Repurposed Drugs & Pulmonary Fibrosis
AI Unveils Potential Life-Saving Information
This began with a reader-based question about whether I could query AI on Idiopathic Pulmonary Fibrosis.
Having had patients with this difficult condition, I conducted an AI review with the idea of ranking the various repurposed drugs and supplements that might help this disease for which there is no cure or even good treatment.
While researching Galectin-3 activity in cancer, we have encountered its major role in promoting the fibrosis of various organs and the role of Galectin-3 inhibitors such as Belapectin and Modified Citrus Pectin in this disease. One must understand that IPF is a complex disease, and fibrosis or scarring cannot be reversed. However, a reasonable goal would be to try to slow the disease’s progression with the help of safe repurposed drugs.
I conducted a search of various repurposed agents including safe nutraceuticals that either block Galectin-3 or have substantial anti-fibrotic activity with specific attention to those that have anti-pulmonary fibrotic action. The results were beyond astonishing; hence I decided to share this immediately.
Here is the ranking, and below this, I feature AI’s discussion with reference links to PubMed supporting articles:
Pulmonary Fibrosis
Idiopathic pulmonary fibrosis (IPF) is a devastating, progressive lung disease characterized by excessive scarring of lung tissue that leads to breathing difficulties and eventual respiratory failure. Current therapeutic options remain limited, creating an urgent need for effective treatments. This report evaluates potential repurposed drugs that target galectin-3 and other fibrotic pathways, assessing their anti-fibrotic activity and potential to slow or reverse pulmonary fibrosis.
Understanding Galectin-3 in Fibrotic Disease
Galectin-3 is a profibrotic β-galactoside-binding lectin that plays a central role in the pathogenesis of various fibrotic conditions, including idiopathic pulmonary fibrosis.
Expression of galectin-3 is significantly upregulated in bronchoalveolar lavage fluid and serum of IPF patients, with further elevation observed during disease exacerbations.
This protein functions as a critical regulator of fibrosis by cross-linking and promoting signaling via multiple cell surface receptors, including integrins and growth factor receptors such as transforming growth factor-β, vascular endothelial growth factor, and platelet-derived growth factor receptors.
Top Ranked Repurposed Drugs for Pulmonary Fibrosis
1. Direct Galectin-3 Inhibitors
TD139/Belapectin
TD139 is a novel and potent small-molecule inhibitor of galectin-3 that has shown promising results in clinical trials. In a randomized, double-blind, multicentre, placebo-controlled phase 1/2a study, inhaled TD139 was well-tolerated with no significant treatment-related side effects in both healthy subjects and IPF patients.
The drug's direct targeting of galectin-3 addresses a fundamental mechanism in fibrosis development, making it a leading candidate for IPF treatment.
Similarly, belapectin (GR-MD-02) is a complex carbohydrate drug that targets galectin-3. Preclinical data in animals have demonstrated robust treatment effects in reversing liver fibrosis and cirrhosis.
Although belapectin has been primarily studied in liver diseases, its mechanism of action suggests potential benefits for pulmonary fibrosis as well.
Modified Citrus Pectin
Modified Citrus Pectin (MCP) represents another promising approach to targeting galectin-3.
This specialized form of pectin has been altered to be more easily absorbed by the digestive tract. Research has shown that MCP binds to galectin-3 molecules, preventing them from fostering harmful inflammation and excessive scar tissue buildup.
A study from the UK demonstrated that MCP interrupted kidney fibrosis by binding to galectin-3, decreasing inflammation and fibrosis in acute kidney injury.
This mechanism suggests significant potential for treating pulmonary fibrosis.
2. Metabolic Modulators
Metformin
Metformin, a first-line antidiabetic drug, has shown remarkable antifibrotic effects in the lungs.
Research published in Nature Communications revealed that metformin exerts potent antifibrotic effects by modulating metabolic pathways, inhibiting TGFβ1 action, suppressing collagen formation, and activating PPARγ signaling in lung fibroblasts derived from IPF patients.
Using genetic lineage tracing in a murine model of lung fibrosis, researchers showed that metformin alters the fate of myofibroblasts and accelerates fibrosis resolution by inducing myofibroblast-to-lipofibroblast transdifferentiation.
This two-arm mechanism warrants further therapeutic evaluation for IPF treatment.
3. Antiparasitic Medications
Ivermectin
Ivermectin, widely known as an antiparasitic drug, has demonstrated promising anti-fibrotic effects. A recent study found that ivermectin treatment significantly ameliorated bleomycin-induced lung fibrosis in male rats.
The mechanism appears to involve reduced inflammation and mitigated oxidative stress-induced toxicity. Specifically, ivermectin at a dosage of 3 mg/kg reversed the effects of bleomycin-induced fibrosis on inflammatory markers and oxidative stress.
Histological assessments confirmed that ivermectin treatment reduced tissue damage and pulmonary fibrosis.
Fenbendazole
Fenbendazole, a benzimidazole anthelmintic agent, has shown efficacy in attenuating bleomycin-induced pulmonary fibrosis in mice.
This drug inhibits the proliferation and migration of lung fibroblasts. Further studies revealed that fenbendazole significantly inhibits glucose consumption and moderates glycolytic metabolism in fibroblasts, activating adenosine monophosphate-activated protein kinase (AMPK) and reducing the activation of the mammalian target of rapamycin (mTOR) pathway.
This, in turn, inhibits TGF-β1-induced fibroblast-to-myofibroblast differentiation and collagen synthesis.
Albendazole
Albendazole has demonstrated effectiveness in attenuating fibroblast to myofibroblast transition by alleviating TGF-β1-induced aerobic glycolysis through the LRRN3/PFKFB3 signaling pathway.
Oral administration of albendazole showed potent antifibrotic effects in mouse models of pulmonary fibrosis induced by bleomycin or SiO2, and in human precision-cut lung slices after TGF-β1 stimulation.
These improvements were evidenced by better lung morphology, reduced myofibroblast formation, and downregulation of α-SMA, collagen type 1, and fibronectin expression in the lungs.
Mebendazole
Although primarily studied in other contexts, mebendazole has demonstrated anti-inflammatory and fibrinolytic properties that could be relevant to pulmonary fibrosis.
Research has shown that mebendazole potently reduced fibrosis by decreasing collagen deposition and down-regulating pro-fibrotic genes in animal models.
These effects suggest potential applicability to pulmonary fibrosis, though more direct studies are needed.
4. Natural Compounds
EGCG (Epigallocatechin gallate)
A UC-San Francisco pilot study found that epigallocatechin gallate (EGCG), a compound found in green tea, was associated with a reversal in fibrosis.
Patients who received EGCG capsules (600 mg daily for 14 days) before undergoing biopsy showed lower levels of fibrotic markers in lung tissue compared to untreated patients.
Additionally, two fibroblast-derived serum biomarkers associated with IPF activity and prognosis decreased during EGCG treatment, suggesting an antifibrotic effect.
Melatonin
Melatonin, a hormone predominantly secreted by the pineal gland, has demonstrated protective effects against lung fibrosis. Research shows that melatonin markedly attenuated bleomycin-induced experimental lung fibrosis in mice and inhibited TGF-β1-induced fibrogenesis in lung fibroblasts.
The protective mechanism involves regulation of the Hippo/YAP1 pathway, with melatonin abolishing increased collagen deposition induced by bleomycin.
The therapeutic potential of melatonin for prevention and reversal of IPF is significant.
Quercetin
Quercetin, a flavonoid found in many fruits and vegetables, has shown effectiveness in enhancing ligand-induced apoptosis in senescent IPF fibroblasts.
Unlike senescent normal lung fibroblasts, IPF lung fibroblasts from patients with stable and rapidly progressing disease were highly resistant to Fas ligand-induced and TNF-related apoptosis-inducing ligand-induced apoptosis.
Quercetin abolished this resistance to death ligand-induced apoptosis in IPF fibroblasts by upregulating FasL receptor and caveolin-1 expression and modulating AKT activation. In vivo, quercetin reversed bleomycin-induced pulmonary fibrosis and attenuated lethality, weight loss, and the expression of pulmonary senescence markers in aged mice.
Curcumin
Curcumin has demonstrated potential therapeutic utility in pulmonary fibrosis through multiple mechanisms.
It inhibits proliferation of lung fibroblasts from normal and IPF patients via cell cycle arrest at the G0/G1 phase. Next-generation sequencing and bioinformatics studies identified that suppression of cell cycle progression was the main cellular function of curcumin in IPF fibroblasts.
Additionally, curcumin inhibits TGF-β-dependent myofibroblast differentiation via inhibition of TGF-β-induced phosphorylation of Smad2/3 and ERK1/2, and inhibits collagen secretion from IPF fibroblasts.
Resveratrol
Resveratrol, a compound found in grapes and red wine, has demonstrated efficacy in alleviating bleomycin-induced pulmonary fibrosis by regulating HIF-1α and NF-κB expression.
This natural compound reduces inflammatory response and lung damage in pulmonary fibrosis models. Masson's trichrome staining revealed that resveratrol improved the lung fibrosis score, with less prominent pathological changes observed in lung tissues treated with moderate to high doses of resveratrol.
The compound's mechanism involves inhibiting HIF-1α expression, with a concomitant decrease in NF-κB levels and reversal of inflammatory and fibrotic marker expression.
Sulforaphane
Sulforaphane, a compound found in cruciferous vegetables, prevents bleomycin-induced pulmonary fibrosis in mice by inhibiting oxidative stress via nuclear factor erythroid 2-related factor-2 (Nrf2) activation.
Sulforaphane treatment reduced lung alveolar destruction, inflammatory infiltration, and the expression of inflammatory and fibrotic markers in rat lung tissue. The compound's antioxidant mechanism provides protection against lung injury and fibrosis development.
5. Other Promising Agents
Doxycycline
Doxycycline, a tetracycline antibiotic, has demonstrated effectiveness in attenuating pulmonary fibrosis by downregulating the TGF-β signaling pathway.
In a study using paraquat-induced pulmonary fibrosis, doxycycline treatments significantly reduced pulmonary coefficient, histopathological score, and collagen content in a dose-dependent manner.
The drug also inhibited the expression levels of plasma inflammation cytokines and reduced inflammatory response at early stages of lung injury. Importantly, doxycycline helped restore the balance of epithelial-mesenchymal cells, a key factor in fibrosis development.
Vitamin C
Vitamin C has shown beneficial effects in treating lung fibrosis induced by paraquat.
Treatment with vitamin C reduced cellular recruitment, including neutrophils, macrophages, and lymphocytes, into the bronchoalveolar lavage fluid of fibrotic mice. It also decreased the secretion of IL-17 (involved in neutrophil migration) and TGF-β (a pro-fibrotic mediator), as well as collagen deposition.
Additionally, vitamin C elevated the levels of antioxidant enzymes superoxide dismutase and catalase, providing protection against oxidative damage in pulmonary fibrosis.
Celecoxib
Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, has demonstrated anti-inflammatory effects in rat lungs with smoke-induced emphysema.
While not directly studied in pulmonary fibrosis, its mechanism suggests potential benefits. Celecoxib inhibited interalveolar wall distance and pulmonary inflammation in the lungs of cigarette smoke-treated rats.
It also inhibited serum NO production, iNOS and COX-2 expression, and PGE2 production in treated lung tissues, attenuating the activation of the NF-κB pathway.
These anti-inflammatory effects could be relevant to fibrotic lung disease.
Conclusion
The search for effective treatments for pulmonary fibrosis continues to be a priority in pulmonary medicine.
Direct galectin-3 inhibitors like TD139, belapectin, and modified citrus pectin show particularly strong promise due to their targeted approach to a key fibrotic mechanism.
Metabolic modulators like metformin offer innovative approaches to fibrosis reversal through cellular reprogramming.
Repurposed antiparasitic medications and natural compounds provide additional therapeutic avenues with demonstrated efficacy in various models of pulmonary fibrosis.
While more clinical studies are needed to confirm efficacy and safety in human IPF patients, these repurposed drugs represent promising candidates for developing new treatment strategies. A combination approach targeting multiple pathways may ultimately provide the most effective management for this challenging disease.
Supporting Articles
Hirani et al. "Target inhibition of galectin-3 by inhaled TD139 in patients with idiopathic pulmonary fibrosis" (2021)
"Breakthrough Research on Modified Citrus Pectin and Galectin-3 for Cardiovascular Disease, Fibrosis and Other Inflammatory Conditions" (Eliaz, 2011)
"Galectin Therapeutics Reports the Positive Outcome of the Fourth Data and Safety Monitoring Board Meeting for NAVIGATE" (Boudes, 2023)
Razi et al. "Ivermectin ameliorates bleomycin-induced lung fibrosis in male rats by suppressing inflammation and oxidative stress" (2024)
Kheirollahi et al. "Metformin induces lipogenic differentiation in myofibroblasts to reverse pulmonary fibrosis" (2019)
Zhao et al. "Melatonin Protects against Lung Fibrosis by Regulating the Hippo/YAP1 Pathway" (2018)
Wang et al. "Fenbendazole Attenuates Bleomycin-Induced Pulmonary Fibrosis in Mice via Suppression of Fibroblast-to-Myofibroblast Differentiation" (2022)
Wang et al. "Resveratrol alleviates bleomycin-induced pulmonary fibrosis via suppressing HIF-1α and NF-κB expression" (2021)
Hohman et al. "Quercetin Enhances Ligand-induced Apoptosis in Senescent IPF Fibroblasts" (2018)
Yan et al. "Sulforaphane prevents bleomycin‑induced pulmonary fibrosis in mice by inhibiting oxidative stress via nuclear factor erythroid 2‑related factor‑2 activation" (2017)
Roh et al. "Celecoxib inhibits inflammatory signaling in cigarette smoke-exposed rat lungs" (2010)
"EGCG (green tea extract) treatment associated with reversal of fibrosis markers in IPF patients" (UCSF pilot study, 2020)
Zeng et al. "Albendazole ameliorates aerobic glycolysis in myofibroblasts to reverse pulmonary fibrosis" (2024)
Hua et al. "Doxycycline attenuates paraquat-induced pulmonary fibrosis by downregulating the TGF-β signaling pathway" (2017)
Amazing stuff !! The same names/substances come up time after time. Well done, Justus R. Hope.
thank you Dr. Hope. We are working to embrace some daily green tea, not exciting taste but what great benefits.