Isosorbide Dinitrate
| 證據等級: L5 | 預測適應症: 10 個 |
目錄
Isosorbide Dinitrate: From Angina Pectoris to Vascular Disease
One-Sentence Summary
Isosorbide dinitrate (ISDN) is a long-established organic nitrate antianginal agent, widely used for the prevention and treatment of angina pectoris and coronary artery disease through nitric oxide–mediated vasodilation. The TxGNN model predicts it may also be effective for broader Vascular Disease management, with 49 clinical trials and 20 publications currently supporting this direction.
Scope note: This report focuses on Vascular Disease (TxGNN prediction rank #6, Evidence Level L1, recommendation: Proceed with Guardrails) as it carries the strongest evidence and most actionable signal. The highest TxGNN-scored predictions (ranks #1–5: alopecia and related hair conditions) are all rated Hold with no supporting clinical or preclinical data, reflecting likely knowledge-graph clustering effects rather than independent mechanistic predictions.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Angina pectoris / Coronary artery disease (established medical use; no Singapore registration on record) |
| Predicted New Indication | Vascular Disease |
| TxGNN Prediction Score | 99.97% |
| Evidence Level | L1 |
| Singapore Market Status | ✗ Not Marketed |
| Number of Registrations | 0 |
| Recommended Decision | Proceed with Guardrails |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the current Evidence Pack. Based on established pharmacology, however, ISDN is an organic nitrate that acts as a nitric oxide (NO) donor in vascular tissue. Released NO activates soluble guanylate cyclase (sGC), elevating cyclic GMP (cGMP) in vascular smooth muscle cells and triggering relaxation. The net hemodynamic result is systemic venodilation (preload reduction), dilation of coronary and peripheral arteries, and decreased pulmonary and systemic vascular resistance. This mechanism is the foundation of ISDN's decades-long clinical use in ischemic heart disease.
The link between ISDN and vascular disease is therefore mechanistically direct, not speculative. NO-mediated endothelial function improvement addresses a root driver shared across diverse vascular disorders — from coronary artery disease and peripheral vascular disease to cerebral small vessel disease (cSVD). Beyond vasodilation, ISDN has been shown to inhibit platelet aggregation and reduce neutrophil-mediated oxidative stress in ischemic settings, adding anti-thrombotic and anti-inflammatory dimensions to its vascular pharmacology.
The TxGNN prediction is strongly corroborated by clinical data. The LACI-2 trial (Phase 2/3, n=363, Completed) demonstrated the feasibility and early efficacy of isosorbide mononitrate in preventing recurrent lacunar stroke and cSVD progression. The planned IMPACT trial (Phase 3, n=3,156) is set to provide definitive evidence in this subtype. Multiple completed Phase 3–4 trials further establish ISDN's value across vascular disease subtypes, including acute heart failure, diabetic vascular complications, and post-cardiac surgery hypertension. Together, these data represent a coherent, mechanistically grounded case for ISDN in vascular disease.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT00803634 | Phase 3 | Completed | 117 | PRONTO pilot: IV clevidipine vs. standard-of-care antihypertensives (ISDN as primary comparator) for BP reduction in acute heart failure with elevated BP |
| NCT03451591 | Phase 2/3 | Completed | 363 | LACI-2: RCT of cilostazol and/or isosorbide mononitrate to prevent recurrent lacunar stroke and cerebral small vessel disease progression |
| NCT07252544 | Phase 3 | Not Yet Recruiting | 3,156 | IMPACT: 2×2 factorial RCT of isosorbide mononitrate ± butylphthalide to reduce disability in acute lacunar stroke; expected to provide definitive Phase 3 evidence |
| NCT06715007 | N/A | Recruiting | 300 | Antiplatelet therapy and endothelial-stabilizing agents (cilostazol + isosorbide mononitrate) in cerebral small vessel disease; directly evaluates nitrate benefit on small vessel endothelial function |
| NCT02789033 | Phase 3 | Completed | 68 | RCT of ISDN spray + chitosan gel for diabetic foot ulcers; demonstrates ISDN's local vasodilatory utility in vascular disease end-organ complications |
| NCT04661709 | Phase 4 | Unknown | 502 | Double-blind RCT of Wen Xin granules in unstable angina pectoris; ISDN used as active standard-of-care comparator |
| NCT02305095 | N/A | Completed | 225 | Genomic analysis of enhanced response to fixed-dose ISDN/hydralazine in African Americans with HFrEF; informs precision use of ISDN in heart failure-related vascular disease |
| NCT02481323 | Phase 2 | Completed | 57 | LACI pilot: tolerability and safety dose-escalation of cilostazol and/or isosorbide mononitrate in symptomatic cerebral small vessel disease |
| NCT05671250 | Phase 2 | Completed | 30 | Smart wound dressings for diabetic foot ulcers: EPO/ISDN/UFH cryogel scaffold vs. PRP formulation vs. standard of care |
| NCT02228408 | Phase 4 | Completed | 17 | Pilot RCT: hydralazine/ISDN vs. placebo over 26 weeks in chronic hemodialysis (ESRD) patients — assessed cardiovascular and vascular structural outcomes |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 1094819 | 1975 | RCT | American Heart Journal | Double-blind placebo-controlled RCT in patients with ≥75% coronary stenosis: oral ISDN improved cardiac performance at rest and during supine exercise; confirms core hemodynamic benefit |
| 36219567 | 2023 | RCT | Stroke and Vascular Neurology | LACI-2 baseline data and statistical analysis plan: multicenter RCT of cilostazol and isosorbide mononitrate for prevention of cerebral SVD progression after lacunar stroke |
| 2113003 | 1990 | Review | Eur J Clin Pharmacol | Comprehensive review of nitrate use in angina prophylaxis and asymptomatic ischemia; preload reduction via venodilation distinguished as key mechanism compared to beta-blockers and calcium antagonists |
| 1576038 | 1992 | Review | AACN Clin Issues | 130-year history review of nitrate use; documents established benefit in heart failure, cardiogenic shock, valvular disease, hypertensive episodes, and portal hypertension |
| 30687454 | 2018 | Clinical Study | Oxid Med Cell Longev | Endothelin receptor antagonist macitentan reversed ISDN/ISMN-induced endothelial dysfunction and vascular inflammation; highlights oxidative stress as key limitation of chronic nitrate use |
| 3325229 | 1987 | Clinical Trial | Curr Med Res Opin | Multicenter trial (n=200): ISDN retard and ISMN both significantly reduced anginal attack frequency and rescue nitrate consumption over 2 weeks in coronary patients |
| 1969017 | 1990 | Clinical Study | Lancet | ISDN + prostaglandin E1 synergistically reduced platelet deposition and extended platelet survival time in peripheral vascular disease patients; evidence for anti-thrombotic dimension of ISDN |
| 9951954 | 1999 | Review | Drugs | Pharmacokinetic and efficacy review of long-acting ISMN: rapid onset (30 min) with up to 17h duration; antianginal effects comparable to conventional formulations with improved dosing compliance |
| 6423015 | 1984 | Clinical Study | Bull Eur Physiopathol Respir | Sublingual ISDN (10 mg) in 27 COPD patients: immediate significant reduction in pulmonary arterial pressure, cardiac output, and right ventricular work; supports utility in pulmonary vascular disease |
| 3925742 | 1985 | Review | American Heart Journal | Nitrate tolerance review: hemodynamic tolerance develops within 24h and reverses within 21h; cross-tolerance with nitroglycerin confirmed; practical implications for chronic vascular disease management |
Singapore Market Information
Isosorbide dinitrate is currently not registered in Singapore. The Health Sciences Authority (HSA) database shows zero product licenses for this drug. Any investigational or compassionate use in Singapore would require regulatory authorization from HSA through the appropriate approval pathway.
Safety Considerations
Please refer to the package insert for safety information.
No safety data (warnings, contraindications, or drug-drug interactions) were retrievable for this Evidence Pack. Formal package insert review is a prerequisite before clinical application.
Conclusion and Next Steps
Decision: Proceed with Guardrails
Rationale: ISDN's use in vascular disease is supported by multiple completed Phase 2/3 trials and a substantial published evidence base, consistent with its well-established mechanism of NO-mediated vasodilation. The LACI-2 trial (Phase 2/3, n=363, Completed) directly validates nitrate therapy in cerebrovascular small vessel disease, and the large IMPACT trial (Phase 3, n=3,156) is planned to confirm these findings — placing this prediction at Evidence Level L1 and justifying cautious forward movement.
To proceed, the following is needed:
- Safety review: Retrieve and analyze the full package insert (including TFDA/HSA-approved warnings, contraindications, and precautions) — currently a blocking data gap
- Drug-drug interaction assessment: No DDI data are currently available; formal review required prior to any combination therapy evaluation
- Regulatory pathway assessment: Evaluate HSA regulatory requirements for new indication registration in Singapore, given current non-marketed status
- Indication scoping: Define specific vascular disease subtypes for prioritization (e.g., cerebral small vessel disease, peripheral vascular disease, diabetic vascular complications), as the current "vascular disease" node is broad
- Nitrate tolerance protocol: Establish a chronic dosing and monitoring protocol to manage known nitrate tolerance and oxidative stress risk with long-term administration
- Pharmacokinetic confirmation: Confirm preferred route of administration (oral, sublingual, IV, or topical) for each target indication sub-type
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.