Fisetin for PAD
(FIRST Trial)
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Northwestern University
Must not be taking: Warfarin, others
Disqualifiers: Amputation, Critical limb ischemia, others
Prior Safety Data
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.
12345Is 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.
12467How 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.
12489Eligibility 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.
Trial 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
Participant Groups
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.
2Treatment groups
Experimental Treatment
Placebo Group
Group I: FisetinExperimental Treatment1 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: PlaceboPlacebo Group1 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.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Northwestern University Feinberg School of MedicineChicago, IL
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Who Is Running the Clinical Trial?
Northwestern UniversityLead Sponsor
References
Fisetin inhibits lipopolysaccharide-induced inflammatory response by activating β-catenin, leading to a decrease in endotoxic shock. [2023]Fisetin is a naturally occurring flavonoid that possesses several pharmacological benefits including anti-inflammatory activity. However, its precise anti-inflammatory mechanism is not clear. In the present study, we found that fisetin significantly inhibited the expression of proinflammatory mediators, such as nitric oxide (NO) and prostaglandin E2 (PGE2), and cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Additionally, fisetin attenuated LPS-induced mortality and abnormalities in zebrafish larvae and normalized the heart rate. Fisetin decreased the recruitment of macrophages and neutrophils to the LPS-microinjected inflammatory site in zebrafish larvae, concomitant with a significant downregulation of proinflammatory genes, such as inducible NO synthase (iNOS), cyclooxygenase-2a (COX-2a), IL-6, and TNF-α. Fisetin inhibited the nuclear localization of nuclear factor-kappa B (NF-κB), which reduced the expression of pro-inflammatory genes. Further, fisetin inactivated glycogen synthase kinase 3β (GSK-3β) via phosphorylation at Ser9, and inhibited the degradation of β-catenin, which consequently promoted the localization of β-catenin into the nucleus. The pharmacological inhibition of β-catenin with FH535 reversed the fisetin-induced anti-inflammatory activity and restored NF-κB activity, which indicated that fisetin-mediated activation of β-catenin results in the inhibition of LPS-induced NF-κB activity. In LPS-microinjected zebrafish larvae, FH535 promoted the migration of macrophages to the yolk sac and decreased resident neutrophil counts in the posterior blood island and induced high expression of iNOS and COX-2a, which was accompanied by the inhibition of fisetin-induced anti-inflammatory activity. Altogether, the current study confirmed that the dietary flavonoid, fisetin, inhibited LPS-induced inflammation and endotoxic shock through crosstalk between GSK-3β/β-catenin and the NF-κB signaling pathways.
Fisetin Suppresses Macrophage-Mediated Inflammatory Responses by Blockade of Src and Syk. [2020]Flavonoids, such as fisetin (3,7,3',4'-tetrahydroxyflavone), are plant secondary metabolites. It has been reported that fisetin is able to perform numerous pharmacological roles including anti-inflammatory, anti-microbial, and anti-cancer activities; however, the exact anti-inflammatory mechanism of fisetin is not understood. In this study, the pharmacological action modes of fisetin in lipopolysaccharide (LPS)-stimulated macrophage-like cells were elucidated by using immunoblotting analysis, kinase assays, and an overexpression strategy. Fisetin diminished the release of nitric oxide (NO) and reduced the mRNA levels of inducible NO synthase (iNOS), tumor necrosis factor (TNF)-α, and cyclooxygenase (COX)-2 in LPS-stimulated RAW264.7 cells without displaying cytotoxicity. This compound also blocked the nuclear translocation of p65/nuclear factor (NF)-κB. In agreement, the upstream phosphorylation events for NF-κB activation, composed of Src, Syk, and IκBα, were also reduced by fisetin. The phospho-Src level, triggered by overexpression of wild-type Src, was also inhibited by fisetin. Therefore, these results strongly suggest that fisetin can be considered a bioactive immunomodulatory compound with anti-inflammatory properties through suppression of Src and Syk activities.
Inhibition of LPS-induced pulmonary inflammation by specific flavonoids. [2021]In the present study, the anti-inflammatory effects of the flavonoids flavone, fisetin and tricetin were evaluated in a mouse model of LPS-induced acute pulmonary inflammation. The flavonoid fisetin significantly reduced lung myeloperoxidase-levels and gene-expression of inflammatory mediators such as IL-6, TNF-alpha, IL-1beta, MIP-1alpha and MIP-2. The LPS-induced gene transcription of HO-1 and SOD2 was also significantly reduced by fisetin. Overall, the anti-inflammatory effects of fisetin in this in vivo model were much more pronounced as compared to the observed effects of flavone or tricetin and the anti-inflammatory glucocorticoid dexamethasone. The results of this study indicate that flavonoids such as fisetin might be potential candidates as pharmaceuticals or nutraceuticals in the treatment of pulmonary inflammatory diseases.
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]Fisetin (3, 7, 3', 4'-tetrahydroxyflavone) is a bioflavonoid found in fruits and vegetables. It exhibits a wide variety of pharmacological properties, including antioxidant, antiinflammatory and anticarcinogenic effects. Recently we have reported the hypoglycemic actions of fisetin. Oral administration of fisetin (10mg/kg body weight) to diabetic rats for 30 days established a significant (P
Anti-inflammatory activity of flavonols via inhibiting MAPK and NF-κB signaling pathways in RAW264.7 macrophages. [2022]Fisetin (Fis), quercetin (Que), and myricetin (Myr) are flavonols with similar structure but different number of hydroxyl groups. The present research focused on the anti-inflammatory effect of these three flavonols in lipopolysaccharide-stimulated RAW264.7 cells. The number and site of hydroxyl group in flavonols obviously affected their anti-inflammation activity. These flavonols suppressed the overproduction of nitric oxide. Fis showed the best activity with an inhibition rate of 52% at 20 μM. Moreover, the flavonols reduced the levels of ROS, TNF-α, and IL-6. The mechanistic study showed that they inhibited the activation of NF-κB and MAPK pathways by suppressing the phosphorylation of IκBα, p65, JNK, ERK, p38, MEK, and reducing the nuclear translocation of NF-κB p65. In addition, the metabolism of the flavonols was examined. The results indicated that Fis was both methylated and glucuronidated. Que and Myr were mainly transformed into methylated products. This study highlights the anti-inflammatory activity of flavonols, particularly Fis, which has the potential for the prevention or treatment of inflammation as an adjuvant medicine or food additive.
Fisetin-Loaded Nanostructured Lipid Carriers: Formulation and Evaluations against Advanced and Metastatic Melanoma. [2023]Fisetin (Fis), a natural flavonoid with anticancer effects, suffers from delivery constraints. Fisetin-nanostructured lipid carriers (NLCs) were developed for better efficacy against metastatic melanoma, employing the design of experiment (DoE) approach. The optimized NLCs depict a particle diameter of 135.0 ± 5.5 nm, a polydispersity index (PDI) of 0.176 ± 0.035, and an entrapment efficiency of 78.16 ± 1.58%. The formulation was stable over a period of 60 days and demonstrated sustained release of the drug (74.79 ± 3.75%) over 96 h. Fis-NLCs depicted at least ∼3.2 times lower IC50 value and ∼1.8 times higher drug uptake at 48 h in A-375 and B16F10 cells compared to that of Fis. It also inhibited the mobility of melanoma cells and induced cell cycle arrest at the G1/S phase. Reverse transcriptase polymerase chain reaction (RT-PCR) and Western blot results show enhanced expression of Nrf2/NQO1 genes and an apoptotic effect by the upregulation of BAX mRNA expression. The protein levels of BAX and p53 were ∼2-fold higher compared with that of pure Fis. In-vivo studies demonstrated 5.9- and 10.7-fold higher inhibition in melanoma-associated metastasis in the lungs and liver, respectively. The outcomes from this study demonstrated Fis-NLCs as an effective tool against melanoma.
Improved neuroprotective activity of Fisetin through SNEDDS in ameliorating the behavioral alterations produced in rotenone-induced Parkinson's model. [2022]Fisetin is a polyphenolic flavonoid reported to have antioxidant, anti-inflammatory, and anti-cancer activities. However, it loses its importance as an effective phytochemical due to its poor water solubility and lower bioavailability. In the present study, the self-nanoemulsifying drug delivery system (SNEDDS) of fisetin was developed in order to improve its pharmacological activity. The developed SNEDDS of fisetin was evaluated for improving the rotenone-induced behavioral changes in the rats, and its efficacy was compared with naïve fisetin. It was noticed that fisetin loaded in the SNEDDS formulation significantly (p
Anti-inflammatory activity of fisetin in human gingival fibroblasts treated with lipopolysaccharide. [2021]Fisetin is an anti-inflammatory flavonoid; however, its anti-inflammatory mechanism is not yet understood. In this study, we evaluated the anti-inflammatory effect of fisetin and its association with mitogen-activated protein kinase (MAPK) and nuclear factor kappa-beta pathways in human gingival fibroblasts (HGFs) treated with lipopolysaccharide (LPS) obtained from Porphyromonas gingivalis. The cell signaling, cell viability, and cyclooxygenase-2 (COX-2) expression of HGFs treated with various concentrations (0, 1, 5, 10, and 15 μM) of fisetin were measured by cell viability assay (MTT), Western blotting, and reverse transcriptase polymerase chain reaction analysis on COX-2. We found that fisetin significantly reduced the synthesis and expression of prostaglandin E2 in HGFs treated with LPS. Activation of extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38 MAPK was suppressed consistently by fisetin in HGFs treated with LPS. The data indicate that fisetin inhibits MAPK activation and COX-2 expression without affecting cell viability. These findings may be valuable for understanding the mechanism of the effect of fisetin on periodontal disease.
Fisetin Ameliorates the Inflammation and Oxidative Stress in Lipopolysaccharide-Induced Endometritis. [2022]Fisetin is a natural flavone of polyphenol, which widely exists in many fruits and vegetables and has many pharmacological activities. However, the mechanism involved remains largely unknown. Here, we investigate the mechanisms of fisetin on the inflammatory response and oxidative stress in LPS-induced endometritis model and bovine endometrial epithelial cell line (BEND).