Isosorbide mononitrate

• CAS: 16051-77-7
• Catalog Number: ACM16051777
• Category: Inhibitors
• Molecular Weight: 191.14
• Molecular Formula: C₆H₉NO₆
• Description: Isosorbide mononitrate(Isosorbide-5-mononitrate) is a nitrate-class compound used for angina pectoris; acts by dilating the blood vessels so as to reduce the blood pressure.
• Synonyms: ISMN; 5-ismn; Isosorbide mononitrate; Isosorbide 5-Nitrate; 1,4:3,6-Dianhydro-D-glucitol 5-nitrate; IS-5-MN; Ismo; ELAN; Isosorbide 5-mononitrate; Momt; isosorbide-5-mononitrate; 1,4:3,6-dianhydro-D-glucitol-5-nitrate; ahr4698; Isosorbide 5-Mononitrate; Coronu; IMDUR; isosorbide nitrate; ELANTAN
• IUPAC Name: [(3S,3aR,6R,6aS)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]nitrate
• SMILES: C1C(C2C(O1)C(CO2)O[N+](=O)[O-])O
• InChI Key: YWXYYJSYQOXTPL-SLPGGIOYSA-N
• Boiling Point: 364.5ºC at 760mmHg
• Melting Point: 88-93ºC
• Flash Point: 174.2ºC
• Density: 1.56g/cm³
• Appearance: White to off-white crystals
• Storage: Powder-20°C, 3 years; 4°C, 2 years; In solvent-80°C, 6 months; -20°C, 1 month.
• EC Number: 240-197-2
• Exact Mass: 191.04300
• Hazard Statements: F:Flammable
• Packing Group: III
• Safety Description: S15-S16-S37/39
• Shipping: Can be shipped at room temperature, where not in use may vary.
• Stability: Stable under normal temperatures and pressures.
• UN Number: 3251

Case Study

Effect of Isosorbide Mononitrate on Daily Activity and Clinical Outcomes in Patients with Heart Failure with Preserved Ejection Fraction

Redfield, Margaret M., et al. The New England Journal of Medicine 373.19 (2015): 1823-1832

This study evaluated the efficacy of isosorbide mononitrate in improving daily activity and clinical outcomes in patients with heart failure with preserved ejection fraction (HFpEF) through a multicenter, double-blind, crossover trial. A total of 110 eligible patients (≥50 years old, ejection fraction ≥50%, with objective evidence of HFpEF) were randomly assigned to two groups: one group received isosorbide mononitrate with a 6-week dose-escalation regimen (30 mg → 60 mg → 120 mg once daily) followed by 6 weeks of placebo, and the other group received placebo first then crossed over to isosorbide mononitrate. The primary endpoint was average daily activity level quantified by accelerometer units during the 120 mg phase, and secondary endpoints included daily activity hours, 6-minute walk distance, quality-of-life scores, and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. Results showed that during the 120 mg phase, isosorbide mononitrate did not improve daily activity (a nonsignificant trend toward lower activity: -381 accelerometer units; P=0.06) but significantly reduced daily activity hours (-0.30 hours; P=0.02) compared with placebo. Across all dose phases, daily activity in the isosorbide mononitrate group was significantly lower (-439 accelerometer units; P=0.02), and activity levels decreased progressively with increasing doses. There were no significant differences between the two groups in 6-minute walk distance, quality-of-life scores, or NT-proBNP levels, while isosorbide mononitrate slightly reduced systolic blood pressure (-3.7 mm Hg; P=0.04) and mean arterial pressure (-2.3 mm Hg; P=0.03). These findings demonstrate that isosorbide mononitrate does not improve daily activity, exercise capacity, or quality of life in HFpEF patients and may even reduce daily activity in a dose-dependent manner.
The in vivo effect of isosorbide mononitrate was verified through a crossover trial design. Patients wore triaxis accelerometers 24 hours a day (except bathing/swimming) to continuously record physical activity, with data processed as 15-minute cumulative accelerometer units and totaled for daily activity quantification. Baseline assessments included echocardiography, 6-minute walk test, Kansas City Cardiomyopathy Questionnaire, Minnesota Living with Heart Failure Questionnaire, and NT-proBNP measurement. During the trial, patients were followed up weekly to monitor side effects and medication compliance, and end-point assessments were repeated after each treatment period. Statistical analysis used a linear mixed model to account for sequence, study period, treatment effects, and correlated measurements within patients, with a two-sided P value of 0.05 considered statistically significant.

Efficacy and Safety of Extended-Release Isosorbide Mononitrate in Patients with Stable Effort Angina Pectoris

Chrysant, Steven G., et al. The American Journal of Cardiology 72.11 (1993): 1249-1256

This study assessed the therapeutic effect and safety of extended-release isosorbide mononitrate in treating stable effort angina pectoris through a multicenter, double-blind, parallel-group clinical trial. A total of 313 eligible patients (≥21 years old, with chronic stable effort-induced angina for at least 3 months, ≥3 attacks per week without treatment) were randomly divided into five groups: placebo group (n=58) and four extended-release isosorbide mononitrate dose groups (30 mg, 60 mg, 120 mg, 240 mg, each n=60-65), all administered once daily in the morning. The primary efficacy endpoint was total treadmill exercise time to moderate angina measured by the standard Bruce protocol, with assessments conducted immediately before dosing, 4 hours and 12 hours after dosing on days 1, 7, 14, 28, and 42. Results showed that after the first dose, all isosorbide mononitrate groups had significantly increased mean total exercise time compared with placebo at 4 and 12 hours (p<0.01), with increases of 30-50 seconds. During long-term treatment, the 120 mg and 240 mg doses maintained significant efficacy: on day 42, total exercise time was 50-60 seconds longer than placebo at 4 hours (p<0.01) and 30-35 seconds longer at 12 hours (p≤0.05). No significant difference was found between any active group and placebo 24 hours after dosing, indicating no zero-hour rebound effect. The drug was well-tolerated, with transient headache being the most common adverse event (38%-57% in active groups vs. 17% in placebo), and no nitrate tolerance was observed over the 6-week treatment period. These studies demonstrate that extended-release isosorbide mononitrate (120 mg and 240 mg once daily) can effectively prolong exercise time to effort-induced angina in long-term therapy, with good safety and no rebound effect or tolerance.
The in vivo efficacy and safety of extended-release isosorbide mononitrate were verified through standardized procedures. Patients underwent a 1-3 week placebo run-in phase to confirm reproducible angina and nitrate responsiveness before randomization. The 120 mg and 240 mg groups received dose titration (60 mg for 4 days, then 120 mg for 3 days) to reduce vascular headache risk. Exercise tests were performed as scheduled, with patients abstaining from sublingual nitroglycerin, food, tobacco, alcohol, and caffeine for at least 3 hours before testing. Safety was evaluated via patient-reported adverse events, clinical observations, and laboratory tests. Statistical analysis used analysis of variance for continuous variables and chi-square or Fisher's exact test for categorical variables, with pairwise comparisons between active treatment and placebo groups to assess efficacy, and repeated-measurement models to evaluate nitrate tolerance.

Inhibitory Effects of Isosorbide Mononitrate on Angiogenesis, Tumor Growth and Metastasis

Pipili-Synetos, Eva, et al. British Journal of Pharmacology 116 (1995): 1829-1834

This study investigated the antiangiogenic, antitumor and antimetastatic effects of isosorbide mononitrate (ISMN), a nitric oxide (NO)-releasing vasodilator, using chick chorioallantoic membrane (CAM) angiogenesis model and Lewis Lung carcinoma (LLC)-bearing mice model, with isosorbide dinitrate (ISDN) as a control. In the CAM model, ISMN (25-210 nmol/disc) dose-dependently inhibited basal angiogenesis, with an inhibition rate ranging from 3.7%-37.4% of the control, and was more potent than ISDN (11.7%-22.3% inhibition). Both ISMN and ISDN (210 nmol/disc) completely reversed the angiogenic effect of α-thrombin. In LLC-bearing C57BL mice, daily intraperitoneal injection of 200 μg/animal ISMN for 14 days significantly reduced the size of primary tumors (1.4±0.14 cm³ vs. 3.3±0.31 cm³ in control, P<0.01) and the number of pulmonary metastatic foci (0.70±0.25 foci/animal vs. 2.25±0.42 foci/animal in control, P<0.01). Increasing the daily dose to 600 μg/animal weakened the antitumor effect. Neither ISMN nor ISDN affected the proliferation of bovine, human endothelial cells or LLC cells in vitro. These studies demonstrate that ISMN inhibits angiogenesis, tumor growth and metastasis in animal models, and its effects are independent of direct inhibition of endothelial cell or tumor cell proliferation, possibly mediated by NO release.
The in vivo effects of ISMN were verified through multiple experimental models. For the CAM assay, fresh fertilized eggs were incubated for 9 days, and sterile discs loaded with ISMN, vehicle and [U-¹⁴C]-labelled proline were placed on the CAM, followed by biochemical evaluation of collagenous protein biosynthesis and morphological counting of blood vessels on day 11. For the animal tumor study, 6-8 week old male C57BL mice were subcutaneously inoculated with 2×10⁶ LLC cells, and 48 hours later received daily intraperitoneal injections of ISMN or vehicle for 14 days. Tumor size was measured with a microvernier, and lung metastatic foci were counted after hematoxylin-eosin staining. NO release from CAM tissue in vitro was detected by chemiluminescence. Cell proliferation assays were performed on endothelial cells and LLC cells with bFGF stimulation, and cell counts were obtained with a Coulter particle counter after 6 days of culture. Statistical analysis was performed using Student's paired or unpaired t test.

Effects of Isosorbide Mononitrate on Pulse Wave Reflection and Blood Pressure in Elderly Patients with Refractory Systolic Hypertension

Stokes, Gordon S., et al. Hypertension 41.2 (2003): 297-301

This study investigated the effects of extended-release isosorbide mononitrate (ISMN) on aortic pulse wave contour and blood pressure in elderly patients with refractory isolated systolic hypertension (ISH), comparing it with angiotensin II (AII) inhibitors (eprosartan and captopril) through two double-blind, randomized, placebo-controlled crossover trials. A total of 16 elderly patients (59-82 years old) with systolic blood pressure 150-200 mm Hg and diastolic blood pressure ≤100 mm Hg were enrolled. Group 1 (11 patients) received single doses of placebo, 60 mg ISMN, 600 mg eprosartan, and 25 mg captopril on separate study days; Group 2 (6 patients) on baseline AII inhibitor therapy received single doses of 60 mg ISMN and placebo. Brachial blood pressure was measured by sphygmomanometry, and aortic pulse wave components were assessed by radial artery applanation tonometry. Results showed that ISMN significantly reduced aortic systolic blood pressure (nadir decrease of 34 mm Hg, P<0.001) and aortic pulse pressure (decrease of 29 mm Hg, P<0.001) in Group 1, with effects more pronounced and prolonged than eprosartan and captopril. Augmentation index (a measure of pulse wave reflection) was decreased by approximately 50% with ISMN (P<0.0001) in both groups, while eprosartan and captopril had no significant effect on this index. ISMN also significantly lowered sitting and standing brachial systolic blood pressure with minor effects on diastolic blood pressure and heart rate. These studies demonstrate that ISMN effectively reduces systolic blood pressure and improves exaggerated pulse wave reflection in refractory ISH, with a mechanism distinct from AII inhibitors.
The in vivo effects of ISMN were verified through standardized measurements and crossover study designs. In both groups, study drugs or placebo were administered in the morning, with blood pressure and pulse wave measurements taken hourly from 8:00 AM to 4:00 PM. Aortic pulse waveform was mathematically derived from radial tonometry data, and augmentation index was calculated as the percentage of augmentation pressure to pulse pressure. Statistical analysis was performed using repeated-measures ANOVA and post hoc paired t tests to compare treatment effects. Group 1 excluded baseline AII inhibitor use to isolate drug effects, while Group 2 evaluated ISMN's efficacy in combination with chronic AII inhibition. All patients maintained stable baseline antihypertensive therapy throughout the study, and study days were separated by 1-2 weeks to avoid carry-over effects.