Isosorbide Dinitrate

證據等級: L5

預測適應症: 10 個

Isosorbide Dinitrate: From Angina Pectoris to Vascular Disease

One-Sentence Summary

Isosorbide dinitrate (ISDN) is a long-established organic nitrate vasodilator, classically deployed for angina pectoris, acute coronary syndromes, and congestive heart failure. The TxGNN model predicts it may be effective for Vascular Disease — a broad category spanning coronary artery disease, peripheral vascular disease, and cerebral small vessel disease — with multiple Phase 2–4 clinical trials and over 20 publications spanning four decades supporting this direction. This prediction closely aligns with ISDN’s established pharmacology and represents both a confirmation of its core application and a genuine extension into emerging vascular disease subtypes.

Note on TxGNN ranking: The top-ranked TxGNN prediction in this Evidence Pack is alopecia (rank 1, score 99.99%), followed by several hair-loss-related conditions (ranks 2, 3, 5, 7). All of these carry zero supporting clinical trials or literature, and the mechanistic rationale is implausible — most likely a knowledge graph topology artifact where alopecia and vascular disease nodes are topologically adjacent. This report therefore focuses on Vascular Disease (rank 6, score 99.97%), which has the highest evidence level (L2) and the most actionable recommendation in this Evidence Pack.

Quick Overview

Item	Content
Original Indication	Angina pectoris / Congestive heart failure (not registered in the Philippines; based on established pharmacology)
Predicted New Indication	Vascular Disease
TxGNN Prediction Score	99.97%
Evidence Level	L2
Philippines Market Status	✗ Not Marketed
Number of Registrations	0
Recommended Decision	Proceed with Guardrails

Why is This Prediction Reasonable?

Currently, detailed mechanism of action data is not available in this evidence pack (DrugBank API query flagged as a data gap). Based on well-established published evidence, isosorbide dinitrate is an organic nitrate that acts as a nitric oxide (NO) donor. It undergoes enzymatic denitration in vascular smooth muscle cells, releasing NO, which activates soluble guanylyl cyclase, raises cyclic GMP, and causes smooth muscle relaxation. At therapeutic doses, the predominant effect is venodilation (preload reduction); at higher doses, arterial dilation (afterload reduction) and coronary vasodilation also occur. ISDN additionally inhibits platelet aggregation through NO/cGMP-mediated pathways, improving microvascular perfusion.

The broad category of “vascular disease” maps directly onto ISDN’s established clinical territories: coronary artery disease, angina pectoris, acute decompensated heart failure, hypertensive emergencies, and peripheral vascular disease. The mechanistic link is straightforward — NO-mediated vasodilation reduces ischemic burden and endothelial dysfunction across the entire vascular tree, regardless of the specific anatomical site affected. This makes the TxGNN prediction mechanistically sound rather than speculative.

Beyond confirming established use, the evidence retrieved in this pack also highlights genuinely novel applications: topical ISDN spray for diabetic foot ulcers (exploiting local vasodilation to promote wound healing), isosorbide mononitrate for cerebral small vessel disease (LACI-2 trial), and the fixed-dose ISDN/hydralazine combination (BiDil) specifically indicated for heart failure in African Americans. These applications demonstrate that ISDN’s mechanism can be extended into new patient populations and delivery routes — representing true repurposing beyond the classic angina indication.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrollment	Key Findings
NCT03451591	Phase 2/3	Completed	363	LACI-2 trial: assessed safety and efficacy of cilostazol and isosorbide mononitrate to prevent recurrent lacunar stroke and progression of cerebral small vessel disease
NCT00803634	Phase 3	Completed	117	PRONTO study: IV clevidipine vs standard-of-care antihypertensives (including ISDN) for blood pressure control in acute heart failure with elevated BP
NCT02789033	Phase 3	Completed	68	Efficacy of ISDN spray combined with chitosan for diabetic foot ulcers — evaluating topical vasodilation as an adjunct wound healing strategy
NCT04661709	Phase 4	Unknown	502	Double-blind RCT: Wen Xin Granules vs ISDN (active control) for unstable angina pectoris with Yang deficiency and blood stasis syndrome
NCT06715007	N/A	Recruiting	300	Antiplatelet therapy and endothelial-stabilizing agents (including isosorbide mononitrate) for cerebral small vessel disease — ongoing
NCT02305095	N/A	Completed	225	Genomic analysis of enhanced response to fixed-dose ISDN/hydralazine in African Americans with HFrEF; GNB3 polymorphism (C825T) as potential predictor of therapeutic efficacy
NCT02228408	Phase 4	Completed	17	Pilot RCT: hydralazine/ISDN vs placebo — safety and cardiovascular effects (cardiac structure, function, blood flow) in hemodialysis-dependent ESRD patients
NCT01513070	Phase 4	Completed	120	Quick-Acting Heart Reliever vs ISDN for 6 months in moderate coronary stenosis — assessed plaque, myocardial perfusion, quality of life, and hard endpoints
NCT02481323	Phase 2	Completed	57	LACI pilot: tolerability and safety of cilostazol and/or isosorbide mononitrate in symptomatic small subcortical stroke — dose escalation design
NCT00000478	Phase 3	Completed	N/A	ACIP study: tested feasibility and methodology for therapies targeting asymptomatic cardiac ischemia — foundational multi-arm trial

Literature Evidence

PMID	Year	Type	Journal	Key Findings
36219567	2023	RCT	Stroke and Vascular Neurology	LACI-2 statistical analysis plan: isosorbide mononitrate for prevention of cerebral SVD progression; targets vascular dementia and lacunar stroke recurrence
29682995	2018	RCT	Diabetes & Vascular Disease Research	Double-blind RCT: topical ISDN spray + chitosan gel shows additive benefit for healing diabetic foot ulcers through local NO-mediated vasodilation
3325229	1987	Comparative Clinical Trial	Current Medical Research and Opinion	Multi-centre study (200 patients): ISDN retard vs isosorbide-5-mononitrate — both reduced anginal attack frequency and sublingual nitrate consumption in coronary heart disease
1969017	1990	Clinical Study	Lancet	ISDN + prostaglandin E1 synergy: reduced platelet deposition and improved platelet survival time in patients with peripheral vascular disease
2113003	1990	Review	European Journal of Clinical Pharmacology	Comprehensive review of nitrates (including ISDN) for angina and myocardial ischemia; venodilatation as primary mechanism; role in coronary dilation and eccentric lesions
1576038	1992	Review	AACN Critical Care Nursing	Nitrates across multiple cardiovascular conditions: angina, heart failure, cardiogenic shock, hypertensive episodes, portal hypertension — clinical monitoring requirements
30687454	2018	Preclinical	Oxidative Medicine and Cellular Longevity	Macitentan (dual ET receptor antagonist) counteracts ISDN/ISMN-induced endothelial dysfunction, oxidative stress, and vascular inflammation — insight into nitrate tolerance management
1094819	1975	Hemodynamic Study	American Heart Journal	Placebo-controlled double-blind study: oral ISDN (10 mg) improves cardiac performance at rest and during supine exercise in angiographically confirmed significant CAD
9951954	1999	Review	Drugs	Long-acting isosorbide mononitrate (Elantan): controlled-release pharmacokinetics, quick onset (30 min), once-daily antianginal dosing, comparative efficacy data
3925742	1985	Review	American Heart Journal	Nitrate tolerance: develops within 24 hours, reversed within 21 hours of withdrawal; cross-tolerance between ISDN and nitroglycerin; clinical implications for dosing intervals

Safety Considerations

Please refer to the package insert for safety information.

Conclusion and Next Steps

Decision: Proceed with Guardrails

Rationale: Multiple Phase 2–4 clinical trials and decades of published literature confirm ISDN’s efficacy across a broad spectrum of vascular disease subtypes. The LACI-2 trial (Phase 2/3, 363 patients, completed) provides the strongest single piece of evidence for a genuinely new application — cerebral small vessel disease — while the diabetic foot ulcer RCT demonstrates an innovative topical delivery route. The vascular disease prediction from TxGNN is mechanistically sound, clinically credible, and well-supported by evidence. However, the drug carries zero Philippines regulatory registration, and critical safety data are absent from this evidence pack.

To proceed, the following is needed:

Philippines FDA registration pathway: ISDN currently has 0 registered products in the Philippines. A new drug application, compassionate use protocol, or parallel importation pathway must be identified before any clinical deployment
Complete MOA and toxicity data: Re-run DrugBank API query for DB00883 to retrieve pharmacodynamics, drug categories, and toxicity profile (currently flagged as Data Gap)
Safety review: Obtain TFDA (or equivalent regulatory) package insert warnings, precautions, and contraindications — no safety data was retrieved in this Evidence Pack
DDI profile: Drug-drug interaction query returned zero results; a manual review of known ISDN interactions (particularly with phosphodiesterase-5 inhibitors, antihypertensives, and other vasodilators) is required before any clinical use recommendation
Target indication specificity: “Vascular disease” is a broad category — clinical teams should define the specific target (cerebral SVD, diabetic foot ulcers, heart failure in specific ethnic populations, or another subtype), as each requires a different formulation, dosing regimen, and monitoring protocol
Route-of-administration decision: Confirm whether oral, sublingual, IV, or topical ISDN is under consideration; evidence quality and safety profile differ substantially by route
Disclaimer

This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.