Применение циклоспорина А у пациентов с COVID-19 при неэффективности первичной иммуносупрессии: ретроспективное когортное псевдорандомизированное исследование

АКТУАЛЬНОСТЬ: Терапия пациентов с новой коронавирусной инфекцией (COronaVIrus Disease 2019 — COVID-19) при прогрессирующем поражении легких на фоне применения глюкокортикостероидов (ГКС) и ингибиторов интерлейкина-6 (ИИЛ-6) до сих пор не разработана. ЦЕЛЬ ИССЛЕДОВАНИЯ: оценка эффективности циклоспорина А у пациентов с COVID-19 при прогрессировании поражения легких и гипоксемической острой дыхательной недостаточностью, получивших патогенетическую терапию ГКС и ИИЛ-6. МАТЕРИАЛЫ И МЕТОДЫ: Ретроспективное когортное псевдорандомизированное моноцентровое исследование (n = 98). Циклоспорин А назначали в первые 72–96 ч после введения ИИЛ-6 при ухудшении состояния пациентов. Пациенты группы сравнения соответствовали основной группе, но не получали терапию циклоспорином А. Первичная конечная точка — госпитальная летальность. Вторичные конечные точки — длительность госпитализации, количество пациентов, поступивших в отделение реанимации и интенсивной терапии (ОРИТ), потребность в респираторной поддержке. РЕЗУЛЬТАТЫ: Летальность составила 12 (22) % в группе циклоспорина и 27 (61) % в группе сравнения, р = 0,001 (относительный риск (ОР) 2,00 [1,12–3,48], р = 0,018), частота поступления в ОРИТ 14 (26 %) против 29 (66 %), р = 0,001 соответственно. В группе циклоспорина на 7-й день более 75 % поражения легочной ткани, по данным компьютерной томографии, было у 26 % пациентов против 52 % в группе сравнения, р = 0,014, потребность в респираторной поддержке (37 % против 63,6 %, р = 0,011); сатурация 88 (82–93 %) против 80 (70–86 %), р = 0,001 соответственно. Необходимость в респираторной поддержке на 11-й день после применения ИИЛ-6 повышала вероятность летального исхода (ОР 7,12 [2,51–20,10], р = 0,001). Факторы риска летального исхода: возраст старше 57,5 года, индекс массы тела более 30 кг/м2, сатурация ниже 85,5 % в день применения ИИЛ-6. Длительность госпитализации составила 18,5 (14–24) дня против 18 (12–24) дней, р = 0,778. ВЫВОДЫ: Циклоспорин А в дополнение к ГКС и ИИЛ-6 для терапии COVID-19 может способствовать снижению летальности, частоты поступления в ОРИТ и потребности в респираторной поддержке

Влияние раннего назначения тоцилизумаба на прогрессирование дыхательной недостаточности у пациентов с COVID-19

The optimal interval for initiating tocilizumab therapy in patients with COVID-19 (COronaVIrus Disease 2019) has not been determined. The aim of the study was to evaluate the effectiveness of prescribing tocilizumab depending on the duration of persistent hyperthermia > 38 °С in patients with SARS-CoV-2 (Severe Acute Respiratory Syndrome-related CoronaVirus 2) associated pneumonia who received tocilizumab according to the Interim Guidelines of the Ministry of Health of the Russian Federation (version at the time of inclusion in the study). Methods. A retrospective cohort study was conducted in hospitalized patients (n = 163) with SARS-CoV-2-associated pneumonia from May 2020 to May 2021. Patients were retrospectively divided into 2 groups depending on the time of tocilizumab administration: ≤ 7 days (n = 61) or ≥ 8 days (n = 102) from the disease onset. Results. Patients who received tocilizumab in the first 7 days had the lower need for CPAP (Continuous Positive Airway Pressure) therapy on day 3 after tocilizumab therapy (HR (Hazard Ratio) – 0.129 (0.039 – 0.430); p = 0.001), a higher probability of a decrease in the volume of lung lesions on computed tomography > 25% a week after the use of tocilizumab (HR – 1.065 (1.036 – 1.093); p = 0.001), the lower probability of hemoglobin oxygen saturation below 92% on day 3 (HR – 0.807 (0.750 – 0.869); p = 0.001), and day 7 (HR – 0.825 (0.772 – 0.883); p = 0.001) after tocilizumab therapy. If CPAP therapy was required on day 3 after administration of tocilizumab, each day of delay in prescribing the drug increased the risk of an adverse outcome 18-fold (HR – 18.24 (5.328 – 62.438); p = 0.001). The duration of hospitalization was significantly lower in the early group than in the late group (10 (8.5 – 15) vs 13.5 (10 – 18) days, respectively; p = 0.02). The mortality was similar (5 (8.2%) vs 6 (5.9%) patients, respectively; p = 0.748). Conclusion. The administration of tocilizumab in the first seven days from the onset of the disease in patients with COVID-19 who developed systemic inflammation and lung damage may prevent the need for escalation of respiratory support and accelerate recovery compared with the later tocilizumab administration.Оптимальный интервал для начала терапии тоцилизумабом у пациентов с COVID-19 (COronaVIrus Disease 2019) не определен. Целью исследования явилась оценка эффективности назначения тоцилизумаба в зависимости от продолжительности стойкой гипертермии > 38 °С у пациентов с пневмонией, ассоциированной с SARS-CoV-2 (Severe Acute Respiratory Syndrome-related CoronaVirus 2), получающих терапию тоцилизумабом согласно Временным методическим рекомендациям Министерства здравоохранения Российской Федерации (версия на момент включения в исследование). Материалы и методы. В период с мая 2020 по май 2021 г. проведено ретроспективное когортное исследование с участием госпитализированных пациентов (n = 163) с SARS-CoV-2-ассоциированной пневмонией. Пациенты были ретроспективно распределены на 2 группы в зависимости от времени назначения тоцилизумаба (≤ 7 (n = 61) или ≥ 8 (n = 102) дней от начала заболевания). Результаты. У пациентов, получивших тоцилизумаб в первые 7 дней, ниже необходимость в СРАР-терапии (поддержание постоянного положительного давления в дыхательных путях (Continuous Positive Airway Pressure – СРАР)) (отношение рисков (ОР) – 0,129 (0,039–0,430); р = 0,001) на 3-и сутки после терапии тоцилизумабом; выше вероятность снижения объема поражения легких по данным компьютерной томографии > 25 % через 1 нед. после применения тоцилизумаба (OP – 1,065 (1,036–1,093); р = 0,001); ниже вероятность насыщения гемоглобина кислородом < 92 % на 3-й (OP – 0,807 (0,750–0,869); р = 0,001) и 7-й (OP – 0,825 (0,772–0,883); р = 0,001) дни после терапии тоцилизумабом. При необходимости в СРАР-терапии на 3-й день после введения тоцилизумаба каждый день задержки назначения препарата увеличивал риск неблагоприятного исхода в 18 раз (OP – 18,24 (5,328–62,438); р = 0,001). Продолжительность госпитализации была значимо ниже в группе раннего назначения препарата, чем в группе позднего назначения (10 (8,5–15) дней vs 13,5 (10–18) дня соответственно; р = 0,02). Летальность в группах была одинаковой (5 (8,2 %) vs 6 (5,9 %) пациентов соответственно; р = 0,748). Заключение. У пациентов с COVID-19 при развитии системного воспаления и поражения легких назначение тоцилизумаба в первые 7 дней от начала заболевания по сравнению с более поздним назначением может предотвратить необходимость эскалации респираторной поддержки и ускорить выздоровление

Resolution of a nonionic surfactant oligomeric mixture by means of DOSY with inverse micelle assistance

DOSY is a recognized, efficient technique in the analysis of mixtures. It relies on the differences in self-diffusion coefficients, which are determined by the molecular size. Nowadays, efforts are directed towards devising matrices able to interact with the components of the mixture with differential affinity, and therefore capable to interfere with the diffusion processes and to display resolving power towards species of close, or even equal molecular weight, like isomers. Usually, commercial nonionic surfactants are mixtures of oligomeric species, since the head group, which is a short polyoxyehtylene chain, is somewhat polydisperse. The embedment of Igepal CA-520, 5 polyoxyethylene iso-octylphenyl ether, in an inverse microemulsion led to the separation of 1H signals of the various oligomeric components. This ensued from the differential partitioning between the oil and the surface of the inverse micelles, which depends on the ethyleneoxide number (EON) of the head groups. Thus, it was possible to ascertain that the length distribution of the polyethyleneoxide chains is ingood agreement with the Poisson distribution theoretically predicted for the polymerization of ethylene oxide. The DOSY spectrum contributed to the assignment of the signals and afforded the partition degree, between the two environments, for each individual oligomeric species, providing further insight into nonionic inverse microemulsions, at present widely employed reaction media in the nanotechnological syntheses

Evolution of the Nonionic Inverse Microemulsion-Acid-TEOS System during the Synthesis of Nanosized Silica via the Sol-Gel Process

The cyclohexane-igepal inverse microemulsion, comprehensively established for the synthesis of silica nanoparticles in an ammonia-catalyzed sol-gel process, was alternatively studied with an acid-catalyzed sol-gel process. Tetraethyl orthosilicate (TEOS) was used as the silica precursor, while two different aqueous phases containing either HNO3 or HCl at two different concentrations, 0.1 and 0.05 M, were examined in the presence and in the absence of NaF, a catalyst of the condensation step. The evolution of the overall reacting system, specifically hydrolysis and polycondensation of reaction intermediates, was monitored in situ by time-resolved small-angle X-ray scattering. No size variation of the inverse micelles was detected throughout the sol-gel process. Conversely, the density of the micellar core increased after a certain time interval, indicating the presence of the polycondensation product. The IR spectra of the reacting mixture were in agreement with such a hypothesis. 1Hand 13CNMRmeasurements provided information on the soluble species, the surfactant, and TEOS. The TEOS consumption was well fitted by means of an exponential decay, suggesting that a first-order kinetics for TEOS transpires in the various systems examined, with rate constants dependent not only on the acid concentration but also on its nature (anion specific effect), on the presence of NaF, and on the amount of water in the core of the inverse micelle. The self-diffusion coefficients, determined by means of PGSTE NMR, proved that a sizable amount of the byproduct ethanol was partitioned inside the inverse micelles. Characterization of the final product was carried out by means of thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and transmission electron microscopy (TEM), which concurrently confirmed that the silica isolated from the inverse nonionic microemulsion is not significantly different from the product of a bulk acid-catalyzed sol-gel synthesis. TEM micrographs illustrated particles with diameters smaller than the diameter of the inverse micelles as determined by SAXS, due to a shrinkage effect, in addition to nanostructured aggregates in the range 20-100 nm

Evolution of the Nonionic Inverse Microemulsion−Acid−TEOS System during the Synthesis of Nanosized Silica via the Sol−Gel Process

The cyclohexane−igepal inverse microemulsion, comprehensively established for the synthesis of silica nanoparticles in an ammonia-catalyzed sol−gel process, was alternatively studied with an acid-catalyzed sol−gel process. Tetraethyl orthosilicate (TEOS) was used as the silica precursor, while two different aqueous phases containing either HNO3 or HCl at two different concentrations, 0.1 and 0.05 M, were examined in the presence and in the absence of NaF, a catalyst of the condensation step. The evolution of the overall reacting system, specifically hydrolysis and polycondensation of reaction intermediates, was monitored in situ by time-resolved small-angle X-ray scattering. No size variation of the inverse micelles was detected throughout the sol−gel process. Conversely, the density of the micellar core increased after a certain time interval, indicating the presence of the polycondensation product. The IR spectra of the reacting mixture were in agreement with such a hypothesis. 1H and 13C NMR measurements provided information on the soluble species, the surfactant, and TEOS. The TEOS consumption was well fitted by means of an exponential decay, suggesting that a first-order kinetics for TEOS transpires in the various systems examined, with rate constants dependent not only on the acid concentration but also on its nature (anion specific effect), on the presence of NaF, and on the amount of water in the core of the inverse micelle. The self-diffusion coefficients, determined by means of PGSTE NMR, proved that a sizable amount of the byproduct ethanol was partitioned inside the inverse micelles. Characterization of the final product was carried out by means of thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and transmission electron microscopy (TEM), which concurrently confirmed that the silica isolated from the inverse nonionic microemulsion is not significantly different from the product of a bulk acid-catalyzed sol−gel synthesis. TEM micrographs illustrated particles with diameters smaller than the diameter of the inverse micelles as determined by SAXS, due to a shrinkage effect, in addition to nanostructured aggregates in the range 20−100 nm