piperidines and Thrombophlebitis

One hundred and ten patients with acute proximal deep-vein thrombosis were randomized in a sequential dose-finding design, to receive continuous intravenous infusion of napsagatran, a novel synthetic thrombin-inhibitor, at a fixed dose of 5 mg/h (n = 37) or 9 mg/h (n = 26), or APTT-adjusted unfractionated heparin (n = 47). Oral anticoagulants were started on the 2nd day and the study drug was discontinued from the 5th treatment day, as soon as the International Normalized Ratio was above 2. Control venogram (97 venogram pairs evaluable) after 5-8 days of treatment showed improvement in 3 napsagatran-treated patients (versus none in heparin-treated patients) and worsening in 4 napsagatran-treated patients (versus 2 in heparin-treated patients). The venographic Marder's score did not change among the treatment groups. New lung scan perfusion defects (99 scintigram pairs evaluable) occurred in 4 (11%), 4 (21%), and 4 (10%) patients in the napsagatran (5 mg/h) group, in the napsagatran (9 mg/h) group, and in the heparin control group, respectively. There was no statistically significant difference in any of these endpoints between the 3 groups. No major bleeding was observed and the rare minor bleedings occurred at a similar rate in the three treatment groups. In conclusion, the ADVENT trial has shown data that suggest comparable efficacy and safety of a synthetic, direct thrombin inhibitor (napsagatran) and conventional heparin therapy for treatment of proximal DVT. These results suggest that synthetic direct thrombin inhibitors are a promising class of antithrombotic agents which deserves further development in this field.

Topics: Adult; Aged; Antithrombins; Blood Coagulation Tests; Female; Follow-Up Studies; Heparin; Humans; Infusions, Intravenous; Male; Middle Aged; Naphthalenes; Partial Thromboplastin Time; Piperidines; Thrombophlebitis

Topics: Acute Disease; Adult; Aged; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Ketanserin; Male; Middle Aged; Pain; Piperidines; Random Allocation; Serotonin Antagonists; Thrombophlebitis

Topics: Adult; Breast Neoplasms; Cerebrovascular Disorders; Drug Costs; Endometrial Neoplasms; Estrogen Antagonists; Estrogens; Female; Fractures, Bone; Humans; Middle Aged; Myocardial Infarction; Osteoporosis, Postmenopausal; Piperidines; Placebos; Pulmonary Embolism; Raloxifene Hydrochloride; Randomized Controlled Trials as Topic; Tamoxifen; Thrombophlebitis

1. The effects of YM-60828, a newly synthesized factor Xa inhibitor, were investigated to analyse the relationship between its antithrombotic effects and its prolongation of template bleeding time in rats. YM-60828 was compared with argatroban, heparin and dalteparin. All agents were intravenously administered as a bolus. 2. In ex vivo studies, YM-60828 and argatroban prolonged both prothrombin time and activated partial thromboplastin time in a dose-dependent manner, while heparin and dalteparin prolonged only activated partial thromboplastin time. 3. In a venous thrombosis model, all agents exerted antithrombotic effects in a dose-dependent manner. The ID50 values of YM-60828, argatroban, heparin and dalteparin were 0.0081 mg kg(-1), 0.011 mg kg(-1), 6.3 iu kg(-1) and 4.7 iu kg(-1), respectively. 4. In an arterio-venous shunt model, all agents exerted antithrombotic effects in a dose-dependent manner. The ID50 values of YM-60828, argatroban, heparin and dalteparin were 0.010 mg kg(-1), 0.011 mg kg(-1), 10 iu kg(-1) and 4.2 iu kg(-1), respectively. 5. In bleeding time studies, all agents prolonged template bleeding time in a dose-dependent manner. ED2 values, the doses causing a 2 fold prolongation of bleeding time in the saline group, of YM-60828, argatroban, heparin and dalteparin were 0.76 mg kg(-1), 0.081 mg kg(-1), 18 iu kg(-1) and 25 iu kg(-1), respectively. 6. The ratio (ED2/ID50) of YM-60828 was more than 30 fold greater than that of heparin and more than 10 fold greater than those of argatroban and dalteparin. 7. These data show that YM-60828 can exert its antithrombotic effects with little prolongation of bleeding time compared with the other currently used anticoagulant agents.

Topics: Animals; Anticoagulants; Arginine; Arteriovenous Shunt, Surgical; Bleeding Time; Blood Proteins; Dalteparin; Factor Xa Inhibitors; Fibrinolytic Agents; Heparin; In Vitro Techniques; Male; Naphthalenes; Partial Thromboplastin Time; Pipecolic Acids; Piperidines; Platelet Aggregation Inhibitors; Rats; Rats, Sprague-Dawley; Sulfonamides; Thrombophlebitis; Thrombosis

The antithrombotic effects of a novel factor Xa inhibitor, YM-60828 ([N-[4-[(1-acetimidoyl-4-piperidyl)oxy]phenyl]-N-[(7-amidino-2-nap hthyl)methyl]sulfamoyl]acetic acid dihydrochloride), in three thrombosis models in guinea pigs were studied in comparison with its effect on bleeding time. The antithrombotic effects of YM-60828 were most pronounced in the venous thrombosis and the arterio-venous shunt models but YM-60828 showed 10-fold weaker effects in the carotid thrombosis model. However, YM-60828 prolonged bleeding time at a much higher dose than that required in all thrombosis models. In conclusion, YM-60828 exerted its antithrombotic effects without prolonging bleeding time in all thrombosis models and may be of clinical value not only in venous thrombosis but also in arterial thrombosis.

Topics: Animals; Antithrombin III; Arteriovenous Shunt, Surgical; Bleeding Time; Carotid Artery Thrombosis; Carotid Artery, Internal; Disease Models, Animal; Factor Xa Inhibitors; Fibrinolytic Agents; Guinea Pigs; Male; Naphthalenes; Piperidines; Thrombophlebitis; Thrombosis

In our study, we demonstrated that DV-7028: (3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-6, 7,8,9-tetrahydro-2H-pyrido [1,2,-a]-1,3,5-triazine-2, 4(3H)-dione maleate)--a selective 5-HT2A receptor antagonist, inhibited thrombus formation in the arterial thrombosis model and was completely ineffective in the prevention of venous thrombosis in the rat. In washed platelets prelabelled with 3H-serotonin, DV-7028 inhibited, in a dose-dependent manner, the collagen-induced secretion of serotonin. However, the uptake of serotonin into platelets was not affected by this substance. Administration of DV-7028 also inhibited platelet aggregation in the whole blood and platelet-rich plasma (PRP) induced by collagen, and diminished serotonin-induced aggregation of rat platelets in the presence of a sensitizing but nonaggregating amount of ADP, whereas it did not modify aggregation in PRP when induced by ADP. DV-7028 caused a concentration-dependent, almost parallel shift to the right of the concentration-response to serotonin for its pressor effect in the rat perfused tail artery. The present data demonstrate that DV-7028 exhibits 5-HT2A receptor antagonistic properties in the rat cardiovascular system, exhibits antithrombotic effect in the model of arterial but not venous thrombosis in rats. These results constitute further evidence of the possible importance of serotonin as a mediator of platelet thrombosis in arteries. Moreover, they can provide a useful tool for the prevention of various thrombotic diseases.

Topics: Animals; Aorta, Abdominal; Bleeding Time; Ketanserin; Male; Piperidines; Platelet Aggregation; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Thrombophlebitis; Thrombosis; Triazines

A sensitive thrombosis model with a high reproducibility was developed in the rat, utilizing stasis of the caval vein and a standardized surgical trauma as the only thrombogenic stimuli. Since no procoagulant substances were used, the results of the present study might be relevant in a clinical situation. The antithrombotic effect of two recently synthesized low-molecular-weight thrombin inhibitors have been compared to dalteparin, (Fragmin) a low-molecular-weight heparin fragment. Each compound was studied at 8 different doses with 10 rats in each group. On a gravimetric basis, the thrombin inhibitor melagatran was twice as potent as dalteparin (ED50 16 and 33 microg/kg per h, respectively). The second thrombin inhibitor, inogatran, had an intermediate effect, with an ED50 of 24 microg/kg per h. No differences in antithrombotic effect were, however, found when the compounds were compared at anticoagulant equivalent doses (same APTT prolongation). A 50% reduction in the mean thrombus weight was obtained when APTT was prolonged to 1.2 to 1.3 times the pretreatment value.

Topics: Animals; Azetidines; Benzylamines; Dalteparin; Disease Models, Animal; Fibrinolytic Agents; Glycine; Heparin, Low-Molecular-Weight; Infusions, Intravenous; Injections, Intravenous; Male; Piperidines; Rats; Rats, Wistar; Thrombin; Thrombophlebitis; Vena Cava, Inferior

Inogatran (MW 439 Da), a new, selective, active site inhibitor of thrombin, was evaluated in three rat models of thrombosis. In the venous thrombosis model, inogatran dose-dependently inhibited thrombus formation with a > 80% antithrombotic effect at a plasma concentration of 0.45 mumol l-1. In the arterial thrombosis model, inogatran dose-dependently inhibited thrombus formation, preserved vessel patency and the mean blood flow. Acetylsalicylic acid (ASA) potentiated the effects of low plasma concentrations of inogatran in the arterial thrombosis model. In the model of rt-PA-induced thrombolysis of a thrombus in the carotid artery, inogatran improved the patency time and the cumulative blood flow during the two hour thrombolysis period more than rt-PA alone. At high therapeutic plasma concentration of inogatran, there was only a moderate prolongation of bleeding time compared with the control value. It is concluded that inogatran is an effective antithrombotic agent both in the venous and arterial thrombosis models and also as adjuvant to rt-PA in the thrombolysis model.

Topics: Animals; Antithrombins; Arginine; Aspirin; Bleeding Time; Disease Models, Animal; Fibrinolytic Agents; Glycine; Heparin; Male; Molecular Weight; Pipecolic Acids; Piperidines; Platelet Aggregation Inhibitors; Rats; Rats, Sprague-Dawley; Sulfonamides; Thrombolytic Therapy; Thrombophlebitis; Thrombosis

Several antithrombotics (heparin, acetylsalicylic acid, sulfinpyrazone and dipyridamole) as well as an antiserotonin ketanserin were tested in a new sensitive model of venous thrombosis in rats. Intravenous injection of hypotonic saline was used for thrombus induction combined with the vena cava ligation. Formation of thrombi was evaluated by their weights. With i.v. heparin, oral sulfinpyrazone and acetylsalicylic acid, i.v. dipyridamole and ketanserin an effective inhibition was obtained, whereas with oral dipyridamole and ketanserin the inhibition remained incomplete.

Topics: Animals; Anticoagulants; Aspirin; Dipyridamole; Disease Models, Animal; Female; Heparin; Ketanserin; Piperidines; Rats; Rats, Inbred Strains; Sulfinpyrazone; Thrombophlebitis; Time Factors

Two highly sensitive models of arterial and venous thrombosis forming with the test of endothelial stability a complementary system with a maximum stress on the role of vascular lesion were used to test a series of four antithrombotic drugs (heparin, acetylsalicylic acid, dipyridamole, sulfinpyrazone) and four drugs with other indications but with an antithrombotic activity in experiment (prenylamine, troxerutin, ketanserin and pizotifen). All drugs, except heparin, were given orally. Whereas heparin, aspirin and prenylamine had mixed effects on both arterial thrombosis (i.e. mostly on platelet functions) as well as on endothelial stability, ketanserin and pizotifen had a predominant effect on the former while dipyridamole, troxerutin and sulfinpyrazone influenced mostly the latter function.

Topics: Animals; Anticoagulants; Arteries; Aspirin; Dipyridamole; Female; Hydroxyethylrutoside; Ketanserin; Piperidines; Pizotyline; Prenylamine; Rats; Rats, Inbred Strains; Sulfinpyrazone; Thrombophlebitis; Thrombosis