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Effects of isosorbide-5-mononitrate on exercise-induced hemodynamic changes in angina pectoris.

Hemodynamic effects of isosorbide-5-mononitrate (ISMN) were studied in 14 patients with effort angina pectoris. Hemodynamic and echocardiographic data were obtained by angina-limited supine multistage bicycle ergometer exercise testing before and 120 minutes after single oral administration of 20 mg of ISMN. Compared with control exercise testing, the ST segment at peak exercise showed less depression after administration of ISMN (p less than 0.001). At rest, systolic and diastolic blood pressure decreased significantly after administration of ISMN (p less than 0.001 and p less than 0.01, respectively). At rest and at peak exercise, pulmonary artery wedge pressure (both p less than 0.001), left atrial volume (both p less than 0.001) and left ventricular end-diastolic volume (both p less than 0.05) decreased, whereas cardiac index, pressure-rate product and systemic vascular resistance did not change significantly after administration of ISMN. Average time to peak plasma ISMN concentration was 90 minutes and average peak plasma concentration was 460 ng/ml with an elimination half-life of 7 hours. These data suggest that the main mechanism of the antianginal action of ISMN is a reduction in left ventricular preload followed by diminution of myocardial oxygen requirements.

Adult↗

Antihypertensive effect of sustained-release isosorbide dinitrate for isolated systolic systemic hypertension in the elderly.

A double-blind, randomized trial was performed in 40 patients, mean age (+/- standard deviation) 80 +/- 4 years, with isolated systolic systemic hypertension to evaluate the antihypertensive effect of oral sustained-release isosorbide dinitrate (ISDN), 20 to 40 mg twice daily, vs placebo. After 12 weeks of treatment, supine systolic blood pressure (BP) decreased from 192 +/- 10 to 162 +/- 12 mm Hg with ISDN (p less than 0.001) and from 189 +/- 10 to 175 +/- 15 mm Hg with placebo (p less than 0.001). On the basis of variance analysis, the decrease in systolic BP was significantly lower with ISDN (27 mm Hg) than with placebo (13 mm Hg). Similar results were observed for supine and erect systolic BP measured at 8 AM and 4 PM, 8 and 12 hours after drug intake. No significant differences in diastolic BP, heart rate or side effects occurred. After the ISDN tapering off-period (2 weeks), systolic BP increased significantly but did not change with placebo. The study provided evidence that in elderly patients with systolic hypertension, sustained-release ISDN induced a selective and sustained decrease in systolic BP, antihypertensive effect was observed 8 and 12 hours after drug administration, and no tolerance phenomenon was noted.

Aged↗

More rapid relief of pain with isosorbide dinitrate oral spray than with sublingual tablets in elderly patients with angina pectoris.

To evaluate the possibility of improving clinical practice in the treatment of angina pectoris, the duration of relief of pain with isosorbide dinitrate (ISDN) oral spray and sublingual tablets were compared in elderly patients with chronic stable angina pectoris. Nine patients (mean age 67 years) were studied in a randomized crossover trial. The patients underwent bicycle ergometry, which resulted in typical chest pain associated with electrocardiographic ST-segment depression in all 9. The patients received ISDN oral spray or sublingual tablets immediately on termination of exercise. At least 6 hours later another ergometry test was performed and the patients were crossed over to the other drug. ISDN spray relieved pain in all patients at a mean duration of 61.6 +/- 24.4 seconds after administration, whereas the duration of relief of pain by ISDN sublingual tablets was 112.4 +/- 70 seconds. The difference was highly significant (p less than 0.0005). It is concluded that clinical practice of treatment of angina pectoris in the elderly can be improved by using ISDN oral spray rather than sublingual tablets. The spray is effective at twice the rapidity of the sublingual tablet.

Administration, Oral↗

Increased exercise tolerance and reduced duration of ischemia after isosorbide dinitrate oral spray in angina pectoris.

The prophylactic and therapeutic anti-ischemic efficacy of isosorbide dinitrate (ISDN) oral spray was assessed in 10 patients with coronary artery disease and stable angina pectoris. The patients entered a randomized crossover study of ISDN spray and placebo, involving bicycle exercise testing. Each patient underwent 2 exercise tests at least 4 hours apart. Immediately before initiation of exercise they received either ISDN spray or placebo and crossed over during the other test. ISDN spray delayed the onset of anginal pain by about 40%, from a mean of 5.1 +/- 1.4 minutes with placebo to 7.2 +/- 1.3 minutes with the active drug (p less than 0.001). Time of onset of ST-segment depression was also significantly prolonged, from 7.1 +/- 1.5 minutes with placebo to 10.2 +/- 1.2 minutes with ISDN (p less than 0.001). The patients achieved a higher double product at onset of pain with ISDN than with placebo. The drug also reduced the time of disappearance of pain after discontinuation of exercise from 3.2 +/- 0.7 to 2.1 +/- 0.8 minutes (p less than 0.001), and the time of disappearance of electrocardiographic changes from 4.2 +/- 0.6 to 2.5 +/- 0.8 minutes (p less than 0.005). These findings indicate that oral ISDN spray is an effective prophylactic for exercise-induced angina. Its rapid onset of action makes it especially suitable for usage immediately before exercise.

Administration, Oral↗

Comparative evaluation of isosorbide-5-mononitrate and nitroglycerin in chronic congestive heart failure.

The hemodynamic effects of isosorbide-5-mononitrate (IS-5-MN) and nitroglycerin were compared in 10 patients with chronic congestive heart failure (CHF). Both drugs were given intravenously, at an infusion rate individually titrated to achieve a maximal increase in cardiac output and a maximal decrease in pulmonary capillary wedge pressure. Both drugs produced the typical hemodynamic responses to nitrates, the most prominent of which were decreases in pulmonary capillary wedge, pulmonary arterial and right atrial pressures, and an increase in cardiac output. Several differences in the response to these 2 drugs were observed. Pulmonary capillary wedge pressure was reduced from 31.5 +/- 3.0 to 19.6 +/- 5.0 mm Hg with nitroglycerin and to 15.0 +/- 3.12 mm Hg with IS-5-MN. Both the absolute and the percent decrease with IS-5-MN were significantly greater (p less than 0.05) than those observed with nitroglycerin. Mean systemic arterial pressure was reduced from 89.2 +/- 11.3 to 79.8 +/- 10.8 with IS-5-MN (difference not significant) and to 67.5 +/- 7.7 mm Hg with nitroglycerin (p less than 0.01). The difference, both in absolute and percent reductions, was statistically significant. Thus, in patients with chronic CHF, IS-5-MN produced a greater decrease in pulmonary capillary wedge pressure (the major beneficial effect of nitrates in this condition) and a smaller decrease in systemic arterial pressure (the potentially deleterious effects of nitrates). These findings indicate a potential advantage of IS-5-MN over nitroglycerin in patients with CHF, particularly in those with CHF of ischemic etiology.

Aged↗

Emergency treatment of severe cardiogenic pulmonary edema with intravenous isosorbide-5-mononitrate.

Intravenous isosorbide-5-mononitrate (IS-5-MN) was administered to 24 patients, mean age 73, with severe respiratory distress after pulmonary edema and acute left heart failure. The condition was due to ischemic cardiopathy in 18 patients (4 with acute myocardial infarctions), congestive cardiomyopathy in 3, hypertensive cardiopathy in 2, and mitral valvular disease in 1. Therapy consisted of an intravenous (i.v.) bolus dose of IS-5-MN, followed by a continuous infusion (mean 8 mg/hour over 24 hours) of i.v. furosemide and additional oxygen. Clinical data were recorded as well as blood gas values and repeated chest radiographs. All patients survived and improved markedly; only 6 needed mechanical ventilation. Most patients had fast respiratory relief, with no untoward reaction, except a brief decrease of blood pressure in a ventilated patient taking morphine. These data indicate that i.v. IS-5-MN is effective and safe for the management of severe acute cardiogenic pulmonary edema.

Acute Disease↗

Dose-ranging study of isosorbide-5-mononitrate in chronic congestive heart failure treated with diuretics and angiotensin-converting enzyme inhibitor.

The hemodynamic response of isosorbide-5-mononitrate (IS-5-MN) to the addition of the widely used therapy of diuretic drugs and the maximally tolerated dose of enalapril for heart failure was assessed in 8 patients with congestive heart failure (CHF) (New York Heart Association class II and III). The diuretic therapy was furosemide, 40 to 80 mg/day, with or without amiloride, 5 to 10 mg/day. The dose of enalapril was 5 to 20 mg/day. Four hours after the administration of the morning dose of enalapril, a Swan-Ganz catheter was positioned in the pulmonary artery. Patients received increasing doses of IS-5-MN to produce a satisfactory decrease in pulmonary capillary wedge pressure. Two of the first 3 patients studied had a large reduction in blood pressure when given 10 mg of IS-5-MN. Subsequent patients were therefore given an initial dose of 5 mg, the total dose being 5 to 20 mg over 2 hours. Results at baseline and 1 hour after the final dose of IS-5-MN are expressed as mean +/- standard deviation. Both pulmonary artery systolic and diastolic pressures decreased significantly (p less than 0.05) by 12.2 +/- 8.9/4.2 +/- 5.2 mm Hg, from 47.2 +/- 16.0/21.6 +/- 6.0 mm Hg to 35.0 +/- 15.2/17.4 +/- 9.3 mm Hg. Pulmonary capillary wedge pressure decreased by 8.6 +/- 4.4 mm Hg, from 22.1 +/- 5.4 to 13.6 +/- 7.5 mm Hg (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

Intravenous isosorbide dinitrate during open-heart surgery and its role in the treatment of right-sided congestive heart failure.

Recent awareness of the importance of the functional integrity of the right ventricle and the effect of raised pulmonary vascular resistance on cardiac output after cardiopulmonary bypass has focused attention on means of protecting right ventricular myocardium and reducing right ventricular afterload during open-heart surgery. A study of the acute effects of bolus intravenous isosorbide dinitrate (ISDN) has shown that after cardiopulmonary bypass, bolus intravenous ISDN produced highly significant (p less than 0.001) decreases in mean pulmonary arterial pressure (13%), pulmonary vascular resistance (23%) and the ratio of pulmonary to systemic vascular resistance (20%), indicating that active pulmonary vasodilation had occurred in the absence of other hemodynamic changes. The results suggest that possibly the acute effect of low-dose ISDN after cardiopulmonary bypass is predominantly exerted on the right ventricular afterload if systemic arterial pressure is not elevated. Two different clinical situations are described in which intravenous ISDN proved beneficial, one being acute pulmonary hypertension after protamine sulphate and the second being acute right-sided congestive heart failure with systemic hypotension unresponsive to conventional therapeutic measures. Thus, ISDN may prove a useful agent for alleviating right ventricular dysfunction at a time of not infrequent cardiovascular instability, the period after bypass.

Cardiac Surgical Procedures↗

Effects of long-term treatment with 120 mg of sustained-release isosorbide dinitrate and 60 mg of sustained-release nifedipine on myocardial perfusion.

Forty patients with coronary artery disease and scintigraphically proven myocardial ischemia were randomized into 2 groups receiving 4 weeks of treatment with either 120 mg of isosorbide dinitrate (ISDN) release or 60 mg of nifedipine release. Control exercise testing and myocardial scintigraphy were continued until anginal pains occurred, and repeated at identical individual workloads at the end of the 4 weeks of drug therapy. Myocardial scintigrams were evaluated by quantitative recording of counts in 60 segments/frame. Twenty patients in the ISDN group (group I) exhibited 47 significantly ischemic areas. The remaining 20 patients (group II), treated with nifedipine, had 50 ischemic areas before therapy. In the ischemic areas in group I, there was a mean difference of 30.9% between counts at rest and during exercise in the pretreatment period, and a difference of 18.1% after therapy (39.0%). In group II, the pretreatment difference was 28.8%, decreasing to 20.6% after therapy (17.8%). Both groups of patients were subsequently subdivided into 3 subsets: (1) significantly improved perfusion, (2) significant worsening, and (3) unchanged myocardial perfusion. Group I had 59.5% of areas with significant improvement and 10.6% of areas with significant worsening. In 29.7% of the areas, the findings were unchanged. Group II had improvement in 40% of areas, of significantly worsened areas in 6%, and unchanged areas in 54%, in both groups myocardial ischemia was reduced by therapy, but ISDN improved myocardial perfusion to a considerably greater extent than did nifedipine.

Adult↗

Effects of isosorbide dinitrates intravenously in high doses over a short period in anterior acute myocardial infarction.

The effects of intravenous isosorbide dinitrate administered in high doses over a short period of time in 17 patients (14 men, 3 women, mean age 67 years) with anterior wall acute myocardial infarction were evaluated. Patients were classified into 2 groups based on the electrocardiographic pattern of acute ischemia. Patients presented with anterior acute myocardial infarction; an electrocardiographic pattern of third-degree ischemia demonstrated a more favorable electrocardiographic and radionuclear angiographic evolution than similar patients who presented with an electrocardiographic pattern of second-degree ischemia.

Adult↗

Effects of a single dose of isosorbide-5-mononitrate on the left ventricular diastolic function in systemic hypertension.

The effect of a single dose of isosorbide-5-mononitrate on left ventricular (LV) diastolic function was assessed by radionuclide ventriculography in 18 hypertensive patients. The effect of the mononitrate on atrial filling also was assessed. As expected, there was a significant decrease in mean blood pressure (120 +/- 17 to 102 +/- 18 mm Hg, p less than 0.005). Global LV ejection fraction did not show a significant change, increasing slightly from 64 +/- 9 to 68 +/- 8% (difference not significant). The mononitrate prolonged the time to peak filling rate from 176 +/- 36 to 195 +/- 29 ms (p less than 0.0001). The percentage of time to peak filling rate from diastole also increased, from 46 to 53% (p less than 0.05), whereas the normalized peak filling rate did not change (2.36 +/- 0.6 to 2.31 +/- 0.6 end-diastolic volumes/s, difference not significant). This effect on LV diastolic function was closely related to a certain reduction in preload, as suggested by the reduction in mean left atrial filling (45 +/- 12 to 40 +/- 13 counts/s, p less than 0.005) and LV diastolic counts, suggesting that the "impairment" of diastolic function induced by nitrates is secondary to the reduction in venous return to the left atrium. The mononitrate did not affect the mean right atrial filling rate (50 +/- 12 to 52 +/- 13 counts/s) and the right ventricular end-diastolic counts, suggesting a primary vasodilatory effect of nitrates on the pulmonary vascular bed.

Adult↗

Effects of sublingual nitrate in patients receiving sustained therapy of isosorbide dinitrate for coronary artery disease.

To examine the effects of sublingual isosorbide dinitrate (ISDN) in patients receiving sustained ISDN therapy, 24 patients with coronary artery disease were divided into 2 groups. Group C comprised 12 patients without sustained ISDN therapy and group N included 12 patients with sustained ISDN therapy. Before and during administration of sublingual ISDN in both groups, aortic systolic pressure, left ventricular end-diastolic pressure and coronary artery diameter were examined at cardiac catheterization. During sublingual ISDN, the aortic systolic pressure decreased by 20 +/- 6% (138 +/- 26 to 112 +/- 27 mm Hg, p less than 0.01) in group C and 10 +/- 6% (127 +/- 26 to 113 +/- 23 mm Hg, p less than 0.01) in group N (p less than 0.01, group C vs group N). The left ventricular end-diastolic pressure decreased by 65 +/- 16% (11 +/- 5 to 4 +/- 3 mm Hg, p less than 0.01) in group C and 43 +/- 14% (12 +/- 5 to 7 +/- 3 mm Hg, p less than 0.01) in group N (p less than 0.01, group C vs group N). During sublingual ISDN, the diameters of the proximal and distal segments of the left anterior descending and circumflex coronary arteries increased more significantly in group C than in group N (p less than 0.01, group C vs group N). Thus, sublingual ISDN produced less reduction of aortic systolic pressure and left ventricular end-diastolic pressure, and less dilation of coronary artery diameter in patients receiving sustained therapy with ISDN than in those without sustained therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Sublingual↗

Evaluation of the efficacy and duration of action of isosorbide mononitrate in angina pectoris.

The magnitude and duration of the antianginal and anti-ischemic effects of isosorbide mononitrate (IS-5-MN), 20 mg, were determined in 10 patients with chronic stable angina pectoris. An exercise test (treadmill, Bruce protocol) was performed before and at 1, 6, 8 and 10 hours after oral administration of the drug. The patients were randomly assigned to receive IS-5-MN or placebo, and after 1 week of therapy were crossed over to the other formulations. The drug increased the exercise duration from 321 to 455 seconds at 1 hour (p less than 0.001). Time to moderate angina increased from 237 to 324 seconds (p less than 0.05) and time to ST depression greater than or equal to 1 mm increased from 150 to 307 seconds (p less than 0.01) at 1 hour. Placebo had no effect on any of the exercise parameters. Although partially attenuated at 6 hours, the effect of IS-5-MN remained statistically significant even at 8 hours, but not at 10 hours. It is concluded that the duration of action of a single tablet of IS-5-MN, given orally, is 8 hours.

Adult↗

Interval treatment of coronary artery disease with sustained-release isosorbide-5-mononitrate.

The possibility of maintaining preload reduction and enhancement of exercise tolerance during an interval treatment with 50 mg/day of sustained-release isosorbide-5-nitrate (IS-5-N) was investigated in 13 patients (aged 54.4 +/- 7.9 years [mean +/- standard deviation]) with angiographically confirmed coronary artery disease and chronic stable angina pectoris. The effects of a single dose (acute test) were compared with those following an 8-day (chronic) regimen of mononitrate administration. Two hours after administration of 50-mg sustained-release IS-5-N, mean resting pulmonary arterial pressure (PAP), measured with a Swan-Ganz catheter, was reduced by 27% (p less than 0.01), and at submaximal exercise level (50 W, 3 minutes) by 34% (p less than 0.001). At individually highest comparable work loads mean PAP was reduced by 28% (p less than 0.01), and at maximal work load the PAP reduction was 21% (p less than 0.05). At the end of 1 week of therapy with sustained-release IS-5-N a slight, clinically irrelevant reduction of hemodynamic effects was recorded. Work capacity increased after 1 hour by 60% (408 +/- 104 vs 653 +/- 147 W x min, p less than 0.001)--still significantly above baseline 10 hours after nitrate administration. No difference from baseline was demonstrable 24 hours after medication. During interval therapy the improved work capacity was fully maintained (chronic, 1 hour: 417 +/- 93 vs 679 +/- 160 W x min, p less than 0.001). During interval therapy with sustained-release IS-5-N, hemodynamics and exercise tolerance were durably improved.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Prevention of creatine kinase-MB release in coronary artery disease and pacing-induced myocardial ischemia by isosorbide dinitrate spray.

The effect of isosorbide dinitrate (ISDN) spray on release of the isoenzyme creatine kinase-MB (CK-MB) after myocardial ischemia induced by atrial pacing was evaluated in 8 patients with coronary artery disease. Atrial pacing to ischemia (ST-segment depression of greater than or equal to 1.5 mm for greater than or equal to 80 ms) resulted in elevation of CK-MB levels in plasma drawn from the coronary sinus, from 1.8 +/- 1.5 to 6.8 +/- 7.0 ng/ml (p less than 0.001) at 30 minutes after onset of ischemia. When atrial pacing was repeated at the same rate after 1 squirt of ISDN spray, 1.25 mg, the CK-MB levels were not altered despite significant ischemic ST-segment depression. It is concluded that ISDN prevents the process responsible for myocardial release of CK-MB, being either micronecroses or a reversible consequence of ischemia.

Administration, Oral↗

A dose-finding study of the hemodynamic effect of isosorbide dinitrate spray in congestive heart failure.

A dose-finding study of the hemodynamic effect of a new formulation of isosorbide dinitrate (ISDN) spray was performed in 12 patients with chronic congestive heart failure. Doses of 1.25, 2.5, 5.0 mg and placebo, as 1 squirt, were randomly given to all patients. Hemodynamic measurements were performed by a Swan-Ganz catheter before and at 30 seconds and 1, 5, 10, 20 and 30 minutes after drug administration and every 30 minutes thereafter, until return of hemodynamic variables to baseline. Hemodynamic improvement evident as decreases in right-sided pressures and an increase in cardiac output was observed within 1 minute from administration of ISDN spray, and peaked at 5 minutes. Near maximal effect was achieved by the 2.5-mg dose. Thus, 2.5 mg of ISDN spray (new formulation) dose. Thus, 2.5 mg of ISDN spray (new formulation) produces rapid, near-maximal hemodynamic improvement in patients with congestive heart failure.

Administration, Oral↗

Comparative evaluation of a new formulation of isosorbide dinitrate oral spray and sublingual nitroglycerin tablets.

The magnitude and time course of the hemodynamic effect of a new formulation of an aqueous solution of isosorbide dinitrate (ISDN) spray were compared with those of sublingual nitroglycerin (NTG) tablets in 12 patients with chronic congestive heart failure. The patients received, in a random order, ISDN spray, 2.5 mg, or sublingual NTG, 0.8 mg. Hemodynamic measurements were performed before and at 1, 3, 5, 10, 20, 30 and 60 minutes after each drug. The second drug was given only after return of the hemodynamic parameters to baseline, plus a washout period of 2 hours. The hemodynamic variables measured were comparable at baseline. Both drugs produced hemodynamic improvement including a decrease in pulmonary capillary wedge pressure (PCWP), right atrial pressure and systemic and pulmonary vascular resistances. Only ISDN spray significantly increased cardiac output. The onset of action of ISDN spray was significantly more rapid than that of NTG. This was primarily evident in the decrease in PCWP. With ISDN spray the decrease started at 1 minute after administration, and at 3 minutes a decrease of 8.6 mm Hg was already found. The corresponding value for sublingual NTG was 1.6 mm Hg. The difference was highly significant (p less than 0.02). The peak effect of ISDN spray on PCWP and right atrial pressure was greater than that of NTG. Thus, the onset of the hemodynamic effect of the new formulation of ISDN spray is much more rapid than that of sublingual NTG tablets. At the doses used, the magnitude of the effect of the ISDN spray on some of the hemodynamic variables is greater than that of sublingual NTG.

Administration, Oral↗

Randomized double-blind comparison of isosorbide dinitrate and nifedipine in variant angina pectoris.

The antianginal and anti-ischemic effect of isosorbide dinitrate (ISDN), 120 mg once daily, and nifedipine, 20 mg twice daily, both in slow-release formulations, were compared in 17 patients with variant angina pectoris in a randomized, double-blind trial. The design included a placebo run-in period and two 6-week crossover periods of active treatment. Mean frequency of angina decreased significantly from 43 attacks per week during the placebo period to 4 per week with ISDN and 8 with nifedipine (p less than 0.001). Sublingual nitroglycerin consumption decreased significantly from 37 tablets per week with placebo to 3 tablets per week with ISDN and 7 with nifedipine (p less than 0.001). Both drugs reduced the silent and symptomatic ST-segment deviations on ambulatory electrocardiographic recording and increased maximal exercise tolerance. Episodes of coronary spasm could be provoked, by hyperventilation, in all patients during the placebo phase but in no patient during therapy with either active drug. Thus, both ISDN and nifedipine, in their slow-release formulations, are effective in the treatment of variant angina pectoris.

Adult↗