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PubMed1987

[Ischemia tolerance of the heart in percutaneous transluminal coronary angioplasty. Controlled study of the effect of isosorbide dinitrate and nifedipine].

In a randomized controlled study, influence of sublingual isosorbide dinitrate (ISDN) and nifedipine on ischemic tolerance of the heart during percutaneous transluminal coronary angioplasty (PTCA) was examined. After dilations without premedication except heparin ten patients received 10 mg ISDN sublingually and dilations after one, five, and ten minutes were repeated, then 20 mg nifedipine sublingually was administered followed by dilations at one, five, ten, and 15 minutes intervals (group A). First 20 mg nifedipine and then 10 mg ISDN were given sublingually with the same repeated dilations in ten patients forming group B. Mean arterial pressure decreased from 111 +/- 11 to 97 +/- 14 mmHg after ISDN (p less than 0.001) in group A and to 86 +/- 12 mmHg after nifedipine (p less than 0.001). In group B arterial pressure remained constant after nifedipine and decreased to 84 +/- 15 mmHg after ISDN (p less than 0.05). Coronary perfusion pressure in group A remained constant at about 27 +/- 11 mmHg and increased in group B from 27 +/- 14 to 31 +/- 20 mmHg after nifedipine and decreased to 20 +/- 16 mmHg after ISDN (n.s.). Dilation period increased in group A from 33 +/- 15 s to 69 +/- 25 s after ISDN (p less than 0.001) and remained constant after nifedipine 67 +/- 23 s. Dilation time in group B increased from 31 +/- 8 s to 49 +/- 17 s after nifedipine (p less than 0.001) and to 81 +/- 46 s after ISDN (p less than 0.001). Time until ST segment depression of greater than 0.1 mV increased from 14 +/- 5 s to 37 +/- 19 s by ISDN in group A and to 33 +/- 16 s after nifedipine (p less than 0.001). Times in group B measured 16 +/- 5 s and 24 +/- 8 s after nifedipine and 39 +/- 24 s after ISDN (p less than 0.05). In groups A and B arrhythmias could be suppressed despite prolonged dilation times only by application of both drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Sublingual↗
PubMed1983

Improved diagnostic yield of radionuclide angiography by quantitative phase analysis during resting angina and following isosorbide dinitrate.

The reliability of quantitative phase analysis of radionuclide angiography in the detection of wall motion abnormalities has been investigated in 15 patients with angina at rest. All patients have been studied in the basal state, during spontaneous or ergonovine-induced ischemia and following isosorbide dinitrate acute i.v. administration in the resolution phase. Quantitative phase analysis provided a more sensitive index of impaired wall motion as compared to global ejection fraction changes. Isosorbide dinitrate rapidly and completely solved ischemic dyssynergies caused by coronary vasospasm.

Adult↗
PubMedDate not supplied

[Isosorbide dinitrate tolerance in the treatment of patients with angina pectoris and the effect of addition of captopril on therapeutic results].

The authors investigated in patients with stable angina the influence of a single dose and of long-term administration of isosorbide dinitrate alone and combined with captopril. Administration of 40 mg Iso-Mack ret. every 8 hours for four weeks did not lead to the development of tolerance. However, captopril added to isosorbide dinitrate tends to improve the investigated indicators after a single dose as well as after long-term treatment. It is probable that concurrent administration of the two drugs causes addition of their vasodilatating action and thus the vascular resistance declines, as well as the cardiac pre-load and after-load and the oxygen consumption of the heart muscle. The authors discuss possible mechanisms of the increased vasodilatation after addition of captopril.

Adult↗
PubMed1987

In vitro evidence of an endothelial cell-dependent antiplatelet activity for isosorbide dinitrate, but not for its 2- and 5-mononitrate metabolites.

In an experimental model in which cultured endothelial cells (EC) and platelets were incubated with autologous plasma, we investigated the pharmacological modulations by isosorbide nitrates (ISN) [isosorbide dinitrate (ISDN) + 2-isosorbide mononitrate (2-ISMN) + 5-ISMN] of the EC-induced inhibition of platelet aggregation; and the associated changes in prostanoid profile of these mixed EC-platelet suspensions. ISDN antiplatelet activities were found to be magnified profoundly by EC, being dependent upon both ISDN concentration and EC number, e.g., 5.10(-5) M ISDN in the presence of 2.10(4) cells, fully arrested ADP-induced aggregation, whereas the same ISDN concentration induced 30% inhibition in control platelet activities. In contrast, there were no significant changes in 2- and 5-ISMN antiaggregating properties, whether incubated in the presence or absence of EC. Thromboxane B2 accumulated noticeably after aggregation, whereas 6-keto-prostaglandin (PG) F1 alpha and PGE2 accumulated poorly in the medium. In the presence of EC, thromboxane B2 accumulation fell in parallel to the extent of aggregation, whereas 6-keto-PGF2 alpha and PGE2 accumulated in the medium. Aspirin-treated, washed ECs still inhibited platelet aggregation. ISDN was the only ISN capable of inducing PG-accumulation profile changes. These results demonstrate the existence of an endothelium-dependent ISDN antiplatelet activity. Furthermore, this effect is specific to ISDN not being shown by its mononitrate metabolites. These results suggest that PG accumulation changes may be a consequence rather than a cause of the inhibition of platelet activity by (ISDN-stimulated) EC.

6-Ketoprostaglandin F1 alpha↗
PubMed1983

Comparison of the antianginal effectiveness of nifedipine, verapamil, and isosorbide dinitrate in patients receiving propranolol: a double-blind study.

Ten men with stable angina not fully relieved by optimal doses of propranolol were given on each of four mornings a single dose of 10 mg nifedipine, 120 mg verapamil, isosorbide dinitrate (5 to 30 mg, previously titrated to lower systolic blood pressure by 15 to 20 mm Hg), or placebo, in double-blind fashion. Bicycle exercise to angina was performed hourly for 8 hr thereafter. All three vasodilators increased exercise time by at least 50% by the first hour (p less than .001), with a gradually diminishing effect persisting for 6 to 8 hr (p less than .01). Although for the group there were no differences in magnitude and duration of effect among the three drugs, in five of the individual patients there were important differences in response favoring one or another vasodilator. We conclude that nifedipine, verapamil, and isosorbide dinitrate are equally effective and reasonably long-acting antianginal supplements to propranolol, although some patients may benefit more from one than another of the three.

Adult↗
PubMed1982

[Chronic aortic and mitral valve regurgitation. Effects of isosorbide dinitrate on systolic function and passive elastic properties of the left ventricle (author's transl)].

A haemodynamic and cineangiographic study was conducted in 20 patients with chronic aortic regurgitation alone or associated with mitral regurgitation before and during i.v. administration of isosorbide dinitrate 5 mg/hour. Freedom from coronary disease had been ascertained. The heart rate and aortic pressure (initially normal), cardiac index (initially low), pulmonary pressures and pulmonary and systemic resistances (slightly raised initially) remained unchanged. On the other hand, the left ventricular (LV) filling pressure, distinctly raised before treatment, was reduced by 17% (p less than 0.05). There was also a 10% reduction in LV end-diastolic volume (from 204 +/- 60- cm3.m2 to 184 +/- 56 cm3,m2; p less than 0.001) and a 14% reduction in LV end-systolic volume (from 104 +/- 39 cm3.m2 to 89 +/- 40 cm3.m3; p less than 0.001). LV geometry, stroke volume and regurgitation volume were unmodified. There was a significant improvement in ventricular function indices, globally reduced before treatment: + 8% for the fiber shortening amplitude (p less than 0.025), + 6% for the ejection fraction (p fiber shortening (p less than 0.01), and + 15% for the ESP: ESV ratio (p less than 0.05). The passive elasticity indices, all increased before treatment, also improved. It is concluded that isosorbide dinitrate improves LV systolic and diastolic functions in patients with chronic valve disease.

Adolescent↗
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↗
PubMed1981

Relationship between the pharmacodynamics and pharmacokinetics of two oral sustained-release formulations of isosorbide dinitrate in normal man.

The relationship between the pharmacodynamics and pharmacokinetics of isosorbide dinitrate (ISDN) following oral administration of 40 mg of two different models. A model assuming an additive contribution of all active drug-related substances in plasma to pharmacological effect, i.e., finger pulse plethysmograph, resulted in estimates of relative potencies of ISDN:2-MN:5-MN (2-MN:2-isosorbide mononitrate; 5-MN:5-isosorbide mononitrate) as being 1:0.1:0.025. The data analysis using a receptor model (plasma concentration-effect curves) yielded sigmoid curves yielded sigmoid curves for 2-MN and 5-MN with similar relative potencies in the range of 20-80% of maximum response providing an upper limit for the pharmacodynamic effect due to ISDN, 2-MN or 5-MN in healthy volunteers.

Delayed-Action Preparations↗
PubMed1985

Endoscopic variceal pressure measurements: response to isosorbide dinitrate.

An endoscopic pressure sensor has been evaluated in the measurement of oesophageal variceal pressure and its response to drug ingestion. The variceal pressure showed a highly significant correlation with the splenic pulp pressure (r = 0.97) in six patients with liver disease of diverse aetiology and with hepatic venous wedge pressure (r = 0.92) in eight alcoholic cirrhotic men. Intraduodenal infusion of isosorbide dinitrate in the cirrhotics produced no change in wedge pressure or endoscopic variceal pressure despite profound falls in arterial systolic pressure. Thus isosorbide dinitrate appears to be of no value in treating portal hypertension. This study establishes the endoscopic pressure sensor as a valuable tool in screening drugs in this condition.

Adult↗
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↗
PubMed1987

Sex- and species-related differences in the biotransformation of isosorbide dinitrate by various tissues of the rabbit and rat.

The biotransformation of isosorbide dinitrate (ISDN) by various tissues of the rabbit and rat was examined. Incubation of 2 X 10(-7) M ISDN at 37 degrees C with tissue homogenates of liver, lung, kidney, intestine, skeletal muscle, aorta, and erythrocytes from the rabbit and rat resulted in a significant disappearance of ISDN after a 30-min incubation (also, 5-min incubation for liver). The disappearance of ISDN in each tissue homogenate was accompanied by an equimolar production of the mononitrate metabolites, isosorbide-2-mononitrate (2-ISMN) and isosorbide-5-mononitrate (5-ISMN), with the exception of liver homogenates where the loss of ISDN could not be accounted for by mononitrate formation. The relative rate of ISDN disappearance in various tissue homogenates was for the male rabbit, liver greater than lung approximately intestine greater than kidney greater than erythrocytes approximately skeletal muscle approximately aorta; for the female rabbit, liver greater than kidney approximately lung approximately intestine greater than erythrocytes approximately skeletal muscle approximately aorta; and for the male rat, liver greater than intestine greater than erythrocytes greater than skeletal muscle greater than lung approximately kidney. A sex difference in the percent disappearance of ISDN was observed in homogenates of lung and intestine from male and female rabbits. In addition, a sex difference in the ratio of metabolite (2-ISMN/5-ISMN) formed by denitration of ISDN was seen in homogenates of lung, skeletal muscle, and erythrocyte lysate.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
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↗
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↗
PubMed1985

Role of isosorbide dinitrate in management of chronic congestive heart failure.

Congestive heart failure is accompanied by a number of compensatory mechanisms that may overshoot the mark. Among these are excessive arteriolar and venous constriction. Nitrates are effective in producing venodilation, redistributing blood from the chest to the periphery, and lowering right and left atrial pressures. Although oral isosorbide dinitrate is effective in producing acute beneficial hemodynamic effects, it usually does not increase exercise tolerance in the short term. Prolonged administration, however, does increase exercise tolerance and improve clinical class. Isosorbide dinitrate can be effectively combined with an arteriolar dilator such as hydralazine, which increases cardiac output. Such vasodilator therapy is symptomatically effective in patients with heart failure, although there is no evidence to date to suggest a prolongation of life.

Administration, Oral↗
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↗
PubMed2000

Effect of penetration enhancers on isosorbide dinitrate penetration through rat skin from a transdermal therapeutic system.

Percutaneous absorption of isosorbide dinitrate (ISDN) from a transdermal therapeutic system (TTS) with or without penetration enhancers was studied. The concentration of ISDN and its metabolites, isosorbide-5-mononitrate (IS-5-MN) and isosorbide-2-mononitrate (IS-2-MN), was determined in rat plasma during a 48 h application of TTS. The increased skin-penetration enhancing effect of oleic acid and propylene glycol in comparison to polyethylene glycol 400 and isopropyl myristate on percutaneous permeation of ISDN was shown. It was expressed by higher values of C(max) and AUC. After the application of TTS, a lower ISDN and molar ratio of its metabolites was observed than after oral administration.

Administration, Cutaneous↗
PubMed1973

Double-blind evaluation of verapamil, propranolol, and isosorbide dinitrate against a placebo in the treatment of angina pectoris.

In the treatment of angina pectoris a double-blind evaluation of verapamil (Cordilox) at two dose levels-namely, 80 mg thrice daily and 120 mg thrice daily-propranolol (Inderal) 100 mg thrice daily, and isosorbide dinitrate (Vascardin) 20 mg thrice daily has been made against a placebo. The assessment was based on relief from daily attacks of angina on effort and the response to a whole-body exercise test. We can find no statistically significant difference between the effects of verapamil (120 mg three times a day) and propranolol (100 mg three times a day) in the treatment of angina of effort. Both of these preparations are more effective than a placebo both in the reduction of daily attacks (P < 0.01) and in the prolongation of exercise test (P < 0.05). Isosorbide dinitrate (20 mg three times a day) appears to be no more effective than a placebo in the treatment of angina on effort, but 14 out of 32 patients experienced headache of such severity that even when the dose was reduced to 10 mg thrice daily this drug therapy had to be withdrawn. Both propranolol (100 mg three times a day) and verapamil (120 mg three times a day) had a significant lowering effect on the diastolic blood pressure as measured with the patient standing (P < 0.01).

Adult↗
PubMed1993

Sorption of isosorbide dinitrate to central venous catheters.

As several studies demonstrated the sorption of isosorbide dinitrate (ISDN) to intravenous delivery systems, a study on the sorption of ISDN to several central venous catheters was performed. Fourteen different catheters were perfused during a 2 h period, under simulated infusion conditions, with ISDN (250 micrograms mL-1) in 0.9% (w/v) sodium chloride. The drug loss to a polyethylene and a silicone catheter was 0.2 and 6.1%, respectively. The sorption to a polyvinylchloride heparin-coated thermodilution catheter was 1-6.9% depending on the length of the catheter. The drug loss to polyurethane catheters of different composition varied between 3.8 and 28.9%. For polyurethane catheters composed of cycloaliphatic polyurethanes an inverse relation was shown between Shore A hardness and sorption.

Adsorption↗