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[The efficacy of isosorbide dinitrate administered in an intravenous bolus in acute cardiogenic pulmonary edema].

STUDY OBJECTIVE: To evaluate the efficacy, safety and tolerability of intravenous (i.v.) isosorbide dinitrate (ISDN) administered as a bolus in the treatment of cardiogenic acute pulmonary edema (CAPE). DESIGN: Clinical, prospective, open, noncontrolled trial. SETTING: Emergency room. PATIENTS AND INTERVENTIONS: Twenty two patients (15 male and 7 female), aged 54 to 80 years (68.4 +/- 6.4) with severe respiratory distress consistent with CAPE were included. The cause of CAPE was chronic ischemic cardiopathy in 13 patients, acute myocardial infarction in four, hypertensive cardiopathy in three and mitral valve disease in two. Patients were excluded from the study because of shock or systolic blood pressure equal or lower than 100 mmHg, severe aortic stenosis, hypertrophic cardiomyopathy and non-cardiogenic pulmonary edema. All patients were placed in the sitting position and received oxygen. Initial therapy consisted of an i.v. bolus of 5 to 10 mg of ISDN. Clinical data were recorded at admission and after 5, 10, 15 and 30 minutes. A new i.v. bolus of ISDN and/or another drug was administered at 5 minutes, when necessary. RESULTS: Fifteen patients treated exclusively with ISDN (in three a second i.v. bolus was necessary) improved markedly. In the remaining seven patients that needed other drugs, the improvement was not so impressive. The mean total dose of i.v. ISDN was 10.34 +/- 3.48 mg. Although all data showed a trend towards improvement, just the following were statistically significant (p < 0.05): pH increased from 7.26 +/- 0.13 to 7.32 +/- 0.9, systolic blood pressure decreased from 192.7 +/- 34.8 mmHg to 155.0 +/- 24.4 mmHg (-19%) and diastolic blood pressure decreased 110.5 +/- 12.7 mmHg to 93.2 +/- 9.1 mmHg (-16%). CONCLUSIONS: In this trial, iv ISDN administered as a bolus in doses ranging from 5 to 20 mg, was effective and safe as a first line agent in the treatment of CAPE. No serious adverse reaction were reported.

Acute Disease↗

Simultaneous determination of isosorbide dinitrate and its mononitrate metabolites in human plasma by capillary gas chromatography with electron-capture detection.

A method for the simultaneous determination of isosorbide dinitrate (ISDN) and its mononitrate metabolites (2- and 5-ISMN) in human plasma by capillary gas chromatography with electron-capture detection was developed. Two internal standards were used: isomannide dinitrate (IMDN) for the determination of ISDN and isomannide mononitrate (IMMN) for the determinations of 2- and 5-ISMN. After addition of the internal standards, the compounds were isolated from plasma by solid-liquid extraction. They were determined by gas chromatography using an electron-capture detector. The reproducibility and accuracy of the method were found suitable in the range of concentrations 2.5-83 ng/ml for ISDN, 2.6-208 ng/ml for 2-ISMN and 2.3-1010 ng/ml for 5-ISMN. The limit of quantitation (LOQ) was about 2.5 ng/ml for each compound. The method was applied to clinical samples.

Chromatography, Gas↗

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↗

Comparison of the effects of dopamine, hydralazine, and isosorbide dinitrate on myocardial hemodynamics in patients with refractory heart failure.

Nine patients with refractory congestive heart failure underwent hemodynamic study first with dopamine and then with oral hydralazine and sublingual isosorbide dinitrate. Although hemodynamic improvement was achieved with both forms of therapy, the beneficial effects of hydralazine alone or with isosorbide were superior to those of dopamine, as manifested by a greater reduction of wedge pressure and greater increase in stroke index. Six patients who demonstrated an increased wedge pressure during dopamine infusion were observed to manifest a louder apical systolic murmur and/or V wave in the wedge pressure tracing suggestive of enhanced mitral regurgitation. The rise in wedge pressure on dopamine could also be a consequence of increased myocardial ischemia and resultant decrease in ventricular compliance. It is possible that a subgroup of patients with heart failure are made worse by dopamine, and in these cases vasodilator therapy may be more beneficial.

Aged↗

A comparison of carvedilol with a combination of propranolol and isosorbide dinitrate in the chronic treatment of stable angina.

The beta-blocking and vasodilating agent carvedilol was compared with a combination of propranolol and isosorbide dinitrate (ISDN) in a double-blind, parallel-group study. After two baseline sitting bicycle exercise tests on placebo, 31 patients with chronic stable angina were asymmetrically randomized to treatment with carvedilol (25 mg b.i.d.) or propranolol-ISDN (80 mg/20 mg b.i.d.) for a period of 6 months. Further exercise tests were performed 2 h after the first dose as well as after 1, 3, and 6 months of treatment. Twenty-seven patients were considered evaluable for efficacy. Differences between the two groups were observed with emphasis on total exercise time and time to 1-mm ST-segment depression. In contrast to a greater peak effect of the first propranolol/ISDN dose, the chronic antianginal and anti-ischemic effects of carvedilol at trough were found to be more marked than those of the combination.

Adrenergic beta-Antagonists↗

Atrial natriuretic factor and isosorbide dinitrate modulate the gating of ATP-sensitive K+ channels in cultured vascular smooth muscle cells.

The effects of atrial natriuretic factor (ANF) and isosorbide dinitrate (ISDN), activators of particulate and soluble guanylate cyclase, respectively, on K+ currents were investigated in patch-clamp recordings of smooth muscle cells cultured from rat thoracic aorta. In the cell-attached patch configuration, ANF enhanced Ca(2+)-activated K+ (KCa) channel activities as reported previously. When KCa channels were blocked with 1 mmol/L tetraethylammonium or 10(-7) mol/L charybdotoxin, ANF and ISDN applied to the bathing solution activated ATP-sensitive K+ (KATP) channels without altering channel conductance. Pretreatment with methylene blue, a guanylate cyclase inhibitor, abolished the effects of ISDN on KATP channels, whereas 8-bromo-cGMP activated these channels, suggesting that the effects of ISDN on KATP channels were mediated by cGMP. Our results suggest that vasorelaxant agents that increase intracellular cGMP concentrations modulate the gating of two major potassium channels, ATP sensitive and Ca2+ activated, that might play an important role in controlling vascular tone by changing the membrane potential.

Adenosine Triphosphate↗

Efficacy of eccentric dosing with sustained-release isosorbide dinitrate in patients with angina pectoris.

OBJECTIVE: To assess the anti-anginal efficacy of eccentric dosing with a sustained-release formulation of isosorbide dinitrate (ISDN) administered twice daily in an eccentric fashion (08:00 and 14:00). DESIGN: A placebo controlled crossover study of 16 patients with chronic stable angina who received, in random order, either placebo or sustained-release ISDN 40 mg twice daily for a period of seven to 10 days. Patients were entered who had reproducible exercise test to the development of moderate angina. All anti-anginal drugs with the exception of beta-blockers were withheld during the study period. The primary end-point was the treadmill walking time to the development of moderate angina. RESULTS: Patients receiving active therapy showed a significant increase in treadmill walking time to moderate angina over that seen with placebo at 3 and 6 h after the morning dose and 3 and 8 h after the afternoon dose. Similar trends occurred for the time to onset of angina and the time to development of 1 mm of ST segment depression on the electrocardiogram. CONCLUSIONS: Eccentric dosing with sustained-release ISDN, 40 mg given 6 h apart, provided significant improvement in exercise performance for up to 14 h during sustained therapy.

Angina Pectoris↗

[Transdermal nitroglycerin in stable effort angina. I. Therapeutic effect and duration of the action of a single dose. Comparison with placebo and isosorbide dinitrate].

To assess the efficacy of 2 doses of a transdermal system for nitroglycerin, 10 and 20 mg (NTTS 10 and NTTS 20) and isosorbide dinitrate 40 mg (ISD 40) on exercise tolerance test, a double-blind within patients placebo (PL) controlled study was performed: 12 male patients, aged 47-71 years, with stable effort angina, with fixed ischemic threshold, received, according to a 4 x 4 latin square design, NTTS 10, NTTS 20, ISD 40 and PL, at 7.00 am on 4 consecutive days. Bicycle exercise tests were performed 4 and 12 hours post-dosing, after which the systems were removed. NTTS 10 and 20 and ISD 40 increased significantly ischemic threshold, anginal threshold and decreased maximal ST depression at the fourth hour. Only NTTS 10 and NTTS 20 showed antiischemic activity after 12 hours. During exercise, at the fourth and twelfth hour, there was no significant difference in rate-pressure product between placebo and NTTS 10 and 20 and ISD 40. Therefore the antiischemic activity of these drugs was not related to a decrease of myocardial oxygen consumption. In conclusion, in comparison with PL, NTTS 10, 20 and ISD 40 had antiischemic and antianginal activity at the fourth hour, while at the twelfth hour this activity was observed only after NTTS 10 and 20, without differences between the 2 doses.

Administration, Cutaneous↗

A comparison of the day-long antianginal effectiveness of nitroglycerin patches with that of three-times-daily isosorbide dinitrate: a double-blind study using dose titration.

Eight men with stable angina, a positive treadmill test, and demonstrated responsiveness to chronic oral isosorbide dinitrate (ISDN) were studied after they had been taking effective doses of ISDN t.i.d. for at least 2 weeks. Exercise tests were performed every 1-2 h until 19.00 hours over one day after the 08.00 hours application of nitroglycerin patches in a previously titrated dose; on another day after the administration of ISDN capsules q5h; and on a third day after placebo patches and capsules. The mean necessary effective patch dose was 125 cm2 (60-220 cm2). The mean exercise duration to angina rose from 271 to 480 s 1 h after nitroglycerin patches (P less than 0.001). Nitroglycerin patches were superior to the placebo throughout the day, but in a declining degree--by 94 s at 19.00 hours (P less than 0.05). ISDN q5h provided peaks of increased walking time to angina 1 h after each dose, but after 3 h exercise time was down to placebo levels. Furthermore, the peaks were of diminishing amplitude: 200 s at 09.00 hours, 150 s at 14.00 hours, but only 70 s at 19.00 hours. Thus, neither nitrate regimen provided continuous near-peak benefit throughout the 11 h period, although nitroglycerin patches had a significantly greater (P less than 0.05) overall effect during the day.

Administration, Cutaneous↗

[Extent of therapeutic effect and duration of 1 capsule of 120 mg isosorbide dinitrate in a slow release form].

In this randomised, double-blind placebo-controlled crossover study we investigated the efficacy of 120 mg isosorbide dinitrate s.r. 12 h after application in comparison to 2 and 6 h in 18 patients with angiographically proven coronary artery disease, stable exercise-induced angina and reproducible ST-segment depression. Bicycle ergometry was performed before, 2, 6 and 12 h after medication and nitrate plasma levels were drawn before each exercise test. After 2 h, the exercise-induced ST-segment depression in comparison to placebo was reduced from 2.3 mm +/- 0.8 to 0.7 +/- 0.5, after 6 h to 1.0 mm +/- 0.8) and after 12 h to 1.9 mm +/- 0.8 (p less than 0.01). 82% of the patients suffering from angina on the control exercise test before medication were free of symptoms 2 and 6 h after ISDN 120 mg s. r., but showed angina again after 12 h. In comparison to the plasma levels 2 h after ingestion, the concentrations in plasma after 12 h were much lower for ISDN, equal for IS-2-MN, and more than double for IS-5-MN. Thus, 12 h after ingestion of 120 mg ISDN s.r. there is still a significant reduction of ST-segment depression. This 12-h benefit is 40% od the maximum effect.

Aged↗

Sublingual isosorbide dinitrate in the acute control of hypertension in patients with severe preeclampsia.

The objective of this study was to evaluate the effectiveness of sublingual isosorbide dinitrate (ID) in the acute control of hypertension in patients with severe preeclampsia. A randomized, double-blind clinical trial with a preinclusion period of response to hydration and rest was performed in 60 patients with severe preeclampsia. The treatment group (30 patients) received 5 mg of sublingual ID, a dose that could be repeated on a second occasion. The control group consisted of 30 patients who received placebo. Both groups continued with rest and hydration during the study. Maternal blood pressure and fetal heart rate were measured in all patients every 10 min until 1 h was completed. Treatment was considered effective when the diastolic blood pressure could be reduced to between 80 and 100 mm Hg. ID was effective in 56.6% of the patients in the first 10 min after its administration and in 96. 6% from 40 to 60 min. In the treatment group the systolic and diastolic blood pressures dropped gradually from 171 +/- 13 and 113 +/- 8 mm Hg, respectively, to 136 +/- 14 and 87 +/- 9 mm Hg. In the placebo group, blood pressure was not reduced. There was no significant difference in fetal heart rate between both groups throughout the study. In conclusion, ID was shown to be effective in the acute control of hypertension in patients with severe preeclampsia, where high blood pressure persists after a period of rest and hydration.

Administration, Sublingual↗

Comparison of transdermal nitrate and isosorbide dinitrate in chronic stable angina.

The effects of transdermal nitrate (TN) (Transiderm-Nitro TTS, Geigy Pharmaceuticals, one 10 cm2 patch daily) and oral isosorbide dinitrate (ISDN) (Sorbitrate, Stuart Pharmaceuticals, 10 mg three times daily) were compared in a group of 20 patients with chronic stable angina pectoris. Treadmill exercise duration was prolonged from a median time of 365 s to 428 s after ISDN (P less than 0.05), but was unchanged after TN. The difference between the active treatments was not significant. Weekly consumption of glyceryl trinitrate (GTN) increased during treatment with TN from a median value of 5.5 to 6.3 (P less than 0.05). A decrease was observed after ISDN (7.8 to 3.9, P = NS), and the difference between the drugs was significant (P less than 0.01). Systolic arterial pressure was significantly lower during the ISDN than during the TN treatment period in both the supine (135 +/- 5 vs 128 +/- 5 mm Hg; P less than 0.05) and standing positions (134 +/- 5 vs 122 +/- 5 mm Hg; P less than 0.05). No change in weekly attack rate, the degree of ST depression at angina on treadmill testing, or the number of episodes of ST depression recorded during a 24 h period by Holter monitoring was observed after either drug. In this study, an antianginal effect was demonstrated for ISDN but not for TN. It is suggested that the dose of TN may have been inadequate to demonstrate such an effect, and further studies using a higher dose schedule will be required.

Administration, Oral↗

Dose- and time-related vasodilator response of conduit coronary arteries to intracoronary isosorbide dinitrate in human beings.

The time course of the vasodilation of different segments of the epicardial coronary vasculature after three different doses of intracoronary isosorbide dinitrate (ISDN) was investigated in angiographically normal coronary arteries in 10 patients with quantitative coronary angiography. In five patients, 0.1 mg and 0.3 mg ISDN were injected intracoronary 30 minutes apart, and the effect of each dose was assessed at 1, 5, 10, and 15 minutes after the administration by serial angiograms. In five additional patients, a single dose of 3 mg was injected and coronary vasodilation was assessed at 1, 5, 10, 15, and 20 minutes. After each dose, dilation of epicardial coronary arteries occurred within 1 minute, peaked at 5 minutes and progressively decreased thereafter. Relative to control, peak percent diameter increase was (mean +/- SEM) 10% +/- 0.9% (p less than 0.01), 18.5% +/- 1.5% (p less than 0.01), and 26% +/- 2.1% (p less than 0.01) after 0.1, 0.3, and 3.0 mg, respectively. When small (1 to 2 mm), medium (2 to 3 mm), and large (greater than 3 mm) vessels were separately analyzed, peak response was respectively 12% +/- 1.3% (p less than 0.01), 9% +/- 1.9% (p less than 0.01), and 7% +/- 1% (p less than 0.05) after 0.1 mg ISDN; 22% +/- 1.8% (p less than 0.01), 16% +/- 1.3% (p less than 0.01), and 12% +/- 0.8% (p less than 0.01) after 0.3 mg; and 38% +/- 2.4% (p less than 0.01), 22% +/- 2.1% (p less than 0.01), and 17% +/- 2% (p less than 0.01) after 3.0 mg. The duration of the response increased with the dose, but was inversely related to the size of the vessel.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Comparison between isosorbide dinitrate aerosol and nifedipine in the treatment of hypertensive emergencies.

BACKGROUND: Nitric oxide donors have been used in the management of hypertensive emergencies (HE). Isosorbide dinitrate aerosol (ISA) is a nitric oxide fast-acting donor. The aim of this study is to compare the efficacy of ISA and nifedipine in the treatment of HE. METHODS: Sixty adult patients with an HE were randomised to receive either ISA (2.5 mg) or nifedipine (10 mg). Patients were given an electrocardiogram (ECG) immediately prior, and 30 min after administering the medication. Blood pressure (BP) was measured every 5 min for the first 30 min, and then every 30 min for a period of 6 h. RESULTS: Blood pressure values for all patients in the ISA group decreased significantly (187 +/- 13/121 +/- 6 to 153 +/- 15/92.3 +/- 7.6 mmHg, P < 0.005). Two of the patients in this group had angor pectoris with evidence of subepicardial ischaemia as seen in the first ECG, both of which disappeared with the drug. Heart rate decreased by 14%. Similarly, all patients in the nifedipine group had significant decreases in BP (190 +/- 23/115 +/- 7 to 153 +/- 26/86 +/- 6 mm Hg, P < 0.005). Their first ECG was normal. Two patients suffered angor pectoris after nifedipine, with subepicardial ischaemia registering in the second ECG. Heart rate increased 11.9% in this group. During the follow-up period, no clinically significant side effects or cases of rebound hypertension were observed in the ISA group, whereas in the nifedipine group, eight patients reported having headaches and four others rebound hypertension. CONCLUSION: Our results show a favourable effect of ISA in the treatment of HE.

Adult↗

[Effects of isosorbide dinitrate injection on acute myocardial infarction. A haemodynamic and gamma-angiographic study (author's transl)].

The haemodynamic and gamma-angiographic effects of isosorbide dinitrate (ISDN) injection were evaluated in 18 patients with recent myocardial infarction by measuring diastolic (DPAP) and systolic (SPAP) pulmonary artery pressures, diastolic (DAP) and systolic (SAP) systemic arterial pressures, cardiac index (CI) and heart rate (HR). Total ejection fraction (EF) was measured by radionuclide angiography. Within the first hour of treatment, there was a significant fall in DPAP (from 25.11 +/- 6.5 to 18.3 +/- 6 mmHg), SPAP (from 47 +/- 11.5 to 36.6 +/- 10 mmHg) and SAP (from 140 +/- 27.8 to 123 +/- 20 mmHg). Changes in DAP, CI and HR were not significant. The drug produced a significant increase in EF (from 32.6 +/- 15 to 35.3 +/- 15 p. cent). On the basis of these results the patients could be divided into three categories: -- Group I patients (n = 5) with EF greater than 45, in whom the haemodynamic effects (fall in DRAP from 20.8 +/- 4.2 to 16.3 +/- 3 mmHg) and the gamma-angiographic effects (increase in EF from 53.8 +/- 6 to 58.6 +/- 3 p. cent) were favourable. -- Group II patients (n = 5) with EF less than 40, in whom the haemodynamic effects (fall in DRAP from 29 +/- 8.5 to 17.8 +/- 6 mmHg) and the gamma-angiographic effects (increase in EF from 23 +/- 9 to 34 +/- 7 p. cent) were still favourable. -- Group III patients (n = 8) with low EF, in whom there were no significant changes in haemodynamic effects (DPAP from 25.3 +/- 3 to 23.4 +/- 5 mmHg) and gamma-angiographic effects (EF from 26 +/- 6 to 25 +/- 5 p. cent). This group corresponds to cases with very extensive necrosis of unfavourable outcome (4 deaths). One may therefore consider that the lack of effectiveness of ISDN in subjects with left ventricular failure and low EF is of poor prognosis and requires more aggressive therapy.

Adult↗

Effect of isosorbide dinitrate on enzymatically estimated infarction size and on clinical condition of the patients of acute myocardial infarction.

With the aim of reducing myocardial infarction size, isosorbide dinitrate (ISDN) was tried in 27 patients of acute myocardial infarction (AMI). There was 11% reduction of infarction size, in the ISDN treated group, in comparison to that of non treated group, though the result was not statistically significant. But, many of the in-hospital complications were significantly less in the treated group. After a critical analysis of the result it was concluded that a statistically insignificant result, as regard reduction of infarction size in AMI, cannot always exclude the utility of a drug therapy in AMI.

Creatine Kinase↗

[Effects of isosorbide dinitrate on systemic haemodynamics, regional coronary blood flow and ST-segment. A study on normal and/or ischaemic dog heart (author's transl)].

In dogs, isosorbide dinitrate (ISDN) reduced venous return, and in spite of mild tachycardia the cardiac output fell by reduction of stroke volume. Depending on modalities of administration, the drug had little or no influence on systemic arterial pressure. Cardiac inotropism remained unchanged. Heart work was consistently reduced. During temporary occlusion of the left coronary artery, ISDN had little effect on regional blood flow in normal myocardial areas but increased transmural blood flow and the endocardium/epicardium perfusion ratio in ischaemic areas. The redistribution of coronary blood flow produced by ISDN to the benefit of ischaemic areas was accompanied by a simultaneous decrease in the intensity of electric ischaemia.

Animals↗

Isosorbide dinitrate in plasma and dialysate during haemodialysis.

In 10 patients with end stage renal disease on regular haemodialysis the plasma concentrations and dialyzer clearance of isosorbide dinitrate (ISDN) were determined after an oral dose of a retarded release formulation of 60 mg ISDN. The maximal plasma concentration of ISDN 2-7 h after oral administration was higher (14 ng/ml) than has been reported in healthy volunteers. The haemodialyzer clearance of ISDN was 92.4 ml/min at a blood flow of 200 ml/min and dialysate flow of 500 ml/min. During a 5-h haemodialysis an average of 0.3 mg ISDN was removed from the patient's circulation, representing about 0.5% of the administered dose and about 3% of the available drug in the circulation. No influence of haemodialysis on the plasma level of ISDN was found.

Aged↗