Abraham Caspi

Oral Glycoprotein IIb/IIIa Inhibition With Orbofiban in Patients With Unstable Coronary Syndromes (OPUS-TIMI 16) Trial

BACKGROUND Although intravenous glycoprotein IIb/IIIa inhibitors are beneficial in patients with acute coronary syndromes, prolonged oral IIb/IIIa inhibition might provide an additional reduction in recurrent events. METHODS AND RESULTS Investigators at 888 hospitals in 29 countries enrolled 10 288 patients with acute coronary syndromes, which was defined as ischemic pain at rest within 72 hours of randomization, associated with positive cardiac markers, electrocardiographic changes, or prior cardiovascular disease. Patients received aspirin and were randomized to receive, for the duration of the trial, (1) 50 mg of orbofiban twice daily (50/50 group), (2) 50 mg of orbofiban twice daily for 30 days followed by 30 mg of orbofiban twice daily (50/30 group), or (3) a placebo. The primary composite end point was death, myocardial infarction, recurrent ischemia requiring rehospitalization, urgent revascularization, or stroke. The trial was terminated prematurely because of an unexpected increase in 30-day mortality in the 50/30 orbofiban group. Mortality through 10 months was 3.7% for the placebo group versus 5.1% in the 50/30 group (P=0.008) and 4.5% in the 50/50 group (P=0.11). There were no differences in the primary end point (22.9%, 23.1%, and 22.8%, for the placebo, 50/30, and 50/50 groups, respectively). Major or severe bleeding (but not intracranial hemorrhage) was higher with orbofiban; it occurred in 2. 0%, 3.7% (P=0.0004), and 4.5% (P<0.0001) of patients, respectively. Exploratory subgroup analyses found that patients who underwent percutaneous coronary intervention had a lower mortality and a significant reduction in the composite end point (P=0.001) with orbofiban. CONCLUSIONS -Fixed-dose orbofiban failed to reduce major cardiovascular events and was associated with increased mortality in this broad population of patients with acute coronary syndromes; however, a benefit was observed among patients who underwent percutaneous coronary intervention.

Comparison of some biochemical characteristics of different citrus fruits

The goal of this investigation was to evaluate the antioxidant properties of some citrus fruits. The contents of dietary fibre, total polyphenols, essential phenolics, ascorbic acid and some trace elements of lemons, oranges and grapefruits were determined and compared with their total radical-trapping antioxidative potential (TRAP). There were no significant differences in the contents of total, soluble and insoluble dietary fibre in the studied peeled fruits or their peels. The contents of total, soluble and insoluble dietary fibre in peels were significantly higher than in peeled fruits (P < 0.05 in all cases). The peeled lemons, oranges and grapefruits contain 164 10.3; 154 10.2 and 135 10.1 and their peels 190 10.6; 179 10.5 and 155 10.3 mg/100 g of total polyphenols, respectively. The content of total polyphenols in peeled lemons and their peels was significantly higher than in peeled oranges and grapefruits and their peels, respectively. The content of total polyphenols in the peels was significantly higher than in peeled fruits (P < 0.05 in all cases). The same results were obtained in the investigation of essential phenolics and ascorbic acid. The content of Fe in peeled lemons and their peels was significantly higher than in peeled oranges and grapefruits and their peels, respectively. Also the TRAP was significantly higher in peeled lemons and their peels than in peeled oranges and grapefruits and their peels, respectively. In all three fruits, the TRAP was significantly higher in peels than in peeled fruits (P< 0.05). In conclusion, lemons possess the highest antioxidant potential among the studied citrus fruits and are preferable for dietary prevention of cardiovascular and other diseases. The peels of all citrus fruits are rich in dietary fibres and phenolic compounds and suitable for industrial processing. # 2001 Published by Elsevier Science Ltd. All rights reserved.

Effect of Mibefradil, a T-Type Calcium Channel Blocker, on Morbidity and Mortality in Moderate to Severe Congestive Heart Failure The MACH-1 Study

BACKGROUND Calcium antagonists have proved disappointing in long-term congestive heart failure (CHF) studies. Mibefradil, a new calcium antagonist that selectively blocks T-type calcium channels, has been shown to be an effective antihypertensive, antianginal, and anti-ischemic agent, and because of its different mechanism of action, it may be beneficial as adjunct therapy in CHF patients. METHODS AND RESULTS This multicenter, randomized, double-blind study compared mibefradil with placebo as adjunct to usual therapy in 2590 CHF patients (NYHA class II to IV; left ventricular fraction <35%). The initial 50-mg daily dose of mibefradil was uptitrated to 100 mg after 1 month and continued up to 3 years. Patients were monitored at 1 week; 1, 2, and 3 months; and every 3 months thereafter. All-cause mortality, cardiovascular mortality, and cardiovascular morbidity/mortality were analyzed by use of the log-rank test (alpha=0.05). Substudies included exercise tolerance, plasma hormone and cytokines, echocardiography, and quality of life. Total mortality was similar between mibefradil- and placebo-treated patients (P=0.151). The 14% increased risk of mortality with mibefradil in the first 3 months was not statistically significant (P=0.093). Treatment groups had similar cardiovascular mortality (P=0.246), cardiovascular morbidity/mortality (P=0.783), and reasons for death or hospitalization. Patients comedicated with mibefradil and antiarrhythmics (class I or III), including amiodarone, had a significantly increased risk of death. Substudies demonstrated no significant differences between treatments. CONCLUSIONS When used as adjunct therapy, mibefradil did not affect the usual outcome of CHF. The potential interaction with antiarrhythmic drugs, especially amiodarone, and drugs associated with torsade de pointes may have contributed to poor outcomes early in the study.

Evaluation of a weight-adjusted single-bolus plasminogen activator in patients with myocardial infarction: A double-blind, randomized angiographic trial of lanoteplase versus alteplase

BACKGROUND Lanoteplase (nPA) is a rationally designed variant of tissue plasminogen activator with greater fibrinolytic potency and slower plasma clearance than alteplase. METHODS AND RESULTS InTIME (Intravenous nPA for Treatment of Infarcting Myocardium Early), a multicenter, double-blind, randomized, double-placebo angiographic trial, evaluated the dose-response relationship and safety of single-bolus, weight-adjusted lanoteplase. Patients (n=602) presenting within 6 hours of acute myocardial infarction were randomized and treated with either a single-bolus injection of lanoteplase (15, 30, 60, or 120 kU/kg) or accelerated alteplase. The primary objective was to determine TIMI grade flow at 60 minutes. Angiographic assessments were also performed at 90 minutes and on days 3 to 5. Follow-up was continued for 30 days. Lanoteplase achieved its primary objective, demonstrating a dose-response in TIMI grade 3 flow at 60 minutes (23.6% to 47.1% of subjects, P<0. 001). Similar results were observed at 90 minutes (26.1% to 57.1%, P<0.001). At 90 minutes, coronary patency (TIMI 2 or 3) increased across the dose range up to 83% of subjects at 120 kU/kg lanoteplase compared with 71.4% with alteplase. Thus, at this dose, lanoteplase was superior to alteplase in restoring coronary patency (difference, 12%; 95% CI, 1% to 23%). The early safety experience in this study suggests that lanoteplase was well tolerated at all doses with safety comparable to that of alteplase. CONCLUSIONS Lanoteplase, a single-bolus, weight-adjusted agent, increased coronary patency at 60 and 90 minutes in a dose-dependent fashion. Coronary patency at 90 minutes was achieved more frequently with 120 kU/kg lanoteplase than alteplase. In this study, safety with lanoteplase and alteplase was comparable. InTIME-II, a worldwide mortality trial, will evaluate efficacy and safety with this promising new agent.

COMPARATIVE CONTENTS OF SOME PHENOLICS IN BEER, RED AND WHITE WINES

Abstract It is generally assumed that the higher the total polyphenols content of a beverage, the greater is its antioxidant activity. Our previous experiments on laboratory animals and clinical investigations showed that the content of total polyphenols is higher in white wine than in beer, but beer possessed a higher antioxidant activity. In order to find the sources, which determine the degree of the antioxidant activity the comparative content of some important phenolics in beer, red and white wines was examine. Total polyphenols, procyanidins, epicatechin, quercetin, ferulic p -coumaric and gallic acids were determined in these beverages. The content of total polyphenols was significantly higher in red wine than in white wine and beer (p

Intrinsic Tryptophan Fluorescence of Human Serum Proteins and Related Conformational Changes

The unfolding of human serum proteins (HSP) was studied by measuring the intrinsic fluorescence intensity at a wavelength of excitation corresponding to tryptophans or typosines fluorescence and surface hydrophobicity. The maxima emission wavelengths (λmax) of human serum albumin (HSA) and human serum globulin (HSG) before beer consumption (BC) were 336.0 and 337.0 nm and after BC shifted to 335.0 and 334.0 nm, respectively. The surface hydrophobicity slightly increased after BC. In a solution of 8 M urea the λmax of BSA shifted to 346.4 and that of BSG to 342.5 nm. In contrast, in the same solution but after BC the λmax positions of HSA and HSG shifted to 355.9 and 357.7 nm, respectively. A decrease in fluorescence intensity, a shift in the maximum of emission, and an increase in surface hydrophobicity which reflected unfolding of proteins were observed. Here we provide evidence that the loosening of the HSP structure takes place primarily in various concentrations of urea before and after beer consumption. Differences in the fluorescence behavior of the proteins are attributed to disruption of the structure of proteins by denaturants as well as by the change in their compactability as a result of ethanol consumption.

Prevalence and significance of unrecognized renal insufficiency in patients with heart failure

AIMS Renal insufficiency (RI) is a strong predictor of adverse outcome in patients with heart failure (HF). We aimed to determine the prevalence of RI being unrecognized and its significance in patients hospitalized with HF. METHODS AND RESULTS We analysed data from a prospective survey of 4102 hospitalized patients with HF. RI [defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2] was present in 2145 (57%) patients but, based on medical records, was unrecognized in 872 [41%, 95% confidence interval (CI) 39-43%] of them. Patients with unrecognized RI were more likely to be women, elderly, and with better functional class, compared with patients with recognized RI. In-hospital and 1 year mortality was significantly higher among patients with recognized and unrecognized RI compared with patients without RI: 6.5 and 7.1 vs. 2.1%, and 38.8 and 30.9 vs. 18.8% (P < 0.001), respectively. After adjustment, recognized and unrecognized RI comparably predicted increased in-hospital mortality: odds ratio (OR) and 95% CI of 2.34 (1.43-3.87), P < 0.001, and 2.30 (1.45-3.72), P < 0.001. After 1 year, recognized RI remained an independent predictor for mortality: OR 1.79 (1.45-2.20), P < 0.001, whereas there was a trend for increased mortality predicted by unrecognized RI: OR 1.22 (0.97-1.53), P = 0.08. CONCLUSION A high proportion of RI remains unrecognized among hospitalized patients with HF. As co-morbid RI has important prognostic and therapeutic implications, patients with HF may benefit from routine assessment of GFR.

Atrial fibrillation and long-term prognosis in patients hospitalized for heart failure: results from heart failure survey in Israel (HFSIS).

AIMS Atrial fibrillation (AF) and heart failure (HF) commonly coexist, and each adversely affects the other. The aim of the study was to prospectively evaluate the impact of AF and its subtypes on management, and early and long-term outcome of hospitalized HF patients. METHODS AND RESULTS Data were prospectively collected on HF patients hospitalized in all public hospitals in Israel as part of a national survey (HFSIS). Atrial fibrillation patients were subdivided into intermittent and chronic AF subgroups. During March-April 2003, we enrolled 4102 HF patients, of whom 1360 (33.2%) had AF [600 (44.1%) intermittent, 562 (41.3%) chronic]. Patients with AF were older (76.9 +/- 10.5 vs. 71.7 +/- 12.6 years, P = 0.0001), males, with preserved LV systolic function. Crude mortality rates for AF patients were progressively and consistently higher during hospitalization and during the 4-year follow-up period, especially in the chronic AF group (P = 0.0001). After covariate adjustment, AF was associated with increased 1-year mortality [HR 1.19, 95% CI (1.03-1.36)]. CONCLUSION AF was present in a third of hospitalized HF patients, and identified a population with increased mortality risk, largely due to co-morbidities.

Effect of isosorbide-5-mononitrate on exercise performance and clinical status in patients with congestive heart failure: Results of the nitrates in congestive heart failure (NICE) study

Background and Aims: Nitrate therapy improves hemodynamics in patients with heart failure, but the chronic effects of oral nitrates on exercise performance and clinical status have not been well studied. Methods: Oral isosorbide-5-mononitrate (ISMN) (50 mg once daily) or placebo was administered to 136 patients (NYHA Class 2–3) treated for heart failure, all receiving captopril and most also furosemide. Endpoints were treadmill exercise time at 12 weeks by modified Naughton protocol (primary), with an additional 12-week follow-up period. Secondary endpoints included left ventricular dimensions, ejection fraction, cardiothoracic ratio, functional class, quality of life, hospitalizations and plasma norepinephrine and atrial natriuretic peptide in a four-center substudy. Results: Intention-to-treat analysis showed that mean change in treadmill exercise duration tended to be greater in patients receiving ISMN than placebo (treatment difference +42 s, 95% CI –5, +90 s at 12 weeks and +21 s, 95% CI –25, +74 s after 24 weeks) (NS). Treatment difference was greater in the prespecified subgroup with ejection fraction 31–40% (+55 s, 95% CI –11, +136 s at 12 weeks and +65 s, 95% CI +3, +147 s) (p = 0.035) at 24 weeks. No deleterious effects (i.e. hypotension) were observed with ISMN, although headache was reported in 19% of the active treatment group (p = 0.0001). Conclusions: ISMN added to captopril increased treadmill exercise time in patients with heart failure and a lesser reduction in baseline ejection fraction, although for the group as a whole, the increase in treadmill time was not significant.

Appropriateness and complications of the use of spironolactone in patients treated in a heart failure clinic

OBJECTIVES The widespread use of spironolactone in patients with congestive heart failure (CHF) has resulted in side effects and complications. We analyzed a cohort of patients treated by a dedicated CHF team, in order to examine the tolerability and safety of spironolactone in clinical practice. METHODS We retrospectively evaluated data on 157 patients who were followed by the Heart Failure clinic of whom 100 patients on maximal treatment (all on β blockers, 99% on ACE inhibitors) received spironolactone. The complications following spironolactone use were defined as: hyperkalemia with serum K 5.2 mEq/l; creatinine 2.0 mg/dl; hyponatremia with serum Na 135 mEq/l, hypotension and side effects such as gynecomastia and abdominal pain. RESULTS At 1 year follow-up 6 patients developed hyperkalemia (range 5.3-5.9), 4 of them had K>5.5 mEq/l. Two patients developed hyponatremia. Six patients stopped spironolactone for: 1-gynecomastia, 2-worsening renal failure and hyperkalemia, 2-hyperkalemia (5.9 mEq/l) and 1 for bradycardia. There was an increase in mean creatinine level at 1 year (1.12±0.35 vs. 1.21±0.38 mg/dl, p=0.02), however, no significant changes were found in GFR (99.9±33.5 vs. 65.7±27.7 ml min(-1)1.73 m(-2), p=ns) and potassium (4.5±0.4 vs. 4.6±0.5 mEq/l, p=ns). We found improvement of GFR by >10% in 19 patients and worsening by >10% in 38 patients. No patient was hospitalized or required urgent treatment for spironolactone-related side effects. CONCLUSIONS In patients with CHF on optimal therapy with ACE inhibitors and β blockers appropriate spironolactone use and close follow-up by a dedicated HF team can minimize the risk for adverse events and complications.