group was zero (no side effects due to the treatment were recorded in the patients), whereas in the patients treated with sinekod® for 3 days the respective value was 0.1+0.3 (true superiority of rengalin by the ANOVA data. TREATMENT - F 1/138=4.7, p=0.03). The efficacy factor of the rengalin was also in its favour (ANOVA: Visit - F 1/138=182, p<0.0001, TREATMENT - F 1/138=7.3, p=0.008). In the patients treated with rengalin there were defected no deviations in the biochemical and general clinical analyses of blood and urine, no adverse reactions characteristic of antitussive drugs of the action. 100-percent adherence to the therapy was stated. 
Conclusion. He antitussive effect of rengalin in the treatment of frequent dry day-time and night-time cough was observed earlier and proved to be comparable with that of butamirate (sinekod®). Rengalin prevented significant exudation and viscid expectoration in many patients, promoted rapid residual in the patients with dry cough and the patients recovery. The use of rengalin for 3 days significantly lowered the percentage of the patients requiring treatment with mucolytics at the subsequent stages of ARI.

Rengalin, a new efficacious and safe antitussive agent. Results of a randomized, comparative, multicenter clinical trial in patients with acute respiratory tract infections

Rengalin is a release-active combination antitussive drug based on antibodies to bradykinin, to histamine and morphine. It acts at various mechanisms of cough reflex by modifying endogenous target molecules and their interaction with receptors. The drug's efficacy, as demonstrated previously in experimental and clinical studies, is mediated by specific release-activity obtained as a result of the production process.
Methods. Efficacy and safety assessment of rengalin in the treatment of cough induced by acute upper respiratory tract infections (URIs) in comparison with a complex codeine-containing drug (codelac®) was performed as part of a multicenter, randomized clinical trial involving 143 patients. All the participants presented with dry/non-productive cough caused by URIs (pharyngitis, laryngitis, tracheitis, tracheobronchitis, bronchitis). The duration of cough varied between 12 hours and 7 days. Rengalin was administered in 73 patients receiving 2 tablets 3 times daily for initial three days, and half reduced doses - for the subsequent four days; codelac® was administered in 70 patients who were given 1 tablet 3 times daily for the entire treatment period (7 days). Primary efficacy endpoints were time to cough resolution and reduction in the severity of the cough (scored using a Cough Severity Scale). One patient in Rengalin group and three patients in Codelac group were withdrawn from the study. The article presents treatment outcomes obtained for 139 participants who completed the study in accordance with the protocol (Per Protokol-analysis). The data analysis was based on a non-inferiority (or comparability) statistical design for efficacy endpoints.
Results. The antitussive effect of rengalin was significantly comparable (р<0.025) with that of codelac®; the time to complete resolution of cough (both daytime and nocturnal) was 7.2+1.0 days (versus 7.0+1.1 in the group of codelac). Rengalin's efficacy was evidenced by a sufficiently reduced cough severity in the initial few days after treatment onset. As a result of the entire 7-day treatment, the severity score was reduced by 3.1+09 (versus 3.1+1.0 in the group of codelac; р<0.05), totaling 0.2+0.5 point in both groups at the end of the administration period. The frequent non-productive/dry cough was fully resolved in 76% of patients. All the participants in Rengalin group achieved either convalescent outcomes or significant improvement; none of the patients developed secondary bacterial complications. Positive changes in the patients' state over the week were finally confirmed by evaluating the total quality of life scores, including physical and mental component scores (SF-36 questionnaire), and total sleep quality scores, which were comparative between patients treated with rengalin and codelac® (р<0.025). At the end of the administration period, the effect of rengalin was rated by the physician investigators as 'pronounced'. The Clinical Global Impression Scale-Efficacy Indices (CGI-EI) in the groups of rengalin and codelac were comparable, equating a score of 3.7+0.5 (р<0.025). The safety outcomes of rengalin treatment were assessed across all 143 randomized patients. The drug's high safety profile was confirmed by the absence of adverse events that could be reliably related to the study treatment, and by monitoring of laboratory variables. Rengalin demonstrated good tolerability and favorable compatibility with other medications for URIs with concomitant pathology. The patients showed 100% treatment compliance.
Conclusions. Rengalin is a new efficacious and safe drug indicated for the treatment of URI-induced cough. The severity of daytime and nocturnal cough begins to decrease as soon as on the first day after rengalin administration, with severity reduction observed throughout the whole treatment period. At the completion of the 7-day administration, cough severity is reduced by almost 100% and its changes are comparable with the outcomes of treatment with codelac®. By targeting various cough reflex mediators, rengalin enables achieving an antitussive effect in the early days after URI onset (in dry, irritative cough episodes), and a pro-tussive effect at later points of treatment. Rengalin promotes resolution of URI-induced cough without development of secondary bacterial complications.

Brizantin – new drug for treatment of nicotine addiction: results of multicenter clinical trial
Original title. Бризантин – новый препарат для лечения никотиновой зависимости: результаты многоцентрового клинического исследования

Author translation
Every year in the world, captured by global tobacco epidemic, 6 million people die because of smoking. Medical researches indicate connection of tobacco smoking with lung cancer, cardiovascular and many other diseases. Frequency of independent refusal of smoking at addicted people doesn't exceed 5%. In most cases they need the help of the doctor and pharmacological therapy to decrease a withdrawal implications. The fact of prescription of medicines (placebo effect) increases the frequency of smoking refusal to 10%. Effective drugs are antidepressants (bupropion), nicotine replacement products and partial agonists of nicotinic receptors (cytisinum, varenicline). However the use can be followed by side effects including nausea, rising of appetite, a headache, insomnia, a sleepiness, giddiness, a dysgeusia, vomiting, an inflation of the stomach and others. The new release-active drug for treatment of nicotine addiction Brizantin is created by the Materia Medika Holding company on the basis of antibodies to brain-specify protein S100 (anti-S100) and a cannabinoid-receptor of 1 type (anti-CB1). Clinical trials showed, antidepressive and anti-anxiety effects of the first component of anti-S100 can be compared by efficiency with amitriptyline, phenazepamum, sertraliny. The second component (anti-CB1) influences CB1-receptors hyper activation of which takes place at chronic smokers and also at persons people with obesity. Normalization of functional activity of the central and peripheric CB1-receptors reduces the need for intake of nicotine and also prevents rising of appetite and a set of weight among the people who left off smoking. Pilot studies proved synergetic anti-addictive effect of two components of Brizantin in their use.

The use of different schemes of antiviral therapy of acute respiratory viral infection in children

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. 

Treatment of ARVI and grippe in ambulatorypolyclinical practice: results of international observing noninterventional programme «ERMITAGE»

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.

Comprehensive evaluation of several treatment combinations used to manage acute respiratory infections in routine paediatric practice

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.

Evaluating changes in the clinical presentation of acute obstructive bronchitis in preschool children using antiviral therapy

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. 

Ergoferon liquid dosage form — efficacious and safe treatment for childhood acute respiratory infections. Interim outcomes of a multi-center, randomized, double-blind, placebo-controlled clinical trial 

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.

Efficacy and safety of ergoferon versus oseltamivir in adult outpatients with seasonal influenza virus infection: a multicenter, open-label, randomized trial.

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.

National and international studies of anaferon for children: effectiveness, safety and use (literature review)
Original title. Отечественные и зарубежные исследования анаферона детского: эффективность, безопасность и опыт применения (обзор литературы)
Anaferon for children

Author translation
Childhood acute respiratory infections (ARIs) are still a subject of much discussion. The reasons are that these infections are highly prevalent and largely “uncontrolled”, and they occur in individuals who, due to their age, are limited in choice of antiviral medications. Current clinical practice in Russia has shifted towards greater use of domestically produced medicines. Anaferon for children is an innovative drug product developed by OOO “NPF “Materia Medica Holding”, a Russian research and manufacturing pharmaceutical company, and authorized for marketing in Russia in 2002. The aim of this review was to systematize and analyze the Russian and internationally published literature on the results of pre-clinical and clinical studies of the efficacy and safety of Anaferon for children in ARIs and other viral infections. Research method: search and analysis. Results. This review reports on pre-clinical study results that demonstrate the product’s molecular mechanism of action underlying its combined antiviral and immunomodulating efficacy. The obtained results are supported by clinical data, and have been described in many scientific publications, including international. The paper also summarizes the results obtained in clinical trials with the product in pediatric subjects with ARI, including influenza. Anaferon for children has been shown to significantly reduce the duration of major clinical symptoms of ARI and influenza, decrease the incidence of bacterial complications, be well-tolerated and have high safety profile. Anaferon for children has been compared to Oseltamivir in an open-label randomized comparative trial that evaluated the efficacy and safety of the two drugs in subjects with influenza. The numerous publications indicate that Anaferon for children not only exerts antiviral effect against most viruses that cause acute respiratory infections, but also has activity against herpes viruses, enteric viruses, and tick-borne encephalitis virus. Studies on Anaferon for children have been discussed in around 800 scientific publications, 50 of which being in foreign languages (including in highly-cited journals).

Activity of ergoferon against lethal influenza A(H3N2) virus infection in mice
Anaferon Ergoferon

BACKGROUND: The influenza A virus accounts for serious annual viral upper respiratory tract infections. It is constantly able to modify its antigenic structure, thus evading host defence mechanisms. Moreover, currently available anti-influenza agents have a rather limited application, emphasizing the further need for new effective treatments. One of them is ergoferon, a drug containing combined polyclonal antibodies - anti-interferon gamma, anti-CD4 receptor and anti-histamine - in released-active form. The purpose of the study was to assess ergoferon antiviral efficacy in mice challenged with the A/Aichi/2/68 (H3N2) influenza virus.
METHODS: The virus was inoculated intranasally at a 90% lethal dose. Ergoferon was administered at 0.4 ml/day per os in a preventive and therapeutic regimen - daily for 5 days prior to and for 16 days after the challenge. The reference product, Tamiflu (oseltamivir), was used as a positive control treatment - at 20 mg/kg/day for 5 days after the challenge. Mice in the negative control group received distilled water which had been utilized for test sample preparation; untreated control animals received no treatment. Antiviral efficacy was assessed by an increase in survival rate, average life expectancy and virus titre reduction in the challenged mouse lungs.
RESULTS: Survival rate and average life expectancy values were increased significantly in groups treated with ergoferon and Tamiflu, as compared with controls. Lung virus titres were reduced in these groups as observed on days 2 and 4 post-inoculation.
CONCLUSIONS: Ergoferon demonstrated antiviral activity by reducing the severity and duration of the major signs of induced influenza infection.

Application of a heterogenes immunoassay for the quality control testing of release-active forms of diclofenac
Efficacy of novel antibody-based drugs against rhinovirus infection: In vitro and in vivo results
Anaferon for children Ergoferon
In vitro screening of major neurotransmitter systems possibly involved in the mechanism of action of antibodies to S100 protein in released-active form

Experimentally and clinically, it was shown that released-active form of antibodies to S100 protein (RAF of Abs to S100) exerts a wide range of pharmacological activities: anxiolytic, antiasthenic, antiaggressive, stress-protective, antihypoxic, antiischemic, neuroprotective, and nootropic. The purpose of this study was to determine the influence of RAF of Abs to S100 on major neurotransmitter systems (serotoninergic, GABAergic, dopaminergic, and on sigma receptors as well) which are possibly involved in its mechanism of pharmacological activity. Radioligand binding assays were used for assessment of the drug influence on ligand–receptor interaction. [35S]GTPγS binding assay, cyclic adenosine monophosphate HTRF™, cellular dielectric spectroscopy assays, and assays based on measurement of intracellular concentration of Ca2+ ions were used for assessment of agonist or antagonist properties of the drug toward receptors. RAF of Abs to S100 increased radioligand binding to 5-HT1F, 5-HT2B, 5-HT2Cedited, 5-HT3, and to D3 receptors by 142.0%, 131.9%, 149.3%, 120.7%, and 126.3%, respectively. Also, the drug significantly inhibited specific binding of radioligands to GABAB1A/B2 receptors by 25.8%, and to both native and recombinant human sigma1 receptors by 75.3% and 40.32%, respectively. In the functional assays, it was shown that the drug exerted antagonism at 5-HT1B, D3, and GABAB1A/B2 receptors inhibiting agonist-induced responses by 23.24%, 32.76%, and 30.2%, respectively. On the contrary, the drug exerted an agonist effect at 5-HT1A receptors enhancing receptor functional activity by 28.0%. The pharmacological profiling of RAF of Abs to S100 among 27 receptor provides evidence for drug-related modification of major neurotransmitter systems.

A randomized, open-label, comparative, 6-month trial of oral ultra-low doses of antibodies to tumor necrosis factor-α and diclofenac in rheumatoid arthritis

Artrofoon (oral ultra-low doses of antibodies to TNF-alpha is a novel drug approved by the Russian Ministry of Health for the treatment of rheumatoid arthritis (RA). The aim of this study was to assess clinical efficacy and safety of artrofoon in RA compared with diclofenac. In a 6-month, randomized, open-label, comparative trial, 60 patients with active RA (eight men and 52 women aged 23 to 62, mean disease duration 10 years) received artrofoon (8 tablets daily, n = 30) or diclofenac (100 mg daily, n = 30). RA signs and symptoms as well as serum levels of inflammatory markers were evaluated before treatment and at months 1, 3 and 6. Most patients in the artrofoon group showed a 20% improvement in major RA symptoms by the end of the study. The clinical effect rose gradually reaching maximum at month 6. In the artrofoon group, 57% of the patients achieved an American College of Rheumatology (ACR) 20% criteria (ACR20) by month 6 versus 20% of those receiving diclofenac. In some patients in the artrofoon arm, serum proinflammatory cytokine levels significantly decreased (> or = 25% reduction). Diclofenac produced a less pronounced clinical effect, and no changes in cytokine profile. Unlike conventional nonsteroidal anti-inflammatory drugs, artrofoon produced no adverse effects and the overall tolerability and safety were excellent. A half-dose treatment with artrofoon (4 tablets daily) was able to sustain clinical improvements over a 6-month follow-up period. To conclude, artrofoon is a safe and effective treatment for rheumatoid arthritis that acts by influencing the inflammatory process.

Sildenafil and a compound stimulating endothelial NO synthase modify sexual incentive motivation and copulatory behavior in male Wistar and Fisher 344 rats

INTRODUCTION: Earlier studies have shown that sildenafil may modify some aspects of male rat sexual behavior and sexual incentive motivation. Stimulation of endothelial nitric oxide synthase (eNOS) has also been reported to affect sexual motivation in old rats.
AIM: To determine the effects of sildenafil and a compound stimulating eNOS on copulatory behavior and sexual incentive motivation in young adult Fisher 344 and Wistar male rats.
METHODS: The rats were selected for a low intromission ratio, and then treated with Impaza (stimulator of eNOS), sildenafil, or Impaza + sildenafil for 28 days. Tests for copulatory behavior and sexual incentive motivation were performed before the beginning of treatment and at days 7, 14, and 28 of treatment.
MAIN OUTCOME MEASURES: Standard parameters of copulatory behavior and sexual incentive motivation. Measurements of penis length at mount, intromission, and ejaculation.
RESULTS: The Fisher 344 rats displayed a higher level of sexual incentive motivation than the Wistar rats, while the copulatory behavior was similar in both strains. Impaza and sildenafil enhanced the sexual incentive motivation after 28 days of treatment in the Wistar rats, but failed to do so in the Fisher 344 rats. The copulatory behavior was unaffected in the Wistar strain, while the Fisher 344 males had an enhanced intromission ratio after treatment with Impaza and sildenafil for 28 days.
CONCLUSIONS: The nitric oxide-guanylyl cyclase pathway seems to be of importance for sexual incentive motivation in animals with a modest baseline level. The different drug effects in the Wistar and Fisher 344 rats can be attributed to baseline differences. The importance of eNOS for sexual functions should not be overlooked.

Subetta treatment increases adiponectin secretion by mature muman adipocytes in vitro
Sexual incentive motivation in old male rats: the effects of sildenafil and a compound (Impaza) stimulating endothelial NO synthase

Several proerectile drugs act on the nitric oxide–cyclic guanosine monophopsphate pathway, which is known to influence rat copulatory behavior. In the present study we evaluated the effects of two proerectile compounds, one (Impaza) acting on endothelial nitric oxide synthase, and the other (sildenafil) on phosphodiesterase 5, on sexual incentive motivation in male rats displaying a spontaneously low level of motivation and copulatory behavior. About 20 months old male Fisher 344 rats were tested in a procedure for evaluating the intensity of sexual incentive motivation and in standard mating tests. For comparison, a group of young (about 4 months) Fisher 344 males was tested in parallel. This group did not receive any drug treatment. Impaza was administered in two doses, daily for 28 days, and sildenafil was given at a dose of 3 mg/kg twice a week during 28 days. Tests for sexual incentive motivation and copulatory behavior were performed immediately before the beginning of drug treatments, and on days 7, 14 and 28 of treatment. All treatment groups displayed a very low level of copulatory behavior and a sexually receptive female was not a more powerful incentive than another male at the tests performed before and on days 7 and 14 of treatment. On day 28 of treatment, the group treated with Impaza, 3 ml, displayed a preference for the sexually receptive female, while no such preference was found in the other groups. Furthermore, the preference score was above that of controls in this group. Both Impaza, 3 ml, and sildenafil reduced approach to the male in the test for sexual incentive motivation, suggesting that social motivation was reduced. These data suggest that compounds affecting the nitric oxide–cyclic guanosine monophopsphate pathway may modify both sexual and social motivation in old rats.

Activity of ultra-low doses of antibodies to gamma-interferon against lethal influenza A (H1N1) 2009 virus infection in mice
Anaferon for children
Dose-dependent antiviral activity of released-active form of antibodies to interferon-gamma against influenza A/California/07/09(H1N1) in murine model
Anaferon for children