The method of treatment pseudophoenix diseases of the orbit

 

(57) Abstract:

The invention relates to ophthalmology, namely oftalmologii, and is intended for the treatment of patients with pseudotumoral orbit. The method includes the use of glucocorticoids and the introduction of additional mielopid retrobulbarno in the upper-outer division of the orbit in a dose 0,006 g in 0.5 ml saline. The method increases the efficiency of treatment of patients with pseudoepherine with decreasing vibrationaly orbit, duration of the disease, the risk of recurrence and improve the quality of life. 2 C.p. f-crystals.

The invention relates to ophthalmology, namely oftalmologii, and is intended to increase the effectiveness of treatment for the prevention of recurrence and improve the quality of life oftalmologicheskiy patients.

The term "pseudotumor" for a long time used to describe a group of diseases non-neoplastic nature, accompanied by an increase in the volume content of the orbit [Diseases of the orbit. - A. F. Brovkin. - 1993. - Moscow. - "Medicine", page 93]. The frequency of the disease is to 11.8% according to different authors. To date, adopted the term idiopathic nonspecific inflammation. It combines three CLASS="ptx2">

The majority of authors in recent years, the opinion of an autoimmune nature of the disease [J. et C. Shields "Atlas of orbital tumors." in 1999, ed. Delois Patterson. - Fhiladelfia, - p. 132]. To date, however, the final question about the cause of the pathogenesis of the disease is not installed. It is not clear why, in spite of the identity of tissues in both orbits, is affected only one orbit, and not two; Nay, more, more often, we deal with isolated lesions of one or two extraocular muscles, but not all. The same happens with the involvement of the lacrimal gland. However, in autoimmune processes are involved both paired organ (diffuse glomerulonephritis). The lack of clear knowledge about the etiopathogenesis of pseudotumor orbit led to the inclusion in this group of diseases sarcoidosis orbit, disease, Wegener, of periarteritis nodosa-vasculitis, in which, as a rule, the process is bilateral.

The defeat of the orbit is characterized by a sudden attack of pain in the eye or in the depth of the orbit, chemosis of the conjunctiva, disorders of visual function, occurrence of diplopia. The disease can affect the orbital tissue diffusely or affect specific tissues, such as the lacrimal gland, extraocular muscles or sclera. In zamonolichivaniem, and bilateral. Data of computer tomography and nuclear magnetic resonance are very variable. [Mottow L. S. et al. Idiopathic inflammatory orbital pseudotumor in childhood. Clinical characteristics. - Arch. Ophthalmol. - 1978, - vol. 96, p. 1410-1416].

Histopathological studies reveal chronic infiltration of the affected tissue by inflammatory cells, lymphocytes and plasma cells without granulomatosis inflammation. In later stages of infiltration is replaced by fibrosis and sclerosis. During this period, along with elements of sclerosing find sites of lymphoid infiltration.

If the diagnosis is suspected clinically and no histological confirmation, first prescribe corticosteroids per os or retro-bulbar injection [Mombaertes I. et al. Current status in the treatment of orbital muositis. - Ophtalmology. in 1997 - vol. 104, p. 402-408]. This method of treatment was the analogue of the present invention.

Most cases respond well to treatment with steroids. However, it is rarely possible to achieve complete stabilization process. The probability steroidantibiotic forms of pseudotumor quite high (37% of cases). Steroidochemistry forms are treated by cytotoxic agents (cyclophosphamide) or radio is possible relapse or re-rate [Mannor G. E et al. Outcome of orbital myositis. Clinical features associated with recurrence. - Ophtalmology. in 1997 - vol. 104, p. 409-414]. Remission lasts from several months to 10 years.

Through treating patients with pseudoepherine orbit (pseudotumoral) we also noted that in some patients, despite the long course of injections of steroids retroorbital does not fully eliminate edema of the upper eyelid and partial ptosis, there remains a feeling of heaviness in the orbit and difficulty of movements extraocular muscles (when involving them in the process). These patients formed the control group (n = 10).

We hypothesized that the reason for incomplete rehabilitation and frequent relapses is the formation of steroid dependence and exchange steroidantibiotic populations of lymphocytes in the orbit. Their presence causes residual swelling of the periorbital tissue and the resumption of autoimmune reactions.

In search of the answer to the questions, we turned to the literature. Unfortunately, in special ophthalmological literature information relating to problems of interest to us, was not. From analogy with other autoimmune diseases, we expanded the search to include systemic lupus erythematosus, diffuse glomerulonephritis is Orme disease is advanced from the 80's. The basis of the development of dependence is the inadequacy of one adaptive mechanism of the immune system, produced in the process of evolution, the conditions that are artificially created in the process of treatment with steroids. In autoimmune tissue damage or organ formed auto-AG, which increase the activity of the immune mechanism of damage. The latter may be mediated by humoral or cell-mediated cytotoxic mechanisms that cause cell damage tissues in situ. In response to tissue damage develops stereotypical reaction of the body in the form of inflammation. Immune response and inflammation - two components of the autoimmune process. The suppression process with steroids, on the one hand, inhibition of inflammation, resulting in improvement clinics: decreased exudation, inflammation. When you try to stop the steroids again develops inflammation, as tissue damage caused by an autoimmune component, not suppressed. The reason for the latter is the formation of glucocorticoid-steroid fraction of lymphocytes. The doctor again forced to return to steroids [Picky Century. And. the Concept of development of glucocorticoid dependence in the treatment of autoimmune sabaragamuwa, clinical immunology and immunopharmacology". - 1998. - Moscow, pp. 139-153].

In view of these disadvantages of the method-analogue will be offered alternative treatment pseudophoenix diseases of the orbit.

The technical result of the proposed method is to reduce vibrationaly and sclerosing of the orbit.

The technical result is achieved due to the combined use of glucocorticoid hormones (steroids and immunomodulators.

As glucocorticoid hormones, you can use celeston or dexason, or diprospan.

As immunomodulators offer to use drugs myelopathies series - Mielopid.

The rationale for the introduction into the treatment scheme immunocorrector was the last literary evidence that among steroidantibiotic fraction of lymphocytes (SHL) has a fraction of T-helper cells and b-lymphocytes that synthesize antibodies. SRFL deposited in the spleen, thymus, lymph nodes in the affected tissue or organ. We hypothesized that SRFL deposited in the lacrimal gland, which is analogous to peripheral lymphoid organ (something like Pieroway plaques), was associated with slis the Holevo process even without direct it involvement [P. K. Coyle Immune-reactive cells in multiple sclerosis mucosal secretions. - J. Neurology. - 1989, - vol. 39 - p. 378-381]. The lacrimal gland in norm secretes a complex of proteins, fats, hormones, growth factors and immunoglobulins. Cells of the lacrimal ducts produce secretory proteins, such as lysozyme and lactoferrin, acting merocrine way. End Department gland secretes immunoglobulins, primary secretaresse immunoglobulin A (IgA) and one protein hormone prolactin. Cells of the lacrimal ducts secrete epidermal growth factor (EGF), which is secreted in tears, and the interstitium of the gland, where it may function as a paracrine mediator. Normal lacrimal gland usually contains a population of plasma cells that produce dimeric IgA, secretory of tears, and a certain number of T-lymphocytes. Among populations of T-lymphocyte suppressor cells usually (OK) surround helper cells two or three layers.

We noticed that one of the symptoms of pseudotumor orbits are complaints or to increase slezootdelenia (early disease), or to emerging persistent dryness and pain in the eye (the final stage), which, in our opinion confirms our proposed concept that the lacrimal gland t is Teruyoshi lacrimal gland, increases significantly, while the secretory epithelial tissue atrophies, being replaced by fibrous connective tissue. Released into the interstitial tissue in increased amounts of immunoglobulins, cytokines, growth factors contribute to the maintenance of the inflammatory process and the subsequent development of fibrosis.

Werdelin proved that cellular proteins may play a role of autoantigens in cases pathway of protein degradation in cells expressing surface molecules class II. It is known that related epithelial cells can act as specialized antigen-presenting cells, when they begin to Express the class II molecules.

Local steroid therapy also significantly alters the quality and quantity of subpopulations of lymphocytes (helper cells, suppressor - cytotoxic T-cells, B-cells, Mature cells), infiltrating the lacrimal gland.

Given the reduction in exposure to steroids functions imposed by nature and the immune system on immunocompetent cells [Gulling E. W. and others, "Influence of prednisolone on suppressor activity autolymphocyte". In kN. "Physiologist. immune homeostasis". J. struct. II Vsesojuzn the definition inflammation of the orbit to enter the drugs immunokorrektiruyuschie steps.

The precedents are in the literature, so that by 1998, clinicians empirically conclude about the feasibility of the joint use of steroids and immunomodulators in a number of autoimmune diseases. For example, Nasonov Century A. and Sigidin I. A. report on the effective treatment of rheumatoid arthritis with steroids and immunomodulators. Similar results were obtained in the treatment of lupus nephritis, asthma [Balabanov, R. M., Egorova O. N. "New approaches to therapy of rheumatoid arthritis". Ter. archive-68, No. 12, - 1996, page 78]. As immunomodulators suggest the use of various drugs (Likopid, immunofan, etc).

Experience to date experience on the use of various immunomodulators in the clinic points out the advantages of endogenous peptides in comparison with the alien for the body chemical compounds or products of microbial origin. Drugs such as elements of the natural metabolic processes that do not disrupt the normal functioning of cells. Endogenous substances included in the metabolic reactions, connecting with specific receptors, the expression of which is determined by processes proteous the ATA is effective in very low doses, they are characterized by high bioavailability, they do not accumulate in the body, disposed in the natural metabolic processes, non-toxic and do not cause side effects.

One source of such immunologically active substance is bone marrow. Russian scientists headed by academician R. C. Petrov first established that the cells of the body produce immunoregulatory peptides, which are called mielopeptides. These compounds possess a wide spectrum of biological activities: stimulate various immune responses, restore disturbances in parts of hemopoiesis, proliferation and differentiation immunocompetent cells, participating in the implementation of the functions of the various subpopulations of lymphocytes. Based on these compounds in the Institute of immunology developed immunokorrektiruyuschie drug MIELOPID.

The drug has successfully passed clinical trials and approved by the Ministry of health of the Russian Federation for medical use in adults and children (Ministry of health N 81 from 29.04.94, Registration card N 94/81/14).

The drug mielopid is a mixture of highly purified low molecular weight peptides, isolated from the culture supernatant of the cells is scattered about with shaking.

Identified six peptides that are included with the product: MP-1, MP-2, MP-3, MP-4, MP-5, MP-6, investigated immunopharmacological the activity of all six. It is established that MP-1 provides immunokorrektiruyuschie effect mielopid, increasing the functional activity of T-cells, helper cells. It causes a 1.5-2-fold increase in the antibody in the culture of cells of lymph nodes. This peptide restores the normal balance of activity of helper and suppressor T-lymphocytes in immunodeficient condition, by binding to specific receptors on the membrane of T-helper cells. The introduction of the MP-1 mice two weeks after gamma-irradiation at a dose of 2 Gy increased the antibody to 80,215,5%, while in irradiated control she was 37,612,5%. MP-1 was completely restored the level of antibody productions in mice treated with cyclophosphamide, and normalized the number of immunological parameters in mice with congenital defects of the immune system.

MP-2 inhibits the proliferation of malignant cells, provides the ability of the drug to prevent the development in the body of malignant tumors in the body. He abolishes the inhibitory effect of toxic products of the tumor is the same. This inhibitor appears, blocking the regulation of lymphocyte differentiation of leukemia cells, thereby suppressing the immune regulatory mechanisms that lead to the development of tumor growth. It is shown that the MP-2 restores mitogen-stimulated proliferative response of T-lymphocytes in human peripheral blood, depressed products leukemia cells HL-60. Method cytofluorimetry shown that this effect MP-2 is implemented due to its ability to restore the phenotype CD3+, CD4+cells, damaged tumor toxins. Adding MP-2 to such "damaged" cells leads to restoration of their phenotype and functional activity.

Despite the differences between the ultimate effects of MP-1 and MP-2 (MT-1 - immunomodulator, MP-2 and antitumor activity), both peptides act on certain subpopulations of T-lymphocytes. Immunofluorescent analysis of double staining of the cells revealed that the MP-1 is associated with T, but not B-cell suspension of mouse splenocytes. Preliminary data showed that the target cells for MP-1 are T-helpers.

Peptide MP-3 stimulates the phagocytic activity of cells of immunity and has a protective effect Si in doses 0,510-7- 0,510-4g/ml caused a dose-dependent enhancement of phagocytic activity of macrophages at 100-130%. The adhesive ability of macrophages was increased only by 20.10%, which indicates that the stimulation of intracellular metabolism in the capture fagocitaria cells. It is not excluded that the protective properties of Mielopid in bacterial infections associated with the activity of the MP-3.

MP-4 affects the differentiation of precursor cells by transferring the cells to a more Mature stage of development as the cultivation of leukemic cell lines HL-60, and bone marrow cells of the mouse. Currently, studies on the elucidation of the mechanisms differentsirovanogo effect MP-4 and its possible role in haematopoiesis.

The properties of the last two fractions of Mielopid are currently under study. They are isolated in pure form.

Mielopid a drug, a wide range of biological activities which can be divided into three groups of effects: immune-boosting, differencirovanie and neurotropic.

Stimulation mielopid processes of differentiation of the precursors of immune cells in the bone marrow results in patients with various the phagocytic cells of the row in the peripheral blood. This effect occurs within 5-10 days after the start of treatment and lasts for 2-3 months after graduation.

Along with the ability to influence the processes of differentiation of immunocompetent cells in the bone marrow, mielopid affects the humoral immune response, increasing the levels of secreted antibodies. In experimental models of immunodeficiency conditions of various etiologies shown that the introduction of the drug restores the level of antibody productions in animals subjected to irradiation, the influence of drugs or antibiotics. Restore the humoral immune response after application of the drug is physiological, without any side effects occurs within 2-3 days after the start of the course and lasts for 2-3 weeks.

Thus, based on pharmacological activity of Mielopid lie immunokorrektiruyuschie effects included in its complex endogenous immunoregulatory peptides bone marrow (mielopeptides). Mielopeptide stimulate the proliferation and differentiation of precursors of immune cells and increase the functional activity of Mature cells effector, repairs the am and accelerates their inactivation. It was the combination of the enumerated effects was used as a basis for preference Mielopid before other drugs immunokorrektiruyuschie series. However mielopid still not used locally, in particular in the pathology of the eye and orbit.

Given the dominant role of local immunological reactions in front of the system, we assumed that the local introduction of Mielopid in orbit in the upper-outer division of the orbit (the localization of the lacrimal gland) is optimal.

We alternated steroid injections with Mielopid in the upper-outer division of the orbits of patients with idiopathic myositis, pseudotumoral the lacrimal gland. The results exceeded expectations. Significantly decreased the recovery time of patients (n = 23) compared with the control group treated with steroids without immunocorrector. Thus, the number of injections of steroids needed for the relief process decreased from 10 to 5-7. Was achieved 100% of rehabilitation patients, even in cases with signs of steroid resistance. Prolonged observation revealed no recurrence in terms from 6 months to 2 years.

Our experience of treating patients has enabled us to offer a method of treatment will pseudonym to introduce steroid injections (1 ml3celestone) in the upper-outer division of the orbit, alternating with injections of mielopid (0,006 g in 0.5 ml3saline) in a day (ana N 5).

Example No. 1.

Patient M 43 years. Diagnosis: idiopathic myositis (involved upper rectus) of the right eye, the left eye is healthy. Operated. The diagnosis was confirmed histologically.

Conducted treatment Celestina (5 injections of 1 ml3). On a background of treatment showed improvement in the reduction of exophthalmos (from 5 mm to 2), the increased mobility of the eyes down (15 degrees), the reduction of ptosis. However, residual effects did not disappear. Treatment connected mielopid on 0,006 g retroorbital. After three injections of everything stoped.

Example No. 2.

Patient P. 58 years. Pseudotumor lacrimal gland on the right.

Started a course of combined treatment celestone and mielopid. For edema process and restore all functions needed 5 injections of both drugs.

1. A method of treating pseudoophonus orbit, including the use of glucocorticoid hormones, characterized in that it further apply immunocorrector mielopid in the form of retro-bulbar injection.

2. The method according to p. 1, is.

3. The method according to p. 2, characterized in that mielopid the use of 0,006 g, dissolved in 0.5 ml of saline.

 

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