Effectiveness and safety of first-generation protease inhibitors in clinical practice: Hepatitis C virus patients with advanced fibrosis

AIM: To evaluates the effectiveness and safety of the first generation, NS3/4A protease inhibitors (PIs) in clinical practice against chronic C virus, especially in patients with advanced fibrosis. METHODS: Prospective study and non-experimental analysis of a multicentre cohort of 38 Spanish hospitals that includes patients with chronic hepatitis C genotype 1, treatment-nai¨ve (TN) or treatment-experienced (TE), who underwent triple therapy with the first generation NS3/4A protease inhibitors, boceprevir (BOC) and telaprevir (TVR), in combination with pegylated interferon and ribavirin. The patients were treatment in routine practice settings. Data on the study population and on adverse clinical and virologic effects were compiled during the treatment period and during follow up. RESULTS: One thousand and fifty seven patients were included, 405 (38%) were treated with BOC and 652 (62%) with TVR. Of this total, 30% (n = 319) were TN and the remaining were TE: 28% (n = 298) relapsers, 12% (n = 123) partial responders (PR), 25% (n = 260) null-responders (NR) and for 5% (n = 57) with prior response unknown. The rate of sustained virologic response (SVR) by intention-to-treatment (ITT) was greater in those treated with TVR (65%) than in those treated with BOC (52%) (P < 0.0001), whereas by modified intention-to-treatment (mITT) no were found significant differences. By degree of fibrosis, 56% of patients were F4 and the highest SVR rates were recorded in the non-F4 patients, both TN and TE. In the analysis by groups, the TN patients treated with TVR by ITT showed a higher SVR (P = 0.005). However, by mITT there were no significant differences between BOC and TVR. In the multivariate analysis by mITT, the significant SVR factors were relapsers, IL28B CC and non-F4; the type of treatment (BOC or TVR) was not significant. The lowest SVR values were presented by the F4-NR patients, treated with BOC (46%) or with TVR (45%). 28% of the patients interrupted the treatment, mainly by non-viral response (51%): this outcome was more frequent in the TE than in the TN patients (57% vs 40%, P = 0.01). With respect to severe haematological disorders, neutropaenia was more likely to affect the patients treated with BOC (33% vs 20%, P = 0.0001), and thrombocytopaenia and anaemia, the F4 patients (P = 0.000, P = 0.025, respectively). CONCLUSION: In a real clinical practice setting with a high proportion of patients with advanced fibrosis, effectiveness of first-generation PIs was high except for NR patients, with similar SVR rates being achieved by BOC and TVR

Resistance of Blastocystis to chlorine and hydrogen peroxide

10.1007/s00436-022-07713-2Parasitology Research1221167-17

In vitro assessment of 3-alkoxy-5-nitroindazole-derived ethylamines and related compounds as potential antileishmanial drugs

Leishmaniasis is a widespread neglected tropical disease complex that is responsible of one million new cases per year. Current treatments are outdated and pose many problems that new drugs need to overcome. With the goal of developing new, safe, and affordable drugs, we have studied the in vitro activity of 12 different 5-nitroindazole derivatives that showed previous activity against different strains of Trypanosoma cruzi in a previous work. T. cruzi belongs to the same family as Leishmania spp., and treatments for the disease it produces also needs renewal. Among the derivatives tested, compounds 1, 2, 9, 10, 11, and 12 showed low J774.2 macrophage toxicity, while their effect against both intracellular and extracellular forms of the studied parasites was higher than the ones found for the reference drug Meglumine Antimoniate (Glucantime®). In addition, their Fe-SOD inhibitory effect, the infection rates, metabolite alteration, and mitochondrial membrane potential of the parasites treated with the selected drugs were studied in order to gain insights into the action mechanism, and the results of these tests were more promising than those found with glucantime, as the leishmanicidal effect of these new drug candidates was higher. The promising results are encouraging to test these derivatives in more complex studies, such as in vivo studies and other experiments that could find out the exact mechanism of action.Authors appreciate the financial support from the Spanish Ministry of Science, Innovation and Universities (projects SAF2015-66690-R and RTI2018-093940-B-I00) and Spanish Ministry of Education and Science (project CSD 2010-00065). R.M.E. is grateful for a FPU grant [FPU14/01537] from the Ministry of Education of Spain and B.A.V. is grateful for an initiation into research grant from FONDECYT 11150559Peer Reviewe

C/EBPβ and Nuclear Factor of Activated T Cells Differentially Regulate Adamts-1 Induction by Stimuli Associated with Vascular Remodeling

Emerging evidence indicates that the metalloproteinase Adamts-1 plays a significant role in the pathophysiology of vessel remodeling, but little is known about the signaling pathways that control Adamts-1 expression. We show that vascular endothelial growth factor (VEGF), angiotensin-II, interleukin-1β, and tumor necrosis factor α, stimuli implicated in pathological vascular remodeling, increase Adamts-1 expression in endothelial and vascular smooth muscle cells. Analysis of the intracellular signaling pathways implicated in this process revealed that VEGF and angiotensin-II upregulate Adamts-1 expression via activation of differential signaling pathways that ultimately promote functional binding of the NFAT or C/EBPβ transcription factors, respectively, to the Adamts-1 promoter. Infusion of mice with angiotensin-II triggered phosphorylation and nuclear translocation of C/EBPβ proteins in aortic cells concomitantly with an increase in the expression of Adamts-1, further underscoring the importance of C/EBPβ signaling in angiotensin-II-induced upregulation of Adamts-1. Similarly, VEGF promoted NFAT activation and subsequent Adamts-1 induction in aortic wall in a calcineurin-dependent manner. Our results demonstrate that Adamts-1 upregulation by inducers of pathological vascular remodeling is mediated by specific signal transduction pathways involving NFAT or C/EBPβ transcription factors. Targeting of these pathways may prove useful in the treatment of vascular disease

In vitro evaluation of leishmanicidal properties of a new family of monodimensional coordination polymers based on diclofenac ligand

Some series of isostructural chains with general formula [M(diclof)(HO)]·(EtOH) have been obtained from reaction between diclofenac ligand (diclof) and first row transition salts (M = Mn (1),Ni (2) and Co (3)). These monodimensional coordination polymers have been characterized and their crystal structures have been solved by X-ray diffraction methods, elucidating isostructural compounds that are chains with water molecules acting as bridge between different metallic centers, while diclofenac ligands are coordinated to the octahedral coordination environment of the same. Magnetic studies of these complexes have revealed the existence of moderate ferromagnetic interactions among manganese, nickel and cobalt ions, with J values of 0.1, 0.60 and 3.3 cm, respectively. It must be highlighted that in vitro leishmanicidal activity of these new complexes has been studied against three different strains of Leishmania spp. showing a higher efficacy than the reference drug Glucantime® and demonstrating the potential of these novel materials based on coordination chemistry.Financial support was provided by Junta de Andalucía , Spain (project number FQM-394 and FQM-1484 ), University of the Basque Country , Spain ( GIU 17/13 ) and the Spanish Ministry of Economy and Competitiveness , Spain ( MCIU/AEI/FEDER , UE) (PGC2018-102052-A-C22 and PGC2018-102052-B-C21). The authors thank for technical and human support provided by SGIker of UPV/EHU , Spain and European funding ( ERDF and ESF, Europe). R.M-E. is grateful for a FPU Grant ( FPU14/01537 ) from the Ministry of Education of Spain

Cuadernos de filosofía moral : unidades didácticas

Las siguientes unidades didácticas están pensadas para que los alumnos puedan trabajar en la clase de ética: 1.Génesis de los valores; 2.Racismo; 3.Pena de muerte y derechos humanos; 4.Feminismo; 5.Ecología y 6. Democracia. Pretenden que los profesores y los alumnos de ética descubran en el ejercicio de la reflexión y el análisis, en la meditación sobre los problemas morales, la extraordianria rareza del ser humano, a medias entre la bestia y el serafín, entre el villano y el héroe, pero siempre necesitado de un momento de detenimiento en la inhumana vorágine de la rutina diaria..MadridBiblioteca de Educación del Ministerio de Educación, Cultura y Deporte; Calle San Agustín, 5; 28014 Madrid; Tel. +34917748000; [email protected]