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PubMed1995

[Intracoronary isosorbide mononitrate versus placebo. A double-blind study with quantitative coronary angiography].

PURPOSE: To evaluate the vasodilation effect of intracoronary isosorbide mononitrate (ISMN) on the coronary arteries, systolic aortic pressure (SAP) and cardiac rhythms. METHODS: Forty patients aged 61 (40-72) years, 30 (75%) male, were randomized to receive on a double blind fashion, 20 mg of ISMN or placebo. The two groups had similar baseline characteristics. Quantitative coronary arteriography [by cardiovascular measurement system (CMS)] and SAP were compared before and after ISMN. We also observed the cardiac rhythm. RESULTS: There were no arrhythmias. Reference vessel diameter increased from 2.6 +/- 0.5 mm before to 2.9 +/- 0.4 mm after ISMN and did not change, mean 2.9 +/- 0.5 mm, before and after placebo. There was a difference between ISMN and placebo (p < 0.0001). There was no difference in the SAP change between the two groups, 4.2 +/- 0.7 mmHg with ISMN and 1.8 +/- 0.5 mmHg with placebo (p = NS). CONCLUSION: ISMN promotes a safe and effective vasodilation of the coronary arteries with no major effects in cardiac rhythm and systolic aortic pressure.

Adult↗
PubMed1977

Blood and tissue levels of [14C]isosorbide dinitrate after oral and intravenous administration to rat.

Rat blood and various tissues were analyzed for levels of isosorbide dinitrate (ISDN), an antianginal drug, after the administration of 14C-labeled compound. Unaltered [14C]ISDN was found in all tissues analyzed and in the circulating blood for up to 4 hours after p.o. or i.v. administration. These results clearly show that ISDN is not completely degraded in a single pass through the liver after either route of administration. ISDN concentration (nanograms of ISDN per gram wet weight of tissue) in vascular tissue were significantly greater than other tissues or the blood.

Administration, Oral↗
PubMed1995

Mechanism of ITF 296-induced vasorelaxation compared to nitroglycerin and isosorbide dinitrate: relationship between relaxation of rabbit aorta and tissue cGMP.

The vasorelaxant properties of ITF 296, a new mononitrate ester, were studied in endothelium-denuded rabbit aortic rings and were compared to nitroglycerin (NTG) and isosorbide dinitrate (ISDN). In norepinephrine-contracted arteries, ITF 296, NTG, and ISDN elicited maximal and concentration-dependent vasodilation with pD2 values of 7.07, 7.95, and 7.2, respectively. The concentration-relaxation curves of ITF 296 were shifted markedly to the right (p < 0.01) in the presence of 10 microM methylene blue (MB) and 3 microM oxyhemoglobin (HbO2), whereas a significant shift to the left (p < 0.01) was observed in the presence of 10 microM M&B-22948 (a specific cGMP phosphodiesterase inhibitor). When KCl (60 mM) was used as contracting agent, a weak relaxation was observed with ITF 296, suggesting the absence of activity on the voltage-dependent Ca2+ channels. A time-dependent increase in cGMP content and a positive correlation between cGMP and vasodilation were observed in norepinephrine-contracted arteries after exposure to a single submaximal concentration of ITF 296 (1 microM). Similar results were obtained with NTG and ISDN, although NTG was found to be more active than ITF 296 or ISDN. The presence of either MB or HbO2 almost completely abolished the increase in cGMP induced by ITF 296, whereas a further increase in cGMP was observed in the presence of isobutylmethylxanthine. No changes in cAMP levels were observed after exposure of the tissues to a concentration of ITF 296 that induced significant elevation in the cGMP content. In the presence of L-cysteine, ITF 296 stimulated semipurified rat lung guanylate cyclase at higher concentrations than those of NTG or ISDN, probably because of its lower rate of nitric oxide (NO) release. These results suggest that, in common with the reference compounds NTG and ISDN, ITF 296-induced vasorelaxation in rabbit aortic rings is mediated by an NO-cGMP mechanism.

Animals↗
PubMed1977

[Effect of sublingual isosorbide dinitrate on hemodynamics in coronary patients with and without congestive heart failure (author's transl)].

In 17 patients with coronary heart disease, hemodynamic measurements were performed before and after sublingual application of 10 mg isosorbide dinitrate (ISDN). 10 patients showed signs of heart failure with pulmonary congestion and a left ventricular filling pressure above 15 mmHg, resting hemodynamics were normal in 7 patients. Eight of the patients with left ventricular failure had sustained acute myocardial infarctions the size of which was assessed by serial determinations of serum creatine phosphokinase. Application of ISDN resulted in a significant decrease of systemic and pulmonary artery pressures and pulmonary capillary wedge and right atrial pressures of patients both with and without left ventricular failure. Cardiac index and stroke index as well as systemic and pulmonary resistances did not change significantly. ISDN did not affect left ventricular stroke work in patients with elevated filling pressures; however, a decrease of normal filling pressures was associated with a decrease of stroke work. Thus, in coronary patients with chronic congestive heart failure, sublingual application of nitrates results in a beneficial hemodynamic unloading. However, if the acute infarct size is taken into account, it can be demonstrated that hemodynamic improvement after ISDN--judged by the relation stroke work/filling pressure--becomes less pronounced with increasing infarct size.

Adult↗
PubMed1997

[Inhibitory effect of isosorbide dinitrate on whole blood aggregation].

Isosorbide dinitrate (ISDN) has an inhibitory effect on platelet aggregation through the generation of nitric oxide (NO). We examined the effect of ISDN on whole blood aggregation using an impedance aggregometer. Blood samples were obtained from 16 patients with acute myocardial infarction and 4 patients with angina pectoris before and after an intravenous administration of ISDN during coronary arteriography. Whole blood obtained from normal healthy donors was used for an in vitro study. Whole blood aggregation after administration of ISDN was significantly inhibited compared to that before administration (36.1 +/- 8.3 vs 43.7 +/- 8.4 omega, p < 0.001), and cyclic guanine monophosphate (c-GMP) concentration increased (5.56 +/- 2.0 vs 5.14 +/- 1.86 p mol/ml, p < 0.05). The inhibitory effect of ISDN was also observed in the in vitro study, in which the effective concentration of ISDN corresponded to the blood level of ISDN (> or = 10(-7) mol) in the clinical setting. The inhibitory effect of ISDN was diminished by the addition of methylene blue or NG-monomethyl-L-arginine monoacetate in the exo vivo and in vitro studies. The concentration of c-GMP was increased by the addition of ISDN to platelets and white blood cell suspended plasma compared to the control (1.93 +/- 0.50 vs 1.77 +/- 0.42 p mol/ml, p < 0.05), but there was no significant difference when ISDN was added to platelet-rich plasma. These results suggest that ISDN inhibits whole blood aggregation through NO generation and white blood cells are important in the mechanism of ISDN action.

Angina Pectoris↗
PubMed1977

[Sublingual isosorbide dinitrate-induced severe hypotension, bradycardia and prelypothymia in patients with acute myocardial infarction (author's transl)].

100 patients with acute myocardial infarction were given 5 mg of sublingual isosorbide dinitrate within 36 hours by the onset of their symptoms. 86 patients did not show any unusual effect after the administration of the drug; their heart rate was only slightly increased and their arterial pressure slightly reduced. 14 patients developed severe systemic arterial hypotension, associated with absolute or relative bradycardia, within 30 minutes of receiving the drug. All the patients complained of fainting and sweating, 1 patient developed a syncope. Symptoms were relieved by raising patients legs in 10 cases, by 0.5 mg Atropina e.v. in 4 cases, 1 case required also external cardiac massage. There was no significant difference between the two groups as regard to the location of myocardial infarction nor to the functional class (according to Killip classification). Possible mechanism producing bradycardia, hypotension and lipothymia after nitrates administration are considered. A vagally mediate reflex possibly elicited by a fall in venous return is the most acceptable hypothesis. The study emphasizes the importance of carefull observation of patients receiving sublingual nitrates during acute myocardial infarction, and the rapid response of bradycardia, hypotension and lipothymia following nitrates administration, to a simple therapy, which avoids other potentially hazardous treatments.

Aged↗
PubMed1997

[Pharmacokinetics of isosorbide dinitrate examined by physiologically-based pharmacokinetic model].

To make a physiologically-based pharmacokinetic model of isosorbide dinitrate (ISDN), the author infused ISDN at 1, 10, 30 micrograms.kg-1.min-1 into anesthetized rabbits and measured concentrations of ISDN and its metabolites (2-ISMN and 5-ISMN) in plasma and in the brain, liver as well as fat tissue. There was the accumulation of ISDN in the brain and fat tissue. There was no significant difference in concentrations of ISDN between the plasma and liver, or in concentrations of its metabolites among plasma, and the tissues of the brain, liver and fat. Using these informations, the author constructed a physiologically-based pharmacokinetic model to human and estimated values were compared with observed values to determine the validity of the model. There was no remarkable differences between the estimated values and observed values. This suggests the validity of the model. The plasma concentrations of ISDN estimated by this model, showed a linear increase (Y = 25 X) with the infusion rate less than 6.0 micrograms.kg-1.min-1. The accumulation of ISDN, especially in the brain was suggested by this model.

Adipose Tissue↗
PubMed1997

[The possibility of the development of isosorbide dinitrate and nifedipine withdrawal syndromes in patients with stable stenocardia of effort].

Exercise tests were performed in 18 patients with stable angina of effort treated with isosorbide dinitrate (ID) or nifedipine (NF) to see whether sharp discontinuation of the above drugs may entail withdrawal syndrome. Exercise tolerance declined 21 and 24 hours after the last administration of NF, 13 and 18 hours after that of ID. Compared to NF, ID tolerance decreased in a less degree. Some of the patients experienced myocardial ischemia in the course of the exercise tolerance tests, there were more frequent anginal episodes, arterial pressure rose. For ID withdrawal syndrome manifested weaker than for NF.

Adult↗
PubMed1997

[Molsidomine and isosorbide dinitrate: a comparative trial of tolerance in long-term intake by IHD patients with stable angina of effort].

Potential tolerance to isosorbide dinitrate (ID) and molsidomine (M) was studied in 18 ischemic heart disease (IHD) patients with stable angina of effort entered in a double blind cross-over trial. Each drug was administered for 3 weeks 4 times a day in individual effective dose. Single doses of ID and M were similar by effectiveness, but after 3 weeks of regular intake their efficacy fell, ID becoming less potent than M. For ID, tolerance after long-term intake manifested in 7 out of 18 patients, for M--in 5 out of 18. Complete tolerance was registered in 3 of 18 and 1 of 18 patients, respectively. Thus, tolerance is possible for the two drugs, but for M it is less pronounced.

Adult↗
PubMed1998

[Actions of pentaerithritol tetranitrate, isosorbide mononitrate and placebo on headache and ability to work of healthy subjects].

In a randomised, double-blind, four-way crossover study, 24 healthy volunteers received 240 mg/d pentaerithritol tetranitrate (PETN, CAS 78-11-5), 150 mg/d PETN, 60 mg/d isosorbide mononitrate slow release (ISMN, CAS 16051-77-7) or placebo in each study period for two days. Headache and disability to work were self-rated six times per day; individual measurements were combined to total scores. ISMN caused headaches more frequently (in approx. 90% of volunteers) and more severe (average total score 15.2) and a greater disability (average total score 6.0) than the high or low PETN-dosage (both in approx. 50%, headache score 4.9 or 6.4, disability score 1.1 or 2.1, resp.) and placebo (in approx. 10%, headache 0.8, disability 0), all these differences were statistically significant (p < 0.01, Wilcoxon). The high PETN-dosage showed a non-significant trend to produce fewer systemic side effects than the low PETN-dosage (not vice versa). With ISMN six volunteers prematurely terminated the study period and one volunteer who was replaced withdrew from the entire study due to side effects; all volunteers completed the study periods with the other medications.

Adult↗
PubMed1998

Anti-ischemic and anti-anginal effects of controlled-release and conventional isosorbide-5-mononitrate in stable angina pectoris.

BACKGROUND: A controlled-release formulation of isosorbide-5-mononitrate (5-ISMN) can be administered once daily to lower the peak plasma concentration of 5-ISMN to avoid peak-related side-effects, prolong duration of action and produce predictable and reproducible plasma concentrations of 5-ISMN. This study was undertaken to compare the anti-anginal and anti-ischemic efficacy of controlled-release 5-ISMN 60 mg administered once daily and conventional 5-ISMN 20 mg given twice daily in patients with stable angina pectoris. METHODS: In 44 patients with stable angina pectoris, controlled-release 5-ISMN and the conventional formulation of 5-ISMN were tested in an open, randomized, cross-over study. The study started with a one-week run-in period, during which nitrates were withdrawn. Patients were then randomly allocated to two-week treatment with controlled-release 5-ISMN 60 mg each morning followed by a one-week placebo washout and then a two-week treatment with the conventional formulation of 5-ISMN 20 mg twice daily, or vice versa. Treadmill exercise testing was performed at the end of the placebo run-in and washout periods and at the end of both active treatment periods. RESULTS: Thirty-nine patients completed the study and were included in the statistical evaluation. Total exercise duration and time to appearance of 1-mm ST depression increased significantly after two weeks of treatment with both drugs compared with placebo. However, the time to onset of chest pain increased significantly only after therapy with controlled-release 5-ISMN. Moreover, controlled-release 5-ISMN produced a more pronounced improvement in total exercise duration than the conventional formulation of 5-ISMN after two weeks of therapy. Adverse events were reported by five (13%) patients receiving controlled-release 5-ISMN and by the same percentage of patients receiving conventional 5-ISMN therapy; most of these events were headache and/or dizziness. CONCLUSIONS: Treatment with 5-ISMN in the controlled-release formulation of 60 mg administered once daily appears more effective in improving total exercise duration and increasing the time to onset of chest pain than the conventional formulation of 5-ISMN in patients with stable angina pectoris. Once-daily administration of controlled-release 5-ISMN is well tolerated and convenient.

Aged↗
PubMed1976

[Prophylactic effect of isosorbide dinitrate on postoperative cardiac complications (author's transl)].

Isosorbide dinitrate (ISD) was administered before, during and after 178 operations performed on 127 patients with arterial occlusive disease. Its influence on postoperative myocardial infarction, heart failure and mortality was tested by comparison with 188 operations performed on 140 patients with hypertension and/or old myocardial infarction receiving no ISD prophylaxis. Risk of cardiac complications was similar in both groups. Mortality in the ISD-treated group was significantly lowered as compared with the control group and was about half of the overall mortality in patients with arterial occlusive disease operated on at our hospital over the past 10 years. This difference depended partly on the influence of ISD on cardiac complications. Post-operative myocardial infarction during ISD prophylaxis occurred in 0.6% of cases as compared with 3.7% in the control group (p less than 0.05), whilst the respective values for postoperative heart failure were 5.7% and 18.2% (p less than 0.001). Both complications are related to absolute or relative hypoxia during the post-operative stress period. ISD is effective by lowering cardiac preload and afterload and thereby diminishing myocardial oxygen demand. ISD is the drug of choice for surgical patients since it provides a steady and long-lasting effect after sublingual absorption. ISD prophylaxis during the perioperative period is indicated in cases with coronary artery disease and with increased cardiac preload or afterload.

Arterial Occlusive Diseases↗
PubMedDate not supplied

Comparative evaluation of three dosages of slow-release isosorbide dinitrate (60, 80, 100 mg) in chronic angina of the aged.

In a single-blind, placebo-controlled study the acute and chronic antianginal effects of three slow-release (SR) new formulations of isosorbide dinitrate (ISDN 60, 80, 100 mg) have been comparatively evaluated in a group of aged affected by chronic stable effort-induced angina. Compared to placebo, overall the active dose paritetically improved the effort tolerance up to 24 h after the first assumption. In the time course of the trial (2 and 4 weeks) the resting hemodynamic changes induced by the first dose were partially blunted without affecting the exercise related-parameters. Also if plasma levels of ISDN and of its metabolites did not correlate to the degree of physical improvement, the peak increase in effort tolerance was observed under 100 mg treatment. Mild to moderate transient headache was experienced by 50% of actively treated and by 20% of placebo treated patients and no other serious adverse effects have been noted. One may conclude that ISDN in slow-release formulations of 60-100 mg isan effective, safe and well tolerated medication in the management of angina in the aged.

Clinical Trial↗
PubMed1997

Isosorbide nitrates, nitroglycerin, and sodium nitroprusside induce vasodilation concomitantly with inhibition of carbonic anhydrase I in erythrocytes.

This study describes the relationship between nitroglycerin, isosorbide dinitrate, sodium nitroprusside, and carbonic anhydrase I, as well as the involvement of this carbonic anhydrase I in vasodilation. Two groups of coronary patients and a group of rabbits underwent treatment with the above-mentioned vasodilating drugs. The activity of red blood cell carbonic anhydrase was monitored and determined by the stopped-flow method. The results show that these drugs inhibit the activity of the isozyme in parallel to their vasodilating effect. The results of this study lead to the hypothesis that through the pH modifications induced by these vasodilators by the inhibition of carbonic anhydrase I, the isozyme may be involved in the regulation of vascular tonus.

Animals↗
PubMed1994

Current Status of Isosorbide-5-Mononitrate Therapy in Chronic Stable Angina Pectoris.

A review was made of all known published data on the use of isosorbide-5-mononitrate (5-ISMN) in chronic stable angina pectoris, and efficacy in terms of exercise testing (bicycle or treadmill) was assessed. Adequate documentation for effectiveness for 12 h with steady-state treatment (2 weeks) of 5-ISMN in immediate-release tablets is available only with a dosage of 20 mg twice daily, taken 7 h apart. For other dosage regimens, efficacy has been documented for 2 or at most 4 h duration after dose intake. Immediate-release tablets of 40 mg are effective only for 2 h in steady-state treatment. These data suggest that tolerance develops to some immediate-release tablet regimens. A satisfactory explanation for this is still lacking. The possibility that a rapid plasma level rise is conducive to tolerance development needs to be tested. Extended-release tablets in strengths from 30 to 100 mg are effective for 12 h after the first dose. In steady-state treatment of 3--6 weeks' duration, 12-h efficacy has been shown only for one brand of extended-release 5-ISMN (Imdur((R))) in doses ranging from 60 to 240 mg taken once daily in the morning. Currently, the best explanation to the maintained efficacy with long-term extended-release 5-ISMN is that the plasma level profile allows for a sufficiently low organic nitrate level for a sufficiently long uninterrupted fraction of the dosage interval, occurring during the night when tablet intake is once daily in the morning. Twice daily dosage every 12 h of extended-release 5-ISMN tablets causes tolerance development. Tolerability is similar for both types of tablets, and overall it is excellent. Headache is a common symptom at initiation of treatment but wanes quickly. No rebound effect in the nitrate-low period has been noted with either regimen. Few well-controlled studies have addressed quality of life efficacy, that is, the influence of symptoms and signs of daily life. Many trials of those reviewed were of suboptimal design, and conclusions were often overstated.

Journal Article↗
PubMed2006

IMOP: randomised placebo controlled trial of outpatient cervical ripening with isosorbide mononitrate (IMN) prior to induction of labour - clinical trial with analyses of efficacy, cost effectiveness and acceptability.

BACKGROUND: There is increasing interest in carrying out pre-induction cervical ripening on an outpatient basis. However, there are concerns about the use of prostaglandins, the agents commonly used in hospital settings for this indication, because prostaglandins induce uterine contractions that may lead to fetal hypoxia. Indeed, in a recent study we demonstrated abnormalities in 9% of fetal heart rate tracings performed following prostaglandin induced cervical ripening at term. In contrast, we confirmed in the same study that isosorbide mononitrate (IMN) (administered on an inpatient basis) was both effective in inducing cervical ripening at term, and was associated with no associated fetal heart rate abnormalities. METHODS/DESIGN: The aim of this study is to determine whether IMN self administered by women on an outpatient basis improves the process of induction of labour. Specifically, we hypothesise that the use of outpatient IMN will result in a shorter inpatient stay before delivery, decreased costs to the health service and greater maternal satisfaction with ripening and induction of labour, compared with placebo treatment. In the study described here (the "IMOP" study), women scheduled for induction of labour at term, and who require pre-induction cervical ripening will be randomised to self-administer at home either IMN 40 mg, or a placebo, each vaginally, at 48 hours, 32 hours and 16 hours before scheduled hospital admission. After admission to hospital, treatment will revert to the usual induction of labour protocol. We will compare the primary outcomes of the elapsed time interval from hospital admission to vaginal delivery, the costs to the health service of induction of labour, and women's experience of induction of labour in the two groups. DISCUSSION: This trial will provide evidence on the efficacy of outpatient IMN for pre-induction cervical ripening at term. We will study a formulation of IMN which is cheap and widely available. If the treatment is effective, acceptable to women, and cost effective, it could be implemented into obstetric practice worldwide. TRIAL REGISTRATION: The trial has been registered on the International Standard Randomised Controlled Trial Number Register (ISRCTN) and given the registration number ISRTN39772441.

Journal Article↗
PubMed1997

Can Extended-Release Isosorbide Mononitrate be Used as Adjunctive Therapy for Systolic Hypertension? An Open Study Employing Pulse-Wave Analysis to Determine Effects of Antihypertensive Therapy.

Augmentation of the systolic ejection pressure wave by an exaggerated reflectance wave, demonstrable by applanation tonometry of the radial artery, is an important contribution to systolic hypertension of the elderly. Therefore, a study of extended-release isosorbide mononitrate, which may reduce the augmentation, was performed in a group of patients aged 49 to 80 years with systolic hypertension. This agent was added, in a dose of 30 to 120 mg once daily, to existing antihypertensive medications and the response of the arterial pulse wave pattern was observed after 7 to 34 weeks of continuing treatment. There were decreases in brachial systolic blood pressure, indirectly measured aortic systolic blood pressure, and pulse wave augmentation. These findings indicate the need for controlled studies of nitrate therapy as an adjunct to treatment with conventional antihypertensive drugs in systolic hypertension of the elderly. The studies should include analysis of pulse waveform to complement conventional sphygmomanometry.

Journal Article↗