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PubMed1988

Comparative pharmacokinetics of isosorbide nitrates after repeated doses of sustained release isosorbide dinitrate.

The plasma kinetics of isosorbide dinitrate (ISDN), isosorbide-5-nitrate (IS-5-N) and isosorbide-2-nitrate (IS-2-N) were investigated in 20 healthy male and female volunteers, after b.i.d. administration over 2 days of sustained release ISDN 20 mg and 40 mg capsules (Iso Mack Retard 20 mg and 40 mg) and of a 40 mg sustained release ISDN tablet as reference formulation. The means of the individual maximum ISDN concentrations during the complete 2-day treatment amounted to 10.4 ng/ml after the 40 mg capsule, 5.3 ng/ml after the 20 mg capsule and 5.3 ng/ml after the reference tablet. The corresponding figures of the metabolically generated IS-5-N were 355.5 ng/ml, 168.8 ng/ml and 161.5 ng/ml, respectively. The measured amounts of IS-5-N are expected to contribute to the overall antianginal effect of at least the 40 mg capsule. According to the b.i.d. schedule, ISDN and the two mononitrates accumulated in the plasma after all three tested formulations. However, during the treatment with the 20 mg and the 40 mg capsules, accumulation was practically completed at the second day, while it was found to be more extended during treatment with the reference product. In terms of areas under the curve, the mean bioavailability of the 40 mg sustained release capsule relative to the reference formulation was 198% with respect to ISDN, and 197% both with respect to IS-2-N and IS-5-N. On the other hand, perfect dose-linearity of all relevant pharmacokinetic parameters of all three measured isosorbide nitrates was observed for the 20 mg and the 40 mg dose of the capsule.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1996

Magnitude and nature of noncompliance with treatment using isosorbide dinitrate in patients with ischemic heart disease.

Isosorbide dinitrate is one of the most commonly prescribed medications for the treatment of ischemic heart disease. It has been demonstrated to be ineffective relative to placebo when taken inappropriately. This study objectively documents the magnitude and nature of compliance in 68 ambulatory patients who were prescribed isosorbide dinitrate three times a day. Each patient received a 9-week supply of medication in a vial equipped with a computerized monitor (MEMS-4 cap; APREX Corporation, Fremont, CA) and were informed as to the purpose of the study. Of the patients, 74% were classified into the low and 16% into the high compliance category, defined as compliant < 70% and > or = 85% of study days, respectively. The mean (+/- SD) percent days in which isosorbide dinitrate was taken three times was 66% (+/- 29), and the mean number of days in which it was taken three times with a 10-hour "nitrate free period" was 53% (+/- 31). It is concluded that the magnitude of noncompliance in patients prescribed isosorbide dinitrate three times daily is substantial (74%). The nature of this noncompliance is often due to failure to observe a 10- to 12-hour nitrate free period. Given the need to take isosorbide dinitrate appropriately and given the demonstrated magnitude of noncompliance, physicians should take these factors into consideration when selecting this agent for the management of coronary artery disease relative to other pharmacologic options.

Aged↗

PubMedDate not supplied

Bioequivalence of a sustained-release isosorbide dinitrate formulation at steady-state.

Isosorbide 2,5-dinitrate and its pharmacologically active metabolites, isosorbide 2-nitrate and isosorbide 5-nitrate, in plasma accumulated to the predicted steady-state after five consecutive oral doses of sustained-release tablets containing 40 mg isosorbide dinitrate at 12-h intervals and after five consecutive oral doses of reference standard-release tablets containing 20 mg at 6-h intervals to 12 subjects in a crossover study. The comparative bioavailability of isosorbide dinitrate, isosorbide 2-nitrate and isosorbide 5-nitrate from the sustained-release tablet was 110 per cent (p greater than 0.05), 89 per cent (p greater than 0.05), and 89 per cent (p less than 0.05), respectively, of that from the reference standard-release tablet. The isosorbide dinitrate plasma level data were the more variable, as expected for a drug of low systemic availability subject to extensive first-pass elimination. The posterior probability that the true bioavailability of isosorbide dinitrate was included within the usually accepted limits of 80-120 per cent was 0.74, a value which is probably insufficient to justify claims of bioequivalence with the reference formulation in respect of extent of availability. In contrast, the posterior probability that the bioavailability of the metabolites isosorbide 2- and 5-nitrate was included within these limits was 0.90 and 0.98, respectively. On the basis of the mononitrate data, these two formulations may be judged bioequivalent in respect of extent of availability despite a formal statistically significant formulation-related effect in the analysis of variance of the isosorbide 5-nitrate bioavailability data. Claims of bioequivalence of isosorbide dinitrate sustained-release formulations may be more economically justified by analysis of the mononitrate plasma concentrations, although concentrations of the formulated parent dinitrate should also be known.

Adolescent↗

PubMed1982

Randomized double-blind comparison of nifedipine and isosorbide dinitrate in patients with coronary arterial spasm.

The effects of nifedinpine and isosorbide dinitrate on the frequency of angina and consumption of nitroglycerin were studied in 19 patients with coronary arterial spasm. After a lead-in phase, the patients were randomized to treatment with either nifedipine or isosorbide dinitrate. After dose titration (40 to 120 mg/day) and evaluation, they were given the alternate therapy. During the initial segment of the double-blind phase, one patient died suddenly (nifedipine phase), one dropped out of the study (nifedipine phase) and another was unable to tolerate therapy (isosorbide dinitrate phase). In the other 16 patients, the mean frequency of angina was less during therapy with both nifedipine (0.69 episode/day, p less than 0.05) and isosorbide dinitrate (0.77 episode/day, p less than 0.05) phases than during the lead-in phase (1.71 episodes/day). The mean frequency of angina was similar in the nifedipine and isosorbide dinitrate phases. A 50 percent or greater decrease in frequency of angina compared with lead-in phase values occurred in 13 of 18 patients during treatment with nifedipine and in 10 of 16 during treatment with isosorbide dinitrate. Of the 16 patients who completed both double-blind phases, 7 showed greater improvement (that is, a 50 percent or greater decrease in frequency of angina) with nifedipine than with isosorbide dinitrate); 6 others showed greater improvement with isosorbide dinitrate, and the other 3 had a less than 50 percent difference in frequency of angina with the two drugs. These findings in a limited number of patients suggest that both nifedipine and isosorbide dinitrate are effective in certain patients with coronary spasm but that neither drug is clearly superior.

Adult↗

PubMed1995

Combined captopril and isosorbide dinitrate during healing after myocardial infarction. Effect on ventricular remodeling, function, mass and collagen.

OBJECTIVES: We sought to compare the effects of captopril plus isosorbide dinitrate versus monotherapy on infarct collagen content and left ventricular remodeling and function during healing after myocardial infarction. BACKGROUND: Captopril or isosorbide dinitrate monotherapy can limit postinfarction dilation. Whether captopril inhibits infarct collagen content, or whether captopril plus isosorbide dinitrate might be more beneficial, is not known. METHODS: In vivo remodeling variables and function (echocardiography), hemodynamic variables, postmortem topography (planimetry) and collagen content (hydroxyproline) were measured in 48 chronically instrumented dogs that were randomized 2 days after left anterior descending coronary artery ligation to 6 weeks of therapy with captopril, isosorbide dinitrate, captopril plus isosorbide dinitrate or placebo. RESULTS: Compared with placebo, the three active therapies decreased blood pressure and left atrial pressure; limited infarct expansion, infarct thinning, noninfarct wall stretching and thickening; limited left ventricular dilation and increase in left ventricular mass; and decreased regional bulging, aneurysm frequency and left ventricular dysfunction. However, the decrease in asynergy and increase in volume ejection fraction were less with captopril or captopril plus isosorbide dinitrate than with isosorbide dinitrate. Infarct thinning and bulging at 6 weeks was also less with isosorbide dinitrate than with captopril. Although initial left ventricular asynergy, final scar sizes and noninfarct collagen content at 6 weeks were similar among the groups, collagen in the center of the infarct scar was less with captopril or captopril plus isosorbide dinitrate than with placebo or isosorbide dinitrate. CONCLUSIONS: Monotherapy with captopril or isosorbide dinitrate, or their combination, improved all remodeling variables, but isosorbide dinitrate improved function more than captopril or captopril plus isosorbide dinitrate. Inhibition of infarct collagen content by captopril suggests that benefits with captopril represent a balance between positive and negative effects, and its combination with isosorbide dinitrate might be advantageous.

Animals↗

PubMed1983

Metabolism of isosorbide dinitrate in the isolated perfused rabbit lung.

The uptake and metabolism of isosorbide dinitrate was investigated in the recirculating isolated perfused rabbit lung and in lung homogenate 9000 X g supernatant. Concentration versus time profiles from the isolated lung experiments indicate rapid metabolism of isosorbide dinitrate and corresponding increases in the metabolites 5-isosorbide mononitrate, 2-isosorbide mononitrate, and isosorbide. The data suggest that the mononitrates formed in the lung tissue were converted to isosorbide at an extraordinarily high rate. Surprisingly, the rate of appearance of completely denitrated isosorbide was greater when isosorbide dinitrate was administered to the lung than when the mononitrate metabolites of isosorbide dinitrate were administered. The results suggest rapid metabolism of a substantial portion of the mononitrates formed endogenously from isosorbide dinitrate before partitioning of mononitrates into the perfusion medium could occur. The metabolism of isosorbide dinitrate in lung homogenate 9000 X g supernatant exhibited a metabolic scheme kinetically different from the intact lung studies, as isosorbide was formed slowly from a mononitrate intermediate and not by a near-simultaneous cleavage of both nitrate ester groups. Intravascular multiple-dose studies did not demonstrate any inhibition between isosorbide dinitrate and the mononitrates.

Animals↗

PubMed1983

Single administration of atenolol does not influence the kinetics of orally given isosorbide dinitrate.

In eight subjects, plasma concentrations of isosorbide dinitrate and its mononitrates after oral administration of 10 mg isosorbide dinitrate were measured on two occasions, once with and once without previous administration of a single dose of atenolol 100 mg. There were no significant changes either in plasma concentration at different times after administration, or in peak plasma concentrations or in area under the curve of the isosorbide dinitrate and mononitrates.

Administration, Oral↗

PubMed1988

The sorption of isosorbide dinitrate to intravenous delivery systems.

The sorption of isosorbide dinitrate from 0.9% sodium chloride and 10% glucose solutions, by intravenous delivery systems has been investigated under simulated infusion conditions. Isosorbide dinitrate was stable in both 0.9% sodium chloride and 10% glucose solutions. Intravenous fluid containers, burettes, a syringe, infusion sets and end-line filters were evaluated. Glass containers, methacrylate butadiene styrene burettes and polybutadiene giving sets did not sorb isosorbide dinitrate. Neither did polypropylene syringes when a 10% glucose solution was used. The sorption of isosorbide dinitrate to end-line filters was unimportant but there was a significant loss to the PVC tubing used to connect the filter housing to the catheter.

Adsorption↗

PubMed1987

Effect of intervals between doses on the development of tolerance to isosorbide dinitrate.

We studied the development of tolerance to isosorbide dinitrate in 12 patients with chronic stable angina pectoris. The effect of 30 mg of isosorbide dinitrate on treadmill exercise performance was assessed before and at one, three, and five hours after a single dose. As compared with placebo, the drug increased treadmill walking time until the onset of angina and until the development of moderate angina over the five-hour observation period (P less than 0.05). The patients then received 30 mg of isosorbide dinitrate twice, three times, and four times daily for a period of one week, and exercise performance was assessed before and at one, three, and five hours after the final morning dose. During sustained treatment two and three times daily, treadmill walking time was longer throughout the five-hour testing period than during the placebo phase (P less than 0.05). In contrast, during treatment four times daily, treadmill walking time was prolonged at one hour (P less than 0.05) but not at three and five hours after the last dose. We conclude that tolerance to the clinical effects of isosorbide dinitrate develops with a sustained dosage of 30 mg four times daily, but not when the drug is given two or three times daily.

Adult↗

PubMed1995

Inhibition of potassium-stimulated dopamine release by the nitric oxide generator isosorbide dinitrate.

In PC12 cells, isosorbide dinitrate (ISDN) and S-nitrosol-acetyl-penicillamine (SNAP), both nitric oxide (NO) generators, attenuated K+ (56 mM)-stimulated release of dopamine. The attenuation was not observed with isosorbide, an ISDN analog lacking NO generating capacity. In this model, A23187 (Ca2+ ionophore), Bay K8644 (Ca2+ slow channel agonist) and veratridine (Na+ channel agonist) stimulated dopamine release. Treatment with ISDN enhanced Bay K8644 and veratridine-evoked dopamine release, while ISDN had no significant effect on the A23187 response. Incubation with 8-bromo-cGMP (membrane permeable cGMP analog) had no effect on basal or stimulated dopamine release in these cells, suggesting NO's response was not mediated by cGMP. In additional studies, K+ (56 mM), Bay K8644 and veratridine elevated cytosolic free calcium levels ([Ca2+]i). ISDN reduced K(+)-stimulated increase in [Ca2+]i, but enhanced the increases of [Ca2+]i induced by Bay K8644 or veratridine. These results suggest NO interacts with K(+)-induced membrane depolarization (possibly by inhibiting membrane conductance to K+) to attenuate Ca2+ influx and Ca(2+)-mediated dopamine secretion stimulated by K+.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

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↗

PubMed1994

[Antianginal effect of transdermal isosorbide dinitrate (multicenter study)].

Efficacy of transdermal isosorbid-dinitrate spray was investigated in 167 of 254 patients with stable angina pectoris. The transdermal application of isosorbid-dinitrate decreased successfully the number of anginal attacks and the sublingual nitroglycerin or isosorbid-dinitrate consumption. Very few side effects were observed and the patients well-being was good during treatment.

Administration, Cutaneous↗

PubMed1989

[Evaluation using serial exercise tests of verapamil alone and combined with isosorbide dinitrate in exertional angina].

The response to verapamil alone and combined with isosorbide dinitrate in a group of 12 patients with severe ischemic heart disease and stable effort angina was assessed by means of serial treadmill testing. The study was randomized, of a square latin design and double-blind. The tested drugs and dosages were 120 mg of verapamil, 120 mg of verapamil plus 20 mg of isosorbide dinitrate and placebo. Patients were serially tested (Bruce protocol) over three consecutive days at 8-9-12 and 16 hours. A significative improvement was observed in several ischemic parameters both with verapamil alone and combined with isosorbide dinitrate, but this improvement was remarkably enhanced with the combination of drugs. The mean exercise time to produce angina improved from 268 +/- 18 sec (basal) to 379 +/- 19 sec (verapamil plus isosorbide dinitrate) and the time for 1 mm ST segment depression from 163 +/- 22 sec (basal) to 257 +/- 19 sec (verapamil plus isosorbide dinitrate) when measured at the last daily test (8 hours after drug administration). It is concluded that both verapamil alone and combined with isosorbide dinitrate at the chosen doses are clinically efficient, significantly improving the ischemic parameters. The combination of verapamil and isosorbide dinitrate resulted in a remarkably better improvement in this group of patients with stable effort angina.

Adult↗

PubMed1981

Sublingual isosorbide dinitrate in severe congestive heart failure.

Sublingual isosorbide dinitrate was administered to 17 patients with severe congestive heart failure to characterize the hemodynamic action of the drug. Isosorbide dinitrate effect was maximal 30-60 min after administration. The most striking effect was a marked fall of the mean pulmonary capillary wedge pressure which dropped from 28 to 20 mm Hg (p less than 0.01). Pulmonary artery systolic pressure dropped from 55 to 43 mm Hg (p less than 0.01) and right atrial pressure from 11 to 8 mm Hg (p less than 0.01). Arterial blood pressure fell slightly whereas no significant change in heart rate or cardiac index was noted. 8 of the 17 patients showed a marked and sustained reduction of their pulmonary capillary wedge pressure. The hemodynamic response was moderate in 2 patients whereas 6 patients showed no appreciable improvement. A symptomatic but transient reduction in arterial blood pressure occurred in the last patient. Patients responding favorably to the drug had significantly higher initial systolic blood pressure that nonresponders (133 vs. 102 mm Hg, p less than 0.01). However, there was no reliable clinical parameter to predict which of the subjects will respond favorably to the administration of isosorbide dinitrate.

Blood Pressure↗

PubMedDate not supplied

Preparation, characterization and in vitro drug release of isosorbide dinitrate microspheres.

Microspheres of isosorbide dinitrate (ISDN) were prepared using the emulsification/solvent evaporation method. The impacts of different factors such as stirring rate, concentration of ethyl cellulose (EC) as matrix polymer, poly vinyl chloride (PVA) as stabiliser and ISDN on the characteristics of the microspheres were investigated. The morphology of microspheres was studied using optical and scanning electron microscopy and it was shown that microspheres had a spherical shape and smooth surface. The particle size distribution of microspheres, analysed by a sieving method, was affected by stirring rate and concentrations of EC, PVA and ISDN. Larger microspheres showed greater drug loading and smaller microspheres showed a faster drug release. The in vitro drug release from microspheres was predictable and reproducible, conforming to the Higuchi model of release kinetics.

Cellulose↗

PubMed1992

[Experimental antithrombotic activity of oral isosorbide dinitrate].

The activity of isosorbide dinitrate (ISDN) a nitrate derivative with platelet anti-aggregant properties, was studied on a model of arterial thrombosis by electric stimulation of the rat carotid arteries. In control animals, occlusive thrombosis occurred in 15.3 +/- 1.0 minutes. When administered orally in dosages of 1 to 30 mg/kg, 30 minutes before stimulation, ISDN prolonged the time to arterial occlusion by a factor of 2 to 3 times. This effect was significant from doses of 1 mg/kg. This anti-thrombotic activity was unchanged by pretreatment of 100 mg/kg I.V. of acetylsalicylic acid, a dose sufficient to inhibit prostacycline synthesis. On the other hand, its activity was completely blocked by the administration of an inhibitor of NO-synthetase, L-nitroarginine methylester (1 mg/kg I.V.). These results show that ISDN is active on a model of arterial thrombosis in the rat by a mechanism independent of prostacycline production but implying a stimulation of the formation of nitric oxide.

Administration, Oral↗

PubMed1988

Long-term reduction of pulmonary hypertension in interstitial lung fibrosis by isosorbide dinitrate.

The effect of isosorbide dinitrate (ID) on the development of pulmonary hypertension (PH) has been examined in 18 patients with idiopathic diffuse interstitial lung fibrosis (IDILF) during two years of treatment. All patients responded favourably to acutely administered ID by a decrease in pulmonary vascular resistance (PVR) by 38 +/- 13% and of the pulmonary arterial pressure (PAP) by 35 +/- 11%. Two years ID therapy led to sustained haemodynamic improvement in patients in whom blood gases were stable PAP was reduced from 38 +/- 5 to 30 +/- 6 mmHg and PVR from 483 +/- 197 to 364 +/- 175 dyne s cm-5. No haemodynamic changes were noted in the subjects with progressive hypoxaemia whereas steady deterioration of central haemodynamics was recorded in those patients who died during the follow-up. It is concluded that some patients with IDILF and PH may benefit from long-term ID treatment, but that the outcome of this treatment cannot be reliably predicted from the results of the initial first ID administration.

Adult↗

PubMed1985

[Efficacy and duration of action of isosorbide-5-mononitrate in the treatment of stable angina of effort. Comparison with sustained-release isosorbide dinitrate].

A new compound, Isosorbide-5-mononitrate (IS-5-MN; 40 mg orally), was compared with sustained-release Isosorbide dinitrate (SRDI; 40 mg orally) in 18 patients with chronic exercise-induced angina pectoris. The patients were studied in a randomized placebo-controlled single-blind trial. Multistage bicycle test with computer-assisted electrocardiographic analysis was performed before, 60-90, 240 and 360 minutes after treatment administration. Both drugs significantly and comparably prolonged exercise time (p less than 0.01) and time to development of 1 mm ST-segment depression (p less than 0.01) at the 3 times of study. At the highest common level of work, ST-segment depression and its integral were significantly reduced by both IS-5-MN and SRDI compared to placebo (p less than 0.01); conversely, the peak ST-segment depression was unaffected. Compared to placebo, a significant increment in maximal heart rate/systolic blood pressure was observed after drug administration. It is concluded that 40 mg of orally administered IS-5-MN is effective during at least 6 hours and that its therapeutic action is comparable to that of SRDI.

Adult↗