Heparins are sulfated polysaccharides with a heterogeneous mixture derived from animal tissues, subject to supply limitations and the risk of animal virus residues. Patients using heparin also face the risks of spontaneous bleeding and thrombocytopenia. Here we reported an efficient riclinoctaose-based approach for rapid chemical synthesis of a structurally defined heparin-like anticoagulant sulfated octasaccharide (SRO). We used sulfur trioxide-pyridine, sulfur trioxide-trimethylamine, and sulfur trioxide-triethylamine complexes as solvents for one-pot O-sulfation and determined the optimal conditions for synthesizing SRO. Sulfur trioxide-trimethylamine provided reasonable control over the degree of substitution between 1.85 and 1.88, revealing a single molecule with a theoretical molecular weight of 2952.96 g/mol. The structural features of the SRO were carried out by Fourier transform infrared spectroscopy and one- and two- dimensional ¹H and ¹³C NMR analysis, revealing sulfation repeatedly present at the fixed positions of C-6/C-2/C-3 and reducing terminals. The anticoagulant activity of SRO was demonstrated by efficiently blocking coagulation in the blood of mice and human. SRO dose-dependently decreased ferric chloride-induced experimental thrombosis in mice. Like heparin, SRO specifically inhibits coagulation factor Xa, but significantly reduces the risk of bleeding compared to heparin. Therefore, we named it octaparin. These results support that octaparin is expected to replace animal-sourced heparin.

01 Oct 2024·eJHaem

Evaluation of bleeding risk in patients who received pirtobrutinib in the presence or absence of antithrombotic therapy

Article

Author: Ruppert, Amy S. ; Kontos, Arrin ; Palomba, M. Lia ; Jurczak, Wojciech ; Compte, Livia ; Flinn, Ian W. ; Alencar, Alvaro J. ; Konig, Heiko ; Cohen, Jonathon B. ; Chatterjee, Anindya ; Tsai, Donald E. ; Zinzani, Pier Luigi ; Lamanna, Nicole ; Tam, Constantine S. ; Fakhri, Bita ; Woyach, Jennifer A. ; Sizelove, Richard

AbstractClinical bleeding events are reported here from 773 patients with B‐cell malignancies receiving pirtobrutinib monotherapy from the phase 1/2 BRUIN study (ClinicalTrials.gov identifier: NCT03740529), either in the presence or absence of antithrombotic therapy (antithrombotic exposed [AT‐E], n = 216; antithrombotic nonexposed [AT‐NE], n = 557). Among the AT‐E cohort, 51.9% received platelet aggregation inhibitors, 36.6% received direct factor Xa inhibitors, 18.5% received heparins, 5.6% received salicylic acid for indications other than platelet aggregation inhibition, and 2.3% received thrombolytics. Warfarin was not permitted. Any‐grade bleeding/bruising events occurred in 97 patients (44.9%; 95% confidence interval [CI], 38.3–51.5) in the AT‐E cohort and 181 patients (32.5%; 95% CI, 28.6–36.4) in the AT‐NE cohort. Most bleeding/bruising events in both cohorts began within the first 6 months of treatment (AT‐E: 65.4%; AT‐NE: 72.5%). Contusion was the most common bleeding/bruising event in both cohorts (AT‐E: 22.7%; AT‐NE: 18.1%). Grade ≥3 bleeding/bruising events were reported in six patients (2.8%) in the AT‐E cohort and 11 patients (2.0%) in the AT‐NE cohort. Bleeding/bruising events requiring or prolonging hospitalization were reported in 2.3% and 1.6% of patients in the AT‐E and AT‐NE cohorts, respectively. No bleeding/bruising events led to pirtobrutinib dose reduction or permanent discontinuation in the AT‐E cohort, and one patient (0.2%) in the AT‐NE cohort experienced an event requiring dose reduction. These data support the safety of pirtobrutinib in patients requiring antithrombotic therapies.

01 Sep 2024·Cardiovascular Revascularization Medicine

Acetylsalicylic acid alone or in combination with either enoxaparin or unfractionated heparin for postoperative thromboprophylaxis in coronary artery bypass surgery patients. A randomised clinical trial assessing surrogate outcomes

Article

Author: Arendrup, Henrik ; Johansson, Pär Ingemar ; Jakobsen, Janus Christian ; Lorenzen, Ulver Spangsberg

INTRODUCTIONCoronary artery bypass graft surgery has considerable effects on patient haemostasis. Heparins as thromboprophylaxis may be beneficial but may also increase the risk of bleeding complications.OBJECTIVESTo assess the effects of heparins on haemostasis in post-coronary artery bypass graft patients.METHODSAcross one year, we randomised 60 participants scheduled for an elective coronary artery bypass graft-procedure with or without aortic valve replacement. The trial was a prospective, open-label (though blinded for the laboratory), randomised, single-centre trial with three intervention groups (n = 20 in each): group 1 received acetylsalicylic acid, group 2 received subcutaneous low molecular weight heparin and acetylsalicylic acid, and group 3 received intravenous unfractionated heparin and acetylsalicylic acid. Primary outcomes were platelet activation (Multiplate® ASPI-test) and time to clot initiation (TEG® R-time). We secondly assessed several additional Multiplate® and TEG® parameters.RESULTSGroup 3 (intravenous unfractionated heparin) compared with group 1 (acetylsalicylic acid alone) showed evidence of 1) increased clot initiation time (R-time + 0.9 min; 95 % CI: +0.4 to +1.4 min; P = 0.009), and 2) decreased 30-min lysis (-1.3 %; 95 % CI: -2.1 to -0.5 %; P = 0.02). The remaining analyses of primary and secondary outcomes showed no evidence of a difference between the three groups.DISCUSSIONIntravenous unfractionated heparins may increase the clot initiation time post-operatively after coronary artery bypass graft surgery and reduce lysis. Otherwise, there seems to be no effect of low molecular weight or unfractionated heparin on haemostatic parameters after coronary artery bypass surgery patients.

100 Deals associated with Hepcidin Inhibition(University of Brescia)

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Indication	Highest Phase	Country/Location	Organization	Date
Anemia	Preclinical	IT	Università degli Studi di Brescia	16 Nov 2012

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