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PubMed1996

Pathophysiological aspects and clinical outcome of intra-anal application of isosorbide dinitrate in patients with chronic anal fissure.

BACKGROUND: Relaxation of the internal anal sphincter can be achieved by local application of exogenous nitric oxide donors. AIM: To evaluate the influence of topical application of isosorbide dinitrate (ISDN) on anal pressure, anodermal blood flow, and fissure healing. PATIENTS: Thirty four consecutive patients (male/female: 18/16; mean age (SEM): 39 (10)) with a chronic anal fissure were studied. METHODS: All patients were treated for at least six weeks or a maximum period of 12 weeks. Before treatment and at three and six weeks 22 patients underwent conventional anal manometry and laser Doppler flowmetry of the anoderm. RESULTS: Within 10 days the fissure related pain was resolved in all patients. At six, nine, and 12 weeks the anal fissure was completely healed in 14, 22, and 30 patients respectively. At three and six weeks manometry was performed at least one hour after the last application of ISDN. These recordings showed a reduction of the maximum resting anal pressure (mean (SD), pretreatment 111 (26) mm Hg; three weeks 86 (19); six weeks 96 (27), p < 0.001). Simultaneous recordings of anodermal blood flow showed a significant increase of flow (pretreatment 0.53 (0.17); three weeks 0.80 (0.16); six weeks 0.76 (0.31), p < 0.005). The mean (SEM) duration of follow up after successful outcome was 11 (5) months. Within this period fissure relapsed in two of 30 patients (7%), eight and 10 weeks after treatment had been stopped. CONCLUSIONS: Local application of ISDN reduces anal pressure and improves anodermal blood flow. This dual effect results in a fissure healing rate of 88% at 12 weeks. This new and simple treatment modality seems to be an attractive alternative for the current available surgical procedures.

Adult↗
PubMed2004

Anti-ischaemic response to sublingual nitroglycerin during oral administration of isosorbide dinitrate in patients with stable angina pectoris: when does cross-tolerance occur?

The purpose of this study was to evaluate the efficacy of sublingual nitroglycerin (NTG) during treatment with oral sustained-release isosorbide dinitrate (ISDN) in two doses: 80 mg and 120 mg. In a double-blind crossover design study 38 men with stable angina initially received either an oral placebo (OP) or ISDN. All patients received either NTG 0.5 mg or sublingual placebo (SLP) 2.5 h after OP ingestion, but only NTG 2.5 h after ISDN. The same pattern was used in the first ingestion and in long-term OP or ISDN therapy for 7 days (OP and ISDN every 6 h, and ISDN once daily). The efficacy of NTG was evaluated by analyzing walking time to ischaemia (WTI) during exercise tests performed 5 minutes after NTG or SLP administration, and the efficacy of ISDN 2 h and 6 h after oral ingestion. In the first ingestion NTG significantly improved WTI ( p < 0.0001) by 42.7% after OP, by 46.5% after 80 mg ISDN and by 52.1% after 120 mg. After long-term OP therapy NTG prolonged WTI ( p < 0.01) by 15.6%, during once-daily ISDN treatment, an 80 mg dose prolonged WTI by 22.8% and a dose of 120 mg by 36.5%. However, NTG did not improve WTI in q.i.d. therapy. Six hours after the first 80 mg ISDN ingestion WTI improved ( p < 0.0001) by 66.0%, and after 120 mg by 58.4%. Following once-daily therapy ISDN prolonged WTI ( p < 0.0001) by 27.2% after an 80 mg dose and by 36.2% after a dose of 120 mg. No improvement was observed in q.i.d. treatment. Thus, severe tolerance to ISDN abolishes the anti-ischaemic effects of NTG, and appropriate regimens of ISDN have considerable anti-anginal effects during chronic administration.

Adult↗
PubMed1990

The poststenotic vessel segment during dynamic exercise: effect of oral isosorbide-dinitrate.

Coronary vasomotion of normal, stenotic, and poststenotic vessel segments was studied in 18 patients with coronary artery disease at rest, during submaximal bicycle exercise, and 5 min after sublingual nitroglycerin or oral isosorbide-dinitrate (ISDN) spray. Patients were divided into two groups: group 1 consisted of 10 patients with no premedication prior to exercise, and group 2 consisted of 8 patients receiving 120 mg long-acting ISDN orally 1 h before the procedure. Quantitative coronary arteriography was carried out in biplane projection using a semi-automatic computer system. The normal vessel segment showed a trend toward a small increase in cross-sectional area during exercise in both groups (+3% in group 1 and +4% in group 2, both NS). After sublingual nitroglycerin following exercise, there was a significant increase in group 1 (+29%, p less than 0.001 vs rest) but not after ISDN spray in group 2 (+5%, NS vs rest). The stenotic vessel segment showed exercise-induced stenosis narrowing in group 1 (-31%, p less than 0.01 vs rest) which was prevented by oral ISDN (+6%, NS vs rest). After exercise, sublingual administration of nitroglycerin or ISDN spray was associated with no significant change in stenosis area in either group. The poststenotic vessel segment showed no significant vasomotion during exercise in both groups (area change +6% in group 1 and +7% in group 2), but poststenotic luminal area increased after sublingual nitroglycerin (group 1: +15%, p less than 0.01 vs rest) or ISDN spray (group 2: +15%, p less than 0.05 vs rest). The mean pulmonary artery pressure increased during exercise from 22 to 39 mmHg (p less than 0.001) in group 1 and from 14 to 27 mmHg (p less than 0.001) in group 2. At rest (p less than 0.001) and during exercise (p less than 0.01) mean pulmonary pressure was lower in group 2 than in group 1. Thus, it is concluded that coronary vasomotion of the poststenotic vessel segment is only minimal during exercise and is not affected by coronary vasomotion of the stenotic vessel segment. Pretreatment with oral ISDN did not influence coronary vasomotion of the poststenotic vessel segment, but prevented exercise-induced stenosis narrowing. In the untreated patients, vasoconstriction of the stenotic vessel segment is limited to the site of the stenosis, and it appears that there is no release of vasoactive substances with vasoconstrictive influences on the poststenotic segment.

Administration, Oral↗
PubMed1994

A new isosorbide dinitrate extended-release formulation: pharmacokinetic and clinical parameters in patients with stable angina pectoris.

In a double-blind, cross-over study the acute clinical efficacy and pharmacokinetic profile of a newly developed isosorbide dinitrate extended-release (ISDN-ER) formulation (10 mg immediate release and 60 mg slow release) were examined in eight angina patients. Exercise tests were done 1 h before and 1, 6 and 10 h after acute ISDN or placebo; similar testing was repeated after 14 days of open-labelled treatment. At 1, 6 and 10 h after administration, ISDN-ER significantly reduced the mean ST depression at highest comparable workload (HCWL) by 0.8, 0.6, and 0.6 mm, respectively. Total exercise duration increased significantly by 46, 42 and 72 s. The rate-pressure product at HCWL was not reduced significantly at any time, while digital plethysmography demonstrated a significant effect on arterial pulse curves throughout the 10 h. After 14 days of once-daily treatment, similar or somewhat attenuated clinical effects were observed. Pharmacokinetic measurements showed a first peak of ISDN at 1-2 h and a second peak at 4-5 h. The 5-isosorbide mononitrate (5-ISMN) metabolite peaked at 5-8 h and remained high at 10 h. After 14 days of treatment, the mean plasma concentrations of ISDN and 5-ISMN before drug were 0 and 69 ng.ml-1, respectively. Thus, satisfactory acute clinical efficacy and low nitrate levels during the night were observed. However, long-term clinical efficacy needs to be established in larger, placebo-controlled trials.

Aged↗
PubMed1991

Use of isosorbide dinitrate for the symptomatic treatment of patients with Chagas' disease achalasia. A double-blind, crossover trial.

1. A randomized, double-blind, placebo-controlled trial was carried out to determine the efficacy of isosorbide dinitrate (ISD) on dysphagia in patients with Chagasic achalasia. 2. Twenty-three patients with Chagas' disease and dysphagia entered the study and 20 (87%) completed the two 7-day treatment periods. Subjects were given either 5 mg ISD (12 patients) or placebo (11 patients) by the sublingual route for the first 7 days. On the 8th day, patients crossed over and began another 7-day period during which they received the opposite, identical-appearing tablets. 3. Scores attributed by uninformed investigators for the frequency and severity of dysphagia were significantly lower (P less than 0.05) following ISD treatment than after the placebo period or for the pretreatment condition. A significantly higher degree of improvement of dysphagia was experienced by the patients during ISD treatment than during the placebo period. Fourteen patients experienced meal-related headaches during ISD, but not placebo treatment. The extent of improvement in general well-being due to ISD was the same when the drug was given in the first or second test period. 4. Our results indicate that ISD, 5 mg by the sublingual route, is effective in alleviating dysphagia in patients with Chagasic achalasia but its usefulness is limited by the high rate of headache as a side effect.

Adolescent↗
PubMedDate not supplied

Perioperative sublingual isosorbide dinitrate for the prevention of cardiac complications in cardiac patients undergoing noncardiac surgery.

One hundred fifty-two consecutive patients with a known or suspected diagnosis of atherosclerotic coronary artery disease were administered 5 mg sublingual isosorbide dinitrate 2 hours and (1/2) hour preoperatively and every 4 hours postoperatively for 3 days, for the prevention of cardiovascular morbidity and mortality, which could result from various noncardiac surgical procedures; 125 patients received general anesthesia. Cardiovascular complications occurred in 3 patients (1.9%). Two patients did not enter the study, owing to side effects of the medication (1.3%). The complications were 1 each (0.6%) of the following: atrial fibrillation, hypotension, and cardiac arrest. Mortality was 0%. These results are exceptionally favorable when compared to the average cardiovascular morbidity rate of 2.8% to 49% in patients assigned to various risk stratifications in the medical literature.

Administration, Sublingual↗
PubMed1982

[Value of isosorbide dinitrate injection in the acute phase of myocardial infarction. Clinical and haemodynamic study (author's transl)].

Left ventricular failure is one of the most common complications of acute myocardial infarction and may have very serious haemodynamic consequences. Isosorbide dinitrate administered by intravenous infusion in doses of 3 to 7 mg/hour had highly beneficial effects on pre-load and frequently improved cardiac output. The results obtained in this series of 10 consecutive patients demonstrate that the drug has very favourable effects on the immediate prognosis of myocardial infarction.

Adult↗
PubMed1978

Haemodynamic effects of isosorbide dinitrate in patients with congestive cardiac failure at rest and during submaximal supine exercise.

Eight patients with chronic congestive cardiac failure secondary to ischaemic heart disease performed submaximal supine exercise before and after 5 mg sublingual isosorbide dinitrate (ISDN) at the time of cardiac catheterisation. Exercise before ISDN produced a poor response in left ventricular performance. After ISDN this response was significantly improved. Compared with the control exercise period cardiac index (CI) increased from mean 2.9 to 3.5 l/mn/m2 (p = less than 0.0025), stroke volume index (SVI) from mean 24 to 29 ml/m2 (p = less than 0.0005) and left ventricular stroke work index (LVSWI) from mean 22 to 28 g-m/m2 (p = less than 0.0025). Although ISDN reduced LVEDP significantly at rest, there were associated small but significant falls in CI, SVI and LVSWI. The improvement in exercise cardiac index was related to the ejection fraction, or the ejection fraction of the contractile section where a left ventricular aneurysm was present. ISDN may be effective in improving exercise tolerance in ambulant patients with chronic congestive cardiac failure.

Administration, Oral↗
PubMed1983

Radiocardiographic assessment of dobutamine and isosorbide dinitrate therapy in patients with mitral stenosis and pulmonary congestion.

Simultaneous hemodynamic and radiocardiographic measurements were performed on 10 patients with mitral stenosis and pulmonary congestion for evaluating the acute effects of dobutamine (DB, 5 micrograms/kg/min), isosorbide dinitrate (ISD, 10 mg sublingually) or a combination of the two. DB alone produced a significant increase of the cardiac index (CI) from 2.9 +/- 0.1 to 3.7 +/- 0.2 L/in/m2 (p less than 0.01), but a modest increase in pulmonary artery diastolic pressure (PADP) and in pulmonary blood volume by approximately 15%, respectively. ISD alone caused a decline in PADP from 26 +/- 2 to 18 +/- 1 mmHg (p less than 0.001), in right heart volume from 300 +/- 36 to 215 +/- 18 ml/m2 (p less than 0.05) and in left heart volume from 321 +/- 28 to 248 +/- 20 ml/m2 (p less than 0.05), but no change in the CI. Combined administration of the two agents resulted in favorable alterations in both hemodynamic variables: PADP decreased from 26 +/- 2 to 20 +/- 1 mmHg (p less than 0.01) and the CI increased from 2.9 +/- 0.1 to 3.3 +/- 0.1 L/min/m2 (p less than 0.05). Thus, DB alone had a tendency to aggravate pulmonary venous congestion in our patients, while ISD is effective in reducing the congestive manifestations of heart failure due to its venodilating effects but less beneficial in increasing the CI. The combined therapy of DB and ISD appears to be extremely effective in restoring an adequate cardiac output and in relieving the symptoms of pulmonary vascular congestion in the presence of mitral stenosis.

Adult↗
PubMed1992

Efficacy of a single dose of slow-release isosorbide dinitrate in the treatment of silent or painful myocardial ischemia in stable angina pectoris.

A double-blind study was performed in 32 patients with stable angina pectoris to assess the effects of slow-release isosorbide dinitrate (ISDN) (a single dose of 120 mg/day) on the frequency and duration of painless and painful ischemic episodes, and on electrocardiographic changes and exercise tolerance. Forty-eight-hour electrocardiographic monitoring and treadmill exercise tests were performed before, and at 20 and 21 days of therapy. Holter monitoring showed a significant decrease in the frequency of painful and silent episodes (p less than 0.001), and in the duration of painful (1,623 +/- 664 seconds vs 323 +/- 161 seconds; p less than 0.001) and silent episodes (2,818 +/- 1,496 seconds vs 223 +/- 102 seconds; p less than 0.001). The magnitude of painful and silent ST-segment depression was significantly reduced (2.7 +/- 0.9 mm to 0.7 +/- 0.7 mm and 2.0 +/- 1.1 mm to 0.7 +/- 0.5 mm, respectively; p less than 0.001). Time of exercise testing to the onset of ST-segment depression (442 +/- 137 seconds vs 858 +/- 110 seconds; p less than 0.001) or anginal pain was doubled (461 +/- 128 seconds vs 830 +/- 130 seconds; p less than 0.001). The work load increased from 6 to 10 METs (p less than 0.001). ISDN in a single dose of 120 mg/day is a valuable drug for stable angina pectoris, decreasing the frequency of silent and painful ischemic episodes and the magnitude of ST-segment depressions, and increasing exercise tolerance. It particularly shortened the duration of silent episodes. For patients' compliance, a once-daily dose of ISDN could be advantageous.

Adult↗
PubMed1994

Sublingual isosorbide dinitrate to improve technetium-99m-teboroxime perfusion defect reversibility.

UNLABELLED: Previous studies demonstrate perfusion defect reversibility in 201Tl reinjection imaging performed after the administration of nitrates. This study tests whether the acute sublingual administration of isosorbide dinitrate (ISDN) could improve the capability of 99mTc-teboroxime to detect reversibility in exercise-induced perfusion defects. METHODS: Ten patients with previous myocardial infarction underwent exercise, redistribution and reinjection 201Tl imaging, 99mTc-teboroxime exercise and rest scans. Following the latter, 5 mg sublingual ISDN were given, 99mTc-teboroxime was reinjected and images collected. RESULTS: The total defect score/patient in the 201Tl images was 10.5 +/- 3.1 (mean +/- s.d.), decreasing to 7.4 +/- 2.7 after redistribution (p < 0.02) and to 4.8 +/- 2.1 after reinjection (p < 0.01 versus redistribution). The total defect score in 99mTc-teboroxime exercise images was 12.7 +/- 3.1 (p < 0.05 versus 201Tl exercise), decreasing to 7.3 +/- 3.3 at rest (p < 0.01 versus exercise, NS versus 201Tl redistribution) and to 5.6 +/- 2.6 in ISDN images (p < 0.02 versus rest, p < 0.05 versus 201Tl redistribution, NS versus reinjection). Of the 44 abnormal segments in 201Tl exercise images, the redistribution scan identified 26 defects as reversible and 18 as fixed. After reinjection, 37 defects appeared reversible and only seven fixed (p < 0.005 versus redistribution). Stress-rest 99mTc-teboroxime classified 33 segments as reversible and 11 as fixed (NS versus both 201Tl protocols). After ISDN, the uptake score increased in 19 segments. Therefore, 37 were classified as reversible and seven as fixed defects (p < 0.01 versus 201Tl redistribution, NS versus 201Tl reinjection). CONCLUSIONS: Sublingual ISDN before 99mTc-teboroxime rest injection seemed to improve the tracer capability of detecting reversibility in exercise-induced perfusion defects.

Administration, Sublingual↗
PubMed2001

Effect of isosorbide dinitrate on nitric oxide synthase under hypoxia.

Nitric oxide synthase (NOS) catalyzes nitric oxide (NO) formation from L-arginine in the presence of molecular oxygen and NADPH. NO is involved in the regulation of microvasculature. Isosorbide dinitrate (ISDN) and glyceryl trinitrate (GTN) have been widely used as vasodilators to treat acute myocardial ischemia, their biological effects being due to the release of NO. In this investigation, the effects of ISDN and GTN on NOS activity in the presence or absence of oxyhemoglobin under hypoxia and normoxia were studied. The apparent K(m) values for molecular oxygen were 21.6 +/- 1.5 and 9.4 +/- 1.3 micromol/l for nNOS and eNOS, respectively. ISDN liberated NO in a concentration- and pH-dependent manner, but no differences between hypoxia and normoxia were observed. The NO release from ISDN was also measured directly by an electron spin resonance spectral method with N-(dithiocarboxy)sarcosine-Fe complex as a NO-trapping agent. ISDN increased nNOS and eNOS activities in the presence of 30 micromol/l oxyhemoglobin under hypoxia, while it did not affect nNOS and eNOS activities under normoxia. In the absence of oxyhemoglobin, ISDN inhibited nNOS and eNOS activities under both hypoxic and normoxic experimental conditions. The rate of oxygen release from oxyhemoglobin under hypoxia was increased 3 times in the presence of 1 mmol/l ISDN. In contrast to ISDN, GTN could not release NO spontaneously, and it also did not affect nNOS and eNOS activities in the absence or presence of 30 micromol/l oxyhemoglobin under both hypoxic and normoxic conditions. These results indicated that the NO release from ISDN is different from that of GTN, and the increase of NOS activity by ISDN in the presence of oxyhemoglobin under hypoxia is ascribed to the increase in molecular oxygen concentration.

Animals↗
PubMed1995

Mechanism of ITF 296-induced vasorelaxation compared to nitroglycerin and isosorbide dinitrate: relationship between relaxation of rabbit aorta and tissue cGMP.

The vasorelaxant properties of ITF 296, a new mononitrate ester, were studied in endothelium-denuded rabbit aortic rings and were compared to nitroglycerin (NTG) and isosorbide dinitrate (ISDN). In norepinephrine-contracted arteries, ITF 296, NTG, and ISDN elicited maximal and concentration-dependent vasodilation with pD2 values of 7.07, 7.95, and 7.2, respectively. The concentration-relaxation curves of ITF 296 were shifted markedly to the right (p < 0.01) in the presence of 10 microM methylene blue (MB) and 3 microM oxyhemoglobin (HbO2), whereas a significant shift to the left (p < 0.01) was observed in the presence of 10 microM M&B-22948 (a specific cGMP phosphodiesterase inhibitor). When KCl (60 mM) was used as contracting agent, a weak relaxation was observed with ITF 296, suggesting the absence of activity on the voltage-dependent Ca2+ channels. A time-dependent increase in cGMP content and a positive correlation between cGMP and vasodilation were observed in norepinephrine-contracted arteries after exposure to a single submaximal concentration of ITF 296 (1 microM). Similar results were obtained with NTG and ISDN, although NTG was found to be more active than ITF 296 or ISDN. The presence of either MB or HbO2 almost completely abolished the increase in cGMP induced by ITF 296, whereas a further increase in cGMP was observed in the presence of isobutylmethylxanthine. No changes in cAMP levels were observed after exposure of the tissues to a concentration of ITF 296 that induced significant elevation in the cGMP content. In the presence of L-cysteine, ITF 296 stimulated semipurified rat lung guanylate cyclase at higher concentrations than those of NTG or ISDN, probably because of its lower rate of nitric oxide (NO) release. These results suggest that, in common with the reference compounds NTG and ISDN, ITF 296-induced vasorelaxation in rabbit aortic rings is mediated by an NO-cGMP mechanism.

Animals↗
PubMed1989

Correlation between isosorbide dinitrate plasma levels and coronary vasodilation after chewing capsules.

In 10 patients with coronary artery disease coronary angiograms were performed in identical projections before and 5, 10 and 15 min after sublingual administration of two chewing capsules with 5 mg of isosorbide dinitrate (ISDN) each. Simultaneously, blood samples were taken for gas-chromatographical determination of nitrate plasma levels. The average ISDN plasma levels amounted to 138 +/- 73 ng/ml, 102 +/- 76 ng/ml and 62 +/- 34 ng/ml in the fifth, tenth and fifteenth min, resp. In the fifteenth min significant isosorbide mononitrate plasma levels (greater than 70 ng/ml) were found only in three patients. Mean diameters of angiographically normal coronary segments were measured with the automatic edge detection system CAAS; they increased by an average of 20 +/- 10%, 26 +/- 11%, and 27 +/- 13% (p less than 0.001) in the fifth, tenth and fifteenth min, resp. Due to hysteresis of the coronary dilation in relation to ISDN plasma levels no significant correlation was found between these parameters. The minimal diameters of seven of 10 coronary stenoses analyzed in seven patients reacted with a maximal increase of 23%-98%. Thus, ISDN chewing capsules may be preferable for rapid and prolonged relief of anginal attacks as well as for potent dilation of epicardial coronary arteries as desired during angiography.

Administration, Sublingual↗
PubMed1994

Potentiation of isosorbide dinitrate effects with N-acetylcysteine in patients with chronic heart failure.

BACKGROUND: Supply of sulfhydryl groups with the administration of N-acetylcysteine (NAC) has been reported to reverse tolerance to nitroglycerin but not to isosorbide dinitrate (ISDN). Lack of interaction between NAC and ISDN was suggested as an explanation for these findings. The present study was therefore designed to further evaluate this hypothesis. For this purpose, we compared the hemodynamic and hormonal effects of ISDN when given alone and in combination with NAC. METHODS AND RESULTS: We performed a randomized, cross-over design evaluation of the hemodynamic and hormonal effects of ISDN and ISDN + NAC in 14 patients with chronic congestive heart failure due to left ventricular systolic dysfunction. The findings of this study demonstrated a substantial NAC-mediated potentiation of ISDN effect on mean right atrial pressure (-11 +/- 21% versus -38 +/- 27%, -17 +/- 20% versus -34 +/- 27%, and -7 +/- 20% versus -25 +/- 26% at 2, 3, and 4 hours, respectively; all P < .05), mean pulmonary artery wedge pressure (-18 +/- 16% versus -33 +/- 14%, -15 +/- 25% versus -33 +/- 19%, -14 +/- 22% versus -25 +/- 22%, and -16 +/- 16% versus -26 +/- 16% at 2, 3, 4, and 5 hours, respectively; all P < .05), mean pulmonary artery pressure (-8 +/- 11% versus -20 +/- 15% at 3 hours, P < .05), and cardiac output (an increase of 2 +/- 16% versus 25 +/- 20% at 4 hours, P < .05). Although there were no significant changes in serum catecholamine levels and plasma renin concentration with both regimens, ISDN + NAC resulted in a greater fall in plasma levels of atrial natriuretic peptide (296 +/- 251 pg/mL after ISDN versus 202 +/- 118 pg/mL after ISDN + NAC, P < .05). CONCLUSIONS: The results of this study provide strong evidence for the existence of an interaction between thiols and ISDN and further support the role of sulfhydryl groups in the activation and therapeutic action of organic nitrates. The discrepancy between the results of this study demonstrating NAC-induced potentiation of ISDN effects and a previous study showing failure to reverse ISDN tolerance with NAC may suggest that ISDN-NAC interaction requires normal intracellular levels of sulfhydryl groups and does not occur after intracellular sulfhydryl group depletion.

Acetylcysteine↗
PubMed1984

Determination of the partitioning, stability, and metabolite formation of isosorbide dinitrate in human and rat blood using an improved gas-liquid chromatographic assay.

A simple and highly sensitive gas-liquid chromatographic method using electron-capture detection has been developed for the simultaneous determination of isosorbide dinitrate (ISDN) and its mononitrate metabolites in rat and human plasma. This method has a limit of quantitation of about 5 ng/ml for the mononitrates and of 1 ng/ml for ISDN using 0.1 ml of plasma, and is thus useful for pharmacokinetic studies of these compounds in small animals, and in humans when the available volume of blood is limited. Using this method, we found the apparent in vitro partitioning ratio of ISDN between erythrocyte and plasma in rat and human blood at 37 degrees C to be 0.22 and 0.13, respectively. In spite of this poor affinity for red blood cells, ISDN degradation in whole blood was mediated primarily via this blood fraction. Loss of ISDN in blood appeared to proceed exclusively through its mononitrate metabolites, resulting in a 6:1 product ratio of the 5-mononitrate to its 2-isomer. These data suggest that although blood degradation of ISDN and erythrocyte partitioning occur per se, these phenomena do not contribute significantly to the very rapid in vivo clearance of ISDN observed in man and in the rat.

Animals↗
PubMed1984

Postural changes and isosorbide dinitrate. A polygraphic study in patients with coronary artery disease.

Sitting or orthostatic positions and trinitrine-like drugs reduce venous return. We focused on the non-invasive assessment of postural-induced cardiovascular stress and isosorbide dinitrate (IDN) induced changes in 8 male patients with coronary artery disease (CAD), using polygraphic recordings by means of a Thermistor Pulse Transducer. The pre-ejection period (PEP) is sensitive to reduced preload and to the positive inotropic state of the myocardium. In addition, the % diastole (RR interval--electromechanical systole/RR interval) has been recently demonstrated to be correlated to coronary perfusion in CAD patients. We observed that IDN in clinostatism and the sitting position reduced preload (longer PEP) with increased heart rate (HR) and did not affect % diastole. In orthostatism, while controls showed an increased HR and prolonged PEP, the HR was higher after IDN, with a fall in PEP and a significant decrease in % diastole. We ascribed this change to adrenergic stimulation by the hypotensive actions of IDN (lowered mean blood pressure) in orthostatism and with a fall in coronary perfusion. Caution should be taken in CAD patients when postural stress could occur during IDN treatment. Moreover, polygraphic studies can be useful to detect individual responses to nitrates and serial recordings could be employed to assess late responses to chronic management with IDN.

Analysis of Variance↗
PubMed1985

Double-blind crossover comparison of the antianginal effects of nifedipine and isosorbide dinitrate in patients with exertional angina receiving propranolol.

A double-blind crossover study was performed on 27 patients with proved fixed coronary artery disease and stable angina pectoris. The study was designed to compare the relative efficacy of two combination therapies, nifedipine plus propranolol and isosorbide dinitrate plus propranolol, in terms of antianginal response and effect on exercise tolerance by evaluation of treadmill testing. The combination of nifedipine and propranolol was superior to the combination of isosorbide and propranolol in reducing the number of anginal attacks (p = 0.03), increasing total exercise time (p less than 0.02), increasing oxygen consumption achieved at end of exercise (p less than 0.03), increasing time to onset of pain (p = 0.003) and increasing oxygen consumption achieved at onset of pain (p = 0.003). Analysis of the rate-pressure products suggests that the difference in these results may be explained by the greater effect of nifedipine on afterload reduction. Although nitroglycerin consumption was reduced from baseline levels during combination nifedipine therapy (p less than 0.001), there was no statistical difference between nifedipine combination therapy and isosorbide combination therapy. In conclusion, although both combination therapies were superior to propranolol therapy alone, the combination of nifedipine and propranolol was more effective than the combination of isosorbide and propranolol in reducing the incidence of angina and improving exercise performance. Side effects were experienced at a similar frequency during both combination therapies.

Adult↗