YM150, An Oral Direct Factor Xa Inhibitor: Combination with Aspirin or Clopidogrel In Arteriovenous Shunt Thrombosis In Rats

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3318-3318
Author(s):  
Yoshiyuki Iwatsuki ◽  
Chinatsu Sakata ◽  
Yumiko Moritani
Keyword(s):  
Platelet Aggregation ◽  
Arterial Thrombosis ◽  
Bleeding Time ◽  
Thrombus Formation ◽  
Control Level ◽  
Factor Xa ◽  
Antiplatelet Agents ◽  
Factor Xa Inhibitor ◽  
Direct Factor ◽  
Silk Thread

Abstract Abstract 3318 Background: YM150, an oral direct factor Xa inhibitor, is currently in clinical development for the prevention of venous thromboembolism in patients undergoing orthopedic surgery, prevention of stroke in patients with atrial fibrillation, and prevention of ischemic events after recent acute coronary syndrome (ACS). The antiplatelet agents aspirin or clopidogrel will likely be co-prescribed with YM150 in ACS. Here, we report the effects of YM150 in combination with aspirin or clopidogrel on thrombus formation, bleeding, platelet aggregation, and coagulation in rats. Methods: The antithrombotic effect was estimated in a rat arteriovenous shunt model. The shunt was formed by attaching a polyethylene tube containing a silk thread to the carotid artery and the contralateral carotid vein. Blood was allowed to circulate in this shunt for 15 min, and then the silk thread was withdrawn from the tube to assess the thrombus weight. YM150, aspirin, or clopidogrel was orally administered 0.5, 1, or 2 h before shunt formation, respectively. At the same time as shunt formation, an incision was made at the sole of the left foot using a template bleeding device (Surgicutt®) to measure bleeding time. To avoid interference with the thrombosis model, blood samples to assess platelet aggregation and prothrombin time were obtained from separate animals at the same time point as shunt formation in the thrombus study. Platelet aggregation was induced using 10 μg/mL of collagen and 5 μM of adenosine 5`-diphosphate (ADP) to assess the effects of aspirin and clopidogrel, respectively. Results: YM150 alone inhibited thrombus formation, with significance at 10 mg/kg and more (P < 0.05). Respective thrombus weights in the control, 3, 10, and 30 mg/kg groups of YM150 were 4.8, 3.6, 2.4, and 2.0 mg. Aspirin alone inhibited thrombus formation, with significance at 100 mg/kg and more (P < 0.01). Respective thrombus weights in the control, 30, 100, and 300 mg/kg group of aspirin were 6.2, 4.2, 2.8, and 1.5 mg. Clopidogrel alone inhibited thrombus formation, with significance at 1 mg/kg and more (P < 0.01). Respective thrombus weights in the control, 0.3, 1, and 3 mg/kg group of clopidogrel were 4.8, 3.6, 2.9, and 1.3 mg. When administered concomitantly with 100 mg/kg of aspirin, YM150 (3, 10, 30 mg/kg) further inhibited thrombogenesis, with significance at 30 mg/kg of YM150 (P < 0.05) and thrombus weights of 2.4, 1.5, and 1.3 mg, respectively. When administered concomitantly with 1 mg/kg of clopidogrel, YM150 (3, 10, 30 mg/kg) further inhibited thrombogenesis, with significance at 30 mg/kg of YM150 (P < 0.05) and thrombus weights of 3.0, 2.0, and 1.5 mg, respectively. Collagen-induced platelet aggregation was reduced to 16.7% of the control level by 100 mg/kg of aspirin, and ADP-induced platelet aggregation was reduced to 74.4% of the control level by 1 mg/kg of clopidogrel. These effects were not changed in the presence of YM150. Prothrombin time and bleeding time were not prolonged by any of the agents alone, and further, these parameters were not affected by combined use of YM150 with either aspirin or clopidogrel. Conclusions: The thrombosis study suggests that both the platelet aggregation and coagulation cascade participate in thrombus formation in this model since both antiplatelet agents and the anticoagulant YM150 were effective. Thus, the thrombosis induced in this model can be considered similar to arterial thrombosis in humans where both platelets and fibrin are involved. Taken together, YM150 is a promising antithrombotic agent that augments the effects of antiplatelet agents against arterial thrombosis without increasing bleeding risk. Disclosures: Iwatsuki: Astellas Phama Inc.: Employment. Sakata:Astellas Phama Inc.: Employment. Moritani:Astellas Phama Inc.: Employment.

Comparison of YM150, an Oral, Direct Factor Xa Inhibitor, with Other Antithrombotic Agents in Rodent Venous and Arterial Thrombosis Models.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3155-3155 ◽  
Author(s):  
Minori Saitoh ◽  
Seiji Kaku ◽  
Toshiyuki Funatsu ◽  
Hiroyuki Koshio ◽  
Tsukasa Ishihara ◽  
...  
Keyword(s):  
Filter Paper ◽  
Arterial Thrombosis ◽  
Bleeding Time ◽  
Thrombus Formation ◽  
Factor Xa ◽  
Thrombin Inhibitor ◽  
Factor Xa Inhibitor ◽  
Direct Factor ◽  
Antithrombotic Effect ◽  
Arterial Thrombus

Abstract YM150, an oral, direct factor Xa inhibitor, is currently being evaluated in Phase II studies as prophylaxis for venous thromboembolism in patients undergoing orthopedic surgery. In the present study, we compared the antithrombotic effect of YM150 with the effects of antithrombin-dependent indirect factor Xa inhibitors, enoxaparin and fondaparinux, and a direct thrombin inhibitor, ximelagatran, in ferric chloride (FeCl3)-induced venous and arterial thrombosis models in rats. We also evaluated the bleeding time in a rat tail transection model. Prior to any experimentation, male Sprague-Dawley rats, which had been fasting for at least 12 h, were anesthetized with urethane (1 g/kg, i.p.) or sodium pentobarbital (50 mg/kg, i.p.). YM150 and ximelagatran were administered intra-duodenally, and both enoxaparin and fondaparinux were given subcutaneously, 30 min prior to induction of thrombus or tail transection. All animals were kept warm with a heating pad during the experiments. Venous and arterial thromboses were produced, respectively, by the 5 min application of 8% FeCl3 soaked filter paper to the external surface of the inferior vena cava and 35% FeCl3 soaked filter paper to the abdominal aorta. The venous thrombosis model was supplemented by using a silk thread venous stenosis. To measure bleeding time, the tail was transected 5 mm from its tip. Blood was carefully blotted each 30 sec with a filter paper. Once a blood stain was observed, we defined bleeding as blood flow sustained over 30 sec. Bleeding time was defined as the sum of the bleeding periods during the 60 min observation in each animal. Administration of intra-duodenal YM150 significantly inhibited both venous and arterial thrombus formation at doses of 10 mg/kg or greater, and 3 mg/kg or greater, respectively. This indicated that YM150 promoted an antithrombotic effect at similar dose ranges for venous and arterial thromboses. In contrast, YM150 did not prolong the bleeding time at doses up to 30 mg/kg. Venous thrombus formation was inhibited by subcutaneous enoxaparin at doses of 100 IU/kg or greater and fondaparinux at doses of 0.03 mg/kg or greater. Arterial thrombus formation was inhibited by subcutaneous administration of 1000 IU/kg enoxaparin and 3 mg/kg fondaparinux. The results indicated that 10–100 times higher doses of these antithrombotics were needed to inhibit arterial thrombosis. Furthermore, enoxaparin at doses of 300 IU/kg or greater and fondaparinux at doses of 1 mg/kg or greater, significantly prolonged the bleeding time, suggesting that these two medications may be associated with increased risk of hemorrhage at concentrations used to prevent arterial thrombosis. At doses of 1 mg/kg or greater, intra-duodenal ximelagatran inhibited both venous and arterial thrombus formation. The dose-response curve for ximelagatran tended to be steeper than that for other anticoagulants tested. Antithrombotic doses of ximelagatran (1 mg/kg or greater), produced similar prolongations of bleeding time as those seen with administration of enoxaparin and fondaparinux. In conclusion, YM150, an oral direct factor Xa inhibitor, shows promise as an antithrombotic drug with potentially wider safety margins than current antithrombin-dependent factor Xa inhibitors and a thrombin inhibitor.

Reversal of anticoagulant effects of edoxaban, an oral, direct factor Xa inhibitor, with haemostatic agents

2012 ◽  
Vol 107 (02) ◽  
pp. 253-259 ◽  
Author(s):  
Toshio Fukuda ◽  
Yuko Honda ◽  
Chikako Kamisato ◽  
Toshiro Shibano ◽  
Yoshiyuki Morishima
Keyword(s):  
Venous Thrombosis ◽  
Prothrombin Complex Concentrate ◽  
Bleeding Time ◽  
Factor Viia ◽  
Thrombus Formation ◽  
Factor Xa ◽  
Factor Xa Inhibitor ◽  
Direct Factor ◽  
Thrombosis Model ◽  
Haemostatic Agents

SummaryEdoxaban, an oral, direct factor Xa inhibitor, has a similar or low incidence of bleeding events compared with other anticoagulants in clinical trials. Therefore, agents to reverse the anticoagulant effects of edoxaban could be desirable in emergency situations. In this study, the reversal effects of haemostatic agents were determined on prothrombin time (PT) prolongation in vitro and bleeding time prolongation in vivo by edoxaban. PT using human plasma was measured in the presence of edoxaban at therapeutic and excess concentrations with the haemostatic agents, prothrombin complex concentrate (PPSB-HT), activated prothrombin complex concentrate (Feiba), and recombinant factor VIIa (rFVIIa). In rats, rFVIIa and Feiba was given during intensive anticoagulation with edoxaban. The haemostatic effect was evaluated in a model of planta template bleeding and a potential prothrombotic effect was evaluated in a venous thrombosis model. PPSB-HT, Feiba, and rFVIIa concentration-dependently shortened PT prolonged by edoxaban. Among these, rFVIIa and Feiba showed potent activities in reversing the PT prolongation by edoxaban. rFVIIa (1 and 3 mg/kg, i.v.) and Feiba (100 U/kg, i.v.) significantly reversed edoxaban (1 mg/kg/h)-induced prolongation of bleeding time in rats. In a rat venous thrombosis model, no potentiation of thrombus formation was observed when the highest dose (3 mg/kg) of rFVIIa was added to edoxaban (0.3 and 1 mg/kg/h) compared with the control. The present study indicated that rFVIIa, Feiba, and PPSB-HT have the potential to be reversal agents for edoxaban.

ADP Plays a Key Role in Thrombogenesis in Rats

1988 ◽  
Vol 59 (02) ◽  
pp. 225-230 ◽  
Author(s):  
J P Maffrand ◽  
A Bernat ◽  
D Delebassée ◽  
G Defreyn ◽  
J P Cazenave ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Bleeding Time ◽  
Thrombus Formation ◽  
Vascular Wall ◽  
Cyclooxygenase Inhibitors ◽  
High Dose ◽  
Silk Thread ◽  
Dense Granules ◽  
Prolonged Bleeding Time ◽  
Venous Shunt

SummaryThe relative importance of ADP, arachidonic acid metabolites and serotonin as thrombogenic factors was evaluated in rats by comparing, after oral administration, the effects of two inhibitors of ADP-induced platelet aggregation (ticlopidine and PCR 4099), three cyclo-oxygenase inhibitors (aspirin, triflusal and indobufen) and a selective serotonin 5HT2 receptor antagonist (ketanserin) on platelet aggregation, in four platelet-dependent thrombosis models and on bleeding time. Platelet aggregation induced by ADP and collagen was completely inhibited by ticlopidine and PCR 4099 whereas only the collagen aggregation was reduced by the cyclo-oxygenase inhibitors. Ketanserin or a depletion of platelet serotonin by reserpine did not affect platelet aggregation. Ticlopidine and PCR 4099 greatly prolonged rat tail transection bleeding time. This is probably related to their known ability to inhibit ADP-mediated platelet aggregation. In contrast, the cyclooxygenase inhibitors did not affect bleeding time at all. Reserpine and ketanserin prolonged bleeding time by interfering with the action of serotonin on the vascular wall. Ticlopidine and PCR4099 were very potent antithrombotics in all the models. Aspirin, only at a high dose, inhibited poorly thrombus formation on a silk thread in an arterio-venous shunt, suggesting that the inhibition of cyclo-oxygenase was not responsible. Triflusal was inactive in all models while indobufen slightly reduced thrombus formation in the silk thread and metallic coil models. Ketanserin and reserpine reduced thrombus only in the metallic coil model. Thrombus formation was greatly reduced in fawn-hooded rats, which lack ADP in their platelet dense granules because of a genetic storage pool deficiency. Taken together, the results obtained with the drugs and with the fawn-hooded rats support the concept that ADP plays a key role in thrombogenesis in rats.

Anticoagulant and anti-platelet effects are maintained following coadministration of otamixaban, a direct factor Xa inhibitor, and acetylsalicylic acid

2006 ◽  
Vol 95 (02) ◽  
pp. 224-228 ◽  
Author(s):  
Markus Hinder ◽  
Annke Frick ◽  
Ronald Rosenburg ◽  
Galina Hesse ◽  
Marie-Laure Ozoux ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Acetylsalicylic Acid ◽  
Platelet Function ◽  
Bleeding Time ◽  
Factor Xa ◽  
Pharmacokinetic Parameters ◽  
Parameter Estimates ◽  
Factor Xa Inhibitor ◽  
Direct Factor ◽  
Geometric Means

SummaryThe pharmacokinetics, pharmacodynamics and safety of the direct factor Xa inhibitor, otamixaban, with and without concomitant acetylsalicylic acid (ASA) were investigated in healthy volunteers. The study was a double-blind, placebo-controlled 3-way crossover study. Sixty-eight male volunteers in total were randomised to otamixaban, ASA, or otamixaban with ASA. ASA (300 mg once a day) was started2 days before and continued on the day of the otamixaban 6-hour IV infusion (0.3 and 0.5 mg/kg). Pharmacokinetic and pharmacodynamic parameters (coagulation markers, platelet function tests and skin bleeding time) were determined. Drug interaction was assessed by the ratios of geometric means and 90 confidence intervals (90% CI)of the parameter estimates.Pharmacokinetic parameters of otamixaban remain ed unchanged with ASA. Ratios of geometric means (90% CI) were for Ceoi 96.54 (91.21–102.19) and 95. 04 (90. 10–100. 24) and for AUC 98. 0 (93. 92–102. 25) and 95. 90 (92. 61–99. 31), for 0. 3 and 0. 5 mg/kg, respectively. No drug interaction was observed between otamixaban andASA on the coagulation and platelet function parameters. Neither otamixaban nor ASA had an effect on skin bleeding time; their co-administration led toa slight prolongation of skin bleeding time above the normal range without any clinically relevant bleeding. This study demonstrated that the desired effects of otamixaban and ASA, namely anticoagulation and platelet inhibition, respectively, are maintained during co-administration of both drugs.

Absence of Pharmacodynamic or Pharmacokinetic Interactions When TAK-442, An Oral, Direct Factor Xa Inhibitor, Is Coadministered with Aspirin or Clopidogrel.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4175-4175 ◽  
Author(s):  
Fran Stringer ◽  
Graham Scott ◽  
Stuart Kupfer ◽  
Charlie Cao ◽  
Masaki Kawamura
Keyword(s):  
Arachidonic Acid ◽  
Salicylic Acid ◽  
Platelet Aggregation ◽  
Bleeding Time ◽  
Factor Xa ◽  
Direct Factor ◽  
Acid Metabolite ◽  
Post Dose ◽  
Clinically Significant ◽  
Global Research

Abstract Abstract 4175 Introduction TAK-442 is a novel orally active, direct Factor Xa (fXa) inhibitor in clinical development for the prevention of venous and arterial thrombotic disorders. Currently, aspirin and clopidogrel are widely used for platelet inhibition in patients with an increased risk of atherothrombotic events, and it is highly likely that TAK-442 may provide incremental anti-thrombotic benefit when used in conjunction with either of these agents. The primary aim of this study was to evaluate the effect of TAK-442 on inhibition of platelet aggregation by aspirin or clopidogrel. Methods Healthy male and female (n=77), subjects were randomly assigned to 1 of 2 treatments groups and received either TAK-442 60 mg or placebo twice daily (BID) for 11 days, with the addition of aspirin 162 mg or clopidogrel 75 mg once daily (QD) from days 5 to 11. Pharmacokinetics were assessed for TAK-442 (days 4 and 11), aspirin/salicylic acid (day 11) and clopidogrel/carboxylic acid metabolite (day 11. Inhibition of fXa (Coatest®) was assessed on day 1 and two hours post dose on days 4 and 11. Platelet aggregation (arachidonic acid-induced for the aspirin group or ADP-induced for the clopidogrel group) was assessed on day -1 and 2 hours post dose on days 4 and 11; bleeding time was assessed on day -1 and 2 hours post dose on day 11. Results Inhibition of arachidonic acid-induced platelet aggregation by aspirin was not affected by TAK-442 (71% for aspirin + TAK-442 and 74% for aspirin + placebo) nor was there any clinically significant effect of TAK-442 treatment on the inhibition of ADP-induced platelet aggregation by clopidogrel (56% for clopidogrel + TAK-442 and 67% for clopidogrel + placebo) at 2 hours post dose on day 11. Likewise, co-administration of TAK-442 did not have a clinically significant effect on the pharmacokinetic profiles of aspirin or clopidogrel. AUC0-24 and Cmax values were increased ≤16% for clopidogrel and ≤13% for the carboxylic acid metabolite. Although aspirin AUC0-24 and Cmax were increased 2- to 3-fold with coadministration (90% confidence intervals were: 76.2% to 741.8% and 90.1% to 825.1%, respectively), the proportional exposure was very low and the variability was high; the values for the active metabolite, salicylic acid, were increased less than 20% with coadministration. TAK-442-mediated inhibition of fXa activity and prolongation of PT, and the PK profile of TAK-442, were unaffected by co-administration with aspirin or clopidogrel. Coadministration of TAK-442 resulted in modest increases in mean bleeding time compared to aspirin with placebo (aspirin + TAK-442: 558 sec vs. aspirin + placebo: 392 sec) and to clopidogrel with placebo (clopidogrel + TAK-442: 893 sec vs. clopidogrel + placebo: 829 sec). TAK-442 was well tolerated, with a low and similar frequency of mild bleeding events with or without aspirin or clopidogrel coadministration. Conclusion This study demonstrated that no clinically meaningful pharmacodynamic or pharmacokinetic interactions were observed when TAK-442 was co-administered with aspirin or clopidogrel. Disclosures: Stringer: Takeda Global Research & Development, Inc.: Employment. Scott:Takeda Global Research & Development, Inc.: Employment. Kupfer:Takeda Global Research & Development, Inc.: Employment. Cao:Takeda Global Research & Development, Inc.: Employment. Kawamura:Takeda Global Research & Development, Inc.: Employment.

CrataBL, a lectin and Factor Xa inhibitor, plays a role in blood coagulation and impairs thrombus formation

2014 ◽  
Vol 395 (9) ◽  
pp. 1027-1035 ◽  
Author(s):  
Bruno R. Salu ◽  
Rodrigo S. Ferreira ◽  
Marlon V. Brito ◽  
Tatiana F. Ottaiano ◽  
José Walber M.C. Cruz ◽  
...  
Keyword(s):  
Arterial Thrombosis ◽  
Bleeding Time ◽  
Antithrombin Iii ◽  
Thrombus Formation ◽  
Factor Xa ◽  
Artery Occlusion ◽  
Control Group ◽  
Thrombosis Model ◽  
Arterial Thrombus ◽  
Induce Cancer Cell Apoptosis

Abstract Arterial thrombosis is an important complication of diabetes and cancer, being an important target for therapeutic intervention. Crataeva tapia bark lectin (CrataBL) has been previously shown to have hypoglycemiant effect and also to induce cancer cell apoptosis. It also showed inhibitory activity against Factor Xa (Kiapp=8.6 μm). In the present study, we evaluated the anti-thrombotic properties of CrataBL in arterial thrombosis model. CrataBL prolongs the activated partial thromboplastin time on human and mouse plasma, and it impairs the heparin-induced potentiation of antithrombin III and heparin-induced platelet activation in the presence of low-dose ADP. It is likely that the dense track of positive charge on CrataBL surface competes with the heparin ability to bind to antithrombin III and to stimulate platelets. In the photochemically induced thrombosis model in mice, in the groups treated with 1.25, 5.0, or 10 mg/kg CrataBL, prior to the thrombus induction, the time of total artery occlusion was prolonged by 33.38%, 65%, and 66.11%, respectively, relative to the time of the control group. In contrast to heparin, the bleeding time in CrataBL-treated mice was no longer than in the control. In conclusion, CrataBL was effective in blocking coagulation and arterial thrombus formation, without increasing bleeding time.

Naproxen Has No Relevant Effect on the Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of BAY 59-7939 - An Oral, Direct Factor Xa Inhibitor.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1873-1873 ◽  
Author(s):  
Dagmar Kubitza ◽  
Michael Becka ◽  
Wolfgang Mueck ◽  
Michael Zuehlsdorf
Keyword(s):  
Clinical Trials ◽  
Venous Thromboembolism ◽  
Plasma Concentration ◽  
Adverse Events ◽  
Orthopaedic Surgery ◽  
Bleeding Time ◽  
Factor Xa ◽  
Factor Xa Inhibitor ◽  
Direct Factor ◽  
Major Orthopaedic Surgery

Abstract BAY 59-7939 is a novel, oral, direct Factor Xa inhibitor in clinical development for the prevention and treatment of thromboembolic disorders. BAY 59-7939 compared favourably with enoxaparin in recent clinical trials of the prevention of venous thromboembolism following major orthopaedic surgery. Possible concomitant medications in patients receiving BAY 59-7939 for either the prevention or treatment of venous thromboembolism include non-steroidal anti-inflammatory drugs (NSAIDs), such as naproxen. This randomized, two-way crossover study was performed to investigate the influence of naproxen on the safety, tolerability, pharmacodynamics, and pharmacokinetics of BAY 59-7939 in 11 healthy male subjects. The study included a run-in period with naproxen. Treatments were: naproxen 500 mg on 2 consecutive days (run-in), followed by a 14-day washout period, and then randomization either to BAY 59-7939 15 mg; or to naproxen 500 mg on the first day, and naproxen 500 mg and BAY 59-7939 15 mg on the second day. There was a 14-day washout period between crossovers. BAY 59-7939, naproxen, and the combination were well tolerated. Adverse events (eight in total) were reported by three subjects, and all were mild in intensity; there were no drug-related, treatment-emergent adverse events. BAY 59-7939 significantly inhibited Factor Xa activity by 35%, and prolonged prothrombin time (by 1.4 times baseline [tb]), activated partial thromboplastin time (1.3 tb), and HepTest (1.9 tb), with no influence from naproxen. No interaction was observed with respect to collagen-stimulated platelet aggregation. BAY 59-7939 and naproxen together significantly increased bleeding time compared with BAY 59-7939 alone; however, this difference was small compared with naproxen alone for all but one subject. This indicates that some subjects may be more sensitive to the combined effect of naproxen and BAY 59-7939. However, analysis of patients’ data from clinical trials after major orthopaedic surgery showed similar bleeding risks in patients with and without co-medication with NSAIDs at BAY 59-7939 doses up to 10 mg twice daily. The area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) for BAY 59-7939 both increased by approximately 10% following co-administration of naproxen; however, this small increase in BAY 59-7939 bioavailability was not considered clinically relevant. In conclusion, there is no relevant interaction between BAY 59-7939 and naproxen, although some individuals may be more sensitive to a combination of these drugs. Initial analysis of data from phase II clinical trials of BAY 59-7939 has shown a similar bleeding risk in patients using NSAIDs concomitantly compared with BAY 59-7939 alone. This will be further substantiated in phase III trials. Parameter Naproxen BAY 59-7939 BAY 59-7939 + naproxen aGeometric mean/geometric coefficient of variation; bMedian relative change from baseline; N=11 for all data Bleeding time (tb)a 1.46/0.583 1.20/0.613 2.17/0.576 Platelet aggregationb 0.052 1.02 0.086 AUC (μg.h/L)a - 1250/28.56 1396/26.30 Cmax (μ g/L)a - 152.9/31.51 165.3/27.69

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