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PubMed1976

Effects of isosorbide dinitrate and nitroglycerin on central circulatory dynamics in coronary artery disease.

This study compares the effects and duration of the effects of 5 mg. of sublingual (SL) isosorbide dinitrate (ISD), 20 mg. of oral ISD, and 0.4 mg. of SL nitroglycerin (TNG) on central circulatory dynamics. Twenty-seven patients with coronary artery disease were evaluated with radioisotope techniques and determinations made of heart rate (HR), blood pressure (BP), cardiac index (CI), stroke volume index (SVI), left ventricular enddiastolic volume index (LVEDVI), and left ventricular ejection fraction (LVEF). There were significant and equivalent reductions in BP, SVI, LVEDVI, and CI 15 minutes after TNG, 1 hour after SL ISD, and 4 hours after oral ISD in addition to comparative increases in HR and EF by all drugs at these same time intervals. The effects of TNG were gone at 30 minutes while changes in LVEDVI, LVEF, and CI were present 4 hours after SL ISD and persistent changes in LVEDVI and SVI present 6 hours after oral ISD. We conclude that nitrates have significant effects on both preload and afterload and that the duration of effects of sublingual and oral ISD are truly long acting as compared to TNG.

Administration, Oral↗
PubMed2005

Muscle regeneration in dystrophic mdx mice is enhanced by isosorbide dinitrate.

Activation of muscle satellite cells, a fundamental step in the success of muscle regeneration is mediated by nitric oxide (NO). In this study, we investigated whether isosorbide dinitrate (ISD), an NO donor, could improve muscle regeneration in dystrophic mdx mice. The right tibialis anterior muscle of mdx and C57Bl/10 mice was injected with bupivacaine (0.3 ml, 33 mg/kg), a myotoxic agent, to induce muscle fiber regeneration. After bupivacaine injection, mice were treated with ISD (30 mg/kg; i.p.), verapamil (a non-NO donor vasodilator, 15 mg/kg, i.p.) or saline solution (vehicle, 0.3 ml, i.p.) for 20 days. Some bupivacaine-injected mice received no pharmacological treatment (control group). Muscle regeneration was evaluated by counting the total number of muscle fibers and measuring myofiber cross-sectional area. ISD significantly improved bupivacaine-induced muscle regeneration in mdx by increasing by 20% the total number of muscle fibers compared to the other groups. Spontaneous muscle regeneration, evaluated in the contralateral non-injected muscle, was not affected. ISD treatment did not affect myofiber cross-sectional area. Verapamil and saline had no effect on muscle regeneration. These results suggested that NO derived from ISD stimulated and/or recruited satellite cells. Pharmacological treatment with ISD could be clinically useful for improving muscle regeneration in Duchenne muscular dystrophy.

Anesthetics, Local↗
PubMed1991

Differences in the antiischaemic effects of molsidomine and isosorbide dinitrate (ISDN) during acute and short-term administration in stable angina pectoris.

The acute and short-term effects of treatment with 10 consecutive doses of isosorbide dinitrate 40 mg t.i.d. and molsidomine 8 mg t.i.d. in slow release formulations were investigated in 10 patients with angiographically documented coronary artery disease and stable angina pectoris according to a randomized, double-blind, double-dummy, cross-over study design using conventional symptom-limited exercise testing. Acute exercise testing 3 h following the first dose of ISDN and molsidomine showed a significant reduction of maximal ST segment depression and of the area above the ST segments. Time to occurrence of 0.1 mV ST segment depression, exercise duration, time to onset of angina and exercise tolerance increased significantly. On the fourth treatment day with ISDN and molsidomine an attenuation of these antiischaemic effects was seen. The mean effects on ST segment depression, area above ST segments, time to occurrence of 0.1 mV ST segment depression, exercise duration, time to onset of angina and exercise tolerance were reduced by 40%, 44%, 47%, 58%, 54% and 65%, respectively, in patients administered ISDN and by 33%, 48%, 58%, 59%, 45% and 60% in those given molsidomine. Thus, following sustained short-term therapy the antiischaemic effects of both drugs seem to be attenuated. In this report no marked differences were found between ISDN and molsidomine.

Angina Pectoris↗
PubMedDate not supplied

[New drug forms of isosorbide dinitrate: the problem of an objective evaluation in patients with ischemic heart disease].

In 7 patients with ischemic heart disease and stable angina pectoris the efficacy of three oral isosorbide dinitrate (ID) formulations, nitrosorbide, isodinite and isodinite-retard, was compared. The antianginal and anti-ischemic effects were assessed in terms of exercise treadmill tests performed prior to and repeatedly after (2, 5 and 7 hours) single-dose administration (in comparison with placebo). The efficacy of isodinite-retard only slightly differed from that of placebo. Isodinite had a more pronounced effect than nitrosorbide, although the duration of isodinite effect was shorter than that of nitrosorbide. Plasma ID and its metabolite, isosorbide-5-mononitrate concentrations mirrored exercise duration changes. ID content in the tablets of all formulations studied corresponded to those indicated by the manufacturer. The differences in the efficacy of ID formulations can be attributed to the differences in their bioavailability. Thus, the method used permitted to reveal significant distinctions in the efficacy of different ID formulations. These distinctions must be taken into account in clinical practice.

Angina Pectoris↗
PubMed1994

Intravenous diltiazem versus isosorbide dinitrate for unstable angina: comparison of coronary angiographic morphology in the unstable and stabilized states.

BACKGROUND: The efficacy of intravenous infusion of diltiazem was compared with that of isosorbide dinitrate (ISDN) for the early treatment of unstable angina. METHODS: Sixty-four patients with at least 70% organic stenosis of the culprit artery and prolonged rest angina were enrolled. Coronary angiography was performed on admission. Subsequently, patients were randomly assigned to receive either intravenous diltiazem or ISDN. Coronary angiography was repeated when the angina was under control, and the findings were compared with those on admission. RESULTS: Diltiazem was more effective than ISDN, and symptoms were resolved in 84% of the diltiazem group compared with 47% of the ISDN group (P = 0.0038). Repeat coronary angiography showed that the degree of stenosis remained unchanged in the majority of patients (n = 47, 75.8%). There was no difference between the two groups with regard to the coronary angiographic findings. CONCLUSIONS: Since diltiazem was more effective than ISDN even though the coronary angiographic findings of the two groups were similar, it is possible that some action other than vasodilatation (such as a direct protective effect on the myocardium) may be responsible for the remission of unstable angina.

Aged↗
PubMed1982

Isosorbide dinitrate alone and in association with intra-aortic balloon counterpulsation in acute myocardial infarction. A clinical study by precordial ECG mapping.

The effects of the association of Isosorbide Dinitrate (ISDN) and Intra-Aortic Balloon Counterpulsation (IABCP) on ECGphic signs (in 24-lead precordial maps) of myocardial damage were studied in 7 patients (pts) with anterior acute myocardial infarction (AMI) without cardiogenic shock and/or pulmonary congestion, admitted to the CCU within 6 hours (hrs) since the chest pain. Matched control group consisted of 7 pts treated with ISDN alone. Analysis of variance showed that the association of IABCP and ISDN influenced favourably (p less than 0.01) the trend of the sigma ST (in all leads and in those with ST segment elevation greater than 0.2 mV), of the ST and of NST. The trend of sigma R was similar in the two groups. sigma Q was influenced either by time and by therapy; NQ was significantly lower (p less than 0.01) in pts treated with ISDN and IABCP. These findings seem to give evidence that the association of ISDN and IABCP may really be effective in reducing and stabilizing the ECG extent of ischemic myocardial injury in pts with transmural AMI without left ventricular failure; however this aggressive therapy cannot have a widespread indication until more reliable criteria for evaluating infarct size are available and larger randomized clinical trials performed.

Assisted Circulation↗
PubMed1992

[Doppler echocardiographic evaluation of vasodilator treatments in patients with cardiac insufficiency. Contribution to the combination of isosorbide dinitrate and captopril].

Hemodynamic evaluation of a vasodilator drug is a difficult exercise in which Doppler echocardiography can be a useful tool. We studied the hemodynamic effect of isosorbide dinitrate (ISDN) by Doppler echocardiography in 7 patients with severe cardiac failure despite prolonged therapy with usually effective doses of captopril. The patients were evaluated before (H0) and 24 hours after treatment by ISDN (120 mg/24 hr) (H24) and 10 minutes after sublingual 0.75 mg of trinitrin (H24 + T). M mode echocardiography did not show any significant changes in chamber dimension as reported after vasodilator therapy in patients without cardiac dilation: in patients with severe left ventricular dilatation a reduction in LV filling pressures causes little if any changes in fractional shortening and ventricular dimensions. Two-dimensional echocardiography showed a reduction in end systolic volume and an increase in ejection fraction, emphasizing the superiority of this technique in cases of abnormal left ventricular function and the sensitivity of indices of systolic function to changes in afterload in these patients. Cardiac output measured by Doppler increased during the study. The maximal acceleration did not change significantly and pulmonary artery pressures were stable after administration of nitrates. ISDN caused a marked change in diastolic mitral flow patterns for which there are several explanations: an effect of ISDN on relaxation or LV compliance or on the conditions of LV filling or on both factors together. The presence of mitral regurgitation and/or atrial arrhythmia prevents the use of Doppler indices for analysis of diastolic LV function.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed2000

[Evaluation of antianginal efficacy of long-term therapy with low dose isosorbide dinitrate in patients with stable angina pectoris].

UNLABELLED: The aim of this study was to evaluate two ways of long-term therapy with lower doses of oral isosorbide dinitrate (ISDN) in normal tablets and in sustained-release form (SR), in patients with stable angina. METHODS: In double-blind, placebo (PL) controlled with cross-over design study 38 male patients with stable angina and angiographically proven coronary artery disease, received ISDN in normal tablets in two doses: 10 mg and 20 mg, and also two doses SR: 20 mg-SR and 40 mg-SR or PL in the first ingestion and in long-term therapy in two 7 day phases: 4-times-daily (4x) every 6 h and 3-times-daily (3x) with 12 h interval. In 3x patients received ISDN only in doses: 20 mg, 20 mg-SR and 40 mg-SR. After the first ingestion and on the last day of long-term phases, exercise stress tests on the treadmill were performed: preceding ingestion, 2 h and 6 h after. Evaluation of antianginal efficacy of ISDN was performed by analysis of walking times: total, to angina and to ischemia (WTI). RESULTS: 6 h after first ingestion all doses of ISDN improved significantly WTI in comparison to PL: 10 mg by 34.6% (p < 0.01), 20 mg by 49.6% (p < 0.0001), 20 mg-SR by 42.9% (p < 0.001) and 40 mg-SR by 52.5% (p < 0.0001). None of the doses improved significantly WTI in the long-term 4x phase, in 3x--only 40 mg-SR by 12.1% (p < 0.05). CONCLUSIONS: Tolerance to anti-anginal efficacy of ISDN in lower doses in long-term therapy 4-times-daily, every 6 h, was found. A 12-h interval is sufficient to prevent tolerance in long-term treatment of sustained-release ISDN in 40 mg dose. Intermitted dosing of nitrates, as a prevention of tolerance, and the practical results of works using other pharmacologic interventions in a clinical setting are discussed in the final section of this paper.

Adult↗
PubMed1985

[Possibility of developing tolerance to the anti-anginal effect of isosorbide dinitrate and verapamil].

Using exercise tests in 22 patients with stable angina of effort, the authors studied the possibility of the development of tolerance to the antianginal effect of isosorbide dinitrate (ID) and verapamil (VP). Within 6-12 weeks of the regular intake of ID, 5 (26%) patients developed complete tolerance, 6 (32%) partial tolerance to the drug. In 8 (42%) patients the effect of ID remained stable. A six-week administration of VP was accompanied by no signs of tolerance to the drug even in the patients who showed tolerance to ID.

Adult↗
PubMedDate not supplied

Quantitative and qualitative modifications of lymphocyte subsets after sublingual administration of isosorbide dinitrate in migraineurs. Preliminary report.

In 22 migraine patients and 5 healthy controls an investigation has been performed on lymphocyte subsets in basal conditions and 90 minutes after sublingual isosorbide dinitrate (IDN) administration. In all patients the drug assumption induced a typical migraine attack with increase in all examined lymphocyte subsets with except of NK cells. A statistically significant increase (p < 0.05) in T lymphocyte subsets we found during the crisis, whereas in healthy controls neither a migraine attack nor any modification in lymphocyte subsets could be observed. These results seem to confirm the immune alteration we have previously found in migraineous patients and suggest the possible role of IDN-stimulated endothelium not only in vasodilatation but also in production of substances responsible of the observed immune modifications.

Administration, Sublingual↗
PubMed1982

Randomized double-blind comparison of nifedipine and isosorbide dinitrate therapy in variant angina pectoris due to coronary artery spasm.

Twelve patients were entered prospectively into a randomized double-blind study comparing the efficacy of nifedipine and isosorbide dinitrate (ISDN) in the treatment of variant angina pectoris due to coronary artery spasm. Using the diary technique, both anginal episodes and nitroglycerin tablets consumed were recorded during the pretrial, no drug period, and both active drug phases. During the baseline pretrial period, an average of 1.1 anginal episodes/day occurred with reduction to 0.28/day during nifedipine treatment and 0.39/day during ISDN treatment. Headache was the major side effect during ISDN treatment, occurring in 9 of 11 (81%) patients; and nonheart failure related pedal edema during nifedipine treatment, occurring in 4 of 12 (33%) patients. Intolerable side effects necessitating cessation of treatment occurred in two patients during nifedipine treatment and in three patients during ISDN treatment. Patients preferred nifedipine over ISDN because of increased efficacy and fewer uncomfortable side effects. We conclude that both nifedipine and ISDN are effective therapy for coronary spasm, but that nifedipine was more effective and was preferred by the majority of patients.

Adult↗
PubMedDate not supplied

Determination of isosorbide dinitrate biotransformation in various tissues of the rabbit by capillary column gas-liquid chromatography.

A selective and sensitive capillary column gas-liquid chromatographic procedure has been developed for the simultaneous determination of isosorbide dinitrate (ISDN) and its mononitrate metabolites in rabbit blood and tissue homogenates. The method has a limit of detection of 0.1 ng ml-1 for ISDN, 1 ng ml-1 for isosorbide 5-mononitrate (5-ISMN), and 2 ng ml-1 for isosorbide 2-mononitrate (2-ISMN). The day-to-day coefficients of variation were 2.5, 6.8, and 11.3 per cent for ISDN, 5-ISMN, and 2-ISMN, respectively. The within-day coefficients of variation were 2.7, 4.9 and 6.5 per cent for ISDN, 5-ISMN, and 2-ISMN, respectively. The procedure was used to determine the biotransformation of ISDN (2 X 10(-7) M) to 5-ISMN and 2-ISMN by various rabbit tissue homogenates. The relative rate of biotransformation of ISDN was liver greater than lung approximately equal to intestine greater than kidney greater than blood approximately equal to skeletal muscle, with the lung and intestine homogenates being about two-thirds as active as liver homogenates. These results indicate that extrahepatic biotransformation of ISDN, especially by lung and intestine, may contribute to the systemic clearance of ISDN in the rabbit.

Animals↗
PubMed1985

High-dose isosorbide dinitrate in management of angina pectoris.

The hypothesis was tested that selected patients with coronary artery disease whose rate of angina attacks do not respond to low doses of isosorbide dinitrate (ISDN) (40 mg/day) may respond to high doses (480 mg/day), tolerate them, and maintain their responsiveness over the long term. Twenty-four patients with grade 3 stable angina pectoris were given a placebo for 4 weeks and then had their ISDN dosages titrated up to 120 mg four times a day during another 6 weeks in a single-blind fashion. The 20 patients who responded to (and tolerated) a high dose of ISDN were maintained at that dose for an average of 1 year. The weekly rate of angina attacks fell by 74%, from 6.05 during placebo to 1.6 (p less than 0.01) during long-term ISDN treatment. Nitroglycerin consumption fell similarly. Patient assessment of activity level, well-being, and angina threshold improved in the majority of patients. The within-patient trend of their weekly rate of angina episodes was stable in 13 patients, downward in six, and upward in only one patient. Exercise performance evaluated by a submaximal graded multistage treadmill test showed a small but nonsignificant improvement of 1.8%. It is concluded that (1) some patients who do not respond to the antianginal action of low-dose ISDN may respond to a high dose and tolerate it, (2) this responsiveness and tolerability may last for over a year, and (3) ISDN may be clinically useful in patients with coronary disease even when exercise performance is not significantly improved.

Adult↗
PubMed2002

Head-up tilt table testing with low dose sublingual isosorbide dinitrate in the evaluation of unexplained syncope: a comparison with isoproterenol infusion.

OBJECTIVES: To investigate the value of head-up tilt table testing (HUTT) with low-dose isosorbide dinitrate (ISDN) in the evaluation of patients with unexplained syncope and to compare the results of HUTT with ISDN and HUTT with isoproterenol. PATIENTS AND METHODS: Forty-three patients with unexplained syncope (21 women, with a mean age of 45.4 18 years) and 18 control subjects without syncope (eight women, with a mean age of 45.8 12 years) were tilted (80 ) for 30 min (passive period). When this period was negative, 2.5 mg sublingual ISDN was administered and patients were observed for an additional 15 min (ISDN period). The first 25 patients studied (10 women, with a mean age of 46.2 18 years) were tested again after a mean period of three weeks using the isoproterenol protocol. After the passive period, intravenous isoproterenol was administered (1 to 3 g/min) to patients lying in the supine position, and they were tilted again (80 ) for 10 min (isoproterenol period). RESULTS: During the passive period, 10 of 43 patients (23%) had a positive response compared with none in the control group. Syncope was observed in another 14 patients and in two control subjects during the ISDN period. The positivity rate (sensitivity) and specificity of HUTT with low dose ISDN were 56% and 89%, respectively. Among the patients (n=25) tested with the isoproterenol protocol, 14 (56%) patients had syncope. The agreement rate between the protocols was 78.9%. CONCLUSIONS: The total positivity rate of HUTT significantly increased with the use of the low dose ISDN, while specificity remained high. Due to its simplicity and tolerability, the ISDN protocol can be chosen when the results of the passive period tilt testing are negative.

Administration, Sublingual↗
PubMedDate not supplied

Comparison of the effects of molsidomine, nitroglycerin and isosorbide dinitrate on experimentally induced coronary artery thrombosis in the dog.

Platelet activation and aggregation in the coronary circulation may be important in the pathogenesis of myocardial ischemia. Molsidomine (M), isosorbide dinitrate (ISDN) and nitroglycerin (NTG) have been found to inhibit platelet aggregation in vitro. In the present study, the activity of these compounds was investigated in a model of coronary artery thrombosis in vivo. Dogs were anesthetized, thoracotomized, and their heart was exposed. An electrode was inserted into the left circumflex coronary artery and set to rest on the intima. Electrical stimulation (9 V, 150 microA) lasted for 6 h. Compounds (each in 2 dose levels) were given as an i.v. infusion starting 30 min after the beginning of the stimulation and lasting for the duration of the experiment. All control (saline-treated) animals underwent thrombotic occlusion of the coronary artery as assessed by flow measurement. On the other hand, 2/8 dogs treated with the lower M dose and 4/8 dogs treated with the higher M dose did not have a coronary occlusion. Neither ISDN nor NTG, at both doses, prevented the coronary occlusion. In control animals thrombus wet weight was 74.43 +/- 11.25 mg. M reduced the thrombus weight in a dose-related manner, while ISDN (marginally) and NTG (significantly at the higher dose) increased this parameter. Following the coronary thrombosis, all control animals developed myocardial infarcts as assessed by the tetrazolium technique. Similarly all animals treated with ISDN and with NTG (at both doses) showed infarcts. However, 3/8 M-dogs did not have a myocardial infarction in the lower as well as in the higher dose groups. The hemodynamic changes induced by the 3 compounds were similar in magnitude. Thus M but not ISDN or NTG showed in this in-vivo study antithrombotic and consequently antiischemic activity.

Animals↗
PubMed1980

[Longterm effect and maintenance therapy with cutaneous isosorbide dinitrate in patients with coronary heart disease (author's transl)].

The aim of this study was to examine the duration of action of a single cutaneous application of a 10% isosorbide dinitrate ointment (ISDN-S) and also to ascertain the possible appearance of nitrate tolerance after 6--8 months' maintenance therapy with ISDN-S. After a single application of the ointment an effect lasting more than 7 hours was confirmed by bicycle ergometry. After longterm therapy an acute test with rapidly acting sublingual ISDN produced an undiminished response thus showing lack of nitrate tolerance.

Coronary Disease↗
PubMed1982

[Dose-effect relationship of isosorbide dinitrate in the treatment of angina pectoris (author's transl)].

Fifteen males with angiographic evidence of coronary heart disease and stable, exercise-induced angina pectoris were given placebo or isosorbide dinitrate (ISDN) in a dialy dose of 30 mg, 120 mg, 240 mg and 480 mg in a randomized single-blind trial. The daily doses were given as a single oral dose of 5 mg, 20 mg, 40 mg and 80 mg tablets. Each dose and placebo was given for seven days. On the seventh day an exercise ECG of standardized level and duration of exercise was recorded. The ischaemia response in the ECG revealed a dose-dependent reduction by 28% (5 mg ISDN), 43% (20 mg), 60% (40 mg) and 73% (80 mg). The number of anginal attacks similarly fell parallel to dose. Plasma level of ISDN and the mononitrates, measured one and four hours after drug intake, rose almost linearly in relation to dose. Oral ISDN thus has a dose-dependent effect on the frequency of angina and ischaemia parameters during ergometric exercise. The protracted anti-anginal effect of ISDN is largely due to its metabolites. At high doses there is presumably an added effect of the high blood level of the basic substance.U

Adult↗
PubMed1985

Isosorbide dinitrate and glyceryl trinitrate: demonstration of cross tolerance in the capacitance vessels.

Cross tolerance to the arterial effects of sublingual glyceryl trinitrate (GTN) has been demonstrated in subjects taking oral isosorbide dinitrate (ISDN). To determine if cross tolerance also develops in the venous system, the effects of 0.6 mg of GTN on venous capacitance were assessed before (stage A) and during (stage B) therapy with ISDN. Venous capacitance was assessed using the radionuclide blood pool method, with relative changes in regional blood volume measured in the forearm in 6 patients and the splanchnic circulation in 4 patients. Heart rate, blood pressure and blood volume were measured before and at 1-minute intervals for 10 minutes after GTN; there was less than 2% variability in regional blood volume during 6 control measurements. During stage A, 5 minutes after GTN, systolic blood pressure (mean +/- standard deviation) decreased by 14% (from 125 +/- 15 to 107 +/- 19 mm Hg, p less than 0.01) and heart rate increased by 17% (from 68 +/- 14 to 80 +/- 17 beats/min, p less than 0.001), while regional blood volume increased to 101 +/- 2% at 1 minute (difference not significant [NS]), 111 +/- 2% at 5 minutes (p less than 0.001) and 107 +/- 3% at 10 minutes (p less than 0.01) relative to baseline measurements.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗