Advanced results of Fortelyzin® use in the FRIDOM1 study and real clinical practice

Aim. To study the effectiveness of Fortelyzin® in subgroups with different body weights in patients with ST-segment elevation acute myocardial infarction (STEMI) in the FRIDOM1 study and real clinical practice.Material and methods. Fortelyzin® was administered in a single-bolus dose of 15 mg over 10 seconds, regardless of the body weight of patients. Metalyse® was administered in a single-bolus dose of 30-50 mg over 10 seconds, depending on body weight. The one-year results of the FRIDOM1 study were evaluated by the clinical centers using telephone contact. Monitoring of Fortelyzin® use was carried out by inpatient physicians, emergency doctors and paramedics by filling out a monitoring sheet in the period from June 2013 to December 2021 in 19243 patients with STEMI.Results. In the FRIDOM1 study, the distribution of patients depending on body weight in the Fortelyzin® (n=190) and Metalyse® (n=191) drug groups was as follows: up to 60 kg — 4 people each (p=1,00); from 60 to 70 kg — 21 and 23 (p=0,87); from 70 to 80 kg — 39 and 43 (p=0,71), from 80 to 90 kg — 63 and 47 (p=0,07); from 90 to 100 kg — 30 and 41 (p=0,19); over 100 kg — 33 people (p=1,00) in each group. The effectiveness of thrombolysis according to electrocardiographic (ECG) data in the Fortelyzin® and Metalyse® groups was as follows: up to 60 kg — 75% each (p=1,00); from 60 to 70 kg — 76% vs 83% (p=0,72); from 70 to 80 kg — 82% vs 86% (p=0,76); from 80 to 90 kg — 81% vs 77% (p=0,64); from 90 to 100 kg — 80% vs 81% (p=1,00); over 100 kg — 79% vs 76% (p=1,00); in total — 80% vs 80% (p=0,87). The effectiveness of thrombolysis according to coronary angiography (CAG) (TIMI 2-3) in the Fortelyzin® and Metalyse® groups was as follows: up to 60 kg — 100% vs 50% (p=0,43); from 60 to 70 kg — 81% vs 67% (p=0,48); from 70 to 80 kg — 74% vs 84% (p=0,41); from 80 to 90 kg — 70% vs 72% (p=1,00); from 90 to 100 kg — 67% vs 66% (p=1,00); over 100 kg — 58% vs 64% (p=0,80); in total — 70% vs 71% (p=0,76). The one-year survival rate in the FRIDOM1 study in the Fortelyzin® and Metalyse® groups was 94% (p=0,91). The administration of Fortelyzin® in patients with STEMI caused blood flow restoration according to ECG data in 14624 of 19243 patients (76%), while according to CAG (TIMI 2-3) — in 3422 of 4805 patients (71%). Inhospital mortality was 5% (n=962), while intracranial hemorrhage developed in 0,5% (n=92).Conclusion. The use of Fortelyzin® in the FRIDOM1 study and in real clinical practice in a single-bolus (10 sec) dose of 15 mg in patients with STEMI with any body weight showed its high efficacy and safety, including at the prehospital stage

Improved functionalization of oleic acid-coated iron oxide nanoparticles for biomedical applications

Superparamagnetic iron oxide nanoparticles can providemultiple benefits for biomedical applications in aqueous environments such asmagnetic separation or magnetic resonance imaging. To increase the colloidal stability and allow subsequent reactions, the introduction of hydrophilic functional groups onto the particles’ surface is essential. During this process, the original coating is exchanged by preferably covalently bonded ligands such as trialkoxysilanes. The duration of the silane exchange reaction, which commonly takes more than 24 h, is an important drawback for this approach. In this paper, we present a novel method, which introduces ultrasonication as an energy source to dramatically accelerate this process, resulting in high-quality waterdispersible nanoparticles around 10 nmin size. To prove the generic character, different functional groups were introduced on the surface including polyethylene glycol chains, carboxylic acid, amine, and thiol groups. Their colloidal stability in various aqueous buffer solutions as well as human plasma and serum was investigated to allow implementation in biomedical and sensing applications.status: publishe

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Fortelyzin® in comparison with Metalyse® for ST-elevated myocardial infarction: one-year results and clinical outcomes of a multicenter randomized study FRIDOM1

Aim. Evaluate the one­year results and clinical outcomes of a multi­center randomized clinical trial FRIDOM1.Material and methods. The study FRIDOM1 was conducted in 11 clinical centers of the Russian Federation in the period 2014­2016. The study included 382 patients with acute ST­elevated myocardial infarction (STEMI), who were randomly divided into the Fortelyzin® and Metalyse®. Thrombolysis was accompanied by anticoagulant and dual antiplatelet therapy followed by percutaneous coronary intervention (PCI). One­year patient status, all­cause mortality, including cardiovascular diseases (CVD), hospitalization, and one­year survival were assessed by telephone contact.Results. The one­year patient status was determined in 186 out of 191 (97,4%) in the Fortelyzin® group and in 185 out of 191 (96,9%) patients in the Metalyse® group. One­year all­cause mortality was 5,9% and 6,5% in the Fortelyzin® and Metalyse® groups, respectively (p=0,83; OR 0,91; 95% CI — 0,42­1,98). One­year mortality from CVD in the Fortelyzin® group is 5,4%, in the Metalyse® group — 6,5% (p=0,67; OR 0,83; 95% CI — 0,37­1,83). All­cause mortality between 30 days and 1 year in the Fortelyzin® group was in 2,2% of patients, CVD — in 1,6%, in the group of Metalise® mortality was in 2,7% of patients (all — CVD). One­year survival was 94,1% and 93,5% in the Fortelyzin® and Metalyse® groups, respectively.Conclusion. The one­year results of the FRIDOM1 study showed the efficacy and safety of a single bolus administration of Fortelyzin® as part of a pharmaco­invasive strategy for treating patients with STEMI, as well as clinical outcomes that are comparable with Metalyse®, including high survival rates and low CVD mortality

Secondary hemophagocytic syndrome in adult patients. Study of 91 patients

Background. Secondary hemophagocytic lymphohystiocytosis (sHLH) is a hyperinflammatory reaction provoked by some trigger (cancer, autoimmune or infection). The majority of affected patients are at high risk of fatal multiple organ failure without getting immunsupressive treatment.Objective. Clinical and laboratory profile of sHLH patients.Materials and methods. Retrospective study included clinical, instrumental and lab data from the 91 patients followed between June 2009 and June 2019. Diagnosis sHLH had been based on HLH-2004 and H-Score criteria. The analyzed parameters had been fever chart, liver and spleen enlargement, changes in the bone marrow; values levels of glutamic pyruvic transaminase, serum glutamic oxaloacetic transaminase, alkaline phosphatase, bilirubin, triglycerides, total ferritin with percentage of glycosylation. All patients with rheumatic disorders or malignancies had received either immunosuppressive or cytotoxic therapy. Febrile patients received anti-infective treatment according to the local routine protocols.Results. The data from 91 patients (41 male and 50 female) had been analyzed. Median age was 58 (2–90) years. The sHLH trigger-diseases spectrum included leukemia/lymphoma (n = 52), infection diseases (n = 11), autoimmune disorders (n = 5), allogenic bone marrow transplantation (n = 13), unidentified (n = 10). A fever with an unknown origin and refractory to antibacterial treatment had been observed in 87 (96 %) patients. Morphological hemophagocytic evidences in the bone marrow had been found in 83 %. Breath shortening, liver failure, neurologic disturbances, systemic effusions, rash, heart failure had been registered in 83 % patients. Detected splenomegaly presented in 56 %. Laboratory changes, median were as following: serum glutamic-pyruvic transaminase (alanine aminotransferase, SGPT) – 92 (39.2–1060.8) IU/L; serum glutamic oxaloacetic transaminase (aspartate aminotransferase, SGOT) – 105 (40–4177) IU/L; alkaline phosphatase – 225 (120.9–989) IU/L; bilirubin – 50.5 (22–559) µmol/L; triglycerides – 3.2 (1.95–8.6) mmol/L; total ferritin – 10000 (597–255000) ng/mL with glycosylation percentage – 20.45 (0–37.8) %. 71 patients received various of HLH-directed therapy courses. The overall survival rate was 27 %, median follow-up – 540 days.Conclusion. The main clinical and instrumental findings in sHLH are fever, refractory to anti-infective treatment, elevation of transaminases, serum alkaline phosphatase, triglycerides, total ferritine with low glycosylated fraction. Early diagnosing and immunesupression are the main factors of survival

PROGNOSTIC SIGNIFICANCE OF POSITRON EMISSION TOMOGRAPHY IN AUTOLOGOUS STEM CELL TRANSPLANTATION FOR NON-HODGKIN’S LYMPHOMA

Objective: evaluation and comparison of positron emission tomography (PET) prognostic value with other predictors of effectiveness in patients with non-Hodgkin’s lymphoma (NHL) receiving high-dose chemotherapy with autologous hematopoietic stem cell transplantation (AHSCT).Materials and methods. The retrospective data on 49 consecutive patients with NHL  receiving high-dose chemotherapy with АHSCT was               analyzed. The median age was 36.2 (7–60)  years. Median follow-up is currently 24 (1–82)  months. Prognostic factors analyzed included sex, response to the initial chemotherapy, time to relapse, second-line chemotherapy regimen type, B-symptoms on relapse, serum lactate dehydrogenase and albumin levels, response assessed by computer tomography (CT), number of chemotherapy lines, condition regimen, PET-scan results before (PET1, n = 49) and after (PET2, n = 39) AHSCT.Results. Two-year overall and event-free survivals were 74.4 and 79.1 %, respectively. Patients with CT-confirmed progression prior to AH-SCT had the worse prognosis. Prognostic significance of PET-status  was shown in chemosensitive patients (partial/complete response).The overall survival in PET1-negative and PET1-positive patients were 95.4 vs 71.0 % (р = 0.019), respectively. In PET2-positive and PET2-negative patients the overall and event-free survivals were 59.8 vs 100 % (р = 0.001) and 54.4 vs 94.4 % (р = 0.02), respectively.     In combined analysis of PET1 and PET2 statuses prognostic significance of PET2 prevailed over PET1 results significance. The multivariate analysis confirmed only PET1 significance for survival prediction.   Conclusion. Chemosensitivity of the tumor, assessed by CT, is the most important prognostic factor. In chemosensitive patients achievement PET1 or PET2 negativity means better prognosis. The patients with PET positivity prior and after AHSCT have the worst prognosis

Experimental study of a crystal positron source

Tungsten crystals oriented on their axis, were submitted to 6 and 10 GeV electron beams on the SPS-CERN transfer lines. The crystals, 4 and 8 mm thick, used alone or associated to 4 mm thick amorphous disk, were studied as positron sources. The emerging positrons were detected by a drift chamber partially immersed in a magnetic field, where their trajectories were reconstructed providing the energy spectrum and the angular distribution. Significant enhancements were observed for the crystal source when compared to the amorphous one of the same thickness. The gain was larger than 3 and 2 for the 4 mm and 8 mm targets, respectively. The presented results look very promising for e/sup +/e/sup -/ linear colliders. (20 refs)