Adenosine

證據等級: L5

預測適應症: 10 個

Adenosine: From Supraventricular Tachycardia to Open-Angle Glaucoma

One-Sentence Summary

Adenosine is a naturally occurring purine nucleoside with well-established clinical use in terminating paroxysmal supraventricular tachycardia (SVT) via rapid intravenous bolus, acting through A1 receptor-mediated AV nodal conduction blockade. The TxGNN model predicts it may be effective for Open-Angle Glaucoma, with 5 clinical trials (including 1 completed Phase 3) and 20 publications currently supporting this direction. Although Adenosine is not currently registered in Singapore, its selective A1 receptor analogue Trabodenoson has already completed a full clinical development programme through Phase 3 for this indication, providing direct pathway validation.

Quick Overview

Item	Content
Original Indication	Paroxysmal supraventricular tachycardia (SVT) — first-line acute IV termination agent
Predicted New Indication	Open-Angle Glaucoma (Primary Open-Angle Glaucoma / Ocular Hypertension)
TxGNN Prediction Score	95.11%
Evidence Level	L2
Singapore Market Status	Not Marketed
Number of Registrations	0
Recommended Decision	Proceed with Guardrails

Why is This Prediction Reasonable?

Adenosine is an endogenous purine nucleoside that exerts its biological effects through four G-protein-coupled receptors: A1, A2A, A2B, and A3. In cardiac tissue, A1 receptor activation via Gi-protein coupling suppresses adenylyl cyclase, lowers intracellular cAMP, and slows AV node conduction — the established mechanism behind its use in terminating SVT. Detailed mechanism of action data from DrugBank was not available in this evidence pack, but the receptor pharmacology of adenosine is extensively characterised in the peer-reviewed literature.

The mechanistic bridge to open-angle glaucoma is biologically coherent. In the trabecular meshwork (TM) — the primary site of conventional aqueous humour outflow — A1 receptor activation engages the same Gi signalling cascade, triggering F-actin cytoskeletal reorganisation and matrix metalloproteinase-2 (MMP-2) activation. This remodels the extracellular matrix of the TM and increases outflow facility through the conventional (trabecular) drainage pathway, thereby reducing intraocular pressure (IOP). Separately, the A3 receptor is selectively upregulated in TM tissue under oxidative stress conditions associated with POAG (PMID 33987224), raising the possibility of complementary neuroprotective effects beyond IOP lowering. The purinergic axis is further implicated by direct measurement: aqueous humour ATP concentrations are significantly elevated in POAG patients (PMID 33963197), where extracellular ATP is rapidly dephosphorylated to adenosine, amplifying endogenous adenosine receptor signalling at the disease site.

The single most compelling piece of evidence is the complete clinical development programme for Trabodenoson (INO-8875), a selective adenosine A1 receptor-mimetic. This progressed from Phase 1/2 (NCT01123785, n=144, completed) through two Phase 2 studies to a completed Phase 3 trial (NCT02565173, n=303) and an ongoing Phase 3 (NCT05405868, n=496, recruiting). Although the completed Phase 3 monotherapy trial did not meet its primary IOP-lowering endpoint, it conclusively establishes that the adenosine A1 pathway is biologically active in the human trabecular meshwork and can be safely targeted pharmacologically. A critical practical constraint for Adenosine itself is its plasma half-life of under 10 seconds after intravenous administration; an ophthalmic topical formulation, prodrug strategy, or structural analogue approach would be necessary for any sustained ocular application.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrollment	Key Findings
NCT02565173	Phase 3	Completed	303	Trabodenoson 3.0%, 6.0% QD or 4.5% BID vs timolol 0.5% BID vs placebo over 12 weeks in OHT/POAG — highest-evidence adenosine A1 pathway RCT; primary IOP endpoint not met with monotherapy, providing critical learning on dosing and patient selection
NCT05405868	Phase 3	Recruiting	496	Nicotinamide to slow visual field loss in open-angle glaucoma (completion June 2027) — active high-enrolment Phase 3 reflecting continued pipeline confidence in neuroprotective approaches to POAG
NCT01123785	Phase 1/2	Completed	144	Trabodenoson (INO-8875) ophthalmic dose-escalation in OHT/POAG — first-in-human adenosine A1 agonist ocular trial; established tolerability, pharmacokinetics, and preliminary IOP-lowering activity
NCT02829996	Phase 2	Completed	201	Trabodenoson + latanoprost fixed-dose combination in OHT/POAG — evaluated combination with a prostaglandin analogue, providing proof-of-concept for adenosine pathway as additive to standard of care
NCT01917383	Phase 2	Completed	101	Trabodenoson added to latanoprost vs timolol in OHT/POAG — validated adenosine A1 pathway as an add-on to prostaglandin therapy with efficacy data that informed Phase 3 sample size calculations

Literature Evidence

PMID	Year	Type	Journal	Key Findings
33405971	2021	Review	Expert Opinion on Investigational Drugs	Comprehensive clinical data review of trabodenoson; confirms A1R adenosine mimetic mechanism via MMP-2 matrix remodelling in trabecular meshwork; Phase 3 candidate positioning for POAG
27002298	2016	Clinical Study	J Ocular Pharmacology & Therapeutics	Dose-escalation of twice-daily trabodenoson over 14–28 days; established safety profile and documented statistically significant IOP reductions across multiple dose levels
33987224	2021	Translational	Annals of Translational Medicine	Bioinformatic analysis identifies A3 adenosine receptor activation under H₂O₂ oxidative stress in POAG trabecular meshwork — dual A1/A3 receptor involvement in disease pathophysiology
28356898	2017	Review	Yale Journal of Biology & Medicine	Comprehensive review of novel pharmacologic candidates for POAG; adenosine receptor agonists classified as a distinct emerging mechanistic class alongside Rho-kinase inhibitors and nitric oxide donors
28480761	2017	Review	Expert Opinion on Pharmacotherapy	Topical glaucoma pharmacology review; adenosine A1 receptor stimulation of trabecular meshwork explicitly cited as a novel outflow-enhancing mechanism distinct from existing classes
29965902	2018	Review	Journal of Glaucoma	Medical management of exfoliation glaucoma; adenosine α1-receptor stimulation grouped alongside Rho-kinase inhibition and NO signalling as recently approved or investigational trabecular-targeting agents
33963197	2021	Metabolomics / Observational	Scientific Reports	Elevated ATP in aqueous humour of POAG patients alongside cytokine dysregulation and metabolic remodelling — directly implicates the purinergic (ATP→adenosine) signalling axis in POAG pathobiology
15914619	2005	Translational	Investigative Ophthalmology & Visual Science	Selective upregulation of A3 adenosine receptor in anterior segment tissues of eyes with pseudoexfoliation syndrome and glaucoma — confirms adenosine receptor system is pathophysiologically relevant across glaucoma subtypes
37525172	2023	Animal Study	Journal of Neuroinflammation	ATP-P2X7R signalling mediates microglial senescence and retinal ganglion cell death in chronic ocular hypertension — demonstrates that the broader extracellular purinergic axis (including adenosine) participates in glaucomatous neurodegeneration
28076854	2017	Review	Ophthalmic Research	20-year (1995–2015) POAG drug development pipeline analysis; adenosine pathway agents identified among the most mechanistically promising emerging categories entering clinical evaluation

Singapore Market Information

Adenosine (DrugBank: DB00640) is currently not registered in Singapore. No product licences from the Health Sciences Authority (HSA) were identified in this analysis. The drug has zero active market authorisations on file, meaning it is unavailable through licensed commercial channels in Singapore.

This is notable because intravenous adenosine formulations for SVT are widely available and used in many other markets (including the United States, European Union, and Taiwan). The absence of Singapore registration may reflect a gap in market access rather than a safety or efficacy concern. Any future clinical use in Singapore — including a potential ophthalmic formulation for glaucoma — would require a full HSA regulatory submission and approval prior to use.

Safety Considerations

Safety data specific to Adenosine (warnings, contraindications, and drug interactions) was not retrieved in this evidence pack. Please refer to the package insert and available product information for complete safety guidance.

For context based on established pharmacology:

Cardiovascular effects of IV adenosine: Transient AV block, sinus bradycardia, chest tightness, flushing, and hypotension are well-documented with intravenous administration. These effects resolve within seconds due to the extremely short plasma half-life.
Route-specific risk: A topical ophthalmic formulation (as would be required for glaucoma) would have minimal systemic absorption and an expected markedly different safety profile compared to IV use.
Bronchospasm risk: Intravenous adenosine is contraindicated in asthma — this would require evaluation in any ophthalmic context.
Drug interactions: Formal DDI data was not available. The interaction with dipyridamole (a potent adenosine reuptake inhibitor that markedly potentiates adenosine effects) is a known concern for IV use.

Conclusion and Next Steps

Decision: Proceed with Guardrails

Rationale: The adenosine A1 receptor pathway has been subjected to a rigorous and complete clinical development programme in POAG, with four completed clinical trials (Phase 1/2 through Phase 3) directly validating the biological mechanism and establishing human safety data. While the Phase 3 monotherapy endpoint was not met by trabodenoson, the pathway remains biologically justified and clinically active, evidenced by an ongoing Phase 3 trial (n=496) and a robust mechanistic and translational literature base. Adenosine itself cannot be used in unmodified form due to its near-instantaneous plasma elimination, making formulation innovation the critical enabler.

To proceed, the following is needed:

Formulation strategy: Define whether the development path uses Adenosine with a topical ophthalmic delivery system (e.g., sustained-release hydrogel, pro-drug) or pivots to a selective A1/A3 receptor agonist analogue that overcomes the half-life limitation
Phase 3 failure analysis: Obtain and review trabodenoson Phase 3 (NCT02565173) full clinical study report to determine whether the primary endpoint miss was due to dosing, patient selection, formulation, or a fundamental pathway limitation — this is essential before committing further resources
Mechanism of action data: Retrieve full DrugBank MOA and pharmacology profile to complete the mechanistic narrative and support regulatory submissions
Singapore regulatory pathway: Initiate HSA pre-submission consultation, as Adenosine is currently unregistered in Singapore; any future glaucoma formulation would require a de novo NDA/NDA-equivalent submission
Safety package: Obtain formal contraindications and DDI data, with particular attention to interactions with prostaglandin analogues (latanoprost, bimatoprost), beta-blockers (timolol), and alpha-agonists — all standard-of-care POAG medications that patients would likely be concurrently using
Ongoing trial monitoring: Track NCT05405868 (Phase 3, completing June 2027) for any results relevant to the broader adenosine neuroprotection hypothesis in glaucoma
Disclaimer

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