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DERMATOVENEREOLOGY
INVENTION
Patent of the Russian Federation RU2278689

METHOD FOR TREATMENT OF TROPHIC SURGERIES AND LONG-TERM INDEPENDENT RAS

METHOD FOR TREATMENT OF TROPHIC SURGERIES AND LONG-TERM INDEPENDENT RAS

The name of the inventor: Emirov Gyramidin Nizamudinovich
The name of the patent holder: Emirov Giramidin Nizamudinovich
Address for correspondence: 367015, Makhachkala, Shamilya Ave., 68, ap. 18, G.N. Emirov
Date of commencement of the patent: 2004.08.19

The invention relates to medicine, namely, to dermatology, and can be used for the treatment of trophic ulcers (TW) and long-term non-healing purulent wounds (DGNR). To do this, in the 1st phase of the wound process, a wound healing composition is applied on the surface of TH and DGRP at the following ratio of the components, by weight: methyluracil 0.9-1.1; Pepsin - 3,6-4,4; Betaine hydrochloride 3,6-4,4; Sodium chloride - 9.0-11.0; Distilled water to 100.0. This composition is applied on cotton carriers. In the second and third phases, fine-cut collagen preparations are applied to the cleaned surface of the TH and DGRS by a layer 3-4 mm thick. Then a layer of cotton carrier is applied to the collagen layer, which is abundantly moistened in the wound healing composition, diluted 1: 2 with distilled water. Over the cotton carrier, a multidirectional micro irrigator is applied, covered with yet another sterile cotton carrier. The method ensures the effectiveness of treatment by accelerating the rejection of necrotic tissues, suppressing the growth of microbes, reducing the risk of generalization of the infection, toxic and allergic phenomena, improving tissue regeneration.

DESCRIPTION OF THE INVENTION

The invention relates to the field of medicine, namely, to therapeutic methods of treatment, and can be used in clinical practice for local enzymatic treatment of trophic ulcers (TW) and long-term non-healing purulent wounds (DGNR).

Known is the method (AC No. 1149977, A 61 K 37/57, 1985) consisting in local application to the surface of TH and DGNR at the following mass% ratio: pepsin -15.0; Ascorbic acid - 30.0; Glucose - 54.25; Hydroperite - 0,75.

A method is known (RU, patent 2174389, A 61 K 9/06, 38/43, A 61 P 17/02, 1999) consisting in the local application to the surface of TH and DGRP of the composition at the following weight ratio: collagenase 160-200 E; Gentamycin sulfate 0.08-0.1; Polyethylene oxide-400 66.0-68.0; Polyethylene oxide-1500 16.5-17.0; Glycerol 10.0-10.1.

As a prototype, which is closest in the aggregate of essential features to the proposed method of treatment, is the method (RU, patent 2160135, A 61 N 5/06, A 61 K 38/43, 1998), consisting of local application to the surface of the TH and DNGR compositions With the following ratio, mass%: pepsin 2.0-4.0; Ascorbic acid 4,0-8,0; Hydroperite 0,1-0,2; Methyluracil 4.0; Polyglucinin to 50.0.

The disadvantages of all the above methods of treating TU and DGNR with proteolytic enzymes active in an acid medium are the following:

1) due to the absence or use of weak organic acids, the optimum pH for pepsin is not created, the antibacterial and necrolytic activity of the compositions used is not sufficient;

2) the activity of the enzymes used in the compositions with these methods is limited in time, due to rapid alkalinization by the wound detachable, which is explained by the absence of buffer additives stabilizing the pH in the TH and DGNR;

3) in many cases, substances that are capable of exerting a cytoprotective effect on regenerating tissues are not used, but are also active stimulants of regenerative processes;

4) these methods do not use the possibility of direct supply of plastic material to the regenerating tissues.

The technical problem solved by the proposed method is to provide effective treatment of TU and DNGR.

The technical result obtained in the implementation of the proposed method in the treatment of TU and DGNR is provided by accelerating necrolysis, enhancing bactericidal action, stimulating regeneration, delivering the necessary nutrient substances for anabolic processes directly to the regenerating tissues, ensuring the protection of regenerating tissues from external influences, Infection.

The achievement of this technical result consists in the local application in the first phase of the wound process of the newly proposed composition, conditionally called "Necracidolizine", with the following ratio, wt.%: Methyluracil 0.9-1.1; Pepsin - 3,6-4,4; Betaine hydrochloride 3,6-4,4; Sodium chloride - 9.0-11.0; Distilled water to 100.0 on cotton carriers. In the second and, in part, the third phase of the wound process, this composition on cotton carriers is used in conjunction with collagen preparations (most often - a small-cut medical catgut).

The most effective ratio of medicinal components in the composition "Necracidolysin" was determined by experimental studies and numerous clinical observations.

All the ingredients included in the composition are allowed for use by the Ministry of Health and the Ministry of Health of the Russian Federation (Vidal 1999 - Medicinal Preparations in Russia: Handbook, Moscow, AstraPharmService, 1991. - 1520 pp.).

The ingredients of the proposed composition do not enter into chemical relations during dissolution, which is proved by the spectrophotometric method.

Pepsin is a gastric enzyme that has the greatest proteolytic activity among all other enzymes in the body.

This enzyme belongs to one of the most numerous groups of enzymes - proteolytic enzymes (proteases). They belong to the class of hydrolases, to a subclass of peptide hydrolases and catalyze the cleavage of proteins and polypeptides. Pepsin hydrolyses peptide bonds and cleaves practically all natural proteins.

Its proteolytic activity is very high - one gram of pure pork pepsin can split 50 grams of chicken protein (Silaev AB An investigation of the proteolytic and chymase activity of food pepsin, Food Technologies, 1975. - No. 5.-C.3). There are various forms of pepsin release: porcine pepsin, from the gastric mucous membrane of calves and lambs (abomin), chicken pepsin (pepsin K), crystalline pepsin (IP) 1: 3000, crystalline pepsin (IP) 1: 10000. The last figures indicate that 1 mg of pepsin can decompose 10000 mg of chicken protein.

Optimal acidity of the medium for its action pH 2 (Andreeva NS Why and why pepsin is stable and active at pH 2? // Molecular biology .- 1994. - T.28, issue 6. - P.1400-1406). The breadth of activity of pork pepsin (abomina) within the pH range from 1.0 to 3.0; And chicken (Pepsin K) - from 1 to 4.0 (Kharitonin VV, Chernenko GT, Sdobnova EA, Khlyabich AG Enzymatic activity and therapeutic action of pepsin K in chronic gastritis with secretory insufficiency // Clinical medicine .- 2003. - № 8. - P.35).

As the ingredient of the proposed composition, the most affordable and cheap pork pepsin was used.

In the literature, we have not found data on the possibility of an overdose of pepsin.

Betaine (N-trimethylglycine, oxineurin, lucine, betaxin) is a natural nitrogenous lipotropic substance of plant origin, a derivative of the natural amino acid glycine. It is a readily soluble in water powder. The molecular formula of betaine C 5 H 11 NO 2 , the chemical formula - (CH 3 ) 3 N + -CH 2 COO - (amphoterene preparation).

In the betaine molecule, there are active methyl groups (CH 3- ), which are necessary for normal metabolism. The addition of a methyl group (methylation) is a necessary stage of the most important biochemical reactions.

The human body can not synthesize methyl groups, but extracts them from food. Due to its direct participation in the methylation reaction, betaine exerts a great influence, in particular, on the lipid metabolism, possessing a lipotropic action, since its composition is close to choline and lecithin. Betaine is involved in methionine metabolism.

In addition, betaine acts as an osmoprotector, i.e. Helps to maintain water balance in cells and tissues (Wettstein M., Haussinger D. Cytoprotection by the osmolytes betaine and taurine in ischemia-reoxygenation injury in the perfused rat liver // Hepatology .- 1997. - Vol.26, No. 6. - P . 1560-1566).

The intake of betaine reduces the aggregation of platelets. Betaine is used in pharmacology for the treatment of liver pathology, treatment of alcoholism with toxic poisoning in the form of food additives in the composition of nutraceutical preparations in doses up to 12 grams per day.

Betaine hydrochloride (or hydrochloride) chemically 1-carboxy-N, N, N-trimethylmethanaminium chloride. A pure 5% solution of betaine hydrochloride has a pH of 1.

Betaine hydrochloride, dissociating in solution to free betaine and diluted hydrochloric acid with a pH of 2-2.5, is used in the composition of tablets "Acidin-pepsin" together with pepsin for ingestion for the purpose of treatment of hyacid gastritis.

In the literature, we have not found data on the possibility of an overdose of betaine and betaine hydrochloride (Izrailet LI, Slin'ko VN On the toxicity of betaine hydrochloride (medical azidin) used as a medical preparation // Hygiene and occupational diseases .- 1974. - Issue 1 - C.41-44).

In the treatment of TH and DGRP, betaine and betaine hydrochloride in the form of a 4% solution (to provide the optimum pH for pepsin) were used for the first time.

Metiuracil (2,4-Dihydroxy-6-methyl-1,2,3,4-tetrahydropyrimidine). White crystalline powder odorless, slightly soluble in water (up to 0.9% at 20 ° C) and alcohol. Methyluracil belongs to the cell-wide stimulants, has anabolic and anti-catabolic activity. These drugs accelerate the processes of cellular regeneration and reproduction; Accelerate wound healing, stimulate cellular and humoral defense factors. The general mechanism of the regenerative action includes the enhancement of the biosynthesis of purine and pyrimidine bases, RNA, functional and enzymatic cellular elements, incl. Phospholipid membranes, as well as stimulation of DNA reduplication and cell division. It should be noted that the process of biosynthesis in the course of both physiological and reparative regeneration requires substrate maintenance (essential amino acids and fatty acids, trace elements, vitamins). Methyluracil has an anti-inflammatory effect. In a wide clinical practice, methyluracil is administered orally at doses of 1 to 6 grams per day, but also in various ointments for topical administration.

Hypertensive chloride solution has long been used in 5% and 10% concentration for local treatment of purulent wounds due to its osmotic effect, which helps to separate wound exudate. Hypertensive solutions of sodium chloride have a local bacteriostatic effect. Used externally, the hypertonic solution of sodium chloride does not have a general-dissociable toxic or locally irritating effect.

For the application of the composition "Necracidolysin" in clinical practice, we obtained the permission of the Pharmaceutical Committee of the USSR for №211-7032 / 24 from 12.03.90.

In the second and, in part, the third phase of the wound process, collagen preparations are added to the composition.

Collagen is the most abundant protein in the human body. About 70% of the dry matter of the skin is collagen.

Collagen composite materials do not have toxic, irritant, antigenic, carcinogenic effects; Are easily lysed by tissue and bacterial proteases with prolonged release of the drugs contained in them. Being decomposed on the surface of TH and DGN into simpler compounds, metabolites of collagen take an active part in the metabolism at the cellular level and stimulate reparative processes (Magomedov AG et al., Trophic ulcers of the lower extremities .- Makhachkala, 2000. - 160 p.).

The method of treatment for this method has been developed, and its effectiveness is confirmed by numerous clinical observations.

For direct treatment, the "Necracidolizin" composition is prepared ex tempore by mixing the weighed ingredients in a flask, followed by the addition of distilled water under normal conditions, and does not require sterilization, since it itself has a pronounced bactericidal activity.

According to the proposed method, in the first phase of the wound process in the first 3-5 days after the corresponding toilet of the surface of the TH and DGN, 6-10 layer gauze wipes are applied under aseptic conditions, moistened with abundantly in the composition "Necracidolysin" in the preferred embodiment: methyluracil 1.0 ; Pepsin 4.0; Betaine hydrochloride 4.0; Sodium chloride 10.0; Distilled water - up to 100.0 (pH 2.0). Frequency of dressing change - 2 times a day.

Subsequently, after cleansing of TU and DNGR from necrotic detachable under aseptic conditions, finely cut collagen (catgut) or other official collagen-containing dressings with a layer 3-4 mm thick is applied to its surface. On the collagen layer, the first layer of gauze bandage (cut according to the contours of TW or DGNR) from 8-10 layers is superimposed in the "Necracidolizine" composition, diluted 1: 2 with distilled water. Above the napkin, a multi-branch micro-irrigator is annularly covered with another 8-10 layer dry, sterile tissue.

A limb site with TI or DNGR is bandaged to prevent the bandage from moving. Through the micro irrigator, a small amount of the "Necracidolizine" composition, diluted 1: 2, is fed into the bandage at a frequency of 1-2 times a day. Change of dressings are made with an interval of 7 days (to control the surface of the TH and DGNR and determine their readiness for autodermoplasty).

If the TG or DGNR heals without the use of autodermoplasty, then with the next dressing after soaking the dressing layers in 3% hydrogen peroxide, if necessary, it can be added to its surface finely cut aseptic collagen (catgut) or other official collagen-containing dressings without completely removing The collagen film remaining on the surface of the granulations.

Examples of specific application of this method.

Example 1

Patient Papernaya K-H.Z., 67 years old, I.b. №735 / 35, entered the clinic on January 14, 1996 with the diagnosis: Primary: varicose veins of both lower extremities. Complications: chronic venous insufficiency of the left leg of the 2nd degree, right - 3rd degree, circular dermatosclerosis and hyperpigmentation in the lower third of the right tibia, trophic ulcer in the lower third of the right tibia along an anterior medial surface of 114 cm 2 . Concomitant diseases - diffuse relapsed goitre, thyrotoxicosis of medium severity; Coronary cardiosclerosis, atrial fibrillation, cardiovascular failure 2A degree; Chronic obstructive bronchitis with asthmatic component; Omission of the walls of the vagina, prolapse of the uterus; Condition after right-sided mastectomy for breast cancer in March 1995.

The patient initially received traditional therapy for 20 days with the use of 150 mg Himopsin for dressing. On February 6, 1997 the skin plasty of the trophic ulcer surface was made. The scraps first took root, the patient was discharged from the hospital, because she refused surgery on the venous system of the lower extremities.

When dispensary observation, it was noted that the flaps began to be quickly discarded, the infection joined and by March 1997, a ulcerous surface with an abundant purulent-necrotic discharge area of ​​84 cm 2 was formed. Its edges are shallow, the skin around is hyperpigmented and sclerotized, eczematized. Staphylococcus aureus was sown from the wounded.

The patient is again hospitalized in a hospital. I.b. No. 842/42. From 3.03.97 to 5.03.97, the treatment with the composition "Necracidolizine" was started according to the following prescription: methyluracil 1.0; Pepsin 4.0; Betaine hydrochloride 4.0; Sodium chloride 10.0; Distilled water - up to 100.0 (pH 2.0). From 6.03.97 to 11.03.97 - the same composition, but diluted with distilled water in a ratio of 1: 2 (pH 2.5).

During this period, the area of ​​the wound surface was reduced to 35 cm 2 . Subsequently, the CT with a change in 7 days were imposed catgut bandages, in which a diluted 1: 2 composition "Necracidolysin" was fed twice a day through a microarche agent. By 3.04.97, the TI completely healed independently.

Subsequently, the patient underwent combined excision of subcutaneous veins of the right n / limb. Recurrence of ulcers was not observed during the next 5 years of follow-up.

Example 2

Patient Kurbanov M., 39 years old, I.b. 988/188, entered on March 19, 1999 with a diagnosis of obliterating endarteritis of the left n / extremity, gangrene of the 1st finger of the left foot. On 27.03.99, operation was performed - left-sided lumbar sympathectomy, exarticulation of the left toe with resection of the metatarsal head. In the postoperative period, as a result of necrosis of the edges of the postoperative wound and attachment of infection, a wound was formed, measuring 6 × 3.5 × 4 cm with abundant purulent necrotic discharge. Staphylococcus aureus was sown.

Since 1.04.99 for two weeks, the wound was treated with bandages with chymotrypsin and 10% sodium chloride solution, but without much effect - the abundant purulent-necrotic discharge from the wound was preserved.

From 14.04.99 to 16.04.99, for three days, with a dressing, after an appropriate toilet with 3% hydrogen peroxide, wipes were applied to the wound surface, which were moistened in the composition "Necracidolizin" according to the following prescription: methyluracil 1, 0; Pepsin 4.0; Betaine hydrochloride 4.0; Sodium chloride 10.0; Distilled water - up to 100.0 (pH 2.0). After cleansing from purulent-necrotic tissues with the appearance of bright red granulations and marginal epithelialization, in order to further stimulate regeneration, a catgut dressing was applied to the DNGR for the next 9 days, in which a diluted 1: 2 "Necracidolizine" PH 2.5).

Full healing of the wound 12 days after the beginning of treatment with the composition "Necracidolizin" together with collagen bandages.

The proposed method of treatment is applied in the clinic in 66 patients with trophic ulcers and long-term non-healing purulent wounds of various etiologies (venous-trophic, ischemic, cicatricial and trophic, etc.).

Clinical effect is observed in the first day after the beginning of treatment. Long-term non-healing purulent wounds and trophic ulcers are cleared from purulent-necrotic discharge on day 3-5, active granulations and marginal epithelialization occur. In the future, together with collagen bandages, another 7-14 days, the method is used to stimulate regeneration and prevent secondary infection.

The advantage of the proposed method is confirmed bacteriologically, cytomorphologically, clinically.

Compared to methods using pancreatic and bacterial proteases, the proposed method accelerates the rejection of necrotic tissues, inhibits the growth of microbes, including antibiotic-resistant ones. The danger of generalization of infection decreases. Toxic and allergic phenomena are excluded. Regeneration of tissues occurs much faster. All this causes a reduction in the duration of treatment by 1.5-2 times and the prevention of relapse in the long-term period.

As a result of clinical trials, the following positive factors of the proposed method of treatment were revealed:

1. for the purpose of proteolysis, the enzyme pepsin from the group of acid hydralases (optimum pH 2) is used in the proposed mixture, since its activity with respect to other enzymes from the group of alkaline hydralases (termatase, papain, chymotrypsin, chymopsin, terrilittin and the like, Whose optimum pH is about 8.5) under different conditions is 2-20 times higher; Pepsin has the strongest collagenase activity;

2. An essential difference is that instead of a weak organic salt, the hydrochloride salt of betaine-betaine hydrochloride, which has amphoteric properties, is used which, decomposing in solution, gives free 1% hydrochloric acid with a pH of 2.0-2.5, optimal for pepsin, and And, acting as a buffer, maintains this pH for 8-12 hours (depending on the amount of wound detachable), which is optimal for the action of pepsin and bactericides affect the pathogenic microflora.

3. The agent increases lymphatic drainage of tissues (it is proved that an increase in the acidity of tissues from 7.35 to 5.9 increases its volume of exudation by 20% due to the influx of lymph, while 10% of the hypertonic sodium chloride solution in the mixture stimulates the outflow of tissue fluid With toxic elements and microflora in the bandage);

4. As active regeneration stimulants and cytoprotectors under conditions of a strongly acidic environment, betaine is used, which is formed during the decomposition of betaine hydrochloride, methyluracil and the acidic medium itself, created on the surface of the TH and DGNR;

5. Products of enzymatic decomposition of collagen (catgut) were used as nutrients and plastic material, delivered directly to regenerating tissues;

6. As a protection of regenerating tissues from external influences and prevention of secondary infection, long-lasting (7 days) superimposed catgut dressings were used in combination with periodic feeding of "Necracidolizine" composition in them.

The combined use of the components of the composition and collagen preparations in this method leads to a pronounced synergism of the effect on TU and DGNR.

Given the low cost of the ingredients used in the composition for treatment according to this method, one can expect a significant cost-effectiveness from introducing it into clinical practice.

CLAIM

1. A method for the treatment of trophic ulcers or long-term non-healing purulent wounds (DGNR), characterized in that in the 1st phase of the wound process, a wound healing composition is applied on the surface of TH and DGNR at the following ratio of components in weight%: methyluracil-0, 9-1.1; Pepsin - 3,6-4,4; Betaine hydrochloride 3,6-4,4; Sodium chloride - 9.0-11.0; Distilled water up to 100.0 on cotton carriers, and in the second and third phases, finely cut collagen preparations are applied to the cleaned surface of TH and DGNP with a layer 3-4 mm thick, then a first layer of cotton carrier is applied to the collagen layer, which is abundantly moistened in the wound healing composition , Diluted 1: 2 with distilled water, a multidirectional micro irrigator is placed over the cotton carrier, covered by another sterile cotton carrier.

2. A method according to claim 1, characterized in that a cotton dressing is used in a 6-10 layer of a gauze bandage.

3. A method according to claim 1, characterized in that small-cut medical catgut or other official collagen-containing dressings are used as collagen preparations.

print version
Date of publication 01.04.2007гг