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The aim of the work was to conduct an analysis of the current state and current trends in the approval of drugs, as well as some aspects of the methodology for their development based on biological molecules and registration.Materials and methods. The material for the analysis was taken from the abstract databases of PubMed, Google Scholar and e-library.ru. The search was carried out using publications for the period from 2008 to 2023, the keywords were as follows: “biologicals”, “new drug approval”, “drug authorization”, “drug development”, “biosimilar”, taking into account various spellings.Results. Over the past 15 years, scientists have been observing revolutionary trends and processes in the field of the drug development, especially biopharmaceuticals. Significant advances have been made in gene, immune and cell therapies, resulting in the approval of such drugs more than doubling over the past ten years. The development of biological drugs includes the identification and testing of molecular targets and requires a deep understanding of the structure and functioning of the polypeptides involved in the development of the effect. The features of these active pharmaceutical substances are a high molecular weight, a complex three-dimensional structure and a high immunogenic potential. Preclinical and clinical studies of biologics have unique challenges. Selecting appropriate animal species, understanding the immunogenicity, and assessing pharmacodynamics and toxicological properties require a multilevel, detailed approach. The article discusses the regulatory framework under which these drugs are registered, summarizing the guidelines provided by international organizations such as the International Council for Harmonization and various national agencies.Conclusion. The analysis highlights the current advances and prospects in the development of biologics, highlighting their key role in future transformations in the treatment of rare diseases and oncology, approaching the era of personalized medicine. Monitoring the development directions and technological approaches, as well as the commitment to global methodological and regulatory aspects can become a catalyst in the development of the Russian pharmacology.

Early therapy response is one of the major prognostic factors influencing an outcome of acute lymphoblastic leukemia (ALL). The purpose of the given work was to define a time point (TP) of fusion gene transcript (FGt) monitoring by reverse-transcriptase PCR that clearly predicts outcome in infants with MLL-rearranged ALL, enrolled onto MLL-Baby protocol. Molecular remission (cMR) was defined as absence of FGt at nested RT-PCR with sensitivity 1 × 10–4 or higher confirmed with negative result in the following time point (ТP). Detection of FGt in bone marrow (BM) was performed by qualitative nested RT-PCR on 15th , 36th and 43th days of therapy (TP1-TP3) and also during consolidation/intensification (ТP4-ТP9). Retrospectively, patients were divided into two groups. First group included 14 patients who achieved cMR by TP4, where two relapses occurred. The second group consisted of four MLL-AF4-positive patients, who did not achieve cMR by TP4. In this group there were 3 relapses. Number of relapses was significantly higher in the second group (odds ratio 18.00; 95 % CI: 1.19-271.47; p = 0.044). 6-years event-free survival (EFS) in the first group was 0.84 ± 0.10, in the second group — 0.25 ± 0.21 (p = 0.023). Cumulative incidence of relapse in the first group was 0.15 ± 0.01, in the second group 0.75 ± 0.08 (p = 0.022). Time of cMR achievement did not correlate with any known prognostic factors including therapy response on day 8, 15 and 36. Slow achievement of cMR corresponds to poor outcome in infant ALL with MLL rearrangements. Persistence of FGt at TP4 allows defining patients with high risk of relapse.

The manufacture of different medicinal products in shared facilities creates a risk of cross-contamination. One of the approaches to select the limits for possible contaminants is based on calculating the permitted daily exposure (PDE), i.e. the dose of an active pharmaceutical ingredient or any other substance contaminating a medicinal product that will not be associated with any adverse events in a human in the case of lifetime exposure. The aim of this study was to provide practical guidance on selecting adjustment factors for calculating PDEs to establish limits for potential contaminants in multi-purpose pharmaceutical facilities. The authors analysed the regulatory requirements and literature needed to establish critical effects of contaminants, outlined possible assumptions in the use of quantitative indicators for measuring toxicity, and described the relationship between the PDE and other indicators of the safety of chemical compounds for human health. The article presents an example of PDE calculation for an investigational hypoglycemic medicinal product using a limited amount of open-source literature data. Thus, the article demonstrates the role of information on the primary pharmacodynamic effects of medicinal products in the assessment of their critical effects, which is necessary to implement the most conservative approaches to PDE calculation. The example of PDE calculation presented in the article may be used to assess cross-contamination risks associated with non-dedicated manufacturing facilities.

Idiopathic thrombocytopenic purpura (ITP), or primary immune thrombocytopenia, is an orphan disease associated with thrombocytopenia. One of the most recent and promising approaches to ITP treatment is the use of thrombopoietin receptor agonists (TPO-RAs). The scope of TPO-RA use is expanding rapidly, which stimulates the development of both innovator and generic (or biosimilar) medicines. The aim of the paper was to assess TPO-RA role in ITP treatment, methodological approaches to TPO-RA development, and feasibility of using the platelet count as a pharmacodynamic marker in bioequivalence studies of peptide TPO-RAs in healthy volunteers. Clinical development of new medicines for the treatment of thrombocytopenia includes comparative, parallel-group trials lasting about a year. The standard approach to bioequivalence studies, which is based on the results of comparative pharmacokinetic studies, can be used in marketing authorisation applications for generic non-peptide TPO agonists, while peptide TPO agonists have to comply with specific requirements for biosimilar products. The orphan status of ITP does not affect the development strategy and study design, but it limits the number of patients that could be included into the study. In the absence of valid surrogate biomarkers of efficacy, demonstration of comparable clinical efficacy of the biosimilar and reference drug is usually required in a randomised, parallel, preferably double-blind comparative study. On the other hand, clinical comparability of the biosimilar and reference drug can also be demonstrated in comparative pharmacodynamic studies, if the selected biomarker is a well-established and valid surrogate marker which correlates with patient clinical outcome. Platelet count is a key parameter in both diagnosis of diseases associated with low platelet levels and assessment of treatment efficacy. Therefore, it can be used as a pharmacodynamic marker in bioequivalence studies of biosimilar peptide TPO-RAs. It was concluded that such studies could be performed in healthy volunteers, and not in patients, whose participation in clinical trials is limited due to the orphan status of ITP.

Objective: to analyze the dynamics of quality of life (QOL) in patients with prior osteoporotic vertebral compression fracture during an 18-month follow-up study. Subjects and methods. The investigation enrolled 219 patients (mean age, 67.6 years) with vertebral fracture from seven centers of the Russian Federation. QOL was assessed four times using the EQ-5D (EuroQoL-5D) and TTO (Time Trade-Off) questionnaires during an 18-month prospective follow-up study. The work was done within the framework of the International Multicenter Study ICUROS (The International Costs and Utilities Related to Osteoporotic Fractures Study) organized by the International Osteoporosis Foundation (www.icuros.org).Results and discussion. The patients with vertebral compression fracture showed a statistically significant decrease in QOL throughout the follow-up period. Immediately after the fracture, there was a dramatic decrease in the total EQ-5D score, followed by its gradual increase. However, the emerging trend in QOL recovery proved to be unstable, and by the end of the 18th month, it was significantly lower than that before the fracture. On the contrary, the TTO questionnaire showed that QOL drastically decreased immediately after fracture, but at month 4 it reached the level that was before the fracture, and remained stable until the end of the follow-up period.Conclusion. The performed investigation enabled us to obtain data on QOL using the EQ-5D (QOL assessment from the social point of view) and TTO (individual QOL assessment) in the population of residents of the Russian Federation, in men and women aged 50 years and older with osteoporotic vertebral compression fracture.

191 consecutive unselected children with acute lymphoblastic leukemia aged from 1 to 16 years were enrolled in the study. Bone marrow samples were obtained at the time of initial diagnostics as well as at days 15 (n = 188), 36 (n = 191), and 85 (n = 187) of remission induction. Minimal residual disease (MRD) was assessed by 6–10-color flow cytometry. Flow cytometry data at day 15 allowed distinguishing three patients groups with significantly different outcome (p ˂ 0.0001): 35.64 % patients with MRD < 0.1 % represented 5-year event-free survival (EFS) of 100 %; 48.40 % cases with 0.1 % ≤ MRD< 10 % had EFS 84.6 ± 4.2 %; 15.96 % patients with very high MRD (≥ 10 %) belonged to group with poor outcome (EFS 56.7 ± 9.0 %). At the end of remission induction (day 36) 36 children (18.85 %) with MRD higher than 0.1 % had significantly worse outcome compared to remaining ones (EFS 49.4 ± 9.0 and 93.5 ± 2.1 % respectively; p ˂ 0.0001). From a clinical standpoint it is relevant to evaluate both low-risk and high-risk criteria. Multivariate analysis showed that day 15 MRD data is better for low-risk patients definition while end-induction MRD is the strongest unfavorable prognostic factor.

Dynamic electroneurostimulation (DENS) is a type of percutaneous electroneurostimulation with a differentiation approach to choosing exposure areas and to optimizing electrocutaneous therapeutic action on the reflexogenic areas and acupuncture points for analgesia and for the treatment of functional disorders.Objective: to study the clinical efficiency and safety of therapy using a DiaDENS-PC apparatus in the treatment of knee osteoarthritis (OA).Subjects and methods. A multicenter randomized double-blind placebo-controlled study was conducted in 132 knee OA patients with pain value above 40 mm on visual analogue scale (VAS) and Lequesne’s index of 4–12. In a study group (n = 66), DENS was carried outwith a DiaDENS-PC apparatus using a trailing electrode applicator to the knee target in a Therapy stimulation mode at a frequency 77 Hz, a power of 15 units. In the placebo group, the similar procedure was performed with a switched-on placebo apparatus that did not differ in appearance from the working apparatus; but produced no electrical pulses. The treatment cycle consisted of 10 sessions lasting 30 min. Changes in Lequesne’s algofunctional index were primary end point. The results of the Get-Up to Go test (in seconds) and changes pain on VAS and WOMAC were used as secondary end points.Results and discussion. Both groups showed a statistically significant reduction of painand improvement of Get-Up and to Go test results by the end of the treatment course (p < 0.0001). Therewas a statistically significant difference in pain in the compared groups after a treatment session during the first (p = 0.037) and second (p = 0.010) visits. The analgesic effect of therapy was observed to persist in the DENS group 2 weeks (p = 0.006) and 1 month (p = 0.070) after treatment termination. After 10 sessions, there was a statistically significant difference between the groups in the Get-Up and Go test (p = 0.033) and Lequesne’s index (p = 0.022). Both groups exhibited a significant decrease in the total WOMAC scores. In the DENS group, positive changes in all subscales were statistically significant starting from the second visit whereas in the control group, the total WOMAC scores improvedonly at the expense of the pain subscale.

Key words: chronic myeloid leukemia, BCR-ABL expression, automated GeneXpert method

Purpose. Endogenous Cushing’s syndrome (CS), usually affecting young and otherwise healthy patients, is a good model to validate the effects of supraphysiological levels of glucocorticoids in humans. This study evaluates circulating levels of extracellular antagonists of Wnt/ß-catenin signaling pathway (sclerostin, Dickkopf1 (Dkkl), secretedfrizzled-related protein 1 (SFRP1)) along with osteoprotegerin (OPG) and soluble receptor activator of nuclear factor kappa-beta ligand (RANKL) in patients with CS as compared to healthy individuals. Materials and methods. Forty patients with clinically and biochemically evident CS and 40 sex, age and body-mass index matched healthy individuals provided fasting serum samples (8:00-10:00AM) for measurement of sclerostin, SFRP1 and Dkkl, RANKL., OPG along with bone turnover markers. Serum samples on RANKL., OPG., Dkkl, SFRP1, sclerostin were frozen and then concurrently measured by an enzyme immunoassay (ELISA) using commercially available reagents. Serum samples on osteocalcin (OC), carboxyterminal cross-linked telopeptide of type I collagen (CTx), cortisol in serum and saliva were assayed by electrochemiluminescence (ECLIA) Cobas e601 Roche. Urinary free cortisol (24hUFC) was measured by an immunochemiluminescence assay (extraction with diethyl ether) on a Vitros ECi. All participants were questioned regarding any recent low traumatic fractures. Patients with CS underwent standard spinal radiographs in anterior-posterior and lateral positions of the vertebrae Th4-L4 (Axiom Icons R200 "Siemens"). Results. Patents with CS (30 (26-40) years old with 24hUFC 2575 (1184-4228) nmol/l (Me (Q25-Q75)) had suppressed OC and normal CTx levels as compared to healthy subjects. A significant correlation, which we observed between OC and CTx (po=0.724 (p

Медико-социальную и экономическую значимость остеопороза определяют его неуклонно нарастающая распространенность, а также затраты на лечение собственно остеопороза и его прямых осложнений - переломов, приводящих к развитию хронической боли, деформации скелета и потере трудоспособности. В Российской Федерации данные об экономических и социальных последствиях остеопоротических переломов практически отсутствуют, и имеют ограниченную ценность для применения в экономике здравоохранения. Исследование проведено в рамках международного многоцентрового исследования ICUROS. Целью исследования являлось единообразное (с использованием единой методологии сбора и анализа данных) изучение странах экономических и социальных последствий остеопоротических переломов. В Российской Федерации в исследовании участвовали 9 центров. В тезисах впервые использована окончательная версия базы данных. Материал и методы. Всего включено 1143 пациента от 50 лет и старше, перенесших низкоэнергетический перелом, из них 251 (21,96%) - с переломами шейки бедра, 255 (22,33%) - с переломами запястья, 219 (19,16%) - с переломами позвонков, 182 (15,92%) - с переломами плечевой кости, и 236 (20,65%) - с переломами лодыжки. Опрос пациентов проводился непосредственно после перелома и касался информации о качестве жизни (КЖ) до перелома и непосредственно после перелома (Фаза I). Далее сбор информации осуществлялся через 4 (Фаза II), 12 (Фаза III) и 18 месяцев (Фаза IV) после перелома. Средний возраст включенных пациентов составил 65,2 года (95% доверительный интервал (ДИ) от 64.65 до 65,72). Одним из интегральных параметров КЖ исследовании был опросник EQ-5D, включающий данные по подвижности, самообслуживанию, повседневной активности, боли и дискомфорту, выраженности тревоги и депрессии. Отдельные шкалы данного опросника были преобразованы в общий балл, стандартизованный к шкале от нуля до единицы. Результаты. Ретроспективные данные о КЖ по стандартизованному суммарному баллу EQ-5D составили 0,824 (95% ДИ: 0,812-0,836). На момент перелома у пациентов значимо падало КЖ - 0,290 (95% ДИ: 0,273-0,307) (р0,05). Выводы. Таким образом, если общая субъективная оценка здоровья по ВАШ возвращается к значениям «до перелома» уже к 4 месяцам после перелома, то суммарный балл по EQ-5D) достигает значений, близких к исходным, только к 12 месяцам, и продолжает улучшаться и через 18 месяцев. Эти данные свидетельствуют о важности изучения отдельных компонентов качества жизни пациентов, входящих в EQ-5D, а не только суммарных результатов.

Динамическая электронейростимуляция (ДЭНС) - вид ЧЭНС, основанный на применении слабых (200-400мкА), низкочастотных (10-200 Гц) импульсных токов, изменяющих форму в зависимости от электрического сопротивления (импенданса) в подэлектродном участке кожи, для воздействия на биологически активные зоны и точки. Цель исследования: изучить клиническую эффективность терапии аппаратом ДиаДЭНС-ПК в лечении остеоартроза коленных суставов (ОА КС). Материалы и методы. Проведено многоцентровое рандомизированное двойное слепое плацебо-контролируемое исследование. Включено 132 пациента с ОА КС с интенсивностью болевого синдрома более 40 мм по ВАШ, с индексом Лекена > 4 и < 12. Группа ДЭНС (66 чел.) получала лечение аппаратом ДиаДЭНС-ПК с помощью выносного электрода - аппликатора на область коленного сустава- мишени в режиме стимуляции - «Терапия», частотой 77 Гц, уровнем мощности - 15 единиц. Курс лечения - 10 процедур, по 30 минут. Группы были исходно сопоставимы по оцениваемым показателям кроме возраста: пациенты группы плацебо были старше группы ДЭНС в среднем на 3,2 года. Осмотр и опрос пациентов проводился до и после 1,3,6,10й процедур лечения, опрос на визитах наблюдения через 2 и 4 недели после окончания курса терапии. Первичная конечная точка исследования: интенсивность боли по ВАШ (мм), вторичные: тест «Встань и иди» (сек), альгофункциональный индекс Лекена, индекс WOMAC. Результаты. Статистически значимое различие в уменьшении боли по ВАШ в сравниваемых группах наблюдалось после первой процедуры лечения (р=0,014) и далее сохранялось по окончании 3й (р=0,018), и 6й процедур (р=0,047) и на визите наблюдения через 2 недели после окончания лечения (р=0,003). Индекс Лекена статистически значимо различался между группами на 10м последнем визите лечения (р=0,001) и через 4 недели на визите наблюдения (р=0,001). Статистически значимая разница между группами показателя теста «Встань и иди» наблюдалась после 6й процедуры лечения (р=0,041), перед 10-й процедурой (р=0,010), и на визитах наблюдения через 2 недели (р=0,018) и через 4 недели (р=0,025). Индекс WOMAC статистически достоверно не различался между группами. Суточная потребность пациентов в нестероидных противовоспалительных препаратах статистически значимо не различалась между группами. Врачи и пациенты достоверно положительно оценили эффективность лечения в конце курса терапии в ДЭНС группе: при оценке пациентами (р=0,004), при оценке врачами (р

BACKGROUND:Patients with endogenous hypercortisolism have reduced bone mineral density (BMD) and trabecular bone score (TBS) that are the causes of secondary osteoporosis and low-traumatic fractures. It is well known that radical treatment (neurosurgery or radiosurgery) of Cushings disease leads to a decline of cortisol levels in all body fluids to normal values. However, it is still uncertain whether bone tissue structure, and particularly its microarchitecture, does recover in remission of the disease. AIMS:To evaluate an influence of hormone activity (presence or absence of remission) in patients with Cushing's disease on changes of bone structure measurements in accordance with DXA values (TBS, BMD, T- and Z-scores), as well as significance of such changes in 12 and 24 months after neurosurgical treatment. MATERIALS AND METHODS:In patients with confirmed active Cushing's disease (ACTH-producing pituitary adenoma) (n = 44) and in control group of healthy volunteers (n = 40), BMD in lumbar spine (L1-L4) and simultaneously TBS, in cut-off points before neurosurgical treatment (in both groups) and in 12 and 24 months after it (only in patients), were assessed. We diagnosed presence or absence of disease remission at cut-offs. All measurements were performed using a GE iDXA device (GE Healthcare Lunar, Madison, Wisconsin, USA). The TBS was calculated simultaneously from taken BMD scans, blinded to clinical outcome using TBS iNsight software v2.1 (Medimaps, Merignac, France). The activity of Cushings disease was evaluated using late-night salivary cortisol (LNSC, at 23:00). To determine the differences in DXA and TBS values before and after neurosurgical intervention depending on remission occurrence, covariate analysis (ANCOVA) was applied. RESULTS:There were found significant changes in TBS, BMD and T-score values in 12 months after neurosurgical treatment associated with presence or absence of disease remission (p = 0.039, 0.046 and 0.048, respectively). No differences in Z-score as well as in all measurements in 24 months, that might be associated with remission occurrence, were revealed. The gain in all DXA measurements (including TBS) during 24 months of observation period was statistically significant when analyzing data using Students paired t-test. However, the values corresponding to the age references had not been achieved for the specified time interval. CONCLUSIONS:Patients with Cushings disease have lower TBS values. In remission conditions TBS is getting significantly higher. The increase in BMD and TBS occurs during 24 months after achieving remission of Cushings disease but doesnt lead to a full restoration of normal bone mass and microstructure throughout observation period of 24 months.

Objective. To study the prevalence of osteoarthritis and joint complaints among urban and rural inhabitants Material and methods. Simultaneous cross-sectional epidemiological study among inhabitants of Revda town and nine rural settlements of Nevijansk farmland in the Sverdlovsk region. Results, questionnaire-based survey showed that the prevalence of joint pain and complaints of joint swelling was higher in the rural population (44,9% and 16,7% correspondingly) compared to town population (26,4% and 6,7% correspondingly), p