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Radionuclide confirmation of the therapeutic value of isosorbide dinitrate in relieving the dysphagia in achalasia.

In fifteen patients with achalasia, we measured lower esophageal sphincter pressures before and after 5 mg of sublingual isosorbide dinitrate. The mean pressure fell significantly, from 36.5 to 18.4 mm Hg (P less than 0.01). The effectiveness of this therapy was confirmed by gamma camera measurement of the esophageal emptying time of a radionuclide test meal which was significantly less after the medication (P less 0.05). The emptying time was invariably longer than 10 minutes before therapy, and in 12 of the 15 patients decreased after therapy to 1-8 minutes, corresponding to the clinical response to the drug therapy. The noninvasive radionuclide technique provides a simple way of assessing the results of drug therapy in achalasia.

Adolescent↗

Effect of sustained release isosorbide dinitrate (EV151) in dogs with experimentally-induced mitral insufficiency.

To investigate the hemodynamic effects on seven anesthetized dogs with experimentally-induced mitral insufficiency, isosorbide dinitrate (ISDN) in sustained release form (EV151) was administered at different dosages (0, 2, 8 and 16 mg/kg). The drug administration resulted in altered pulmonary arterial wedge pressure (preload), and cardiac output and total systemic resistance (afterload). Arterial pressure increased in the control group and in animals receiving 2 mg/kg, but decreased in animals 1-2 hr after receiving 8 and 16 mg/kg dosages. Cardiac output increased in animals receiving 2, 8 and 16 mg/kg dosages, with concomitant decreases in total systemic resistance. ISDN caused mild vasodilation at 2 mg/kg and severe vasodilation at 8 and 16 mg/kg. Future experiments on non-anesthetized dogs may be of benefit.

Animals↗

Effects of chronic oral administration of isosorbide dinitrate on in vitro contractility of rat arterial smooth muscle.

In this study, we examined the effects of in vitro and in vivo treatment with isosorbide dinitrate (ISDN) on the in vitro response of isolated rat aorta. The in vitro treatment of isolated aorta with ISDN (100 microM) for 2 hr had no effect on the ISDN-induced relaxation of norepinephrine-induced contraction. In the aorta isolated from the rats treated with a high dose (90 mg/kg) of ISDN for 7-14 days, in contrast, the relaxant effect of ISDN was significantly reduced. However, the relaxant effect of sodium nitroprusside was only slightly attenuated by the treatment with a high dose of ISDN for 14 days; and the relaxant effects of 8-bromo-cGMP, levcromakalim and verapamil were unchanged. These results suggest that tolerance to ISDN was obtained only after the in vivo chronic treatment with a high dose of ISDN. ISDN may desensitize the nitric oxide-generating step rather than inactivate guanylate cyclase or the downstream pathways.

Administration, Oral↗

[Assay of plasma isosorbide dinitrate and its metabolites after oral administration of immediate and delayed-action forms].

This paper describes a kinetic comparative study of plasma concentrations of isosorbide dinitrate (ISDN) and its mononitrate derivatives (2-ISMN or 5-ISMN) after oral administration of a sustained release form of ISDN or a (non) sustained release form of 5-ISMN. The blood extracts determinations were performed by electron capture gas chromatography which is an accurate and sensitive method suitable for the quantitation of concentrations in the nanogram per ml range. The results are in good agreement with those of the literature. The standard form of 5-ISMN is rapidly absorbed. The Tmax value is approximately 1H with a corresponding Cmax value close to 400 ng/ml. For the sustained release drugs, the Tmax increases to 6H and Cmax is nearly half the 5-ISMN standard form value. Considering the administered dose, it seems better to use 5-ISMN than ISDN. For a long lasting treatment of angina pectoris and ischaemic cardiac diseases, both forms can be used.

Administration, Oral↗

Effect of a combination of pindolol and isosorbide dinitrate on ischemic ST-segment depression and exercise ability in angina pectoris.

The antianginal action of a fixed combination of pindolol (7.5 mg) and isosorbide dinitrate (ISDN, 30 mg slow release) was compared with placebo in sixteen patients with stable, exercise-induced angina pectoris. Exercise tests were performed on a bicycle ergometer before and 90 min after the oral application of active drug or placebo. All patients showed an ischemia-induced ST-depression in the ECG during and shortly after exercise. There was no effect of placebo on blood pressure, heart rate, ST-segment depression or work tolerance. The combination of pindolol and ISDN significantly reduced systolic blood pressure and heart rate at rest and during exercise. ST-segment depression was reduced (2 p less than or equal to 0.001), when compared with placebo at the same workload. Mean total work was higher (2 p less than or equal to 0.001) after active drug, leading to an improved exercise-tolerance in 11 out of 16 patients.

Adult↗

Comparative evaluation of a new formulation of isosorbide dinitrate oral spray and sublingual nitroglycerin tablets.

The magnitude and time course of the hemodynamic effect of a new formulation of an aqueous solution of isosorbide dinitrate (ISDN) spray were compared with those of sublingual nitroglycerin (NTG) tablets in 12 patients with chronic congestive heart failure. The patients received, in a random order, ISDN spray, 2.5 mg, or sublingual NTG, 0.8 mg. Hemodynamic measurements were performed before and at 1, 3, 5, 10, 20, 30 and 60 minutes after each drug. The second drug was given only after return of the hemodynamic parameters to baseline, plus a washout period of 2 hours. The hemodynamic variables measured were comparable at baseline. Both drugs produced hemodynamic improvement including a decrease in pulmonary capillary wedge pressure (PCWP), right atrial pressure and systemic and pulmonary vascular resistances. Only ISDN spray significantly increased cardiac output. The onset of action of ISDN spray was significantly more rapid than that of NTG. This was primarily evident in the decrease in PCWP. With ISDN spray the decrease started at 1 minute after administration, and at 3 minutes a decrease of 8.6 mm Hg was already found. The corresponding value for sublingual NTG was 1.6 mm Hg. The difference was highly significant (p less than 0.02). The peak effect of ISDN spray on PCWP and right atrial pressure was greater than that of NTG. Thus, the onset of the hemodynamic effect of the new formulation of ISDN spray is much more rapid than that of sublingual NTG tablets. At the doses used, the magnitude of the effect of the ISDN spray on some of the hemodynamic variables is greater than that of sublingual NTG.

Administration, Oral↗

Hemodynamic effects of intravenous isosorbide dinitrate and nitroglycerine in acute myocardial infarction and elevated pulmonary artery wedge pressure.

We compared in a randomized fashion the hemodynamic effects of intravenous (IV) isosorbide dinitrate (ISDN) and nitroglycerine (NTG) in 45 patients with acute myocardial infarction and elevated pulmonary artery wedge pressure (Paw). Titration of ISDN dose to lower Paw greater than or equal to 25 percent resulted in a fall of this parameter from 32 +/- 8 to 24 +/- 5 mm Hg and was associated with a fall in mean blood pressure (96 +/- 15 to 90 +/- 14 mm Hg, p less than 0.05), systemic vascular resistance (1715 +/- 572 to 1548 +/- 414 dynes X s X cm-5, (p less than 0.05), pulmonary vascular resistance (182 +/- 106 to 154 +/- 78 dynes X s X cm-5, p less than 0.05) and mean right atrial pressure (11 +/- 4 to 7 +/- 4 mm Hg, p less than 0.05). In addition, ISDN significantly (p less than 0.05) increased cardiac index from 2.37 +/- 0.54 to 2.54 +/- 0.59 L/min/m2, stroke volume index from 28 +/- 8 to 31 +/- 8 ml/m2, and stroke work index from 28 +/- 11 to 31 +/- 12 g X m/m2. The ISDN dose ranged from 50 to 533 micrograms/min (mean +/- SD 326 +/- 176 micrograms/min) and could not be predicted from baseline hemodynamic values. A comparison between the effect of ISDN and NTG in doses producing comparable reduction in Paw showed similar hemodynamic changes. It was concluded that IV ISDN in patients with elevated mean pulmonary artery wedge pressure due to acute myocardial infarction results in a decrease in right and left ventricular preload and afterload and improvement of cardiac output and cardiac work. The effective dose ranges from 50 to 533 micrograms/min and cannot be predicted from baseline hemodynamic values. In doses producing comparable reduction in Paw, ISDN and NTG had similar hemodynamic effects.

Aged↗

[The possibility of the development of isosorbide dinitrate and nifedipine withdrawal syndromes in patients with stable stenocardia of effort].

Exercise tests were performed in 18 patients with stable angina of effort treated with isosorbide dinitrate (ID) or nifedipine (NF) to see whether sharp discontinuation of the above drugs may entail withdrawal syndrome. Exercise tolerance declined 21 and 24 hours after the last administration of NF, 13 and 18 hours after that of ID. Compared to NF, ID tolerance decreased in a less degree. Some of the patients experienced myocardial ischemia in the course of the exercise tolerance tests, there were more frequent anginal episodes, arterial pressure rose. For ID withdrawal syndrome manifested weaker than for NF.

Adult↗

Effects of an oral dose of isosorbide dinitrate on platelet function and fibrinolysis in healthy volunteers.

1. A randomised double-blind placebo-controlled study was performed to investigate the effects of isosorbide dinitrate (ISDN; 20 mg orally) on various aspects of platelet function and fibrinolysis in vivo in 12 healthy volunteers. 2. Measurements were performed at rest (before and after tablet ingestion) and during platelet activation by adrenaline (0.4 nmol kg-1 min-1; 30 min infusion). 3. At rest, ISDN did not alter plasma concentrations of beta-thromboglobulin (beta TG). EC50 values for ADP induced aggregation in vitro (Born aggregometry) or ex vivo filtragometry readings. Adrenaline markedly increased platelet aggregability in vivo as measured by filtragometry and elevated levels of beta TG in plasma. ISDN treatment did not affect these responses in the group as a whole. 4. Individuals responding to ISDN with more pronounced vasodilatation at rest showed a lesser increase in aggregability during the ensuing adrenaline infusion (r = -0.66, P = 0.02) despite higher adrenaline levels during ISDN. In individuals showing a significant decrease in systolic blood pressure (n = 8) ISDN tended to attenuate the adrenaline induced increase in platelet aggregability (filtragometry; P = 0.08), despite higher plasma adrenaline and noradrenaline levels after ISDN ingestion. 5. Plasma concentrations of ISDN and its active metabolites isosorbide-5-mononitrate and isosorbide-2-mononitrate were not correlated to haemodynamic or platelet variables. 6. Fibrinolytic activity (t-PA antigen and activity, PAI-1 antigen and activity) increased similarly during the adrenaline infusion following ISDN and placebo. 7. It is concluded that ISDN may affect platelet aggregation responses to adrenaline in vivo, but only in individuals showing significant haemodynamic responses to ISDN.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

[Differential effects of isosorbide dinitrate and nitroprusside on pial vessel diameter in cats].

Changes in pial vessel diameter combined with regional cerebral blood flow (CoBF) during infusion of vasodilating drugs, isosorbide dinitrate (ISDN) 5 micrograms/kg/min and nitroprusside (NTP) 5 micrograms/kg/min, compared with haemorrhagic hypotension were studied in cats anesthetized with halothane (1.0%). Pial arteries and veins were measured by image-splitting technique and were each divided into three groups according to the reference diameter: I; < 50 microns, II; 51 < microns < 100, III; 101 < microns. With either drug, the mean blood pressure (mBP) decreased by 10-20%. There was significant decrease in cerebral vascular resistance with ISDN compared with haemorrhagic hypotension while CoBF (H2 clearance) remained unchanged. Dilatation of pial arteries depending on vessel size with ISDN was two-hold compared with haemorrhagic hypotension without any change in all veins. Consistent and significant dilation of veins (I and II) was observed only during NTP infusion. These findings indicate the differential effect of ISDN and NTP on pial arteries and veins.

Animals↗

Nitrate tolerance: comparison of nicorandil, isosorbide dinitrate, and nitroglycerin in anesthetized dogs.

Development of tolerance to nicorandil (NCR), N-(2-hydroxyethyl)nicotinamide nitrate (ester), was compared with that to nitroglycerin (NTG) or isosorbide dinitrate (ISDN) in dogs. An intracoronary arterial (i.a.) injection of NCR (20 micrograms), ISDN (30 micrograms), or NTG (1 microgram) caused coronary vasodilation. Development of tolerance (including cross-tolerance) was determined by examining whether the coronary vasodilating effect of i.a. injection of these drugs was attenuated by a 2-h infusion of NCR, ISDN, or NTG. The effect of i.a. injection of NCR was not affected by i.v. infusion of either NCR (10 micrograms/kg/min), ISDN (10 or 30 micrograms/kg/min), or NTG (1 or 3 micrograms/kg/min). The effects of i.a. injection of NTG and ISDN, however, were attenuated by the NTG or ISDN infusion, whereas they were unaffected by the NCR infusion. Additionally, the coronary vasodilating effect of NCR infusion (30 micrograms/kg/min) or ISDN (30 micrograms/kg/min). These results suggest that NCR does not produce tolerance, whereas NTG and ISDN do, and that there is no cross-tolerance between NCR and NTG, or ISDN in terms of the coronary vasodilating effect.

Anesthesia↗

[Comparison between the hemodynamic effects of nitroglycerine ointment and oral isosorbide dinitrate in the treatment of left ventricular failure (author's transl)].

The hemodynamic effects of standard dose of Nitroglycerin (NTG) ointment (23 +/- 4 mg) and oral Isosorbide Dinitrate (ISDN) 10 mg were compared in the treatment of left ventricular failure. Ten patients, 8 males and 2 females (mean age 59 +/- 9 years), affected by acute myocardial infarction (7 cases). Ischemic cardiomyopathy (2 cases) and hypertensive cardiomyopathy (1 case) were submitted to right heart catheterization by triple lumen Swan-Ganz catheter. Heart Rate (HR), mean Arterial Pressure (AP), Right Atrial Pressure (RAP), mean Pulmonary Artery Pressure (PAP), Pulmonary Wedge Pressure (PWP), Stroke volume (SV), Cardiac Index (CI), Stroke Work Index (SWI), Systemic Vascular Resistances (SVR), Pulmonary Total Resistances (PTR) were controlled every 30 minutes until the disappearance of the hemodynamic effects. ISDN did not produce any statistically significant changes; on the contrary NTG ointment caused significant changes in: (formula: see text). Decrease of RAP, PAP, PWP, PTR and increase of SV, CI, SWI were statistically significant from 30 until 180 minutes after NTG ointment administration. These changes were statistically different from those produced by ISDN (p less than 0,05). Thus NTG ointment, at this dose, improved cardiac performance, while oral ISDN 10 mg did not. It is concluded that the hemodynamic effects of NTG ointment are prompt and sustained.

Administration, Oral↗

Hemodynamic time course of acute and chronic isosorbide dinitrate treatment at rest and during exercise in patients with stable ischemic heart disease.

HYPOTHESIS: The study was undertaken to establish differences between venous and arterial isosorbide dinitrate (ISDN) effects during acute and chronic treatment, hemodynamics at rest, and during supine exercise. METHODS: These effects were assessed invasively in 16 patients with stable ischemic heart disease before and at hourly intervals for 4 h after administration of peroral 30 mg ISDN. Eight patients were previously untreated (acute group), and eight were treated with 30 mg ISDN asymmetrically b.i.d. for two weeks (chronic group). RESULTS: Prior to ISDN administration, right atrial, mean pulmonary artery, pulmonary artery wedge, and mean arterial pressure (RAP, MPAP, PAWP, and MAP) rose from normal resting to pathologic values during exercise. One h after ISDN administration, all exercise pressures were normalized (p < 0.001). During the following 3 h, exercise RAP rose similarly in both groups (p < 0.01), while MPAP rose particularly in the chronic group (p < 0.001). Exercise PAWP and MAP, however, remained low in the acute group, but increased markedly in the chronic group (p < 0.01), particularly from the third to the fourth hour after ISDN. CONCLUSION: The daily, asymmetric administration of 30 mg ISDN b.i.d. maintained beneficial, anti-ischemic effects for 2 to 3 h after a morning dose of the drug, but thereafter attenuation of the effects occurred in the arteries but not in the veins.

Exercise Test↗

[Effects of isosorbide dinitrate on left and right ventricular systolic time intervals in patients after myocardial infarction].

The purpose of the study was to assess effects various doses of isosorbide dinitrate (ISDN) on left and right ventricular systolic time intervals in patients after myocardial infarction. The study population consisted of 25 patients who were eight weeks after their first transmural myocardial infarction. Twelve patients were given 5 mg of ISDN by an intravenous infusion for 60 min, and remaining 13 patients were given 10 mg of ISDN in a similar manner. Subgroups did not differ with respect to their initial arterial blood pressure (mean = 133.3) 82.9 vs 134.3 (87.1 mm Hg) and systolic pulmonary arterial pressure (mean = 27.2 vs 28.8 mm Hg). The infarct localization was also similar. Left ventricular systolic time intervals were calculated noninvasively, whereas right ventricular systolic time intervals were measured from simultaneous electrocardiographic, phonocardiographic and pulmonary arterial pressure tracings. Both left and right ventricular systolic time intervals were determined before and at 15 and 60 min after the drug administration. Student's t-test for unpaired and paired variables was used to test for statistical significance. Changes in the parameters studied at 60 min of the ISDN infusion were greater than at 15 min, and therefore only they are taken into account in the presentation of the results. During a 5 mg infusion of ISDN arterial blood pressure showed a tendency to decrease. Left ventricular ejection time shortened (-3.9%) and the pre-ejection period lengthened (+ 21.9%). The pulmonary artery pressure showed minimal tendency to decrease. The right ventricular systolic time intervals showed a similar tendency but the changes were not significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

The acute effects of low flow oxygen and isosorbide dinitrate on left and right ventricular ejection fractions in chronic obstructive pulmonary disease.

The objectives of this study were to determine the effects of low flow oxygen and isosorbide dinitrate on rest and exercise biventricular ejection fractions in patients with chronic obstructive pulmonary disease and to relate these ejection fraction responses to changes in pressure and flow. Nine patients with stable, moderate to severe chronic obstructive pulmonary disease who had no prior history of heart failure performed supine exercise with simultaneous hemodynamic and radionuclide ventriculographic monitoring. Eight patients performed a second exercise during low flow oxygen breathing and five performed a third exercise after ingesting 10 mg oral isosorbide. Oxygen led to a decrease in exercise pulmonary artery pressure in all subjects and a decline in total pulmonary resistance in five of the seven in whom it was measured. Right ventricular ejection fraction increased 0.05 or more only in subjects who had a decrease in total pulmonary resistance. Isosorbide fed to an increase in rest and exercise right and left ventricular ejection fractions with simultaneous decreases in pulmonary artery pressure, total pulmonary resistance, blood pressure and arterial oxygen tension. These results suggest that in patients with chronic obstructive pulmonary disease but without a history of right heart failure, the right ventricular systolic functional response to low flow oxygen and isosorbide at rest and exercise is, in part, determined by changes in total pulmonary resistance. The chronic relation between right ventricular ejection fraction and pulmonary hemodynamics in patients with chronic obstructive pulmonary disease remains to be evaluated.

Blood Pressure↗

[Pharmacokinetics of 14C-isosorbide dinitrate after administration in various sustained-release formulations].

To study the influence of various in vitro release rates and of coadministration with food on bioavailability of isosorbide dinitrate (ISDN; isoket retard 40) and its mononitrate metabolites from sustained-release formulations the pharmacokinetics of two experimental batches of tablets with different release rates containing 40 mg 14C-ISDN each were studied in six human volunteers. One of the formulations was not only administered after fasting but aslo with a standard meal. In all cases approx. 80% of the administered radioactivity were recovered in the urine and 5% in the faeces during 3 days demonstrating extensive absorption. Any influence of release rates or food on absorption rates could not be detected. When administered after fasting either formulation was bioequivalent. Coadministration of a meal enhanced ISDN plasma levels in some subjects although no statistically significant difference in extent of bioavailability was observed. Availability of the mononitrates was unaffected by food.

Adult↗

[ Combined therapy with isosorbide dinitrate, propranolol and nifedipine in patients with chronic ischemic heart disease].

Forty six patients with stable effort angina were treated with a combination of propranolol, nifedipine, and isosorbide dinitrate which produced a more profound anti-antianginal effect than each of them given alone. The combination also exerted more marked antihypertensive and antiarrhythmic effects. The combined therapy with the three drugs caused a moderate reduction in heart rate and peripheral resistance, but failed to result in clear-cut disturbances in the orthostatic regulation of the circulatory system. There was a more infrequent and less pronounced ST-segment depression, less marked pressor responses and higher heart rate with the combined therapy during exercise; the cardiac index also increased as before therapy. Physical fitness increased to a greater extent than with monotherapy. The combined therapy with three drugs is indicated when monotherapy fails and that with two agents is indicated when patients have concurrent essential hypertension and cardiac arrhythmias.

Adult↗