Production of solid dosage forms of immunoglobulin products

At the moment, there are no scientific publications devoted to the technological aspects of production of immunoglobulin solid dosage forms. The aim of the study was to review Russian and foreign literature on production of immunoglobulin solid dosage forms, and present the results of the authors’ own research. The authors analysed data of the National Register of Medicines of the Russian Federation as of mid-2021 on the authorised medicines with a generic name ‘globulin in a solid dosage form’, and summarised their characteristics. They reviewed data on the qualitative and quantitative composition of excipients used in lyophilisation, preparation of tablets and capsules. A number of examples were used to illustrate the effect of technological parameters of immunoglobulin solid form production on the quality of the finished products. It was demonstrated that the production of solid forms of immunoglobulin products prevents aggregation and fragmentation of proteins during storage, which affect the product’s specific activity, and also help to preserve the product’s target characteristics for a longer period of time as compared to liquid dosage forms of immunoglobulins. The results of the study may be used as a basis for development of a manufacturing technology for solid forms of immunoglobulin products

Experimental Substantiation of New Presentation Form of Cholera Diagnostic Sera

Objective of the study is experimental substantiation of possibility to produce new presentation form of cholera diagnostic sera – lyophilizate in bottles. Materials and methods. Cholera diagnostic sera. Liophylization was performed in Martin Christ Epsilon 2-6D. Residual moisture of dry sera was determined using humidity meter Sartorius MA 150. Solubility of experimental samples was assessed visually. pH was evaluated by potentiometry with the help of PK SevenExcellence-475 Mettler Toledo device, measuring pH/ORP/Ion content/conductivity/concentration. Specific activity and specificity was analyzed through expanded agglutination reaction, using relevant control strains of cholera vibrio. Results and conclusions. Experimentally justified is the possibility to lyophilize cholera diagnostic sera in flasks. Specified are the optimum parameters of lyophilization. It is determined that lyophilization does not result in deterioration of properties, as judging by the quality indicators they meet the requirements of regulatory documentation. Using accelerated aging test, it is demonstrated that the new presentation form of cholera diagnostic sera – lyophilizate in flasks – maintains their specific activity within five years term (the set out shelf life), which fully conform to normative standards

Ribosomal profiling as a tool for studying translation in plants: main results, problems and future prospects

The expression of eukaryotic genes can be regulated at several stages, including the translation of mRNA. It is known that the structure of mRNA can affect both the efficiency of interaction with the translation apparatus in general and the choice of translation initiation sites. To study the translated fraction of the transcriptome, experimental methods of analysis were developed, the most informative of which is ribosomal profiling (RP, Ribo-seq). Originally developed for use in yeast systems, this method has been adapted for research in translation mechanisms in many plant species. This technology includes the isolation of the polysomal fraction and high-performance sequencing of a pool of mRNA fragments associated with ribosomes. Comparing the results of transcript coverage with reads obtained using the ribosome profiling with the transcriptional efficiency of genes allows the translation efficiency to be evaluated for each transcript. The exact positions of ribosomes determined on mRNA sequences allow determining the translation of open reading frames and switching between the translation of several reading frames – a phenomenon in which two or more overlapping frames are read from one mRNA and different proteins are synthesized. The advantage of this method is that it provides quantitative estimates of ribosome coverage of mRNA and can detect relatively rare translation events. Using this technology, it was possible to identify and classify plant genes by the type of regulation of their expression at the transcription, translation, or both levels. Features of the mRNA structure that affect translation levels have been revealed: the formation of G2 quadruplexes and the presence of specific motifs in the 5’-UTR region, GC content, the presence of alternative translation starts, and the influence of uORFs on the translation of downstream mORFs. In this review, we briefly reviewed the RP methodology and the prospects for its application to study the structural and functional organization and regulation of plant gene expression

CUTANEOUS MANIFESTATIONS OF ANGIOIMMUNOBLASTIC T-CELL LYMPHOMA

Background: Angioimmunoblast T-cell lymphoma (AITL) is a rare T-cell lymphoproliferative disease that is accompanied by generalized lymphadenopathy, hepatosplenomegaly, intoxication symptoms and extranodal lesions. The extranodal manifestations of the disease frequently involve various skin changes. One of the first such manifestations is maculopapular rashes observed in about half of AITL patients and usually preceding the appearance of lymphadenopathy. Other forms of skin lesions accompany the disease considerably less frequently.Aim: To characterize the range of skin changes in patients suffering from AITL, to establish a correspondence between the nature of skin changes and their histological picture.Materials and methods: 54 AITL patients were being treated at the National Research Centre for Hematology from 2000 to 2017, with the male/female ratio being 30/24. The median age was 61 (29–81) years.Results: Changes in the skin were observed in 24 (44.4 %) of 54 AITL patients, out of whom 18 (75 %) and 6 (25 %) were male and female patients, respectively. Maculopapular rash was observed in 22 (91.7 %) out of 24 patients. The morphological and molecular investigations of skin biopsy specimens exhibiting maculopapular rash demonstrated nonspecific reactive changes. Patients with maculopapular rash demonstrated an increase in the level of total (polyclonal) IgE. Specific skin lesions detected in 8 (14.8 %) cases were represented by a ‘livedo reticularis’, focal skin hyperpigmentation, erythroderma, left eyelid tumour and tumour in 3, 2, 1, 1 and 1 cases, respectively.Conclusion: Maculopapular rash frequently observed in AITL patients is a reactive process not associated with a specific skin lesion. Specific skin lesions in AITL are much less common and can be represented by various forms. In some AITL cases, skin changes of the reactive and tumour nature can be simultaneously observed

Methodological approaches for producing doubled haploids in sugar beet and red beet (Beta vulgaris L.)

The in vitro production of doubled haploids is a biotechnological path of an accelerated development of parental lines in F1-hybrid breeding programs. Unlike the traditional inbreeding method requiring 5 to 6 generations to reach a suf­ficient homozygosity of lines, the number of generations to produce pure lines of beet by haploid technologies is reduced to 2. The production of doubled haploids by gynogenesis is the most common biotechnological approach in sugar and red beets. Protocols for the production of doubled haploids for B. vulgaris species are few and have been developed mainly for sugar beets. There are no protocols for the production of doubled haploids for red beet (B. vulgaris convar. esculenta Salisb.), and the protocols developed for sugar beet (B. vulgaris convar. saccharifera Alef.) are ineffective for red beet, even though these two crops belong to the same species. The greatest success has been achieved in the production of doubled haploids by gynogenesis through isolated ovule culture, especially in sugar beet. Studies on the production of doubled haploids by androgenesis were actively carried out in the 1970s and 1980s and did not lead to the production of regenerated plants. However, at present, there is renewed interest among researchers in this approach, and scientists in different countries are conducting studies of Beta vulgaris androgenesis through isolated microspore culture. This article provides an overview of studies devoted to the production of doubled haploids, addressing the main problems of doubled haploid technologies, and methods to increase the frequency of embryogenesis and doubled haploid plant formation in B. vulgaris crops

Immunoglobulinopathies in patients with angioimmunoblastic T-cell lymphoma

Contex. Angioimmunoblastic T-cell lymphoma (AITL) is a rare form of non-Hodgkins lymphoma, characterized by generalized lymphadenopathy, hepatosplenomegaly and dysproteinemia. Hypergammaglobulinaemia is revealed in 50-83% pts with AITL. However, the characteristics of immunoglobulinopathies observed in AITL are scarce. Objective: The aim of the study was to characterize quantitative and qualitative immunoglobulinopathies in patients with AITL at the onset of the disease. Patients and methods. 55 patients with newly diagnosed AITL were enrolled in the study, the male/female ratio was 30/25; median age was 61 (29-81) years. Diagnosis was based on standard WHO criteria. Immunochemical studies of blood serum included serum protein electrophoresis/immunofixation, nephelometric quantification of total immunoglobulins, serum free light chain assay. Results. Quantitative and qualitative immunoglobulinopathies were determined in 49 (89,1%) of 55 pts. Quantitative immunoglobulinopathies were revealed in 47 (85.5%) of 55 cases, qualitative - in 14 (25,5%). Combination quantitative and qualitative immunoglobulinopathies was observed in 12 (21,8%) of 55 pts. The detected immunoglobulinopathies were divided into 4 groups: polyclonal hypergammaglobulinaemia, hypogammaglobulinaemia, oligoclonal gammapathy, and monoclonal gammapathy. Polyclonal hypergammaglobulinaemia was marked in 41 (74.5%) of 55 pts, elevated level of IgG was determined in 27 (49,15%) of 55 cases, IgM - in 18 (32,7%) and IgA - in 21 (38.2%). Interestingly, polyclonal IgE hypergammaglobulinaemia was detected in 12 (48,0%) of 25 cases of performed studies. Hypogammaglobulinaemia was detected in 8 (14,5%) of 55 cases. Oligoclonal gammapathy was determined in 4 (7.3%) of 55 pts. Monoclonal gammapathy was revealed in 11 (20,0%) of 55 cases. The amount of monoclonal immunoglobulin varied from 2.6 to 14.1 g/l. Monoclonal immunoglobulin Gk was detected in 5 of 11 pts, Gλ - in 2, Mλ - in 2, Mk - in 2. Monoclonal gammapathy was accompanied by polyclonal hypergammaglobulinaemia in 9 of 11 cases, hypogammaglobulinaemia - in 2. Conclusions. Quantitative and qualitative immunoglobulinopathies are observed in most patients at the onset of AITL. Quantitative abnormalities were determined more often than qualitative. Monoclonal gammapathy can be a manifestation of lymphoproliferation and other concomitant disorders. The prognostic value of immunochemical parameters is still unclear and requires dynamic observation and study

First experience of using Brentuximab vedotin and modified program NHL-BFM-90 in the front-line treatment of patient with anaplastic large-cell lymphoma: a case report and a review of literature

Nodal anaplastic ALK-negative large cell lymphoma (nALCL, ALK-) is a Т-cell lymphoma that is characterized by aggressive clinical course and low sensitivity to СНОР (cyclophosphamide, doxorubicin, vincristine, prednisolone) and other chemotherapy regimen. In the article we present a literature review and describe our clinical case of nALCL, ALK-. For the first time a combination of Brentuximab vedotin with modified program NHL-BFM-90 was used as a first-line therapy. As a result of immunochemotherapy a complete antineoplastic effect was obtained. For consolidation of this effect high-dose chemotherapy with following autologous blood stem cell transplantation was performed. The chosen treatment tactics allowed to achieve a complete remission in a medium risk group patient

Получение твердых лекарственных форм препаратов иммуноглобулиновой природы

At the moment, there are no scientific publications devoted to the technological aspects of production of immunoglobulin solid dosage forms. The aim of the study was to review Russian and foreign literature on production of immunoglobulin solid dosage forms, and present the results of the authors’ own research. The authors analysed data of the National Register of Medicines of the Russian Federation as of mid-2021 on the authorised medicines with a generic name ‘globulin in a solid dosage form’, and summarised their characteristics. They reviewed data on the qualitative and quantitative composition of excipients used in lyophilisation, preparation of tablets and capsules. A number of examples were used to illustrate the effect of technological parameters of immunoglobulin solid form production on the quality of the finished products. It was demonstrated that the production of solid forms of immunoglobulin products prevents aggregation and fragmentation of proteins during storage, which affect the product’s specific activity, and also help to preserve the product’s target characteristics for a longer period of time as compared to liquid dosage forms of immunoglobulins. The results of the study may be used as a basis for development of a manufacturing technology for solid forms of immunoglobulin products.На данный момент отсутствуют научные издания, посвященные технологическим вопросам производства твердых лекарственных форм препаратов иммуноглобулиновой природы. Цель работы — обзор отечественной и зарубежной литературы, посвященной вопросам получения твердых лекарственных форм препаратов иммуноглобулиновой природы, а также представление результатов собственных исследований по этому вопросу. Проанализированы сведения Государственного реестра лекарственных средств в Российской Федерации по состоянию на середину 2021 г. о зарегистрированных препаратах с группировочным наименованием — глобулин в твердой лекарственной форме, дана их характеристика. Рассмотрены данные о качественном и количественном составе вспомогательных веществ, используемых при лиофилизации, получении таблеток и капсул. На ряде примеров показано влияние технологических параметров процессов получения твердых лекарственных форм препаратов иммуноглобулиновой природы на качество препаратов. Подтверждено, что получение препаратов иммуноглобулиновой природы в твердой форме предотвращает агрегацию и фрагментацию белков в процессе хранения, негативно влияющих на специфическую активность препарата, а также способствует более длительному сохранению целевых характеристик в сравнении с жидкими иммуноглобулинами. Результаты проведенного анализа могут быть положены в основу при создании технологии изготовления твердых форм препаратов иммуноглобулиновой природы

ВОЗМОЖНОСТИ МЕТОДА УЛЬТРАЗВУКОВОГО ИССЛЕДОВАНИЯ В РАННЕЙ ДИФФЕРЕНЦИАЛЬНОЙ ДИАГНОСТИКЕ ТУБЕРКУЛЕЗА ЛИМФАТИЧЕСКИХ УЗЛОВ

In the past decade, there has been a significant increase in the prevalence tuberculosis of the peripheral lymph nodes. This is the reason for improvement the methods of medical imaging of the tuberculous lymphadenitis. The most informative methods include a morphological study of tuberculosis of lymph node biopsy. The article presents the results of ultrasound investigations in detecting early changes in tuberculous lymphadenitis. The results of ultrasound examination were compared to the multislice-computed tomography (MSCT), findings of histological examination and autopsy.Рост удельного веса туберкулеза периферических лимфатических узлов в структуре заболеваемости внелегочным туберкулезом в последнее десятилетие является существенной проблемой, требующей совершенствования методик лучевой диагностики, так как на сегодняшний день наиболее информативным методом является морфологическое исследование патологического материала. В статье представлены результаты возможностей ультразвукового метода в выявлении ранних туберкулезных изменений в лимфатических узлах на стадии образования туберкулезной гранулемы у детей и взрослых с подозрением на туберкулез лимфатических узлов. Выявлены ультразвуковые изменения в структуре лимфатических узлов, которые могут служить специфическими маркерами стадий протекания туберкулезного процесса. Результаты ультразвукового исследования были сопоставлены с данными мультиспиральной компьютерной томографии (МСКТ), заключениями гистологического исследования и аутопсии