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PubMed1997

[Effects of inhalated isosorbide dinitrate on endothelin and nitric oxide and its therapeutic efficacy for experimental guinea-pigs with asthma].

To probe into the correlation between the changes of endothelin and nitric oxide in bronchial alveolar lavage fluid (BALF) and the treatment of inhaling isosorbide dinitrate on experimental guinea pigs with asthma, we divided 25 guinea pigs randomly into three groups (Control group, Asthma group, Isosorbide dinitrate group), and induced some subjects by inhalation of aerosolized ovalbumin as the model of asthma to investigate the endothelin (ET) and nitric oxide (NO) level in BALF as well as the pathological change of the respiratory tract. We found that the level of endothelin and nitric oxide in BALF were all elevated in experimental guinea pigs with asthma, but the degree of increase of NO in BALF was lower than that of ET. The NO and the ET levels in BALF were negative correlation (r = -0.8050, P < 0.01). After having been treated with aerosolized isosorbide dinitrate, the NO level in BALF was significantly elevated and the ET level in BALF was decreased in comparison with the asthma group (P < 0.001, respectively). Moreover, the eosinophile infiltration, exoserosis, and epithalaxia of the respiratory tract of the guinea-pigs were all lightened. The results suggest that inhaled isosoratory dinitrate could be used for treating asthma, and its mechanism may be elevation of NO level and decrease of ET level in BALF.

Administration, Inhalation↗
PubMed1992

[Acute hemodynamic effects of SIN-1 and isosorbide dinitrate in stable left ventricular failure: a comparative double-blind, cross-over study].

The acute hemodynamic effects of intravenous SIN-1 (1 mg) and sublingual isosorbide dinitrate (5 mg) were investigated in 12 patients (8 men and 4 women) between 38 and 80 years of age and suffering from stable chronic left ventricular failure (NYHA Classes III-IV) secondary to ischemic myocardiopathy (n = 5), hypertensive disease (n = 2) or idiopathic disorder (n = 5) corresponding to the following hemodynamic inclusion criteria: stable condition, cardiac index > or = 2 l/min/m2, mean capillary pressure > or = 18 mmHg and < or = 28 mmHg. Previous treatments were continued with the exception of vasodilators and diuretics which were stopped 24 hours earlier. The hemodynamic data from this cross-over, double-blind double-dummy trial were collected for two 60-hour periods separated by a washout period of 120 minutes. Simultaneously, venous samples were taken for the assay of plasma levels of SIN-1. The heart rate, cardiac output, pulmonary artery resistance and blood pressure were not affected by either SIN-1 or isosorbide dinitrate. An obvious reduction (> 15% of the basal value) in the mean capillary pressure, pulmonary artery pressure and mean right atrial pressure was observed in 10 subjects after SIN-1 and in 7 patients isosorbide dinitrate. A statistically non-significant trend towards a more marked effect (number of patients responding and maximum amplitude of pressure reduction) which occurred more rapidly and lasted longer was observed after SIN-1. Analysis of the relationship between the pharmacodynamics and pharmacokinetics of SIN-1 suggests that an active metabolites is involved. No adverse effects were reported.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1985

[Effects of isosorbide 5-mononitrate on cardiovascular function. (I). Effects on the left ventricular system].

Effects of isosorbide 5-mononitrate (5-ISMN) on cardiovascular function were compared with those of isosorbide dinitrate (ISDN), verapamil and propranolol. In anesthetized open-chest dogs, intravenous injection of 5-ISMN (1 mg/kg, 3 mg/kg) scarcely decreased cardiac contractile force (CCF) and heart rate (HR). The systolic blood pressure (SBP) fell in a dose-dependent manner, and the degree of the change was greater than that in diastolic blood pressure (DBP). Especially, left ventricular pressure (LVP) and left ventricular dp/dt (LVdp/dt) were significantly decreased, and a considerable reduction in left ventricular end-diastolic pressure (LVEDP) was also observed. Intravenous injection of verapamil (0.3 mg/kg) considerably lowered DBP. While HR, CCF, LVP and LVdp/dt were markedly decreased, LVEDP showed a moderate increase. Propranolol (0.5 mg/kg, i.v.) greatly decreased LVdp/dt together with HR and CCF. Conversely, LVEDP showed a slight increase. There was no change in SBP, DBP and LVP. The vasodilating potency of 5-ISMN was 150 times smaller than that of ISDN on the contractile response in isolated rabbit thoracic aorta. On the other hand, in terms of decrease in pulse pressure, the potency exhibited by 5-ISMN was about 4 times (intravenous administration in anesthetized dogs) or 1.5 times (oral administration in conscious dogs) smaller than that of ISDN. The present results suggest that 5-ISMN shows a high bioavailability and a potency comparable to ISDN, especially in the case of peroral administration. Taking these results together with the fact that transient left ventricular failure occurs during myocardial ischemia into consideration, it is thought that peroral 5-ISMN preparation may be useful in the therapy of angina pectoris.

Animals↗
PubMed1987

Hemodynamic effects of oral isosorbide-5-mononitrate and dinitrate in ischemic heart failure.

Isosorbide-5-mononitrate (ISMN), the main metabolite of isosorbide dinitrate (ISDN) was recently introduced in clinical use. The hemodynamic effects of oral ISMN and ISDN, administered in equal doses, were studied in a randomized, crossover fashion in 20 patients with pump failure of ischemic etiology. Baseline hemodynamic criteria for admission into the study were: pulmonary capillary wedge pressure (PCW) of at least 20 mmHg and systolic arterial pressure (AP) above 90 mmHg. Hemodynamic parameters were serially measured and systemic vascular resistance was calculated up to 6 h postadministration of either ISMN or ISDN single dose (40 mg). Maximal effects obtained were statistically significantly different from baseline. While ISMN and ISDN appeared to be equipotent in reducing the filling pressure, with a maximum effect reached in 60-120 min, the mononitrate maintained its effects for a longer period.

Administration, Oral↗
PubMed1999

Effects of isosorbide dinitrate on electrocardiography, hemodynamics, and ventilation in patients with exercise-induced elevation of pulmonary artery wedge pressure.

BACKGROUND: The mechanisms underlying exertional hyperpnea in patients with coronary artery disease and transient left ventricular dysfunction are still not fully understood. HYPOTHESIS: The study was undertaken to investigate whether the ventilatory response to exercise reflects the effects of acute medical treatment of exercise-induced left ventricular dysfunction, and to evaluate mechanisms relevant to excessive exertional ventilation. METHODS: In 11 male patients, aged 65.2 +/- 6.0 years, all with pulmonary artery wedge pressure (PAWP) > 25 mmHg and ST depression > 2 mm during moderate supine exercise, ventilation (V), oxygen uptake (VO2), hemodynamics, electrocardiogram (ECG), and arterial and mixed venous blood gases were examined during supine rest and exercise, before and at hourly intervals after peroral intake of 30 mg isosorbide dinitrate (ISDN). Six similar patients were examined with the same protocol without ISDN administration and comprised a control group. RESULTS: Before administration of ISDN, exercise PAWP was 35.3 +/- 5.9 mmHg, ECG showed 2.77 +/- 1.06 mm ST depression, and V/VO2 was 31.8 +/- 4.8 l/l. One h after ISDN administration, exercise mean PAWP was 11.0 +/- 2.5 mmHg (p < 0.001), ST depression 0.59 +/- 0.8 mm (p < 0.001), whereas V/VO2 was unchanged, 30.1 +/- 5.3 l/l. Two h later, PAWP remained reduced and there were only minor ST depressions, while V/VO2 remained high. Exercise cardiac index (CI) and mixed venous oxygen tension (PvO2), initially 4.7 +/- 0.67 l/min/m2 and 3.54 +/- 0.35 kPa, respectively, remained at the same low level throughout the study. In the six nontreated patients, there were no significant changes in ST depression, exercise PAWP, or exertional ventilation. CONCLUSION: Isosorbide dinitrate treatment markedly improved exercise-induced left heart dysfunction, whereas excessive ventilatory response was unaffected, even after 3 h. Thus, measurements of the exercise hyperpnea did not properly reflect effective reduction of myocardial ischemia.

Aged↗
PubMed2000

Isosorbide dinitrate inhibits platelet adhesion and aggregation in nonthrombolyzed patients with acute myocardial infarction.

BACKGROUND: Apart from their vasodilatatory properties, nitrates have been shown to inhibit platelet aggregation. The effects of nitrates on platelet adhesion have not been studied. Nonselected patients with acute myocardial infarction (AMI) have been suggested to gain no benefit from administration of nitrates. However, the importance of nitrates may be greater in a subgroup of nonthrombolyzed patients with AMI. HYPOTHESIS: Isosorbide dinitrate (ISDN) decreases platelet adhesion and aggregation in nonthrombolyzed patients with AMI. METHODS: Consecutive 48 men with AMI, not eligible for thrombolytic therapy because of late presentation (> 12 h), were prospectively randomized 2:1 to double-blind ISDN (mean dose 2.4 +/- 0.9 mg/h) (n = 33) or placebo (0.9% sodium chloride) (n = 15) infusion. All patients received aspirin. Blood samples were taken at baseline (no study medication) and 3 h into ISDN or placebo infusion. Platelet adhesion to collagen was measured in the ethylene diamine tetraacetic acid (EDTA)-platelet rich plasma by recording changes in light transmission with an optical aggregometer. Platelet aggregation was measured using the Born's method. RESULTS: Isosorbide dinitrate significantly decreased both platelet adhesion and aggregation. No effect was seen in the placebo group. CONCLUSIONS: In patients with AMI who do not receive thrombolytic therapy, ISDN effectively inhibits platelet adhesion and aggregation. These effects of nitrates may be of therapeutic and prognostic significance in this group of patients.

Adult↗
PubMedDate not supplied

Comparison of the effects of dopamine, hydralazine, and isosorbide dinitrate on myocardial hemodynamics in patients with refractory heart failure.

Nine patients with refractory congestive heart failure underwent hemodynamic study first with dopamine and then with oral hydralazine and sublingual isosorbide dinitrate. Although hemodynamic improvement was achieved with both forms of therapy, the beneficial effects of hydralazine alone or with isosorbide were superior to those of dopamine, as manifested by a greater reduction of wedge pressure and greater increase in stroke index. Six patients who demonstrated an increased wedge pressure during dopamine infusion were observed to manifest a louder apical systolic murmur and/or V wave in the wedge pressure tracing suggestive of enhanced mitral regurgitation. The rise in wedge pressure on dopamine could also be a consequence of increased myocardial ischemia and resultant decrease in ventricular compliance. It is possible that a subgroup of patients with heart failure are made worse by dopamine, and in these cases vasodilator therapy may be more beneficial.

Aged↗
PubMed1981

Pharmacokinetics of isosorbide dinitrate in rhesus monkey, cynomolgus monkey, and baboon.

At 2 min after intravenous injection of isosorbide dinitrate (1 mg/kg), mean plasma drug concentrations were 565 +/- 66 (SD), 586 +/- 43, and 1572 +/- 253 ng/ml in the rhesus monkey, cynomolgus monkey, and baboon, respectively. Following a relatively short distribution phase, mean plasma concentrations declined with half-lives of 62, 23, and 24 min in these three species, respectively. The time course of plasma concentrations could be described by a two-compartment open model, although a one-compartment open model was adequate for obtaining some pharmacokinetic parameters. Statistically significant differences among the species were observed in areas under the plasma concentration-time curves, plasma half-lives, and volumes of distribution. The pharmacokinetics kinetics of isosorbide dinitrate in baboons most closely resembled those in humans.

Animals↗
PubMed1983

Validation of high-performance liquid chromatographic methods for analysis of sustained-release preparations containing nitroglycerin, isosorbide dinitrate, or pentaerythritol tetranitrate.

The assay of sustained-release tablets or capsules containing nitroglycerin, isosorbide dinitrate, or pentaerythritol tetranitrate by high-performance liquid chromatography is described. Acetonitrile was found to be the sample preparation solvent with the most general applicability to these products. Anisole was used as an internal standard for nitroglycerin and pentaerythritol tetranitrate, while 4-chloroacetanilide was used for isosorbide dinitrate. The method, which uses a C18 bonded-phase column, a methanol-water mobile phase, and 214-nm detection, was shown to be accurate, linear, and reproducible.

Acetonitriles↗
PubMed1984

Isosorbide dinitrate plasma concentrations and bioavailability in human subjects after administration of standard oral and sublingual formulations.

The bioavailability of isosorbide dinitrate from formulations containing 5, 10, and 20 mg in tablets and 10 mg in solution for oral use and 5 mg in tablets for sublingual use, has been compared. When adjusted for dose, the peak mean plasma drug concentrations after oral administration were similar (e.g., 9.2 ng/mL after a 10-mg tablet) and about one-half that obtained after sublingual administration. Drug concentrations declined monoexponentially with mean half-lives ranging from 25-36 min. The relative bioavailability of isosorbide dinitrate from the oral formulations was not significantly different (p greater than 0.05) over the dose range studied, whereas the relative bioavailability after sublingual administration was about twice as great (p less than 0.01) as that after oral administration. The plasma drug concentration-time profile after administering the 5-mg sublingual tablet was similar to that obtained after administering orally a solution containing 10 mg, indicating that the latter should be as clinically effective as the former.

Administration, Oral↗
PubMed1991

The effect of isosorbide-mononitrate eye drops on the human intraocular pressure and aqueous humor dynamics.

In a randomized, double-masked, single drop study the effect of topical isosorbid-mononitrate (ISMO) 0.5% eye drops, the main metabolite of isosorbid-dinitrate, widely used in the treatment of coronary heart diseases, was studied in patients suffering from open angle glaucoma or ocular hypertension. There was no statistically significant IOP change within 8 hours posttreatment after topical administration of ISMO 0.5%. There were no side effects after application of the ophthalmic solution of ISMO 0.5%. There were no significant changes in blood pressure and pulse rate either. A 2% ophthalmic solution of ISMO was investigated with respect to a response on the aqueous humor dynamics in 10 healthy volunteers. Anterior chamber fluorophotometry revealed a mean increase in aqueous flow of 39% within 3 hours after topical application (P less than 0.01). However, in comparison to the placebo treated fellow eyes there were no statistical significant difference in aqueous humor flow during the time of investigation. There was a statistical significant reduction of IOP during the same time period (p less than 0.03) in all treated eyes.

Aqueous Humor↗
PubMed1994

A new isosorbide dinitrate extended-release formulation: pharmacokinetic and clinical parameters in patients with stable angina pectoris.

In a double-blind, cross-over study the acute clinical efficacy and pharmacokinetic profile of a newly developed isosorbide dinitrate extended-release (ISDN-ER) formulation (10 mg immediate release and 60 mg slow release) were examined in eight angina patients. Exercise tests were done 1 h before and 1, 6 and 10 h after acute ISDN or placebo; similar testing was repeated after 14 days of open-labelled treatment. At 1, 6 and 10 h after administration, ISDN-ER significantly reduced the mean ST depression at highest comparable workload (HCWL) by 0.8, 0.6, and 0.6 mm, respectively. Total exercise duration increased significantly by 46, 42 and 72 s. The rate-pressure product at HCWL was not reduced significantly at any time, while digital plethysmography demonstrated a significant effect on arterial pulse curves throughout the 10 h. After 14 days of once-daily treatment, similar or somewhat attenuated clinical effects were observed. Pharmacokinetic measurements showed a first peak of ISDN at 1-2 h and a second peak at 4-5 h. The 5-isosorbide mononitrate (5-ISMN) metabolite peaked at 5-8 h and remained high at 10 h. After 14 days of treatment, the mean plasma concentrations of ISDN and 5-ISMN before drug were 0 and 69 ng.ml-1, respectively. Thus, satisfactory acute clinical efficacy and low nitrate levels during the night were observed. However, long-term clinical efficacy needs to be established in larger, placebo-controlled trials.

Aged↗
PubMed1986

Dose-dependent effects of isosorbide-5-mononitrate on the venous, arterial and coronary arterial system of conscious dogs.

Isosorbide-5-mononitrate (IS-5-MN), the main metabolite of isosorbide dinitrate shows antianginal efficacy and is being used increasingly as a drug for practical therapy. In conscious dogs we therefore measured the effects of increasing doses of IS-5-MN on hemodynamic parameters and the diameter of the circumflex artery. We found a dose dependent reduction of the mean right atrial pressure, the systolic blood pressure and a dilatation of the circumflex artery. For all three parameters threshold dosages were between 0.01 and 0.03 mg/kg. On the contrary peripheral and coronary resistance did not change at doses less than or equal to 0.3 mg/kg. The heart rate was significantly increased only at doses above 1 mg/kg and the diastolic blood pressure also showed a tendency to fall only at doses above 1 mg/kg. Cardiac output and coronary flow were not significantly altered over the entire dose range investigated, with the exception of a transient rise in coronary blood flow after the injection of 2.5 mg/kg IS-5-MN. From our results we can deduce that in the low dose range reduction of preload and dilatation of large arteries are the main effects of IS-5-MN. In contrast, no reduction of the coronary or peripheral resistance is to be expected.

Animals↗
PubMed1984

Controlled, eight-hour haemodynamic study of a sustained-release formulation of isosorbide dinitrate in moderate left ventricular failure.

The aim of the study was to assess the duration of the haemodynamic effects of a new sustained-release oral formulation of isosorbide dinitrate (ISDN). Twenty patients (17 men and 3 women; mean age 60 years) with acute myocardial infarction (10 anterior, 10 inferior) complicated by moderate left ventricular failure took part in a randomized controlled trial. Ten patients were randomly assigned to the placebo group and 10 to the ISDN group, who received 40 mg sustained release isosorbide dinitrate. Haemodynamic variables were measured before treatment, after 0.5 and 1 h and then every 2 hours up to the 8th hour after treatment. There was no significant change in any haemodynamic parameter in the placebo group, during the study period. In the ISDN group there was a significant fall in pulmonary artery diastolic pressure at 4 and 8 h, from 19.0 +/- 1.0 mm Hg to 16.5 +/- 1.2 mm Hg and 15.5 +/- 0.8 mmHg, respectively. The mean pulmonary capillary wedge pressure fell progressively from 17.9 +/- 1.0 to 12.5 +/- 1.2 mmHg at 2 h (p less than 0.001 in comparison with the placebo group. The fall remained significant up to 8 h. There was no statistically significant change in heart rate, cardiac index, systemic blood pressure or systemic and pulmonary vascular resistances. On the whole the cardiac index remained unchanged. There were numerous individual variations of cardiac index in relation to the initial mean pulmonary capillary wedge pressure and the magnitude of its fall following administration of ISDN. The change in cardiac index was inversely correlated with the control cardiac index (r = -0.69, p less than 0.02).

Delayed-Action Preparations↗
PubMed1981

First data on effects and pharmacokinetics of isosorbide-5-mononitrate in normal man.

Isosorbide-5-mononitrate (IS-5-MN) 5, 10, 20, 30, 40 and 50 mg were administered orally to 2 healthy male volunteers. The pharmacological effect was determined using digital pulse plethysmography and the orthostatic tilting test, and at the same time side effects were monitored. The threshold of oral activity of IS-5-MN was found to be 5 mg. The maximum response was reached with doses of 20-30 mg. The duration of action of this dose was approximately 8 h. Higher doses did not lead to any further increase, but rather to a decrease in the pharmacological response, while the side-effects, such as headaches, dizziness and nausea, became more prominent. In a randomized, double-blind, three-way cross-over study in 11 female volunteers IS-5-MN 30 mg proved to be more potent with respect to pharmacological activity than sustained released ISDN 20 mg (isosorbide dinitrate), whereas there was no difference in side-effects. Thus, it can be estimated that IS-5-MN 20 mg is approximately equivalent to 20 mg sustained released ISDN. IS-5-MN is rapidly absorbed after oral administration and the maximum concentration in serum was reached 1.2 +/- 0.2 h after doses of 10 to 50 mg. The pharmacokinetics showed dose-linearity. The compound was eliminated with an average half life of 4.04 +/- 0.16 h, which is appropriate for a reasonably prolonged duration of action without the need for a sustained release formulation.

Adult↗
PubMed1981

Pharmacokinetics of intravenous and oral isosorbide - 5 - mononitrate.

The pharmacokinetics of isosorbide-5-mononitrate (IS-5-MN) has been studied in two groups of healthy volunteers after oral (n = 20) and intravenous (n = 11) administration of 20 mg, which had previously been proved to be as effective as 20 mg sustained-release isosorbide dinitrate (ISDN). IS-5-MN in serum was measured by gas chromatography using capillary columns. The kinetic calculations were carried out with a newly developed model, which assumes a virtual volume of distribution dependent on time. IS-5-MN is rapidly (invasion half-life 4.1 min) and completely absorbed from the gastro-intestinal tract without any first pass metabolism. The maximum concentration of 480 micrograms/l was reached 1.2 h after oral administration of 20 mg. The substance was distributed throughout the total body water (distribution coefficient: 0.62), and was eliminated with a terminal t1/2 of 4.1 and 4.6 h after oral and intravenous administration, respectively. Total body clearance was 115ml/min. Thus, IS-5-MN is unlike ISDN with respect to the absence of first-pass metabolism and an 8-times longer half-life. The consequences for therapy are discussed.

Administration, Oral↗
PubMed1988

The effect of food on the absorption of slow-release isosorbide-5-mononitrate tablets.

The influence of food on the absorption characteristics of slow release isosorbide-5-mononitrate tablets was investigated in 10 normal healthy volunteers. There were no differences in the peak concentration achieved or the area under the curve, but the peak concentration occurred later when the drug was administered after food. The apparent elimination half-life ranged from 4.7 to 10.1 h. Bioavailability of slow-release isosorbide-5-mononitrate is therefore unaffected by food, but there is a slower rate of absorption.

Absorption↗
PubMed1982

Pharmacokinetics of intravenous isosorbide-dinitrate.

The kinetics of isosorbide dinitrate (ISDN) after i.v. administration and the absolute availability of an oral slow release preparation (SR) were studied in young healthy volunteers. ISDN and the 2- and 5-mononitrates of isosorbide (2-MN, 5-MN) were determined by GLC. After i.v. administration plasma levels of ISDN declined biexponentially and could be adequately described by an open two compartment body model. Distribution half-life was extremely rapid (2-5 min). Terminal disappearance had a half-life of 67 (62-75) min (mean, range). Total plasma clearance was 1.6 (1.2-2.2) litres X min-1, thus approaching liver blood flow. Nevertheless, absolute systemic availability (F) or oral ISDN amounted to 22% (16-29%). Assuming that oral ISDN is completely absorbed and blood levels do not exceed serum levels, an upper limit of hepatic clearance (liver blood flow 1.5 litres X min-1 X (1-F/100)) can be estimated, which is significantly smaller (p less than 0.05) than the measured clearance. This finding is best interpreted by assuming that ISDN is partly eliminated by extrahepatic routes, which is further substantiated by a different pattern of metabolites after i.v. and oral dosing. Whereas after i.v. administration more 2-MN is produced, 5-MN is the main metabolite after oral ISDN. Since the glutathione-S-transferases are found in the cytosol of most cells, it seems likely that other organs than the liver contribute to the metabolism of ISDN.

Administration, Oral↗