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This paper studies the healing effect of recombinant human epidermal growth factor (EGF) on chronic diabetic foot ulcers. A total of 89 patients (65 male and 24 female) aged from 36 to 82 years (average of 54) enrolled for the prospective, open-label trial, crossover study. Predetermined criteria were used for diagnosis and classification of ulcer. The average duration of ulcer was 6 months (range from 3 to 27 months) prior to study. Upon study, the ulcers were debrided and treated with hydrocolloid or composite dressing depending on the condition of the wound. If treatment effect was minimal using advanced dressing for 3 weeks, patients were crossed over to twice-a-day treatment with 0.005% EGF and advanced dressing. Among the patients, 21 patients showed improvement using hydrocolloid or composite dressing alone and 68 patients were crossed over to treatment with EGF and advanced dressing. In the EGF-treated patients, complete healing was noted in 52 patients within an average of 46 days (range from 2 to 14 weeks). Recurrence was not noted during the 6-month observation. But 5 patients showed new lesions different from the prior site. Sixteen patients required further interventions. This paper suggests that topical treatment with EGF combined with advanced dressing may have positive effects in promoting healing of chronic diabetic foot wounds.
BACKGROUND:: Diabetic foot ulcer is a major health care problem that leads to amputation.
METHODS:: Patients with full-thickness diabetic neurotrophic foot ulcers present for longer than 8 weeks without healing were entered into one of five randomized, prospective, blinded clinical trials comparing treatment with platelet-derived growth factor (PDGF) or placebo gel for up to 20 weeks. The purpose of these trials was to assess the safety and efficacy of PDGF used with good wound care. Each patient had an adequate arterial blood supply, was free of infection, was off-loaded, and was extensively débrided. The ulcers had been present for at least 8 weeks.
RESULTS:: A total of 922 patients were entered into the study. Analysis of ulcers with a baseline area of less than 10 cm (95 percent of patients) showed that patients treated with PDGF at 100 mug/g had a significant increase in complete healing compared with patients given placebo (50 percent versus 36 percent, p < 0.007). PDGF also decreased the time to complete healing by 30 percent (14 weeks versus 20 weeks, p = 0.01). Adverse events were similar in both treatment groups, as were recurrent ulcer rates.
CONCLUSION:: PDGF applied once daily was effective in healing chronic diabetic neurotrophic foot ulcers when used in conjunction with good wound care.
OBJECTIVE: To compare the platelet enrichment ratio of platelet-rich plasma (PRP) prepared by different centrifuge methods and to compare the concentration of growth factors released from autologous platelet-rich gel (APG) with the whole blood.
METHODS: Thirteen diabetic patients with refractory skin lesions were enrolled in APG treatment. (1) Three kinds of centrifuge methods were selected for PRP by 11 diabetic patients: A (n = 6): 529 x g for 4 minutes in the first centrifuge and 854 x g for 6 minutes in the second centrifuge; B (n = 5): 313 x g for 4 minutes in the first centrifuge and 1,252 x g for 6 minutes in the second centrifuge; C (n = 5): 176 x g for 5 minutes in the first centrifuge and 1,252 x g for 5 minutes in the second centrifuge. Platelet counted on the whole blood and PRP was determined. The APG, produced by combining the PRP with thrombin and calcium gluconate (10:1) was used by patients. (2) PDGF-BB, TGF-beta1, VEGF, EGF, and IGF-1 were measured in the APG and the whole blood using the enzyme-linked immunosorbent assay method.
RESULTS: (1) The average platelet concentration was higher in group B [(1,363.80 +/- 919.74) x 10(9)/L] than in groups A [(779.67 +/- 352.39) x 10(9)/L)] and C [(765.00 +/- 278.78) x 10(9)/L] and the platelet recovery rate was 75.2% +/- 21.0% in group B. (2) The concentration of growth factors all increased with the increasing platelet number. On average, for the whole blood as compared with APG, the PDGF-BB concentration increased from (145.94 +/- 133.24) pg/mL to (503.81 +/- 197.86) pg/mL (P < 0.05); TGF-beta1 concentration increased from (3.31 +/- 2.27) ng/mL to (5.67 +/- 4.80) ng/mL (P < 0.05); IGF-1 concentration increased from (14.54 +/- 35.34) ng/mL to (110.56 +/- 84.36) ng/mL (P < 0.05); and EGF concentration increased from (160.73 +/- 71.10) pg/mL to (265.95 +/- 138.43) pg/mL (P < 0.05). No increase was found for VEGF (P > 0.05). (3) There was positive correlation between the platelet concentration and PDGF-BB and TGF-beta1 (r = 0.627, r = 0.437, P < 0.05). (4) Thirteen diabetic repractory dermal ulcers received APG treatment for 18 times, 9 ulcers (69.2%) and 10 sinuses (88.3%) were cured at the end of 12-week treatment.
CONCLUSION: The method of group B is the best centrifuge method. A variety of growth factors are detected and released from the platelets at significant levels in APG. There is positive correlation between the platelet concentration and PDGF-BB and TGF-beta1.
An Evidence-Based Model Comparing the Cost-effectiveness of Platelet-Rich Plasma Gel to Alternative Therapies for Patients with Nonhealing Diabetic Foot Ulcers.
Dougherty EJ. Adv Skin Wound Care. 2008 Dec;21(12):568-575.
Quote:
OBJECTIVE:: A cost-effectiveness analysis compared the potential economic benefit of an autologous, platelet-rich plasma (PRP) gel to alternative therapies in treating nonhealing diabetic foot ulcers.
DESIGN:: An economic model used peer-reviewed data to simulate clinical and cost outcomes and quality-adjusted life-years (QALYs) associated with PRP gel and other treatment modalities. PATIENTS:: The model varies rates of healing, recurrence, infection, amputation, death, and associated costs for a hypothetical group of 200,000 patients with full-thickness, nonhealing diabetic foot ulcers for 5 years or until death.
MAIN OUTCOME MEASURES:: The model simulates the clinical, cost, and QALY outcomes associated with PRP gel versus other modalities in treating nonhealing diabetic foot ulcers over a 5-year period.
MAIN RESULTS:: The average 5-year direct wound care cost per modality and QALYs were PRP gel, $15,159 (2.87); saline gel, $33,214 (2.70); standard of care, $40,073 (2.65); noncontact kilohertz ultrasound therapy, $32,659 (2.73); human fibroblast-derived dermal substitute, $40,569 (2.65); allogenic bilayered culture skin substitute, $24,374 (2.79); bilayered cellular matrix, $37,340 (2.71); negative pressure wound therapy, $20,964 (2.81); and recombinant human platelet-derived growth factor BB, $47,252 (2.69).
CONCLUSION:: Use of PRP gel resulted in improved quality of life and lower cost of care over a 5-year period than other treatment modalities for nonhealing diabetic foot ulcers. Although actual treatment outcomes may differ from those modeled, PRP gel represents a potentially attractive treatment alternative for insurers and health care providers to address the cost burden and health effects of nonhealing diabetic foot ulcers.
A patent has just been granted this: Methods for enhancing healing of diabetic foot ulcers by injecting epidermal growth factor (EGF)
Quote:
The invention relates to the use of Epidermal Growth Factor (EGF) in a preferably-injectable pharmaceutical composition which is administered by means of infiltration into and around chronic cutaneous ischaemic lesions in order to prevent diabetic foot amputation. Said composition can be administered to recently-created surgical surfaces damaged by the effect of acute reperfusion with oxygenated blood following prolonged ischaemia, thereby preventing further surgical procedures and favouring the preservation of the extremity. The aforementioned composition can be used to improve (i) the cell microenvironment, thereby increasing the reparative and defensive capacity and viability of the is tissues and (ii) the cicatrisation of cutaneous ischaemic lesions, thereby stimulating cell proliferation. The invention is suitable for use in human, veterinary and experimental medicine, specifically in vascular angiology and surgery, dermatology, burn treatment and reconstructive surgery and geriatric medicine. Said composition can be used for recalcitrant ulcers which are associated with lesions in the macro and/or microvasculature, patients with inadequate lymphatic and/or venous return and ulcers or other lesions which are difficult to cicatrise and/or heal.
DETAILED DESCRIPTION OF THE INVENTION
Quote:
The object of the invention herein described is the use of an injectable pharmaceutical composition containing Epidermal Growth Factor (EGF) that enhances tissue survival and adaptation to hipoxia; which allows for the healing of cutaneous ischemic and chronic ulcers of skin and adjacent soft tissues in an irreversible manner. The composition allows for the healing of ischemic ulcerative or not type wounds or those wounds exposed to and damaged by the process of reperfusion with arterial blood on the skin and sift adjacent tissues. It is defined the ischemic wound in this context as that of skin and soft tissues of the lower limb as a result of a failure in the peripheral perfusion due to a long term damage of large and small vessels in a diabetic patient. The wounds affected by the reperfusion process are mostly created upon amputation or sharp debridement when the oxygenated blood supply is reinitiated following prolonged periods of territorial hemodynamic perfusion silence. Alternatively, these processes may appear following revascularization surgical procedures in diabetic patients.
The use of EGF in these lesions attenuates the progressive tissue deterioration, particularly in the legs and the feet associated to blood flow failure and toxin storage in the tissues.
The composition of the invention has shown to trigger and steadily sustain the process of healing in chronic ischemic wounds in which the current art therapy has been unsuccessful. By using this composition limb amputation is unnecessary when there are no other medical choices available for the ischemic and chronic wound. The composition has proved to be useful as well in reducing the damages associated to surgical reperfusion allowing for the complete healing of ulcers in ischemic/infected/neuropathic feet. The process of cellular arrest on the wound edges and the subsequent tissue fading are overtly aborted with this therapy. This excludes the need for further and progressive sharp debridements and partial amputations. The composition by mean of a generally cytoprotective and rescue effects enhances the healing of ischemic/infectious/neuropathic diabetic foot ulcers.
The composition is applied by mean of local infiltration within the wound margins and bottom of the lesions, and might contain the polypeptide obtained by natural, recombinant or synthetic technologies. The administration procedure is like a local anesthetic blockade inserting the needle in different point into and around the lesion, so that all the deep bottom surface and edges are flushed with the composition. The composition is deposited into 4 to 20 infiltration points so that in between each point the distance must be no longer that 1,5 cms. The number of points to be covered is according to that skilled in the art. Such wounds with bigger size will require a larger number of instillation points. The skilled in the art will perceive a couple of well recognized effects on the administration time: local edema and local resistance to the composition flushing. Sharp debridement of wound edges and bottom will be according to the experience of the skilled in the art. In general terms sharp debridements and minor amputations are significantly reduced upon treatment progression. If along the treatment period edges become atonic, they can be conservatively debrided and later infiltrations are to be carried out in a sub-epithelial space. Infiltrations are usually conducted on alternate days of a week so that in each week three infiltration sessions are conducted. The number of infiltration points in each session depends upon the size of the wound, ordinarily ranging between 4-20. In infectious/ischemic wounds as in stages IV and V according to Wagner's classification the outbreak of granulation tissue is following the sixth infiltration session. In less severe wounds, it is possible to see some response since the first week of treatment, so after three infiltration sessions. Alternatively, in very severe ischemia associated to total deficit of peripheral beat and anemia below 9 g/L the treatment has been used under daily bases. In these patients granulation evidences are imitated around the ninth session of infiltration. In all the cases the total volume to inject is about 1 milliliter, so that an ulcer may receive a total volume of 4-20 mL of the composition. It is preferably the use of hypodermic needles 271/2. The composition may contain the EGF polypeptide obtained from a natural source, via chemical synthesis or by mean of recombinant DNA technology. The use of the pharmaceutical composition containing EGF described herein has permitted the complete tissue regeneration of chronic and ischemic lesions whereas the procedure is minimally invasive. The use of the composition has also reduced the number of surgical interventions and the number of minor or major amputations. In other cases, the use of the herein described invention has allowed (I) removal of ischemic capsules with no need for surgical procedures. This is probably due to the emergence of a new remodeling granulation tissue from deep zones, which pushes up and detaches the necrotic material. (II) The growth of a new intra cutaneous fibroangiogenic tissue, consequent to successive infiltrations, before going to amputation as for examples in toes, so that there is a previous pro-granulating environment. This contributes to limit and to abort the septic complications, enhances wound healing and attenuates the reperfusion damages.
The components of the pharmaceutical composition are as follows:
Epidermal growth factor (EGF): Cytoprotective agent that allows for the activation of cellular self-defense mechanisms when administered into the ulcer. EGF promotes adaptation and survival rescue of cells within stressful conditions. EGF triggers is apoptosis in aged fibroblasts as those damaged and/or aged, and acts as a survival factor to others that are eventually rescued. EGF plays a selective pressure within the microenvironment, where adapted cells are committed to proliferate. Due to its cytoprotective effect, ischemia/reperfusion damages are prevented. The composition contains 10-1000 micrograms/ml of sterile vehicle. EGF may be natural, synthetic or recombinant. EGF may be in liquid form, suspended in water, in solution with a buffer, freeze-dried to be dissolved, etc. EGF may be as a powder of fine granulate, and to be applied by mean of high pressure shooting device. EGF may be administered as in its DNA form within a proper genetic construct suitable for its expression transiently transfected human cells.
Polyethyleneimine (PEI): This is highly positively charged--protonated chemical compound that enhances the interaction of EGF with its receptor, prolongs its half life in the extracellular matrix and prevents its intracellular degradation, so that in this way its biological effects are amplified. It may be found in the formulation in a molar relation of 1:1 with EGF up to 1 (EGF): 10 (PEI).
Sodium Phosphate Buffer: Chemical stabilizer. Its pH is about 6.5 and in a molar range concentration of 5-100 mM. The optimal range in the formulation is 10-20 mM.
O-Raffinose: Stabilizing agent for the freeze drying process. Concentrations of 5-50 mg/ml can be used whereas its optimal rage is 8-20 mg/ml.
L-Glycine: Isotonizing agent. Concentrations of 5-50 mg/ml can be used whereas its optimal rage is 10-20 mg/ml.
Fibronectin: Promotes the stability of EGF as its biological functioning. It promotes the interaction between EGF and its cellular receptors. It is in a range from 10-20 mcg/mL.
Levan: This is a protecting agent for EGF when it is in solution. It acts screen agent for EGF. Facilitates its biodistribution within the extracellular space. In the composition it is found in a range from 1-20 mgs/mL.
The pharmaceutical composition might combine EGF as well with the following active principles:
Rutin: Phlebotonic and phlebotrophic. It might be present in the formulation at concentrations of 20-1000 .mu.g/ml. It might be used as a free Rutin hydrate or as a lyophilized salt of Rutin, as in a sulphate.
Lidocaine: Trophic agent. Lidocaine contributes to attenuate the local secretion of pro-inflammatory cytokines, as the expression of adhesion molecules within the vascular lumen. In the formulation lidocaine is used as a chlorhydrate and its concentration might be present in a range of 5-40 mg/ml.
Adenosine tri-phosphate (ATP): It plays vasodilator and pro-metabolic effects. Its concentration in the formulation ranges from 0.05 to 20 mg/ml as a sodium salt or free acid.
Guanosine triphosphate (GTP): Enhances local vasodilatation. It is present in the formulation as a sodium salt. Its concentration ranges from 1 to 100 mg/ml.
Amide of the nicotinic acid (Nicotinamide): Renders useful anabolic substrates for the cells. Its concentration ranges from 1 to 130 mg/ml.
L-Arginine: Contributes to the regulation of the vascular tone. Useful in the formulation as hydrochloride crystals. Its concentration ranges from 1-100 ng/ml.
Heparin: Cytoprotective, pro-mitogenic agent. Useful in the formulation as a sodium salt, in a concentration ranging from 1 to 10 .mu.g/ml (0.1-1 U).
EXAMPLES
A total number of 9 patients received therapy with the pharmaceutical composition. All the patients shared the following characteristics: 1. All the patients were affected by type-II diabetes mellitus, with an evolution of 10-25 years, basically treated with oral hypoglycemiants. 2. A history of difficult healing was registered for all the patients. Some patients had undergone previous contra lateral amputations. 3. All the wounds treated corresponded to diabetic limb chronic ulcers, being classified as ischemic/infectious/neuropathic diabetic foot or mixed forms. Stages IV or V according to Wagner's classification predominated for all the wounds. 4. All the wounds treated with the present formulation might be considered as recalcitrant or difficult to heal wounds; some with one month or more of age. 5. All the wounds were about or larger than 20 cm.sup.2; in most case ulcers depth involved the periosteum, having bone tissue overtly exposed. Among, them a patient is included with concomitant ischemic calcaneous. 6. All the patients treated were highly prone to amputation 7. All the patients were followed after hospital discharge and none of them has recurred so far. Neither late adverse reactions nor local ischemia signs were observed. No adverse reactions have been registered upon time.
Treatment was based on deep perilesional infiltrations over at least five different and equidistant points of the wound bottom and contours. The syringe needle must always be oriented toward the central basement area of the wound bottom, to the edges and/or to tunnels when exist. On each injection point, 1 ml of solution is deposited. No unwanted reactions are observed along or next to the treatment, except the ordinary local sore. The formulation always borne EGF as main active principle, while in some instances, the formulation contained some of the above mentioned active principles. In all the patients treated toes, foot, or major amputations procedures were prevented. The total number of infiltration sessions for each patient is shown in each example.
Example 1
Patient ACDF, 49 years old, female. Patient bearing an ischemic/infectious diabetic foot, affected by type-II diabetes mellitus with an evolution of 16 years, the patient had undergone prior sympathectomy and supracondilial amputation of the right limb a couple and half years ago. The first finger of the left foot was surgically removed while showing an ulcerative, humid, atonic, and difficult-to-heal lesion despite many minor surgical debridements to remove ischemic capsules, revitalize the edges and the bottom of the wound. The amputation shaft turned ischemic, with cyanotic and atonic edges following 5 days of the surgery. The infiltration of the composition is initiated expecting spontaneous re-epithelialization of the ulcer. From the fourth infiltration it was noticed a dramatic change of the aspect of the wound, starting a productive granulation tissue, bleeding, and that after a few days it was resurfaced with epithelium. The patient received a total of 9 sessions of infiltration (3/weeks and therefore three weeks of treatment). Following re-epithelialization she was discharged from hospital. Has shows a satisfactory evolution with recurrence.
Example 2
Patient ERC, 66 years old, female. Patient with a 12 yr. evolution of type-II diabetes mellitus, bearing an ischemic infectious foot and lacking distal beatings. A minor is transmetatarsal amputation was practiced having a large tunnel downward. The base of the amputation turned cyanotic, ischemic, atonic, and with large deposit of a yellow component. The infiltrations are begun with the expectance of producing granulation tissue and a spontaneous second intent healing. The wounded foot had completely healed, granulated and resurfaced with epithelium, including the tunnel after 11 infiltration sessions. It included a lateral tunnel of about 4 cms In depth. Evidences of scar remodeling are observed in this patient for the first time.
Example 3
Patient ECS, 63 years old, female. Patient type-II diabetes mellitus since she was 41 years old. She is bearing an ischemic infectious foot and with a previous contralateral infra-condilial amputation. She is admitted to receive amputation of her first toe due to severe ischemia. Upon surgery an ischemic capsule is implanted on the base of the next toe that extended back and downward. At this point the lesion is atonic, and no healing progress is observed. Fingers and adjacent soft tissues are removed, opening a large and deep edge, resembling a 6 cms length tunnel. Ischemic and necrosis signs recurred on day 3 post-surgery. Wound contours turn cyanotic and ischemic three days later. The composition infiltrations are initiated expecting a second intent healing response. Complete healing was achieved following 11 sessions when the patient had fully re-epithelialized the wound with well-keratinized epithelium. The patient was discharged from hospital. Scar remodeling was also observed.
Example 4
Patient RNP, 69 years old, male. A patient with a 12 yr. old evolution of type-II diabetes, with distal beatings deficit, bearing an ischemic/infectious foot. The patient undergoes a transmetatarsal amputation due to ulcerative lesions, recalcitrant to heal with current art therapy. On the surgical area ischemic plaques were onset and the healing process did not show to progress any longer. Patient complained of spontaneous pain on bed. The cyanosis extended around the surgery contours and there was negligible bleeding during debridements. The ischemic plaques were surgically removed, and on day 4.sup.th post-surgery infiltrations therapy were initiated. Evidences of tissue improvement were observed on day 6 post-infiltration, so that spontaneous pain disappeared, and being overtly expressed a red granulation tissue. Following 12 infiltration sessions, the patient had completely re epithelialized the wound, so it means 4 weeks of treatment. He was discharged from hospital and has evolved well with no recurrence upon a 12-months follow up.
Example 5
Patient ISV, 74 years, female. Patient afflicted by diabetes since 30 years ago. She is bearing an ischemic/infectious foot. There is a previous transmetatarsal amputation and a history of deficit of healing. She is admitted due to necrotic lesion of the 5.sup.th toe. The surgery is practiced and ischemic plaques appear over the next few days. She received further debridement and an external extensive edge is opened with exposed periosteum in the inferior and external side of the foot. The edge became ischemic over the next 48 hours, thus, the infiltration therapy is introduced trying to achieve a spontaneous second intent heal, including the edge. After the 6.sup.th infiltration a useful and bleeding granulation tissue arises. The lesion favorably responded to the treatment and was fully epithelialized following 11 sessions. The patient has had a satisfactory evolution following hospital discharge.
Example 6
Patient RDR, 44 years old, male. A patient affected by type-II diabetes since 12 years ago. He bears an ischemic/infectious diabetic foot that due to ischemic lesions on two toes receives transmetatarsal amputation. The patient lacks distal beatings and shows clinical evidences of insufficient peripheral perfusion. He has a history of healing failure on the contralateral tibial region. Following amputation cyanotic foci appeared on the cutaneous contours of the wound. The infiltration is begun with the expectance of rendering sufficient granulation tissue to host an auto-graft, or to heal and remodel by second intent. On the 4.sup.th infiltration the first sprouts of granulation tissue appear and reanimation of the wound edges, which also were normochromic and hypertrophic. The auto-graft was unnecessary. By carrying out 15 infiltration sessions (5 weeks) there was no required to make a self auto-grafting. Upon hospital discharge has had a successful evolution.
Example 7
Patient RGR, 49 years old, female. This is diabetes patient since about 10 years with painful claudicating along 100 meters walk and difficult to heal histories. She has had several recalcitrant ulcers on the paratibial area of both limbs. The lesion to be treated is an ischemic ulcer on the lower third of the left leg on its lateral external side with approximately 6.4 cms of diameter and 0.5 cm depth. The ulcer has progressed for two months with no healing. The first approach was conservative debridement of bottom and edges, starting the treatment on the other day. The lesion began to granulate on third infiltration, with contraction of the edges and proliferation of a simple neo-epithelium that eventually became stratified and keratinized. 12 infiltrations sessions were carried out (4 weeks of treatment). Following hospital discharge has satisfactorily.
Example 8
Patient GPJ, 57 years old. The patient has a 12 years evolution of a type-II diabetes mellitus. He bears an ischemic/infectious diabetic foot with no sign of tibial beatings. He suffers a transmetatarsal amputation due to ischemia and necrosis of 4 toes of the right foot. Seven days after the amputation the healing process is halted and the wound edges became cyanotic and devitalized with no evidence of wound repair. The infiltrations are initiated as an alternative maneuver of other surgical interventions. After 9 sessions (3 weeks) the patient had fully re-epithelialized. Upon hospital discharge he has successfully evolved with no complications.
Example 9
Patient DLF, 51 years old, male. A patient with type-II diabetes history and asthma of about 20 years ago. The patient is admitted with a perforating plantar ulcer with severe ischemia and necrosis of the surrounding tissue. The left foot had almost fully demised. The Calcaneus ends up after surgery with an exposed periosteum. Infiltrations are initiated and tried as an alternative of immediate amputation. The only possibility was the uprising of a productive and vascularized granulation tissue suitable to host a skin graft. There were a total of 15 infiltration sessions including the Calcaneus. Upon the 5.sup.th infiltration the granulation tissue starts to bud. When the 15 infiltration sessions were concluded (5 weeks) grafting was implanted. The patient has successfully evolved. He is currently able to walk by himself.
Repair effect of diabetic ulcers with recombinant human epidermal growth factor loaded by sustained-release microspheres.
Dong X, Xu J, Wang W, Luo H, Liang X, Zhang L, Wang H, Wang P, Chang J. Sci China C Life Sci. 2008 Nov;51(11):1039-44.
Quote:
In this study the w/o/w extraction-evaporation technique was adopted to prepare poly(lactic-co-glycolic acid) (PLGA) microspheres loading recombinant human epidermal growth factor (rhEGF). The microspheres were characterized for morphology by transmission electron microscopy (TEM) and particle size distribution. The release performances, the proliferation effects and therapeutic effects of rhEGF-loaded PLGA microspheres were all studied. The results showed that these spherical microspheres had a narrow size distribution and a high drug encapsulation efficiency (85.6%). RhEGF-loaded microspheres enhanced the growth rate of fibroblasts and wound healing more efficiently than pure rhEGF. The number of the proliferating cell nuclear antigen (PCNA) in the epidermis layer with the microsphere treatment was significantly larger than those of the control groups. Overall locally sustained delivery of rhEGF from biodegradable PLGA microspheres may serve as a novel therapeutic strategy for diabetic ulcer repair.
Intralesional administration of epidermal growth factor-based formulation (Heberprot-P) in chronic diabetic foot ulcer: treatment up to complete wound closure.
Fernández-Montequín JI, Betancourt BY, Leyva-Gonzalez G, Mola EL, Galán-Naranjo K, Ramírez-Navas M, Bermúdez-Rojas S, Rosales F, García-Iglesias E, Berlanga-Acosta J, Silva-Rodriguez R, Garcia-Siverio M, Martinez LH. Int Wound J. 2009 Feb;6(1):67-72.
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Previous studies have shown that an epidermal growth factor-based formulation (Heberprot-P) can enhance granulation of high-grade diabetic foot ulcers (DFU). The aim of this study was to explore the clinical effects of this administration up to complete wound closure. A pilot study in 20 diabetic patients with full-thickness lower extremity ulcers of more than 4 weeks of evolution was performed. Mean ulcer size was 16.3 +/- 21.3 cm(2). Intralesional injections of 75 microg of Heberprot-P three times per week were given up to complete wound healing. Full granulation response was achieved in all 20 patients in 23.6 +/- 3.8 days. Complete wound closure was obtained in 17 (85%) cases in 44.3 +/- 8.9 days. Amputation was not necessary in any case and only one relapse was notified. The most frequent adverse events were tremors, chills, pain and odour at site of administration and local infection. The therapeutic scheme of intralesional Heberprot-P administration up to complete closure can be safe and suitable to improve the therapeutic goal in terms of healing of chronic DFU.
Analysis of patient cost for recombinant human platelet-derived growth factor therapy as the first-line treatment of the insured patient with a diabetic foot ulcer.
Lantis JC 2nd, Boone D, Gendics C, Todd G. Adv Skin Wound Care. 2009 Apr;22(4):167-71.
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INTRODUCTION: The 2-year cost of a new diabetic foot ulcer (DFU) is estimated to be $27,987. These costs are thought to be secondary to hospitalization, amputation, and the duration of care. Treatments that accelerate rapid and complete healing of DFUs reduce the need for hospitalization, thus reducing the costs of care. One of the therapies previously shown to lead to more rapid and complete wound healing of DFUs is recombinant human platelet-derived growth factor (rhPDGF). Many centers, however, do not initiate rhPDGF therapy, based on patient cost issues. Therefore, many centers reserve a potentially cost-saving therapy as a second- or third-line therapy. The goal of the authors' analysis was to examine the actual cost to patients of a policy of initiating rhPDGF as the initial therapy for appropriately debrided DFUs. METHODS: A 12-month retrospective analysis of all patients presenting to a tertiary care referral wound practice with the diagnosis of DFUs was performed. The algorithm the authors followed specified that all wounds of patients with an ankle brachial index of greater than 0.7 and a diagnosis of DFUs (that were not enrolled in a research protocol) were debrided widely (ie, all wounds were debrided sharply with a 45-degree bevel on the border and the bases of the wounds were sharply debrided to a clean granular base), provided off-loading, and initiated on rhPDGF at the patients' first center visit. The patient payer mix and average cost-per-patient per year were analyzed, and the average number of tubes of rhPDGF was recorded. RESULTS: There were 121 patients with the diagnosis of DFUs, representing 766 visits. A total of 187 tubes of rhPDGF were prescribed for these 121 patients over the course of 12 months. There was an average use of 1.54 tubes per patient. The primary payer mix was Medicare, 44%; Medicaid, 27%; and private-payer mix, 29%, representing 10 companies. The average patient cost per tube was $28, the average cost for Medicare was $25 (many with secondary payers, as data predate 2006 Medicare D), Medicaid was $2, and private insurance was $71. Therefore, the average patient cost per course of therapy was $42. DISCUSSION: The average cost to patients with prescription benefits for a course of rhPDGF therapy, over a diverse and representative patient mix, is less than $50 in an inner-city tertiary care facility. Thus, patient cost alone should not provide a barrier to initiating active therapy in the form of rhPDGF to the patient presenting with a DFU. This early initiation could potentially lead to lower overall health costs by improving wound-healing outcomes.
The efficacy and safety of epidermal growth factor in treatment of diabetic foot ulcers: the preliminary results.
Tuyet HL, Nguyen Quynh TT, Vo Hoang Minh H, Thi Bich DN, Do Dinh T, Le Tan D, Van HL, Le Huy T, Doan Huu H, Tran Trong TN. Int Wound J. 2009 Apr;6(2):159-66
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Objective: To evaluate the efficacy and safety of recombinant human epidermal growth factor (rh-EGF) in healing foot ulcers in diabetic patients.
Methods: A total of 28 subjects with foot ulcers were recruited into the pilot study. Patients who had obvious peripheral arterial disease, trans-tibial amputation, plastic surgery or skin flap, and skin graft were excluded. The properly debrided wounds and the non closure wounds after toe amputation were included. When the wounds became clean or uninfected, they received twice-a-day treatment with 0.005% Easyef and hydrocolloid dressing. The size and severity of the wounds were evaluated. Others such as blood sugar, renal and hepatic function, serum albumin, vascular condition, foot infection or osteomyelitis were assessed.
Results: All of 28 patients had positive response of granulation (100%). Complete healing was noted in 13 out of 23 subjects and finished 8-week follow-up (56.5%). The rates of wound closure were 43.3%, 59.9%, 68.7%, and 84.8% in week 2, 4, 6 and 8, respectively, regardless of the severity. Being dropped out, three patients needed further interventions. No skin allergic reaction. Over-granulation was observed in one female patient (3.7%), but as minor.
Conclusions: Easyef has positive effects on healing of moderate-to-severe foot ulcers and demonstrated being safe to diabetic patients. The drug had high tolerability and compliance.
BACKGROUND: G-CSF increases the release of neutrophil endothelial progenitor cells from the bone marrow, and improves neutrophil functions, which are often impaired in people with diabetes.
OBJECTIVES: To examine the effects of adjunctive G-CSF compared with placebo or no growth factor added to usual care on rates of infection, cure and wound healing in people with diabetes who have a foot infection.
SEARCH STRATEGY: We searched the Cochrane Wounds Group Specialised Register (Searched 16/3/09); the Cochrane Central Register of Controlled Trials (The Cochrane Library, issue 1 2009); Ovid MEDLINE (1950 to March Week 1 2009); Ovid EMBASE (1980 to 2009 Week 11); EBSCO CINAHL (1982 to March Week 2 2009); LookSmart's Find Articles (January 1990 to January 2008); conference proceedings and references lists in the included studies.
SELECTION CRITERIA: Randomised controlled trials (RCTs) that evaluated the effect of adding G-CSF to usual care in people with a diabetic foot infection.
DATA COLLECTION AND ANALYSIS: Three review authors independently assessed trial eligibility, methodological quality and extracted data. Relative risk (RR), or for continuous outcomes, mean differences (MD), with 95% confidence intervals (CI) were reported. In the case of low or no heterogeneity studies were pooled using a fixed-effect model.
MAIN RESULTS: We identified and included five eligible trials with a total of 167 patients. The investigators administered various G-CSF preparations, at different doses and for different durations of time. Adding G-CSF did not significantly affect the likelihood of resolution of infection or wound healing, but it was associated with a significantly reduced likelihood of lower extremity surgical interventions (RR 0.37; 95 % CI 0.20 to 0.68), including amputation (RR 0.41; 95 % CI 0.18 to 0.95). Moreover, providing G-CSF reduced the duration of hospital stay (MD, -1.40 days; 95 % CI, -2.27 to -0.53 days), but did not significantly affect the duration of systemic antibiotic therapy (MD, -0.27 days; 95 % CI, -1.30 to 0.77 days).
AUTHORS' CONCLUSIONS: The available evidence is limited, but suggests that adjunctive G-CSF treatment in people with a diabetic foot infection, including infected ulcers, does not appear to increase the likelihood of resolution of infection or healing of the foot ulcer. However, it does appear to reduce the need for surgical interventions, especially amputations, and the duration of hospitalisation. Clinicians might consider adding G-CSF to the usual treatment of diabetic foot infections, especially in patients with a limb-threatening infection, but it is not clear which patients might benefit.
Systematic review of economic evaluations of human cell-derived wound care products for the treatment of venous leg and diabetic foot ulcers.
Langer A, Rogowski W. BMC Health Serv Res. 2009 Jul 10;9(1):115.
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ABSTRACT: BACKGROUND: Tissue engineering is an emerging field. Novel bioengineered skin substitutes and genetically derived growth factors offer innovative approaches to reduce the burden of diabetic foot and venous leg ulcers for both patients and health care systems. However, they frequently are very costly. Based on a systematic review of the literature, this study assesses the cost-effectiveness of these growth factors and tissue-engineered artificial skin for treating chronic wounds.
METHODS: On the basis of an extensive explorative search, an appropriate algorithm for a systematic database search was developed. The following databases were searched: BIOSIS Previews, CRD databases, Cochrane Library, EconLit, Embase, Medline, and Web of Science. Only completed and published trial- or model-based studies which contained a full economic evaluation of growth factors and bioengineered skin substitutes for the treatment of chronic wounds were included. Two reviewers independently undertook the assessment of study quality. The relevant studies were assessed by a modified version of the Consensus on Health Economic Criteria (CHEC) list and a published checklist for evaluating model-based economic evaluations.
RESULTS: Eleven health economic evaluations were included. Three biotechnology products were identified for which topical growth factors or bioengineered skin substitutes for the treatment of chronic leg ulceration were economically assessed: (1) Apligraf(R), a bilayered living human skin equivalent indicated for the treatment of diabetic foot and venous leg ulcers (five studies); (2) Dermagraft(R), a human fibroblast-derived dermal substitute, which is indicated only for use in the treatment of full-thickness diabetic foot ulcers (one study); (3) REGRANEX(R) Gel, a human platelet-derived growth factor for the treatment of deep neuropathic diabetic foot ulcers (five studies). The studies considered in this review were of varying and partly low methodological quality. They calculated that due to shorter treatment periods, fewer complications and fewer inpatient episodes the initial cost of the novel biotechnology products may be offset, making the treatment cost-effective or even cost-saving. The results of most studies were sensitive to initial costs of the products and the evidence of effectiveness.
CONCLUSIONS: The study results suggest that some growth factors and tissue-engineered artificial skin products feature favourable cost-effectiveness ratios in selected patient groups with chronic wounds. Despite the limitations of the studies considered, it is evident that health care providers and coverage decision makers should take not only the high cost of the biotechnology product but the total cost of care into account when deciding about the appropriate allocation of their financial resources. However, not only the cost-effectiveness but first of all the effectiveness of these novel biotechnology products deserve further research.
Treatment of nonhealing diabetic foot ulcers with a platelet-derived growth factor gene-activated matrix (GAM501): Results of a Phase 1/2 trial.
Mulder G, Tallis AJ, Marshall VT, Mozingo D, Phillips L, Pierce GF, Chandler LA, Sosnowski BK. Wound Repair Regen. 2009 Oct 12. [Epub ahead of print]
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The results from a Phase 1/2 study of a replication-defective adenovirus encoding human platelet-derived growth factor (PDGF)-B formulated in a bovine collagen (Ad-5PDGF-B; 2.6% collagen; GAM501) gel for nonhealing neuropathic diabetic foot ulcers is reported. The primary objectives of the study were to evaluate the safety, maximum-tolerated dose, and preliminary biological activity of GAM501. Fifteen patients enrolled into the study with chronic, nonhealing ulcers received either a single administration of GAM501 at one of three dose levels, or up to four administrations of GAM501 at 1-week intervals. All patients received standard of care treatment including debridement and were required to wear an off-loading shoe. GAM501 was found to be safe and well tolerated with no evidence of systemic or local toxicity at all doses so no maximum-tolerated dose was reached. Serum antibody titers to platelet-derived growth factor-B homodimer and collagen were negative and adenoviral DNA was not detected in the blood. In the 12 patients that completed the study, ulcer closure was observed by Month 3 in 10 patients, seven of whom received a single application of GAM501. In conclusion, GAM501 did not appear to have any toxicity at doses that showed biological activity. GAM501 holds promise as a potentially effective treatment for nonhealing diabetic foot ulcers.
EGF and diabetic foot ulcer healing
Linear Mode
