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PubMedDate not supplied

Erythrityl tetranitrate compared with isosorbide dinitrate. Effects on systolic time intervals and nitrate modification of effects of food.

The pharmacologic effects of erythrityl tetranitrate (ETN) and isosorbide dinitrate (ISDN) were compared to placebo using systolic time intervals (STI) in a randomized, double-blind study in 15 fasted male volunteers. Sublingual doses of ETN 5 mg, ISDN 5 mg, and placebo were administered to each volunteer at weekly intervals, and measurements of heart rate and STI [pre-ejection period (PEP), left ventricular ejection time (LVET), and PEP/LVET ratio] were made serially for up to 6 hours after each dose. STI were determined using ear densitography. Evaluation of the pharmacologic effects of ETN and ISDN were based on placebo-corrected changes from baseline values. Ejection time index (ETI) [LVET corrected for heart rate] was shortened, but the changes were not statistically significant for either drug. However, after ETN and ISDN, statistically significant (p less than 0.05) changes in PEP and PEP/LVET ratio were demonstrated for up to 240 minutes after dosing. Unexpected marked changes in the baseline corrected PEP/LVET ratio were observed following food at 4 hours after dosing. This suggests increased inotropy during the postprandial period.

Adult↗
PubMed1977

Sustained hemodynamic and antianginal effect of high dose oral isosorbide dinitrate.

Twenty-one patients with documented coronary atherosclerotic heart disease were studied to determine the effect of high dose oral isosorbide dinitrate (ISDN) on heart rate, blood pressure, and exercise time until angina pectoris. Patients were tested in two phases, initially with 0.4 mg of sublingual nitroglycerin and with sublingual placebo, and then with oral ISDN, mean dose 29 mg, and oral placebo. Both phases of the study were conducted in a randomized, double-blind, crossover manner. After ISDN was compared to oral placebo, heart rate increased at 30 to 300 min (P less than 0.01) (peak increase 18 beats/min at 60 min), and systolic blood pressure decreased from 45 to 300 min (P less than 0.005) (peak decrease 18 mm Hg at 60 min). Exercise time at 2 min after sublingual nitroglycerin increased 51% as compared to oral placebo, exercise time increased 54% at 1 hr (P less than 0.005), 37% at 3 hr (P less than 0.01), and 12% at 5 hr (NS). Twelve of 21 patients (57%) improved their exercise time until angina larger than or equal to 25% at 1 hr after oral ISDN. The exercise response to sublingual nitroglycerin was a good predictor of this response to oral ISDN.

Administration, Oral↗
PubMed1991

Randomized double-blind comparison of the effects of isosorbide dinitrate retard, verapamil sustained-release, and their combination on myocardial ischemic episodes.

The antianginal and anti-ischemic efficacy of isosorbide dinitrate (ISDN) retard 120, verapamil 120 sustained-release (s.r.) and their combination was evaluated in 30 patients with chronic angina pectoris. The study was a randomized, double-blind crossover comparison. The evaluation was determined by exercise testing and 24-hour electrocardiographic ambulatory monitoring. The sum of ST-segment depression at comparable exercise levels was reduced by 37% (p less than 0.001) after verapamil 120 s.r. and by 45% (p less than 0.001) after combination therapy. After ISDN retard 120 the sum of ST-segment depression was also slightly reduced by 18% without attaining statistical significance. Total walking time and time to angina pectoris during treadmill exercise were significantly prolonged after all treatments. The sum of ST-segment depression in the 24-hour Holter ECG was reduced by 46% (p less than 0.001) after verapamil and by 39% (p less than 0.01) after combined therapy. After ISDN retard 120 the mean reduction was 34% (p less than 0.01). In conclusion, the result of the study indicated that ISDN retard 120, verapamil 120 s.r. and a combination of both drugs are effective in reducing the frequency and duration of ischemic episodes in patients with ischemic heart disease.

Adult↗
PubMed1989

The development and reversal of tolerance to antianginal effect of isosorbide dinitrate in patients with effort angina.

The development and reversal of tolerance to the hemodynamic and anti-anginal effects of isosorbide dinitrate in a sustained release form (ISDN-SR) were investigated in 11 male patients (mean age 58.9 y.o.) with stable effort angina. Treadmill exercise test, evaluation of hemodynamic parameters and measurement of plasma ISDN concentrations were performed during the control period, on the 1st, 7th and 14th days of therapy with 40 mg of ISDN-SR orally every 8 h and, subsequently, on the day when ISDN-SR was re-administered after a 72 h placebo period (17th day). Initially, exercise tolerance time (ETT) was prolonged significantly (p less than 0.001) by ISDN-SR from 257 +/- 50 sec in the control period to 434 +/- 55 sec on day 1. This prolongation was significantly reduced with sustained therapy and ETT was shortened to 332 +/- 69 sec on the 7th day (p less than 0.01 vs day 1) and 326 +/- 73 sec on the 14th day (p less than 0.01 vs day 1). The effects of ISDN-SR initially observed were restored after a 72 h placebo period and ETT was prolonged to 432 +/- 57 sec on the 17th day. The resting heart rate was increased significantly (p less than 0.01 vs control) and systolic blood pressure was decreased (p less than 0.001 vs control) by ISDN-SR on day 1. These changes were also diminished significantly (p less than 0.01 vs day 1) with sustained therapy and were restored after a 72 h nitrate-free interval.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1992

Antianginal and anti-ischemic efficacy of nicorandil in comparison with isosorbide-5-mononitrate and isosorbide dinitrate: results from two multicenter, double-blind, randomized studies with stable coronary heart disease patients.

The purpose of the two double-blind studies summarized in this article was to compare the antianginal and anti-ischemic effects of nicorandil with those of two different nitrate preparations. A total of 129 patients with stable New York Heart Association functional class II or III coronary heart disease were enrolled in the studies. Ninety-five patients received nicorandil, 34 received isosorbide dinitrate (ISDN), and 63 received isosorbide-5-mononitrate (MN). In study 1, nicorandil was compared with MN in a crossover design with 54 protocols eligible for efficacy assessment of MN and 52 eligible for nicorandil, respectively. Twenty milligrams of nicorandil and 20 mg MN administered b.i.d. for 4 weeks were equally effective in the treatment of stress-induced angina. Both drugs prolonged bicycle exercise tolerance and reduced weekly anginal attack rates. In study 2, nicorandil and ISDN were administered to two parallel groups of patients at a dose of 10 mg t.i.d. for 2 weeks and then 20 mg t.i.d. for 4 weeks. Under the assumption that the repetitive administration of nitrates with short dosing intervals might induce the development of tolerance to the nitrate mechanism of action, the t.i.d.-dosing regimen had been chosen in this study. Thirty-two protocols from those receiving nicorandil and 34 protocols from those receiving ISDN were eligible for efficacy assessment. Both drugs increased exercise capacity and reduced ST-segment depression at identical work loads with no significant difference between groups (p > 0.05). For both drugs, the higher doses were more effective than the lower doses. tolerance to the nitrate mechanism of action did not develop with either drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Plasma disposition and hemodynamic effects of a single oral dose of isosorbide dinitrate in human males and females.

The goal of the present work was to determine the plasma disposition and hemodynamic effects of isosorbide dinitrate (ISDN) in human males and females. Fourteen healthy human volunteers took part in the study; seven males, 21.7 +/- 2.5 y (SD), and seven females, 20.7 +/- 3.4 y. Measurements of forearm blood flow (FBF), vascular conductance (FVC), and venous capacitance (Cv) were obtained by venous occlusion plethysmography, whereas blood pressure was measured by automatic sphygmomanometry. Blood samples were taken through a catheter placed in the antecubital vein at 0, 15, 30, 45, 60, 90, 120, 360, 480, 720, and 1440 min following a single 10 mg oral dose of ISDN. Plasma concentrations of ISDN and its mononitrate metabolites, isosorbide-2-mononitrate (2-ISMN) and isosorbide-5-mononitrate (5-ISMN), were determined by large bore capillary column gas-liquid chromatography. Hemodynamic measurements were made at corresponding experimental times up to 480 min. No differences were observed in the disposition of ISDN, 2-ISMN or 5-ISMN between the male and female volunteers. In addition, the plasma concentrations of ISDN and its mononitrate metabolites did not consistently correlate with the hemodynamic changes of the individual subjects. Diastolic blood pressure was significantly decreased for a 0.5 h period starting at 30 min, which was the time at which plasma ISDN concentrations peaked, and which preceded the time when the plasma concentrations of 2-ISMN and 5-ISMN were maximal. These observations indicate that, for a single 10 mg oral dose of ISDN, there were no gender-dependent differences in the plasma disposition of the parent drug or its mononitrate metabolites, and the vascular changes responsible for the decrease in diastolic blood pressure in these volunteers occurred in vascular beds other than those of skeletal muscle as represented by forearm blood flow.

Administration, Oral↗
PubMed1997

[Molsidomine and isosorbide dinitrate: a comparative trial of tolerance in long-term intake by IHD patients with stable angina of effort].

Potential tolerance to isosorbide dinitrate (ID) and molsidomine (M) was studied in 18 ischemic heart disease (IHD) patients with stable angina of effort entered in a double blind cross-over trial. Each drug was administered for 3 weeks 4 times a day in individual effective dose. Single doses of ID and M were similar by effectiveness, but after 3 weeks of regular intake their efficacy fell, ID becoming less potent than M. For ID, tolerance after long-term intake manifested in 7 out of 18 patients, for M--in 5 out of 18. Complete tolerance was registered in 3 of 18 and 1 of 18 patients, respectively. Thus, tolerance is possible for the two drugs, but for M it is less pronounced.

Adult↗
PubMed1994

Differential effects of the novel NO-donating drug pirsidomine and isosorbide dinitrate on the venous vascular bed.

Sixteen healthy male subjects were investigated on four occasions when they received either placebo, 10 mg isosorbide dinitrate (ISDN), or 2.5 or 10 mg pirsidomine, a novel NO-donating drug. A constant-rate iv. infusion of a subsystemic dose (average 42 ng.min-1, SD 20.5) of noradrenaline in a dorsal hand vein was begun 1 h before drug treatment. It did not cause systemic changes but reduced the venous hand vein diameter by about 50%. This venoconstrictor response was approximately halved by 10 mg ISDN. Pirsidomine, in contrast, did not affect the in situ venoconstrictor responses to noradrenaline. ISDN and pirsidomine reduced systemic resting blood pressure. ISDN and 10 mg pirsidomine were approximately equipotent in reducing systolic blood pressure, both in terms of the duration and the extent of the effect (maximum average reduction of ISDN -6.7, 95% CI -10.3 to -3.0; and 10 mg pirsidomine -7.6, 95% CI -11.3 to -4.0 mmHg, respectively); 2.5 mg pirsidomine was less effective (-4.1, 95% CI -7.8 to -0.5). ISDN and 10 mg pirsidomine were also similarly effective in reducing diastolic blood pressure (ISDN -8.4 mmHg, 95% CI -10.5 to -6.2; 10 mg pirsidomine -6.0 mmHg, 95% CI -8.2 to -3.9; 2.5 mg pirsidomine -2.8 mmHg, 95% CI -5.0 to -0.6) but the effects of ISDN were longer lasting. Although similar with regard to their putative mechanism(s) of action and likely arterial/arteriolar effects, pirsidomine and ISDN seem to affect the venous vascular bed in distinctly different ways.

Adult↗
PubMed1984

Dose-response relation of antianginal activity of isosorbide dinitrate.

Eleven men with angiographic evidence of coronary heart disease and stable, exercise-induced angina pectoris were given placebo (P) or isosorbide dinitrate (ISDN) in a daily dose of 30, 120, 240 or 480 mg, in a randomized single-blind trial. The daily doses were administered 6 times a day as single oral doses of 5, 20, 40 and 80 mg. Each dose or placebo was given for 7 days. Before therapy was begun, and on the seventh day of each treatment period, an exercise ECG with standardized level and duration of exercise was recorded. Subsequently, a 4-week treatment period with 480 mg/day was carried out at the end of which another stress test was performed. The was followed by a final 2-week placebo period. The frequency of anginal attacks per week tended to decrease with increasing nitrate doses, but decreased significantly only after the highest dose (480 mg/day) compared with placebo. Continuation of therapy with 480 mg/day maintained the reduced rate of anginal attacks. The ischemic response, expressed as the sum of ST-segment depressions in the exercise ECG, revealed a dose-dependent reduction of 26% (30 mg/day), 39% (120 mg/day) (p less than 0.01), 63% (240 mg/day) (p less than 0.01) and 72% (480 mg/day) (p less than 0.01), respectively. At the end of the 4-week treatment period with 480 mg/day, antianginal efficacy was found to be moderately reduced, showing a 56% reduction of ischemic response compared to the placebo trial. The time of onset of angina during exercise testing was also delayed in relation to the dosage given.(ABSTRACT TRUNCATED AT 250 WORDS)

Angina Pectoris↗
PubMed1984

[Development of tolerance with regard to the anti-ischemic effect of isosorbide dinitrate in regular multiple daily administration].

In previous studies it had been shown that during longterm treatment of coronary artery disease with isosorbide dinitrate (ISDN) in sustained-release form, there was no reduction in exercise-induced ST-segment depression, no decrease in the rate of anginal attacks or nitrate consumption and no changes in blood pressure or heart rate [1, 4]. To determine to what extent tolerance development is a fundamental property of longterm administration of ISDN, this study, carried out according to a randomized, double-blind, cross-over, placebo-controlled protocol (Figure 1), was undertaken. The anti-ischemic effects of 40 mg ISDN were analyzed after acute administration and during longterm treatment with 40 mg four times daily in eleven patients with stable angina pectoris and reproducible ST-segment depression. Additionally, the influence of this therapy on the anti-ischemic effects of 0.8 mg sublingually-administered nitroglycerin (GTN) was assessed in ten of the eleven patients. On acute administration, 40 mg ISDN led to a reduction in ST-segment depression at one hour from 2.05 to 0.18 mm (p less than 0.01), and at six hours from 2.35 to 1.20 mm (p less than 0.01) (Figure 2, Table 1). During chronic treatment, statistically significant changes were no longer detectable. In eight of the eleven patients there was a complete loss of effects; in the remaining three, a marked attenuation was observed (Figure 3). Acute administration of 40 mg ISDN resulted in plasma concentrations of 221 ng/ml 5-ISMN, 53 ng/ml 2-ISMN and 23 ng/ml ISDN (Figure 6, Table 2).(ABSTRACT TRUNCATED AT 250 WORDS)

Angina Pectoris↗
PubMed1990

Myocardial infarction following sublingual administration of isosorbide dinitrate.

A 78-year-old with healed septal necrosis suffered a recurrent myocardial infarction of the anterior wall following the administration of isosorbide dinitrate 5 mg sublingually. After detailing the course of events, we discuss the role of paradoxical coronary spasm and hypotension-mediated myocardial ischemia occurring downstream to significant coronary arterial stenosis in the pathophysiology of acute coronary insufficiency.

Administration, Sublingual↗
PubMed1993

Controlled-release isosorbide dinitrate pellets. Part I: Design and evaluation of controlled-release capsule dosage form.

Design and evaluation of 8-h controlled-release isosorbide dinitrate capsules representing 20.0 and 40.0 mg of the drug are described. The formulation conforms to the total drug incorporated in the dosage form. In vitro dissolution studies indicate that the formulations behave as controlled-release dosage forms. Studies of storage at 30 +/- 2 and 40 +/- 2 degrees C at relative humidities of 72.0 and 90.0%, respectively, indicate that both temperature and humidity accelerate the degradation of the formulation. These results indicate the need of controlled packaging conditions during manufacture of these capsules.

Body Fluid Compartments↗
PubMed1993

Influence of isosorbide dinitrate on superior mesenteric artery impedance in humans.

In a randomized, double-blind, placebo-controlled crossover study the acute effect of isosorbide dinitrate (ISDN) on the superior mesenteric artery velocity waveform was studied in 10 healthy subjects (mean age 48.2 years) over a 10-minute period. The superior mesenteric artery pulsatility index (PI), which quantifies the blood velocity waveform, increased from the second minute following sublingual administration of 5 mg ISDN (basal PI 4.88 +/- 0.32) and reached its upper level (8.22 +/- 1.38) from the fourth minute on. In comparison with placebo, the significant rise of PI (second minute) occurred before the significant decrease of systolic blood pressure (ninth minute) and before the significant increase in the heart rate (fourth minute). Diastolic and mean arterial blood pressures remained unchanged. These observations suggest an immediate vasoconstrictive effect of ISDN on the resistance vessels of the vascular bed of the superior mesenteric artery.

Aged↗
PubMed1992

Vasodilator properties of nitroglycerin and isosorbide dinitrate during cardiopulmonary bypass.

In a placebo-controlled trial, we have studied the vasodilator properties of bolus doses of nitroglycerin (TNG) and isosorbide dinitrate (ISDN) in 32 patients during cardiopulmonary bypass with a constant pump flow. Blood volume of the venous reservoir and mean arterial pressure were recorded for 10 min after drug administration to detect changes in venous capacitance and arteriolar resistance, respectively. The venous capacitance-increasing effects of TNG 200 micrograms and ISDN 1,600 micrograms were initially identical and significant at 2 and 3 min after the bolus. Thereafter, the effect of TNG began to decline, while that of ISDN remained significant until the end of the study. TNG 200 micrograms decreased arterial pressure slightly more than ISDN 1,600 micrograms, but the effect of both drugs lasted for only 1-2 min. TNG and ISDN were equipotent in increasing venous capacitance when administered in a bolus dose ratio of 1:8 during CPB, but the venodilator effect of ISDN lasted longer than that of TNG. The duration of the arteriolar dilator effect was very short with both drugs.

Adult↗
PubMed1983

Effect of noradrenaline, sodium nitrite and isosorbide dinitrate on albumin transport in the wall of the excised rabbit common carotid artery.

The effects of noradrenaline (NA), sodium nitrite (NaNO2) and isosorbide dinitrate (ISDN) on the steady state distribution of 125I-labelled albumin in the wall of excised rabbit common carotid arteries were studied. The vessels were incubated in Tyrodes solution either at relaxed length and zero transmural pressure (non-pressurized) or at in vivo length and a transmural pressure of 70 mm Hg (pressurized). Label was applied in the same concentration at both the luminal and outer surfaces. The mean medial uptake in pressurized vessels was greater after treatment with 10(-7) M NA than after additional treatment with either 10(-3) M NaNO2 or 10(-3) M ISDN. The opposite was found for non-pressurized vessels. The medial uptake by NA-treated pressurized vessels was greater than that by NA-treated non-pressurized vessels, while the reverse was found for NaNO2- or ISDN-treated vessels. We conclude that the different patterns of uptake seen in these vessels results from the relative effects of externally applied stress (elongation and pressurization), smooth muscle tone and convection through the wall, on the properties of the interstitium, and possibly from the effects of the vasoactive agents on endothelial permeability.

Albumins↗
PubMed1996

Pre- and afterload reduction in chronic mitral regurgitation: a double-blind randomized placebo-controlled trial of the acute and 2 weeks' effect of nifedipine or isosorbide dinitrate treatment on left ventricular function and the severity of mitral regurgitation.

1. The acute effect and effect of 14 days' treatment with isosorbide dinitrate (ISDN) and nifedipine (NIF) was evaluated by radionuclide cardiography in patients with chronic mitral regurgitation and sinus rhythm. 2. In 23 patients with clinically stable disease blood pressure was lowered by 15% and left ventricular volume was reduced by 16-20% after 20 mg sublingual ISDN causing combined pre- and afterload reduction. Afterload reduction alone induced by 10 mg NIF resulted in an acute 9% decrease in left ventricular endsystolic volume, whereas forward stroke volume increased by 30%, and regurgitation fraction tended to decrease. No haemodynamic effects could be detected after 14 days' treatment with 20 mg ISDN orally twice daily (preload reduction), whereas 20 mg NIF twice daily (afterload reduction) caused an increase in forward stroke volume (18%) and a decrease in both regurgitant volume (20%) and regurgitation fraction (22%) without affecting blood pressure or heart rate. 3. ISDN and NIF have beneficial acute haemodynamic effects in patients with chronic mitral regurgitation probably due to their pre- and afterload reducing properties. The reduction in regurgitation induced by NIF appears to be sustained after 14 days therapy.

Administration, Oral↗
PubMed1985

Hemodynamic effects of molsidomine, isosorbide dinitrate, and nifedipine at rest and during exercise.

In the first study the hemodynamic effects of standard doses of molsidomine (2 mg intravenously), isosorbide dinitrate (ISDN) (5 mg sublingually), and nifedipine (20 mg sublingually) were assessed at rest and under exercise conditions in a group of 30 patients with coronary heart disease. With the patients at rest both molsidomine and ISDN were associated with prompt reductions in left ventricular end-diastolic pressure and mean pulmonary artery pressure, whereas nifedipine was associated with slight reductions in left ventricular end-diastolic pressure and mean pulmonary artery pressure that did not attain statistical significance. Nifedipine and ISDN caused a decrease in mean aortic blood pressure, which resulted in a reactive increase in heart rate that was only significant with nifedipine. After administration of molsidomine, there was no significant change in mean aortic pressure at rest. There were reductions in stroke volume index and cardiac index after administration of molsidomine and ISDN. Nifedipine, however, was associated with significant increases in stroke volume index and cardiac index. None of the three test substances caused changes of contractility parameters. Under exercise conditions reductions in left ventricular end-diastolic pressure, mean pulmonary pressure, and mean aortic pressure were documented following administration of molsidomine, ISDN, and nifedipine. There were no major changes in maximum heart rate or stroke volume index during exercise with any of the three drugs. However, nifedipine was associated with a significant increase in cardiac index, whereas molsidomine and ISDN produced no major changes.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Contribution of isosorbide-5-mononitrate, a major metabolite of isosorbide dinitrate (ISDN), to the hemodynamic effect of ISDN administered orally in conscious dogs.

This study was designed to determine the extent, to which isosorbide-5-mononitrate (5-ISMN) contributes to the hemodynamic effect of isosorbide dinitrate (ISDN) in conscious dogs. Test drugs (ISDN or 5-ISMN) were given orally. Either ISDN or 5-ISMN produced a decrease in blood pressure dose-dependently, the decrease in pulse pressure being specific; the pattern of blood pressure change induced by ISDN or 5-ISMN was different from that induced by nifedipine or prazosin. The effect of ISDN (2 mg/kg) was almost equivalent to that of 5-ISMN (4 mg/kg) and the effect of ISDN (4 mg/kg) to that of 5-ISMN (8 mg/kg). After administration of ISDN, both ISDN and 5-ISMN appeared in the plasma, and the effect of ISDN well-correlated with the increase in the plasma concentration of 5-ISMN. Contribution of 5-ISMN to the effect of ISDN was estimated to be about 30% from the value of the plasma concentration of 5-ISMN at 3 to 4 hr after administration, when the maximal response to ISDN occurred. Based on the data of the area under the plasma concentration curve of 5-ISMN (from 0 to 10 hr after administration), the fraction of biotransformation to 5-ISMN from ISDN was calculated to be 73.6 to 76.6% (based on moles). Because the ability of 5-ISMN to decrease pulse pressure was about 1/2 (or 41% based on moles) of that of ISDN, the contribution of 5-ISMN to the effect of ISDN was estimated to be about 30% in total, the value being similar with that estimated at 3 to 4 hr after administration.

Administration, Oral↗