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PubMedDate not supplied

Effect of sustained-release isosorbide dinitrate on post-prandial gastric emptying and gastroduodenal motility in healthy humans.

Nitric oxide (NO) is an inhibitory neurotransmitter released by non-adrenergic and non-cholinergic neurons that innervate the smooth muscles of the gastrointestinal tract. We examined whether NO, derived from a sustained-release preparation of isosorbide dinitrate, influenced gastric emptying and gastroduodenal motility after a meal. Eleven healthy volunteers participated in a double-blind, placebo-controlled, cross-over study. Each subject ingested 40 mg isosorbide dinitrate orally as a sustained-release formulation or oral placebo, in random order. Gastric emptying and gastroduodenal motility were measured using scintigraphic and manometric techniques. Isosorbide dinitrate did not change the area under the curve of gastric retention versus time, and did not influence the frequency of antral contractions as assessed at 15-min intervals or the integrated duodenal motility index, as recorded over consecutive 15-min periods. A 40 mg single dose of sustained-released isosorbide dinitrate does not seem to alter gastric emptying or gastroduodenal motility after a meal.

Administration, Oral↗
PubMed1981

Comparison of acute haemodynamic effects of nifedipine and isosorbide dinitrate in patients with heart failure following acute myocardial infarction.

The acute haemodynamic effects of nifedipine (10 mg sublingually) and isosorbide dinitrate (5 mg sublingually) were compared in 13 patients with heart failure due to acute myocardial infarction. Nifedipine induced a significant reduction in systolic (from 122 +/- 5 to 107 +/- 3 mm Hg: mean +/- SEM; P less than 0.002) and diastolic blood pressure (from 85 +/- 3 to 75 +/- 2 mm Hg; P less than 0.01). Heart rate did not change significantly, nor did mean right atrial pressure. The mean pulmonary arterial pressure was lowered from 31 +/- 2 to 27 +/- 2 mm Hg (P less than 0.005). The left ventricular filling pressure decreased from 24 +/- 1 to 19 +/- 1 mm Hg (P less than 0.0001). A significant increase in cardiac index (from 2.33 +/- 0.13 to 2.69 +/- 0.15 l/min per m2; P less than 0.001) and in stroke volume index (from 24 +/- 2 to 28 +/- 2 ml/beats per m2; P less than 0.005) was registered. Systemic vascular resistance fell from 1742 +/- 145 to 1308 +/- 85 dynes/sec per cm-5 (P less than 0.00005). After isosorbide dinitrate was administered a significant reduction in mean right atrial pressure (from 9.5 +/- 1.6 to 5.1 +/- 1.2 mm Hg; P less than 0.0001), in mean pulmonary arterial pressure (from 32 +/- 1 to 23 +/- 1 mm Hg; P less than 0.00001) and in left ventricular filling pressure (from 23 +/- 1 to 16 +/- 1 mm Hg; P less than 0.0001) was seen. No significant change in systolic and diastolic blood pressure, heart rate, cardiac index, stroke volume index and systemic vascular resistance was registered. No side-effects were seen after nifedipine and isosorbide dinitrate were administered.

Adult↗
PubMed1977

Plasma isosorbide dinitrate concentrations in human subjects after administration of standard and sustained-release formulations.

After sublingual administration of 5 mg of isosorbide dinitrate, mean plasma concentrations (+/-SD) peaked (8.9+/-3.1 ng/ml) at 15 min after dosing and declined with a half-life of 30 min. After oral administration of 5 mg, mean concentrations peaked (3.1+/-0.7 ng/ml) at 30 min and declined with a half-life of 40 min. After oral administration of 20 mg in a sustained-release tablet, mean concentrations initially peaked (1.4+/-1.2 ng/ml) at 40 min, declining to 0.9+/-0.5 ng/ml after 8 hr. Mean concentrations were maintained above half the mean peak level during 10 hr. Because of probable rapid first-pass metabolism, the bioavailability of isosorbide dinitrate after administration of the oral dose of the standard tablet was 58% of that from the sublingual dose, and the bioavailability from the sustained-release tablet was 47% of that from the sublingual dose of the standard tablet. The time course of mean plasma concentration data could be described by a one-compartment model; but a more complex model, taking the pass effect into account, probably is needed for a better description of the pharmacokinetics of isosorbide dinitrate.

Administration, Oral↗
PubMed1985

Coronary artery dilation and hemodynamic responses after isosorbide dinitrate therapy in patients with coronary artery disease.

The response to sublingual isosorbide dinitrate (ISDN) was studied in 10 men with suspected coronary artery disease undergoing coronary arteriography. A Swan-Ganz catheter was placed in the pulmonary artery to record hemodynamic response. Diseased coronary segments were identified during routine Judkins selective coronary angiograms. Sublingual isosorbide dinitrate (ISDN) (5 or 10 mg) was then given with the catheters in place. Multiple sequential single-view coronary angiograms and pulmonary and systemic hemodynamic responses were recorded over 30 minutes after drug administration. At 30 minutes, there was a 53% reduction (p less than 0.01) in pulmonary capillary wedge pressure and a 15% decrease (p less than 0.05) in systemic and pulmonary vascular resistance, with a net 13% decrease (p less than 0.01) in cardiac output and 20% decrease (p less than 0.01) in mean arterial pressure. Quantitative arteriography demonstrated substantial dilation of luminal cross-sectional area in both normal and diseased coronary arterial segments. Normal epicardial segments were grouped according to luminal area (1 to 4, 4 to 8 and more than 8 mm2) and demonstrated maximal area dilation at 10 minutes of 55% (p less than 0.01), 29% (p less than 0.01) and 16% (p less than 0.05), respectively. Diseased epicardial segments (stenosis 50% or greater) dilated 51% (p less than 0.01) at 10 minutes. Calculated stenosis resistance decreased 40% (p less than 0.01). Diseased segments in small and middle-sized arteries (1 to 8 mm2) are 4 times more reactive than those in larger arteries (more than 8 mm2), with peak dilation of 77 vs 21% (p less than 0.01) at 30 minutes.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiography↗
PubMed1991

Clinical response and effects on left ventricular function of isosorbide dinitrate added to propranolol or diltiazem monotherapy in patients with chronic stable angina.

Twenty-four patients were randomized to a double-blind, triple placebo controlled, latin square protocol to examine the relative efficacy of propranolol or diltiazem given as monotherapy or in combination with isosorbide dinitrate. Treatment phases were preceded and followed by placebo control periods. At the end of each phase, symptom-limited treadmill exercise stress tests were performed, as well as rest and exercise radionuclide ventriculography. Both forms of monotherapy were effective in reducing episodes of angina and nitroglycerin use, and in improving exercise tolerance. Diltiazem monotherapy was associated with slightly higher treadmill times (509.9 +/- 123 s) compared to propranolol (462.7 +/- 131 s, P less than 0.05). The addition of isosorbide dinitrate to either form of monotherapy allowed no further improvement in any of the measured clinical responses. Radionuclide ventriculography showed no significant difference in resting left ventricular function. The addition of isosorbide dinitrate to propranolol showed a reduction in end diastolic volume in keeping with a reduction in preload. In response to exercise, stress-induced left ventricular dysfunction was equal in all groups except for the diltiazem-nitrate combination, which was associated with a higher ejection fraction (56.2 +/- 8.6%) compared to monotherapy (52.6 +/- 10.9%, P less than 0.01). A higher cardiac output could be achieved in the groups treated with diltiazem; this was related to increased heart rate and maintenance of stroke volume. It was concluded that diltiazem is equally effective as propranolol for the treatment of chronic stable angina and, in terms of exercise capacity and cardiac output, superior to beta-blockade. The addition of isosorbide dinitrate appears to impart no overt benefits, but some evidence suggests a reduction in left ventricular decompensation in the face of stress.

Adult↗
PubMed1979

[Effects on the systemic and coronary circulation of 2 nitrate derivatives, intravenous trinitrin and sublingual isosorbide dinitrate, administered during atrial pacing].

The changes in the systemic and coronary circulations produced by intravenous trinitrin 0.38 +/- 0.125 mg/hour and sublingual isosorbide dinitrate 5 mg were studied in 24 patients with coronary artery disease. When given during rapid atrial pacing both drugs decreased pulmonary capillary pressures (p less than 0.001), cardiac and coronary output (p less than 0.001 and p less than 0.01) and myocardial oxygen consumption (p less than 0.01). At these dosages, intravenous trinitrin has no significant effect on average systemic blood pressure or left ventricular work index; the coronary arterial resistances increased (p less than 0.005). Isosorbide dinitrate significantly decreased average systemic blood pressure and the left ventricular work index (p less than 0.001); there was no significant difference in the coronary arterial resistances; the decrease in coronary blood flow observed after sublingual isosorbide dinitrate seems partly due to a decreased perfusion pressure. The beneficial effect of these nitrite derivatives seems to be mainly related to a reduced preload.

Administration, Oral↗
PubMed2002

[Development of nitrate tolerance in individual patients with stable angina pectoris in various phases of therapy with oral isosorbide dinitrate].

The aim of the work was an individual assessment of the effect on coronary reserve exerted by the widely used drug from the group of nitrates--isosorbide dinitrate (ISDN) in conventional and slow-release (SR) presentations, in various doses. The patients--38 males with stable coronary disease were given orally, by randomised double blind method, conventional isosorbide dinitrate (ISDN) in 10 and 20 mg doses, and slow-release isosorbide dinitrate in 20 mg SR, 40 mg SR, 80 mg SR and 120 mg SR doses, or placebo for the first time and for 7 days: four times daily, three times daily (with a 12-hour break), twice daily (with an 18-hour break) and once daily. In each of the therapeutic methods, walking times were analysed during exercise test six hours following drug administration, that is total time (TT), time to angina (TA) and time to ischaemia (TI). A prolongation by > or = 20% of walking times after ISDN administration as compared to placebo in > 50% of patients was accepted as significant improvement. Six hours after the first administration, a significant improvement of TT, TA and TI as compared to placebo was observed in the case of ISDN 20 mg, 40 mg SR, 80 mg SR and 120 mg SR. After administration of the drugs four times daily no significant improvement was observed after any dose. After administration of the drugs thrice daily, significant improvement was found in the case of TA (80 mg SR) and TI (20 mg SR, 40 mg SR and 120 mg SR), after twice daily administration--in the case of TI (40 mg SR and 80 mg SR) and after once daily administration--in the case of TT (80 mg SR), TA (120 mg SR) and TI (40 mg SR, 80 mg SR and 120 mg SR). In > 50% of patients, the coronary activity of ISDN in higher doses persists for six hours in the case of the first time administration; continuous therapy leads to tolerance development and intermittent therapy makes possible to avoid it. Tolerance does not depend on patients' sensitivity to nitrates.

Administration, Oral↗
PubMed1992

[Effect of isosorbide dinitrate on vasomotricity-cytosolic calcium coupling during aging in the rat].

Simultaneous measurement of vasomotricity and variations of cytosolic calcium concentrations (mobilisation of intracellular calcium) on a preparation of a normotensive Wistar rat caudal artery allowed analysis of the vasomotricity-cytosolic calcium coupling with respect to age and after administration of isosorbide dinitrate. Vasomotricity was evaluated from changes in perfusion pressure (delta P) of arterial segments perfused at a steady flow state. These segments were exposed to a fluorescent probe, fura 2, the variations of the intensity of emission of which, at wave lengths of 340 and 380 nm, reflect variations in cytosolic calcium concentration (delta R%). The "efficacy" of the vasomotricity-cytosolic calcium coupling was estimated from the delta P/delta R% ratio. In the rat, ageing is accompanied by a reduction in vasomotricity and efficacy of the coupling during noradrenalin stress testing. However, these two parameters recorded during contractions induced by the calcium in a depolarising medium do not change with age. Isosorbide dinitrate reduces vasoconstriction and the delta P/delta R% ratio during noradrenalin stimulation in the young rat. The effect is less pronounced in older rats. Isosorbide dinitrate also reduced the vasomotricity and efficacy of coupling but to a lesser degree during vaso-constriction induced by the calcium in a depolarising medium, without changing the mobilisation of intracellular calcium irrespective of the age of the animals. In conclusion, ageing seems to affect the vasomotricity-cytosolic calcium coupling mainly during receptor stimulation (noradrenalin) rather than during depolarising stimulation (calcium in a depolarising medium). Isosorbide dinitrate acts mainly on the same depolarising stimulation, independent of age.

Aging↗
PubMed1982

[Coronary artery dilatation induced by isosorbide dinitrate injection (author's transl)].

Twenty-six patients were given 3 mg isosorbide dinitrate either by direct intra-coronary injection (17 patients) or by intravenous injection ( patients), 5 minutes after an injection of 0.4 mg methylergometrine. In all 26 patients isosorbide dinitrate dilated the coronary arteries to a diameter that was 26% greater than the smallest diameter observed with methylergometrine and 14.8% greater than the basal diameter. The response was highly significant at 30 seconds, maximal at 2 minutes and lasted more than 10 minutes. At the dosage level used in this study, there was no significant difference between the two groups of patients. However, a rapid fall in systemic arterial pressure was noted after peripheral intravenous injection.

Coronary Vessels↗
PubMed2003

The effect of isosorbide dinitrate, a donor of nitric oxide, on maternal cerebral blood flow in gestational hypertension and preeclampsia.

OBJECTIVE: The purpose of this study was to investigate the effect of a nitric oxide donor on cerebral perfusion pressure and other blood flow index values in the maternal middle cerebral and basilar arteries. STUDY DESIGN: Sublingual tablets of 5-mg isosorbide dinitrate were administered to 19 hypertensive pregnant patients. Doppler velocimetry of the middle cerebral and basilar arteries was obtained with a transcranial Doppler with the use of the transtemporal and suboccipital approach. RESULTS: The mean (+/-SEM) flow velocity in the middle cerebral artery significantly decreased from a baseline of 65.9 +/- 3.1 cm/s to 55.2 +/- 2.2 and 52.0 +/- 2.1 cm/s at 10 and 20 minutes (P <.0001). Resistance area product insignificantly increased from a baseline of 2.0 +/- 0.1 before isosorbide dinitrate to 2.19 +/- 0.11 at 20 minutes. No significant changes were observed in the resistance and pulsatility indices in the middle cerebral artery. The cerebral perfusion pressure did not change significantly after isosorbide dinitrate (84.5 +/- 7.3, 80.8 +/- 6.6, and 78.5 +/- 5.0 mm Hg at 0, 10, and 20 minutes, respectively) nor did the cerebral blood flow index. CONCLUSION: The results obtained demonstrate that cerebral perfusion pressure is unaltered by isosorbide dinitrate, despite significant changes in maternal blood pressure and in blood flow velocities in the middle cerebral artery.

Administration, Sublingual↗
PubMed1975

Clinical and circulatory effects of oral isosorbide dinitrate in patients with angina during exercise.

Isosorbide dinitrate was given orally to 6 patients with anginal pain on exertion and its effect on exercise capacity, ECG and other hemodynamic parameters was compared with the control values and with the results of a group of 6 patients who received a placebo. The drug seems to affect favourably the working capacity and the ECG on exercise for a longer period than NTG while we do not observe a placebo effect.

Adult↗
PubMed1983

Acute and chronic isosorbide dinitrate therapy in congestive heart failure: demonstration of improved exercise capacity and differing arterial and venous tolerance during chronic administration.

Thirty patients with congestive heart failure underwent a double-blind study after randomization into either isosorbide dinitrate or placebo. The initial dose (40 mg orally) of isosorbide dinitrate reduced resting and exercise pulmonary artery, pulmonary capillary wedge, and systemic blood pressure and pulmonary and systemic vascular resistance without improving exercise tolerance. Chronic dosing (40 mg orally every 6 h for 3 months) increased exercise tolerance and maintained a reduction in resting and exercise pulmonary artery and pulmonary capillary wedge pressures and pulmonary resistance, while systemic pressure and resistance returned to baseline. Chronic oral isosorbide dinitrate (40 mg every 6 h) improves exercise capacity over a 3-month period with disparate tolerance effects on systemic arterial, systemic venous, and pulmonary vasculature.

Heart Failure↗
PubMed1993

Controlled-release isosorbide dinitrate pellets. Part II: In vivo studies.

Isosorbide dinitrate (ISDN) capsules containing 20.0 and 40.0 mg of the drug (reported earlier in Part I of this series) were evaluated in vivo in eight healthy volunteers in a double-blind study with marketed sustained-release preparations containing 20.0 and 40.0 mg of ISDN. The results were normalized by administering placebo and four conventional ISDN tablets, each containing 5.0 mg of ISDN, to the same group of volunteers in a separate study. The blood pressure of the volunteers was monitored for 8 h. The results indicate that the capsules prepared in the laboratory with the new formulation gave controlled release when compared with the respective marketed SR product.

Adult↗
PubMed1988

Circadian investigation of interval therapy with isosorbide dinitrate in coronary heart disease.

One of the most promising concepts in nitrate therapy is interval therapy, a dosage scheme with marked changes of nitrate concentrations in the 24-h interval. In a single-blind, placebo-controlled study in patients with coronary heart disease we investigated the circadian anti-ischaemia and haemodynamic response to interval therapy with isosorbide dinitrate (120 mg sustained release 1 X 1). 10 male patients (46-75 years, mean 60 years) with chronic stable angina and ST-segment depression during exercise entered the trial. At the end of a 10-day placebo period (medication at 8 am) three exercise tests were performed (10 am, 2 pm, 6 pm), recording ST-segment changes, pulmonary capillary wedge pressure (PCP) and cardiac index (CI). Spontaneous ischaemic events were detected by Holter monitoring until 8 am the next day. After three weeks of therapy with isosorbide dinitrate, the protocol was repeated (statistics: paired t-test, *P less than 0.05). PCP was reduced by 8.3 mmHg* at 10 am, 8.0 mmHg at 2 pm, 2.9 mmHg (NS) at 6 pm with a concomitant increase of cardiac index (+0.8,* +0.7*, +0.3 NS l min-1 m-2). While the haemodynamic improvement was maximal in the morning the anti-ischaemia effect (reduction of ST-depression) was constant during the active day (-0.40*, -0.50*, -0.43* mm). Four transient ischaemia episdodes at night were recorded under placebo, none under isosorbide dinitrate. In conclusion, all parameters studied demonstrate the effectiveness of chronic interval therapy with isosorbide dinitrate.

Aged↗
PubMed1984

Comparative quality tests of two types of sustained release preparation of isosorbide dinitrate.

Two commercial sustained release preparations of isosorbide dinitrate (ISDN), capsules (preparation A) and tablets (preparation B), were tested for content uniformity and dissolution pattern. The deviations in contents of the single doses from the declared content ranged from -7.7% to +9.7% which conformed to the standard (+/- 15%) of the Japanese Pharmacopeia X (JP X). Dissolution tests were performed using the rotating basket method described in JP X. The dissolution medium were No. 1 and 2 solutions (pH 1.2 and 6.8, respectively) specified in JP X disintegration test, and 0.05 M phosphate buffer solutions (pH 3.0 and 5.0). The dissolution patterns of both preparations were independent on the pH of the medium. However, there was a marked difference between the dissolution rates of the two: after 8 hr of the test, the rates of preparation A were 85-89%, but those of preparation B were only 42-50%. From preparation A a somewhat constant release of ISDN continued until the 6 hr. ISDN was determined by the HPLC method.

Capsules↗
PubMed1983

[Comparative antianginal, hemodynamic and pharmacokinetic effects of isosorbide-2-mononitrate and isosorbide dinitrate in the rat].

The effect of isosorbide 2-mononitrate (IS-2-MN) was compared with that of isosorbide dinitrate (ISDN) in rats regarding the antianginal, haemodynamic and pharmacokinetic properties. The antianginal effect of IS-2-MN in equal oral dose persisted 3 times longer in the rat than did ISDN. In the same oral dosage, the two compounds caused the equal reduction of the number of deaths after an acute myocardial infarction. The intravenous or enteral administration of a single IS-2-MN dose caused an increasingly dose-dependent reduction of the systolic and mean arterial blood pressure in anaesthetized rats. The amounts of IS-2-MN required for the purpose were identical for both kinds of application. The fall of the systolic and mean arterial blood pressure due to ISDN is approx. 22 times weaker after enteral administration than it is after intravenous application. The hypotensive effect of ISDN or IS-2-MN could be antagonized by pre-treatment of the animals with i.v. dihydroergotamine (DHE). The half-life of IS-2-MN in the rat was unchanged after increase of the oral doses. The bioavailability of IS-2-MN in the rat was 100%. 1 h after oral or intravenous administration of IS-2-MN to the rat, the concentrations in the walls of aorta abdominalis and aorta thoracica and in the walls of vena cava caudalis and vena thoracica were distinctly greater than in the blood or in the other tissues examined.

Angina Pectoris↗
PubMed1994

Comparison of the hemodynamic responses to molsidomine and isosorbide dinitrate in congestive heart failure.

To evaluate the mechanisms involved in nitrate tolerance, we randomized 23 patients with congestive heart failure resulting from coronary artery disease to an isosorbide dinitrate or a molsidomine infusion. The drugs were titrated to decrease pulmonary capillary wedge pressure by > or = 30% or > or = 10 mm Hg. Then isosorbide dinitrate, molsidomine, or placebo was infused in a double-blind randomized manner for 24 hours. In all patients, treatment with enalapril was begun > or = 48 hours before the beginning of the protocol and was continued throughout the study to avoid renin-angiotensin activation. The pulmonary capillary wedge pressure remained significantly decreased at 24 hours during molsidomine infusion only. No significant increase in catecholamines occurred. Because molsidomine differs from organic nitrates by its property of directly stimulating guanylate cyclase without depending on thiol group availability, these results suggest that impaired biotransformation of nitrates is involved in tolerance induced by high doses of isosorbide dinitrate in congestive heart failure.

Biotransformation↗
PubMed1978

Hemodynamic effects of cutaneously administered isosorbide dinitrate ointment.

With a view to testing the hemodynamic effects of a 10% isosorbide dinitrate ointment, about 40 mg of the drug was applied to the skin of nine cardiologically healthy volunteers. The ensuing hemodynamic changes were followed up for six hours by means of noninvasive techniques including echocardiography. As early as 30 min after drug application, significant decreases in heart rate, cardiac output, systolic blood pressure and intracardiac diameters were recorded. Only systolic blood pressure had returned to initial values by the end of the observation period. Isosorbide dinitrate ointment diminished myocardial oxygen consumption for a duration beyond six hr, by reducing pressure and heart-rate work of the left ventricle.

Administration, Topical↗