RU2405546C1 - Method of polychemotherapeutic enteropathy prevention and treatment - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention belongs to medicine, notably to oncology, and can be used in prevention and treatment of enteropathy due to intensive cytostatic polychemotherapy. To achieve this Enterosgel (Methylsiliconic acid hydrogel) is administered during whole course of polychemotherapy and after it. After cytostatic treatment during Enterosgel administration additionally nonabsorbable enteral antiseptic ersefuril is administered. normobiotics - Hylac-forte and Primadophilus™ Bifidus are administered when level of leukocytes in blood gets higher then 1000/mcl.

EFFECT: method ensures prevention of necrotic processes, reparation of gastro-intestinal mucous lining and fast arresting of enteropathy due to toxic metabolites enterosorption, elimination of pathogenic and opportunistic microbes and regulation of intestinal flora balance.

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Description

The invention relates to medicine and can be used in oncological practice for the prevention and treatment of enteropathy, developing against the background of the use of high-dose chemotherapy (including myelo-ablative regimes) including high-dose with transplantation of autologous cells of hematopoietic precursors.

The invention is devoted to a problem, the relevance of which, including in oncology, has increased in recent decades due to the increased use in practice of aggressive antitumor treatment with high doses of cytostatic drugs, which can significantly extend the patient's life. However, one of the most formidable complications of this type of treatment is enteropathy, which complicates the course of the underlying disease and makes it difficult to conduct chemotherapy.

Currently, special methods for the prevention and pathogenetic treatment of this syndrome, aimed at repairing the mucous membranes of the gastrointestinal tract (GIT), do not exist. In the clinical practice of hematological and oncological hospitals for patients with lymphoproliferative diseases with a high risk of developing a fast-moving and life-threatening infection, several enteropathy therapy methods are used.

The use of p-tyrosol as a means for the prevention and treatment of toxic enteropathies caused by cytostatic is known (RU 2058148). In accordance with the known method, the damaging effect of cytostatics on the small intestine is reduced by the use of the preparation p-tyrosol, which is a psychostimulating and adaptogenic drug. However, this invention is made only at the level of the experimental model. In addition, the use of psychostimulating and adaptogenic drugs in the oncology clinic is sharply limited due to their ambiguous effect on the tumor process - the possibility of stimulating tumor growth, inducing the spread of metastases, etc.

There is also a method of correcting the microflora of the gastrointestinal tract (RU 2217156), which includes a complex effect on the body through detoxification using enterosorbents in the form of pectins (herbal preparations) and the actual correction using probiotics in order to improve the biological balance of the gastrointestinal tract in various therapeutic conditions. However, the known method relates only to the period of treatment. In addition, in the description of the known method, the sequence of administration of the sorption preparation in combination with eubiotics (preparations of lacto- and bifidumbacteria) during the treatment period is not presented; it is recommended that the course be carried out with all drugs at the same time. This dramatically changes the pathogenetic orientation of treatment.

There is also known a method of complex symptomatic treatment of patients with lymphoproliferative diseases with a high risk of developing a fast-moving and life-threatening infection, which consists of several stages ("Clinical Oncohematology" ./ Edited by M.A. Volkova, M .: Medicine, 2001). Firstly, it is early decontamination of the gastrointestinal tract with systemic antibacterial drugs (ciprofloxacin, ofloxacin, norfloxacin, co-trimoxazole) for the purpose of erradication of opportunistic and pathogenic microflora in patients with presumed long-term and deep myelotoxic agranulocytosis, mucosal infection, mucosal injury or . Antibacterial drugs are prescribed throughout the course and post-course period until the level of leukocytes is restored to more than 1000 / μl. In the case of the development of a systemic infectious process, antibiotics of a wide spectrum of action are additionally prescribed. Secondly, with the development of the obvious picture of enteropathy, the patient is transferred to complete parenteral nutrition with sufficient daily energy value, the addition of vitamins, electrolytes. However, prolonged use of broad-spectrum antibacterial drugs can lead to a change in the nature of the intestinal microflora with the appearance of resistant strains of microorganisms, the development of enzyme pathologies, aggravation of immunodeficiency states, and a decrease in the quality of life of patients. Therefore, with the above method of treating enteropathy, the principles of preserving the functional usefulness of intestinal epithelial cells are not practiced and the possibility of correcting digestive disorders is not realized.

Closest to the claimed combination of essential features is a method for correcting already developed dysbiotic disorders in patients with tumor diseases of the blood system who received combined cytostatic and antibacterial therapy with correction of dysbiotic disorders with Hilak forte (Maksimov IK “Changing the intestinal microflora and methods for its correction in patients with neoplastic diseases of the blood system during polychemotherapy. "Abstract of dissertation for the degree of candidate n Auk, M., 2004.) Adopted as a prototype.

The essence of the prototype method is as follows. Patients on the background of cytostatic and antibacterial therapy with systemic drugs (cotrimoxazole, gentamicin, ofloxacin) received Hilak-Forte 60 drops 3 times a day. It is known that this drug promotes the regeneration of the physiological flora of the intestine biologically, which is expressed by the stabilization or normalization of the profile of short-chain fatty acids in the intestinal discharge. In this case, optimal conditions arise for the growth of obligate microorganisms and due to this, the regeneration of the damaged intestinal wall is ensured. However, there is no principle of direct preservation of intestinal epithelial cells and, as a result, there is a high probability of a change in the nature of enteropathies (replacement of the leading pathogen, imbalance of the intestinal normoflora), and with prolonged and massive use of antibacterial therapy, the creation of secondary immunodeficiency states, enzymatic pathologies. All this is associated with the need for further measures to normalize the intestinal microflora and its function. The process of treating enteropathy in this way is lengthy and ineffective.

The invention is aimed at solving the problem of prevention and treatment of enteropathies developing against the background of aggressive cytostatic therapy, including myeloabalative, in particular in patients with hemoblastosis.

Use in clinical practice of the proposed method allows to achieve several technical (medical) and economic results:

- rapid relief of the clinical manifestations of emerging enteropathies, a decrease in the frequency and severity of disorders of abdominal digestion after high-dose courses of chemotherapy;

- improving the quality of life of patients receiving chemotherapy treatment;

- accessibility and low cost of treatment.

These technical and therapeutic results in the implementation of the invention are achieved due to the fact that, as in the known method, the prevention and treatment of enteropathy, developing against the background of intensive cytostatic polychemotherapy, is carried out by the introduction of antibacterial drugs and the drug Hilak-forte.

A feature of the proposed method is that it provides a complex effect, including enterosorption of toxic metabolites by administering enterosgel throughout the course of polychemotherapy and in the post-cycle period, elimination of opportunistic organisms by introducing non-absorbable enteroseptic drug in the form of the drug ercefuril in the post-cycle period of intestine and regulation flora by the introduction of normobiotics in the form of preparations hilak-forte and primadofilus bifidus after restoration of the content anija leukocytes to a level of more than 1000 / L.

The invention consists in the following.

One of the most formidable complications of antitumor treatment with high doses of antitumor cytostatic drugs is enteropathy - a violation of the digestive tract.

In immunocompromised patients with impaired intestinal barrier function and myelodepression (neutropenia), endotoxemia translocates bacteria through the mucous membrane to other organs and tissues, which may be accompanied by the development of additional foci of infection, bacteremia and septic state. In this case, the intestine itself can be a powerful source of endotoxemia. This is largely due to the penetration of bacterial and metabolic toxins from the chyme into the body against the background of increased permeability of the intestinal wall and subsequent toxic damage to organs and detoxification systems, homeostasis regulation systems (liver, kidneys, immune and coagulation systems, etc.).

The inventors have developed a comprehensive scheme for the prevention and treatment of enteropathies that develop when intensive (high-dose) courses of polychemotherapy are used, in particular, in patients with lymphoproliferative diseases, combining the universality of the intact effect on the intestinal epithelium and normal gastrointestinal microflora while suppressing pathogenic and conditionally pathogenic intestinal microflora. The scheme can also be used against a background of deep neutropenia (myelotoxic agranulocytosis).

The indicated scheme includes three synergistic complementary sequential stages: 1 - enterosorption of toxic metabolites, 2 - elimination of opportunistic organisms by introducing a nonabsorbable enteroseptic nitrofuran series, 3 - regulation of the equilibrium of the intestinal flora using normobiotics.

The primary stage is sorption therapy, which helps prevent serious cytopathic damage to the intestinal epithelium by cytostatics, facilitates the subsequent correction of dysbiotic disorders of the intestinal microflora, which ultimately leads to a significant improvement in the quality of life of patients - dyspeptic manifestations in the form of diarrhea, vomiting, flatulence, etc. are significantly reduced. For the implementation of the first stage of treatment - enterosorption, the enterosgel preparation, which is a silicon organ, was selected nical porous matrix having a globular structure, having a high bio- and hemocompatibility which does not damage the gastrointestinal mucosa (regeneratively acting even on the last), without disturbing the wall digestion. Unlike other known carbon enterosorbents, consisting of highly dispersed silicas, enterosgel is characterized by obvious selectivity - it most actively sorb toxic molecular metabolites and practically does not bind electrolytes and high molecular weight substances. In addition, enterosgel selectively interacts with the intestinal microflora: it actively sorb more than 1 million bacteria on 1 mm of the surface and inhibits the vital activity of many pathogenic and conditionally pathogenic microorganisms, and does not affect indigenous microflora. It can be used for a long time without causing intestinal atony. Enterosgel is prescribed from the start of chemotherapy and throughout the post-course period.

At the second stage in the post-course period with the development of leukopenia of III-IV art. or from the 1st day of the post-transplantation period after autologous transplantation of blood stem cells to the moment of restoration of hemogram parameters (leukocytes more than 1000 / μl), conditionally pathogenic organisms are eliminated with the aim of partial decontamination of the gastrointestinal mucosa by introducing non-absorbable enteroseptics.

For this purpose, “ercefuril” is used - a broad-spectrum antibacterial agent, a derivative of nitrofuran. The drug blocks a number of redox enzyme reactions in the cells of microorganisms, activates the immune system - increases phagocytosis and complement titer. Effective against gram-positive (Staphylococcus Spp., Streptococcus spp., Haemophilus influenzae) and gram-negative (Salmonella spp., Klebsiella spp., Enterobacter spp., Escherichia colli, Shigella spp., Proteus spp.) Microorganisms. It is able to restore intestinal eubiosis; when infected with enterotropic viruses, it prevents the development of bacterial superinfection.

The third component of complex treatment is the introduction of normobiotics (pre- and probiotics) in order to restore normal intestinal microflora.

As a prebiotic, “Hilak-forte” was used, which contains an optimized set of metabolic products of the strains of lactobacilli (LactoBacillus acidofilus DSM 4149, LactoBacillus helveticus DSM 4183) and normal intestinal microorganisms (Esherichia colli DSM 4087, Streptococcus fa86alis, DSM, milk DSM 4086 , amino acids, lactose. It was established that this prebiotic has the property of optimizing the functional state of the intestine. The drug realizes its positive effect on the physiological functions of the microorganism as a result of modulation of immune responses, changes in the function of macrophages, production of cytoxins, and activation of the immune system. Prebiotic, normalizing the water-electrolyte balance and pH in the intestinal lumen, is a soft regulator of the motor function of the colon, contributes to the rapid restoration of intestinal biocenosis through the normalization of the normal microflora of bifidobacteria and lactobacteria, and stimulates the synthesis of epithelial cells of the intestinal wall.

As a probiotic, the complex preparation Primadofilus bifidus was used, which contains strains of Lactobacillus rhamnosus, Lactobacillus acidophilus, Bifidobacteri um breve, Bifidobacterium longum; maltodextrin, magnesium stearate. It has antagonistic activity against opportunistic flora, competitively displacing it in violation of intestinal microbiocenosis. It restores the balance of intestinal microflora, increases the number of beneficial microorganisms in the intestines, protects against excessive reproduction of harmful, including rotting, bacteria and yeast fungi, improves digestion, and increases the formation of B vitamins.

Thus, the use of the developed consistent and synergistic scheme for the prevention and treatment of enteropathy can reduce the frequency and severity of characteristic complications. At the same time, there are no significant changes in the composition of the normal intestinal microflora, the clinical manifestations of enteropathy are less pronounced, which in turn prevents the development of severe infectious complications, and leads to an improvement in the quality of life of patients. The use of this scheme for the prevention and treatment of enteropathy changes the approaches to the accompanying therapy in patients with hemoblastoses. Good compliance of the applied scheme is very important, undesirable reactions to drug components were practically absent.

Using the proposed method can significantly reduce the cost of treatment by reducing the cost of drugs, equipment and labor costs.

The method is as follows.

Simultaneously with the start of polychemotherapy courses and in post-course periods, the patient is prescribed enterosgel in a standard dosage.

In the post-course period with the development of stage III-IV leukopenia or in the post-transplant period from the 1st day after autologous blood stem cell transplantation, ercefuril is administered until the leukocyte level is restored (7-10 days).

In the post-course period after the restoration of the leukocyte level of more than 1000 / μl, the prebiotic Hilak-forte and the probiotic Primadofelus are prescribed.

The evaluation criteria for the therapy were: the dynamics of the symptoms of intestinal dyspepsia, clinical manifestations of intoxication (fever, etc.) and the results of a laboratory study. For a laboratory evaluation of the treatment results, the authors used the principle of coprological monitoring, including bacterioscopy of stained smears according to Gram and Zil-Nielson, while conducting a standard coprological examination of native preparations stained with methylene blue and Lugol's solution. For bacteriological evaluation of the composition of the intestinal microflora, a cultural study was used with the isolation of bacteria and fungi, determination of their sensitivity to antibacterial and antifungal drugs.

In MNII them. P.A. Herzen, the claimed scheme for the prevention and treatment of the development of enteropathy and severe infectious complications was used in the treatment of a group of patients (15 people) who underwent high-dose PCT courses for the underlying disease. A significant reduction in the severity of enteropathy was noted compared with the control group (12 people). Severe enteropathy in the first group was noted in only one case. Clinically, in 70% of cases, the frequency of stool was from 1 to 3 times a day. According to the coprogram, only in one case (7.1%) revealed destruction of the mucous membrane of the distal colon. According to the bacteriological study of feces, morphotypes of obligate microorganisms were found 45% more often: lactobacilli, bifidumobacteria, fecal enterococci, clostridia - eubacteria. The bacterioscopic picture was represented by the dominance of gram-positive microflora, which is approaching normal. At the same time, in the control group of patients, the microbiota of the large intestine was in most cases dominated by gram-negative bacteria (rods and cocci), or it was a picture approaching a monoculture (often the morphotype of large enterococci, which in a culture study was defined as multi-resistant species of Enterococcus casseliflavus and Enterococcus faecium). Also in the control group, fungal spores were often present (82%), and often budding cells and mycelium were often determined, which indicates the special pathogenicity and virulence of the fungi.

In a cultural study, the seeding rate of opportunistic microflora (gram-negative enterobacteria, often with signs of hospital resistance - with extended-spectrum beta-lactamase; multiply resistant enterococci, methicillin-resistant staphylococci, multiple-resistant pseudomonas aeruginosa) in the group treated with the method according to the lower - 12% compared with 40% in the control group, and the selection of mushrooms 32% versus 70%. At the same time, the secretion of Candida non-albicans and non-Candida fungi decreased. These indicators indicate a change in the microbiota of the large intestine towards the normalization of microflora in quantitative and qualitative indicators.

Execution examples

1. Patient B.N.A., 53 years old. Diagnosis: diffuse b-cell lymphoma, IV st. Conducted 8 courses of first-line polychemotherapy. In connection with the progression of the tumor process, an intensive course of the second line was carried out. Given the high risk of developing enteropathy, prophylactically, the patient was prescribed enterosgel 15 g × 3 times a day from the first day of chemotherapy until the end of the post-course period. In the early post-course period (since the development of myelotoxic agranulocytosis), ercefuril was added (800 mg per day for 7 days). After restoring the hemogram, the intestinal enteroseptic was canceled, the administration of enterosgel was continued, probiotics (primadofilius-bifidus 1 caps. Per day) and Hilak-fort 40 drops 3 times a day were added. In the period after the PCT course, there were no clinical changes from the gastrointestinal tract, stool frequency 1 time per day without pathological impurities. Antibacterial drugs were not used, parenteral nutrition and hunger were not prescribed. In the study of coprograms in dynamics, only accelerated evacuation of food through the intestines was noted. Bacterioscopy revealed morphotypes of obligate microorganisms, the dominance of gram-positive microflora. During a cultural study, representatives of obligate microflora predominated, microorganisms with signs of hospital resistance were not isolated.

2. Patient M.S.M., 35 years old. Diagnosis: Late relapse of lymphogranulomatosis, II B Art. condition after 2 courses of second-line chemotherapy. Partial remission. In order to consolidate the achieved effect, the patient underwent a high-dose course of polychemotherapy followed by transplantation of autologous hematopoietic cells. Given the high risk of damage to the gastrointestinal mucosa and the development of severe infectious complications, the preventive use of enterosgel was started 15 g × 3 times a day from the beginning of PCT. On the 1st day of the post-transplant period, the intake of ercefuril was started at 200 mg × 4 times. After the leukocyte level was restored to more than 1000 / μl of the hemogram indices, the enteroseptic was canceled, the administration of enterosgel was continued, probiotics were added (primadofilus-bifidus 1 caps. Per day and Hilak-fort 40 drops 3 times a day). In the post-course period, there were no clinical changes from the gastrointestinal tract, the frequency did not exceed 1 time per day without pathological impurities. First-line systemic antibiotic therapy and antifungal therapy for febrile neutropenia and a catheter associated infection were performed. Due to the lack of clinical manifestations of enteropathy and severe mucositis, complete parenteral nutrition was not carried out. In a dynamic study of the coprogram, abnormal digestion was not observed, only accelerated evacuation of food through the intestines was noted. Bacterioscopy revealed morphotypes of obligate microorganisms, the dominance of gram-positive microflora. During a cultural study, representatives of obligate microflora predominated, microorganisms with signs of hospital resistance were not isolated.

The inventive method has significant advantages and meets the criteria of patentability.

Claims (1)

A method for the prevention and treatment of enteropathies developing against the background of intensive cytostatic polychemotherapy by administering antibacterial drugs and the Hilak-forte drug, characterized in that they carry out a complex effect, including administering the enterosgel drug throughout the course of polychemotherapy and in the post-cycle period, the introduction of non-absorbable enteroseptic in the form the drug ercefuril in the post-course period and the introduction of normobiotics in the form of preparations hilak-forte and primadofilus bifidus after rebound leukocyte up to a level of more than 1000 / μl.