scholarly journals Azolo[1,5-a]pyrimidines and Their Condensed Analogs with Anticoagulant Activity

Molecules ◽  
2022 ◽  
Vol 27 (1) ◽  
pp. 274
Author(s):  
Konstantin V. Savateev ◽  
Victor V. Fedotov ◽  
Vladimir L. Rusinov ◽  
Svetlana K. Kotovskaya ◽  
Alexandr A. Spasov ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Anticoagulant Activity ◽  
Dabigatran Etexilate ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Antiviral Agents ◽  
Multiple Organ ◽  
Thrombin Time ◽  
Cytokine Storm ◽  
Reference Drug

Hypercytokinemia, or cytokine storm, is one of the severe complications of viral and bacterial infections, involving the release of abnormal amounts of cytokines, resulting in a massive inflammatory response. Cytokine storm is associated with COVID-19 and sepsis high mortality rate by developing epithelial dysfunction and coagulopathy, leading to thromboembolism and multiple organ dysfunction syndrome. Anticoagulant therapy is an important tactic to prevent thrombosis in sepsis and COVID-19, but recent data show the incompatibility of modern direct oral anticoagulants and antiviral agents. It seems relevant to develop dual-action drugs with antiviral and anticoagulant properties. At the same time, it was shown that azolo[1,5-a]pyrimidines are heterocycles with a broad spectrum of antiviral activity. We have synthesized a new family of azolo[1,5-a]pyrimidines and their condensed polycyclic analogs by cyclocondensation reactions and direct CH-functionalization and studied their anticoagulant properties. Five compounds among 1,2,4-triazolo[1,5-a]pyrimidin-7-ones and 5-alkyl-1,3,4-thiadiazolo[3,2-a]purin-8-ones demonstrated higher anticoagulant activity than the reference drug, dabigatran etexilate. Antithrombin activity of most active compounds was confirmed using lipopolysaccharide (LPS)-treated blood to mimic the conditions of cytokine release syndrome. The studied compounds affected only the thrombin time value, reliably increasing it 6.5–15.2 times as compared to LPS-treated blood.

scholarly journals Azolo[1,5-a]pyrimidines and Their Condensed Analogs with Anticoagulant Activity

2021 ◽  
Author(s):  
Konstantin V. Savateev ◽  
Victor V. Fedotov ◽  
Vladimir L. Rusinov ◽  
Svetlana K. Kotovskaya ◽  
Alexandr A. Spasov ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Anticoagulant Activity ◽  
Dabigatran Etexilate ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Antiviral Agents ◽  
Multiple Organ ◽  
Thrombin Time ◽  
Cytokine Storm ◽  
Reference Drug

Hypercytokinemia, or cytokine storm, is one of the severe complications of viral and bacterial infections, involving the release of abnormal amounts of cytokines, resulting in a massive inflammatory response. Cytokine storm is associated with COVID-19 and sepsis high mortality rate by developing epithelial dysfunction and coagulopathy, leading to thromboembolism and multiple organ dysfunction syndrome. The anticoagulant therapy is an important tactic to prevent thrombosis in sepsis and COVID-19, but recent data show the incompatibility of modern direct oral anticoagulants and antiviral agents. It seems relevant to develop dual-action drugs with antiviral and anticoagulant properties. At the same time it was shown that azolo[1,5-a]pyrimidines are heterocycles with a broad spectrum of antiviral activity. We have synthesized a new family of azolo[1,5-a]pyrimidines and their condensed polycyclic analogs by cyclocondensation reactions and direct CH-functionalization and studied their anticoagulant properties. Five compounds among 1,2,4-triazolo[1,5-a]pyrimidin-7-ones and 5-alkyl-1,3,4-thiadiazolo[3,2-a]purin-8-ones demonstrated higher anticoagulant activity than the reference drug, dabigatran etexilate. Antithrombin activity of lead compounds was confirmed using lipopolysaccharide (LPS) treated blood to mimic conditions of cytokine release syndrome. The studied compounds affected only the thrombin time value, reliably increasing it 6.5–15.2 times as compared to LPS-treated blood.

Determination of anticoagulant activity of direct oral anticoagulants: the current state of knowledge and a single center experience

2017 ◽  
Vol 53 (3) ◽  
pp. 161-168
Author(s):  
Tadeusz Góralczyk ◽  
Anetta Undas
Keyword(s):  
Anticoagulant Activity ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Thrombin Time ◽  
Routine Laboratory ◽  
Pharmacological Mechanism ◽  
Emergency Procedures ◽  
Single Center Experience

Direct oral anticoagulants (DOACs) increasingly replace vitamin K antagonists in the treatment and prevention of venous thromboembolism, and stroke prevention in non-valvular atrial fibrillation. Due to their predictable pharmacological mechanism, no diet restrictions and lack of interaction with most drugs, DOACs do not require routine laboratory monitoring. However, in cases of suspected concentrations beyond the expected range or a need for an emergent surgical procedure, access to laboratory methods for reliable DOACs determination is necessary. In a routine laboratory, the anticoagulant effect of dabigatran can be determined using methods based on ecarin or the modified dilute thrombin time. Rivaroxaban, apixaban and edoxaban may be measured using the chromogenic anti-FXa assays. Our own experience (the longest in Poland) from the John Paul II Hospital laboratory with the 24-hour availability of DOACs measurement involves determinations of dabigatran (n = 136), rivaroxaban (n = 374) and apixaban (n = 22) in outpatients and hospitalized patients between May 2013 and April 2017. Determination of the level of DOACs should be available 24/7 in highly specialized medical centers, especially in those which perform emergency procedures for treating patients with acute stroke and hemorrhages.

scholarly journals Idarucizumab, a Specific Antidote for Dabigatran: Immediate, Complete and Sustained Reversal of Dabigatran Induced Anticoagulation in Elderly and Renally Impaired Subjects

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 344-344 ◽  
Author(s):  
Stephan Glund ◽  
Joachim Stangier ◽  
Michael Schmohl ◽  
Viktoria Moschetti ◽  
Wouter Haazen ◽  
...  
Keyword(s):  
Vitamin K Antagonists ◽  
Dabigatran Etexilate ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Anticoagulant Effect ◽  
Thrombin Time ◽  
Double Blind ◽  
Male And Female ◽  
Increased Risk ◽  
Pharmacologically Active

Abstract Introduction Oral anticoagulation is an effective therapy to prevent and treat thromboembolic events. So far, Vitamin K antagonists have been the main drug of choice. Recently, the advent of the direct oral anticoagulants (DOAC) has changed medical practice significantly; nevertheless all anticoagulants are associated with an increased risk of bleeding. Bleeding management can be achieved through established therapies; however specific antidotes are not yet available for these agents to further facilitate patient management in cases needed. Previously the dabigatran antidote (idarucizumab) has demonstrated immediate, complete and sustained reversal of dabigatran induced anti-coagulation in healthy male volunteers. In the present study it was determined whether and to what extent doses of up to 5 g idarucizumab would reverse the anticoagulant effects of dabigatran in male and female healthy mid-aged, elderly and renally impaired volunteers. In addition, it was tested whether oral intake of dabigatran etexilate 24 hrs after idarucizumab treatment could restore dabigatran related anticoagulation. It was further tested if a second administration of idarucizumab 2 months later was safe and well tolerated. Methods Safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of idarucizumab were investigated in a randomized, double-blind, placebo controlled two-way cross-over study in 46 male and female volunteers. Dabigatran etexilate (DE), 220 mg bid in healthy subjects and 150 mg bid in subjects with mild or moderate renal impairment (CLCR60 to <90 or 30 to <60 [mL/min], respectively) was given over 4 days to achieve the steady state conditions. Idarucizumab doses of 1 g, 2.5 g, 5 g or 5 g given as 2x2.5 g one hour apart were administered as 5 min i.v. infusion 2 hrs after the last dose of DE. Concentrations of unbound dabigatran were determined as a measure of pharmacologically active dabigatran. The anticoagulant effect of dabigatran and its reversal were assessed by coagulation time measurements, including diluted Thrombin Time (dTT, Hemoclot® DTI assay), Ecarin Clotting Time (ECT) and activated Partial Thromboplastin Time (aPTT). Results All administered doses of idarucizumab were safe and well tolerated. PK measurements of unbound dabigatran indicated that idarucizumab binding and thus reversal of the anticoagulant effect of dabigatran occurred immediately after end of infusion. Prolongation of clotting times induced by dabigatran was reversed to baseline at the end of the 5 minute infusion of the antidote. This was consistently demonstrated by all clotting assays. Sustained reversal over the entire observation period was observed for idarucizumab doses of 2.5 g, 5 g and 2x2.5 g. For the 1g dose, there was partial return of dabigatran induced anticoagulation around 2-4 hours after i.v. infusion. Also a second administration of idarucizumab (two months after the first) was safe and resulted in complete reversal. In addition, PD and PK measurements at selected time points and in comparison to placebo treatment confirmed that effective dabigatran anticoagulation could be re-established 24 hours after administration of idarucizumab. Conclusions The dabigatran antidote, idarucizumab, was well tolerated under all conditions tested. The administration of 5 g or 2x2.5 g led to sustained reversal of dabigatran induced anticoagulation in male and female subjects of different age and renal function. In addition, idarucizumab administered 2 months apart achieved the same degree of reversal. Dabigatran anticoagulation could be re-established 24 hrs after idarucizumab dosing. These results support the use of a total dose of 5 g idarucizumab as an effective dose in further clinical testing. Disclosures Glund: Boehringer Ingelheim: Employment. Off Label Use: Idarucizumab, a specific antidote for dabigatran, is in clinical development.. Stangier:Boehringer Ingelheim: Employment. Schmohl:Boehringer Ingelheim: Employment. Moschetti:Boehringer Ingelheim: Employment. Haazen:SGS Life Science Services (contracted by Boehringer Ingelheim to conduct the study): Employment. De Smet:SCS Boehringer Ingelheim Comm. V.: Employment. Gansser:Boehringer Ingelheim: Employment. Norris:Boehringer Ingelheim: Employment. Lang:Boehringer Ingelheim: Employment. Reilly:Boehringer Ingelheim: Employment.

scholarly journals Update on Edoxaban for the Prevention and Treatment of Thromboembolism: Clinical Applications Based on Current Evidence

2015 ◽  
Vol 2015 ◽  
pp. 1-19 ◽  
Author(s):  
Ali Zalpour ◽  
Thein Hlaing Oo
Keyword(s):  
Vitamin K Antagonists ◽  
Dabigatran Etexilate ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Factor Xa ◽  
Coagulation Factors ◽  
Current Evidence ◽  
Thrombin Inhibitor ◽  
Prevention And Treatment ◽  
Financial Impacts

Vitamin K antagonists (VKA) and heparins have been utilized for the prevention and treatment of thromboembolism (arterial and venous) for decades. Targeting and inhibiting specific coagulation factors have led to new discoveries in the pharmacotherapy of thromboembolism management. These targeted anticoagulants are known as direct oral anticoagulants (DOACs). Two pharmacologically distinct classes of targeted agents are dabigatran etexilate (Direct Thrombin Inhibitor (DTI)) and rivaroxaban, apixaban, and edoxaban (direct oral factor Xa inhibitors (OFXaIs)). Emerging evidence from the clinical trials has shown that DOACs are noninferior to VKA or low-molecular-weight heparins in the prevention and treatment of thromboembolism. This review examines the role of edoxaban, a recently approved OFXaI, in the prevention and treatment of thromboembolism based on the available published literature. The management of edoxaban in the perioperative setting, reversibility in bleeding cases, its role in cancer patients, the relevance of drug-drug interactions, patient satisfaction, financial impacts, and patient education will be discussed.

scholarly journals Direct oral anticoagulant monitoring: what laboratory tests are available to guide us?

Hematology ◽  
2019 ◽  
Vol 2019 (1) ◽  
pp. 194-197 ◽  
Author(s):  
Ravi Sarode
Keyword(s):  
Clinical Decision Making ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Rapid Assessment ◽  
Clinical Decision ◽  
The United States ◽  
Thrombin Inhibitor ◽  
Thrombin Time ◽  
Clinical Scenarios

Abstract Direct oral anticoagulants (DOACs) are increasingly used in the treatment and prophylaxis of thromboembolism because of several advantages over vitamin K antagonists, including no need for laboratory monitoring. However, it has become increasingly important in certain clinical scenarios to know either actual DOAC concentration (quantitative) or presence of DOAC (qualitative). These clinical conditions include patients presenting with major bleeding or requiring urgent surgery who may need a reversal or hemostatic agent, extremes of body weight, failed therapy, etc. Prothrombin time and activated partial thromboplastin time are variably affected by factor Xa inhibitors (FXaIs) and direct thrombin inhibitor (DTI), respectively, depending on reagents’ sensitivity, and hence, they cannot be relied on confidently. Thrombin time is highly sensitive to very low amounts of DTI; thus, normal value rules out a clinically significant amount. Liquid chromatography mass spectrometry accurately measures DOAC levels but is clinically impractical. Dilute thrombin time and ecarin-based assays using appropriate calibrators/controls provide an accurate DTI level. Anti-Xa assay using corresponding FXaI calibrators/controls provides accurate drug levels. However, these assays are not readily available in the United States compared with some other parts of the world. Heparin assays using anti-Xa activity often have a linear relationship with calibrated FXaI assays, especially at the lower end of on-therapy levels, and they may provide rapid assessment of drug activity for clinical decision making. Currently, there is very limited knowledge of DOAC effect on viscoelastic measurements. Although there is uniformity in expression of DOAC concentrations in nanograms per milliliter, a universal FXaI DOAC assay is urgently needed.

scholarly journals Reversal of direct oral anticoagulants: a practical approach

Hematology ◽  
2016 ◽  
Vol 2016 (1) ◽  
pp. 612-619 ◽  
Author(s):  
Andrew W. Shih ◽  
Mark A. Crowther
Keyword(s):  
Phase 1 ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Antibody Fragment ◽  
Factor Xa ◽  
Factor Xa Inhibitors ◽  
Severe Bleeding ◽  
Thrombin Time ◽  
Ancillary Benefits ◽  
Reversal Agents

Abstract Direct oral anticoagulants (DOACs) have at least noninferior efficacy compared with other oral anticoagulants and have ancillary benefits, including overall better safety profiles, lack of the need for routine monitoring, rapid onset of action, and ease of administration. Reversal of these agents may be indicated in certain situations such as severe bleeding and for perioperative management. DOAC-associated bleeding should be risk stratified: patients with moderate or severe bleeding should have the DOAC discontinued and reversal strategies should be considered. Laboratory testing has limited utility in the acute management of bleeding; thrombin time and activated partial thromboplastin time may be useful for excluding clinically relevant levels of dabigatran. Prothrombin time is potentially useful for rivaroxaban and edoxaban, but calibrated anti-Xa assays are optimal for determining clinically relevant levels of factor Xa inhibitors. Because specific reversal agents are not widely available, supportive care and interventions for local hemostasis remain the cornerstones of therapy in the patient with DOAC-associated bleeding. Nonspecific reversal agents should be considered only in the event of severe bleeding because their efficacy is unknown, and they are associated with risk of thrombosis. Recent results from phase 3/4 studies demonstrate efficacy for an antidote to dabigatran (idarucizumab, a monoclonal antibody fragment with specificity for dabigatran) and an antidote to factor Xa inhibitors (andexanet alfa, a recombinant and inactive form of factor Xa that binds inhibitors). A universal reversal agent (ciraparantag) for many anticoagulants, including the DOACs, shows promise in results from phase 1 and 2 studies.

scholarly journals The Comparison of Therapeutic Efficacy Between Dabigatran Versus Warfarin in Patients With Nonvalvular Atrial Fibrillation

2021 ◽  
Vol 27 ◽  
pp. 107602962110447
Author(s):  
Hongxia Li ◽  
Lei Zhang ◽  
Ming Xia ◽  
Chi Zhang ◽  
Tingbo Jiang
Keyword(s):  
Atrial Fibrillation ◽  
Dabigatran Etexilate ◽  
Oral Anticoagulants ◽  
International Normalized Ratio ◽  
Thrombin Time ◽  
Nonvalvular Atrial Fibrillation ◽  
Coagulation Assays ◽  
Warfarin Group ◽  
Dose Warfarin ◽  
Coagulation Status

Background Novel oral anticoagulants and warfarin are widely used for stroke prevention in patients with atrial fibrillation. The anticoagulation status of patients receiving warfarin or rivaroxaban has been studied. In this study, we aimed to evaluate the effect of dabigatran and warfarin on preventing thrombin generation (TG). Methods This retrospective study enrolled 237 nonvalvular atrial fibrillation (NVAF) subjects treated with 110 mg dabigatran etexilate twice daily and 224 NVAF patients received adjusted-dose warfarin (international normalized ratio [INR] of 2 to 3)). Coagulation assays, prothrombin fragment 1  +  2 (F1+2), calibrated automated thrombogram, and thrombin–antithrombin complex (TAT) were detected at the steady state. Results Activated partial thromboplastin time (APTT), antithrombin III activity, fibrinogen, and lag time showed no difference between the two groups. Compared to the dabigatran group, prothrombin time and INR values were higher in the warfarin group (all P < .001). Thrombin time, endogenous thrombin potential, peak TG (Cmax), F1+2, and TAT were lower in the warfarin group. The inhibition of TG was still stronger in the warfarin group when the patients were divided into subgroups. Conclusion Conventional coagulation assays are suboptimal for assessing the coagulation status of dabigatran. TG could be used as supplementary assays to evaluate the anticoagulation effect of oral anticoagulants. Our results suggest that warfarin may inhibit TG more aggressively than dabigatran in patients regardless of age and kidney function.

scholarly journals Monitoring and reversal of direct oral anticoagulants

Hematology ◽  
2015 ◽  
Vol 2015 (1) ◽  
pp. 117-124 ◽  
Author(s):  
Adam Cuker ◽  
Deborah Siegal
Keyword(s):  
Prothrombin Complex Concentrate ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Antibody Fragment ◽  
Factor Xa ◽  
Factor Xa Inhibitors ◽  
Severe Bleeding ◽  
Thrombin Time ◽  
Reversal Agents ◽  
Routine Monitoring

Abstract Although the direct oral anticoagulants (DOACs) do not require routine monitoring and reduce bleeding compared with warfarin, there are special circumstances in which laboratory measurement or reversal of their anticoagulant effect may be indicated. The dilute thrombin time and ecarin-based assays are able to quantify dabigatran across a broad range of concentrations, but are not widely available. A normal thrombin time excludes clinically relevant levels and a normal activated partial thromboplastin time probably excludes excess levels of dabigatran. Factor Xa inhibitors may be quantified with an anti-Xa assay calibrated with drug-specific standards. A normal prothrombin time probably excludes excess levels of rivaroxaban and edoxaban, but not apixaban. Patients with minor and moderate DOAC-associated bleeding can be treated with supportive care and general hemostatic measures. Nonspecific reversal agents (eg, prothrombin complex concentrate, activated prothrombin complex concentrate) are of unproven benefit, carry a risk of thrombosis, and should be reserved for severe bleeding. Specific reversal agents, such as idarucizumab (a monoclonal antibody fragment that binds dabigatran) and andexanet alfa (a recombinant factor Xa variant that binds factor Xa inhibitors but lacks coagulant activity), are in clinical development.

Effect of new chalcone analogues on hemostasis in animals with experimental «сytokine storm»

2021 ◽  
Author(s):  
Д.И. Поздняков ◽  
В.М. Руковицина ◽  
А.В. Сосновская ◽  
Е.А. Олохова
Keyword(s):  
Platelet Aggregation ◽  
Antithrombin Iii ◽  
Serum Levels ◽  
Thrombin Time ◽  
Cytokine Storm ◽  
Reference Drug ◽  
Soluble Fibrin ◽  
Fibrin Monomer ◽  
Antithrombin Iii Activity ◽  
D Dimer

Введение. «Цитокиновый шторм» представляет собой расстройство иммунной системы с выраженной гиперцитокинемией, характеризующееся развитием коагуляционных нарушений с высоким уровнем летальности. Цель исследования: оценить влияние новых аналогов халкона на изменение реакций гемостаза у крыс в условиях экспериментального «цитокинового шторма». Материалы и методы. Исследование было выполнено на 80 крысах- самцах линии Wistar, разделенных на 8 равных групп по 10 особей. «Цитокиновый шторм» моделировали путем внутрибрюшинного введения липополисахарида в дозе 10 мг/кг. Исследуемые соединения в дозе 20 мг/кг интраперитонеально и препарат сравнения — гепарин (20 ЕД/кг, подкожно) вводили через 60 мин после моделирования патологии. Через 24 ч в сыворотке крови у крыс оценивали содержание фибриногена, D-димера, растворимых фибрин-мономерных комплексов (РФМК), активность антитромбина III (АТ-III), тромбиновое время (ТВ) и степень АДФ-стимулированной агрегации тромбоцитов. Результаты. Применение аналогов халкона способствовало восстановлению гемостатических реакций, что выражалось в снижении концентраций фибриногена, D-димера, РФМК, степени агрегации тромбоцитов и повышении активности АТ-III и ТВ. При этом в ряду изучаемых веществ соединение, содержащее гидроксил во 2-м положении и метильную группу в 5-м положении, проявляло несколько больший уровень фармакологической активности, нежели остальные исследуемые соединения. Заключение. На основании полученных данных можно предположить актуальность дальнейшего изучения аналогов халкона как средств, нормализующих гемостаз при гиперцитокиновых расстройствах. Background. «Cytokine storm» is a disorder of the immune system with severe hypecytokinemia, characterized by the development of coagulation disorders with a high level of mortality. Objectives: to evaluate the effect of new chalcone analogues on changes of hemostasis reactions in rats under the conditions of an experimental «cytokine storm». Materials/Methods. The study was performed on 80 male Wistar rats divided into 8 equal groups of 10 individuals. The «cytokine storm» was modeled in animals by intraperitoneal injection of lipopolysaccharide at a dose of 10 mg/kg. The test-compounds at a dose of 20 mg/kg intraperitoneally and the reference drug — heparin (20 U/kg, subcutaneously) were administered 60 minutes after the pathology simulation. After 24 hours, the serum levels of fi brinogen, D-dimer, soluble fibrin-monomer complexes, antithrombin III activity, thrombin time, and the degree of ADP-stimulated platelet aggregation were evaluated in rats. Results. The study showed that the use of chalcone analogues contributed to the restoration of hemostasis reactions, which was expressed in a decrease in theconcentration of fibrinogen, D-dimer, soluble fibrin-monomer complexes, the degree of platelet aggregation, and an increase in antithrombin III activity and thrombin time. At the same time, among the studied substances, the compound containing hydroxyl in the 2nd position and the methyl group in the 5th position showed a slightly higher level of pharmacological activity than the other test compounds. Conclusions. Based on the obtained data, it is actuality to assume the relevance of further study of chalcone analogues as agents that normalize hemostasis in hypercytokine disorders.

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

2021 ◽  
Author(s):  
Jack Ansell ◽  
Sasha Bakhru ◽  
Bryan E Laulicht ◽  
Gregory Tracey ◽  
Stephen Villano ◽  
...  
Keyword(s):  
Steady State ◽  
Anticoagulant Activity ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Hot Flashes ◽  
Elderly Subjects ◽  
Reversal Agent ◽  
Post Dose ◽  
Healthy Elderly ◽  
Complete Reversal

Abstract 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.

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