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PubMed1981

[Plethysmographic researches on the beginning and duration of the pharmacological action of an isosorbide dinitrate drugs with prolonged action (author's transl)].

Taking into consideration a previous work, where we experimented the pharmacological action of different products of nitrite retard and from which resulted the absolute superiority of isosorbide dinitrate, we considered interesting to repeat the experimentation with a new form of isosorbide dinitrate characterized by an action duration more prolonged in the time owing to the particular freeing of the active principle. In 20 patients free from peripheral vasculopathy it was enregistered the rheogram with derivation back-feet-big toe in base condition and at 1st, 3rd, 5th and 10th hour from the administration of Nitrosorbide Retard 20 mg. The product action, put in evidence by the appearance of the typical pulse by nitrite, begins the first hour, it reaches the maximum at the 5th hour on average and it clearly lasts until the 10th hour. Therefore it is demonstrated the practical usefulness of this product in the daily clinical medicine considered its characteristics of action rapidity, duration and steadfastness.

Adult↗
PubMed1990

Effect of sublingual isosorbide dinitrate in portal hypertension.

Nitrates decrease portal pressure by decreasing portal venous inflow and resistance. We studied over 20 minutes the effect of 10 mg isosorbide dinitrate sublingual on intrasplenic pulp pressure, mean arterial pressure and heart rate, in 13 patients with cirrhotic or non-cirrhotic portal hypertension. The pulp pressure fell progressively over 20 minutes, from mean 43.6 +/- 2.4 (SEM) to 35.6 +/- 1.8 cm H2O (p less than 0.001). This was accompanied initially by a significant fall in mean arterial pressure (85.8 +/- 1.9 to 80.4 +/- 2.7 mmHg at 4 minutes; p less than 0.01) and rise in heart rate (92.5 +/- 5.0 to 102.6 +/- 5.9 per minute at 6 minutes; p less than 0.02), following which these parameters remained stable. One patient developed giddiness due to hypotension at 15 minutes. We conclude that sublingual isosorbide dinitrate decreases pulp pressure in cirrhotic and non-cirrhotic portal hypertensives, but this is initially accompanied by significant hemodynamic changes.

Administration, Sublingual↗
PubMed1983

A new oral slow release form of isosorbide dinitrate. Effect on the hemodynamics and exercise capacity of patients with angina.

To assess the bioavailability of a new oral and slow release form of isosorbide dinitrate (ISDN-SR), we evaluated 12 patients with confirmed coronary artery disease, chronic stable angina pectoris and abnormal maximal exercise tests (angina-limited and associated with greater than or equal to 0.1 mV ST displacement). Each patient was known to have an increased exercise time after 0.4 mg of sublingual nitroglycerin. Patient responses to exercise on the treadmill at two, four, six, and eight hours after the double-blind administration of 40 mg of ISDN-SR were compared to an identical placebo. It is concluded that 40 mg of this slow release form of isosorbide dinitrate is bioavailable for at least eight hours as demonstrated by significantly improved exercise capacity of the majority (64 percent) of angina patients in this study, each of whom demonstrated anginal limitation to exercise and favorable responses to 0.4 mg of sublingual nitroglycerin.

Administration, Oral↗
PubMed1984

Determination of isosorbide dinitrate and its mononitrate metabolites in human plasma using Extrelut purification and capillary column gas-liquid chromatography.

A rapid, accurate and sensitive method for the determination of isosorbide dinitrate (internal standard: isomannide dinitrate) and its 2- and 5-mononitrate metabolites (internal standard: isoidide mononitrate) in 1.0 ml of human plasma has been developed. Before chromatographic quantitation by gas-liquid chromatography with electron-capture detection, isosorbide nitrates were purified by Extrelut chromatography (recovery about 90%), eliminating most of the endogenous interferences. Routine limit of quantitation and reproducibility were 0.5, 2.0 and 10.0 ng/ml and 6, 8 and 7% for isosorbide dinitrate and the 2- and 5-mononitrates, respectively. This method allowed the behaviour of this vasodilating drug and its metabolites to be studied in humans.

Chromatography, Gas↗
PubMed1985

Pharmacokinetics and pharmacodynamics of isosorbide dinitrate.

It has long been believed that organic nitrates, including isosorbide dinitrate (ISDN), are completely metabolized during their first passage through the liver and that oral therapy with this class of compounds is thus irrational. In the past few years, convincing data have been obtained in patients showing that intact ISDN is significantly bioavailable to the systemic circulation after oral administration; the oral bioavailability is about 20% relative to an intravenous dose and about 45% relative to a sublingual dose, with the balance metabolized to isosorbide mononitrates. These pharmacologically active metabolites have longer biologic half-lives than ISDN and are thus believed to contribute to the sustained duration of action of this drug. After acute dosing, changes in the pharmacologic effects of ISDN mirror those in plasma concentration. However, after long-term therapy, partial nitrate tolerance develops despite elevated plasma ISDN concentrations. Available evidence suggests that during sustained dosing, nitrate metabolism is generally reduced throughout the body; thus reduced hepatic and peripheral tissue metabolism raises plasma ISDN concentrations while reduced vascular tissue metabolism decreases the metabolic activation (perhaps to nitrosothiols?) necessary for vascular relaxation.

Administration, Oral↗
PubMed1993

Bioavailability and pharmacokinetics of a new isosorbide dinitrate spray preparation in healthy volunteers.

In the course of this study the bioavailability and pharmacokinetic profile of a newly developed 2.5 mg (per valve release) oral isosorbide dinitrate (ISDN, CAS 87-33-2) spray preparation (Isoket Spray) were determined and compared with the results for an already marketed reference spray preparation following single application. For this purpose, the test and reference spray were examined in 18 healthy volunteers according to a randomized 2-way cross-over design. Blood samples were collected during 12 h p.a. and plasma concentrations of ISDN and its metabolites isosorbide-2-mononitrate (IS-2-MN) and isosorbide-5-mononitrate (IS-5-MN) were quantified by a GC-method. Both sprays showed mean maximum concentrations of ISDN in plasma of nearly 18 ng/ml about 7 min after drug intake with arithmetic mean values for the areas under the curve AUC0-12 of 7.01 (test spray) and 7.30 h.ng/ml (reference spray). For the metabolic products IS-2-MN and IS-5-MN (values for the reference spray in brackets) the corresponding maximum concentrations were 4.15 (4.21) ng/ml and 16.1 (15.9) ng/ml, respectively, and for the areas under the curve AUC0-12 values of 9.75 (9.92) h.ng/ml for IS-2-MN and 104.3 (99.7) h.ng/ml for IS-5-MN in the mean were calculated. Statistical evaluation of all pharmacokinetic parameters revealed bioequivalence between the two preparations. Typical side-effects known and described under isosorbide dinitrate therapy were also observed in this study.

Adolescent↗
PubMed1982

[Hemodynamic effects of a transdermal formulation of isosorbide dinitrate and its pharmacokinetics in conscious dogs].

Transdermal application of isosorbide dinitrate (ISDN) in the form of a tape (ISDN-Tape) to conscious dogs, in a dose of 40 mg/dog, caused a slow decrease in pulse pressure. The maximum effect was obtained 12 hour after application. The pulse pressure was still under the initial level even after 48 hours of application. In contrast, a sustained-release tablet of ISDN (ISDN-SR-Tablet), given in a dose of 40 mg/dog, significantly decreased the pulse pressure of conscious dogs by reducing systolic pressure and slightly elevating diastolic pressure. The plasma concentrations of ISDN and its two metabolites, isosorbide 2-mononitrate (2-ISMN) and isosorbide 5-mononitrate (5-ISMN), were measured by gas chromatography after application of ISDN-Tape or ISDN-SR-Tablets. The time course pattern of the plasma concentration of ISDN after application of the both preparations ran quite parallel with their decreasing effect on the pulse pressure. After application of the ISDN-Tape, the plasma concentration of ISDN was maintained at a higher level than after the application of the ISDN-SR-Tablet. The maximum plasma concentrations of the two metabolites, however, were considerably lower in the case of the ISDN-Tape than in the case of the ISDN-SR-Tablet. These results were ascribed to the fact that ISDN given through the transdermal route, in contrast to that given by the peroral route, does not undergo the first-pass effect in the liver. It was concluded that the transdermal dosage form of ISDN, which possesses a more prolonged pharmacologic effect than the oral dosage form, may be useful in the prevention and cure of angina pectoris.

Administration, Topical↗
PubMed1983

Prolonged plasma half-life after oral isosorbide dinitrate in patients with angina pectoris.

The plasma concentration of isosorbide dinitrate (ISDN) was monitored up to 24 h after a chronic oral dose of 60 mg in six patients with coronary artery disease. A terminal half-life of 7.7 +/- 2.6 h (mean +/- s.d.) was observed. The presence of this prolonged disappearance phase provided at least a partial explanation for the observed accumulation of ISDN in plasma after chronic dosing on a six hourly regimen.

Angina Pectoris↗
PubMed1984

Bronchodilator effect of sublingual isosorbide dinitrate in asthma.

The bronchodilating effect of 5 mg sublingual isosorbide dinitrate (ISDN) was studied in 10 patients with bronchial asthma, using the double-blind randomised cross-over method with matched placebo. In a further 20 asthmatics the effect of sublingual ISDN was compared with that of metaproterenol given by a metered dose inhaler to a total dose of 2.25 mg, again using the cross-over method. The forced oscillation method was used to measure respiratory resistance (Rrs) and spirometry was used to measure vital capacity (VC) and forced expiratory volume in one second (FEV1). 5 minutes after administration of ISDN Rrs had decreased (p less than 0.05) and VC (p less than 0.01) and FEV1 (p less than 0.01) were significantly increased. The changes were still present after 15, 30 and 60 min. The placebo had no significant effect. ISDN increased FEV1 less than metaproterenol, and the difference between them was statistically significant (p less than 0.05). However, there was no significant difference between ISDN and metaproterenol in the improvement in Rrs and VC. Of the total of 30 patients, 11 experienced headache and 4 had transient hypotension after ISDN administration. These side effects subsided spontaneously. It was concluded that sublingual ISDN had a bronchodilating effect in stable asthmatics.

Adult↗
PubMed1991

[Clinical studies of isosorbide dinitrate spray in postoperative patients].

We investigated the effect of isosorbide dinitrate (ISDN) single spray, containing 1.25 mg of ISDN, on cardiovascular and respiratory functions in eight postoperative patients. Concentrations of plasma ISDN and its metabolites were also investigated. Hemodynamic as well as blood gas studies were performed at 4 points (before, plus 10, 30 and 60 minutes after administration of ISDN) and the blood levels of ISDN and its metabolites were measured at 5 points (before, plus 5, 10, 30 and 60 minutes after administration of ISDN). Mean arterial pressure (MAP), mean pulmonary arterial pressure (MPAP), cardiac index (CI), pulmonary capillary wedge pressure (PCWP) and central venous pressure (CVP) decreased significantly and heart rate (HR) increased significantly at 10 and 30 minutes after the spray. The maximum changes observed of each parameters were MAP 7%, MPAP 22%, CI 9%, PCWP 33%, CVP 36% and HR 6%. Systemic and pulmonary vascular resistance indices did not change significantly throughout the study. PaO2 decreased significantly only at 10 minutes after the spray. Plasma ISDN concentration showed the maximum value of 56.3 ng.ml-1 at 5 minutes after the spray. After this value, the concentrations decreased rapidly. From this study, we conclude that single spray of ISDN is effective in decreasing preload promptly, but it is not effective in decreasing afterload. When using the spray, we should pay attention to pulmonary oxygenation.

Adult↗
PubMed1985

Isosorbide dinitrate and nifedipine in variant angina pectoris.

The efficacy of isosorbide dinitrate (ISDN) in variant angina is enhanced by the addition of a calcium antagonist. A prospective double-blind, crossover trial of ISDN, 40 to 120 mg/day, and nifedipine, 40 to 120 mg/day, in 19 patients with variant angina and various degrees of coronary atherosclerosis showed that although both agents were equally effective in controlling angina of vasospastic origin, some patients responded better to one or the other drug. Such response could not be predicted by demographic factors, ECG changes, or degree of coronary atherosclerosis. Since quantitative angiography done in a similar group of patients showed that intracoronary nitroglycerin, 200 micrograms, was a more potent vasodilator than sublingual nifedipine, 10 mg (p less than 0.01), the calcium antagonists may have a different mechanism of preventing variant angina attacks and may act in an additive or synergistic fashion when administered in combination with long-acting nitrates. Such a combination will increase coronary blood flow, reduce ventricular volume and end-diastolic pressure, and reduce systemic arterial resistance. Coronary vasospasm may be directly prevented by a general inhibition of smooth muscle contraction by the calcium antagonist. Clinical studies suggest that combination therapy significantly improves the long-term prognosis of patients with variant angina and reduces the need for bypass surgery. Thus combining ISDN with a calcium antagonist is a rational and effective treatment for variant angina.

Angina Pectoris, Variant↗
PubMed2003

Decrease in plasma NOx concentration by isosorbide dinitrate, an organic nitrate ester.

It has been suggested that isosorbide dinitrate (ISDN)-induced venodilation could be ascribed to preferential accumulation of the agent in venous tissues, resulting in higher concentrations of nitric oxide (NO). Here, the authors investigated whether the venodilating effect of ISDN is associated with a preferential increase in plasma concentrations of NOx (NO2- and NO3-, stable end-products of NO) in venous blood than arterial blood. Plasma NOx was measured by high-performance liquid chromatography-Griess system with a sensitivity of 0.01 microM for NO2- and 0.1 microM for NO3-. Arterial and venous blood samples were obtained after coronary angiography from the aorta and right atrium of patients with or without ischemic heart disease. Nicardipine, a calcium channel blocker, was used as a non-NO-related arteriovasodilator. At 1 mg i.v., it did not cause any changes in NOx concentration in arterial and venous blood irrespective of hemodynamic changes. However, ISDN (3 mg i.v.) increased NO2- and decreased NO3- in both arterial and venous blood, with concomitant venodilation. Further analysis revealed that plasma NO increased in the pulmonary circulation and this increase was preserved after nicardipine and ISDN, and that ISDN, but not nicardipine, increased plasma NO3- in the pulmonary circulation. The authors did not detect higher concentrations of NOx in venous blood relative to their level in arterial blood. Further studies are necessary to clarify the kinetics of NO and NO-related compounds in the whole body.

Aged↗
PubMed1992

[Response of coronary arteries to the intracoronary injection of isosorbide dinitrate. Dose-response curve].

The coronary vasodilator properties of isosorbide dinitrate (ISDN) are well known but the dosage remains empirical. The aim of this study was to construct a dose-response curve to ISDN with respect to vasoconstriction induced by ergometrine. The heart rate, aortic pressure and coronary angiography were analysed before and 3 and 5 minutes after I.V. injection of 0.4 mg of methylergometrine and 3 minutes after intracoronary injection of 5, 15, 60, 240 and 1,000 micrograms of ISDN in 10 patients with an average age of 53.2 +/- 10.8 years (ISDN group). Six other patients with an average age of 56.5 +/- 12.8 years comprised the control group and only received ergometrine. The coronary diameters were measured by quantitative coronary angiography using the CAESAR system of automatic contour detection. Three coronary segments with angiographically normal appearances and a resting diameter greater than or equal to 1.85 mm were analysed in each patient. With respect to the maximal constriction observed 5 minutes after the injection of methylergometrine, the percentage increase in coronary diameter was 9 +/- 7%, 26 +/- 12%, 33 +/- 15%, 38 +/- 14% and 39 +/- 16% after 5, 15, 60, 240 and 1,000 micrograms of ISDN respectively (p less than 0.005 vs control). A plateau effect was observed after a cumulative dose of 80 micrograms and administration of higher doses of 240 and 1,000 micrograms only caused mild nonsignificant additional increase in vessel diameter. In comparison with the control group, the systolic blood pressure only fell significantly with doses greater than 240 micrograms of ISDN (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary Angiography↗
PubMed1993

[Comparison of the effects of molsidomine retard and isosorbide dinitrate retard in patients with stable angina pectoris using an ergometry test].

In 24 men with angina after exertion the authors assessed, using ergometry, the action of molsidomine retard and isosorbide dinitrate retard after a single dose and after tree-week administration of the drug. The authors found that 8 mg of molsidomine retard in a single dose had a somewhat more potent effect than 40 mg isosorbide dinitrate retard. After prolonged administration the effect of both drugs on haemodynamics diminished and in molsidomine a significant decline of action was observed before development of a reduced S-T segment on the ECG. After three weeks' administration the effects of both drugs were comparable. After neither drug clinically significant tolerance developed when the drug was administered every 8 hours. In the conclusion the authors discuss possible mechanisms involved in development of tolerance.

Adult↗
PubMed1984

Controlled, eight-hour haemodynamic study of a sustained-release formulation of isosorbide dinitrate in moderate left ventricular failure.

The aim of the study was to assess the duration of the haemodynamic effects of a new sustained-release oral formulation of isosorbide dinitrate (ISDN). Twenty patients (17 men and 3 women; mean age 60 years) with acute myocardial infarction (10 anterior, 10 inferior) complicated by moderate left ventricular failure took part in a randomized controlled trial. Ten patients were randomly assigned to the placebo group and 10 to the ISDN group, who received 40 mg sustained release isosorbide dinitrate. Haemodynamic variables were measured before treatment, after 0.5 and 1 h and then every 2 hours up to the 8th hour after treatment. There was no significant change in any haemodynamic parameter in the placebo group, during the study period. In the ISDN group there was a significant fall in pulmonary artery diastolic pressure at 4 and 8 h, from 19.0 +/- 1.0 mm Hg to 16.5 +/- 1.2 mm Hg and 15.5 +/- 0.8 mmHg, respectively. The mean pulmonary capillary wedge pressure fell progressively from 17.9 +/- 1.0 to 12.5 +/- 1.2 mmHg at 2 h (p less than 0.001 in comparison with the placebo group. The fall remained significant up to 8 h. There was no statistically significant change in heart rate, cardiac index, systemic blood pressure or systemic and pulmonary vascular resistances. On the whole the cardiac index remained unchanged. There were numerous individual variations of cardiac index in relation to the initial mean pulmonary capillary wedge pressure and the magnitude of its fall following administration of ISDN. The change in cardiac index was inversely correlated with the control cardiac index (r = -0.69, p less than 0.02).

Delayed-Action Preparations↗
PubMed1987

The haemodynamic and anti-ischaemic effects of a single tablet of 80 mg isosorbide dinitrate in slow-release formulation and a review of nitrate tolerance.

There is increasing evidence that relatively constant plasma nitrate concentrations induced by 3-times-daily administration of isosorbide dinitrate can lead to an attenuation or even complete loss of the drug's anti-ischaemic effects (nitrate tolerance). We therefore assessed the dependence of nitrate tolerance development from the haemodynamic and anti-ischaemic effects of a slow-release tablet formulation of isosorbide dinitrate 80 mg, administered according to different daily dosage regimens in patients with angina. It was found that a once-daily regimen, with its consequent peak and trough plasma nitrate concentrations, is capable of protecting against exercise-induced myocardial ischaemia for about 12 hours with the circumvention of nitrate tolerance.

Adult↗
PubMed1981

Postural hypotension and tachycardia during hydralazine--isosorbide dinitrate therapy for chronic heart failure.

Supine and upright hemodynamic measurements were performed in 10 patients with chronic congestive heart failure, before and during vasodilator therapy with hydralazine and isosorbide dinitrate. This combination of drugs produced significant improvement in supine hemodynamic measurements, with the pulmonary capillary wedge pressure decreasing from 26 +/- 5 to 18 +/- 5 mm Hg (mean +/- SD, p less than 0.01) and stroke volume index increasing from 25 +/- 6 to 39 +/- 6 ml/m2 (p less than 0.01), without any significant change in heart rate (HR) or mean arterial pressure (MAP). However, with the patients upright, HR rose significantly (87 +/- 17 to 99 +/- 17 beats/min, p less than 0.05) and MAP fell (84 +/- 10 to 66 +/- 11 mm Hg, p less than 0.001) compared with measurements before treatment. These patients also exhibited potentially deleterious postural changes in HR, MAP, cardiac output, stroke volume index and stroke work index during therapy with the combination of hydralazine and isosorbide dinitrate. Although diuretic therapy (which had been withheld for 12 hours in eight subjects but only for 6 hours in two others) may have played a role in producing these changes, postural hypotension or tachycardia was not noted before vasodilator therapy or during therapy with nitrates or hydralazine. Repeat catheterization after 3 months in six patients revealed a lessening of the postural effects. These findings indicate the need to perform upright as well as supine hemodynamic measurements during the initiation of vasodilator therapy and suggest the need for particular caution in patients with ischemic heart disease.

Heart Failure↗
PubMed1990

The influence of isosorbide dinitrate and molsidomine on migration of polymorphonuclear neutrophils in vivo.

There is evidence that accumulation of polymorphonuclear neutrophils exacerbates injury to the tissues during acute myocardial infarction. To evaluate the influence of the vasodilator drugs, isosorbide dinitrate and molsidomine on migration of polymorphonuclear neutrophils, the "skin chamber" method was used. The number of neutrophils harvested from the chamber after oral treatment with isosorbide dinitrate increased from 27.65 +/- 9.02 X 10(6)/cm2 to 69.08 +/- 11.41 X 10(6)/cm2. Migration of neutrophils after molsidomine did not change significantly. Both drugs exert a similar effect on vascular smooth muscle cells. The difference in the influence on migration of granulocytes might be the result of an additional effect of molsidomine on formation of thromboxane and/or effects on the lipoxygenic pathway of arachidonic acid.

Acute Disease↗