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.

SALICYLATE-WARFARIN INTERACTION: EFFECTS ON SYSTEMIC ANTICOAGULATION, BLEEDING TIME, AND EXPERIMENTAL VENOUS THROMBOSIS

1987 ◽  
Author(s):  
M C Roncaglioni ◽  
I Reyers ◽  
A P Bolognese Dolessandro ◽  
C Cerletti ◽  
M B Donati ◽  
...  
Keyword(s):  
Drug Treatment ◽  
Venous Thrombosis ◽  
Bleeding Time ◽  
Inferior Vena ◽  
Vena Cava ◽  
Male Rats ◽  
Bleeding Complications ◽  
Control Group ◽  
Association Group ◽  
Systemic Anticoagulation

The potential benefit of the aspirin/warfarin association as an antithrombotic treatment has been matter of debate in view of the major haemorrhagic effect reported with this drug combination. We have tested the effect of such association in a model of venous thrombosis already shown to be prevented by a fully anticoagulant schedule of warfarin. CD-COBS male rats were treated for three days with either warfarin (0.1 mg/kg i.v. once a day) or salicylate (175 mg/kg i.p. twice a day) or their combination (W+S). Systemic anticoagulation (thrombotest), template bleeaing time and occurrence of experimental venous thrombosis (ligature of inferior vena cava) were followed. Treatment with W or S alone did not affect template bleeding time, whereas the association (W+S) did (320+35 sec versus 120± 10 sec in the control group, p<0.01). Thrombotest was only slightly prolonged by single drug treatment (W= 43%, S=48% versus 90% of controls) but strongly prolonged in the association group (S+W=5%; p<0.001). The mechanism of this combined effect may be multifaceted; competition of both drugs for protein binding and the anticoagulant effect of salicylate itself could contribute. In any case, neither the incidence nor the weight of the thrombus were reduced by any drug treatment. Thus, W+S, in contrast to W alone (<5% thrombotest), was unable to prevent or reduce venous thrombosis, while prolonging bleeding time. Bleeding complications reported in clinical trials by the association of W and aspirin might not be solely due to the antiplatelet effect of aspirin.

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.

Ecarin Clotting Time: a Predictive Coagulation Assay for the Antithrombotic Activity of Argatroban in the Rat

1998 ◽  
Vol 79 (01) ◽  
pp. 228-233 ◽  
Author(s):  
Catherine Lunven ◽  
Christine Girardot ◽  
Irène Lechaire ◽  
Denise Girard ◽  
Marie-Christine Charles ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Arterial Thrombosis ◽  
Predictive Marker ◽  
Clotting Time ◽  
Antithrombotic Effect ◽  
Antithrombotic Activity ◽  
Thrombosis Model ◽  
Antithrombotic Effects ◽  
Ecarin Clotting Time ◽  
Predictive Assay

SummaryWe studied the use of the Ecarin Clotting Time (ECT) as a predictive assay of the antithrombotic effects of argatroban in a new tissue factor-dependent model of venous thrombosis and a model of arterial thrombosis in the rat. Heparin was used as a reference anticoagulant.Infusions of argatroban dose-dependently increased the ECT across the range of doses required for antithrombotic activity in models of venous and arterial thrombosis (1.25-40 μg/kg/min). The TT was only useful as a marker in the case of venous thrombosis, since, in the arterial thrombosis model, the clotting times were >200 s in the majority of animals receiving antithrombotic doses. The aPTT is not sufficiently sensitive to be predictive of an antithrombotic effect in the venous model, and shows only modest increases in the arterial thrombosis model. Heparin did not significantly increase the ECT at antithrombotic doses in the venous thrombosis model, and only increased the ECT by 53% at 40 μg/kg/min in the arterial model, despite a marked antithrombotic effect. Both the TT and aPTT were dose-dependently increased by heparin at doses active in the venous model, whereas both parameters were >200 s at doses active in the arterial thrombosis model.Thus, the ECT provides a predictive marker for the antithrombotic activity of argatroban in both venous and arterial thrombosis, at least in the rat.

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.

Animal Models of Thrombosis Help Predict the Human Therapeutic Concentration of PRT54021, a Potent Oral Factor Xa Inhibitor.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 901-901 ◽  
Author(s):  
Keith Abe ◽  
Gail Siu ◽  
Susan Edwards ◽  
Pei Hua Lin ◽  
Bing Yan Zhu ◽  
...  
Keyword(s):  
Animal Models ◽  
Venous Thrombosis ◽  
Thrombin Generation ◽  
Ex Vivo ◽  
Vena Cava ◽  
Factor Xa ◽  
Fold Change ◽  
In Vivo Models ◽  
Antithrombotic Activity ◽  
Fxa Inhibitor

Abstract Factor Xa (fXa) inhibition has resulted in the emergence of a new class of antithrombotics. Pharmacodynamic monitoring of these agents has proven problematic. The present study was designed to determine the target concentration of an oral fXa inhibitor required for clinical trials using both thrombin generation assays and three in vivo models and determine whether clotting assays such as activated partial thromboplastin time (aPTT) and prothrombin time (PT) would be suitable for monitoring human dosing. PRT54021 (PRT021) is a potent inhibitor of human fXa (Ki=117pM). PRT021 and fondaparinux, an indirect fXa inhibitor, both significantly inhibited TAT and F1.2 generation in human whole blood. Compared to a therapeutic level of fondaparinux (200nM), PRT021 (200nM) was more potent in suppressing both markers. Multiple doses of PRT021 were evaluated in three animal models. The first model, which measured clot accretion on cotton threads placed in rabbit abdominal vena cava, compared inhibition of thrombus mass by PRT021 to that of supratherapeutic doses of enoxaparin (a LMW heparin). The second model compared the ability of PRT021 to maintain vessel patency under arterial flow conditions in FeCl3 induced thrombosis in rat carotid artery to that achieved by enoxaparin or clopidogrel (an antiplatelet agent). The third model investigated inhibition of 111In labeled platelet deposition on dacron grafts and expansion chambers placed in femoral arteriovenous shunts in baboons. PRT021 and enoxaparin were administered as IV infusions and clopidogrel was dosed orally for three days. Ex vivo PT and aPTT were measured in all models. The models encompass stringent criteria of arterial and venous thrombosis and PRT021 produced dose-responsive antithrombotic activity in each of the three models. The efficacy of PRT021 compared favorably to supratherapeutic levels of enoxaparin and clopidogrel. Unlike in the rodent models, efficacy in primates was attained at a much lower dose with minimal prolongation of PT. Species specificity was also demonstrated by in vitro extensions of PT and aPTT in rat, rabbit, baboon and human plasma. A 2X change of PT was attained at concentrations of 8.9, 1.6, 1 and 0.4μM respectively. The data indicate that doses of PRT021 that inhibit thrombin generation in human blood and that provide anticoagulation similar to baboon dosed at 0.49mg/kg may be sufficient to prevent venous thrombosis in humans. Comparative modeling of extents of change in PT to levels of antithrombotic efficacy also leads us to predict that human therapeutic activity for PRT021 may be attained without concurrent changes in ex vivo clotting parameters. The targeted concentration is currently being tested in Phase II trials for its ability to prevent venous thromboembolism in orthopedic surgery patients. Model of Thrombosis Agent, Dose Antithrombotic Activity aPTT fold change PT fold change Rabbit vena cava PRT021,3mg/kg 76% inhibition 2.22 2.34 Rabbit vena cava Enoxaparin, 1.6mg/kg 96% inhibition 2.06 2.01 Rat carotid PRT021,19.1mg/kg 90% patency 1.69 2.20 Rat carotid Enoxaparin, 7.6mg/kg 70% patency 3.49 1.19 Rat carotid Clopidogrel, 3mg/kg/day 80% patency 1.03 1.01 Baboon arteriovenous PRT021,0.49mg/kg 90% inhibition (venous), 32% inhibition (arterial) 1.29 1.17

scholarly journals Right ventricular failure and pulmonary hypertension at recurrent thromboembolism of small branches of the pulmonary artery in cancer patients

2015 ◽  
Vol 96 (4) ◽  
pp. 492-497
Author(s):  
I A Kamalov ◽  
M G Tukhbatullin
Keyword(s):  
Heart Failure ◽  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Venous Thrombosis ◽  
Malignant Tumors ◽  
Vena Cava ◽  
Right Heart Failure ◽  
Main Group ◽  
Control Group ◽  
Right Heart

Aim. Develop new approaches to the diagnosis of right heart failure and pulmonary hypertension in recurrent thromboembolism of small branches of the pulmonary artery in patients with malignant tumors. Methods. 83 patients with malignant tumors of various localizations were examined and followed-up. The main group included 49 patients with malignant tumors of various localizations and related venous thrombosis. The control group included 34 patients who did not have venous thrombosis. Patients in both groups underwent ultrasonography of inferior vena cava system veins and echocardiography at intervals of 3-4 days during the diagnosis and treatment of malignant tumors. Right ventricle ejection fraction and systolic pressure in the pulmonary artery were calculated at echocardiography. Results. No signs of inferior vena cava system veins thromboses, right heart failure, pulmonary hypertension were identified in patients of the control group while setting up the diagnosis and treatment of malignancies. In 38 out of 49 patients of the main group, right ventricular failure and pulmonary hypertension of varying severity were detected. The condition of 46 patients of the main group gradually improved after treating with anticoagulants. Conclusion. Recanalization of venous thrombosis is accompanied by frequent rejection of micro thrombi and embolization of small branches of pulmonary artery, causing right heart failure and pulmonary hypertension, which can be promptly detected by repeated echocardiography.

Experimental Pharmacology of Hirunorm: a Novel Synthetic Peptide Thrombin Inhibitor

1996 ◽  
Vol 76 (03) ◽  
pp. 384-392 ◽  
Author(s):  
Rocco Cirillo ◽  
Annalisa Lippi ◽  
Alessandro Subissi ◽  
Giancarlo Agnelli ◽  
Marco Criscuoli
Keyword(s):  
Venous Thrombosis ◽  
Arterial Thrombosis ◽  
Coronary Thrombosis ◽  
Vena Cava ◽  
Thrombin Inhibitor ◽  
Similar Species ◽  
Thrombin Activity ◽  
Experimental Pharmacology ◽  
Anaesthetized Rats

SummaryEnhanced thrombin activity has been associated with coronary thrombosis and with acute and long-term complications following coronary balloon angioplasty. Blocking thrombin activity with specific inhibitors is proposed as a promising antithrombotic therapy. We describe the anticoagulant and antithrombotic properties of hirunorm, a novel synthetic 26-aminoacid peptide thrombin inhibitor, in comparison with r-hirudin and hirulog-1. Hirunorm was equipotent to hirulog-1 and 1/30 as potent as r-hirudin in blocking a-thrombin amidolytic activity (IC50 = 10 ± 2,15 ± 1 and 0.3 ± 0.1 nM, respectively), but it did not affect trypsin, plasmin and t-PA activities at 10 μM. All the compounds inhibited clot-bound thrombin to clots prepared by thrombin hydrolysis of purified fibrinogen in buffer. Hirunorm and hirulog-1 showed similar species-dependent potency in doubling basal in vitro clotting times of human, rat and rabbit plasma (EC200 varied 70 to 200 nM for TT, 0.7 to 16 μM for aPTT and 0.8 to 17 μM for PT), while r-hirudin was always at least three times more active. When assayed by HPLC or by bioassay of the intact peptide, hirunorm was stable against a-thrombin and plasma hydrolases, but it was catabolized by rat liver and kidney enzymes. Venous thrombosis was produced in anaesthetized rats by vena cava ligation following a procoagulant serum injection. Intravenous and subcutaneous hirunorm inhibited venous thrombosis at doses (≤0.3 mg/kg) two-three times higher than those of r-hirudin. Hirulog-1 was as active as hirunorm only after i. v. infusion. Arterial thrombosis was obtained in the anaesthetized rat by chemical (FeCl2) stimulation of a common carotid and i.v. infused hirunorm (1-3 mg/kg/30 min) inhibited it dose-dependently; r-hirudin was partly active only at 3 mg/kg, but hirulog-1 was inactive at either dose. Full antithrombotic doses of hirunorm did not affect the bleeding time as measured from punctured mesenteric vessels, in anaesthetized rats. In conclusion, hirunorm is a potent peptide thrombin inhibitor endowed with antithrombotic activity in models of venous and arterial thrombosis.

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