Variation in intravenous iron use internationally and over time: the Dialysis Outcomes and Practice Patterns Study (DOPPS)

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The Foundations of the Development of Technologies of the Synthesis of Radiopharmaceuticals

The selection of precursors (for example chelating agents) and development of a technique of chemical modification of the target molecules retaining its ability to bind to specific receptors are very important in the synthesis of radiopharmaceuticals. As some important precursors for target radiopharmaceuticals omega-iodo-aliphatic carboxylic acids and their esters can be used. We have developed an environmentally safe process for producing omega-iodoaliphatic carboxylic acids and their esters of the available, inexpensive and low toxic aliphatic cyclic ketones. We proposed a new method for the synthesis of the chelating agents omega-thia- or (bis(2-hydroxyethyl)amino)- aliphatic carboxylic acids (chelate 1 and chelate 2), which was caused by the existing disadvantages in the existing methods. Thus, based on our method the precursors (chelates) with yield of over 70-90% on the final stage were synthesized, and then the high effectiveness in producing target radiopharmaceuticals using different biomolecules was showed. 99mTc-chelates complexes were prepared with radiochemical purity >91% and found to be stable at room temperature for six hours

In Vitro Evaluation of a Specific Radiochemical Compound Based on 99mTc-labeled DARPinG3 for Radionuclide Imaging of Tumors Overexpressing Her-2/neu

It is still necessary to search for new informative diagnostic methods to detect malignant tumors with overexpression of Her-2/neu, which are characterized by the aggressive course of the disease, rapid rate of tumor growth and low rates of relapse-free and overall survival. In recent years, the radioisotope techniques for detection of specific tumor targets have been developing actively. Purpose: to develop a chemically stable radiochemical compound for the targeted imaging of cells overexpressing Her-2/neu. Material and methods: The study was performed using 2 cell lines .The human breast adenocarcinoma HER2-overexpressing cell line BT-474 was chosen to detect specific binding. As a control, HER2-negative human breast adenocarcinoma MCF-7 was used. The human breast adenocarcinoma BT-474 and MCF-7 cell lines were seeded in chamber-slides at the density of 35,000 cells/ml in trypsin-EDTA (PanEco) medium and grown overnight at 37°C. After that both cell lines were washed with Phosphate buffered saline (PBS) and distributed into test tubes to 1 ml (5 millions cells in each). After adding 100 [mu]l (70 MBq) studied complex of 99mTc-DPAH-DARPinG3 was incubated for 40 min at +4°C. Washing was performed three times with buffer PBS and 5% Bovine Serum Albumin (BSA). The characteristics of the binding specificity of the test set with the HER-2/neu receptor were determined by direct radiometric and planar scintigraphy. Nonparametric Mann-Whitney test was used to assess the differences in the quantitative characteristics between groups. Results: The output of the labeled complex was more than 91%, with a radiochemical purity of more than 94%. When carrying out a visual scintigraphic assessment much greater intensity accumulation of radiotracer was observed in the studied cell culture surface receptor overexpressing Her-2/neu. The results of direct radiometric also showed higher accumulation of the radiopharmaceutical in the adenocarcinoma cell line BT-474 human breast cancer overexpressing Her-2/neu compared to the control group. Conclusion: The preclinical studies demonstrated a high in vitro stability of the study compound, as well as its accumulation in the cell group overexpressing Her-2/neu

Possibilities of radionuclide visualization of HER2/neu-positive breast cancer using a radiopharmaceutical based on recombinant targeting molecules DARPin9_29

Epidermal growth receptor HER2/neu is still of great interest, the overexpression of which is most often observed in patients with breast cancer and accounts for 15–20 % of cases. Present methods of HER2/neu determination have a number of significant drawbacks. In recent years, alternative framework proteins are used for the targeted radionuclide imaging. Molecules of DARPin (Design Ankyrin Repeat Protein) are one of representatives of scaffolds. Material and methods. The study included 4 breast cancer patients (T1-2N0-1M0) who were not receiving systemic therapy at the time of the study: in 2 patients, HER2/neu overexpression was noted, in 2 patients – not detected. HER2/neu status was determined using an immunohistochemical method and a FISH assay. At the preclinical stage, radiopharmaceutical 99mTc-DARPin9_29 was injected intravenously to all patients, «WholeBody» scintigraphy and single-photon emission computed tomography were performed 2 hours after injection. Results. The distribution of radiopharmaceuticals in organs 2 hours after injection revealed the greatest accumulation in the liver and kidneys. In studying of tumor/background indicator it was revealed that values of the studied parameter in patients with overexpression of HER2 receptors are more than 3 times higher than the values in the subgroup of patients with negative expression of this marker. Conclusion. According to the results of preliminary studies, the 99mTc-DARPin9_29 demonstrated significant differences between tumors with and without HER2/neu overexpression

Research of effectiveness of natural and modified sorbents for wastewater treatment based on mica quartzite treatment waste

Results of a research of efficiency of sorbents on the basis of the waste of production and processing of micaceous quartzites (MQ), montmorillonite clays (MC) modified by humic connections (HC), received by extraction of waste brown coal are shown. Chemical composition of mica quartzite processing waste depending on the fraction size was previously investigated: element structure by method of the power-dispersive X-ray fluorescent analysis and mineral structure by method of X-ray phase analysis, for purpose of interrelation establishment between the structure of fraction and adsorptive properties of the received composite sorbents and also for the purpose of an exception as a part of MQ and, respectively, a sorbent of dangerous and toxic substances I-III of hazard classes. The efficiency of adsorption of the obtained sorbents was studied, an increase in sorption activity was found depending on composition of sorbent and method of modification (preliminary temperature processing and drawing on a surface of a sorbent of HC nano- and a microdimensional layer). It is determined that the greatest efficiency of adsorption of ions of heavy metals is observed for the sorbent which underwent temperature modification at 800о C and then HC covered with a layer up to 1% of masses. Use of waste of MQ containing 40–60% of quartz (SiO2) in composition with MC and with further modification of a surface (up to 1% of masses.) humic connections will allow receiving highly effective, universal and inexpensive sorbents for sewage treatment from heavy metals and other pollutants. The offered composite sorbents will allow to solve several ecologically important problems in a complex: to carry out effective purification of industrial sewage (machine and instrument-making, metallurgical, petrochemical and other enterprises) of heavy metals ions and to utilize waste of micaceous quartz processing of and brown coal extraction

Analysis of the renewal of assortment portfolios in the pharmaceutical production sector of the Ural federal district

The purpose of the study is to evaluate the assortment structure of the renewal of industrial assortment portfolios of medicines in the Ural Federal District to assess the contribution of regional manufacturers to meet demand in the domestic pharmaceutical market.Цель исследования — оценить ассортиментную структуру обновления промышленных ассортиментных портфелей лекарственных препаратов в УрФО для оценки вклада региональных производителей в покрытие спроса на отечественном фармацевтическом рынке

Альтернативные каркасные белки в радионуклидной диагностике злокачественных образований

This review discusses a relatively new class of targeted molecules that is being actively studied for radionuclide diagnosis and treatment of malignancies. The full-size antibodies used so far have non-optimal pharmacological properties, slow distribution in the body, poor penetration into the tissue and kidney excretion, and high immunogenicity, which significantly complicates their use in clinical practice. Over the past decade, a new class of targeted molecules, called “non-immunoglobulin scaffolds” have become popular; they have all the requirements for optimal delivery of a radionuclide to tumor cells. Scaffolds usually are smaller in size in comparison with antibodies, but they are larger than peptides, and are characterized by high affinity and optimal biochemical, biophysical, biological, and economic features. The advantages of such proteins are their stable structure, good penetration into tissues, the possibility of additional functionalization and expression in the bacterial system, which ensures low production costs.The results of preclinical and clinical studies for diagnosis of malignancies using such proteins as affibody, adnectin, DARPins, etc., have demonstrated their high specificity, affinity, good tolerance and low immunogenicity. В настоящем обзоре обсуждается относительно новый класс направленных адресных молекул, активно исследующийся в отношении радионуклидной диагностики и лечения злокачественных образований. Используемые до настоящего времени полноразмерные антитела обладают неоптимальными фармакологическими свойствами, медленным распределением в организме, плохим проникновением в ткани, выведением почками и высокой иммуногенностью, что существенно затрудняет их применение в клинической практике. В течение последнего десятилетия большую популярность приобретают таргетные молекулы, получившие название «альтернативные каркасные белки» (АКБ) или «скаффолды» и отвечающие всем требованиям для оптимальной доставки радионуклида к опухолевым клеткам. Обычно АКБ имеют меньшие размеры по сравнению с антителом, но большие, чем пептиды, и характеризуются высокой аффинностью и оптимальными биохимическими, биофизическими, биологическими и экономическими характеристиками. Преимуществами таких белков являются их стабильная структура, хорошее проникновение в ткани, возможность дополнительной функционализации и ýкспрессия в бактериальной системе, обеспечивающая низкую стоимость производства.Результаты проведенных к настоящему моменту доклинических и клинических исследований для диагностики злокачественных образований с использованием таких представителей АКБ, как аффибоди, аднектин, дарпины и пр., продемонстрировали высокую специфичность, аффинность, хорошую переносимость и низкую иммуногенность используемых препаратов.

Способ получения и изучение биологических свойств меченной йодом-123 производной аминоглюкозы

Search and synthesis of glucose derivatives for nuclear medicine is of great current interest. Being a promising analogue of glucose, D-glucosamine iodine labeled glucose derivatives can be applied in rheumatoid arthritis radionuclide diagnostics and therapy as a radiopharmaceutical.The purpose of the study. Synthesis of a new iodine labeled D-glucosamine derivative; development of the iodine-123 labeling method and the obtained glucose derivative biostudy.Materials and methods. Synthesis of 2-N-(6-iodohexanoyl)-D-glucosamine was carried out through established techniques in organic chemistry. Infrared spectroscopy and nuclear magnetic resonance spectroscopy were used to establish the test compound structure. Isotope change between iodine-127 and iodine-123 of glucosamine derivative was conducted using the heating of mix of the compound and Na123I in acetone. The radio-TLC method was applied to estimate the radiochemical purity of 2-N- (6-iod-123-hexanoyl) -D-glucosamine. The safe application and test of drug pharmacokinetic parameters study was performed on intact Wistar male rats.Results. An original 2-N-(6-iodohexanoyl)-D-glucosamine synthesis method was proposed. According to the method, an intermediate synthesis succimide-1-yl 6-iodohexanoate was obtained by the cyclohexanone oxidative cleavage reaction. The radiochemical purity of 2-N-(6-iodo-123-hexanoyl)-D-glucosamine was more than 97%.Conclusion. 2-N-(6-iodohexanoyl)-D-glucosamine was synthesized and iodine-123 labeled. When investigating the proposed radiopharmaceutical safety and pharmacokinetics, it was shown the drug lacks acute toxicity through intravenous injection and is excreted renally by glomerular filtration.В настоящее время являются актуальными поиск и синтез производных глюкозы для ядерной медицины. В последние годы D-глюкозамин является перспективным аналогом глюкозы, модифицированные йодпроизводные которого, возможно, могут быть применены в радионуклидной диагностики, и радиойодтерапии ревматоидного артрита в качестве радиофармацевтического препарата (РФП).Цель исследования. Синтез нового йодсодержащего производного D-глюкозамина, разработка методики его мечения йодом-123 и биологическое изучение свойств полученного препарата.Материалы и методы. Синтез 2-N-(6-йодгексаноил)-D-глюкозамина проводили с использованием общепринятых приемов в органической химии. Для установления структуры исследуемого соединения использовали инфракрасную спектроскопию и спектроскопию ядерно-магнитного резонанса. Изотопный обмен стабильного йода-127, присутствующего в алифатической цепи, на его радиоактивный аналог – йод-123 проводили при нагревании смеси полученного производного D-глюкозамина с натрий йодидом Na123I в ацетоне с последующим синтезом в твердой фазе. Для оценки радиохимической чистоты 2-N-(6-йод123гексаноил)-D-глюкозамина использовали метод хроматографии в тонком слое сорбента. Изучение безопасности применения и фармакокинетических параметров исследуемого препарата производилось на интактных самцах крыс линии Вистар.Результаты. Была предложена оригинальная методика синтеза 2-N-(6-йодгексаноил)-D-глюкозамина, по которой промежуточный продукт синтеза сукцимид-1-ил 6-йодгексаноат был получен по реакции окислительного расщепления циклогексанона, являющейся экологически безопасной. Радиохимическая чистота 2-N-(6-йод123гексаноил)-D-глюкозамина составила более 97%. Заключение. Синтезирован 2-N-(6-йодгексаноил)-D-глюкозамин и проведено его мечение йодом-123. При исследовании безопасности применения и изучении фармакокинетики предлагаемого РФП было показано, что препарат не обладает острой токсичностью при внутривенном введении и выводится почками путем клубочковой фильтрации

Разработка способа получения производного октреотида для диагностики нейроэндокринных опухолей

Currently the development of technologies for labeling somatostatin with technetium-99m for diagnosing radionuclide neuroendocrine tumors is under way. Somatostatin analogues are binded with technetium99m only by the preliminary addition of a chelating agent. Therefore, it is important to develop a method for preparation of an octreotide derivative by modifying octreotide with precursors: ligands with high chelating ability for its tight binding with technetium-99m. ω-Bis(pyridin-2-ylmethyl)amino)aliphatic acids can be used successfully as such precursors.The purpose of the study was to develop a method for obtaining a new octreotide derivative for diagnosing neuroendocrine tumors.Materials and methods. The somatostatin octreotide analogue was used as the object of the study; succinimid-1-yl 6-(bis(pyridin-2-ylmethyl)amino)hexanoate was used as a chelating agent. Methods of high performance liquid chromatography and mass spectrometry were used to separate and analyze the synthesized compounds.Results. A method to produce an original octreotide derivative using a succinimid-1-yl 6-(bis(pyridin2-ylmethyl)amino)hexanoate as a chelating agent was proposed. The conditions of analytical and semipreparative HPLC for the analysis and purification of the active octreotide derivative (a monosubstituted derivative of the amino acid residue of D-phenylalanine) were suggested.Conclusion. The synthesized derivative of octreotide has a chelating center for strong binding to technetium-99m in its structure, which can be useful for diagnosing neuroendocrine tumors. Введение. В настоящее время разработка технологии мечения аналогов соматостатина технецием99м (99mTc) для радинуклидной диагностики нейроэндокринных опухолей активно проводится по всему миру. Аналоги соматостатина, к которым относится октреотид, связываются с 99mTc только путем предварительного присоединения к ним хелатирующего агента. Поэтому актуальным является модификация октреотида прекурсорами с высокой хелатирующей способностью для прочного связывания 99mTc. В качестве таких прекурсоров успешно могут применяться ω-бис(пиридин-2- илметил)амино)алифатические кислоты.Цель исследования. Разработка способа получения нового производного октреотида, пригодного для диагностики нейроýндокринных опухолей.Материалы и методы. В качестве объекта исследования использовали октреотид – аналог соматостатина. В качестве бифункционального хелатирующего агента использовали сукцинимид-1-ил 6-(бис(пиридин-2-илметил)амино)гексаноат, синтезированный по модифицированной методике с учетом специфики агента. Для разделения и анализа синтезированных соединений применяли методы высокоýффективной жидкостной хроматографии и масс-спектрометрии.Результаты исследования. Предложен способ получения производного октреотида с применением хелатирующего агента сукцинимид-1-ил 6-(бис(пиридин-2-илметил)амино)гексаноата в среде 10 ммоль PBS (рН = 6,0) с добавлением 20%-го ацетонитрила в течение 24 ч. Разработаны условия для анализа и очистки активного производного октреотида с использованием аналитической и полупрепаративной жидкостной хроматографии.Заключение. Впервые в результате модификации октреотида по остатку D-фенилаланина создан центр хелатирования для технеция-99м на основе ω-бис(пиридин-2-илметил)амино)алифатических кислот. Производное октреотида является перспективным для дальнейшего изучения его функциональной пригодности для диагностики нейроэндокринных опухолей.