Chemotherapy method for treating malignant tumors in the abdominal cavity, small pelvis and retroperitoneal space

FIELD: medicine.

SUBSTANCE: method involves introducing water-soluble chemopreparation as a course in lymphotropic way. Riva-Rocci apparatus cuff is applied to lower part of femur and pressure of 40 mm of mercury column is created. 20 ml of chymotrypsin dissolved in 0.5% Novocain solution is subcutaneously introduced into the middle area of lateral shank surface 30 min later. Water-soluble chemopreparations are slowly subcutaneously introduced 0.5 cm below the chymotrypsin injection place in 5-7 min as single dose. The cuff is left in swollen state for 2 h. After having taken off the cuff, 50 ml of 0.5% Novocain solution is subcutaneously introduced into the place of previous water-soluble chemopreparations injection. Then the lower extremity is dressed with elastic bandage. The lymphotropic water-soluble chemopreparations introduction procedure is carried out once a day combined with standard chemotherapy course. Detralex is daily given to the patient on the background of the chemotherapy course at a dose of 2 pills twice a day combined with subcutaneous Fraxiparin injections introduced at a dose of 0.3 ml once a day.

EFFECT: avoided surgical intervention; increased antitumor effectiveness; reduced risk of recurrences, metastases and toxic complications.

5 dwg

 

The invention relates to medicine, namely to Oncology, and can be used in complex treatment of cancer patients with malignant tumors of the abdominal, pelvic and retroperitoneal space III-IV century, including the elderly and elderly with comorbidities.

The application of complex methods (surgery+chemotherapy) treatment resulted in increased radical operations by performing them in larger ablation and optimal anatomical boundaries [Jackman A.L. et al. Combination raltitrxed with other cytoxic agents rationale and preclinical oservations // Eur. J.Ccancer., 1999. - V.35. - Suppl. 1. - P.3-8].

Of the most famous routes of administration of drugs in the human body, intravenous, intraarterial, endolymphatic, autohemotherapy most common intravenous. However, the use of intravenous systemic chemotherapy has shown its low efficiency in severe gastrointestinal and bone marrow toxicity, for example in the treatment of colorectal cancer [Lagunov NR. et al. Some of the issues of cancer of the colon and rectum // Etiopathogenesis, diagnosis and treatment of tumors. Tbilisi 1980. - V.2. - S-200].

The known method endolymphatic chemotherapy [Maksimov G.K. Experience radical and preserves the effective treatment of colon cancer. Rostov-on-don, 2001. - S-172], we have chosen as an analogue. This surgical method for direct injection of drugs directly into the lymphatic system. He is one of the least toxic but effective ways XT. Direct introduction of the cytostatic agent in lymphatic channel provides a direct summation of the drug to the tumor and the metastases in the regional lymph nodes. Is a small surgical intervention with the aim of identifying and catheterization of peripheral lymph vessel on the rear foot; then the catheter is slowly inserted half yearly dose of chemotherapy. After 6 days is catheterization of peripheral lymph vessel on the rear of the other foot and the catheter is slowly inserted the rest of the half yearly dose of chemotherapy. Surgery is performed through 7-14 days after the last endolymphatic introduction, during the most pronounced reduction of the biological activity of the tumor due to the XT. The disadvantage of this method analiticheskoi chemotherapy is the difficulty of performing surgical procedures in an outpatient setting or in specialized hospitals.

Known "Method lymphotropic administering drugs [Levin, Y.M. basis of the medical lymphology. Moscow, 1986. - Pp.118-135], we have chosen in to the operation of the prototype. This indirect (non-surgical) route of administration of drugs in the lymphatic channel. The method is as follows: on the lower third of the thigh is applied cuff apparatus of the Riva-Rocci and creates a pressure of 40 mm Hg Increase in pressure in the venous system of the lower extremities leads to a redistribution of interstitial fluid outflow in favor of lymphatic microvasculature, is the expansion of lymphatic vessels with increasing lymphatic drainage. After 30 minutes subcutaneously injected with 10 mg of chymotrypsin dissolved 10 ml of 0.5% solution of novocaine to enhance the permeability of lymphatic vessels in the area of the middle third of the lateral surface of the tibia, where it is expressed in lymphatic vascular network. After another 5-7 minutes at 0.5 cm below the point of addition of chymotrypsin introduced water-soluble drugs. The cuff on the thigh remains in an inflated position for another 2 hours. However, this method has its drawbacks: it is not adapted to lymphotropic the introduction of water-soluble drugs, and the introduction of the above described method except antitumor effect as expressed by the reaction of the local tissues, namely dry demarcated necrosis, areas of aseptic inflammatory infiltration of the skin, flectere, erysipelas in the injection of drugs and Bo is it expressed General toxic effect in comparison with the developed method.

The aim of the invention is the enhancement of the antitumor effect of chemotherapy, creating a high concentration of chemotherapy in lymph in combination with decreasing frequency General toxic and local complications effects of chemotherapy in patients with malignant tumors of the abdominal, pelvic and retroperitoneal space.

The invention consists in the use of chemotherapy with lymphotropic the introduction of water-soluble drugs according to the following scheme:

1. Detralex at a dose of 2 tablets 3 times a day, every day, throughout the course of chemotherapy.

2. Low molecular weight anti - Fraxiparine, which is introduced in the standard dose of 0.3 ml subcutaneously 1 times a day, every day, throughout the course chemotherapy under the control of PETIT, VSC, the coagulation of blood.

3. On Nizhniy third of the thigh is applied cuff apparatus of the Riva-Rocci and creates a pressure of 40 mm Hg

4. After 30 minutes subcutaneously injected 20 ml of 0.5% procaine solution of chymotrypsin (20 mg) in region middle third of the lateral surface of the tibia.

5. After another 5-7 minutes at 0.5 cm below the point of addition of chymotrypsin slowly, subcutaneously injected water-soluble drugs daily dose of calculating the area of the patient's body.

6. The cuff on the thigh remains in an inflated position the AI another 2 hours.

7. After removing the cuff, in place of previous drug administration, subcutaneously introduced to 50 ml of 0.5% solution of novocaine.

8. After injection of novocaine is elastic bandaging of the lower extremities.

This procedure is performed 1 time per day during the entire course of chemotherapy. The course is designed for an average 5 lymphotropic introductions when using scheme 5-fluorouracil/leucovorin, and when adjuvant chemotherapy is performed 1 time per month for 6-12 months. If carried out the neoadjuvant chimiotherapie as previously described, the surgical treatment is planned for 7-14 days after completion of the course.

This objective is achieved in that for improving the efficiency of complex treatment of patients with malignant tumors of the abdominal, pelvic and retroperitoneal water-soluble drugs, such as 5-fluorouracil/leucovorin, entered lymphotropic developed by us for the scheme in the lower limb in a daily dose calculated on a body surface area. To do this, in addition to the algorithm of the method lymphotropic administering drugs [Levin, Y.M. basis of the medical lymphology. Moscow, 1986. - Pp.118-135] simultaneously with lymphotropic the introduction of water-soluble chemotherapeutic agents during chemotherapy is used:

- Detralex at a dose of 2 tablets 3 the Aza in the day, to stimulate lymphatic drainage and lymph sorption in the lower extremities, to enhance the penetration of drugs in the peripheral lymphatic channel and increase the concentration of these drugs in the lymph;

- low molecular weight anticoagulants, for example Fraxiparine, which is introduced in the standard dose of 0.3 ml subcutaneously 1 time a day every day under the control of PETIT, the Commission for the prevention of thrombus formation in lymphatic and venous vascular bed during administration of chemotherapy;

- 0.5% solution of novocaine, which is introduced to 50 ml subcutaneously in place of previous injections of chemotherapy, immediately after removing the cuff from the hip, to reduce local cytotoxic effect by additional cultivation residual amounts of chemicals in the tissues and at the same time to re-stimulate their lymph sorption;

- elastic bandaging of the lower extremities after subcutaneous injection of novocaine at the end of the procedure lymphotropic the introduction of water-soluble drugs to improve venous outflow and prevention of venous thrombosis of the lower extremities.

Thus, the enhanced method lymphotropic administer medicines adapted to the introduction of water-soluble drugs.

The invention "Method of chemotherapy in the treatment of malignant neoplasms of the bruche the second cavity, pelvic and retroperitoneal space is new, so not as well-known in the field of treatment of cancer patients these localizations application of improved methods lymphotropic the introduction of water-soluble drugs, resulting in more use of Detralex, fraxiparina, solution of novocaine and elastic bandaging of the lower extremities in the algorithm of the method.

The proposed method achieved the highest concentration of water-soluble drugs in the lymphatic system. The concentration of drugs in the lymphatic system up to 4 times more when they lymphotropic introduction than with standard parenteral methods introduction [Levin, Y.M. basis of the medical lymphology. M., 1986 P.123].

Drugs interacting with lymph, gain increased tumorotropic and produce the induction of immunological tolerance lymphocytes [Bondar G.V. et al. The determination of individual sensitivity to 5-fluorouracil in patients with malignant tumors in different locations. Antibiot khimioter. 1999 44:25-8]. This leads to the enhancement of the antitumor effect of chemotherapy with reduced total and local toxicity effects of chemotherapy.

The invention "Method of chemotherapy in the treatment of malignant tumors of the abdominal cavity, pelvis and retroperitoneal space is industrially applicable as it m which can be used in health care, in medical institutions of surgical and oncological profile in breast care clinics, cancer research institutes, as well as outpatient primary medical oncologist.

An example of a specific implementation of the Method of chemotherapy in the treatment of malignant tumors of the abdominal cavity, pelvis and retroperitoneal space."

Patient K., 85 years, the case history No. 159, was admitted to the surgical Department of the Krasnodar Regional Clinical Hospital for war veterans on 10 January 2003 with complaints of weakness, constipation, the admixture of small amounts of serous discharge and mucus in the stool, weight loss of 5 kg over the past few months.

Considers herself a patient since September 2002, when first appeared the above complaints. The patient was examined as an outpatient at the place of residence, where he was diagnosed with a tumor of the rectum, with verification of the diagnosis of adenocarcinoma. Consulted in the Regional oncologic dispensary, where it was recommended that palliative care is the excretion of 2-barreled colostomy.

Objective status: overall condition is satisfactory. Clear consciousness, the contact is available. Physique correct, low power. Weight 48 kg, height 146 cm, body surface area 1.4 m2. The skin and mucous membranes normal coloration and humidity, a few pale. Peripheral limp the nodes are not enlarged. In the lungs vesicular breathing, wheezing no. NPV 18 in minutes heart sounds priglusheni, arrhythmic. Pulse 78 in minutes HELL 130/70 mm Hg Language damp, not lined. Stomach is not enlarged, symmetrical, not swollen, soft, painless. Pathological lesions in the abdominal cavity is not palpated. Symptoms of peritoneal irritation negative. Liver at the edge of the costal arch. The spleen is not enlarged. Peristalsis is satisfactory. Gases depart. Chair 1 time in 3 days, decorated or pasty with a small amount of serous discharge with mucus. Urination is not broken. Symptom tapping negative on both sides.

Per rectum: Perianal region without visible pathological changes. The tone of the sphincter is reduced. In the anal canal 2-3 cm from the edge of the anus to the front wall has a rough in Central crateriform tumor, cartilaginous consistency, moderate narrowing of the bowel lumen to 1.5, see the tumor Sizes: 6 cm in length, thickness 3 see

Diagnosis: cancer of the rectum T3NxMx II CL gr.

The survey: FY gr. CL, abdominal ultrasound, FCC, EGD.

The survey data for distant metastases is not received.

In the preoperative period, patients received a course of neoadjuvant lymphotropic chemotherapy scheme leucovorin/5-fluorouracil. Calculation per meter square square tel is: 5-fluorouracil 425 mg per 1 m 2leucovorin 20 mg per 1 m2. When lymphotropic the introduction of a single dose amounted to: 5-fluorouracil 600 mg, leucovorin - 28 mg. Just 5 lymphotropic introductions. Dose rate amounted to: 5-fluorouracil - 3000 mg, leucovorin - 140 mg.

Common complications of toxic reactions neoadjuvant lymphotropic chemotherapy was not. Local complications: infiltration of the skin 2×2 cm, cropped compress (Dimexidum + claforan + analgin).

On the 12th day after the end of the course neoadjuvant lymphotropic chemotherapy marked signs of recanalization of the rectum increase clearance to 3.0 cm and reduction of tumor size by 40-50%.

Operation on the 15th day after the end of the course neoadjuvant LHT - 6.02.03, Made radical abdomino-perineal extirpation of the rectum. The postoperative period was uneventful. Healing the wounds of the anterior abdominal wall and perineum primary intention. The patient was discharged to outpatient treatment 27.02.03,

In September 2003, the patient underwent planned tests in the x/o CCCVVV. The patient's condition is satisfactory, active no complaints. Performed the FCC, FG gr. CL, fibrogastroduodenoscopy, abdominal ultrasound. Data for recurrence and distant metastases at the time of the survey no.

For morphological and histochemical studies of the material is taken, representing the mucosal biopsies is blocki rectum, areas on the border of the tumor, and the tumor itself. Subsequent biopsy specimens for biopsy studies in the same patient produced during radical surgery, abdomino-perineal removing the rectum, that is, on the 15th day after the end of the course neoadjuvant lymphotropic chemotherapy.

A biopsy of the intestine were fixed in 10% solution of neutral formalin and embedded in paraffin according to the standard technique [Merkulov, G. A. Course histopathological techniques. - Publishing house of Medicine, Leningrad Department, 1962. - P.44-53]. The slice thickness of 7 μm were stained with hematoxylin and eosin. In addition, applied complex histochemical staining techniques and processing of histological sections. Fibrous connective tissues revealed aldehyde-fuchsin - chromotrope - aniline blue. Nucleic acid was studied on preparations stained with methyl green - Pronina.

Histologically colorectal cancer in this patient was presented to moderately differentiated the dark-cell adenocarcinoma. Tubular structures of the tumor contained atypical cells with hyperchromic elongated nuclei and basophilic cytoplasm (figure 1). Tumor cells have not produced mucoid. In the stroma of the tumor revealed a slight lymphoid infiltration.

As a result of the course lymphotropic chemotherapy in on wholeway tissue were focal areas of devastation parenchyma due to its degradation with the formation of slit-like cavities, in the lumen of which was to reveal some degenerative modified cancer cells (figure 2). However, intense leukocyte infiltration in areas of the collapse of the cancerous tissue was not observed.

Typical was the prevalence of alternative changes, mainly in the peripheral parts of the tumor growth, where in response to destructive processes were stimulated fibroblast response (Fig.3, 4). Intensification of the sclerotic processes have led to the growth of fibrous tissue around the preserved parts of the tumor (figure 5). In connection with the death of the peripheral areas of the tumor eliminated manifestations of infiltrating growth of adenocarcinoma in the surrounding tissue.

Changed and histological characteristics of the tumor parenchyma. There was a tendency to solicitatio tumor structures. Increased diversity in the intensity of coloration of nuclei in their shape and size (6). Significantly increased the number of cancer cells with round light nuclei with condensed in the form of clumps at the nuclear envelope chromatin (6, 7), which is an expression of the mechanism of destruction of cancer cells by apoptosis. Significantly decreased basophilia and pyroninophilia cytoplasm of cancer cells, which indicates a sharp drop belkovosinteticescuu function of cancer cells. The number of normal and patologicheskaia decreased by 12%.

Thus, morphological study has allowed to establish that the reduction of the cancer occurs due to the partial destruction of the parenchyma. When the death of cancer cells at the periphery of the tumor eliminated is important histological feature of malignancy in the form of infiltrating growth, what can be related to a reduced risk of cancer recurrence after surgical removal of the tumor.

Fouling connective tissue preserved parts of the tumor is the type of encapsulation that dissociates cancer cells from the vasculature. This fact can be explained by the reduction in the incidence of metastasis in patients who received a course lymphotropic chemotherapy.

Conducted a pilot study of this method in 30 patients with colorectal cancer who underwent neoadjuvant lymphotropic chemotherapy according to the scheme of leucovorin/5-fluorouracil. Identified the reduction of symptoms of colorectal cancer; tumor shrinkage, which, in turn, leads to higher resectability. There is a significant reduction of General and local toxicity of chemotherapeutic agents entered lymphotropic developed by us for the way. The study of therapeutic pathomorphosis of the tumor after neoadjuvant lymphotropic chemotherapy scheme leucovorin/5-fluorouracil showed signs with which to achieve the biological activity of the tumor, reducing the risk of intraoperative dissemination of malignant cells and involves improving long-term results, namely the reduction in the percentage of metastasis and recurrence of colorectal cancer in the late postoperative period.

Technical and economic efficiency "Way of chemotherapy in the treatment of malignant tumors of the abdominal cavity, pelvis and retroperitoneal space" is that the proposed method chemotherapy with lymphotropic the introduction of water-soluble drugs are more simple in comparison with endolymphatic way, is a non-surgical way and can be applied ambulatory health visitor or doctor-oncologist. While retaining the advantage of direct contact of the chemical with lymph observed in the endolymphatic way of chemotherapy, and also a decrease in the frequency of General toxic and local complications of chemotherapy.

The way the chemotherapy in the treatment of malignant tumors of the intestine, including lymphotropic course introduction water-soluble drugs by the following procedure: on the lower third of the thigh impose a cuff apparatus of the Riva-Rocci and create a pressure of 40 mm Hg after 30 min subcutaneously injected with 20 ml of 0.5%procaine of rest the RA chymotrypsin in the area of the middle third of the lateral surface of the tibia, after 5-7 min at 0.5 cm below the point of addition of chymotrypsin slowly subcutaneously injected water-soluble drugs in one dose, then leave the cuff in an inflated position for another 2 h, characterized in that after removal of the cuff in place of the previous drug administration subcutaneously injected with 50 ml of 0.5%solution of novocaine, and then produce elastic bandaging of the lower limb, the procedure lymphotropic drug administration carried out 1 time per day in accordance with chemotherapy, calculated according to the standard scheme, in addition, throughout the course of chemotherapy, the patient is daily administered Detralex 2 tablets 3 times a day and Fraxiparine 0.3 ml subcutaneously 1 time per day.



 

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25 cl, 11 dwg, 3 ex, 1 tbl

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to (i) essentially crystalline melagatran in the form of hydrate, which is characterized by x-ray diffraction pattern on powder having crystalline peaks with following d values: 21.1, 10.5, 7.6, 7,0, 6.7, 6.4, 6.2, 5.7, 5.4, 5.3, 5.22, 5,19, 5.07, 4.90, 4.75, 4,68, 4.35, 4.19, 4.00, 3.94, 3.85, 3.81, 3.73, 3.70, 3.63, 3.52, 3.39, 3.27, 3,23, 3.12, 3.09, 3.06, 2.75, 2.38, and 2.35 Å and/or water content 4.3%; and (ii) essentially crystalline melagatran in the form of anhydrate, which is characterized by x-ray diffraction pattern on powder having crystalline peaks with following d values: 17.8, 8.9, 8.1, 7.5, 6.9, 6.3, 5.9, 5.6, 5.5, 5.4, 5.3, 5.2, 5.0, 4.71, 4.43, 4.38, 4.33, 4.14, 4.12, 4.05, 3.91, 3.73, 3.61, 3.58, 3.56, 3.47, 3.40, 3.36, 3,28, 3.24, 3.17, 3.09, 3.01, 2.96, 2.83, 2.54, 2.49, 2.41, 2.38, and 2.35 Å. Invention also relates to a method for preparation of indicated form, a method for interconversion of anhydrite form, to use of indicated compounds as pharmaceutical agent, and to preparation of drugs. Pharmaceutical preparation is suitable for treatment of condition, in case of which inhibition of thrombin is needed or desirable. Invention provides a method for treatment of such condition.

EFFECT: increased chemical stability and solid state stability as compared to amorphous forms of melagatran.

14 cl, 4 dwg, 3 tbl, 9 ex

FIELD: medicine, endocrinology, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition comprising epidermal growth factor (EGF) used in treatment of wounds on skin and soft tissues of lower limb in diabetic patient. Method of treatment involves topical infiltration of EGF-containing solution into different points and by contours of tissue damaged zone to provide administration of the solution into wound in the total volume 4-20 ml and irrigation of all deep surface of wound base and edges with the indicated composition. Invention provides prevention of diabetic limb amputation, stimulation of cellular proliferation in patients with foot ulcer being especially in geriatrics.

EFFECT: valuable medicinal properties of pharmaceutical composition.

19 cl, 1 tbl, 9 ex

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