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At least 289 records · Page 16Linked to original sources
PubMed1994

Propranolol plus isosorbide-5-mononitrate for portal hypertension in cirrhosis: long-term hemodynamic and renal effects.

The effect on kidney function, vasoactive systems and ascites outcome of long-term treatment with propranolol plus isosorbide-5-mononitrate, a combined therapy proven more effective than propranolol alone in decreasing portal pressure in the cirrhotic patient, is unknown. Thirty cirrhotic patients who survived acute variceal bleeding and were treated with propranolol plus isosorbide-5-mononitrate were studied. Portal and systemic hemodynamics (n = 15), inulin clearance, free water clearance, plasma renin activity, aldosterone concentration and prostaglandin E2 excretion (n = 20) were measured before and after 3 mo of treatment. In addition, data on ascites outcome in the entire series after a mean follow-up of 9.6 mo were compared with those of 30 patients undergoing elective sclerotherapy and with those of 30 patients treated with propranolol alone matched for age, sex, presence of ascites, Child-Pugh class and mean follow-up length included in other randomized controlled trials. Combined therapy significantly decreased the hepatic venous pressure gradient and azygos blood flow. In addition, no changes in inulin clearance, free water clearance, plasma renin activity, aldosterone concentration and prostaglandin E2 excretion occurred, despite a mild decrease in mean arterial pressure. Moreover, no differences among the three groups of patients studied in ascites outcome were found. These results suggest that long-term treatment with propranolol plus isosorbide-5-mononitrate does not impair kidney function, vasoactive systems or ascites outcome in cirrhotic patients.

Aldosterone↗
PubMed2000

Long-term results of a clinical trial of nadolol with or without isosorbide mononitrate for primary prophylaxis of variceal bleeding in cirrhosis.

It is clearly established that beta-blockers decrease the risk of a first variceal bleeding in cirrhosis. We have recently shown that the addition of isosorbide mononitrate to nadolol decreases the rate of variceal bleeding in patients with cirrhosis and varices, compared with nadolol alone, after a median follow-up of 30 months. It is not established if the long-term treatment with the combination continues to be beneficial. Therefore, we assessed the long-term effect of this combination on first variceal bleeding, complications, and death. One hundred forty-six cirrhotic patients with esophageal varices included in a previously published multicenter, randomized study comparing nadolol (40-160 mg/d) with the combination nadolol plus isosorbide mononitrate (10-20 mg 3 times per day) were followed up for up to 7 years (median follow-up, 55 months). The primary end-point was variceal bleeding of any severity. Twenty-four patients (16 in the nadolol group, and 8 in the combination group) experienced variceal bleeding (log rank test, P =.02). Cumulative risk of bleeding was 29% and 12%, respectively (95% CI for the difference, 1%-23%). Two and 4 patients, respectively, had bleeding from portal hypertensive gastropathy (log rank test, P =.20). Thirty and 25 patients, respectively, died during follow-up (log rank test, P =.13). Twelve and 10 patients, respectively, had de novo occurrence of ascites during follow-up (log rank test, P =.29). In conclusion, nadolol plus isosorbide mononitrate is significantly more effective than nadolol alone in the long-term use. Side effects are few, and no deleterious effects on ascites occurrence or on survival occur after long-term use of this combination.

Adolescent↗
PubMed2003

Potentiation of radiation-induced regrowth delay by isosorbide dinitrate in FSaII murine tumors.

Oxygen deficiency in tumors reduces the efficacy of nonsurgical treatment modalities such as conventional radiotherapy and chemotherapy. Since tumor perfusion is directly affected by the vascular resistance to flow of vessels feeding the tumor, vasodilator drugs might be a way to increase tumor blood flow and oxygenation. The effects of nitric oxide (NO) donor administration on tumor oxygenation, perfusion and radiation sensitivity were studied in the FSaII tumor model. Local tumor oxygenation was measured using electron paramagnetic resonance oximetry and a fiberoptic probe, OxyLite. We concomitantly measured the modulation of tumor blood flow by laser Doppler flowmetry. We determined FSaII tumor regrowth delay after isosorbide dinitrate administration and irradiation compared to carbogen breathing before irradiation and with X-rays alone. Administration of the NO donor improved the FSaII tumor pO(2) concomitant with an increase in tumor blood flow. We also demonstrated an increase in FSaII tumor radiation sensitivity after isosorbide dinitrate administration, which was similar to the effect of carbogen breathing in the same tumor model. Administration of isosorbide dinitrate could be considered in terms of improvement in tumor blood flow and a possible concomitant increase in accessibility of chemosensitizing agents to the tumor, particularly in terms of modification of the tumor response to irradiation.

Animals↗
PubMed1997

Pharmacokinetics of isosorbide dinitrate in healthy volunteers after 24-hour intravenous infusion.

No studies have examined the pharmacokinetics of isosorbide dinitrate (ISDN) after infusion of long duration, even though such infusions are used in patients. We therefore measured ISDN and its active metabolites, isosorbide-5-mononitrate (IS5MN) and isosorbide-2-mononitrate (IS2MN), in plasma of 9 healthy volunteers who received a continuous intravenous infusion of ISDN for 24 hours at a dose rate that lowered diastolic blood pressure by 10% during the first 30 minutes of infusion. All subjects tolerated the infusion except one who experienced intolerable headache. Five subjects received 1 microgram.min-1.kg-1, one 2 micrograms.min-1.kg-1, and two 4 micrograms.min-1.kg-1 ISDN, whereas the full rate of 6 micrograms.min-1.kg-1 was used continuously in one subject. At all infusion rates the plasma concentrations of ISDN were higher at 24 hours than at earlier times, suggesting that a steady-state condition had not been reached at that time. The same was true for the mononitrate metabolites, which reached higher plasma concentrations and were cleared more slowly than the parent compound after the end of the infusion. Apparent elimination half-lives of ISDN, IS2MN, and IS5MN were 67 +/- 10 minutes, 115 +/- 13 minutes, and 272 +/- 38 minutes, respectively. Comparison of low-rate infusions (1 and 2 micrograms.min-1.kg-1) with high-rate infusions (4 and 6 micrograms.min-1.kg-1) showed that the plasma concentration ratios at 24 hours of mononitrate metabolites to parent drug and apparent plasma clearance of ISDN were almost halved at the higher infusion rates.

Adult↗
PubMed1977

Electron-capture GLC determination of nanogram to picogram amounts of isosorbide dinitrate.

A GLC method for the determination of plasma isosorbide dinitrate using electron-capture detection is described. The organic nitrates are especially suited for electron-capture detection if the detector temperature is optimized for maximum sensitivity, e.g., 175 degrees. Proper maintenance of the detector and column assures reproducible data in the low nanogram range. The extraction procedure described is simple, efficient, and expedient for processing large numbers of samples. The method was used to study plasma levels in four human volunteers after a single dose of a 5-mg chewable isosorbide dinitrate tablet. Concentration levels of isosorbide dinitrate as low as 0.5 ng/ml of plasma can be measured by this procedure.

Adult↗
PubMed1977

Plasma isosorbide dinitrate concentrations in human subjects after administration of standard and sustained-release formulations.

After sublingual administration of 5 mg of isosorbide dinitrate, mean plasma concentrations (+/-SD) peaked (8.9+/-3.1 ng/ml) at 15 min after dosing and declined with a half-life of 30 min. After oral administration of 5 mg, mean concentrations peaked (3.1+/-0.7 ng/ml) at 30 min and declined with a half-life of 40 min. After oral administration of 20 mg in a sustained-release tablet, mean concentrations initially peaked (1.4+/-1.2 ng/ml) at 40 min, declining to 0.9+/-0.5 ng/ml after 8 hr. Mean concentrations were maintained above half the mean peak level during 10 hr. Because of probable rapid first-pass metabolism, the bioavailability of isosorbide dinitrate after administration of the oral dose of the standard tablet was 58% of that from the sublingual dose, and the bioavailability from the sustained-release tablet was 47% of that from the sublingual dose of the standard tablet. The time course of mean plasma concentration data could be described by a one-compartment model; but a more complex model, taking the pass effect into account, probably is needed for a better description of the pharmacokinetics of isosorbide dinitrate.

Administration, Oral↗
PubMed1984

On the haemodynamic differences between sodium nitroprusside, nitroglycerin, and isosorbide nitrates. Comparison of their vasorelaxant effects in vitro and of their inactivation in vivo.

In organ bath studies, the sensitivity of isolated renal arteries and veins of the rabbit to sodium nitroprusside (SNP), nitroglycerin (GTN), and two isosorbide nitrates was compared. For isosorbide-dinitrate and isosorbide-5-mononitrate, a 7 to 20 times greater sensitivity of veins than of arteries was found explaining their known in vivo predilection for the capacitance vessels. To SNP and GTN, the immediate response was practically identical; a moderately greater sensitivity of the veins at threshold concentrations ( EC10 ), and a similar sensitivity of veins and arteries at the EC50 was observed with both drugs. However, on prolonged exposure (30 min), the relaxant response to GTN faded to a greater extent in arteries than in veins which may be a factor in the in vivo preference of GTN for the capacitance vessels. In anaesthetized rats, the hypotensive response to SNP and to GTN either infused i.v. or into the femoral artery, was compared. With GTN, the hypotensive response was the same by either route of administration. In contrast, the hypotensive response to SNP was considerably reduced on infusion into the femoral artery; an inactivation of SNP by 34% on passage through the hind-leg was calculated. The resulting decrease in venous over arterial blood levels of SNP could outweigh the somewhat greater sensitivity of veins than of arteries found in the organ bath, and may account for the balanced effect of SNP on resistance and capacitance vessels known to exist in vivo.

Animals↗
PubMed1985

Pharmacokinetics and metabolism of isosorbide-dinitrate after intravenous and oral administration.

The bioavailabilities of a conventional and two slow release 20 mg isosorbide dinitrate (ISDN) formulations were compared after oral administration in a three way cross-over study in 8 male volunteers. In a further group of 6 male volunteers the pharmacokinetics and metabolism of ISDN were investigated after intravenous infusion of a median dose of 14.1 mg for 2.5 h. A new analytical procedure was developed for the determination of isosorbide-5-mononitrate-2-glucuronide (IS-5-MN-2-Glu) and of isosorbide (IS). Kinetic data analysis on a molar basis was performed by the program package KIN-PAK providing model independent parameters. The median elimination half-lives of ISDN, IS-5-MN, IS-2-MN and IS-5-MN-2-Glu were 0.7, 5.1, 3.2 and 2.5 h, respectively. The systemic clearance of ISDN was 3.71/min and the distribution volume 2521 (3.1 l/kg). Apart from IS-5-MN-2-Glu, with a renal clearance of 5.9 l/min which suggested substantial glucuronidation in the kidney, the renal clearances of ISDN, IS-5-MN, IS-2-MN and the corresponding amounts excreted were negligible. 27.8% of the administered ISDN was excreted as IS-5-MN-2-Glu (8.7%) and IS (19.1%). Calculations based on the two mononitrate metabolites formed from ISDN showed an incomplete recovery of 84.1%, leading to the assumption that a simultaneous denitration to IS must have occurred. The rate of denitration at each nitro group in ISDN was almost twice as high as for the same position in the corresponding mononitrate.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1981

Availability of isosorbide dinitrate, diazepam and chlormethiazole, from i.v. delivery systems.

The loss of isosorbide dinitrate from aqueous solutions stored in plastic infusion bags and/or infused through plastic giving sets was investigated. During simulated infusions, the loss of isosorbide dinitrate was found to be flow-rate dependent. The clinical and pharmacokinetic significance of this loss is discussed. Infusion o isosorbide dinitrate from a glass syringe through high density polyethylene tubing overcame the loss associated with its administration via plastic infusion bags and intravenous giving sets. This method was also applied successfully to minimise the previously reported loss of diazepam and chlormethiazole during infusions.

Adsorption↗
PubMed1980

Effects and pharmacokinetics of isosorbide dinitrate in normal man.

18 subjects were given isosorbide dinitrate (ISDN) 5 mg sublingually and serum concentrations of ISDN, 2-isosorbide mononitrate (2-ISMN) and 5-isosorbide mononitrate (5-ISMN) were measured, as well as changes in digital plethysmographic amplitude, heart rate, ECG, blood pressure and Schellong's test. ISDN was rapidly absorbed and metabolized, having an elimination half-life of 29 min. Its metabolites 2-ISMN and 5-ISMN had longer half-lives of 1.75 and 7.6 h respectively. The amplitude of the alpha-wave of the digital plethysmograph did not change significantly either in the pre-drug period or after placebo administration. It increased within 4 min of administration of ISDN, and reached a maximum after 14 min; the effect lasted for about 2 h. ISDN lowers blood pressure and increases heart rate in most volunteers, but in 3 of the 18 subjects severe hypotension occurred, accompanied by severe, reversible bradycardia, which was probably due to vagal reflexes initiated by the markedly diminished ventricular enddiastolic volume (LVEDV) and pressure (LVEDP). No correlation could be demonstrated between the serum concentration of ISDN and/or its vasoactive metabolites and changes in plethysmographic amplitude.

Female↗
PubMed1988

Influence of exercise on plasma concentrations of isosorbide dinitrate.

As the fall in hepatic blood flow caused by exercise is expected to decrease the elimination of high extraction drugs, the influence of exercise on the fate of the anti-anginal drug isosorbide dinitrate has been assessed. Isosorbide dinitrate 10 mg was given orally, after an overnight fast, on 2 different days to 7 healthy volunteers and the plasma concentrations of the parent compound and its mononitrate metabolites were measured. Heavy bicycle exercise from the 45th to the 105th min after intake of the drug on one of the experimental days did not change the plasma isosorbide dinitrate concentrations as compared to those on the rest day. The concentrations of both mononitrates were lower on the exercise day, but the difference was already present before the exercise started.

Administration, Oral↗
PubMed1986

Pharmacokinetics of isosorbide dinitrate and its mononitrate metabolites after intravenous infusion.

Plasma concentrations of isosorbide dinitrate (ISDN) and its two active metabolites 2-isosorbide mononitrate (2-ISMN) and 5-isosorbide mononitrate (5-ISMN) have been measured during and for 6 hr after intravenous infusion at a rate of 2.5 mg/hr during 1.75 hr in six cardiac patients, by a capillary gas chromatographic method. Data were analyzed by simultaneous modeling of the observed kinetics of the three compounds. Two or three phases were detected on the postinfusion ISDN concentration-time curves. ISDN concentrations declined with a mean terminal half-life of 2.81 hr +/- 0.7 SD. The mean systemic clearance of ISDN (2.9 L/min +/- 0.7 SD) and its mean total volume of distribution (259 L +/- 48 SD) were relatively high. Plasma 5-ISMN concentrations were 5- to 6-fold greater than those of 2-ISMN during the whole observation period. Maximum levels of 2-ISMN (6.7 ng/ml +/- 0.9 SD) and of 5-ISMN (27 ng/ml +/- 6 SD) occurred within a few minutes after the end of infusion. The mean half-lives of 2-ISMN (1.59 hr +/- 0.19 SD) and of 5-ISMN (3.78 hr +/- 0.79 SD) estimated by the model were smaller than those calculated by a model-independent method (2.95 hr +/- 0.41 SD and 5.98 hr +/- 2.22, respectively), but were in good agreement with those reported in the literature following separate administration of both metabolites to man. This study shows how such modeling can distinguish between metabolite formation and elimination processes and allow the determination of metabolite half-lives after administration of the precursor drug.

Adult↗
PubMed2004

Randomized, prospective trial comparing 0.2 percent isosorbide dinitrate ointment with sphincterotomy in treatment of chronic anal fissure: a two-year follow-up.

PURPOSE: The aim of this trial was to compare lateral internal sphincterotomy with local 0.2 percent isosorbide dinitrate in the treatment of chronic anal fissure to minimize surgical complications such as minor fecal incontinence. METHODS: Fifty-four patients with chronic anal fissure were randomized in a prospective trial to either sphincterotomy or local 0.2 percent isosorbide dinitrate. All patients had anal function tests before and 5 weeks after treatment. RESULTS: In the ointment group, 18 patients (67 percent) healed at 5 weeks and 24 (89 percent) healed at 10 weeks of treatment. Maximum resting anal pressure was reduced 30 percent. Eight patients (30 percent) had minor side effects. In the surgical group, 26 patients (96 percent) healed at 5 weeks and 100 percent healed at 10 weeks after treatment, with 33 percent reduction in maximum resting anal pressure. Forty-four percent of patients had minor fecal incontinence, which remained in 15 percent after 24 months follow-up. No statistical difference in maximum resting anal pressure was found between groups ( P = 0.16), but the percentage of healing at 5 weeks was greater in the surgical group ( P < 0.001). CONCLUSIONS: Isosorbide dinitrate ointment must be considered as the first choice of treatment in patients with chronic anal fissure. Surgery should be indicated if chemical sphincterotomy fails.

Administration, Topical↗
PubMed1994

Comparison of the hemodynamic responses to molsidomine and isosorbide dinitrate in congestive heart failure.

To evaluate the mechanisms involved in nitrate tolerance, we randomized 23 patients with congestive heart failure resulting from coronary artery disease to an isosorbide dinitrate or a molsidomine infusion. The drugs were titrated to decrease pulmonary capillary wedge pressure by > or = 30% or > or = 10 mm Hg. Then isosorbide dinitrate, molsidomine, or placebo was infused in a double-blind randomized manner for 24 hours. In all patients, treatment with enalapril was begun > or = 48 hours before the beginning of the protocol and was continued throughout the study to avoid renin-angiotensin activation. The pulmonary capillary wedge pressure remained significantly decreased at 24 hours during molsidomine infusion only. No significant increase in catecholamines occurred. Because molsidomine differs from organic nitrates by its property of directly stimulating guanylate cyclase without depending on thiol group availability, these results suggest that impaired biotransformation of nitrates is involved in tolerance induced by high doses of isosorbide dinitrate in congestive heart failure.

Biotransformation↗
PubMed1984

Cardiorespiratory effects of isosorbide dinitrate and nifedipine in combination with nadolol: a double-blind comparative study of beneficial and adverse antianginal drug interactions.

Combinations of 2 or 3 drugs are often used to treat angina pectoris, but their combined cardiorespiratory effects have not been investigated. Using a randomized, double-blind, placebo-controlled protocol, the effects of nadolol alone and nadolol in combination with isosorbide dinitrate and nifedipine were compared, in low and high doses, on antianginal efficacy, respiratory functions and arterial blood oxygen saturation (SaO2) in 19 patients with stable angina pectoris. A complete assessment including a bicycle exercise test with the measurement of the sum of ST-segment depression in all leads (sigma ST) was carried out every 2 weeks. The frequency of anginal attacks and nitroglycerin consumption was reduced significantly (p less than 0.001) by nadolol alone and in combination with the other drugs. Nadolol caused a slight reduction in the forced expiratory volume in 1 second, which was improved by isosorbide dinitrate and nifedipine. The sigma ST profile (basal, at peak exercise and 2 and 5 minutes after exercise) was decreased by nadolol alone and in combination with the other drugs, although the greatest reduction was achieved with large doses of nifedipine and nadolol. The rest and postexercise SaO2 decreased after nadolol alone and in combination with isosorbide dinitrate, but recovered to pretrial values after nifedipine and nadolol. With all drug combination, sigma ST depression was greater when the postexercise SaO2 was less than 92%, and decreased (p less than 0.05) in the same patients when their postexercise SaO2 was greater than 92%.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1985

Isosorbide dinitrate sublingual therapy for inferior myocardial infarction: randomized trial to assess infarct size limitation.

To assess the potential of isosorbide dinitrate sublingual therapy for limiting myocardial infarct size, 41 patients with inferior acute myocardial infarction (AMI) were studied. Twenty patients were randomly assigned to the control group and 21 to the treatment group. Patients in the treatment group received 10 mg of isosorbide dinitrate every 2 hours for 72 hours. To estimate infarct size, QRS scoring, peak creatine kinase (CK) serum levels and CK curves were used. There were no significant differences between the 2 groups in maximal or cumulative activity of CK or QRS score (percent of left ventricle infarcted: 16% in the control group, 17% in the treatment group). In both groups the QRS score increased significantly by 13 hours after AMI, and the increase was highly significant by 19 to 23 hours. Thus, sublingual isosorbide dinitrate at the dosage given did not reduce infarct size in patients with inferior AMI.

Administration, Oral↗
PubMed1989

Effects of diltiazem alone or with isosorbide dinitrate or with atenolol both acutely and chronically for stable angina pectoris.

To establish the contribution of combination therapy in stable angina, the short- and long-term effects of diltiazem (120 mg and 360 mg/day, respectively), and the additive effects of sublingual isosorbide dinitrate, 10 mg, and atenolol, 100 mg, were studied in 11 patients with chronic stable angina using an open-label sequential design. All patients underwent exercise testing without therapy, and with each drug and their combinations. Exercise time and heart rate-blood pressure product were measured at 1-mm ST-segment depression, or at peak exercise if the test result was negative. Exercise time increased from a control value of 8.0 +/- 2.3 minutes (mean +/- standard deviation) to 11.4 +/- 2.4 minutes (p less than 0.0001) after the administration of isosorbide dinitrate, to 11.3 +/- 1.8 minutes (p less than 0.001) after short-term diltiazem and to 12.4 +/- 1.5 minutes (p less than 0.001) after long-term diltiazem. The rate-pressure product increased from a control value of 19,070 +/- 3,564 to 24,431 +/- 4,795 beats/min X mm Hg (p less than 0.0001) after isosorbide dinitrate, to 22,287 +/- 4,753 beats/min X mm Hg (p less than 0.01) after short-term diltiazem and to 21,812 +/- 3,976 beats/min X mm Hg (p less than 0.007) after long-term diltiazem. The addition of atenolol to long-term diltiazem significantly reduced the rate-pressure product compared with long-term diltiazem alone (21,812 +/- 3,976 vs 13,926 +/- 2,880 beats/min X mm Hg, (p less than 0.002), although there was no further significant increase in exercise time (12.4 +/- 1.5 vs 13.3 +/- 1.6 minutes).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Efficacy of isosorbide-5-mononitrate on painful and silent myocardial ischemia after myocardial infarction.

The anti-ischemic efficacy of isosorbide-5-mononitrate, 20 mg 3 times daily, on silent myocardial ischemia after myocardial infarction was studied in 28 Chinese patients with use of 48 hours of ambulatory electrocardiographic monitoring in a randomized, crossover, single-blind, placebo-controlled study. Isosorbide mononitrate reduced both painful and painless episodes of ischemia compared with placebo. The number of total ischemic episodes was reduced 88%, duration of ischemia 94%, time-ischemia integral 95%, and total maximal ST-segment depression 86% (p less than 0.01). The drug did not alter the heart rate and blood pressure, and had no evident adverse effect. Thus, isosorbide mononitrate is effective and well tolerated in postinfarction patients with silent ischemia.

Adult↗