Agent for correcting pulmonary tissue disorders under cytostatic exposure

FIELD: medicine.

SUBSTANCE: what is presented is using Histochrom (same as echinochrome A or pentahydroxyethyl naphthoquinone) as an agent able to prevent pulmonary fibrosis developed under cytostatic agents. The invention can be used for the pharmacological prevention and correction of the pulmonary tissue disorders caused by administering the cytostatic agents.

EFFECT: preventing hypertrophy of interalveolar connective tissue in the lungs associated with administering bleomycin.

4 dwg, 1 tbl

 

The invention relates to medicine, namely to pulmonology, Oncology and can be used for pharmacological prevention and correction of disorders in the lung tissue, developing with cytotoxic drug therapy.

A number of antibiotics, bleomycin including, has a pronounced cytostatic effect and is used in therapy of malignant tumors. But complications caused by cytotoxic drugs, severely limit the applicability of these medicines. The most severe side effect is a rapidly progressive fibrosis of the lungs, causing respiratory failure and death [Azambuja E., Fleck J. F., R. G. Batista, Menna Barreto S. S. Bleomycin lung toxicity: who are the patients with increased risk? // Pulmonary Pharmacology and Therapeutics. - 2005. - Vol. 18. - P. 363 to 366]. In this regard, relevant is the problem of finding pharmacological agents for the prevention and treatment of pathological changes in the lungs caused by cytotoxic agents.

For therapy of lung fibrosis currently treated with corticosteroids ['antin-Ozerkis D., A. Rubinowitz, Evans J., Homer, R. J., Matthay R. A. Interstitial lung disease in the connective tissue diseases // Clin. Chest. Med. - 2012. - Vol. 33, N 1. - P. 123-149.], mucolytic agent with antioxidant N-acetylcysteine [Demedts M., Behr, J., R. Buhl, U. Costabel, R. Dekhuijzen, H. M. Jansen Highdose acetylcysteine in idiopathic pulmonaryfibrosis // N Engl. J. Med. - 2005. - Vol. 353. - P. 2229-2242.], set�soobrazayuschie compound D-penicillamine [M. Jinnin, Ihn h, Asano Y, Yamane K, Yazawa N, Tamaki K. Effect of D-penicillamine on pulmonary fibrosis in patients with systemic sclerosis // Ann. Rheum. Dis. - 2003. - Vol. 62, N 10. - R. 1019-1020], the drug colchicine is due to pharmacological group of agents affecting uric acid metabolism [E. Fiorucci, G. Lucantoni, G. Paone et al. Colchicine, cyclophosphamide and prednisone in the treatment of mild-moderate idiopathic pulmonary fibrosis: comparison of three currently available therapeutic regimens // Eur. Rev. Med. Pharmacol. Sci. - 2008. - Vol. 12, N 2. - P. 105-111].

Identified antifibrotics action sympatholytic of reserpine [Skurikhin, E. G., E. S. Khmelevskaya, Pershina ov, etc. anti-inflammatory Mechanisms and antifibrotics action sympatholytic in a toxic pulmonary fibrosis // Bulletin of experimental biology and medicine, 2012. - N 5. - Pp. 590-595.], the neuroleptic haloperidol [Patent RU 2455991, 20.07.2012, bull. No. 20.], immobilized hyaluronidase [Digi A. M., Skurikhin, E. G., Ermakov N. N., Reztsova A. M., Pershina Ov, E. S. Khmelevskaya, Krupin, V. A., Stepanova I. E., Reztsova, V. M., A. V. Artamonov, Bakharev A. A., Magonov P. G., Kinst D. N. Antifibrotics effects immobilized hyaluronidase during repeated injury of the alveolar epithelium bleomycin // Bulletin of experimental biology and medicine, 2013. - No. 4. - Pp. 499-504].

The problem solved by this invention, is expanding Arsenal of tools that can prevent abnormalities in the lung tissue at cytotoxic effects.

The technical result - before�tramenie development of lung fibrosis and lymphoid infiltration of the bronchi in the cytotoxic effect.

The technical result is achieved by the use of) as a means of multifactorial actions that can prevent the development of lung fibrosis and lymphoid infiltration of the bronchi in the introduction of cytotoxic drugs.

A) (echinochrome A, or pentahydroxyflavone) is included in the Register of medicinal products permitted for use in the Russian Federation [Great Russian encyclopedia of drugs, M., 2001, "Remedium", volume 2, p. 171]. Pharmacotherapeutic group: anti-oxidant agent.

A) interacts with active forms of oxygen, free radicals, reduces the number of products of lipid peroxidation, is a chelator of metals of variable valence [Lebedev V. A., Ivanova M. V., Levitsky D. O. Echinochrome, a naturally occurring iron chelator and free radical scavenger in artificial and natural membrane systems // Life Sci. - 2005. - Vol. 76, No. 8. - P. 863-875.].

A) has a membrane stabilizing, anti-hypoxia and anti-inflammatory effect, is used in cardiology [RF Patent 2137472, 1999; Order of the Ministry of health of the Russian Federation from 18.03.99 No. 91 about allowing medical use of drugs. Appendix No. 2], ophthalmology [RF Patent 2248820, 2005; Order of the Ministry of health of the Russian Federation from 18.03.99 No. 91 about allowing medical use of drugs. Appendix No. 2], neurology [RF Patent 2266737, 2005]. Proposed application) concurrently�e diuretics [RF Patent 2408367, 10.01.2011, bull. No. 1].

Use) as a means of multifactorial actions that can prevent abnormalities in the lung tissue, caused by the introduction of cytostatics in the patent and scientific and medical literature is not described. New in the present invention is that a) can be used as a means capable of preventing back disorders in the lung tissue, caused by the introduction of cytostatics. New in the present invention is the use of a) on the day of administration of cytostatic, 2-, 3-, 4 -, and 5 days after administration of the cytostatic agent.

Application) for a new purpose became possible due to the identified authors of the new feature of the product: due to the multifactorial actions to prevent fibrosis of the lung tissue that develops under the influence of cytostatics.

Distinctive features showed in the inventive combination of new properties that are not explicitly derived from the prior art in this field and become obvious to the specialist. Identical set of features not found in the analyzed patent and scientific and medical literature.

The invention can be used to improve the efficiency of cytostatic drug therapy in experiment and clinic.

Based on the foregoing, the invention conforms to the� the criteria of patentability "Novelty", "Inventive step" and "Industrial applicability".

The proposed action) were studied in an experimental model of lung injury induced by administration of a cytostatic, antitumor antibiotic bleomycin. Pulmonary fibrosis is a side effect of bleomycin. One molecular mechanism for the formation of bleomycin-induced lung fibrosis is considered to be oxidative stress. Bleomycin-induced overproduction of reactive oxygen species, free radicals initiates and supports the processes of destruction in the lungs and subsequent growth of connective tissue [T. Teke, E. Maden, A. Kiyici et al. Cigarette smoke and bleomycininduced pulmonary oxidative stress in rats // Exp. Ther. Med. - 2012. - Vol. 4, N 1. - P. 121-124].

The invention is as follows.

Experimental animals - immature white rats divided into three groups of 10 animals in each group.

The first group or the group "bleomycin+)" - rats, who at the age of 24 days intramuscularly once injected bleomycin in a dose of 3 mg/kg; additionally, on the day of administration of bleomycin, 2-, 3-, 4 -, and 5 days after that, the animals administered intramuscularly) at a dose of 0.3 mg/kg (in the form of the drug "Solution")" 0,02% for injection").

The second group or the group "bleomycin" - rats in the same dose and in the same mode injected bleomycin, � also a 0.9% solution of NaCl in an equivolume amount and in the same mode, the drug is "a Solution")" 0,02% for injection".

The third group or the group of intact rats.

Slaughtering of the animals of all groups is carried out simultaneously, on reaching the age of 50 days, by decapitation. The right lung was fixed in fluid Carnoy, pour in the wax. Slices with a thickness of 6 μm, stained with hematoxylin and eosin, and subjected to histological examination and morphometry, including definition of specific volume of gaps of the alveoli and interalveolar septa and their relationships.

Biogenesis of reactive oxygen species (ROS) in the lungs are examined by the chemiluminescence method (CML). The CML algorithm analysis includes identification: S-sp - sum for 1 minute spontaneous CML, the value of which directly correlates with the intensity of ROS generation; h is the amplitude of a quick flash of Fe2+- induced fluorescence, reflecting the content of lipid hydroperoxide; Sind-1 - sum for 4 minutes Fe+2- induced fluorescence, the value of which depends on the rate of formation of peroxide radicals; S-luc - sum for 1 minute, lucigenin-dependent illumination, the magnitude of which directly correlates with the formation of the superoxide anion radical; S-lum - sum 1 minute luminol-dependent CML, the value of which directly depends on the intensity of formation of the hydroxyl radical; H is the amplitude H202induzirovanny�th luminol-dependent luminescence the magnitude of which is inversely correlated with lipid resistance of the substrate; Sind-2 - sum for 2 minutes H202- induced luminol-dependent CML, the magnitude of which is inversely correlated with the antiradical activity of antioxidant protection. The intensity of CML, measured in mV, calculated per 1 g of wet tissue taken during slaughtering of animals, and expressed in relative units. Mathematical processing of the results is carried out using standard methods of variation statistics. The significance of differences was evaluated using parametric t-test or non-parametric U-Mann-Whitney test.

Example. In the study of histological preparations of the lungs of rats treated with bleomycin, revealed a pronounced thickening of the interalveolar septa (Fig. 1). Interalveolar septa contain significantly increased the number of fibroblasts, macrophages, leukocytes. Hypertrophy of the interalveolar connective tissue is diffuse in nature and are most pronounced in the subpleural region (Fig. 2). The morphometric analysis revealed that the ratio of the bulk density of the interalveolar septa and gleams of alveoli in rats of the group "bleomycin" is 1,04±0,08, whereas in intact animals was 0.77±0,096 (P<0,05). In the walls of the bronchi lesions occur whether�vodnoy infiltration, sometimes covering most of the perimeter of the bronchi (Fig. 3).

Results CML-analysis (table) indicate that the lungs of rats of the group "bleomycin" in comparison with the performance of the group "intact" significantly increased the levels of generation of reactive oxygen species (Ssp), including superoxide anion radicals (Slue), hydroxyl radicals (Slum) of peroxide radicals (Sind-1) - 2,5-, 2,6-, 2.5 - and 3.0 times, respectively. Increased content of lipid hydroperoxide (h) in 2.9 times. The overproduction of reactive oxygen species, free radicals accompanied by a weakening of the antioxidant antioxidant and peroxide resistance, as evidenced by the return dynamics of the corresponding CML-indicators: increase in Sind-2 3.3-fold and H in 3.0 times. Such disturbances in the "generation - detoxification" reactive oxygen species indicate the presence of severe oxidative stress in the lungs of animals and thrown down to the cytostatic effects of bleomycin.

Therefore, the effect of bleomycin causes the development of lung connective tissue (fibrosis), lymphoid infiltration of the bronchi, of oxidative stress.

The introduction of animals), which was injected bleomycin, has a pronounced effect on the lungs of rats (Fig. 4). Overview when examining the products, the lungs of rats of the group "bleomycin+)" not detected ISU�trofie interalveolar connective tissue. This is confirmed by the results morphometrics: the ratio of the specific volume of the interalveolar partitions to a specific volume of gaps of the alveoli is 0.8±0,06, which is close to that of intact animals (0,77±0,096) and significantly lower than in animals of group "bleomycin" (1,04±0,08, P<0,05). In addition, a) prevents the development of lymphoid infiltration of the bronchi.

The introduction of) corrects violations of the generation and detoxification of ROS in the lungs of rats that received an injection of bleomycin (table). The magnitudes of all CML-parameters characterizing the severity of oxidative stress, in the bleomycin+)" significantly less than in the group of "bleomycin" 1.7-2.2 times.

Thus, due to the multifactorial action) prevents the development of important implications of toxic effects of bleomycin on the lung - expansion of the interalveolar connective tissue (fibrosis) and lymphoid infiltration of the bronchi, also corrects oxidative stress.

Application) as a tool that can prevent the fibrosis of the lung tissue that develops under the influence of cytostatics.



 

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