Herberprot-P 75

Epidermal growth factor (FRE), human recombinant (h.rec)

heberprot-p-75PHARMACOLOGICAL CATEGORY: Stimulation agent of cicatrization and cytoprotector
COMMERCIAL NAME: Herberprot-P
GENERIC NAME:  Epidermal growth factor (FRE) , human recombinant (hrek)
CHEMISTRY NAME: Epidermal growth factor (FRE) , human recombinant (hrek)
SIMILAR MEDICAMENT AT MARKET: There is no
PHARMACEUTIC FORM: Lyophilized Injection in glass bottles
WAY OF USING: Intralesionally (directly on the lesion)

Characteristic of the package:

Bottle for injection 6R, pipes of hydrolytic glass of the I class, of the first class, crystal, light color, capacity 6 ml, which contains as the active principle FCEhrec; the cap of bromobutyl and flip-off coat. It can be used in the doses from 25 to 75μg.

Pharmacology

Pharmacokinetics

Physiological levels FCE in the plasma are not noticeable, but the platelets contain significant levels (approximately 500pmol/1012 of platelets). After coagulation, the concentrations of FCE exceed 130 pmol/L, which is enough to induce mitosis and cell migration.

Pharmacokinetic profiles of the applied 125I-FCEhrec, its effect to the organs and ways of elimination were the subjects of analyses. The studies on rats and dogs were done by one application of the medicine, in the usual way or in the endovenous one. The highest levels, expressed in the equivalent ng per a gram of tissues rose to kidneys, liver, skin and stomach.

According to the data of radioactivity, on every 96 hours it is noticed the reducing of the value which is adequate to 78% product in urine. The kinetic functioning of FCEhrec by injecting into veins is characterized by a fast phase of distribution followed by a slower phase of elimination, of both blood and plasma. It is shown that liver and kidneys are key organs for the fast phase of distribution. The concentration of blood was usually smaller than the concentration of plasma. FCEhrec is not distributed in the blood part of the cell, which happens because of the lack of receptors in this kind of cells. FCEhrec is degraded fast and significantly in an organism before it is excluded by urine, the main way of elimination, according to these results. It has been realized that kidneys are the main organs which take part in metabolism of FCEhrec. It hardly exists the passage from FCEhrec when it is applied usually, as well as with animals with untouched skin, as well as with those with lesions.

In one pharmacokinetic study after the application of  Herberpot-P to the lesion of 25μg or 75μ, three times a week for the patients with foot diabetic ulcers of the I and II degree according to Vagner, the maximum quantities of plasma FCEhrec rose 5-15 minutes from the time of application. (Tmax). The elimination was fast, about 2 hours. The average value AUC for 25 μg were 85.1 1pgh/ml, both after the first (I period), and also after 15 injections (II period), while for 75μg were 197.8 i 243 pg.h/ml in the periods I and II, which indicates that there were no accumulation of FCEhrec during the treatment. No differences between the doses in t1/2 were noticed in the average time of keeping in body, approximately 1 hour. In urine, no increase in elimination of FCEhrec in the following 48 hours from the injection was noticed, comparing to the group which received placebo, because of which FCEhrec in urine should endogenously be adequate to the product. In this study, there came to complete healing of wounds of 87,5% patients in the term of 12 weeks after beginning the treatment with any dose.

Pharmacodynamics

The effect of epidermal growth factor (FRE) has been studied thoroughly in the process of cicatrization. It relates to the simple protein molecule, which has molecular weight of 6045 Dalton isoelectric point of 4,6 and consists of 53 amino acids. It stimulates the proliferation of fibroblast and epithelia cells. It represents the possible mitogen activity over the epidermal cells, smooth muscles of vessels, fibroblast and keratinocytes, among others. The first biological effects attributed to FRE were premature open of eyelids and premature teeth growth when, by their mother, the medicine was transferred to newly born rats. Later it was isolated from human urine thanks to Cohen and Carpenter and after that, its presence was registered in various liquids in organism such as sweat, saliva, gastric liquid, colostrums, amniotic and seminal acid.

This molecule regulates growth, differentiation and metabolism of various cells. It stimulates migration and proliferation of fibroblast which enable the synthesis and postponing of collagen. They are also chemoattractant and mitogen because of endothelial and epithelial cells.

The FRE is efficient thanks to the joining to a special receptor which is situated in the membrane of white cells. The receptor is a glycoprotein which has a tyrosine and kinase effect. It is noticed the presence of this receptor on various lines of human cells except on hematopoietic ones. It is placed in relatively big quantities in skin.

Various studies of experimental pharmacodynamics are done by applying FRE by parents to their offspring in which their trophy and protective function has been demonstrated. For the rats which were subject to total transversal axotomy of sciatic nerve in the cocoxophemoral area showed the effect of nerve protector of perilesional injection FREhrek by the stimulation of the reaction of morphofunctional regeneration of axon and the synthesis has been proved that the treatment a) contributed the renewed motor nerve realization to 60 days from the day of trauma after treating by FREhrek for 20 days; b) contributed the renewal of axon and myelin and prevented or eased the changes of intra-axial degeneration; c) prevented or postponed the beginning of trophy changes of which external tissues (skin and additions) as well as the occurrence of ulcers on soles and necrosis on toes.

In two studies done on rodents: in one case with hypodermic burns of 8-9% and in the other with damage on many organs caused by thioacetamide, it came to reducing mortality and reduce of gastrointestinal and renal damage on treated animals with the dose of 30 μg/kg inter-peritoneal FREhrek. On the other hand, the protection of the type dose-effect has been registered at FREhrek in the models of the damage on liver and ischemia/reperfusion on the kidney, while testing the dose of 500 to 750 μg/Kg in the peritoneal way. The markers of oxidative stress, such as Malondialdehyde, were pretty less present in the treated groups.

On the biopsies of the tissues of granulation of the patient treated by Herberpot-P it was noticed neoannogenesis of microvasculature in the cases of ischemia and proliferate reaction of neuropaths.

Indications- Use only according to the doctor’s prescription

Heberprot-P is recommended, together with the other usual therapies, for the purpose of treating diabetic foot with neuropathic and ischemic ulcers, of the size of more than 1 cm2, for the purpose of stimulating the creation of useful tissue of granulation which would allow the closure by legal intention or by the autograft of a leg, the way it has been presented by various clinical studies. In the first pilot study with 14 patients with diabetic ulcers on legs, of the sizes between 21 and 78 cm2,  of the III and IV degree according to Vagner, most of them ischemic without any other alternative therapy,  to 25 of them Herberprot-P was applied to the lesion 3 times a week until the tissue of granulation was created or maximum of 20 injection. The complete response was obtained (>75% of the area of ulcer was covered by the tissue of granulation), to 7 (50%) of the patients in 33 days averagely of which the lesion is completely closed (in 57 days averagely) and the amputation prevented. Only to one of the patients came to the relapse later that year. The product was safe, advertised as the best medicament against pains in the area where the injection is applied.

There followed the testing in many centers, blind studies between 25 and 75 μg during every injection, three times a week until the complete granulation or 8 weeks. 41 patients with lesions were included with the addition of more than 20 cm2 as the average value, of the degrees III and IV according to Vagner, more than 65% ischemic. There came to complete granulation to 82.6 to 61.1% in the period from 3.8 to 4.9 weeks of treatment as the average value for the groups of 75 μg to 25μg. The complete epithelization in 20 weeks after the beginning of the treatment was noticed for 56% and 50% of the patients. In the continuation of the year, to one of the patients in the group of 75μg there came to the reappearance of the lesion. There came the conclusion that the product is effective and safe in the creation of useful tissue of granulation, removing cicatrization and reduction of the risk of amputation (for 66%) of the patients with the advanced phase of diabetic lesions of legs and great risk of amputating. The most frequent harmful events were: local infection (19,6%), hardness and pain in the area of the injection (17.1%), shivering from the cold (14.6%), trembling (12.2%) and fever (9.8%).

Two long-term monitoring have been published. In the first one, Herberprot-P was spread all over the country and given to the patients in the advanced phase of ulcers, of the degrees III or IV according to Vagner, with the value higher than average which amounted 20 cm2, in the dose of  25μg, 3 times a week until it came to the complete granulation, to 73 % of the patients until the complete closure of the lesions, in the average of 75 days, to 82,8% there did not come to amputation. The most frequent symptoms were: pain (20%), hardness (10.8%), fever (9.7%), trembling (7,5%), shivering from cold (5.4%), excessive granulation (4.3%), local infection (4.3%), lymphangitis (2.2%).

In the second study, 20 patients were included and they were treated by this medicine in the dose of 75 μg per an injection, 3 times a week until the lesions were closed. All of the patients had the granulation in averagely 23 days. There came to complete closure of lesions in 80% of the cases averagely in 35 days. None of the patients had amputation. The medicine was tolerated. In two cases patients left the study for the reasons not in connection with the medicine. The most frequent symptoms were: pain in the zone of injection (45%), shivering from cold (40%), trembling (30%), weakness (25%), and local infection (10%).

Finally, the blind study was completed with affirmation, multi-centric, random, controlled by placebo, where three groups of treatment were compared (Herbprot-P 75μg, 25μg i placebo) to the patients in the advanced phase of diabetic ulcers on their legs (the degrees III or IV according to Vagner, more than 50% ischemic, with the average size of the location of the lesion of more than 20 cm2). The injections were given 3 times a week until the complete granulation or to the maximum of 8 weeks. The injection Heberpot-P, on both the levels of dose, was 30% more successful than placebo according to the number of patients to whom more than 50% of the lesions were covered by the tissue of granulation for 2 weeks of treatment. In the end of the treatment, the number of patients who had a complete granulation was significantly greater with the dose of 75 μg (87%) comparing to placebo (58%) (IC 95% for the difference of: 9.8%, 47.1%). The advantage of the treatment was more obvious in the “clean” neuro-infection cases than in the ischemic ones. The time until the complete reaction was 3 weeks in both groups which received Herbprot-P and 5 weeks in the group which got a placebo.

That difference was statistically significant for both doses. In the continuation of 12 months, there came to compete closure, without the relapse in 77% of the cases which had the dose of  75μg per an injection averagely 25.4 weeks, while 56% of those who had a placebo managed to be cured, averagely in 36.2 weeks (IC 95% for the difference of: 1,1%, 41.1%, test log rank which measures the time of treatment: p=0.045). The treatment was safe. There were no harmful consequences connected to the product. The harmful consequences which appeared in the study and which were considered as in connection with the product were: shivering from cold (32% i 17% in the groups 75μg and 25μg) and trembling (21% i 8%). The other consequences, connected to the giving of the injection appeared in the similar number in the group placebo: pain (31% of all the patients) and hardness (24.2%) of the injection zone.

Later, when continuing the using of the medicine, the patients with diabetic ulcers on feet of any degree were treated in Cuba. In the analysis of the information for 1850 patients, there came to the complete granulation in 80,4% of the patients with the ulcers of the I or II degree according to  Vagner, in 3,4 ±2.7 weeks and in 75.8% of those who had the ulcers of the III or IV degrees in 4.3±2.9 weeks. The granulation was better for the patients with the “clean” neuropathic ulcers (86.5%) than for those ones with ischemia (64.7%). Of 1349 patients: the complete closure of the lesions happened in 72.6% cases with the ulcers of the I or II degree according to  Vagner, and in 60.4% of those who had the ulcers of the III or IV degrees. 51.3% of the ischemic and 73.1of the  „clean“ neuropaths completely healed the lesions.

Contraindications

Heberprot-P is not recommended:

To the patients who used to be hypersensitive to the medicine or any of its ingredients. The medicine Heberprot-P is forbidden to the patients with oncologic pathologies near the location of the injection of the medicine. It is not recommended to the patients with decompensate   cardiopathy, diabetic coma or diabetic ketoacidosis.

Precautions:

The application of biological products has to be careful and necessary measures have to be made in cases of unexpected complications. Before the use of Heberprot-P other health problems have to be stopped, such as: infection or osteomyelitis. For the patients with ischemia caused by peripheral macroangiopathy, the reperfusion of the diseased part of the body has to be done. It is not known whether Heberprot-P is in breast milk. It is not recommended to the mothers in lactation. For now, there is no enough information which allows its usage to pregnant women and pediatric patients, because of which a doctor has to make the balance of benefits and risks in each case. The medicine should be given with caution to the patients with previous cases of ischemic cardiopathy and renal insufficiency with creatinine of more than mmol/L.

It is necessary to do the appropriate treatment of the infection before using Heberprot-P.

Warning:

The treatment should be done by professionals who possess necessary diagnostic installations, as well as who have enough experience in treating diabetic foot. That medicine should be used only before the expiration of the period written on the package. The solution Heberprot-P has to be injected immediately after the preparation.

Harmful consequences:

During the clinical examination of Heberprot-P, 345 patients were included, of which 196 had harmful consequences. The most frequently reported harmful consequences are: pain and hardness of the location of injection, shivering from cold, local infection, trembling and fever.

Interaction of the medicines:

It is not known whether Heberprot-P reacts with other medicines in everyday use. That is why it is not recommended to be used with other medicines.

Overdosing:

There were no cases of overdosing and there is not any known medicine which annuls this one. Because of its local application of Heberprot-P and because of circulation compromise of diabetic patients in the advanced phase of lesions, there is little probability for appearing systematic consequences.

Dosing and the way of preparation:

Heberprot-P has to be used with the adequate care about the ulcer of diabetic foot, which is related to the removing of lesions, soothing the zones of pressure and systematic medicines. The adequate diagnosis and treatment of the infection of the ulcer has to be done before using Heberprot-P. On the lesions for which it is suspected that are malign, the biopsy must be done for the purpose of removing neoplasia before using Heberprot-P. Heberprot-P is used (25 or 75μg) dissolved in 5 ml of water by injection 3 times a week in the lesions. In the case of lesions of the area larger than 20 cm2 or with the signs of ischemia (absence of pulse: the sign by pressuring a wrist/arm <0.8) it is recommended the injection of the dose of 75μg. The injection will be given until the complete granulation of the lesion, until it is closed with graft or until 8 weeks of treatment is completed. The treatment has to be stopped when it is reached the useful tissue of granulation which would cover the whole lesion or until the area is reduced to less than 1 cm2.

Infiltrations have to be applied after treating the lesions: on the edge of ulcers, with needles of 26Gx1/28 and on the bottom, in the case of deep lesions the needle of 24Gx1 1/28 should be used.

The first, the cleanest zones of the lesions have to be infiltrated and the needle should be changed in various locations of injection in order to avoid possible transfer of infection from one place to another. After that, the lesion should be covered with wet gauze and salt in order to be wet and clean.

Package:

  • Box x1 bottle with lyophilized FREhrek of (25 to 75)μg depending on the dose.
  • Box x 6 bottle with lyophilized FREhrek of (25 to 75)μg depending on the dose.

A box contains:

  • 1 bottle with lyophilized FREhrek of (25 to 75)μg depending on the dose.
  • 1 bottle of 5 ml water for the injection
  • 1 sterile syringe 5ml with the needle of  23Gx1 1/8
  • 2 sterile needle of 24Gx1 1/28
  • 2 sterile needle of 26Gx1/28
  • 1 prospect

Instructions for use. Management and removing the product:

Use every bottle of Heberprot-P per a patient.

Avoid damages and entrance of contamination of the bottle by bacteria.

Professionals who give this medicine should adequately wash their hands and put on gloves before the injection of Heberprot-P.

Avoid prolongation of the infections on lesions. Changing needles is recommended for injecting on other parts of the lesions.

When the treatment is over the rest of medicine should be thrown away.

Conditions for storage. Maturity.

Heberprot-P should be stored on the temperature from 2 to 8○C.

The expiration date is written on the label and on the box of the product.

Always keep the medicine in its original package.

Keep the product out of reach of children.

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