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PubMed1995

Comparison of the therapeutic efficacy of continuous and intermittent injection of isosorbide dinitrate: a randomized study on unstable angina.

Therapeutic efficacy of intermittent and continuous injection of isosorbide dinitrate (ISDN) was compared in 22 patients (mean age 64 +/- 10, 18 males and 4 females) with unstable angina at rest. They were randomized into 2 groups that received either continuous (10 mg/h, group A) or intermittent (10 mg/10 min every 2 hours, group B) injection of ISDN for 3 days (phase 1). Each injection protocol was switched (phase 2) and subsequently switched back to the initial protocol (phase 3) in a cross-over fashion. The serum concentrations of ISDN, 2-isosorbide mononitrate (2-ISMN) and 5-ISMN were measured serially during both intermittent and continuous injection protocols. In addition, the incidence and duration of angina and changes in systolic blood pressure were analyzed. There were 3 treatment-failure cases during the intermittent injection period and 1 during the continuous injection period. Three of these treatment-failure cases developed small acute myocardial infarcts despite emergent coronary arteriography followed by intra-coronary thrombolysis and percutaneous balloon angioplasty. There was no difference in therapeutic efficacy between continuous and intermittent ISDN in terms of the incidence, duration of angina attacks and the number of patients whose angina was suppressed. After bolus injection of ISDN (10 mg/10 min), the serum concentration of ISDN increased rapidly and returned to the control level at 60 minutes after the injection. The serum 5-ISMN and 2-ISMN concentrations also increased immediately after injection and then decreased gradually reaching statistically insignificant level to the control values at 60 minutes after injection. With continuous injection, ISDN and its metabolites increased gradually and reached similar but slightly lower serum concentrations to the peak levels during intermittent injection. We conclude that the therapeutic efficacy of intermittent and continuous injection of ISDN is similar in patients with unstable angina.

Adult↗
PubMed1985

Role of isosorbide dinitrate in patients with unstable angina pectoris.

The development of hemodynamic facilities permitted observations after isosorbide dinitrate (ISDN) administration over a 4-hour period in patients with a history of unstable angina pectoris and documented anatomic coronary artery disease. The patients had no evidence of left ventricular failure and were free of pain during the period of sublingual and oral ISDN administration. Beneficial influences on venous return and arterial blood pressure were manifested as declines in preload and afterload, along with reduction in the mechanical work of the ventricle and, finally, increases in the diastolic compliance of the ventricle. These hemodynamic changes were shown to persist 8 to 12 times as long as the brief influence of nitroglycerin. Thus hemodynamic evidence was provided for the first time on the beneficial influence of oral and sublingual ISDN on venous, arterial, and left ventricular myocardial muscle in patients with unstable angina pectoris.

Angina Pectoris↗
PubMed1982

Comparative study of the haemodynamic effects of oral molsidomine and isosorbide dinitrate in man.

The haemodynamic effects of oral molsidomine 4 mg and sustained-release isosorbide dinitrate (ISDN) 40 mg have been compared in 10 patients recovering from acute myocardial infarction. After both drugs pulmonary arterial, pulmonary capillary wedge and systemic arterial blood pressure were reduced to about the same extent. The maximum effect was reached 1.5 to 2 h after ingestion of both drugs, but the effect of molsidomine declined during the following 2 h and control values were almost reached after 4 h. After ISDN there was no rebound during the observation period of 6 h. Unlike molsidomine, ISDN reduced total peripheral resistance, so cardiac output and stroke volume index remained constant despite the reduction in cardiac preload. It is concluded that sustained release ISDN 40 mg and molsidomine 4 mg are about equieffective doses in terms of reduction of cardiac preload, but that the effect of molsidomine is of shorter duration. Since molsidomine alone causes venous pooling, cardiac output and stroke volume index are reduced, which may be an untoward side effect in patients with severe heart failure.

Cardiac Output↗
PubMed1986

Cardiovascular effects of isosorbide dinitrate infused intravenously into anaesthetized dogs.

The cardiohaemodynamic response and the development of tolerance to isosorbide dinitrate (ISDN) were examined in anaesthetized, open-chest dogs. ISDN, infused intravenously (i.v.) for 2 h at a rate of 10 or 30 micrograms/kg per min, decreased systemic blood pressure (systolic, mean and diastolic; SBP), left ventricular (LV) systolic and end-diastolic pressure, LVdP/dt max, pressure-rate product and coronary blood flow. No significant changes in heart rate (HR) and coronary vascular resistance were observed. Intravenous ISDN significantly attenuated the vasodilator effect of bolus intracoronary (i.a.) glyceryl trinitrate (GTN, 1 micrograms), and ISDN (30 micrograms), whereas that of bolus i.a. nicorandil (mononitrate, 20 micrograms) remained unaffected. Just after acute tolerance towards i.a. ISDN was provoked 1 h after starting ISDN infusion (30 micrograms/kg per min, i.v.), the combined infusion of ISDN (i.v.) and nicorandil (30 micrograms/kg per min) was instigated for a further hour. Also, 1 h after the onset of vehicle infusion (i.v.), the combined infusion of vehicle and nicorandil (30 micrograms/kg per min, i.v.) was started. There were essentially no significant differences between the corresponding values concerning the coronary vascular responses obtained from the two combined infusion groups.

Animals↗
PubMed1990

Randomized double-blind comparison of isosorbide dinitrate and nifedipine in variant angina pectoris.

The antianginal and anti-ischemic effect of isosorbide dinitrate (ISDN), 120 mg once daily, and nifedipine, 20 mg twice daily, both in slow-release formulations, were compared in 17 patients with variant angina pectoris in a randomized, double-blind trial. The design included a placebo run-in period and two 6-week crossover periods of active treatment. Mean frequency of angina decreased significantly from 43 attacks per week during the placebo period to 4 per week with ISDN and 8 with nifedipine (p less than 0.001). Sublingual nitroglycerin consumption decreased significantly from 37 tablets per week with placebo to 3 tablets per week with ISDN and 7 with nifedipine (p less than 0.001). Both drugs reduced the silent and symptomatic ST-segment deviations on ambulatory electrocardiographic recording and increased maximal exercise tolerance. Episodes of coronary spasm could be provoked, by hyperventilation, in all patients during the placebo phase but in no patient during therapy with either active drug. Thus, both ISDN and nifedipine, in their slow-release formulations, are effective in the treatment of variant angina pectoris.

Adult↗
PubMed1988

Increased exercise tolerance and reduced duration of ischemia after isosorbide dinitrate oral spray in angina pectoris.

The prophylactic and therapeutic anti-ischemic efficacy of isosorbide dinitrate (ISDN) oral spray was assessed in 10 patients with coronary artery disease and stable angina pectoris. The patients entered a randomized crossover study of ISDN spray and placebo, involving bicycle exercise testing. Each patient underwent 2 exercise tests at least 4 hours apart. Immediately before initiation of exercise they received either ISDN spray or placebo and crossed over during the other test. ISDN spray delayed the onset of anginal pain by about 40%, from a mean of 5.1 +/- 1.4 minutes with placebo to 7.2 +/- 1.3 minutes with the active drug (p less than 0.001). Time of onset of ST-segment depression was also significantly prolonged, from 7.1 +/- 1.5 minutes with placebo to 10.2 +/- 1.2 minutes with ISDN (p less than 0.001). The patients achieved a higher double product at onset of pain with ISDN than with placebo. The drug also reduced the time of disappearance of pain after discontinuation of exercise from 3.2 +/- 0.7 to 2.1 +/- 0.8 minutes (p less than 0.001), and the time of disappearance of electrocardiographic changes from 4.2 +/- 0.6 to 2.5 +/- 0.8 minutes (p less than 0.005). These findings indicate that oral ISDN spray is an effective prophylactic for exercise-induced angina. Its rapid onset of action makes it especially suitable for usage immediately before exercise.

Administration, Oral↗
PubMed1987

Isosorbide dinitrate blocks thromboxane synthesis caused by CO2 in dog heart-lung preparation.

Effects of isosorbide dinitrate (ISDN) on coronary flow and arterial prostaglandin (PG) concentrations were investigated, using dog heart-lung preparations. Two kinds of gases (low and high CO2 gases) were used for the artificial respiration. Low CO2 gas contained 55% O2 and 0.2% CO2, whereas high CO2 gas contained 55% O2 and 8% CO2. Administration of ISDN into a blood reservoir at high CO2 caused an increase in coronary sinus blood flow, which was blocked by indomethacin, but not at low CO2. In the absence of ISDN, the arterial concentration of thromboxane (TX) B2 was larger at high CO2 than at low CO2. ISDN attenuated such an increase in TXB2 concentration caused by CO2. The arterial concentration of 6-keto PGF1 alpha was altered by neither CO2 nor ISDN, but slightly increased with time. Indomethacin lowered the concentrations of 6-keto PGF1 alpha and TXB2. These results suggested that the arterial CO2 tension enhanced the TXA2 synthesis and that ISDN inhibited such a relation between CO2 and TXA2 synthesis. Additionally, the vasodilatory effects of PGI2 was enhanced by elevating the arterial CO2 tension. Thus, the increase in canine coronary flow at high CO2 in the presence of ISDN may be related to the inhibitory effects of ISDN on the TXA2 synthesis enhanced by the high arterial CO2 tension and the facilitatory effects of CO2 on the PGI2-induced vasodilation.

Animals↗
PubMed1988

Cooling down unstable angina with high dosage of isosorbide dinitrate (ISDN) continuously infused.

The aim of this study was to explore the capability of isosorbide dinitrate (ISDN) infusion to quench the 'hot phase' of unstable angina, a real cardiological emergency. Fifteen patients consecutively admitted to CCU because of angina at rest, with at least 4 ischaemic attacks per day, resistant to the usual therapy with oral and/or topical nitrates and calcium-antagonists, were included in the study. During ischaemia the electrocardiogram showed ST-segment elevation in 7 patients, ST-segment depression in 4, an alternation of ST-segment elevation and depression in 3 and pseudonormalization of a basally negative T wave in 1 patient. History of exertional angina with variable degrees of effort was reported in 6 patients and 9 had an old myocardial infarction. Coronary arteriography performed in 10 patients showed a significant stenosis of 1, 2 and 3 vessels in 5, 2 and 3 patients, respectively. ISDN infusion was started at 1.0 mg h-1, and was increased stepwise when persistence of ischaemic episodes had to be faced. The mean dosage infused was 3.5 mg h-1 (range 1.00-12). The mean duration of intravenous therapy was 8.3 days (range 2-25). Eleven of the 15 patients (73%) showed an effective decrease in the number of ischaemic episodes during ISDN infusion, as assessed by regression and variance analysis. After discharge (mean follow-up 59 months, range 2-96), 7 patients were free from ischaemic attacks, 3 underwent coronary by-pass surgery, 2 complained of some attacks and 3 died (2 because of sudden death three years after this study). In conclusion, ISDN infusion--individually tailored for dosage and duration--can be effective in 'cooling down' the storm of ischaemic episodes in unstable angina. An effective intravenous therapy with nitrates can represent, in some patients, a temporal remedy on the way to elective coronary bypass surgery and/or towards elective PTCA. Furthermore, in a sizeable number of patients with unstable angina, this approach can attain a complete abolishment of the ischaemic attacks.

Adult↗
PubMed1987

Comparison of nifedipine and isosorbide dinitrate when added to maximal propranolol therapy in stable angina pectoris.

A study was performed to compare isosorbide dinitrate and nifedipine as adjunctive therapy in 14 patients with coronary artery disease and stable angina pectoris taking maximal beta-blocking drugs. Drug titration phases ensured maximal therapy of propranolol, isosorbide or nifedipine. The combination of nifedipine and propranolol was more effective than the combination of isosorbide and propranolol in reducing angina and increasing exercise capacity (323 vs 416 seconds, p less than 0.005) during exercise treadmill testing. Nifedipine produced a greater reduction in systolic blood pressure at submaximal exercise than isosorbide. Global and regional ejection fraction at rest and exercise was assessed with radionuclide ventriculography. The substitution of nifedipine for isosorbide depressed the global ejection fraction at rest (0.61 to 0.56 p less than 0.05) and produced a slight improvement in exercise ejection fraction (0.47 to 0.51, difference not significant). The decrease in ejection fraction from rest to exercise was 0.14 to 0.04 with nifedipine (p less than 0.005). The benefit of nifedipine compared with isosorbide occurred in regions with marked exercise-induced ischemia. In patients treated with maximal beta-blocking therapy, nifedipine is an effective alternative to isosorbide as a combination agent with propranolol. The salutary effects of nifedipine included afterload reduction with exercise and possible improvements in coronary blood supply.

Angina Pectoris↗
PubMed1983

Different hemodynamic actions of trinitroglycerin and isosorbide dinitrate in patients with acute myocardial infarction.

The hemodynamic effects of intravenously administered trinitroglycerin (TNT) and isosorbide dinitrate (ISDN) in stechiometric equivalent doses were studied in 30 patients with acute myocardial infarction. Both drugs were given over 30 min in every patient, and the stability of the condition of the patient was checked by administering the initial drug again. Measurements were made by right heart catheterization using a balloon tip thermodilution catheter and a catheter in the radial artery. TNT and ISDN have different hemodynamic effects. By multivariate analysis it could be shown that TNT is a venous dilator, lowering mainly pulmonary capillary pressure, while ISDN acts more as a mixed vasodilator, diminishing mainly peripheral vascular resistance and increasing cardiac output. These drugs have, therefore, a different spectrum of indications in patients with acute myocardial infarction.

Cardiac Output↗
PubMed1983

Haemodynamic and clinical effects of isosorbide-dinitrate in patients with severe effort angina on beta-blocking treatment.

The effect of isosorbide-dinitrate (ISDN) 20 mg 4 times daily against placebo has been tested in 12 patients with stable effort induced angina pectoris receiving prophylactic treatment with metoprolol. ISDN did not decrease the attack rate or nitroglycerine consumption, nor was exercise tolerance increased after it. Left ventricular function, assessed by radionuclide ventriculography, increased in 6 out of 8 patients (p less than 0.1). It is concluded that ISDN has no place in the treatment of haemodynamically intact patients with severe angina pectoris in spite of beta-blocking treatment, but that it may be of value in the treatment of patients with left ventricular failure, including those whose left ventricular failure has been brought about by beta-blocking treatment necessitated by angina pectoris.

Adult↗
PubMed1991

An attempt to use artificial membranes to investigate cellular membrane permeation--application to nitroglycerin and isosorbide dinitrate.

The pharmacodynamic efficiency of nitroglycerin (TNG) is 3 to 4 times higher than that of isosorbide dinitrate (ISDN). In a previous work the authors have shown that this difference is partially due to the transmembrane diffusion potential of the molecules. The aim of this present study is to confirm this hypothesis by using artificial solid lipid membranes and thus to validate the method which will be used to predict the transmembrane diffusion of drugs. Two types of artificial membranes, having nearly the same liposolvent properties as the biological membrane, are tested to investigate intracellular drug penetration. These artificial membranes are fitted on the Dibbern's three phases apparatus: the Resomat 2. The results are in accordance with the data obtained on erythrocyte membranes showing that both drugs have a good transmembrane diffusibility and also that TNG presents a quicker intracellular penetration than ISDN. These results contribute to validate this method, using artificial membranes, to predict the intracellular penetration of molecules.

Cell Membrane↗
PubMed1984

Haemodynamics and plasma concentrations following sublingual GTN and intravenous, or inhaled, isosorbide dinitrate.

We measured plasma nitrate levels and haemodynamics following sublingual glyceryl trinitrate (GTN) (0.5 mg), or isosorbide dinitrate (ISDN) administered intravenously (0.5 mg) or by inhalation (1.25 mg) in 23 patients undergoing cardiac catheterisation for investigation of chest pain. Peak levels were detected at 90 s and 5 min following intravenous and inhaled ISDN respectively and at 3 min following sublingual GTN. Intravenous and inhaled ISDN produced similar plasma levels at 30 s and both were significantly greater than following sublingual GTN. Plasma levels were maintained for longer following inhaled ISDN than intravenous ISDN or sublingual GTN. Haemodynamic responses were qualitatively similar following each treatment; reduction in pulmonary vascular resistance and pressure and left ventricular end diastolic pressure occurred in each group. Heart rate, cardiac output and LV dP/dt.P-1 remained unchanged. Maximal haemodynamic responses were greater following ISDN than GTN, with little difference between the two preparations of ISDN. Haemodynamic responses were more sustained following inhaled ISDN than following sublingual GTN or intravenous ISDN, the latter two being similar in this respect. These findings suggest that inhaled ISDN may provide more rapid and sustained relief from angina than sublingual GTN.

Absorption↗
PubMed2001

[The comparison of the efficacy of atenolol and isosorbide dinitrate therapy in chronic hypotension patients with stable angina pectoris].

Antianginal efficacy of atenolol (A) and isosorbide dinitrate (ID) was compared in a long-term randomized, single-blind, crossover, placebo controlled trial in 71 patients with combined stable angina pectoris and chronic hypotension (Hpts) and in 38 normotensive patients with angina of effort (Npts). Paired bicycle tests showed anti-ischemic activity of drugs: A in 75% and ID in 49% of Hpts, A in 83% and ID in 82% of Npts. Antianginal effect of 25 mg A was observed in 49% of Hpts (vs 6% of Npts; p < 0.01). Secondary resistance to A effect was developed on the treatment week 2-4 in 13% of Hpts (vs 0 in Npts) tolerance to ID effect--on week 1-2 in 71% of Hpts (vs 15% of Npts; p < 0.01) as evidenced by T1-199 exercise myocardial scintigraphy. Hpts needed individual ID therapy with a long-term ID-free period during 8-16 days (vs 3-5 in Npts; p < 0.05) to avoid tolerance. Stable antianginal ID effect manifested with a decrease of myocardial perfusion defect size by 43.1 +/- 1.3% (p < 0.05).

Adrenergic beta-Antagonists↗
PubMed1987

Comparative vasorelaxing profiles of nicorandil, isosorbide dinitrate and nitroglycerin in isolated coronary arteries of the dog.

The vasorelaxing effects of nicorandil (NCR), isosorbide dinitrate (ISDN) and nitroglycerin (NTG) were studied in isolated canine coronary arteries. In rings of coronary arteries precontracted with prostaglandin F2 alpha (3 x 10(-6) M) or KCl (30 mM), removal of the endothelium significantly augmented the relaxing effects of NCR, while it did not affect those of ISDN and NTG. In unrubbed rings precontracted with KCl (30 mM), methylene blue (5 x 10(-6) M) significantly inhibited vasorelaxing responses to the three drugs. The order of the inhibition was as follows: NTG greater than ISDN greater than NCR. When the unrubbed tissue was incubated with NTG (10(-5) M) or ISDN (10(-4) M) for 10 min, it developed acute tolerance in relaxing response to NTG or ISDN. Unlike NTG and ISDN, NCR did not develop any tolerance. The treatment with N-acetylcysteine (5 x 10(-5) M) tended to potentiate relaxant effects of NTG and to reduce the degree of acute tolerance to NTG. The results suggest that cGMP plays a role in the relaxation of the coronary artery induced by the drugs and furthermore that the mode of the vasorelaxing action of NCR may be somewhat different from that of NTG or ISDN.

Acetylcysteine↗
PubMed1995

Antagonism of cyanide toxicity by isosorbide dinitrate: possible role of nitric oxide.

In a search for improved cyanide antidotes, the efficacy of isosorbide dinitrate (ISDN), was compared with that of the known cyanide antidote, NaNO2. ISDN was as effective as an optimal dose of NaNO2 in protecting mice against cyanide lethality. To study the mechanism involved, the extent of formation of the cyanide scavenger, methemoglobin, in the action of ISDN was determined. ISDN (300 mg/kg, p.o.) increased methemoglobin from 5 to 10% of total hemoglobin, while, in contrast, NaNO2 (100 mg/kg, i.p.) increased methemoglobin levels to 50% of total hemoglobin. Lowering the dose of NaNO2 to 30 mg/kg reduced methemoglobin levels to approximately 10% of total hemoglobin and in turn nearly abolished its antidotal effect. Decreasing methemoglobin to less than control levels using methylene blue failed to abolish cyanide antagonism by ISDN. Thus, methemoglobin formation by ISDN does not account for its antidotal action. Further studies comparing the respiratory depressant effects of cyanide in the presence of ISDN or NaNO2 also indicated that these two antidotes have different mechanisms of action. Efforts to produce tolerance to the antidotal effect of ISDN against cyanide toxicity were unsuccessful. It is suggested that the well-known ability of ISDN to generate nitric oxide may account for the noted cyanide antagonism.

Administration, Oral↗
PubMed1986

Isosorbide dinitrate and pulsatile arterial haemodynamic variables in hypertension.

The effect of a sustained-release oral isosorbide dinitrate (ISDN) preparation on cerebral and forearm circulation was determined in 16 patients with mild to moderate essential hypertension. Measurements were made by pulsed Doppler velocimetry in the common carotid and the brachial arteries. Pulse wave velocity of the forearm was simultaneously recorded by means of strain gauge arterial mechanography allowing non-invasive evaluation of compliance and characteristic impedance of the brachial artery. Four hours after ISDN ingestion, the patients exhibited a significant decrease in blood pressure without a change in heart rate. An increase in carotid and brachial artery diameter was shown whereas blood flow increased only in the forearm. Resistance decreased significantly in both carotid and brachial vascular beds but only in the brachial vascular bed was the baseline resistance directly correlated with the change in brachial bed resistance. Concerning pulsatile large artery parameters, pulse wave velocity and characteristic impedance diminished, and brachial artery compliance increased significantly. The tangential tension of carotid and brachial arteries did not change. An increase in plasma renin activity was observed and related to the vasodilating effect on small arteries of the brachial vascular bed. This study showed that the antihypertensive effects of ISDN were accompanied by a strong vasodilatory action on small and large arteries and by an improvement in the pulsatile behaviour of large arteries.

Adult↗