RU2288730C2 - Method of treatment of oncogynecological patients and gel for its realization - Google Patents

Abstract

FIELD: medicine, oncology, gynecology, pharmacy.

SUBSTANCE: invention relates to a method for treatment of oncogynecological patients by using gel developed for this aim. For 12-14 days before surgery operation and for 7-10 days in post-operative period tinrostim is administrated in patients in systemic regimen in the dose 0.5-1.0 mg, 2 times per a day. Also, in post-operative period gel is used additionally, 2 times per 24 h by topical applying wherein gel comprises the following components, g/l: tinrostim, 0.05-0.1; chitosan, 30.0-35.0; ascorbic acid, 19-21, and distilled water, the balance. Based on selected doses and duration of treatment the proposed method provides immunostimulating effect of phagocytosis, humoral and cellular immunity and normalizes their indices in oncogynecological patients in using selected dose in treatment and duration of treatment that allows the immediate carrying out the following course of radiotherapy and chemotherapy.

EFFECT: enhanced effectiveness of treatment.

2 cl, 10 ex

Description

The invention relates to medicine and can be used for the prevention and treatment of postoperative complications in gynecological oncology.

Currently, surgical and chemotherapeutic methods of treatment are one of the main components of comprehensive and combined treatment programs for patients with malignant tumors. Moreover, the complication rate of all operated patients ranges from 2 to 12%. The main reason for the development of postoperative infectious complications is a decrease in all parameters of the immune system, and therefore, for the treatment of oncological diseases to be effective, correction of the state of the body's defense systems is necessary.

Known means and methods of treating postoperative infectious complications, combining both local and general effects on the body when using one drug.

A known method of treating locally advanced cancer, including surgery with subsequent antitumor treatment and the simultaneous administration of biostimulants systemically (patent RU No. 2090203, IPC 6 A 23 K 35/78, publ. 09/20/1997).

The disadvantage of this method is that as a biostimulant use a herbal preparation, namely Eleutherococcus, and only systemically, which is not enough in the treatment of gynecological oncological diseases.

A known method and means for the treatment of gynecological diseases, combining the use of antibiotics and biostimulants, and the biostimulator is used both locally and systemically. As a biostimulant, solcoseryl is used, which is a product of animal origin, namely, cattle blood extract. Solcoseryl is administered intramuscularly or intravenously for 1-2 ampoules per day and is applied topically in the form of a 20% gel and / or 5% ointment of solcoseryl (Mashkovsky MD Medicines. M., 1985, v. 2, p. 158).

The disadvantage of this treatment is its duration (4-8 weeks). In addition, this tool is not used for the treatment of postoperative gynecological diseases.

Closest to the claimed invention in terms of features is a method for the treatment of gynecological oncological patients, including surgical intervention (Kozachenko V.P. Uterine cancer. M: Medicine, 1983, pp. 58-100, 126-137).

The disadvantage of this method of treatment of gynecological oncological patients is that in this method they use only surgical intervention without the use of biologically active substances that contribute to faster tissue regeneration.

A means is known in which chitosan is used as a base. This tool "Polymed" is used topically in the treatment of infected wounds (patent RU No. 2140264. IPC 6 A 61 K 31/00, 31/18, 38/02, publ. 10/27/1999).

The disadvantage of Polymeda is its multicomponent nature, and it is also used only locally.

Known "Pharmaceutical composition having a healing effect." It consists of a peptide, which is a growth factor for fibroblasts, and a cationic polyelectrolyte from the chitosan group (patent No. 2080872, IPC 6 A 61 K 38/02, 31/73).

The disadvantage of this tool is that it is not used to treat purulent postoperative complications.

Known means containing polyvinyl alcohol, chitosan, organic acid, biologically active substance, glutaraldehyde, ethyl alcohol and water (RF patent No. 2219955, IPC 7 A 61 L 15/32, 15/22, A 61 P 17/02).

The disadvantage of this tool is its multicomponent nature and the use of a plant product as a biologically active substance.

The closest analogue to the claimed technical solution is a gel containing biologically active substances of a medical leech (Semikoz N.G. et al. Evaluation of the effectiveness of the use of a gel containing biologically active substances of a medical leech for the prevention and treatment of radiation epithelitis in patients with vulvar cancer. Oncology, 2001, 3, No. 2).

The main task, the inventive method and gel for its implementation are aimed at, is to increase the efficiency of treatment of gynecological oncological patients who underwent surgical interventions, as well as expanding the arsenal of wound healing agents.

The problem is solved in that according to the method of treating oncogynecological patients, including surgical intervention, according to the invention, the patients are administered tinrostim in a dose of 0.5-1.0 within 12-14 days before surgery and for 7-10 days in the postoperative period mg 2 times a day, and in the postoperative period an additional topical 2 times a day use a gel of the following composition and component ratio, g / l: tinrostim 0.05-0.1, chitosan 30.0-35.0, ascorbic acid 19- 21, distilled water - the rest.

Tinrostim is an immunotropic peptide isolated from the nervous tissue of Far Eastern squid. The main target of tinrostim in the body are cells of the monocytic-macrophage series. It enhances all the functions of the cells of this system - absorption and killing of foreign cells, the synthesis of cytokines (IL-1, gamma-IFN, etc.), has anti-infectious, anti-inflammatory, reparative and leukopoietic effects.

Tinrostim is a biologically active food supplement with a pronounced immunostimulating effect on all parameters of the immune system, namely phagocytosis, humoral and cellular immunity. It is harmless, non-toxic, has antihistamines and analgesic properties.

Due to these properties of tinrostim and its use systemically 12-14 days before surgery, 0.5-1.0 mg twice a day daily, and after surgery, it is simultaneously used systemically in the same doses for 7-10 days and locally in the form of the inventive gel of the following composition and ratio of components, g / l: tinrostim 0.05-0.1, chitosan 30.0-35.0, ascorbic acid 19-21, distilled water - the rest allows accelerating tissue regeneration, eliminating postoperative complications and speed up the healing process.

The selected parameters of doses and time of exposure are based both on theoretical studies of the patterns of development of adaptive reactions that increase the antitumor resistance of the body, and on clinical trials. Changing the dosage or time parameters in the direction of increasing or decreasing compared with the claimed parameters leads to a decrease or increase in the cost of treatment effectiveness.

In addition, the local use of tinrostim as part of the inventive gel of the following composition and ratio of components, g / l: tinrostim 0.05-0.1, chitosan 30.0-35.0, ascorbic acid 19-21, distilled water - the rest, thanks its consistency allows it to be applied both to the bottom of the wound and to inaccessible places.

The use of systemic tinrostim 12-14 days before surgery, 0.5-1.0 mg 2 times a day in the morning and evening hours, regardless of food intake, is especially indicated for cancer patients with concomitant diseases and adverse prognostic factors: obesity, diabetes , moderate and severe anemia, intraoperative blood loss, forced prolonged hospitalization before surgery, prolonged surgery (2 hours or more), excessive use of coagulation, previous radiation or chemotherapy. Subsequent (after surgery) the use of systemic tinrostim 0.5-1.0 mg 2 times a day for 7-10 days with the simultaneous introduction of the inventive gel into the vagina, which helps to prevent the development of stump. For the treatment of cultitis, the inventive gel is applied on a tampon to the vaginal stump for 2 hours once a day, after which the tampon is removed. This manipulation is repeated for 7-10 days.

For the treatment of postoperative wounds, the inventive gel is used, which is applied from the tube to the entire surface of the wound, and the inventive gel is injected into inaccessible edges and the bottom of the wound using a syringe. A bandage is applied to the wound (for 6 hours) in order to remove excess exudate. The procedure is repeated daily for 7-10 days. The implementation of these procedures ensures the prevention of complications in the stump area and postoperative wound.

In all patients (group 1 - 20 people) who received tinrostim systemically in the preoperative period according to the above scheme and after surgery and locally, healing of the postoperative wound occurred by primary intention up to 10 days. Healing of the vaginal stump without necrosis and inflammation also occurred in 7-10 days. Clinical and biochemical blood parameters reach the initial level by 4-5 days after surgery.

In patients (group 2 - 5 people) who did not receive tinrostim systemically and locally, the development of cultitis and secondary wound healing up to 14 days were observed. Clinical and biochemical blood parameters reliably approached the initial level only by 10 days of the postoperative period.

In general, the following has been established:

1. the temperature in patients of the first group returned to normal by day 3, in patients of the second group by day 6;

2. pain was observed in patients of the first group up to 5-6 days, in the 2nd group up to 9-10 days;

3. purulent-necrotic process of vaginal stump in patients of the first group stops by 7-8 days, in patients of the 2nd group by 10-12 days, and in some cases by 14-15 days;

4. the blood formula in patients of the first group returned to normal by day 8-9, in patients of the second group by day 12-14;

5. hospital stay in patients of the first group is 3-4 days less than in patients of the second group.

The following examples illustrate the invention without limiting it.

Example 1

Patient N., 60 years old, No. of medical history 7808.

Diagnosis: Endometrial cancer 1 tbsp.

The concomitant diagnosis is obesity of the IV century, diabetes mellitus II, moderate severity, subcompensated. Hypertension II Art. Received 14 days before surgery systemically with Tinrostim 1.0 mg 2 times a day in the morning and evening. After abdominal surgery, she systematically received 1.0 mg of tinrostim 2 times a day in the morning and evening hours, and twice a day the claimed gel was applied topically to the wound and vagina for 10 days. Healing occurred by primary intention without discrepancy. The patient was discharged from the hospital on the 15th day after the operation to continue the II stage of treatment - postoperative radiation therapy in the radiology department. All elements of the blood test are normal. The immunogram is completely normal.

AF for blood stain was before treatment - 22.8 ± 1.6%, AF - 1.6 ± 0.3; after treatment with the inclusion of tinrostim, AF increased to 72.0 ± 3.4%, and AF increased to 4.6.

Example 2

Patient M., 49 years old, medical history No. 7688. Diagnosis: endometrial cancer 1 tbsp. Before surgery, she did not receive systemic tinrostim. The postoperative period was complicated on the 6th day by suppuration of the hematoma, necrosis of the postoperative wound and cultitis.

After abdominal surgery, a tabletted tinrostim was applied systemically (1.0 mg 2 times a day for 10 days) and the inventive gel was applied topically to the wound and vagina for 10 days (2 times a day). This contributed to the early rejection of purulent-necrotic tissue, cleansing the wound and the appearance of fresh granulations by the 6th day after treatment. The use of the inventive gel in the course of treatment of the patient prevented the development of apaneurosis defects, with subsequent eventuation. Due to active granulation, early secondary sutures were not overlapped. Wound healing by secondary intention occurred by day 16. In this case, the wound could not be distinguished from healed by primary intention. The blood formula returned to normal by day 8. The immunogram is completely normal

The phagocytic index (AF) for polymorphonuclear leukocytes (PN) of the blood before treatment was 28.6 ± 2.4%, and the phagocytic number (PS) was 1.6 ± 0.3. After treatment with the inclusion of tinrostim, AF was 66.7 ± 3.4%, and AF was 3.8 ± 0.9.

Example 3

Patient I., 33 years old, medical history No. 4664. Diagnosis: cervical cancer Ib art. after surgical treatment. An operation was performed - expanded hysterectomy with appendages according to Wertheim.

In the preoperative period, the patient took systemically twice a day for 12 days a 0.5 mg tinrostim per dose, after the operation for 7 days, systemically tinrostim in the same dose and the topically declared gel in order to prevent stump. Discharged on the 13th day after the operation to continue the II stage of treatment - postoperative radiation therapy in the radiology department, since all elements of the blood test are normal. The immunogram is completely normal.

AF for blood stain was before treatment 33.8 ± 4.1%, AF - 1.9 ± 0.6; after treatment - AF - 69.6 ± 4.8, AF - 4.2 ± 1.1.

Example 4

Patient G., 60 years old, No. of medical history 2374

Diagnosis: cancer of the ovary III tbsp. in the process of complex treatment. Concomitant diagnosis: IHD. Cardiosclerosis, coming rhythm disturbance. Chronic pancreatitis.

In the preoperative period, the patient took systemically twice a day for 12 days with 1.0 mg tinrostim per dose.

An operation was performed - supravaginal amputation of the uterus with appendages. Resection of the greater omentum. Drainage. Blood loss - 800 ml. Blood transfusion, erythrocyte mass in a volume of 169 ml. In the postoperative period of a hematoma in the area of a postoperative wound. After surgery, for 7 days, she systemically took tinrostim in the same dose. The area of the postoperative wound twice a day for 10 days was applied the claimed gel. Wound healing occurred without necrosis. Discharged on the 11th day. The immunogram is normal. The blood formula returned to normal on the 9th day. Ten days later, she underwent a course of polychemotherapy according to the CMF scheme; she transferred the procedure satisfactorily without immunosuppression.

The AF for blood stain before treatment was 35.6 ± 4.1, the AF was 2.5 ± 1.4; after treatment with inclusion of tinrostim, the AF was 75.4 ± 4, and the AF was 4.5 ± 0.6.

Example 5

Patient S., 70 years old, No. of medical history 1586

Diagnosis: Ovarian cancer, Art. IV

Cytoreductive operation was performed due to the generalized process.

In the preoperative period, the patient took systemically twice a day for 12 days a 0.5 mg tinrostim per dose. After surgery for 10 days, she systemically took tinrostim in the same dose. The area of the postoperative wound twice a day for 7 days was applied the claimed gel. Wound healing occurred without necrosis. The immunogram and hemogram parameters returned to normal.

AF for blood stain before treatment was 24.4 ± 3.1%, AF - 2.1 ± 0.4; after treatment - AF - 78.2 ± 3.8; PS - 4.2 ± 0.9.

Example 6

Patient A., 47 years old, No. of medical history 349.

Diagnosis: trophoblastic disease. Invasive cystic drift.

Bleeding. The patient acted urgently.

An operation was performed - hysterectomy with appendages. In the preoperative period, the patient did not receive tinrostim. On the 8th day of the postoperative period, cultitis, intoxication syndrome and suppuration of the wound developed. From the 9th day, a change in antibacterial drugs and detoxification therapy was carried out. Wound cleansing occurred only on day 18.

AF for blood stain before treatment was 28.5 ± 2.1%, AF - 1.3 ± 0.1; after treatment - AF - 35.2 ± 3.1%; PS - 2.1 ± 0.3. The immunogram returned to normal only 1.5 months after surgery.

The patient was discharged on the 23rd day of the postoperative period.

Polychemotherapy was performed after the intoxication syndrome subsided.

Example 7

Patient K., 47 years old. The medical history N 7686. The diagnosis of endometrial cancer 1 tbsp. Concomitant diagnosis - 4th grade obesity. Type 1 diabetes mellitus of moderate severity. The postoperative period was complicated on the 5th day by necrosis of the postoperative wound and cultitis. The patient received a preoperative placebo preparation (tablets containing neither tinrostim nor any other medications), in the postoperative period, a chitosan gel containing no tinrostim, in the vagina to prevent cultivation. Secondary tension suture healing was noted only on the 17th day, and stump was stopped on the 10th day after the operation period.

The immunogram returned to normal 38 days after surgery.

AF for blood stain before treatment was 30.2 ± 2%, AF - 1.4 ± 0.1. After treatment - AF - 43.6 ± 1.8%, AF - 1.9 ± 0.2. Thus, the use of only chitosan gel and the rejection of the systemic use of tinrostim led to a long wound healing process, while it healed by secondary intention, as well as a longer period of normalization of immunological parameters.

The phagocytosis indices in PN blood counts grew less than when using tinrostim locally and systemically.

Example 8

Patient M., 52 years old. The diagnosis of cervical cancer Ib Art. Enhanced hysterectomy with appendages was performed. Before surgery, the patient received per os placebo tablets not containing tinrostim. In the postoperative period, chitosan gel was used on the wound with the aim of preventing cultitis. The postoperative period was complicated on the 5th day by suppuration of the postoperative wound and cultitis. Granulation appeared already on the 5th day, which is much earlier than with the traditional method of treatment. However, the phagocytosis indices of PN stains increased by the time of discharge not very significantly (AF before treatment - 25.6 ± 3.4%, AF - 1.6 ± 0.2; after treatment - AF - 42.4 ± 2.1% AF - 3.4 ± 0.7). The immunogram returned to normal only 30 days after surgery.

As can be seen from the above examples, the use of tinrostim systemically and locally allows patients immediately after treatment to continue the course of radio and chemotherapy without immunosuppression.

To achieve this goal, namely the treatment of gynecological oncological patients who underwent surgical interventions, use the gel of the following composition and ratio of components, g / l:

Tinrostim - 0.05-0.1, Chitosan - 30.0-35.0, vitamin C - 19-21, distilled water - the rest.

The combination of properties of the components that make up the inventive topical gel provides its regenerative effect, enhances phagocytic processes in the wound, as well as immunocorrective, antimycotic and antibacterial effects.

The inventive gel is a stable texture and can be stored at room temperature for a year without losing its biological activity and physico-chemical properties.

As mentioned above, as biologically active substances use tinrostim isolated from the nervous tissue of the Far Eastern squid.

Alkaline polysaccharide - chitosan, obtained from the crab shell, which has a high sorption ability, wound healing effect, anticoagulant, antithrombogenic, bactericidal and antitumor activity. Being a natural product, it is absolutely safe and compatible with body tissues.

Due to the specifics of the wounds, their inaccessibility, it is best to use a mixture of chitosan and tinrostim in the form of a gel. To do this, they are diluted in water, in which ascorbic acid is previously dissolved to create a barrier to pathogenic microorganisms.

The inventive gel, created on the basis of chitosan and tinrostim immobilized on it, has a prolonged property, this allows to reduce the dosage of the active principle in the inventive gel when applied topically. At the same time, chitosan adsorbs necrotic products, and tinrostim stimulates phagocytosis in polymorphonuclear leukocytes and monocytes / macrophages and has a regenerating effect on the wound surface, resulting in rapid healing of the wound.

The indicated value of the ingredients used in the preparation of the inventive gel is based both on deep experimental studies of the effect of tinrostim on the healing process, and on clinical trials. A quantitative change in them led to a decrease in the clinical effect or an increase in the cost of treatment.

With a ratio of tinrostim-chitosan mixture and water in a ratio of 1: <(3-3.5), the gel consistency is liquid (flowing, and at 1:> (3-3.5) it is too thick. The optimal ratio is 1: (3 -3.5).

Examples of specific performance.

Example No. 1

To prepare 1 liter of the inventive gel, take 210 ml of a 2% solution of ascorbic acid, which is prepared by dissolving 20 g of ascorbic acid in 1 liter of water. In a 2% solution of ascorbic acid, 30 g of chitosan powder is added (at a ratio of chitosan: ascorbic acid solution - 1: 7), the mixture is stirred for 3-4 hours at a temperature of 30-35 ° C until the chitosan is completely dissolved and the gel forms. Then, 0.05 g of tinrostim is added to the gel with constant stirring. The volume is adjusted with distilled water to 1 liter and stirred until a homogeneous gel-like mass is formed. The finished gel has a slightly acidic environment (pH 5.9-6.0), such a pH value is quite acceptable for an external therapeutic agent.

The composition of the gel, g / l:

Tinrostim - 0.05;

chitosan - 30.0;

ascorbic acid - 20.0;

distilled water - the rest.

Tinrostim was taken in an amount of 0.05 g per 1 liter of the inventive gel for the following reasons - for one application, 2 to 3 ml of gel is necessary, i.e. 1 liter of the inventive gel contains from 500 to 333 doses. So in one dose of the claimed gel for the application will contain from 0.05 to 0.1 mg of tinrostim.

Example No. 2

The gel is prepared analogously to example No. 1, however, the number of starting components is as follows:

The composition of the gel, g / l:

Tinrostim - 0.1;

chitosan - 35.0;

ascorbic acid - 19.0;

distilled water - the rest.

The finished gel has a slightly acidic environment (pH 5.9-6.0), such a pH value is quite acceptable for an external therapeutic agent.

Biomedical tests of the gel were carried out in the Department of Oncogynecology of the Primorsky Territory Oncology Center jointly by the staff of the Immunology Laboratory of the Research Institute of Epidemiology and Microbiology of the Siberian Branch of the Russian Academy of Medical Sciences and a gynecological oncologist.

The inventive gel was used as part of chitosan + tinrostim in the treatment of cancer patients with postoperative complications (seromas, hematomas, discrepancy of the edges of the wound, suppuration of the wound). All patients had reduced T-cell and phagocytic immunity, which is characteristic of cancer patients. The gel was applied to the area of the postoperative wound 2 times a day. Patients in the control group received conventional treatment without the claimed gel.

The effectiveness of the application of the inventive gel, consisting in reducing the time of regeneration of the seam (in the experimental group - 8 days, in the control - 16 days) was established. When applying the inventive gel to a purulent wound, prevention of the development of aponeurosis and eventation defects, earlier than control, rejection of purulent-necrotic tissues, cleansing the wound and the appearance of fresh granulations was noted.

Researchers issued a conclusion on the high wound healing ability of the gel obtained by the above method, used as an external agent in the treatment of operated oncological patients.

Conclusions: the inventive gel is an effective wound healing external agent.

In the present application for the grant of a patent, the requirement of the unity of the invention is met, since the method and gel are designed to solve the same problem, namely, increasing the effectiveness of the treatment of gynecological oncological patients who underwent surgery.

Each of the claimed inventions meets the condition of patentability “novelty”, since there are no analogues that are characterized by sets of features identical to all the features of the claimed method and gel for its implementation.

The invention has an inventive step, since for the specialist gynecological oncologist, the claimed technical solution does not explicitly follow from the level of medicine in this field of oncology.

The invention is “industrially applicable”, as it can be widely used in healthcare in the treatment of gynecological oncological diseases, and the gel can be made in the required quantities, since its components are commercially available.

Claims (2)

1. A method of treating gynecological oncological patients, including surgery, characterized in that within 12-14 days before surgery, and within 7-10 days in the postoperative period, tinrostim is administered systemically at a dose of 0.5-1.0 mg 2 times per day, and in the postoperative period an additional topical 2 times a day use a gel of the following composition and ratio of components, g / l: tinrostim 0.05-0.1, chitosan 30.0-35.0, ascorbic acid 19-21, distilled water - the rest. 2. A gel for the treatment of gynecological oncological patients who underwent surgical interventions, characterized in that they use a gel of the following composition: tinrostim, chitosan, ascorbic acid, distilled water, with the following ratio of components, g / l: Tinrostim 0.05-1 Chitosan 30-35 Vitamin C 19-21 Distilled water Rest