Antibody-Based Ticagrelor Reversal Agent in Healthy Volunteers.

BACKGROUND: Ticagrelor is an oral P2Y12 inhibitor that is used with aspirin to reduce the risk of ischemic events among patients with acute coronary syndromes or previous myocardial infarction. Spontaneous major bleeding and bleeding associated with urgent invasive procedures are concerns with ticagrelor, as with other antiplatelet drugs. The antiplatelet effects of ticagrelor cannot be reversed with platelet transfusion. A rapid-acting reversal agent would be useful. METHODS: In this randomized, double-blind, placebo-controlled, phase 1 trial, we evaluated intravenous PB2452, a monoclonal antibody fragment that binds ticagrelor with high affinity, as a ticagrelor reversal agent. We assessed platelet function in healthy volunteers before and after 48 hours of ticagrelor pretreatment and again after the administration of PB2452 or placebo. Platelet function was assessed with the use of light transmission aggregometry, a point-of-care P2Y12 platelet-reactivity test, and a vasodilator-stimulated phosphoprotein assay. RESULTS: Of the 64 volunteers who underwent randomization, 48 were assigned to receive PB2452 and 16 to receive placebo. After 48 hours of ticagrelor pretreatment, platelet aggregation was suppressed by approximately 80%. PB2452 administered as an initial intravenous bolus followed by a prolonged infusion (8, 12, or 16 hours) was associated with a significantly greater increase in platelet function than placebo, as measured by multiple assays. Ticagrelor reversal occurred within 5 minutes after the initiation of PB2452 and was sustained for more than 20 hours (P\u3c0.001 after Bonferroni adjustment across all time points for all assays). There was no evidence of a rebound in platelet activity after drug cessation. Adverse events related to the trial drug were limited mainly to issues involving the infusion site. CONCLUSIONS: In healthy volunteers, the administration of PB2452, a specific reversal agent for ticagrelor, provided immediate and sustained reversal of the antiplatelet effects of ticagrelor, as measured by multiple assays. (Funded by PhaseBio Pharmaceuticals; ClinicalTrials.gov number, NCT03492385.)

Time-asymmetry of probabilities versus relativistic causal structure: an arrow of time

There is an incompatibility between the symmetries of causal structure in relativity theory and the signaling abilities of probabilistic devices with inputs and outputs: while time-reversal in relativity will not introduce the ability to signal between spacelike separated regions, this is not the case for probabilistic devices with space-like separated input-output pairs. We explicitly describe a non-signaling device which becomes a perfect signaling device under time-reversal, where time-reversal can be conceptualized as playing backwards a videotape of an agent manipulating the device. This leads to an arrow of time that is identifiable when studying the correlations of events for spacelike separated regions. Somewhat surprisingly, although time-reversal of Popuscu-Roerlich boxes also allows agents to signal, it does not yield a perfect signaling device. Finally, we realize time-reversal using post-selection, which could lead experimental implementation.Comment: 4 pages, some figures; replaces arXiv:1010.4572 [quant-ph

Evidence supporting idarucizumab for the reversal of dabigatran.

Idarucizumab is a monoclonal antibody fragment specifically targeted to dabigatran. It has demonstrated prompt and durable reversal of the anticoagulant effects of dabigatran in animal studies and phase 1 studies of young, elderly, and renally impaired volunteers. Although elective invasive procedures and most bleeding complications in dabigatran-treated patients can be managed by temporarily stopping dabigatran therapy and using supportive measures, there are rare clinical situations that require urgent reversal of the anticoagulant effect of dabigatran. The effectiveness and safety of 5 g of intravenous idarucizumab is being investigated in a prospective, open-label, single-cohort study in patients with serious bleeding or in those requiring an urgent procedure. In an interim analysis of the first 90 participants, idarucizumab rapidly and completely reversed the anticoagulant activity of dabigatran in 88%-98% of participants, and there were no safety concerns, with no deaths or serious adverse events being attributable to idarucizumab. Supported by these interim results, idarucizumab has been approved in the United States and the European Union for use when reversal of the anticoagulant effects of dabigatran is needed for emergency surgery/urgent procedures or in patients with life-threatening or uncontrolled bleeding. Clinical use of idarucizumab should follow the same processes as patient enrollment in this study, which is projected to be completed in 2016. The outcomes achieved with this specific reversal agent are likely to be of continued interest to treating physicians

The Law of Demand in Tiebout Economies

We consider a general equilibrium local public goods economy in which agents have two distinguishing characteristics. The first is 'crowding type', which is publicly observable and provides direct costs or benefits to the jurisdiction (coalition or firms) the agent joins. The second is taste type, which is not publicly observable, has no direct effects on others and is defined over private good, public goods and the crowding profile of the jurisdiction the agent joins. The law of demand suggests that as the quantity of a given crowding type (plummers, lawers, smart people, tall people, nonsmokers, for example) increases, the compensation that agents of that type receive should go down. We provide counterexamples, however, that show that some agents of a given crowding type might actually benefit when the proportion of agents with the same crowding type increases. This reversal of the law of demand seems to have to do with interaction effect between tastes and skills, something difficult to study without making these classes of characteristics distinct. We argue that this reversal seems to relate to the degree of difference between various patterns of tastes. In particular, if tastes are homogeneous, the law of demand holds.

Bleeding with direct oral anticoagulants vs warfarin: clinical experience.

The risk of bleeding in the setting of anticoagulant therapy continues to be re-evaluated following the introduction of a new generation of direct oral anticoagulants (DOACs). Interruption of DOAC therapy and supportive care may be sufficient for the management of patients who present with mild or moderate bleeding, but in those with life-threatening bleeding, a specific reversal agent is desirable. We review the phase 3 clinical studies of dabigatran, rivaroxaban, apixaban, and edoxaban in patients with nonvalvular atrial fibrillation, in the context of bleeding risk and management

Analysis of Clinical Outcomes and Cost-Effectiveness of Neuromuscular Blocking Drug Reversal in Patients with Obstructive Sleep Apnea

Non-depolarizing neuromuscular blockers are used during many surgical procedures to induce muscle relaxation for tracheal intubation and improve surgical conditions for surgeons. The use of these medications requires an agent to be given to fully reverse the effects of the neuromuscular blocking drug. Historically, neostigmine has widely been used as the primary reversal agent. However, sugammadex, a recently FDA approved drug, is also available for the reversal of common neuromuscular blocking drugs, rocuronium and vecuronium. In the literature, sugammadex is widely regarded as a clinically superior reversal agent. But its use is commonly limited to emergent situations due to the high price associated with the drug. A risk associated with reversal agents is incomplete recovery from the neuromuscular blockade that can lead to postoperative pulmonary complications. Patients with certain comorbidities are at higher risk for postoperative pulmonary complications (PPCs). Patients with obstructive sleep apnea already struggle with airway obstruction and may be at higher risk for adverse outcomes after the use of neuromuscular blocking agents (NMBAs). Therefore, this project seeks to provide evidence-based recommendations for NMBA reversal in patients diagnosed with or identified as at risk for OSA through a literature search and synthesis. Therefore, the project developed evidence-based practice recommendations utilizing the John Hopkins Nursing Evidence-Based Practice Model by asking a practice question, evaluating, and translating findings into practice. The project will also outline a plan for implementation and evaluation of outcomes such as cost effectiveness and clinical outcomes

Emerging considerations in the reversal of neuromuscular blockade and residual block

Incomplete recovery following reversal of neuromuscular blockade can present as a clinical problem in surgical patients. Emerging pharmacologic solutions may prevent such adverse outcomes in the future. We briefly review two methods of pharmacologic reversal of neuromuscular blockade. Both methods of reversal are effective. However the early studies of the new compound, sugammadex has been shown to achieve a more rapid, stable reversal of steroidal based neuromuscular blocking agents compared to neostigmine. Due to the novel mechanism of action of this agent, sugammadex has been demonstrated to be effective even when administered during profound neuromuscular block, without evidence of recurarization

Statistical mechanics of money

In a closed economic system, money is conserved. Thus, by analogy with energy, the equilibrium probability distribution of money must follow the exponential Gibbs law characterized by an effective temperature equal to the average amount of money per economic agent. We demonstrate how the Gibbs distribution emerges in computer simulations of economic models. Then we consider a thermal machine, in which the difference of temperatures allows one to extract a monetary profit. We also discuss the role of debt, and models with broken time-reversal symmetry for which the Gibbs law does not hold.Comment: 7 pages, 5 figures, RevTeX. V.4: final version accepted to Eur. Phys. J. B: few stylistic revisions and additional reference

Reversing factor Xa inhibitors - clinical utility of andexanet alfa

Approximately half of patients started on an oral anticoagulant in the USA now receive one of the newer direct oral anticoagulants (DOACs). Although there is an approved reversal agent for the direct thrombin inhibitor dabigatran, a specific reversal agent for the anti-factor Xa (FXa) DOACs has yet to be licensed. Unlike the strategy to reverse the only oral direct thrombin inhibitor with idarucizumab, which is a humanized monoclonal antibody fragment, a different approach is necessary to design a single agent that can reverse multiple anti-FXa medications. Andexanet alfa is a FXa decoy designed to reverse all anticoagulants that act through this part of the coagulation cascade including anti-FXa DOACs, such as apixaban, edoxaban and rivaroxaban, and indirect FXa inhibitors such as low-molecular-weight heparins. This narrative reviews the development of andexanet alfa and explores its basic science, pharmacokinetics/pharmacodynamics, animal models, and human studies

Antisickling agent in an extract of unripe pawpaw (Carica papaya): Is it real?

Investigations into antisickling and reversal of sickling activities of an aqueous extract of unripe pawpaw (Carica papaya) were carried out on blood from sickle cell patients (Haemoglobin SS, HbSS) using 2% sodium metabisulphite in a sickling test. The minimum concentration of the extract that achieved maximum antisickling in vitro and the fraction of the extract where the antisickling agent resides were determined. Our findings confirmed both antisickling and reversal of sickling activities ofthe extract. It was established that 1.0 g of unripe pawpaw in 1.0 ml of physiological saline was the minimum concentration that achieved maximum antisickling. Solvent partitioning of the extract withethyl acetate and butanol revealed that the antisickling agent in the extract of unripe pawpaw resides in the ethyl acetate fraction as this fraction prevented sickling of Hb SS red cells and reversed sickled HbSS red cells in 2% sodium metabisulphite whereas the butanol and aqueous fractions had none of these properties. We concluded that extract of unripe pawpaw really has antisickling agent and that thisantisickling agent lies in the ethyl acetate fraction of the extract