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PubMed1995

Early hemodynamic effects at rest with acute and chronic isosorbide dinitrate treatment in patients with ischemic heart disease.

Asymmetric dosage regimens are used to circumvent development of nitrate tolerance and are believed to restore totally the hemodynamic responsiveness to an acute dosage of nitrates. This study assessed invasively the hemodynamics during supine rest before and for 50 min after peroral 30 mg isosorbide dinitrate (ISDN) in 16 patients with stable ischemic heart disease; 8 previously untreated patients (NT group) and 8 patients treated asymmetrically b.i.d. with 30 mg ISDN for 14 days prior to the invasive investigation (T group). Before initiation of treatment, both groups had identical mean arterial pressure (MAP) and heart rate (HR). On the day of invasive investigation, before intake of ISDN, MAP was higher in the T group but unchanged in the NT group. After the intake of ISDN, right atrial pressure (RAP), mean pulmonary arterial pressure, and pulmonary arterial wedge pressure declined markedly within 10 to 15 min in both groups, while MAP showed a more protracted decline, reaching a new level only after 25 to 30 min. In the NT group, HR accelerated markedly and remained elevated throughout the observation period, whereas in the T group HR showed no significant alteration after ISDN intake. At the end of the observation period, the cardiac index (CI) was definitely reduced in the NT group, but remained unchanged in the T group, while the systemic vascular resistance index was unchanged in the former and was clearly reduced in the latter. It is concluded that the fall in MAP in the NT group was solely due to a fall in CI, and that the decline in RAP and venous return in the NT group induced neurohumoral reflexes leading to a rise in HR and prevention of arterial dilation, whereas in the T group, already influenced by chronic treatment, such acute counterregulatory responses were markedly attenuated or absent.

Aged↗
PubMed1995

Plasma concentrations and coronary vasodilation after sublingual and intracoronary administration of isosorbide dinitrate.

To investigate the relationship between plasma levels and coronary vasodilation after administration of isosorbide dinitrate (ISDN), the plasma concentration and diameters of six segments of the left coronary artery were measured before and after sublingual (SL) ISDN (5 mg) and left intracoronary (IC) administration of ISDN (3 mg) in 12 patients. After SL-ISDN, the systolic aortic pressure decreased with no significant concomitant changes in heart rate or diastolic aortic pressure. After IC-ISDN, all hemodynamic parameters showed significant changes, and these were greater after IC-ISDN than those after SL-ISDN. The individual mean vasodilation of six segments induced by SL- and IC-ISDN, were 23 +/- 9 and 35 +/- 11% (p < 0.01), respectively. Before SL-ISDN, ISDN was not detected in plasma. After SL- and IC-ISDN, however, the plasma values of the ISDN were 36.1 +/- 53.3 and 101.5 +/- 90.0 ng/ml (p < 0.01), respectively. Thus, both coronary vasodilative responses and plasma ISDN levels after IC-ISDN were significantly greater than those after SL-ISDN. However, neither the individual mean coronary vasodilation nor the hemodynamic changes correlated significantly with plasma ISDN levels. Consequently, with administration of the same dose, the coronary vasodilative response to ISDN did not correlate with plasma levels. Furthermore, IC-ISDN dilutes coronary arteries more effectively than SL-ISDN.

Administration, Sublingual↗
PubMed1996

Hemodynamic time course of acute and chronic isosorbide dinitrate treatment at rest and during exercise in patients with stable ischemic heart disease.

HYPOTHESIS: The study was undertaken to establish differences between venous and arterial isosorbide dinitrate (ISDN) effects during acute and chronic treatment, hemodynamics at rest, and during supine exercise. METHODS: These effects were assessed invasively in 16 patients with stable ischemic heart disease before and at hourly intervals for 4 h after administration of peroral 30 mg ISDN. Eight patients were previously untreated (acute group), and eight were treated with 30 mg ISDN asymmetrically b.i.d. for two weeks (chronic group). RESULTS: Prior to ISDN administration, right atrial, mean pulmonary artery, pulmonary artery wedge, and mean arterial pressure (RAP, MPAP, PAWP, and MAP) rose from normal resting to pathologic values during exercise. One h after ISDN administration, all exercise pressures were normalized (p < 0.001). During the following 3 h, exercise RAP rose similarly in both groups (p < 0.01), while MPAP rose particularly in the chronic group (p < 0.001). Exercise PAWP and MAP, however, remained low in the acute group, but increased markedly in the chronic group (p < 0.01), particularly from the third to the fourth hour after ISDN. CONCLUSION: The daily, asymmetric administration of 30 mg ISDN b.i.d. maintained beneficial, anti-ischemic effects for 2 to 3 h after a morning dose of the drug, but thereafter attenuation of the effects occurred in the arteries but not in the veins.

Exercise Test↗
PubMed1997

Double-blind randomized multicenter study on the efficacy of trapidil versus isosorbide dinitrate in stable angina pectoris.

BACKGROUND: Trapidil is an inhibitor of phosphodiesterase I-IV with resulting positive lusitropic, vasodilating, and antiplatelet effects. HYPOTHESIS: This study was undertaken to compare the antianginal efficacy of trapidil with that of isosorbide dinitrate (ISDN) in patients with stable angina pectoris. METHODS: We studied 95 patients with stable angina pectoris who were randomized into a double-blind parallel group study with either oral trapidil or ISDN. After a 1-week run-in period and a 2-week wash-out phase, the patients received either trapidil 200 mg t.i.d. (n = 48) or ISDN 20 mg t.i.d. (n = 47) for 12 weeks. All antianginal medication, except sublingual glyceryl trinitrate (GTN), was discontinued during the study. Patients underwent an exercise electrocardiogram on an ergometer bicycle according to a modified Bruce protocol before and at 6 and 12 weeks during treatment. RESULTS: The workload capacity increased from 583 +/- 281 W.min before treatment to 833 +/- 444 W.min after 12 weeks of treatment in the trapidil group (p < 0.01) and from 555 +/- 276 W.min to 827 +/- 361 W.min in the ISDN group (p < 0.01). The anginal attacks per week as well as the use of GTN decreased significantly in both groups. After 12 weeks of therapy, the cumulative ST-segment depression during exercise decreased by 67% in the trapidil patients and by 23% in the ISDN patients. Compared with baseline, the double product at the 75 W level was reduced in both groups after 12 weeks of treatment. Blood pressure and heart rate at rest remained nearly unchanged. Overall, no statistical difference was found between the two study groups. The tolerability was good. CONCLUSION: Oral trapidil therapy is safe and effective in stable angina pectoris and is equivalent to standard therapy with ISDN.

Administration, Oral↗
PubMed2001

Continuous long-term dosing with oral slow-release isosorbide dinitrate does not reduce incidence of cardiac events in patients with healed myocardial infarction.

BACKGROUND: In the short term, isosorbide dinitrate (ISDN) is considered to be therapeutically effective. The long-term effects of treatment with slow-release ISDN are less clear. HYPOTHESIS: The study was undertaken to investigate the effects of continuous, long-term dosing with oral slow-release ISDN on the incidence of cardiac events in patients with healed myocardial infarction (MI). The study was carried out in accordance with the intention-to-treat principle. METHODS: In all, 1.102 in- and outpatients, of either gender, with healed MI were randomly divided into groups treated with ISDN (n = 470) and not treated with ISDN (n = 632). Patients in the ISDN group received a continuous regimen of 20 mg of oral, long-acting ISDN three times a day, after meals. The mean observation period was 15.0 +/- 18.5 months. The primary endpoints were nonfatal and fatal recurrent MI, death from congestive heart failure, and sudden death. RESULTS: There were no significant differences in the baseline characteristics of the patients in the ISDN and no-treatment groups; nevertheless, significantly more patients in the ISDN group experienced cardiac events. In the ISDN group, 35 patients (7.4%) experienced cardiac events during the observation period, versus only 28 patients (4.4%) in the no-treatment group (p < 0.05; odds ratio 1.74; 95% confidence interval 1.04-2.90). CONCLUSION: Continuous long-term dosing with oral, slow-release ISDN does not reduce and probably increases the incidence of cardiac events among patients with healed MI.

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↗
PubMed1979

Effects of isosorbide dinitrate on pulmonary hypertension in chronic obstructive pulmonary disease.

Eighteen patients with chronic obstructive pulmonary disease with pulmonary hypertension were studied to assess the hemodynamic response to acute oxygen administration and to oral isosorbide dinitrate (ISDN). All 18 patients had baseline hemodynamic measurements and hemodynamic measurements during low-flow nasal oxygen. Following a second baseline measurement, patients received either oral ISDN (11 patients) or placebo (7 patients) in a randomized, double-blind protocol. Heart rate decreased with oxygen administration but there were no other significant hemodynamic changes. With oral ISDN, there was a significant fall in pulmonary artery and brachial artery pressure. Cardiac output, right atrial pressure, pulmonary wedge pressure, and pulmonary vascular resistance all fell but not significantly. We conclude that oral ISDN is effective in reducing pulmonary hypertension in patients with chronic obstructive pulmonary disease.

Blood Pressure↗
PubMed1995

Long-term effect of nadolol or nadolol plus isosorbide-5-mononitrate on renal function and ascites formation in patients with cirrhosis. GTIP Gruppo Triveneto per l'Ipertensione Portale.

The association beta-blockers plus nitrates has been reported to impair renal function and renal sodium handling, leading to increased risk of development of ascites, or worsening of a preexisting ascites, or increase in the requirements of diuretic agents. In 81 patients with cirrhosis and esophageal varices, participating in a multicenter controlled clinical trial of prophylaxis of variceal bleeding comparing nadolol (NAD) plus isosorbide-5-mononitrate (I5M) with NAD alone, renal function, presence of ascites, and diuretic requirements were assessed at inclusion and after 6 months of follow-up. No significant variation in s-urea or s-creatinine was observed in either group, Three patients in the nadolol group and two in the NAD plus I5M developed ascites at 6 months (P = .70), and a need to increase diuretic regimen was observed in four and three patients, respectively (P = .76). Decrease in heart rate and in mean arterial pressure was similar in the two groups. There was a significant correlation between increases in s-creatinine and decrease in mean arterial pressure in the whole series (P = .015). Only in patients treated with the association was there a significant larger proportion of patients ascitic who became anascitic, than of patients anascitic who became ascitic (P = .03). In patients treated with the association, there was a significantly larger decrease in hepatic venous pressure gradient (P = .05). It is concluded that patients treated with the association NAD plus I5M are not at increased risk of developing renal dysfunction or worsening of ascites compared with patients treated with NAD alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Absorption of isosorbide-5-mononitrate at specific sites in the gastrointestinal tract.

As part of a development program for controlled- and extended-release formulations of isosorbide-5-mononitrate (ISMN), the rate and extent of drug absorption was evaluated after site-specific delivery in the gastrointestinal (GI) tract. Seven healthy male subjects received, on separate occasions, 20 mg of ISMN solution orally and via nasogastric tube to the jejunum, terminal ileum, and ascending colon. Compared with oral administration (AUC 2,963 hr x ng/mL, Cmax 442 ng/mL, Tmax 0.81 hr), placement of drug directly into the jejunum did not change the extent (AUC 2,844 hr x ng/mL) but increased the rate of absorption (Cmax 630 ng/mL, Tmax 0.28 hr) due to direct placement of drug into the intestine. Administration to the terminal ileum resulted in a rate of absorption comparable to that from the jejunum (Tmax 0.28 hr) but a reduction in extent (mean AUC 2,377 hr x ng/mL). Delivery to the ascending colon resulted in a further decrease in the extent (AUC 2,017 hr x ng/mL) and a "slowing" of the rate of absorption compared with the two intestinal sites (Cmax 392 ng/mL, Tmax 0.68 hr). Overall, bioavailability throughout the GI tract was sufficient to support development of controlled- and extended-release formulations.

Administration, Oral↗
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↗
PubMed1982

NMR determination of isosorbide dinitrate and beta-adrenergic blocking agents in tablets.

An NMR spectroscopic method for the determination of isosorbide dinitrate, alone or together with alprenolol or propranolol, is described. Spectra are determined in dimethyl sulfoxide-d6 containing maleic acid or 1,4-dinitrobenzene as internal standards. Both synthetic mixtures and commercial formulations were assayed, and the results were compared using compendial procedures.

Adrenergic beta-Antagonists↗
PubMed1984

High-performance liquid chromatographic determination of the nitrate esters isosorbide dinitrate, pentaerythritol tetranitrate, and erythrityl tetranitrate in various tablet forms.

A reliable, sensitive, and specific assay for isosorbide dinitrate pentaerythritol tetranitrate, and erythrityl tetranitrate in sublingual, uncoated, sustained-release, and chewable dosage forms, using high-performance liquid chromatography, is described. The nitrate ester dosage forms were dissolved in methanol, filtered, and injected directly into the liquid chromatograph. A variable-wavelength UV detector, operated at 220 nm, and a reverse-phase C18 microporous silica column were employed. The mobile phase was methanol-water (40:60). The proposed method is quantitative and reproducible.

Chromatography, High Pressure Liquid↗
PubMed1991

A new multiple-unit oral floating dosage system. II: In vivo evaluation of floating and sustained-release characteristics with p-aminobenzoic acid and isosorbide dinitrate as model drugs.

In a previous study, we developed a multiple-unit type of oral floating dosage system, which is a new type of floating pill composed of both an effervescent layer and a swellable membrane layer coated on sustained-release pills. The system was shown to have excellent floating ability and sustained-release characteristics in vitro, irrespective of the pH and viscosity of the medium. In the present study, the floating ability and the sustained-release characteristics of the system in the gastrointestinal tract have been evaluated in vivo. In beagle dogs and humans in the fed state, most of the new type of pills containing barium sulfate were floating in the stomach at 10 min, and they kept floating for at least 3 h after administration (observed by periodic X-ray photographs), while some control pills without the effervescent layers were already transited into the small intestine by 3 h. Moreover, in order to evaluate the sustained-release characteristics of the drug from the new type of floating pills, p-aminobenzoic acid (PABA), with a limited absorption site, and isosorbide dinitrate (ISDN), with wide absorption sites in the gastrointestinal tract, were employed as model drugs. Floating pills of the new type, with the same sustained-release rate as that of non-floating pills (control pills) were prepared. In beagle dogs in the fed state, the new type of floating pills containing PABA showed higher plasma PABA levels at 5 and 6 h after dosing and 1.61 times greater AUC than the control pills.(ABSTRACT TRUNCATED AT 250 WORDS)

4-Aminobenzoic Acid↗
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

Controlled-release isosorbide dinitrate pellets. Part II: In vivo studies.

Isosorbide dinitrate (ISDN) capsules containing 20.0 and 40.0 mg of the drug (reported earlier in Part I of this series) were evaluated in vivo in eight healthy volunteers in a double-blind study with marketed sustained-release preparations containing 20.0 and 40.0 mg of ISDN. The results were normalized by administering placebo and four conventional ISDN tablets, each containing 5.0 mg of ISDN, to the same group of volunteers in a separate study. The blood pressure of the volunteers was monitored for 8 h. The results indicate that the capsules prepared in the laboratory with the new formulation gave controlled release when compared with the respective marketed SR product.

Adult↗
PubMed2006

An extensive study on isosorbide-5-mononitrate acid adducts for quantification in human plasma using liquid chromatography/electrospray ionization tandem mass spectrometry and its application to bioequivalence sample analysis.

A rapid and sensitive liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) method for the determination of isosorbide-5-mononitrate (5-ISMN), used in the treatment of angina pectoris, in human plasma is described. The quantification of 5-ISMN was performed via stable acetate adduct formation with a high relative abundance. The plasma filtrate obtained after solid-phase extraction (SPE), using a polymer based, hydrophilic-lipophilic balanced (HLB) cartridge, was submitted directly to reversed-phase high-performance liquid chromatography separation followed by ESI and detection of the resulting ions using triple-quadrupole mass spectrometry in selected reaction monitoring (SRM) mode. There was no significant matrix effect on the analysis. For validation of the method, the recovery of the free analyte response was compared to that obtained from an optimized extraction method. The analyte stability was examined under conditions mimicking the sample storage, handling, and analytical procedures. The extraction procedure yielded extremely clean extracts with a recovery of 95.51% and 93.98% for iossorbide-5-mononitrate and topiramate (internal standard (IS)), respectively. The calibration curves were linear for the dynamic range of 10.0 to 1000.0 ng/mL with a correlation coefficient r > or = 0.9985. The intra-assay and inter-assay precision for the samples at the lower limit of quantification (LLOQ) were 9.02 and 13.30%, respectively. The intra-assay accuracies at LLOQ, LQC, MQC and HQC levels varied from 98.13 to 118.15, 102.34 to 105.21, 100.69 to 109.68, and 95.76 to 102.92%, respectively, while the inter-assay accuracies ranged from 93.10 to 118.15, 93.03 to 107.04, 86.97 to 109.68 and 86.18 to 105.85%, respectively, at these levels. The method is rugged and fast with a total run time of 2 min. The method was successfully applied for a bioequivalence study in 24 human subject samples after oral administration of 60 mg extended release (ER) formulations.

Acetylation↗
PubMed1990

The poststenotic vessel segment during dynamic exercise: effect of oral isosorbide-dinitrate.

Coronary vasomotion of normal, stenotic, and poststenotic vessel segments was studied in 18 patients with coronary artery disease at rest, during submaximal bicycle exercise, and 5 min after sublingual nitroglycerin or oral isosorbide-dinitrate (ISDN) spray. Patients were divided into two groups: group 1 consisted of 10 patients with no premedication prior to exercise, and group 2 consisted of 8 patients receiving 120 mg long-acting ISDN orally 1 h before the procedure. Quantitative coronary arteriography was carried out in biplane projection using a semi-automatic computer system. The normal vessel segment showed a trend toward a small increase in cross-sectional area during exercise in both groups (+3% in group 1 and +4% in group 2, both NS). After sublingual nitroglycerin following exercise, there was a significant increase in group 1 (+29%, p less than 0.001 vs rest) but not after ISDN spray in group 2 (+5%, NS vs rest). The stenotic vessel segment showed exercise-induced stenosis narrowing in group 1 (-31%, p less than 0.01 vs rest) which was prevented by oral ISDN (+6%, NS vs rest). After exercise, sublingual administration of nitroglycerin or ISDN spray was associated with no significant change in stenosis area in either group. The poststenotic vessel segment showed no significant vasomotion during exercise in both groups (area change +6% in group 1 and +7% in group 2), but poststenotic luminal area increased after sublingual nitroglycerin (group 1: +15%, p less than 0.01 vs rest) or ISDN spray (group 2: +15%, p less than 0.05 vs rest). The mean pulmonary artery pressure increased during exercise from 22 to 39 mmHg (p less than 0.001) in group 1 and from 14 to 27 mmHg (p less than 0.001) in group 2. At rest (p less than 0.001) and during exercise (p less than 0.01) mean pulmonary pressure was lower in group 2 than in group 1. Thus, it is concluded that coronary vasomotion of the poststenotic vessel segment is only minimal during exercise and is not affected by coronary vasomotion of the stenotic vessel segment. Pretreatment with oral ISDN did not influence coronary vasomotion of the poststenotic vessel segment, but prevented exercise-induced stenosis narrowing. In the untreated patients, vasoconstriction of the stenotic vessel segment is limited to the site of the stenosis, and it appears that there is no release of vasoactive substances with vasoconstrictive influences on the poststenotic segment.

Administration, Oral↗
PubMed1988

Comparative study of time-course of hemodynamic effect of isosorbide dinitrate spray and sublingual tablets in patients with pulmonary congestion.

We compared the time-course of the hemodynamic effect of isosorbide dinitrate (ISDN), 5 mg, in the form of sublingual tablet and oral spray, in 15 patients with isolated chronic pulmonary congestion (pulmonary arterial end-diastolic pressure of 15 mmHg or more in the presence of normal or only slightly reduced cardiac index). Both formulations produced significant reductions in the pulmonary arterial end-diastolic pressure. The effect of ISDN tablet (sublingually) became evident at 10 minutes after administration and was maximal at 30 minutes. The effect of ISDN oral spray became evident at 3 minutes and reached a peak at 10 minutes. The magnitude of hemodynamic response was similar. These findings indicate that ISDN oral spray is superior to ISDN sublingual tablets for rapid relief of pulmonary congestion.

Administration, Sublingual↗