Registro sanitario de Heberprot-P®, medicamento biotecnológico innovador para el tratamiento de las úlceras del pie diabético / Sanitary registration of Heberprot-P®, an innovative biotechnological drug for the treatment of diabetic foot ulcers

Introducción: Heberprot-P® obtuvo su primer registro sanitario en Cuba en el año 2006, actualmente está aprobado en otros 26 países. Objetivo: Describir el proceso de registro sanitario en México, del medicamento biotecnológico Heberprot-P® para el tratamiento de las úlceras del pie diabético. Métodos: El proceso de registro sanitario de Heberprot-P® siguió las pautas de la reglamentación sanitaria de México sobre la base de la Ley general de salud y el Reglamento de insumos para la salud. Se revisaron además la Farmacopea de los Estados Unidos Mexicanos y las normas oficiales mexicanas en función de cumplir las exigencias para la comercialización de medicamentos en este territorio. Resultados: El proceso de registro se inició en junio de 2017 en México con acciones en función de completar los documentos e informaciones exigidas en el expediente de registro sanitario a presentarse. Entre ellos resaltan las consideraciones del Subcomité de Evaluación de Productos Biotecnológicos y el Comité de Moléculas Nuevas, la evaluación del expediente por un Tercero Autorizado y documentos emitidos por el Centro Nacional de Farmacovigilancia e Instituto Mexicano de la Propiedad Industrial. Se presentó la solicitud del registro sanitario ante Cofepris y esta se aprobó en mayo de 2018. Conclusiones: El trabajo con grupos de expertos permitió a la autoridad mexicana hacer un trabajo más expedito basado en las evidencias de las evaluaciones realizadas que son parte de la información del registro sanitario. Como resultado de este proceso, se otorgó el Registro Sanitario a Heberprot-P® en mayo de 2018 y Cofepris lo reconoció como un medicamento biotecnológico innovador(AU)

Introduction: Heberprot-P® obtained its first Sanitary Registration in Cuba in 2006, and it is currently approved in 26 other countries. Objective: Describe the sanitary registration process in Mexico of the biotechnological drug Heberprot-P® for the treatment of diabetic foot ulcers. Methods: The sanitary registration process of Heberprot-P® followed the guidelines of the sanitary regulations of Mexico on the basis of the General Health Law and the Regulation of Supplies for Health. The Pharmacopoeia of the United Mexican States and the official Mexican standards were also revised in order to comply with the requirements for the marketing of medicines in this territory. Results: The registration process began in June 2017 in Mexico with actions to complete the documents and information required in the sanitary registration file to be submitted. Among them are the considerations of the Sub-committee on the Evaluation of Biotechnological Products and the Committee on New Molecules, the evaluation of the file by an Authorized Third Party and documents issued by the National Center for Pharmacovigilance and the Mexican Institute of Industrial Property. The application for sanitary registration was submitted to Cofepris and this was approved in May 2018. Conclusions: The work with groups of experts allowed the Mexican authority to do a more expeditious work based on the evidence of the evaluations carried out that are part of the information of the sanitary registry. As a result of this process, Heberprot-P® was granted the Sanitary Registry in May 2018 and COFEPRIS recognized it as an innovative biotechnological medicine(AU)

Active post-marketing surveillance of the intralesional administration of human recombinant epidermal growth factor in diabetic foot ulcers.

BACKGROUND: After several exploratory and confirmatory clinical trials, the intralesional administration of human recombinant epidermal growth factor (hrEGF) has been approved for the treatment of advanced diabetic foot ulcers (DFU). The aim of this work was to evaluate the effectiveness and safety of this procedure in medical practice. METHODS: A prospective, post-marketing active pharmacosurveillance was conducted in 41 hospitals and 19 primary care polyclinics. Patients with DFU received hrEGF, 25 or 75 µg, intralesionally 3 times per week until complete granulation of the ulcer or 8 weeks maximum, adjuvant to standard wound care. Outcomes measured were complete granulation, amputations, and adverse events (AE) during treatment; complete lesion re-epithelization and relapses in follow-up (median: 1.2; maximum 4.2 years). RESULTS: The study included 1788 patients with 1835 DFU (81% Wagner's grades 3 or 4; 43% ischemic) treated from May 2007 to April 2010. Complete granulation was observed in 76% of the ulcers in 5 weeks (median). Ulcer non-ischemic etiology (OR: 3.6; 95% CI: 2.8-4.7) and age (1.02; 1.01-1.03, for each younger year) were the main variables with influence on this outcome. During treatment, 220 (12%) amputations (171 major) were required in 214 patients, mostly in ischemic or Wagner's grade 3 to 5 ulcers. Re-epithelization was documented in 61% of the 1659 followed-up cases; 5% relapsed per year. AE (4171) were reported in 47% of the subjects. Mild or moderate local pain and burning sensation, shivering and chills, were 87% of the events. Serious events, not related to treatment, occurred in 1.7% of the patients. CONCLUSIONS: The favorable benefit/risk balance, confirms the beneficial clinical profile of intralesional hrEGF in the treatment of DFUs.

Glucose toxic effects on granulation tissue productive cells: the diabetics' impaired healing.

Type 2 diabetes mellitus is a metabolic noncommunicable disease with an expanding pandemic magnitude. Diabetes predisposes to lower extremities ulceration and impairs the healing process leading to wound chronification. Diabetes also dismantles innate immunity favoring wound infection. Amputation is therefore acknowledged as one of the disease's complications. Hyperglycemia is the proximal detonator of systemic and local toxic effectors including proinflammation, acute-phase proteins elevation, and spillover of reactive oxygen and nitrogen species. Insulin axis deficiency weakens wounds' anabolism and predisposes to inflammation. The systemic accumulation of advanced glycation end-products irreversibly impairs the entire physiology from cells-to-organs. These factors in concert hamper fibroblasts and endothelial cells proliferation, migration, homing, secretion, and organization of a productive granulation tissue. Diabetic wound bed may turn chronically inflammed, procatabolic, and an additional source of circulating pro-inflammatory cytokines, establishing a self-perpetuating loop. Diabetic fibroblasts and endothelial cells may bear mitochondrial damages becoming prone to apoptosis, which impairs granulation tissue cellularity and perfusion. Endothelial progenitor cells recruitment and tubulogenesis are also impaired. Failure of wound reepithelialization remains a clinical challenge while it appears to be biologically multifactorial. Ulcer prevention by primary care surveillance, education, and attention programs is of outmost importance to reduce worldwide amputation figures.

Active post-marketing surveillance of the intralesional administration of human recombinant epidermal growth factor in diabetic foot ulcers

Background: After several exploratory and confirmatory clinical trials, the intralesional administration of human recombinant epidermal growth factor (hrEGF) has been approved for the treatment of advanced diabetic foot ulcers (DFU). The aim of this work was to evaluate the effectiveness and safety of this procedure in medical practice.Methods: A prospective, post-marketing active pharmacosurveillance was conducted in 41 hospitals and 19 primary care polyclinics. Patients with DFU received hrEGF, 25 or 75 μg, intralesionally 3 times per week until complete granulation of the ulcer or 8 weeks maximum, adjuvant to standard wound care. Outcomes measured were complete granulation, amputations, and adverse events (AE) during treatment; complete lesion re-epithelization and relapses in follow-up (median: 1.2; maximum 4.2 years). Results: The study included 1788 patients with 1835 DFU (81 porcent Wagners grades 3 or 4; 43 porcentischemic) treated from May 2007 to April 2010. Complete granulation was observed in 76 porcent of the ulcers in 5 weeks (median). Ulcer non-ischemic etiology (OR: 3.6; 95 porcent CI: 2.8-4.7) and age (1.02; 1.01-1.03, for each younger year) were the main variables with influence on this outcome. During treatment, 220 (12 porcent) amputations (171 major) were required in 214 patients, mostly in ischemic or Wagners grade 3 to 5ulcers. Re-epithelization was documented in 61 porcent of the 1659 followed-up cases; 5 porcent relapsed per year. AE (4171) were reported in 47 porcent of the subjects. Mild or moderate local pain and burning sensation, shivering and chills, were 87 porcent of the events. Serious events, not related to treatment, occurred in 1.7 porcent of the patients. Conclusions: The favorable benefit/risk balance, confirms the beneficial clinical profile of intralesionalhrEGF in the treatment of DFUs(AU)

Epidermal growth factor in clinical practice - a review of its biological actions, clinical indications and safety implications.

Chemotaxis, mitogenesis, motogenesis and cytoprotection are common cellular events involved in both tumourigenesis and tissue repair, which appear amplified upon growth factors exposure. Epidermal growth factor (EGF) promotes these events in epithelial and mesenchymal cells through the binding to a specific tyrosine kinase receptor. In experimental oncology settings, EGF does not initiate malignant transformation but exhibits 'tumour promotion'. These observations have raised doubts on the clinical use of EGF despite solid demonstrations of efficacy in experimental conditions and clinical trials. The results of a Pubmed and Bioline investigation on EGF clinical uses and preclinical safety data are presented here. EGF topical administration has been used since 1989 to enhance the healing process of a variety of peripheral tissues wounds (16 clinical reports), as well as its intravenous, oral and rectal administration for gastrointestinal damages (11 clinical reports). EGF therapeutic efficacy and excellent tolerability seem demonstrated. Lack of long-term adverse effects is highlighted in those studies with 6, 12 and 24 months of patients follow-up. Although post-treatment follow-up may fall short for malignant growth, there are no reports on evidences linking EGF clinical use with cancer. A multicentre, nationwide survey in Cuba, 15 years after randomly using silver sulphadiazine with EGF or not in burn victims yielded that cancer incidence was comparable between EGF-treated and control subjects and that such incidence rate does not differ from the age-matched national incidence for those 15-year period. All the animal species subjected to long-term EGF systemic administration exhibit dose-dependent and reversible epithelial organs hyperplasia with no changes in cells phenotypic differentiation. Histotypic pre-malignant markers were not identified. The results emerged from co-carcinogenesis studies and from transgenic mice over-expressing EGF are conflicting and indicate that EGF overexposure, either innate or postnatal, may not be sufficient to transform cells. The ability of EGF to heal injured tissues in life-threatening scenarios or to assist in preventing physical and social disability advocates for its clinical use under a rational medical risk/benefit balance.

Growth-hormone-releasing peptide 6 (GHRP6) prevents oxidant cytotoxicity and reduces myocardial necrosis in a model of acute myocardial infarction.

Therapies aimed at enhancing cardiomyocyte survival following myocardial injury are urgently required. As GHRP6 [GH (growth hormone)-releasing peptide 6] has been shown to stimulate GH secretion and has beneficial cardiovascular effects, the aim of the present study was to determine whether GHRP6 administration reduces myocardial infarct size following acute coronary occlusion in vivo. Female Cuban Creole pigs were anaesthetized, monitored and instrumented to ensure a complete sudden left circumflex artery occlusion for 1 h, followed by a 72 h reperfusion/survival period. Animals were screened clinically before surgery and assigned randomly to receive either GHRP6 (400 microg/kg of body weight) or normal saline. Hearts were processed, and the area at risk and the infarct size were determined. CK-MB (creatine kinase MB) and CRP (C-reactive protein) levels and pathological Q-wave-affected leads were analysed and compared. Evaluation of the myocardial effect of GHRP6 also included quantitative histopathology, local IGF-I (insulin-growth factor-I) expression and oxidative stress markers. GHRP6 treatment did not have any influence on mortality during surgery associated with rhythm and conductance disturbances during ischaemia. Infarct mass and thickness were reduced by 78% and 50% respectively, by GHRP6 compared with saline (P<0.01). More than 50% of the GHRP6-treated pigs did not exhibit pathogological Q waves in any of the ECG leads. Quantitative histopathology and CK-MB and CRP serum levels confirmed the reduction in GHRP6-mediated necrosis (all P<0.05). Levels of oxidative stress markers suggested that GHRP6 prevented myocardial injury via a decrease in reactive oxygen species and by the preservation of antioxidant defence systems (all P<0.05). Myocardial IGF-I transcription was not amplified by GHRP6 treatment compared with the increase induced by the ischaemic episode in relation to expression in intact hearts (P<0.01). In conclusion, GHRP6 exhibits antioxidant effects which may partially contribute to reduce myocardial ischaemic damage.