Biochemical and Pharmacological Profiles of YM150, an Oral Direct Factor Xa Inhibitor.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 911-911 ◽  
Author(s):  
Yoshiyuki Iwatsuki ◽  
Takeshi Shigenaga ◽  
Yumiko Moritani ◽  
Mami Suzuki ◽  
Tsukasa Ishihara ◽  
...  
Keyword(s):  
Oral Administration ◽  
Dose Level ◽  
Bleeding Time ◽  
Control Group ◽  
Cynomolgus Monkeys ◽  
Thrombosis Model ◽  
Antithrombotic Effects ◽  
Ic50 Values ◽  
Fxa Inhibitor ◽  
Prothrombin Activation

Abstract YM150 is an oral direct FXa inhibitor used as prophylaxis for venous thromboembolism in patients undergoing elective primary hip replacement surgery (Blood106: 530a (abstract#1865), 2005). No preclinical data has been reported for this compound so far. The biochemical and pharmacological properties of YM150 were evaluated in this study. In addition, the anticoagulation activity of orally administered YM150 was compared with that of YM466, a 1st generation FXa inhibitor, in fed cynomolgus monkeys and in bile duct-cannulated rats. The Ki values for YM150 and YM-222714, its major metabolite, against human FXa were 0.031 and 0.020 μM, respectively (n=4). Those for other serine proteases, such as trypsin, plasmin, and thrombin, were greater than 10 μM. YM150 and YM-222714 doubled the FXa clotting time and PT at 2.0 and 1.8 μM, and 1.2 and 0.95 μM, respectively (n=4). They also strongly inhibited prothrombin activation induced by free Xa, prothrombinase, and whole-blood clots with similar IC50 values (0.025–0.082 μM, n=5). In contrast, enoxaparin was much less effective at inhibiting prothrombin activation induced by prothrombinase or clots than prothrombin activation induced by free Xa (IC50 values: 330, 120, and 3.5 mU/mL, respectively, n=5). In the thromboplastin-induced venous thrombosis model in rats, YM150 (0.3–10 mg/kg i.d.) exerted its antithrombotic effects dose-dependently, with significance at 1 mg/kg (ED50: 0.97 mg/kg, n=6). YM150 prolonged the PT slightly at 10 and 30 mg/kg (1.2 and 1.4 times that of the control group), but the template bleeding time was not affected at 30 mg/kg. Although warfarin also exerted antithrombotic effects dose-dependently and with significance at 0.2 mg/kg (ED50: 0.12 mg/kg, n=6), this dose level markedly prolonged PT and bleeding time (4.4 and 2.2 times that of the control group). In an arterio-venous shunt thrombosis model in rabbits, YM150 (1–10 mg/kg p.o.) exerted antithrombotic effects dose-dependently and with significance at 10 mg/kg (ED50: 4.8 mg/kg, n=6), but did not prolong bleeding time at any dose level. Warfarin also exerted antithrombotic effects dose-dependently and with significance at 0.1 mg/kg/day (ED50: 0.29 mg/kg, n=6). Bleeding time was prolonged significantly at this dose level (control: 3.5 min warfarin: 5.8 min). The plasma concentrations of YM-222714 were 129+/−73.7, 396+/−224, and 3,641+/−902 ng/mL after dosing 1, 3, and 10 mg/kg, respectively, while those of YM150 was substantially lower (less than 125+/−265 ng/mL at 10 mg/kg). In fasted cynomolgus monkeys, oral administration of either YM150 (3–30 mg/kg) or YM466 (1–10 mg/kg) dose-dependently prolonged PT. The anticoagulation activity of YM466 was 3 times that of YM150, but this activity decreased significantly in the presence of food, while that of YM150 did not. The peak plasma anti-FXa activity after oral administration of 3 mg/kg YM150 to bile duct-cannulated rats and sham-operated rats were 67.7% and 68.5%, respectively. In contrast, those of 3 mg/kg YM466 were 57.4% and 26.2%, respectively. These data suggest that food or bile interferes with YM150 less than it does with YM466. In conclusion, YM150 is a promising oral FXa inhibitor that carries a bleeding risk that is less than that of warfarin. It also seems be well-absorbed without interference by food or bile. The in vivo antithrombotic activity of YM150 after oral administration was also determined to be produced by its active metabolite, YM-222714.

Abstract 1033: Simultaneous Clot-targeted Factor Xa Inhibition And Selective Blockade Of Activated GPIIb/IIIa On Platelets Results In Delayed But Potent Antithrombotic Effects Without Bleeding Time Prolongation.

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Christoph E Hagemeyer ◽  
Steffen U Eisenhardt ◽  
Nicole Bassler ◽  
Patrick Stoll ◽  
Meike Schwarz ◽  
...  
Keyword(s):  
Bleeding Time ◽  
Specific Binding ◽  
Factor Xa ◽  
Single Chain ◽  
Occlusion Time ◽  
Selective Blockade ◽  
Thrombosis Model ◽  
Fibrinogen Binding ◽  
Antithrombotic Effects

Background: We generated phage-display-derived anti-GPIIb/IIIa single-chain antibodies (e.g. scFv SCE5) that specifically bind to the activated GPIIb/IIIa only and thus specifically block activated platelets only. ScFv SCE5 demonstrates strong antithrombotic potency, comparable to the conformation-unspecific blockers tirofiban and eptifibatide. In contrast bleeding times were not prolonged with scFv SCE5. Here we now use the possibility to add effector molecules using molecular biology methods. The highly potent anticoagulant TAP (tick anticoagulant peptide), which is a direct factor Xa (fXa) inhibitor, was used as an effector molecule. Methods and Results: We genetically fused the activation-specific scFv with TAP, expressed the constructs in E.coli and purified the 39 kDa protein via its Histag binding to Nickel beads. Specific binding of the fusion molecules MA2/SCE5-TAP and strong inhibition of fibrinogen binding was proven in flow cytometry; anti-fXa activity was demonstrated in chromogenic assays. In vivo anticoagulative efficiency was determined by Doppler-flow in a ferric chloride-induced carotid artery thrombosis model in mice. Prolongation in occlusion time with SCE5-TAP was significantly stronger compared to SCE5 alone, recombinant TAP, non-binding mut-scFv-TAP as well as the clinical used drugs enoxaparine and eptifibatide. In contrast to the other anticoagulants tested, bleeding time was not prolonged by SCE5-TAP. Flow experiments studying platelet adhesion on collagen revealed a possible mechanism for the unique finding of a fully normal bleeding time: LIBS exposure on adhering platelets and as such the anticoagulative targeting potency of SCE5-TAP was delayed until considerable layers of platelets were deposited. Conclusions: The combination of activation-specific GPIIb/IIIa blockade and fXa inhibition in one clot-targeted molecule further improves in-vivo antithrombotic efficiency without causing any bleeding time prolongation. The delay of the observed targeting effect may allow a sealing of injuries with platelet layers but may be in time for the prevention of occlusive platelet aggregates. The described blockers represent a new type of highly selective drugs that warrant further clinical development.

scholarly journals Antioxidant, Anti-Inflammatory and Antithrombotic Effects of Ginsenoside Compound K Enriched Extract Derived from Ginseng Sprouts

Molecules ◽  
2021 ◽  
Vol 26 (13) ◽  
pp. 4102
Author(s):  
In-Hee Baik ◽  
Kyung-Hee Kim ◽  
Kyung-Ae Lee
Keyword(s):  
Bleeding Time ◽  
Radical Scavenging Activity ◽  
Radical Scavenging ◽  
Raw 264.7 Cells ◽  
Control Group ◽  
Compound K ◽  
Antithrombotic Effects ◽  
Macroporous Adsorption Resin ◽  
Anti Inflammatory ◽  
Factor Α

Partially purified ginsenoside extract (PGE) and compound K enriched extract (CKE) were prepared from ginseng sprouts, and their antioxidant, anti-inflammatory and antithrombotic effects were investigated. Compared to the 6-year-old ginseng roots, ginseng sprouts were found to have a higher content of phenolic compounds, saponin and protopanaxadiol-type ginsenoside by about 56%, 36% and 43%, respectively. PGE was prepared using a macroporous adsorption resin, and compound K(CK) was converted and enriched from the PGE by enzymatic hydrolysis with a conversion rate of 75%. PGE showed higher effects than CKE on radical scavenging activity in antioxidant assays. On the other hand, CKE reduced nitric oxide levels more effectively than PGE in RAW 264.7 cells. CKE also reduced pro-inflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL)-1β and IL-6 than PGE. Tail bleeding time and volume were investigated after administration of CKE at 70–150 mg/kg/day to mice. CKE administered group showed a significant increase or increased tendency in bleeding time than the control group. Bleeding volume in the CKE group increased than the control group, but not as much as in the aspirin group. In conclusion, ginseng sprouts could be an efficient source of ginsenoside, and CKE converted from the ginsenosides showed antioxidant, anti-inflammatory and antithrombotic effects. However, it was estimated that the CKE might play an essential role in anti-inflammatory effects rather than antioxidant effects.

Antithrombotic effects by oral administration of novel proteinase fraction from earthworm eisenia andrei on venous thrombosis model in rats

2007 ◽  
Vol 30 (4) ◽  
pp. 475-480 ◽  
Author(s):  
Chul Kyu Lee ◽  
Jang Sik Shin ◽  
Byung Su Kim ◽  
II Hwan Cho ◽  
Young Shik Kim ◽  
...  
Keyword(s):  
Oral Administration ◽  
Venous Thrombosis ◽  
Eisenia Andrei ◽  
Thrombosis Model ◽  
Antithrombotic Effects

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.

Repeated Oral or Subcutaneous LMWH Has similar Antithrombotic Activity in a Rat Venous Thrombosis Model: Antithrombotic Activity Correlates With Heparin on Endothelium When Orally Administered

2016 ◽  
Vol 22 (3) ◽  
pp. 264-272 ◽  
Author(s):  
Linda M. Hiebert
Keyword(s):  
Single Dose ◽  
Oral Administration ◽  
Venous Thrombosis ◽  
Anticoagulant Activity ◽  
Vena Cava ◽  
Antithrombotic Activity ◽  
Thrombosis Model ◽  
Normal Ranges ◽  
Long Term Treatment ◽  
Antithrombotic Effects

Low-molecular-weight heparins (LMWHs) endure as important drugs for thromboprophylaxis. Although clinical use relies on the subcutaneous (SC) route, our previous studies show that single-dose orally administered LMWHs have antithrombotic activity. Since thromboprophylaxis requires long-term treatment, we examined antithrombotic effects of subacute oral LMWHs in a rat venous thrombosis model and compared results to SC or single-dose oral administration. We measured LMWH in endothelium and plasma, weight change and complete blood counts (CBC). Oral LMWH tinzaparin (3 × 0.1 mg/kg/12 or 24 hours) or reviparin (3 × 0.025 mg/kg/24 hours) significantly decreased thrombosis compared to saline. In the subacute study (60 × 0.1 mg/kg/12 hours), oral or SC tinzaparin significantly reduced thrombosis compared to saline but not to single or 3 × 0.1 mg/kg/12 hours oral tinzaparin. Antithrombotic effects were similar between oral and SC administration. LMWH was found on endothelium following oral but not SC administration. Endothelial concentrations were significantly correlated with incidence of stable thrombi ( P = 0.021 and 0.04 for aortic and vena cava endothelium respectively, χ2 test) and total thrombi ( P = 0.003 for vena cava endothelium). Anti-Xa activity was significantly greater for oral or SC LMWH than saline and significantly greater for SC versus oral LMWH. Values for CBCs were within normal ranges (mean ± 2 SD). There was no evidence of bleeding. Weight gain was similar between groups. In conclusion, subacute oral and SC LMWH have similar antithrombotic effects. Antithrombotic activity with oral administration is correlated with endothelial LMWH concentrations but not with plasma anticoagulant activity.

scholarly journals The recombinant plant Bauhinia bauhinioides elastase inhibitor reduces rat thrombus without alterations in hemostatic parameters

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Cleide Oliveira ◽  
Mayara Vioto Valois ◽  
Tatiana Fontes Ottaiano ◽  
Antonio Miranda ◽  
Daiane Hansen ◽  
...  
Keyword(s):  
Bleeding Time ◽  
Vena Cava ◽  
Serum Levels ◽  
Cathepsin G ◽  
Control Group ◽  
Elastase Inhibitor ◽  
Thrombosis Model ◽  
Recombinant Plant ◽  
Keratinocyte Chemoattractant ◽  
Plant Protease

AbstractThe anti-inflammatory effects of the plant protease inhibitor BbCI (Bauhinia bauhinioides cruzipain inhibitor), which blocks elastase, cathepsin G, and L, and proteinase 3 has been demonstrated. Here, we investigated the recombinant rBbCI-His(6) (containing a histidine tail) in an experimental venous thrombosis model of vena cava (VC) ligature in rats, comparing to heparin. We evaluate the effects of the inhibitors (native or recombinant) or heparin on the activated partial thromboplastin time (aPTT) and prothrombin time (PT) in human and rat plasmas. The rats undergoing treatment received a saline solution or increasing concentrations of rBbCI-His(6), heparin, or a mixture of both. After 4 h of ligature VC, thrombus, if present was removed and weighed. aPTT, PT, and cytokines were measured in blood collected by cardiac puncture. aPTT, PT, and bleeding time (BT) were also measured at the time of VC (vena cava) ligature. rBbCI-His(6) (0.45 or 1.40 mg/kg) does not alter aPTT, PT or BT. No differences in coagulation parameters were detected in rBbCI-His(6) treated rats at the time of VC ligature or when the thrombus was removed. There was a significant decrease in the weight of thrombus in the animals of the groups treated with the rBbCI-His(6) (1.40 mg/kg), with the rBbCI-His(6) mixture (1.40 mg/kg) + heparin (50 IU/kg) and heparin (100 IU/kg) in relation to control group (saline). The growth-related oncogene/keratinocyte chemoattractant (GRO/KC) serum levels in rats treated with rBbCI-His(6) (1.40 mg/kg) or heparin (200 IU/kg) were reduced. In the experimental model used, rBbCI-His(6) alone had an antithrombotic effect, not altering blood clotting or bleeding time.

Hexachlorobenzene toxicity in the monkey ovary: III. Ultrastructure induced by high (10 mg/kg) dose exposure

1991 ◽  
Vol 49 ◽  
pp. 130-131
Author(s):  
A. Singh ◽  
A. Dykeman ◽  
J. Jarrelf ◽  
D. C. Villeneuve
Keyword(s):  
Present Report ◽  
Reproductive Toxicity ◽  
Control Group ◽  
Primate Model ◽  
Human Follicular Fluid ◽  
Thin Sections ◽  
Cynomolgus Monkeys ◽  
Cacodylate Buffer ◽  
Induction Cycle ◽  
Comprehensive Study

Hexachlorobenzene (HCB), a persistent and mobile organochlorine pesticide, occurs in environment. HCB has been shown to be present in human follicular fluid. An objective of the present report, which is part of a comprehensive study on reproductive toxicity of HCB, was to determine the cytologic effects of the compound on ovarian follicles in a primate model.Materials and Methods. Eight Cynomolgus monkeys were housed under controlled conditions at Animal facility of Health and Welfare, Ottawa. Animals were orally administered gelatin capsules containing HCB mixed with glucose in daily dosages of 0.0 or 10 mg/kg b.w. for 90 days; the former was the control group. On the menstrual period following completion of dosing, the monkeys underwent an induction cycle of superovulation. At necropsy, one-half of an ovary from each animal was diced into ca. 2- to 3-mm cubed specimens that were fixed by immersion in 2.5% glutaraldehyde in 0.1 M cacodylate buffer (pH 7.3). Subsequent procedures followed to obtain thin sections that were examined in a Hitachi H-7000 electron microscope have been described earlier.

Antithrombotic Effects and Bleeding Time Prolongation with Synthetic Platelet GPIIb/llla Inhibitors in Animal Models of Platelet-Mediated Thrombosis

1994 ◽  
Vol 71 (01) ◽  
pp. 095-102 ◽  
Author(s):  
Désiré Collen ◽  
Hua Rong Lu ◽  
Jean-Marie Stassen ◽  
Ingrid Vreys ◽  
Tsunehiro Yasuda ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Bleeding Time ◽  
Bolus Injection ◽  
Cell Injury ◽  
Ex Vivo ◽  
Thrombus Formation ◽  
Femoral Vein ◽  
Thrombotic Occlusion ◽  
Antithrombotic Effects

SummaryCyclic Arg-Gly-Asp (RGD) containing synthetic peptides such as L-cysteine, N-(mercaptoacetyl)-D-tyrosyl-L-arginylglycyl-L-a-aspartyl-cyclic (1→5)-sulfide, 5-oxide (G4120) and acetyl-L-cysteinyl-L-asparaginyl-L-prolyl-L-arginyl-glycyl-L-α-aspartyl-[0-methyltyrosyl]-L-arginyl-L-cysteinamide, cyclic 1→9-sulfide (TP9201) bind with high affinity to the platelet GPIIb/IIIa receptor.The relationship between antithrombotic effect, ex vivo platelet aggregation and bleeding time prolongation with both agents was studied in hamsters with a standardized femoral vein endothelial cell injury predisposing to platelet-rich mural thrombosis, and in dogs with a carotid arterial eversion graft inserted in the femoral artery. Intravenous administration of G4120 in hamsters inhibited in vivo thrombus formation with a 50% inhibitory bolus dose (ID50) of approximately 20 μg/kg, ex vivo ADP-induccd platelet aggregation with ID50 of 10 μg/kg, and bolus injection of 1 mg/kg prolonged the bleeding time from 38 ± 9 to 1,100 ± 330 s. Administration of TP9201 in hamsters inhibited in vivo thrombus formation with ID50 of 30 μg/kg, ex vivo platelet aggregation with an ID50 of 50 μg/kg and bolus injection of 1 mg/kg did not prolong the template bleeding time. In the dog eversion graft model, infusion of 100 μg/kg of G4120 over 60 min did not fully inhibit platelet-mediated thrombotic occlusion but was associated with inhibition of ADP-induccd ex vivo platelet aggregation and with prolongation of the template bleeding time from 1.3 ± 0.4 to 12 ± 2 min. Infusion of 300 μg/kg of TP9201 over 60 min completely prevented thrombotic occlusion, inhibited ex vivo platelet aggregation, but was not associated with prolongation of the template bleeding time.TP9201, unlike G4120, inhibits in vivo platelet-mediated thrombus formation without associated prolongation of the template bleeding time.

Comparison of the Anticoagulant and Antithrombotic Effects of Synthetic Thrombin and Factor Xa Inhibitors

1990 ◽  
Vol 63 (02) ◽  
pp. 220-223 ◽  
Author(s):  
J Hauptmann ◽  
B Kaiser ◽  
G Nowak ◽  
J Stürzebecher ◽  
F Markwardt
Keyword(s):  
Factor Xa ◽  
Thrombin Inhibitors ◽  
Factor Xa Inhibitors ◽  
Venous Stasis ◽  
Clotting Time ◽  
Thrombosis Model ◽  
Activity Factor ◽  
Antithrombotic Effects

SummaryThe anticoagulant effect of selected synthetic inhibitors of thrombin and factor Xa was studied in vitro in commonly used clotting assays. The concentrations of the compounds doubling the clotting time in the various assays were mainly dependent on their thrombin inhibitory activity. Factor Xa inhibitors were somewhat more effective in prolonging the prothrombin time compared to the activated partial thromboplastin time, whereas the opposite was true of thrombin inhibitors.In vivo, in a venous stasis thrombosis model and a thromboplastin-induced microthrombosis model in rats the thrombin inhibitors were effective antithrombotically whereas factor Xa inhibitors of numerically similar IQ value for the respective enzyme were not effective at equimolar dosageThe results are discussed in the light of the different prelequisiles and conditions for inhibition of thrombin and factor Xa in the course of blood clotting.

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