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At least 19 recordsLinked to original sources
PubMed1990

Concentrations of isosorbide dinitrate, isosorbide-2-mononitrate and isosorbide-5-mononitrate in human vascular and muscle tissue under steady-state conditions.

The concentrations of isosorbide dinitrate (ISDN), isosorbide-5-mononitrate (IS-5-MN) and isosorbide-2-mononitrate (IS-2-MN) were determined in plasma (PL), saphenous vein wall (SV) and pectoral muscle (PM) from 8 patients undergoing coronary bypass surgery. The patients were pretreated for 2 days with ISDN 240 mg per day (standard release formulation) in 4 doses of 40 mg and one dose of 80 mg. The plasma and tissue samples were obtained during the operation, 10-12 h after the last dose. Isosorbide-2-mononitrate and isosorbide-5-mononitrate were present in plasma and tissues in the same concentration ranges with molar concentration ratios of 0.88 (IS-2-MN: PM/PL), 0.85 (IS-5-MN: PM/PL), 0.99 (IS-2-MN: SV/PL) and 1.06 (IS-5-MN: SV/PL). Mean ISDN concentrations in tissue were considerably higher than in plasma; the molar concentration ratios were 4.9 (SM/PL) and 7.21 (SV/PL). The accumulation of ISDN in vessel walls may contribute to its greater vascular action compared to the mononitrates, but it may also facilitate the development of tolerance during long-term treatment.

Aged↗
PubMed1991

Comparison of the effect of isosorbide-5-mononitrate and isosorbide dinitrate in a slow-release form on exercise-induced myocardial ischemia.

A randomized, double blind, placebo-controlled crossover study on 20 patients with exercise-induced angina pectoris and reproducible ST-segment depression during exercise-stress test was performed to compare the effect of a single dose of 120 mg of isosorbide dinitrate in a slow-release form with that of a twice-daily application of 20 mg of isosorbide-5-mononitrate. Symptom-limited exercise tests were done, and nitrate plasma levels were measured in the subjects 6, 10, and 24 hours after the first administration of the drug. Both drugs produced a highly significant reduction in the size of exercise-induced ST-depressions (P less than .001) 6 and 10 hours after the first administration of isosorbide dinitrate as well as 6 hours after the first and 4 hours after the second dose of isosorbide-5-mononitrate. The effect was still significant (P less than .05) 24 hours after the administration of isosorbide dinitrate in a slow-release form and 18 hours after the second dose of isosorbide-5-mononitrate. In the case of the drug isosorbide dinitrate, nitrate plasma levels for its metabolite, isosorbide-5-mononitrate, were highest 10 hours after first application. In the case of the drug isosorbide-5-mononitrate, nitrate plasma levels were highest 4 hours after the second dose. Two 20 mg doses of isosorbide-5-mononitrate and a single dose of 120 mg isosorbide dinitrate in a slow release form have a comparable effect on the reduction of exercise-induced ST-segment depressions.

Adult↗
PubMed1991

Controlled release isosorbide-5-mononitrate in angina pectoris: a comparison with standard formulation isosorbide dinitrate.

In a randomized, double-blind, placebo controlled, crossover study, the antianginal and anti-ischemic effects of a controlled release formulation of isosorbide-5-mononitrate 60 mg once daily and of a standard formulation of isosorbide dinitrate 30 mg qid, were assessed during the first day of treatment and after seven days of sustained therapy. In comparison to placebo, the acute administration of isosorbide-5-mononitrate increased treadmill walking time at 4 and 8 h, and isosorbide dinitrate prolonged treadmill walking time when tested at 4 h after each of the first three doses. During sustained therapy, isosorbide dinitrate produced no significant changes over placebo values. Isosorbide-5-mononitrate prolonged treadmill walking time 4, 8 and 12 h after morning dosing by 54, 41 and 52 s, but these changes were not significant compared to placebo. Treadmill walking time was, however, significantly greater at 4 and 12 h during isosorbide-5-mononitrate therapy compared with isosorbide dinitrate. There was no significant difference in treadmill walking time during acute and sustained therapy with isosorbide-5-mononitrate indicating a lack of tolerance; there was a complete loss of effect during sustained qid therapy with isosorbide dinitrate.

Angina Pectoris↗
PubMed1992

Effects of isosorbide-5-mononitrate and isosorbide-2-mononitrate on the contractile and electrical activity and on the content of cyclic nucleotides in isolated heart muscles of the guinea-pig and dog.

Isosorbide-5-mononitrate and isosorbide-2-mononitrate, the metabolites of isosorbide dinitrate, were studied for their effects on the contractile and electrical activity and on the content of cyclic nucleotides in isolated heart muscles of guinea-pig and dog. Isosorbide-5-mononitrate at all concentrations tested and isosorbide-2-mononitrate at low concentrations did not produce significant changes in the mechanical activity of guinea-pig heart preparations. Isosorbide-2-mononitrate in concentrations above 10(-4) M inhibited the contractility and shortened the action potential of guinea-pig and dog heart muscle. Neither mononitrate had an effect on cAMP concentration but both induced a significant elevation of cGMP content in guinea-pig heart tissue, the effect of isosorbide-2-mononitrate being greater.

Animals↗
PubMed1990

Nitrates: why and how should they be used today? Current status of the clinical usefulness of nitroglycerin, isosorbide dinitrate and isosorbide-5-mononitrate.

Nitrates are highly effective both in terminating acute attacks of angina pectoris and in the prophylaxis of symptomatic and asymptomatic myocardial ischemia. Preload reduction by venodilatation is the prevailing mechanism of nitrates in patients with chronic stable angina and is the unique feature distinguishing them from beta and calcium-channel blockers. Nitrates dilate coronary arteries not only in pre- and poststenotic vessels, but also in eccentric lesions. In patients with endothelial dysfunction, nitrates seem to be the physiological substitute for endothelium-derived relaxing factor. During the past decade, however, there has been substantial evidence of a clinically relevant loss of the anti-ischemic effects ("nitrate tolerance"). Many studies with oral dosing of isosorbide dinitrate or isosorbide-5-mononitrate at least three times daily have proven nitrate tolerance in patients with coronary artery disease and/or congestive heart failure. Complete loss of anti-ischemic effects after repetitive, continuous patch attachments has also been found. As we first showed in 1983, intermittent therapy with once-daily ingestion of high-dose sustained-release isosorbide dinitrate was successful in preventing the development of tolerance. Similarly, tolerance to isosorbide-5-mononitrate also does not develop when it is ingested once daily. It is now generally accepted that a daily low-nitrate interval is required to prevent tolerance development. Although the minimal patch-free interval required to prevent tolerance needs further investigation, a 12-h patch-free interval should prevent tolerance in most patients. The prolonged duration of action of once-daily high-dosage administration of sustained-release formulations, the improved patient compliance with a single daily administration, and the increased likelihood of maximal anti-ischemic effects are important reasons for recommending high single daily doses of isosorbide dinitrate or isosorbide-5-mononitrate.

Angina Pectoris↗
PubMed1990

Comparison of the effects of a controlled-release formulation of isosorbide-5-mononitrate and conventional isosorbide dinitrate on exercise performance in men with stable angina pectoris.

Thirty-three men with stable exercise-induced angina pectoris entered a randomized, double-blind, crossover study in which controlled-release isosorbide-5-mononitrate 60 mg once daily was compared with conventional isosorbide dinitrate 20 mg 3 times daily. Each drug was given for 2 weeks. Twenty-eight patients completed the study and data on exercise variables are available in 23 patients. Treatment with either drug resulted in significant antianginal effects, when measured 6 hours after a single dose and after 2 weeks of therapy compared with baseline placebo; however, there were significantly fewer signs of myocardial ischemia during treatment with isosorbide-5-mononitrate. There was no evidence of tolerance to either drug treatment but a significant attenuation of resting blood pressure (but not of exercise blood pressure) was observed with both drugs. Headache was the only clinically significant adverse event during therapy and it occurred more frequently in the isosorbide dinitrate treatment group (p less than 0.05 vs placebo); 3 such patients had to withdraw from the study because of headache. Thus, once-daily, controlled-release isosorbide-5-mononitrate appears as effective as conventional isosorbide dinitrate 3 times daily in patients with stable angina pectoris. The once-daily administration is convenient and improves patient compliance.

Angina Pectoris↗
PubMedDate not supplied

Assessment of antianginal efficacy of long-acting sustained release isosorbide dinitrate in comparison with short-acting isosorbide dinitrate.

A quadruple blind randomized cross-over study evaluated the therapeutic efficacy of twice a day long acting sustained release isosorbide dinitrate (SRISDN) in comparison with 4 times daily of the short acting isosorbide dinitrate in 18 patients with stable angina pectoris (NYHA class II-III) with a positive exercise treadmill test. The antianginal effect of sustained release isosorbide dinitrate (SRISDN) (exercise duration 472.61 +/- 112.49 sec and anginal episodes per week (1.33 +/- 1.18) was not significantly different (p less than 0.05) when compared to conventional isosorbide dinitrate (exercise duration 468.33 +/- 135.28 sec and anginal episodes per week 1.55 +/- 104). Twice a day long acting sustained release isosorbide dinitrate is as effective as four times a day conventional short acting isosorbide dinitrate. Such a regimen is likely to lead to a better patient compliance and ease of antianginal therapy.

Adult↗
PubMedDate not supplied

Nitrate tolerance: hemodynamic effects of intravenous isosorbide dinitrate after sustained oral isosorbide dinitrate administration.

To determine whether hemodynamic effects of isosorbide dinitrate (ISDN) diminish and disappear during sustained administration, nine patients with recent myocardial infarction received 10 mg of ISDN intravenously before and 1, 4, 12, 24, and 48 weeks after sustained oral administration of 20 mg of the slow-release form of ISDN four times daily. Blood pressure always decreased after intravenous ISDN; the decrease tended to be diminished when preceded by oral ISDN, but no further attenuation in blood pressure was noted. The decrease in blood pressure was associated with consistent and nonsignificant increases in heart rate after intravenous ISDN. Plasma ISDN levels were not affected by prior oral ISDN. Plasma isosorbide 2-mononitrate and isosorbide 5-mononitrate levels were consistently higher when preceded by oral ISDN. The results suggest that the hemodynamic and metabolic properties of ISDN are preserved even after sustained therapy.

Administration, Oral↗
PubMed1992

Antianginal and anti-ischemic efficacy of nicorandil in comparison with isosorbide-5-mononitrate and isosorbide dinitrate: results from two multicenter, double-blind, randomized studies with stable coronary heart disease patients.

The purpose of the two double-blind studies summarized in this article was to compare the antianginal and anti-ischemic effects of nicorandil with those of two different nitrate preparations. A total of 129 patients with stable New York Heart Association functional class II or III coronary heart disease were enrolled in the studies. Ninety-five patients received nicorandil, 34 received isosorbide dinitrate (ISDN), and 63 received isosorbide-5-mononitrate (MN). In study 1, nicorandil was compared with MN in a crossover design with 54 protocols eligible for efficacy assessment of MN and 52 eligible for nicorandil, respectively. Twenty milligrams of nicorandil and 20 mg MN administered b.i.d. for 4 weeks were equally effective in the treatment of stress-induced angina. Both drugs prolonged bicycle exercise tolerance and reduced weekly anginal attack rates. In study 2, nicorandil and ISDN were administered to two parallel groups of patients at a dose of 10 mg t.i.d. for 2 weeks and then 20 mg t.i.d. for 4 weeks. Under the assumption that the repetitive administration of nitrates with short dosing intervals might induce the development of tolerance to the nitrate mechanism of action, the t.i.d.-dosing regimen had been chosen in this study. Thirty-two protocols from those receiving nicorandil and 34 protocols from those receiving ISDN were eligible for efficacy assessment. Both drugs increased exercise capacity and reduced ST-segment depression at identical work loads with no significant difference between groups (p > 0.05). For both drugs, the higher doses were more effective than the lower doses. tolerance to the nitrate mechanism of action did not develop with either drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMedDate not supplied

Effects of isosorbide-5-mononitrate and isosorbide-2-mononitrate on isolated dog aorta: vascular relaxation and increase in cyclic GMP.

The effects of isosorbide-5-mononitrate (IS-5-MN) and isosorbide-2-mononitrate (IS-2-MN) on vascular smooth muscle tone and on cyclic nucleotide levels were studied in isolated dog aorta. The effects of the mononitrates were compared with that of the relatively well-studied vasorelaxing agent sodium nitroprusside (NP). The substances induced concentration-dependent relaxation of the aortic rings contracted with noradrenaline. The potency order was: NP greater than IS-2-MN greater than IS-5-MN. IS-5-MN and IS-2-MN did not cause significant changes in the cAMP levels in dog aortic preparations. In sharp contrast, definite rises in the cGMP levels were observed in dog aortic rings after treatment with the mononitrates. With respect to both phenomena, IS-2-MN proved to have a stronger effect compared to IS-5-MN. These data support the hypothesis that an increase in cGMP is responsible for the relaxation of vascular smooth muscle by organic nitrates.

Analysis of Variance↗
PubMed1991

[Comparison of the clinical and hemodynamic effects of nitroglycerin, isosorbide dinitrate and isosorbide-5-mononitrate in acute myocardial infarction].

One hundred and eighty patients with acute myocardial infarction (MI) were followed up. The patients were divided into 3 groups: (1) those receiving glyceryl trinitrate (GTN) (n = 43); (2) those on isosorbide dinitrate (ISDN) (n = 66); (3) those on isosorbide-5-mononitrate (IS-5-MN) (n = 71). In all the groups, the drugs were given by long-term continuous oligovolumic infusion. Following 24 hours of administration, 66.7, 47.3, and 17.1% increases in infusion rates were required in 74.4, 72.7, and 26.8% of the patients from Groups 1, 2, and 3, respectively. All the agents produced a pronounced antianginal effect and resulted in alleviated acute left ventricular failure. The in-hospital mortality rates were 16.2, 16.7, and 12.7% in Groups 1, 2, and 3, respectively. GTN, ISDN, and IS-5-MN caused adverse effects in 4.7, 18.2, and 2.8% of the patients from Groups 1, 2, and 3, respectively.

Adult↗
PubMedDate not supplied

A pharmacokinetic model for isosorbidedinitrate, isosorbide-2-mononitrate, and isosorbide-5-mononitrate.

A pharmacokinetic model is proposed to describe the plasma levels of isosorbidedinitrate (ISDN) and its two pharmacologically active metabolites, isosorbide-2-mononitrate (IS-2MN) and isosorbide-5-mononitrate (IS-5MN), following the oral administration of several 20-mg sustained release formulations of ISDN. Absorption of ISDN from the gastrointestinal tract appears first-order. A three compartment model is used to describe ISDN systemic plasma levels with t1/2 alpha = 7 min, t1/2 beta = 48 min and t1/2 gamma = 7.5 hr. The long t1/2 gamma is due to the slow release of ISDN from a peripheral compartment. ISDN undergoes extensive first-pass hepatic metabolism to IS-2MN and IS-5MN. The metabolic pathways appear to be close to saturation at an ISDN dose of 20 mg. Both IS-2MN and IS-5MN systemic plasma levels can be described by one compartment models with first-order elimination (respective elimination half-lives are 1.9 and 5.1 hr). The central compartment volumes of distribution for ISDN, IS-2MN and IS-5MN (116, 57, and 38 liters, respectively) are in agreement with reported literature values. This model is of particular usefulness as a formulation tool in designing sustained release ISDN formulations of the type investigated here since the observed first-order absorption rate constant correlates well with the in vitro first-order dissolution rate constant. Therefore, for these formulations, plasma levels can be simulated using data generated from in vitro dissolution studies, thus obviating the need for multiple human bioavailability studies.

Adult↗
PubMed1989

Effect of pertussis toxin and the cGMP lowering agent LY83583 on the relaxation induced by nitrates in isolated bovine mesenteric artery. A comparison between glyceryl trinitrate, isosorbide dinitrate and isosorbide 5-mononitrate.

The effect of pertussis toxin (PTX) and the cyclic GMP-lowering agent LY83583 on the relaxatory response induced by glyceryl trinitrate (GTN), isosorbide dinitrate (ISDN) and isosorbide-5-mononitrate (ISMN) in bovine mesenteric artery was investigated. Pretreatment with PTX (100 ng/ml; 2h) induced a 100-fold right shift of the concentration-effect curve for GTN, while no effect on the relaxatory response elicited by ISDN and ISMN was seen 10 microM LY83583 markedly reduced the relaxatory effect of all the organic nitroesters. Based on the different sensitivity towards PTX it is suggested that GTN induces vascular smooth muscle relaxation by a partly different mechanism than ISDN and ISMN. However, cGMP seems to play a crucial role in mediating the relaxatory response of all the tested organic nitroesters since LY83583 profoundly suppressed the relaxatory response.

Aminoquinolines↗
PubMed1992

[The effects of isosorbide dinitrate spray on the coronary artery and its modification by the preceding chronic oral therapy with long acting isosorbide dinitrate].

The vasodilatory effect of a new formula of isosorbide dinitrite (ISDN) spray on the left coronary artery was studied by comparing its effects in 46 consecutive patients who subsequently received intracoronary injection with ISDN (2.5 mg). In addition, the influence long acting and ISDN for chronic cases on the vasodilatory effects of ISDN spray and on subsequent intracoronary injection of ISDN was investigated. The patients were divided into two groups, those who had had chronic oral ISDN (Group N; 29 patients) and those who had not (Group O; 17 patients). The vasodilatory effect of ISDN spray was evaluated in segments; 5, 6, 8, 11 and 12 by AHA classification and it dilated those segments by 9.9%, 13.2%, 21.5%, 15.6% and 23.5% respectively. Subsequent intracoronary injection of ISDN dilated those segments by 10.4%, 14.0%, 27.2%, 17.9% and 29.1% respectively. The differences in the degree of vasodilation caused by ISDN spray and that caused by injection in segments 8, 11, 12 were statistically significant. However, the per cent dilation of ISDN spray in segments 5 in group N was 5.9%, and 18.4% in group O, revealing a significant difference depending on previous chronic administration of long acting ISDN. We conclude that ISDN spray did dilate the coronary artery, and subsequent intracoronary administration of ISDN dilated it further in the distal portions of the left coronary artery. Long acting oral ISDN for chronic cases seemed to attenuate the vasodilatory action of ISDN.

Administration, Oral↗
PubMed1990

Nifedipine and isosorbide dinitrate alone and in combination for patients with chronic stable angina: a double-blind crossover study.

Since not all patients tolerate beta-blockers, the efficacy of nifedipine and isosorbide dinitrate was evaluated alone and in combination in patients with stable angina pectoris. The study was a randomized double-blind crossover design with patients titrated to maximally tolerated doses of both drugs. Phases included isosorbide dinitrate alone, nifedipine alone, and isosorbide dinitrate plus nifedipine in combination, with efficacy determined by stress testing. Eleven men and one woman patient with a mean age of 60 years and a mean of five anginal episodes/week completed the study. Patients were in New York Heart Association (NYHA) classes I, II, and III. With nifedipine alone compared with isosorbide dinitrate alone, patients had fewer angina attacks/week (p less than 0.02), exercised longer before experiencing angina (p less than 0.03), and had less ST segment depression during (p less than 0.03) or after (p less than 0.05) exercise. When patients received isosorbide dinitrate plus nifedipine, only time to onset of angina during exercise (p less than 0.05) was significantly different from the response with isosorbide dinitrate alone. Analysis of variance between nifedipine and isosorbide dinitrate plus nifedipine was not significant. Diastolic blood pressure with isosorbide dinitrate plus nifedipine (p less than 0.04) was lower than with isosorbide dinitrate alone. No significant differences in systolic blood pressure were noted between the treatment groups. The drugs alone and in combination were relatively well tolerated. Nifedipine alone may be superior to isosorbide dinitrate alone. The combination of isosorbide dinitrate plus nifedipine demonstrated no advantage over nifedipine alone compared with isosorbide dinitrate alone.

Angina Pectoris↗