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At least 19 recordsLinked to original sources
PubMed2007

Complementary effects of thienopyridine pretreatment and platelet glycoprotein IIb/IIIa integrin blockade with eptifibatide in coronary stent intervention; results from the ESPRIT trial.

OBJECTIVES: This analysis sought to investigate the complementary effect of thienopyridine pretreatment and platelet glycoprotein (GP) IIb/IIIa integrin blockade in coronary stent intervention. BACKGROUND: Definitive evidence supporting combined antiplatelet therapy consisting of thienopyridine pretreatment and GP IIb/IIIa receptor blockade in patients undergoing percutaneous coronary intervention (PCI) with stent implantation is limited. METHODS: We retrospectively analyzed clinical outcomes by thienopyridine use in the 2,040 patients randomized to eptifibatide or placebo who underwent PCI in the ESPRIT trial. RESULTS: A total of 901 patients received a loading dose of thienopyridine before PCI (group 1), 123 received thienopyridine pretreatment without a loading dose (group 2), and 1,016 were not treated with thienopyridine before PCI (group 3). The composite incidence of death or myocardial infarction at 30 days was significantly lower in group 1 than in groups 2 and 3 combined (OR, 0.71 [95%CI, 0.52-0.99]; P = 0.0417). A similar trend was seen for the composite of death, myocardial infarction, or urgent target vessel revascularization (unadjusted OR, 0.77 [0.57-1.05]; P = 0.1025). After adjusting for baseline characteristics, these differences were no longer significant. No interactions were identified with eptifibatide assignment for any of the group comparisons. CONCLUSIONS: Pretreatment with a loading dose of thienopyridine lowers the rate of ischemic complications regardless of treatment with a GP IIb/IIIa inhibitor. Conversely, the efficacy of eptifibatide is maintained whether or not a loading dose of a thienopyridine is administered. Optimal outcomes are achieved in patients receiving thienopyridine pretreatment along with platelet GP IIb/IIIa inhibitor therapy.

Aged↗
PubMed2006

Prevalence, predictors, and outcomes of premature discontinuation of thienopyridine therapy after drug-eluting stent placement: results from the PREMIER registry.

BACKGROUND: Although drug-eluting stents (DES) significantly reduce restenosis, they require 3 to 6 months of thienopyridine therapy to prevent stent thrombosis. The rate and consequences of prematurely discontinuing thienopyridine therapy after DES placement for acute myocardial infarction (MI) are unknown. METHODS AND RESULTS: We used prospectively collected data from a 19-center study of MI patients to examine the prevalence and predictors of thienopyridine discontinuation 30 days after DES treatment. We then compared the mortality and cardiac hospitalization rates for the next 11 months between those who stopped and those who continued thienopyridine therapy. Among 500 DES-treated MI patients who were discharged on thienopyridine therapy, 68 (13.6%) stopped therapy within 30 days. Those who stopped were older, less likely to have completed high school or be married, more likely to avoid health care because of cost, and more likely to have had preexisting cardiovascular disease or anemia at presentation. They were also less likely to have received discharge instructions about their medications or a cardiac rehabilitation referral. Patients who stopped thienopyridine therapy by 30 days were more likely to die during the next 11 months (7.5% versus 0.7%, P<0.0001; adjusted hazard ratio=9.0; 95% confidence interval=1.3 to 60.6) and to be rehospitalized (23% versus 14%, P=0.08; adjusted hazard ratio=1.5; 95% confidence interval=0.78 to 3.0). CONCLUSIONS: Almost 1 in 7 MI patients who received a DES were no longer taking thienopyridines by 30 days. Prematurely stopping thienopyridine therapy was strongly associated with subsequent mortality. Strategies to improve the use of thienopyridines are needed to optimize the outcomes of MI patients treated with DES.

Aged↗
PubMed2000

Thienopyridine derivatives (ticlopidine, clopidogrel) versus aspirin for preventing stroke and other serious vascular events in high vascular risk patients.

BACKGROUND: The most widely studied and prescribed antiplatelet agent for the prevention of stroke and other serious vascular events among high vascular risk patients is aspirin. Aspirin inhibits platelet activation by inhibiting platelet cyclooxygenase and thromboxane production, and reduces the odds of a serious vascular event by about a quarter. The thienopyridines (ticlopidine and clopidogrel) inhibit platelet activation by a different mechanism to aspirin (blocking the ADP receptor on platelets), and so may be more effective than aspirin. OBJECTIVES: The objective of this review was to determine the effectiveness and safety of thienopyridine derivatives (ticlopidine and clopidogrel) versus aspirin for the prevention of serious vascular events (stroke, myocardial infarction (MI) or vascular death) in patients at high risk of such events, and specifically in patients with a previous TIA or ischaemic stroke. SEARCH STRATEGY: We searched the Cochrane Stroke Group trials register (most recent search: March 1999) and the Antithrombotic Trialists' database, and also contacted Sanofi pharmaceutical company. SELECTION CRITERIA: All unconfounded, double blind, randomised trials directly comparing ticlopidine or clopidogrel with aspirin in high vascular risk patients. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed trial quality. Additional data were sought from the principal investigators of the largest trial. MAIN RESULTS: Four trials involving a total of 22,656 high vascular risk patients were included. The trials were of high quality and comparable. Aspirin was compared with ticlopidine in three trials (3471 patients) and with clopidogrel in one trial (19,185 patients). Allocation to a thienopyridine was associated with a modest, yet statistically significant, reduction in the odds of a serious vascular event (12. 0% vs 13.0%; OR: 0.91, 95% CI: 0.84 to 0.98; 2p = 0.01), corresponding to the avoidance of 11 (95% CI: 2 to 19) serious vascular events per 1000 patients treated for about two years. There was also a reduction in stroke (5.7% vs 6.4%; OR: 0.88, 95% CI: 0.79 to 0.98; 7 [95% CI: 1 to 13] strokes avoided per 1000 patients treated for two years). Compared with aspirin, thienopyridines produced a significant reduction in the odds of gastrointestinal haemorrhage and other upper gastrointestinal upset, but a significant increase in the odds of skin rash and of diarrhoea. However, the increased odds of skin rash and diarrhoea were greater for ticlopidine than for clopidogrel. Allocation to ticlopidine, but not clopidogrel, was associated with a significant increase in the odds of neutropenia (2.3% vs 0.8%; OR: 2.7, 95% CI: 1.5 to 4.8). In the subset of patients with TIA/ischaemic stroke, the results were similar to those for all patients combined. However, since these patients are at particularly high risk of stroke, allocation to a thienopyridine was associated with a larger absolute reduction in stroke (10.4% vs 12.0%; OR: 0.86, 95% CI: 0.75 to 0.97; 16 [95% CI: 3 to 28] strokes avoided per 1000 patients treated for two years). REVIEWER'S CONCLUSIONS: The available randomised evidence shows that the thienopyridine derivatives are modestly but significantly more effective than aspirin in preventing serious vascular events in patients at high risk (and specifically in TIA/ischaemic stroke patients), but there is uncertainty about the size of the additional benefit. The thienopyridines are also associated with less gastrointestinal haemorrhage and other upper gastrointestinal upset than aspirin, but an excess of skin rash and diarrhoea. The risk of skin rash and diarrhoea is greater with ticlopidine than with clopidogrel. Ticlopidine, but not clopidogrel, is associated with an excess of neutropenia and of thrombotic thrombocytopenic purpura.

Aspirin↗
PubMed2005

Endothelial action of thienopyridines and thienopyrimidinones in the isolated guinea pig heart.

Antiplatelet thienopyridines (ticlopidine, clopidogrel) and their thienopyrimidinone congeners, induce prostacyclin-dependent thrombolysis in vivo. Here we tested whether thienopyridines (ticlopidine, clopidogrel, and its enantiomer without antiplatelet properties) and structurally related thienopyrimidinones release NO from coronary endothelium in the isolated guinea pig heart, perfused according to Langendorff technique. The involvement of endothelium-derived NO in coronary vasodilation induced by these agents was assessed by effect of L-N(G)-nitro-arginine methyl ester (L-NAME). In addition, effect of thienopyridines or thienopyrimidinones on nitrite accumulation in cultured endothelium was assayed. Tienopyridines (10-100 micromol L(-1)) and thienopyrimidinones (10-30 micromol L(-1)) produced concentration-dependent increase in coronary flow comparable to that induced by acetylcholine (0.1 micromol L(-1)) or bradykinin (3 nmol L(-1)) which was inhibited by L-NAME (by 50-70%) but not by indomethacin. Furthermore, thienopyridines and thienopyrimidinones caused NO release from cultured endothelial cells. In conclusion, both thienopyridines independently from their antiplatelet action and their thienopyrimidinone congeners that are devoid of antiplatelet action stimulate coronary endothelium to release NO. Endothelial action of these compounds merits further investigation.

Animals↗
PubMed2000

Thienopyridines or aspirin to prevent stroke and other serious vascular events in patients at high risk of vascular disease? A systematic review of the evidence from randomized trials.

BACKGROUND AND PURPOSE: Aspirin is the most widely studied and prescribed antiplatelet drug for patients at high risk of vascular disease. We aimed to establish how the thienopyridines (ticlopidine and clopidogrel) compare with aspirin in terms of effectiveness and safety. METHODS: We did a systematic review of all unconfounded randomized trials comparing either ticlopidine or clopidogrel with aspirin for patients at high risk of vascular disease. The primary outcome was vascular events (stroke, myocardial infarction, or vascular death). Adverse outcomes were intracranial and extracranial hemorrhage, upper and lower gastrointestinal disturbances, neutropenia, thrombocytopenia, and skin rash. RESULTS: In 4 trials among 22 656 patients (including 9840 presenting with a transient ischemic attack/ischemic stroke), the thienopyridines reduced the odds of a vascular event by 9% (odds ratio 0.91, 95% CI 0.84 to 0. 98; 2P=0.01), preventing 11 (95% CI 2 to 19) events per 1000 patients treated for approximately 2 years. The thienopyridines produced significantly less gastrointestinal hemorrhage and upper gastrointestinal upset (indigestion/nausea/vomiting) than did aspirin. Both thienopyridines increased the odds of skin rash and of diarrhea (ticlopidine by approximately 2-fold and clopidogrel by approximately one third). Only ticlopidine increased the odds of neutropenia. CONCLUSIONS: The thienopyridines appear modestly more effective than aspirin in preventing serious vascular events in high-risk patients. Clopidogrel appears to be safer than ticlopidine and as safe as aspirin, making it an appropriate, but more expensive, alternative antiplatelet drug for patients unable to tolerate aspirin. However, there is insufficient information to determine which particular types of patients would benefit most, and which least, from clopidogrel instead of aspirin.

Aspirin↗
PubMed2000

Thrombolysis by thienopyridines and their congeners.

We propose that anti-platelet thienopyridines, such as ticlopidine or clopidogrel, are thrombolytic owing to endothelial release of prostacyclin (PGI2) and tissue plasminogen activator (t-PA). In this study we used anaesthetised Wistar rats with extracorporal circulation in which arterial blood superfused thrombi which adhered to a strip of collagen. Weight of thrombi was continuously monitored. When administered intravenously, clopidogrel or its R enantiomer deprived of anti-platelet action, both at doses of 3 mg x kg(-1), produced lost in weight of thrombi by 14.1 +/- 1.3% or 16.0 +/- 1.4% (n = 9), and at doses 10 mg x kg(-1) by 28.3 +/- 2.3% or 30.4 +/- 1.9% (n = 8), respectively. Maximum of thrombolysis occurred 30-45 min following the drug administration. Ticlopidine at a dose of 30 mg x kg(-1) reduced weight of thrombi by 33.7 +/- 1.7% (n = 32). Thrombolytic action of ticlopidine was accompanied by a rise in 6!keto-PGF1alpha blood levels from 0.42 +/- 0.10 to 1.58 +/- 0.29 ng x ml(-1) and t-PA antigen plasma levels from 4.70 +/- 1.00 to 12.90 +/- 1.15 ng x ml(-1) (n = 7). Five out of eleven tested thienopyridine congeners with pyrimidine or pyrimidinone instead of pyridine rings had thrombolytic potencies similar to that of clopidogrel (ED30s at a range of 6.2-11.4 mg x kg(-1)). A substantial increase in thrombolytic potency (ED30s at a range of 0.3-2.1 mg x kg(-1)) was observed for congeners in which thienyl ring was condensed with an additional cyclopentyl, cyclohexyl or cycloheptyl structures or in which thienopyridine complex was replaced for a pyridopyrimidine one. We claim that thienopyridines, independently of their delayed anti-platelet action, do produce immediate thrombolysis in vivo. This new activity emulates capacity of their native, non-metabolised molecules to release prostacyclin and tissue plasminogen activator. We have also shown that structural changes in molecules of thienopyridines may intensify their thrombolytic potency.

Animals↗
PubMed2005

Bleeding complications associated with combinations of aspirin, thienopyridine derivatives, and warfarin in elderly patients following acute myocardial infarction.

BACKGROUND: Combinations of aspirin with thienopyridine derivatives (clopidogrel bisulfate or ticlopidine hydrochloride) and/or warfarin sodium are increasingly being used in various cardiac conditions. However, little is known about the bleeding risks associated with these combinations, particularly in elderly individuals at the population level. This study estimates the bleeding risks associated with combinations of aspirin, thienopyridine derivatives, and warfarin in elderly patients. METHODS: We conducted a population-based observational cohort study using linked administrative databases. A total of 21,443 elderly survivors of acute myocardial infarction between 1996 and 2000 were studied. Patients were divided into 5 groups according to drug exposure: aspirin alone, warfarin alone, aspirin plus a thienopyridine derivative (antiplatelet combination), aspirin plus warfarin (anticoagulant combination), and aspirin plus warfarin plus a thienopyridine derivative (3-drug combination). Hospitalizations for bleeding events were examined. RESULTS: Hospitalizations for bleeding were observed in 1428 patients (7%). Compared with rates of patients receiving aspirin alone (0.03 per patient-year), rates of bleeding were higher among patients receiving the antiplatelet combination (0.07 per patient-year), the anticoagulant combination (0.08 per patient-year), and the 3-drug combination (0.09 per patient-year). Compared with aspirin alone, the adjusted odds ratios (95% confidence intervals) for bleeding were 1.65 (1.02-2.73) for patients receiving the antiplatelet combination and 1.92 (1.28-2.87) for patients receiving the anticoagulant combination. Only 1 of 141 patients in the 3-drug combination group had a bleeding event. CONCLUSION: In practice, antiplatelet and anticoagulant combinations lead to modest increases in bleeding risk in elderly patients, but the overall risk is small.

Age Factors↗
PubMed2000

The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial programme; rationale, design and baseline characteristics including a meta-analysis of the effects of thienopyridines in vascular disease.

BACKGROUND: Other than aspirin, there are few oral antithrombotic treatments with proven efficacy in patients with acute coronary syndrome. In this report, we present the rationale, design and baseline characteristics of the Clopidogrel in Unstable angina to prevent Recurrent ischaemic Events (CURE) trial, which includes a meta-analysis of the effects of thienopyridines in patients with vascular disease. METHODS AND RESULTS: Combined data from randomized trials of thienopyrindines in patients with atherosclerotic disease demonstrated a 29% reduction in vascular events when compared with placebo/control (n=2392) (OR 0.71, 95% CI 0.58-0.86, P=0.0006) and a 10% reduction in vascular events when compared with aspirin (n=22 254) (OR 0.91, 95% Cl 0.84-0.99, P=0.039). Similarly, randomized trials of aspirin plus thienopyridines in patients undergoing intracoronary stenting, demonstrated a marked benefit of aspirin plus ticlopidine in reducing death or myocardial infarction compared with aspirin alone (OR 0.23, 95% CI 0.11-0.49, P=0.0001) or aspirin plus warfarin (OR 0.51, 95% CI 0.33-0.78, P=0.002). Whether these benefits extend to the much larger population of patients with acute coronary syndrome is unknown. CURE is an international, randomized, double-blind trial, in which patients with acute coronary syndrome will be randomized to receive either a bolus dose of clopidogrel (300 mg) followed by 75 mg per day for 3-12 months, or matching placebo. Both groups will receive aspirin. The co-primary efficacy end-points of CURE are: (1) the composite of cardiovascular death, myocardial infarction or stroke; and (2) the composite of cardiovascular death, myocardial infarction, stroke or refractory ischaemia. CURE will recruit approximately 12 500 patients with acute coronary syndrome (from 28 countries) and its power to detect moderate treatment benefits will be in the region of 80-90%, while maintaining an overall type I error (alpha) of 0.05. The baseline characteristics of the study population are consistent with at least a moderate risk group of patients with acute coronary syndrome. CONCLUSIONS: Randomized trials of thienopyridines in patients with vascular disease demonstrate that thienopyridines are effective in reducing vascular events when compared with placebo/control or aspirin, as well as when used in combination with aspirin in patients undergoing intracoronary stent implantation. The CURE trial is a large international study to determine if acute and long-term treatment with the combination of clopidogrel and aspirin is superior to aspirin alone in patients with acute coronary syndrome.

Angina, Unstable↗
PubMed2002

The thienopyridines.

Platelet adhesion, activation, and aggregation are key processes in the pathogenesis of coronary disease. Inhibition of these processes forms the cornerstone of therapy for coronary artery disease and particularly of acute coronary syndromes (ACS). Aspirin was the only available antiplatelet therapy for over 100 years, and it improves clinical outcome in a wide range of clinical situations. However, aspirin only inhibits platelet activation mediated by thromboxane A2, allowing platelet activation to occur through innumerable other pathways. As a result, adverse ischemic events are common when aspirin alone is used for the treatment of coronary disease, including ACS, during coronary interventions (particularly during stent implantation), and following coronary vascular brachytherapy (VBT). In these clinical situations, the presence of either thrombus, deep injury to the vessel wall, or delayed vascular reendothelialization leads to intense and often prolonged platelet activation, overwhelming the relatively weak effects of aspirin. The development of the thienopyridines, a class of antiplatelet drugs that reduce adenosine diphosphate-(ADP) mediated platelet activation, has significantly improved clinical outcomes in many coronary conditions. Widespread use of ticlopidine, the first available thienopyridine, was limited by frequent side-effects, including life-threatening neutropenia and thrombotic thrombocytopenic purpura. Following the introduction of clopidogrel, a thienopyridine with an excellent safety profile, dual antiplatelet therapy with aspirin and clopidogrel has become standard therapy following coronary stent implantation and coronary VBT. In patients presenting with ACS, the addition of clopidogrel to aspirin has now been proven to reduce ischemic events. The most important limitation of dual antiplatelet therapy is the increased bleeding risk as compared with aspirin alone, particularly in patients undergoing coronary artery bypass grafting during the index hospitalization. However, for many patients with ACS, combination therapy is appropriate.

Clopidogrel↗
PubMed2006

Thienopyridines in percutaneous coronary interventions: standard procedures and high risk subsets.

Due to the significant clinical and economic consequences of subacute stent thrombosis and the use of more complex devices (brachytherapy, drug eluting stents) in a variety of clinical situations (i.e. acute coronary syndromes), initiation and duration of a combined antiplatelet therapy using aspirin and a thienopyridine drug has become an issue of ongoing discussion in interventional cardiology. This review will provide a short introduction into the pathophysiology of stent thrombosis before standard procedures and critical issues on the use of thienopyridines in the setting of coronary interventions are discussed. Furthermore, clinically relevant issues that are not clearly covered by recommendations or guidelines like thienopyridines after coronary interventions in patients on chronic oral anticoagulation are also addressed.

Angioplasty, Balloon, Coronary↗
PubMed2003

Resistance to thienopyridines: clinical detection of coronary stent thrombosis by monitoring of vasodilator-stimulated phosphoprotein phosphorylation.

We carried out a prospective evaluation of a new vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay in order to detect patients with high-risk coronary subacute stent thrombosis (SAT) despite thienopyridine regimen. Twenty healthy donors (group 1) without any medication were compared to 16 stented patients (group 2) treated by ticlopidin or clopidogrel initiated 2 days before stenting and aspirin (250 mg/day). No difference in platelet reactivity was noted between group 1 and group 2 treated only with aspirin (72.00% +/- 4.17% vs. 69.73% +/- 5.62%, respectively; P = NS). Significant differences were found between patients of group 2 treated with aspirin alone (69.73% +/- 5.62%), after 2.0 days (60.14% +/- 9.60%; P < 0.05), and after 4.8 +/- 1.3 days (48.37% +/- 11.19%; P < 0.05) with thienopyridine-aspirin. Among 1,684 consecutive stented patients, 16 patients who presented an SAT (group 3) were compared with 30 other stented patients free of SAT (group 4). We found a significant difference between group 3 (63.28% +/- 9.56%) and group 4 (39.80% +/- 10.9%; P < 0.0001). VASP phosphorylation analysis may be useful for the detection of coronary SAT.

Aged↗
PubMed2006

Short-term triple therapy with aspirin, warfarin, and a thienopyridine among patients undergoing percutaneous coronary intervention.

OBJECTIVES: To assess bleeding complications among patients undergoing percutaneous coronary intervention (PCI) and receiving triple therapy of warfarin, aspirin, and a thienopyridine. BACKGROUND: Triple therapy of warfarin, aspirin, and a thienopyridine is strongly discouraged, given the potential risk of bleeding complications. METHODS AND RESULTS: Post-PCI patients receiving triple therapy thereafter underwent assessment for bleeding complications. Continuous variables are presented as median (25th-75th percentiles). The study group included 180 patients (80% males; age 65 (52, 75.5)). PCI was on an urgent/emergent basis in 86.6%. The main indications for warfarin use were left ventricular mural thrombus and atrial fibrillation (46.9 and 36.9% respectively). Glycoprotein IIb/IIIa receptor antagonists were used in 47.7%. Post-PCI triple therapy duration was 30 days (30, 30). During the post-triple therapy, 104 patients (57.8%) continued treatment with warfarin and aspirin for 376 days (150, 775). During the triple therapy period, 20 patients developed bleeding complications, (mean INR 2.1 +/- 0.7 at 7 (6, 8.5) days post-PCI): 2 major groin hematoma (initial phase of warfarin treatment during overlap with heparin) and 18 minor. During post-triple therapy, primarily under warfarin and aspirin, 19 patients developed bleeding complications: 1 major and 18 minor. CONCLUSION: Short-term triple therapy after PCI was not associated with prohibitively high bleeding complication rates, and thus should be favorably considered in patients with a clear indication for warfarin use.

Aged↗
PubMed1989

Agonist and antagonist properties of benzazepine and thienopyridine derivatives at the D1 dopamine receptor.

Nine structurally related 1-phenyl-1H-3-benzazepine derivatives and two thienopyridines were tested for agonist and antagonist properties at the adenylate cyclase-coupled D1 dopamine receptor in homogenates of the striatum of the rat. The benzazepines SK&F 77434 and SK&F 82958, both of which contain a catechol ring, were agonists; the intrinsic activity of SK&F 77434 was similar to that of SK&F 38393, whereas SK&F 82958 was a full agonist. The remaining benzazepines inhibited the stimulation of adenylate cyclase by dopamine. Antagonist potency depended on the nature of the substituent at position 7 of the benzazepine molecule, 7-halogen compounds being the most potent. The Ki values, obtained from analysis of the antagonism of dopamine-stimulated adenylate cyclase, were significantly correlated with the Ki values for displacement of D1 ligands in binding experiments. Furthermore, antagonist activity of the resolved racemic benzazepine SK&F 83566 resided almost exclusively in the R-enantiomer. The thienopyridine derivatives SK&F 89641 and SK&F 89145 were partial agonists with greater efficacies than SK&F 38393.

Adenylyl Cyclase Inhibitors↗
PubMed2002

Anti-angiogenic effects of the thienopyridine SR 25989 in vitro and in vivo in a murine pulmonary metastasis model.

Neovascularisation is a key step in tumour growth and establishment of distant metastases. We have recently demonstrated that the thienopyridine SR 25989 an enantiomer of the anti-aggregant clopidogrel (Plavix) lacking anti-aggregant activity, inhibits endothelial cell proliferation in vitro by increasing the expression of endogenous thrombospondin-1, a natural potent inhibitor of angiogenesis. The anti-angiogenic effect of SR 25989 was further assessed in vitro in a quantitative assay of angiogenesis comprising a fragment of rat aorta embedded in a fibrin gel and in vivo in a pulmonary metastatic model using C57BL/6 mice inoculated in the foot pad with the highly metastatic melanoma cell line B16 F10. SR 25989 induced a dose dependent inhibition of spontaneous microvessel development in vitro reaching half maximal inhibition at around less than 50 microM and caused platelet derived growth factor induced angiogenesis to regress as a function of thienopyridine concentration. In vivo, SR 25989 did not alter significantly the growth rate of the primary tumour in the foot pad and did not inhibit development of inguinal nodes which appeared after amputation. However, the number and size of lung metastases were reduced in treated animals when examined at the time of sacrifice. In addition, the few metastases over 1 mm3 did not show any neovascularisation, as confirmed by negative von Willebrand immunostaining and in contrast to intense vascularisation seen in metastases developed by control mice. These results confirm that SR 25989 possesses potent anti-angiogenic properties and is able to inhibit metastatic dissemination and growth. The lack of effect on the primary tumour and inguinal nodes illustrates the complexity of the mechanisms involved in tumoural neo-angiogenesis and points out the possibility for distinct processes leading to neovascularisation in primary tumour as opposed to metastases.

Angiogenesis Inhibitors↗
PubMed2003

The thienopyridine derivatives (platelet adenosine diphosphate receptor antagonists), pharmacology and clinical developments.

The thienopyridines, ticlopidine and clopidogrel, are antiplatelet drugs. They are prodrugs and are metabolised in the liver to active metabolites that are non-competitive antagonists of the platelet adenosine diphosphate receptor, P2Y12. Inhibition of platelet aggregation by these drugs is delayed until 24-48 h after administration, with maximal inhibition achieved after 3-5 days. Recovery of platelet function after drug withdrawal is slow (7-14 days). Ticlopidine and clopidogrel are effective in preventing atherothrombotic events in cardiovascular, cerebrovascular and peripheral vascular disease. Gastrointestinal side effects and skin rashes are common. However, neutropenia and thrombotic thrombocytopenic purpura are significant and sometimes fatal adverse effects of ticlopidine. Clopidogrel appears to offer several advantages over ticlopidine: a more rapid onset of action and a lower incidence of neutropenia and thrombotic thrombocytopenic purpura.A combination of clopidogrel and aspirin has become standard for antithrombotic therapy in cardiovascular disease. The anaesthetic considerations of patients taking the thienopyridine compounds are discussed.

Anesthesia↗
PubMed2004

Stent thrombosis in patients treated with thienopyridines: clinical description of 10 cases.

Subacute stent thrombosis (SAST) is a major thrombotic complication of coronary stenting. Its occurrence has been substantially reduced by thienopyridine treatment. However, information on clinical profile of patients with SAST in clopidogrel era is limited. In order to define the incidence and factors predisposing to stent thrombosis, we analyzed the computerized angiographic database of three interventional cardiology centers. Out of a total number of 5903 percutaneous coronary interventions (PCIs) with stent implantation, we found 10 patients with SAST (0.17%). The indication for PCI was usually an early invasive approach (90%) during an acute coronary syndrome. All patients were treated with an apparently optimal antithrombotic regimen (90% received heparin or LMWH and 70% received IIb/IIIa receptor inhibitors and all given aspirin). In each of the patients, we could identify high-risk angiographic findings. SAST presentation was always clinically significant with definite myocardial infarction in 100% of cases. 80% of cases occurred during the first six days post PCI. Two patients had a recurrent event. Finally, despite earlier reports of atorvastatin-mediated inhibition of clopidogrel activation we did not find any patient with SAST taking both drugs. Thus, patients with stent thrombosis during thienopyridine treatment usually exhibit high-risk angiographic features. Prospective studies should be performed to elucidate drug interactions that may reduce clopidogrel efficacy and contribute to stent thrombosis.

Aged↗
PubMed2001

Molecular identification and characterization of the platelet ADP receptor targeted by thienopyridine antithrombotic drugs.

ADP plays a critical role in modulating thrombosis and hemostasis. ADP initiates platelet aggregation by simultaneous activation of two G protein-coupled receptors, P2Y1 and P2Y12. Activation of P2Y1 activates phospholipase C and triggers shape change, while P2Y12 couples to Gi to reduce adenylyl cyclase activity. P2Y12 has been shown to be the target of the thienopyridine drugs, ticlopidine and clopidogrel. Recently, we cloned a human orphan receptor, SP1999, highly expressed in brain and platelets, which responded to ADP and had a pharmacological profile similar to that of P2Y12. To determine whether SP1999 is P2Y12, we generated SP1999-null mice. These mice appear normal, but they exhibit highly prolonged bleeding times, and their platelets aggregate poorly in responses to ADP and display a reduced sensitivity to thrombin and collagen. These platelets retain normal shape change and calcium flux in response to ADP but fail to inhibit adenylyl cyclase. In addition, oral clopidogrel does not inhibit aggregation responses to ADP in these mice. These results demonstrate that SP1999 is indeed the elusive receptor, P2Y12. Identification of the target receptor of the thienopyridine drugs affords us a better understanding of platelet function and provides tools that may lead to the discovery of more effective antithrombotic therapies.

Adenosine Diphosphate↗
PubMed1999

Thienopyridines: effects on cultured endothelial cells.

In cultured endothelial cells harvested from human umbilical vein (HUVEC) or bovine aorta (BAEC) the 30 min incubation with calcium ionophore A 23187 (1 microM) or ticlopidine (100 microM) caused an increase in nitrite generation in HUVEC from basal 227 +/- 37 to 372 +/- 60 or to 325 +/- 33 pmoles per 10(6) cells, respectively, and in BAEC from basal 182 +/- 17 to 378 +/- 18 or to 423 +/- 66 pmoles per 106 cells (n = 6), respectively. Calcium ionophore A 23187 (1 microM) or ticlopidine (100 microM) next to 30 min incubation with BAEC increased release of 6-keto-PGF 1alpha from basal level of 9.4 +/- 1.8 to 96.2 +/- 5.1 or to 99.5 +/- 10.2 pmoles per 10(6) cells, respectively. The pretreatment with aspirin (300 microM) cut down this rise to 4.2 +/- 0.1 pmoles per 10(6) cells (n = 8). Basal cytoplasmic calcium levels, [Ca2+]i, in immortalised HUVEC cell line - ECV304, HUVEC and BAEC were 47.7 +/- 3.3 nM (n = 53), 68.3 +/- 5.0 nM (n = 30) and 53.1 +/- 3.0 nM (n = 15), respectively. In these cultured endothelial cells calcium ionophore A 23187 (0.1 microM) produced net maximum rise in [Ca2+]i by 157 +/-27 nM (n = 16)[ ECV304], by 107 +/- 58 nM (n=4) [HUVEC], and by 231.0 +/- 41.3 nM (n = 8) [BAEC], respectively, while ticlopidine (30 microM) produced net maximum rise in [Ca2+]i by 30.0 +/- 3.2 nM (n=9)[ECV304], 48.8 +/- 15.6 nM (n = 4)[HUVEC] and 28.4 +/- 5.4 nM (n = 8)[BAEC], respectively. Effect of ticlopidine on [Ca2+]i was not only weaker than that of calcium A 23187 but also its maximum appeared after a lag period that was 2 3 times longer than that for A23187. In ECV304 clopidogrel at concentrations of 10, 30 and 100 microM produced maximum increment of [Ca2+]i by 16.5 +/- 3.8 nM (n = 7), 47.0 +/- 6.9 nM (n = 8) and 67.2 +/- 8.3 nM (n = 8), respectively. Incubation of BAEC with A23187 (microM), ticlopidine or clopidogrel (100 microM) for 2 h did not influence viability of cultured endothelial cells. We claim that thienopyridines, independently of their delayed anti-platelet properties ex vivo do release NO and PGI2 from cultured endothelial cells in vitro. The above endothelial action of thienopyridines might be mediated by a rise in [Ca2+]i, however, this possibility has not been proved.

6-Ketoprostaglandin F1 alpha↗