POLYFLUOROALKYL-2-(HET)ARYLHYDRAZONO-1,3-DICARBONYL COMPOUNDS IN INTRAMOLECULAR CYCLIZATION REACTIONS

This work was financially supported by the Program UB RAS (Grant number 18-3-3-13)

Clinical and laboratory characteristics of tick-borne rickettsiosis related to <i>Rickettsia sibirica</i> and <i>Candidatus Rickettsia tarasevichiae</i>

The Siberian tick-borne typhus (STT) is the most common tick-borne rickettsiosis (TBR) in Russia, registered in 17 administrative territories of the Southern Siberia and the Far East. The aim of this study was to describe clinical picture, pathological data and results of laboratory diagnostics during fatal mixed infection caused by two Rickettsia species most common in Russia — pathogenic Rickettsia sibirica and poorly examined Candidatus R. tarasevichiae, including identification of its etiological agents. A four-year-old girl in Krasnoyarsk Krai in a hyperendemic focus of the Siberian tick-borne typhus after tick sucking revealed typical TBR symptoms (scab at the site of tick suction, fever, spotted rash, myalgia) and meningeal syndrome, which is not typical for the Siberian tick-borne typhus. The child died on the seventh day of illness. Autopsy data (hepatosplenomegaly; cerebral edema, which was the immediate cause of death) and the results of histological examination (productive vasculitis of the brain, spinal cord and skin, polymorphic cell perivascular infiltrates in the liver and lungs, serous meningitis, myeloid hyperplasia of the spleen and lymph nodes, interstitial lymphoid infiltration in the myocardium) confirmed the clinical diagnosis of tick-borne rickettsiosis. The patient’s blood and brain samples were tested for a wide range of tick-borne pathogens and enteric viruses that cause brain damage using PCR followed by sequencing of the positive samples. The DNA of Rickettsia sibirica and Candidatus Rickettsia tarasevichiae was found in both blood and brain samples. R. sibirica was identified by the nucleotide sequences of gene fragments gltA, ompA and ompB, and Candidatus R. tarasevichiae — by the gltA and ompB genes using nested PCR and sequencing. All amplified fragments were sequenced in both directions; the obtained sequences were deposited in the GenBank database under the inventory numbers MK048467–MK048475. We have not identified other tick-borne pathogens or intestinal viruses in the patient samples able to result in meningeal syndrome. The area where the child was sucked by the tick belongs to the regions with a high incidence of STT. Several species of mites coexist in this area; of these, Haemaphisalis concinna, the carrier of R. sibirica, dominates the populations of Ixodes mites, while Ixodes persulcatus, the main reservoir of Candidatus R. tarasevichiae, is less common. As a result of the conducted studies, for the first time in the Russian Federation, a verified case of a lethal infection associated with two species of Rickettsia — Rickettsia sibirica and Candidatus R. tarasevichiae — was identified and described

ВАКЦИНАЦИЯ ВЗРОСЛЫХ ПРОТИВ ПНЕВМОКОККОВОЙ ИНФЕКЦИИ В РОССИЙСКОЙ ФЕДЕРАЦИИ: СОЦИАЛЬНЫЕ И ФАРМАКОЭКОНОМИЧЕСКИЕ АСПЕКТЫ

Vaccination against pneumococcal infections by 13-valent conjugate vaccine (PCV13) can significantly reduce morbidity and mortality.The study has been aimed to evaluate the social and pharmacoeconomic aspects of PCV13 vaccination of 65-year-old patients with various risks of pneumococcal infection.Material and methods. Markov model with 5 and 15 years time horizon was used for the analysis from the position of the health care system.The analysis was carried out for 65-year-old citizens with low (absence of immunocompromized conditions and chronic diseases), moderate (patients with chronic diseases without immunodeficiency) and high (immunocompromized conditions) risk of pneumococcal infection as well as for the entire population of 65-year-old citizens, regardless of the risk level.In base-case assumption has been made that 1 dose of PCV13 should be administered for the patients from low and moderate risk groups and in the high-risk group 1 dose of PCV13 and in 8 weeks a dose of polysaccharide pneumococcal vaccine (PPV23) should be given.The treatment and physician visit costs have been calculated using CHI rates for St. Petersburg in 2018. Vaccination cost was calculated using the auction price to purchase PCV13 and PPV23 in 2018.Results. Vaccination of 1 cohort of 65-year-old citizens in Russian Federation within 5 years will result in prevention of 2200 deaths, 3900 cases of invasive pneumococcal diseases (IPD) and 48700 cases of community-acquired pneumonia. In 15 years prevention of about 4,3 thousand deaths, 6,6 thousand IPD and 101,1 thousand cases of CAP will be provided.Within 15-year horizon the cost-effectiveness ratio will be RUR 30,3, 82,4 and 410,0 thousand per QALY in high, moderate and low risk groups, respectively. Even if the time horizon is reduced to 5 years the PCV13 vaccination can be considered as an economically high-efficient intervention in moderate and high risk groups (cost-effectiveness ratio - RUR 279,2 and 221,7 thousand / QALY, respectively).In the 15-year-horizon noting the distribution of 65-yearolds by risk levels the cost-effectiveness ratio of PCV13 in population as a whole will be RUR 216,4 thousand / QALY. If moderate and high risk groups only are vaccinated, the average cost-effectiveness ratio will drop to RUR 67,6 thousand /QALY. At universal PCV13 vaccination of 65 years old in 5 year time horizon return of investment to the health care system budget will be 33.2% and at vaccination of persons with moderate and high risk return of investment will be 44.0%. With the assumption of vaccination during the planned physician visit (without additional visit) the return to the budget will be 46.8% and 60.9% for vaccination of all 65-year-olds and patients from the moderate and high risk groups, respectively.Conclusions. Vaccination of the 65-year-old persons against PCV13 pneumococcal infection in Russian Federation can be considered as a highly socially and economically effective intervention resulting in significant reduction of pneumococcal infection incidence and related mortality. The cost-effectiveness of vaccination is increasing along with the level of the risk. PCV13 vaccination of patients with moderate and high risk only provides a significant reduction in the burden for the health care budget in comparison with the vaccination of the entire population of 65-year-olds.Вакцинация против пневмококковых инфекций 13-валентной конъюгированной вакциной (ПКВ13) позволяет существенно снизить соответствующую заболеваемость и летальность.Цель: оценка социальных и фармакоэкономических аспектов вакцинации ПКВ13 65-летних пациентов с различным уровнем риска пневмококковой инфекции.Материалы и методы. Анализ осуществляли методом марковского моделирования с позиции системы здравоохранения. Временной горизонт – 5 и 15 лет.Анализ проводили для 65-летних граждан с низким (пациенты без нарушений иммунитета и хронических заболеваний), умеренным (пациенты без нарушений иммунитета с наличием хронических заболеваний) и высоким (пациенты с нарушениями иммунитета) риском развития пневмококковых инфекций, а также для всей популяции 65-летних граждан, независимо от уровня риска.В базовом варианте предполагали, что в группах низкого и умеренного риска осуществляется вакцинация 1 дозой ПКВ13, а в группе высокого риска – 1 дозой ПКВ13 и 1 дозой полисахаридной пневмококковой вакцины (ППВ23) через 8 недель. Затраты на терапию пневмококковых инфекций рассчитывались на основе тарифов ОМС по СанктПетербургу на 2018 г.Затраты на вакцинацию рассчитывались на основе цены аукционов по закупке ПКВ13 и ППВ23 за 2018 г. и затрат на визит к терапевту в соответствии с тарифом ОМС.Результаты. При вакцинации 1 когорты 65-летних граждан в РФ за 5 лет будут предотвращены около 2,2 тыс. летальных исходов, 3,9 тыс. случаев инвазивной пневмококковой инфекции (ИПИ) и 48,7 тыс. случаев заболевания внебольничной пневмонией. За 15 лет количество предотвращенных летальных исходов составит около 4,3 тыс., предотвращенных случаев ИПИ – 6,6 тыс., а предотвращенных случаев заболевания внебольничной пневмонией – 101,1 тыс.Коэффициент эффективности затрат составляет при 15-летнем горизонте 30,3, 82,4 и 410,0 тыс. руб. в расчете на дополнительный год жизни с учетом качества QALY в группах высокого, умеренного и низкого риска соответственно. Даже при снижении временного горизонта до 5 лет, в группах умеренного и высокого риска вакцинация ПКВ13 может рассматриваться как экономически высокоэффективное вмешательство (коэффициент эффективности затрат – 279,2 и 221,7 тыс. руб./QALY соответственно).С учетом распределения 65-летних граждан по уровням риска, при 15-летнем горизонте средняя эффективность затрат на вакцинацию ПКВ13 в популяции в целом составит 216,4 тыс. руб./QALY. Если осуществлять вакцинацию только граждан из групп умеренного и высокого риска, средний коэффициент «затраты/эффективность» снизится до 67,6 тыс. руб./QALY.При вакцинации всех 65-летних граждан за 5 лет в бюджет системы здравоохранения вернется 33,2%, при вакцинации только пациентов из групп высокого и умеренного риска – 44,0%. При допущении о вакцинации в ходе планового визита к врачу (без дополнительного визита) доля средств, которые вернутся в бюджет системы здравоохранения, составит 46,8% и 60,9% при вакцинации всех 65-летних граждан и пациентов из групп умеренного и высокого риска соответственно.Выводы. Вакцинация граждан РФ в возрасте 65 лет против пневмококковой инфекции ПКВ13 может рассматриваться в качестве социально и экономически высокоэффективного вмешательства, обеспечивающего существенное снижение заболеваемости пневмококковыми инфекциями и обусловленной ею летальности. Экономическая эффективность вакцинации возрастает с увеличением риска развития пневмококковых инфекций в вакцинируемой группе. Вакцинация ПКВ13 только пациентов из групп умеренного и высокого риска обеспечивает существенное снижение нагрузки на бюджет по сравнению с вакцинацией всей популяции 65-летних граждан.

Derivatives of 9-phosphorylated acridine as butyrylcholinesterase inhibitors with antioxidant activity and the ability to inhibit β-amyloid self-aggregation: potential therapeutic agents for Alzheimer’s disease

We investigated the inhibitory activities of novel 9-phosphoryl-9,10-dihydroacridines and 9-phosphorylacridines against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and carboxylesterase (CES). We also studied the abilities of the new compounds to interfere with the self-aggregation of β-amyloid (Aβ42) in the thioflavin test as well as their antioxidant activities in the ABTS and FRAP assays. We used molecular docking, molecular dynamics simulations, and quantum-chemical calculations to explain experimental results. All new compounds weakly inhibited AChE and off-target CES. Dihydroacridines with aryl substituents in the phosphoryl moiety inhibited BChE; the most active were the dibenzyloxy derivative 1d and its diphenethyl bioisostere 1e (IC50 = 2.90 ± 0.23 µM and 3.22 ± 0.25 µM, respectively). Only one acridine, 2d, an analog of dihydroacridine, 1d, was an effective BChE inhibitor (IC50 = 6.90 ± 0.55 μM), consistent with docking results. Dihydroacridines inhibited Aβ42 self-aggregation; 1d and 1e were the most active (58.9% ± 4.7% and 46.9% ± 4.2%, respectively). All dihydroacridines 1 demonstrated high ABTS•+-scavenging and iron-reducing activities comparable to Trolox, but acridines 2 were almost inactive. Observed features were well explained by quantum-chemical calculations. ADMET parameters calculated for all compounds predicted favorable intestinal absorption, good blood–brain barrier permeability, and low cardiac toxicity. Overall, the best results were obtained for two dihydroacridine derivatives 1d and 1e with dibenzyloxy and diphenethyl substituents in the phosphoryl moiety. These compounds displayed high inhibition of BChE activity and Aβ42 self-aggregation, high antioxidant activity, and favorable predicted ADMET profiles. Therefore, we consider 1d and 1e as lead compounds for further in-depth studies as potential anti-AD preparations. Copyright © 2023 Makhaeva, Kovaleva, Rudakova, Boltneva, Lushchekina, Astakhova, Timokhina, Serebryakova, Shchepochkin, Averkov, Utepova, Demina, Radchenko, Palyulin, Fisenko, Bachurin, Chupakhin, Charushin and Richardson.122041400110-4; FFSN-2021-0005; Alternatives Research and Development Foundation, ARDF; University of Michigan, U-M; Russian Foundation for Basic Research, РФФИ: 19-29-08037; Russian Science Foundation, RSFThis research was partly supported by grant # 22-13-00298 of the Russian Science Foundation and IPAC RAS State Targets Project # FFSN-2021-0005; quantum-chemical calculations were supported the IBCP RAS State Targets Project # 122041400110-4. The synthesis of the compounds was financially supported by the Russian Foundation for Basic Research (research project # 19-29-08037). Support for RR’s contributions to the computer modeling components of the work was provided in part by a grant from the Alternatives Research and Development Foundation (ARDF) and an Mcubed grant from the University of Michigan

Powerful Potential of Polyfluoroalkyl-Containing 4-Arylhydrazinylidenepyrazol-3-ones for Pharmaceuticals

4-Arylhydrazinylidene-5-(polyfluoroalkyl)pyrazol-3-ones (4-AHPs) were found to be obtained by the regiospecific cyclization of 2-arylhydrazinylidene-3-(polyfluoroalkyl)-3-oxoesters with hydrazines, by the azo coupling of 4-nonsubstituted pyrazol-5-oles with aryldiazonium chlorides or by the firstly discovered acid-promoted self-condensation of 2-arylhydrazinylidene-3-oxoesters. All the 4-AHPs had an acceptable ADME profile. Varying the substituents in 4-AHPs promoted the switching or combining of their biological activity. The polyfluoroalkyl residue in 4-AHPs led to the appearance of an anticarboxylesterase action in the micromolar range. An NH-fragment and/or methyl group instead of the polyfluoroalkyl one in the 4-AHPs promoted antioxidant properties in the ABTS, FRAP and ORAC tests, as well as anti-cancer activity against HeLa that was at the Doxorubicin level coupled with lower cytotoxicity against normal human fibroblasts. Some Ph-N-substituted 4-AHPs could inhibit the growth of N. gonorrhoeae bacteria at MIC 0.9 μg/mL. The possibility of using 4-AHPs for cell visualization was shown. Most of the 4-AHPs exhibited a pronounced analgesic effect in a hot plate test in vivo at and above the diclofenac and metamizole levels except for the ones with two chlorine atoms in the aryl group. The methylsulfonyl residue was proved to raise the anti-inflammatory effect also. A mechanism of the antinociceptive action of the 4-AHPs through blocking the TRPV1 receptor was proposed and confirmed using in vitro experiment and molecular docking. © 2022 by the authors.FFSN-2021-0005; Russian Foundation for Basic Research, РФФИ: 20-03-00312; Russian Science Foundation, RSF: 21-13-00390This work was financially supported by the Russian Science Foundation (grant No 21-13-00390 for V.I.S.): the synthesis and analysis of compounds, antimicrobial evaluation, cytotoxicity, analgesic and anti-inflammatory activity, mechanism of analgesia, molecular docking; by the Russian Foundation for Basic Research (grant No 20-03-00312 for Y.V.B.): esterase profile of compounds; antioxidant activity in ABTS and FRAP tests were performed in the frame of IPAC RAS State Targets Project FFSN-2021-0005

Эффективность затрат на вакцинацию против пневмококковой инфекции взрослых из групп риска в рамках федеральных и региональных программ

The aim. of the work was to evaluate the cost-effectiveness of vaccination with the 13-vaIent pneumococcal conjugate vaccine (PCV13) and its combination with the 23-valent pneumococcal polysaccharide vaccine (PPV23) of immunocompetent adult patients with different levels of risk of pneumococcal infection.Material and methods. Cost-effectiveness analysis was carried out by a modeling method, with a horizon of 15 years from the position of the healthcare system, and. taking into account the social perspective. The analysis was performed, for 20, 40, and 60 year oId patients with 1, 2, and 3 risk factors. In accordance with national recommendations, the vaccination. regimen included, the introduction, of PC 1 dose of PPV23 one year later. In addition, the analysis was performed, for vaccination, with 1 dose of PCV13.The efficacy of PCV13 and PPV23 in different age groups corresponded, to the results of foreign studies, taking into account the data of a Russian study of the serotypic landscape of pneumococci with community-acquired, pneumonia, which required, hospitalization.The cost of treating pneumococcal infections was calculated. on the basis of the mandatory medical insurance rates in St. Petersburg for 2019. The cost of vaccination, for federal programs was calculated, on the basis of the PCV13 price of 1199 rubles per dose, and. for regional programs — 1518.63 rubles per dose. The cost of PPV23 in both, cases corresponded. to the weighted average price of auctions for 2019 (1639 rubles per dose).Indirect costs were calculated, on the basis of data on average wages in the Russian Federation, and. employment of citizens of various age groups.Costs and. life expectancy were discounted, at 3.5% per year.Results. The number of cases of infection prevented, and. the amount of costs averted, increase with increasing risk level. Moreover, with age, the number of deaths caused, by these diseases increases significantly. The volume of prevented, direct medical and. general costs per 1 vaccinated, patient varies from 0.41-2.95 thousand, rubles and. 1.00-6.82 thousand, rubles, respectively. Vaccination, of patients with 3 risk factors is most cost-effective.Conclusion. When analyzed, from the perspective of the healthcare system., vaccination, against pneumococcal infection with PCV13+PPV23 in 60-year-old. patients with at least 1 risk factor and. patients of any age with at least 2 risk factors can be considered as cost-effective. Vaccination with 1 dose of PCV13 of patients of any age with at least 1 risk factor in the analysis from the perspective of the healthcare system, can be considered, as a cost-effective intervention.Цель: оценка эффективности затрат, на вакцинацию 13-валентной пневмококковой конъюгированной вакциной (ПКВ13) и ее сочетанием, с 23-валентной пневмококковой полисахаридной вакциной (ППВ23) иммунокомпетентных взрослых пациентов с различным, уровнем риска пневмококковой инфекции.Материалы и методы: анализ эффективности затрат осуществляли методом, моделирования с горизонтом. 15 лет. с позиции системы здравоохранения и с учетом. социальной перспективы. Анализ проводили для 20-, 40- и 60-летних пациентов с 1, 2 и 3 факторами риска.В соответствии с национальными рекомендациями режим, вакцинации предполагал введение 1 дозы. ПКВ13 и 1 дозы ППВ23 через год. Кроме того, анализ проводили для вакцинации 1 дозой ПКВ13.Эффективность ПКВ13 и ППВ23 в разных возрастных группах соответствовала результатам, зарубежных исследований с учетом, данных российского исследования серотипового пейзажа пневмококков при внебольничной пневмонии, потребовавшей госпитализации.Затраты, на терапию пневмококковых инфекций рассчитывались на основе тарифов ОМС по Санкт-Петербургу на 2019 г. Затраты, на вакцинацию ПКВ13 рассчитывались в рамках федеральных программ на основе цены. ПКВ13, равной 1199 руб. за дозу, в рамках региональных программ. — 1518,63 руб. за дозу. Затраты, на ППВ23 в обоих случаях соответствовали средневзвешенной цене аукционов за 2019 г. (1639 руб. за дозу).Расчет, непрямых затрат, осуществлялся на основе данных по средней заработной плате в РФ и занятости граждан различных возрастных групп.При проведении анализа затраты, и продолжительность жизни дисконтировали на 3,5% в год.Результаты: количество предотвращенных при вакцинации случаев инфекции и объем, предотвращенных затрат, увеличиваются с увеличением, уровня риска. При этом с возрастом существенно возрастает количество обусловленных данными заболеваниями летальных исходов.Объем предотвращенных прямых медицинских и общих затрат, в расчете на 1 вакцинированного варьирует в пределах 0,41—2,95 тыс. руб. и 1,00—6,82 тыс. руб. соответственно. Максимальная эффективность затрат характерна для пациентов с 3 факторами риска.Выводы: при анализе с позиции системы здравоохранения в качестве экономически высокоэффективной может, рассматриваться вакцинация против пневмококковой инфекции ПКВ13 с введением, через год ППВ23 60-летних пациентов с как минимум. 1 фактором, риска и пациентов любого возраста с как минимум. 2 факторами риска.Вакцинация 1 дозой ПКВ13 пациентов любого возраста с как минимум 1 фактором риска при анализе с позиции системы здравоохранения может, рассматриваться как экономически высокоэффективное вмешательство

Вакцинопрофилактика пневмококковой инфекции у детей

Pneumococcal infection remains one of the leading reasons for infant mortality from vaccine-preventable infections. Today vaccination is the most effective way to prevent diseases caused by antibiotic-resistant pneumococci. In the article, authors present current approaches to vaccinal prevention of pneumococcal diseases. The plan of action for carrying out active immunoprophylaxis of pneumococcal infection is explained in detail for both healthy children and patients from risk groups for severe pneumococcal diseases development. The published work is based on key points of the guidelines of the Ministry of Health of the Russian Federation on vaccinal prevention of pneumococcal infection (developed and approved by the professional association of pediatricians «The Union of Pediatricians of Russia»).Пневмококковая инфекция остается одной из ведущих причин детской смертности от вакциноуправляемых инфекций. Вакцинация на сегодняшний день является наиболее эффективным направлением профилактики заболеваний, вызываемых устойчивыми к антибактериальным препаратам пневмококкам. В статье коллективом авторов представлены актуальные подходы к вакцинопрофилактике болезней пневмококковой этиологии. Подробно разъяснен алгоритм действий при проведении активной иммунопрофилактики пневмококковой инфекции как здоровых детей, так и пациентов из групп риска по развитию тяжелых форм пневмококковых заболеваний. Публикация основана на ключевых позициях методических рекомендаций Министерства здравоохранения РФ по вакцинопрофилактике пневмококковой инфекции (разработанных и утвержденных профессиональной ассоциацией детских врачей «Союз педиатров России»).КОНФЛИКТ ИНТЕРЕСОВАвторы статьи подтвердили отсутствие конфликта интересов, о котором необходимо сообщить

ASSESSMENT OF ANTIARRHYTHMIC ACTIVITY AND SAFETY OF NEW DERIVATIVES OF MORPHOLINOACETIC ACID

Study of the anti-arrhythmic influence of the new organic synthesis’s products was the purpose of an actual research. Such characteristics of these compounds as acute toxicity, anti-arrhythmic and pro-arrhythmic activity were studied. The mostly strongly marked effect was discovered while using M-0 and M-18. These compounds showed the highest anti-arrhythmic activity and the lowest toxicity. It was also discovered that M-18 compound is less dangerous than M-0 one due to absence of the certainly expressed spill-over effect of an arrhythmogenic action

ANTIARRHYTHMIC ACTIVITY MONOGAMISTIC AMIDES AND HYDRAZIDES 1,4-DICARBOXYLIC ACIDS

The antiarrhythmic activity of 19 derivatives 1,4-dicarboxylic acids in experiments on white mice on the model of chlorocalcium arrhythmia and acute toxicity of 6 compounds. As a standard, the drug «Lidocaine» was used. Two compounds showed an antiarrhythmic effect exceeding the standard effect by 6 times [ED50=7.3 mg/kg (5.3÷10.0)] and 3 times [ED50=6.9 mg/kg (5.0÷9.5)]. 4-Aminobenzoylhydrazide itaconic acid has antiarrhythmic activity, the same derivatives of succinic, maleic, citraconic and dimethylmaleic acids are not active. Isonicotinoylhydrazide phthalic acid exceeds the antiarrhythmic activity of the standard, the same hydrazides of maleic, dimethylmaleic and tetrachlorophthalic acids do not possess an antiarrhythmic effect