Ulcer Treatment

1. PREPARED BY
DR. MAHA NOUR ABU HAJLEH
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 EASYEF® Spray.
 Wound healing.
 Phases of acute wound healing.
 Complications in wound healing.
 Epidermal growth factor (EGF).
 Mechanism of action of EGF.
 Recombinant DNA Technology.
 Diabetic foot ulcers (DFUs).
 Radiation induced oral mucositis (MO).
 References.
Contents

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EASYEF®

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 Dermal solution recombinant human Epidermal Growth Factor
(EGF), 0.005% composition to induce skin cell and keratocyte
regeneration.
 Daewoong has developed a novel system for producing
recombinant human EGF DWP401 [1].
EASYEF® spray

5.  Active ingredient
2 ml contains recombinant human Epidermal Growth Factor 1 mg
(1,200,000 IU) , (Host cell: Escherichia coli JM101, Vector:
pTE105) [1].
 Action
Is originally developed by Daewoong pharmaceutical Co., Ltd.
Seoul, Korea.
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EASYEF® spray

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 Action
 It is a dermal solution spray used for the complete healing of
diabetic foot ulcers.
 It has the effects of Re-epithelization, promotion of Granulation
tissue and Angiogenesis.
 Complete healing was defined as full epithelialization of the
wound with absence of discharge [7].
EASYEF® spray

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 Indications
Effective in curing keratohelcosis, corneal disorders, wounds,
diabetic ulcer, bedsore.

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 Dosage and administration
 EASYEF®, is composed of two parts: the active ingredient and
the diluent.
 After mixing the active ingredient with attached solvent, apply it
to an wound twice a day.
 It was applied topically over the wound and covered with
hydrocolloid dressing. Dressing was changed twice daily.
EASYEF® spray

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 Contraindications
Patients with known hypersensitivity to any component of this drug.
 Side effects
Easyef has not occurred specific adverse reactions.
 Storage
Store at 2-8ºC in a refrigerator. Do not freeze.
EASYEF® spray

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 Precautions
For children, administrate carefully under the supervision of
parents. Rash or overgrowth of cells may occur.
 Pregnancy and nursing women
As the safety for pregnancy has not been established, administration
to women who are pregnant or at risks of becoming pregnant should
be made only when the benefit of treatment is judged to exceed than
the risks.
EASYEF® spray

11.  Is a complex physiological process involving the interplay among
various types of cells, growth factors, extracellular matrix (ECM)
components, and proteinases [2] [3].
 During the normal wound healing process, the phases of
hemostasis, inflammation, proliferation, and remodeling occur
sequentially in a continuous and sometimes overlapping fashion
[2] [4].
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Wound healing

12. 1. Hemostasis and Inflammation
 Injury to the skin exposes intravascular platelets to sub endothelial
collagen, leading to thrombin formation [4].
 Platelets activated by thrombin release several growth factors
eventually forming a hemostatic plug [3].
{epidermal growth factor (EGF), heparin-binding EGF-like growth factor, insulin-
like growth factor 1 (IGF-1), platelet-derived endothelial cell growth factor, platelet-
derived EGF, platelet-derived growth factor (PDGF), transforming growth factor
(TGF)-alpha and TGF-beta (TGF-β) }[3, 4] .
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Phases of acute wound healing

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1. Hemostasis and Inflammation (cont.)
 These growth factors diffuse into surrounding tissues and
chemotactically attract neutrophils and monocytes into the
wound [5].
 The monocytes differentiate into macrophages, which mediate a
series of processes vital for normal wound healing .This acute
inflammatory process lasts 1-2 days in uncomplicated wounds
[5].

14. 2. Proliferation (Granulation Tissue Formation)
 Is characterized by the formation of granulation tissue and
initiation of angiogenesis [2].
 Granulation tissue is composed of fibroblasts, neovasculature, and
macrophages in a loose matrix of collagen, hyaluronic acid (HA),
and fibronectin, and it eventually fills the wound area [2].
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3. Remodeling (Maturation)
 Is the final phase of wound healing and can last from 3 weeks to
2 years post-injury [2].

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17. 1- A chronic wound
Wound that does not heal in an orderly set of phases or in a timely
fashion [6].
 A number of pathophysiological factors can cause the failure of
normal wound healing, including inflammation, infection,
malnutrition, age, diabetes, tissue maceration, pressure
necrosis, and renal impairment [6] .
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Complications in wound healing

18. 2-A scar
 Is a densely bundled orientated collagen fibrous tissue that
replaces normal tissue after injury. Scars are caused by an
overproduction of immature collagen during the remodeling
phase [12] [15].
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 EGF was discovered by cohen in mouse salivary glands in 1962.
 Is a single-chain polypeptide composed of 53 amino acids,
molecular weight of about 6,200 daltons , and exists in a number
of tissues and fluids in the body [9].
 Six cysteine residues in the sequence of hEGF from three disulfide
bonds are required for hEGF to be biologically active.
Epidermal growth factor (EGF)

20.  Human EGF was discovered in human urine as an inhibitor of
gastric acid secretion [7].
 It can stimulate the proliferation and differentiation of epithelial
tissue and facilitate skin regeneration and wound healing [7].
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Epidermal growth factor (EGF)

21.  In dermatology, EGF can be used as a healing agent for skin
wounds, such as diabetic ulcers, bed sores, venous stasis
ulcers, skin burns and surgical incisions [8 ].
 In ophthalmology, EGF can be utilized as a healing agent for
corneal ulcers and ophthalmic surgery, such as corneal
transplantation and excimer laser keratectomy, and the
prevention of corneal degeneration [8 ].
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 It is also a good candidate for the treatment of gastric ulcers
because it inhibits gastric acid secretion and regenerates gastric
mucosal layer [9].
 Topical application of rhEGF also showed promising therapeutic
efficacy and minimal toxicity on chemotherapy-induced oral
mucositis (OM) in patients with head and neck cancer [7] [9].

23. 1.Re-epithelialization : EGF promotes epithelial cells to proliferate
and move to fill wounds.
2. Promotion of granulation tissue : EGF stimulates fibroblasts in
dermal tissue to facilitate dermal cells to differentiate and
proliferate.
3. Angiogenesis : EGF promotes endothelial cells to proliferate to
regenerate blood vessels [9].
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Mechanism of action of EGF

24. Mechanism of EGF Action
Mechanism of EGF Action
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25.  This technology involves the insertion of DNA fragments from
a variety of sources, having a desirable gene sequence via
appropriate vector [11].
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Recombinant DNA Technology

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 Enzymatic cleavage is applied to obtain different DNA fragments
using restriction endo-nucleases for specific target sequence DNA
sites followed by DNA ligase activity to join the fragments to fix
the desired gene in vector.
 The vector is then introduced into a host organism, which is
grown to produce multiple copies of the incorporated DNA
fragment in culture, and finally clones containing a relevant DNA
fragment are selected and harvested [11].
Recombinant DNA Technology

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Recombinant DNA Technology

28.  Highly purified recombinant human epithelial growth factor
(rhEGF) enhanced the mucosal wound-healing process [7], and is
biologically identical to human EGF [10].
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29.  Common form of chronic wound.
 Approximately 20% of all diabetic patients experience one in
their lifetime [12].
 DFUs are primarily caused by peripheral neuropathy, both
sensory and motor, as well as vascular disease coupled with an
unrecognized repetitive minor trauma due to high glucose levels
[12].
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Diabetic foot ulcers (DFUs)

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 Ulceration often occurs due to the loss of pain sensation, which
results in severe infection or peripheral ischemia and can lead to
amputation [13].
Diabetic foot ulcers (DFUs)

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Chronic diabetic foot ulcer

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Treatment of diabetic foot ulcer with Easyef

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Comparison of healing rate of diabetic foot ulcer with placebo and Easyef

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Treatment of radiation induced oral mucositis with placebo and Easyef

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Comparison of healing rate of radiation induced oral mucositis with
placebo and Easyef

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(A) Excisional wound 2 days after treatment with recombinant human EGF.
(B) Full epithelialization 2 weeks after
treatment.
(C) Well-maintained status of the treated area without scarring at 6 months of
follow-up [14].

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References
1-EGF Approved for Treatment of Diabetic Foot Ulcer Asia-Pacific Biotech News
2001.05:428-440. Vol. 5 • No. 18 • 2001.
2-Park, J.W., Hwang, S.R. and Yoon, I.S., 2017. Advanced growth factor delivery systems
in wound management and skin regeneration. Molecules, 22(8), p.1259.
3.Braund, R.; Hook, S.; Medlicott, N.J. The role of topical growth factors in chronic
wounds. Curr. Drug Deliv. 2007, 4, 195–204. [CrossRef] [PubMed].
4-Traversa, B.; Sussman, G. The role of growth factors, cytokines and proteases in wound
management. Primary Intent. 2001, 9, 161.
5- Kiritsy,C.P.; Lynch,A.B.; Lynch,S.E.Role ofgrowthfactorsincutaneouswound healing: A
review. Crit. Rev. Oral Biol. Med. 1993, 4, 729–760. [CrossRef] [PubMed].
6-Mekkes, J.R.; Loots, M.A.; Van Der Wal, A.C.; Bos, J.D. Causes, investigation and
treatment of leg ulceration. Br. J. Dermatol. 2003, 148, 388–401. [CrossRef] [PubMed].

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7- Hong, J.P., Jung, H.D. and Kim, Y.W., 2006. Recombinant human epidermal growth
factor (EGF) to enhance healing for diabetic foot ulcers. Annals of plastic surgery, 56(4),
pp.394-398.
8- Tsang MW, Kam G, Keubg WKR, et al. Human epithelial growth factor enhances
healing of diabetic foot ulcers. Daibetes Care. 2003;26:1856– 1861.
9- Kim, J.W., Kim, M.G., Lee, H.J., Koh, Y., Kwon, J.H., Kim, I., Park, S., Kim, B.K., Oh,
J.M., Im Kim, K. and Yoon, S.S., 2017. Topical Recombinant Human Epidermal Growth
Factor for Oral Mucositis Induced by Intensive Chemotherapy with Hematopoietic Stem
Cell Transplantation: Final Analysis of a Randomized, Double-Blind, Placebo-Controlled,
Phase 2 Trial. PloS one, 12(1), p.e0168854.
10-Jacobsen, P. and Berglind, L., 1988. Persistence of oxytetracycline in sediments from
fish farms. Aquaculture, 70(4), pp.365-370.
11- Khan, S., Ullah, M.W., Siddique, R., Nabi, G., Manan, S., Yousaf, M. and Hou, H.,
2016. Role of Recombinant DNA Technology to Improve Life. International journal of
genomics, 2016
References

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12- Park, J.W., Hwang, S.R. and Yoon, I.S., 2017. Advanced growth factor delivery
systems in wound management and skin regeneration. Molecules, 22(8), p.1259.
13- Martin, P.; Nunan, R. Cellular and molecular mechanisms of repair in acute and
chronic wound healing. Br. J. Dermatol. 2015, 173, 370–378. [CrossRef] [PubMed].
14-Suh, D.W., Lew, B.L. and Sim, W.Y., 2014. Using recombinant human epidermal
growth factor for the successful treatment of an excisional wound without a primary
closure. Dermatologic Surgery, 40(6), pp.706-708.
15-Kim, Y.S., Lew, D.H., Tark, K.C., Rah, D.K. and Hong, J.P., 2010. Effect of
recombinant human epidermal growth factor against cutaneous scar formation in murine
full-thickness wound healing. Journal of Korean medical science, 25(4), pp.589-596.
References

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