Инъекции эпидермального фактора роста (Heberprot P) в ложе и по краям ран, обусловленых синдромом диабетической стопы
В течение 15 лет, с 2001 г., мы применяем инъекционный метод введения эпидермального
фактора роста (Heberprot P, 0,75 мкг), разработанный для лечения рубцов в Центре биотехнологий (Гавана, Куба). Действительно, 159 000 пациентов в более чем 25 странах получили
соответствующее лечение, при котором частота высокой ампутации нижних конечностей составила всего 9-11%. В настоящей статье описан опыт авторов по лечению самых тяжелых язв,
вызванных синдромом диабетической стопы, за последние 15 лет.
Ключевые слова:инъекции эпидермального фактора роста, Heberprot P, диабетическая стопа, язвы
Клин. и эксперимент. хир. Журн. им. акад. Б.В. Петровского. 2017. № 4. С. 70-74.
Статья поступила в редакцию: 20.08.2017. Принята в печать: 10.10.2017.
Diabetic foot ulcers (DFU) are a significant health
care problem affecting around 15% of the people with
diabetes mellitus in their lifetime . The annual
incidence of DFU is more than 2% in all diabetic
patients and largely rises when peripheral neuropathy is present . This condition is an important
economic burden to medical care systems demanding
7-20% of the total expenditures on diabetes.
Basic treatment for good wound care in DFU in-
cludes strict metabolic control, debridement, offloading (i.e. relieving pressure from the wound area), dressings and antimicrobials. New therapies are emerging
for low-grade, neuropathic ulcers such as recombinant
human platelet-derived growth factor [3-4] and artificial skin substitutes. For high-grade ulcers, which
are more likely to progress to amputation, advances in
therapy have been scarce .
Epidermal growth factor (EGF) plays an important role in the regulation of cell growth, proliferation and differentiation that can be useful to enhance wound healing. Evidences of the beneficial
effect of topical EGF application in low-grade, neuropathic ulcers have been shown in clinical trials.
However, the effect of topical EGF formulation can
be abated, especially in high-grade wounds since an
increased protease activity has been identified.
Direct intralesional administration of an EGF-
based formulation (Heberprot-P) can overcome
this limitation, as has been reported in previous
studies and recently confirmed in a randomised,
double-blinded, placebo controlled phase III trial
In these initial studies, however, Heberprot-P intralesional treatment was continued until a complete
granulation response or up to a maximum of 8 weeks.
Thus, the safety profile of this intervention modality
under a more prolonged application schedule had
not be .
In this paper we introduce to you in the principal
results we had during our experience using Heberprot
P in the treatment of diabetic foot ulcers, during the
last 10 years (Fig. 1-4).
Fig. 2. Protocol for
A pilot study was performed  in 20 patients
older than 18 years with diabetes mellitus and
fullthickness lower extremity ulcer with more than
4 weeks of evolution. Informed consent to participate
in the study was given by the patients. Exclusion criteria
were foot ulcer area 1 cm2, cardiopathy (recent acute
myocardial infarction, unstable angina or uncontrolled
heart failure), renal failure (serum creatinine.
200 mmol/l and oligoanuria), malignancies, pregnancy and nursing. The exclusion criteria were evaluated
during an initial period (2 weeks) when patients
received only the standardised good.
Wound care and no more than a 30% decrease in
the ulcer size was required. Any sign or symptom of
infection should be solved before inclusion as well.
This study was approved by institutional review
Patients were treated with intralesional
injections of a lyophilized formulation of Heberprot-P
containing 75 mg (1 vial) of EGF, three times a week
on alternate days up to complete wound healing.
Recombinant, human EGF was obtained from a
transformed Saccharomyces cerevisiae strain at the
Center for Genetic Engineering and Biotechnology
of Havana and contained a mixture of the EGF1-51
and EGF1-52 forms. The dose selectionwas based
on a better risk-benefit balanceobserved with
75 mg in the accumulated clinical data with this
Heberprot-P was administered together with a
standardized good wound care regimen.
Ulcers were cleansed daily using saline or
chlorhexidine in case of contamination or infection.
Sharp debridement was indicated whenever necessary
to remove necrotic tissue. Saline-moistened gauze
dressing was used and the affected area was pressure
off-loaded. Broad-spectrum antibiotics were used
to treat infections, whereas metabolic control was managed with insulin alone or combined with oral
hypoglycemic drugs. Patients were initially hospitalized at ‘Hermanos Amejeiras’ Hospital up to favorable
clinical response (granulation, wound area reduction,
no infection or requirement for invasive procedure
and adequate metabolic control). The follow up for
treatment completion was carried out at the Health
Lodging ‘Manuel Fajardo’, supervised by the same
Evaluation consisted of baseline and weekly
clinical examinations. Data on demography, personal
pathological history, type and duration of diabetes
and its current treatment, peripheral neuropathy,
peripheral vascular disease and wound examination were documented. Wound area was determined
by planimetry using a wound measurement system (Visitrak; Smith & Nephew, Mull, UK). Ankle/brachial index was taken at baseline. Ulcers were
classified in grades according to Wagner-Meggit
classification . Laboratory tests were performed at
baseline and thereafter whenever required, including
blood cell count, haemoglobin, haematocrit,globular
sedimentation rate, creatinine and aspartate amino-transferase, which were performed by routine clinical
Blood glucose was measured more frequently for
the patients’ metabolic control. Wound cultures were
performed before and during therapy if necessary to
monitor infections. Foot infection was defined clinically based on the presence of purulent secretions
or at least two signs or symptoms of inflammation.
The primary efficacy endpoint was complete wound
closure defined as skin re-epithelialization without
drainage or dressing requirements.
Other variables recorded were complete granula-
tion response, time to complete closure, time to complete granulation response and indication of amputation. Safety was monitored by daily adverse events
evaluation during treatment. Data were double entered and validated on Microsoft Visual FoxPro ver-
sion 5.0 and then imported to SPSS version 13.0 for
further analysis. Continuous variables were expressed
as mean ± SD. Categorical variables were given as
absolute values and percentages. The confidence intervals (CI) for the probabilities of complete granulation and complete wound closure were estimated
using a Bayesian logistic model for fixed effects in-
WinBUGS14 package. Kaplan-Meier curves for time
to complete granulation and complete wound closure
were also calculated.
They all suffered type 2 diabetes mellitus. Five
patients (25%) received insulin. Mean ulcer size was
16,3±21,3 cm2. In 9 (45%) patients wounds were localized on the sole, 2 of them embracing calcaneus.
Other localizations were toes in 8 (40±0%), foot
external edge in 2 (10±0%) and internal edge in 1
(5±0%) patients. The principal risk factors were previous history of ulcer in 13 (65±0%) patients, history
of amputation in 10 (50±0%) and foot deformity
in 10 (50±0%) patients.
Complete treatment compliance was reported
in 17 (85%) patients. Voluntary interruption was
reported in 3 (15%) cases. Complete granulation
response was achieved in all patients, including the
three abandoners, at a mean time of 23,6±3,8 days
(95% CI: 15,6-31,5). Complete wound closure was ob-
tained in 17 (85%) patients (95% CI: 0,64-0,95). The
mean time to complete closure was 4,3±8,9 days (95%
CI: 26,9-61,8). Amputation was not necessary in any
case and relapse was reported in one patient after
6 months of complete closure (Fig. 5).
Fig. 5. Clinical results of the use of Heberprot-P
for ulcers of different
In another study we can read about the results in
a multicenter, doubled blind placebo control trial, in
149 patients. Below, we highlight the results.
A multicenter double-blind placebo-controlled
trial was carried out to evaluate the intra-lesional
infiltration of recombinant epidermal growth
factor (EGF) in Wagner’s grade 3 or 4 diabetic
foot ulcers (DFUs). Subjects (149) were randomized to receive EGF (75 or 25 μg) or placebo,
3 times per week for 8 weeks and standard good
wound care. The main endpoint was granulation
tissue covering >50% of the ulcer at 2 weeks.
It was achieved by 19/48 controls versus 44/53
in the 75 μg group [odds ratio (OR): 7,5; 95% confidence interval (CI): 2,9-18,9] and 34/48 in the 25 μg group (OR: 3,7; 1,6-8,7). Secondary out-come variables such as end-of-treatment complete
granulation response (28/48 controls, 46/53 with
75 μg and 34/48 with 25 μg EGF), time-to-complete response (controls: 5 weeks; both EGF dose
groups: 3 weeks), and wound closure after follow-up (25/48 controls, 40/53 with 75 μg and 25/48
with 25 μg EGF) were also treatment dependent.
Multivariate analyses yielded that complete granulation response (28/48 controls, 46/53 with 75 μg
and 34/48 with 25 μg EGF), time-to-complete response (controls: 5 weeks; both EGF dose groups:
3 weeks), and wound closure after follow-up (25/48
controls, 40/53 with 75 μg and 25/48 with 25 μg
EGF) were also treatment dependent. Multivariate analyses yielded that they were significantly enhanced by 75 μg EGF treatment and neuropathic
versus ischemic ulcers. Most adverse events were
mild and no drug-related severe adverse reactions
were reported. It was concluded that recombinant human EGF (rhEGF) local injections offer a
favourable risk-benefit balance in patients with
In summary, the finding that the EGF intralesional
infiltrations enhance the healing of recalcitrant ischaemic and of complicated and extensive neuropathic
diabetic lower extremity lesions offers new hopes for
the diabetic wound healing armamentarium. It confirms the role of EGF as potent tissue repair agent under particular delivery circumstances.
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