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[Intermittent claudication: topical treatment with isosorbide dinitrate ointment. Preliminary results].

Following the casual observation reported by one anginal patient of ours, of improvement of its claudicatio intermittens with application of isosorbide dinitrate ointment directly on the leg suffering pain, we undertook a study to assess the possible use of the drug in peripheral vascular disease in a group of 10 patients suffering of a severe form of claudicatio intermittens. The effect of the drug was tested 1) by the subjective valuation of the patient itself 2) by treadmill stress tests performed at constant rate. In this case were used as reference parameters the distance walked without any symptoms and the maximal distance reached by each patient. The treadmill stress test was performed in basal condition and after longterm administration of isosorbide dinitrate ointment 100 mg three times a day for 30-45 days. In 5 patients the control test was repeated twice in different days to evaluate the reproducibility of the measure that resulted good, while other 5 patients performed the test one hour following the application of the drug in order to assess a possible acute effect of the drug that was not present in any patient. All the patients noted an improvement in their walking capacity but only after 15-20 days of treatment. In basal condition the distance walked without any symptoms by the patients was on the average m. 51 (+/- 52) and the maximal distance reached was m. 143 (+/- 111), while after the treatment were m. 151 (+/- 136) and m. 384 (+/- 203) with a difference highly significative (p less than 0.05 and p less than 0.01 respectively). From our data although preliminary, it is apparent that longterm local application of isosorbide dinitrate is effective in the treatment of patients with peripheral vascular disease and that the action of the drug seems to be related to a local effect.

Administration, Topical↗

Effects and pharmacokinetics of isosorbide dinitrate in normal man.

18 subjects were given isosorbide dinitrate (ISDN) 5 mg sublingually and serum concentrations of ISDN, 2-isosorbide mononitrate (2-ISMN) and 5-isosorbide mononitrate (5-ISMN) were measured, as well as changes in digital plethysmographic amplitude, heart rate, ECG, blood pressure and Schellong's test. ISDN was rapidly absorbed and metabolized, having an elimination half-life of 29 min. Its metabolites 2-ISMN and 5-ISMN had longer half-lives of 1.75 and 7.6 h respectively. The amplitude of the alpha-wave of the digital plethysmograph did not change significantly either in the pre-drug period or after placebo administration. It increased within 4 min of administration of ISDN, and reached a maximum after 14 min; the effect lasted for about 2 h. ISDN lowers blood pressure and increases heart rate in most volunteers, but in 3 of the 18 subjects severe hypotension occurred, accompanied by severe, reversible bradycardia, which was probably due to vagal reflexes initiated by the markedly diminished ventricular enddiastolic volume (LVEDV) and pressure (LVEDP). No correlation could be demonstrated between the serum concentration of ISDN and/or its vasoactive metabolites and changes in plethysmographic amplitude.

Female↗

Comparative effects of theophylline and isosorbide dinitrate on exercise capacity in stable angina pectoris, and their mechanisms of action.

While the role of nitrates in the prevention and treatment of myocardial ischemia is well established, the use of theophylline, proposed almost a century ago, is still controversial. Also controversial is its mechanism of action, initially thought to be coronary dilation. In this randomized, single-blind study, the acute effects on exercise capacity of sublingual isosorbide dinitrate (10 mg) and of intravenous theophylline ethylenediamine (7 mg/kg) were assessed in 10 patients with chronic stable angina and positive exercise test. After the administration of theophylline, the time to onset of angina, the heart rate-blood pressure product at 1-mm ST-segment depression and the exercise duration were similar to that after isosorbide dinitrate administration (9.8 +/- 2.3 vs 9.3 +/- 1.7 minutes, 207 +/- 41 vs 207 +/- 48 beats/min.mm Hg.10(-2) and 10.8 +/- 2 vs 10.4 +/- 2 minutes, respectively). Both drugs significantly (p less than 0.001) improved all these parameters compared to the baseline exercise test. The effect of the 2 drugs on the diameters of angiographically normal segments of large epicardial coronary arteries was then assessed using computerized quantitative angiography in 10 other patients with stable angina. Whereas theophylline failed to increase the coronary diameters compared to that in the baseline angiogram (2.9 +/- 0.6 vs 2.9 +/- 0.6 mm, respectively), the subsequent administration of isosorbide dinitrate resulted in an increase up to 3.2 +/- 0.7 mm (p less than 0.02). Thus, in patients with stable angina, theophylline delays the onset of angina, increases the ischemic threshold and prolongs the exercise duration to the same degree as isosorbide dinitrate.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

[Management of hypertension emergencies in elderly patients with isosorbide dinitrate aerosol].

In this clinical trial, we assessed the effectiveness and safety of isosorbide dinitrate spray administered through the oral mucosa in 20 elderly patients (> 60 years old) with a hypertensive emergency (mean arterial pressure > 140 mmHg and target-organ damage). The patents were given a first dose of 1.25 mg of spray when they were admitted; a second dose was administered 15 min. later if the mean arterial pressure had not decreased by > 15%. An electrocardiogram (ECG) was done on every patient immediately prior and 30 min. after administering the medication. Three patients (15%) had a good response with one dose while 17 patients (85%) required a second dose. Thirty patients had a significant reduction in arterial blood pressure (193 +/- 91,123 +/- 5.4 to 154 + 7.1/92.5 + 6.2 mmHg p < 0.005) as well as of the mean arterial pressure (146.8 +/- B to 113 +/- 5 mmHg 23%, p < 0.005 > in a period of 30 min. No adverse effects, rebound hypertension nor severe hypotension were observed. These figures remained under control for 3 h. Both ECG, were normal. A reduction of 13.5% heart rate was obtained (p < 0.005). Our observations suggest that isosorbide dinitrate aerosol is an effective and safe alternative for the treatment of elderly patients with hypertensive emergencies.

Age Factors↗

ITF 296, a new endothelium-independent vasodilator: comparison with nitroglycerin and isosorbide dinitrate.

The effects of a new nitrate ester derivative, ITF 296, on large conductance and small resistance coronary arteries were investigated and compared with those of nitroglycerin and isosorbide dinitrate in chronically instrumented conscious dogs with an intact or with a deendothelialized large coronary artery. In a wide range of doses, ITF 296 (0.3-3 micrograms/kg), nitroglycerin (0.1-0.3 micrograms/kg), and isosorbide dinitrate (0.3-10 micrograms/kg) induced a highly selective dilatation of the large conductance vessels, an effect that was dose-dependent. At 30-fold higher doses, the three drugs also dilated coronary arterioles, an effect that preceded dilatation of large arteries but was transient. Qualitatively, ITF 296 therefore exhibits the same pattern of coronary effects as nitroglycerin and isosorbide dinitrate. Quantitatively, ITF 296 was 6.6-fold less potent than nitroglycerin at dilating large coronary arteries, but its effects on these vessels were of longer duration. Three days after endothelium removal, the vasodilation observed during reactive hyperemia or induced by acetylcholine were almost completely abolished. In contrast, the vasodilating effects of ITF 296 (30-100 micrograms/kg) and nitroglycerin (1 microgram/kg) were not significantly different from those observed before endothelium removal, thus indicating that these two drugs dilate the large conductance coronary arteries through an endothelium-independent mechanism.

Animals↗

[Effect of isosorbide dinitrate (sorbonit) on the exercise reaction in patients with coronary disease and in healthy individuals].

The study aimed at evaluating an effect of a single dose of isosorbide dinitrate (Sorbonit) on the exercise reaction in the patients with coronary disease of various degree and in healthy individuals. The study involved 20 male patients of mean age 54.0 +/- 4.5 years with history of myocardial infarction and 12 healthy males of mean age 45.6 +/- 5.0 years. Ergometric test has been performed twice: prior to and 15 minutes after sublingual administration of isosorbide dinitrate in the dose of 10-15 mg. The first test has been interrupted when horizontal ST load exceeded 1 mm or contractions rate was 60% of the maximum value. Similar loads have been used after the administration of Sorbonit. The following parameters have been evaluated: heart rate (HR), systolic blood pressure (BPS), HR x BPS, lactate level (LA), and cardiac index. The value of the load has been measured with the aid of oxygen consumption (VO2). Significant depression of ST segment (less than 3 mm) in the exercise ECG has been noted in 8 patients following isosorbide dinitrate. Exercise tolerance has increased in these patients - CI increased during exercise following drug administration (VO2 the same as prior to the drug administration), and VO2/CI has became closer - physiological.

Coronary Disease↗

Comparative clinical trial of isosorbide 5-mononitrate and sustained-release isosorbide dinitrate in ischaemic heart disease.

A double-blind crossover study, with placebo periods preceding each active treatment, was carried out in 29 patients with ischaemic heart disease to compare the clinical efficacy of isosorbide 5-mononitrate 40 mg twice daily and the same regimen of sustained-release isosorbide dinitrate. Assessment was by bicycle ergometry, symptomatology and blood nitrate level measurements. After 2-weeks' therapy with isosorbide 5-mononitrate, mean ST segment depression at the highest comparable exercise level for each patient was reduced by 32.5% (p less than 0.01), the mean maximum exercise level was increased from 87 to 102 Watts (17.8%, p less than 0.01), and mean work capacity was increased from 581 Watts-minutes to 783 Watts-minutes (34.6%, p less than 0.01). With sustained-release isosorbide dinitrate, ST segment depression was reduced by 16.5% (p less than 0.05); maximum exercise level showed only a small non-significant increase, from 89 to 97 Watts (8.6%), but work capacity increased (p less than 0.05) from 593 Watts-minutes to 705 Watts-minutes (18.9%). There was no significant difference between drugs as regards ST segment reduction but a slight difference in favour of isosorbide 5-mononitrate (p less than 0.05) in terms of maximal exercise level and work capacity. Both drugs resulted in very small reductions in blood pressure (p less than 0.001 for systolic with isosorbide 5-mononitrate; p less than 0.01 for systolic and p less than 0.05 for diastolic with sustained-release isosorbide dinitrate). Heart rate and rate-pressure product changed little with either drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Angina Pectoris↗

Effects of isosorbide dinitrate on portal hypertension in alcoholic cirrhosis.

It has recently been reported that vasodilators lower portal pressure in patients with cirrhosis. This effect, however, is not definitively proven. The effect of isosorbide dinitrate (5 mg sublingually) on splanchnic and systemic hemodynamics was investigated in 13 patients with alcoholic cirrhosis and portal hypertension. The administration of isosorbide dinitrate reduced hepatic venous pressure gradient by 34% (P less than 0.001), mean arterial pressure by 30% (P less than 0.001), cardiac index by 17% (P less than 0.001) and systemic vascular resistance by 11% (P = 0.05). Hepatic blood flow was not affected by the treatment. Significant correlations were found between the decrease in hepatic venous pressure gradient and that of cardiac index (P less than 0.05) and mean arterial pressure (P less than 0.05). These data indicate that isosorbide dinitrate lowers portal pressure in patients with cirrhosis. Decrease in cardiac output, rise in splanchnic arterial vascular resistance and decrease in porto-hepatic resistance seem to participate in determining the effect.

Adult↗

Gas-liquid chromatographic determination of isosorbide dinitrate in tablets.

A gas-liquid chromatographic (GLC) method is described for determining isosorbide dinitrate (ISDN) in tablets. ISDN is extracted from tablet excipients by a 2-phase system composed of water-ethyl ether, and detected and quantitated with a flame ionization detector after separation from the internal standard (glyceryl tributyrate) on a 3% OV-210 column. Ten replicate assays on 2 different batches of tablets, each containing 5 mg ISDN, gave coefficients of variation of 1.16 and 1.48%, respectively. Comparison of results obtained for tablets containing 5, 10, and 40 mg ISDN, and for diluted isosorbide dinitrate raw material containing 25% ISDN, showed good correlation among the GLC, USP colorimetric, and USP polarographic procedures. Assay of synthetic mixtures containing ISDN, isosorbide-2-mononitrate, and isosorbide-5-mononitrate demonstrated that the GLC procedure is specific for ISDN, whereas the USP polarographic procedure is subject to interference from the mononitrates.

Chromatography, Gas↗

Effect of enalapril, hydralazine plus isosorbide dinitrate, and prazosin on hospitalization in patients with chronic congestive heart failure. The V-HeFT VA Cooperative Studies Group.

BACKGROUND: Hospitalization of persons with congestive heart failure for recurrent heart failure or other complications is common. METHODS AND RESULTS: Male patients aged 18-75 with chronic heart failure were randomized in two sequential trials designed to study the efficacy of vasodilator therapy. Patients were evaluated every 3 months, and information regarding hospitalizations between visits was obtained from the patient, his family, and/or hospital records. Hospitalization data also were obtained for patients who had died between scheduled clinic visits. Hospitalizations were not recorded if a patient died during transit to the hospital or in the hospital emergency department before admission. In Vasodilator-Heart Failure Trial (V-HeFT) I, no significant difference in number of patients hospitalized or number of hospitalizations was noted among the treatment groups, although there was a trend for fewer and delayed cardiac hospitalizations in the hydralazine plus isosorbide dinitrate arm in which the survival was greater. In V-HeFT II, no difference in hospitalizations was apparent between the enalapril and hydralazine plus isosorbide dinitrate arms. Univariate predictors of hospitalization for all causes were reduced peak oxygen consumption (VO2) during exercise (p < 0.0001), reduced exercise duration (p < 0.0001), increased cardiothoracic ratio on chest radiograph (p < 0.0001), increased age (p < 0.03), and use of antiarrhythmic drugs (p < 0.013), whereas multivariate predictors were reduced peak VO2 (p < 0.0001), use of antiarrhythmic drugs (p < 0.015), and increased cardiothoracic ratio (p < 0.03). Univariate predictors of hospitalization for heart failure were peak VO2 (p < 0.0001), LVEF (p < 0.0001), reduced exercise duration (p < 0.0001), elevated cardiothoracic ratio (p < 0.0001), and elevated plasma norepinephrine (p < 0.0001). Multivariate predictors were exercise duration (p < 0.0001), LVEF (p < 0.04), elevated cardiothoracic ratio (p < 0.03), plasma norepinephrine (p < 0.0005), and coronary artery disease (p < 0.02). Time to first hospitalization, cause specific or overall, was considerably shorter for patients with baseline peak VO2 < 10 mL.kg-1 x min-1 compared with those with peak VO2 > 15 mL.kg-1 x min-1. CONCLUSIONS: Despite better survival in patients randomized to hydralazine plus isosorbide dinitrate compared with placebo and better survival in patients randomized to enalapril compared with hydralazine plus isosorbide dinitrate, no significant differences between the treatment groups were apparent in the incidence of hospitalization or time to first hospitalization for congestive heart failure, for cardiac reasons other than congestive heart failure, or for other causes. V-HeFT I and V-HeFT II data demonstrate no treatment effect on hospitalization, perhaps reflecting in part the effectiveness of the Veterans Affairs special heart failure clinics in dealing with worsening heart failure on an outpatient basis. Identification of predictors of hospitalization were similar in both studies.

Drug Therapy, Combination↗

[Treatment of ischemic heart disease with beta-receptor blockers and isosorbide dinitrate (author's transl)].

The effects of a beta-receptor blocker (Betadrenol), an isosorbide dinitrate preparation (Isoket) and the combination of the two substances (Betaket) were compared with a placebo in a controlled double blind trial in 20 patients with confirmed attacks of angina pectoris and/or ischemic changes in the ECG on ergometer exercise. Important assessment criteria of the efficacy were regression of ischemic ECG changes on standardized ergometer exercise, increase in load resistance and the nitroglycerine requirement. Treatment with the combination of betablocker and isosorbide dinitrate (Betaket) was more effective in comparison to treatment with the individual substances.

Adrenergic beta-Antagonists↗

Management of acute heart failure following myocardial infarction: hemodynamic advantages of isosorbide dinitrate over frusemide.

The immediate hemodynamic effects of intravenous frusemide (1 mg/kg) and intravenous isosorbide dinitrate (50-200 micrograms/kg/h) were compared in a prospective, randomized, between-group study in 28 men with radiographic and hemodynamic evidence of left ventricular failure following acute myocardial infarction. The diuresis induced by frusemide reduced the left-heart filling pressure and cardiac output and transiently raised systemic blood pressure. In contrast, isosorbide dinitrate was accompanied by a reduction in systemic blood pressure and peripheral resistance, with the result that the cardiac output was not decreased despite a large fall in the pulmonary vascular and left-heart filling pressures. The results indicate that reduction of excessive preload by venodilatation may be hemodynamically superior to that induced by diuresis in terms of both reducing myocardial oxygen consumption and maintaining peripheral perfusion. The influence of these contrasting treatments on the prognosis of these high-risk patients warrants further study.

Adult↗

Determination of isosorbide dinitrate in pharmaceutical products by HPLC.

A high-performance liquid chromatographic (HPLC) assay for isosorbide dinitrate in pharmaceutical formulations is described. The method employs a reversed-phase C18 column with a mobile phase containing methanol/water/acetate buffer and is specific for isosorbide dinitrate with respect to its 2- and 5-mononitrate degradation products and other organic polynitrate esters. The method is applicable to the analysis of the diluted bulk drug and dosage forms, including sublingual, oral, chewable, and timed-release preparations.

Chromatography, High Pressure Liquid↗

Protective effects of nipradilol, isosorbide dinitrate, and bunazosin on coronary artery constriction induced by intracoronary injection of acetylcholine in pigs.

STUDY OBJECTIVE: Protective effects of nipradilol, a newly synthesised vasodilating beta adrenoceptor antagonist, isosorbide dinitrate, and bunazosin on coronary artery constriction induced by intracoronary injection of acetylcholine were determined by coronary arteriography and compared in vivo in pigs. DESIGN: Acetylcholine (12.5, 25, 50, 100 and 200 micrograms) was given into the right coronary artery under left ventricular pacing to maintain constant systemic haemodynamics. Percentage narrowing of the major epicardial coronary artery was used as an indicator of constriction of the large coronary arteries, and the time required for the contrast medium to reach the posterior descending coronary artery from the ostium of the right coronary artery (blood flow delay) was used as an indicator of constriction of the small coronary arteries. SUBJECTS: 15 farm pigs weighing 80 to 90 kg were used. MEASUREMENTS AND MAIN RESULTS: A marked blood flow delay of over 7.0 s (control: less than or equal to 1.8 s) with less than 34% narrowing of the epicardial major coronary artery was observed in 13 of 15 pigs with 12.5-50 micrograms of acetylcholine, and in the other two pigs with 100 micrograms of acetylcholine. When marked blood flow delay occurred, the perfused right ventricular myocardium became macroscopically anaemic (ischaemic). Over 75% narrowing of the major epicardial coronary artery was induced in six of the 15 pigs, and over 50% narrowing in 12, with marked blood flow delay with 100 to 200 micrograms of acetylcholine. However, after intracoronary infusion of 10 micrograms of nipradilol, acetylcholine induced narrowing in the epicardial major coronary artery was significantly reduced from 44-79% in control to 19-37% despite 200 micrograms of acetylcholine, though the time delay in coronary blood flow did not change significantly. By pretreatment with intracoronary isosorbide dinitrate (2.5 mg), the percent narrowing of the large coronary artery and the time delay in coronary blood flow were significantly reduced (narrowing from 32-84% to 10-27%; time delay from 7.6-41.6 s to 2.7-22.7 s). Pretreatment with intracoronary bunazosin, an alpha 1 adrenoceptor antagonist (100 micrograms), showed no protective effect on narrowing of the epicardial major coronary artery or blood flow delay. CONCLUSIONS: Isosorbide dinitrate prevents coronary artery constriction induced by acetylcholine in swine. Nipradilol prevents large, but not small, coronary artery constriction, probably through a direct nitrate like vasodilating action.

Acetylcholine↗

[Antithrombotic effects of molsidomine, isosorbide dinitrate and verapamil in a laser-induced thrombosis model].

Antithrombotic effects of molsidomine, isosorbide dinitrate and verapamil obtained from the Casela Riedel Pharma GmbH, Frankfurt/Main, Germany have been studied in the laser-induced rat thrombosis model. The investigations were carried out on male Wistar rats weighing 200-300 g. Thrombus formation was induced in small mesenteric arteries--25-35 microns diameter using argon laser. An interference contrast system based on a Leitz Orthoplan microscope for the evaluation of thrombus formation was used. The number of laser injuries needed to induce a defined thrombus proved to be a useful way to quantitate the results in this thrombosis model. All agents showed dose dependent antithrombotic effect in our laser model. Molsidomine and verapamil inhibited 30 min after single i.v. injection in minimal dose 1 mg/kg and in dose 5 mg/kg 2 hours after oral administration thrombus formation in small mesenteric arteries. Isosorbide dinitrate in higher doses: 10 mg/kg 30 min after i.v. injection and 20 mg/kg after oral feeding showed significant antithrombotic effect. Antithrombotic effect of administration of minimal effective doses of all agents lasted longer than 4 hours but less than 6 hours. All drugs in effective antithrombotic doses after intravenous injection showed also inhibitory effect on rat platelet adhesion to the siliconized glass and bovine subendothelial extracellular matrix.

Animals↗

Randomized, prospective trial comparing 0.2 percent isosorbide dinitrate ointment with sphincterotomy in treatment of chronic anal fissure: a two-year follow-up.

PURPOSE: The aim of this trial was to compare lateral internal sphincterotomy with local 0.2 percent isosorbide dinitrate in the treatment of chronic anal fissure to minimize surgical complications such as minor fecal incontinence. METHODS: Fifty-four patients with chronic anal fissure were randomized in a prospective trial to either sphincterotomy or local 0.2 percent isosorbide dinitrate. All patients had anal function tests before and 5 weeks after treatment. RESULTS: In the ointment group, 18 patients (67 percent) healed at 5 weeks and 24 (89 percent) healed at 10 weeks of treatment. Maximum resting anal pressure was reduced 30 percent. Eight patients (30 percent) had minor side effects. In the surgical group, 26 patients (96 percent) healed at 5 weeks and 100 percent healed at 10 weeks after treatment, with 33 percent reduction in maximum resting anal pressure. Forty-four percent of patients had minor fecal incontinence, which remained in 15 percent after 24 months follow-up. No statistical difference in maximum resting anal pressure was found between groups ( P = 0.16), but the percentage of healing at 5 weeks was greater in the surgical group ( P < 0.001). CONCLUSIONS: Isosorbide dinitrate ointment must be considered as the first choice of treatment in patients with chronic anal fissure. Surgery should be indicated if chemical sphincterotomy fails.

Administration, Topical↗

A controlled comparison of oxyfedrine, isosorbide dinitrate and placebo in the treatment of patients suffering attacks of angina pectoris.

1 In a group of 23 patients with documented ischaemic heart disease who experienced angina pectoris, oral oxyfedrine (24 mg three times daily) was compared with isosorbide dinitrate (10 mg three times daily) and placebo in a double-blind double-crossover clinical trial. 2 Isosorbide dinitrate appeared no better than placebo, either in terms of symptomatic relief or ECG responses to exercise. Thirty eight per cent of patients complained of headaches and 28% had to cease taking the drug for this reason. 3 Oxyfedrine produced statistically significant improvements in both symptom level (P < 0.01) and ECG ST-segment responses to exercise (P < 0.01). The only side effect noted was a reversible loss of taste sensation by one patient. 4 Neither drug produced any adverse changes in any haematological or biochemical parameters. 5 Oxyfedrine is, therefore, to be preferred to isosorbide dinitrate, being both much better tolerated and more efficacious.

Adult↗

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

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

Acetonitriles↗