Niclosamide

證據等級: L5

預測適應症: 10 個

Niclosamide: From Anthelmintic (Tapeworm Infection) to Heart Disease

One-Sentence Summary

Niclosamide is a WHO Essential Medicine and FDA-approved anthelmintic drug, classically used to treat intestinal tapeworm infections by disrupting parasitic mitochondrial oxidative phosphorylation. The TxGNN model predicts it may be effective for Heart Disease with a score of 99.88%, with 3 registered clinical trials (all withdrawn or terminated before enrollment, yielding zero usable data) and 15 publications retrieved, several of which are animal and human-cell studies directly demonstrating cardioprotective effects.

Quick Overview

Item	Content
Original Indication	Tapeworm infections (anthelmintic)
Predicted New Indication	Heart Disease
TxGNN Prediction Score	99.88%
Evidence Level	L3
India Market Status	✗ Not Marketed
Number of Registrations	0
Recommended Decision	Hold

Why is This Prediction Reasonable?

Niclosamide is a salicylanilide anthelmintic whose classical mechanism kills intestinal cestodes by uncoupling mitochondrial oxidative phosphorylation, collapsing their proton gradient and starving them of ATP. Importantly, this mitochondrial-targeting property does not vanish in human tissues — research over the past decade has revealed that niclosamide also inhibits multiple intracellular signaling pathways that are central to cardiac pathophysiology, including Wnt/β-catenin, STAT3, mTOR/AMPK, and NF-κB.

Three specific mechanistic links to heart disease have been identified in the literature. First, niclosamide modulates TMEM16A (a calcium-activated chloride channel expressed in vascular smooth muscle and cardiac fibroblasts), affecting vascular tone and fibrotic remodeling — though the direction of effect appears context-dependent and warrants caution. Second, inhibition of Wnt/β-catenin reduces adverse cardiac remodeling, a pathway activated after myocardial injury. Third, STAT3 inhibition counters the neurohormonal activation that drives progressive heart failure. The most compelling preclinical evidence comes from PMID 34736968, which demonstrated that niclosamide directly attenuated pressure overload-induced heart failure in mice by enhancing cardiomyocyte mitochondrial respiration and ATP output. Separately, PMID 39515588 showed that niclosamide inhibited osteogenic calcification of human heart valvular interstitial cells via the AMPK/mTOR pathway, with direct relevance to calcific aortic valve disease.

Currently, detailed mechanistic data (MOA) from DrugBank is unavailable due to a data gap. Based on published literature, niclosamide’s multi-pathway inhibitory profile provides a biologically plausible bridge from its anthelmintic origins to cardiac applications, but the absence of any completed clinical trial in cardiac indications means this prediction remains at an exploratory stage.

Clinical Trial Evidence

Important context: The three trials below were retrieved via a Niclosamide + heart disease search. None were specifically designed to treat cardiac indications — they targeted COVID-19 or inflammatory bowel disease. None enrolled patients or generated outcome data.

Trial Number	Phase	Status	Enrollment	Key Findings
NCT04542434	Phase 2	Withdrawn	0	Double-blind RCT for moderate COVID-19 with GI symptoms; withdrawn before any enrollment. No data available. Cardiac relevance is indirect via COVID-19 complications.
NCT04372082	Phase 3	Withdrawn	0	Hydroxychloroquine + Diltiazem + Niclosamide combination for non-severe COVID-19 in patients with cardiovascular comorbidities; withdrawn before enrollment. No data available.
NCT03521232	Phase 1/2	Terminated	27	Niclosamide enema (150 mg and 450 mg) for mild-to-moderate ulcerative proctitis; terminated early. Provides limited systemic safety and pharmacokinetic data, but no cardiac endpoints.

Literature Evidence

Listed in order of direct relevance to heart disease:

PMID	Year	Type	Journal	Key Findings
34736968	2021	Animal Study	Eur J Pharmacol	Niclosamide attenuated pressure overload-induced heart failure in mice; enhanced mitochondrial respiration and ATP production in cardiomyocytes — direct in vivo cardiac validation
39515588	2024	Cell Study (Human-derived)	Biochem Pharmacol	Niclosamide inhibited calcification of human heart valvular interstitial cells via AMPK/mTOR pathway; directly relevant to calcific aortic valve disease
38288981	2024	Nanoparticle/Animal Study	ACS Appl Mater Interfaces	Platelet membrane-encapsulated niclosamide nanoparticles activated STAT3/Bcl-2 to protect against myocardial infarction injury in mice; proof-of-concept for targeted cardiac delivery
38814250	2024	Mechanistic/Cell Study	J Gen Physiol	Under physiological Ca²⁺ conditions, niclosamide potentiates (not inhibits) TMEM16A and induces vasoconstriction — a key safety signal requiring dose-response characterization
39102426	2024	Mechanistic Study	PLoS Pathog	SARS-CoV-2 spike-induced senescent syncytia exacerbate heart failure; niclosamide may interrupt this pathway, linking its antiviral TMEM16 inhibition to cardiac benefit in post-COVID patients
36684586	2022	Cell Study	Front Cardiovasc Med	Screening of >3,000 FDA/EMA drugs identified niclosamide as a top inhibitor of TMEM16F-mediated platelet procoagulant activity triggered by SARS-CoV-2 spike protein — relevant to COVID-associated thrombosis and cardiac injury
33827113	2021	Cell Study	Nature	Niclosamide identified as the most effective TMEM16 inhibitor blocking SARS-CoV-2 spike-induced syncytia; connects antiviral mechanism to pulmonary and cardiac pathology
41453737	2025	Mechanistic/Animal	Am J Transplant	TMEM16F-CLIC1 interaction mediates dendritic cell cross-decoration after heart transplantation in mice; niclosamide is implicated as a potential modulator of this rejection pathway

India Market Information

Niclosamide is not currently marketed in India. No drug licenses or registrations are on record with CDSCO. Any development for a new cardiac indication would require a full regulatory pathway from the ground up, including IND filing, local clinical trials, and new drug application submission.

Safety Considerations

Safety package insert data (key warnings, contraindications) is not available in this evidence pack due to a data gap — the TFDA package insert has not yet been retrieved.

A clinically significant safety signal has emerged from the literature that is directly relevant to any cardiac application:

TMEM16A potentiation and vasoconstriction (PMID 38814250): Under physiological calcium concentrations, niclosamide was found to potentiate rather than inhibit TMEM16A, leading to acute vasoconstriction. This off-target cardiovascular effect is opposite to what an antifibrotic/cardioprotective agent would ideally produce, and must be fully characterized before cardiac indication development proceeds.

Please also refer to the standard anthelmintic package insert for general warnings and contraindications.

Conclusion and Next Steps

Decision: Hold

Rationale: While the mechanistic case for niclosamide in heart disease is scientifically coherent — backed by direct animal and human cell data — no clinical trial has ever targeted a cardiac indication, all retrieved trials produced zero data, the drug is not marketed in India, and a potential vasoconstriction safety signal has been identified that directly conflicts with a cardioprotective profile.

To proceed, the following is needed:

MOA data gap closure: Retrieve full DrugBank pharmacology entry (DB06803) to confirm primary cardiac molecular targets and off-target profile
Safety package insert: Download and parse the TFDA/reference country package insert PDF to extract key warnings, contraindications, and hematological monitoring requirements
DDI database: Resolve the missing DDI data file (ddinter_code_A.csv) and re-query for interactions with common cardiac co-medications (antihypertensives, anticoagulants, statins)
TMEM16A safety resolution: Commission a dose-response study to define the concentration range at which niclosamide potentiates vs. inhibits TMEM16A, and determine whether therapeutic oral doses reach levels that cause vasoconstriction
Bioavailability assessment: Niclosamide has notoriously poor systemic absorption via the oral route; cardiac applications will likely require novel formulations (nanoparticles, prodrugs, or IV) — a formulation strategy must be defined
Indication narrowing: “Heart disease” is too broad for a development program. Based on available evidence, calcific aortic valve disease (PMID 39515588, human cell data) or heart failure with preserved ejection fraction (PMID 34736968, animal model) are the most tractable sub-indications to pursue first
Regulatory pathway mapping: Since niclosamide is not registered in India, a full regulatory development plan (Phase 1 safety in Indian population → cardiac Phase 2) must be scoped before any go decision
Disclaimer

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