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PubMed1976

[Orally administered nitroderivates: efficacy and duration of the effects of isosorbide dinitrate (author's transl)].

The effects of 20 mg of orally administered isosorbide dinitrate on 10 patients with stable angina pectoris were studied by means of exercise tests. First, the reproducibility of the angina threshold of each patient was controlled; then the effects after 60, 150 and 210 minutes after administration of the drug and of a placebo, given in a random sequence, were studied. No significant changes of the parameters examined were observed after the placebo. A significant increase of duration of exercise and total amount of work performed before appearance of angina were observed after the drug. These changes were maximal in tests made 60 minutes after administration of the drug, declining thereafter; nevertheless, statistically significant differences from placebo were also observed in tests performed after 150 and 210 minutes. The appearance of ischemic ST changes was retarded by the administration of the drug. Disappearance of pain after interruption of exercise was significantly quicker when compared with the observations made after placebo.

Administration, Oral↗
PubMed1979

Isosorbide dinitrate in acute and chronic heart failure.

The hemodynamic effects of sublingual isosorbide dinitrate (ISD) were studied in 12 patients with congestive heart failure (CHF) of many causes. The duration of CHF in the chronic group varied from 3 to 62 months (mean, 29.5). Hemodynamic parameters were obtained serially before and 10, 20, 30, 45, 60, and 120 min after a 5 to 15 mg dose of ISD sublingually. The hemodynamic effects were pronounced at 45 min and returned to control levels in 120 min. Heart rate did not change. Hemodynamic parameters that changed after ISD were mean arterial pressure (-7%, p less than 0.05), mean pulmonary artery pressure (-17%, p less than 0.05), and mean pulmonary capillary wedge pressure (-29%, p less than 0.005). Mean cardiac index (+3%, p = NS) and mean stroke work index rose (+9.4%, P X NS); mean total systemic resistance fell (-10%, p = NS). Thus the duration of hemodynamic effects of ISD is less than 2 hr and sublingual ISD induces beneficial reduction of pulmonary capillary wedge pressure in patients with acute and chronic CHF without increasing cardiac index and stroke work index.

Acute Disease↗
PubMed1984

Isosorbide dinitrate disposition in the rat: metabolite pharmacokinetics and interactions.

The pharmacokinetics of isosorbide dinitrate (ISDN) and its isomeric mononitrate metabolites (2- and 5-ISMN) were examined in the rat. At a dose of 2 mg/kg, the oral bioavailability of ISDN was found to be about 40%. This finding corrects a previous belief that organic nitrates, when administered via the oral route, are completely metabolized by hepatic first-pass metabolism. ISDN was metabolized exclusively via its mononitrate metabolites, with the 5-ISMN being the principal product (about 90%). The ratio of 2- to 5-ISMN produced was dependent on the route of administration, being 0.18 +/- 0.03 after i.v. dosing and 0.11 +/- 0.03 after oral dosing (both mean +/- S.D.). 2-ISMN was found to decrease the plasma clearance of ISDN; this metabolite interaction occurred when drug and metabolite were administered either at the same or different intravascular sites. 5-ISMN did not affect ISDN plasma clearance when these compounds were administered at different intravascular sites. However, when 5-ISMN and ISDN were given at the same vascular site, a decrease in plasma ISDN clearance was observed. These results provide an interesting example of divergent pharmacokinetic interactions exhibited by two isomeric metabolites.

Animals↗
PubMed1997

Influence of diet on the single-dose pharmacokinetics of isosorbide 5-mononitrate and sustained-release isosorbide dinitrate.

The influence of diet on the single-dose pharmacokinetics of isosorbide 5-mononitrate (IS-5-MN) and sustained-release isosorbide dinitrate (ISDN) was studied in 8 healthy male volunteers. The subjects received either a low-calorie/low-fat diet (LCFD) or a high-calorie/high-fat diet (HCFD) according to a cross-over schedule and were administered the drug in tablet form after breakfast. The study was conducted first in 8 subjects who received a 20 mg IS-5-MN tablet and then in 6 of these individuals who received a 20 mg sustained-release ISDN tablet. After oral doses of IS-5-MN, the plasma drug levels declined monoexponentially and could be described by a one-compartment open model. There were no significant differences in the pharmacokinetic parameters for IS-5-MN between the LCFD and the HCFD. After administration of sustained-release ISDN, the plasma ISDN levels showed marked variations both between and within individuals. The increase in the mean AUC0-12 values for ISDN with the HCFD was found to exceed 60%, although there was no significant difference between the two diets.

Administration, Oral↗
PubMed1987

The effect of isosorbide dinitrate on the arterial vascular bed: a dose response study in dogs.

Isosorbide dinitrate (ISDN) was infused stepwise intraarterially into the left hindlimb (5.7-364.8 micrograms/kg/min.) into six dogs. The mean local vascular resistance was decreased by 32% in the left hindlimb after a dose of up to 91.2 micrograms/kg/min. corresponding to a 1.6-fold increase in the left femoral artery blood flow, without significant changes in the control limb or central haemodynamics. The muscular blood flow in the adductor magnus muscle obtained by the Xenon washout technique remained unchanged in 6 of 7 other dogs at ISDN infusion rates of 91.2 micrograms/kg/min., indicating that the increase in femoral artery blood flow was not a consequence of increased muscular blood flow. The arterio-venous extraction fraction of radioactive microspheres was lower in the experimental leg during ISDN infusion when compared with the control leg, suggesting that AV-shunts are opened during ISDN infusion. In addition to the well-known effect on preload, the present results confirm that ISDN also acts on afterload. Thus, ISDN may be classified as a mixed agent acting on both pre- and afterload which is in agreement with some previous studies.

Animals↗
PubMed1985

Effect of sustained release isosorbide dinitrate on exercise performance.

The duration of action and hemodynamic mechanisms of isosorbide dinitrate in a sustained release formula (ISDSR) were examined over a 24-hour period. 20 patients with effort angina pectoris were divided randomly into two groups, one group received a single dose of 40 mg ISDSR (at 07.30 h) and the other, two doses of 40 mg ISDSR (at 07.30 and 13.30 h). Every patient had four exercise tests on the first (placebo) day and second (ISDSR) day and a single test on the third (placebo) day. Effort tolerance was improved significantly (p less than 0.05) with ISDSR and this lasted for more than 10 h. The double product was compared to ISDSR. Improvement was achieved by a decrease in blood pressure and an increase in heart rate. There were no signs of increased ischemia (ST segment depression) with the prolongation of exercise time. The antianginal and hemodynamic effects of ISDSR were more pronounced in the patients who received two doses of ISDSR. Thus, ISDSR improved effort tolerance for a prolonged period by inducing a sustained decrease of blood pressure and increase in heart rate in patients with effort-induced angina pectoris.

Adult↗
PubMed1991

[The effect of isosorbide dinitrate spray on patients receiving coronary artery bypass grafting].

The effect of isosorbide dinitrate (ISDN) spray on hemodynamics and coronary artery diameter was studied in 10 patients with ischemic heart disease. Significant decrease in systolic blood pressure and systolic and diastolic pulmonary artery pressure was recognized at 2 minutes after spray. But there were no significant changes in heart rate and diastolic blood pressure. The diameter of the right coronary artery was 2.6 +/- 0.3 mm before ISDN, which significantly increased to 3.5 +/- 0.4 mm after ISDN. Then, the effect of ISDN on saphenous vein (SV) graft and internal thoracic artery (ITA) graft in 5 patients receiving coronary artery bypass grafting was assessed. The diameter of ITA was 1.7 +/- 0.2 mm before ISDN, and that was 2.0 +/- 0.2 mm after ISDN. The increase was recognized in all patients. The diameter of SV was 4.0 +/- 0.3 mm before ISDN, and that was 4.0 +/- 0.3 mm after ISDN. The diameter of the left anterior descending artery was 1.9 +/- 0.2 mm before ISDN, and that was 2.4 +/- 0.4 mm after ISDN. It was concluded that ISDN spray had a vasodilation effect on ITA graft as well as coronary artery. ISDN spray was expected to be useful for the solution of graft spasm and rapid abortion of anginal attacks even after coronary surgery.

Administration, Oral↗
PubMed1994

[Pharmacokinetics of isosorbide dinitrate studied by the extrapolation model].

To make a pharmacokinetic model of isosorbide dinitrate (ISDN), we infused ISDN at 1, 10 or 30 micrograms.kg-1.min-1 into anesthetized rabbits and measured concentrations of ISDN and its metabolites (2-ISMN and 5-ISMN) in plasma, urine and bile. We found the concentration gradient of ISDN between arteries and veins and between the ascending aorta and femoral artery. These concentration gradients may occur due to metabolism and accumulation of ISDN in many organs and tissues, let alone the vascular endothelium. There was no significant difference in plasma concentrations of ISDN or its metabolites between the hepatic vein and femoral vein. It seems that ISDN is metabolized in various organs and tissues. By ISDN infusion of more than 10 micrograms.kg-1.min-1, the plasma concentration of ISDN showed a pronounced increase. It appears that there is metabolic saturation of ISDN. Using these informations, we extrapolated the model to human and the estimated values were compared with observed values to determine the validity of the extrapolation model. There was no remarkable differences between the estimated values and observed values. This suggests the validity of the model. The plasma concentrations of ISDN, estimated by this extrapolated model, showed a linear increase (Y = 30X) with the flow rate range of 0.2-5.0 micrograms.kg-1.min-1, when the metabolic rate was normal. With ISDN infusion of more than 5.0 micrograms.kg-1.min-1, the plasma concentrations of ISDN showed a pronounced increase. In the conditions of impaired metabolism, the plasma concentrations of ISDN increase exponentially.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Comparative evaluation of intravenous isosorbide dinitrate and nitroglycerin in patients with acute myocardial infarction.

The efficacy of isosorbide dinitrate (ISDN) and nitroglycerin was studied in 115 patients with acute transmural myocardial infarction admitted to the Coronary Care Unit not later than 12 h after the onset of chest pain: 58 patients not later than 2 h after the onset of chest pain, 49 after 3-6 h and 8 patients in the period of 6-9 h. There were 69 men and 45 women, mean age 62.4 +/- 0.9 years. The duration of the preceding clinically evident coronary artery disease was in 12 patients 1 year, in 29 2-3, in 22 4-5 and in 16 patients 6 years or more. In 36 cases the chest pain of acute infarction was the first presentation of coronary artery disease. Thirty-seven patients had a previous myocardial infarction. Fifty patients had concomitant systemic hypertension. The patients were divided into 3 groups depending on the type of therapy received: group I, receiving anticoagulants only, served as control; patients of groups II and III received, in addition to the anticoagulants, intravenous ISDN or nitroglycerin, respectively. The patients were monitored for recurrent chest pain, electrocardiographic changes, clinical parameters and cardiac enzyme changes. ISDN, at a dose of 10 mg/h over the first 3 days of infarction, had marked antianginal effect, limited the dimensions of the necrotic area, reduced the number of ischemic relapses and the development of heart failure. Compared to nitroglycerin, ISDN exerted a more prolonged action (up to 12 h), did not affect heart rate and blood pressure, and had a marked antiarrhythmic effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1983

Isosorbide dinitrate kinetics and dynamics after intravenous, sublingual, and percutaneous dosing in angina.

Isosorbide dinitrate (ISDN) kinetics and dynamics were examined after various routes of administration for angina. Given intravenously, ISDN kinetics were apparently linear over the range of infusion rate (0.083 and 0.133 mg/min) and duration (15 min and 1 and 2 hr) studied. Mean +/- SD systemic clearance of ISDN was 3.4 +/- 1.4 l/min and volume of distribution (VdSS or Vdarea) about 100 l. These data are consistent with the presence of extensive extrahepatic metabolism. In six patients, sublingual ISDN (5 mg) was also given and mean bioavailability of 59% (19% to 93%) for this route was determined. For this group, sublingual absorption of intact ISDN was incomplete and variable. The presence of a longer disappearance t 1/2 after sublingual dosing suggested that the input process may be rate limiting. After percutaneous application of a topical formulation (100 mg over an area of 400 cm2), steady-state plasma concentrations at about 7 ng/ml were maintained from 6 to 24 hr. The bioavailability of the topical application was estimated at 30%. At the doses given, intravenous ISDN had no apparent effect on heart rate but induced significant reduction in standing systolic blood pressure. The effect vs the ISDN concentration profile was described by a hysteresis loop, indicating that changes in blood pressure response lag behind changes in plasma ISDN concentration. After intravenous dosing, peak plasma ISDN concentration and peak effect (maximum change in standing systolic blood pressure). At the doses used, both sublingual and percutaneous ISDN induced less distinct circulatory changes than the intravenous infusion.

Absorption↗
PubMed1985

Assessment of dermal glyceryl trinitrate and isosorbide dinitrate for patients with angina pectoris.

Dermal nitrate preparations are claimed to be useful in the treatment of angina, as their slow absorption by-passing the liver leads to a sustained action. Ten patients with angina were exercised on a treadmill after dermal application of 16.64 mg glyceryl trinitrate or 100 mg isosorbide dinitrate or placebo. Exercise duration was significantly increased at one and three hours for both nitrate preparations but not at six hours after application. The calculated workload achieved was significantly increased (p less than 0.01) at one and three hours for both preparations and at six hours (p less than 0.05) for isosorbide dinitrate. Headaches were common with glyceryl trinitrate cream. The dermal nitrate preparations studied had a duration of antianginal action similar to that of oral nitrate tablets. Aside from their value when the oral route cannot be used or absorption may be delayed, dermal nitrate preparations have no advantage over oral preparations for angina pectoris.

Administration, Topical↗
PubMed1981

Polarcardiographic (triaxicardiometric) study on the effect of isosorbide dinitrate on exercise-induced myocardial ischemia.

30 patients suffering from stable angina pectoris were studied by triaxicardiometric (polarcardiographic) method. Triaxicardiometry including the X, Y, Z Frank leads, azimuth (H degrees), elevation (V degrees) angle derivations and spatial magnitude (M) tracings were taken at rest and after submaximal bicycle ergometer exercise. After receiving 30 mg/day isosorbide dinitrate for a minimum of 5 days the whole procedure was repeated, stored by an analogue tape recorder and evaluated by a TPA/i computer. It has been stated that the method of triaxicardiometry has an excess sensitivity on the demonstration of ischemic alteration of anterior and posterobasal left ventricular wall compared to the traditional X, Y, Z leads. According to the pre- and post-exercise bicycle ergometer testing estimated by triaxicardiometry, isosorbide dinitrate caused a significant reduction of subendocardial myocardial ischemia.

Angina Pectoris↗
PubMed1989

Influence of electric foot shock on pharmacokinetics of isosorbide dinitrate orally administered to rats.

The influence of emotional stress on the pharmacokinetics of isosorbide dinitrate (ISDN) was studied in rats. Plasma levels of orally administered ISDN and metabolites (5-isosorbide mononitrate and 2-isosorbide mononitrate) were lower in rats emotionally stressed by foot shock than in non-stressed control rats. The decrease in the ISDN levels may be mainly due to the delay of drug absorption from the gastrointestinal tract.

Administration, Oral↗
PubMed1993

Hydralazine and isosorbide dinitrate combination improves exercise tolerance in heart failure. Results from V-HeFT I and V-HeFT II. The V-HeFT VA Cooperative Studies Group.

BACKGROUND: To better define the effects of long-term vasodilator therapy on exercise performance in chronic congestive heart failure, we compared placebo with prazosin and with the combination of hydralazine and isosorbide dinitrate (Hyd-Iso) in 642 men over a 5-year period in V-HeFT I. METHODS AND RESULTS: Patients were randomized (double-blind) to 20 mg of prazosin daily or 300 mg of hydralazine plus 160 mg daily of isosorbide dinitrate or placebo. We compared enalapril (20 mg daily), a converting enzyme inhibitor, with Hyd-Iso in 804 men over another 5-year period in V-HeFT II: Background therapy in both trials consisted of digitalis and diuretics. Serial bicycle ergometric exercise was performed with gas exchange measurements during progressive incremental work rates to a symptom-limited peak end point. Gas exchange anaerobic threshold (ATge) measurement was performed in the second trial. In V-HeFT I, an increase in peak VO2 with Hyd-Iso compared with placebo approached significance at 2 months (p < 0.16) and was significant (p < 0.04) at 1 year. In V-HeFT II, Hyd-Iso significantly increased peak VO2 compared with enalapril (p < 0.01 at 3 months, p < 0.02 at 6 months and 2 years). The changes in ATge measurements were not statistically different between the two treatment groups in V-HeFT II: CONCLUSIONS: Combination therapy with Hyd-Iso was more effective in increasing peak VO2 than placebo, prazosin, or enalapril in patients with mild-to-moderate congestive heart failure. Long-term data were confounded by mortality and other events, which may have led to an underestimate of the benefits of Hyd-Iso over placebo and an underestimate of the long-term benefits of enalapril on exercise performance. Therefore, short-term improvement in exercise performance is a suitable therapeutic end point, but long-term studies should more appropriately assess mortality.

Anaerobic Threshold↗
PubMed1976

Hemodynamic changes associated with angina pectoris induced by maximal treadmill exercise: effect of sublingual isosorbide dinitrate on systolic time intervals.

A technique for the study of patients with angina pectoris has been described, in which systolic time interval (STI) measurements are obtained at intervals after the onset of stress-induced angina. The technique is uniquely suited to the evaluation of anti-anginal drugs. Sublingual isosorbide dinitrate (SISD) was randomly alternated with a placebo (P) tablet in a double-blind study of 20 patients with stable angina pectoris. After SISD, compared to placebo, a highly significant shortening of Q-S2 and LVET occurred (p less than 0.001) which lasted throughout the entire 120 minute study period. The hemodynamic basis for these differences was felt to be improved myocardial contractility secondary to a reduction in systemic vascular resistance and reduced venous return induced by the SISD. A significant prolongation of PEP occurred at 60 minutes post-SISD (p less than 0.01). This was attributed to an increase in the gradient between LVEDP and aortic diastolic pressure resulting from reduced venous return after SISD. The PEP/LVET ratio was significantly increased up to 60 minutes after SISD (P less than 0.05). Heart rate was uniformly higher post-SISD, compared to post-placebo values; the differences were highly significant up to 60 minutes (P less than 0.001) and remained significant at 120 minutes (p less than 0.05). The time to angina was significantly longer (immediately post SISD, p less than 0.05; 30 min, p less than 0.001; 60 mins, p less than 0.05; 120 mins, p less than 0.05); and the work load greater, for 120 minutes following SISD: the increase in the latter was highly significant for 30 minutes after SISD (p less than 0.001) and remained significant up to 120 minutes (60 mins, p less than 0.05; 120 mins, p less than 0.05). These observations were attributed to an improvement in myocardial function due to the sublingual isosorbide dinitrate. A high degree of correlation was found to exist between heart rate and the STI. This correlation was negative for the QS2 interval (-0.996) and LVET (-0.993) and positive for PEP (+0.817) and the PEP/LVET ratio (+0.950).

Aged↗
PubMed1980

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

Small doses of oral nitrates are ineffective antianginal agents. However, large doses of oral nitrates individually titrated to produce long-acting hemodynamic effects may be effective antianginal agents in many patients. The dose of nitrate prescribed should be titrated by blood pressure and heart rate measurements, the presence of adverse side effects, and by exercise tolerance studies before and during treatment. We would strongly recommend gradual reduction rather than an abrupt discontinuation of chronic, high-dose nitrate therapy in patients with angina pectoris to avoid possible nitrate dependence withdrawal effects. We would also recommend that continuous nitrate antianginal prophylaxis not be used in patients with angina pectoris whose symptons are readily controlled with less intensive nitrate therapy used as needed. Partial hemodynamic tolerance develops after chronic use of high-dose oral isosorbide dinitrate but the antianginal efficacy of both sublingual nitroglycerin and of high doses of oral isosorbide dinitrate is unimpaired. Patients with congestive heart failure have also had clinical and hemodynamic improvement following chronic nitrate therapy.

Administration, Oral↗
PubMed1989

Drug plasma levels and coronary vasodilation after isosorbide dinitrate chewing capsules.

Five, ten and fifteen min after sublingual administration of 10mg isosorbide dinitrate (ISDN) in chewing capsules, in 10 patients with coronary artery disease, ISDN plasma levels were correlated with the dilation of epicardial coronary arteries as well as with changes in aortic blood pressure and heart rate. Due to the rapid and extensive drug absorption, maximal ISDN plasma levels averaged 138 +/- 73 ng ml-1 and were already obtained after 5 min; they declined to 102 +/- 76 and 62 +/- 34 ng ml-1 in the 10th and 15th min respectively. In 7 patients isosorbide mononitrate plasma levels were still negligibly low (less than 30 ng ml-1). Mean diameters of 'normal' coronary segments increased by an average of 20 +/- 10%, 26 +/- 11% and 27 +/- 13% (P less than 0.001) at 5, 10 and 15 min respectively compared to control. The maximal drop in systolic aortic pressure (147 +/- 19 to 115 +/- 15 mmHg; P less than 0.01) as well as the maximal increase in heart rate (66 +/- 4 to 80 +/- 11 beats min-1; P less than 0.01) were observed in the 15th min; diastolic aortic pressure and double product remained constant. Due to the long persistence of coronary dilation and haemodynamic changes, none of these drug effects correlated significantly with the ISDN plasma levels. In addition, the minimal diameters of 10 coronary stenoses were measured in 7 patients; with ISDN 7 stenoses showed dilation ranging from 23% to 98%.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Sublingual↗
PubMed1990

Lack of effect of verapamil and isosorbide dinitrate on the hepatic clearance of indocyanine green in cirrhosis.

1. Vasodilators are currently under investigation as possible therapeutic agents in the treatment of portal hypertension. Among them calcium-channel antagonists and organic nitrates have been of particular interest. Few and conflicting data, however, have been reported on their effect on liver function. 2. Twenty patients with biopsy-proven alcoholic cirrhosis were studied before and 25-35 min following the acute administration of 5 mg verapamil i.v. (eight patients) or 5 mg isosorbide dinitrate sublingually (12 patients). The plasma clearance of indocyanine green (ICG) and its intrinsic hepatic clearance were used as indices of liver function. Seven further patients were investigated before and after a placebo infusion according to the same methodology. 3. No significant change in ICG kinetics was found after verapamil or isosorbide dinitrate.

Adult↗