Retrospective analysis of effectiveness of fingolimod in real life setting in Turkey (REFINE).

BACKGROUND: During multiple sclerosis (MS) treatment different modes of action such as lateral (interferon beta to glatiramer acetate or glatiramer acetate to interferon beta) or vertical (interferon beta/glatiramer acetate to fingolimod) drug switch can be performed. This study aims to investigate the clinical effectiveness of switching from the first-line injectable disease modifying treatments (iDMTs) to fingolimod (FNG) compared to switching between first-line iDMTs. METHODS: This is a multicenter, observational and retrospective study of patients with relapsing-remitting MS who had lateral and vertical switch. The observation period included three key assessment time points (before the switch, at switch, and after the switch). Data were collected from the MS patients' database by neurologists between January 2018 and June 2019. The longest follow-up period of the patients was determined as 24 months after the switch. RESULTS: In 462 MS patients that were included in the study, both treatments significantly decreased the number of relapses during the postswitch 12 months versus preswitch one year while patients in the FNG group experienced significantly fewer relapses compared to iDMT cohort in the postswitch 12 months period. FNG cohort experienced fewer relapses than in the iDMT cohort within the postswitch 2 year. The mean time to first relapse after the switch was significantly longer in the FNG group. DISCUSSION: The present study revealed superior effectiveness of vertical switch over lateral switch regarding the improvement in relapse outcomes. Patients in the FNG cohort experienced sustainably fewer relapses during the follow-up period after the switch compared the iDMT cohort. Importantly, switching to FNG was more effective in delaying time to first relapse when compared with iDMTs.

Galectin-9 supports primary T cell transendothelial migration in a glycan and integrin dependent manner.

Adaptive immunity relies on the efficient recruitment of T cells from the blood into peripheral tissues. However, the current understanding of factor(s) coordinating these events is incomplete. Previous studies on galectin-9 (Gal-9), have proposed a functionally significant role for this lectin in mediating leukocyte adhesion and transmigration. However, very little is known about its function in T cell migration. Here, we have investigated the role of the Gal-9 on the migration behaviour of both human primary CD4+ and CD8+ T cells. Our data indicate that Gal-9 supports both CD4+ and CD8+ T cell adhesion and transmigration in a glycan dependent manner, inducing L-selectin shedding and upregulation of LFA-1 and CXCR4 expression. Additionally, when immobilized, Gal-9 promoted capture and firm adhesion of T cells under flow, in a glycan and integrin-dependent manner. Using an in vivo model, dorsal air pouch, we found that Gal-9 deficient mice display impaired leukocyte trafficking, with a reduction in pro-inflammatory cytokines/chemokines generated locally. Furthermore, we also demonstrate that Gal-9 inhibits the chemotactic function of CXCL12 through direct binding. In conclusion, our study characterises, for the first time, the capture, adhesion, and migration behaviour of CD4+ and CD8+ T cells to immobilised /endothelial presented Gal-9, under static and physiological flow conditions. We also demonstrate the differential binding characteristics of Gal-9 to T cell subtypes, which could be of potential therapeutic significance, particularly in the treatment of inflammatory-based diseases, given Gal-9 ability to promote apoptosis in pathogenic T cell subsets.

Pulmonary delivery of favipiravir inhalation solution for COVID-19 treatment: in vitro characterization, stability, in vitro cytotoxicity, and antiviral activity using real time cell analysis.

Favipiravir, an RNA-dependent RNA polymerase (RdRp) inhibitor, is used to treat patients infected with influenza virus and most recently with SARS-CoV-2. However, poor accumulation of favipiravir in lung tissue following oral administration has required an alternative method of administration that directly targets the lungs. In this study, an inhalation solution of favipiravir at a concentration of 2 mg mL-1 was developed and characterized for the first time. The chemical stability of inhaled favipiravir solution in two different media, phosphate buffer saline (PBS) and normal saline (NS), was investigated under different conditions: 5 ± 3 °C, 25 ± 2 °C/60% RH ± 5% RH, and 40 ± 2 °C/75% RH ± 5% RH; in addition to constant light exposure. As a result, favipiravir solution in PBS revealed superior stability over 12 months at 5 ± 3 °C. Antiviral activity of favipiravir was assessed at the concentrations between 0.25 and 3 mg mL-1 with real time cell analyzer on Vero-E6 that were infected with SARS-CoV-2/B.1.36. The optimum concentration was found to be 2 mg mL-1, where minimum toxicity and sufficient antiviral activity was observed. Furthermore, cell viability assay against Calu-3 lung epithelial cells confirmed the biocompatibility of favipiravir at concentrations up to 50 µM (7.855 mg mL-1). The in vitro aerodynamic profiles of the developed inhaled favipiravir formulation, when delivered with soft-mist inhaler indicated good lung targeting properties. These results suggest that favipiravir solution prepared with PBS could be considered as a suitable and promising inhalation formulation for pulmonary delivery in the treatment of patients with COVID-19.

Pulmonary Delivery of Favipiravir in Rats Reaches High Local Concentrations without Causing Oxidative Lung Injury or Systemic Side Effects.

Favipiravir displays a rapid viral clearance, a high recovery rate and broad therapeutic safety; however, its oral administration was associated with systemic side effects in susceptible patients. Considering that the pulmonary route could provide a high drug concentration, and a safer application with less absorption into systemic circulation, it was aimed to elucidate whether favipiravir delivered via soft-mist inhaler has any deleterious effects on lung, liver and kidney tissues of healthy rats. Wistar albino rats of both sexes (n = 72) were placed in restrainers, and were given either saline or favipiravir (1, 2.5, 5 or 10 mg/kg in 1 mL saline) by inhalation within 2 min for 5 consecutive days. On the 6th day, electrocardiographic recording was obtained, and cardiac blood and lung tissues were collected. Favipiravir did not alter cardiac rhythm, blood cell counts, serum levels of alanine transaminase, aspartate transaminase, blood urea nitrogen, creatinine, urea or uric acid, and did not cause any significant changes in the pulmonary malondialdehyde, myeloperoxidase activity or antioxidant glutathione levels. Our data revealed that pulmonary use of favipiravir via soft-mist inhaler enables a high local concentration compared to plasma without oxidative lung injury or cardiac or hepatorenal dysfunction.

Risk factors influencing mortality related to Stenotrophomonas maltophilia infection in hematology-oncology patients.

Stenotrophomonas maltophilia infection is of concern in patients with cancer. Antibiotics active against S. maltophilia are rarely used in the treatment of febrile neutropenia, making it important to identify the factors influencing mortality in cancer patients with S. maltophilia infection. The objective of this study was to analyze the clinical characteristics and outcomes of cancer and hemopathic patients with S. maltophilia infection and assess the factors influencing the mortality. The microbiology laboratory records of Erciyes University, Faculty of Medicine Hospital were reviewed to retrospectively identify patients with S. maltophilia infection between January 2007 and June 2011. A total of 38 patients (25 male, 13 female) were eligible for the study. The median age of the patients was 53 years. The underlying disease was hematological malignancy and disorders in 76.3 % (29 cases), solid tumors in 15.8 % (six cases), aplastic anemia in 7.9 % (three cases), while 18.4 % (seven cases) were hematopoietic stem cell transplantation (HSCT) recipients. An indwelling central venous catheter was used in 32 cases (84.2 %). Twenty-seven patients (71.1 %) were neutropenic at the onset of infection. Nine patients (23.7 %) were receiving corticosteroid therapy. The overall 14-day mortality rate was 50 %. Three of the patients received empirical antibacterial treatment, and three HSCT recipients received trimethoprim-sulfamethoxazole prophylaxis, which is active against S. maltophilia. Severe sepsis (OR 13.24, 95 % confidence interval (CI) 1.62-108.57) and the duration of the treatment (OR 0.73, 95 % CI 0.60-0.90) were related to death based on logistic regression analysis findings. In immunocompromised hematology-oncology patients with severe sepsis, S. maltophilia should be considered as a possible cause of infection, and should be given effective empirical antibiotic treatment immediately; the antimicrobial spectrum may be narrowed according to results of antibiotic susceptibility test.