Isosorbide-5-mononitrate in angina pectoris: plasma concentrations and duration of effects after acute therapy.

In a double-blind, randomized, crossover study, the duration of effects of single oral doses of 20 and 40 mg isosorbide-5-mononitrate (IS-5MN) and matching placebo were studied in 12 male patients with angina pectoris. Plasma IS-5MN concentrations (mean +/- SD) 2 and 6 hours after administration were 300 +/- 60 and 144 +/- 43 ng/ml after 20 mg IS-5MN and 551 +/- 191 and 376 +/- 129 ng/ml after 40 mg IS-5MN. Exercise time to the onset of angina 2 and 6 hours after administration increased after 20 mg IS-5MN (5.88 +/- 1.85; P less than 0.001 and 5.08 +/- 1.97 minutes; P less than 0.002) and 40 mg IS-5MN (6.17 +/- 1.88; P less than 0.001 and 5.78 +/- 1.72 minutes; P less than 0.001) in comparison to placebo (4.57 +/- 1.22 and 4.15 +/- 1.22 minutes). Similarly, total exercise duration increased at 2 (P less than 0.001) and 6 hours (P less than 0.002) after both doses of IS-5MN. Compared with placebo, ECG ST segment depression during exercise was less (P less than 0.05) 2 hours after both doses of IS-5MN. Thus single oral doses of 20 and 40 mg IS-5MN exert antianginal and anti-ischemic effects for at least up to 6 hours.

Duration of effects and tolerance of slow-release isosorbide-5-mononitrate for angina pectoris.

Isosorbide-5-mononitrate (IS-5MN) is an active metabolite of isosorbide dinitrate, but unlike its parent compound, is nearly 100% bioavailable after oral administration. Once-a-day therapy with a slow-release formulation of IS-5MN is used widely in Europe for 24-hour prophylaxis of angina pectoris. In a randomized, crossover, double-blind, placebo-controlled study, the duration of effects of 50 and 100 mg of slow-release IS-5MN were evaluated after the first dose and after once-a-day therapy for 1 week in 9 patients with stable angina pectoris. Compared with placebo values, standing blood pressure decreased (p less than 0.001) and exercise time to the onset of angina and total exercise duration increased (p less than 0.008 and p less than 0.003) at 4 hours, but not at 20 or 24 hours after first dose of 50 and 100 mg of slow-release IS-5MN. After once-a-day therapy for 1 week, no improvement in exercise duration or reduction in ST-segment depression was seen after 50 or 100 mg of slow-release IS-5MN at 4, 20 or 24 hours despite high plasma IS-5MN concentrations. Thus, despite therapeutic plasma concentrations, 50 and 100 mg of slow-release IS-5MN did not exert antianginal or anti-ischemic effects at 20 and 24 hours after the first dose and at 4, 20 and 24 hours after sustained once-a-day therapy for 1 week.

Usefulness of twice-daily isosorbide-5-mononitrate in preventing development of tolerance in angina pectoris.

Development of tolerance to nitrates during long-term therapy is a major concern. It has been suggested that isosorbide-5-mononitrate (IS-5MN), an active metabolite of isosorbide dinitrate, administered twice daily 12 hours apart does not lead to development of tolerance. The duration of effects of IS-5MN at a dose of 20 and 40 mg and of placebo was studied in patients with angina pectoris who responded to nitrates after the first dose (n = 12) and after 1 week of twice-daily therapy (n = 9). The study was double-blind, randomized and crossover in design. Compared with placebo values, after the first dose of 20 and 40 mg IS-5MN, exercise duration was higher at 2 hours (p less than 0.001) and 6 hours (p less than 0.02). After 1 week of twice-daily therapy at these doses, exercise duration increased at 2 hours (p less than 0.05) but not at 6 or 10 hours after the dose. After the first dose of 20 and 40 mg IS-5MN, standing systolic blood pressure decreased at 2 hours (p less than 0.02). Blood pressure did not change significantly after chronic therapy. Tolerance to antianginal effects during twice-daily therapy with 20 and 40 mg of IS-5MN developed despite higher plasma IS-5MN concentrations at 2 and 6 hours during twice-daily therapy than after the first dose. The tolerance during twice-daily therapy with IS-5MN was characterized by a reduced peak effect at 2 hours and shortened duration of action compared with first-dose effects.

Disposition and absolute bioavailability of furosemide in healthy males.

Furosemide (40 mg) was administered to 18 healthy adult males as an intravenous dose, an oral solution, and in tablet form. The pharmacokinetics of intravenous furosemide were studied, determining a total body clearance rate of 117.6 +/- 41.3 ml/min and a harmonic mean half-life of 78 min. The mean absolute bioavailability determined by ratio of areas under the plasma-time curves was 64 and 71% for the solution and tablet, respectively. The mean absolute bioavailability determined by the ratio of urinary cumulative excretion data was 61 and 66% for the solution and tablet, respectively. The absolute bioavailability of furosemide determined with plasma and urine data were not significantly different. Thus, urine data alone may be used to establish bioavailability of furosemide. Inspection of plasma-time curves revealed secondary maxima in several subjects, suggesting enterohepatic cycling.

Esophageal involvement in Wegener's granulomatosis: a case report and review of the literature.

Wegener's granulomatosis is characterized by a granulomatous arteritis involving the upper and lower respiratory tracts, progressive glomerulonephritis and systemic symptoms attributable to small vessel vasculitis. Although multisystemic manifestations are frequent, involvement of the gastrointestinal tract is uncommon. Cases have been reported of intestinal perforation, ulceration and hemorrhage. A patient whose initial presentation of Wegener's granulomatosis was odynophagia secondary to esophageal vasculitis is described. Endoscopy revealed multiple punched out ulcerations in the esophagus, which resolved with standard therapy for systemic Wegener's granulomatosis. There are only two previous reports of symptomatic esophageal vasculitis in patients with Wegener's granulomatosis. These reports illustrate the need to consider odynophagia as a reflection of disease activity as opposed to complications of immunosuppressive therapy.

Work and growth: A review of research on the impact of work experience on adolescent development.

Work has not been extensively studied as a context for adolescent development, even though increased work experience has been widely recommended as a means of improving the transition of adolescents to adulthood. Studies of the impact of work experience on adolescent socialization, defined broadly, suggest that work has beneficial results that persist over time. Developmental theorists and critics of conventional patterns of workplace organization remind us, however, that current knowledge is inadequate to specify optimal types and amounts of work experience for adolescents. Studies of narrower outcomes of work experience - career knowledge and plans, job-related attitudes, behavior, and skills - are less persuasive. An ecological strategy is recommended for future research. Such research should consider the varying effects of different kinds of work experience on different adolescents and should seek those effects in settings other than the workplace and over long periods.

Participatory-democratic work and adolescents' mental health.

Five arguments are advanced for the proposition that participatory-democratic workplaces best promote the mental health of adolescents. These arguments are based on (a) adolescent development theory, (b) research on adolescent work, (c) the goal of preparing adolescents to assume optimally healthful adult jobs, (d) the proposition that participatory-democratic work is optimal for all workers, and (e) the trend toward increased worker participation in adult workplaces. This rationale is given an initial test by means of case studies of three adolescent work settings, one of which was participatory-democratic by the authors' definition. Only the adolescents in this work setting showed statistically significant growth in work-related social reasoning as measured by a pre- and poststructural interview.

Aspirin for the prevention of vascular death in women.

OBJECTIVE: To review current information relevant to the use of aspirin for preventing vascular death in women, and to provide recommendations based on this information. DATA SOURCES: References from pertinent articles are identified throughout the text. DATA SYNTHESIS: Based on current information, low-dose aspirin is not recommended as primary prevention for cardiovascular death in women; efforts are better focused at promoting risk-factor reduction. Low-dose aspirin is recommended for reducing further cardiovascular morbidity and mortality in women with known cardiovascular disease. Women presenting with unstable angina or myocardial infarction should receive aspirin 325 mg as soon as the diagnosis is confirmed, and this dosage should be continued on a chronic basis. Women who have experienced transient ischemic attacks or ischemic stroke should receive aspirin 1000 mg/d, with a subsequent dosage reduction to 325 mg/d in patients who do not tolerate the higher dose. CONCLUSIONS: Current recommendations are based on the results of studies that involved few women. Further investigation of antiplatelet agents for primary and secondary prevention of vascular death in women is needed.

Rapid-release and coat-core formulations of nisoldipine in treatment of hypertension, angina, and heart failure.

Nisoldipine, a dihydropyridine calcium antagonist, has greater vascular selectivity than other calcium channel antagonists and does not depress the intact myocardium in vivo. It should be taken on an empty stomach. Both rapid-release and coat-core formulations are available for clinical use, but only the coat-core formulation extends antihypertensive, antiischemic, and antianginal effects throughout the dosing interval when given once daily. The coat-core formulation in daily doses of 10 to 40 mg does not cause the proischemic effects reported with the rapid-release formulation. When given as monotherapy, the coat-core formulation is highly effective in lowering blood pressure to a similar extent as other long-acting calcium channel blockers, diuretics, beta-blockers, or angiotensin-converting enzyme (ACE) inhibitors. The antihypertensive effects are potentiated when the coat-core formulation of nisoldipine is given in combination with lisinopril. In patients with stable angina pectoris nisoldipine coat-core increases exercise duration, reduces anginal frequency and myocardial ischemia, and is effective as monotherapy or in combination with a beta-blockers. In monotherapy the drug is as effective as other long-acting calcium channel blockers or a beta-blocker. The effects of nisoldipine coat-core in patients with heart failure are unclear at present.

Transdermal nitroglycerin patches in angina pectoris. Dose titration, duration of effect, and rapid tolerance.

The duration of effect of transdermal nitroglycerin patches was studied in 14 patients with angina pectoris. By titrating the dose to achieve specific circulatory effects, we chose a patch size that produced a consistent fall in systolic blood pressure of 10 mm Hg or greater for each patient (10 cm2 in 7 patients, 20 cm2 in 5, and 40 cm2 in 2; releasing 5, 10, and 20 mg of nitroglycerin per 24 hours, respectively). The effects of these individualized patches were compared with those of placebo patches. Compared with placebo, nitroglycerin patches increased exercise duration to the onset of angina (257 +/- 72 compared with 383 +/- 130 seconds, p less than 0.0001) and total exercise time (338 +/- 89 compared with 456 +/- 119 seconds, p less than 0.0001) and decreased ST segment depression (1.0 +/- 0.5 compared with 0.6 +/- 0.4 mm, p less than 0.05) at 4 hours but not at 24 and 48 hours. We conclude that nitroglycerin patches do not show objective evidence of antianginal or antiischemic effects for 24 hours. Tolerance to the circulatory and antianginal effects probably develops within 24 hours of patch application.