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. Subjects received apixaban (Study 1) 10 mg orally twice daily for 3.5 days or rivaroxaban (Study 2) 20 mg orally once daily for 3 days. At steady-state anticoagulation subjects were randomized 3:1 to a single intravenous dose of ciraparantag (Study 1: 30, 60, or 120 mg; Study 2: 30, 60, 120, or 180 mg) or placebo. Efficacy was based on correction of the whole blood clotting time (WBCT) at multiple timepoints over 24 h. Subjects and technicians performing WBCT testing were blinded to treatment. Complete reversal of WBCT within 1 h post-dose and sustained through 5 h (apixaban) or 6 h (rivaroxaban) was dose related and observed with apixaban in 67%, 100%, 100%, and 17% of subjects receiving ciraparantag 30 mg, 60 mg, 120 mg, or placebo, respectively; and with rivaroxaban in 58%, 75%, 67%, 100%, and 13% of subjects receiving ciraparantag 30 mg, 60 mg, 120 mg, 180 mg, or placebo, respectively. Adverse events related to ciraparantag were mild, transient hot flashes or flushing. Conclusions Ciraparantag provides a dose-related reversal of anticoagulation induced by steady-state dosing of apixaban or rivaroxaban. Sustained reversal was achieved with 60 mg ciraparantag for apixaban and 180 mg ciraparantag for rivaroxaban. All doses of ciraparantag were well tolerated.

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. Ciraparantag reaches maximum concentration within minutes after IV administration with a half-life of 12 to 19 minutes. It is primarily hydrolyzed by serum peptidases into 2 metabolites, neither of which has substantial activity. Ciraparantag and its metabolites are recovered almost entirely in the urine. In animal models of bleeding (rat tail transection and liver laceration), a single IV dose of ciraparantag given at peak concentrations of the anticoagulant, but before the bleeding injury, significantly reduced the blood loss. Ciraparantag, given after the bleeding injury, also significantly reduced blood loss. It appears to have substantial ability to reduce blood loss in animal models in which a variety of anticoagulants are used and has potential as a useful DOAC reversal agent.

There is an unmet need for agents that can rapidly reverse the effects of the direct oral anticoagulants (DOACs) in emergency settings. Ciraparantag, an anticoagulant reversal agent with broad activity, binds directly to anticoagulant molecules including DOACs, enoxaparin and unfractionated heparin, without binding to endogenous coagulation factors or other plasma proteins. Ciraparantag has been shown to reverse anticoagulation in healthy volunteers treated with edoxaban and enoxaparin, as measured by whole blood clotting time (WBCT).

Introduction: There is an unmet need for safe and effective anticoagulant reversal agents, with rapid onset of effects, for use in cases such as serious or life-threating bleeding, prior to urgent or emergency surgery, after major trauma, or in cases of anticoagulant overdose. Ciraparantag, an anticoagulant reversal agent with broad activity, binds directly to anticoagulant molecules including direct oral anticoagulants (DOACs), enoxaparin, and unfractionated heparin, without binding to endogenous coagulation factors or other plasma proteins. Two Phase 2 studies evaluated the safety and efficacy of ciraparantag for reversal of anticoagulation induced by apixaban or rivaroxaban in healthy adults. Methods: Two randomized, placebo-controlled, dose-ranging studies were conducted in healthy subjects 50-75 years of age. Subjects received apixaban or rivaroxaban until steady state. Study 1 subjects received apixaban 10 mg orally twice daily for 3.5 days. Study 2 subjects received rivaroxaban 20 mg orally once daily for 3 days. At steady-state anticoagulation subjects were randomized 3:1 to a single intravenous (IV) dose of ciraparantag (Study 1: 30, 60, or 120 mg; Study 2: 30, 60, 120 or 180 mg) or placebo. Efficacy was based on manual whole blood clotting time (WBCT) at multiple timepoints over 24 hours beginning at 15 minutes after dosing. Subjects and technicians performing the WBCT testing were blinded to treatment. WBCT measures were performed in triplicate (simultaneous testing by 3 different evaluators) at 3 separate timepoints to analyze inter-observer variability using an analysis of variance (ANOVA) model with effects for observer and subject. Results: In Study 1 (apixaban), 49 subjects were randomized to receive study drug (36 ciraparantag, 13 placebo) and completed the study as planned. In Study 2 (rivaroxaban), 64 subjects were randomized to receive study drug (48 ciraparantag, 16 placebo) and all but one subject completed the study as planned. Ciraparantag demonstrated a rapid and dose-dependent reversal of apixaban and rivaroxaban anticoagulation as measured by the proportion of subjects whose WBCT decreased to within 10% above baseline at 15 minutes after study drug infusion. A lower dose of ciraparantag was required to achieve reversal of apixaban in a large fraction of subjects compared to the dose required for reversal of rivaroxaban (Figure). Reversal of anticoagulation was sustained in these subjects throughout the 24-hour measurement period. In both studies, there was good agreement among the triplicate manual WBCT measurements; all inter-observer coefficient of variance values were <5%. Ciraparantag was well tolerated; the most frequent adverse events were mild, transient sensations of warmth during or soon after infusion. Conclusions: In healthy subjects at steady-state levels of anticoagulation, ciraparantag single IV doses were well tolerated and produced rapid reversal of anticoagulation in high proportions of subjects within 15 minutes of administration (the first timepoint assessed) at doses ≥60 mg for apixaban and at a dose of 180 mg for rivaroxaban which were maintained throughout the 24-hour measurement period. Figure. Proportion of subjects with WBCT reversed to within 10% above baseline at 15 minutes and 30 minutes after dosing Disclosures Ansell: Amag Pharmaceuticals, Inc.: Consultancy. Bakhru:Pherosphere Technologies, Inc.: Current Employment. Luo:Amag Pharmaceuticals, Inc.: Current Employment. Villano:Amag Pharmaceuticals, Inc.: Consultancy. OffLabel Disclosure: Ciraparantag is an investigational drug being evaluated for the reversal of anticoagulation induced by direct oral anticoagulant (DOAC) therapies.

Efficient and safe access to targeted therapeutic sites is a universal challenge in minimally invasive medical intervention. Percutaneous and transluminal needle insertion is often performed blindly and requires significant user skill and experience to avoid complications associated with the damage of underlying tissues or organs. Here, we report on the advancement of a safer needle with a radial mechanical clutch, which is designed to prevent overshoot injuries through the automatic stopping of the needle once a target cavity is reached. The stylet-mounted clutch system is inexpensive to manufacture and compatible with standard hypodermic or endoscopic needles, and therefore can be adapted to achieve safe access in a myriad of minimally invasive procedures, including targeted drug delivery, at-home and in-hospital intravenous access, laparoscopic and endo- and trans-luminal interventions. Here, we demonstrate the clutch needle design optimization and illustrate its potential for rapid and safe minimally invasive cannulation.

Una bateria (12) para su uso en dispositivos electronicos y que se ingiere de manera segura en un cuerpo que ejerce una tension aplicada predeterminada en un tracto digestivo del cuerpo, comprendiendo la bateria: una parte superior de celda en un anodo (14); un cuenco de celda en un catodo (16); un revestimiento sensible a presion que comprende un compuesto de efecto tunel cuantico que cubre al menos una de la parte superior de celda en el anodo (14) y el cuenco de celda en el catodo (16) y que proporciona propiedades conductoras sensibles a presion incluyendo un umbral de tension de compresion de tal manera que, cuando una tension por encima del umbral de tension de compresion se aplica al revestimiento de material compuesto de efecto tunel (22), el revestimiento de material compuesto de efecto tunel (22) se coloca en un estado conductor en el que los electrones son capaces atravesar el revestimiento de material compuesto de efecto tunel (22); y una junta (18) que aisla y separa la parte superior de celda en el anodo (14) y el cuenco de celda en el catodo (16), en donde el umbral de tension de compresion es mayor que la tension aplicada predeterminada asociada al tracto digestivo del cuerpo, y en donde o bien: (i) la bateria (12) comprende ademas un sello estanco al agua (30) que se extiende entre el revestimiento sensible a presion y la junta (18), inhibiendo de este modo la bateria (12) de cortocircuitar en un fluido conductor por debajo del umbral de tension de compresion, o (ii) el revestimiento sensible a presion es un revestimiento impermeable al agua que se extiende hasta la junta (18) y que cubre completamente la al menos una de la parte superior de celda en el anodo (14) y el cuenco de celda en el catodo (16) para no dejar ninguna superficie expuesta.

Background: Ciraparantag is a small molecule drug candidate in clinical development as a reversal agent for the Xa direct oral anticoagulants (DOACs) and low molecular weight heparin (LMWH). In previous clinical trials, ciraparantag has shown complete and sustained reversal of the Xa DOAC, edoxaban, and the LMWH, enoxaparin, following a single intravenous (i.v.) bolus dose, as measured by whole blood clotting time (WBCT) [1-3].

Abstract 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. To date, there is no such assay available, especially for the direct factor Xa inhibitors. This report describes the performance of a new, rapid turnaround, point-of-care (PoC) assay for measuring the activity of a range of anticoagulants, including DOACs and heparins, in emergency situations and for routine measurement in high-risk patients. Perosphere Technologies' PoC coagulometer is a handheld instrument that performs individual coagulation tests on samples of fresh whole blood (∼10 µL) with clotting activated by glass contact and endpoint determination performed by infrared spectroscopy. In preclinical studies using rats anticoagulated with therapeutic doses of edoxaban or enoxaparin, the PoC coagulometer showed a strong linear correlation between pharmacokinetic parameters and clotting time with edoxaban (r 2 = 0.994) and with enoxaparin (r 2 = 0.967). These preclinical results suggest that this PoC coagulometer would be ideal to assess the pharmacodynamic effects of anticoagulants and their reversal agents. The PoC bedside instrument delivers results within minutes and requires no more than a drop of whole blood. Studies are underway to confirm these results in humans and to further characterize the performance of the instrument.

The time-dependent bioadhesive performance of various polymers was evaluated using a texture analyzer apparatus and freshly excised rat small intestinal tissue. A series of novel bioadhesive polymers were prepared by conjugating L-phenylalanine, L-tyrosine, and L-DOPA to either a low molecular weight poly (butadiene-maleic anhydride) or a high molecular weight poly (ethylene-maleic anhydride). Bioadhesive force was characterized as a function of time relative to polycarbophil, a slightly cross-linked poly (acrylic acid)-derivative, revealing different fracture strengths and tensile work for each of the six backbone-side chain conjugations that were studied. While polycarbophil showed a rapid and significant loss of bioadhesion over the testing period, the newly developed synthetic polymers were able to maintain their bioadhesive performance over the course of 91 min with the overall magnitude of bioadhesion corresponding to the hydrogen bonding potential of the associated side chains. These results highlight the potential of these polymers for use in the development of more effective bioadhesive oral drug delivery systems.

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 cira-parantag (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.

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 300 mg) or placebo (8: 2 ratio) approximately 4 h after a single subcutaneous dose of enoxaparin, 1.5 mg/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 100 mg to 300 mg. The anticoagulation reversal occurred rapidly after bolus injection and persisted for the duration of the study. At 12 h and 24 h, 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 300 mg. (C) 2016 Elsevier Ltd. All rights reserved.

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.

Warfarin has been the centre of oral anticoagulant therapy for over 60 years. Recent development of new oral anticoagulants (NOACs) has provided a safe and effective alternative for stroke prevention in patients with atrial fibrillation and for prevention of venous thromboembolism. Determination of their use in acute coronary syndrome has been hampered by increases in bleeding events in most large trials, especially when used with antiplatelet therapy. NOACs have equal or superior efficacy and safety profiles compared to warfarin, fewer drug interactions; no dietary restrictions; predictable responses that eliminates monitoring; a rapid onset eliminates bridging with parenteral anticoagulants; and a potential reduction in mortality in patients with atrial fibrillation. There are reports of bleeding events and deaths associated with NOACs. Haemorrhage associated with dabigatran and warfarin were the most common safety issues for anticoagulants reported to the United States Food and Drug Administration in 2012. The lack of a NOAC reversal agent is a significant clinical concern for many physicians. Current reversal agents for unfractionated heparin, low molecular weight heparins and warfarin are less than optimal, and there are no effective reversal agents for NOACs. Development programs for anticoagulant reversal of the NOACs have three approaches: multiple coagulation factor replacement, large molecules (recombinant antibodies or altered coagulation factors) that either bind to or substitute for the coagulation factor while the anticoagulant itself is either being excreted or metabolized, and a small molecule specifically designed to bind to the NOACs and heparins and prevent them from binding to the coagulation factor targets.

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