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PubMed2000

Isosorbide-2-mononitrate reduces the consequences of myocardial ischaemia, including arrhythmia severity: implications for preconditioning.

The effects of the intracoronary administration of isosorbide-2-mononitrate (ISMN; 3 microg kg(-1) min(-1)), a major metabolite of isosorbide dinitrate, were examined in chloralose-urethane anaesthetized dogs before and during a 25 min, acute occlusion of the left anterior descending coronary artery. The only significant haemodynamic effects of ISMN administration were a slight (-11 +/- 2 mmHg) decrease in arterial blood pressure and a decrease (< 12%) in diastolic coronary vascular resistance. Coronary occlusion in the presence of ISMN led to a markedly reduced incidence and severity of ventricular arrhythmias compared to those in control, saline-infused dogs. There were fewer ectopic beats (62 +/- 35 versus 202 +/- 72; p < 0.05), a lower incidence (25% versus 75%; p < 0.05) and number of episodes (0.7 +/- 0.4 versus 4.3 +/- 2.1; p < 0.05) of ventricular tachycardia and fewer dogs fibrillated during the ischaemic period (17% versus 82%; p < 0.05). More dogs given ISMN survived the combined ischaemia-reperfusion insult (50% versus 0%; p < 0.05). Changes in ST-segment elevation (recorded by epicardial electrodes) and in the degree of inhomogeneity of electrical activation within the ischaemic area were much less pronounced throughout the occlusion period in dogs given ISMN. These results add weight to the hypothesis that the previously reported antiarrhythmic effects of ischaemic preconditioning, and of the intracoronary administration of nicorandil, involve nitric oxide.

Animals↗
PubMed1983

Hepatic extraction of isosorbide dinitrate in cardiac patients.

Hepatic extraction of organic nitrates, including that of isosorbide dinitrate (ISDN), has been thought to be nearly complete in man but has never been directly measured. We examined the time course of plasma ISDN and metabolite concentrations in arterial and hepatic venous blood in four cardiac patients receiving an intravenous ISDN infusion. Apparent hepatic extraction of ISDN was high (90%) at the beginning of infusion but fell to about 44% 1 hr after termination of infusion. The decrease in ISDN concentration gradient across the liver correlates with an increase in plasma isosorbide-5-mononitrate concentration, but a cause-and-effect relationship resulting from metabolite inhibition cannot be established. The time-averaged hepatic extraction of ISDN, at about 70%, agreed with its oral bioavailability in patients.

Biological Availability↗
PubMed1990

Effects of isosorbide dinitrate on the pattern of arterial blood flow in healthy human subjects.

1. Blood velocity measurements have been made in the superficial femoral artery, 10 cm downstream of the common femoral artery bifurcation, in healthy human subjects, using a multi-channel Doppler ultrasound device. 2. In a randomized double-blind protocol, the effects of isosorbide dinitrate were examined during a 2 h period. 3. The changes induced by isosorbide dinitrate include: (i) an increase in the width of the artery and a reduction in brachial arterial blood pressure, implying relaxation of arterial smooth muscle; (ii) an increase in reverse flow and a decrease in time-averaged mean velocity associated with a relatively small decrease of the velocity excursion during the cardiac cycle, implying an increase in flow pulsatility; and (iii) an alteration of the flow pattern both in the core and near the vessel walls.

Adult↗
PubMed2002

Fissurectomy and isosorbide dinitrate for chronic fissure in ano not responding to conservative treatment.

BACKGROUND: Although lateral sphincterotomy heals chronic fissure in ano in over 90 per cent of cases it is a surgical technique with inherent complications. To avoid such complications, chronic fissure in ano was treated by fissurectomy in this study. To enhance postoperative tissue perfusion allowing stable wound healing, fissurectomy was combined with temporary chemical sphincterotomy by a nitric oxide donor cream. METHODS: Seventeen consecutive patients (ten women) with chronic fissure in ano not responding to conservative management underwent diathermy fissurectomy. After operation patients used a 1 per cent isosorbide dinitrate cream. Postoperative follow-up continued until wounds had healed, at which time anal endosonography was performed. A telephone inquiry into fissure recurrence and continence status was made. RESULTS: Seventeen patients underwent fissurectomy, without postoperative complications. All wounds had healed within 10 weeks. No fissure recurrence was seen after a median follow-up of 29 months. Histopathology showed non-specific scar tissue without signs of internal anal sphincter fibrosis. Postoperative endosonography showed no evidence of new internal sphincter defects. CONCLUSION: In the treatment of chronic anal fissure not responding to chemical sphincterotomy with nitric oxide donors, fissurectomy in combination with isosorbide dinitrate cream may be a sphincter-sparing surgical technique.

Adult↗
PubMed2002

Allergic reactions to glyceryl trinitrate and isosorbide dinitrate demonstrating cross-sensitivity.

Glyceryl trinitrate (nitroglycerin) has been in use for relief of angina for over a hundred years, but allergic reactions to it or to other organic nitrates rarely feature in the medical literature. Most of the case reports describe reactions to transdermally applied nitroglycerin. We report a case of a localized allergic reaction to nitroglycerin transdermal patches that developed when these were worn for the first time after 7 days of uneventful treatment with intravenous isosorbide dinitrate. The reaction evolved into a severe and generalized maculopapular rash with facial swelling when intravenous isosorbide dinitrate was re-administered 10 days later. Subsequent patch testing with a transdermal nitroglycerin patch and a placebo nitroglycerin-free patch provoked a reaction to the nitroglycerin patch but not to the placebo, thus excluding allergy to other constituents of the nitroglycerin patch.

Administration, Cutaneous↗
PubMed2002

Banding ligation versus nadolol and isosorbide mononitrate for the prevention of esophageal variceal rebleeding.

BACKGROUND & AIMS: beta-blockers and banding ligation are effective in the prevention of variceal rebleeding. However, the relative efficacy and safety remains unresolved. METHODS: One hundred twenty-one patients with a history of esophageal variceal bleeding were enrolled. Patients were randomized to undergo regular endoscopic variceal ligation (EVL group, 60 patients) until variceal obliteration, or drug therapy by using nadolol plus isosorbide mononitrate (N+I group, 61 patients) during the study period to prevent rebleeding. RESULTS: After a median follow-up period of 25 months, recurrent upper gastrointestinal bleeding developed in 23 patients in the EVL group and 35 patients in the N+I group (P = 0.10). Recurrent bleeding from esophageal varices occurred in 12 patients (20%) in the EVL group and 26 patients (42%) in the N+I group (relative risk = 0.45; 95% confidence interval, 0.24-0.85). The actuarial probability of rebleeding from esophageal varices was lower in the EVL group (P = 0.01). The multivariate Cox analysis indicated that the treatment was the only factor predictive of rebleeding. Treatment failure occurred in 8 patients (13%) in the EVL group and 17 patients (28%) in the N+I group (P = 0.01). Fifteen patients in the EVL group and 8 patients of the N+I group died (P = 0.06). Complications occurred in 17% of the EVL group and in 19% of the N+I group (P = 0.6). CONCLUSIONS: Our trial showed that ligation was more effective than nadolol plus isosorbide-5-mononitrate in the prevention of variceal rebleeding, with similar complications in both treatment modalities. However, there is no significant difference in the survival rate between the 2 groups.

Adult↗
PubMed2004

Comparison of the relaxant effects of a new oxime-nitrate derived from isosorbide-5-mononitrate and the parent drug.

The transformation of isosorbide-5-mononitrate (CAS 16051-77-7, IS-5-MN) to the corresponding keto derivative and its ketoxime (oxime-nitrate derivative of isosorbide) is described. The effects of IS-5-MN and the new oxime-nitrate (ON) on the endothelial and smooth muscle cells of isolated rings of the rat superior mesenteric artery were examined. After contraction induced by phenylephrine, IS-5-MN (10(-8)-10(-4) mol/l) caused a concentration-dependent relaxation. Removal of the vascular endothelium strongly potentiated this effect. On the other hand, the new ON (10(-8)-10(-4) mol/l) was a more potent relaxant than the parent drug, but its effect was not dependent on the vascular endothelium. The inhibitory effect of the artery without endothelium to the new ON was more pronounced than that to IS-5-MN. The mechanism of the relaxant effect of the new compound consisted in the liberation of nitric-oxide (NO) which activated guanylate cyclase (GC), upon which accumulation of cyclic guanosine monophosphate (cGMP) occurred, which was the second messenger leading to relaxation. Tolerance to the frequent applications of the new compound was not observed, moreover a slight increase of the effect was detected in comparison with IS-5-MN for which tolerance was observed to a great extent. Clinically, the new ON could be favorable in all types of angina in comparison with the classical IS-5-MN.

Animals↗
PubMed1998

Endoscopic papillary dilation by balloon and isosorbide dinitrate drip infusion for removing bile duct stone.

BACKGROUND: Endoscopic papillary dilation (EPD) by balloon in the management of bile duct stones has recently been claimed to be effective for removing bile duct stones. METHODS: Without endoscopic sphincterotomy, we attempted to remove large or multiple bile duct stones through EPD combined with drip infusion of isosorbide dinitrate in 35 patients. Isosorbide dinitrate, at a rate of 5 mg/h, was administered intravenously, and a balloon dilator with a 10-mm diameter was inflated within 3 min across the papilla. Stones were then smashed using a mechanical lithotriptor, and the fragments were extracted with a basket or the balloon. RESULTS: Extraction of stones was successful in 33 (94%) of 35 patients by the combined therapy. Two of them (6%) developed mild pancreatitis. CONCLUSION: EPD combined with medical sphincter dilation was effective for large and multiple bile duct stones.

Adult↗
PubMed1988

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↗
PubMed1993

Efficacy of isosorbide-5-mononitrate versus nifedipine in preventing spontaneous and ergonovine-induced myocardial ischaemia. A double-blind, placebo-controlled study.

This study was designed to assess the efficacy of oral nifedipine as compared to oral isosorbide-5-mononitrate in the prevention of spontaneous and induced vasospastic myocardial ischaemia. Twenty-one patients admitted to the Coronary Care Unit as a result of angina at rest underwent both Holter monitoring and an echo-ergonovine test during placebo and following either isosorbide-5-mononitrate or nifedipine according to a double-blind randomized trial. Both drugs caused a statistically significant reduction in spontaneous (87% and 95%, respectively) and induced ischaemic attacks (66% and 75%, respectively). No significant difference was found between the two drugs.

Administration, Oral↗
PubMed1988

Control of the anti-thrombogenic endothelial cell defense by short- and long-term exposure of cultured endothelial cells to isosorbide nitrates.

Anti-thrombogenic endothelial cell defense (ATECD) refers to the overall properties that enable the endothelium to prevent circulating blood platelets adhering to, or aggregating on the vascular wall. The basic characteristics of ATECD have been further investigated in cultured arterial endothelial cells (EC). Freshly obtained endothelium cells (ECs) and confluent, quiescent Passage 0 ECs, similarly expressed ATECD, whereas subconfluent dividing ECs and senescent ECs both elicited a markedly lowered ATECD. When ECs were successively exposed to fresh platelets, ATECD was progressively exhausted until a plateau (50% of control ATECD) was reached after the third exposure of ECs to platelets. Similarly, platelet response to the aggregating agent was markedly lowered after the first exposure of ECs to platelets, whereas such an inhibition of platelet activity by ECs was much less pronounced in subsequent exposure of ECs to fresh platelets. Under acute pharmacological circumstances, isosorbide dinitrate (ISDN) antiplatelet activities were found to be profoundly magnified by ECs, thus revealing an EC-mediated antiplatelet activity for ISDN, but not for its mononitrate metabolites, 2-ISMN and 5-ISMN. Long-term exposure of ECs to isosorbide nitrates (ISNs) revealed that ISDN, as well as 2-ISMN elicited an ATECD-stimulation priming effect on ECs, although in the presence of 5-ISMN (a poor antiplatelet agent) the ISN overall effect upon ATECD was less than 50% of what would have been expected by cumulating individual ISN effects. It is concluded that ATECD provides a highly differentiated function for ECs; the ATECD mechanisms involve antiaggregating factors that may be trapped by platelets; and, finally, ATECD may be stimulated by ISDN both under acute and under chronic pharmacological circumstances.

Animals↗
PubMed1991

Comparison of anti-platelet properties of molsidomine, isosorbide-5-mononitrate and placebo in healthy volunteers.

The purpose of the present work was to investigate the ex vivo platelet-inhibiting properties of the nitric oxide-containing vasodilator, molsidomine, and the organic nitrate, isosorbide-5-mononitrate, in comparison with placebo. Ex vivo platelet aggregation in 11 healthy volunteers was measured before, as well as 30 and 60 min after, the intake of either 4 mg molsidomine, 20 mg isosorbide-5-mononitrate (ISMN) or placebo in a randomized double-blind fashion. The release of thromboxane was also determined. Threshold doses of platelet-activating factor (PAF) to induce irreversible aggregation were significantly increased by 100 and 120% 30 and 60 min after molsidomine. Slopes of aggregation curves (aggregation induced with 50 and 200 nM PAF) were significantly reduced after molsidomine (P less than 0.01). Small platelet-inhibiting effects were also observed after ISMN and after placebo intake. The release of thromboxane was not influenced when platelets were maximally stimulated either during clotting of whole blood or during aggregation of platelet-rich plasma with a high dose of PAF. Thromboxane release with a low dose of PAF was reduced 30 and 60 min after drug intake, independent of whether molsidomine, ISMN or placebo was applied. The data indicate that the usual clinical doses of molsidomine, but not of ISMN inhibit platelet aggregation in healthy man.

Adult↗
PubMed1983

Intravenous isosorbide dinitrate in acute left ventricular failure--a dose--response study.

The haemodynamic effects of intravenous isosorbide dinitrate (Cedocard) in patients with severe acute left ventricular failure have been assessed using incremental infusion rates from 50 to 800 micrograms min-1. For most patients most of the fall in pulmonary arterial diastolic pressure occurred by 200 micrograms min-1, with little further fall at higher doses. At 200 micrograms min-1 pulmonary arterial diastolic pressure fell from 29 to 23 mgHg (P less than 0.001), there was no significant change in cardiac index (1.9 to 2.0 L min-1 m-2) or heart rate (108 to 108 beats min-1). Despite high doses, no side effects were observed. Intravenous isosorbide dinitrate is effective and safe in the management of acute severe left ventricular failure. In most patients an infusion rate of about 200 micrograms min-1 produces optimal haemodynamic effects.

Adult↗
PubMed1988

Comparison of the antianginal efficacy of isosorbide dinitrate (ISDN) 40 mg and verapamil 120 mg three times daily in the acute trial and following two-week treatment.

Fourteen male patients with exertion-related angina pectoris and reproducible ST-segment depression on stress testing were each treated with isosorbide dinitrate (ISDN) 40 mg three times daily, verapamil 120 mg three times daily and placebo three times daily for two weeks according to a double-blind cross-over protocol. The mean improvement of exercise-induced ST-segment depression amounted to 73% on the first day of ISDN treatment (P less than 0.001) and to 54% following acute administration of verapamil (P less than 0.001). On the last day of continuous treatment, the antianginal efficacy of ISDN was somewhat mitigated (reduction of ST-segment depression: 54%; P less than 0.001), while the effect of verapamil remained unchanged (55%, P less than 0.001). The double product (heart rate x systolic blood pressure) at the end of stress testing decreased most pronouncedly on day 1 of ISDN treatment (-21%; P less than 0.01). On chronic testing, both drugs similarly influenced this parameter: 10-11% (P less than 0.05). The mean global ejection fraction (EF) assessed by gated blood pool scintigraphy on day 13 showed a stress-induced fall from 49 to 44% (P less than 0.05) after the administration of placebo. The respective values with ISDN were 53% at rest and 52% on exercise (n.s.), and after giving verapamil 50% and 47% (n.s.). Thus, ISDN 40 mg and verapamil 120 mg displayed beneficial anti-ischaemic effects in patients with stable exertion-related angina pectoris after acute and chronic administration. The efficacy of ISDN declined somewhat in the course of the two-week treatment, whereas that of verapamil remained unchanged. Beneficial effects of both drugs were also demonstrated with regard to the rate-pressure product. Isosorbide dinitrate 40 mg and verapamil 120 mg administered three times daily can be recommended for the acute and chronic therapy of patients with stable angina.

Acute Disease↗
PubMedDate not supplied

Arteriolar or venous dilatation in left ventricular failure following acute myocardial infarction: a haemodynamic trial of hydralazine and isosorbide dinitrate.

We undertook a randomised between-group comparison of the haemodynamic effects of arteriolar dilatation and venodilatation in 20 males, following acute myocardial infarction, with persisting left ventricular failure after pretreatment with intravenous frusemide. All had radiographic pulmonary oedema and a pulmonary artery occluded pressure (PAOP) exceeding 15 mm Hg. The average cardiothoracic ratio was 52% (range 48-65%). Following control haemodynamic measurements, 10 patients received intravenous hydralazine (0.15 mg/kg) and 10 received intravenous isosorbide dinitrate infusion (50-200 micrograms/kg/h). Subsequent measurements were made at 30, 60, and 90 min. Isosorbide dinitrate reduced the PAOP by 3 mm Hg (p less than 0.01) and the mean systemic arterial pressure by 9 mm Hg (p less than 0.05) without significant change in the heart rate, cardiac output, or systemic vascular resistance. In contrast, hydralazine reduced the PAOP and systemic arterial pressure by a similar amount, but this was accompanied by a reduction in the systemic vascular resistance (p less than 0.01) and an increase in the cardiac output (p less than 0.01), heart rate (p less than 0.01), and stroke volume (p less than 0.01). This randomised study defines the contrasting haemodynamic results of arteriolar dilatation and venodilation in patients with resistant left ventricular failure following acute myocardial infarction. The different pharmacodynamic effects of these two methods of circulatory manipulation suggest that they are not mutually exclusive and together may offer therapeutic advantages.

Aged↗
PubMed1992

Modulation of inotropic therapy by venodilation in acute heart failure: a randomised comparison of four inotropic agents, alone and combined with isosorbide dinitrate.

The effects of four inotropic agents with differing ancillary properties [a cardiac glycoside (digoxin), a combined alpha- and beta-adrenergic agonist (dobutamine), a beta-adrenergic agonist (prenalterol), and a phosphodiesterase inhibitor (amrinone)] alone and with subsequent addition of isosorbide dinitrate were compared in 48 consecutive acute myocardial infarction patients with radiographic and haemodynamic (pulmonary artery occluded pressure greater than 18 mm Hg) left ventricular failure. All agents with the exception of dobutamine reduced the elevated left heart filling pressure; only digoxin and dobutamine augmented the cardiac stroke volume index. All drugs except digoxin reduced the SVRI; an arteriolar constrictor response was evident 60 min after digoxin and a tachycardia resulted after combined alpha- and beta- and beta-adrenergic stimulations (dobutamine and prenalterol, respectively). The addition of isosorbide dinitrate reversed the inotrope-induced elevations of systemic arterial pressure and resulted in additional reductions in left heart filling pressure. These data suggest that, in the absence of substantial venodilator properties in an inotropic compound, reduction in elevated left heart filling pressure is not achieved with inotropic therapy alone in acute left ventricular failure and combining a venodilator may be haemodynamically advantageous.

Adult↗
PubMed1998

Clinical comparison of antiischemic efficacy of isosorbide dinitrate and molsidomine.

In 16 patients with documented coronary artery disease, the extent and duration of acute antiischemic and hemodynamic effects of monotherapies with 120 mg of sustained-release isosorbide dinitrate once daily and 8 mg of sustained-release molsidomine 3 times daily were compared according to a randomized, double-blind, cross-over and placebo-controlled protocol including exercise testing for assessment of ST-segment depression (ST) at an identical workload and determination of plasma concentrations of both substances. Up to 8 h after dosing in the morning, more marked and sustained effects were observed with the nitrate (ST at 2 h, -82%; p < 0.001; at 8 h, -64%; p < 0.01) than with molsidomine (2 h, -68%; p < 0.001; at 8 h, -9%; NS). At 12 h, no more meaningful actions were detectable with isosorbide dinitrate (-13%, NS) despite plasma concentrations still within a range otherwise considered therapeutically effective, whereas with molsidomine, at 4 h after renewed dosing, this parameter was reduced by 38% (p < 0.01). However, therapeutic coverage over a 24-h period could be demonstrated on neither regimen, in the case of the nitrate because of the development of early tolerance, and in the case of molsidomine with its meaningfully shorter half-life because of the necessity of increasing the dosing frequency even further. No meaningful adverse effects were observed with either regimen. Nonresponders, overall a minority on one treatment, responded completely to the alternative regimen and vice versa.

Blood Pressure↗
PubMed1987

The acute effects of intravenous isosorbide dinitrate during cardiac surgery.

The acute effects of intravenous isosorbide dinitrate during open heart surgery were studied in 15 adult patients. Consistent and significant (p less than 0.001) reductions in pulmonary vascular resistance (25% before, 23% after, cardiopulmonary bypass) and mean pulmonary artery pressure (14% before, 13% after, cardiopulmonary bypass) were observed in the absence of significant changes in cardiac index, mean systemic arterial pressures or right or left atrial filling pressures. These findings indicate that after cardiopulmonary bypass, when right ventricular dysfunction with raised pulmonary vascular resistance may occur, selective reduction of right ventricular afterload with isosorbide dinitrate may prove beneficial.

Blood Pressure↗