Reduction of hepatotoxicity of nimesulide in mechanochemically obtained composition with disodium salt of glycyrrhizic acid

Nimesulide (NIM) is a nonsteroid anti-inflammatory drug which acts as a selective cyclooxygenase 2 inhibitor and is widely used for acute pain treatment. In medical practice, a large amount of data has been collected describing the effect of NIM on the body, while a hepatotoxic side effect of the drug has been found. The exact mechanisms of such NIM-induced hepatotoxicity largely remain unknown but likely involve the intermediate reaction of its metabolism. Reduction of the hepatotoxic side effect of NIM is an actual problem for pharmacology. The aim of the present research was to evaluate the hepatotoxicity of the mechanochemically obtained composition of NIM with glycyrrhizic acid disodium salt (Na2GA) compared to pure NIM and a physical mixture of NIM with Na2GA. Material and methods. CD-1 mice were orally administered for 14 days: 1 group – mechanochemical composition NIM/Na2GA (1:10, m/m) at a dose of 1650 mg/kg; 2 group – physical mixture of NIM with Na2GA (1:10, m/m) at a dose of 1650 mg/kg; 3 group – pure NIM at a dose of 600 mg/kg (which pharmacokinetically corresponds to 1650 mg/kg of NIM/Na2GA); 4 group – vehicle (distilled water). The liver damage was assessed using histological studies and enzymatic activity of the alanine aminotransferase and aspartate aminotransferase in blood serum. Results. Histological analysis did not detect any changes in the liver of NIM/Na2GA-treated animals in comparison with a water-treated group. On the opposite, NIM given alone or as a physical mixture with Na2GA induced severe hepatotoxicity in experimental mice. Biochemical analysis of the blood serum revealed that mechanochemical NIM/Na2GA composition significantly reduced activity of the alanine aminotransferase (about 1.5 times) and aspartate aminotransferase (1.3 times) as compared with the pure NIM. Conclusions. The results obtained indicate a high potential for the practical application of the NIM/Na2GA mechanochemical composition

Development and laboratory production of virus-like immune-stimulating complexes based on saponins and evaluation of their adjuvant potential using mice immunisation with influenza antigens

The COVID-19 pandemic has exacerbated the public’s need for effective vaccines. Consequently, significant financial support has been provided to developers of a number of innovative vaccines, including the vaccines with saponin-based adjuvants. In 2021, the World Health Organisation recommended Mosquirix, the first malaria vaccine, which contains a saponin adjuvant. An anti-covid vaccine by Novavax is in the approval phase. A promising approach to vaccine development is presented by the use of virus-like immune-stimulating complexes (ISCOMs) containing saponins and by the creation of combinations of ISCOMs with antigens. The aim of the study was to develop, produce and characterise virus-like immune-stimulating complexes based on saponins of Quillaja saponaria, as well as similar saponins of Russian-sourced Polemonium caeruleum. Materials and methods: The ISCOM adjuvants, Matrix-BQ and Matrix-BP, were produced using liquid chromatography and examined using electron microscopy. Balb/c mice were immunised intraperitoneally and intramuscularly with ISCOM-antigen preparations. Afterwards, the immunised animals were challenged with the influenza virus strain, A/California/4/2009(H1N1)pdm09, adapted and lethal to mice. The serum samples were examined using haemagglutination inhibition (HI) tests. Results: The authors produced the ISCOMs containing saponins of Quillaja saponaria and Polemonium caeruleum. After one intramuscular injection of either of the ISCOM-antigen preparations with 1 µg of each of A/Brisbane/02/2018 (H1N1) pdm09, A/Kansas/14/2017 (H3N2), and B/Phuket/3073/2013 haemagglutinin antigens (HAs), HI tests detected serum antibody titres to the corresponding antigens of ≥1:40. Two intramuscular injections of the ISCOM-antigen preparation containing 50 ng of each of the HAs and Matrix-BQ resulted in a protective response. In some animals, two intraperitoneal injections of ISCOM-antigen preparations resulted in the maximum antibody titre to the A/Kansas/14/2017 (H3N2) vaccine strain of 1:20,480. Two intramuscular injections of a test preparation containing 5 µg, 1 µg, 200 ng, or 50 ng of each of the HAs and Matrix-BQ or a control preparation containing 5 µg, 1 µg, or 200 ng of each of the HAs (commercially available vaccines) to the mice that were afterwards infected with the lethal influenza strain protected the experimental animals from death. Conclusions: The ISCOM-based preparations had high immunostimulatory activity in the mouse-model study. The presented results indicate the potential of further studies of ISCOM-based preparations in terms of both vaccine and immunotherapeutic development

Overview of the Epidemiological Situation on Highly Pathogenic Avian Influenza Virus in Russia in 2018

Analyzed was modern epidemiological situation on highly pathogenic avian flu in 2018. Prognosis for possible further distribution of viruses in the territory of Russia was made. In 2018, the situation on highly pathogenic avian flu in Russia was challenging. This was due to the spread of the viruses clade 2.3.4.4, which caused multiple outbreaks among wild birds and poultry in European part of Russia. In addition, A/H5N6 avian influenza virus circulation was for the first time detected in the Saratov Region during routine avian influenza virus surveillance. In May, 2018 two different lineages of avian influenza A/H9N2 were isolated during the outbreaks that occurred at several poultry plants in Primorsk Territory and Amur Region of Russia. Subsequently, that virus subtype continued spreading in Russia, which was recorded by detection of the A/H9N2 influenza virus in wild birds in the Khabarovsk and Tomsk Regions of Russia. Thus, it is shown yet again that the territory of Russia plays an  important geographical role in the spread of avian influenza viruses

Experimental infection of H5N1 HPAI in BALB/c mice

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The efficacy of complex solid dispersions of anthelmintics against experimental trichinellosis

The purpose of the research is to study the influence of various technological factors on obtaining of complex solid dispersions of anthelmintics with polyvinylpyrrolidone and licorice extract on anthelmintic efficacy in experimental trichinellosis of white mice.Materials and methods. The study of the nematodocidal activity of complex solid dispersions samples based on fenbendazole (FBZ), fenasal (FNS) and praziquantel (PZQ) with polyvinylpyrrolidone (PVP) and licorice extract (LE) obtained by mechanochemical technology at different ratios of components and different exposure times was carried out on 130 white mice experimentally infected with Trichinella spiralis in two experiments. On the 3rd day after infection, the animals were divided into experimental groups of 10 animals each. Samples of various complex solid dispersions of anthelmintics were administered intragastrically to the mice of the experimental groups at a dose of 2 mg/kg according to the active substance. FBZ substance was used as the basic drug at a dose of 2 mg/kg according to the active substance. Animals of the control groups did not receive the drugs. The animals were killed by decapitation on the 4th day after experimental drug samples administration, and the activity of the drugs was counted according to the results of helminthological necropsy of the intestine, the efficacy was calculated by the type of control test.Results and discussion. The efficacy of complex solid dispersions of FBZ and FNS with PVP polymer was higher in comparison with the activity of complexes with LE at the same duration of mechanochemical treatment in a roller mill. The FBZ activity decreased from 67.05 to 37.77% with a decrease in the duration of mechanochemical treatment from 24 h to 5 h and the efficacy of the FBZ : FNS complex with LE turned out to be almost at the level of the basic drug when treated for 1 h. The use of mechanochemical technology for obtaining of a solid dispersion of FBZ : FNS with PVP for targeted delivery makes it possible to increase the anthelmintic efficacy by 2.7 times compared with the activity of the FBZ substance, and with LE by 2.2 times. It was noted that complex solid dispersions of PBZ with PZQ have lower biological activity in comparison with compositions of FBZ with FNS

Thyroid cancer risk in Belarus among children and adolescents exposed to radioiodine after the Chornobyl accident

BACKGROUND: Previous studies showed an increased risk of thyroid cancer among children and adolescents exposed to radioactive iodines released after the Chornobyl (Chernobyl) accident, but the effects of screening, iodine deficiency, age at exposure and other factors on the dose-response are poorly understood. METHODS: We screened 11 970 individuals in Belarus aged 18 years or younger at the time of the accident who had estimated (131)I thyroid doses based on individual thyroid activity measurements and dosimetric data from questionnaires. The excess odds ratio per gray (EOR/Gy) was modelled using linear and linear-exponential functions. RESULTS: For thyroid doses \u3c5 \u3eGy, the dose-response was linear (n=85; EOR/Gy=2.15, 95% confidence interval: 0.81-5.47), but at higher doses the excess risk fell. The EOR/Gy was significantly increased among those with prior or screening-detected diffuse goiter, and larger for men than women, and for persons exposed before age 5 than those exposed between 5 and 18 years, although not statistically significant. A somewhat higher EOR/Gy was estimated for validated pre-screening cases. CONCLUSION: 10-15 years after the Chornobyl accident, thyroid cancer risk was significantly increased among individuals exposed to fallout as children or adolescents, but the risk appeared to be lower than in other Chornobyl studies and studies of childhood external irradiation

CHARACTERIZATION OF AVIAN INFLUENZA H5N8 VIRUS STRAINS THAT CAUSED THE OUTBREAKS IN THE RUSSIAN FEDERATION IN 2016–2017

Objective of the study is to investigate biological properties of avian influenza virus strains that caused the outbreaks in Russia in 2016–2017.Materials and methods. The study was performed using advanced virological and molecular-biological methods in state-of-the-art equipment.Results and conclusion. In 2016, the outbreaks among wild birds and poultry caused by highly pathogenic avian influenza H5N8 virus have occurred in the territory of the Russian Federation. In May, 2016 an outbreak of H5N8 among wild birds was registered in the territory of the Republic of Tyva. In October-November, 2016 influenza virus H5N8 was isolated in the territory of the Republics of Tatarstan and Kalmykia, Krasnodar and Astrakhan Regions of Russia. In 2017 avian influenza H5N8 has become widespread in European part of Russia and caused multiple outbreaks among wild birds and poultry. Results of the investigations of the isolated strains show that all of them are highly pathogenic and belong to the clade 2.3.4.4. Molecular-genetic and virological analysis has revealed the differences between the viruses isolated in 2016–2017 and the virus of the same clade 2.3.4.4 that was isolated in 2014

Разработка и лабораторное получение вирусоподобных иммуностимулирующих комплексов на основе сапонинов, оценка их адъювантных свойств при иммунизации мышей гриппозными антигенами

The COVID-19 pandemic has exacerbated the public’s need for effective vaccines. Consequently, significant financial support has been provided to developers of a number of innovative vaccines, including the vaccines with saponin-based adjuvants. In 2021, the World Health Organisation recommended Mosquirix, the first malaria vaccine, which contains a saponin adjuvant. An anti-covid vaccine by Novavax is in the approval phase. A promising approach to vaccine development is presented by the use of virus-like immune-stimulating complexes (ISCOMs) containing saponins and by the creation of combinations of ISCOMs with antigens. The aim of the study was to develop, produce and characterise virus-like immune-stimulating complexes based on saponins of Quillaja saponaria, as well as similar saponins of Russian-sourced Polemonium caeruleum. Materials and methods: The ISCOM adjuvants, Matrix-BQ and Matrix-BP, were produced using liquid chromatography and examined using electron microscopy. Balb/c mice were immunised intraperitoneally and intramuscularly with ISCOM-antigen preparations. Afterwards, the immunised animals were challenged with the influenza virus strain, A/California/4/2009(H1N1)pdm09, adapted and lethal to mice. The serum samples were examined using haemagglutination inhibition (HI) tests. Results: The authors produced the ISCOMs containing saponins of Quillaja saponaria and Polemonium caeruleum. After one intramuscular injection of either of the ISCOM-antigen preparations with 1 µg of each of A/Brisbane/02/2018 (H1N1) pdm09, A/Kansas/14/2017 (H3N2), and B/Phuket/3073/2013 haemagglutinin antigens (HAs), HI tests detected serum antibody titres to the corresponding antigens of ≥1:40. Two intramuscular injections of the ISCOM-antigen preparation containing 50 ng of each of the HAs and Matrix-BQ resulted in a protective response. In some animals, two intraperitoneal injections of ISCOM-antigen preparations resulted in the maximum antibody titre to the A/Kansas/14/2017 (H3N2) vaccine strain of 1:20,480. Two intramuscular injections of a test preparation containing 5 µg, 1 µg, 200 ng, or 50 ng of each of the HAs and Matrix-BQ or a control preparation containing 5 µg, 1 µg, or 200 ng of each of the HAs (commercially available vaccines) to the mice that were afterwards infected with the lethal influenza strain protected the experimental animals from death. Conclusions: The ISCOM-based preparations had high immunostimulatory activity in the mouse-model study. The presented results indicate the potential of further studies of ISCOM-based preparations in terms of both vaccine and immunotherapeutic development.Пандемия COVID-19 обострила потребность общества в эффективных вакцинных препаратах. В этих условиях существенную финансовую поддержку получили разработчики ряда инновационных вакцин, в том числе вакцин, в состав которых входят адъюванты на основе сапонинов. В 2021 г. ВОЗ была одобрена первая противомалярийная вакцина Mosquirix, содержащая сапонины. На стадии одобрения находится вакцина Novavax против COVID-19. Перспективным подходом к созданию вакцин является использование вирусоподобных иммуностимулирующих комплексов (ИСКОМ) на основе сапонинов и создание на их основе комплексов с антигеном (ИСКОМ-антиген). Цель работы: получение и изучение вирусоподобных иммуностимулирующих комплексов на основе сапонинов Квиллайи мыльной (Quillaja saponaria), а также аналогов на основе сапонинов Синюхи голубой (Polemonium caeruleum), полученных из отечественного сырья. Материалы и методы: с применением метода жидкостной хроматографии получали препараты ИСКОМ адъювантов — Матрикс-BQ и Матрикс-BP. Проведено электронно-микроскопическое исследование препаратов. Иммунизацию мышей Balb/c препаратами ИСКОМ-антиген проводили интраперитонеально и внутримышечно. Иммунизированных животных заражали адаптированным летальным для мышей штаммом вируса гриппа A/California/4/2009 (H1N1) pdm09. Образцы сыворотки крови иммунизированных животных исследовали в реакции торможения гемагглютинации (РТГА). Результаты: получены ИСКОМ, содержащие сапонины Синюхи голубой и Квиллайи мыльной. В образцах сыворотки крови животных, однократно внутримышечно иммунизированных препаратом ИСКОМ-антиген, содержащим по 1 мкг гемагглютинина каждого из штаммов вирусов гриппа A/Brisbane/02/2018 (H1N1) pdm09, A/Kansas/14/2017 (H3N2), B/ Phuket/3073/2013, значения титров антител в РТГА составили более 1:40 к соответствующим антигенам. При двукратном внутримышечном введении препарата ИСКОМ-антиген, содержащего 50 нг каждого антигена, был выявлен протективный ответ. Максимальные значения титров антител в РТГА выявлены при двукратном интраперитонеальном введении препарата ИСКОМ-антиген и составили 1:20480 к гемагглютинину вакцинного штамма A/Kansas/14/2017 (H3N2). Показано, что двукратное внутримышечное введение 5 мкг, 1 мкг, 200 нг, 50 нг препарата ИСКОМ-антиген и 5 мкг, 1 мкг, 200 нг контрольного антигена коммерчески доступной вакцины мышам, впоследствии зараженным летальным штаммом вируса гриппа A/California/4/2009 (H1N1)pdm09, защищает экспериментальных животных от гибели. Выводы: полученные препараты на основе ИСКОМ обладали высокой иммуностимулирующей активностью в исследовании на мышиной модели. Представленные результаты свидетельствуют о перспективности дальнейшего изучения препаратов на основе ИСКОМ при разработке как противовирусных, так и иммунокорректирующих препаратов

Эффекты одно- и семикратного введения комплекса альбендазола с динатриевой солью глицирризиновой кислоты хомячкам, инвазированным Opisthorchis felineus

The purpose of the research is to evaluate the effect of albendazole as part of the supramolecular complex with disodium salt of glycyrrhizic acid obtained by solid-phase mechanical treatment.Materials and methods. The anthelmintic activity of the complex and its effect on the host organism was assessed on hamsters infected with Opisthorchis felineus by single and 7-fold administration at 45 days after infection. After 21 days, we counted the number of helminthes in the liver, and conducted a morphometric analysis of the liver and spleen, and detected biochemically the activity of alanine aminotransferase and aspartate aminotransferase in the animals’ blood serum.Results and discussion. The number of O. felineus significantly decreased after 7-fold, but not a single, administration of albendazole (ABZ) and ABZ-Na2GA complex (1 : 10). The administrated substances had no effect on the weight gain of the animals and the daily consumption of the pellets. At the same time, ABZ only as part of the complex normalized the weight of the liver and spleen in hamsters infected with O. felineus and reduced the alanine aminotransferase activity. Consequently, a longer administration of ABZ as part of the complex with disodium glycyrrhizinate has not only a pronounced anthelmintic effect, but also improves some of the physiological parameters of hamsters to a greater extent than a pure substance.Цель исследований – оценить действие альбендазола в составе супрамолекулярного комплекса с динатриевой солью глизирризиновой кислоты, полученного методом твердофазной механической обработки.Материалы и методы. Оценку антигельминтного действия комплекса и его влияния на организм хозяина проводили на хомячках, инвазированных Opisthorchis felineus, при одно- и семикратном введении через 45 сут после заражения. Через 21 сутки после этого подсчитывали число гельминтов в печени; проводили морфометрический анализ печени и селезенки, а также биохимическое определение активности ферментов аланинаминотрансферазы и аспартатаминотрансферазы в сыворотке крови животных.Результаты и обсуждение. Число O. felineus существенно снижалось после семикратного, но не однократного, введения альбендазола (АБЗ) и комплекса АБЗ-Na2ГК (1 : 10). Вводимые вещества не оказывали влияния на прирост массы тела животных и суточное потребление гранул. При этом только в составе комплекса АБЗ нормализовал массу печени и селезенки у инвазированных O. felineus хомячков и снижал активность фермента аланинаминотрансферазы. Следовательно, более длительное введение АБЗ в составе комплекса с динатрия глицирризинатом оказывает не только выраженный антигельминтный эффект, но и в большей степени, чем чистое вещество, улучшает некоторые физиологические показатели хомячков