Publications in Scientific Journals

The results and findings of studies of preclinical and clinical efficacy and safety of the Company’s medications and their components are published in Russian and foreign peer-reviewed scientific journals, including those indexed by international bibliographic databases.

List of publications

The experience of using drug Afalaza for treatment of lower urinary symptoms in treatment-naive patients with benign prostatic hyperplasia
Introduction. Benign prostatic hyperplasia (BPH) is one of the most common diseases in men over 50 years. The prevalence of the BPH increases with age, and pathologic features of BPH are found in about 90% of men over 80 years. Aim. The aim of the study was to study the efficacy and safety of Afalaza for the treatment of lower urinary tract symptoms (LUTS) in treatment-naïve patients with BPH.
Materials and methods. A multicenter study of using Afalaza for the treatment of LUTS in treatment-naïve patients with BPH was carried out in 9 urological centers in Moscow. A total of 80 treatment-naïve patients with BPH were enrolled. The improvement in the total score of IPSS, IIEF-5 and QoL after 30 weeks of therapy was evaluated as well as changes in prostate volume and maximum urinary f low rate (Qmax).
Results. After 30 weeks of therapy, there was a significant decrease in the total IPSS score. A decrease in the total IPSS score by 5.5 points (+37.9%) from 14.5±4.0 at the baseline to 9.0±4.1 at the visit 9 was seen. The QoL decreased by 1.8 (-38.3%) points from 4.7±1.0 at the baseline. The Qmax also changed from 12.7±4.6 to 16.4±5.7 (+28.3%) after 30 weeks of therapy. At the visit 9, the total IIEF5 score increased by 3.4±4.4 (+19.9%) from 17.1±4.3 at the baseline. In addition, prostate volume decreased from 42.7±11.1 at baseline to 41.0±9.8 cc post-treatment (-5.15%). A reduction of post-void residual urine volume from 26.0±25.3 at baseline to 17.7±24.2 (-31.9%) post-treatment was also shown.
Conclusion. The results of a multicenter study demonstrate the efficacy of Afalaza for treatment of treatment-naïve patients with LUTS/BPH. Afalaza reduces prostate volume and improves an erectile function.
Efficacy and safety of Afalaza in men with symptomatic benign prostatic hyperplasia at risk of progression: a multicenter, double-blind, placebo-controlled, randomized clinical trial
Introduction. In order to investigate the efficacy and safety of Afalaza in men with benign prostatic hyperplasia (BPH) at risk of progression, this multicenter, double-blind, placebo-controlled, randomized clinical trial was performed. Derived by technological treatment of antibodies to prostate-specific antigen (PSA) and endothelial nitric oxide synthase (eNOs), Afalaza was previously proved to modulate its molecular targets. The mechanism of action of the drug is associated with the modulating effect of the antibiodies (RA-Abs) on the molecular targets (PSA and eNOS) by way of conformational changes.
Material and methods. A total of 249 patients aged 45–60 years with BPH and moderate lower urinary tract symptoms (LUTS), total prostate volume (TPV) ≥30 cm3, Qmax 10–15 ml/s, and serum PSA<4 ng/ml were randomly assigned to receive either Afalaza (n = 125) or placebo (n = 124) for 12 months. Changes in BPH/LUTS symptoms (according to the International Prostate Symptom Score), Qmax, TPV, PSA, BPH clinical progression, occurrence of acure urinary retention (AUR) events or BPH-related surgery were estimated as the study endpoints.
Results. IPSS mean change was -3.7 ±3.0 (95% CI -4.3 to -3.2) after 12 months of Afalaza (vs. -2.9 ±2.4; 95% CI -3.3 to -2.4 in placebo; р = 0.02). Qmax growth was 2.5 ±4.3 ml/s (vs. 1.4 ±3.3 in placebo; p = 0.049), TPV reduced by 11.8 ±16.0% (vs. 6.5 ±14.7%; p = 0.01, and PSA remained unchanged. Afalaza therapy resulted in a significant decrease in the total sum of BPH progression symptoms (p = 0.01). The maximum effect of Afalaza was registered after 12 months without a tendency to form a ‘plateau’. During the study, no patients experienced AUR or BPH-related surgery.
Conclusions. A 12-month course of Afalaza therapy is effective and safe for patients with BPH. The results of end points measurements revealed asignificant advantage of Afalaza compared to placebo in the overall symptoms benefit and a decline in the risk of BPH progression. NCT01716104.
Subetta – a new activator of the insulin receptor
Original title. Субетта – новый активатор рецептора инсулина
Author translation
Despite the variety of antidiabetic drugs, most patients with type 2 diabetes mellitus (DM2) do not achieve individual treatment goals. Due to poor control of glycemia at any stage of the disease, it is necessary to adjust therapy in a timely manner. For this, as a rule, the dose of the drug taken should be increased or another antidiabetic drug should be added. As a modern approach to the treatment of DM2, a• ecting the leading component of pathogenesis – insulin resistance, Subetta in a complex therapy can be considered. e article presents data on the mechanism of action of the Subetta, endothelium protective properties and some results of hypoglycemic e› ciency according to the results of clinical trials.
Efficacy and safety of Subetta add-on therapy in type 1 diabetes mellitus: The results of a multicenter, double-blind, placebo-controlled, randomized clinical trial
BACKGROUND: To examine efficacy of Subetta as an add-on to insulin therapy in patients with type 1 diabetes mellitus (T1DM) a multicenter, double-blind, placebo-controlled, randomized clinical trial was performed. Derived by technological treatment of antibodies to insulin receptor β-subunit and endothelial NO synthase Subetta was previously proved to activate insulin signaling pathway.
A total of 144 randomized patients with poor glycemic control in basal-bolus insulin regime were included in intention-to-treat analysis in Subetta add-on therapy or placebo (n = 72 in both groups). Hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), basal and prandial insulin doses, number of hypoglycemia episodes confirmed by self-monitoring of blood glucose were recorded for 36 weeks.
RESULTS: The baseline characteristics of subjects did not differ between the two groups. HbA1c mean (±standard deviation) change was -0.59 ± 0.99% (95% CI -0.84 to -0.37) after 36 weeks in Subetta (vs. -0.20 ± 1.14%; 95% CI -0.44 to 0.11 in placebo; p = 0.028). The rate of overall hypoglycemia events was 7.9 per patient year (95% CI 7.1-8.6) in Subetta group and 7.6 (95% CI 6.9-8.4) in Placebo group (p = 0.63). The basal and total insulin doses did not change at the end of 36 weeks in both groups.
CONCLUSIONS: Subetta add-on therapy boosting insulin activity and improving glycemic control in patients with T1DM is proved to be beneficial.

Methodological approach to diagnostics and pharmacological correction of stress in dogs and cats
The problem of stress, psychological and behavioral disorders in animals gain more and more attention in the recent years. A lot of research is being held to determine pathogenetic mechanisms of stress, diagnostic approaches and methods of its treatment. This article considers the physiological, psychological and biochemical aspects of stress. The special role of brain-specific S100 protein in the stress pathogenesis is described. Authors also give methodological recommendations for veterinarians on the use of behavioral scales for dogs and cats.
Use of Drug Anoten against Anxiety and Stress in Cats: Results of a Blind Placebo-Controlled Study
Blind placebo-controlled study of the antistress drug Anoten was conducted on 32 stressed shelter cats. Animals were divided into 2 groups based on the emotional and mental status. All cats were treated with Anoten or placebo daily during the 14 days. General clinical indicators and psycho-emotional state were registered. At the end of the research the cats were subjectively evaluated for mental changes. No statistical differences were found in general clinical indicators assessment. However, psycho-emotional state by the CSS (Kessler and Turner Сat-Stress-Score) as well as integrative score status was significantly improved in cats receiving Anoten in comparison with placebo.
Results of the Blind Placebo-Controlled Trial of the Novel Anti-Stress Drug Anoten Efficacy against Neurotic Disorders in Dogs
The blind placebo controlled trial was conducted in 20 dogs with signs of neurotic disorders to confirm the efficacy and safety of the anti-stress and antianxiety drug Anoten. Clinical and emotional-psychological state of animals was recorded every day during the 14 days. The obtained data showed that emotional and mental state was improved in dogs receiving Anoten compared with dogs receiving placebo according to RASS (Richmond Agitation Sedation Scale) and integral scales. Differences between groups were statistically significant. Clinical scores of animals were similar in Anoten and placebo groups, which proves the drug’s tolerance and safety.
Released-activity (contemporary view of homeopathy and non-homeopathy)
Original title. Релиз-активность (современный взгляд на гомеопатию и негомеопатию)
Author translation
This essay presents the data that provide an up-to-date insight into the ‘low dose’ issue, demonstrate prospects of their use and pull back the veil of secrecy from homeopathy.
The phenomenon of release activity and the hypothesis of "spatial" homeostasis
When analyzing the technology of multiple sequential reductions in concentration of parent substance we have discovered a novel physical phenomenon. It was shown that dilutions of parent substance prepared using this technology have one common peculiarity - they are capable to exert direct modifying effect on parent substance altering spatial structure of parent substance and consequently its physical, chemical and biological properties. Technologically processed dilutions also exert activity when they do not contain molecules of parent substance. We have defined a newly revealed modifying activity manifested in the process of multiple sequential reductions in concentrations and associated with vehicle as release-activity while the drugs exerting modifying activity we have called release-active drugs. Having analyzed the ceffects of a drug in the whole range of doses - toxic, therapeutic, low doses as well as release-active form of a drug we came to a conclusion that there were supramolecular spatial matrices with the structure, which was identical to the one of a certain substance, and combines body molecules into semantic molecular assemblies. All biological systems unlike nonliving nature have dual structure - both individual and specific ones. Enhancement in any body spatial complexity is its key feature from the point of view of evolution development; that is why all processes - both normal physiologic and pathologic ones - shall comply with superiority of preservation of a body spatial structure hierarchy (hypothesis of spatial homeostasis).
Dose–response effect of antibodies to S100 protein and cannabinoid receptor type 1 in released-active form in the light–dark test in mice
Earlier studies have shown that combination of antibodies to S100 protein and to cannabinoid receptor type 1 in released-active form (Brizantin) may possess anxiolytic properties and decrease nicotine dependence. Released-active form of antibodies is a novel approach that permits to modify natural functions of the target molecule (antigen) under investigation. The aim of the present study was to evaluate the anxiolytic-like effect of Brizantin in the light–dark test in mice, according to its ability to influence the number of entries into the lit compartment and the total time spent there. Three doses of Brizantin (2.5, 5, and 10 mL/kg) were compared with diazepam (1 mg/kg), placebo, and vehicle control. Anxiolytic-like effect of the tested drug was shown to be dose dependent, with an increasing trend from 2.5 to 10 mL/kg. Brizantin in its highest dose significantly increased studied behavioral parameters, although its effect was less pronounced than that of the reference drug diazepam (1 mg/kg).
The spatial homeostasis hypothesis

From studies on the effects of “high dilutions” on organisms, it was found that their administration induces a delicate physiological (molecular and cellular) response. Occasionally, physiological reactions can become atypical (pathological) individual reactions. To resolve this paradox, the spatial homeostasis hypothesis has been proposed. It considers pathological processes as tools used by living systems, in order to retain their spatial integrity (symmetry), allowing them to properly reflect the geometry of the surrounding world and thus, to be a part of the evolutionary process. This article addresses an interdisciplinary subject and is aimed at natural scientists (physicists, chemists, and biologists) as well as philosophers.

Anti-inflammatory and anti-allergic features of antibodies to histamine in release-active form: review of experimental and clinical researches

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

Basic principles on the prevention of acute respiratory infections in often affected children
Original title. Основные принципы профилактики острых респираторных инфекций у часто болеющих детей

Author translation
From clinical-laboratory features acute respiratory infections and the incidence of hospital infections often ill children versus rarely suffering from the children's wards of St.Petersburg has developed guidelines for the prevention of respiratory infections. Was shown efficiency of causal and immunorehabilitation therapy for routine and emergency prevention in different groups often ill children.

Prevention and treatment of acute respiratory infections in children with asthma

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

Author translate
The Acute Respiratory Viral Infections (ARVI) and flu are still the most widespread diseases in pediatric practice (90% of all infectious pathology in children). It is well-known more often ARVI develop at the children visiting the preschool institutions (PI) - this category of children is characterized by frequent emergence of repeated episodes of ARVI (recurrent infections). Anaferon for children is effective drug for the treatment and prevention of ARVI. The effectiveness of Anaferon for children during secondary preventive and therapeutic courses is not reduced.

Modern approaches to the treatment of the functional gastrointestinal disorder and overlap syndrome

Aim - to analyze the modern view on pathogenesis, clinical symptoms and therapy of functional gastrointestinal diseases (FGID) and overlap syndrome. FGID include a number of separate gastrointestinal disorders, characterized by alterations in motility, visceral sensation, and mucus function, that are not associated with structural alterations. The pathogenesis of FGID seems to imply disturbance in brain-gut interactions. The most common functional disorders are irritable bowel syndrome (IBS) and functional dyspepsia (FD). As defined by Rome IV criteria overlap syndrome is one of the modern problem in therapy of FGID. The estimated prevalence of IBS and FD overlap is 42-87%. Since FGID has a huge impact on patient’s psychological condition and the quality of life it is important to treat symptoms of FGID effectively. Symptomatic treatment (antispasmodics, laxative, prokinetics, herbal extracts) has either short-term effect or low impact on patient's improvement. Thus pathogenetic therapy should be the therapy of choice for FGID and overlap syndrome treatment. The aim of FGID therapy is to reduce symptoms effectively, to avoid the symptom recurrence and overlap syndrome. Kolofort with pathogenetic action is safe and effective in FGID treatment and provide high level of patient’s compliance.

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.

Acute bronchitis: influence of the scheme of therapy on the course of disease
Original title. Острый бронхит: влияние схемы терапии на течение заболевания

Author translation
Aim: comparative clinical assessment of efficiency and drug safety of Rengalin and fenspiride. The research was made with participation of 54 patients: 26 people in Rengalin's group and 28 in the group of fenspiride. Therapy duration in both groups was for 7 days. The following criteria were considered: cooperative clinical index (characterizes total disappearance of symptoms at the end of therapy), terms of stopping of day and night cough, average value of the cooperative cough index during observation (from visit 1 to visit 3), CGI-EI scale GPAs, assessment of efficiency and commitment to the therapy. 
Results: both Rengalin, and fenspiride are effective, but the combination of therapeutic properties of Rengalin is more preferable in treatment of acute bronchitis. Тhe number of recovered patients prevailed tin the Rengalin's group, р<0,01, and also on CGI-EI scale, р<0,001. 
Conclusion. Regalin is preferred for the treatment of acute bronchitis.

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.

The new possibilities for the treatment of chronic cough associated with postnasal drip

Cough is considered to be one of the leading clinical symptoms associated with the pathological changes in the respiratory system. Notwithstanding a great variety of therapeutic pharmaceutical products possessed of the antitussive action, physicians tend the give preference to the preparations producing the combined effect. The present article reports the results of the clinical study designed to evaluate the effectiveness and safety of the application of rengalin exhibiting the combined antitussive, anti-inflammatory, and broncholytic action in the patients presenting with the postnasal drip syndrome. The comparison of the therapeutic effects of rengalin with those of other therapeutic modalities frequently employed for the management of postnasal drip give evidence of the high efficiency of this product for the optimization of the treatment of this condition and the associated chronic cough.

New possibilities of effective cough therapy in acute respiratory infections in children

The paper represents the results of a multicenter comparative randomized clinical study of medication for the treatment of cough based on release-active antibodies in liquid dosage form when used for cough therapy in acute respiratory infections (ARI) of upper airways in children. The results confirm the efficiency and safety of medication for the treatment of cough based on release-active antibodies (in the form of a liquid for oral administration) for treating cough in children with ARI.

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.

Modern immunomodulators in treatment of patients with acute respiratory diseases complicated by community-acquired pneumonia

The article features the results of studying the therapeutic efficacy of the immunomodulator Anaferon that induces synthesis of endogenous interferons in adult patients with ARD complicated by community-acquired pneumonia. It has been shown that the use of Anaferon permitted to reduce the terms of development of the main clinical symptoms of disease, enhance levels of helper T-lymphocyte phenotypes stimulated by IFN-а and IFN-y by the convalescence period.

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.

Results of multicenter study of efficacy and safety of divaza in the treatment of the asthenic and mild to moderate cognitive disorders in elderly and senile subjects

Objective. To study the efficacy and safety of divasa in elderly and senile subjects with asthenic and mild to moderate cognitive disorders. Material and methods. The study included 126 patients with clinically significant asthenia and mild to moderate cognitive disorders. Asthenia was assessed with MFI-20, cognitive disorders with MMSE, clock drawing test and verbal association test. All patients were treated with divasa in dose 2 tablets 3 times a day.
Results and conclusion. The efficacy and safety of divasa in asthenic and mild to moderate cognitive disorders in elderly and senile subjects were shown. There is a need for a multicenter placebo-controlled trial on the efficacy of divasa to treat cognitive and asthenic disorders in elderly patients.

Current possibilities in pharmacotherapy of anxiety disorders in children and adolescents

Objective  to assess the efficacy and safety of tenoten for kids in the treatment of children and adolescents with anxiety disorders. Material and methods. It was conducted a multicenter, double-blind, placebo-controlled trial of the drug tenoten for kids at a dose of 1 tablet 3 times a day for 12 weeks. The study included 98 patients (boys and girls from 5 to 15 years with a confirmed diagnosis of anxiety disorder), randomized into two groups: the first included 48 patients treated tenoten for kids, in the second — 50 patients receiving placebo. 
Results and conclusion. Tenoten for kids has a strong anti-anxiety effect both on the results of self-assessment of patients, and on the reports of parents. This anxiolytic activity of the drug manifested most significantly in children aged 5 to 7 years. In addition, in patients 8—15 years of treatment spent tenoten for kids to regress the symptoms of anxiety disorders by anxiety subscales SCAS «Separation anxiety», «panic attacks and agoraphobia» and «social phobia». Throughout the course of treatment tenoten for kids have been no adverse events. 

Afala in the treatment of patients with BPH: efficacy and safety
Original title. Афала в лечении пациентов с аденомой предстательной железы: эффективность и безопасность

Author translation
The double-blind, placebo-controlled, randomized clinical trial involving 94 patients has evaluated the efficacy and safety of domestic preparation afala in patients with symptoms of I-II stages benign prostatic hyperplasia (BPH). It was shown that a 6-month course of treatment with afala at a dose of 2 tablets 4 times a day resulted in a significant reduction in the severity of urinary disorders, estimated by total IPSS score, relative to baseline values and compared to placebo therapy. The most pronounced therapeutic effects of the drug were registered in respect of irritative symptoms of BPH. According uroflowmetry, peak flow rate after 6 months of treatment was increased by more than 50%. Significant clinical benefit persisted not only within the 6-month course of therapy, but 3 months after. Long-term therapy had no effect on the concentration of total, free and complex PSA, testosterone (total and free), dihydrotestosterone, and prolactin in the blood. Absence of adverse effects, biochemical abnormalities, changes in clinical blood and urine confirmed the safety of 6-month therapy. 

Combined therapy of erectile dysfunction 

Presented the results of comparative studies of effectiveness of mono- and combined therapy with Impaza and phosphodiesterase 5 inhibitors (sildenafil, tadalafil, vardenafil). Application of Impaza – the only drug increasing the level of endogenous NO, allowed to restore endothelial function and as well to increase the effectiveness of erectile dysfunction oral monotherapy with phosphodiesterase 5 inhibitors due to their combination with Impaza.

Complex therapy of anxiety states in patients with somatic profile

There is a close relationship between the development of anxious, depressive and other neurotic disorders and brain specific S-100 protein. Tenoten composition includes a release-active antibodies to brain specific S-100 protein (R-AA S-100). The efficiency of destination Tenoten in complex therapy of anxiety disorders in patients of somatic profile in the dose of 1-2 tablets 3 times a day, 4 weeks therapy course. The initial decrease in anxiety level observed after 2 weeks of therapy. Tenoten antianxiety effect is not inferior such anxiolytic as tofisopam and antidepressants as clonazepam and phenazepamum.

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. 

A new drug for treatment of influenza and acute respiratory viral infections

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.

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.

The inhibitory effect of ergoferon on respiratory syncytial virus infectivity in vitro
Original title. Способность препарата эргоферон подавлять инфицирующую активность респираторно-синцитиального вируса in vitro

Author translation
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.

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)

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).

Study of hypoglycemic activity of subetta and rosiglitazone on the model of streptozotocin-induced diabetes mellitus in rats

Antidiabetic activity of Subetta was revealed on the model of streptozotocin-induced diabetes mellitus in rats. Intragastric administration of this preparation in a dose of 5 ml/kg for 50 days reduced blood glucose levels, urine levels of glucose and ketone bodies, restored glucose tolerance in the oral glucose test, improved general condition and increased the survival rate of animals. The effectiveness of the drug was not inferior to that of rosiglitazone (8 mg/kg).

Subetta enhances sensitivity of human muscle cells to insulin

Addition of Subetta to insulin (10 nM) increased insulin-stimulated glucose uptake 43% (p<0.001). Moreover, glucose uptake stimulated by insulin (10 nM) in the presence of Subetta was similar to that stimulated by 300 nM insulin. These findings suggest that Subetta significantly enhanced insulin sensitivity of tissues through stimulation of glucose transport to myocytes mediated by glucose transporter 4.

Cytogenetic effects of antibodies to gamma-interferon in ultralow doses

Single and course administration of ultralow doses of antibodies gamma-interferon did not increase the incidence of cytogeneticabnormalities in bone marrow cells from BALB/c mice and produced no genotoxic effect on Drosophila melanogaster wing cells in the test of somatic mosaicism.

Preclinical toxicological study of release-active preparations for prediction of their pharmacological activity and side effects

We studied chronic toxicity of a few release-active preparations: Dietressa (release-active preparation of affinity-purified antibodies to type 1 cannabinoid receptor), Divasa (releaseactive preparation containing a combination of affinity-purified antibodies to brain-specific S-100 protein and endothelial NO-synthase), Cardostin (release-active preparation containing a combination of affinity-purified antibodies to C-terminal fragment of angiotensin II type 1 receptor and endothelial NO-synthase), and Bation (release-active preparation containing a combination of affinity-purified antibodies to IFN-γ and CD4). We evaluated not only side and toxic effects, but also the relationships between these effects and pharmacological activities of the preparations. The data of preclinical toxicological studies of the release-active preparations can be used for prediction of their pharmacological activity.

Preclinical studied of general toxic properties of preparations containing ultralow doses of antibodies to endogenous regulators

Preclinical study of the safety of 6 preparations containing ultralow doses of antibodies to endogenous regulators showed that they are relatively safe, are well tolerated by animals in doses more than 1000-fold surpassing the therapeutic dose for humans, and produce no general toxic effect on the organism of laboratory animals.

Study of efficacy of anaferon pediatric in mice infected by pandemic influenza virus A(H1N1/09)V

AIM: To study efficacy of anaferon pediatric in mice infected by pandemic influenza virus A(H1N1/09)v. 
MATERIALS AND METHODS: Influenza virus strain A/California/07/2009 (H1N1)v was used. Three groups of BALB/c mice intranasally inoculated with influenza virus were studied. First group received solution of Anaferon pediatric during 5 days before and 8 days after inoculation, 2nd group received Tamiflu during 5 days after inoculation. Distilled water was administered orally to mice from control group. 
RESULTS: It was shown that Anaferon pediatric used as preventive and treatment agent in mice intranasally inoculated with 100% infectious dose of influenza virus strain A/ California/07/2009 (H1N1)v had antiviral effect, which expressed in 10-fold decreased reproduction of influenza virus in lungs of infected mice compared to control group measured 4, 6, and 8 days after inoculation. 
CONCLUSION: Use of anaferon pediatric before and after inoculation with influenza virus A(H1N1/09)v was not less effective than use of Tamiflu after inoculation.

Antiviral activity of ergoferon against group a rotavirus

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.

The novel oral drug subetta exerts an antidiabetic effect in the diabetic Goto-Kakizaki rat: comparison with rosiglitazone

The aim of the present study was to evaluate the potential antidiabetic effects of two-component drug Subetta and its components (release-active dilutions of antibodies to β-subunit insulin receptor (RAD of Abs to β-InsR) and to endothelial nitric oxide synthase (RAD of Abs to eNOS)) in Goto-Kakizaki (Paris colony) (GK/Par) diabetic rats. Subetta was administered orally for 28 days once daily (5 mL/kg) and compared to its two components (2.5 mL/kg), Rosiglitazone (5 mg/kg), and vehicle (5 mL water/kg). At day 28, fasting plasma glucose levels were significantly decreased only in Subetta and Rosiglitazone groups as compared to vehicle (P<0.01):147±4 mg/dL and 145±4 mg/dL and 165±4 mg/dL, respectively. The data of glucose tolerance test showed that Subetta and RAD of Abs to β-InsR (similar to Rosiglitazone) prevented significantly (P<0.01) the age-related spontaneous deterioration of glucose tolerance as seen in the control group. Subetta and RAD of Abs to β-InsR did not significantly modify the glucose-induced insulin secretion. Chronic administration of Subetta and RAD of Abs to β-InsR improves glucose control, to an extent similar to that of Rosiglitazone. We hypothesize that Subetta and RAD of Abs to β-InsR mostly act via an insulin-sensitizing effect upon target tissues.

Antibodies to calcium-binding S100B protein block the conditioning of long-term sensitization in the terrestrial snail

The effects of antibodies to calcium-binding S100B protein diluted to 10(-12) (LAS100B) on the long-term sensitization in the Helix lucorum snail (neurobiological model of the anxious-depressive state) were evaluated. The administration of LAS100B prior to conditioning of long-term sensitization in the terrestrial snail 10 min prior to the first electric stimulus) prevents strengthening of the defensive reaction of withdrawing the ommatophores (eye tentacles) and the defensive reaction of closing the pneumostome. This effect is termed "protective", as it prevents the conditioning of long-term sensitization. At the same time, snails given an injection of saline developed long-term sensitization with a significant strengthening of the defensive reactions of withdrawing the ommatophores and closing the pneumostome. When LAS100B was administered before long-term sensitization in advance, the membrane and threshold potentials of premotor interneurons, which regulate defensive behaviour, decreased to a significantly lesser extent compared to the long-term sensitization arm. It is possible that the "protective" effect is linked to the mechanisms of maintaining the membrane potential and changes in extra- and intracellular balance of calcium-binding S100B protein.

Application of a heterogenes immunoassay for the quality control testing of release-active forms of diclofenac

We report on a specially designed diclofenac-ELISA for the determination of diclofenac in the presence of release-active forms of diclofenac in lactose dissolved in water solutions according to a predefined schedule in single-blind experiments. In accordance with the objective of this project, a number of experiments were conducted to determine the optimal ELISA conditions for detecting potential modulatory effects of release-active forms of diclofenac depending on their ability to affect the binding of diclofenac to anti-diclofenac antibodies. As a feature, the diclofenac antibodies were previously incubated with manufactured pharmaceutical samples containing release-active forms of diclofenac or placebo. For comparison of the sample types, measured in ELISA optical densities were chosen. For statistic analysis, Student's two-sample t-test and single-factor ANOVA were applied. The extremely low concentrations of diclofenac of 0.01, 0.05 and 0.1 ng mL(-1) seem most appropriate for routine assay performance. The source of diclofenac used for standard solution preparation is not important but it could be important as the source of diclofenac for release active form of diclofenac preparation. As an outcome, the ELISA appeared to be suitable for the detection of the modifying effects of release-active forms of diclofenac toward the pharmaceutical substance in vitro.

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.

Improvement of memory by means of ultra-low doses of antibodies to S-100B antigen

Antigen S-100B of nervous tissue, according to the data of numerous studies, affects the mechanisms of nervous system plasticity and memory. The influence of ultralow doses of antibodies to S-100B (6C dilution, according to the homeopathic pharmacopoeia) has been studied on three learning behavioral models on Wistar rats, which were inhibitory avoidance, choosing of bowls with sucrose and feeding behavior cessation after auditory signal. For all three tasks, parameters of reproduction of the learned skills improved after per oral administration of potentiated antibodies to S-100B antigen immediately after learning. Possible mechanisms of the anti-S-100B antibodies influence on memory formation are discussed.

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.

Effects of release-active antibodies to CD4 receptor on the level of lck-kinase in cultured mononuclear cells from human peripheral blood

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.

Investigation of changes in NO content during long-term sensitization in edible snail using EPR-spectroscopy: effects of antibodies to calcium-binding protein S-100

EPR-spectroscopy experiments (electron paramagnetic resonance) demonstrated a decrease in NO production in the nervous system and heart of edible snail Helix lucorum after formation of long-term sensitization, a neurobiological model of anxiety and depression. The protective effect of antibodies to Ca(2+)-binding protein S-100 in dilution of 10(-12) on the formation of long-term sensitization was accompanied by partial recovery of NO synthesis in the nervous system and heart. These findings indicate that the imbalance in Ca(2+)-binding protein S-100 can lead to inhibition or modulation of some processes during plastic reorganization in the body and especially during pathological processes.

Anxiolytic activity of tenoten and diazepam depends on conditions in Vogel conflict test

We compared two modifications of Vogel conflict test and assessed anxyolitic activity of two drugs: diazepam (benzodiazepine anxiolitic) and tenoten (ultra-low doses of antibodies to S-100 protein) in both modifications of the test. It was found that the intensity of anxiolitic effect of the drugs depends on the conditions of Vogel test.

Release-active antibodies to S100 protein are able to improve the experimental allergic encephalomyelitis

AIM: To reveal the effects of release-active antibodies to S100 protein in an animal model of multiple sclerosis.
MATERIAL AND METHODS: Sixty female Wistar rats, aged 12 weeks, were included in the study. The pathology was induced by subcutaneous injection of the spinal cord homogenate. Afterwards the rats received a water solution of release-active antibodies to S100 protein (2,5 ml/kg/day, tenoten) or distilled water intragastrically during 30 days. Intramuscular injections of glatiramer acetate (4 mg/kg/day, copaxone) were used as a positive control.
RESULTS AND CONCLUSION: Release-active antibodies to S100 protein enhanced the latency period of the disease, reduced its peak intensity and compensated the loss of body weight of the animals. The experimental drug effect was similar to the results of copaxone injections.

Anti-inflammatory, analgesic and immunomodulatory activity of RA anti-TNF-α — the active ingredient of artrofoon and kolofort drugs

The article describes preclinical and clinical trial results (focusing on experimental data), that demonstrate broad spectrum of specific pharmacological activity and safety as well as mechanism of action for tumor necrosis factor α antibodies in release active form (RA anti-TNFα).

Immunotropic properties of anaferon and anaferon pediatric

Anaferon and pediatric anaferon based on release-active antibodies to interferon-gamma (R-A antibodies to INF-gamma) proved to be efficient in the treatment of many viral infections. Immunomodulating (immunotropic) properties of the drugs were revealed in the preclinical studies at many Russian and foreign research medical institutions and are reviewed herein. Anaferon and pediatric anaferon stimulated the humoral and cellular immune responses and increased the neutrophil and macrophage activity. The crucial mechanism of the immunotropic action of R-A antibodies to INF-gamma was the effect on the system of interferons and in particular on INF-gamma and functionally conjugated cytokines, resulting in normalization of the functional activity of the innate factors of the immune defense and increasing of the antiviral action. The broad spectrum of the immunotropic activity provided the success of anaferon and anaferon pediatric for more than 10 years in the treatment and prophylaxis of the diseases associated with disorders in the immune system functional state.

Structure and dynamics of the insulin receptor: implications for receptor activation and drug discovery

Recently, major progress has been made in uncovering the mechanisms of how insulin engages its receptor and modulates downstream signal transduction. Here, we present in detail the current structural knowledge surrounding the individual components of the complex, binding sites, and dynamics during the activation process. A novel kinase triggering mechanism, the ‘bow-arrow model’, is proposed based on current knowledge and computational simulations of this system, in which insulin, after its initial interaction with binding site 1, engages with site 2 between the fibronectin type III (FnIII)-1 and -2 domains, which changes the conformation of FnIII-3 and eventually translates into structural changes across the membrane. This model provides a new perspective on the process of insulin binding to its receptor and, thus, could lead to future novel drug discovery efforts.

 Subetta increases phosphorylation of insulin receptor β-subunit alone and in the presence of insulin 

It has been previously shown that Subetta (a drug containing released-active forms of antibodies to the insulin receptor β-subunit and antibodies to endothelial nitric oxide synthase) stimulated insulin-induced adiponectin production by mature human adipocytes in the absence of insulin. Therefore, it was assumed that Subetta could activate the insulin receptor. To confirm this hypothesis, the capacity of Subetta to activate the insulin receptor in mature human adipocytes in the absence or presence of the insulin was investigated. Cells were incubated either with Subetta or with vehicle, or with basal medium for 3 days. Then, adipocytes were treated with water or insulin (100 nm) for 15 min. Following treatment, lysates were prepared and phosphorylation of insulin receptor β-subunits was analyzed by western blot analysis. It was shown that Subetta significantly increased (P<0.001) the ‘phosphorylated-insulin receptor β-subunit/total insulin receptor β-subunit' ratios in both the presence and the absence of insulin. These results support previously published data and indicate that Subetta could activate the insulin receptor through the effect on its β-subunits, whose conformational state is essential for insulin receptor activation. This action might serve as one of the primary mechanisms of the drug's antidiabetic effect.

Subetta treatment increases adiponectin secretion by mature muman adipocytes in vitro

PURPOSE: To investigate the mechanism of action in peripheral tissues of novel complex drug containing release-active dilutions of antibodies to the beta subunit of the insulin receptor and antibodies to endothelial nitric oxide synthase (Subetta), which has shown efficacy in animal models of diabetes.
METHODS: Human mature adipocytes were incubated either with Subetta, with one of negative controls (placebo or vehicle), with one of nonspecific controls (release-active dilutions of antibodies to cannabinoid receptor type I or release-active dilutions of rabbit nonimmune serum), or with dimethyl sulfoxide (DMSO) at 37°C in a humidified incubator at 5% CO2 for three days. Rosiglitazone was used as reference drug. Secretion of adiponectin was measured by quantitative enzyme-linked immunosorbent assay (ELISA).
RESULTS: Only Subetta significantly stimulates adiponectin production by mature human adipocytes. Nonspecific controls did not significantly affect adiponectin secretion, resulting in adiponectin levels comparable to background values of the negative controls and DMSO.
CONCLUSION: Increasing adiponectin production in absence of insulin by Subetta probably via modulating effect on the beta subunit of the insulin receptor might serve as one of the mechanisms of the antidiabetic effect of this drug. These in vitro results give first insight on possible mechanism of action of Subetta and serve as a background for further studies.

Antibodies to S100 proteins have anxiolytic-like activity at ultra-low doses in the adult rat

S100 proteins are small calcium-binding proteins interacting with numerous intra- and extra cellular targets involved in diverse physiological functions. In particular, S100 proteins may be involved in the regulation of anxiety-related behaviour. In the present study, the effects of affinity-purified antibodies to S100 proteins administered orally at ultra-low doses were evaluated in pre-clinical tests for anxiolytic-like activity in the adult rat. In the Vogel conflict test in the rat, antibodies to S100 proteins increased punished drinking (anti-conflict effect) at 5 and 7.5 mL kg(-1), but not at 2.5 or 10 mL kg(-1). Antibodies to S100 proteins increased the percentage of entries into the open arms of an elevated plus-maze at 10 mL kg(-1), but not at lower doses. Taken together, these results indicate the presence of anxiolytic-like activity for antibodies to S100 proteins over the dose range 5-10 mL kg(-1) in the adult rat.

Farmacological effects of anti-S 100 in release-active form and mechanisms of their realization

Antibodies to 5100 proteins (anti-5100) in release-active form (RA anti-5100) are an active component of some domestic drugs(tenoten, tenoten for children, divaza, brizantin, kolofort and proproten-100). The authors present the results of preclinical and clinical trials (with detailed consideration of experimental data) which demonstrated a wide spectrum of specific pharmacological activity and safety as well as mechanisms of anti-5100 action.

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.

Perspectives of the novel drug divaza in the treatment of chronic cerebral ischemia

The present paper reviews preclinical research of divaza, the combination of release-active antibodies to brain-specific 5100 protein and release-active antibodies to endothelial NO-synthase. Preclinical studies have revealed that the specific pharmacological activity of the compounds is retained in the combination, and the components mutually potentiate each other's effects. The previous research have demonstrated high efficacy of divaza in the experimental models of cerebral ischemia and neurodegenerative diseases. Divaza also displays the antihypoxant and antioxidant activity in the animal models of hypoxia by reducing the pathological changes of brain tissue. Significant reduction of the lipid peroxidation process in the affected brain regions can be one of the mechanisms of this effect. In standard experimental models of anxiety and depression, divaza positively influences the psycho-emotional state of animals.

Use of piezoelectric immunosensors for detection of interferon-gamma Interaction with specific antibodies in the presence of released-active forms of antibodies to interferon-gamma

In preliminary ELISA studies where released-active forms (RAF) of antibodies (Abs) to interferon-gamma (IFNg) were added to the antigen-antibody system, a statistically significant difference in absorbance signals obtained in their presence in comparison to placebo was observed. A piezoelectric immunosensor assay was developed to support these data and investigate the effects of RAF Abs to IFNg on the specific interaction between Abs to IFNg and IFNg. The experimental conditions were designed and optimal electrode coating, detection circumstances and suitable chaotropic agents for electrode regeneration were selected. The developed technique was found to provide high repeatability, intermediate precision and specificity. The difference between the analytical signals of RAF Ab samples and those of the placebo was up to 50.8%, whereas the difference between non-specific controls and the placebo was within 5%–6%. Thus, the piezoelectric immunosensor as well as ELISA has the potential to be used for detecting the effects of RAF Abs to IFNg on the antigen-antibody interaction, which might be the result of RAF’s ability to modify the affinity of IFNg to specific/related Abs.

Dose-dependent antiviral activity of released-active form of antibodies to interferon-gamma against influenza A/California/07/09(H1N1) in murine model

The assessment of dose-response is an essential part of drug development in terms of the determination of a drug's effective dose, finding the safety endpoint, estimation of the pharmacokinetic profile, and even validation of drug activity, especially for therapeutic agents with a principally novel mechanism of action. Drugs based on released-active forms of antibodies are a good example of such a target. In this study, the efficacy of the antiviral drug Anaferon for children (released-active form of antibodies to interferon-gamma) was tested in a dose-dependent manner (at doses of 0.13, 0.2, 0.4, 0.8 ml/mouse/day) in a murine model of acute pneumonia induced by influenza virus pandemic strain A/California/07/09 (H1N1). Administration of the drug at the two highest doses led to: a reduction in the virus infectious titer in lung tissue up to 4.2 lgEID50/20 mg of tissue; infected animals' life prolongation up to 6.7 days; an increase in the survival rate of up to 40% and a decrease in morphological signs of inflammation when compared to the control animals. In this study, the dose-response effect of Anaferon for Children was demonstrated on mice for the first time. This finding is especially important for drugs with a principally novel mechanism of action like drugs based on released-active forms of antibodies. J. Med. Virol. 89:759-766, 2017.