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PubMed1997

Twenty-four hour plasma profile of sustained-release isosorbide mononitrate in healthy volunteers and in patients with chronic stable angina. Two open label trials.

AIMS: The plasma profile of a single dose of isosorbide mononitrate 25 mg (Elantan LA25) in healthy volunteers and in angina patients was examined. METHODS: In volunteers and patients, blood samples for pharmacokinetics were obtained pre-dosing and at intervals for 24 h after dosing. RESULTS: This formulation exhibited rapid absorption and plasma levels were maintained at > 100 ng ml-1 for up to 9 to 12 h. CONCLUSIONS: A comparison of the pharmacokinetics of Elantan LA25 in volunteers and patients indicates that the profiles are similar.

Adult↗
PubMed1998

Tolerance to isosorbide dinitrate in isolated strips of rabbit corpus cavernosum.

The aim of this study was to investigate whether prolonged exposure to a high concentration of isosorbide dinitrate (ISDN) would result in tolerance being developed against its relaxant activity in strips of corpus cavernosum, pre-contracted by phenylephrine. Under these conditions, relaxation induced by ISDN was found to be significantly reduced. Strips made tolerant to ISDN remained fully responsive to sodium nitroprusside and papaverine. Electrical field stimulation evoked relaxations which were persistent in the presence of tolerance-inducing conditions. These results indicate that desensitization of guanylate cyclase activity is not likely to be the operating mechanism for nitrate tolerance. We suggest that tolerance may result from the impairment of biotransformation of ISDN in rabbit cavernosal smooth muscle.

Animals↗
PubMed2000

Acute and chronic effects of isosorbide-5-mononitrate administration on effective renal plasma flow and the renin-aldosterone system in cirrhotic patients.

BACKGROUND AND AIMS: Isosorbide-5-mononitrate (ISMO) has been shown to be effective in reducing the risk of variceal bleeding in patients with cirrhosis. However, recent studies have suggested that this drug compromises renal function. The present study was conducted to assess the acute and chronic effects of ISMO on effective renal plasma flow (ERPF) and the renin-aldosterone profile in cirrhotic patients. METHODS: Fifteen cirrhotic patients were included in the present study. The mean arterial pressure (MAP), heart rate (HR), serum renin concentration (SR), ERPF and plasma aldosterone concentration (PA) were checked before ISMO treatment (baseline study), after a single oral dose of 20 mg ISMO (acute effect study) and after 3 weeks of ISMO treatment (chronic effect study). RESULTS: Our data showed that the oral administration of a single dose (20 mg) of ISMO to cirrhotic patients was associated with significant decreases in ERPF (from 405.18 to 369.06 mL/min) and MAP (from 93.26 to 86.40 mmHg), and increases in HR (from 65.53 to 70.06 beats/min), SR (from 24.15 to 54.41 pg/mL), and PA (from 105.1 to 148.7 pg/mL). However, no significant changes were observed in HR, MAP, PA, SR, or ERPF after 3 weeks of ISMO treatment when compared with the baseline study. CONCLUSIONS: The administration of ISMO causes a decrease in ERPF in cirrhotic patients and its use in patients with renal impairment should be considered cautiously.

Adult↗
PubMed1997

Haemodynamic correlates of early and delayed responses to sublingual administration of isosorbide dinitrate in migraine patients: a transcranial Doppler study.

In normal subjects or migraine patients, nitrates induce a non-specific early headache caused by vasodilation of intracranial arteries. In migraineurs a delayed headache response to nitrates may have a typical clinical profile of a spontaneous migraine attack. The cerebral vasomotor changes of this delayed response require further study. Isosorbide dinitrate (IDN), an exogenous nitric oxide (NO) donor, was given at a dose of 5 mg sublingually and a bilateral transcranial Doppler device was used to monitor bilateral mean velocity (Vm) changes at the middle cerebral artery (MCA) after IDN administration and until delayed headache occurred. Spontaneous migraine-like headache occurred only in migraine patients during the delayed phase after IDN and was accompanied by a prolonged arterial vasodilation compared to normal subjects. This vasomotor response was more evident on the customary side of the head pain of a spontaneous migraine attack. Our findings suggest a particular vasomotor response to nitrates in migraine patients. This response is associated with the nitrate-induced headache and it is not evident in healthy pain-free controls during the delayed phase after administration of an NO donor. Owing to the short half-life of NO, the neurotransmitter released by IDN, and because of the late onset of headache, we believe the mechanism is unlikely to be vascular in origin, but may have a neurogenic component.

Administration, Sublingual↗
PubMed1998

Indomethacin increases the effect of isosorbide dinitrate on cerebral hemodynamic in migraine patients: pathogenetic and therapeutic implications.

Intracerebral vascular reactivity induced by the nitric oxide (NO) donor isosorbide dinitrate (IDN, 5 mg sublingually) is more major and longer-lasting in migraine patients who develop delayed headache in response to the drug. The headache is purportedly due to neuronally-mediated vascular mechanisms. Indomethacin inhibits prostaglandin synthesis, which is involved in NO generation. Indomethacin also decreases cerebral blood flow by constricting precapillary resistance vessels. In the present study, the hemodynamic effects of indomethacin were evaluated in migraine patients and healthy controls by means of transcranial Doppler monitoring. Indomethacin caused a significant decrease in mean flow velocity in the middle cerebral artery. This was an additional effect to the mean velocity decrease induced by IDN. The interactions between the two drugs suggest that their effects on cerebral hemodynamics (and pain) may be of relevance both in understanding the role of NO in migraine pathogenesis and in evaluating symptomatic treatments for migraine attacks.

Adult↗
PubMedDate not supplied

Comparison of vasoactive response of left and right internal thoracic arteries to isosorbide-dinitrate and nitroglycerin: an in vitro study.

OBJECTIVE: The internal thoracic artery (ITA) is the most important graft in coronary artery bypass grafting. Its distal region is, however, prone to vasospasm. We studied the effects of nitroglycerin (NTG) and isosorbide-dinitrate (DSDN) on distal segments of left versus right ITA. METHODS: Rings of distal segments (6 to 9 mm proximal to bifurcation) of the human left and right ITA were studied. After baseline contraction of the rings, achieved using 60 mmol/L of KCl, they were exposed to increasing doses of ISDN and NTG (10 to 100 microg/ml), and dose-response curves were recorded. RESULTS: The contractile response of left ITA rings to KCl were significantly lower than those of right ITA rings (1.87 +/- 0.25 g versus 3.5 +/- 0.61 g, p < 0.005). Both nitrates inhibited the contractile response in a concentration-dependent manner, with relaxing effects of ISDN higher than those of NTG (p < 0.01) in both left and right ITA rings. CONCLUSIONS: The distal segment of the left ITA is less prone to vasospasm than that of the right. ISDN has a considerably higher relaxant effect on this segment than NTG. We therefore recommend favoring high doses of ISDN over NTG as an antispastic measure.

Coronary Artery Bypass↗
PubMed1997

Effects of isosorbide-5-mononitrate compared with propranolol on first bleeding and long-term survival in cirrhosis.

BACKGROUND & AIMS: Isosorbide-5-mononitrate (Is-5-Mn) exerts beneficial hemodynamic effects in portal hypertension, yet the long-term clinical value is uncertain. The aim of this study was to determine the long-term effects of Is-5-Mn vs. propranolol (Pro) on first bleeding, complications, and death in cirrhosis. METHODS: One hundred eighteen patients included in a previously published randomized trial comparing Is-5-Mn (20 mg three times daily) with Pro were followed up for up to 7 years (range, 2-91 months). Fifty-seven patients received Is-5-Mn and 61 received Pro. RESULTS: Thirty episodes of first upper bleeding occurred; 16 were in the Is-5-Mn group. Actuarial probability of bleeding did not differ between the two groups. Endoscopic variceal red signs were the only independent predictors of early bleeding. Of the 52 patients who died, 28 were in the Is-5-Mn group. The likelihood of death was greater among patients assigned to Is-5-Mn than to Pro, but only in patients older than 50 years (72% vs. 48% at 6 years; P = 0.006). Child-Pugh score, bleeding, age, and assignment to Is-5-Mn were independent predictors of death. The likelihood of death without bleeding was also higher (P = 0.05) in the Is-5-Mn group. CONCLUSIONS: Is-5-Mn is as effective as Pro in preventing early bleeding but is associated with higher long-term mortality.

Adrenergic beta-Antagonists↗
PubMed2002

Primary prophylaxis of variceal hemorrhage: a randomized controlled trial comparing band ligation, propranolol, and isosorbide mononitrate.

BACKGROUND & AIMS: This randomized controlled trial compared variceal band ligation (VBL), propranolol (PPL), and isosorbide-5-mononitrate (ISMN) in the prevention of first esophageal variceal bleed. METHODS: Over a 6-year period, 172 patients with cirrhosis, grade II or III esophageal varices that had never bled, were recruited; 44 into VBL, 66 into PPL, and 62 into ISMN. Baseline patient characteristics: age, 55 +/- 11 years; Child-Pugh score, 8 +/- 2; 65% alcohol-induced cirrhosis; follow-up period, 19.7 +/- 17.6 months (range, 0.13-72.1 months), were comparable in the 3 groups. RESULTS: On intention-to-treat analysis, variceal bleeding occurred in 7% of patients randomized to VBL, 14% to PPL, and 23% to ISMN. The 2-year actuarial risks for first variceal bleed were 6.2% (95% confidence interval [CI], 0.0%-15.0%) for VBL, 19.4% (95% CI, 0.1%-32.4%) for PPL, and 27.7% (95% CI, 14.2%-41.2%) for ISMN. A significant number of patients reported side effects with drug treatment (45% PPL and 42% ISMN vs. 2% VBL; P = 0.00), resulting in withdrawal from treatment in 30% of PPL and 21% of ISMN patients. There were no statistically significant differences in mortality rates in the 3 groups. In as-treated analysis, there was a statistically significant difference in actuarial risk for bleeding at 2 years between VBL and ISMN (7.5%, 95% CI, 2.5%-10.6% vs. 33.0%, 95% CI, 15%-49%, respectively, log rank test P = 0.03) but not between VBL and PPL. CONCLUSIONS: VBL was equivalent to PPL and superior to ISMN in preventing first variceal bleed. The side-effect profile for pharmacotherapy was considerable.

Antihypertensive Agents↗
PubMed1996

Long-term administration of isosorbide-5-mononitrate does not impair renal function in cirrhotic patients.

Isosorbide-5-mononitrate (Is-5-Mn), alone or combined with beta-blockers, has been proposed for prophylaxis of variceal bleeding in cirrhosis. However, renal insufficiency, might be an important undesirable effect of this therapy, especially in patients with ascites. We assessed the changes in renal function induced in 26 cirrhotic patients by acute or chronic administration of Is-5-Mn. The acute administration of 20 mg of Is-5-Mn to 21 patients reduced mean blood pressure (83.4 +/- 2.4 vs. 92.8 +/- 3.4 mm Hg, P < .001), urine volume (5.5 +/- 0.8 vs. 8.7 +/- 1.1 mL/min, P < .05), urine sodium excretion (114 +/- 19 vs. 244 +/- 41 muEq/min, p < .001), urine potassium excretion (41 +/- 3.4 vs. 67 +/- 8.5 muEq/min, P < .001), and atrial natriuretic factor (74 +/- 10 vs. 98 +/- 12 pg/mL, P < .005). The glomerular filtration rate was decreased in the 11 patients with ascites (57 +/- 9 vs. 68 +/- 12 mL/min, P < .05), and plasma renin activity was increased in 4 ascitics. Twenty-one patients (16 from the acute study + 5 other patients) were given Is-5-Mn for 3 months at the dose of 80 mg/d. This did not affect blood pressure and renal function in patients without ascites, but reduced mean blood pressure (91.9 +/- 3.4 vs. 89.6 +/- 3 mm Hg, P < .05), urine volume (5.8 +/- 1.1 vs. 3.4 +/- 0.9 mL/min, P < .05), and urine sodium excretion (205 +/- 38 vs. 99 +/- 16 muEq/min, P < .01) in those with ascites. There were no changes in glomerular filtration rate and renal plasma flow, while plasma renin activity increased in only 3 patients with ascites and 1 without. Systemic hemodynamics and renal function of cirrhotic patients, especially those with ascites, are affected adversely by acute administration of Is-5-Mn. Long-term administration of the drug is well tolerated by compensated patients and does not affect renal plasma flow nor glomerular filtration rate, but can induce hypotension and sodium retention in patients with ascites.

Ascites↗
PubMed1997

Hemodynamic evaluation of the addition of isosorbide-5-mononitrate to nadolol in cirrhotic patients with insufficient response to the beta-blocker alone.

The association beta-blockers plus isosorbide-5-mononitrate (I5M) has been proposed for the treatment of portal hypertension in patients with insufficient response to beta-blockers alone, according to hemodynamic criteria. The mechanism of action in these patients is not clearly defined. Fifteen patients with cirrhosis and esophageal varices were evaluated by hepatic venous pressure gradient (HVPG) measurement and duplex-Doppler ultrasonography before and after 1 month of treatment with nadolol. Nine patients who did not exhibit a decrease in HVPG to 12 mm Hg or a percent decrease greater than 20% were classified as poor responders, and were studied again with the same methodology after 3 months of chronic administration of nadolol + I5M 20 mg twice per day. In poor responders, mean HVPG decrease after nadolol was 8.9% +/- 2.8%, and after the combination, it was 25.7% +/- 1.7% (P = .004). All patients except one became good responders to the association. Portal blood flow (PBF) decreased significantly after nadolol (P = .004), and remained unchanged after the addition of nitrates. Resistance to portal blood flow (RPBF) increased after nadolol (P = .02) and returned to baseline values during combined treatment (P = .03). In good responders, an adequate decrease in HVPG was associated with a decrease in PBF (P = .06) but no change in RPBF. A wide spectrum of combined changes in PBF and in RPBF after nadolol was observed in poor responders, ranging from no change in either parameter to a marked decrease in PBF counterbalanced by a marked increase in RPBF. The addition of I5M was followed in most cases by larger effects on resistance than on flow. Doppler parameters were not significantly correlated with the HVPG response to nadolol alone or associated with I5M. It is concluded that good hemodynamic responders to nadolol differ from poor responders in the lack of increase in RPBF after the drug. The addition of nitrates to nadolol is effective in decreasing portal pressure in most poor responders to nadolol alone. A decrease in outflow resistance is the main mechanism involved.

Adrenergic beta-Antagonists↗
PubMed2000

Isosorbide mononitrate and propranolol compared with propranolol alone for the prevention of variceal rebleeding.

The aim of this study was to test the effectiveness of isosorbide-5-mononitrate (IM) as an adjunct to propranolol (PR) in the prevention of variceal rebleeding. Ninety-five cirrhotic patients with variceal bleeding were randomly assigned to treatment with PR + IM (46 patients) or PR alone (49 patients). Eighteen patients in the PR + IM group and 28 in the PR group had rebleeding during the 2 years after randomization. The actuarial probability of rebleeding 2 years after randomization was lower in the PR + IM group (40.4% vs. 57.4%) but the difference was not significant (P =. 09). However, the decrease in the risk of rebleeding reached statistical significance after stratification according to age, i.e. less than 50 versus >/=50 years old, (P =.03) or by adding an additional year of follow-up (P =.05). No significant difference was found in rebleeding index and survival. The multivariate Cox analysis indicated first, that both treatment (P =.03) and age (P =. 001) were factors predictive of rebleeding and second, that PR + MI reduced the risk of rebleeding by half (relative risk: 0.51, 95% confidence interval: 0.28-0.95). Seven patients in the PR + MI group and 1 patient in the PR group had to discontinue one of the drugs because of adverse events (P =.03). These results suggest that the addition of IM improves the efficacy of PR alone in the prevention of variceal rebleeding in cirrhotic patients. However no beneficial effects were observed on other parameters reflecting the efficacy of treatment.

Adrenergic beta-Antagonists↗
PubMed2003

Low doses of isosorbide mononitrate attenuate the postprandial increase in portal pressure in patients with cirrhosis.

Postprandial hyperemia is associated with a significant increase in portal pressure in cirrhosis, which may contribute to progressive dilation and rupture of gastroesophageal varices. In cirrhosis, an insufficient hepatic production of nitric oxide (NO) may impair the expected hepatic vasodilatory response to increased blood flow, further exaggerating the postprandial increase in portal pressure. This study was aimed at investigating whether low doses of an oral NO donor might counteract the postprandial peak in portal pressure. Twenty-three portal hypertensive cirrhotics, 8 of them under propranolol therapy, were randomized to receive orally 5-isosorbide mononitrate (ISMN; 10 mg; n = 11) or placebo (n = 12) and a standard liquid meal 15 minutes later. Hepatic venous pressure gradient (HVPG), mean arterial pressure (MAP), and hepatic blood flow (HBF) were measured at baseline and 15, 30, and 45 minutes after a meal. ISMN significantly attenuated the postprandial increase in portal pressure as compared with placebo (peak HVPG increase: 2.4 +/- 1.4 mm Hg vs. 5.2 +/- 2.1 mm Hg, P =.002). Percentual increases in HBF were similar in both groups. MAP decreased slightly in ISMN group (-7.5% +/-.5%; P <.01 vs. baseline). These effects were also observed in patients on chronic propranolol therapy. In conclusion, hepatic NO supplementation by low doses of ISMN effectively reduces the postprandial increase of portal pressure in cirrhosis, with only a mild effect on arterial pressure. The same was observed in patients receiving propranolol. Our results suggest that therapeutic strategies based on selective hepatic NO delivery may improve the treatment of portal hypertension.

Aged↗
PubMed2003

Propranolol plus placebo versus propranolol plus isosorbide-5-mononitrate in the prevention of a first variceal bleed: a double-blind RCT.

Nonselective beta-blockers are very effective in preventing first variceal bleeding in patients with cirrhosis. Treatment with isosorbide-5-mononitrate (IS-MN) plus propranolol achieves a greater reduction in portal pressure than propranolol alone. The present multicenter, prospective, double-blind, randomized, controlled trial evaluated whether combined drug therapy could be more effective than propranolol alone in preventing variceal bleeding. A total of 349 consecutive cirrhotic patients with gastroesophageal varices were randomized to receive propranolol + placebo (n = 174) or propranolol + IS-MN (n = 175). There were no significant differences in the 1- and 2-year actuarial probability of variceal bleeding between the 2 groups (propranolol + placebo, 8.3% and 10.6%; propranolol + IS-MN, 5% and 12.5%). The only independent predictor of variceal bleeding was a variceal size greater than 5 mm. However, among patients with varices greater than 5 mm (n = 196), there were no significant differences in the incidence of variceal bleeding between the 2 groups. Survival was also similar. Adverse effects were significantly more frequent in the propranolol + IS-MN group due to a greater incidence of headache. There were no significant differences in the incidence of new-onset or worsening ascites or in impairment of renal function. In conclusion, propranolol effectively prevents variceal bleeding. Adding IS-MN does not further decrease the low residual risk of bleeding in patients receiving propranolol. However, the long-term use of this combination drug therapy is safe and may be an alternative in clinical conditions associated with a greater risk of bleeding.

Adrenergic beta-Antagonists↗
PubMed1975

[Effect of nitroglycerin in acute myocardial infarction. III. Isosorbide dinitrate in patients with or without left-heart failure (author's transl)].

The oral effectiveness of isosorbide dinitrate (Isoket) was tested in 21 pateints with acute myocardial infarction. Patients were divided into two groups according to thier initial left-ventricular filling pressure (more or less than 20 mm Hg). In both groups there was a highly significant decrease in pulmonary artery pressure. In group I (less than 20 mm Hg) the left-ventricular filling pressure fell from 13.6 +/- 4.0 to 7.1 +/- 2.6 mm Hg, while in group II it fell from 26.9 +/- 4.6 to 19.0 +/- 3.6 mm Hg (P less than 0.001). The cardiac output fell in group I from 5.1 +/- 1.0 to 4.5 +/- 0.9 l/min, while in group II there was a significant rise from a low value (3.5 +/- 0.8 l/min) to 4.1 +/- 0.9 l/min (P less than 0.001). In both groups there was a slight but not significant fall in arterial blood pressure, while heart rate remained constant.

Acute Disease↗
PubMed1996

[Effect of the vasodilator isosorbide dinitrate on ocular circulation].

BACKGROUND: Vasodilator drugs are increasingly being discussed as possible antiglaucomatous substances. Aim of the present study is to evaluate, from a hemodynamic point of view, the vasodilator drug isosorbide dinitrate (ISDN) regarding its suitability for glaucoma therapy. METHODS: 20 healthy subjects (mean age: 28 yrs) volunteered to participate in the study. In randomized order, each subject received one tablet containing 40 mg ISDN (sequels) or--in a second trial--one tablet placebo (+500 mg of the analgetic metamizol, respectively, for prophylaxis of nitrate headache). 1 h before as well as 1, 3, 5, and 7 hrs after medication, the following variables were determined using oculo-oscillo-dynamography: systolic ophthalmic artery pressure (SOAP), systolic ocular perfusion pressure (SOPP), ocular pulsation amplitude (OPA) and the product OPA x heart rate (HR). Intraocular pressure (IOP) as well as systolic and diastolic brachial artery pressures (SBAP, DBAP) were also measured. RESULTS: After administration of ISDN (+analgetic), the variables SBAP, SOAP and SOPP were significantly (p = 0.01) lowered compared to placebo (+analgetic), and also the IOP tended to be lower (p = 0.08). The maximum reduction was found 3-5 hrs after medication: SBAP 10.9 mm Hg (9%), SOAP 12.5 mm Hg (14%), SOPP 11.3 mm Hg (14.5%), and IOP 1.5 mm Hg (12%). The relation SOAP vs. SBAP was significantly (p = 0.0004) linear, the correlation coefficient amounted to 0.39. DBAP remained unchanged, HR was increased by 4-7 beats/min (p = 0.08). OPA and the product OPA x HR showed highly significant decreases by maximum values of 44% and 40%, respectively. CONCLUSION: ISDN (+analgetic) caused a reduction of SOAP and SOPP, which can be accounted for by the reduced systolic systemic blood pressure. In addition, there was a decrease of OPA and of the product OPA x HR (a measure of pulsatile ocular blood flow), which finding may be explained by a cardiac stroke volume reduction that is typical for nitrates. Due to these hemodynamic effects and due to the only weak IOP reduction, ISDN does not appear to be suitable for glaucoma therapy.

Adult↗
PubMed1987

[Bioavailability of delayed-action and non-delayed-action preparations of isosorbide-5-nitrate].

In a randomized crossover study on twelve healthy test subjects, the plasma concentration of isosorbide-5-nitrate (IS-5-N) after oral administration of 40 mg IS-5-N daily from two standard preparations (two tablets Ismo 20 or Corangin 20) and two sustained release preparations with 40 mg or 60 mg IS-5-N (one tablet Corangin 40 or Corangin 60) once a day was determined. The concentrations were measured in the first and in the third dose interval (24 hours). The respective pharmacokinetic parameters (AUC, Cmax and tmax) of the first and the third day only differed slightly. The two standard formulations proved to be bioequivalent. With the two sustained release preparations, maximum plasma concentrations attained after five to six hours were measured which were lower by roughly the factor 2. The sustained release preparations showed a low loss of bioavailability of 13-19% as compared to the nonretarded standard formulations.

Adult↗
PubMed1983

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

The haemodynamic effect of isosorbide-5-mononitrate (ISMN) was studied in 20 patients with coronary heart disease. Three hours after the first and single dose of 50 mg ISMN, both at rest and on exercise there was a significant decrease in pulmonary artery mean pressure of 30%, while heart rate and systemic blood was an anti-anginal effect, as objectified by the angina threshold and return to normal of previously depressed S-T segments during exercise. After administration of 50 mg ISMN, three times daily for seven days, a single dose of 50 mg ISMN on the eighth day produced a fall in pulmonary artery mean pressure three hours after administration, of only 25% at rest and 20% on exercise, while the anti-anginal effect remained unchanged. Six hours after administration there were no significant changes in haemodynamic variables compared with the initial values. The reduced fall in pulmonary artery mean pressure during chronic administration is interpreted as the development of tolerance with decreased venous pooling, while the unchanged anti-anginal effect is explained by the site of action of the nitrate on the coronary arteries and on the collateral circulation with positive blood redistribution.

Adult↗
PubMed1982

[Dose-effect relationship of isosorbide dinitrate in the treatment of angina pectoris (author's transl)].

Fifteen males with angiographic evidence of coronary heart disease and stable, exercise-induced angina pectoris were given placebo or isosorbide dinitrate (ISDN) in a dialy dose of 30 mg, 120 mg, 240 mg and 480 mg in a randomized single-blind trial. The daily doses were given as a single oral dose of 5 mg, 20 mg, 40 mg and 80 mg tablets. Each dose and placebo was given for seven days. On the seventh day an exercise ECG of standardized level and duration of exercise was recorded. The ischaemia response in the ECG revealed a dose-dependent reduction by 28% (5 mg ISDN), 43% (20 mg), 60% (40 mg) and 73% (80 mg). The number of anginal attacks similarly fell parallel to dose. Plasma level of ISDN and the mononitrates, measured one and four hours after drug intake, rose almost linearly in relation to dose. Oral ISDN thus has a dose-dependent effect on the frequency of angina and ischaemia parameters during ergometric exercise. The protracted anti-anginal effect of ISDN is largely due to its metabolites. At high doses there is presumably an added effect of the high blood level of the basic substance.U

Adult↗