Risultati per: Cardiovascolari Alfa 1-agonisti

Circulation, Volume 150, Issue Suppl_1, Page A4139743-A4139743, November 12, 2024. Background:Alfa-tubulin detyrosination is one of the post-translational modifications of tubulin c-terminal tail, observed in failing cardiomyocytes. Tubulin is known to regulate mitochondrial function, however, the effects of detyrosinated α-tubulin on mitochondrial function remains unrevealed.Methods and Results:We tested the effects of α-tubulin detyrosination on mitochondrial function with tubulin tyrosine ligase knocked out (TTL KO) H9C2 and Vasohibin 1 overexpressed (VASH1 OE) H9C2 cells, which had high amounts of detyrosinated α-tubulin. Alfa-tubulin detyrosination reduced mitochondrial respiration and mitochondrial membrane potential. Moreover, we found mitophagy, evaluated with Mito-Keima fluorescence and LC3 lipidation, were suppressed in TTL KO and VASH1 OE cells. Mitochondria in detyrosinated α-tubulin increasing cells contained less ubiquitinated proteins, suggesting that α-tubulin detyrosination might inhibit Parkin-mediated mitophagy. Next, we overexpressed VASH1 in the mouse heart with AAV9 to validate the effects of detyrosinated α-tubulin on cardiac function. Cardiomyocyte-restricted overexpression of VASH1 led to heart failure with preserved ejection fraction (HFpEF) evidenced by prolonged isovolumic relaxation time and increased mitral E/E’ ratio. Cardiac VASH1 OE mice also displayed a reduction in running distance during exercise exhaustion test. The VASH1 OE heart showed suppressed LC3 lipidation, suggesting decreased mitophagy.Conclusion:We demonstrated α-tubulin detyrosination reduces mitochondrial function through the inhibition of mitophagy, leading to HFpEF progression. Our study elucidates that α-tubulin detyrosination may act as a potential target for the novel therapy for HFpEF patients.

This phase 2 nonrandomized controlled trial evaluates the safety and response rates of bintrafusp alfa in patients with recurrent or metastatic cervical cancer.

Studio, dimostrata l’efficacia di un test predittivo nelle donne

New England Journal of Medicine, Volume 391, Issue 3, Page 235-246, July 18, 2024.

Circulation, Volume 149, Issue 16, Page 1315-1318, April 16, 2024.

Il rischio di morte è 4 volte più alto, vaccino potrebbe ridurlo

Nel 15% dei Paesi europei sono segnalati tra 500 e 600 farmaci mancanti e nel 27% più di 600. Anche l’Italia non è esente

Circulation, Volume 148, Issue Suppl_1, Page A15557-A15557, November 6, 2023. Introduction:Andexanet is FDA approved for reversal of life-threatening bleeding from factor Xa (FXa) inhibitors rivaroxaban and apixaban and off-label for urgent surgical reversal. Data are lacking on processes to ensure prompt andexanet dosing.Hypothesis:Presentation-to-andexanet time depends on clinical, demographic, and hospital factors.Goals:To identify factors impacting presentation-to-andexanet time and post-andexanet adverse outcomes.Methods:We retrospectively studied patients at a 23-hospital system who received andexanet from November 3, 2019, to March 4, 2023. Abstractors manually coded demographics, comorbidities, anticoagulant use, andexanet indication, and clinical pathway time stamps. The primary outcome was presentation-to-andexanet time. Secondary outcomes were post-andexanet major thromboembolism or bleeding, and in-hospital mortality.Results:110 patients were analyzed (mean age 77.4 years, 71.3% White). Most patients were on lower dose FXa inhibitors without antiplatelets; 77% had at least 2 vascular comorbidities. Andexanet was used most for intracranial hemorrhage (ICH) (80%); 7% of doses were for urgent surgery (Table 1). Median presentation-to-andexanet time was 219 minutes. Linear regression showed non-ICH bleeding was associated with greater time to andexanet dose. More post-treatment thromboembolism or bleeding occurred at tertiary academic hospitals (p = 0.02). In-hospital mortality did not differ among hospital types (Table 2).Conclusions:In a retrospective study, a non-ICH site was associated with greater median time to andexanet dose. More post-andexanet adverse events occurred at tertiary hospitals.

Background
The interleukin-22 cytokine (IL-22) has demonstrated efficacy in preclinical colitis models with non-immunosuppressive mechanism of action. Efmarodocokin alfa (UTTR1147A) is a fusion protein agonist that links IL-22 to the crystallisable fragment (Fc) of human IgG4 for improved pharmacokinetic characteristics, but with a mutation to minimise Fc effector functions.

Methods
This randomised, phase 1b study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of repeat intravenous dosing of efmarodocokin alfa in healthy volunteers (HVs; n=32) and patients with ulcerative colitis (n=24) at 30–90 µg/kg doses given once every 2 weeks or monthly (every 4 weeks) for 12 weeks (6:2 active:placebo per cohort).

Results
The most common adverse events (AEs) were on-target, reversible, dermatological effects (dry skin, erythema and pruritus). Dose-limiting non-serious dermatological AEs (severe dry skin, erythema, exfoliation and discomfort) were seen at 90 μg/kg once every 2 weeks (HVs, n=2; patients, n=1). Pharmacokinetics were generally dose-proportional across the dose levels, but patients demonstrated lower drug exposures relative to HVs at the same dose. IL-22 serum biomarkers and IL-22-responsive genes in colon biopsies were induced with active treatment, and microbiota composition changed consistent with a reversal in baseline dysbiosis. As a phase 1b study, efficacy endpoints were exploratory only. Clinical response was observed in 7/18 active-treated and 1/6 placebo-treated patients; clinical remission was observed in 5/18 active-treated and 0/6 placebo-treated patients.

Conclusion
Efmarodocokin alfa had an adequate safety and pharmacokinetic profile in HVs and patients. Biomarker data confirmed IL-22R pathway activation in the colonic epithelium. Results support further investigation of this non-immunosuppressive potential inflammatory bowel disease therapeutic.

Trial registration number
NCT02749630.

Biomarcatori ed esami diagnostici più precisi cambiano i paradigmi di prevenzione. Non può essere più divisa solo tra primaria e secondaria, bisogna sempre più tener conto del danno d’organo. Servono poi un nuovo approccio per l’assistenza al paziente fragile e campagne informative sull’arteriopatia periferica

Il convegno di Motore Sanità al Palazzo Pirelli di Milano

Cardiologi, controlli regolari. Iss, salgono casi tra sanitari

Circulation, Ahead of Print. BACKGROUND:Andexanet alfa is a modified recombinant inactive factor Xa (FXa) designed to reverse FXa inhibitors. ANNEXA-4 (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors) was a multicenter, prospective, phase-3b/4, single-group cohort study that evaluated andexanet alfa in patients with acute major bleeding. The results of the final analyses are presented.METHODS:Patients with acute major bleeding within 18 hours of FXa inhibitor administration were enrolled. Co-primary end points were anti-FXa activity change from baseline during andexanet alfa treatment and excellent or good hemostatic efficacy, defined by a scale used in previous reversal studies, at 12 hours. The efficacy population included patients with baseline anti-FXa activity levels above predefined thresholds (≥75 ng/mL for apixaban and rivaroxaban, ≥40 ng/mL for edoxaban, and ≥0.25 IU/mL for enoxaparin; reported in the same units used for calibrators) who were adjudicated as meeting major bleeding criteria (modified International Society of Thrombosis and Haemostasis definition). The safety population included all patients. Major bleeding criteria, hemostatic efficacy, thrombotic events (stratified by occurring before or after restart of either prophylactic [ie, a lower dose, for prevention rather than treatment] or full-dose oral anticoagulation), and deaths were assessed by an independent adjudication committee. Median endogenous thrombin potential at baseline and across the follow-up period was a secondary outcome.RESULTS:There were 479 patients enrolled (mean age, 78 years; 54% male, 86% White; 81% anticoagulated for atrial fibrillation at a median time of 11.4 hours since last dose, with 245 (51%) on apixaban, 176 (37%) on rivaroxaban, 36 (8%) on edoxaban, and 22 (5%) on enoxaparin. Bleeding was predominantly intracranial (n=331 [69%]) or gastrointestinal (n=109 [23%]). In evaluable apixaban patients (n=172), median anti-FXa activity decreased from 146.9 ng/mL to 10.0 ng/mL (reduction, 93% [95% CI, 94–93]); in rivaroxaban patients (n=132), it decreased from 214.6 ng/mL to 10.8 ng/mL (94% [95% CI, 95–93]); in edoxaban patients (n=28), it decreased from 121.1 ng/mL to 24.4 ng/mL (71% [95% CI, 82–65); and in enoxaparin patients (n=17), it decreased from 0.48 IU/mL to 0.11 IU/mL (75% [95% CI, 79–67]). Excellent or good hemostasis occurred in 274 of 342 evaluable patients (80% [95% CI, 75–84]). In the safety population, thrombotic events occurred in 50 patients (10%); in 16 patients, this occurred during treatment with prophylactic anticoagulation that began after the bleeding event. No thrombotic episodes occurred after oral anticoagulation restart. Specific to certain populations, reduction of anti-FXa activity from baseline to nadir significantly predicted hemostatic efficacy in patients with intracranial hemorrhage (area under the receiver operating characteristic curve, 0.62 [95% CI, 0.54–0.70]) and correlated with lower mortality in patients