Ocrelizumab in treatment of primary-progressive multiple sclerosis: systematic review

Aim. To analyze the efficacy, safety and pharmacoeconomic indicators of ocrelizumab in adult patients with primary progressive multiple sclerosis (PPMS). Methods. An information search was conducted in the databases Embase, PubMed, Cochrane and eLibrary.ru. The levels of evidence were determined in the studies. Results. Therapy with ocrelizumab compared with placebo characterized by a decrease in the rate of progression of the disease. Treatment with ocrelizumab was associated with a significant slowdown in progression compared to other drugs: rituximab, fingolimod, myelin basic protein peptide 82–98, intravenous immunoglobulin; plasmapheresis / plasma metabolism, corticosteroids, general irradiation of lymphoid tissue, and other most common adverse events: infusion reactions, nasopharyngitis, upper tract respiratory and urinary tract infections, headaches. Life years and quality-adjusted life years for patients receiving ocrelizumab were 16.11 and 3.33, compared with 15.61 and 2.75 for patients receiving better supportive care, respectively. The annual average potential impact on the budget for 1 patient with PPMS in the treatment of ocrelizumab for 5 years ranged from $ 18,300 to 44 200. Conclusions. Ocrelizumab is the only drug that has proven its clinical efficacy in the previously non-curable type of multiple sclerosis, PPC, with risk profile acceptable with respect to clinical benefits

ВЛИЯНИЕ СПОНТАННОЙ МИКРОФЛОРЫ ФЕРМЕНТИРОВАННЫХ МЯСНЫХ ПРОДУКТОВ ИЗ КОНИНЫ НА ОБРАЗОВАНИЕ БИОЛОГИЧЕСКИ АКТИВНЫХ ПЕПТИДОВ

At present, different methods are used to accumulate functional peptides in meat raw materials, including the use of spontaneous microflora during autolysis, the use of the microbial enzymes (the application of starter cultures) and the use of the non-microbial enzymes (enzymes of animals and plant origin). Each method has its own specific characteristics of an impact on raw materials, which requires their detail study. This paper examines an effect of spontaneous microflora of fermented meat products from horsemeat on formation of biologically active peptides. Using the T-RFLP analysis, it was established that in air dried and uncooked smoked sausages produced with the use of the muscle tissue of horsemeat as a raw material, a significant proportion of microflora was presented by lactic acid microorganisms. The highest content of lactic acid microflora was observed in sample 1 (52.45 %), and the least in sample 3 (29.62 %). Sample 2 had the medium percent content of microflora compared to samples 1 and 3 — 38.82 %. It is necessary to note that about 25 % of microflora was unculturable; i.e., it had metabolic processes but did not grow on culture media. In the samples, the representatives of Actinobacteria and Pseudomonadales were found. Pathogenic and conditionally pathogenic microflora was not detected. Not only quantitative but also qualitative changes were observed in the studied samples. For example, in samples 1 and 2, the fractions of amilo-1,6-glucosidase, fast-type muscle myosin-binding-protein C; glucose-6-phosphate isomerase; fast skeletal muscle troponin I, phosphoglycerate kinase, pyruvate kinase and skeletal muscle actin were found, which were absent or reduced in sample 3. Therefore, in the studied product, good preservation of the main spectra of muscle proteins was observed, and the identified fractions, apparently, can be sources of new functional peptides. Not only quantitative but also qualitative changes were observed in the studied samples. For example, in samples 1 and 2, the C-terminal fragments of the myosin heavy chain were found, which were absent in sample 3. Also, the significant content of myoglobin was revealed in samples 2 and 3, and the myosin light chain was found in sample 1. Therefore, in the studied product, good preservation of muscle proteins myosin and myoglobin, which can be a source of new functional peptides, was observed. Based on the results of tandem mass-spectrometry, the proteins and natural short peptides present in the analyzed extracts were identified by the obtained masses. They belonged mainly to different peptides of equine myoglobin. Also, we identified several fragments, among which fast skeletal muscle troponin T and muscle creatine kinase were found. The obtained materials can be regarded as an experimental basis for the directed impact of starter cultures with a possibility to predict the protein and peptide composition of a finished product including with the aim of obtaining biologically active peptides.В настоящее время для накопления в мясном сырье функциональных пептидов используют различные методы, в том числе включающие использование спонтанной микрофлоры в ходе автолиза, использование ферментов микробного происхождения (применение стартовых культур) и использование ферментов немикробного происхождения (ферменты животного и растительного происхождения).  Каждый из методов имеет свои специфические особенности воздействия на сырье, что требует их детального изучения. В данной статье рассматривается влияние спонтанной микрофлоры ферментированных мясных продуктов из конины на образование биологически активных пептидов. С использованием T-RFLP-анализа установлено, что в составе микрофлоры сыровяленой и сырокопченой колбас, произведенных с использованием мышечной ткани конины в виде мясного сырья, значительная часть микрофлоры представлена молочнокислыми микроорганизмами. Так, наибольшее содержание молочнокислой микрофлоры наблюдается в образце № 1 (52,45 %), а наименьшее — в образце № 3 (29,62 %). В образце № 2 наблюдается среднее процентное содержание микрофлоры по сравнению с образцами № 1 и № 3 — 38,82 %. Следует также отметить, что приблизительно 25 % микрофлоры относится к некультивируемой, т.е. имеющей метаболические процессы, но не дающей роста на питательных средах. В образцах обнаружены представители актиномицетов и псевдомонад. Патогенной и условно-патогенной микрофлоры не обнаружено. Сравнительное протеомное исследование методом электрофореза трех видов колбас из конины, выработанных с использованием стартовых культур по различным технологиям, показало количественные и качественные различия по нескольким белковым фракциям. Наибольшее отличие в количестве белковых полос наблюдается между образцами № 1/№ 2 и № 3. Белковый профиль конины в образце № 3 имел значительное количественное отличие от белковых профилей образцов № 1 и № 2. Так, количественное содержание белковых полос в образце № 3 в диапазоне молекулярных масс 45–250 кДа всего 4, в то время как в образцах № 1 и № 2 их вдвое больше. В исследуемых образцах наблюдаются не только количественные, но и качественные изменения. Так, в образце № 1 и № 2 обнаружены фракции амило-1,6-глюкозидазы, миозин связывающего белка С быстрого типа,  глюкозо-6-фосфат изомеразы, тропонина I быстрых скелетных мышц, фосфоглицераткиназы, пируваткиназы и скелетномышечного актина, отсутствующие или уменьшающиеся в образце №3. Таким образом, в исследуемой продукции наблюдалась  сохранность основного спектра мышечных белков, а идентифицированные фракции очевидно, могут быть источниками новых функциональных пептидов. По результатам тандемной масс-спектрометрии по полученным массам были идентифицированы природные короткие пептиды, которые присутствовали в анализируемых экстрактах. В основном все они относились к разным пептидам конского миоглобина.  Также было идентифицировано несколько фрагментов, среди которых обнаруживались тропонин-Т скелетномышечный быстрого типа и мышечная креатинкиназа. Полученные материалы можно рассматривать как экспериментальную основу для направленного воздействия стартовых культур с возможностью прогнозирования белкового и пептидного состава готового продукта, в т.ч. с целью получения биологически активных пептидов в них

Моноклональное антитело окрелизумаб для терапии рассеянного склероза у взрослых пациентов: систематический обзор

Aim: To analyze the efficacy, safety and pharmacoeconomic aspects of using ocrelizumab in adult patients with relapsing/remitting multiple sclerosis (R/R MS).Materials and Methods. We used the commonly accepted PICo(S) questionnaire with the following specifics: the population – patients with R/R MS; the intervention – ocrelizumab; the comparators – all disease-modifying treatments for MS; the outcomes – the annualized relapse rate, confirmed disability progression, MRI results, quality-adjusted years of survival (QALYs), adverse events, and other clinical outcomes. The search for the relevant information was conducted in 2018 by using the embase, PubMed, Cochrane and eLibrary.ru databases and the «ocrelizumab» AND «multiple sclerosis» keywords. The levels of evidence and conclusiveness of the cited studies were also assessed.Results. Treatments with ocrelizumab resulted in a lower rate of disease progression as compared with interferon β -1a. As evidenced by a randomized clinical trial, the annualized relapse rate estimated after 96 weeks was lower with ocrelizumab than that with interferon β-1a (0.16 vs. 0.29, 47% decrease, p<0.001). For most secondary end points, patients on ocrelizumab showed better outcomes than those on interferon β-1a. In the ocrelizumab group, the most common adverse events were caused by reactions to the drug infusion, nasopharyngitis, upper respiratory and urinary tract infections, and headaches. No cases of progressive multifocal leukoencephalopathy have been reported so far. ocrelizumab is more clinically effective than the first-line disease-modifying therapies; this conclusion also refers to patients with the aggressive (highly active) form of MS. ocrelizumab showed the efficacy similar to the second-line disease-modifying therapies, but it had a more favorable safety profile. The pharmacoeconomic indices showed that using ocrelizumab had a positive impact on the budget in the long-term perspective.Conclusions. ocrelizumab can be considered as the main treatment alternative for patients with highly active MS and patients with a high risk of progressive multifocal leukoencephalopathy. However, an additional assessment of the risk caused by rare adverse events is needed. Цель. Проведение сравнительного анализа эффективности, безопасности и клинико-экономических показателей препарата окрелизумаб (Окревус®) в терапии рецидивирующих форм рассеянного склероза (РРС) у взрослых пациентов.Материалы и методы. Определены критерии PICo(S): популяция – больные с РРС; интервенция – окрелизумаб; компараторы – все препараты, изменяющие течение РС (ПИТРС); результаты – среднегодовая частота обострений, степень прогрессирования инвалидизации, результаты МРТ, годы жизни с поправкой на качество (QALYs), нежелательные явления (НЯ) и другие клинические результаты; вид исследований – все прямые и непрямые сравнения интервенции с одним или несколькими компараторами. Информационный поиск проведен в 2018 г. в базах данных embase, PubMed, Cochrane, eLibrary.ru по ключевым словам «ocrelizumab» и «multiple sclerosis». Оценен уровень доказательности и убедительности результатов отобранных публикаций.Результаты. Терапия окрелизумабом характеризовалась более низкими показателями активности и прогрессирования заболевания, чем терапия интерфероном β-1a: годовая частота обострений на неделе 96 значительно ниже в группе окрелизумаба, чем в группе интерферона β-1a в РКИ (0,16 против 0,29, снижение на 47%; р<0,001). Окрелизумаб эффективнее, чем интерферон β-1a по большинству вторичных конечных точек. Наиболее частые НЯ у пациентов, получавших окрелизумаб: инфузионные реакции, инфекции, в частности назофарингит, инфекции мочевыводящих и верхних дыхательных путей, головная боль. Случаев прогрессирующей мультифокальной лейкоэнцефалопатии (ПМЛ) не отмечено. Окрелизумаб превосходит по клинической эффективности ПИТРС первой линии терапии, в том числе в популяции взрослых пациентов с агрессивной (высокоактивной) формой течения РС. В сравнении с ПИТРС второй линии окрелизумаб имеет сходную эффективность, но более благоприятный профиль безопасности. Клинико-экономические показатели свидетельствуют о значительной пользе окрелизумаба и положительном влиянии на бюджет в долгосрочной перспективе.Выводы. Окрелизумаб может рассматриваться в качестве главной альтернативы для терапии пациентов с высокоактивным РС и имеющим высокий риск развития ПМЛ, однако требуется дополнительная оценка для изучения риска развития редких НЯ.

Ocrelizumab therapy and long-term outcomes in multiple sclerosis: clinical and MRI-efficacyand safety profile

Ocrelizumab (Ocrevus®) is a humanized anti-CD20 monoclonal antibody approved for the treatment of adults with relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS). The article presents data on the clinical and MRI efficacy and safety profile of ocrelizumab for the long-term use in patients with MS of various forms of the course. The authors performed the search, systematization and analysis of the pooled data of clinical studies and real clinical practice. Five-year follow-upof ocrelizumab therapy showed a compelling and clinical ly significant advantage in reducing the disease progression in patients with PPMS. After five-year ocrelizumab therapy in patients with PPMS, the study showed a reduction of the proportion of patients with disease progression and degree of brain atrophy, and more frequent achievement of the disease inactivity status (NEDA) as compared to patients with two- year delayed initiation of ocrelizumab therapy. The safety profile of the drug corresponds to the results obtained in the controlled periods of clinical trials

Economic burden of systemic sclerosis: systematic review

Background. Systemic sclerosis (SSc) is a severe orphan disease, one of the systemic pathologies of connective tissue. This disease has a significant negative impact on the patient’s quality of life and has a high mortality rate. Treatment of its various complications imposes a great financial burden on the healthcare system. The difficulties of daily functioning and social adaptation and the overall burden of SSc for patients, as well as their caregivers, also contribute to the economic component of the disease.Aim. To assess the social and economic burden of SSc.Materials and methods. A systematic review was conducted according to the PRISMA guidelines using predefined PICO(S) criteria. The search was carried out in December 2019 using the MeSH terms in the Embase, MEDLINE / PubMed, Cochrane library databases. The publication date range was 10 years. To identify Russian-language studies, an additional search was conducted in eLIBRARY.ru and the Internet network. The evidence levels of the included studies were determined.Results. A total of 934 studies were identified from all databases; 53 publications were selected for eligibility; 9 of which were included in the final review. There were no studies identified to assess the burden of SSc in Russia, so the evaluations were based on foreign studies. The estimates of the annual direct costs per patient with SSc for the past decade were almost similar in different countries: 5 038 Canadian dollars in Canada, 11 607 Australian dollars in Australia, 17 365-22 016 US dollars in the USA, and 1 413-17 300 Euros in Europe (an average of about 8 000 euros). The cost structure was dominated by direct medical costs for hospitalization and drug therapy and indirect costs were mostly associated with the loss of productivity and early retirement. The costs associated with the diffuse cutaneous form of SSc were statistically higher if compared to the costs for the limited form of the disease. Among the clinical manifestations of the disease, lung lesions and gastrointestinal problems made the largest contribution to the economic burden.Conclusion. SSc is associated with significant healthcare resource use compared to the general population. The economic burden of SS has grown significantly in recent years, and this trend is global. At the same time, it is difficult to evaluate the disease costs in Russia due to a lack of information on the patient population

AN INFLUENCE OF SPONTANEOUS MICROFLORA OF FERMENTED HORSEMEAT PRODUCTS ON THE FORMATION OF BIOLOGICALLY ACTIVE PEPTIDES

At present, different methods are used to accumulate functional peptides in meat raw materials, including the use of spontaneous microflora during autolysis, the use of the microbial enzymes (the application of starter cultures) and the use of the non-microbial enzymes (enzymes of animals and plant origin). Each method has its own specific characteristics of an impact on raw materials, which requires their detail study. This paper examines an effect of spontaneous microflora of fermented meat products from horsemeat on formation of biologically active peptides. Using the T-RFLP analysis, it was established that in air dried and uncooked smoked sausages produced with the use of the muscle tissue of horsemeat as a raw material, a significant proportion of microflora was presented by lactic acid microorganisms. The highest content of lactic acid microflora was observed in sample 1 (52.45 %), and the least in sample 3 (29.62 %). Sample 2 had the medium percent content of microflora compared to samples 1 and 3 — 38.82 %. It is necessary to note that about 25 % of microflora was unculturable; i.e., it had metabolic processes but did not grow on culture media. In the samples, the representatives of Actinobacteria and Pseudomonadales were found. Pathogenic and conditionally pathogenic microflora was not detected. Not only quantitative but also qualitative changes were observed in the studied samples. For example, in samples 1 and 2, the fractions of amilo-1,6-glucosidase, fast-type muscle myosin-binding-protein C; glucose-6-phosphate isomerase; fast skeletal muscle troponin I, phosphoglycerate kinase, pyruvate kinase and skeletal muscle actin were found, which were absent or reduced in sample 3. Therefore, in the studied product, good preservation of the main spectra of muscle proteins was observed, and the identified fractions, apparently, can be sources of new functional peptides. Not only quantitative but also qualitative changes were observed in the studied samples. For example, in samples 1 and 2, the C-terminal fragments of the myosin heavy chain were found, which were absent in sample 3. Also, the significant content of myoglobin was revealed in samples 2 and 3, and the myosin light chain was found in sample 1. Therefore, in the studied product, good preservation of muscle proteins myosin and myoglobin, which can be a source of new functional peptides, was observed. Based on the results of tandem mass-spectrometry, the proteins and natural short peptides present in the analyzed extracts were identified by the obtained masses. They belonged mainly to different peptides of equine myoglobin. Also, we identified several fragments, among which fast skeletal muscle troponin T and muscle creatine kinase were found. The obtained materials can be regarded as an experimental basis for the directed impact of starter cultures with a possibility to predict the protein and peptide composition of a finished product including with the aim of obtaining biologically active peptides

Ocrelizumab – a monoclonal antibody – in the treatment of adult patients with multiple sclerosis: a systematic review

Aim: To analyze the efficacy, safety and pharmacoeconomic aspects of using ocrelizumab in adult patients with relapsing/remitting multiple sclerosis (R/R MS).Materials and Methods. We used the commonly accepted PICo(S) questionnaire with the following specifics: the population – patients with R/R MS; the intervention – ocrelizumab; the comparators – all disease-modifying treatments for MS; the outcomes – the annualized relapse rate, confirmed disability progression, MRI results, quality-adjusted years of survival (QALYs), adverse events, and other clinical outcomes. The search for the relevant information was conducted in 2018 by using the embase, PubMed, Cochrane and eLibrary.ru databases and the «ocrelizumab» AND «multiple sclerosis» keywords. The levels of evidence and conclusiveness of the cited studies were also assessed.Results. Treatments with ocrelizumab resulted in a lower rate of disease progression as compared with interferon β -1a. As evidenced by a randomized clinical trial, the annualized relapse rate estimated after 96 weeks was lower with ocrelizumab than that with interferon β-1a (0.16 vs. 0.29, 47% decrease, p<0.001). For most secondary end points, patients on ocrelizumab showed better outcomes than those on interferon β-1a. In the ocrelizumab group, the most common adverse events were caused by reactions to the drug infusion, nasopharyngitis, upper respiratory and urinary tract infections, and headaches. No cases of progressive multifocal leukoencephalopathy have been reported so far. ocrelizumab is more clinically effective than the first-line disease-modifying therapies; this conclusion also refers to patients with the aggressive (highly active) form of MS. ocrelizumab showed the efficacy similar to the second-line disease-modifying therapies, but it had a more favorable safety profile. The pharmacoeconomic indices showed that using ocrelizumab had a positive impact on the budget in the long-term perspective.Conclusions. ocrelizumab can be considered as the main treatment alternative for patients with highly active MS and patients with a high risk of progressive multifocal leukoencephalopathy. However, an additional assessment of the risk caused by rare adverse events is needed

OBSERVATIONS OF THE MUTUAL PHENOMENA OF THE GALILEAN MOONS IN 2009

The instrumental and ephemeris preparation for the photometric observations of the mutual phenomena in the system of planetary satellites was conducted within the PHEMU09 project. Several reliable light curves and more than two tens of preparatory photometric observations of various mutual phenomena in the Jovian system were obtained. The observation data were processed, and the moments of the greatest phases of the phenomena were defined. The difference of moments of the observed greatest phases of the phenomena and the ephemerides, computed by the theory of V. Lainey, is about 0.02÷0.5 minutes. To construct an improved theory of motion of the Jovian moons, the observations are to be used for the concluding processing in the IMCCE (Institute de Mecanique et de calcul des ephemerides, France) that coordinates the PHEMU09 campaign

Социально-экономическое бремя системной склеродермии: систематический обзор

Background. Systemic sclerosis (SSc) is a severe orphan disease, one of the systemic pathologies of connective tissue. This disease has a significant negative impact on the patient’s quality of life and has a high mortality rate. Treatment of its various complications imposes a great financial burden on the healthcare system. The difficulties of daily functioning and social adaptation and the overall burden of SSc for patients, as well as their caregivers, also contribute to the economic component of the disease.Aim. To assess the social and economic burden of SSc.Materials and methods. A systematic review was conducted according to the PRISMA guidelines using predefined PICO(S) criteria. The search was carried out in December 2019 using the MeSH terms in the Embase, MEDLINE / PubMed, Cochrane library databases. The publication date range was 10 years. To identify Russian-language studies, an additional search was conducted in eLIBRARY.ru and the Internet network. The evidence levels of the included studies were determined.Results. A total of 934 studies were identified from all databases; 53 publications were selected for eligibility; 9 of which were included in the final review. There were no studies identified to assess the burden of SSc in Russia, so the evaluations were based on foreign studies. The estimates of the annual direct costs per patient with SSc for the past decade were almost similar in different countries: 5 038 Canadian dollars in Canada, 11 607 Australian dollars in Australia, 17 365-22 016 US dollars in the USA, and 1 413-17 300 Euros in Europe (an average of about 8 000 euros). The cost structure was dominated by direct medical costs for hospitalization and drug therapy and indirect costs were mostly associated with the loss of productivity and early retirement. The costs associated with the diffuse cutaneous form of SSc were statistically higher if compared to the costs for the limited form of the disease. Among the clinical manifestations of the disease, lung lesions and gastrointestinal problems made the largest contribution to the economic burden.Conclusion. SSc is associated with significant healthcare resource use compared to the general population. The economic burden of SS has grown significantly in recent years, and this trend is global. At the same time, it is difficult to evaluate the disease costs in Russia due to a lack of information on the patient population.Введение. Системная склеродермия (СС) является тяжелым орфанным заболеванием из группы системных патологий соединительной ткани. Заболевание оказывает существенное негативное влияние на качество жизни больных и имеет высокую смертность. Лечение различных осложнений СС несет большую финансовую нагрузку на систему здравоохранения. Трудности повседневного функционирования и социальной адаптации и общее бремя болезни для пациентов, а также лиц, осуществляющих уход за ними, также вносят вклад в экономическую составляющую данного заболевания.Цель. Оценка социально-экономического бремени (СЭБ) СС.Материалы и методы. Систематический обзор проведен согласно руководству PRISMA и с использованием определенных критериев PICO(S). Поиск литературы проведен в декабре 2019 г. в базах данных Embase, MEDLINE/PubMed, CochraneLibrary среди англоязычных публикаций, глубина поиска – 10 лет. Для выявления русскоязычных исследований дополнительно проведен поиск в eLIBRARY.ru и поисковых интернет-системах. Оценено качество отобранных исследований.Результаты. При проведении систематического обзора выявлено 934 публикации; в результате 1-го этапа скрининга отобрано 53 работы; после второго этапа отобрано девять публикаций, которые вошли в итоговый обзор. Не выявлено работ по оценке бремени СС в России, поэтому оценки основаны на зарубежных исследованиях. Оценки ежегодных прямых затрат на одного пациента с СС за последнее десятилетие схожи в разных странах: в Канаде – 5 038 канадских долларов, в Австралии – 11 607 австралийских долларов, в США – от 17 365 до 22 016 долларов США, в Европе – от 1 413 до 17 300 евро (в среднем около 8 тыс. евро). В структуре затрат преобладают прямые медицинские затраты на госпитализацию и лекарственную терапию и косвенные, связанные с утратой производительности и досрочным выходом на пенсию. Затраты, связанные с диффузной формой заболевания, статистически выше по сравнению с затратами на лимитированную форму СС. Среди клинических проявлений болезни наибольший вклад в экономическое бремя вносят поражения легких и проблемы с ЖКТ.Выводы. CC связана со значительным использованием ресурсов здравоохранения по сравнению с общей популяцией. Экономическое бремя СС значительно возросло за последние годы, и данная тенденция является общемировой. При этом оценить затраты на данное заболевание в РФ затруднительно из-за недостатка информации о российской популяции пациентов