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At least 1,207 records · Page 67Linked to original sources
PubMed1995

Inhibition of angiogenesis, tumour growth and metastasis by the NO-releasing vasodilators, isosorbide mononitrate and dinitrate.

1. The effect of the nitric oxide (NO)-producing nitrovasodilators isosorbide mononitrate (ISMN) and isosorbide dinitrate (ISDN) were assessed on (a) the in vivo model of angiogenesis of the chick chorioallantoic membrane (CAM) and (b) on the growth and metastatic properties of the Lewis Lung carcinoma (LLC) in mice. 2. Isosorbide 5-mononitrate (ISMN) and isosorbide dinitrate (ISDN), inhibited angiogenesis in the CAM dose-dependently. ISMN was more potent in inhibiting this process. Both compounds were capable of completely reversing the angiogenic effect of alpha-thrombin. These effects of ISMN and ISDN on angiogenesis were comparable to those previously observed with sodium nitroprusside which generates NO non-enzymatically. 3. Mice, implanted intramuscularly with LLC, received daily i.p. injections of ISMN for 14 days resulting in a significant decrease in the size of the primary tumour and a reduction in the number and size of metastatic foci in the lungs. ISDN had a similar but less pronounced effect than that observed with ISMN. 4. Addition of ISMN or ISDN to cultures of bovine, rabbit and human endothelial cells and to cultures of LLC cells had no effect on their growth characteristics. 5. These results indicate that ISMN and ISDN inhibit angiogenesis and tumor growth and metastasis in an animal tumour model. The possibility should therefore be considered that these nitrovasodilators which are widely used therapeutically and have well characterized pharmacological profiles, may also possess antitumour properties in the clinic.

Animals↗
PubMed1992

Vasodilator therapy enhances neutrophil tissue migration.

Very little is known about the effect of vasoactive substances on migration of polymorphonuclear neutrophils in vivo. We evaluated the effect of oral treatment with isosorbide dinitrate on neutrophil migration into a sterile skin inflammatory focus in man with the use of "skin chamber technique". Isosorbide dinitrate increased the number of neutrophils harvested in the chamber as well as the "granulocyte clearance". Thus, vasoactive agent may increase neutrophil extravasation and subsequent tissue migration.

Administration, Oral↗
PubMed1987

Role of nitrates in congestive heart failure.

The systemic vasoconstriction that is characteristic of patients with congestive heart failure involves arteriolar constriction, reduction in arterial compliance and reduction in venous capacitance, all of which contribute to the increased impedance and increased preload that aggravate the hemodynamic abnormality. Nitrates are effective in increasing arterial compliance and venous capacitance and thus have a favorable acute hemodynamic effect in heart failure. Long-term studies suggest that this favorable effect is maintained in response to high dose oral isosorbide dinitrate therapy and that it is associated with relief of symptoms and improved exercise tolerance. When combined with hydralazine, isosorbide dinitrate therapy has been shown in the Veterans Administration study to prolong survival in patients with class II and III congestive heart failure. Therefore, long-term nitrate therapy appears to have an important potential in patients with heart failure. It may now be appropriate to use nitrates not only to relieve symptoms, but also to improve long-term outlook in this syndrome.

Dosage Forms↗
PubMed1985

Postural influences on the hemodynamic responses to vasodilating drugs in congestive heart failure.

Supine and upright hemodynamic measurements were performed in 58 patients with congestive heart failure to assess the effects of postural change on the hemodynamic responses to vasodilating drugs. The patient population was divided into three treatment groups and was studied before and after isosorbide dinitrate, nifedipine, or clonidine treatment. When the hemodynamic responses in the upright position were compared with the supine values, isosorbide dinitrate (40 mg orally) evoked a greater reduction in mean systemic blood pressure and stroke volume with augmented increases in heart rate, mean pulmonary artery pressure, and pulmonary vascular resistance while the patient was upright. Nifedipine (10 mg orally) when studied in the upright position caused additional augmentation of cardiac output and stroke volume index with further reduction in total systemic vascular resistance compared with supine values. No position-related changes in hemodynamic measurements were noted with clonidine (0.1 mg orally).

Adult↗
PubMed1999

Long-acting isosorbide mononitrate.

Elantan long (EL) is the only long-acting isosorbide mononitrate formulation based on a controlled membrane principle. 30% of the dose is available for immediate release and the remaining 70% is gradually released over time. After oral administration, isosorbide mononitrate EL has a quick onset of action (30 minutes) and effects are evident for up to 17 hours. The antianginal effects of once-daily isosorbide mononitrate EL 50 to 100mg were generally similar to those of conventional isosorbide mononitrate or isosorbide dinitrate 10 to 20mg twice or 3 times daily, or sustained-release nifedipine 20mg twice or 3 times daily. Patients tended to show a better response with once-daily isosorbide mononitrate EL 50mg than with bupranolol 100mg. Patients showed significantly greater improvement in some quality-of-life indices with once-daily isosorbide mononitrate EL than with twice or 3 times daily regimens of conventional isosorbide mononitrate or isosorbide dinitrate. Tolerance did not develop after 13 months of once-daily administration of isosorbide mononitrate EL. No rebound increase in incidence of ischaemic episodes was observed after discontinuation of the drug.

Angina Pectoris↗
PubMed1998

Renal artery vasomotion: in vivo assessment in the pig with intravascular Doppler.

Intravascular Doppler is widely used for experimental studies in the coronary circulation. We designed this study to assess baseline bloodflow and arteriolar resistance in the porcine renal circulation and to study the vasomotor responses of vasoactive drugs. In anesthesized piglets (n = 15), renal arterial diameter was measured with quantitative angiography and blood flow velocity with a Doppler wire (Cardiometrics). Bloodflow and resistances were calculated at baseline and after injection of vasoactive drugs (isosorbide dinitrate, papaverine). This allowed us to determine the renal bloodflow reserve (the capacity of the kidney to augment basal bloodflow). Injection of isosorbide dinitrate was associated with an increase in average peak velocity of 64% (P < 0.01) and a small (from 4.5 to 4.74, P < 0.01) but significant increase in renal artery diameter, resulting in an increase in bloodflow of 82% (P < 0.01) and a decrease in arteriolar resistance of 46% (P < 0.01). Bloodflow returned to baseline (4.76 +/- 1.48 mL/s) approximately 5 min after isosorbide injection. Average Peak Velocity increased almost twofold after papaverine injection (60 +/- 10 to 108 +/- 24 cm/sec, P < 0.01). There was a significant (P < 0.01) increase in arterial bloodflow of 96% in the right and 79% in the left renal artery after injection of papaverine with a corresponding significant (P < 0.01) decrease in arteriolar resistance of 49% in the right and 44% in the left renal artery. Using a combination of quantitative angiography and intravascular Doppler allows easy measurement of baseline renal blood flow and of the effects of vasodilator drugs on bloodflow and resistance. The results show that a vasodilatator reserve exists in the renal circulation but is less marked than that reported in the coronary circulation.

Animals↗
PubMed1998

Syncope in a 65-year-old woman after nitrate ingestion.

A 65-year-old woman with angina pectoris presented with syncope after sublingual ingestion of isosorbide dinitrate (5 mg). Her response to a postural challenge test, without medication, was normal. In a postural challenge test after administration of isosorbide dinitrate (5 mg), blood pressure decreased from 120/67 to 65/35 mmHg, followed by syncope with a sudden decrease in pulse rate from 85 to 60 beats/min. No evidence of myocardial infarction was detected. Elderly patients for whom nitrate has been prescribed should be warned of the occurrence of hypotension, leading to unconsciousness.

Administration, Sublingual↗
PubMed2006

Generalized gamma frailty model.

In this article, we present a frailty model using the generalized gamma distribution as the frailty distribution. It is a power generalization of the popular gamma frailty model. It also includes other frailty models such as the lognormal and Weibull frailty models as special cases. The flexibility of this frailty distribution makes it possible to detect a complex frailty distribution structure which may otherwise be missed. Due to the intractable integrals in the likelihood function and its derivatives, we propose to approximate the integrals either by Monte Carlo simulation or by a quadrature method and then determine the maximum likelihood estimates of the parameters in the model. We explore the properties of the proposed frailty model and the computation method through a simulation study. The study shows that the proposed model can potentially reduce errors in the estimation, and that it provides a viable alternative for correlated data. The merits of proposed model are demonstrated in analysing the effects of sublingual nitroglycerin and oral isosorbide dinitrate on angina pectoris of coronary heart disease patients based on the data set in Danahy et al. (sustained hemodynamic and antianginal effect of high dose oral isosorbide dinitrate. Circulation 1977; 55:381-387).

Angina Pectoris↗
PubMed1996

Nitric oxide donors increase cytosolic ionized calcium in cultured human intestinal epithelial cells.

We used fluorescence spectrophotometry, digital-imaging fluorescence microscopy, and the fluorescent dye, Fura-2, to measure the effects of several different nitric oxide (NO.) donors on intracellular levels of ionized calcium ([Ca2+]i) in cultured Caco-2BBe cells, a human enterocytic cell line. Incubation of Caco-2BBe cells with sodium nitroprusside (SNP) or isosorbide dinitrate for 2 h significantly increased [Ca2+]i. The effects of both agents were concentration dependent. The lowest concentrations of SNP or isosorbide dinitrate capable of increasing [Ca2+]i were .625 mM and 10 mM, respectively. Chelation of extracellular Ca2+ with 2 mM EGTA abrogated the increase in [Ca2+]i induced by SNP. In contrast, blockade of voltage-gated Ca2+ channels with 2 mM NiCl2 or 200 microM verapamil failed to affect SNP-induced alterations in [Ca2+]i. Using NBD-phallicidin to stain polymerized (F)-actin, we found that incubation of Caco-2BBe cells with SNP results in actin polymerization, particularly in the periphery of cells. We conclude that NO. increases [Ca2+]i and promotes actin polymerization in a cultured enterocytic cell line.

Caco-2 Cells↗
PubMed1988

Pharmacokinetics of organic nitrates in man: an overview.

The pharmacokinetics of glyceryl trinitrate are still not completely understood. The substance disappears rapidly from plasma largely by extrahepatic mechanisms. It is converted in glyceryl dinitrates and glyceryl mononitrates. After transdermal application of a controlled delivery system, plasma concentrations of glyceryl trinitrate can be maintained over the time period of application but, as for other routes, there are important intra- and inter-individual variations and fluctuations. Isosorbide dinitrate disappears less rapidly from the body; it is converted to the isosorbide mononitrates. Plasma concentrations of isosorbide dinitrate and mononitrates are quite predictable in different circumstances, e.g. on application of oral sustained release formulations. Measurement of the plasma concentrations of nitrates has been used to characterize different preparations and routes of administration. However, these plasma concentrations cannot be used to predict the effect, probably because of the important counter-regulation and tolerance which develop rapidly after administration of the drugs.

Absorption↗
PubMed1982

Vasodilators and prostaglandin inhibitors in primary pulmonary hypertension.

Ten women with primary pulmonary hypertension had resting hemodynamic measurements taken before and after the nonparenteral administration of various vasodilators and prostaglandin inhibitors. Only sublingual isoproterenol, alone or combined with sublingual isosorbide dinitrate, effected a substantial (greater than 20%) drop in pulmonary vascular resistance; this decrease was accompanied by little change in pulmonary artery pressure. Isosorbide dinitrate was the only drug that elicited any reduction in pulmonary artery pressure; pulmonary vascular resistance decreased modestly. The oral administration of diazoxide, hydralazine, phentolamine, and tolazoline elicited little change in pulmonary artery pressure or resistance. Except for tolazoline, all these agents significantly decreased systemic blood pressure and resistance. Prostaglandin inhibition by indomethacin (acute and chronic dosing) increased pulmonary and systemic vascular resistances and reduced cardiac output. Aspirin combined with dipyridamole elicited no changes. The vasodilators and prostaglandin inhibitors studied evoked little improvement in resting pulmonary hemodynamic abnormalities in primary pulmonary hypertension.

Adolescent↗
PubMed1976

Treatment of congestive heart failure.

In treating heart failure, the physician must remain cognizant of pathophysiology as he prescribes and monitors therapy. In addition to seeking underlying and precipitating causes of the patient's heart failure, he must treat the congestive state by enhancing myocardial contractility, controlling excessive fluid retention, and reducing afterload. Figure 7 summarizes the theoretical shifts on a patient's left ventricular function curves that might occur with therapy. Left ventricular function might move from point A to point B with diuretic therapy, but overdiuresis could aggravate symptoms of low cardiac output, including postural hypotension. Digitalis would effect a shift from A to C. Isosorbide dinitrate would produce a shift from A to D in a patient not on digitalis and from C to D in a patient already receiving digitalis. Isosorbide dinitrate, in conjunction with more usual therapeutic measures, has proved clinically beneficial in the treatment of heart failure.

Benzothiadiazines↗
PubMed1996

Comparison of subgroups assigned to medical regimens used to suppress cardiac ischemia (the Asymptomatic Cardiac Ischemia Pilot [ACIP] Study).

This report focuses on the subset of 235 patients from the Asymptomatic Cardiac Ischemia Pilot (ACIP) study receiving randomly assigned medical therapy to treat angina and suppress ischemia detected on ambulatory electrocardiography: 121 patients received the sequence of atenolol and nifedipine, and 114 diltiazem and isosorbide dinitrate. After 12 weeks of therapy, the primary end point (absence of ambulatory electrocardiographic (ECG) ischemia and no clinical events) was reached in 47% of atenolol/nifedipine- versus 31% of diltiazem/isosorbide dinitrate-treated patients (adjusted p = 0.03). A trend to increased exercise time to ST depression was seen in the atenolol and nifedipine versus diltiazem and isosorbide dinitrate regimens (median treadmill duration 5.8 vs 4.8 minutes; p = 0.04). However, when adjusted for baseline imbalances in ambulatory ECG ischemia, the 2 medical combinations were similar in suppression of ambulatory ECG ischemia. In both medication regimens, an association between mean heart rate and ischemia on ambulatory electrocardiography after 12 weeks of treatment was observed so that patients on either regimen with a mean heart rate > 80 beats/min had ischemia detectable almost twice as often as those with a mean heart rate < 70 beats/min (p < 0.001).

Angina Pectoris↗
PubMed2001

Variant angina with a strong spasmodic trait.

A 55-year-old man came to the hospital because of chest pain, mostly occurring in the early morning at rest. He had to get isosorbide dinitrate intravenously with continuous infusion. Following ergonovine provocation test, total occlusion of mid-left anterior descending artery was identified with marked elevation of ST segment as exercise test showed despite isosorbide dinitrate.

Angina Pectoris, Variant↗
PubMed1992

Persistent hemodynamic improvement with short-term nitrate therapy in patients with chronic congestive heart failure already treated with captopril.

To evaluate the therapeutic potential of organic nitrates in patients with chronic congestive heart (CHF) failure already treated with angiotensin-converting enzyme (ACE) inhibitors, the temporal hemodynamic effects of oral isosorbide dinitrate, 40 to 120 mg administered every 6 hours to 11 nitrate responders who had been treated with captopril 89 +/- 32 mg/day, were studied. The administration of isosorbide dinitrate resulted in a significant decline in mean right atrial pressure, from 13 +/- 6 mm Hg at baseline (mean value of measurements performed every 2 hours for 24 hours with captopril therapy) to 9 +/- 4 mm Hg at 1 hour with persistent effect for most of the study period. Mean pulmonary artery pressure decreased from 38 +/- 7 mm Hg at baseline to 29 +/- 9 mm Hg at 1 hour, with effect persisting for 24 hours. Mean pulmonary artery wedge pressure also decreased from 24 +/- 6 to 15 +/- 7 mm Hg at 1 hour and remained significantly reduced for 20 hours. Systemic blood pressure demonstrated a transient decrease lasting 2 hours after initiation of therapy which was asymptomatic in all patients. The results of this study demonstrate a preserved vasodilatory effect of organic nitrates in patients already treated with ACE inhibitors. Nitrates mediated improvement in right and left ventricular filling pressures, and reduction of pulmonary hypertension demonstrates a rationale for the use of these therapeutic methods in combination and suggest the need for long-term evaluation of the effect of nitrate therapy in patients with chronic CHF already treated with ACE inhibitors.

Adult↗
PubMed1992

Nitric oxide donors increase mucus gel thickness in rat stomach.

Instillation of the nitric oxide (NO) generator isosorbide dinitrate (0.1-1 mM) into the rat gastric lumen in vivo produced a dose-related increase in mucus gel thickness that was prevented by coadministration of oxyhaemoglobin (10 microM). Isosorbide dinitrate did not induce epithelial cell damage. S-Nitroso-N-acetyl-penicillamine (0.3 mM) and dibutyryl cyclic GMP (1 mM) also increased mucus thickness. These findings, along with the presence of NO synthase in the gastric mucosa, imply a role for NO in vivo in mediation of gastric mucus release.

Animals↗
PubMed1987

[Comparative evaluation of the efficacy of nitrosorbide and nitroglycerin in acute myocardial infarct patients].

Intravenous isosorbide dinitrate and nitroglycerin administered within early hours of myocardial infarction have a marked antianginal effect, stabilize the size of necrotic focus and promptly control acute left-ventricular insufficiency. Unlike nitroglycerin, isosorbide dinitrate has a more lasting action and does not affect heart rate and arterial blood pressure. It can therefore be used more extensively in patients with acute myocardial infarction.

Acute Disease↗
PubMedDate not supplied

Isosorbide 5-mononitrate pharmacokinetics in humans.

When isosorbide 5-mononitrate was intravenously infused at a rate of 4 mg h-1 for 2.5 h to five human subjects, its concentrations in plasma increased slowly to 185 ng ml-1 +/- 5 per cent C.V. at 2.5 h and a steady-state plasma level was not reached during the infusion. When the infusion was discontinued, plasma drug concentrations declined with an elimination half-life of 4.2 h +/- 6 per cent C.V. The systemic clearance after the infusion doses was 132 ml min-1 +/- 18 per cent C.V. and the volume of distribution was 48.4 +/- 16 per cent C.V. After equal oral doses of 10 mg, the peak plasma isosorbide 5-mononitrate concentration of 191 ng ml-1 +/- 16 per cent C.V. was reached at 1.1 h +/- 30 per cent C.V., and plasma levels declined with a terminal half-life of 4.9 h. The complete systemic availability of isosorbide 5-mononitrate indicated that pre-systemic elimination after the oral doses was negligible. A one-compartment open model appeared adequate to describe the plasma level data after intravenous infusion and oral dose. After single oral doses of 10 mg isosorbide dinitrate, the peak plasma concentration of the 5-mononitrate metabolite of 72 ng ml-1 +/- 27 per cent C. V. occurred at 1.7 h +/- 41 per cent C.V. Approximately 50 per cent (range 22--68 per cent) of the oral dose of isosorbide dinitrate circulated in plasma as the 5-mononitrate metabolite. The pharmacokinetics of isosorbide mononitrates are markedly different to those of the parent dinitrate and these differences follow from the greater systemic availability and volume of distribution of the mononitrates.

Adult↗