Sasha Bakhru

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

Summary 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. Serial assessments of the pharmacokinetics and pharmacodynamic effects of ciraparantag were performed. Eighty male subjects completed the study. Following edoxaban (60 mg), a single IV dose of ciraparantag (100 to 300 mg) demonstrated full reversal of anticoagulation within 10 minutes and sustained for 24 hours. Fibrin diameter within clots was restored to normal 30 minutes after a single dose of 100 to 300 mg ciraparantag as determined by scanning electron microscopy and change in fibrin diameter quantified by automated image analysis. Potentially related adverse events were periorbital and facial flushing and cool sensation following IV injection of ciraparantag. Renal excretion of ciraparantag metabolite was the main elimination route. There was no evidence of procoagulant activity following ciraparantag as assessed by D-dimer, prothrombin fragments 1.2, and tissue factor pathway inhibitor levels. In conclusion, ciraparantag in healthy subjects is safe and well tolerated with minor, non-dose limiting adverse events. Baseline haemostasis was restored from the anticoagulated state with doses of 100 to 300 mg ciraparantag within 10–30 minutes of administration and sustained for at least 24 hours. Institution where the work was performed: Duke University Clinical Research Unit, Duke University Medical Center, Durham, NC USA

Compositional and structural changes in LiNbO3 following deep He+ ion implantation for film exfoliation

The physical mechanism of He-ion-based exfoliation in Z-cut LiNbO3 is investigated. Rutherford backscattering/channeling, nuclear-reaction analysis, and transmission electron microscopy are used to examine the compositional and structural changes caused by deep ion implantation followed by thermal annealing. Lattice disruption, He-bubble formation, and Li depletion are observed in the implantation region, as well as the onset of exfoliation. The implications of these observations for the crystal ion slicing method are discussed.

Electro-optically tunable second-harmonic-generation gratings in ion-exfoliated thin films of periodically poled lithium niobate

The authors demonstrate that thin, single-crystal films fabricated by ion exfoliation of a bulk periodically poled LiNbO3 (PPLN) crystal reduced the tuning voltages for electro-optically tunable harmonic generation in PPLN devices. The tuning voltage of ±150V resulted in 0.5nm total tuning of the second harmonic signal in the authors’ 10-μm-thick device, compared to an order of magnitude higher tuning voltage value needed in a comparable bulk device.

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

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, 1.5mg/kg. Safety, pharmacokinetic and pharmacodynamic effects were assessed. RESULTS Complete reversal of enoxaparin anticoagulation, measured by a reduction of whole blood clotting time, was observed in all subjects who received a single ciraparantag dose ranging from 100mg to 300mg. The anticoagulation reversal occurred rapidly after bolus injection and persisted for the duration of the study. At 12h and 24h, the differences in whole blood clotting time in the treated group compared to placebo were no longer significant, consistent with the decline in enoxaparin concentrations and anticoagulation effects. No procoagulant signals were detected as measured by D-dimer, F1.2, and tissue factor pathway inhibitor levels. Ciraparantag was well tolerated with only transient, minor side effects. CONCLUSION Ciraparantag reverses the whole blood clotting time induced by enoxaparin in a dose related manner and produces no procoagulant signal or deleterious adverse events in doses up to 300mg.

Reversal Agents in Development for the New Oral Anticoagulants

Abstract 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. These agents have undergone phase I clinical testing, appear to be well tolerated in healthy volunteers, and are effective in neutralizing their respective targets. All 3 are currently undergoing or entering into a phase II or III clinical study. This article reviews the available data for idarucizumab, andexanet alfa, and PER977.

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. PER977 was rapidly eliminated from the blood with little to no accumulation. PER977 was negative for genotoxicity and did not alter neurological, respiratory, or cardiovascular function. Maximum tolerated doses for PER977 were 40 (rat) and 35 mg/kg (dog), and greater than 80 mg/kg (rat) for BAP. The no observable adverse effect level (NOAEL) for 14-day intravenous exposure to both rats and dogs was 20 mg/kg/d. For BAP, the NOAELs for 14-day intravenous exposure to rats and dogs were 5 and 20 mg/kg, respectively. Based on these results, a safe and conservative dose level of 19.4 mg/d was used for the PER977 first in human study.

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. These devices are fabricated by electric-field poling of a series of electrooptic prisms in a bulk crystal followed by high-energy ion implantation and subsequent etching of the poled samples. Such a single-crystal thin-film scanner, while having the same scanning functionality as with a bulk device, has an order-of-magnitude reduction in its required voltage; for example, a series of two prisms, of 2mm in total length, yields a deflection angle of 0.7 at 100V compared to more than 1.7kV for the same device in standard 200 microm-thick LiNbO3 wafers.

Origin of highly spatially selective etching in deeply implanted complex oxides

The origin of the rate of anomalously high spatially selective etching of a buried heavily implanted region in complex oxides is studied. Single-crystal LiNbO3 samples are prepared with a 0.4μm wide implanted region at depth of 10μm, using 5×1016cm−2 fluence of 3.8MeV He+, and wet etched after a low-temperature anneal. An etch-rate enhancement of 104 is found after implantation and low-temperature 175–275°C post-implantation annealing. Experiments using time-resolved optical microscopy, x-ray diffraction, and proximal-probe microscopy show that this enhancement arises from the more rapid etch-solution transport in the microdomain network formed in the implanted region after annealing.The origin of the rate of anomalously high spatially selective etching of a buried heavily implanted region in complex oxides is studied. Single-crystal LiNbO3 samples are prepared with a 0.4μm wide implanted region at depth of 10μm, using 5×1016cm−2 fluence of 3.8MeV He+, and wet etched after a low-temperature anneal. An etch-rate enhancement of 104 is found after implantation and low-temperature 175–275°C post-implantation annealing. Experiments using time-resolved optical microscopy, x-ray diffraction, and proximal-probe microscopy show that this enhancement arises from the more rapid etch-solution transport in the microdomain network formed in the implanted region after annealing.

PER977 REVERSES LOW MOLECULAR WEIGHT HEPARIN IN ADDITION TO IIA AND XA NEW ORAL ANTICOAGULANTS

There is no approved reversal agent or coagulation assay for low molecular weight heparin (LMWH). Given the significant number of bleeds on LMWH (reported as 12.7% or approximately 137,000 patients in the US annually), there is an urgent and unmet need for a reversal agent and rapid, point of care

Large-area regular nanodomain patterning in He-irradiated lithium niobate crystals

Large-area ferroelectric nanodomain patterns, which are desirable for nonlinear optical applications, were generated in previously He-implanted lithium niobate crystals by applying voltage pulses to the tip of a scanning force microscope. The individual nanodomains were found to be of uniform size, which depended only on the inter-domain spacing and the pulse amplitude. We explain this behavior by the electrostatic repulsion of poling-induced buried charges between adjacent domains. The domain patterns were imaged by piezoresponse force microscopy and investigated by domain-selective etching in conjunction with focused ion beam etching followed by scanning electron microscopy imaging. In order to optimize the He-irradiation parameters for easy and reliable nanodomain patterning a series of samples subjected to various irradiation fluences and energies was prepared. The different samples were characterized by investigating nanodomains generated with a wide range of pulse parameters (amplitude and duration). In addition, these experiments clarified the physical mechanism behind the facile poling measured in He-irradiated lithium niobate crystals: the damage caused by the energy loss that takes place via electronic excitations appears to act to stabilize the domains, whereas the nuclear-collision damage degrades the crystal quality, and thus impedes reliable nanodomain generation.