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 well-established organic nitrate used globally for over 60 years to treat angina pectoris and heart failure, but currently not registered in India. The TxGNN model predicts it may be effective for Vascular Disease — encompassing coronary artery disease, acute heart failure, and cerebral small vessel disease — with multiple completed Phase 3 clinical trials and 20 publications supporting this direction. With a TxGNN prediction score of 99.97% and an evidence level of L1, this represents the strongest actionable repurposing signal in this analysis.

Quick Overview

Item	Content
Original Indication	Angina pectoris / Heart failure (globally established; no Indian registration on record)
Predicted New Indication	Vascular Disease
TxGNN Prediction Score	99.97%
Evidence Level	L1
India Market Status	✗ Not Marketed
Number of Registrations	0
Recommended Decision	Proceed with Guardrails

Note on prediction selection: The TxGNN model’s highest-ranked predictions by score (Ranks 1–5: alopecia-related conditions and pulmonary hypertension) carry L5 or L3 evidence levels and have no or limited clinical trial data. Vascular Disease (TxGNN model score rank 1,018) is selected as the primary repurposing focus because it has the strongest clinical evidence and the most actionable regulatory pathway for Indian market introduction.

Why is This Prediction Reasonable?

Currently, detailed mechanism of action data is not available in this Evidence Pack. Based on established pharmacology, isosorbide dinitrate is an organic nitrate that acts as a prodrug for nitric oxide (NO). In vascular smooth muscle, NO activates guanylyl cyclase, raising cGMP levels and causing smooth muscle relaxation. This produces three complementary effects: (1) venous dilation that reduces cardiac preload, (2) arterial dilation that lowers afterload, and (3) direct coronary artery dilation that improves myocardial oxygen delivery. These actions explain ISDN’s foundational role in managing ischemic and congestive cardiac conditions.

These mechanisms map directly onto the pathophysiology of multiple vascular disease subtypes. In coronary artery disease and angina, ISDN reduces myocardial oxygen demand while improving perfusion — an approach validated across decades of clinical trials. In acute decompensated heart failure, the combined preload and afterload reduction relieves pulmonary congestion and improves cardiac output. A newer and important repurposing direction is cerebral small vessel disease (lacunar stroke): NO-mediated endothelial protection may slow progressive ischemic injury in small cerebral arteries, a hypothesis now being tested in dedicated Phase 2/3 RCTs (LACI-2 programme). The secondary prediction of pulmonary hypertension (L3 evidence, 20 publications) also carries mechanistic plausibility — NO-mediated pulmonary vascular dilation can reduce pulmonary vascular resistance — though systemic hypotension risk limits selectivity.

Critically, ISDN is not currently registered in India despite a robust, decades-long international evidence base. India carries a significant burden of coronary artery disease, heart failure, and cerebrovascular disease — all conditions for which ISDN has documented clinical benefit. Introducing this drug represents a regulatory repurposing opportunity rather than a purely scientific one: the science is established globally, and the gap is market access.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrollment	Key Findings
NCT00803634	Phase 3	Completed	117	PRONTO trial: IV ISDN as standard-of-care comparator against clevidipine for blood pressure control in acute heart failure with elevated BP — highest-grade direct ISDN evidence in this dataset
NCT03451591	Phase 2/3	Completed	363	LACI-2: cilostazol + isosorbide mononitrate vs placebo for lacunar stroke and cerebral small vessel disease prevention — signals a new cerebrovascular repurposing direction for nitrates
NCT02135315	N/A	Completed	1,500	Intensive vs standard BP control in NSTE-ACS; ISDN included as part of standard care — large real-world outcome dataset supporting routine vascular disease use
NCT02481323	Phase 2	Completed	57	Isosorbide mononitrate ± cilostazol for cerebral small vessel disease: safety, tolerability, and cognitive endpoint pilot — new repurposing signal with completed data
NCT02228408	Phase 4	Completed	17	Hydralazine/ISDN combination vs placebo in hemodialysis-dependent ESRD: 26-week safety and cardiovascular effects — relevant to high-risk renal population
NCT01513070	Phase 4	Completed	120	ISDN vs TCM formula (Quick-Acting Heart Reliever) in moderate coronary stenosis: 6-month anginal frequency, plaque assessment, and quality-of-life outcomes
NCT02789033	Phase 3	Completed	68	Phase 3 RCT: topical ISDN spray + chitosan gel in diabetic foot ulcers — peripheral vascular disease application, demonstrates local vasodilation benefit
NCT03072121	Phase 4	Unknown	440	Coronary artery disease not amenable to revascularization; ISDN as active comparator/combination component against Shexiang Baoxin Pill
NCT04661709	Phase 4	Unknown	502	Unstable angina pectoris double-blind RCT; ISDN as standard-of-care comparator — large active-controlled evidence base
NCT00000478	Phase 3	Completed	N/A	ACIP study: asymptomatic cardiac ischemia pilot — foundational Phase 3 trial establishing ISDN therapy methodology in silent ischemia

Literature Evidence

PMID	Year	Type	Journal	Key Findings
3325229	1987	Comparative RCT	Current Medical Research and Opinion	Multi-centre RCT (n=200 coronary patients): ISDN retard vs isosorbide-5-mononitrate — comparable reduction in weekly anginal attack frequency and rescue nitrate consumption
1094819	1975	Placebo-controlled	American Heart Journal	Double-blind study: oral ISDN 10 mg significantly improved cardiac output at rest and during supine exercise in patients with ≥75% coronary stenosis vs placebo
805037	1975	Clinical Trial	Chest	Chewable ISDN 5 mg vs sublingual NTG during treadmill exercise in 20 patients with documented ischemic heart disease; complete angina relief achieved in all patients despite continued exertion
36219567	2023	RCT	Stroke and Vascular Neurology	LACI-2 statistical analysis plan: isosorbide mononitrate for cerebral SVD — first rigorous RCT design targeting NO-mediated endothelial protection in lacunar stroke prevention
29682995	2018	RCT	Diabetes & Vascular Disease Research	Double-blind RCT: topical ISDN spray + chitosan gel improved diabetic foot ulcer healing outcomes vs standard care alone — demonstrates peripheral vascular efficacy
1576038	1992	Review	AACN Clinical Issues in Critical Care Nursing	Comprehensive 130-year review: nitrates for angina, infarct size limitation, intractable heart failure, cardiogenic shock, severe valve regurgitation, hypertensive episodes, and portal hypertension
9951954	1999	Review	Drugs	Long-acting isosorbide mononitrate: 30-minute onset, up to 17-hour duration, antianginal efficacy comparable to conventional preparations — formulation strategy reference
3925742	1985	Review	American Heart Journal	Nitrate tolerance: demonstrable within 24 hours, reversible within 21 hours of withdrawal, cross-tolerance with nitroglycerin — critical consideration for chronic dosing strategy
1969017	1990	Clinical Study	Lancet	ISDN + prostaglandin E1 synergy in peripheral vascular disease: reduced platelet deposition and improved platelet survival time — mechanistic rationale for combination approaches
30687454	2018	Experimental Study	Oxidative Medicine and Cellular Longevity	Endothelin receptor antagonist macitentan reversed ISDN-induced endothelial dysfunction and vascular oxidative stress in animals — relevant insight for long-term nitrate safety management

India Market Information

Isosorbide dinitrate currently has no registered products in India. This represents a significant market gap, given the drug’s extensive international evidence base and the high prevalence of cardiovascular disease in the Indian population.

Item	Status
Market Status	✗ Not Marketed
Total Registered Products	0
Available Dosage Forms	None on record
Approved Indications	None on record

Safety Considerations

Drug-Drug Interactions (141 total interactions recorded):

The following are the most clinically relevant interactions, particularly in the context of common comorbidities in Indian patients:

Interacting Drug	Level	Clinical Relevance
Canagliflozin	Moderate	SGLT2 inhibitor — additive blood pressure lowering; monitor closely in diabetic patients
Dapagliflozin	Moderate	SGLT2 inhibitor — same class concern; important given high diabetes prevalence in India
Empagliflozin	Moderate	SGLT2 inhibitor — same class concern
Ertugliflozin	Moderate	SGLT2 inhibitor — same class concern
Morphine	Moderate	Additive vasodilation and hypotension; caution in acute coronary syndrome management
Bupropion	Moderate	Monitor blood pressure during concurrent use
Rosiglitazone	Moderate	Thiazolidinedione — additive blood pressure reduction
Sapropterin	Moderate	BH4 cofactor for nitric oxide synthase — potential amplification of NO effect
Dronabinol / Nabilone	Moderate	Cannabinoids — additive hypotension risk
Opium	Moderate	Opioid class — combined vasodilatory and CNS depressant concern
Omeprazole	Minor	Minimal clinical significance

Complete warnings, contraindications, and special population data were not available in this Evidence Pack. Please refer to the reference country package insert (e.g., EMA, US FDA, or UK MHRA labelling for isosorbide dinitrate) for full prescribing information before clinical use.

Conclusion and Next Steps

Decision: Proceed with Guardrails

Rationale: Isosorbide dinitrate carries Level 1 clinical evidence across multiple vascular disease subtypes, including completed Phase 3 trials and 60+ years of global real-world use. India’s high cardiovascular disease burden and the drug’s complete absence from the Indian market create a strong case for formal introduction — provided the regulatory and safety data gaps identified below are resolved.

To proceed, the following is needed:

Safety documentation (blocking): Obtain full package insert or SmPC from a reference regulatory authority (US FDA, EMA, or MHRA); warnings and contraindications are currently unavailable and constitute a blocking data gap
Mechanism of action confirmation: Complete DrugBank API query for DB00883 to formally document MOA for regulatory submission
Regulatory pathway assessment: Determine the appropriate Indian CDSCO pathway — new drug application, reference product approval, or abbreviated route — given the drug’s established global status
DDI risk stratification: Prioritize review of the 141 documented interactions, especially SGLT2 inhibitors (moderate-level interactions), given high co-prescription prevalence in Indian diabetic/cardiovascular patients
Nitrate tolerance management plan: Establish eccentric dosing schedule (nitrate-free interval) to mitigate tolerance development during chronic use
Formulation decision: Determine optimal dosage form (sublingual tablet, oral sustained-release, IV, or topical spray) aligned with target indication and Indian distribution infrastructure
Secondary indication monitoring: Track emerging Phase 2/3 data for cerebral small vessel disease (LACI-2 programme) and pulmonary hypertension (L3 signal with 20 publications) for future label expansion opportunities
Disclaimer

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