Способ получения соли олигогексаметиленгуанидина высокой степени чистоты

Objectives. Given that microorganisms can become resistant to certain groups of drugs and considering also their ability to form biofilms, the development of new drugs that are active against adapted microflora is required. This study focused on the development of a new method for the synthesis of a promising compound, the branched hydrosuccinate oligohexamethylene guanidine (OHMGsucc), with high purity that meets the standards of the 14th edition State Pharmacopeia of the Russian Federation (SPRF). Previously proposed methods have managed to isolate this product, which, however, complies with the requirements of the outdated SPRF. Therefore, the main aim of this study was to update the regulatory framework for the indicated OHMG salt for its further use in the pharmaceutical industry according to modern standards.Methods. To control the residual impurities of hexamethylenediamine (HMDA) and guanidine hydrochloride (GHC), high-performance liquid chromatography (HPLC) was applied using a Thermo Scientific Dionex UltiMate 3000 chromatograph, and the chromatographic signals of the test solution with those of a standard sample solution obtained by a previously published conventional method were compared.Results. The HPLC experimental data indicated a significant difference in the quantitative content of HMDA and GHC observed for the new and older preparation method of the branched OHMGsucc, suggesting that the method disclosed in this article can be used to obtain highly pure OHMGsucc.Conclusions. The specified compound was standardized with the parameter “related impurities” according to the current (14th) edition of the SPRF. The effectiveness and reproducibility of the proposed method was experimentally confirmed. In addition, a process diagram for the preparation of the indicated OHMG salt was prepared.Цели. На фоне приобретения микроорганизмами резистентности к определенным группам лекарственных средств, а также способностей образовывать биопленки, требуются новые препараты, активные против адаптированной микрофлоры. Cтатья посвящена изысканию способа получения перспективного соединения – разветвленного гидросукцината олигогексаметиленгуанидина с высокой степенью чистоты, соответствующей нормам Государственной Фармакопеи 14 издания. Так как предложенные ранее методы позволяли получить продукт, удовлетворяющий требованиям устаревшей Государственной Фармакопеи, то основной целью являлась актуализация нормативной базы в отношении указанной соли олигогексаметиленгуанидина для ее дальнейшего применения в фармацевтической отрасли согласно современным стандартам.Методы. Для контроля примесных соединений – гексаметилендиамина и гуанидина гидрохлорида применяли высокоэффективную жидкостную хроматографию, которую проводили на хроматографе Thermo Scientific Dionex UltiMate 3000 методом внешнего стандарта.Результаты. На основании экспериментальных данных, полученных с помощью высокоэффективной жидкостной хроматографии, отображена разница в количественном содержании остаточных примесей в составе субстанции разветвленного гидросукцината олигогексаметиленгуанидина, полученной двумя разными способами. Отмечено, что способ, предложенный авторами настоящей статьи, позволяет снизить их содержание по сравнению с конвенциональным методом.Выводы. Согласно представленным данным проведена стандартизация указанного соединения по параметру «Родственные примеси» в соответствии с актуальным на данный момент изданием Государственной Фармакопеи. Вследствие того, что эффективность предложенного метода экспериментально подтвердилась, на заключительном этапе работы была составлена технологическая схема получения указанной соли олигогексаметиленгуанидина

Реализация фармацевтической разработки с применением многофакторного анализа многокритериальной оптимизации на примере этапа очистки гидросукцината олигогексаметиленгуанидина

Objectives. The study set out to use mathematical modeling, in particular the method of multifactorial analysis of multicriteria optimization (MAMO), in the development of a pharmaceutical product.Methods. After carrying out experimental tests based on the proposed algorithmic sequence, the obtained data were interpreted using MAMO.Results. The possibility of using MAMO to solve the applied problem of purifying oligohexamethyleneguanidine hydrosuccinate (OHMG-HS), considered as a pharmaceutical precursor for the creation of medicines, was demonstrated.Conclusions. The expediency of using the proposed algorithm as a tool for pharmaceutical development is substantiated by identifying dependencies of the influence of purification conditions on the final content of admixtures in the target product.Цели. Данное исследование посвящено использованию математического моделирования, в частности метода многофакторного анализа многокритериальной оптимизации (МАМО), в фармацевтической разработке.Методы. В ходе исследования была предложена алгоритмическая последовательность эксперимента и проведены необходимые испытания. Полученные данные были интерпретированы при помощи МАМО.Результаты. Изучена возможность применения МАМО для решения прикладной проблемы очистки гидросукцината олигогексаметиленгуанидина (ОГМГ-ГС), рассматриваемого в качестве фармацевтической субстанции для создания лекарственных средств.Выводы. Были выявлены зависимости влияния условий очистки на конечное содержание примесей в целевом продукте и доказана целесообразность использования предложенного алгоритма в качестве инструмента фармацевтической разработки

Investigation of oncolytic potential of vaccine strains of yellow fever and tick-borne encephalitis viruses against glioblastoma and pancreatic carcinoma cell lines

Introduction. Flaviviruses, possessing natural neurotropicity could be used in glioblastoma therapy using attenuated strains or as a delivery system for antitumor agents in an inactivated form. Objective. To investigate the sensitivity of glioblastoma and pancreatic carcinoma cell lines to vaccine strains of yellow fever and tick-borne encephalitis viruses. Materials and methods. Cell lines: glioblastoma GL-6, T98G, LN-229, pancreatic carcinoma MIA RaCa-2 and human pancreatic ductal carcinoma PANC-1. Viral strains: 17D yellow fever virus (YF), Sofjin tick-borne encephalitis virus (TBEV). Virus concentration were determined by plaque assay and quantitative PCR. Determination of cell sensitivity to viruses by MTT assay. Results. 17D YF was effective only against pancreatic carcinoma tumor cells MIA Paca-2 and had a limited effect against PANC-1. In glioblastoma cell lines (LN229, GL6, T98G), virus had no oncolytic effect and the viral RNA concentration fell in the culture medium. Sofjin TBEV showed CPE50 against MIA Paca-2 and a very limited cytotoxic effect against PANC-1. However, it had no oncolytic effect against glioblastoma cell lines (LN229, T98G and GL6), although virus reproduction continued in these cultures. For the GL6 glioblastoma cell line, the viral RNA concentration at the level with the infection dose was determined within 13 days, despite medium replacement, while in the case of the LN229 cell line, the virus concentration increased from 1 × 109 to 1 × 1010 copies/ml. Conclusion. Tumor behavior in organism is more complex and is determined by different microenvironmental factors and immune status. In the future, it is advisable to continue studying the antitumor oncolytic and immunomodulatory effects of viral strains 17D YF and Sofjin TBEV using in vivo models

An effective method for preparation of high purity oligohexamethylene guanidine salts

Objectives. Given that microorganisms can become resistant to certain groups of drugs and considering also their ability to form biofilms, the development of new drugs that are active against adapted microflora is required. This study focused on the development of a new method for the synthesis of a promising compound, the branched hydrosuccinate oligohexamethylene guanidine (OHMGsucc), with high purity that meets the standards of the 14th edition State Pharmacopeia of the Russian Federation (SPRF). Previously proposed methods have managed to isolate this product, which, however, complies with the requirements of the outdated SPRF. Therefore, the main aim of this study was to update the regulatory framework for the indicated OHMG salt for its further use in the pharmaceutical industry according to modern standards.Methods. To control the residual impurities of hexamethylenediamine (HMDA) and guanidine hydrochloride (GHC), high-performance liquid chromatography (HPLC) was applied using a Thermo Scientific Dionex UltiMate 3000 chromatograph, and the chromatographic signals of the test solution with those of a standard sample solution obtained by a previously published conventional method were compared.Results. The HPLC experimental data indicated a significant difference in the quantitative content of HMDA and GHC observed for the new and older preparation method of the branched OHMGsucc, suggesting that the method disclosed in this article can be used to obtain highly pure OHMGsucc.Conclusions. The specified compound was standardized with the parameter “related impurities” according to the current (14th) edition of the SPRF. The effectiveness and reproducibility of the proposed method was experimentally confirmed. In addition, a process diagram for the preparation of the indicated OHMG salt was prepared

Wellness and Coping of Physicians Who Worked in ICUs During the Pandemic: A Multicenter Cross-Sectional North American Survey*

ObjectivesFew surveys have focused on physician moral distress, burnout, and professional fulfilment. We assessed physician wellness and coping during the COVID-19 pandemic.DesignCross-sectional survey using four validated instruments.SettingSixty-two sites in Canada and the United States.SubjectsAttending physicians (adult, pediatric; intensivist, nonintensivist) who worked in North American ICUs.InterventionNone.Measurements and main resultsWe analysed 431 questionnaires (43.3% response rate) from 25 states and eight provinces. Respondents were predominantly male (229 [55.6%]) and in practice for 11.8 ± 9.8 years. Compared with prepandemic, respondents reported significant intrapandemic increases in days worked/mo, ICU bed occupancy, and self-reported moral distress (240 [56.9%]) and burnout (259 [63.8%]). Of the 10 top-ranked items that incited moral distress, most pertained to regulatory/organizational ( n = 6) or local/institutional ( n = 2) issues or both ( n = 2). Average moral distress (95.6 ± 66.9), professional fulfilment (6.5 ± 2.1), and burnout scores (3.6 ± 2.0) were moderate with 227 physicians (54.6%) meeting burnout criteria. A significant dose-response existed between COVID-19 patient volume and moral distress scores. Physicians who worked more days/mo and more scheduled in-house nightshifts, especially combined with more unscheduled in-house nightshifts, experienced significantly more moral distress. One in five physicians used at least one maladaptive coping strategy. We identified four coping profiles (active/social, avoidant, mixed/ambivalent, infrequent) that were associated with significant differences across all wellness measures.ConclusionsDespite moderate intrapandemic moral distress and burnout, physicians experienced moderate professional fulfilment. However, one in five physicians used at least one maladaptive coping strategy. We highlight potentially modifiable factors at individual, institutional, and regulatory levels to enhance physician wellness