Epidermal Growth Factor in Healing Diabetic Foot Ulcers: From Gene Expression to Tissue Healing and Systemic Biomarker Circulation
July 2020, Vol 22, No 3

Lower-extremity diabetic ulcers are responsible for 80% of annual worldwide nontraumatic amputations. Epidermal growth factor (EGF) reduction is one of the molecular pillars of diabetic ulcer chronicity, thus EGF administration may be considered a type of replacement therapy. Topical EGF ad­ministration to improve and speed wound healing began in 1989 on burn patients as part of an acute-healing therapy. Further clinical studies based on topically administering EGF to different chronic wounds resulted in disappointing out­comes. An analysis of the literature on unsuccessful clinical trials identified a lack of knowledge concerning: (I) molecular and cellular foundations of wound chronicity and (II) the phar­macodynamic requisites governing EGF interaction with its receptor to promote cell response. Yet, EGF intra- and perile­sional infiltration were shown to circumvent the pharmacody­namic limitations of topical application. Since the first studies, the following decades of basic and clinical research on EGF therapy for problem wounds have shed light on potential uses of growth factors in regenerative medicine. EGF’s molecular and biochemical effects at both local and systemic levels are diverse: (1) downregulation of genes encoding inflammation mediators and increased expression of genes involved in cell proliferation, angiogenesis and matrix secretion; (2) EGF in­tervention positively impacts both mesenchymal and epithelial cells, reducing inflammation and stimulating the recruitment of precursor circulating cells that promote the formation of new blood vessels; (3) at the subcellular level, upregulation of the EGF receptor with subsequent intracellular trafficking, includ­ing mitochondrial allocation along with restored morphology of multiple organelles; and (4) local EGF infiltration resulting in a systemic, organismal repercussion, thus contributing to attenuation of circulating inflammatory and catabolic reac­tants, restored reduction-oxidation balance, and decreased toxic glycation products and soluble apoptogenic effectors. It is likely that EGF treatment may rearrange critical epigenetic drivers of diabetic metabolic memory.

KEYWORDS
Epidermal Growth Factor, diabetes, diabetes complications, wound healing, diabetic foot, amputation, ulcer, Cuba

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Heberprot-P: un nuevo producto para el tratamiento de las úlceras complejas del pie diabético
Selecciones 2013

La úlcera del pie diabético es una de las principales complicaciones de la diabetes mellitus. Se ha demostrado que los diabéticos tienen una reducción de las concentraciones de los factores de crecimiento en sus tejidos, en particular del factor de crecimiento epidérmico. Esta reducción perjudica la cicatrización de las heridas, conduce a la cronicidad del trastorno y eventualmente a la amputación. La úlcera del pie diabético isquémico es la más difícil de tratar y tiene el mayor riesgo de amputación.

La inyección del factor de crecimiento epidérmico en los planos profundos y los bordes de la úlcera, estimula una respuesta farmacodinámica más eficaz del crecimiento del tejido de granulación y del cierre de la herida. El factor de crecimiento epidérmico que se inyecta en el nicho de la úlcera también puede asociarse con otras proteínas celulares externas al nicho, aumentando así la proliferación y la migración celular.

El Heberprot-P es un producto cubano novedoso, que contiene factor de crecimiento epidérmico humano recombinante para la infiltración perilesional e intralesional. Las evidencias muestran que acelera la curación de las úlceras profundas y complejas, tanto isquémicas como neuropáticas, y reduce las amputaciones relacionadas con la diabetes.

Los ensayos clínicos del Heberprot-P en pacientes con úlceras del pie diabético han demostrado que la infiltración local repetida de este producto puede mejorar la cicatrización de las heridas crónicas con seguridad y eficacia. Como resultado, el Heberprot-P se registró en Cuba en 2006 y en 2007 fue incluido en el Cuadro Básico de Medicamentos y aprobado para su comercialización. Su registro en otros 21 países ha permitido el tratamiento de más de 150 000 pacientes.

El Heberprot-P es el tratamiento único para las úlceras crónicas más complicadas y rebeldes, por lo general asociadas con el riesgo de amputación. La inyección local en úlceras diabéticas complejas ha demostrado una favorable relación riesgo-beneficio al acelerar la curación, reducir la recurrencia y atenuar el riesgo de amputación. La realización de otros ensayos y la extensión mundial del Heberprot-P brindarían la oportunidad de evaluar las potencialidades del producto para enfrentar una importante necesidad médica no satisfecha.

PALABRAS CLAVE úlcera del pie diabético, Heberprot-P, amputación, curación, necesidad médica insatisfecha, EGFhr, Cuba

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Heberprot-P: A Novel Product for Treating Advanced Diabetic Foot Ulcer
January 2013, Vol 15, No 1

Diabetic foot ulcer is a principal diabetic complication. It has been shown that diabetic patients have decreased growth factor concentrations in their tissues, particularly epidermal growth factor. Growth factor shortage impairs wound healing, which leads to chronic nonhealing wounds and sometimes eventual amputation. Ischemic diabetic foot ulcer is the most difficult to treat and confers the highest amputation risk.

Injecting epidermal growth factor deep into the wound bottom and contours encourages a more effective pharmacodynamic response in terms of granulation tissue growth and wound closure. Epidermal growth factor injected into the ulcer matrix may also result in association with extracellular matrix proteins, thus enhancing cell proliferation and migration.

Heberprot-P is an innovative Cuban product containing recombinant human epidermal growth factor for peri- and intra-lesional infiltration; evidence reveals it accelerates healing of deep and complex ulcers, both ischemic and neuropathic, and reduces diabetes-related amputations.
Clinical trials of Heberprot-P in patients with diabetic foot ulcers have shown that repeated local infiltration of this product can enhance healing of chronic wounds safely and efficaciously. As a result, Heberprot-P was registered in Cuba in 2006, and in 2007 was included in the National Basic Medications List and approved for marketing. It has been registered in 15 other countries, enabling treatment of more than 100,000 patients.

Heberprot-P is a unique therapy for the most complicated and recalcitrant chronic wounds usually associated with high amputation risk. Local injection in complex diabetic wounds has demonstrated a favorable risk–benefit ratio by speeding healing, reducing recurrences and attenuating amputation risk. Further testing and deployment worldwide of Heberprot-P would provide an opportunity to assess the product’s potential to address an important unmet medical need.

KEYWORDS Diabetic foot ulcer, Heberprot-P, amputation, healing, unmet medical need, rhEGF, Cuba

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