RU2804781C1 - Medicinal product for the treatment of ulcer defects in "diabetic foot" syndrome - Google Patents

Abstract

FIELD: medicine; dermatology; endocrinology.

SUBSTANCE: invention is intended for the treatment of ulcers in patients with complicated forms of diabetic foot syndrome. A medicinal product for the treatment of ulcerative defects in diabetic foot syndrome in the form of a liquid contains sodium selenite, metronidazole, dimethyl sulfoxide and distilled water. The components are used in the declared quantities.

EFFECT: invention makes it possible to create a highly effective agent having both anti-inflammatory, reparative and regenerative effects for the treatment of ulcerative defects without any allergic reactions.

1 cl, 4 tbl, 6 ex

Description

The invention relates to medicine, namely to surgery, and can be used to treat patients with complicated forms of diabetic foot.

The problem of treating complications of diabetes mellitus (DM) continues to be relevant in modern medicine, including diabetology. According to the World Health Organization, the number of patients diagnosed with diabetes is currently about 160 million people, and by 2025 the number of patients with this diagnosis is predicted to double. One of the most dangerous complications of diabetes is diabetic foot syndrome (DFS) [2, 7, 9, 11, 12,17, 19, 23, 24, 25].

The development of purulent-destructive processes in the lower extremities in patients with DFS significantly reduces the quality of life, leading to early loss of ability to work and disability. The risk of amputation at different levels of the limb in patients with diabetes mellitus is 17-45 times higher than in the general population. The mortality rate of patients with DM due to the development of DS is 20-30%. In addition, diabetic foot is a complication that leads to long-term hospitalization, rehabilitation, and significant costs associated with treatment.

Treatment of SDS in decompensated forms of type 2 diabetes mellitus, despite a large arsenal of methods and means, does not always provide the desired result for these purposes, therefore the development of alternative treatment methods and the search for new drugs for complex treatment that differentially affect the course of the wound process is very relevant.

There is a known method of treating destructive forms of diabetic foot syndrome. The method is used for purulent-necrotic lesions of the lower extremities with high resistance of microorganisms to antibiotics, and it consists in the local use of a 1% solution of hydrochloric acid. A bandage moistened with a solution of hydrochloric acid is applied to the wound surface, previously coated with a broad-spectrum antibiotic. Dressings are repeated daily for 9-12 days until granulation appears. Further treatment of the granulating wound is carried out using traditional methods [17].

The disadvantage of this method is the increase in treatment time due to the fact that daily applications of a 1% hydrochloric acid solution can lengthen the duration of the hydration phase of the inflammatory process without affecting tissue regeneration, while having a locally irritating effect on the soft tissue surrounding the defect. In addition, local use of antibiotics can lead to the development of superinfection (candidiasis), allergies, circulatory disorders (thrombocytopenia, leukopenia)

There is a known method of treating ulcerative defects in diabetic foot syndrome, including the use of Activtex napkins with various medicinal substances that suppress the entire spectrum of microbial flora present in the wound, reduce pain and accelerate wound healing (chlorhexidine, tocopherol, rutin, ascorbic acid, furagin, chlorophyllipt ). Bandages are applied every two days in a certain sequence. The course of treatment lasts 12 days and is repeated until the defect heals [16].

The disadvantage of this method is the lack of effectiveness and duration of treatment. Complete closure of the defect by day 20 was observed in only 20% of patients.

There is a known method of treating long-term non-healing wounds using an ointment containing streptokinase, carboxymethylcellulose, dimethyl sulfoxide and distilled water. The use of ointment allows you to accelerate tissue regeneration processes and achieve cure in cases of ineffectiveness of other medications. After washing, 0.5 cm ³ of ointment is applied to the wound daily. Wounds heal within 2-6 weeks [15, 22].

The disadvantage of using ointment is the long healing time. In addition, streptokinase, which is part of it, is a fibrinolytic agent and even when used topically can cause spontaneous systemic bleeding in patients with erosive and ulcerative lesions of the gastrointestinal tract, arterial hypertension, diabetic retinopathy, oncology, and also possible hyperallergic reactions of the body to ointment ingredients.

A means for stimulating reparative processes in a wound was chosen as a prototype [13]. The product contains sodium selenite, dimethyl sulfoxide and distilled water in certain proportions and can be used to treat wounds of various etiologies in experimental animals. Moreover, after stopping the inflammatory process, regenerative processes occur faster and are more active. By stimulating reparative processes in the wound, the product makes it possible to increase the effectiveness of treatment, which is manifested in the appearance of full-fledged granulation tissue on the 4th day of treatment, and complete wound healing on the 9th day.

The disadvantage of this drug is that it was developed for the treatment of wounds in an experiment and does not provide effective therapy at all stages of treatment of the wound process.

The objective of the invention is to create a highly effective agent that simultaneously has anti-inflammatory, reparative and regenerative effects, allowing the treatment of ulcerative defects without causing allergic reactions.

This technical result is achieved by the fact that the medicinal composition for the treatment of ulcerative defects in diabetic foot syndrome, according to the invention, contains sodium selenite, dimethyl sulfoxide, metronidazole and distilled water in the following ratios of components wt.%:

Sodium selenite: 0.15-0.2;

Metronidazole: 0.25-0.26;

Dimethyl sulfoxide: 20.0-25.0;

Distilled water - the rest.

The selection of the main medicinal ingredients in the proposed medicinal composition is based on the following criteria:

Sodium selenite (Na ₂ SeO ₃ ) is an inorganic compound, in accordance with the Register of Medicines of the Russian Federation, it belongs to the pharmacological group of antihypoxants and antioxidants. The active principle of the compound is selenium (Se), the key biochemical function of which is the construction and functioning of glutathione peroxidase, one of the main antioxidant enzymes [1, 2, 3, 4].

Metronidazole (metragyl) is an anti-inflammatory and antimicrobial drug that exhibits high activity against a large number of both aerobic and anaerobic pathogenic microorganisms. In addition, the immunomodulatory effect of the drug on the course of the wound process has been proven, expressed in the correction of deficient components of the immune defense, namely the normalization of the phagocytic activity of peripheral blood leukocytes, elimination of the imbalance of subpopulations of T-cell lymphocytes, reduction in the number of pro-inflammatory cytokines and antigen-dependent suppressors [26, 27].

Dimethyl sulfoxide (DMSO) refers to organic sulfoxides, a dipole, aprotic, coordinating solvent. DMSO is low-toxic and has a high ability to dissolve a huge number of substances. The drug penetrates well through biological membranes, transporting drugs, and exhibits anti-inflammatory and analgesic effects in a concentration of 20-25% solution in the treatment of wounds and skin ulcers [8].

The quantitative composition of the main ingredients is selected based on doses not exceeding the average daily therapeutic doses used in clinical practice.

The technical result to be achieved by the creation of this invention is to increase the effectiveness of treatment of patients with ulcerative defects with DDS syndrome, reduce treatment time by using a combined agent that can enhance the activity of action, and prolong the therapeutic effect.

The present invention is illustrated by specific examples of implementation, which, however, are not the only possible ones, but clearly demonstrate the possibility of achieving the required technical result. In the studied ranges, all ingredients have a pronounced anti-inflammatory, antioxidant and reparative effect without local irritant and allergic effects on surrounding tissues.

Example 1. The drug is prepared by mixing the ingredients per 100.0 ml of liquid: 0.15 mg of sodium selenite is added to the flask and dissolved in 10.0 ml of distilled water. Then 50.0 ml of metronidazole solution (5 mg/ml) is added to the flask. Then 20.0 ml of 99% dimethyl sulfoxide concentrate is added to the contents of the flask to prepare a solution for external use. Distilled water is added to the contents, bringing the volume to 100.0 ml. The finished composition is a colorless, transparent liquid, without sediment, with a slight specific odor, stored in bottles at room temperature or in the refrigerator at +4°C.

Example 2. Carry out similarly to example 1, except that sodium selenite is used at a dose of 0.17 mg, metronidazole 52.0 ml (5 mg/ml) and 23.0 ml. 99% dimethyl sulfoxide concentrate, add distilled water to bring the volume to 100.0 ml. The finished composition is a colorless, transparent liquid, without sediment, with a slight specific odor, stored in bottles at room temperature or in the refrigerator at +4°C.

Example 3. Carry out similarly to example 1, except that sodium selenite is used at a dose of 0.20 mg, metronidazole 54.0 ml (5 mg/ml) and 25.0 ml of 99% dimethyl sulfoxide concentrate, add distilled water to bring the volume to 100, 0 ml. The finished composition is a colorless, transparent liquid, without sediment, with a slight specific odor, stored in bottles at room temperature or in the refrigerator at +4°C.

Example 4. Patient Z., 48 years old, was treated at the Clinical Hospital of Russian Railways Medicine, Chita in 2022 with a diagnosis of trophic ulcer of the right ankle joint. Diabetes mellitus type 1, severe. Micro-macroangiopathy. Hypertension degree II, stage I, risk 3. Has been ill for the last 13 years. The area of the ulcer is 4x5 cm on the postero-outer surface of the right ankle joint. Microbial contamination - 10 ⁶ . The department carried out infusion therapy and dressings using the drug according to example 1. Dressings with the claimed drug did not cause pain. After 2-3 applications, a noticeable improvement was noted: swelling and hyperemia of the tissue decreased. On the 3rd day the inflammation was completely stopped. Microbial contamination 10 ³ . Cytogram-regenerator type. The proposed composition was easily tolerated without allergic reactions in hospital and clinic settings. By day 4, the area of the ulcer decreased by half. The patient was discharged for outpatient treatment. We continued dressings with the stated product. On the 7th day the ulcer healed. When examining the patient after 2 months, no recurrence of the trophic ulcer was noted.

Example 5. Patient K., 50 years old, was treated at the Clinical Hospital of Russian Railways Medicine, Chita in 2022 with a diagnosis of diabetes mellitus type 2, stage of decompensation. Micro-macroangiopathy. Obesity 2 degrees. Long-term non-healing trophic ulcer of the left ankle joint. The wound area is 4x6 cm on the outer surface of the medial malleolus, covered with fibrin plaque. Microbial contamination - 10 ⁵ . The department carried out vascular, symptomatic and dressings using the drug according to the example. The drug was well tolerated without allergic reactions. On the 3rd day the inflammation was completely stopped. Microbial contamination - 10 ² . The type of cytograms is regenerative. In the process of treatment and dressings on the 4th day, the wound shrunk by half, and on the 7th day the healing of the ulcer was noted.

Example 6. Patient Ya., 52 years old, was treated in 2013 with a diagnosis of diabetes mellitus type 2, decompensation. Complication: Dabetic foot syndrome. Neuroischemic variant. Trophic ulcer of the left foot, stage II (Wagner) Concomitant pathology: ischemic heart disease. Stable angina pectoris 2 fc. class Hypertension stage 2, degree 1, risk 3. Wound area 5×4 cm on the anterior surface of the dorsum of the left foot. Microbial contamination - 10 ⁷ . The department carried out vascular therapy and dressings using the drug according to example 3. Good tolerability was observed without allergic reactions. On day 2, signs of inflammation completely disappeared. Microbial contamination - 10 ² . Cytogram type is regenerative. In the process of treatment and dressings, by the 3rd day the ulcer had halved its size, dimensions 2×2× cm. Complete healing of the wound took place in up to 7 days.

The proposed medicinal composition is easily applicable in hospital and clinic settings.

The method is performed as follows.

After taking the wound discharge to determine the level of contamination of the ulcer with microorganisms per 1 gram (ml) of tissue, pre-treatment of the defect with a 0.5% aqueous solution of chlorhexedine, bandages with the declared drug were applied to the ulcer surface, which were changed daily during the patient’s treatment in the hospital. In the comparison group, local treatment of ulcerative defects was carried out in the traditional way using levomekol ointment (the first phase of the wound process). In the second phase of the wound process, a selenium-based medicinal composition (prototype) was used in this group to stimulate regenerative processes [6, 13].

As infusion therapy, drugs were administered at a daily dose of rheopolyglucin - 5.3 ml/kg in combination with a solution of trental 2% - 2.6 mg/kg; 0.9% NaCl solution - 500 ml in combination with a soluble form of the drug cytoflavin 20 ml for a course of treatment of 10 days.

According to the stated method of treatment, 16 patients were treated (the main group); in the comparison group, 16 patients were also under observation. A total of 32 patients. All patients had a decompensated form of diabetes mellitus, complicated by diabetic foot syndrome with trophic ulcers of the second degree according to the Wagner F.W. classification. (1981).

Evaluation of treatment results was carried out according to the following criteria: 1) indicators of capillary blood flow with measurement of partial oxygen tension in the ulcerative defect, the content of pro-inflammatory cytokines and glutathione peroxidase in the blood serum; 2) timing of cleansing of the ulcerative defect from purulent-necrotic tissue and fibrin film; 3) the timing of the reduction in microbial contamination per 1 gram of tissue; 4) the timing of the formation of granulation tissue; 4) healing time of ulcers; 5) a bed-day in a hospital. In addition, cytological studies were carried out that reflected the inflammatory or regenerative type of cytograms of ulcerative defects during local treatment in various ways.

The positive technical result achieved when using the claimed invention is that as a result of the combined treatment of patients with diabetic foot syndrome, complicated by trophic ulcers with the presence of pathogenic microflora, the effectiveness of treatment increases, namely, in comparison with standard treatment, the main spectral parameters of the capillary blood flow, in a shorter period of time, the ulcerative defect is cleansed from necrotic tissue and fibrin film and microbial contamination is reduced to minimal values, earlier periods of formation of granulation tissue are noted, indicators of antioxidant and immune status are normalized, the healing time of ulcers and hospital bed days are reduced (Table 2, 3).

During a cytological examination in fingerprint smears on the 1st day in patients of both groups, cellular elements were represented by a large number of neutrophilic granulocytes (77.3±2.4%) with signs of degeneration in the form of cell swelling and fragmentation of nuclei. There were single monocytic cells - macrophages (1-2%), with pronounced degenerative changes. Connective tissue cells were absent (Table 3). On the 3rd day of treatment, patients in the main group in all observations showed positive dynamics, which was manifested in a significant decrease in the number of neutrophil leukocytes to 45.2±2.8% of the total number of cells, most of them were without signs of degeneration. Noteworthy was the increase in the number of macrophages to 16.7±1.4% in the field of view and the appearance of polyblasts (12.8±0.8%), which tended to be arranged in nests. On the 5th day of treatment, by the time full-fledged granulations grew in the wounds, cytograms were represented by a large number of polyblasts, which most often had a nested arrangement and accounted for 26.5±5.2% of the total number of cells, their active transformation into pro- and fibroblasts, which were located in nests of 7-8 in the field of view.

In the comparison group on the 3rd day, there was a less significant decrease in the number of neutrophil leukocytes (up to 60.5±3.7%), most of them were without signs of degeneration, many microorganisms were inside the cells in various stages of destruction. There was an increase in the number of histiocytic cells (polyblasts), which amounted to 7.7±0.5% of the total number of cells. By the 6th day of treatment, the cytograms of the majority of patients (12 patients) showed a decrease in microbial cells, histiocytes were represented by a nested arrangement of polyblasts (up to 11.6±0.7%), they were transformed into profibroblasts (Table 4).

Thus, the proposed medicinal composition, eliminating local inflammation, protects the ulcer from secondary infection due to the action of dimethyl sulfoxide and metronidazole introduced into the composition, while sodium selenite has a pronounced antioxidant effect in the area of the pathological focus in conditions of tissue ischemia, and metronidazole has an immunomodulatory effect, which significantly improves reparative processes, thereby reducing the healing time of ulcers. The inflammatory process in the treatment of wound ulcerative defects subsides earlier, and regenerative processes occur faster and are more active than in patients in the comparison group. The method allows to increase the effectiveness of treatment by reducing the risk of suppuration, the formation of full-fledged granulation tissue, and reducing the healing time of ulcers.

The clinical effectiveness of the claimed medicinal product and comparison drugs is illustrated by the following examples.

Example. Main group.

Patient N., 62 years old, was hospitalized with a diagnosis of diabetes mellitus type 2, decompensation. Complication: Dabetic foot syndrome. Neuroischemic variant. Plantar ulcer of the left foot, stage II (Wagner) Concomitant pathology: ischemic heart disease. Stable angina pectoris 2 fc. class Hypertension stage 2, 2 degrees, risk 4. From the anamnesis: an ulcer on the foot has been bothering me for the last 6 months. He was treated independently, treated with a 0.05% aqueous solution of chlorhexidine, used bandages with solcoseryl ointment, and curiozone without effect. On the plantar surface of the arch of the left foot, there is a moderate bone deformation of the bones, a round ulcerative defect, up to 2.5×3.2×0.5 cm in diameter, with black areas along the edges. Moderate swelling, hyperemia of soft tissues. Palpation is painless. Before admission: pO ₂ of the ulcer - 5.8 mm Hg. Glutathione peroxidase level 8.8 MM/min. l; IL-1α=174 pkg/ml, TNFα=176 (pkg/ml). The type of cytogram is inflammatory. Microbial contamination - 10 ⁷ . Intravenous infusion therapy was prescribed based on drugs in a daily dose of rheopolyglucin - 400.0 ml in combination with a solution of trental 2% - 5.0 ml; 0.9% NaCl solution - 500 ml in combination with a soluble form of the drug Cytoflavin 20 ml, course of treatment No. 5. This therapy was carried out against the background of insulin therapy.

Local treatment was started with the claimed medicinal composition, which was moistened with gauze swabs and applied to the wound in the form of a bandage daily throughout the entire period of hospitalization.

During the treatment, cleansing of the wound ulcerative defect was noted on day 2, a decrease in microbial contamination by 1 gram of tissue below the critical level of 10 ⁵ - on day 3.

The dynamics of laboratory parameters were as follows. On day 6 _{, pO2} of the ulcer is 19 mm Hg. The glutathione peroxidase level was 22 mm/min. l; IL-1α - 35 pkg/ml, TNFα - 97 (pkg/ml). The type of cytograms is regenerative. The ulcer healing period (epithelialization) was 7 days, the number of days spent in the hospital was 7 bed/days.

Example. Comparison group.

Patient K., 57 years old, was hospitalized with a diagnosis of diabetes mellitus type 2, subcompensation. Complication: Macroangiopathy of the lower extremities. Trophic ulcer of the right ankle joint, stage II (Wagner) Concomitant pathology: Hypertension, stage 2, degree 2, risk 4. AKO stage 2. From the anamnesis: according to the patient, about a month ago, an ulcerative defect formed in the area of the right ankle joint along the posterolateral surface. She was treated on an outpatient basis with 0.5% aqueous chlorhexidine and 0.5% dioxide solution, without effect. Over the last 3 days, areas of necrosis appeared, with signs of perifocal inflammation, and pain in the area of the ulcer began to bother me. Notes an increase in body temperature to 37C. Diabetes mellitus type 2 since 2015, takes antihyperglycemic drugs (Siofor 1000 mg per day, average glycemic level 7.5-11.5 mmol/l). A trophic ulcer of irregular shape, dimensions 3.0×2.0×0.2 cm is determined on the back surface of the right ankle joint, the bottom is made of purulent-fibrinous plaque, elements of the Achilles tendon are visible. Moderate hyperemia, swelling of the soft tissues around the ulcer. Pain on palpation. Microbial contamination - 10 ⁶ .

Before admission: pO ₂ ulcers - 5.9 mm Hg. The level of glutathione peroxidase in the blood serum was 9.8 MM/min.l; IL-1α=168 pkg/ml, TNFα=182 (pkg/ml). The type of cytograms is degenerative-inflammatory. Intravenous infusion therapy was prescribed based on drugs in a daily dose of rheopolyglucin - 400.0 ml in combination with a solution of trental 2% - 5.0 ml; 0.9% NaCl solution - 500 ml in combination with a soluble form of the drug Cytoflavin 20 ml, course of treatment No. 7. Local treatment with water-soluble ointment "Levomekol" was started in the first phase of the inflammatory process using bandages that were changed once a day. During treatment, cleansing of the wound ulcerative defect was noted on the 5th day of observation, a decrease in microbial contamination per 1 gram of tissue below 10 ⁵ - on the 5th day. In the second phase of the wound process, when treating an ulcerative defect, a medicinal composition based on selenium was used in the form of dressings, which were changed once a day. The dynamics of laboratory parameters were as follows. 6 days. pO ₂ ulcers - 7-8 mm Hg. Glutathioperoxidase level: 11 mm/min. l; IL-1α=134 pkg/ml, TNFα=171 (pkg/ml). The type of cytogram is inflammatory.

At the end of treatment (day 10). pO ₂ - 11 mm Hg. Glutatin peroxidase level 14 MM/min. l; IL-1α=104 kg/ml, TNFα=131 (pkg/ml). Cytogram type: regenerative. The wound healing period was 12 days, the number of days spent in the hospital was 12.

Thus, the claimed drug for the treatment of trophic ulcers in diabetic foot syndrome is a highly effective drug that simultaneously has anti-inflammatory, antioxidant, regenerative and reparative effects. The claimed agent increases the effectiveness of treatment of patients with trophic ulcers, reduces treatment time and does not cause allergic reactions.

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Claims (5)

A medicinal product for the treatment of ulcerative defects in diabetic foot syndrome in the form of a liquid containing dimethyl sulfoxide, distilled water, sodium selenite, characterized in that it additionally contains metronidazole in the following ratios of components, wt. %: Sodium selenite 0.15-0.2; Metronidazole 0.25-0.26; Dimethyl sulfoxide 20.0-25.0; Distilled water - the rest.