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David C Sane

Publications and source records attributed to David C Sane.

At least 19 recordsLinked to original sources
PubMed2007

Roles of transglutaminases in cardiac and vascular diseases.

All transglutaminases share the common enzymatic activity of transamidation, or the cross-linking of glutamine and lysine residues to form N epsilon (gamma-glutamyl) lysyl isopeptide bonds. The plasma proenzyme factor XIII is responsible for stabilizing the fibrin clot against physical and fibrinolytic disruption. Another member of the transglutaminase family, tissue transglutaminase or TG2 is abundantly expressed in cardiomyocytes, vascular cells and macrophages. The transglutaminases have a variety of functions independent of their transamidating activity. For example, TG2 binds and hydrolyzes GTP, thereby fostering signal transduction by several G protein coupled receptors. Accumulating evidence points to novel roles for factor XIII and TG2 in cardiovascular biology including: (a) modulating platelet activity, (b) regulating glucose control, (c) contributing to the development of hypertension, (d) influencing the progression of atherosclerosis, (e) regulating vascular permeability and angiogenesis (f) and contributing to myocardial signaling, contractile activity and ischemia/reperfusion injury. In this review, we summarize the cardiovascular biology of two members of the family of transglutaminases, Factor XIII and TG2.

Animals↗
PubMed2006

Effect of genetic variations in platelet glycoproteins Ibalpha and VI on the risk for coronary heart disease events in postmenopausal women taking hormone therapy.

Millions of women still use postmenopausal hormone therapy (HT). We genotyped 2090 women in Heart and Estrogen/progestin Replacement Study for functional polymorphisms in GP1BA and GP6 and assessed the coronary heart disease (CHD) event rate over 5.8 years of follow-up. In patients receiving placebo, there was an increased CHD death/myocardial infarction (MI)/unstable angina (UA) event rate in carriers of the GP1BA -5C allele (adjusted [adj] P = .006). HT increased the hazard ratio (HR) of CHD events in patients with the GP1BA -5TT genotype by 16% and reduced the HR in patients with the TC+CC genotypes by 46% (adj interaction P < .001). HT reduced the HR in patients with the GP6 13254TT genotype by 17% but increased the HR in patients with the TC+CC genotypes by 35% (adj interaction P < .001). Furthermore, HT increased the HR of CHD events in patients with the GP1BA -5TT plus GP6 13254TC+CC genotypes by 57% and reduced the HR in patients with the GP1BA -5TC+CC plus GP6 13254TT genotypes by 55% (adj interaction P < .001). In postmenopausal women with established CHD, these polymorphisms of platelet genes were predictors of CHD events and significantly modified the effects of HT on CHD risk. It will be important to replicate these findings in other studies.

Aged↗
PubMed2006

Angiotensin II type 1 receptor blockade prevents alcoholic cardiomyopathy.

BACKGROUND: Activation of the renin-angiotensin system (RAS) may contribute to the development of alcoholic cardiomyopathy. We evaluated the effect of angiotensin II (Ang II) type 1 receptor (AT1) blockade on the development of alcoholic cardiomyopathy. METHODS AND RESULTS: We serially evaluated left ventricular (LV) and cardiomyocyte function and the RAS over 6 months in 3 groups of instrumented dogs. Eight animals received alcohol (once per day orally, providing 33% of total daily caloric intake); 6 received alcohol and irbesartan (5 mg.kg(-1).d(-1) PO); and 8 were controls. Compared with controls, alcohol ingestion caused sustained RAS activation with progressive increases in plasma levels of Ang II, renin activity, LV angiotensin-converting enzyme activity, and LV myocyte Ang II AT(1) receptor expression. The RAS activation was followed by a progressive fall in LV contractility (E(ES), alcohol-fed dogs 3.9+/-0.8 versus control dogs 8.1+/-1.0 mm Hg/mL); reductions in the peak velocity of myocyte shortening (78.9+/-5.1 versus 153.9+/-6.2 microm/s) and relengthening; and decreased peak systolic Ca2+ transient ([Ca2+]iT) and L-type Ca2+ current (I(Ca,L); P<0.05). Irbesartan prevented the alcohol-induced decreases in LV and myocyte contraction, relaxation, peak [Ca2+]iT, and I(Ca,L). With alcohol plus irbesartan, plasma Ang II, cardiac angiotensin-converting enzyme activity, and AT1 remained close to control values. CONCLUSIONS: Chronic alcohol consumption produces RAS activation followed by progressive cardiac dysfunction. The cardiac dysfunction is prevented by AT1 receptor blockade.

Alcoholism↗
PubMed2006

Nicotine upregulates the expression of P2Y12 on vascular cells and megakaryoblasts.

BACKGROUND: P2Y12 is the major platelet receptor that mediates ADP-induced aggregation. P2Y12 is also expressed by vascular cells. The factors that regulate P2Y12 expression have not been determined. Since nicotine (NIC) has effects on platelet activation and vascular function, and because nicotinic and purinerigic receptors may interact, we determined whether nicotine altered P2Y12 expression. METHODS: Four cell lines (human coronary artery endothelial cells, HCAEC; human umbilical vein endothelial cells, HUVEC; human aortic smooth muscle cells, HASMC; and human megakaryoblastic cells, MEG-01) were cultured in the absence or presence of nicotine. Immunoblotting for P2Y12, P2Y2, and actin was performed. RESULTS: Nicotine, at concentrations of 0.1-1.0 microM, induced P2Y12 (but not P2Y2) expression in all the four cell lines. HASMC exhibited the greatest induction with a sixfold mean increase in P2Y12 expression in response to 0.25 microM nicotine. The induction was inhibited by nicotinic acetylcholine receptor antagonists. Healthy smokers were observed to have higher P2Y12 expression in platelet lysates compared to non-smokers. CONCLUSION: Nicotine induces the expression of P2Y12 in vascular cells and megakaryoblasts, and is mediated by nicotinic acetylcholine receptors. Smokers exhibit higher platelet P2Y12, possibly mediated via nicotine. These results may contribute to a better understanding of the effects of cigarette smoking on platelet activation and the vessel wall. CONDENSED ABSTRACT: The factors that regulate the expression of P2Y12, the platelet ADP receptor, have not been determined. Four cell lines (human coronary artery endothelial cells, HCAEC; human umbilical vein endothelial cells, HUVEC; human aortic smooth muscle cells, HASMC; and human megakaryoblastic cells, MEG-01) were cultured in the absence or presence of nicotine. Nicotine, at concentrations of 0.1-1.0 microM, induced P2Y12 expression in all the four cell lines. HASMC exhibited the greatest induction with a sixfold mean increase in P2Y12 expression in response to 0.25 microM nicotine. The induction was inhibited by nicotinic acetylcholine receptor antagonists. Healthy smokers were observed to have higher P2Y12 expression in platelet lysates compared to non-smokers. These results may contribute to a better understanding of the effects of cigarette smoking on platelet activation and the vessel wall.

Adult↗
PubMed2006

Valsartan inhibits platelet activity at different doses in mild to moderate hypertensives: Valsartan Inhibits Platelets (VIP) trial.

BACKGROUND: Previous in vitro studies have suggested that valsartan produces significant inhibition of human platelets, probably targeting angiotensin I platelet receptors. To test whether valsartan inhibits platelet activity in mild to moderate hypertensives we conducted the randomized Valsartan Inhibits Platelets (VIP) trial. METHODS AND RESULTS: Seventy-five patients with mild to moderate hypertension were randomized to valsartan 80 (n = 25), valsartan 160 (n = 29), or valsartan 320 mg/d (n = 21) for 9 weeks. Platelet function was assessed at baseline, week 5, and week 9 by aggregometry, flow cytometry, and cartridge-based analyzer. Independently of dose and duration, valsartan provided early sustained significant inhibition of adenosine diphosphate-induced platelet aggregation, decreased shear-induced activation measured with PFA-100 analyzer, and diminished expression of GP IIb/IIIa activity measured by PAC-1 antibody, GPIb (CD42b), vitronectin receptor (CD51/61), P-selectin (CD62p), lysosome-associated membrane protein (CD107a), and CD40-ligand (CD154). The antiplatelet properties of valsartan were more profound in patients with diabetes (n = 28) when compared with the nondiabetic group (n = 47). In subgroup analyses of patients with diabetes there appeared to be stronger inhibition of the platelet receptors, a significant decrease of adenosine diphosphate- and collagen-induced platelet aggregation, and more profound inhibition of GP IIb/IIIa activity. CONCLUSIONS: In the randomized VIP trial, valsartan produced sustained inhibition of platelet aggregation and major platelet receptors. The antiplatelet properties of valsartan were not dose or time dependent. In subgroup analyses patients with diabetes with mild to moderate hypertension tended to have greater platelet inhibition, a finding which, if confirmed in future studies suggests possible additional advantages for using valsartan in this high-risk population.

Aged↗
PubMed2006

Unfractionated heparin reduces the anti-platelet effects of abciximab but not eptifibatide during PCI.

In 29 patients undergoing percutaneous coronary intervention (PCI), we obtained blood samples at baseline, 10 minutes after standard weight-based abciximab (n=15) or double-bolus eptifibatide (n=14) and 5 minutes after unfractionated heparin (UFH; 70 U/kg bolus). The median percent inhibition was significantly higher in the eptifibatide group compared with the abciximab group both before (96.5% [94-100] vs. 85% [77-89.5] [adenosine diphosphate; ADP]; 89.5% [84-95] vs. 59% [37.5-76.5] [thrombin receptor agonist peptide; TRAP], p<0.001 for both) and after UFH (95% [93-100] vs. 79% [68.8-87.5] [ADP]; 82% [77-93] vs. 51% [34.5-71.3] [TRAP], p<0.001 for both). Addition of UFH significantly reduced platelet inhibition in the abciximab group (85% [77-89.5] vs. 79% [68.8-87.5] [ADP]; 59% [37.5-76.5] vs. 51% [34.5-71.3] [TRAP], p<0.05 for both) but not in the eptifibatide group (96.5% [94-100] vs. 95% [93-100] [ADP]; 89.5% [84-95] vs. 82% [77-93] [TRAP], p=ns for both). Eptifibatide achieved superior platelet inhibition before but especially after UFH compared with abciximab.

Abciximab↗
PubMed2006

PCI with and without abciximab after upstream eptifibatide use: outcomes in high-risk patients.

BACKGROUND: Abciximab is often used to treat high-risk patients during percutaneous coronary intervention (PCI). Recent data indicate, however, that upstream and postprocedural treatment with low-dose glycoprotein (GP) IIb/IIIa inhibitors may be more beneficial than abciximab during and after PCI. Whether abciximab can be used safely or effectively during PCI for high-risk patients after upstream treatment with eptifibatide in patients with acute coronary syndromes (ACS) is not known. METHODS: Clinical outcomes were evaluated in 289 patients with ACS who had upstream treatment with eptifibatide, and abciximab (EA) during PCI, and compared to 560 ACS patients who had both upstream and interventional treatment with eptifibatide (EE). RESULTS: Bleeding and vascular complications of the two groups were similar. Overall, 1-year major adverse cardiac event (MACE) rates were similar: 26.0% in the EA group and 25.2% in the EE group; p = 0.82. In patients with unstable angina, the hazard of MACE at 1 year was higher with EA than EE, 1.98 (1.23-3.18), due to significantly higher rates of repeat revascularization in the EA group. In patients with myocardial infarction (MI), the hazard of MI or death at 1 year was lower in the EA than the EE group, 0.50 (0.27-0.93). CONCLUSION: In this single-center observational study, the use of abciximab for PCI after upstream use of eptifibatide for ACS was safe. Abciximab was of no benefit in patients with unstable angina, but was associated with lower MI or death in patients with MI. These observations are consistent with recent findings indicating that abciximab is of benefit in patients with NSTEMI, but not lower-risk patients.

Abciximab↗
PubMed2005

Preprocedural white blood cell count and major adverse cardiac events late after percutaneous coronary intervention in saphenous vein grafts.

Elevation of white blood cells (WBCs) is associated with worse outcomes in patients with coronary artery disease (CAD), including patients undergoing percutaneous coronary intervention (PCI) of native coronary arteries, but this relation has not been studied in patients with saphenous vein graft disease undergoing PCI. A total of 530 patients who underwent PCI of saphenous vein grafts from May 1997 to July 2002 were followed for >3 years. Major adverse coronary events (MACEs) were assessed as a composite of death, myocardial infarction, or revascularization during follow-up (mean 2.7 years). Patients with MACEs (n = 287) were younger and had more thrombotic and ostial lesions (p < 0.05) than those without MACEs (n = 243). The preprocedural WBC count was also significantly higher in the MACE group than in the non-MACE group (8.1 x 10(3)/mul, range 6.6 to 10.1, vs 7.0 x 10(3)/mul, range 5.6 to 8.2; p < 0.001). After adjusting for covariates, multiple logistic regression analysis revealed the preprocedural WBC count to be an independent predictor for MACEs (odds ratio 1.2; 95% confidence interval 1.1 to 1.3, p < 0.001). Patients in the highest quartile of the preprocedural WBC level had a significantly increased risk of MACEs (lowest vs highest quartile, 41.3% vs 72.4%; odds ratio 3.7; 95% confidence interval 2.2 to 6.3). Thus, an elevated preprocedural WBC count is associated with increased risk of MACEs in patients undergoing PCI for saphenous vein graft lesions.

Aged↗
PubMed2005

Statin therapy may be associated with lower mortality in patients with diastolic heart failure: a preliminary report.

BACKGROUND: No therapy has been shown to improve survival in heart failure (HF) with a normal ejection fraction (EF). There are plausible reasons to hypothesize that statins may be of benefit in HF with a normal EF. METHODS AND RESULTS: We evaluated 137 patients with HF and an EF > or =0.50. The effect of treatment received at study entry on survival was determined. During a follow-up of 21+/-12 months, 20 deaths were observed. Treatment with an ACE inhibitor or receptor blocker, beta-blocker, or calcium blocker had no significant effect on survival. In contrast, treatment with a statin was associated with a substantial improvement in survival (relative risk of death [95% CI] 0.22 [0.07 to 0.64]; P=0.006). Patients receiving statins had higher baseline LDL cholesterol than those not receiving statins (153+/-45 versus 98+/-33 mg/dL, P<0.01). After statin therapy, LDL cholesterol levels fell to a similar level (101+/-32 mg/dL) as in patients not receiving statins (98+/-33 mg/dL). After adjustment for differences in baseline clinical variables between groups (hypertension, diabetes, coronary artery disease, and serum creatinine), statin therapy was associated with lower mortality (adjusted relative risk of death [95% CI] 0.20 [0.06 to 0.62]; P=0.005). Similarly, after propensity matching, statin therapy was associated with improved survival (log-rank 6.12; P=0.013) and a trend toward improved survival without cardiovascular hospitalization (log-rank 3.02; P=0.082). CONCLUSIONS: Statin therapy may be associated with improved survival in patients with HF and a normal EF.

Adult↗
PubMed2005

Engineering of a recombinant vitamin K-dependent gamma-carboxylation system with enhanced gamma-carboxyglutamic acid forming capacity: evidence for a functional CXXC redox center in the system.

The vitamin K-dependent gamma-carboxylation system in the endoplasmic reticulum membrane responsible for gamma-carboxyglutamic acid modification of vitamin K-dependent proteins includes gamma-carboxylase and vitamin K 2,3-epoxide reductase (VKOR). An understanding of the mechanism by which this system works at the molecular level has been hampered by the difficulty of identifying VKOR involved in warfarin sensitive reduction of vitamin K 2,3-epoxide to reduced vitamin K(1)H(2), the gamma-carboxylase cofactor. Identification and cloning of VKORC1, a proposed subunit of a larger VKOR enzyme complex, have provided opportunities for new experimental approaches aimed at understanding the vitamin K-dependent gamma-carboxylation system. In this work we have engineered stably transfected baby hamster kidney cells containing gamma-carboxylase and VKORC1 cDNA constructs, respectively, and stably double transfected cells with the gamma-carboxylase and the VKORC1 cDNA constructs in a bicistronic vector. All engineered cells showed increased activities of the enzymes encoded by the cDNAs. However increased activity of the gamma-carboxylation system, where VKOR provides the reduced vitamin K(1)H(2) cofactor, was measured only in cells transfected with VKORC1 and the double transfected cells. The results show that VKOR is the rate-limiting step in the gamma-carboxylation system and demonstrate successful engineering of cells containing a recombinant vitamin K-dependent gamma-carboxylation system with enhanced capacity for gamma-carboxyglutamic acid modification. The proposed thioredoxin-like (132)CXXC(135) redox center in VKORC1 was tested by expressing the VKORC1 mutants Cys(132)/Ser and Cys(135)/Ser in BHK cells. Both of the expressed mutant proteins were inactive supporting the existence of a CXXC redox center in VKOR.

Animals↗
PubMed2005

Safety of abciximab administration during PCI of patients with previous stroke.

OBJECTIVES: To examine the frequency of cerebrovascular complications among patients receiving abciximab (AB) undergoing PCI with prior intracranial hemorrhage (ICH) or recent (< 2 years) ischemic strokes. BACKGROUND: AB improves clinical outcomes in high-risk patients undergoing percutaneous coronary intervention (PCI); however, the safety of AB in patients with prior stroke has not been adequately studied. METHODS: A database review of 7,244 consecutive PCIs, from 7/97 to 10/01, identified 6,190 PCIs performed with AB among which 515 interventions were performed in patients with prior stroke history [ICH or recent ischemic stroke, (n = 101) and remote (> 2 years) ischemic stroke, (n = 414)]. RESULTS: The post-PCI stroke rate was significantly higher in patients with prior stroke (2.06% vs. 0.35%, p < 0.001 for all stroke; 0.38% vs. 0.03%, p = 0.023 for ICH). The incidence of ICH among the AB-treated group was 0.065%; a history of prior stroke did not increase the incidence of ICH in the AB-treated group (0.39% vs. 0.0%, p = ns). Moreover, the post-PCI stroke rate was similar between the prior ICH or recent ischemic stroke-group and remote ischemic stroke-group (2 vs. 1.9%; OR: 1.03; 95% CI: 0.21-4.90; p = ns for all strokes; 2% vs. 1.5%; OR: 1.4; 95% CI: 0.27-6.91; p = ns for ischemic stroke). Importantly, no ICH occurred in patients with recent ischemic or any prior ICH stroke. CONCLUSIONS: Abciximab, in addition to aspirin, heparin and ADP-inhibitors does not increase the risk of stroke in patients with prior stroke undergoing PCI.

Abciximab↗
PubMed2005

Mast cell tryptase: a new biomarker in patients with stable coronary artery disease.

Mast cells may participate actively in the inflammatory process of atherosclerotic plaques by releasing proteolytic enzymes and various other pro-inflammatory substances. We hypothesized that increased levels of mast cell tryptase, could be an important biomarker in patients with stable coronary artery disease (CAD). We measured tryptase in 102 patients without acute coronary syndromes undergoing cardiac catheterization. Patients with significant CAD [> or =50% stenosis in > or =1 artery (n=66)] had significantly higher serum tryptase than patients with normal angiography (n=13) or non-significant CAD [<50% stenosis (n=23)]. The median, 25th and 75th percentiles for tryptase in these two groups were 8.38 (6.4 and 10.7)mug/L versus 6.78 (5.61 and 9.72) microg/L, p=0.014. Patients in the highest quartile of tryptase levels had a 4.3-fold risk for CAD [Odds ratio (OR): 4.3; 95% confidence interval (CI): 1.08-17.19; p=0.04]. In a multivariate regression analysis, tryptase remained an independent predictor for CAD along with age (OR: 1.178; 95% CI: 1.021-1.359, p=0.025). High circulating tryptase levels may be a result of chronic low-grade inflammatory activity present in atherosclerotic plaques. Tryptase measurements may emerge as a novel way of identifying asymptomatic patients with CAD, and represent a new biomarker of therapeutic efficacy in patients with CAD.

Aged↗
PubMed2005

Differences in baseline characteristics and in-hospital outcomes in patients with or without prior stroke undergoing percutaneous coronary intervention.

BACKGROUND: Percutaneous coronary intervention (PCI) is increasingly used in patients with high-risk baseline characteristics. A prior stroke may identify patients who have a higher risk for post-PCI complications. However, no comparative data exist on post-PCI outcomes of patients with or without prior stroke. METHODS: Review of a PCI database of 9,088 consecutive PCIs from July 1997 to December 2002 identified 812 PCIs in patients with a history of prior stroke and 8,044 PCIs without prior stroke. RESULTS: Patients with prior stroke had high-risk baseline characteristics [diabetes, hypertension, hyperlipidemia, smoking, peripheral arterial disease, congestive heart failure, chronic renal failure, history of prior myocardial infarction and prior coronary artery bypass graft (CABG)] and high-risk coronary anatomy (p < 0.001 for each one). The triple composite (death, myocardial infarction and emergent CABG) and the triple composite plus post-PCI stroke were higher in patients with prior stroke (11.2% vs. 4.8%; p < 0.001; z = 7.617 and 12.1% vs. 5.0%; p < 0.001; z = 8.271, respectively. CONCLUSION: Patients with prior stroke constitute a high-risk PCI cohort with higher rates of in-hospital adverse events. A prior stroke history should be considered in evaluating potential candidates for PCI.

Aged↗
PubMed2004

Absence of interaction between atorvastatin or other statins and clopidogrel: results from the interaction study.

BACKGROUND: Some, but not all, post hoc analyses have suggested that the antiplatelet effects of clopidogrel are inhibited by atorvastatin. We sought to address this issue prospectively by performing serial measurements of 19 platelet characteristics using conventional aggregometry, rapid analyzers, and flow cytometry. METHODS: The Interaction of Atorvastatin and Clopidogrel Study (Interaction Study) was designed for patients undergoing coronary stenting. All patients (n = 75) received 325 mg of aspirin daily for at least 1 week and 300 mg of clopidogrel immediately prior to stent implantation. They had been taking atorvastatin (n = 25), any other statin (n = 25), or no statin (n = 25) for at least 30 days prior to stenting. The main outcome measure was comparison of platelet biomarkers 4 and 24 hours after clopidogrel administration between study groups. RESULTS: At baseline, patients from both statin groups exhibited diminished platelet aggregation and reduced platelet expression of G-protein-coupled protease-activated thrombin receptor (PAR)-1. There were no significant differences in measured platelet characteristics among the study groups 4 and 24 hours after clopidogrel intake, with the exception of a lower collagen-induced aggregation at 24 hours and a constantly diminished expression of PAR-1 in patients treated with any statin. CONCLUSIONS: Statins in general, and atorvastatin in particular, do not affect the ability of clopidogrel to inhibit platelet function in patients undergoing coronary stenting. These prospective data also suggest that statins may inhibit platelets directly via yet unknown mechanism(s) possibly related to the regulation of the PAR-1 thrombin receptors.

Aged↗
PubMed2004

IRAK1 serves as a novel regulator essential for lipopolysaccharide-induced interleukin-10 gene expression.

Being one of the key kinases downstream of Toll-like receptors, IRAK1 has initially thought to be responsible for NFkappaB activation. Yet IRAK1 knock-out mice still exhibit NFkappaB activation upon lipopolysaccharide (LPS) challenge, suggesting that IRAK1 may play other un-characterized function. In this report, we show that IRAK1 is mainly involved in Stat3 activation and subsequent interleukin-10 (IL-10) gene expression. Splenocytes from IRAK1-deficient mice fail to exhibit LPS-induced Stat3 serine phosphorylation and IL-10 gene expression yet still maintain normal IL-1beta gene expression upon LPS challenge. Mechanistically, we observe that IRAK1 modification upon LPS challenge leads to its modification, nuclear distribution, and interaction with Stat3. IRAK1 can directly use Stat3 as a substrate and cause Stat3 serine 727 phosphorylation. In addition, nuclear IRAK1 binds directly with IL-10 promoter in vivo upon LPS treatment. Atherosclerosis patients usually have elevated serum IL-10 levels. We document here that IRAK1 is constitutively modified and localized in the nucleus in the peripheral blood mononuclear cells from atherosclerosis patients. These observations reveal the mechanism for the novel role of IRAK1 in the complex Toll-like receptor signaling network and indicate that IRAK1 regulation may be intimately linked with the pathogenesis and/or resolution of atherosclerosis.

Animals↗
PubMed2004

Magnitude and time course of platelet inhibition with Aggrenox and Aspirin in patients after ischemic stroke: the AGgrenox versus Aspirin Therapy Evaluation (AGATE) trial.

The European Stroke Prevention Study showed greater stroke prevention for Aggrenox than either for aspirin or dipyridamole alone. To test whether Aggrenox has superior antiplatelet properties to aspirin alone we conducted the AGgrenox versus Aspirin Therapy Evaluation (AGATE) trial. Forty patients with prior ischemic stroke not taking aspirin for at least 30 days were randomized to Aggrenox (2 pills/daily) or aspirin (81 mg plus matching placebo/daily) for 30 days. Platelet function was assessed at baseline, 24 h, and days 3, 7, 15, and 30 by aggregometry, flow cytometry and cartridge-based analyzers. Both Aggrenox and aspirin provided fast and sustained platelet inhibition. Aggrenox(R), however, especially after 15 days, showed significant prolongation of the closure time (P=0.04), diminished expression of platelet/endothelial cell adhesion molecule-1 (PECAM-1) (P=0.01), glycoprotein IIb (GPIIb) antigen (P=0.02), and GPIIb/IIIa activity (P=0.01) by PAC-1 C antibody, CD63 (P=0.03), as well as inhibition of Protease Activated Receptors (PAR-1) associated with intact (SPAN12, P=0.01) and cleaved (WEDE15, P=0.01) thrombin receptors as compared with aspirin. Surprisingly, GPIb expression increased, especially after aspirin. In the randomized trial of small sample size, aspirin and Aggrenox produced fast and sustained platelet inhibition. In 25 of 90 direct comparisons, Aggrenox was superior to aspirin, whereas in 4 of 90, aspirin was superior to Aggrenox. In 61 of 90 direct comparisons, aspirin and Aggrenox were equivalent. Aggrenox was associated with a profound reduction of PAR-1 receptors, an observation that may be related to the greater clinical benefit of Aggrenox compared with Aspirin in preventing recurrent stroke.

Aged↗
PubMed2004

Final results of the ReoPro readministration registry.

Because of its potential for antigenicity, theoretical concerns related to readministration of abciximab have been raised. We conducted the ReoPro Readministration Registry to assess the efficacy and safety of abciximab readministration. A total of 1,342 patients who underwent percutaneous coronary intervention and who received abciximab for at least a second time were recruited. Safety end points were hypersensitivity reactions, major bleeding, and thrombocytopenia (TCP). Human antichimeric antibody (HACA) titers were determined before and after readministration. Procedural success was 98% and was not influenced by the number of courses of abciximab or the presence of HACA. There were no cases of anaphylaxis. There were 5 minor allergic reactions, none of which required termination of the infusion. Clinically significant bleeding occurred in 31 patients (2.3%), including 1 (0.07%) with intracranial hemorrhage. TCP (<100 x 10(9)/L) developed in 5% of patients; profound TCP (<20 x 10(9)/L) occurred in 2%. In patients who received abciximab within 1 month of a previous treatment (n = 115), the risk of developing TCP and profound TCP was 16.5% and 12.2%, respectively. Having a positive HACA before readministration was not correlated with adverse clinical outcomes or bleeding, but was associated with TCP (14.1% vs 4.4%, p = 0.002) and profound TCP (5.6% vs 1.6%, p = 0.036). Readministration of abciximab can be accomplished without severe allergic responses and with a bleeding and efficacy profile similar to first-time administration. However, the rate of severe and profound TCP is increased relative to first-time administration, particularly when the time between treatments is <30 days or when HACA is present.

Abciximab↗