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PubMed1992

Pharmacokinetics of isosorbide mononitrate.

Pharmacokinetic studies show that isosorbide mononitrate is rapidly absorbed after oral administration, reaches peak concentrations within an hour, undergoes no significant first-pass metabolism, and is virtually 100% bioavailable. The half-life is approximately 5 hours, the volume of distribution is 0.62 liter/kg, and the systemic clearance is 115 mL/min. Only 1-2% of an orally administered dose is excreted unchanged in the urine, with the remainder being eliminated as inactive metabolites. Isosorbide mononitrate follows dose-linear kinetics after single and multiple doses. Its pharmacokinetic profile is consistent and highly reproducible and is unchanged in the elderly and in patients with coronary artery disease, renal failure, or liver cirrhosis. An asymmetrical dosage regimen of isosorbide mononitrate has been shown to provide antianginal efficacy for at least 12 hours. Because asymmetrical dosing creates irregular, sawtooth-like changes in plasma concentrations and a fall below a critical threshold level during the night, tolerance does not develop.

Drug Administration Schedule↗
PubMed1992

Effects of 8:00 a.m. and 2:00 p.m. doses of isosorbide-5-mononitrate during twice-daily therapy in stable angina pectoris.

"Trough" plasma concentrations of isosorbide-5-mononitrate (IS-5-MN), an active metabolite of isosorbide dinitrate, of less than 95 ng/ml are considered necessary to prevent development of tolerance to isosorbide dinitrate and IS-5-MN. In a double-blind, crossover, placebo-controlled study, the effects of IS-5-MN during twice daily eccentric therapy were evaluated in 18 patients with reproducible exercise-induced angina who were nitrate responders. In a random order, patients received either placebo or IS-5-MN (20 mg) at 8 a.m. and 2 p.m. for 1 week each. Average trough plasma IS-5-MN concentrations before the 8 a.m. and 2 p.m. doses were 67 and 226 ng/ml, respectively, and increased to 382 and 488 ng/ml 2 hours after the 8 a.m. and 2 p.m. doses, respectively. Despite a more than threefold higher trough plasma IS-5-MN concentration before the 2 p.m. dose than before the 8 a.m. dose, the increase in exercise duration 2 hours after the doses was similar (1.21 minutes [21%] after 8 a.m. dose, and 1.08 minutes [19%] after 2 p.m. dose). These increases in exercise duration after IS-5-MN were significantly (p less than 0.01) greater than those observed after placebo (0.17 minutes [3%] after 8 a.m. dose, and -0.05 minute [-0.5%] after 2 p.m. dose). Reduction in standing systolic blood pressure at 2 hours after the doses was also nearly identical after the 8 a.m. and 2 p.m. doses of IS-5-MN (21 [15%] and 19 [14%] mm Hg, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1991

Oral administration of isosorbide dinitrate inhibits arterial thrombosis in rats.

The effect of isosorbide dinitrate, a nitrovasodilator known to inhibit platelet function, was examined in a model of electrically induced carotid artery thrombosis in rats. In the dose range of 1-30 mg/kg isosorbide dinitrate, administered orally, significantly delayed carotid occlusion. These results demonstrate that isosorbide dinitrate has antithrombotic activity and it is suggested that this antithrombotic activity is due to the generation of nitric oxide.

Administration, Oral↗
PubMed1996

The effect of isosorbide dinitrate on uterine artery and umbilical artery flow velocity waveforms at mid-pregnancy.

OBJECTIVE: To study the effect of isosorbide dinitrate, a nitric oxide donor, on the maternal cardiovascular system and on uterine and umbilical artery blood flow velocities in mid-pregnancy. METHODS: Eighteen women with low-risk pregnancy at 17-24 weeks' gestation were given a single 5-mg dose of sublingual isosorbide dinitrate, a nitrovasodilator. Blood flow velocity waveforms in the ascending uterine artery and in the umbilical artery were measured by an image-directed, pulsed color Doppler ultrasound scan before and after the medication was administered. Maternal blood pressure (BP) and heart rate were also obtained. RESULTS: The mean arterial BP decreased from 86 mmHg (95% confidence interval [CI] 72-99) to a nadir of 73 mmHg at 6 minutes (95% CI 61-85, P < .04). Mean maternal heart rate increased from 85 beats per minute (95% CI 80-90) to 96 beats per minute at 6 minutes (95% CI 87-105, P < .01). Mean systolic-diastolic flow velocity ratio (S/D) in the umbilical artery rapidly declined from 4.18 (95% CI 3.80-4.56), reaching a nadir of 3.12 at 6 minutes (95% CI 2.65-3.84, P < .001). The S/D in the uterine artery decreased from 4.83 (95% CI 3.99-5.56) to a nadir of 4.02 at 10 minutes (95% CI 3.41-4.63, P < .001). CONCLUSION: Isosorbide dinitrate, a donor of nitric acid, lowers mean maternal BP and reduces the Doppler impedance in the umbilical and uterine arteries. This drug could prove to be beneficial when endothelial cell dysfunction leads to insufficient synthesis and release of endothelium-derived relaxing factor, resulting in generalized vasoconstriction and increased resistance to flow in the uteroplacental circulation.

Adolescent↗
PubMed1992

Modification of platelet function by isosorbide dinitrate in patients with coronary artery disease.

The effect of a four weeks oral treatment with 100 mg isosorbide dinitrate (ISDN) daily on platelet function was evaluated in 40 patients (aged 40-65 years) with proven coronary artery disease. Isosorbide dinitrate decreased platelet reactivity to ADP (p less than 0.001), increased platelet sensitivity to PGI2 (p less than 0.01) while the production of TXB2 from exogenous arachidonic acid substrate and from endogenous substrate were both significantly reduced. Circulating platelet aggregates as measured by the Wu-test were markedly reduced (p less than 0.001) but there was little change in the plasma concentration of the platelet proteins beta-thromboglobulin and platelet factor 4. Overall, platelet activation correlated with smoking, hypertension and a family history of coronary artery disease. The reduced platelet activation seen during treatment with isosorbide dinitrate may contribute to the therapeutic benefit seen with this drug in patients with coronary artery disease.

Adenosine Diphosphate↗
PubMed1981

Comparison of acute haemodynamic effects of nifedipine and isosorbide dinitrate in patients with heart failure following acute myocardial infarction.

The acute haemodynamic effects of nifedipine (10 mg sublingually) and isosorbide dinitrate (5 mg sublingually) were compared in 13 patients with heart failure due to acute myocardial infarction. Nifedipine induced a significant reduction in systolic (from 122 +/- 5 to 107 +/- 3 mm Hg: mean +/- SEM; P less than 0.002) and diastolic blood pressure (from 85 +/- 3 to 75 +/- 2 mm Hg; P less than 0.01). Heart rate did not change significantly, nor did mean right atrial pressure. The mean pulmonary arterial pressure was lowered from 31 +/- 2 to 27 +/- 2 mm Hg (P less than 0.005). The left ventricular filling pressure decreased from 24 +/- 1 to 19 +/- 1 mm Hg (P less than 0.0001). A significant increase in cardiac index (from 2.33 +/- 0.13 to 2.69 +/- 0.15 l/min per m2; P less than 0.001) and in stroke volume index (from 24 +/- 2 to 28 +/- 2 ml/beats per m2; P less than 0.005) was registered. Systemic vascular resistance fell from 1742 +/- 145 to 1308 +/- 85 dynes/sec per cm-5 (P less than 0.00005). After isosorbide dinitrate was administered a significant reduction in mean right atrial pressure (from 9.5 +/- 1.6 to 5.1 +/- 1.2 mm Hg; P less than 0.0001), in mean pulmonary arterial pressure (from 32 +/- 1 to 23 +/- 1 mm Hg; P less than 0.00001) and in left ventricular filling pressure (from 23 +/- 1 to 16 +/- 1 mm Hg; P less than 0.0001) was seen. No significant change in systolic and diastolic blood pressure, heart rate, cardiac index, stroke volume index and systemic vascular resistance was registered. No side-effects were seen after nifedipine and isosorbide dinitrate were administered.

Adult↗
PubMed1985

Double-blind randomised crossover trial comparing isosorbide dinitrate cream and oral sustained-release tablets in patients with angina pectoris.

Percutaneous isosorbide dinitrate cream and sustained-release tablets were compared in a double-blind randomised crossover trial in 28 patients with coronary artery disease and chronic stable angina pectoris. Twenty-two patients completed the trial. Both preparations significantly increased the mean exercise time to the onset of angina (P less than 0.001) and to termination of exercise (P less than 0.001) compared to the pre-treatment period. There were no significant differences between the cream and tablets with respect to frequency of anginal attacks, glyceryl trinitrate consumption, heart rate and ST segment depression at the onset of angina, ST segment depression at maximal exercise and the double product of heart rate and systolic blood pressure at maximal exercise. Equal numbers of patients expressed preference for cream and tablets. We conclude that in this group of patients isosorbide dinitrate sustained-release tablets have no clinical advantage over isosorbide dinitrate cream which, may, therefore, be of particular value for those patients with angina pectoris who dislike taking tablets or who prefer this form of nitrate preparation.

Administration, Oral↗
PubMed1996

Improved extraction procedure for the assay of isosorbide-5-mononitrate in serum.

A procedure is described for the extraction of isosorbide-5-mononitrate from serum with diethyl ether-n-butyl acetate (15:1, v/v). After extraction, the diethyl ether is evaporated at room temperature and the nitrate remains dissolved in the relatively non-volatile n-butyl acetate phase. Glassware must be used throughout as the recovery of isosorbide-5-mononitrate is not reproducible when plastic tubes or plastic pipettes are used. The extraction recovery of isosorbide-5-mononitrate from serum is 67 +/- 7%, measured relative to external standards.

Chromatography, Gas↗
PubMed1977

Hemodynamic assessment of oral peripheral vasodilator therapy in chronic congestive heart failure: prolonged effectiveness of isosorbide dinitrate.

To evaluate the effectiveness of oral vasodilator therapy in chronic congestive heart failure, 20 mg of isosorbide dinitrate or placebo was administered orally in double-blind fashion to 25 patients with congestive heart failure. In 15 patients receiving isosorbide dinitrate, pulmonary arterial wedge pressure decreased 5 minutes to 5 hours after drug administration; the peak reduction was observed at 1 hour (from 23 to 14 mm Hg; P less than 0.001). Wedge pressure decreased to normal (12 mm Hg or less) in 8 of the 15 patients (Group I) but remained greater than 12 mm Hg in 7 (Group II). Reductions in mean systemic arterial pressure, systemic vascular resistance and pressure-time per minute also occurred. Indexes of pump output were unchanged in the 15 who received isosorbide dinitrate but tended to decrease slightly in Group I. Stroke index (from 23 to 26 cc/m2) and stroke work index (from 21.4 to 24.1 g-m/m2) increased slightly but significantly (P less than 0.05) in Group II. Thus the prinicpal hemodynamic action of isorbide dinitrate is marked and sustained reduction in left ventricular filling pressure without pronounced effect on cardiac output. This agent should be used in congestive heart failure primarily for relief of congestive symptoms.

Administration, Oral↗
PubMed2002

Crystal structure of the cyclomaltohexaose (alpha-cyclodextrin) complex with isosorbide dinitrate. Guest-modulated channel-type structure.

The crystal structure of the 2:1 complex of cyclomaltohexaose (alpha-cyclodextrin, alpha-CD) with isosorbide dinitrate was determined by single-crystal X-ray analysis. In the crystal with the space group C2, two cyclomaltohexaose molecules form a head-to-head dimer with the secondary hydroxy-group sides facing each other. The dimer unit is stacked along the crystallographic c-axis to form a channel-type structure. The isosorbide dinitrate molecule is encapsulated in the cylindrical cavity of the cyclomaltohexaose dimer. The dimeric structure exhibits pseudo twofold symmetry, and the guest molecule is disordered on the local symmetry axis. The isosorbide moiety is located at the center of the dimer cavity, and the nitrate groups penetrate into the cyclomaltohexaose rings. The guest molecule modulates the dimer structure to attain the most stable accommodation into the cavity. The cyclomaltohexaose molecules are laterally shifted away from each other to create the cavity fitted to the shape of the guest molecule. As the result, the intermolecular hydrogen bonds between secondary hydroxy-groups are not fully formed, but the dimeric structure is stabilized by the interaction with the guest molecule.

Carbohydrate Conformation↗
PubMed2002

Randomized trial of isosorbide mononitrate versus misoprostol for cervical ripening at term.

OBJECTIVES: To assess the adverse effects of isosorbide mononitrate (IMN) compared with misoprostol for cervical ripening at term. METHODS: One hundred and seven women with term pregnancies referred for induction of labor with Bishop scores of 6 or less were randomly allocated to receive either a 40-mg IMN tablet vaginally (n = 55) or 50 microg misoprostol vaginally (n = 52) every 6 h for a maximum of three doses. They were sent to the labor ward for amniotomy or oxytocin if either their Bishop scores were more than 6 or their cervices were not ripe 24 h after the treatment. Adverse effects, progress, and outcomes of labor were assessed. RESULTS: Isosorbide mononitrate was associated with fewer adverse effects especially uterine tachysystole (0 vs. 19.2%, P < 0.01) and hyperstimulation (0 vs. 15.4%, P < 0.01). The time from start of medication to vaginal delivery in IMN group was significantly longer (25.6 +/- 6.1 vs. 14 +/- 6.9 h, P < 0.01). Oxytocin was needed in 51 women (92%) of the isosorbide mononitrate group and six women (11%) of the misoprostol group (P < 0.001). The cesarean rate was not significantly different between the groups, but the major indications were different: dystocia (45%) in the IMN group vs. persistent non-reassuring fetal heart rate pattern (56%) in the misoprostol group. CONCLUSIONS: Cervical ripening with IMN resulted in fewer adverse effects, but was less effective than misoprostol.

Adult↗
PubMed1987

Effects of isosorbide dinitrate on portal hypertension in alcoholic cirrhosis.

It has recently been reported that vasodilators lower portal pressure in patients with cirrhosis. This effect, however, is not definitively proven. The effect of isosorbide dinitrate (5 mg sublingually) on splanchnic and systemic hemodynamics was investigated in 13 patients with alcoholic cirrhosis and portal hypertension. The administration of isosorbide dinitrate reduced hepatic venous pressure gradient by 34% (P less than 0.001), mean arterial pressure by 30% (P less than 0.001), cardiac index by 17% (P less than 0.001) and systemic vascular resistance by 11% (P = 0.05). Hepatic blood flow was not affected by the treatment. Significant correlations were found between the decrease in hepatic venous pressure gradient and that of cardiac index (P less than 0.05) and mean arterial pressure (P less than 0.05). These data indicate that isosorbide dinitrate lowers portal pressure in patients with cirrhosis. Decrease in cardiac output, rise in splanchnic arterial vascular resistance and decrease in porto-hepatic resistance seem to participate in determining the effect.

Adult↗
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↗
PubMed2000

Effect of penetration enhancers on isosorbide dinitrate penetration through rat skin from a transdermal therapeutic system.

Percutaneous absorption of isosorbide dinitrate (ISDN) from a transdermal therapeutic system (TTS) with or without penetration enhancers was studied. The concentration of ISDN and its metabolites, isosorbide-5-mononitrate (IS-5-MN) and isosorbide-2-mononitrate (IS-2-MN), was determined in rat plasma during a 48 h application of TTS. The increased skin-penetration enhancing effect of oleic acid and propylene glycol in comparison to polyethylene glycol 400 and isopropyl myristate on percutaneous permeation of ISDN was shown. It was expressed by higher values of C(max) and AUC. After the application of TTS, a lower ISDN and molar ratio of its metabolites was observed than after oral administration.

Administration, Cutaneous↗
PubMed1987

Investigation of the gastrointestinal transit and in vivo drug release of isosorbide-5-nitrate pellets.

An oral formulation of controlled-release isosorbide-5-nitrate pellets has been used to investigate the location of pellets in the gastrointestinal (GI) tract and, in parallel, to measure the drug absorption from these locations. Using the method of gamma scintigraphy the transit times and spreading of pellets in the GI tract have been determined. The method of numeric deconvolution was applied to calculate the drug input into the systemic circulation. The results indicate that a well-absorbed substance such as isosorbide-5-nitrate is absorbed from the stomach and small intestinal in a manner that is controlled by the properties of the pellets. Drug absorption is reduced in the colon. The average transit time from mouth to colon is 6 to 8 hr, which represents the maximum acceptable time for drug release for this oral controlled-release preparation. Taking into account these relations an isosorbide-5-nitrate pellet formulation with a bioavailability of 84% has been developed that maintained the minimal therapeutic plasma level for more than 16 hr after application.

Delayed-Action Preparations↗
PubMed1985

Isosorbide dinitrate bioavailability, kinetics, and metabolism.

We studied the kinetics of isosorbide dinitrate (ISDN) after a dose of 5 mg iv and the bioavailability of a sublingual and an oral preparation of ISDN. Plasma levels of isosorbide 5-mononitrate (IS-5-MN), isosorbide 2-mononitrate (IS-2-MN), and ISDN were determined by GLC. After intravenous and sublingual dosing, ISDN plasma levels declined biexponentially and could adequately be described by an open two-compartment body model. Distribution was rapid; the t1/2 was 4.7 minutes after intravenous injection and 8.7 minutes after sublingual dosing. The volume of distribution at steady state was 90 L. The terminal disappearance t1/2 was 54.7 minutes after intravenous injection, 48.8 minutes after sublingual dosing, and 47.7 minutes after oral dosing. Total plasma clearance was 136 L/hr, exceeding normal liver plasma flow and indicating extrahepatic metabolism of ISDN. ISDN bioavailability after oral (10 mg) or sublingual dosing (10 mg) was similar (about 29%), indicating that the first-pass effect cannot be avoided by sublingual ISDN dosing. After intravenous ISDN, mononitrate plasma levels could be adequately described by another two-compartment body model. The terminal t1/2 was 4.33 hours for IS-5-MN and 1.83 hours for IS-2-MN. Noncompartmental calculations of the mononitrate levels revealed 100% systemic availability after oral and sublingual ISDN. We assume that ISDN was completely absorbed from the gastrointestinal tract, but 70% was metabolized during the first pass through the liver. After 5 mg iv ISDN, 16 mumol IS-5-MN and 5.3 mumol IS-2-MN reached systemic circulation. The entire dose of ISDN was converted to its two metabolites in a ratio of 3:1 (i.e., 75% IS-5-MN and 25% IS-2-MN).

Administration, Oral↗
PubMed1996

Differing actions of the acute administration of propranolol and isosorbide-5-mononitrate on the portal circulation.

BACKGROUND: The aim of this study was to clarify the actions of propranolol and isosorbide-5-mononitrate upon the portal circulation. METHODS: Portal haemodynamics were assessed in 16 patients with transjugular intrahepatic portosystemic stent shunts. A reverse thermodilution catheter was positioned in the portal vein, and portal vein pressure and portal vein flow were measured directly. The effects of propranolol 80 mg and isosorbide-5-mononitrate 20 mg over 1 h were determined independently. RESULTS: This demonstrated that propranolol reduced both portal pressure gradient (7.7 +/- 2.3 to 5.5 +/- 2.1 mmHg, P < 0.01) and portal vein flow (925 +/- 123 to 597 +/- 99 mL/min, P = 0.01) significantly, implying a reduction in splanchnic inflow as its main effect. In contrast, isosorbide-5-mononitrate tended to increase portal vein flow (814 +/- 186 to 911 +/- 211 mL/min; P = 0.06) whilst reducing portal pressure significantly (108 +/- 12 to 92 +/- 10 mmHg P = 0.014). This suggests a fall in intrahepatic resistance and provides no evidence for baroreceptor-mediated reflex splanchnic vasoconstriction. CONCLUSIONS: These drugs act upon different variables contributing to portal hypertension and so they may have a powerful synergistic effect in combination. Direct measurement of portal vein flow is a valuable method for assessing the pharmacological modulation of portal venous inflow.

Blood Pressure↗
PubMed2002

Evaluation of the bioequivalence and pharmacokinetics of two tablet formulations of isosorbide-5-mononitrate after single oral administration in healthy volunteers.

The pharmacokinetic parameters of two oral formulations of 20 mg tablets of isosorbide-5-mononitrate (CAS 16051-77-7, Dilavenil as test and another commercially available preparation as reference) were compared in an open-label, randomized, single oral dose, two-period cross-over design in 20 healthy volunteers under fasting conditions. Plasma concentrations of isosorbide-5-mononitrate were measured by a validated gas chromatographic assay. The parametric 90% confidence intervals of the geometric mean values of the test/reference ratios were 101.2% to 108.5% (point estimate: 104.7%) for AUC0-variation of, 101.6% to 110.7% (point estimate: 106.2%) for AUC0-t, and 98.1% to 115.5% (point estimate: 106.1%) for Cmax, within the acceptance criteria for bioequivalence (80%-125%). Tmax values were analyzed by the nonparametric Wilcoxon test and the difference was not statistically significant. Therefore, it is concluded that the test and reference isosorbide-5-mononitrate formulations are bioequivalent for both the extent and the rate of absorption.

Adult↗