Topical Fluoxetine as a Potential Nonantibiotic Adjunctive Therapy for Infected Wounds

Yoon, Dokyoung; Nguyen, Chuong; Bagood, Michelle D.; Fregoso, Daniel R.; Yang, Hsin-Ya; Lopez, Andrea I. Medina; Crawford, Robert W.; Tran, Jennifer; Isseroff, R. Rivkah

doi:10.1016/j.jid.2020.11.016

Cited by 9 publications

(9 citation statements)

References 15 publications

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“…Ex vivo wound infection was established as we have reported 29 . Briefly, discarded human skin was acquired from a panniculectomy procedure under a UC Davis IRB‐approved protocol.…”

Section: Methodsmentioning

confidence: 99%

“…Ex vivo wound infection was established as we have reported. 29 Briefly, discarded human skin was acquired from a panniculectomy procedure under a UC Davis IRBapproved protocol. The skin was trimmed of any attached adipose tissue and washed in 3X antibiotic-antimycotic solution (ABAM; Gibco, Waltham, MA) dissolved in PBS, then washed in PBS.…”

Section: Human Ex Vivo Skin Wound Infectionmentioning

confidence: 99%

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Beta adrenergic receptor antagonist can modify Pseudomonas aeruginosa biofilm formation in vitro: Implications for chronic wounds

et al. 2022

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Non-healing wounds are a major medical challenge, affecting over 6.5 million people in the US alone, with associated healthcare costs of about $16 billion annually. They can result in prolonged hospitalizations, work loss, disability, poor quality of life, and in diabetic patients with foot ulcers, amputation of the affected limb in 25% of patients. Though chronic ulcers may arise from different underlying diseases, the unifying feature is chronic infection, driving persistent inflammation that prolongs the healing process. One of the most frequently cultured or genetically identified pathogens in skin wounds is Pseudomonas aeruginosa.This species avidly forms biofilms in the wound that impede bacterial eradication by the host's immune mechanisms and limit efficacy of systemic antibiotics. Thus, non-antibiotic approaches to limit the growth and biofilm formation of this wound pathogen would be an advance in the treatment of chronic wounds.Prior work has demonstrated that the growth of other microbial species can be modulated by catecholamine agonists and antagonists of the adrenergic receptors (ARs). Here, we demonstrate that not only can the growth of this common wound pathogen be modulated by catecholamines, but also that the beta-AR antagonists can significantly decrease their growth, and importantly, limit their ability to form biofilms. These findings suggest that beta adrenergic antagonists may have a therapeutic role in the treatment of chronic skin wounds.

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“…Ex vivo wound infection was established as we have reported 29 . Briefly, discarded human skin was acquired from a panniculectomy procedure under a UC Davis IRB‐approved protocol.…”

Section: Methodsmentioning

confidence: 99%

Section: Human Ex Vivo Skin Wound Infectionmentioning

confidence: 99%

Beta adrenergic receptor antagonist can modify Pseudomonas aeruginosa biofilm formation in vitro: Implications for chronic wounds

et al. 2022

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“…Prior studies have demonstrated that topical administration of fluoxetine improves diabetic and non-diabetic wound contraction and closure [12], decreases wound inflammation, and minimizes infection [13].…”

Section: Introductionmentioning

confidence: 99%

“…To expand on these treatments, here we have developed a programmable bioelectronic bandage capable of delivering the drug fluoxetine (brand name: Prozac) as a personalized treatment regimen to accelerate wound healing in mice ( Figure 1 ). Prior studies have demonstrated that topical administration of fluoxetine improves diabetic and non-diabetic wound contraction and closure [12], decreases wound inflammation, and minimizes infection [13].…”

Section: Introductionmentioning

confidence: 99%

Programmable delivery of fluoxetine via wearable bioelectronics for wound healing in vivo

Li,

Yang,

Asefifeyzabadi

et al. 2023

Preprint

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The ability to deliver drugs with precise dosages at specific time points can significantly improve disease treatment while reducing side effects. Drug encapsulation for gradual delivery has opened up the doors for superior treatment regimen. To expand on this ability, programming bioelectronic devices to deliver small molecules enables ad-hoc personalized therapeutic profiles that are more complex than simple gradual release. Here, we introduce a wearable bioelectronic bandage with an integrated electrophoretic ion pump that affords on-demand drug delivery with precise dose control. Delivery of fluoxetine to wounds in mice resulted in a 27.2% decrease in the macrophage ratio (M1/M2) and a 39.9% increase in re-epithelialization, indicating a shorter inflammatory phase and faster overall healing. Programmable drug delivery using wearable bioelectronics in wounds introduces a broadly applicable strategy for the long-term delivery of a prescribed treatment regimen with minimal external intervention.

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“…[38][39][40][41] Considering the remarkable safety profile of FX 42,43 as well as the aforementioned growing body of evidence supporting its additional beneficial biological effects, it is not surprising that repositioning it to treat various diseases and pathological conditions has already been suggested. 30,31,44,45 Thus, in the current study, we aimed to further explore its putative beneficial effects on human epidermal keratinocytes.…”

Section: Introductionmentioning

confidence: 99%

Fluoxetine exerts anti‐inflammatory effects on human epidermal keratinocytes and suppresses their endothelin release

Tóth,

Ádám,

Arany

et al. 2023

Experimental Dermatology

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Fluoxetine is a safe antidepressant with remarkable anti‐inflammatory actions; therefore, we aimed to investigate its effects on immortalized (HaCaT) as well as primary human epidermal keratinocytes in a polyinosinic‐polycytidylic acid (p(I:C))‐induced inflammatory model. We found that a non‐cytotoxic concentration (MTT‐assay, CyQUANT‐assay) of fluoxetine significantly suppressed p(I:C)‐induced expression and release of several pro‐inflammatory cytokines (Q‐PCR, cytokine array, ELISA), and it decreased the release of the itch mediator endothelins (ELISA). These effects were not mediated by the inhibition of the NF‐κB or p38 MAPK pathways (western blot), or by the suppression of the p(I:C)‐induced elevation of mitochondrial ROS production (MitoSOX Red labeling). Instead, unbiased activity profiling revealed that they were most likely mediated via the inhibition of the phosphoinositide 3‐kinase (PI3K) pathway. Importantly, the PI3K‐inhibitor GDC0941 fully mimicked the effects of fluoxetine (Q‐PCR, ELISA). Although fluoxetine was able to occupy the binding site of GDC0941 (in silico molecular docking), and exerted direct inhibitory effect on PI3K (cell‐free PI3K activity assay), it exhibited much lower potency and efficacy as compared to GDC0941. Finally, RNA‐Seq analysis revealed that fluoxetine deeply influenced the transcriptional alterations induced by p(I:C)‐treatment, and exerted an overall anti‐inflammatory activity. Collectively, our findings demonstrate that fluoxetine exerts potent anti‐inflammatory effects, and suppresses the release of the endogenous itch mediator endothelins in human keratinocytes, most likely via interfering with the PI3K pathway. Thus, clinical studies are encouraged to explore whether the currently reported beneficial effects translate in vivo following its topical administration in inflammatory and pruritic dermatoses.

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Topical Fluoxetine as a Potential Nonantibiotic Adjunctive Therapy for Infected Wounds

Cited by 9 publications

References 15 publications

Beta adrenergic receptor antagonist can modify Pseudomonas aeruginosa biofilm formation in vitro: Implications for chronic wounds

Beta adrenergic receptor antagonist can modify Pseudomonas aeruginosa biofilm formation in vitro: Implications for chronic wounds

Programmable delivery of fluoxetine via wearable bioelectronics for wound healing in vivo

Fluoxetine exerts anti‐inflammatory effects on human epidermal keratinocytes and suppresses their endothelin release

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