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The value of Tc-99m MIBI SPECT during isosorbide dinitrate infusion in assessment of viable myocardium in patients with myocardial infarction.

Tc-99m MIBI myocardial SPECT has shown promise for evaluation of coronary artery disease. But its role in predicting myocardial viability is still under investigation. The purpose of this study was to evaluate the value of Tc-99m MIBI myocardial SPECT during isosorbide dinitrate (ISDN) infusion in the assessment of myocardial viability. Thirty-seven patients with previous myocardial infarction (the infarct age ranged from < or = 30 days to 900 days) were studied, of them 13 patients had Tc-99m MIBI studies before and after coronary artery bypass grafting (CABG). The results showed that out of 134 segments with hypoperfusion at resting SPECT, 56 segments (41.8%) had an increase in Tc-99m MIBI uptake during ISDN infusion. Among them, 17 segments (30.4%) were normalized, 6 segments (10.7%) were significantly improved and 33 segments (58.9%) were improved. The degree of improvement in perfusion was related to the age of the myocardial infarction. In 13 patients with CABG, of 31 segments with improvement in perfusion post CABG, 25 segments (80.6%) showed perfusion improvement during ISDN infusion, and of 28 segments with improved wall motion post CABG, 23 segments (82.1%) showed improvement in perfusion during ISDN infusion. Tc-99m MIBI SPECT during ISDN infusion may therefore be a useful approach for assessing myocardial viability.

Adult↗

Effect of isosorbide dinitrate ointment on anal fissure.

BACKGROUND/AIMS: Until recently, the treatment of choice for anal fissure was surgery, consisting of a partial lateral internal sphincterotomy. This treatment has a high complication rate: impaired continence is reported in 8-30% of the patients in the literature. Therefore, recently nonsurgical treatment modalities have been developed, such as local application of isosorbide dinitrate (ISDN) ointment. This treatment has comparable effectiveness with lower complication rates. To study the effect of ISDN on the healing of anal fissures in a general surgical practice, a prospective study was performed in our hospital. METHODS: In the period between June 1997 and January 2000, 100 consecutive patients with anal fissure were treated with ISDN. RESULTS: Of these 100 patients, 93 were healed within 8 weeks and 7 patients had no response and were operated. Of the 93 patients with primary healing fissures, 13 patients had recurrence during the 1-year follow-up. Seven of them were cured with ISDN, and the remaining 6 patients needed surgery. The only complication observed in this study was temporary headache which was observed in 7 patients. CONCLUSIONS: The primary healing rate of anal fissures was 93% with ISDN. In case of recurrence, 54% (7/13) could again be treated successfully with ISDN. Therefore, we recommend ISDN as first choice treatment for primary and recurrent anal fissures.

Administration, Topical↗

Isosorbide dinitrate does not interfere with heparin anticoagulation: a placebo-controlled comparison with nitroglycerin in patients scheduled for coronary artery surgery.

The possible nitrate-induced heparin resistance was studied intraoperatively in 40 patients undergoing coronary artery bypass grafting. The patients were randomized to receive a continuous infusion of placebo, nitroglycerin (0.5 microgram kg-1 min-1) or isosorbide dinitrate (0.5 or 2.5 micrograms kg-1 min-1). After the infusion had been administered, prior to the institution of cardiopulmonary bypass, for at least 60 min, porcine intestine heparin 300 I.U. kg-1 (as divided in two consecutive doses of 100 and 200 I.U. kg-1, respectively) was administered to achieve systemic anticoagulation. Activated coagulation time values and plasma heparin anti-X, activity showed no significant differences between the groups before and after the administration of heparin. It is concluded that in doses given in the present study, organic nitrates do not interfere with the anticoagulation effect of large doses of heparin required for the conduction of cardiopulmonary bypass.

Adult↗

Haemodynamic correlates of early and delayed responses to sublingual administration of isosorbide dinitrate in migraine patients: a transcranial Doppler study.

In normal subjects or migraine patients, nitrates induce a non-specific early headache caused by vasodilation of intracranial arteries. In migraineurs a delayed headache response to nitrates may have a typical clinical profile of a spontaneous migraine attack. The cerebral vasomotor changes of this delayed response require further study. Isosorbide dinitrate (IDN), an exogenous nitric oxide (NO) donor, was given at a dose of 5 mg sublingually and a bilateral transcranial Doppler device was used to monitor bilateral mean velocity (Vm) changes at the middle cerebral artery (MCA) after IDN administration and until delayed headache occurred. Spontaneous migraine-like headache occurred only in migraine patients during the delayed phase after IDN and was accompanied by a prolonged arterial vasodilation compared to normal subjects. This vasomotor response was more evident on the customary side of the head pain of a spontaneous migraine attack. Our findings suggest a particular vasomotor response to nitrates in migraine patients. This response is associated with the nitrate-induced headache and it is not evident in healthy pain-free controls during the delayed phase after administration of an NO donor. Owing to the short half-life of NO, the neurotransmitter released by IDN, and because of the late onset of headache, we believe the mechanism is unlikely to be vascular in origin, but may have a neurogenic component.

Administration, Sublingual↗

Comparative hemodynamic effects of chewable isosorbide dinitrate and nitroglycerin in patients with congestive heart failure.

Vasodilators are known to be effective in improving the hemodynamics of congestive heart failure by increasing cardiac output and reducing left ventricular filling pressure (LVFP). Long acting agents are needed to augment the practicality and availability of chronic vasodilator therapy. In the present study the vascular effects of chewable isosorbide dinitrate (CHIS), sublingual nitroglycerin (NTG) and placebo (P) were compared in eight patients with high LVFP due to heart failure. Patients with LVFP (pulmonary wedge pressure) over 14 mm Hg were given CHIS, 10 mg, NTG, 0.6 mg, and P, two chewable tablets, in random fashion. Heart rate (HR), blood pressure (BP) and LVFP were monitored for three hours after each drug. HR was not significantly affected by any drug, although it rose slightly after NTG and fell after CHIS. Significant reduction of BP occurred only after NTG, with peak effect at five minutes, but lasting only 15 minutes. NTG reduced LVFP 5.1 mm Hg (19.5%, P, less than 0.05), at peak effect, but LVFP was no longer significantly lower by 20 minutes after NTG. After CHIS, LVFP fell significantly within five minutes, reached a peak reduction of 8.6 mm Hg (32;7%, P less than 0.01) at 15 minutes, and remained significantly lower through three hours. Thus CHIS provides a nitrate action of rapid onset and sustained effect that may be useful for chronic vasodilator therapy of heart failure.

Administration, Oral↗

Comparative effects of nifedipine, verapamil, isosorbide dinitrate and propranolol on exercise-induced angina pectoris.

According to the experimental model of a 5 X 5 Latin square, 5 treatments were studied single blind in 5 patients, affected by stable-effort angina, by means of exercise tests. In the period of maximal supposed effect the following treatments were investigated: placebo (P), 1 tablet, orally; isosorbide dinitrate (ISDN), 5 mg, sublingually; propranolol (Pr), 40 mg, orally; nifedipine (N), 10 mg, orally; verapamil (V), 160 mg, orally. Placebo, compared with its own control tests, did not change any of the examined parameters. Comparison of the 'active' treatments with P showed the following results. All the treatments increased the duration of work before ECG positivity appearances. An increase in duration of work and total work performed before angina was seen after administration of ISIDN, N and V; the improvement observed after treatment with Pr was not significant. Comparison of treatments showed that work performance before angina was the same after administration of ISDN, N and V; these treatments were more effective than that with 40 mg Pr. Duration of work before ECG positivity was significantly longer after ISDN and N than after Pr. The changes in heart rate, maximal arterial pressure, ejection time index and triple product confirmed the activity of the administered doses. According to the observed effects on exercise tolerance, in comparison with P the same level of work was performed with the same triple product after Pr, and with lower triple products after ISDN, N and V.

Angina Pectoris↗

Reduction of myocardial ischemic injury with sublingual isosorbide dinitrate.

Twenty-one patients with acute anterior myocardial infarction had precordial ST segment mapping, using a system of 42 leads, at 0, 2, 4, 8, 24, and 48 hours (control group). Eleven patients (treatment group) had maps on admission and after 30-45 minutes; then serial maps were performed at similar intervals after 5-10 mg of isosorbide dinitrate (ISD). There were no significant differences in age, sex, functional class, mean time elapsed between onset of chest pain and admission, and inhospital mortality between the groups. Controls had a higher incidence of recurrent MI (6 patients vs 2) compared with the ISD group (P less than 0.05).The sum of ST segment elevations in all leads (ΣST) was similar in both groups on admission and remained at the same level in controls for 48 hours. One hour after ISD the blood pressure decreased significantly; ΣST and the number of leads with more than 1 mm ST elevation (NST) decreased significantly (62±10 to 31±4 / 26±1 to 19±2) (P less than 0.01). In the ISD group serial ST maps showed significant decreases (52±5 vs 28±4; 44±4 vs 26±2; 45±4 vs 29±3; 51±5 vs 28±3, 52±8 vs 28±2, respectively at 2, 4, 8, 24 and 48 hours), suggesting reduction of ischemic injury by ISD.Estimation of infarct size (in units from R wave height and Q and S wave depths in leads I, AVL and V(1)-V(6)) indicated a reduction in the ISD group on days one, two and seven. Total CPK, SGOT and LDH levels were similar on admission; at 24 and 48 hours after admission CPK values were not significantly different but SGOT and LDH were lower in the treated group.

Aged↗

Intravenous isosorbide dinitrate infusion in the management of unstable angina pectoris refractory to conventional medical therapy.

During the past 2 years, 102 patients were treated for unstable angina pectoris (AP) in our department. Fifteen of them had recurrent chest pain at rest despite treatment with various anti-anginal agents, or prolonged chest pain unresponsive to sublingual nitroglycerin; they received intravenous isosorbide dinitrate (ISDN) infusion. A rapid bolus injection of 2 to 6 mg followed by an infusion of 2 to 5 mg/hr was given to 10 patients with acute chest pain, and 5 patients, who were free of chest pain at the time, but had repeated episodes of angina in the past 24 hours, were given ISDN infusion without a bolus injection. Chest pain disappeared completely in 13 patients, but recurred in 2 of them when the dose was tapered. Two other patients experienced recurrent chest pain during ISDN infusion, and additional boluses were given. The hospital course was uneventful in 11 patients. Four patients who had recurrent anginal attacks underwent emergency coronary cineangiography under intraaortic ballon counterpulsation and aorto-coronary bypass surgery. There were no hospital deaths, no one had subsequent acute myocardial infarctions, and only 2 patients had mild to moderate headache as a side effect. Although the patient population is small, intravenous ISDN infusion is useful in the management of severe unstable AP.

Acute Disease↗

[Use of isosorbide dinitrate and antagonists of angiotensin II in patients with stable angina pectoris in early stages of cardiac insufficiency].

Effects were studied of isosorbite dinitrate and antagonists of angiotensin II in patients with stable angina presenting with incipient stages of cardiac insufficiency. Changes in the ejection fraction, phases in passive and active filling of the left ventricle can be used as a prognostic criterion for efficiency of a long-term combined therapy involving the use of isosorbid dinitrate and renitec or cozaar.

Angina Pectoris↗

[Pulmonary artery pressure measurement for assessment of bioavailability of isosorbide dinitrate and pentaerythritol tetranitrate (author's transl)].

In a double-blind cross-over study with 9 patients suffering from ischemic cardiomyopathy with cardiac failure, the effect of 3 different drug preparations on pulmonary artery pressure (PA-pressure) was studied. Iso-Ameritrat is a new drug-combination consisting of a sweet-tasting wrap containing 2.5 mg Isosorbide Dinitrate (ISDN) and of a bitter-tasting core containing 10 mg Pentaerythritol Tetranitrate (PETN) and 200 mg Meprobamate. A statistically significant decrease of PA-pressure values could be observed already 3 minutes after administration of Iso-Ameritrat. Within the next minutes this decrease even augmented and lasted over the whole period of measurement (30 minutes). After administration of the second drug preparation (Ameritrat), containing 10 mg PETN and 200 mg Meprobamate in the core, but not any nitrate in the wrap a slight but also statistically significant decrease of PA-pressure values could be documented. Therefore a sublingual resorption of PETN can be assumed. The precise beginning of the effect of PETN couldn't be assured, but it must be within 5 minutes. A thir preparation, containing only 200 mg Meprobamate in the bitter tasting core caused no significant decrease of PA-pressure values.

Adult↗

Role of hemoglobin in the differential biotransformation of glyceryl trinitrate and isosorbide dinitrate by human erythrocytes.

Incubation of 2 X 10(-7) M glyceryl trinitrate (GTN) at 37 degrees C with human red blood cells resuspended in saline resulted in a 73.4 +/- 3.5% (S.D.) elimination of GTN after 10 min. The elimination of GTN was accompanied by the appearance of an equimolar amount of the GTN metabolites. The biotransformation of GTN and another organic nitrate, isosorbide dinitrate (ISDN), was examined in more detail using the 25,000 X g supernatant fraction of human red blood cells (RBC-SF). Incubation of 2 X 10(-7) M GTN or ISDN at 37 degrees C with RBC-SF resulted in a 46.3 +/- 7.3% (S.D.) elimination of GTN after 40 min and a 51.8 +/- 5.9% (S.D.) elimination of ISDN after 240 min. The elimination of the parent organic nitrate was accompanied by the appearance of an equimolar amount of metabolites. The biotransformation of ISDN was inhibited completely by pretreatment of the RBC-SF with trypsin, N-ethylmaleimide or heating at 65 degrees C, whereas GTN biotransformation was only inhibited partially by these treatments. Biotransformation of GTN was inhibited partially by pretreatment of the RBC-SF with CO or potassium ferricyanide; these treatments had no effect on ISDN biotransformation. Treatment of the RBC-SF with the combination of N-ethylmaleimide plus CO or trypsin plus CO resulted in complete inhibition of GTN biotransformation. We conclude that ISDN biotransformation by erythrocytes is a sulfhydryl-dependent enzymatic process, whereas the biotransformation of GTN is due to a combination of a sulfhydryl-dependent enzymatic process and an interaction with reduced hemoglobin.

Adult↗

Control of perioperative hypertension during coronary artery surgery. A randomised double-blind study comparing isosorbide dinitrate and nitroglycerin.

A reduction in the causes of myocardial ischaemia remains of prime importance during coronary artery surgery. Hypertension with the ensuing increase in myocardial oxygen demand is a major factor in the aetiology of perioperative myocardial ischaemia. Nitroglycerin (NTG) has long been used beneficially to reduce myocardial oxygen demand by its effects on the systemic and peripheral vascular resistances. An alternative nitrate, isosorbide dinitrate (ISDN) is now available as an intravenous preparation, and may offer technical advantages, both due to its stability in solution and also its longer in vivo half-life. We designed and carried out a multi-centre study to compare and evaluate the efficacy of ISDN and NTG in the management of perioperative hypertension in 85 patients undergoing elective coronary artery surgery. A total of 288 events in which the systolic blood pressure (SBP) exceeded a predetermined trigger value were observed. ISDN was successful in treating hypertension in 63% of the events, whereas NTG had an 83% success. The SBP was significantly lowered after treatment with either ISDN, 155 mmHg to 138 mmHg, or NTG, 160 mmHg to 130 mmHg. The mean successful dose rate for ISDN was 6.5 micrograms kg-1 min-1, whereas for NTG this was 3.8 micrograms kg-1 min-1. In the ISDN group less events took place possibly due to the longer duration of this drug. In many previous studies NTG has been found to be effective in controlling hypertension; ISDN offers and alternative approach in reducing hypertension.

Coronary Artery Bypass↗

Comparison of coronary responses to intracoronary and intraaortic ergonovine and isosorbide dinitrate in patients with atypical chest pain.

Fifty patients with atypical chest pain were studied to compare coronary responses to intracoronary and intraaortic ergonovine. The diameters of the proximal, middle (1) and (2) (proximal segments of segments 2 and 3 [AHA classification], respectively), and distal segments of the right coronary artery were measured before and after intracoronary ergonovine (4 micrograms/minute over 4 minutes) and isosorbide dinitrate (ISDN) (2 mg) in 24 patients, and before and after intraaortic ergonovine (0.2 mg) and ISDN (5 mg) in 26. Mean vasoconstriction by intracoronary and intraaortic ergonovine were 13 +/- 1.5% and 9 +/- 0.8%, respectively (p < 0.02). Irrespective of the methods of administration, the responses to ergonovine were similar in the 4 segments. Mean vasodilation by intracoronary and intraaortic ISDN, which were used to quantify the degree of basal coronary tone, were 25 +/- 2.2% and 27 +/- 1.5%, respectively (p = not significant [NS]). There were significant negative linear correlations between the responses to ergonovine and ISDN in the middle (2) (r = -0.51; p < 0.05) and distal (r = -0.53; p < 0.01) segments in patients with intracoronary injection, and the proximal (r = -0.41; p < 0.05), middle (1) (r = -0.66; p < 0.01) and middle (2) (r = -0.69; p < 0.01) segments in patients with intraaortic injection. These observations indicate that low-dose administration of intracoronary ergonovine produces sufficient coronary vasoconstriction, similar to or slightly greater than that of intraaortic ergonovine in patients with atypical chest pain, but basal coronary tone may influence the vasoreactivity to ergonovine.

Aorta↗

Regional blood flow and hemodynamics in the rabbit with adriamycin cardiomyopathy: effects of isosorbide dinitrate, dobutamine and captopril.

We have studied the effects of captopril, nitrates and dobutamine on hemodynamics and regional blood flow in the conscious rabbit with adriamycin cardiomyopathy. Rabbits were injected twice weekly with adriamycin (1 mg.kg-1 bw.) for 8 weeks and subsequently maintained for 2 weeks without adriamycin in order to allow recovery from any noncardiac effects. Doses of drug for investigation (captopril, 300 micrograms.kg-1.min-1; isosorbide dinitrate, 10 micrograms.kg-1.min-1; and dobutamine, 10.9 micrograms.kg-1.min-1) were chosen in anticipation of a 20% increase of cardiac output in animals with heart failure. In animals with heart failure myocardial blood flow was increased by dobutamine and to a lesser extent by captopril. Renal blood flow was increased only by captopril and nitrates. Cerebral blood flow was reduced by captopril in control animals but unaltered in animals with heart failure. The observed alterations of blood flow were similar to those known to occur in humans and indicate that this is a useful model of heart failure for the evaluation of new drugs.

Animals↗

Effects of sodium nitroprusside, isosorbide dinitrate, isoproterenol, phentolamine and prazosin on hepatic venous responses to sympathetic nerve stimulation in the cat.

Hepatic blood volume was recorded by a plethysmographic technique in cats anesthetized with pentobarbital. The effects of three doses of each vasodilator drug were measured on arterial and portal pressures, hepatic blood volume in the denervated liver and on the portal pressure and hepatic venous responses to sympathetic nerve stimulation. Isosorbide dinitrate caused a small reduction in basal hepatic venous tone increasing hepatic blood volume by up to 15%; it had no effect on the responses to sympathetic nerve stimulation. Isoproterenol increased hepatic venous tone perhaps by stimulation of angiotensin formation and the responses to stimulation of the hepatic nerves were reduced because of this increased basal tone. Sodium nitroprusside produced a small decrease in basal venous tone and only large doses produced any reduction in the venous responses to hepatic nerve stimulation. The evidence that nitroprusside is a venodilator requires reexamination. Phentolamine had no effect on basal venous tone but markedly reduced the responses to sympathetic nerve stimulatiqn. When compared to phentolamine, prazosin produced comparable effects on arterial pressure but much less reduction in the hepatic venous responses to sympathetic stimulation. It is suggested that the alpha receptor blocking action of prazosin is selective for arterioles and this may explain the minor incidence of postural hypotension during clinical use.

Animals↗

Immediate effects of hydralazine-isosorbide dinitrate combination on exercise capacity and exercise hemodynamics in patients with left ventricular failure.

Resting hemodynamics improve during vasodilator administration in patients, with congestive heart failure (CHF), but the effects of these agents on exercise is unknown. Twenty-two patients with class II or III CHF performed bicycle exercise to symptomatic maximum before and 90 minutes after random double-blind administration of oral hydralazine (100 mg) and isosorbide dinitrate (40 mg) (11 patients, group 1) or placebo (11 patients, group 2). Exercise duration was unchanged after treatment in either group. Maximal oxygen consumption changed insignificantly in both groups, from 12.6 +/- 1.2 (SEM) to 13.6 +/- 1.6 ml/kg/min in group 1, and from 11.7 +/- 1.4 to 13.4 +/- 1.7 ml/kg/min in group 2. Maximal cardiac index was unchanged in both group 1 (4.00 +/- 0.33 to 4.41 +/- 0.29 l/min/m2) and group 2 (4.11 +/- 0.43 to 4.14 +/- 0.42 l/min/m2). Systemic vascular resistance at peak exercise was also unchanged in both group 1 (14.1 +/- 1.6 to 11.8 +/- 1.0 units) and group 2 (14.7 +/- 1.6 to 13.5 +/- 1.6 units). at submaximal exercise (300 kilopond-meters/min), however, cardiac index after treatment increased in group 1 (0.51 +/- 0.18 l/min/m2, p less than 0.05) and systemic vascular resistance decreased (-3.3 +/- 1.3 units, p less than 0.05), but were unchanged in group 2. Thus, although vasodilators do not improve maximal exercise capacity acutely, they can improve hemodynamics at lower work loads which may, therefore, be better tolerated in patients with CHF.

Adult↗

Therapeutic effects of nitric oxide-donor isosorbide dinitrate on atherosclerosis-induced alterations in hemodynamics and arterial viscoelasticity are independent of the wall elastic component.

Whether the arterial elastic structures are involved in the beneficial effects of long-term treatment with organic nitrates on atherosclerosis-induced changes in hemodynamics and arterial wall viscoelastic properties, are case for angiotensin-converting enzyme (ACE) inhibitors, is not known. In the present study, atherogenic (A) diet, and isosorbide dinitrate (ISDN) (I) (60 mg Risordan LP, daily dose) were given concomitantly for 4 months to adult Pitman-Moore minipigs (A + I animals, n = 8), which were compared with A (n = 8) or control (C, n = 8) animals. Blood flow was investigated by hemodynamics in the hindlimb arterial bed; and wall rheology, histomorphometry and elastin; and desmosine (DES) and isodesmosine (IDE) contents in the abdominal aorta. Atherosclerosis prominently impaired the function of capacitance and resistance arteries, altered blood pressure contours, increased aortic stiffness and wall tension, and reduced parietal viscoelasticity through viscous component blunting. The treatment with ISDN significantly improved aortic pulsatility, arteriolar opposition to blood flow, and blood pressure (BP) contours by restoring, at least in part, the wall viscoelastic properties. However, there was no significant change in the area of the pressure-diameter curve hysteresis between the three animal groups. In contrast, ISDN reduced neither the cross-sectional area of lesions nor the losses in wall elastin content and had no influence on lipid accumulations in vessels and in the blood. The present results demonstrate that the beneficial hemodynamic and wall viscoelastic effects elicited by ISDN in atherosclerotic minipigs are not accounted for by therapeutic properties of the nitric oxide (NO) donor against alterations of elastic structures, but by the viscoelastic properties in the arterial wall.

Animals↗

Evaluation by patients with heart failure of the effects of enalapril compared with hydralazine plus isosorbide dinitrate on quality of life. V-HeFT II. The V-HeFT VA Cooperative Studies Group.

BACKGROUND: Two new questionnaires concerning the quality of life of patients with heart failure were used in a randomized, controlled trial to determine if the patients' perceptions of the effects of enalapril on their daily activities and sense of well-being were different from those of a group treated with hydralazine and isosorbide dinitrate. METHODS AND RESULTS: The questionnaires were completed at baseline and at 3 months, 6 months, and subsequently every 6 months during follow-up, which averaged 2.5 years (range, 0.5-5.7 years). Data from the questionnaires were reliable as indicated by correlation coefficients between repeated baseline scores of 0.88 and 0.87. Both treatment groups showed a progressive deterioration in quality of life as measured by both questionnaires. The questionnaire scores of the two treatment groups were not significantly different at any follow-up visit. Furthermore, there were no differences between treatments among subgroups defined by baseline questionnaire scores, peak oxygen consumption, ejection fraction, previous vasodilator use, and plasma norepinephrine concentration. CONCLUSIONS: Although several factors may limit the generalization of these results, the lack of a difference with regard to patients' quality of life is an important consideration for the evaluation of the relative therapeutic efficacy of these vasodilators.

Attitude to Health↗