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At least 973 records · Page 54Linked to original sources
PubMed2003

Inhibition of arterial thrombosis by a protease-activated receptor 1 antagonist, FR171113, in the guinea pig.

The antiplatelet and antithrombotic effects of FR171113, 3-(4-chlorophenyl)-2-(2,4-dichlorobenzoylimino)-5-(methoxycarbonyl methylene)-1,3-thiazolidin-4-one, a non-peptide protease-activated receptor 1 (PAR1) antagonist, were evaluated in guinea pigs. FR171113 inhibited Ser-Phe-Leu-Leu-Arg-Asn-NH2 (a synthetic PAR1 agonist peptide)-induced and thrombin-induced aggregation of guinea pig platelets in a concentration-dependent manner in vitro (IC50=1.5 and 0.35 microM, respectively). Subcutaneous administration of FR171113 (0.1-3.2 mg/kg) produced a dose-dependent inhibition of platelet aggregation ex vivo. The ED50 value of FR171113 for platelet aggregation was 0.49 mg/kg s.c. However, FR171113 did not have an inhibitory effect on ADP- or collagen-induced platelet aggregation in vitro and ex vivo. One hour after FR171113 treatment at 1.0 mg/kg s.c., significant inhibition of arterial thrombosis without a prolongation of thrombin time or coagulation time was seen in the FeCl3-induced carotid artery thrombosis model in guinea pigs. Furthermore, FR171113 did not prolong bleeding time even at 32 mg/kg s.c., which is a much higher dose than that required in the thrombosis model. These observations indicate that FR171113 has desirable antiplatelet effects both in vitro and in vivo and that its in vivo antithrombotic activity is efficacious without causing a prolongation of bleeding time.

Animals↗
PubMed2001

Anticoagulation with a selective thrombin inhibitor in a woman with heparin-induced thrombocytopenia.

BACKGROUND: Heparin-induced thrombocytopenia is an immunologic complication of heparin therapy with potentially serious venous and arterial thrombotic sequelae. Progression to overt thrombosis is the most serious complication, occurring in approximately 0.5% of heparin-treated patients. Previous strategies for treatment of the associated thrombosis with heparin-induced thrombocytopenia have frustrated clinicians with poor outcomes. CASE: A 45-year-old woman with stage IB endometrial cancer underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy, and pelvic lymphadenectomy. She suffered a pulmonary embolism postoperatively. The pulmonary embolism was treated with heparin, and heparin-induced thrombocytopenia and central vein catheter-related thrombosis developed. She underwent thrombectomy and was successfully anticoagulated with a selective thrombin inhibitor instead of heparin. CONCLUSION: This treatment should be considered for patients with heparin-induced thrombocytopenia in either a prophylactic or a treatment regimen.

Anticoagulants↗
PubMed2000

In vitro and in vivo studies of AT-1362, a newly synthesized and orally active inhibitor of thrombin.

AT-1362 was found to be a potent, selective, and competitive inhibitor of thrombin, with a Ki value of 6.7 nM. In a rat model of venous thrombosis induced by partial stasis and endothelial disruption, the ID(50) values (a dose required to obtain 50% inhibition of thrombus formation over each vehicle group) of AT-1362 and argatroban were 0.03 mg/kg i.v. plus 0.5 microg/kg/minute and 0. 13 mg/kg i.v. plus 8.7 microg/kg/minute, respectively, and the antithrombotic effect of AT-1362 without prolongation of bleeding time lasted for 2 hours and disappeared 4 hours after oral administration of 30 mg/kg. In the rat tail transection model, the BT(2) values (a dose causing two-fold prolongation of the bleeding time over each vehicle group) of AT-1362 and argatroban were 0.56 mg/kg i.v. plus 9.3 microg/kg/minute and 1.1 mg/kg i.v. plus 73.3 microg/kg/minute, respectively. The reduction of thrombus formation and the prolongation of bleeding time were correlated with an ex vivo activated partial thromboplastin time (APTT) for both drugs. AT-1362 at 0.3 mg/kg i.v. plus 5 microg/kg/minute and argatroban at 0.6 mg/kg i.v. plus 40 microg/kg/minute significantly (p<0.05 and p<0.01, respectively) improved the vessel patency in a FeCl(2)-induced carotid artery thrombosis model in rats. These results suggest that AT-1362 may be a potent antithrombotic agent for the treatment of thrombotic diseases.

Administration, Oral↗
PubMed2001

Changes in blood viscosity by heparin and argatroban.

Anticoagulants are effective for preventing both venous and arterial thrombosis. Although antithrombotic agents have been reported to reduce thrombin formation, to our knowledge, the relation between blood viscosity (BV) and antithrombotic agents has not been examined. We examined the effects on whole BV of various dosages of the antithrombotic agents-heparin sodium and argatroban. Thirty microliters of either drug was added to 3-ml samples of blood obtained from healthy male volunteers. Whole BV was then immediately examined with an oscillation-type viscometer. When either agent was added, BV decreased and coagulation time increased dose dependently. BV was 4.5+/-0.3 mPa.s in untreated blood but decreased in a dose-dependent manner to a minimum of 2.5+/-0.3 mPa.s with heparin sodium and decreased dose dependently in a sigmoid manner with argatroban. Because thrombin generation is inhibited in all antithrombotic therapies, this inhibition might be reflected by changes in BV. Our results suggest that BV in accordance with blood coagulability are indexes of thrombotic tendency and that decreasing BV prevents life-threatening thromboembolic conditions.

Adult↗
PubMed2002

Argatroban therapy does not generate antibodies that alter its anticoagulant activity in patients with heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is an immune-mediated syndrome that can lead to limb- and life-threatening thrombosis. Argatroban, a small synthetic molecule (Argatroban; GlaxoSmithKline, Philadelphia, PA), and lepirudin, a protein of non-human origin (Refludan; Aventis, Bridgewater, NJ), are direct thrombin inhibitors that have been used successfully for anticoagulant therapy in HIT patients. It has been reported that between 44-74% of lepirudin-treated HIT patients develop drug-specific antibodies that either enhance or suppress the anticoagulant activity of lepirudin. By contrast, there have been no reported patient experiences suggestive of unexpected loss or enhancement of argatroban's anticoagulant effect in clinical trials, including those in HIT patients, or in postmarketing safety surveillance of over 4,800 patients treated in Japan. To confirm the lack of antibodies in argatroban-treated patients with HIT, we examined plasma for anticoagulant-altering activity and reviewed dosing patterns of re-exposed patients. Paired, pre-therapy and post-therapy (> or =7 days) plasma pools exhibited comparable in vitro anticoagulant responses (aPTT and antithrombin activity) to argatroban supplementation. Argatroban at 5 microg/mL similarly prolonged aPTTs of normal plasma pretreated with IgG isolated from pre-therapy versus post-therapy plasma (P>0.6). In trials, mean argatroban doses during initial therapy versus re-exposure were not different among individuals anticoagulated for the treatment or prophylaxis of thrombosis (P=0.60) or during percutaneous coronary interventions (P=0.79), with no discernable pattern of suppression or enhancement of argatroban anticoagulation. Consistent with the lack of reported patient experiences suggestive of unexpected loss or enhancement of argatroban's anticoagulant effect across clinical trials and post-marketing safety surveillance, these data support the lack of anti-argatroban antibodies that affect drug activity in argatroban-treated HIT patients.

Antibodies↗
PubMed2003

Management of heparin-induced thrombocytopenia: a critical comparison of lepirudin and argatroban.

Heparin-induced thrombocytopenia (HIT) is a transient hypercoagulability state initiated, paradoxically, by the anticoagulant, heparin. It is characterized by antibody-induced activation of platelets, leading to thrombin generation. Many patients with HIT develop thrombosis; even when heparin is stopped because of "isolated HIT" detected during routine platelet count monitoring, 25-50% of patients subsequently develop symptomatic thrombosis. Thus, an alternative anticoagulant should be substituted for heparin when HIT is strongly suspected. Two direct thrombin inhibitors (DTIs), lepirudin and argatroban, have been studied for prevention and treatment of thrombosis in HIT patients. Lepirudin is a polypeptide that binds irreversibly to the fibrin-binding and catalytic sites on thrombin (bivalent inhibitor). In contrast, argatroban is a synthetic, small-molecule DTI that binds reversibly to the catalytic site alone (univalent inhibitor). Results of historically controlled clinical trials suggest both agents are effective for preventing and treating thrombosis in HIT. However, these agents have not been compared directly, and important differences in study design limit conclusions from indirect comparison. For example, lepirudin was given for 12-14 days (mean) in treatment studies of thrombosis complicating HIT, whereas argatroban was given only for 6-7 days, a difference that could explain apparent lower thrombosis rates (and greater bleeding) with lepirudin. Recently, the transition from DTI therapy to oral anticoagulation in patients with deep venous thrombosis (DVT) complicating HIT has been identified as a risk period for coumarin-induced venous limb gangrene. Thus, the DTI should be given alone during acute HIT, with oral anticoagulants deferred until substantial resolution of the thrombocytopenia has occurred.

Anticoagulants↗
PubMed1997

Adjuvant effect of argatroban on staphylokinase induced thrombolysis of platelet rich thrombi in rat mesenteric venules in vivo.

Effective, therapeutic thrombolysis should not only promote dissolution of fibrin but should also regulate continued thrombin-induced fibrin formation and the accumulation of platelets on the thrombotic lesion. The aim of the present study was to assess the use of a synthetic, low molecular weight thrombin inhibitor, argatroban in association with a well defined thrombolytic agent in a reproducible animal model of thrombolysis in vivo. Thrombi were formed in rat mesenteric venules with a helium neon (He-Ne) laser in the presence of Evans blue and were stabilised for 10 minutes. Thrombi formed in this manner were shown by transmission electron microscopy to be composed mainly of platelets. Thrombolysis was induced with recombinant staphylokinase in the presence and absence of argatroban and the process was monitored using computerised image analysis. Co-infusion of argatroban at a dose of 2.0 mg/kg/h with staphylokinase significantly enhanced the rate of thrombolysis. The results suggested that administration of the thrombin inhibitor together with the fibrinolytic agent moderated platelet-dependent mechanisms and led to a more rapid restoration of blood vessel patency.

Animals↗
PubMed1997

Inhibition of collagen-induced platelet aggregation by argatroban in patients with acute cerebral infarction.

Platelet aggregation induced by collagen is enhanced in patients with cerebral thrombosis [1], and platelet aggregates and activation products such as beta-thromboglobulin appear in the circulation, particularly during the acute phase [2]. It is known that the presence of activated platelets markedly amplifies thrombin generation by the prothrombinase complex. Platelet aggregation, for which thrombin is the most potent stimulator, is effected by the activation of the thrombin receptor. Activated platelets likely provide the principal surfaces on which intrinsic coagulation factors and prothrombinase assemble in vivo. Moreover, the blood coagulation cascade is simultaneously enhanced during the acute phase of cerebral infarction, resulting in thrombin production and fibrin formation [3]. Cerebral arterial thrombosis is thought to be initiated by rupture of atherosclerotic plaque. Platelets adhere to the constituents of the plaque, and platelet aggregation and the formation of thrombin occur rapidly. The presence of activated platelets involving thrombin generation in cerebral infarction remains to be further clarified. The present study in patients with acute cerebral infarction was undertaken to determine whether argatroban, a direct thrombin inhibitor, is effective in inhibiting collagen-induced platelet aggregation. It is well known that argatroban inhibits not only thrombin cleavage of fibrinogen with a Ki of 19 nM, but also thrombin-mediated platelet activation with a Ki of 40 nM [4]. We evaluated whether the sensitivity of platelets to collagen is increased in the presence of a trace amount of thrombin associated on platelets, at a concentration that does not induce platelet aggregation in acute cerebral infarction. The study also measured the inhibitory effect, if any, of the addition of argatroban during platelet hyperactivation induced by collagen.

Acute Disease↗
PubMed1998

Synergistic antithrombotic effects of argatroban and ticlopidine in the rat venous thrombosis model.

Argatroban, a synthetic thrombin inhibitor, and ticlopidine, an anti-platelet agent, are major antithrombotic agents. We investigated the antithrombotic effects of a combination of argatroban and ticlopidine in the rat venous thrombosis model. Argatroban or ticlopidine inhibited thrombus formation in a dose-dependent manner; 50% inhibition (ED50) is obtained with 1.0 mg/kg/h (infusion) argatroban or 30 mg/kg (p.o.) ticlopidine. The combination of argatroban and ticlopidine inhibited thrombus formation in a dose-dependent manner; ED50 is obtained with 0.25 mg/kg/h argatroban plus 10 mg/kg ticlopidine and 0.5 mg/kg/h argatroban plus 3 mg/kg ticlopidine, whereas 0.5 mg/kg/h argatroban alone or 10 mg/kg ticlopidine alone had negligible effect (<20% inhibition). Isobole analysis showed that the antithrombotic effects of the combination of argatroban and ticlopidine involved synergism with potentiation. In contrast, the combination of argatroban and ticlopidine did not prolong the bleeding time synergistically. These data showed that the combination therapy of argatroban and ticlopidine should be clinically beneficial, but the different administration route may restrict the clinical usage.

Animals↗
PubMed2000

Antithrombotic treatment (argatroban vs. heparin) in coronary angioplasty in angina pectoris: effects on inflammatory, hemostatic, and endothelium-derived parameters.

To evaluate the suitability of two anticoagulants (heparin vs. argatroban) as adjunctive drugs during and after elective conventional percutaneous transluminal coronary angioplasty, we compared the changes in inflammatory, hemostatic, and endothelium-derived markers in groups of patients with stable angina treated with the two drugs during percutaneous transluminal coronary angioplasty. Twenty-seven patients were randomly allocated to either group 1 (15 patients who received an empiric dose of heparin and aspirin as anticoagulant), or group 2 (12 patients who received an alternative regimen of argatroban and aspirin). Both drugs were administered as a bolus followed by continuous infusion for 96 hours during and after percutaneous transluminal coronary angioplasty. There were no differences in the inflammatory response induced by percutaneous transluminal coronary angioplasty in both groups, but the fibrinogen concentration significantly decreased during percutaneous transluminal coronary angioplasty in group 2. Decreased platelet counts and increased mean platelet volume were observed during percutaneous transluminal coronary angioplasty in both groups. The levels of prothrombin fragment 1+2 and thrombin antithrombin III complex increased markedly during percutaneous transluminal coronary angioplasty. Group 2 showed a more rapid return to the baseline levels of these two markers than group 1. Secondary fibrinolysis was evidenced by a steep increase of D-dimer after percutaneous transluminal coronary angioplasty in both groups. In contrast to the significant decrease in antithrombin activities during percutaneous transluminal coronary angioplasty in group 1, no marked change in these markers was found in group 2. Although the levels of von Willebrand factor and plasminogen activator inhibitor-1 showed essentially the same changes in both groups during and after percutaneous transluminal coronary angioplasty, more markedly increased levels of tissue type plasminogen activator and type plasminogen activator-plasminogen activator inhibitor-1 complex after percutaneous transluminal coronary angioplasty were found in group 1 than in group 2. While neither drug had any effect on the percutaneous transluminal coronary angioplasty-induced inflammatory response, argatroban may more effectively inhibit the generated thrombin and prevent antithrombin consumption during and after percutaneous transluminal coronary angioplasty.

Aged↗
PubMed2002

Direct thrombin inhibitors in acute coronary syndromes: principal results of a meta-analysis based on individual patients' data.

BACKGROUND: To obtain more reliable and precise estimates of the effect of direct thrombin inhibitors in the management of acute coronary syndromes, including patients undergoing percutaneous coronary intervention, we undertook a meta-analysis based on individual patients' data from randomised trials comparing a direct thrombin inhibitor (hirudin, bivalirudin, argatroban, efegatran, or inogatran) with heparin. METHODS: We included trials that involved at least 200 patients. The primary efficacy outcome was death or myocardial infarction, and the primary safety outcome was major bleeding. Data from individual trials were combined by use of a modified Mantel-Haenszel method. FINDINGS: In 11 randomised trials, 35,970 patients were assigned up to 7 days' treatment with a direct thrombin inhibitor or heparin and followed up for at least 30 days. Compared with heparin, direct thrombin inhibitors were associated with a lower risk of death or myocardial infarction at the end of treatment (4.3% vs 5.1%; odds ratio 0.85 [95% CI 0.77-0.94]; p=0.001) and at 30 days (7.4% vs 8.2%; 0.91 [0.84-0.99]; p=0.02). This was due primarily to a reduction in myocardial infarctions (2.8% vs 3.5%; 0.80 [0.71-0.90]; p<0.001) with no apparent effect on deaths (1.9% vs 2.0%; 0.97 [0.83-1.13]; p=0.69). Subgroup analyses suggested a benefit of direct thrombin inhibitors on death or myocardial infarction in trials of both acute coronary syndromes and percutaneous coronary interventions. A reduction in death or myocardial infarction was seen with hirudin and bivalirudin but not with univalent agents. Compared with heparin, there was an increased risk of major bleeding with hirudin, but a reduction with bivalirudin. There was no excess in intracranial haemorrhage with direct thrombin inhibitors. INTERPRETATION: Direct thrombin inhibitors are superior to heparin for the prevention of death or myocardial infarction in patients with acute coronary syndromes. This information should prompt further clinical development of direct thrombin inhibitors for the management of arterial thrombosis.

Angina, Unstable↗
PubMed1992

Effects of CGS 19755 and dizocilpine (MK 801) on delayed time discrimination performance.

The effects of the competitive NMDA (N-methyl-D-aspartate) receptor antagonist CGS 19755 and the non-competitive NMDA receptor antagonist dizocilpine (MK 801) on time discrimination and short-term memory were investigated in rats trained on a delayed time discrimination task. In a two-lever operant chamber, pressing one lever was correct and reinforced with a food pellet after presentation of a stimulus light for 2 s (SD(short)); pressing the opposite lever was correct after presentation of a stimulus light for 8 s (SD(long)). CGS 19755 (3.0 mg/kg) attenuated performance, decreased nose-pokes (an activity necessary to trigger the presentation of the discriminative stimulus and the presentation of the response levers), and increased response latencies (time from 'opportunity to leverpress' to 'actual leverpress'). The highest dose of dizocilpine (0.2 mg/kg) tested also attenuated performance. Further, the number of nose-pokes and response latencies were not altered by any dose of dizocilpine. With increasing delays, saline-injected animals developed a bias towards reporting an occurrence of an SD(long), independent of the actual stimulus presented. This bias was attenuated or even reversed by CGS 19755 (3.0 mg/kg) and (0.2 mg/kg). Our results suggest that NMDA receptors are directly or indirectly involved in time discrimination performance.

Animals↗
PubMed2002

Combined argatroban and edaravone caused additive neuroprotection against 15 min of forebrain ischemia in gerbils.

We investigated whether or not a combination of the selective thrombin inhibitor, argatroban, and the free radical scavenger, edaravone (MCI-186), ameliorates postischemic hypoperfusion and decreases mortality after 15 min of forebrain ischemia in the gerbil. Argatroban or edaravone alone significantly increased postischemic cerebral blood flow and attenuated brain edema after reperfusion. However, only the combination increased the survival ratio (P<0.05 by Mantel-Cox) and protected the damage of neuronal cells. The present study indicates that anticoagulants and free radical scavengers reciprocally function to inhibit the progression of ischemic cell damage and that a combination of these types of drugs will help to improve the outcomes after cerebral ischemia.

Animals↗
PubMed1998

Focal ischemia enhances the adverse effect potential of N-methyl-D-aspartate receptor antagonists in rats.

Recent clinical trials with non-competitive and competitive N-methyl-D-aspartate (NMDA) receptor antagonists in patients with stroke have shown that these patients develop more adverse effects, particularly psychomimetic effects such as hallucinations and agitation, than normal volunteers at equivalent doses. We therefore examined whether such increased adverse effect potential of NMDA antagonists also occurs in a rat model of permanent focal ischemia. For this purpose, the right middle cerebral artery was occluded under halothane anesthesia, and behavioral alterations in response to the non-competitive NMDA antagonist, MK-801 (dizocilpine), were recorded after recovery from anesthesia. Behavioral alterations in ischemic rats were compared with those in sham-lesioned rats in a blinded fashion. MK-801 (0.4 mg/kg) induced psychomimetic-like stereotyped behaviors which were about twice as intense in ischemic than in non-ischemic rats. A similar trend for enhanced adverse effects was seen with the competitive NMDA antagonist CGS 19755 (Selfotel). Although more NMDA antagonists have to be tested to draw definite conclusions, the present data may indicate that enhanced sensitivity of stroke patients to adverse effects of NMDA antagonists can be predicted by use of a focal ischemia model in rats, thus allowing use of this model for developing novel cytoprotective strategies targeted to minimize glutamatergic excitotoxicity with reduced adverse effect potential.

Animals↗