Injectable anticoagulants are widely used in medical procedures to prevent unwanted blood clotting. However, many lack safe, effective reversal agents. Here, we present new data on a previously described RNA origami-based, direct thrombin inhibitor (HEX01). We describe a new, fast-acting, specific, single-molecule reversal agent (antidote) and present in vivo data for the first time, including efficacy, reversibility, preliminary safety, and initial biodistribution studies. HEX01 contains multiple thrombin-binding aptamers appended on an RNA origami. It exhibits excellent anticoagulation activity in vitro and in vivo. The new single-molecule, DNA antidote (HEX02) reverses anticoagulation activity of HEX01 in human plasma within 30 s in vitro and functions effectively in a murine liver laceration model. Biodistribution studies of HEX01 in whole mice using ex vivo imaging show accumulation mainly in the liver over 24 h and with 10-fold lower concentrations in the kidneys. Additionally, we show that the HEX01/HEX02 system is non-cytotoxic to epithelial cell lines and non-hemolytic in vitro. Furthermore, we found no serum cytokine response to HEX01/HEX02 in a murine model. HEX01 and HEX02 represent a safe and effective coagulation control system with a fast-acting, specific reversal agent showing promise for potential drug development.

UNASSIGNED: Fentanyl and fentanyl analogs (F/FA) have become increasingly common adulterants in counterfeit prescription pills and illicit street drug mixtures due to their ease of synthesis and exceedingly high potency. The ongoing epidemic of fatal overdoses fueled by F/FA continues to highlight the need for longer-acting therapies than naloxone (NLX), the current gold-standard for reversing opioid overdoses, which shows limited efficacy to prevent renarcotization associated with F/FA toxicity. A novel opioid reversal agent based on covalent naloxone nanoparticles (cNLX-NP) has been shown to blunt fentanyl-induced respiratory depression out to 48 hr, demonstrating its potential therapeutic utility. The purpose of this study was to characterize how rapidly cNLX-NP reverses fentanyl-induced respiratory effects as well as the duration of its protective effects.
UNASSIGNED: Sprague Dawley male rats (n=6/group) were tested on an oximeter for baseline percent arterial oxygen saturation (%SaO2) challenged with 0.1 mg/kg SC fentanyl and 15 min later given 10 mg/kg IM doses of NLX, nalmefene (NLMF), or cNLX-NP and continuously monitored via oximetry for 10 minutes. One week later the experiment was repeated using a 1:1 mixture of NLX:cNLX-NP as the reversal agent in the rats that previously received NLX alone.
UNASSIGNED: While both NLX and NLMF rapidly reversed %SaO2 to baseline within 1 min, rats that received cNLX-NP did not return to >90% SaO2 levels until 9 min after administration. Similarly, heart and breath rates returned to baseline within 1 min of treatment with NLX and NLMF but did not return to baseline until 10 minutes after cNLX-NP administration. In contrast, NLX:cNLX-NP reversed all fentanyl-induced respiratory depressive effects within one minute.
UNASSIGNED: While cNLX-NP alone may not sufficiently reverse F/FA overdose in a timely manner, mixing free NLX with cNLX-NP can provide a mechanism to both rapidly reverse fentanyl-related effects and maintain extended protection against synthetic opioid toxicity. These data support further development of cNLX-NP as a fast-acting and long-lasting antidote to treat F/FA-induced respiratory depression and overdose, and potentially prevent renarcotization in humans.

BACKGROUND: Despite millions of COVID-19 cases in the United States, it remains unknown whether a history of COVID-19 infection impacts the safety of pharmacologic myocardial perfusion imaging stress testing (pharmacologic MPI).
OBJECTIVE: The aim of this study was to assess if a prior COVID-19 infection was associated with a higher risk of complications during and following pharmacologic MPI testing.
METHODS: This retrospective cohort analysis included 179 803 adults (≥18 years) from the PharMetrics® Plus claims database who underwent pharmacologic MPI between March 1, 2020 and February 28, 2021. Patients with a history of COVID-19 infection (COVID-19 group) were compared with propensity-score matched no-COVID-19 history group for reversal agent use, 30-day resource use, and post-MPI cardiac events/procedures.
RESULTS: The most commonly used stress agent was regadenoson (91.7%). The COVID-19 group (n = 6372; 3.5%) had slightly higher: reversal agent use (difference 1.13% [95% confidence interval [CI]: 0.33, 1.92]), all-cause costs (difference USD $128 [95% CI: $73-$181]), and office visits (81.5% vs. 77.0%) than the no-COVID-19 group. Prior COVID-19 infection did not appear to impact subsequent cardiac events/procedures.
CONCLUSIONS: COVID-19 history was associated with slightly higher reversal agent use, all-cause costs, and office visits after pharmacologic MPI; however, the differences were not clinically meaningful. Concerns for use of stress agents in patients with prior COVID-19 do not appear to be warranted.

Factor Xa (FXa) inhibitors are widely used for stroke prevention in patients with nonvalvular atrial fibrillation, and for the treatment and prevention of deep venous thrombosis and pulmonary embolism. Compared with warfarin, individual FXa inhibitors are associated with a lower risk of major bleeding. Nevertheless, bleeding remains a feared complication of any anticoagulant therapy. Despite their demonstrated safety, implementation of FXa inhibitors in clinical practice may have been limited by the lack of a specific antidote. Recently, however, the United States Food and Drug Administration and the European Medicines Agency approved andexanet alfa for reversal of anticoagulation in patients treated with rivaroxaban or apixaban who have life-threatening or uncontrolled bleeding. This review will discuss andexanet alfa\'s mode of action, indication for use and efficacy, with a focus on its appropriate use in clinical practice. Unnecessary usage should be prevented as this may compromise patient safety. Assessment of potentially suitable patients by a multidisciplinary team, use according to the institutional protocol and central storage, all contribute to proper use of andexanet alfa. A practical tool to direct appropriate use of andexanet alfa is proposed.

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Overexpression of ABCG2 transporter in cancer cells has been linked to the development of multidrug resistance (MDR), an obstacle to cancer therapy. Our recent study uncovered that the MET inhibitor, tepotinib, is a potent reversal agent for ABCB1-mediated MDR. In the present study, we reported for the first time that the MET inhibitor tepotinib can also reverse ABCG2-mediated MDR in vitro and in vivo by directly binding to the drug-binding site of ABCG2 and reversibly inhibiting ABCG2 drug efflux activity, therefore enhancing the cytotoxicity of substrate drugs in drug-resistant cancer cells. Furthermore, the ABCB1/ABCG2 double-transfected cell model and ABCG2 gene knockout cell model demonstrated that tepotinib specifically inhibits the two MDR transporters. In mice bearing drug-resistant tumors, tepotinib increased the intratumoral accumulation of ABCG2 substrate drug topotecan and enhanced its antitumor effect. Therefore, our study provides a new potential of repositioning tepotinib as an ABCG2 inhibitor and combining tepotinib with substrate drugs to antagonize ABCG2-mediated MDR.

Background: Intracranial hemorrhage is a severe and possibly fatal consequence of anticoagulation therapy. Idarucizumab is used in dabigatran-treated patients suffering from intracranial hemorrhage (ICH) to reverse the anticoagulant effect of dabigatran. Systematic review of real-life mortality in these patients is missing. Objectives: A review of all published dabigatran-related ICH cases treated with idarucizumab was performed. We aimed to estimate in-hospital mortality rate in these patients. Method: We searched PubMed and Scopus for all published cases of ICH in idarucizumab/dabigatran-treated patients until May 15, 2021. The assessed outcome was in-hospital mortality. Results: We identified six eligible studies (case series) with 386 patients and 54 single case reports. In-hospital mortality rate was 11.4% in the case series and 9.7% in the case reports. Conclusions: Our analysis provides clinically relevant quantitative data regarding in-hospital mortality in idarucizumab/dabigatran-treated patients with ICH, which is estimated to be 9.7-11.4%.

Two acyclic CB[n]-type hosts (1 and 2) which possess four 2° or 3° amide arms are reported; 1 and 2 are slightly soluble in water and do not self-associate. Host 2 has four 3° amide arms that exist as a mixture of E- and Z-isomers. 1H NMR was used to qualitatively investigate the binding properties of 1 and 2 which indicates they retain the essential binding features of macrocyclic CB[n] hosts (e.g. cavity binding of hydrophobic residues and portal binding of cationic groups). We measured the Ka values of 1 and 2 toward guests 6 - 12, methamphetamine, and fentanyl by ITC to evaluate their potential as in vivo sequestration agents. Neutral hosts 1 and 2 bind less tightly than tetraanionic hosts M1, ACB1, and ACB2. We attribute the lower Ka values to the absence of secondary ion-ion (ammonium•••sulfonate or ammonium•••carboxylate) electrostatic interactions for host•guest complexes of 1 and 2. The secondary amide functionality on 1 decreases affinity by formation of intramolecular NH•••O=C H-bonds. Tertiary amide host 2 binds even more weakly than 1 due to backfolding of the amide N-CH3-groups of 2 into its own cavity. The x-ray crystal structure of 2 supports this conclusion.

Acyclic cucurbit[n]uril molecular containers 1 and 2C3 have previously been shown to strongly bind to the neuromuscular blocking agents rocuronium, vecuronium, pancuronium, and cisatracurium in vitro by optical methods and to reverse neuromuscular block in vivo in rats. In this paper we study the in vitro binding of a panel of acyclic CB[n]-type receptors toward the four neuromuscular blocking agents and acetylcholine to develop structure-binding affinity relationships. The selected variants include those with different aromatic sidewalls (e.g. 1Me4 with dimethyl o-xylylene walls; 3 with 1,8-linked naphthalene walls), with different glycoluril oligomer lengths (e.g. 4 and 5 based on glycoluril trimer), and with different linker lengths between aromatic wall and SO3 - solubilizing group (e.g. 2C2 - 2C4). Based on the analysis of complexation induced changes in 1H NMR chemical shift we conclude that the hydrophobic regions of the guests bind in the hydrophobic cavity of the hosts with the cationic moieties of the guest binding at the ureidyl C=O portals by ion-dipole and ion-ion interactions. The thermodynamic parameters of binding were determined by direct and competition isothermal titration calorimetry experiments. We find that hosts 4 and 5 based on glycoluril trimer form significantly weaker complexes with the streroidal NMBAs than with the analogues hosts based on glycoluril tetramer (1 and 2C3). Similarly, hosts 1Me4 and 3 with different length and height aromatic walls do not exhibit the extreme binding constants displayed by 2C3 but rather behave similarly to 1. Finally, we find that hosts 2C2 and 2C4 bind only slightly more weakly to the NMBAs than 2C3, but retain the ability to discriminate against acetylcholine, and possess higher inherent water solubility than 2C3. Host 2C4, in particular, holds potential for future in vivo applications.

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