The use of the medication Heberprot-P with some 290,000 patients, in twenty countries, has demonstrated the possibility of ensuring the healing of open wounds, ischemic ulcers, and those caused by diabetic foot disease, increasing the formation of granulation tissue, and thus reducing the need for amputation.
The medicine, created at Cuba's Genetic Engineering and Biotechnology Center (CIGB), contains as its active ingredient recombinant human epidermal growth factor, a peptide of 53 amino acids that couples with a receptor to activate anabolic metabolism, promoting the synthesis of amino acids and proteins, thus leading to cell division.
The product, considered unique and the first of its kind, is administered directly to the diabetic patient's ulcerated tissue, generating accelerated healing of the wound. The basic principles of its functioning were based on the research of U.S. scientist Stanley Cohen, in the 1960s, who observed the behavior of many animals which lick their wounds, applying large quantities of saliva, a pattern common among humans, as well, especially when it comes to cuts or burns on our fingers.
Dr. Manuel Raíces Pérez-Castañeda, a member of the CIGB promotion and communications team, related that professor Cohen was able to isolate epidermal growth factor, in 1962, thinking that in the future this molecule could be used in healing therapies, but at the time the technology to purify large quantities did not yet exist.
"Beginning in the 1980s, with the development of genetic engineering, it became possible for scientists to move genes from an initial host cell to another which was easier to manipulate, principally in microbial fermenters like bacteria and yeasts, developing rapid, effective, sophisticated biotechnological procedures. These bacteria and yeasts can fabricate complex molecules of great therapeutic value at an attractive cost, and within a very brief time period," the Cuban researcher explained.
Cuba became involved in the cloning of genes in the 1980s, as one of the world's pioneer countries in the field of biotechnology. Epidermal growth factor (EGF) was among the first molecules cloned in our country through genetic engineering, achieving the addition of silver sulfadiazine, used in treating burns. Produced in this way was the medication Hebermin, currently in use in burn units across Cuba's public health system, allowing for the recovery of patients with first degree burns over much of their bodies.
By 1994, Cuban researcher Jorge Berlanga, a member of the biomedical wound healing team at the CIGB, developed a model in rats to study the use of epidermal growth factor in the management of neuropathy, one of the complications of diabetes.
This investigation consisted of cutting thesciatic nerve in rats' extremities and injecting epidermal growth factor to stimulate the regeneration of nerve cells at the site of the cut. If regeneration occurred, it could be expected that measurements could be taken of variations or improvement in the transmission of nervous impulses from one end of the nerve to another, through the cut segment. "The fundamental purpose was to see if, with the introduction of the medication, regeneration of the sciatic nerve could be achieved, and with that, address the neuropathy. This was the genesis of Heberprot P," Dr. Raíces explained.
"Berlanga began to observe that the animals receiving the injection of epidermal growth factor did not develop ulcers or lose toes. While the negative or placebo controls, given injections of water, developed scabs and lost extremities," he continued.
The door was opened to research on the treatment of diabetic foot ulcers, with severe effects on nerve endings in extremities. Until that moment (1994), researchers and clinicians who treated diabetic foot ulcers has used topical medications with different ingredients active on the surface of wounds, thus the injection of EGF was a notable change and a pioneering move in the management of this pathology.
Research through 2001 focused on demonstrating the effectiveness and safety of the new treatment in animals, comparing the advantages noted with the injection of epidermal growth factor, as opposed to topical applications. A second line of investigation showed that at deeper levels within the tissue, there were more receptors for the growth factor than present at the surface. Thus injection of EGF was recognized, backed by scientific data published in distinguished international journals.
By 2001, a request for permission to move to clinical trials was submitted to Cuban regulatory authorities, and the first Phase 1 trials were conducted with 29 patients who had severe ulcers on their extremities, and faced the likely prospect of amputation.
"These experiments were conducted at the National Institute for Angiology and Vascular Surgery, by expert doctors familiar with the treatment of such ulcers.
They validated the new therapy, since in this first trial, around 59% of all patients evaluated experienced healing of their open wounds," Dr. Raíces said.
Between 2001 and 2005, the Phase 2 and 3 trials were initiated and concluded at several different public health care system centers. At these sites, showing improvement were 86% of patients with complicated diabetic foot ulcers, which with treatment developed high levels of effective granulation and healing.
The next year, the treatment was registered in Cuba, and another challenge emerged for Cuban medicine - training doctors, vascular surgeons, angiologists, podiatrists, intensive care nurses, etcetera, in the use of Heberprot-P.
This national program began in 2007, and ten years later, the medication is used in 458 health care centers in the country's 15 provinces and the Isle of Youth Special Municipality. Thanks to the results achieved, patients themselves, their families, and the health professionals involved have become the best promoters of Heberprot-P.
Dr. Raíces noted, "The main outcome of this study consisted in taking a statistically rigorous count of the cases treated to measure results, detect errors, rectify them, and move forward."
During 2010 and 2011, research was conducted in seven Cuban hospitals to determine the results among doctors using Heberprot-P and those of doctors not yet including the medication in their procedures. The compilation of this data on three occasions has shown that, among patients admitted to hospitals with complicated ulcers, who did not receive treatment with the medication, 29.6% required an amputation. However, those patients admitted with this condition who were initially treated with Heberprot-P, had an amputation rate of only 5.6% - more than four times lower.
In 2012 and 2013, a Phase 4 post-commercialization study was done of some 2,000 Cuban patients who had received the treatment. This led to two very important international publications, showing the benefits of Heberprot-P in the treatment of diabetic foot ulcers.
The advantages were so obvious that the drug was included in the country's list of basic medications in 2013, and soon became standard treatment in such cases here, the doctor reported.
Currently some 458 Cuban health care centers at the primary, secondary, and tertiary levels, offer patients therapy with Heberprot-P. They have disseminated the pharmaceutical properties of the medication which promotes the growth of granulation tissue, productive in patients with ulcers that do not heal, even promoting the development of new blood vessels at the site of the open wound.
Among Cuban centers that today use Heberprot-P is the Diabetic Treatment Clinic in Havana. At this institution, it has been observed that the medication stimulates the secretory phase of the granulation process, particularly in neuropathic patients, producing the narrowing of the wound and its restoration, according to endocrinologist Dr. Ana Ibis Conesa González.
She reported that patients recruited for treatment have open ulcers, fungal lesions, infections, and arterial insufficiency. Before applying the medication, patients' metabolic parameters are tested, to ensure that they are at a normal level. They are also given antibiotics to prevent sepsis, before an angiologist, nurse, or licensed podiatrist administers the treatment.
RN Ivón Gómez Jiménez reported that she was trained to administer Heberprot-P in a course on diabetic foot disease. She learned that the medication is injected in and around the wound.
Diluted in 5ml of distilled water, the drug is injected with an appropriate hypodermic needle at a depth 0.1cm. The treatment is offered as an ambulatory service, although the patient must be bandaged and walk as little as possible. When granulation is adequate, the patient receives follow-up care from an endocrinologist during office visits with topical treatment, until the wound is fully closed.
According to all those interviewed, Heberprot-P offers many therapeutic benefits that accelerate healing, and could serve to reduce the number of lower extremity amputations in all national health care systems.