Antithrombotic Activity of a New Benzimidazole Derivative in the Thrombosis Model in Mice

Введение: Тромбоциты являются ключевыми медиаторами патогенеза артериальных тромбозов и атеросклероза. Поэтому изучение антиагрегантных средств на предмет антитромботической активности на различных моделях артериальных и венозных тромбозов является актуальным. Цель исследования: изучение антитромботической активности соединения РУ-1144 (производного бензимидазола) в сравнении с ацетилсалициловой кислотой (АСК) и клопидогрелом на моделях артериального и венозного тромбозов. Материалы и методы: Артериальный тромбоз моделировали на сонной артерии крыс-самцов аппликацией постоянного электрического тока. Воздействие на сосуд выполняли до момента полной окклюзии, регистрируемой на мониторе доплерографа. Венозной тромбоз моделировали на крысах-самцах полной перевязкой нижней полой вены на 24 ч; через сутки проводили изъятие тромба из сосуда и его взвешивание. В экспериментальных группах животным внутрижелудочно вводили соединение РУ-1144 и препараты сравнения — АСК и клопидогрел, в контрольной группе животным внутрижелудочно вводили дистиллированную воду. Для подтверждения отсутствия влияния хирургических манипуляций на организм животного в исследование модели венозного тромбоза была включена группа ложнооперированных крыс. Результаты: На модели артериального тромбоза установлена более высокая антитромботическая активность соединения РУ-1144 по сравнению с АСК и клопидогрелом в 2,5 и 7,4 раза соответственно. В модели венозного тромбоза соединение РУ-1144 уменьшало среднюю массу венозных тромбов в 5,3 раза по сравнению с группой контроля и превосходило по антитромботической активности АСК и клопидогрел в 3,5 и 1,9 раза. Заключение: Соединение РУ-1144 способно предотвращать патологические процессы, связанные с тромбообразованием, не только в сонной артерии, но и в нижней полой вене. Background: Platelets are key mediators of the pathogenesis of arterial thrombosis and atherosclerosis. So, that is actual to study antithrombotic activity of antiplatelet agents in various models of arterial and venous thromboses. Objectives: to study the antithrombotic activity of RU-1144 compound (benzimidazole derivative) as compared with acetylsalicylic acid (ASA) and clopidogrel on models of arterial and venous thromboses. Materials/Methods: Arterial thrombosis was modeled on the carotid artery of male rats by application of direct electric current. Exposure was performed until full vessel occlusion recorded by Dopplerograf. Venous thrombosis was modeled on male rats by complete ligation of vena cava inferior for 24 hours; a day later the thrombus was removed from the vessel and weighed. In the experimental groups the animals were injected intragastrically with the compound RU-1144 and the comparison drugs — ASA and clopidogrel; in the control group the animals were administered distilled water intragastrically. To confirm the absence of the effect of surgical manipulations on the animal’s organism, a group of false-operated rats was included in the study of venous thrombosis model. Results: In arterial thrombosis model RU-1144 compound had a higher antithrombotic activity as compared with ASA and clopidogrel by 2.5 and 7.4 times, respectively. In venous thrombosis model RU-1144 compound reduced the average weight of venous clots by 5.3 times as compared with the control group and exceeded antithrombotic activity of ASA and clopidogrel by 3.5 and 1.9 times. Conclusions: RU-1144 compound capable to prevent the pathological processes associated with thrombus formation in carotid artery as well as in vena cava inferior.

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Comparative Studies of an Orally-active Factor Xa Inhibitor, YM-60828, with other Antithrombotic Agents in a Rat Model of Arterial Thrombosis

Thrombosis and Haemostasis ◽

10.1055/s-0037-1615007 ◽

1998 ◽

Vol 79 (02) ◽

pp. 410-416 ◽

Cited By ~ 32

Author(s):

Kazuo Sato ◽

Yumiko Sakai ◽

Fukushi Hirayama ◽

Hiroyuki Koshio ◽

Yuta Taniuchi ◽

...

Keyword(s):

Electrical Stimulation ◽

Arterial Thrombosis ◽

Thrombus Formation ◽

Factor Xa ◽

Test Drug ◽

Antithrombotic Agent ◽

Antithrombotic Activity ◽

Thrombosis Model ◽

Treatment And Prevention ◽

Orally Active

SummaryWe examined the antithrombotic activity of a novel synthetic inhibitor of factor Xa, YM-60828, in an electrically-induced carotid artery thrombosis model in rats. In the first experiment, the antithrombotic activity of YM-60828 after i.v. infusion was compared with those of heparin, darteparin and argatroban. Test drug was administered by i.v. infusion from 30 min before electrical stimulation to the end of the experiment. YM-60828 at 1 mg/kg/h significantly improved patency status, prolonged the time to occlusive thrombus formation and duration of patency. Heparin at 300 U/kg/h also improved these parameters, but were accompanied by a marked increase in systemic coagulation time. In the second experiment, the antithrombotic activity of YM-60828 after oral administration was compared with those of ticlopidine, cilostazol, aspirin, beraprost, ethyl icosapentate and warfarin. Test drug was orally administered to fasted rats 60 min before electrical stimulation. YM-60828 at 30 mg/kg p.o., but not ticlopidine, cilostazol, aspirin, beraprost, ethyl icosapentate or warfarin, significantly reduced the incidence of occlusion and improved carotid arterial patency. These results suggest that YM-60828 may be a promising antithrombotic agent for the treatment and prevention of arterial thrombosis which can be given by oral as well as intravenous administration.

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EXPERIMENTAL THROMBUS FORMATION AND HAEMOSTASIS OF DIFFERENT LOW MOLECULAR WEIGHT HEPARINS AND DOSAGES

10.1055/s-0038-1644162 ◽

1987 ◽

Author(s):

R A Zimmerman ◽

C T Rieger ◽

K Hübner ◽

C W Harenber ◽

W Kübler

Keyword(s):

Molecular Weight ◽

Thrombus Formation ◽

Factor Xa ◽

Bleeding Complications ◽

Maximum Effect ◽

Low Molecular Weight ◽

Antithrombotic Effect ◽

Low Molecular Weight Heparins ◽

Antithrombotic Activity ◽

Thrombosis Model

Low molecular weight heparin induces a higher anti factor Xa (a-Xa) and a lower antithrombin activity in plasma in comparison to conventional heparin. From this constellation a more pronounced antithrombotic effect and a minor incidence of bleeding Complications has been suggested.Therefore the antithrombotic activity of heparins was studied in a standardized experimental thrombosis model in rabbits. Three low molecular weight heparins with a mean molecular weight of 4.200 (heparin I),4.000 (heparin II),4.600 Dalton (heparin III) and standard heparin were tested at different dosages in 120 experiments. In the first series the dose of 60 anti Xa units (a-Xa U) given initially and 60 a-Xa U/kg/h induced a reduction of the thrombus size by 40 % (heparin I),37 % (heparin II) and 53 % (heparin III) and a prolongation of the aPTT to 45 (heparin I),66 (heparin II) and 79 sec (heparin III). The a-Xa activity was minor than 0.1 U/ml. In the second series heparins were given to aim at an a-Xa activity of 0.2-0.3 U/ml. Thereby the thrombus formation could be reduced by 84 % (heparin I), 62 % (heparin II) and 39 % (heparin III). aPTT and a-Xa activity were measured at 65.5 sec and 0.22 a-Xa U/ml (heparin I),67.3 sec and 0.3 a-Xa U/ml (heparin II) and 67.5 and 0.31 a-Xa U/ml (heparin III),respectively. In the third series the increase of the a-Xa activity to more than 0.3 U/ml showed no further reduction of the thrombus formation by heparin I, while heparins II and III already at this level reachedthe antithrombotic activity of heparin I.Our data on three different low molecular weight heparins demonstrate that already a heparin level ranging at a minimal a-Xa activity induces a clear and statistically significant antithrombotic effect. A higher heparin dosage with higher a-Xa activity increases the antithrombitic effect. At a level of 0.2-0.3 a-Xa U/ml an obvious and maximum effect could be reached, but the further elevation of the a-Xa activity produced no further antithrombotic action.

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THE ROLE OF A 3-0 SULFO GROUP IN THE GLUCOSAMINE RESIDUE OF A SYNTHETIC OLIGOSACCHARIDE FOR THE DETERMINATION OF ANTITHROMBOTIC ACTIONS

10.1055/s-0038-1644181 ◽

1987 ◽

Author(s):

J M Walenga ◽

J Fareed ◽

M Petitou ◽

J C Lormeau ◽

M Samama ◽

...

Keyword(s):

Sulfo Group ◽

Factor Xa ◽

Antithrombotic Effect ◽

Antithrombotic Activity ◽

Thrombosis Model ◽

Factor Xa Inhibition

We have previously reported on the antithromboticaction of a chemically synthesized heparin pentasaccharide which exhibits high affinity to anti thrombinIII and sole anti-factor Xa activity. In order to investigate the relative importance of the 3-0 sulfo group of this pentasaccharide, we evaluated the in vitro and in vivo antithrombotic activity of a synthetic pentasccharide devoid of the sulfo group at the third position of the glucosamine residue. In amidolytic and clot-based assays the 3-0 de- sulfated pentasaccharide (3-0-DP) failed to exhibit any antifactor Xa actions at concentrations <100 ug/ml in humanor rabbit plasmas, whereas pentasaccharide showed strong factor Xa inhibition at 1.0 ug/ml IK-=3.2x10 M)and at 10.0 ug/ml in rabbit plasma (K.=9.0×10™7 M). Using a rabbit stasis thrombosis model in which thrombosis was induce by human serum or an activated pro-thrombin complex concentrate, 3-0-DP failed to produce any antithrombotic action in acute intravenous regimens at dosages up to 200 ug/kg. In these two models, pentasaccharide produced >80% inhibition of induced thrombosis. These studies demonstrate the critical importance of the 3-0 sulfo group in this heparin pentasaccharide for the determination of antithrombotic activity, and that in this type of oligosaccharide, anti-factor Xa activity is responsible for producing the antithrombotic effect.

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Antithrombotic activity of AT-1015, a potent 5-HT2A receptor antagonist, in rat arterial thrombosis model and its effect on bleeding time

European Journal of Pharmacology ◽

10.1016/s0014-2999(01)01432-7 ◽

2001 ◽

Vol 433 (2-3) ◽

pp. 157-162 ◽

Cited By ~ 25

Author(s):

Hideaki Kihara ◽

Hajime Koganei ◽

Ken Hirose ◽

Hiroshi Yamamoto ◽

Ryota Yoshimoto

Keyword(s):

Receptor Antagonist ◽

Arterial Thrombosis ◽

Bleeding Time ◽

Antithrombotic Activity ◽

Thrombosis Model

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Effect of Different Doses of Acetylsalicylic Acid on the Antithrombotic Activity of Clopidogrel in a Mouse Arterial Thrombosis Model

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.118.311404 ◽

2018 ◽

Vol 38 (10) ◽

pp. 2338-2344 ◽

Cited By ~ 8

Author(s):

Ran Ni ◽

Nima Vaezzadeh ◽

Ji Zhou ◽

Jeffrey I. Weitz ◽

Marco Cattaneo ◽

...

Keyword(s):

Acetylsalicylic Acid ◽

Arterial Thrombosis ◽

Antithrombotic Activity ◽

Thrombosis Model ◽

Different Doses

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Enoxaparin Produces Sustained Antithrombotic Effects in Comparison to Fondaparinux and Rivaroxaban: Clinical Implications.

Blood ◽

10.1182/blood.v114.22.3128.3128 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3128-3128

Author(s):

Walter Jeske ◽

Nicholas Masse ◽

Joseph Emanuele ◽

He Zhu ◽

Elizabeth McGeehan ◽

...

Keyword(s):

Therapeutic Dose ◽

Thrombin Generation ◽

Conflicts Of Interest ◽

Therapeutic Drug ◽

Moderate Increase ◽

Antithrombotic Activity ◽

Blood Samples ◽

Thrombosis Model ◽

Duration Of Effect ◽

Antithrombotic Effects

Abstract Abstract 3128 Poster Board III-65 Enoxaparin (Lovenox®), fondaparinux (Arixtra®) and rivaroxaban (Xarelto®) have been shown to be effective in mediating antithrombotic effects in post-surgical indications. Because of marked differences in the pharmacokinetic and pharmacodynamic behavior of these drugs we hypothesized that after the last dosage, the duration of the residual antithrombotic activity of the various drugs also differs. In order to compare the duration of effect of these three drugs, a rabbit stasis-thrombosis model (RSTM) utilizing FEIBA as the thrombogenic challenge and a rabbit ear bleeding model (REBM) were employed. Individual groups of rabbits (n=5) were treated with doses to mimic prophylactic, therapeutic and supratherapeutic (5x therapeutic) drug levels. Enoxaparin and fondaparinux were administered subcutaneously and rivaroxaban was administered by oral gavage. Blood samples were collected at baseline and at 16-18 hours post-administration of the last dose on day 1 or after 4 days of repeated dosing in the RSTM or at 3 hours post-administration in the REBM. At the 16-18 hour time point, circulating anti-Xa levels were not observed in any of the treatment groups. Despite this, enoxaparin treated animals exhibited a strong antithrombotic response following administration of the therapeutic dose (clot score = 1.3 ± 0.6 vs. 2.7 ± 0.6 for saline controls). Dosing once daily for four days did not enhance the antithrombotic activity of enoxaparin. In the plasmatic thrombin generation assays, a reduction in thrombin generation was noted in samples from enoxaparin-treated animals. For enoxaparin, no increase in bleeding was observed at prophylactic or therapeutic doses when compared to saline. An increase in bleeding (∼5 fold vs. saline) was observed at 3 and 6 hours post-administration of the ‘overdose’. A dose-dependent increase in anti-Xa activity was observed in blood samples collected 3 hours post-administration. For fondaparinux, no increase in bleeding was observed with any of the doses tested. There was a moderate increase in anti-Xa activity in the samples from rabbits treated with the ‘overdose’ of fondaparinux. This level was comparable to that observed with the therapeutic dose of enoxaparin. These studies suggest that enoxaparin produces a sustained antithrombotic effect in contrast to rivaroxaban and fondaparinux. These observations underscore that residual/sustained antithrombotic effects of enoxaparin may be partly responsible for the prolonged antithrombotic actions associated with the clinical use of enoxaparin. Disclosures No relevant conflicts of interest to declare.

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