Fisetin for PAD

(FIRST Trial)

Overseen By Mary McDermott, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Northwestern University

Must not be taking: Warfarin, others

Disqualifiers: Amputation, Critical limb ischemia, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 16 weeks

34 Participants Needed

Trial Summary

What is the purpose of this trial?

The investigators propose a pilot randomized trial to gather preliminary data to test the hypothesis that Fisetin will reduce abundance of senescent cells in blood, skeletal muscle, and both subcutaneous and inter muscular adipose tissue and improve 6-minute walk distance in 34 people with peripheral artery disease (PAD). the investigators will determine whether greater declines in abundance of cells with senescent markers are associated with greater improvement in 6-minute walk distance in people with peripheral artery disease. In exploratory analyses, the investigators will assess whether Fisetin reduces interleukin-6 (IL-6) and novel senescent markers in adipose tissue, muscle, and/or blood.

Will I have to stop taking my current medications?

The trial requires that people taking certain medications, like warfarin and other drugs that are sensitive to specific enzymes, must stop taking them for at least two days before and ten hours after each study drug dose. If you're on these medications, you'll need to pause them during the trial as specified.

What evidence supports the effectiveness of the drug fisetin for treating PAD?

Research shows that fisetin has strong anti-inflammatory properties, which could be beneficial for conditions like PAD (peripheral artery disease) that involve inflammation. Studies have demonstrated that fisetin can reduce inflammation by blocking certain pathways in cells, suggesting it might help manage PAD symptoms. ^{1 2 3 4 5}

Is fisetin generally safe for humans?

Fisetin, a natural compound found in fruits and vegetables, has been studied for its antioxidant and anti-inflammatory properties. While these studies primarily focus on its effects in animal models, they do not report significant safety concerns, suggesting it may be generally safe. However, more research in humans is needed to confirm its safety profile. ^{1 2 4 6 7}

How is the drug fisetin unique for treating PAD?

Fisetin is unique for treating PAD (peripheral artery disease) because it is a natural compound found in fruits and vegetables with strong anti-inflammatory and antioxidant properties, which may help reduce inflammation and oxidative stress in blood vessels, unlike traditional treatments that primarily focus on improving blood flow. ^{1 2 4 8 9}

Eligibility Criteria

This trial is for people with peripheral artery disease (PAD), which can cause limited mobility and difficulty walking. Participants must have specific vascular lab evidence of PAD or a drop in ABI after the heel-rise test. It's not suitable for those who don't meet these criteria.

Inclusion Criteria

My ankle-brachial index (ABI) is 0.90 or lower.

I have been diagnosed with PAD based on vascular tests or angiography.

My ABI is between 0.90 and 1.00, and it drops by 20% or more after a physical test.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Fisetin or placebo for two days every 14 days over a 4-month period

16 weeks

Bi-weekly visits for dosing

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Fisetin

Trial Overview The study tests if Fisetin, a compound thought to reduce cell aging, can decrease senescent cells and improve walking distance over six minutes compared to a placebo. The effects on inflammation markers and other aging indicators will also be explored.

Participant Groups

Group I: Fisetin Experimental Treatment 1 Intervention

Sharp Clinical Services will provide fisetin (100 mg capsules). Randomized participants will receive fisetin 20 mgs/kg once daily for two days, followed by 12 days without therapy. Fisetin will be dosed in 100 mg tablets. Dosing will be rounded to the nearest 100 mg. For example, a 73 kg participant with a dose of 1,460 mg (i.e.73 kg x 20 mg) receives 1,500 mgs daily (i.e. 15 x 100 mg capsules) for two days every 14 days.

Group II: Placebo Placebo Group 1 Intervention

Sharp Clinical Services will provide placebo (100 mg capsules). Randomized participants will receive placebo 20 mgs/kg once daily for two days, followed by 12 days without therapy. Placebo will be dosed in 100 mg tablets. Dosing will be rounded to the nearest 100 mg. For example, a 73 kg participant with a dose of 1,460 mg (i.e.73 kg x 20 mg) receives 1,500 mgs daily (i.e. 15 x 100 mg capsules) for two days every 14 days.

Who Is Running the Clinical Trial?

Northwestern University

Lead Sponsor

Trials

1,674

Recruited

989,000+

Findings from Research

Fisetin, a natural flavonoid, effectively reduces inflammation by inhibiting proinflammatory mediators and cytokines in macrophages, as demonstrated in a study using LPS-stimulated RAW 264.7 cells.

The study also showed that fisetin protects against LPS-induced mortality and inflammation in zebrafish larvae by modulating the GSK-3β/β-catenin and NF-κB signaling pathways, highlighting its potential as an anti-inflammatory agent.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fisetin inhibits lipopolysaccharide-induced inflammatory response by activating β-catenin, leading to a decrease in endotoxic shock. Molagoda, IMN., Jayasingha, JACC., Choi, YH., et al.[2023]

Fisetin, a flavonoid, effectively reduces inflammation in macrophage-like cells by decreasing the release of nitric oxide and lowering the levels of inflammatory markers without being toxic to the cells.

The anti-inflammatory effects of fisetin are linked to its ability to inhibit key signaling pathways, specifically by suppressing the activities of Src and Syk, which are involved in the activation of NF-κB, a major regulator of inflammation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fisetin Suppresses Macrophage-Mediated Inflammatory Responses by Blockade of Src and Syk. Kim, JH., Kim, MY., Kim, JH., et al.[2020]

In a mouse model of acute pulmonary inflammation, the flavonoid fisetin significantly reduced levels of inflammatory markers and mediators, outperforming other flavonoids and the glucocorticoid dexamethasone.

Fisetin's ability to lower myeloperoxidase levels and gene expression of inflammatory mediators suggests it could be a promising candidate for treating pulmonary inflammatory diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibition of LPS-induced pulmonary inflammation by specific flavonoids. Geraets, L., Haegens, A., Brauers, K., et al.[2021]

Fisetin, a bioflavonoid found in fruits and vegetables, significantly reduced blood glucose and glycosylated hemoglobin levels in diabetic rats after 30 days of treatment at a dose of 10 mg/kg, while also increasing plasma insulin levels.

The study demonstrated that fisetin helps regulate carbohydrate metabolism by normalizing the activities of key enzymes in the liver and kidneys of diabetic rats, suggesting its potential as a therapeutic agent for managing diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modulatory effects of fisetin, a bioflavonoid, on hyperglycemia by attenuating the key enzymes of carbohydrate metabolism in hepatic and renal tissues in streptozotocin-induced diabetic rats. Prasath, GS., Subramanian, SP.[2021]

Fisetin (Fis) demonstrated the strongest anti-inflammatory effects among the flavonols tested, inhibiting nitric oxide production by 52% at a concentration of 20 μM in lipopolysaccharide-stimulated RAW264.7 cells.

The study revealed that these flavonols, particularly Fis, work by inhibiting key inflammatory pathways (NF-κB and MAPK) and reducing pro-inflammatory markers like TNF-α and IL-6, suggesting their potential use in preventing or treating inflammation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-inflammatory activity of flavonols via inhibiting MAPK and NF-κB signaling pathways in RAW264.7 macrophages. Zhong, R., Miao, L., Zhang, H., et al.[2022]

Fisetin-nanostructured lipid carriers (NLCs) significantly enhance the delivery and efficacy of fisetin against metastatic melanoma, showing a 3.2 times lower IC50 value and 1.8 times higher drug uptake in cancer cells compared to pure fisetin.

In vivo studies revealed that Fis-NLCs resulted in 5.9- and 10.7-fold greater inhibition of melanoma metastasis in the lungs and liver, respectively, indicating their potential as an effective treatment strategy for melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fisetin-Loaded Nanostructured Lipid Carriers: Formulation and Evaluations against Advanced and Metastatic Melanoma. Kumar, H., Chand, P., Pachal, S., et al.[2023]

The self-nanoemulsifying drug delivery system (SNEDDS) significantly enhanced the effectiveness of fisetin in improving behavioral changes in rats induced by rotenone, outperforming naïve fisetin in both efficacy and bioavailability.

SNEDDS formulation not only improved the anti-Parkinsonian effects of fisetin at lower doses but also demonstrated neuroprotective properties by reducing neuronal damage, indicating a promising approach for enhancing the therapeutic potential of fisetin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved neuroprotective activity of Fisetin through SNEDDS in ameliorating the behavioral alterations produced in rotenone-induced Parkinson's model. Kumar, R., Kumar, R., Khurana, N., et al.[2022]

Fisetin, an anti-inflammatory flavonoid, effectively reduces inflammation in human gingival fibroblasts by inhibiting the activation of MAPK pathways and decreasing COX-2 expression when exposed to lipopolysaccharide (LPS).

The study demonstrated that fisetin does not negatively impact cell viability while significantly lowering prostaglandin E2 synthesis, suggesting its potential as a safe therapeutic option for managing periodontal disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-inflammatory activity of fisetin in human gingival fibroblasts treated with lipopolysaccharide. Gutiérrez-Venegas, G., Contreras-Sánchez, A., Ventura-Arroyo, JA.[2021]

Fisetin significantly reduces inflammation and oxidative stress in both an animal model (BALB/c mice) and in bovine endometrial epithelial cells (BEND) exposed to LPS, indicating its potential as a therapeutic agent against inflammatory conditions.

The protective effects of fisetin are linked to its ability to inhibit TLR4-mediated pathways and activate the Nrf2/HO-1 pathway, which together help reduce harmful reactive oxygen species (ROS) and pro-inflammatory cytokines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fisetin Ameliorates the Inflammation and Oxidative Stress in Lipopolysaccharide-Induced Endometritis. Jiang, K., Yang, J., Xue, G., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Fisetin inhibits lipopolysaccharide-induced inflammatory response by activating β-catenin, leading to a decrease in endotoxic shock. [2023]

2. Korea (South) pubmed.ncbi.nlm.nih.gov

Fisetin Suppresses Macrophage-Mediated Inflammatory Responses by Blockade of Src and Syk. [2020]

3. United States pubmed.ncbi.nlm.nih.gov

Inhibition of LPS-induced pulmonary inflammation by specific flavonoids. [2021]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Modulatory effects of fisetin, a bioflavonoid, on hyperglycemia by attenuating the key enzymes of carbohydrate metabolism in hepatic and renal tissues in streptozotocin-induced diabetic rats. [2021]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Anti-inflammatory activity of flavonols via inhibiting MAPK and NF-κB signaling pathways in RAW264.7 macrophages. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Fisetin-Loaded Nanostructured Lipid Carriers: Formulation and Evaluations against Advanced and Metastatic Melanoma. [2023]

7. Germany pubmed.ncbi.nlm.nih.gov

Improved neuroprotective activity of Fisetin through SNEDDS in ameliorating the behavioral alterations produced in rotenone-induced Parkinson's model. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Anti-inflammatory activity of fisetin in human gingival fibroblasts treated with lipopolysaccharide. [2021]

9. New Zealand pubmed.ncbi.nlm.nih.gov

Fisetin Ameliorates the Inflammation and Oxidative Stress in Lipopolysaccharide-Induced Endometritis. [2022]