Ciraparantag reverses the anticoagulant activity of apixaban and rivaroxaban in healthy elderly subjects.

Aims: Ciraparantag is a reversal agent for anticoagulants including direct oral anticoagulants. The aim was to evaluate the efficacy and safety of ciraparantag to reverse anticoagulation induced by apixaban or rivaroxaban in healthy elderly adults.

Methods And Results: Two randomized, placebo-controlled, dose-ranging trials conducted in healthy subjects aged 50-75 years.

Ciraparantag, an anticoagulant reversal drug: mechanism of action, pharmacokinetics, and reversal of anticoagulants.

Ciraparantag, an anticoagulant reversal agent, is a small molecule specifically designed to bind noncovalently by charge-charge interaction to unfractionated heparin and low-molecular-weight heparin. It shows binding characteristics that are similar to those of direct oral anticoagulants (DOACs). A dynamic light-scattering methodology was used to demonstrate ciraparantag's binding to the heparins and DOACs and its lack of binding to a variety of proteins including coagulation factors and commonly used drugs.

A Novel Whole Blood Point-of-Care Coagulometer to Measure the Effect of Direct Oral Anticoagulants and Heparins.

The direct oral anticoagulants (DOACs) currently require no monitoring for routine therapy of atrial fibrillation or venous thromboembolism. Measurement of activity, however, may be important in patients with major and life-threatening bleeding, patients needing emergent surgery, in reversal situations, or in patients at high risk of bleeding or thrombosis due to underlying conditions. For these patients, a widely available and rapid turnaround assay would be optimal.

Single-dose ciraparantag safely and completely reverses anticoagulant effects of edoxaban.

Of the new direct oral anticoagulants, direct factor Xa inhibitors are limited by the absence of a proven reversal agent. We assessed the safety, tolerability and impact on anticoagulation reversal of ciraparantag (PER977) alone and following a 60 mg dose of the FXa inhibitor edoxaban. Escalating, single IV doses of ciraparantag were administered alone and following a 60 mg oral dose of edoxaban in a double-blind, placebo-controlled fashion to healthy subjects.

Ciraparantag safely and completely reverses the anticoagulant effects of low molecular weight heparin.

Unlabelled: Major bleeding with low molecular weight heparin (LMWH) therapy occurs in up to 5% of patients and its anticoagulation is only partially reversed by protamine sulfate. We studied the ability of ciraparantag (PER977), a novel agent that reverses LMWH in preclinical studies, to reverse LMWH in healthy volunteers.

Methods: In this phase 1/2 trial, 4 cohorts of 10 healthy volunteers received escalating doses of ciraparantag (100 to 300mg) or placebo (8:2 ratio) approximately 4h after a single subcutaneous dose of enoxaparin, 1.

Nonclinical Safety Assessment of PER977: A Small Molecule Reversal Agent for New Oral Anticoagulants and Heparins.

A new molecular entity, PER977 (di-arginine piperazine), is in clinical development as an anticoagulant reversal agent for new oral anticoagulants and heparins. The good laboratory practices (GLP)-compliant studies were conducted to evaluate the toxicity of PER977 and its primary metabolite, 1,4-bis(3-aminopropyl)piperazine (BAP). PER977 and BAP were negative for systemic toxicity in dogs and rats.

Reversal agents in development for the new oral anticoagulants.

The new oral anticoagulants have many advantages over vitamin K antagonists, but they are still associated with a troublesome incidence of major bleeding. Additionally, the absence of a reversal agent for the new oral anticoagulants is a barrier to their more widespread use. Currently, there are 3 potential reversal agents in development: idarucizumab is a humanized murine monoclonal antibody fragment directed specifically at dabigatran; andexanet alfa is a recombinant modified decoy factor Xa that binds to factor Xa inhibitors; and PER977 is a small molecule that binds to factor Xa and IIa inhibitors and to heparin-based anticoagulants through charge interaction.

Oral delivery of proteins by biodegradable nanoparticles.

Successful administration of therapeutic proteins via the oral route has long eluded the drug delivery community; a variety of factors, both physical and physiological, have hindered the myriad approaches to increasing the bioavailability of orally administered therapeutic proteins, including: 1) pre-systemic degradation by enzymes and 2) poor penetration of the intestinal mucosa and epithelium. Even when bypassing the harsh, acidic environment of the stomach, the intestines pose significant obstacles to systemic uptake. For example, the lining of the gastrointestinal tract comprises a thick wall of epithelial cells covered by a layer of polysaccharides and mucus.

TNRC9 downregulates BRCA1 expression and promotes breast cancer aggressiveness.

Although the linkage between germline mutations of BRCA1 and hereditary breast/ovarian cancers is well established, recent evidence suggests that altered expression of wild-type BRCA1 might contribute to the sporadic forms of breast cancer. The breast cancer gene trinucleotide-repeat-containing 9 (TNRC9; TOX3) has been associated with disease susceptibility but its function is undetermined. Here, we report that TNRC9 is often amplified and overexpressed in breast cancer, particularly in advanced breast cancer.

Enhanced cellular uptake and long-term retention of chitosan-modified iron-oxide nanoparticles for MRI-based cell tracking.

Tracking cells after therapeutic transplantation is imperative for evaluation of implanted cell fate and function. In this study, ultrasmall superparamagnetic iron oxide nanoparticles (USPIO NPs) were surface functionalized with water-soluble chitosan, a cationic polysaccharide that mediates enhanced endocytic uptake, endosomal escape into the cytosol, and subsequent long-term retention of nanoparticles. NP surface and chitosan were independently fluorescently labeled.

Three-dimensional microfiber devices that mimic physiological environments to probe cell mechanics and signaling.

Many physiological systems are regulated by cells that alter their behavior in response to changes in their biochemical and mechanical environment. These cells experience this dynamic environment through an endogenous biomaterial matrix that transmits mechanical force and permits chemical exchange with the surrounding tissue. As a result, in vitro systems that mimic three-dimensional, in vivo cellular environments can enable experiments that reveal the nuanced interplay between biomechanics and physiology.

Direct and cell signaling-based, geometry-induced neuronal differentiation of neural stem cells.

Neural Stem Cells (NSCs) are multipotent precursors inhabiting the subventricular and hippocampal subgranular regions of the adult mammalian brain, able to self-renew and differentiate into neurons, astrocytes, and oligodendrocytes, the three primary neural cell types of the adult brain. NSC fate is influenced by the physical and chemical microenvironment experienced by the cell, both in vitro and in vivo. Towards characterizing the influence of topographical, geometric cues on NSC fate, we fabricated highly aligned, single- and double-layer polystyrene nanofiber meshes.

Low-voltage planar-waveguide electrooptic prism scanner in Crystal-Ion-Sliced thin-film LiNbO3.

We report on the use of thin, i.e. 10 microm-thick, single-crystal LiNbO3, in low-voltage electrooptic prism scanners.