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

2001 ◽  
Vol 433 (2-3) ◽  
pp. 157-162 ◽  
Author(s):  
Hideaki Kihara ◽  
Hajime Koganei ◽  
Ken Hirose ◽  
Hiroshi Yamamoto ◽  
Ryota Yoshimoto
Keyword(s):  
Receptor Antagonist ◽  
Arterial Thrombosis ◽  
Bleeding Time ◽  
Antithrombotic Activity ◽  
Thrombosis Model

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

1998 ◽  
Vol 79 (02) ◽  
pp. 410-416 ◽  
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.

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.

Antiplatelet and Antithrombotic Activity of SL65.0472, a Mixed 5-HT1B/5-HT2A Receptor Antagonist

2001 ◽  
Vol 85 (03) ◽  
pp. 521-528 ◽  
Author(s):  
Janine Lorrain ◽  
Sylvette Lochot ◽  
Monique Delahaye ◽  
Alain Lalé ◽  
Pierre Savi ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Platelet Activation ◽  
Human Platelet ◽  
Platelet Rich Plasma ◽  
Thrombus Formation ◽  
Shape Change ◽  
Antithrombotic Activity ◽  
Thrombosis Model ◽  
Artery Thrombosis ◽  
Ic50 Values

SummaryThe antiplatelet and antithrombotic activity of SL65.0472 (7-fluoro-2-oxo-4-[2-[4-(thieno [3,2-c]pyrin-4-yl) piperazin-1-yl]ethyl]-1,2-dihydroquinoline-acetamide), a mixed 5-HT1B/5-HT2A receptor antagonist was investigated on 5HT-induced human platelet activation in vitro, and in rat, rabbit and canine platelet dependent thrombosis models. SL65.0472 inhibited 5-HT-induced platelet shape change in the presence of EDTA (IC50 values = 35, 69 and 225 nM in rabbit, rat and human platelet rich plasma (PRP)), and also inhibited aggregation induced in human PRP by 3-5 μM 5-HT + threshold concentrations of ADP (0.5-1 M) or collagen (0.3 g/ml) with mean IC50 values of 49 ± 13 and 48 ± 6 nM respectively. SL65.0472 inhibited thrombus formation when given both intravenously 5 min and orally 2 h prior to assembly of an arterio-venous (A-V) shunt in rats as from 0.1 and 0.3 mg/kg respectively. It was active in a rabbit A-V shunt model with significant decreases in thrombus weight as from 0.1 mg/kg i. v. and at 10 mg/kg p. o. The delay to occlusion in an electric current-induced rabbit femoral artery thrombosis model was increased by 251% (p <0.05) after 20 mg/kg p. o. SL65.0472 (30 μg/kg i. v.) virtually abolished coronary cyclic flow variations (7.2 ± 1.0/h to 0.6 ± 0.6/h, p <0.05) and increased minimum coronary blood flow (1.2 ± 0.8 ml/ min to 31.8 ± 8.4 ml/min, p <0.05) in a coronary artery thrombosis model in the anaesthetised dog. Finally, SL65.0472 significantly increased the amount of blood lost after rat tail transection at 3 mg/kg p. o. Thus the anti-5-HT2A component of SL65.0472 is reflected by its ability to inhibit 5-HT-induced platelet activation, and platelet-rich thrombus formation.

Study of a new benzimidazole derivative having in its structure a sterically hindered phenolic substituent on models of arterial and venous thrombosis

2020 ◽  
Author(s):  
А.А. Спасов ◽  
А.Ф. Кучерявенко ◽  
К.А. Гайдукова ◽  
В.С. Сиротенко ◽  
О.Н. Жуковская
Keyword(s):  
Venous Thrombosis ◽  
Arterial Thrombosis ◽  
Benzimidazole Derivative ◽  
Vena Cava ◽  
Male Rats ◽  
Control Group ◽  
Vena Cava Inferior ◽  
Antithrombotic Activity ◽  
Thrombosis Model ◽  
Venous Thromboses

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.

scholarly journals Prevention of platelet aggregation and arterial thrombosis using a modified Shenzhu Guanxin Formula

2020 ◽  
Vol 48 (10) ◽  
pp. 030006052094132
Author(s):  
Manting Huang ◽  
Huanlin Wu ◽  
Jianping Wu ◽  
Qiuxiong Chen ◽  
Dezhi Zou ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Arterial Thrombosis ◽  
Bleeding Time ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Dependent Manner ◽  
Antithrombotic Agent ◽  
Beneficial Effects ◽  
Thrombosis Model ◽  
Carotid Arterial

Objective Modified Shenzhu Guanxin Formula (mSGF) has beneficial effects in coronary artery disease. Previously, we found that mSGF inhibited platelet aggregation in rats. In the present study we further investigated the antiplatelet and antithrombotic activities of mSGF in rats. Methods Rats were orally administered mSGF (4.2, 8.4, or 16.8 g crude drug/kg), the adenosine 5′-diphosphate (ADP) receptor antagonist clopidogrel (7.875 mg/kg), or saline once a day for 7 days. The effects of mSGF on platelet aggregation were measured. Levels of cyclic adenosine monophosphate (cAMP) and phosphoinositide 3-kinase (PI3K) signaling were analyzed by ELISA and western blotting, respectively. The antithrombotic effect of mSGF was investigated using a FeCl3-induced carotid arterial thrombosis model and effects on bleeding time were assessed in a rat tail transection model. Results mSGF significantly inhibited ADP-induced platelet aggregation in a dose-dependent manner, elevated cAMP levels and inhibited phosphorylation of extracellular signal-regulated kinase (ERK) and PI3K/protein kinase B (Akt). Moreover, mSGF dose-dependently inhibited thrombosis in a FeCl3-induced carotid arterial thrombus model and had a significantly smaller effect on bleeding time compared with clopidogrel. Conclusions mSGF represents a potent and safe antithrombotic agent whose antiplatelet activity is probably mediated through blockade of PI3K/Akt signaling and increased cAMP generation.

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