RU2278689C2 - Method for treatment of trophic ulcer and long-term open septic wound - Google Patents

Abstract

FIELD: medicine, dermatology, in particular treatment of trophic ulcer (TU) and long-term open septic wound (LTOSW).

SUBSTANCE: claimed method includes application of wound-healthing composition onto TU and LTOSW in the first step of wound process. Said composition contains (mass %): methyluracil 0.9-1.1; pepsin 3.4-4.4; bentaine hydrochloride 3.6-4.4; sodium chloride 9.0-11.0; and balance up to 100,0: distilled water. In the second and third phases fine cut collagen preparations in form of 3-4 mm thickness layer are applied on purified TU and LTOSW surface. Then cotton carrier freely moistened with wound-healthing composition diluted with water in ratio of 1:2 is layered onto collagen layer. Multihole microirrigator and further sterile cotton carrier are sequentially applied over abovementioned cotton carrier.

EFFECT: effective treatment due to accelerated abruption of necrotic tissues, inhibition of microbial growth, decreased risk of infective, toxic and allergic affects, and improved tissue regeneration.

2 ex, 3 cl

Description

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

There is a known method (AS No. 1149977, A 61 K 37/57; 1985) consisting in local application to the surface of TN and DNGR in the following ratio, wt.%: Pepsin - 15.0; ascorbic acid - 30.0; glucose - 54.25; hydroperite - 0.75.

The known method (RU, patent 2174389, A 61 K 9/06, 38/43, A 61 P 17/02; 1999), which consists in local application to the surface of TJ and DNGR composition in the following ratio wt.%: Collagenase 160-200 E; gentamicin 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, the closest in the set of essential features to the proposed method of treatment, is a method (RU, patent 2160135, A 61 N 5/06, A 61 K 38/43; 1998), which consists in local application to the surface of TN and DNGR composition in the following ratio, wt.%: pepsin 2.0-4.0; ascorbic acid 4.0-8.0; hydroperite 0.1-0.2; methyluracil 4.0; polyglucin up to 50.0.

The disadvantages of all of the above methods of treating TB and DNGR with proteolytic enzymes active in an acidic environment 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 insufficient;

2) the activity of the enzymes used in the compositions with these methods is limited in time, due to the rapid alkalization of the wound, due to the lack of buffer additives that stabilize the pH in TN and DNGR;

3) in many cases, substances that can have a cytoprotective effect on regenerating tissues, as well as being active stimulants of regenerative processes, are not used;

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

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

The technical result obtained by the implementation of the proposed method in the treatment of TB and DNGR is provided by accelerating necrolysis, enhancing bactericidal effects, stimulating regeneration, delivering the necessary nutrients for anabolic processes directly to regenerating tissues, ensuring the protection of regenerating tissues from external influences, and ensuring the prevention of secondary infection.

Achieving the indicated technical result consists in local application in the first phase of the wound healing process of the newly proposed composition, conditionally called "Necratsidolizin", in 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 up to 100.0 on cotton media. In the second and partially third phases of the wound healing process, this composition on cotton carriers is used in conjunction with collagen preparations (most often with finely chopped medical catgut).

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

All the ingredients in the composition of the composition are approved for use by the Ministry of Health and Social Development of the Russian Federation (Vidal - 1999 - Medicinal Products in Russia: Reference Book. M., AstraPharmService, 1991. - 1520 p.).

The ingredients of the proposed composition when dissolved do not enter into a chemical relationship with each other, which is proved by spectrophotometric method.

Pepsin is a gastric enzyme with the highest 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 the subclass of peptide hydrolases and catalyze the breakdown of proteins and polypeptides. Pepsin hydrolyzes peptide bonds and breaks down almost all natural proteins.

Its proteolytic activity is very high - one gram of pure pork pepsin can break down 50 grams of chicken protein (Silaev AB Study of the proteolytic and chymase activity of food pepsin // Food Technology. - 1975. - No. 5. - C.3). There are various forms of pepsin release: porcine pepsin, from the gastric mucous membrane of calves and lambs of young age (abomin), chicken pepsin (pepsin K), crystalline pepsin (IP) 1: 3000, crystalline pepsin (IP) 1: 10000. Recent figures suggest that 1 mg of pepsin can break down 10,000 mg of chicken protein.

The optimal acidity of the medium for its action is pH 2 (Andreeva N.S. Why and why is pepsin stable and active at pH 2? // Molecular Biology. - 1994. - T.28, issue 6. - S.1400-1406). The breadth of activity of pork pepsin (abomin) in the range of pH from 1.0 to 3.0; and chicken (pepsin K) - from 1 to 4.0 (Kharitonin V.V., Chernenko G.T., Sdobnova E.A., Khlyabich A.G. Enzymatic activity and therapeutic effect of pepsin K in chronic gastritis with secretory insufficiency // Clinical medicine. - 2003. - No. 8. - P.35).

As an ingredient of the proposed composition was used the most affordable and cheapest pork pepsin.

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

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

Betaine molecule contains active methyl groups (CH ^3- ), which are necessary for normal metabolism. The addition of a methyl group (methylation) is an essential step in the most important biochemical reactions.

The human body cannot synthesize methyl groups, but extracts them from food. Due to its direct participation in the methylation reaction, betaine has a great influence, in particular, on lipid metabolism, having a lipotropic effect, since it is close in composition to choline and lecithin. Betaine is involved in the metabolism of methionine.

In addition, betaine acts as an osmoprotector, i.e. helps 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).

Betaine intake decreases platelet aggregation. Betaine is used in pharmacology for the treatment of liver pathology, the treatment of alcoholism in toxic poisoning in the form of food additives as part of nutraceutical preparations in doses up to 12 grams per day.

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

Betaine hydrochloride, which dissociates in solution into free betaine and diluted hydrochloric acid with a pH of 2-2.5, is used as part of Acidin-Pepsin tablets in combination with pepsin for oral administration in order to treat hypacid gastritis.

In the literature, we have not encountered data on the possibility of an overdose of betaine and betaine hydrochloride (Izralet L.I., Slinko V.N. On the toxicity of betaine hydrochloride (medical acidin) used as a medicine // Hygiene and occupational diseases. - 1974. - Issue 1. - P.41-44).

In the treatment of TN and DNGR, betaine and betaine hydrochloride in the form of a 4% solution (to ensure the optimum pH for pepsin) was used for the first time.

Metiuratsil (2,4-dioxi-6-methyl-1,2,3,4-tetrahydropyrimidine). Flavourless white crystalline powder, slightly soluble in water (up to 0.9% at a temperature of 20 ° C) and alcohol. Methyluracil belongs to general cell stimulants, has anabolic and anti-catabolic activity. These drugs accelerate the processes of cell regeneration and reproduction; accelerate wound healing, stimulate cellular and humoral defense factors. The general mechanism of regenerative action includes enhancing the biosynthesis of purine and pyrimidine bases, RNA, functional and enzymatic cellular elements, including membrane phospholipids, as well as the stimulation of DNA reduplication and cell division. It should be noted that the process of biosynthesis during both physiological and reparative regeneration needs substrate support (essential amino and fatty acids, trace elements, vitamins). Methyluracil has an anti-inflammatory effect. In wide clinical practice, methyluracil is used orally in doses of 1 to 6 grams per day, as well as in various ointments for topical application.

The hypertonic chloride solution has long been used in 5% and 10% concentrations for local treatment of purulent wounds due to its osmotic effect, which contributes to the separation of wound exudate. Hypertonic solutions of sodium chloride have a local bacteriostatic effect. Applied externally, a hypertonic solution of sodium chloride does not have a general resorptive toxic or locally irritating effect.

For the use of the composition "Necratsidolizin" in clinical practice, we obtained permission of the Pharmaceutical Committee of the USSR No. 211-7032 / 24 of 03/12/90.

In the second and partially third phases of the wound healing process, collagen preparations are added to the composition.

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

Collagen composites do not have toxic, irritating, antigenic, carcinogenic effects; easily lyzed by tissue and bacterial proteases with prolonged release of the preparations contained in them. Decomposing on the surface of TN and DNGR into simpler compounds, collagen metabolites take an active part in metabolism at the cellular level and stimulate reparative processes (Magomedov A.G. et al. Trophic ulcers of the lower extremities. - Makhachkala, 2000. - 160 p.).

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

For direct treatment, the composition "Necratsidolizin" is prepared ex tempore by mixing weighed portions of the 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 healing process, in the first 3-5 days after the corresponding toilet, the surfaces of TB and DNGR under aseptic conditions are applied 6-10 layer gauze napkins, abundantly moistened in the composition "Necratsidolizin" 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). Bandage change frequency - 2 times a day.

Subsequently, after the TNT and DNGR have been cleansed of the necrotic discharge under aseptic conditions, finely chopped collagen (catgut) or other official collagen-containing dressings with a thickness of 3-4 mm are applied to its surface. The first layer of a gauze dressing (cut according to the contours of TJ or DNGR) of 8-10 layers, abundantly moistened in the composition "Necratsidolizin" diluted 1: 2 with distilled water, is applied to the collagen layer. On top of the napkin, a multi-hole microirrigator is superimposed ring-wise, covered with another 8-10 layer dry sterile napkin.

A limb site with TJ or DNGR is bandaged to prevent displacement of the dressing. Through a microirrigator, a small amount of the Necratsidolizin composition diluted in a ratio of 1: 2 is fed into the dressing at a frequency of 1-2 times a day. Dressings are changed at an interval of 7 days (to control the surface of TN and DNGR and determine their readiness for autodermoplasty).

If TJA or DNGR heals without the use of autodermoplasty, then at the next dressing after soaking the dressing layers in 3% hydrogen peroxide, if necessary, you can add collagen (catgut) finely chopped under aseptic conditions or other official collagen-containing dressings without completely removing it the collagen film remaining on the granulation surface.

Examples of specific applications of this method.

Example 1

Patient Papernaya KH.Z., 67 years old, I.b. No. 735/35, was admitted to the clinic on January 14, 1996 with a diagnosis of: Primary: varicose veins of the saphenous veins of both lower extremities. Complications: chronic venous insufficiency of the left leg of 2 degrees, right - 3 degrees, circular dermatosclerosis and hyperpigmentation in the lower third of the right lower leg, trophic ulcer in the lower third of the right lower leg along the anteromedial surface of 114 cm ² . Concomitant diseases - diffuse recurrent goiter, moderate thyrotoxicosis; coronary cardiosclerosis, atrial fibrillation, cardiovascular insufficiency 2A degree; chronic obstructive bronchitis with an asthmatic component; prolapse 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 conventional therapy for 20 days using 150 mg of chymopsin per dressing. 02/06/97, made plastic surgery of the surface of the trophic ulcer. The flaps initially took root, the patient was discharged from the hospital, as she refused surgery on the venous system of the lower extremities.

During follow-up observation, it was noted that the flaps began to be quickly rejected, the infection joined, and by March 1997 an ulcer surface with an abundant purulent-necrotic discharge of 84 cm ^{2 was formed} . Its edges are gentle, the skin around is hyperpigmented and sclerotic, eczematized. Staphylococcus aureus is seeded from the wound discharge.

The patient is again hospitalized in a hospital. I.b. No. 842/42. From 03.03.97 to 03.03.97, treatment with the Necratsidolizin composition 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 March 6, 1997 to March 11, 1997, 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 . In the future, catgut dressings were applied to TB with a change after 7 days, into which a diluted 1: 2 composition “Necratsidolizin” was applied twice a day through the microirrigator. By April 3, 1997, TJ had completely healed on its own.

Subsequently, the patient produced a combined excision of the saphenous veins of the right n / limb. No ulcer recurrence was observed during the next 5 years of follow-up.

Example No. 2.

Patient Kurbanov M., 39 years old, I.b. 988/188, was admitted March 19, 1999 with a diagnosis of obliterating endarteritis of the left n / limb, gangrene of the first toe of the left foot. 03/27/99, the operation was performed - left-side lumbar sympathectomy, exarticulation of 1 finger of the left foot with resection of the head of the metatarsal bone. In the postoperative period, as a result of necrosis of the edges of the postoperative wound and the attachment of infection, a wound 6 × 3.5 × 4 cm in size was formed with an abundant purulent-necrotic discharge. Staphylococcus aureus is seeded.

From 1.04.99, for two weeks, the wound was treated with dressings with chymotrypsin and 10% sodium chloride solution, but without any particular effect - the abundant purulent-necrotic discharge from the wound persisted.

From April 14, 1999 to April 16, 1999, for three days, when dressing, after the appropriate toilet with 3% hydrogen peroxide, wipes were applied to the surface of the wound, abundantly moistened in the composition "Necratsidolizin" according to the following recipe: methyluracil 1, 0; pepsin 4.0; betaine hydrochloride 4.0; sodium chloride 10.0; distilled water - up to 100.0 (pH 2.0). After purification from purulent-necrotic tissues with the appearance of bright red granulations and marginal epithelization in order to further stimulate regeneration over the next 9 days, a catgut dressing was applied to the DNGR, into which a diluted 1: 2 composition “Necratsidolizin” was applied twice a day ( pH 2.5).

Complete wound healing 12 days after the start of treatment with the composition "Necratsidolizin" together with collagen dressings.

The proposed method of treatment was used in a clinic in 66 patients with trophic ulcers and long-term non-healing purulent wounds of various etiologies (venous-trophic, ischemic, scar-trophic, etc.).

The clinical effect is observed on the first day from the start of treatment. Long-term non-healing purulent wounds and trophic ulcers are cleared of purulent-necrotic discharge for 3-5 days, active granulation and marginal epithelization appear. In the future, together with collagen dressings, another 7-14 days the method is used to stimulate the regeneration and prevention of secondary infection.

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

Compared with methods using pancreatic and bacterial proteases, the proposed method accelerates the rejection of necrotic tissues, inhibits the growth of microbes, including those resistant to antibiotics. The risk of generalization of infection is reduced. Toxic and allergic effects are excluded. Tissue regeneration is much faster. All this leads to a reduction in treatment time by 1.5-2 times and the prevention of relapse in the long term.

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

1. for the purpose of proteolysis, the proposed mixture used the enzyme pepsin from the group of acidic hydralases (optimum pH 2), since its activity with respect to other enzymes from the group of alkaline hydralases (termitase, papain, chymotrypsin, chymopsin, terrilitin, etc., the optimum pH of which is about 8.5) under various conditions is 2-20 times higher; pepsin also has the strongest collagenase activity;

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

3. the drug increases lymphatic drainage of tissues (it is proved that increasing the acidity of tissues from 7.35 to 5.9 increases its exudation volume by 20% due to lymph flow, while at the same time, a 10% hypertonic sodium chloride solution in the mixture stimulates the outflow of tissue fluid with toxic elements and microflora in a bandage);

4. as active stimulants of regeneration and cytoprotectors in 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 TN and DNGR;

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

6. as a protection of regenerating tissues from external influences and prevention of secondary infection, long-term (7 days) applied catgut dressings were used in combination with periodic feeding of the composition “Necratsidolizin” to them.

The combined use of the components of the composition and collagen preparations in this method leads to a pronounced synergy of effects on TN and DNGR.

Given the low cost of the ingredients used in the composition for treatment by this method, one can expect significant economic efficiency from its introduction into clinical practice.

Claims (3)

1. A method of treating trophic ulcers (TN) or long-term non-healing purulent wounds (DNGR), characterized in that in the first phase of the wound healing process, a wound healing composition is applied on the surface of the TB and DNGR in the following ratio of components in 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 up to 100.0 on cotton carriers, and in the second and third phases finely chopped collagen preparations are applied to the cleansed surface of TJ and DNGR with a layer of 3-4 mm thick, then the first layer of a cotton carrier, abundantly moistened in a wound healing composition is applied to the collagen layer diluted in a 1: 2 ratio with distilled water, a multi-hole microirrigator is applied over a cotton carrier, covered with another sterile cotton carrier. 2. The method according to claim 1, characterized in that as a cotton carrier use a gauze bandage in 6-10 layers. 3. The method according to claim 1, characterized in that finely chopped medical catgut or other official collagen-containing dressings are used as collagen preparations.