Efficacy and safety of the first domestic pegilated interferon alpha-2b «Pegaltevir» at chronic hepatitis C: pilot data of phase III clinical study

Aim of investigation. Comparative assessment of efficacy and safety of Pegaltevir and PegIntron in within pattern of combined antiviral therapy in previously untreated patients with chronic hepatitis C.Material and methods. Overall 140 patients with chronic hepatitis C, who received no antiviral therapy previously were included in original study. Patients were randomized in 4 groups. Groups differed in relation to received drug and hepatitis C virus genotype. All patients received 1,5 mkg per 1 kg body weight per week of Pegaltevir or PegIntron and 800–1400 mg of ribavirin per day. Preliminary estimation of drug efficacy was based on rates of rapid and early virologic response (RVR and EVR) achievement, dynamics of biochemical tests, dynamics of blood level of peginterferon alpha and neopterin. Safety features were estimated as well.Results. Comparative analysis has demonstrated absence of statistically significant distinctions of RVR and РВО rates at application of two peginterferon alpha-2b drugs. There were no differences in frequency of achievement of serologic response, as well as safety in Pegaltevir and PegIntron groups. Dynamics of blood concentration of peginterferon alpha correlated to neopterin concentration both in Pegaltevir group and in PegIntron group.Conclusions. Study results have shown high rates of RVR and РВО achievement, and acceptable safety profile of Pegaltevir, comparable with that of PegIntron at chronic hepatitis C in previously untreated patients

Anti-cancer drug validation: the contribution of tissue engineered models

Abstract Drug toxicity frequently goes concealed until clinical trials stage, which is the most challenging, dangerous and expensive stage of drug development. Both the cultures of cancer cells in traditional 2D assays and animal studies have limitations that cannot ever be unraveled by improvements in drug-testing protocols. A new generation of bioengineered tumors is now emerging in response to these limitations, with potential to transform drug screening by providing predictive models of tumors within their tissue context, for studies of drug safety and efficacy. Considering the NCI60, a panel of 60 cancer cell lines representative of 9 different cancer types: leukemia, lung, colorectal, central nervous system (CNS), melanoma, ovarian, renal, prostate and breast, we propose to review current Bstate of art^ on the 9 cancer types specifically addressing the 3D tissue models that have been developed and used in drug discovery processes as an alternative to complement their studyThis article is a result of the project FROnTHERA (NORTE-01-0145-FEDER-000023), supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). This article was also supported by the EU Framework Programme for Research and Innovation HORIZON 2020 (H2020) under grant agreement n° 668983 — FoReCaST. FCT distinction attributed to Joaquim M. Oliveira (IF/00423/2012) and Vitor M. Correlo (IF/01214/2014) under the Investigator FCT program is also greatly acknowledged.info:eu-repo/semantics/publishedVersio

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field

РІШЕННЯ ЗАДАЧ ОПТИМІЗАЦІЇ КОНСТРУКЦІЙ ІЗ ЗАСТОСУВАННЯМ СУЧАСНИХ ПРОГРАМНИХ КОМПЛЕКСІВ

The task of optimization by the system of the spatial design Solid Works with the integrated module of the eventual-element analysis Cosmos Works decides on the example of pivot beam of passenger carriageНа примере шкворневой балки пассажирского вагона решается задача оптимизации с помощью системы пространственного моделирования Solid Works с интегрированным модулем конечно-элементного анализа Cosmos Works.На прикладі шкворневої балки пасажирського вагона вирішується задача оптимізації з допомогою системи просторового моделювання Solid Works з інтегрованим модулем кінцево-елементного аналізу Cosmos Works

ОЦІНКА СУПРОТИВУ НЕСУЧИХ КОНСТРУКЦІЙ РУХОМОГО СКЛАДУ ЦИКЛІЧНИМ НАВАНТАЖЕННЯМ З УРАХУВАННЯМ ВПЛИВУ РІВНОМІРНОЇ КОРОЗІЇ

In conditions of long-term operation the bearing structures of a rolling stock are subject to action of an environment.It causes their uniform corrosion and decrease in bearing ability of the structures. The article is devoted to a technique of the account of uniform corrosion in problems of forecasting of a residual resource of railway structures.В условиях длительной эксплуатации несущие конструкции подвижного состава подвергаются действию внешней среды. Это вызывает их равномерную коррозию и снижение несущей способности конструкций. Статья посвящена методике учета равномерной коррозии в задачах прогнозирования остаточного ресурса железнодорожных конструкций.В умовах тривалої експлуатації несучі конструкції рухомого складу піддаються дії зовнішнього середовища. Це викликає їх рівномірну корозію та зниження несучої здатності конструкції. Стаття присвячена методиці врахування рівномірної корозії в задачах прогнозування залишкового ресурсу залізничних несучих конструкцій

УДОСКОНАЛЕННЯ КОНСТРУКЦІЇ КУЗОВІВ ПАСАЖИРСЬКИХ ВАГОНІВ ДЛЯ ШВИДКІСНИХ ПЕРЕВЕЗЕНЬ

The article offers some options of improving design and reducing the weight of passenger car bodies and develops a mathematical model for studying the strained-deformed state of the body. Some practical results have been presented.Предлагаются варианты совершенствования конструкции и снижения веса кузовов пассажирских вагонов. Разработана математическая модель для изучения напряженно-деформированного состояния кузова. Приведены некоторые результаты.Пропонуються варіанти удосконалення конструкції і зниження ваги кузовів пасажирських вагонів. Розроблена математична модель для вивчення напружено-деформованого стану кузова. Наведені деякі результати

Pegilated interferon alpha 2b «Pegaltevir» chronic hepatitis C treatment (randomized clinical trial)

Aim of investigation. Nowadays the question, whether pegylated interferon should be completely abandoned in the treatment of chronic hepatitis C (CHC) is still open. Beneficial interferon properties include: absence of mutagenic capacity for hepatitis C virus and drug interaction, stimulation of host immune response. These qualities formed the basis for development of the Russian pegilated interferon-alpha 2b (Pegaltevir®, LLC «FARMAPARK», Russia) and carrying out doublestaged randomized open clinical trial: study of safety, tolerability and pharmacokinetics of Pegaltevir® at single injection of increasing doses in various groups of healthy volunteers - the I stage; studying of efficacy and safety of Pegaltevir® in comparison to PegIntron® (Schering-Plough, USA) at CHC as a part of double antiviral therapy with ribavirin (Rebetol®, Schering-Plough, USA) - the II stage. This article presents results of the II phase of investigation. Material and methods. Original study included 140 adult antiviral treatment-naive patients with CHC and compensated liver function. Patients (aged 18 to 70 years) were distributed into four groups. Group 1 (main group, Pegaltevir®/Rebetol® treatment) - 55 patients, HCV genotype 1; group 2 (comparison group, PegIntron®/Rebetol® treatment) - 20 patients, HCV genotype 1; group 3 (main group, Pegaltevir®/Rebetol® treatment) - 47 patients, non-genotype 1 (2 and 3); group 4 (comparison group, PegIntron®/ Rebetol ® treatment) with non-genotype 1 (2 and 3). Assessment of Pegaltevir® efficacy was carried out in 4 weeks (rapid virologic response, RVR) and 12 weeks of treatment (early virologic response, EVR) in groups 1 and 3 in comparison to corresponding scores in groups 2 and 4 (primary criteria of efficacy were estimated in all 140 patients enrolled in original study. The response rate at the moment of secession of antiviral therapy, the sustained virologic response (SVR), histologic response (comparison of paired liver biopsies) served as secondary efficacy criteria and were estimated in 129 patients who completed treatment. The safety analysis was carried out for each patients included in the protocol who received at least one Pegaltevir® dose in comparison to patients who received at least one dose of PegIntron®, - respectively 102 and 38 patients. Results. RVR was comparable in the Pegaltevir® and PegIntron® groups: 65,6 and 82,4% respectively (p>0,05). RVR frequency genotype one patients was 45,3% in Pegaltevir® treatment group and 66,7% in PegIntron® treatment group (p>0,1). At patients with non-genotype 1 (2 and 3): 92,5 and 100% respectively (p>0,05). RVO did not significantly differ in the studied groups: 91,6 and 97,1% for all genotypes respectively (р>0,1). RVO rate for genotype 1 patients in Pegaltevir® group was 86,8%, in PegIntron® treatment group - 94,4% (р>0,1), in non-genotype 1 patients (2 and 3) it reached 97,6 and 100% in the specified patient groups (р>0,1). Response rate at the moment of treatment secession for Pegaltevir® and PegIntron® was 87,4 and 97,1% respectively for all genotypes (р>0,05). In patients with HCV genotype 1 this score Pegaltevir® treatment group reached 79,3%, in PegIntron® group - 94,4% (р> 0,05), in non-genotype 1 patients (2 and 3) - 97,6 and 100% respectively (р>0,1). SVR rate at Pegaltevir® treatment was 82,1% (for all genotypes), PegIntron® - 82,4% (for all genotypes, p>0,1). In HCV genotype 1 patients in Pegaltevir® treatment group SVR made 73,6%, in PegIntron® treatment group - 83,3%, p>0,1, for non-genotype 1 (2 and 3) - 92,9 and 81,3%, p>0,1. No significant differences between basic and control groups at analysis of paired liver biopsies for fibrosis stage reduction rate, absence of negative changes for fibrosis severity and proportion of patients with fibrosis progression were found. Pegaltevir® and PegIntron® treatment groups were comparable safety profile, adverse events were expected, mainly of mild and moderate severity. Conclusion. The hypothesis of identical efficacy of the Russian drug Pegaltevir® tested in the protocol in comparison to PegIntron® was correct and proved. Safety of Pegaltevir® was comparable to safety of PegIntron® as well