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PubMed2006

Effect of intermittent administration of sustained release isosorbide dinitrate (sr-ISDN) in rats with pressure-overload heart.

Recent studies have demonstrated the benefits of nitric oxide (NO) on myocardial hypertrophy and myocardial fibrosis. It was suggested that NO has a protective effect on myocardial cell through the neurohormonal system. This effect serves to highlight the important role of NO in maintaining the function and form of heart with chronic heart failure. However, there are no known reports about on the effect of prolonged administration of nitrate on pressure over-load heart. This study was conducted to examine the long-term effect of oral nitrate therapy in rats with pressure-overloaded heart. An abdominal aorta constricted (AC) model of pressure-overloaded heart was created in male Wistar rats. Sustained release isosorbide dinitrate (sr-ISDN) (5 mg/kg once a daily) was administered to the rats once a daily for 12 weeks. The animals were euthanized during the study period, and the heart was collected and weighed. Histopathological examination was performed to evaluate the effect of sr-ISDN on myocardial hypertrophy and fibrosis. The ratio of heart to body weight increased significantly in AC rat and this increase was significantly prevented by sr-ISDN treatment. Histopathological examination showed significant increase in fibrotic area of AC rat compared to sham rat, this increase was inhibited by sr-ISDN treatment. Cardiomyocyte transverse diameter was significantly increased in AC rat compared with sham rat, but this increase tended to decrease by sr-ISDN treatment. In conclusion, intermittent administration with sr-ISDN has mild effect in inhibiting cardiac hypertrophy and marked effect in inhibiting fibrosis due to pressure-overload.

Administration, Oral↗
PubMed1998

Evidence of interaction between fluoxetine and isosorbide dinitrate on neuroleptic-induced catalepsy in mice.

Drugs which influence 5-HTergic mechanisms can modify neuroleptic-induced catalepsy (NC) in rodents, a phenomenon produced by striatal dopamine (DA) receptor blockade. Previous research also suggests a role for endogenous nitric oxide (NO) in the modulation of striatal DAergic neurotransmission; in addition, NO seems to play a role in the 5-HT reuptake mechanism. It is known that clomipramine potentiates NC in mice, but the reported effects of selective 5-HT reuptake inhibitors (SSRIs) in this model are rather contradictory. We then decided to re-address this issue, investigating the effect of fluoxetine (FX), an SSRI, on NC. In view of the ubiquitous role of NO as a central neuromodulator, we also studied the effect of isosorbide dinitrate (ID), a centrally active NO donor, and how both drugs interact to affect the phenomenon of NC. Catalepsy was induced in male albino mice with haloperidol (H; 1 mg/kg, i.p.) and measured at 30-min interval by means of a bar test. Drugs (FX, ID and FX + ID) or saline (controls) were injected i.p. 30 min before H, with each animal used only once. FX (5 mg/kg) significantly reduced NC, with maximal attenuation (about 74%) occurring at 150 min after H. ID (5 mg/kg) also inhibited NC (150 min: 62% attenuation). The combined drugs (FX + ID group), however, caused a great potentiation of NC (4.7-fold at its maximum, at 90 min). The effect observed with ID is compatible with the hypothesis that NO increases DA release in the striatum. The attenuation of NC observed with FX may be due to a preferential net effect on the raphe somatodendritic synapse, where inhibitory 5-HT1A autoreceptors are operative. The enhancement of NC caused by combined administration of FX and ID suggests the presence of a pharmacodynamic interaction, whose mechanism, still unclear, may be related to a decrease in striatal DA release.

Animals↗
PubMed1991

Coronary artery distensibility in Kawasaki disease--evaluation by intracoronary infusion of isosorbide dinitrate in long-term follow-up.

The coronary artery lesions in Kawasaki disease (KD) are thought to be a possible risk factor for atherosclerosis in the long term from the pathological point of view. Here we report results of a comparative control study to investigate the distensibility of the coronary artery in KD. A total of 146 patients were divided into 5 groups as follows. (I) Normal group (N); consisting of 44 patients with a known history of KD but with no coronary artery lesion. Among this group of patients those who each showed a regression in their coronary artery aneurysms were divided into 2 subgroups according to the time since onset of KD. (II) A group in the early stage after regression (ER); consisting of 18 patients with a known history of KD followed for 1.8 +/- 0.6 years. (III) A group in the later stage after regression (LR); consisting of 22 patients with a known history of KD followed for 9.4 +/- 2.8 years. (IV) an abnormal group (A); consisting of 21 patients followed for 7.9 +/- 4.0 years with a persistent aneurysm and/or stenosis in a coronary artery at the time of this study. And (V) a control group (C); consisting of 41 patients with a congenital heart disease such as a small ventricular septal defect or mild pulmonary stenosis or patent ductus arteriosus and no history of KD. In each case, the coronary artery diameter was measured by angiography before and after intracoronary infusion of isosorbide dinitrate (ISDN).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1992

[Non-invasive methods in the study of the elastic properties of the thoracic aorta. Effect of isosorbide dinitrate].

The role of the great arteries is to distribute and stock blood. Pulsatile discontinuous flow is transformed to a continuous flow system. The elastic properties of the aorta play a major role in these functions. It is generally agreed that changes in these elastic properties may lead to the development of left ventricular hypertrophy. The evaluation of the aorta has, until recently, depended on invasive hemodynamic and angiographic techniques. In addition, the measurement of pulse wave velocity, though useful, is a global and only an approximate method. Transoesophageal echocardiography (TEE) enables accurate measurement of the aortic diameter and its systolo-diastolic variations. The accuracy of these measurements has been validated in vitro and the reproducibility is much better than with previously used techniques. Previous studies have shown an improvement of the elastic properties of the great arteries with nitrate derivatives. In recent studies using TEE, isosorbide dinitrate caused dilatation of the descending thoracic aorta and thereby improved its elastic properties. The development of tonometry techniques in our department has resulted in the finding of excellent correlations between carotid and aortic pulse pressures measured non-invasively. The association of TEE and tonometry thereby provides a direct approach to the evaluation of aortic compliance. It has then become possible to study the effects of nitrate derivatives on the aortic compliance of elderly patients in whom it is the most reduced.

Aorta, Thoracic↗
PubMed1986

Adenosine, dipyridamole and isosorbide dinitrate are ineffective to prevent the sympathetic initiation of poststenotic myocardial ischemia.

An activation of cardiac sympathetic nerves increases coronary vascular resistance distal to severe stenoses and induces ischemia of the dependent myocardium. The selective alpha 2-adrenoceptor antagonist rauwolscine and the calcium antagonist nifedipine prevent both poststenotic vasoconstriction and ischemia. To exclude the possibility that the beneficial action of nifedipine is based on unspecific coronary dilation rather than a functional antagonism against alpha 2-adrenoceptor mediated poststenotic vasoconstriction we now tested coronary dilatory drugs with a different underlying mechanism. The left ventrolateral cervical cardiac sympathetic nerve was stimulated in 12 anesthetized, vagotomized dogs. A severe stenosis of left circumflex coronary artery was defined by the absence of a postocclusive reactive hyperemia. Sympathetic stimulation increased end-diastolic poststenotic resistance from 0.45 +/- 0.10 to 0.83 +/- 0.18 mmHg X min X 100 g/ml and induced a net lactate production of the poststenotic myocardium. Adenosine (50 micrograms/kg X min i.c., n = 5), dipyridamole (0.2 mg/kg i.v., n = 3) and isosorbide-dinitrate (1 mg i.c., n = 4) did not prevent the increase in resistance and the net lactate production. Thus the effectiveness to prevent alpha 2-adrenergic poststenotic coronary constriction appears to be specific for alpha 2-antagonists and calcium antagonists.

Action Potentials↗
PubMed1991

A new multiple-unit oral floating dosage system. II: In vivo evaluation of floating and sustained-release characteristics with p-aminobenzoic acid and isosorbide dinitrate as model drugs.

In a previous study, we developed a multiple-unit type of oral floating dosage system, which is a new type of floating pill composed of both an effervescent layer and a swellable membrane layer coated on sustained-release pills. The system was shown to have excellent floating ability and sustained-release characteristics in vitro, irrespective of the pH and viscosity of the medium. In the present study, the floating ability and the sustained-release characteristics of the system in the gastrointestinal tract have been evaluated in vivo. In beagle dogs and humans in the fed state, most of the new type of pills containing barium sulfate were floating in the stomach at 10 min, and they kept floating for at least 3 h after administration (observed by periodic X-ray photographs), while some control pills without the effervescent layers were already transited into the small intestine by 3 h. Moreover, in order to evaluate the sustained-release characteristics of the drug from the new type of floating pills, p-aminobenzoic acid (PABA), with a limited absorption site, and isosorbide dinitrate (ISDN), with wide absorption sites in the gastrointestinal tract, were employed as model drugs. Floating pills of the new type, with the same sustained-release rate as that of non-floating pills (control pills) were prepared. In beagle dogs in the fed state, the new type of floating pills containing PABA showed higher plasma PABA levels at 5 and 6 h after dosing and 1.61 times greater AUC than the control pills.(ABSTRACT TRUNCATED AT 250 WORDS)

4-Aminobenzoic Acid↗
PubMedDate not supplied

Comparative evaluation of three dosages of slow-release isosorbide dinitrate (60, 80, 100 mg) in chronic angina of the aged.

In a single-blind, placebo-controlled study the acute and chronic antianginal effects of three slow-release (SR) new formulations of isosorbide dinitrate (ISDN 60, 80, 100 mg) have been comparatively evaluated in a group of aged affected by chronic stable effort-induced angina. Compared to placebo, overall the active dose paritetically improved the effort tolerance up to 24 h after the first assumption. In the time course of the trial (2 and 4 weeks) the resting hemodynamic changes induced by the first dose were partially blunted without affecting the exercise related-parameters. Also if plasma levels of ISDN and of its metabolites did not correlate to the degree of physical improvement, the peak increase in effort tolerance was observed under 100 mg treatment. Mild to moderate transient headache was experienced by 50% of actively treated and by 20% of placebo treated patients and no other serious adverse effects have been noted. One may conclude that ISDN in slow-release formulations of 60-100 mg isan effective, safe and well tolerated medication in the management of angina in the aged.

Clinical Trial↗
PubMed1985

Comparison of buccal nitroglycerin and oral isosorbide dinitrate for nitrate tolerance in stable angina pectoris.

Sixteen patients with chronic stable angina pectoris were studied to compare the hemodynamic and antianginal effects of buccal nitroglycerin (GTN) in a dose of 3 mg administered 3 times daily and oral isosorbide dinitrate (ISDN) in a dose of 30 mg administered 4 times daily. Compared with placebo, both oral ISDN and buccal GTN treatment induced a decrease in systolic blood pressure at rest over a 5-hour period during acute but not during sustained therapy. Neither buccal GTN nor oral ISDN modified the changes in systolic blood pressure during exercise. Both treatment programs were associated with a higher exercise heart rate during acute therapy. During sustained treatment with buccal GTN, the heart rate during exercise remained greater than that during placebo throughout the 5-hour test period, but during treatment with oral ISDN, only the exercise heart rate at 1 hour was greater than that seen with placebo. Treadmill walking time to the onset of angina and to the development of moderate angina increased significantly during acute therapy with both buccal GTN and oral ISDN. The clinical efficacy of buccal GTN was maintained after 2 weeks of 3-times-daily therapy. In contrast, during 4-times-daily therapy with oral ISDN, treadmill walking time was prolonged for only 1 hour after drug administration. This investigation indicates that tolerance develops during 4-times-daily therapy with oral ISDN, but 3 times daily therapy with buccal GTN is not associated with diminished antianginal effects.

Aged↗
PubMed1982

[Isosorbide dinitrate in the treatment of threatening myocardial infarction (author's transl)].

Thirty patients with threatening myocardial infarction were treated with intravenous isosorbide trinitrate. Eight patients had increasingly severe angina, 6 had de novo crescendo angina, 3 had Prinzmetal angina and 13 had signs of impending extension of a previous infarct. In all cases the anginal attacks occurred spontaneously. The drug was administered in association with a beta-blocker or a calcium antagonist. The initial dosage was 33 mcg/min and dosage adjustments ranged from 16 to 130 mcg/min. the main duration of treatment was 3.6 days. Pain was controlled in all patients. Anginal attacks ceased completely and permanently in 24, but the remaining 6 became isosorbide dinitrate-dependent and could only be weaned by aortocoronary bypass. The effects on the drug on heart rate and blood pressure remained moderate and never interfered with dosage adjustments. Coronary artery angiography was performed without any trouble in 25 patients, 21 of whom underwent myocardial revascularization by venous grafts.

Adult↗
PubMed1993

[Effect of isosorbide dinitrate on pulmonary venous compliance].

Irreversible poor pulmonary venous compliance (PV comp) could worsened natural course of patients (pts) with high pulmonary capillary wedge pressure especially pts with mitral stenosis. Nitrates (isosorbide dinitrate-ISDN) possessing venous dilating action could increase PV comp in most of pts. The main aim of that study was to assess hemodynamic effects of ISDN, in pts with MS, with special emphasis on PV com changes. PV comp was estimated according to Hirakawa equation (dV/dp = 0.4*k2*SV/(v-d) in 35 pts with MS, during preoperative right heart catheterisation with VYGON 5155-180 thermodilution catheters during rest and effort in supine position (25W). The same protocol was performed after Iso-Mack sprawy 3.75 mg. According to the PV comp response to ISDN, pts were divided in two groups: good responders (I)-15% and higher increase in PV comp and poor responders (II). ISDN increased PV comp in the whole group according to the response to ISDN, there were significant differences in stroke volume index (SVI) and heart rate (HR). In the group of good responders mean right atrial pressure (RA), mean pulmonary artery pressure (PAP), mean pulmonary wedge pressure (PWP) decreased significantly with simultaneous slight not significant decrease in SVI and not significant increase of HR. In the group of poor responders SVI decreased significantly by about 20% with significant increase of HR. In conclusion significant decrease in pulmonary pressures (PAP, PWP) in pts with good response to ISDN are secondary to the increase of PV comp, while among poor responders the same effects are due to diminished flow secondary to the decrease of the systemic venous return.

Adult↗
PubMed2005

Cost-effectiveness of fixed-dose combination of isosorbide dinitrate and hydralazine therapy for blacks with heart failure.

BACKGROUND: Fixed-dose combination of isosorbide dinitrate/hydralazine (ISDN/HYD) improved clinical outcomes in the African-American Heart Failure Trial (A-HeFT). We assessed the resource use, costs of care, and cost-effectiveness of ISDN/HYD therapy in the A-HeFT trial population. METHODS AND RESULTS: We obtained resource use data from A-HeFT, assigning costs through the use of US federal sources. Excluding indirect costs, we summarized the within-trial experience and modeled cost-effectiveness over extended time horizons, including a US societal lifetime reference case. During the mean trial follow-up of 12.8 months, the ISDN/HYD group incurred fewer heart failure-related hospitalizations (0.33 versus 0.47 per subject; P=0.002) and shorter mean hospital stays (6.7 versus 7.9 days; P=0.006). When study drug costs were excluded, both heart failure-related and total healthcare costs were lower in the ISDN/HYD group (mean per-subject heart failure-related costs, 5997 dollars versus 9144 dollars; P=0.04; mean per-subject total healthcare costs, 15,384 dollars versus 19,728 dollars; P=0.03). With an average daily drug cost of 6.38 dollars, ISDN/HYD therapy was dominant (reduced costs and improved outcomes) over the trial duration. Assuming that no additional benefits accrue beyond the trial, we project the cost-effectiveness of ISDN/HYD therapy using heart failure-related costs to be 16,600 dollars/life-year at 2 years after enrollment, 37,100 dollars/life-year at 5 years, and 41,800 dollars/life-year over lifetime (reference case). CONCLUSIONS: ISDN/HYD therapy, previously shown to improve clinical outcomes, also reduced resource use and costs in A-HeFT, primarily because of a large reduction in hospitalizations. Long-term use of ISDN/HYD therapy should be associated with a favorable cost-effectiveness profile in this population.

Black People↗