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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/18—Growth factors; Growth regulators
  • A61K38/1808—Epidermal growth factor [EGF] urogastrone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
  • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
  • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
  • A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
  • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/465—Nicotine; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
  • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
  • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
  • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
  • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
  • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
  • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
  • A61K31/708—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
  • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
  • A61K31/727—Heparin; Heparan
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/39—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• the present invention relates to the use of a pharmaceutical composition containing Epidermal Growth Factor (EGF), preferably for injection and to be administered by infiltration into and around chronic ischemic skin lesions, for the prevention of diabetic foot amputation. . It can also be administered on newly created surgical surfaces and damaged by the effect of acute reperfusion with oxygenated blood after prolonged ischemia. This prevents surgical reinterventions and promotes limb preservation.
• EGF Epidermal Growth Factor
• metabolic correction which is based on the general control of risk factors and functional rest of the affected area.
• Another commonly used procedure is the use of antibiotics and early debridement of the fistulized pathways. It is performed whatever the perfusion situation of the infected foot.
• Hemorrheological Therapy which is based on the prevalence shown in the diabetic patient of hemorrhagic disorders and their role in the infection.
• Vasoactive therapy which has been used in local perfusion disorders, both due to macro and microangiopathy, with certain prostanoids acting at the tissue level.
• the patient's cardiocirculatory, renal and hepatic functions must be previously assessed, taking into account the frequent involvement of the first two in diabetic patients. They have also been used for certain states, platelet antiaggregants, and thrombolytic agents.
• the revascularization technique in the diabetic or non-diabetic ischemic patient is risky, expensive and not applicable to all patients, being its very limited indication, as well as endovascular surgery, which has shown viability limitations, both in the arterial sectors Aorto-ll ⁇ aco as Femoro-Popl ⁇ teo, attributable to calcification and greater lesional sectoriality.
• Lumbar sympathectomy is today exceptionally practiced in diabetic patients. The existence of a more or less evolved autonomic neuropathy makes it ineffective. Recently, the US Federal Food and Drug Administration (FDA) approved the use of human recombinant platelet-derived growth factor (PDGF) to stimulate the healing of neuropathic ulcers of the diabetic foot.
• FDA Federal Food and Drug Administration
• PDGF platelet-derived growth factor
• the results of the most recent, double-blind, multi- centric and randomized clinical trial show only 50% efficacy (T. Jeffery Wieman, Janice M. Smiell, Yachin Su. Efficacy and safety of topical gel formulation of recombinant human platelet-derived growth factor -BB (Becaplermin) in patients with chronic neuropathic diabetic ulcers. Diabetes Care 1998, 21: 822-827).
• the lesions treated in the trial with the recombinant PDGF-BB are incomparable in relation to the type and magnitude of which we have managed to heal with our invention.
• the test is performed on neuropathic lesions with a normal supply of arterial blood.
• the treated lesions are classifiable as grades IV - V of the Wagner scale with a severe ischemic component.
• All lesions included in our treatment scheme included a size greater than 20 square centimeters and from 10 to 40 millimeters deep.
• a critical aspect is the high recurrence rate reported in the PDGF-BB trial, being 30% in three months.
• Another recent invention for the treatment of extensive acute skin lesions such as burns, or chronic such as venous ulcers has been the creation of equivalent substitutes for human bioartificial skin. There are no controlled clinical studies in ischemic ulcers of the diabetic foot, and it is unlikely that these products can control the underlying ischemic process as a cause of healing failure (Editorial. New Skin for O ⁇ d. Developments in Biological Skin Substitutes. Arch Dermatol 1998; 134: 344-348).
• the object of this invention is the use of an injectable pharmaceutical composition containing Epidermal Growth Factor (EGF), which is capable of stimulating tissue survival and adaptation to hypoxia;
• EGF Epidermal Growth Factor
• the composition also allows irreversible healing of chronic skin lesions, of an ulcerative nature or not, classifiable as ischemic, or of those wounds damaged by the effect of reperfusion with arterial blood on the skin and adjacent soft tissues.
• ischemic injury is defined as those that occur in the skin and soft parts of the lower extremities of the diabetic patient, as a result of a pre-existing failure of peripheral perfusion due to damage to large and small vessels.
• the composition of the invention has been shown to start and maintain in a stable and irreversible way the healing process of chronic skin ulcers refractory to existing treatments, preventing the practice of amputations when there is no other alternative for the ischemic limb. It is particularly useful for preventing damage associated with surgical reperfusion, so that it is possible to control the atony and devitalization of tissues, to the point that it is unnecessary to continue removing areas of the limb.
• the composition by An initial mechanism of cytoprotection and rescue allows the healing of ischemic / infectious and neuropathic diabetic foot ulcers.
• the composition of the invention is used by local infiltration. This means the direct instillation of the composition in deep areas of the edges and the bottom of the lesions.
• the administration is carried out in the form of a block by inserting the needle at different points of the lesion, more or less equidistant and covering the entire deep surface of the fundus and contours of the lesions. Administration must be done by depositing the composition between 4 and 20 local infiltration points, and there must be a distance of 1 to 1.5 centimeters between the points.
• the number of points to be covered is at the discretion of the specialist who performs the infiltrations. Obviously, extensive and deep lesions are going to demand a greater number of instillation points.
• the specialist must perceive two effects at the time of administration: local edema and resistance of the tissue to the entry of the composition.
• the performance of practices such as resuscitation of edges and bottom of the wound will be at the discretion of the specialist; These practices are often significantly reduced as the treatment progresses. If at some point atony of the edges of the epithelium can be seen when a mature granulation tissue already exists, the epithelium can be conservatively resuscitated, and then proceed to infiltrate the sub-epithelial position.
• infiltration has been used as a treatment scheme on alternate days in a week, so that three infiltration sessions are held every week. The number of infiltration points in each session depends on the size of the lesion, but ranges from 4-20.
• ischemic / infectious lesions classifiable as grade IV and V of the Wagner scale the onset of granulation tissue outbreak is observed from the sixth session of infiltrations. In less severe lesions, it is possible to observe the beginning of response from the first week of treatment, that is, after three infiltration sessions. Alternatively, in cases of very severe ischemia with total absence of pulses, and patients with anemia below 9 g / l of hemoglobin, the treatment has been applied daily. In these patients, evidence of granulation begins at the ninth infiltration session.
• the composition may contain the EGF polypeptide, obtained naturally, by chemical synthesis, or by recombinant DNA technology. With the use of the pharmaceutical composition containing EGF of the present invention it has been possible to regenerate tissue in chronic and ischemic lesions, being little invasive, and capable of reducing the number of surgical interventions and amputations.
• the use of the present composition has allowed (I) the elimination of ischemic capsules or scabs without the need for surgical procedures. This is related to the formation of new remodeling tissue in the deep planes, which pushes and releases the necrotic material. (II) The establishment of a neoformation tissue, fibroangiogenic, intracutaneous, resulting from successive infiltrations, before performing an amputation, for example of fingers, which causes a pro-granulating tissue to exist before the surgical act itself, which limits sepsis, promotes healing and mitigates the risks of reperfusion if necessary.
• the components of the pharmaceutical composition are the following:
• EGF Epidermal Growth Factor
• the EGF can be in powder or fine granulated form and can be applied by means of a high pressure firing device. EGF can be administered in the form of deoxyribonucleic acid (DNA) in an appropriate genetic construct for expression in transiently transfected human cells.
• DNA deoxyribonucleic acid
• PEI Polyethyleneimine
• Sodium Phosphate buffer Chemical stabilizer It is at a pH of 6.5 and in a molar concentration range between 5-100 milliMolar (mM), and at an optimal range of 10-20 milliMolar (mM).
• O-Raffinose Stabilizing agent in the lyophilization process. Concentrations of 5-50 milligrams / milliliter, and at an optimal range of 8-20 milligrams / milliliter can be used.
• L-Glycine L-Glycine. Isotonizing agent It can be used at concentrations of 5-50 milligrams / milliliter, and at an optimal range of 10-20 milligrams / milliliter.
• Fibronectin It favors the stability of EGF and its biological function. It favors the interaction of EGF with cells and their response. It is present in the formulation in ranges from 10 to 200 micrograms / ml.
• Levana EGF protective agent in solution exerts screen effect. It contributes to its biodistribution in the extracellular space. It is present in the formulation in ranges from 1 to 20 milligrams / ml.
• the pharmaceutical composition can also combine EGF with the following active ingredients:
• Phlebotonic and phlebotrophic It may be present in the formulation in concentrations of 20 micrograms / ml to 1000 micrograms / ml. Use it as a simple routine hydrate or in the form of lyophilized salt in the form of routine sulfate.
• Lidocaine Trophic It helps reduce the local production of pro-inflammatory cytokines and the expression of adhesion molecules of the vascular wall.
• lidocaine hydrochloride Present in the form of lidocaine hydrochloride and can be at a fluctuating concentration between 5 to 40 milligrams / ml.
• Adenosine triphosphate (ATP) It exerts vasodilator and pro-metabolic effect.
• It may be present in the form of sodium salt or free acid, at a fluctuating concentration between 0.05 to 20 milligrams / ml.
• GTP Guanosine triphosphate
• Nictinic acid amide (Nictoinamide). Provides substrates for cell anabolic. It can be used at a fluctuating concentration between 1 to 130 milligrams / ml. L-Arginine It favors the regulation of vascular tone. It is used in the form of hydrochloride crystals, being able to be at a fluctuating concentration between 1 to 100 nanograms / ml.
• Heparin Cytoprotector Use it in the form of sodium salt, being able to be at a fluctuating concentration between 1 to 10 micrograms / ml (0.1-1 U).
• Type II diabetes mellitus with evolution from 10 to 25 years, mostly medicated with oral hypoglycemic agents.
• All lesions of the lower limbs treated corresponded with the clinical-pathological classification of ischemic / infectious diabetic foot or ischemic / neuropathic diabetic foot or mixed forms. Grades IV or V of the Wagner classification.
• the treatment consisted of performing deep perilesional infiltrations in at least five or six equidistant points at the edges of the lesion, always directing the needle towards the base of the ulcer or deep into the surgical wedge. At each point a volume of 1 milliliter (mi) of the composition was deposited. No undesirable reactions were detected except pain from injection.
• the composition administered always contained EGF as the main active ingredient, in some cases it was tested in combination with any of the aforementioned active ingredients. In the 9 treated patients the amputation of fingers, foot, or limb as appropriate. The total number of infiltration sessions that each patient received is referred to in the examples.
• Example 1 ACDF patient, 49 years of age and female sex. Patient with infectious ischemic foot, type II diabetes with 16 years of evolution, who had undergone sympathectomy and supracondylar amputation of the right limb 2 1/2 years ago. The first toe of the left foot is amputated for showing an ulcerative, moist, atonic lesion, rebel to heal despite the fact that several surgical cures were performed to remove ischemic capsules, practice debridement and revitalize the edges and bottom of the lesion. The basis of the amputation became ischemic, with cyanotic and atonic edges 5 days after the intervention. The treatment of the infiltrations is begun, waiting for the spontaneous epithelization of the lesion.
• an ischemic capsule is implanted in the surgical area and the base of the adjacent finger.
• the lesion becomes atonic and the progress of healing stops.
• the fingers are disarticulated and open a latero-inferior wedge that was transformed into a tunnel of approximately 6 cm. of length.
• the lesion became again ischemic and with evidence of necrosis of some areas of the edges.
• the treatment with the infiltrations begins with the expectation of healing by second intention.
• the lesion had healed completely, covered with a well-keratinized epithelium, " discharging from the hospital. Remodeling of the lesion was observed.
• Example 4. RNP patient, 69 years old, male sex.
• the evidence of improvement began at the sixth infiltration session, the pain disappearing and the outbreaks of granulation tissue begin from the bottom of the bloody area: after 12 infiltration sessions the patient had completely epithelized; that is to say at 4 weeks of treatment. He was discharged from hospital. It has evolved satisfactorily without recurrences for a period of three months.
• Example 5 ISV patient, 74, female sex. Diabetic for 30 years. With an infectious ischemic diabetic foot. Contralateral transmetatarsal amputation. History of deficit in the healing process. Enter for maintaining a necrotic lesion of the fifth finger. It is amputated and ischemic plaques appear that are surgically removed. Finally it is left with a wedge of the infero-outer edge of the foot, with exposed periosteum. At 48 hours the wedge showed signs of ischemia. It is decided to start treatment with the infiltrations hoping to fill the lesion, including the wedge with granulation tissue; that is, a spontaneous scarring by second intention. At the end of the sixth infiltration, there was already an outbreak of useful and bleeding granulation tissue.
• the lesion responded favorably to treatment resulting in epithelized after 11 sessions. It has evolved satisfactorily after hospital discharge.
• Example 6 RDR patient, 44 years old, male. Diabetic for 12 years. Carrier of an infectious ischemic diabetic foot who receives transmetatarsal amputation due to ischemic lesions of the fingers. Lacking distal pulses, and clinical evidence of peripheral perfusion insufficiency. History of failed healing process in the contralateral tibial region. After the amputation is performed, cyanotic foci appear on the skin's edges. The infiltration begins with the expectation of creating granulation tissue to support an autograft or to reshape and heal by second intention.
• Example 7 Patient RGR. Female sex, 49 years old. Diabetic patient about 10 years ago, with a history of painful claudication at 100 meters, and scarring deficit. He has detoured with several ulcers in the para-tibial region of both members, which have been difflious to treatment.
• the lesion that is decided to treat is an ischemic ulcer in the lower third of the left leg, on its outer lateral face, approximately 6.4 centimeters in diameter and 5 millimeters deep, with a two-month evolution without response. Initially a resuscitation of edges and bottom was performed, beginning the treatment with infiltrations the next day. The lesion began to show granular background at the third infiltration, progressed with contraction of the edges and proliferation of a simple epithelium that then stratified and keratinized. A total of 12 infiltration sessions (4 weeks of treatment) were performed. After hospital discharge, it has evolved satisfactorily.
• Example 8 GPJ patient. 57 years old Diabetic from 12 years ago. Carrier of an infectious ischemic foot, and lacking posterior tibial pulse. A transmetatarsal amputation is performed due to ischemia and four-finger necrosis of the right limb. Seven days after the amputation, the healing process in the surgical base is stopped, areas of the cutaneous edges are cyanotic and devitalized. Infiltrative treatment is tested before continuing with surgical interventions. After 9 sessions (3 weeks) on patient had completely epithelized. After hospital discharge, it has evolved without complications.
• Example 9 DLF patient. 51 years old, male. Type II diabetic for about 20 years and asthmatic. It is received with a bad plantar perforator with no other option than amputation due to the severe degree of local ischemic and necrotic involvement. There was almost total loss of the left foot plant. The calcaneus area culminates with exposed periosteum. It is treated with infiltrations as a pre-amputation alternative. The only expected possibility was the presence of a granulation tissue sufficiently established and vascularized to support an autograft. 15 infiltration sessions were conducted throughout the area including the calcaneus. From the fifth administration, the tissue outbreak began to be appreciated. After the 15 infiltration sessions (5 weeks), the autograft could be performed. The patient has evolved satisfactorily, is supported and wanders.

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