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PubMed1986

Influence of beta-blocker coadministration on the kinetics of isosorbide mononitrate and dinitrate.

The influence of beta-blocker coadministration on the kinetics of oral isosorbide-5-mononitrate (ISMN) and isosorbide dinitrate (ISDN) was studied in healthy volunteers. In the first study, 12 subjects ingested 20 mg ISMN on three occasions: in the control state, during coadministration of metipranolol (20 mg 3 times daily), or during metoprolol (100 mg twice daily). There were no significant differences among the three phases in peak serum ISMN concentration (470 ng/ml), the time of peak (0.6 h after dose), elimination half-life (4.5 h), or oral clearance (142 ml/min). In the second study, 10 subjects received 20 mg ISDN in the control state and again during coadministration of propranolol (80 mg 3 times daily). There were no differences between the two phases in peak serum ISDN concentration (20 ng/ml) or the time of peak (0.6 h). Propranolol increased, although not significantly, ISDN clearance (16.5 vs 12.3 L/min, P less than 0.1), and had no effect on total area under the curve for ISMN, the major metabolite of ISDN. Thus, therapeutic doses of these beta-blockers have a minimal influence on the kinetics of single doses of ISMN or ISDN in healthy individuals.

Adrenergic beta-Antagonists↗
PubMed2000

Treatment of acute strangulated internal hemorrhoids by topical application of isosorbide dinitrate ointment.

Exogenous nitric oxide has been shown useful in decreasing the internal anal sphincter tone. This study investigated the role of isosorbide dinitrate in the treatment of patients with acute strangulated internal hemorrhoids, thereby avoiding the risk of continence disturbances following conventional surgical treatment. Four male patients (median age 35 years, range 30-42) with acute strangulated hemorrhoids were treated with 1% isosorbide dinitrate. The ointment was applied to the anoderm. This application was repeated every 3 h during daytime for 2 weeks. Significant pain relief was achieved within 1 day, while transient mild headache was experienced during the first 2 days. Within 1 week the hemorrhoids became reducible. Thereafter the hemorrhoids could be treated adequately by rubber band ligation. The alternative treatment of patients with acute strangulation of prolapsed internal hemorrhoids is effective. This nonsurgical, i.e., reversible reduction of sphincter tone is an attractive alternative.

Acute Disease↗
PubMed2005

Comparison of isosorbide mononitrate (Mono Mack) and misoprostol (Cytotec) for cervical ripening in the first trimester missed abortion.

OBJECTIVE: The objective of this study was to compare NO-donor isosorbide mononitrate to misoprostol, both applied as vaginal tablets for cervical ripening prior to first trimester curettage in patients with missed abortion. MATERIALS AND METHODS: Thirty women with missed abortion were assigned after a random list to be treated either with 200 microg gemeprost (Cytotec, Pfizer, Germany) or with 40 mg isosorbide mononitrate for cervical priming at least 3 h before curettage. Vaginal bleeding or the intracervical presence of products of conception was documented. The largest number of Hegar's dilator, which could be introduced without difficulty and the largest number of Hegar's dilator at which cervical dilation was performed and the ease of mechanical dilation was assessed. RESULTS: There were no significant differences in cervical ripeness before procedure nor in ease of dilation. In the misoprostol group, the cervical canal was more dilated before any procedure (median of Hegar's dilator 6 vs. 5) and after dilation (median of Hegar's dilator 11 vs. 10), although this difference was not significant. Vaginal bleeding occurred in two patients in each group. Products of conception were only found in the cervix of one patient of the misoprostol group. SYNOPSIS: Vaginal application of isosorbidemononitrate in cervical priming prior to curettage abortion is as effective as vaginal application of misoprostol.

Abortifacient Agents, Nonsteroidal↗
PubMed1975

Hemodynamic and metabolic effects of isosorbide dinitrate in chronic congestive heart failure.

To assess the potential beneficial effects of a nonparenteral vasodilator, sublingual isosorbide dinitrate (5 to 15 mg.) was administered in 12 patients with chronic congestive heart failure refractory to conventional therapy. Hemodynamic measurements were performed before and at 15 minute intervals after drug administration for 90 minutes. Venous capacitance was measured at 5 minute intervals. Myocardial metabolism was also studied in five patients before and after drug administration. Hemodynamic effects were characterized by a modest decrease in mean arterial pressure (85 +/- 3 to 78 +/- 2 [S.E.M.] mm. Hg) and substantial decrease in right atrial (10 +/- 1 to 6 +/- 1), pulmonary arterial (39 +/- 4 to 30 +/- 4) and pulmonary capillary wedge pressures (28 +/- 2 to 21 +h- 2). These changes were accompanied by an increase in venous capacitance (2.46 +/- 0.16 to 3.99 +/- 0.24 c.c./100 c.c. of tissue). Along with a decrease in left ventricular filling pressure, cardiac index increased (1.99 +/- 0.13 to 2.37 +/- 0.15 L./min/M.2). No significant effect on heart rate was seen. Delta P/delta t, an index related to left ventricular dp/dt, increased in all but one patient (253 +/- 31 to 298 +/- 39 mm. Hg/sec.) (p less than 0.02 for all changes) in the face of decreased preload and afterload and unchanged heart rate, suggesting improved contractile state. A decrease in coronary blood flow (165 +/- 13 to 131 +/- 15 c.c./min.) and myocardial oxygen consumption (18.1 +/- 1.6 to 14.5 +/- 1.6 c.c./min.) was noted (p less than 0.02). No change in arterial-coronary sinus oxygen difference or lactate extraction was observed. These data demonstrate that the objectives of therapy in congestive heart failure, namely improved forward output and decreased ventricular filling pressures, can be achieved without metabolic deterioration by using sublingual isosorbide. The mechanisms responsible are related to diminished impedence to ventricular ejection and peripheral pooling of blood. Since the duration of action does not usually exceed 90 minutes, frequent drug administration may be a source of patient inconvience.

Administration, Oral↗
PubMed1985

Pharmacokinetics and pharmacodynamics of isosorbide dinitrate.

It has long been believed that organic nitrates, including isosorbide dinitrate (ISDN), are completely metabolized during their first passage through the liver and that oral therapy with this class of compounds is thus irrational. In the past few years, convincing data have been obtained in patients showing that intact ISDN is significantly bioavailable to the systemic circulation after oral administration; the oral bioavailability is about 20% relative to an intravenous dose and about 45% relative to a sublingual dose, with the balance metabolized to isosorbide mononitrates. These pharmacologically active metabolites have longer biologic half-lives than ISDN and are thus believed to contribute to the sustained duration of action of this drug. After acute dosing, changes in the pharmacologic effects of ISDN mirror those in plasma concentration. However, after long-term therapy, partial nitrate tolerance develops despite elevated plasma ISDN concentrations. Available evidence suggests that during sustained dosing, nitrate metabolism is generally reduced throughout the body; thus reduced hepatic and peripheral tissue metabolism raises plasma ISDN concentrations while reduced vascular tissue metabolism decreases the metabolic activation (perhaps to nitrosothiols?) necessary for vascular relaxation.

Administration, Oral↗
PubMed1985

Role of isosorbide dinitrate in management of chronic congestive heart failure.

Congestive heart failure is accompanied by a number of compensatory mechanisms that may overshoot the mark. Among these are excessive arteriolar and venous constriction. Nitrates are effective in producing venodilation, redistributing blood from the chest to the periphery, and lowering right and left atrial pressures. Although oral isosorbide dinitrate is effective in producing acute beneficial hemodynamic effects, it usually does not increase exercise tolerance in the short term. Prolonged administration, however, does increase exercise tolerance and improve clinical class. Isosorbide dinitrate can be effectively combined with an arteriolar dilator such as hydralazine, which increases cardiac output. Such vasodilator therapy is symptomatically effective in patients with heart failure, although there is no evidence to date to suggest a prolongation of life.

Administration, Oral↗
PubMed1985

Coronary artery dilation and hemodynamic responses after isosorbide dinitrate therapy in patients with coronary artery disease.

The response to sublingual isosorbide dinitrate (ISDN) was studied in 10 men with suspected coronary artery disease undergoing coronary arteriography. A Swan-Ganz catheter was placed in the pulmonary artery to record hemodynamic response. Diseased coronary segments were identified during routine Judkins selective coronary angiograms. Sublingual isosorbide dinitrate (ISDN) (5 or 10 mg) was then given with the catheters in place. Multiple sequential single-view coronary angiograms and pulmonary and systemic hemodynamic responses were recorded over 30 minutes after drug administration. At 30 minutes, there was a 53% reduction (p less than 0.01) in pulmonary capillary wedge pressure and a 15% decrease (p less than 0.05) in systemic and pulmonary vascular resistance, with a net 13% decrease (p less than 0.01) in cardiac output and 20% decrease (p less than 0.01) in mean arterial pressure. Quantitative arteriography demonstrated substantial dilation of luminal cross-sectional area in both normal and diseased coronary arterial segments. Normal epicardial segments were grouped according to luminal area (1 to 4, 4 to 8 and more than 8 mm2) and demonstrated maximal area dilation at 10 minutes of 55% (p less than 0.01), 29% (p less than 0.01) and 16% (p less than 0.05), respectively. Diseased epicardial segments (stenosis 50% or greater) dilated 51% (p less than 0.01) at 10 minutes. Calculated stenosis resistance decreased 40% (p less than 0.01). Diseased segments in small and middle-sized arteries (1 to 8 mm2) are 4 times more reactive than those in larger arteries (more than 8 mm2), with peak dilation of 77 vs 21% (p less than 0.01) at 30 minutes.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiography↗
PubMed1986

Acute and sustained effects of isosorbide 5-mononitrate in stable angina pectoris.

Isosorbide 5-mononitrate (IS 5-MN) is an active metabolite of isosorbide dinitrate and is widely used as an antianginal agent. The acute and subacute (2 weeks) effects of IS 5-MN, 40 mg twice daily, were evaluated in 18 patients with stable angina pectoris using computerized exercise testing and a placebo-controlled, double-blind, randomized trial protocol. There were 2 phases of 2 weeks each in which patients received placebo or active IS 5-MN. Acute testing (8 patients) was performed 2 hours after the first dose and subacute testing 2 hours after the morning dose on day 14. Acute testing showed an increase in exercise time from a mean (+/- standard error of mean) of 8.2 +/- 0.6 minutes to 11.1 +/- 0.5 minutes (p less than 0.001) after a single dose of IS 5-MN. Time to 1 mm of ST depression increased significantly and peak exercise ST-segment depression decreased significantly. Rest and peak exercise heart rate increased significantly during acute testing with IS 5-MN; blood pressure did not change significantly. After 2 weeks of therapy, exercise time had not changed (9.9 +/- 0.6 with placebo to 9.7 +/- 0.6 minutes). The beneficial effects on ST-segment variables were sustained at 2 weeks. The data suggest that there is an attenuation of effect with respect to exercise time and sustained beneficial effect on the ST-segment variables. This may be a result of development of partial tolerance to IS 5-MN after 2 weeks of therapy.

Adult↗
PubMed1987

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.

Aged↗
PubMed1987

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.

Adult↗
PubMed1988

Sustained-release isosorbide mononitrate (50 mg): optimization of a once-daily dosage form for long-term treatment of angina pectoris.

A capsule formulation containing 50 mg of isosorbide mononitrate has been developed, 30% of which is in a nonsustained-release form to ensure rapid attainment of initial plasma levels. The remaining 70% is in a sustained-release form that ensures a long-lasting effect and the convenience of once-daily dosing. This formulation of sustained-release isosorbide mononitrate (Elantan LA 50 mg) provides plasma levels greater than 100 ng/ml for 17 hours after oral administration. For the remaining 7 hours, the nitrate plasma level ranges between 50 and 100 ng/ml.

Adolescent↗
PubMed1988

Acute effect of various doses of isosorbide-5-mononitrate on hemodynamic and exercise performance in coronary artery disease.

The optimal dose of nitrates is still controversial, as chronic usage of too high a dose may result in a decrease in vascular response. The dose should be determined to reduce preload acutely, and not to decrease the activity during chronic therapy. To determine this dose, 50 patients with angiographically confirmed coronary artery disease were studied. The effects on heart rate and mean systemic and pulmonary arterial pressures at rest and during exercise, and work capacity and duration were measured. The patients were classified into 5 groups, receiving placebo or isosorbide-5-mononitrate, 5, 10, 20 and 50 mg, respectively, as a single oral dose. Placebo had no effect on the measured parameters. All doses of isosorbide-5-mononitrate reduced mean pulmonary arterial pressure: 10 mg--by 16% at rest and 24% during exercise; 20 mg--24% and 34%, respectively (a near maximal effect); and 50 mg--27% and 38%. Similar results were found also for work capacity: 10 mg increased work capacity by 33%; 20 mg--79%; and 50 mg--56%. Thus, the therapeutically optimal single dose is about 20 mg. Higher doses produce no additional benefit and increase the risk for tolerance development.

Adult↗
PubMed1989

Comparison of nifedipine, propranolol and isosorbide dinitrate on angiographic progression and regression of coronary arterial narrowings in angina pectoris.

Calcium antagonists and beta blockers may retard or inhibit atherogenesis. This study investigated whether nifedipine or propranolol influences coronary atherosclerosis in humans. In selected patients with effort angina and proven coronary artery disease, the cineangiographic pattern after 2-year therapy with nifedipine (group 1, 39 patients), propranolol (group 2, 36 patients) or isosorbide dinitrate (group 3, 38 patients) was compared to that before treatment. The disease evolved to a different extent in the 3 groups. Patients with evidence of progression of old narrowings and appearance of new narrowings were significantly fewer in group 1 (31% and 10%) than in group 2 (53% and 34%) and group 3 (47% and 29%). The number of stenoses with evidence of progression was significantly smaller after nifedipine (14), and larger after propranolol (39) compared with group 3 (24). Thus, nifedipine seemed more protective than the other 2 drugs against coronary atherosclerosis. The coronary risk factors were normal in the nifedipine group and remained so with treatment, suggesting that they were dissociated from influences on atherosclerosis. The evolution, as judged by the number of narrowings with progression, appeared significantly (p less than 0.01) worse with propranolol than with isosorbide dinitrate. Propranolol caused unfavorable modifications of serum lipids; there was a 28% increase in total triglycerides and a 25% decrease in high density lipoprotein cholesterol at 12 months in group 2.

Angina Pectoris↗
PubMed1989

Sustained effect of and lack of development of tolerance to controlled-release isosorbide-5-mononitrate in chronic stable angina pectoris.

Tolerance has been shown to develop when nitrate preparations are used in such a manner as to produce plasma levels within the therapeutic range continuously over a 24-hour period. However, a period of reduced or low nitrate plasma levels of a few hours per day may limit or completely prevent tolerance development. In 18 patients with chronic stable angina pectoris, a single 60-mg daily dose of a controlled-release preparation of isosorbide-5-mononitrate (ISMN) was compared with the administration of 30 mg, 4 times daily, of immediate-release isosorbide dinitrate (ISDN) in a double-blind, randomized, placebo-controlled, crossover study. The comparisons were carried out on the first day of therapy and after 11 to 14 days of continuous therapy to assess the duration of effectiveness and the development of tolerance. On short-term therapy, both drugs produced a significant improvement in treadmill walking times to moderate angina in comparison with placebo. The values for ISMN were 87 +/- 99 seconds (23%) at 12:30 P.M., 72 +/- 91 seconds (19%) at 5 P.M. and 51 +/- 81 seconds (13%) at 8:30 P.M. For ISDN, the respective values were 71 +/- 83 seconds (19%), 89 +/- 98 seconds (24%) and 79 +/- 87 seconds (21%). There were no significant differences between drugs. Plasma nitrate levels for each drug paralleled the improvements in exercise performance.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Efficacy of isosorbide mononitrate in angina pectoris.

The rapid development of tolerance has limited the applicability of oral and transdermal nitrates in the long-term management of patients with chronic stable angina pectoris. Recent well-controlled trials have demonstrated that asymmetrical, or eccentric, dosing of oral isosorbide mononitrate, in which 20-mg doses are taken at 8 A.M. and 3 P.M., provides at least 12 hours of antianginal coverage. There is no evidence for the development of tolerance with this schedule, which allows for a 17-hour nitrate withdrawal period. Likewise, the asymmetrical 20-mg twice daily regimen has not been associated with the zero-hour effect that has been reported with higher oral doses of isosorbide mononitrate and with intermittent nitroglycerin patch therapy. This approach also avoids the development of a clinical rebound phenomenon, as measured by increased episodes of angina and nitroglycerin consumption, compared with the pretreatment period, during the nitrate-free interval at night and the early hours of the morning.

Angina Pectoris↗
PubMed1983

Sex-related difference in the metabolism of isosorbide dinitrate following incubation in human blood.

Isosorbide dinitrate (ISDN) (at a concentration of 100 ng/ml) was incubated aerobically at 37 degrees in whole blood from five male and five female normal volunteers. Following incubation of the blood samples for 0, 30, 60, 120, 240 and 360 min, the samples were centrifuged and the plasma was assayed for ISDN. A linear relationship was observed between the logarithm of the concentration of ISDN remaining and incubation time, and there was a significant difference between the T1/2 of ISDN in blood from males (90.6 min) and females (161.4 min). Very little ISDN metabolism was observed when ISDN was incubated with plasma rather than whole blood. When erythrocytes, resuspended in saline, were incubated with ISDN, there was a time-dependent loss of ISDN from the saline incubation medium. Investigation of the soluble fraction obtained after hemolysis of these erythrocytes also showed a time-dependent loss of ISDN. The saline incubation medium contained sufficient concentrations of the two major ISDN metabolites (isosorbide 2- and 5-mononitrate) to account for the observed disappearance of ISDN. The results indicate that ISDN is metabolized in the cellular compartment of blood and that the metabolic rate in males is greater than that in females.

Adult↗
PubMed1987

Comparison of the inhibitory effects of nicorandil, nitroglycerin and isosorbide dinitrate on vascular smooth muscle of rabbit aorta.

The inhibitory effects of nicorandil, nitroglycerin and isosorbide dinitrate on the contractions induced by 10(-6) M norepinephrine or by 65.4 mM K+ were compared in the vascular smooth muscle of rabbit aorta. These compounds relatively selectively inhibited the contraction induced by norepinephrine. Norepinephrine induced a sustained contraction in the aorta depolarized with high K+ and treated with 10(-6) M verapamil, and this contraction was also inhibited by these compounds. The increase in Ca2+ influx induced by norepinephrine, but not by high K+, was inhibited by the three compounds. The norepinephrine-induced transient contraction, which is due to release of stored Ca2+, was inhibited by these compounds. The inhibitory effects of nicorandil and nitroglycerin on this contraction were attenuated by high-K+ depolarization. Methylene blue (10(-5) M) antagonized and M&B 22948 (10(-5) M) potentiated the inhibitory effects of these compounds. These results suggest that nicorandil, nitroglycerin and isosorbide dinitrate have a similar mechanism of action. These compounds inhibit the norepinephrine-induced sustained contraction possibly by inhibiting the Ca2+ influx through receptor-linked Ca2+ channels, and inhibit the transient contraction by membrane hyperpolarization and also by direct inhibition of Ca2+ release although other mechanism of action may also be involved.

Animals↗
PubMed1989

Reduction of portal pressure by isosorbide-5-mononitrate in patients with cirrhosis. Effects on splanchnic and systemic hemodynamics and liver function.

The results of a study to characterize the effects of the oral administration of isosorbide-5-mononitrate (Is-5-Mn), the active metabolite of isosorbide dinitrate, on portal hypertension in 23 patients with cirrhosis are reported. Patients received 20 mg of Is-5-Mn (n = 10), 40 mg (n = 9), or a placebo (n = 4). No significant changes were observed after the administration of the placebo. However, both doses of Is-5-Mn significantly reduced portal pressure, as evaluated by measurements of the hepatic venous pressure gradient. The fall in portal pressure averaged 10% after the 20-mg dose and 18% after 40 mg and was maintained for the 2 h of observation. Reduction of portal pressure was due to a decrease in the wedged hepatic vein pressure, with no changes in the free hepatic venous pressure. After the 20-mg dose, the decrease in portal pressure was associated with an increase in hepatic blood flow (16%), suggesting a fall in hepatic vascular resistance. However, after the 40-mg dose, a reflex splanchnic vasoconstriction elicited by the fall in arterial pressure (-19%) appeared to contribute to the greater reduction in portal pressure, as suggested by a significant decrease in azygos blood flow (-15%). These beneficial effects on portal pressure were not associated with adverse effects on liver function, as evaluated by measurements of the hepatic clearance of indocyanine green and the hepatic intrinsic clearance. Neither dose of Is-5-Mn caused significant changes in these quantitative parameters of liver function. These findings suggest that Is-5-Mn could be a potentially useful and safe agent in the treatment of portal hypertension.

Adult↗