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PubMed1987

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

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

Animals↗
PubMed1988

[The effect of time and dosage of isosorbide mononitrate on objective and subjective parameters in angina pectoris].

The efficacy of the isosorbide mononitrate preparations ISMN-20 (elantan 20) and ISMN-50 (elantan long) and the influence of the time of dosage on the quality of life was investigated in 3624 patients with the clinical diagnosis coronary heart disease and stable angina pectoris in an open multi-center trial. The frequency of attacks was significantly reduced (p less than 0.001) during 4 weeks of therapy. 35.4% of patients were free from attacks by the end of the trial. Consumption of acute nitrates decreased from an average of 5 to 2 applications per week. Circadian rhythm in the patients' profile of attacks remained unchanged under mononitrate therapy which allows the conclusion that this therapy is well adapted to the daily routine. The times of dosage of ISMN-20 (in the morning and at lunch-time or in the morning and in the evening) both had an identically good effect on the reduction of the attacks at night. ISMN-20 as well as ISMN-50 proved to provide efficient protection at night. After 4 weeks of therapy 86% of the patients showed an improvement of the loads of daily routine (climbing stairs, fast walking etc.). 71% noted an improvement in former limited recreational activities and 76.5% a relief concerning former limited activities in their job. 79.6% of patients felt an improvement of their quality of life by the mononitrate treatment. 70.8% of study patients were motivated for a consequent long-term therapy with the mononitrate with priority for the sustained release preparation.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1986

[Anti-angina action and tolerance of isosorbide-5-mononitrate or nifedipine in retard form].

Twelve patients with stable angina and reproducible depression of the ST-segment during bicycle exercise of at least 0.15 mV were assessed in a double-blind randomized cross-over study. Patients were treated either with 50 mg isosorbide-5-mononitrate (IS-5-MN) daily or 2 X 20 mg nifedipine retard daily or the combination of both drugs for 2 weeks. The sum of ST-segment depression at maximal exercise was reduced by nifedipine and IS-5-MN to the same amount, while ST-segment reduction was highest during treatment with the combination of both drugs. The best exercise duration and maximal working capacity were also recorded during combination treatment. However, patient appreciation concerning efficacy and side-effects was best with nifedipine, slightly worse with IS-5-MN, and only one patient judged the combination of both drugs as good.

Angina Pectoris↗
PubMed1986

The therapeutic role of isosorbide-5-mononitrate+ in stable and unstable angina pectoris.

Various studies on the pharmacodynamic and clinical properties of isosorbide-5-mononitrate (IS-5-MN) indicate that this drug is effective in the treatment of stable angina pectoris. Acute and chronic studies, in fact, show an improved performance and an amelioration of the clinical status in patients under treatment. On the other hand, acute studies on vasospastic and mixed angina, two common clinical manifestations of coronary artery disease, have demonstrated the capability of IS-5-MN in preventing episodes of transient myocardial ischemia. In analogy with other forms of nitrates, it is clear that IS-5-MN has a positive effect both on the coronary tree (preventing vasoconstriction) and on those hemodynamic parameters which influence the myocardial oxygen demand (reducing myocardial oxygen consumption). Further information is needed, however, to clarify the issue of tolerance development after chronic administration; so far it appears that tolerance may develop when patients are treated with doses of IS-5-MN greater than 20 mg t.i.d.. On the basis of the clinical studies carried out with IS-5-MN, and its favourable pharmacological profile, it is foreseeable that this drug will have an increasing role in the treatment of angina pectoris.

Angina Pectoris↗
PubMed1986

[Long term therapy of coronary heart disease with 120 mg slow release isosorbide dinitrate once a day. Study of duration of action and development of tolerance].

Twenty-one patients (3 women, 18 males, mean age 55.7 +/- 6 years) with coronary heart disease proven by coronary angiography entered a double blind randomised study with isosorbide dinitrate slow release 120 mg once a day. 2, 12 and 24 hours after acute medication patients underwent a symptom-limited exercise-ECG. The following parameters were measured: ST-depression, blood pressure, heart rate and working capacity. After one week of therapy the same parameters were measured to look for the development of tolerance. Two and twelve hours after acute medication working capacity increased to 220% and 139% respectively. After 24 hours there was no statistically significant effect. The sum of ST-depression in three leads decreased from 4.85 +/- 3.02 mV to 1.87 +/- 0.96 mV (38.5%; p less than 0.05) 2 hours after medication, and to 2.10 +/- 1.73 mV 12 hours after medication. 24 hours after medication there was still a slight but not significant reduction of ST-depression. There was no statistically significant effect in the placebo group. After one week of therapy there was a slight reduction of action, but no development of tolerance.

Clinical Trials as Topic↗
PubMed1986

Enhanced platelet sensitivity to prostacyclin after isosorbide-5-mononitrate in patients with stable angina pectoris.

Recently the possibility that nitrates inhibit platelet function in man has been explored in vitro and in vivo. We have studied the effect of isosorbide-5-mononitrate (ISMN), a stable and long-acting organic nitrate, on platelet function in vivo. Given orally within the current therapeutic range, the drug has practically no effect on platelet aggregation nor thromboxane generation in platelet-rich plasma in response to ADP, collagen, arachidonate, epinephrine and PAF. Synergistic effects of prostacyclin and ISMN on inhibition of ADP-induced platelet aggregation have been observed. Thus, local inhibition of platelet aggregation might not have been detectable, due to the short half-life in vitro of prostacyclin.

Adult↗
PubMed1986

Sarcolemmal dependence of isosorbide dinitrate-induced relaxation of aortic smooth muscle.

Studies were conducted to determine if ISDN antagonizes the contractile responses to calcium of chemically-skinned aortic smooth muscle preparations. Isosorbide dinitrate relaxed intact aortic smooth muscle segments in a dose-dependent manner (0.01-100 microM). At all concentrations tested, ISDN was unable to relax triton-skinned smooth muscle preparations. However, the tension development of skinned preparations was inhibited by trifluoperazine (10 microM), a calmodulin antagonist. These results suggest that the relaxation of intact aortic smooth muscle preparations induced by ISDN is not related to an interference with calmodulin-dependent contractile events.

Animals↗
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↗
PubMed1979

[Isosorbide-dinitrate in myocardial perfusion (author's transl)].

UNLABELLED: The effect of isosorbide dinitrate (ISDN) (10 mg sublingually) on myocardial perfusion during ischemic conditions was analyzed in 14 patients with angiographically severe coronary artery disease and typical angina pectoris, using the 201-Thallium-myocardial scintigraphy. All patients underwent two identical scintigrams with the same work load during bicycle ergometry; a control scintigram leading to angina and ST-depressions of greater than 0.1 mV was followed 4--6 weeks later by a scintigram after ISDN; all drugs -- except sublingual nitroglycerin -- were withheld for an entire week. -- RESULTS: 25 of 39 new or enlarged, exercise-induced defects (64%) were normalyzed after ISDN; 14 new or enlarged defects remained unchanged (p less than 0.0005). In the 11 patients, in whom ISDN led to complete abolishment of angina, 23 of 30 new defects (76%) were normalized against none in the 3 patients with persistent angina and ST-depressions. Quantitation of perfusion was attempted by calculating the average impulse rate (counts/min/matrix point): in those patients reacting favorably to ISDN average impulse rate decreased significantly especially in the normal area (p less than 0.001), resulting in a more homogeneous distribution of Thallium activity, indicating a marked reduction in local oxygen consumption.

Adult↗
PubMed1985

[Possibility of developing tolerance to the anti-anginal effect of isosorbide dinitrate and verapamil].

Using exercise tests in 22 patients with stable angina of effort, the authors studied the possibility of the development of tolerance to the antianginal effect of isosorbide dinitrate (ID) and verapamil (VP). Within 6-12 weeks of the regular intake of ID, 5 (26%) patients developed complete tolerance, 6 (32%) partial tolerance to the drug. In 8 (42%) patients the effect of ID remained stable. A six-week administration of VP was accompanied by no signs of tolerance to the drug even in the patients who showed tolerance to ID.

Adult↗
PubMed1985

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

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

Adult↗
PubMed1985

[Long-term therapy of stress angina pectoris by a single daily administration of 120 mg isosorbide dinitrate in retard form. Comparison of monotherapy and combination therapy with atenolol and nifedipine].

This study was undertaken to determine whether an effective antianginal treatment without tolerance development can be carried out with intermittent nitrate administration on a regimen with a single daily dose of 120 mg isosorbide dinitrate (ISDN) in sustained-release form (SR), as well as whether the concomitant administration of 100 mg atenolol or 100 mg atenolol and 20 mg nifedipine renders an additive antiischemic effect. In two independently performed investigations, the duration of action of a single dose of 120 mg ISDN SR was assessed after its initial administration in addition to the anti-ischemic effect during long-term treatment, each according to a randomized, double-blind, crossover, placebo-controlled protocol in a total of 15 patients with angiographically-documented coronary artery disease, stable angina pectoris and reproducible ST-segment depression during exercise. The test phases of four weeks each were separated by one week placebo phases. After completion of the study, for a further eight weeks, 120 mg ISDN SR was given together with 100 mg atenolol in the morning. Exercise testing was carried out after four weeks of treatment in a control period before and at two hours after administration of 120 mg ISDN SR with 100 mg atenolol as well as after another four weeks in a control period before and after concomitant administration of 120 mg ISDN SR, 100 mg atenolol and 20 mg nifedipine in sustained release form.(ABSTRACT TRUNCATED AT 250 WORDS)

Angina Pectoris↗
PubMed1985

Haemodynamic effects of Isodinit (isosorbide dinitrate) in acute myocardial infarction.

In 26 patients with acute transmural myocardial infarction, the authors studied the effect of sublingual Isodinit (isosorbide dinitrate) on haemodynamic indicators: in 12 patients on heart rate, pulmonary and peripheral arterial pressure, in 14 (of whom 6 with normal and 8 with elevated diastolic pulmonary pressure) moreover on cardiac output and peripheral vascular resistance. The results showed a decrease in pulmonary arterial pressure by 35%, in peripheral arterial pressure by 10-14%, and a slighter fall in peripheral vascular resistance; the heart rate did not substantially change. In patients with normal diastolic pulmonary artery pressure, the cardiac and stroke index and the stroke work index decreased, whereas in patients with elevated pulmonary pressure these indicators did not significantly change. The effect of sublingual Isodinit occurs 5-7 min after its administration and reaches its maximum between the 15th--45th min; after 2 hrs the effect ceases. The preparation is suitable for the treatment of congestive heart failure in acute myocardial infarction.

Adult↗
PubMed1985

Effects of isosorbide dinitrate on pancreatic exocrine secretion in the dog.

The effects of isosorbide dinitrate (ISDN) on pancreatic exocrine secretion were investigated after intravenous administration in the whole animal and after close-arterial administration on the isolated and blood-perfused dog pancreas preparations. ISDN (10-100 micrograms/kg), injected into the femoral vein, caused a dose-dependent increase in flow rate of pancreatic juice and in protein concentration of the pancreatic juice. Close-arterial injections of ISDN (100-1000 micrograms) produced a dose-dependent increase in perfusion blood flow, flow rate of pancreatic juice and protein concentration of the pancreatic juice without affecting its bicarbonate concentration. These vascular and secretory effects were not modified by pretreatment with atropine. From these data, it is suggested that ISDN induces pancreatic enzyme secretion by acting directly on the acinar cells of the pancreas.

Animals↗
PubMed1985

[Pharmacology of isosorbide dinitrate after transdermal application].

Different organic nitrates exhibit markedly different in vitro partition coefficients, P. The lipophilic character, of which P is a measure, is the most important physico-chemical property which influences the penetration of nitrate molecules through the skin. It follows that there are several possibilities for developing formulations in which the diffusion of the molecules through the layers of the epidermis is furthered. A transdermal spray of isosorbide dinitrate (ISDN, TD Spray Iso Mack) was administered to volunteers and blood concentrations of the nitrate were measured. The results demonstrate that therapeutically effective amounts of the nitrate do in fact penetrate through the various levels of the skin. In addition pharmacokinetic measurements confirm that ISDN penetrates from the sprayed on film into the surface of the skin within 20 min and is then slowly released from the epidermis into the capillaries of the corium. An advantage of the administration of ISDN through the skin lies in the avoidance of the rapid metabolism of the drug which takes place during its first passage through the liver (first-pass effect). The protracted efficacy of the transdermal spray in the treatment of patients with coronary disease is, therefore, due to the unchanged ISDN and not, as with oral treatment, to pharmacologically active metabolites.

Administration, Topical↗
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↗
PubMed1979

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

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

Animals↗
PubMed1979

Serum concentrations of isosorbide dinitrate produced by a sustained-release capsule.

The bioavailability of isosorbide dinitrate (ISDN) and the time course of its serum concentration produced by a standard 20-mg tablet and a sustained-release capsule were compared in six normal volunteers. Following administration of the tablet, serum ISDN concentrations reached a peak of 29 ng/ml at 0.5 h, declined monoexponentially with a t1/2 of 25.5 min, and disappeared after 2 to 3 h. Following the administration of the sustained-release capsule, serum ISDN concentrations reached a plateau of 4 ng/ml between 2 and 5 h, and declined slowly and nonlinearly up to and including the 10-h point. The total amount of ISDN absorbed was 1.32 times greater with the standard tablet; following the absorption of the capsule, there was truncation of the serum concentration curve due to ongoing absorption at and beyond 10 h.

Administration, Oral↗