A multi-center study on the regenerative effects of erythropoietin in burn and scalding injuries: study protocol for a randomized controlled trial

Günter, Christina Irene; Bader, Augustinus; Dornseifer, Ulf; Egert, Silvia; Dunda, Sebastian E.; Grieb, Gerrit; Wolter, Timm P.; Pallua, Norbert; Wild, Tobias von; Siemers, Frank; Mailänder, P.; Thamm, Oliver C.; Ernert, Carsten; Steen, Michael; Sievers, R.; Reichert, Bert; Rahmanian-Schwarz, Afshin; Schaller, H.-E.; Hartmann, Bernd; Otte, Max; Kehl, Victoria; Ohmann, Christian; Jelkmann, Wolfgang; Machens, Hans‐Günther

doi:10.1186/1468-6708-14-124

Cited by 21 publications

(19 citation statements)

References 29 publications

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“…EPO can protect epidermis, dermis, and its vital structures, in particular capillaries and blood vessels, from further damage following burn injury [28]. In fact, it has been demonstrated that erythropoietin may also act on nonhaematopoietic tissues via the EPOR, stimulating tissue healing, particularly following injury [29, 30].…”

Section: Resultsmentioning

confidence: 99%

Epoetin Alpha and Epoetin Zeta: A Comparative Study on Stimulation of Angiogenesis and Wound Repair in an Experimental Model of Burn Injury

Irrera

Bitto

Pizzino

et al. 2015

BioMed Research International

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Deep second-degree burns are characterized by delayed formation of granulation tissue and impaired angiogenesis. Erythropoietin (EPO) is able to stimulate angiogenesis and mitosis, activating vascularization and cell cycle. The aim of our study was to investigate whether two biosimilar recombinant human erythropoietins, EPO-α and EPO-Z, may promote these processes in an experimental model of burn injury. A total of 84 mice were used and a scald burn was produced on the back after shaving, in 80°C water for 10 seconds. Mice were then randomized to receive EPO-α (400 units/kg/day/sc) or EPO-Z (400 units/kg/day/sc) or their vehicle (100 μL/day/sc 0.9% NaCl solution). After 12 days, both EPO-α and EPO-Z increased VEGF protein expression. EPO-α caused an increased cyclin D1/CDK6 and cyclin E/CDK2 expression compared with vehicle and EPO-Z (p<0.001). Our study showed that EPO-α and EPO-Z accelerated wound closure and angiogenesis; however EPO-α resulted more effectively in achieving complete skin regeneration. Our data suggest that EPO-α and EPO-Z are not biosimilars for the wound healing effects. The higher efficacy of EPO-α might be likely due to its different conformational structure leading to a more efficient cell proliferation and skin remodelling.

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Section: Resultsmentioning

confidence: 99%

Epoetin Alpha and Epoetin Zeta: A Comparative Study on Stimulation of Angiogenesis and Wound Repair in an Experimental Model of Burn Injury

Irrera

Bitto

Pizzino

et al. 2015

BioMed Research International

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“…Several studies have demonstrated the efficacy of tissue-protective molecules, including EPO, CEPO and pHBSP, in various models of wound healing such as burn injury (34) and cutaneous punch wound (27,35), A case report on the effect of EPO on the healing of skin ulcers was reported (36) and a multicenter clinical trial is ongoing with EPO in burn and scald injuries (37). Whilst the possible wound healing actions of EPO have been investigated in other contexts, most of these studies have focused on skin wounds and their inflammatory and microvascular complications.…”

Section: Discussionmentioning

confidence: 99%

Low Oxygen Tension Primes Aortic Endothelial Cells to the Reparative Effect of Tissue-Protective Cytokines

Heikal

Ghezzi

Mengozzi

et al. 2015

Mol Med

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Erythropoietin (EPO) has both erythropoietic and tissue-protective properties. The EPO analogues carbamylated EPO (CEPO) and pyroglutamate helix B surface peptide (pHBSP) lack the erythropoietic activity of EPO but retain the tissue-protective properties that are mediated by a heterocomplex of EPO receptor (EPOR) and the β common receptor (βCR). We studied the action of EPO and its analogues in a model of wound healing where a bovine aortic endothelial cells (BAECs) monolayer was scratched and the scratch closure was assessed over 24 h under different oxygen concentrations. We related the effects of EPO and its analogues on repair to their effect on BAECs proliferation and migration (evaluated using a micro-Boyden chamber). EPO, CEPO and pHBSP enhanced scratch closure only at lower oxygen (5%), while their effect at atmospheric oxygen (21%) was not significant. The mRNA expression of EPOR was doubled in 5% compared with 21% oxygen, and this was associated with increased EPOR assessed by immunofluorescence and Western blot. By contrast, βCR mRNA levels were similar in 5% and 21% oxygen. EPO and its analogues increased both BAECs proliferation and migration, suggesting that both may be involved in the reparative process. The priming effect of low oxygen tension on the action of tissue-protective cytokines may be of relevance to vascular disease, including atherogenesis and restenosis.

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“…These promising clinical results in patients with skin wounds of dissimilar etiologies have encouraged others to initiate clinical investigations whose aim is to assess EPO's action in different wound types. For example, Gunter et al . announced the initiation of a prospective, randomized, double‐blind, multicenter study in 150 patients with burn and scald injuries in order to investigate the effect of systemic 150 IU/kg body weight EPO treatment for 21 days.…”

Section: Epo and Wound Healing: Clinical Findingsmentioning

confidence: 99%

“…Therefore, clinical trials whose aim is to assess the safety and efficacy of EPO as potential treatment for wound healing especially in patients with DM are needed. Such a clinical trial whose aim is to assess the efficacy of systemic administered EPO in 150 patients suffering of burn and scalding injuries was announced by Gunter et al . in 2013.…”

Section: Clinical Considerationsmentioning

confidence: 99%

Erythropoietin, a novel repurposed drug: An innovative treatment for wound healing in patients with diabetes mellitus

Hamed

Bennett

Demiot

et al. 2013

Wound Repair Regeneration

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Developing a new drug is expensive: the cost of going from bench to bedside is about $US1 billion. Therefore, the repurposing of an approved drug is potentially rewarding because it expands the drug's existing therapeutic profile and preempts additional development costs. As the safety profile of a repurposed drug is already well known, any new investigations could then focus on its efficacy and other therapeutic benefits. Recombinant erythropoietin (EPO) is a potential candidate for repurposing because the results of numerous studies have shown that systemic and topical EPO is therapeutically beneficial when it is administered to healthy and diabetic animals with acute and chronic skin wounds and burns. Moreover, the molecular mechanisms of EPO's actions have been elucidated: EPO acts on those nonhematopoietic cells which are involved in the innate immune response where it promotes cellular proliferation and differentiation, exerts its cytoprotective actions, and inhibits apoptosis. In this review, the mechanism of EPO's action in skin wound healing is reviewed, and its potential for treating acute and chronic skin wounds and stimulating tissue regeneration in diabetic patients is discussed.

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A multi-center study on the regenerative effects of erythropoietin in burn and scalding injuries: study protocol for a randomized controlled trial

Cited by 21 publications

References 29 publications

Epoetin Alpha and Epoetin Zeta: A Comparative Study on Stimulation of Angiogenesis and Wound Repair in an Experimental Model of Burn Injury

Epoetin Alpha and Epoetin Zeta: A Comparative Study on Stimulation of Angiogenesis and Wound Repair in an Experimental Model of Burn Injury

Low Oxygen Tension Primes Aortic Endothelial Cells to the Reparative Effect of Tissue-Protective Cytokines

Erythropoietin, a novel repurposed drug: An innovative treatment for wound healing in patients with diabetes mellitus

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