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PubMed1979

Comparative effects of nifedipine, verapamil, isosorbide dinitrate and propranolol on exercise-induced angina pectoris.

According to the experimental model of a 5 X 5 Latin square, 5 treatments were studied single blind in 5 patients, affected by stable-effort angina, by means of exercise tests. In the period of maximal supposed effect the following treatments were investigated: placebo (P), 1 tablet, orally; isosorbide dinitrate (ISDN), 5 mg, sublingually; propranolol (Pr), 40 mg, orally; nifedipine (N), 10 mg, orally; verapamil (V), 160 mg, orally. Placebo, compared with its own control tests, did not change any of the examined parameters. Comparison of the 'active' treatments with P showed the following results. All the treatments increased the duration of work before ECG positivity appearances. An increase in duration of work and total work performed before angina was seen after administration of ISIDN, N and V; the improvement observed after treatment with Pr was not significant. Comparison of treatments showed that work performance before angina was the same after administration of ISDN, N and V; these treatments were more effective than that with 40 mg Pr. Duration of work before ECG positivity was significantly longer after ISDN and N than after Pr. The changes in heart rate, maximal arterial pressure, ejection time index and triple product confirmed the activity of the administered doses. According to the observed effects on exercise tolerance, in comparison with P the same level of work was performed with the same triple product after Pr, and with lower triple products after ISDN, N and V.

Angina Pectoris↗
PubMed1983

Concentration and time-dependent relationships between isosorbide dinitrate-induced relaxation and formation of cyclic GMP in coronary arterial smooth muscle.

This study is based on the hypothesis that isosorbide dinitrate (ISDN)-induced relaxation of coronary arterial smooth muscle is causally linked to formation of cyclic (c) GMP. The hypothesis requires the extent of relaxation to be correlated to both time-and concentration-dependent increases in coronary content of cGMP. Accordingly, studies were performed with bovine coronary arterial strips to determine the relationships among isometric force and coronary content of cGMP and cAMP with respect to time of exposure to and concentration of ISDN. Cyclic nucleotide levels were determined by radioimmunoassay. No change in cAMP levels was observed during ISDN-induced relaxation of KCl contracted strips. In sharp contrast, cGMP levels increased significantly with time of exposure and concentration of ISDN stimulation. Moreover, the addition of methylene blue, a reported inhibitor of guanylate cyclase, to the bathing medium significantly inhibited the relaxation and cGMP increase during ISDN stimulation. In addition, prolonged exposure to ISDN resulted in a redevelopment of force with a parallel decrease in cGMP content. The increase in cGMP during ISDN stimulation also occurs in the absence of depolarization by KCl and in an essentially Ca++-free medium. These data support the hypothesis that the relaxation of coronary arterial strips in response to ISDN stimulation is causally linked to cGMP.

Animals↗
PubMed1983

Isosorbide dinitrate ointment in Raynaud's disease.

In a double-blind, cross-over study the efficacy of isosorbide dinitrate (ISDN) ointment was studied in 12 patients (eight men, four women) with vasospastic Raynaud's phenomenon during the winter. ISDN (200 mg) and placebo respectively were applied to the fingers three times a day for 3 weeks. The efficacy of the drug was judged by patients' reports on the number and duration of Raynaud's attacks, measurements of digital systolic pressures (Doppler method), and photoplethysmography of the fingers before and 3 min after local cooling in ice water. No difference in severity or duration of vasospastic attacks was found in patients treated with ISDN or placebo. There was only a slight, nonsignificant increase (+15%) in digital systolic pressure and amplitudes of digital pulse in the ISDN group. It was concluded that topical ISDN ointment seems to be ineffective for patients with Raynaud's phenomenon.

Blood Pressure↗
PubMed1984

Effect of a combination of pindolol and isosorbide dinitrate on ischemic ST-segment depression and exercise ability in angina pectoris.

The antianginal action of a fixed combination of pindolol (7.5 mg) and isosorbide dinitrate (ISDN, 30 mg slow release) was compared with placebo in sixteen patients with stable, exercise-induced angina pectoris. Exercise tests were performed on a bicycle ergometer before and 90 min after the oral application of active drug or placebo. All patients showed an ischemia-induced ST-depression in the ECG during and shortly after exercise. There was no effect of placebo on blood pressure, heart rate, ST-segment depression or work tolerance. The combination of pindolol and ISDN significantly reduced systolic blood pressure and heart rate at rest and during exercise. ST-segment depression was reduced (2 p less than or equal to 0.001), when compared with placebo at the same workload. Mean total work was higher (2 p less than or equal to 0.001) after active drug, leading to an improved exercise-tolerance in 11 out of 16 patients.

Adult↗
PubMedDate not supplied

Nitroglycerin and isosorbide dinitrate in pulmonary hypertension of chronic obstructive pulmonary disease.

The effects of sublingual isosorbide dinitrate (ISDN; 10 mg) or nitroglycerin (NTG; 1 mg) on pulmonary hemodynamics, gas exchange and pulmonary function were studied during right heart catheterization in two series of 27 patients with COPD. An immediate significant decrease of pulmonary arterial pressure, cardiac output and work of the right ventricle was obtained with both drugs, but NTG only was able to reduce the pulmonary vascular resistance. Arterial oxygen tension did not decrease, but venous O2 tension did, with no change in blood lactate. NTG had also a slight bronchodilating effect. After chronic use, no improvement of pulmonary function or gas exchange was observed but NTG lowered pulmonary vascular resistances significantly. The effects observed during the acute study were reproduced after six weeks with the same doses of both drugs. NTG appears effective in reducing pulmonary arterial hypertension mainly by vasodilation while the ISDN effect seems due only to the decreased cardiac output.

Hemodynamics↗
PubMed1984

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

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

Angina Pectoris↗
PubMed1984

[Hemodynamic study during 48 hours of delayed-release isosorbide dinitrate (repeated oral administration) in the acute phase of myocardial infarction complicated by left ventricular insufficiency].

The aim of this study was to evaluate the haemodynamic effects of slow release isosorbide dinitrate (IDN) 40 mg oral preparation over a 48 hour period in patients with acute myocardial infarction complicated by left ventricular failure. Fourteen patients (8 male, 6 female) were treated by repeat dose ISD (8 hourly) and the haemodynamic changes were recorded at 1 hr, 2 hrs, 6 hrs, 12 hrs, 24 hrs, and 48 hrs. After 48 hours treatment the heart rate was unchanged; mean arterial blood pressure fell from 109.5 +/- 5.6 mmHg to 93.5 +/- 6.2 mmHg (-15%) (p less than 0.01). Cardiac index rose from 2.4 +/- 0.57 1/min/m2 to 2.8 +/- 0.65 1/min/m2 (+16%) (NS); diastolic pulmonary artery pressure fell from 22.5 +/- 7.07 mmHg to 13.7 +/- 4.5 mmHg (-39%) (p less than 0.003); systolic pulmonary artery pressure fell from 40.5 +/- 12.2 mmHg to 28.6 +/- 11.6 mmHg (-30%) (NS). Systemic vascular resistance fell from 2 095.2 +/- 63 dynes/s/cm5 to 1 537 +/- 60 dynes/s/cm5 (-22.3%) (NS). Finally, total pulmonary resistance fell from 561.9 +/- 15 dynes/s/cm5 to 301.9 +/- 14.5 dynes/s/cm5 (-47%) (p less than 0.003). The most valuable effect was therefore the reduction in left ventricular filling pressures which was maximal after about 48 hours. Two groups of patients were identified according to the clinical outcome. The patients in Group I (11 cases) were improved by the fall in diastolic pulmonary artery pressure, the rise in cardiac index and the reduction of systemic valvular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
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↗
PubMed1984

Fate of orally given isosorbide dinitrate in cirrhotic patients.

In 5 out of 7 patients with cirrhosis and extensive shunting, plasma concentrations of isosorbide dinitrate after oral administration of 10 mg of the substance were markedly higher than those found in subjects without hepatic disease. The explanation could be a higher bioavailability and/or a lower systemic clearance, due to shunting and hepatic cell dysfunction. The difference was confirmed by the calculation of the areas under the concentration-time curves.

Administration, Oral↗
PubMed1984

[Bioavailability of isosorbide-5-mononitrate from delayed-action formulations].

The relative bioavailability of isosorbide-5-mononitrate (IS-5-MN) has been determined after a 3-day period of dosing with 20 mg in standard-release reference tablets and sustained-release capsules at 12-h intervals, 40 mg in sustained-release capsules (Olicard 40 retard) at 24-h intervals and after single oral dose of 60 mg sustained-release capsules (Olicard 60 retard), in a cross-over study with 12 human subjects. Accumulation factors of 1.1-fold or 1.2-fold occurred during administration of 20 mg in standard- or sustained-release tablets and capsules respectively at 12-h intervals, and negligible accumulation of drug occurred after administration of 40 mg in sustained-release capsules at 24-h intervals or was calculated by the superposition principle to occur after doses of 60 mg in sustained-release capsules at 24-h intervals. The mean extent of bioavailability of IS-5-MN from the 20 mg, 40 mg and 60 mg sustained-release capsules was 79%, 67% and 70% respectively, of that from the standard-release reference tablets. The posterior probability that the bioavailability of IS-5-MN was included within the limits 60%-90% of the reference tablets was 97%, 86% and 95% for the 20 mg, 40 mg and 60 mg sustained-release capsules respectively. Means of peak plasma levels of IS-5-MN after administration of the sustained-released capsules were linearly related to the doses administered.(ABSTRACT TRUNCATED AT 250 WORDS)

Biological Availability↗
PubMed1983

Plasma isosorbide dinitrate concentrations and effect after chewable and high-dose, sustained-release formulations.

Isosorbide dinitrate (ISDN) was given to eight healthy volunteers either as 5 mg chewable ISDN hourly or as 40-mg, slow-release formulation every 8 h. Plasma concentration of ISDN and its two metabolites were measured during one dosing interval at steady state. Mean steady-state plasma concentration (Cpss) during the interval was taken as a measure for bioavailability. Cpss after bucal absorption was similar to that after the sustained-release preparation. Relative bioavailability of the latter reached 111%. The effect of ISDN was measured by digital plethysmography (DPG) during the first dosing interval and after 10 and 48 h, when a steady state had been reached with each formulation. DPG changes were of similar magnitude during the first 10 h, but showed a 30% decrease after 48 h. This tolerance is probably due to physiologic counterregulation. Changes in DPG reflect effects of ISDN which can be used during short-term application of the drug to assess systemic bioavailability. Development of tolerance, however, precludes the use of DPG to assess bioavailability in long-lasting steady-state experiments.

Adult↗
PubMed1983

Chronic treatment and tolerance with high doses of isosorbide dinitrate in a slow release form in patients with angina pectoris.

Nine men with angiographically proven coronary sclerosis and a reproducible ischemic response on the exercise ECG were treated for 9 weeks with a dose of 180-240 mg isosorbide dinitrate slow release (ISDN sr) daily. In the week before the beginning of the treatment (week 1) and in the week after its conclusion (week 10), exercise tests were carried out before and 1 and 3 h after administration of 60 mg ISDN sr or placebo. This part of the investigation was double-blind, cross-over and randomized. In an open study carried out during the 2nd-9th weeks, exercise tests were carried out weekly before and 1 and 3 h after the usual morning dose of 60 mg ISDN sr. The interval between the morning exercise and the last evening dose was 8-10 h. Exercise duration and required level of exertion remained constant during the entire study. The sum of ischemic ST-segment depression during and after exercise, heart rate (ECG) and blood pressure (RR) were all measured. Both before and after the period of treatment 60 mg ISDN sr produced a significant reduction in ST-segment depression after 1 and 3 h. During the treatment phase no significant improvement in comparison to controls could be observed from the 7th week onward. However, even in controls the ST-segment depression was less in the 8th and 9th weeks than during the first few weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1983

Anti-ischemic effects of an 80-mg tablet of isosorbide dinitrate in sustained-release form before and after 2 weeks treatment with 80 mg once daily or twice daily.

The purpose of this study was to investigate whether the anti-ischemic effects of a single 80-mg tablet of isosorbide dinitrate in sustained-release form are attenuated after 2 weeks of twice-daily administration. In order to follow a double-blind protocol with respect to the 12-h interval, we also evaluated, in randomized order, another group of patients receiving the tablets once daily. Parameters for assessment of the anti-ischemic effects were changes in exercise-induced ST-segment depression and the simultaneously recorded left ventricular ejection fraction, as determined by radionuclide ventriculography. The ST-segment depression was measured completely blind; the left ventricular ejection fraction was calculated automatically with a clinically validated software. In the group that received the tablets once daily (n = 10) none of the patients showed any signs of attenuation of the beneficial anti-ischemic effects. However, seven of the 12 patients who received the tablets twice daily demonstrated significant attenuation. Thus, based on analysis of the presently available studies, in order to guarantee maintenance of the anti-ischemic benefits, a once-daily high dose of ISDN in sustained-release form (80 mg or even higher) is recommended.

Coronary Disease↗
PubMed1983

Hemodynamic effects of isosorbide-5-mononitrate in acute and chronic treatment of coronary heart disease.

Hemodynamic effects of isosorbide-5-mononitrate (IS-5-MN) were studied in 20 patients with coronary heart disease. Three hours after the first administration of 50 mg IS-5-MN we found a significant decrease in mean pulmonary artery pressure, while heart rate and arterial blood pressure remained unchanged. Concomitant with the hemodynamic effects we found a decrease in angina pectoris and normalization of exercise-induced ST depression. After 50 mg IS-5-MN three times daily for 1 week the repeated acute administration of a single dose of 50 mg produced a fall in mean pulmonary artery pressure at rest (-25%) and during exercise (-20%), while the antianginal effect was unchanged. Six hours after a repeated single dose we found no change in hemodynamic parameters as compared with the control levels before treatment. The decreased effect on the pulmonary artery pressure under chronic treatment is discussed as a development of tolerance with decrease of venous pooling. The unchanged antianginal effect is difficult to understand, and may be interpreted as due to an influence on the coronary vessels and collateral blood flow.

Aged↗
PubMed1983

Antiplatelet effects of isosorbide dinitrate in man.

Variable antiplatelet effects have been described for various antianginal drugs, including beta-blockers, verapamil, and nifedipine. To assess and characterize a possible similar effect of nitrates, platelet-rich plasma (PRP) from 22 healthy donors was incubated with scalar concentrations (1.25, 12.5, 125 micrograms/ml) of isosorbide dinitrate (ISDN) and with the vehicle alone for periods of 5 and 10 min. Platelet aggregation was successively induced by ADP (0.4-1.2 microM), adrenaline (0.8-8 microM), collagen (16.7 micrograms/ml), arachidonic acid (AA; 1 mM) and thrombin (0.5-2 U/ml). At the end of aggregation thromboxane (TX) B2 levels in PRP were assessed by RIA. A dose-dependent decrease in both platelet aggregation and TXB2 levels by all the inducers tested was demonstrated with both incubation times. Maximum inhibition of platelet aggregation was observed with ADP and adrenaline (72.0% and 55.6% respectively with 10-min incubation and the highest ISDN concentration. P less than 0.01 and P less than 0.05 respectively). A reduction in TXB2 levels in PRP was also observed, but reached statistical significance (P less than 0.01) only for AA-induced TXB2 generation. For an in vivo study ISDN was infused for periods of 30 min at 4 mg/h in 11 angina patients, and for periods of 20 min at 30 mg/h in an other eight, under ECG and arterial blood pressure monitoring. ADP- and adrenaline-induced aggregation and TXB2 production, and determination of circulating platelet aggregates (CPA) were performed in basal conditions and at 5, 15, 30 and 90 min from infusion start in the first group, at 5, 15, and 80 min in the second group.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1983

Effects of disease, route of administration, cigarette smoking, food intake on the pharmacokinetics and circulatory effects of isosorbide dinitrate.

The major goal of this study was to examine the clinical pharmacology of isosorbide dinitrate (ISDN) under various conditions of clinical use. Orally administered ISDN is subjected to extensive metabolism during its first passage through the liver. It is not known, however, whether the systemic availability and the circulatory effects of oral ISDN might be affected in clinical conditions under which hepatic blood flow and/or metabolic activity might have been altered. Sublingual (5 mg) and oral (30 mg) ISDN were given under fasting conditions on two separate occasions to (a) patients with angina pectoris (AP), n = 8; (b) patients with chronic congestive heart failure (CHF), n = 9; (c) smoking AP patients, n = 7; and (d) nonsmoking AP patients, n = 9. Patients in group (a) were also given oral ISDN after a standard breakfast. Circulatory effects, i.e., heart rate, systolic and diastolic pressures were measured over 3 h after sublingual dosing and 6 h after oral dosing in both the supine and standing positions. Plasma ISDN concentrations were measured by gas chromatography over the same periods. The systemic availability of oral ISDN was found to be about half that of sublingual ISDN, but the intersubject variability was large. Thus some individuals absorbed oral ISDN as well as they did sublingual ISDN, while others only absorbed oral ISDN minimally. The extent of oral ISDN absorption was not statistically different between patients with AP and CHF, between smokers and nonsmokers, or between the fasting and postprandial conditions, although there was a trend for higher plasma ISDN concentrations in smokers. Food reduced the apparent absorption rate of oral ISDN.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1983

[Pharmacokinetics of 14C-isosorbide dinitrate after administration in various sustained-release formulations].

To study the influence of various in vitro release rates and of coadministration with food on bioavailability of isosorbide dinitrate (ISDN; isoket retard 40) and its mononitrate metabolites from sustained-release formulations the pharmacokinetics of two experimental batches of tablets with different release rates containing 40 mg 14C-ISDN each were studied in six human volunteers. One of the formulations was not only administered after fasting but aslo with a standard meal. In all cases approx. 80% of the administered radioactivity were recovered in the urine and 5% in the faeces during 3 days demonstrating extensive absorption. Any influence of release rates or food on absorption rates could not be detected. When administered after fasting either formulation was bioequivalent. Coadministration of a meal enhanced ISDN plasma levels in some subjects although no statistically significant difference in extent of bioavailability was observed. Availability of the mononitrates was unaffected by food.

Adult↗