Purpose: To test the hypothesis that intra- and interreader reproducibility for measuring the lipid-rich necrotic core (LR-NC) size is significantly improved with gadolinium (Gd) contrast-enhanced magnetic resonance imaging (CEMRI) compared to non-CEMRI.Materials and Methods: Thirty-seven individuals with > 50% carotid artery stenosis underwent carotid MRI at 1.5T (pre- and postcontrast T1-weighted (T1W), T2-weighted (T2W), proton density-weighted (PDW), and three-dimensional time-of-flight (TOF) sequences). Two independent readers measured the mean area of the LR-NC from the precontrast images only, followed by a second measurement using the additional postcontrast images. One reader repeated the measurements after an interval of five months. Intra- and interreader reproducibility was analyzed by means of the intraclass correlation coefficient (ICC), coefficient of variation (CV), and standard deviation (SD).Results: The CV decreased from 33.7% to 8.8% for intrareader measurements of the LR-NC, and from 33.5% to 17.6% for interreader measurements. The SD was significantly smaller with CEMRI than with non-CEMRI (P = 0.003 and P = 0.006, respectively). The ICC increased from 0.94 to 0.99 and from 0.85 to 0.93 for the intra- and interreader measurements, respectively.Conclusion: Reader reproducibility for in vivo MRI quantification of LR-NC size is significantly improved by the addition of Gd contrast in individuals with > 50% carotid stenosis.

Orbofiban is a unique antiplatelet agent that inhibits the binding of fibrinogen to gycoprotein (GP) IIb/IIIa integrin receptors and thus prevents platelet aggregation induced by various agents. However, recent studies indicate that treatment with orbofiban does not reduce the incidence of recurrent ischemic events. The mechanisms underlying the lack of benefit of orbofiban in patients with acute coronary syndromes are not completely clear. The purpose of this study was to characterize the effects of orbofiban on cellular activation (neutrophil superoxide generation) and surface expression of adhesion molecules of circulating neutrophils (CD18, CD11b, and L-selectin) and platelets (P-selectin and GP IIb/IIIa) in patients with acute coronary syndromes. After 5–7 days, orbifiban (50 mg BID) did not reduce PMN adhesion molecule expression and ex vivo-stimulated PMN superoxide generation—as was observed in the placebo group, without orbofiban. In contrast, orbofiban induced marked reductions in GP IIb/IIIa and P-selectin expressions after 5–7 days of treatment. The sustained neutrophil activation observed with orbofiban may have a role on the recurrent thrombotic events observed with orbofiban treatment in the OPUS-TIMI 16 trial.

A key role has been established for platelet activation and thrombus formation in the pathogenesis of acute coronary syndromes, and restenosis after percutaneous interventions. Antiplatelet agents that have a wider spectrum of activity than aspirin, and clopidogrel would be expected to provide improved antithrombotic protection. Preclinical studies were used to predict clinical efficacy of orally active GPIIb/IIIa antagonists such as xemilofiban, sibrafiban, lefradafiban, and orbofiban, While clinical trials have shown potent and sustained platelet inhibition, outcomes of trials with these first generation GPIIb/IIIa compounds have been disappointing. The active moiety of orbofiban is a potent and specific inhibitor of fibrinogen binding to GPLIb/IIIa, leading to inhibition of platelet aggregation to a wide variety of agonists. Studies comparing inhibition of aggregation and bleeding suggest that chronic inhibition of platelet aggregation can be achieved without major bleeding side effects. Thrombus formation is prevented in canine models of thrombosis. Orbofiban is approximately 28% bioavailable with a t(1/2) of 18 hr. The high bioavailability, long half-life, and potential safety suggest orbofiban would be suitable for chronic oral administration. Clinical data demonstrate that orally administered orbofiban has the desired pharmacodynamic effect of inhibiting platelet aggregation but does not demonstrate clinical benefit when examined in large-scale trials. (C) 2001 John Wiley & Sons, inc.

The Controlled ONset Verapamil INvestigation of Cardiovascular Endpoints (CONVINCE) Trial differs from many other clinical trials in hypertension by including obesity as one of the cardiovascular risk factors that qualifies a person for enrollment. Obesity was defined for this study as body weight > 25% over ideal using 1977 Metropolitan Life Tables, or BMI > 28.5 kg/m2. Obesity was the most common risk factor in CONVINCE; it was reported (as a single “yes/no” checkbox) for 50.5% of the 16,602 enrolled subjects. Both younger age and female gender were significantly associated with obesity: among the 4129 subjects between 55-59 years of age, obesity was found in 58%; only 28.8% of those over age 80 were obese. Obesity was found among 56% of the women, but only 43.5% of the men. Younger women were also over-represented among subjects enrolled in CONVINCE with obesity as their only risk factor. After an average of 2.6 years of follow-up, 567 primary events (cardiovascular death, stroke, or myocardial infarction) were reported by clinical sites; 229 were in obese subjects. In a Cox proportional hazards model adjusting only for age and gender, the relative risk for a primary event was significantly lower among obese subjects (RR = 0.79, 95% CI: 0.66-0.94). After adding race/ethnicity, SBP, and other baseline cardiovascular risk factors to the model, the adjusted relative risk for obesity was 0.98 (95% CI: 0.82-1.17). These data show that obesity was a common risk factor in the CONVINCE study population (especially in younger women), and suggest that in the short-term, obesity was not a significant independent risk predictor for cardiovascular death, stroke, or myocardial infarction.

Background Clinical studies have demonstrated the efficacy of intravenous administration of agents that block platelet glycoprotein IIb/IIIa receptors in the setting of percutaneous coronary revascularization. Although the optimal duration of treatment has not been determined, more prolonged receptor blockade has been associated with increased efficacy. Orally active glycoprotein IIb/IIIa receptor antagonists may be advantageous and required for chronic therapy. Methods and Results Thirty patients with unstable angina who were undergoing percutaneous coronary interventions were randomized to placebo or Xemilofiban 35 mg orally before and 20 to 25 mg TID for 30 days after angioplasty. Bleeding events, platelet aggregation, and pharmacokinetic and hematologic parameters were assessed during hospitalization and at 2 and 4 weeks after drug initiation. Xemilofiban produced a rapid, sustained, marked inhibition of platelet aggregation. ADP-induced platelet aggregation at 2 hours after the initial dose at 2 and 4 weeks was 15%, 8%, and 11% in the Xemilofiban group compared with 80%, 68%, and 69% in the placebo group. Among 20 patients randomized to Xemilofiban there was 1 death after emergency coronary bypass surgery complicated by severe bleeding diathesis, and 3 patients had major bleeding events. Patients on Xemilofiban for 30 days reported episodes of mild mucocutaneous bleeding. Conclusions Xemilofiban, an orally active glycoprotein IIb/IIIa receptor inhibitor, produced rapid, sustained, extensive inhibition of platelet aggregation for a period of up to 30 days. At the dose initially tested, however, acute major bleeding and mucocutaneous bleeding during chronic administration were encountered.

This double-blind, placebo-controlled, parallel-group, multicenter study was designed to evaluate the safety and efficacy of a new controlled-onset, extended-release formulation of verapamil hydrochloride called physiologic pattern release (PPR) verapamil. The study was conducted at 24 sites (13 United States, 5 Canada, 6 overseas; see Appendix). Following a 1- to 3-week single-blind placebo lead-in period, 278 patients with chronic stable angina pectoris (247 males, 31 females, mean age 60.8 years, range 32 to 78) were randomly assigned to 1 of 4 once-daily, fixed-dose treatment groups: verapamil 180, 360, or 540 mg, or placebo. PPR verapamil at all doses significantly increased (p < 0.05) time to moderate angina and symptom-limited exercise duration, and verapamil 360 mg significantly increased (p < 0.05) time to ≥1 mm ST-segment depression, after 4 weeks of treatment when assessed 24 hours after the previous dose. Larger doses of verapamil were associated with proportionately greater improvements in exercise tolerance. Frequency of anginal attacks was also reduced by verapamil. The most frequently observed adverse events were dizziness, headache, constipation, and nausea. The incidence of constipation was high (20.9%) within the 540 mg treatment group. This verapamil formulation can be clinically titrated within a 180 to 540 mg dosing range, permitting effective oncedaily administration for the treatment of chronic stable angina.

This single-blind, placebo-controlled study evaluated the tolerability and pharmacodynamic (PD) response of the first dose of the oral GPllb/llla receptor antagonist, SC-54684A (ethyl 3S-[[4-[[4(amino-iminomethyl)phenyl]amino]-l,4-dioxobutyl]amino]-4-pentynoate, monohydrochloride). SC-54684A (SC) is the pro-drug of the active compound, SC-54701A. Six healthy male subjects received 50mg of SC (free base) and 2 received placebo (PBO). Results of the inhibition to AOD (20μM) induced platelet aggregation are shown below:

A review of the literature investigating an alternative method of administering doxorubicin on a weekly basis demonstrates a lower incidence of doxorubicin-induced cardiomyopathy, as judged by endomyocardial biopsy techniques and by an apparent lower incidence of CHF as compared to older reports in the literature utilizing conventional tri-weekly administration. However, none of these studies has utilized objective methods for verifying cardiac function. The precise reason why weekly administration may induce lesser degrees of damage to the myocardium is not clearly understood. However, it appears that the lower serum concentrations obtained with this dosing regimen result in lower myocardial tissue concentrations of the drug. Though the initial data are encouraging, larger clinical trials are necessary to establish a lower incidence of cardiotoxicity with weekly low-dose doxorubicin administration. Such studies, if specifically designed to evaluate changes in myocardial function, will resolve the questions and hopefully establish the advantages of this encouraging new therapeutic modality.