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.

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.

Co-Administration of YM150, An Oral Direct Factor Xa Inhibitor, and Naproxen Does Not Result In Clinically Relevant Changes to the Pharmacodynamic or Pharmacokinetic Profile of Either Agent

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4393-4393
Author(s):  
Marten Heeringa ◽  
Alberto Garcia-Hernandez ◽  
Takeshi Kadokura ◽  
Dorien Groenendaal – van de Meent ◽  
Gregory Strabach ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Combination Treatment ◽  
Maximum Concentration ◽  
Factor Xa ◽  
Major Surgery ◽  
Combination Group ◽  
Global Development ◽  
Direct Factor ◽  
Post Dose ◽  
Arithmetic Means

Abstract Abstract 4393 Background: YM150, a potent oral direct factor Xa (FXa) inhibitor, is in development for the prevention of venous thromboembolism after major surgery and of thromboembolic events in subjects with atrial fibrillation. After administration, YM150 is rapidly and extensively metabolized into YM-222714, which predominantly determines antithrombotic effect. Naproxen, a non-steroidal anti-inflammatory drug with antiplatelet properties that inhibits cyclooxygenase (COX)-1 and COX-2 isoenzymes, and similar mode of action drugs will likely be co-prescribed with YM150 in clinical practice. This study assessed the interaction of YM150 and naproxen following co-administration in healthy males. Methods: A Phase I, randomized, open-label, 3-period crossover study (≥14-day washout between periods) compared the pharmacodynamic (PD) and pharmacokinetic (PK) properties of YM150 and naproxen given alone and in combination. Subjects received YM150 60 mg once daily and/or naproxen 500 mg twice daily for 6 and 4 days, respectively. Primary endpoint was change in skin bleeding time (SBT); assessors were blinded to treatment. Change from baseline (BL; pre-dose on Day 1) to 3 h post final dose in SBT was calculated to Day 4 for naproxen alone and Day 6 for YM150 alone and the combination group, thereby reflecting the respective times to achieve steady state (SS). Secondary PD endpoints included minimum FXa activity (FXamin), maximum prothrombin time (PTmax), maximum activated partial thromboplastin time (aPTTmax) and platelet aggregation. Blood and urine PK parameters (maximum concentration [Cmax], time to maximum concentration [tmax], area under the curve [AUC] and renal clearance [CLR]) and safety were also assessed. Blood samples for PK and PD variables were taken at SS on the final day of dosing (pre-dose and up to 24 h post-dose). Data are presented as arithmetic means. Results: 26 subjects were randomized and received treatment (mean age, 30.4 yrs); 6 subjects prematurely discontinued (consent withdrawal, n=3; adverse event [AE], n=2; protocol violation, n=1). Co-administration of YM150 and naproxen did not result in additive increases in SBT (Table). From BL to SS, mean (standard deviation [SD]) SBT (sec) increased from 317 (89.2) to 430 (111) after YM150 alone, from 306 (79.0) to 621 (230) after naproxen alone and from 332 (84.1) to 721 (259) after combination treatment. YM150 inhibited FXa activity and increased PTmax and aPTTmax; co-administration with naproxen did not influence these outcomes (Table). Naproxen decreased collagen-induced platelet aggregation, with no additive effect when co-administered with YM150 (Table). The PK of YM-222714 was generally unchanged when YM150 was administered alone or with naproxen (tmax 1.70 vs 1.45 h; Cmax 1535 vs 1497 ng/mL; AUCtau 11,644 vs 11,369 ng·h/mL; CLR 2.39 vs 3.42 L/h); the PK profile of YM150 itself was similarly unchanged (tmax 1.43 vs 1.17 h; Cmax 7.94 vs 8.23 ng/mL; AUCtau 79.8 vs 66.6 ng·h/mL; CLR 4.91 vs 6.67 L/h). Naproxen PK were also unchanged when co-administered with YM150. Overall, YM150 alone, naproxen alone and combination treatment were safe and well tolerated. Only one subject experienced AEs considered related to treatment (gingival bleeding and epistaxis); combination treatment was discontinued. One other subject discontinued due to an AE unrelated to study drug (gastroenteritis). No clinically relevant changes in laboratory parameters, vital signs or physical assessments were observed. Conclusions: Co-administration of YM150 with naproxen did not result in additive increases in SBT or clinically relevant changes in the PD or PK profiles of either agent; the combination was generally safe and well tolerated. Observed changes in FXa activity, PT and aPTT confirm the antithrombotic potency of YM150 and YM-222714, which was unaltered upon co-administration with naproxen. YM150 has no clinically relevant interaction with naproxen. Disclosures: Heeringa: Astellas Pharma Global Development Europe: Employment. Garcia-Hernandez:Astellas Pharma Global Development Europe: Employment. Kadokura:Astellas Pharma Inc.: Employment. Groenendaal – van de Meent:Astellas Pharma Global Development Europe: Employment. Mol:Astellas Pharma Global Development Europe: Employment. Eltink:Astellas Pharma Global Development Europe: Employment. Heinzerling:Astellas Pharma Global Development Europe: Employment.

The d-Enantiomer Form of Indobufen Totally Accounts for the Anti-Cyclooxygenase and Antiplatelet Activity Ex Vivo and for the Increase in Bleeding Time by Indobufen in Man

1992 ◽  
Vol 67 (02) ◽  
pp. 258-263 ◽  
Author(s):  
Raffaele De Caterina ◽  
Rosa Sicari ◽  
An Yan ◽  
Walter Bernini ◽  
Daniela Giannessi ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Platelet Aggregation ◽  
Plasma Levels ◽  
Bleeding Time ◽  
Ex Vivo ◽  
Random Sequence ◽  
Antiplatelet Agent ◽  
Antiplatelet Drug ◽  
Double Blind

SummaryIndobufen is an antiplatelet drug able to inhibit thromboxane production and cyclooxygenase-dependent platelet aggregation by a reversible inhibition of cyclooxygenase. Indobufen exists in two enantiomeric forms, of which only d-indobufen is active in vitro in inhibiting cyclooxygenase. In order to verify that also inhibition of platelet function is totally accounted for by d-indobufen, ten patients with proven coronary artery disease (8 male, 2 female, age, mean ± S.D., 58.7 ± 7.5 years) were given, in random sequence, both 100 mg d-indobufen and 200 mg dl-indobufen as single administrations in a double-blind crossover design study with a washout period between treatments of 72 h. In all patients thromboxane (TX) B2 generation after spontaneous clotting (at 0, 1, 2, 4, 6, 8, 12, 24 h), drug plasma levels (at the same times), platelet aggregation in response to ADP, adrenaline, arachidonic acid, collagen, PAF, and bleeding time (at 0, 2, 12 h) were evaluated after each treatment. Both treatments determined peak inhibition of TXB2 production at 2 h from administration, with no statistical difference between the two treatments (97 ±3% for both treatments). At 12 h inhibition was 87 ± 6% for d-indobufen and 88 ± 6% for dl-indobufen (p = NS). Inhibition of TXB2 production correlated significantly with plasma levels of the drugs. Maximum inhibitory effect on aggregation was seen in response to collagen 1.5 pg/ml (63 ± 44% for d-indobufen and 81 ± 22% for dl-indobufen) and arachidonic acid 0.5-2 mM (78 ± 34% for d-indobufen and 88 ± 24% for dl-indobufen) at 2 h after each administration. An effect of both treatments on platelet aggregation after 12 h was present only for adrenaline 2 μM (55 ± 41% for d-indobufen and 37 ± 54% for dl-indobufen), collagen 1.5 pg/ml (69 ± 30% for d-indobufen and 51 ± 61% for dl-indobufen), arachidonic acid 0.5-2 mM (56 ± 48% for d-indobufen and 35 ± 49% for dl-indobufen). The extent of inhibition of TX production and the extent of residual platelet aggregation were never significantly different between treatments. Bleeding time prolongation was similar in the two treatment groups without showing a pronounced and long lasting effect (from 7.0 ± 2.0 min to 10.0 ± 3.0 min at 2 h and 8.0 ± 2.0 min at 12 h for d-indobufen; from 6.0 ±1.0 min to 8.5 ± 2.0 min at 2 h and 8.0 ± 1.0 min at 12 h for dl-indobufen). These results demonstrate that the biological activity of dl-indobufen as an antiplatelet agent in vivo is totally accounted for by d-indobufen.

Combined effects of a factor Xa inhibitor YM466 and a GPIIb/IIIa antagonist YM128 on thrombosis and neointima formation in mice

2004 ◽  
Vol 92 (12) ◽  
pp. 1221-1228 ◽  
Author(s):  
Yoshiyuki Iwatsuki ◽  
Kazumi Hayashi ◽  
Yumiko Moritani ◽  
Tomoko Nii ◽  
Keiji Miyata ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Vascular Injury ◽  
Coronary Angioplasty ◽  
Bleeding Time ◽  
Factor Xa ◽  
Neointima Formation ◽  
Combined Effects ◽  
Test Drug ◽  
Thrombotic Occlusion ◽  
Acute Thrombosis

SummaryThrombosis and neointima formation limit the efficacy of coronary angioplasty. Factor Xa inhibitors and GPIIb/IIIa antagonists have shown to be effective on acute thrombosis and late neointima formation, however, their combined effects remain to be elucidated. Vascular injury was induced by FeCl3 in the carotid artery in mice. For thrombosis studies, the test drug was orally administered 1 hour before vascular injury. For neointima studies, the test drug was orally administered 1 hour before and twice daily for 1 week after vascular injury, and then histological analysis was performed 3 weeks after vascular injury. YM466 inhibited thrombotic occlusion at 30 mg/kg with prolongation of prothrombin time (PT), and tail transection bleeding time (BT) was affected at 100 mg/kg. YM466 also inhibited neointima formation at 10 mg/kg. YM128 inhibited thrombotic occlusion and neointima formation at 10 and 30 mg/kg, respectively, with inhibition of platelet aggregation and prolongation of BT. In contrast, the combination of 10 mg/kg YM466 and 3 mg/kg YM128 inhibited thrombotic occlusion and neointima formation without affecting PT, platelet aggregation and BT. Concomitant inhibition of factor Xa and GPIIb/IIIa may provide a safer and more effective therapeutic regimen for treatment of coronary angioplasty.

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.

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.

Propofol-Induced Bleeding Dyscrasia: A Case Report.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3894-3894
Author(s):  
Rabih C. Fahed ◽  
Thomas K. Schulz2
Keyword(s):  
Arachidonic Acid ◽  
Platelet Aggregation ◽  
Bleeding Time ◽  
Postoperative Bleeding ◽  
Sigmoid Resection ◽  
Von Willebrand Disease ◽  
Prior History ◽  
Normal Platelet ◽  
Anesthetic Drugs ◽  
Relative Safety

Abstract Propofol is one of the most commonly used anesthetic drugs, with rapid induction, maintenance and recovery times. Its relative safety has resulted in it becoming a popular choice for general anesthesia. A 56 y o woman with no prior history of bleeding underwent laparoscopic cholecystectomy. Postoperatively she experienced bleeding to the degree that open laparotomy was required to achieve hemostasis.Two years later, she underwent open sigmoid resection under propofol anesthesia for refractory diverticulitis. Severe postoperative bleeding ensued, necessitating IV fluid resuscitation and transfusion of packed red blood cells.Template bleeding time was repeatedly greater than 20 minutes on the first postoperative day. Platelet count, coagulation studies, von Willebrand disease assays, fibrinogen level and fibrinolytic system assays were found to be normal. Platelet aggregation in response to arachidonic acid was decreased at 9% (reference 60 - 120 %). The patient received platelet transfusions; hemostasis was achieved and the template bleeding time returned to normal on the second postoperative day and remained normal on repeat testing several weeks later. A few reports have shown an increased bleeding with propofol, which is thought to be related to inhibition of thromboxane A2 synthesis and increased synthesis of leucocyte nitric oxide. Some studies show increased bleeding even without any change in the template bleeding time. In summary, we report a case of a propofol-induced life threatening bleeding dyscrasia associated with a prolonged template bleeding time and platelet aggregation studies consistent with decreased response to arachidonic acid. This rarely reported complication should always be in the differential diagnosis of postoperative bleeding given the widespread usage of propofol anesthesia in major surgeries.

Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Anti-Vwf Nanobody® ALX-0681 After Single and Multiple Subcutaneous Administrations to Healthy Volunteers.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1063-1063 ◽  
Author(s):  
Khalid Abd-Elaziz ◽  
Pieter W. Kamphuisen ◽  
Christophe Lyssens ◽  
Mariska Reuvers ◽  
Izaak den Daas ◽  
...  
Keyword(s):  
Single Dose ◽  
Platelet Aggregation ◽  
Healthy Volunteers ◽  
Dose Level ◽  
Multiple Dose ◽  
Phase I Trial ◽  
Post Dose ◽  
Dose Cohort ◽  
Clinically Significant ◽  
Dose Levels

Abstract Abstract 1063 Poster Board I-85 ALX-0681 is a humanized bivalent Nanobody®, that binds to the A1 domain of von Willebrand factor (vWF) and hence blocks its interaction with platelet receptor GPIb-IX-V. Given its mode of action, ALX-0681 could provide an alternative treatment option for thrombotic thrombocytopenic purpura (TTP), a rare and life-threatening condition characterized by systemic platelet aggregation in the microcirculation mediated by activated vWF multimers. The goal of this Phase I trial in healthy volunteers was to determine the maximum tolerated dose (MTD) or biologically effective dose (BED) and the Phase II dosing and scheduling of ALX-0681, in order to support the further clinical development of ALX-0681 in TTP patients. In total, 36 healthy volunteers were included in this randomized, placebo-controlled study to evaluate the safety of single ascending doses and multiple doses of ALX-0681 administered subcutaneously (s.c.) (Table 1). Table 1 Dosing schedule for Phase I trial with ALX-0681 Cohort Dose (mg) Number of daily doses Subjects receiving ALX-0681 Subjects receiving placebo Single dose Cohort 1 2 1 3 1 Cohort 2 4 1 3 1 Cohort 3 8 1 3 1 Cohort 4 16 1 3 1 Cohort 5 10 1 3 1 Multiple dose Cohort 6 10 7 6 2 Cohort 7 10 14 6 2 Study endpoints included safety (dose limiting toxicities, adverse events (AEs) and immunogenicity), pharmacokinetics (PK), pharmacodynamics (PD) and pharmacological efficacy of ALX-0681. The latter endpoint was addressed by measuring the ristocetin cofactor (RICO) biomarker, reflecting vWF mediated inhibition of platelet aggregation. ALX-0681 was safe and well tolerated at all dose levels (Table 2). One unrelated SAE (meniscus lesion) occurred. The number of observed signs of bleeding and bruises increased with increasing treatment duration. However, all these events were of mild intensity. No signs of immunogenicity were observed for a minimum of 45 days after the last injection. Table 2 Summary of main safety results (number (%) of subjects with event) Dose level Subjects (n) AE SAE Bleeding Hematoma at injection site Hematoma at blood sampling site Other hematoma Single dose 2 mg 3 2 (67) 0 (0) 1 (33) 0 (0) 1 (33) 0 (0) 4 mg 3 2 (67) 0 (0) 1 (33) 0 (0) 0 (0) 0 (0) 8 mg 3 3 (100) 0 (0) 0 (0) 0 (0) 1 (33) 0 (0) 16 mg 3 3 (100) 0 (0) 0 (0) 0 (0) 0 (0) 1 (33) 10 mg 3 1 (33) 0 (0) 0 (0) 0 (0) 1 (33) 0 (0) Placebo 5 3 (60) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) Multiple dose 10 mg (7d) 6 6 (100) 1 (17) 5 (83) 1 (17) 0 (0) 3 (50) Placebo (7d) 2 2 (100) 0 (0) 1 (50) 0 (0) 1 (50) 0 (0) 10 mg (14d) 6 6 (100) 0 (0) 5 (83) 5 (83) 4 (67) 5 (83) Placebo (14d) 2 2 (100) 0 (0) 1 (50) 0 (0) 0 (0) 0 (0) PK analysis showed a rapid increase in ALX-0681 plasma concentration (tmax = 4-10 h post dose), followed by a slow elimination phase (t1/2 = 10-78 h). All subjects dosed with ALX-0681 at 8 mg or higher showed complete inhibition of RICO activity to < 20% with an onset of 1-6 h post dose. This inhibition was maintained until 12-360 h post dose, depending on the dose level (Table 3). Overall, 20 (74%) and 17 (63%) of ALX-0681 treated subjects experienced a drop in vWF and FVIII levels below 50% of pre-dose levels, respectively. These events were all transient and not clinically significant. Table 3 Summary of main PD results (number (%) of subjects with event) Dose level Subjects (n) RICO < 20% vWF < 50% FVIII < 50% Subjects (%) Start (h)* Stop (h)* Single dose 2 mg 3 2 (67) 2-4 12-18 3 (100) 0 (0) 4 mg 3 2 (67) 4-6 18-36 1 (33) 1 (33) 8 mg 3 3 (100) 2-4 18-48 3 (100) 3 (100) 16 mg 3 3 (100) 1-4 48 0 (0) 2 (67) 10 mg 3 3 (100) 2-6 24-36 3 (100) 3 (100) Placebo 5 0 (0) NA NA 0 (0) 0 (0) Multiple dose 10 mg (7d) 6 6 (100) 2-4 168-192 5 (83) 3 (50) Placebo (7d) 2 0 (0) NA NA 0 (0) 0 (0) 10 mg (14d) 6 6 (100) 2-4 336-360 5 (83) 5 (83) Placebo (14d) 2 0 (0) NA NA 0 (0) 0 (0) * Time relative to first administration NA: not applicable In conclusion, ALX-0681 administered s.c. for up to 14 days was well tolerated and did not result in any clinically significant AEs. No local reactions, local intolerances or signs of clinically relevant bleeding were reported. The PD marker indicated complete inhibition of vWF mediated platelet aggregation following single daily s.c. injections of 10 mg, which was maintained over the 2 weeks treatment period. Multiple daily administration of s.c. injections of ALX-0681 did not result in an immunogenic reaction for a minimum of 45 days following completion of treatment. Based on the results of this study, ALX-0681 development will be advanced into a Phase II study in TTP patients to investigate the safety and efficacy of ALX-0681 in the target patient population. Disclosures: Abd-Elaziz: Ablynx NV: Consultancy. Kamphuisen:Ablynx NV: Consultancy. Lyssens:Ablynx NV: Employment. Reuvers:Ablynx NV: Consultancy. den Daas:Ablynx NV: Consultancy. Van Bockstaele:Ablynx NV: Employment. Vercruysse:Ablynx NV: Employment. Ulrichts:Ablynx NV: Employment. Baumeister:Ablynx NV: Employment. Crabbe:Ablynx NV: Employment. Compernolle:Ablynx NV: Employment. Holz:Ablynx NV: Employment.

Neutralization Of Hemorrhage Induced By Direct Factor Xa and Thrombin Inhibitors In a Rat Model

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3644-3644 ◽  
Author(s):  
Walter Jeske ◽  
Vicki Escalante ◽  
Brian McGuire ◽  
Jeanine M. Walenga ◽  
Jawed Fareed ◽  
...  
Keyword(s):  
Rat Model ◽  
Bleeding Time ◽  
Factor Xa ◽  
New Drugs ◽  
Thrombin Inhibitors ◽  
Medical Emergency ◽  
Individual Treatment ◽  
Direct Factor ◽  
Major Hemorrhage ◽  
Prolonged Bleeding

Abstract Introduction Direct factor Xa and thrombin inhibitors (apixaban, Bristol-Myers Squibb, Princeton, NJ; rivaroxaban, Bayer Healthcare, Leverkusen, Germany; dabigatran, Boehringer Ingelheim, Ridgefield, CT) have shown favorable efficacy profiles in comparison to standard therapy in a variety of clinical conditions including the prevention of stroke in patients with non-valvular atrial fibrillation. Although clinical trials have shown that the safety of these new drugs in terms of the incidence of major hemorrhage is similar or better than with conventional therapies, there remains concern over the ability to reverse their anticoagulant effects in cases of overdose or medical emergency. Prothrombin complex concentrates (PCCs) have been used to reverse the effect of warfarin and in cases of significant bleeding in patients with coagulopathy. PCCs may be useful in modulating hemorrhage caused by the new oral anticoagulant drugs. This study tested the ability of three PCCs to reverse bleeding induced by apixaban, rivaroxaban or dabigatran in a standardized rat model. Methods Following anesthesia with an IM injection of ketamine and xylazine, male Sprague-Dawley rats were anticoagulated by an IV injection of apixaban (100 or 300 µg/kg), rivaroxaban (100 or 300 µg/kg) or dabigatran (50 or 100 µg/kg). After 5 minutes, rats were treated with vehicle, a 3-factor PCC (Profilnine, Grifols Biologicals, Los Angeles, CA), a 4-factor PCC (Beriplex, CSL Behring, Marburg, Germany) or an activated 4-factor PCC (FEIBA, Baxter, Deerfield, IL). Five minutes after PCC administration, a standardized tail snip was performed and the time for bleeding to stop was measured. Upon cessation of bleeding, a blood sample was collected by cardiac puncture and the rat was humanely euthanized. Platelet poor plasma was prepared from the blood samples and was analyzed using PT, aPTT and PiCT assays. Results for individual treatment groups were compared using one-way ANOVA (SigmaPlot 12, Systat, San Jose, CA). Results While at a dose of 100 µg/kg, apixaban did not increase the bleeding time vs. saline (6.25 ± 0.8 vs. 6.0 ± 1.7 min), a dose of 300 µg/kg apixaban significantly prolonged the bleeding time (17.1 ± 5.6; p=0.024). Administration of Beriplex at doses up to 10 U/kg did not shorten the bleeding time. 10 U/kg Profilnine shortened bleeding time, but not completely to baseline (9.8 ± 4.2 min). The administration of FEIBA dose-dependently prolonged bleeding beyond that seen with apixaban alone (22.6 ± 11.4 and 37.5 ± 5.2 min for doses of 5 and 10 U/kg, respectively; p<0.001 apixaban + 10 U/kg FEIBA vs. apixaban alone). Doses of 100 and 300 µg/kg rivaroxaban prolonged bleeding time (20.8 ± 2.5, p=0.002 vs. saline; 25.0 ± 10.0 min, p<0.001 vs. saline, respectively). While 10 U/kg Beriplex or Profilnine shortened the bleeding time, Profilnine was more effective (9.7 ± 3.2 min; p=0.508 vs. saline). FEIBA at a dose of 5 U/kg did not reverse rivaroxaban-induced bleeding. Dabigatran caused a dose-dependent increase in bleeding time which could be prevented by the administration of Beriplex or Profilnine (10 U/kg). As with apixaban, the administration of FEIBA enhanced the bleeding seen with dabigatran (50.3 ± 8.3 vs. 15.9 ± 1.2 min; p<0.001). As it was hypothesized that the increased bleeding observed following FEIBA administration may be due to a Protein C mediated facilitation of fibrinolysis, additional groups of rats were anticoagulated with apixaban or rivaroxaban and then treated with FEIBA + 10 mg/kg epsilon aminocaproic acid. In these rats, the bleeding times were comparable to those in non-anticoagulated rats (6.7 ± 5.0 min with apixaban; 7.7 ± 6.4 min with rivaroxaban). Discussion PCCs appear useful for neutralizing bleeding induced by direct factor Xa and thrombin inhibitors. Owing to their different compositions, each PCC exhibits a distinct neutralization profile. Co-administration of a fibrinolytic inhibitor with a PCC may enhance the effectiveness of hemorrhage reversal. Disclosures: Jeske: Bristol-Myers Squibb: Research Funding.

Monitoring of acetyl salicylic acid-induced platelet inhibition with impedance aggregometry in children with systemic-to-pulmonary shunts

2012 ◽  
Vol 23 (2) ◽  
pp. 225-232 ◽  
Author(s):  
Birgitta S. Romlin ◽  
Håkan Wåhlander ◽  
Eva Strömvall-Larsson ◽  
Mats Synnergren ◽  
Fariba Baghaei ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Salicylic Acid ◽  
Platelet Aggregation ◽  
Therapeutic Range ◽  
Platelet Inhibition ◽  
Acetyl Salicylic Acid ◽  
Shunt Thrombosis ◽  
Shunt Implantation ◽  
Paediatric Patients ◽  
Impedance Aggregometry

AbstractBackgroundShunt thrombosis after implantation of systemic-to-pulmonary shunts in paediatric patients is common. Acetyl salicylic acid is used for anti-thrombotic treatment; however, the effect is rarely monitored, although it is known that the response varies. The aim was to determine the effects of acetyl salicylic acid medication on platelet aggregation in children with systemic-to-pulmonary shunts.MethodsA total of 14 children – median age 12 days; ranging from 3 to 100 days – were included in a prospective observational longitudinal study. All children were treated with oral acetyl salicylic acid (3–5 milligrams per kilogram once daily) after shunt implantation. Acetyl salicylic acid-dependent platelet aggregation in whole blood was analysed with impedance aggregometry (Multiplate®) after addition of arachidonic acid. Analyses were carried out before the primary operation, before and 5 and 24 hours after the first acetyl salicylic acid dose, and after 3–6 months of treatment. The therapeutic range for acetyl salicylic acid was defined as a test result less than 60 units.ResultsAcetyl salicylic acid reduced the arachidonic acid-induced platelet aggregation in all but one patient. Of the patients, 93% were in the therapeutic range 5 hours after acetyl salicylic acid intake, 86% were in the range after 24 hours, and 64% after 3–6 months.ConclusionsAcetyl salicylic acid reduces platelet aggregation after shunt implantation in paediatric patients, but a considerable percentage of the children are outside the therapeutic range. Monitoring of platelet aggregation has the potential to improve anti-platelet treatment after shunt implantation by identifying children with impaired acetyl salicylic acid response.

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