Topical Administration of Pirfenidone Increases Healing of Chronic Diabetic Foot Ulcers: A Randomized Crossover Study

Janka-Zires, Marcela; Almeda‐Valdés, Paloma; Uribe-Wiechers, Ana Cecilia; Juárez-Comboni, Sonia Citlali; López-Gutiérrez, Joel; Escobar-Jiménez, Jarod Jazek; Gómez-Pérez, Francisco J.

doi:10.1155/2016/7340641

Cited by 22 publications

(23 citation statements)

References 16 publications

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“…A synthetic chemical, prifenidone (PFD), was found to modulate the expression of TNF-α, TGF-β, FGF, PDGF, and VEGF, giving it anti-fibrotic and anti-inflammatory properties. In two phase III clinical trials, topical PFD addition to conventional treatment significantly improved healing in DFUs [104,105].…”

Section: Non-endogenous Moleculesmentioning

confidence: 99%

The discovery and development of topical medicines for wound healing

Öhnstedt

Tomenius

Vågesjö

et al. 2019

Expert Opinion on Drug Discovery

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Introduction: Chronic, nonhealing skin wounds claim >3% of the health-care budget in industrialized countries, and the incidence is rising. Currently, two parallel trends influence innovations within the field of wound healing: the need to reduce spread of antibiotic resistance and the emerging use of health economy and value-based models. Areas covered: This review focuses on the discovery of drug candidates and development of treatments aiming to enhance wound healing in the heterogeneous group of patients with nonhealing wounds. Expert opinion: Nonhealing wounds are multifaceted and recognized as difficult indications. The majority of products currently in use are medical device dressings, or concepts of negative pressure or hyperbaric oxygen treatment. Global best practice guidelines for the treatment of diabetic foot ulcers recommend debridement, redressing, as well as infection control, and are critical to the lack of coherent clinical evidence for many approved products in active wound care. To accelerate wound healing, there is an emerging trend toward biologics, gene therapy, and novel concepts for drug delivery in research and in the pipeline for clinical trials. Scientific delineation of the therapeutic mechanism of action is, in our opinion, vital for clinical trial success and for an increased fraction of medical products in the pharmaceutical pipeline.

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Section: Non-endogenous Moleculesmentioning

confidence: 99%

The discovery and development of topical medicines for wound healing

Öhnstedt

Tomenius

Vågesjö

et al. 2019

Expert Opinion on Drug Discovery

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“…The results of an early study with carboxymethylcellulose dressing suggesting that the intervention improved ulcer depth were not born out by a large outcome blind RCT . Two recent RCTs with topical Pirferidone (with potential anti‐inflammatory/antifibrotic properties) had methodological limitations; neither were blinded, results were analysed per protocol, and there was a high dropout rate in one, and an unexpectedly low healing rate in the control group in the other . Four RCTs of products designed to promote healing; Chitosan and Isosorbide dinitrate, hyaluronic acid, an acellular flowable matrix, and the proteolytic fraction from latex P1G10 provided little support for the use of these agents in clinical practice because of a small number of recruited patients, nonblinding, per protocol analysis, and/or high drop‐out rates.…”

Section: Recommendationsmentioning

confidence: 99%

Guidelines on use of interventions to enhance healing of chronic foot ulcers in diabetes (IWGDF 2019 update)

Rayman

Vas

Dhatariya

et al. 2020

Diabetes Metabolism Res

166

183

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The International Working Group on the Diabetic Foot (IWGDF) has published evidence‐based guidelines on the prevention and management of diabetic foot disease since 1999. In conjunction with advice from internal and external reviewers and expert consultants in the field, this update is based on a systematic review of the literature centred on the following: the Population (P), Intervention (I), Comparator (C) and Outcomes (O) framework; the use of the SIGN guideline/Cochrane review system; and the 21 point scoring system advocated by IWGDF/EWMA. This has resulted in 13 recommendations. The recommendation on sharp debridement and the selection of dressings remain unchanged from the last recommendations published in 2016. The recommendation to consider negative pressure wound therapy in post‐surgical wounds and the judicious use of hyperbaric oxygen therapy in certain non‐healing ischaemic ulcers also remains unchanged. Recommendations against the use of growth factors, autologous platelet gels, bioengineered skin products, ozone, topical carbon dioxide, nitric oxide or interventions reporting improvement of ulcer healing through an alteration of the physical environment or through other systemic medical or nutritional means also remain. New recommendations include consideration of the use of sucrose‐octasulfate impregnated dressings in difficult to heal neuro‐ischaemic ulcers and consideration of the use of autologous combined leucocyte, platelet and fibrin patch in ulcers that are difficult to heal, in both cases when used in addition to best standard of care. A further new recommendation is the consideration of topical placental derived products when used in addition to best standard of care.

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“…While the exact mechanism(s) of PFD remain unknown, previous studies demonstrated its effectiveness at mitigating myofibroblast differentiation, proliferation, and profibrotic cytokine production in both in vitro and in vivo models of lung, liver, and renal fibrosis [22,23]. The potential of PFD as a topical therapeutic agent for use during wound healing [24,25] or following HTS development [26] has been suggested, however the mechanism by which PFD exerts its antifibrotic properties on dermal cells has not been fully described [24][25][26][27][28].…”

Section: Introductionmentioning

confidence: 99%

Pirfenidone reduces profibrotic responses in human dermal myofibroblasts, in vitro

Hall

Wells

Leung

2018

Laboratory Investigation

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Pirfenidone (PFD) is a synthetic small molecule inhibitor with demonstrated anti-inflammatory and antifibrotic properties in vitro and in vivo. The exact mechanism(s) of PFD action remain unclear, due in part to the broad effects of this drug on the complex processes involved in inflammation and fibrosis. While PFD is FDA-approved for the treatment of idiopathic pulmonary fibrosis, the efficacy of this compound for the treatment of dermal fibrosis has not yet been fully characterized. Dermal fibrosis is the pathological formation of excess fibrous connective tissue of the skin, usually the result of traumatic cutaneous injury. Fibroproliferative scarring, caused by delayed wound healing and prolonged inflammation, remains a major clinical concern with considerable morbidity. Despite efforts to identify a therapeutic that targets the fibrotic pathways involved in wound healing to mitigate scar formation, no satisfactory dermal antifibrotic has yet been identified. We aim to better elucidate the antifibrotic mechanism(s) of PFD activity using an in vitro model of dermal fibrosis. Briefly, cultured human dermal fibroblasts were stimulated with TGF-β1 to induce differentiation into profibrotic myofibroblast cells. A dose-dependent reduction in cellular proliferation and migration was observed in TGF-β1-stimulated cells when treated with PFD. We observed a clear inhibition in the development of essential myofibroblast mechanoregulatory machinery, including contractile F-actin stress fibers containing α-SMA and large super-mature focal adhesions. PFD treatment significantly reduced protein levels of major ECM components type I and type III collagen. PFD targeted the p38 MAPK signaling pathway and mitigated profibrotic gene expression profiles. This in vitro data promotes PFD as a potential therapeutic agent for the treatment of dermal fibrosis.

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Topical Administration of Pirfenidone Increases Healing of Chronic Diabetic Foot Ulcers: A Randomized Crossover Study

Cited by 22 publications

References 16 publications

The discovery and development of topical medicines for wound healing

The discovery and development of topical medicines for wound healing

Guidelines on use of interventions to enhance healing of chronic foot ulcers in diabetes (IWGDF 2019 update)

Pirfenidone reduces profibrotic responses in human dermal myofibroblasts, in vitro

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