A lifetime risk for a diabetic ulcer in patients suffering from diabetes type 1 or 2 is approximated to 25%, meaning that every fourth person with diabetes will develop diabetic ulcer (1) . Diabetic foot ulcers represent a medically significant disease complication, with a high incidence of morbidity and mortality in the modern world. Risks for the development of this serious condition are well established and include the loss of sensation as a consequence of diabetes induced neuropathy, previous occurrences ulcers or amputations, infection, trauma, and the consequences of chronic ischemia due to poor peripheral vascularization (2) . Contemporary treatment options for diabetic foot ulcers are still limited, directly resulting in amputation being the frequent therapeutic solution for the majority of severe ulcers. Recent advancements in medical science regarding treatment for diabetes and its' complications have shown that the use of epidermal growth factor (Heberprot-P) as the treatment of diabetic foot ulcer may lead to the complete wound healing, significantly reducing the risk of amputation.
Most Recent Scientific Data
It is now well recognized that diabetic patients have decreased amounts of epidermal growth factor (EGF) in tissues which directly results in wound healing impairment and subsequently to the increased risk of amputation. EGF is directly responsible for the growth of epithelial and subepithelial tissues, and promotes reparation processes of tissues that are damaged (3) .
Heberprot-P is an innovative recombinant human EGF developed for acceleration of healing process of deep and complex ulcers in both neuropathic and ischemic types of diabetic ulcers. It currently represents the unique treatment for the most complicated diabetic wounds which are linked with a high risk for amputation. Efficacy and safety of Heberprot-P have been investigated in numerous clinical trials worldwide, with results demonstrating full wound healing, reduction of ulcer recurrence, as well as a reduction in amputations rates. Heberprot-P has proven to be a safe and well-tolerated treatment option for the treatment of severe diabetic ulcers, with adverse events mostly consisted of mild and transitory local reactions (4) .
A recent extensive meta-analysis involving 2365 participants conducted for the purpose of investigating the effects of growth factors on the healing of diabetic ulcers concluded that growth factors (EGF among them) may lead to complete healing of diabetic foot ulcers (5) . Another meta-analysis and systematic review of literature data conducted on 294 patients also identified favorable patient outcomes following treatment with recombinant human EGF (6) . Efficacy of Hebeprot-P was recently investigated in a clinical study involving patients having extensive, full-thickness lower extremity ulcers. Administration of Heberprot-P resulted in complete granulation followed by complete wound closure in 94% of patients. After one year follow-up, only one patient had a relapse of foot ulcer (7) . The interesting mechanistic of healing effects of EGF (Hebeprot-P) has also been investigated recently. It was recognized that diabetic patients have elevated oxidative stress and low antioxidant reserves. Application of EGF resulted in significant reduction of oxidative stress and elevation in antioxidant reserves, directly returning balance to oxidative processes in diabetic patients (8) .
The safety profile was recently investigated in the longitudinal, multicenter, post-marketing surveillance study which included 260 patients. The results were in line with the already known safety profile of Heberprot-P. Most frequently reported adverse events were mild and reversible in nature, including localized Burning sensation and pain at the injection site, as well as systemic reactions such as chills and shivering (9) . In conclusion, the benefits of Heberprot-P significantly outweigh the risks of this therapy. Heberprot-P can be safely administered to diabetic patients without the risk of serious and irreversible adverse reactions.
Advancements in Treatment
The recognized therapeutic potential of Heberprot-P prompted another clinical trial that would assess the efficacy and safety of Heberprot-P in patients with high-grade diabetic ulcers. The study is conducted at the eminent Dasman Diabetes Institute in Kuwait. Results of numerous studies are promising and justify the further testing of Heberprot-P, a unique and first-in-class therapeutic option for complicated diabetic ulcers. This provides the opportunity to further evaluate beneficial potentials of Heberprot-P and addresses the unmet medical need of introducing an effective therapeutic modality in the treatment of complex and serious diabetic foot ulcers.
The Unmet Need
An accumulated body of scientific evidence clearly indicates that the use of growth factors (especially recombinant human EGF) is beneficial for complicated diabetic foot ulcers with very high success rates. Current antimicrobial treatments, as well as the broad spectrum of different procedures involving surgery and drugs, have failed to decrease amputation rates and successfully treat this serious complication of diabetes. Heberprot-P is a registered treatment for diabetic foot ulcers in dozens of countries worldwide, and it has been successfully used in over 100.000 patients suffering from complex ulcers.
The need for an effective treatment clearly remains, and Heberprot-P has demonstrated to be an effective solution where standard therapeutic options fail. According to the most current data published by the Center for Disease Control (CDC), more than 100 million Americans have diabetes or prediabetes (10) , which represents a high-risk burden for diabetic foot ulcers, considering that every fourth diabetic patient may develop this condition. Complete regression of the most complicated ischemic diabetic
ulcers has been achieved in a significant portion of diabetic patients. Heberprot-P would address therapeutic needs of patients, in which amputation represents the only treatment option.
1. Comprehensive foot examination and risk assessment: a report of the task force of the foot care interest group of the American Diabetes Association, with endorsement by the American Association of Clinical Endocrinologists. Boulton AJ, Armstrong DG, Albert SF, Frykberg RG, Hellman R, Kirkman MS, Lavery LA, Lemaster JW, Mills JL Sr, Mueller MJ, Sheehan P, Wukich DK, American Diabetes Association, American Association of Clinical Endocrinologists. s.l. : Diabetes Care, 2008, Vol. 31(8). 1679.
2. Diabetes in America, 2nd Edition. National, Diabetes Data Group. s.l. : National Institutes of Health, Washington, D.C. 409.
3. Epidermal growth factor in the treatment of diabetic foot ulcers: an update. Tiaka EK, Papanas N, Manolakis AC, Georgiadis GS. s.l. : Perspect Vasc Surg Endovasc Ther., 2012, Vol. 24(1). 37-44. 4. Heberprot-P: A Novel Product for Treating Advanced Diabetic Foot Ulcer. Jorge Berlanga DVM MS PhD, José I. Fernández MD, Ernesto López MS, Pedro A. López MD PhD, Amaurys del Río MD, Carmen Valenzuela MS, Julio Baldomero MD, Verena Muzio MD PhD, Manuel Raíces PhD, Ricardo Silva PhD, Boris E. Acevedo MD PhD, Luis Herrera MD PhD. s.l. : MEDICC Rev, 2013, Vol. 15(1). 11.
6. Efficacy of Topical Recombinant Human Epidermal Growth Factor for Treatment of Diabetic Foot Ulcer: A Systematic Review and Meta-Analysis. Yang S, Geng Z, Ma K, Sun X, Fu X. s.l. : Int J Low Extrem Wounds, 2016, Vol. 15(2). 120-5.
7. Efficacy of intralesional recombinant human epidermal growth factor in chronic diabetic foot ulcers. Dumantepe M, Fazliogullari O, Seren M, Uyar I, Basar F. s.l. : Growth Factors, 2015, Vol. 33(2). 128-32.
8. Healing enhancement of diabetic wounds by locally infiltrated epidermal growth factor is associated with systemic oxidative stress reduction. Ojalvo AG, Acosta JB, Marí YM, Mayola MF, Pérez CV, Gutiérrez WS, Marichal II, Seijas EÁ, Kautzman AM, Pacheco AE, Armstrong DG. s.l. : Int Wound J, 2017, Vol. 14(1). 214-225.
9. Characterization of adverse events during the treatment with heberprot-p® in four Cuban provinces. Alina Ramona Alvarez Crespo, Liuba Alonso Carbonell, Isis Belkis Yara Alos, Ana Julia Garcia Milian, María Acelia Marrero Miragaya. s.l. : Horizonte Sanitario, 2017, Vol. 17.
10. National Center for Chronic Disease Prevention and Health Promotion. National Diabetes Statistics Report, 2017. s.l. : Center for Disease Control, 2017.
Diabetes is no longer considered life threatening, nonetheless diabetes and complications due to diabetes, when not under control, remain to be sixth leading cause of death having a higher mortality rate than some cancers such as prostate cancer, breast cancer and colon cancer. Of the most common and most severe complications of diabetes is diabetic foot ulcer which affects an approximate 15% – 20% of people with diabetes and frequently leads to amputation of the lower limb (about 84% of lower extremity amputation is due to this condition).
Diabetic foot ulcer occurs when an ulcer or a wound develop in an area in the lower legs or feet which do not heal or are difficult to treat leading to the exposure of the underlying tissue and becoming susceptible to infections..
Symptoms and Rating
It is not uncommon for people with diabetes to have diabetic foot ulcers for some time without being aware of the development. Some of the symptoms to look for include:
Thick yellow toenails
Bad odor from foot
Tight skin, swelling, redness or other infection symptoms
Muscle pain or cramps that occur with activity and go away with rest
discoloration of foot
Ulcers or sores on the foot
Based on the Wagner Grading System, diabetic foot ulcers are rated between 0 to 5:
0 – the foot is normal but is at risk of developing diabetic foot ulcers
1 – slight ulceration without infection
2 – ulcers with exposed tendons and joints
3 – large scale ulceration with infection
4 – gangrene of toe(s) or forefoot
5 – hind-foot or mid-foot gangrene
CAUSES OF DIABETIC FOOT ULCER
One of the main contributing factors to developing diabetic foot ulcer is peripheral neuropathy.(nerve damage) which arises due to an increase, ever a slight one, in blood sugar level. Due to nerve damage and loss of sensations and the ability to feel pain, foot damage, even from such simple things as pressure from shoes or a small cut, go unnoticed and unprotected resulting in worsening skin loss, blisters and a possibility of a serious infection than may progress in a matter of days.
Narrowing of the arteries (peripheral arterial disease) due to diabetes reduces the blood supply to the feet and is another diabetic complication that contribute to the development of diabetic foot ulcers. An injury to an area with poor blood circulation takes longer to heal and is more difficult to treat making it prone to developing ulcers or gangrene (decomposition of cells due to lack of blood flow).
EPIDERMAL GROWTH FACTOR (EGF) AND DIABETES
A number of studies have shown that diabetic patients have a decreased amount of growth factor concentrations, mainly epidermal growth factor (EGF). Naturally found in the body, EGF stimulate and promote cell growth and regeneration by binding to its receptors -epidermal growth factor receptors (EGFR). Epidermal growth factor acts as a healing agent in that it speeds wound recovery by triggering the synthesis of collagen, elastin and hyaluronic acid.
It follows then for diabetic people with a reduced amount of EGF have more of a likelihood to have impaired wound healing to such extremes as to develop severe complications that may require amputation of the lower limb.
Heberprot-P is an innovative Cuban product with EGF as the main ingredient given to patients suffering from ulcers that are non healing and non responding to other conventional treatments. It remains to be the only alternative treatment to amputation for diabetic foot ulcers. About 160,000 diabetic foot ulcer patient have been treated with Heberprot-P with success reducing the the risk of amputation by 77%.
The use of Heberprot-P for diabetic foot ulcers has a significant influence on a patient’s overall quality of life in that it not only accelerates the healing process, reduces the number of surgeries needed for the removal of damaged tissue and reduces the risk of development of such complications as infections and gangrene but it also reduces risk of amputation and reduces hospitalization costs.
Heberprot-P is parenteral administered and is free of preservatives. It has demonstrated a favorable risk–benefit and has proven to be well tolerated with mild to moderate side effects, with pain and burning sensation at administration site the most frequent.
According to the World Health Organization (WHO), Heberprot-P was registered in Cuba in 2006 and is now registered in 15 other countries, making it possible to treat more than 100,000 patients; applications for its registration are under review in other countries, including Brazil, China, the Russian Federation, South Africa and the Arab states of the Persian Gulf.
Heberprot-P has won the World Intellectual Property Organization (WIPO) Gold Medal and the Best Young Inventor Award at the International Invention Exhibition in Geneva, Switzerland.
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