RU2234921C1 - Method for treatment of fungus-like mycosis - Google Patents

Abstract

FIELD: medicine, dermatology.

SUBSTANCE: invention relates to a method for treatment of fungus-like mycosis. Method involves administration of ridostinum as an inductor of endogenous interferon as intramuscular injections in the dose 8 mg, 2 times per a week, 6 injections for a course. Prednisolon is prescribed simultaneously with ridostinum in the dose 0.5 mg/kg/day for 21 days followed by reducing the dose by 2.5 mg for 3 days. Treatment results to attainment of high clinical effectiveness in patients at the II-d and III-d stage of process and reduces complication risk.

EFFECT: improved method for treatment.

3 tbl, 2 ex

Description

The invention relates to medicine, namely to dermatology, and can be used to treat malignant lymphoma of the skin.

One of the types of chronic, severe skin pathology are malignant skin lymphomas (ZLK), which belong to the general group of human lymphoproliferative diseases, type of non-Hodgkin's lymphomas (N. A. Probatova, N. N. Tupitsin, E. V. Fleishman. Basic principles and diagnostic criteria for the revision of the European-American classification of lymphoid tumors (T-cell lymphomas, Hodgkin's disease) // Archive pathology. -1998. -№4. - P.61-70). According to the accepted classifications (REAL, 1994; WHO, 1996; EORTC, 1997), ZLK are divided into T- and B-cell immunovariants, where T-cell malignant skin lymphomas (T-ZLK) comprise 65-80% of all skin lymphomas. Among T-ZLK, the most common nosological form is mushroom mycosis (the classic three-stage form of Aliber-Bazin and the erythrodermic form of Allopo-Benier) (Skin and sexually transmitted diseases: a Guide for doctors. - T.3 / Edited by Yu.K. Skripkin. - 1996. - P.100-105; Rodionov A.N., Barbinov V.V., Kazakov D.V. Histological diagnosis of skin lymphomas // Journal of Dermatovenereology and Cosmetology. -1997. - No. 1. - P.5- 14; Yastrebov V.V., Raznatovsky I.M. Lymphomas of the skin. - 2000. - P.3-74).

Currently, for the treatment of systemic (nodal) lymphomas, there are a significant number of standardized protocols that regulate the doses and regimens for the administration of pathogenetically significant drugs (glucocorticosteroids, cytostatics, etc.), while there are no protocols for the treatment of malignant skin lymphomas (Essential drugs for chemotherapy Cancer // Bulletin of the WHO. - 1994. - T.72, No. 5. - C.3-8). The current situation makes it relevant to search for new drugs for the treatment of ZLK, especially mushroom mycosis (GM), and the development of scientifically-based regimens and recommendations for their use.

In the literature of recent years, a special place is occupied by reports on the use of ZLK therapy methods, combined in the group "biological response modifiers" - (biological response modifiers - MBO), which include natural and recombinant interferons, cytokines, retinoids (Heald P. The treatment of cutaneous T-cell lymphoma with a novel retinoid.// Clin. Lymphoma. - 2000. - Vol. 1 (1) .- P.45-49; Duvic M. Treatment of cutaneous T-cell lymphoma from a dermatologist's perspective // Clin Lymphoma. - 2000. - Vol. 1 (1). - P.15-20, 2000).

1. It was found that interferons (α, β, and γ) have a pleotropic effect on lymphocytes: they activate macrophages and EC cells, increase the expression of antigens of the main histocompatibility complex on macrophages and target cells, and cause re-expression of phenotypic markers on malignant lymphoid cells, which is important for the inhibition of the tumor process, and also have an anti-tumor effect through depression of the expression of proto-oncogenes c-myc and c-ras, c-fos (Berezhnaya N.M., Chekhun V.F. Interleukin system and cancer. - K .: DIA, 2000 .-- 224 p .; Greenway HT Interferon- coming of ag e // Arch. Dermatol. - 1990. - Vol. 126. - P.1080-1082; Baron S., Tyring SK The Interferons: machanisms of action and clinical application // JAMA. - 1991. - Vol.266. - P.1375-1380; Hakansson A., Gustafsson B., Krysander L., Hakansson L. Effect of IFN-alpha on tumor-infiltrating mononuclear cells and regressive changes in metastatic malignant melanoma // J. Interferon-Cytokine Res. -1998 . - Vol. 18 (1). - P.33-39).

Summarizing the results of more than 20 reports on the clinical use of IFN drugs in the treatment of T-ZLK, G. Burg in his monograph "Strategies for Immunointerventions in Dermatology" (Springer-Verlag Berlin Heidelberg. - 1997. - P.164, P.322, 324) concludes the effectiveness of this group of immunomodulatory agents, in particular IFN-alpha, in the form of monotherapy in an average of 60% of patients, and in 50% of patients with partial remission of the process, and only in 10% with complete clinical remission. The experience of using IFN drugs in the treatment of patients with GM is also presented in the few works of domestic researchers and indicates moderate clinical efficacy of the applied interferon therapy regimens in the treatment of patients with GM at various stages of the development of the process (table 1).

At the same time, the use of official IFN drugs in therapeutic doses (30-50 million ME per course) leads to the development of side effects: flu-like clinical symptoms, fever, leuko- and thrombocytopenia, hepatocellular destruction, significantly worsens the quality of life of patients during therapy ( Caplan EH, Rosen ST, Norris DB Phase II study of recombinant human interferon for treatment of cutaneous T-cell lymphoma // J. Natl. Cancer Inst. - 1990. - Vol. 82. - P.208-212; Burg G. et al. Cutaneous Lymphomas // Current Probl. Dermatol. - 1997. - Vol. 9 (5) .- P.137-204; Haley HR Durable loss of a malignant T-cell clone in a stage IV cutaneous T-cell lymphoma patient treated with high-dose interferon and photop heresis // J. Am. Acad. Dermatol. - 1999. - Vol. 41 (5) .- P.880-883).

Thus, immunotherapy with T-ZLK with the introduction of exogenous interferons, providing a comprehensive antitumor effect, demonstrates moderate clinical efficacy in combination with a high risk of side effects, and also has a high cost (Lamotkin I.A., Slezina L.V. Analysis of the cost of examination and treatment of patients with skin lymphomas in the dermatological department of a multidisciplinary medical institution // Bulletin of dermatol. and venereol. - 2001. - No. 4. - P.33-34).

At the same time, there is an alternative way of interferonization, devoid of the above drawbacks, the essence of which is the “inclusion” in the patient’s body of their own mechanisms for the production of endogenous interferon in biologically adequate amounts with the introduction of its inductors (Ershov F.I. The interferon system is normal and pathological. - M .: Medicine, 1996. - 240 p .; Ershov F.I., Tuzulakhova E.B. Inductors of interferon - a new generation of immunomodulators // Vestnik RAMS. - 1999. - No. 4. - P.52-56). However, in the treatment of T-ZLK, a similar approach to treatment has not been practically applied before, which served the purpose of developing a new method for the treatment of GM (T-cell malignant lymphoma of the skin).

The prototype of the invention is a method of treating T-ZLK (GM), which consists in conducting immunotherapy with interferon-alpha2 at a dose of 3-5 million ME 3 times a week for 2-3 months. This method was used to treat 14 patients with T-ZLK: 4 with stage 2 and 10 with stage 3 development of the pathological process. The therapy was effective in 9 out of 14 patients (64.3%), of which no complete clinical remission was achieved in any patient, partial remission was recorded in 7 patients, and minimal improvement in 2 patients. In 5 out of 14 patients, interferon monotherapy led to the progression of the disease (I. Lamotkin, Skin lesions in malignant lymphoproliferative diseases: Diss. Doctor of Medical Sciences. - St. Petersburg. - 2001, - 227 p.). At the same time, in the course of interferon therapy of patients with T-ZLK, poor tolerance of treatment was noted, the formation of concomitant adverse events, such as severe chills, hyperthermia, anorexia, nausea, weight loss, depression, etc. (Faradzhev Z.G. Lymphoproliferative diseases skin and Kaposi’s sarcoma (pathogenesis and treatment methods): Dis ... doctor of medical sciences, M., 1990. - 278 p .; IA Lamotkin Skin lesions in malignant lymphoproliferative diseases: Dis ... doctor honey Science. - St. Petersburg, - 2001, - 227 p.).

An alternative to the introduction of exogenous interferon are methods of increasing the synthesis of intrinsic interferons by activated lymphocytes. Known drug ridostin, which has a multifunctional immunomodulating effect and belongs to the group of interferon inducers (IFN).

Ridostin is a new domestic early-type interferon inducer, the main active principle of which is double-stranded ribonucleic acid (ds RNA) of killer strains of Saccharomyces cerevisiae yeast. Ridostin is a mixture of sodium salts of double-stranded and single-stranded ribonucleic acid (5 mg), sodium chloride (3 mg) in the form of a white lyophilized porous mass. The main characteristic of the drug is interferon-inducing activity (alpha, beta, and gamma interferons), proven in clinical trials on volunteers and in clinical practice, when the administration of ridostine led to an increase in serum α-interferon titers during the first 6 hours in 93 % of the subjects and persisted during the day in 60% of patients (Nesterova G.F. Biological activity of double-stranded RNA // Biotechnology. - 1990. - No. 4. - P.7-12; Ershov F.I., Tuzulakhova E.B. Interferon Inductors - A New Generation of Immunomodulators // B ticipant of Medical Sciences -. 1999. - №4 -. S.52-56). Ridostin was shown to not only enhance the synthesis of all types of interferon, but also increase the level of interleukins (IL-1, IL-6), as well as tumor necrosis factor alpha in the blood (Bondar I.A. Ridostin in the treatment of diabetes mellitus // Tez. Report III of the Russian National Congregation “Man and Medicine”, - M., 1996. - P.81). Preclinical trials of the drug showed a decrease in the vaccination of experimental tumors, the frequency of their metastasis and a decrease in the proliferative potentials of tumor cells, which is associated with the correction of the IFN system (stimulation of its unrealized potential), as well as with the regulatory effect of ridostine on the function of macrophages and T-lymphocytes (Ingel F.I. Antimutagenic effect of the drug of species-specific interferon // Vestnik Rossiyskoy AMN. - 1993. - No. 3. - P.20-23; Barinsky I.F., Posevaya T.A., Lavrukhina L.A., Kosyakova N.P. Antitumor the effect of double-helix inducers of interferon (larifan, ridostin) and reaferon in the experiment // Vopr. Virology. - 1994. - T.39. - No. 4. - P.179-182; Kadagidze Z.P. Immunological approaches to the use of cytokines in complex treatment of malignant neoplasms // Questions of oncohematology. - 1995. - T.41. - No. 2. - S.45-47).

The established immunomodulating properties of ridostin, including those with an increase in the antitumor potentials of the body, are recorded in the Register of Medicines of the Russian Federation (Edition 1999-2002) and substantiate the possibility of its use as an adjuvant in the complex treatment of diseases, including proliferative, accompanied by disorders immune status.

The pathogenetic use of glucocorticosteroid (GCS) hormones in the treatment of lymphoid neoplasia is known. Prednisolone - a synthetic analogue of the glucocorticosteroid hormone cortisone, has anti-inflammatory, anti-allergic, desensitizing, immunosuppressive and antitoxic effects. The immunosuppressive effect is realized in suppressing the migration of bone marrow stem cells and B cells, disrupting the interaction of T and B lymphocytes, and inhibiting the development of lymphoid tissue (Mashkovsky MD Medicines, part II. - 1997. - P.28-30 ) In the treatment of T-ZLK, systemic and topical GCS hormones (mainly prednisolone) are used as monotherapy in doses of 60-30 mg / day, which is however more applicable in patients with early stages of T-ZLK and provides a satisfactory clinical effect of achieving remission only in 43 , 8% of patients with stage 3 disease development (A. Rodionov, Erythrodermic skin lymphoma (Study Guide). - Leningrad, 1989, 67 pp .; Kalamkaryan A.A., Berenbein B.A., Potekaev N.S. Modern problems of the clinic, diagnosis, pathogenesis, treatment of malignant lymphomas skin and sarcoma Kaloshi // Vestnik dermatologii i venereologii. - 1991. - No. 7. - P.18-26; Lezvinskaya EM. Cytological diagnosis of malignant lymphomas of the skin, proceeding by the type of erythroderma: Dis .... doctor med. Sciences. - M., 1997, 239 p.). Thus, corticosteroids monotherapy with hormones is effective in the early stages of the development of the process (GM stages 1 and 2), is relatively effective in patients with stage 3 disease.

The purpose of the invention is to increase the effectiveness of the treatment of T-ZLK while reducing the risk of clinical complications from the therapy.

The goal is realized by the appointment of patients with T-ZLK (GM) inducer of endogenous interferon ridostin and the corticosteroid hormone prednisolone in a therapeutic dose with a gradual decrease. The method of treatment is used in a specialized dermatological department with a full hospital regimen (or in a day hospital).

Patients with ZLK were treated with GC hormones in a starting dose of 0.5 mg / kg / day, in the first 2 weeks infusion, then orally at a dose of 0.5 mg / kg / day, followed by a dose reduction of 2.5 mg in 3 days. Against the background of corticosteroids, ridostine was administered.

In accordance with the general recommendations for the use of ridostine, the drug was administered intramuscularly at 8 mg of the active substance dissolved in ex tempore in 2.0 ml of water for injection. Ridostin was prescribed from 1 week of general therapy of patients, was administered 2 times a week with an interval of 2-3 days, for a total of 4-6 injections of the drug.

The duration of the main course of treatment was up to 30 days, after which oral therapy with corticosteroids was continued with a dose reduction.

Positive clinical dynamics, as a rule, began in the first weeks of therapy and was expressed in a decrease in hyperemia and infiltration in the foci, a decrease in the intensity of itching and burning of the skin. During the administration of ridostin and after completion of the course, the symptoms continued to regress, and by 4-6 weeks of treatment the state of erythroderma was practically resolved, the infiltrative-plaque rashes flattened, the spotted manifestations disappeared, often leaving hyperpigmented skin areas during the regression.

The proposed method was used in the treatment of 13 patients with T-ZLK, 9 of whom were in a state of erythroderma (according to the classification of TNM - stage III of the development of the process), 4 patients with GM2 (stage IIA) with partial erythroderma phenomena from 39 to 70 years old, including 3 women and 10 men. The duration of the disease ranged from 2.5 to 6 years.

The diagnoses were histologically verified in the clinic UrNIID-ViI. Previously, patients were treated mainly with the use of systemic and topical corticosteroids, which made it possible to achieve extremely short clinical remission (3-5 months). Anamnestically and clinically, patients of this group were distinguished by frequent exacerbations of the process (from 3 to 6 episodes), the rapid development of erythroderma, accompanied by the occurrence of pyogenic complications on the skin, and the presence of a concomitant pathology of inflammatory systems and organs.

Table 2 shows our own clinical efficacy data of the modified method of treatment with T-ZLK by ridostin in comparison with the data of I. Lamotkin. (2001), who used interferon - alpha 2.

From the data of table 2 it can be seen that the described treatment method did not lead to the progression of the process in any patient, in contrast to the prototype, where in 35.7% of patients after interferon therapy the process progressed. In all patients, after completion of therapy with ridostin, clinical improvement was achieved: in 1 patient, minimal, in equal proportions (6 patients - 46.2%), partial and complete remission. The comparison method was significantly less effective: in 14.3% of patients - minimal improvement, and in 50% - only partial remission of the disease. In addition, in the treatment with ridostin, side effects were recorded only in 2 patients (15.4%), they were easily stopped, did not require discontinuation of the drug.

The clinical efficacy of ridostin therapy was accompanied by significant changes in the immune status of patients with T-ZLK (GM) after the end of treatment (table 3). Ridostin treatment determined a significant increase in the serum interferon-gamma content reduced before the start of therapy and even a tendency to exceed the normative indicator, which indicated the pathogenetic effect of the drug. The achievement of the clinical effect after the end of the therapy with ridostin was also accompanied by a unidirectional increase in the populations of CD8 +, CD16 + lymphocytes and cells expressing the apoptosis-associated receptor, which indicated a significant activation of antitumor immunity factors determining the possibility of regress of lymphoid neoplasia.

The use of the proposed method of therapy is illustrated by the following examples.

Example 1. Patient P-in., 52 years. He was admitted with complaints of rashes on the skin of the trunk and extremities, intense constant skin itching. He has been ill with this disease for 2 years, notes a continuously recurring course of the disease, despite the ongoing therapy (desensitizing, detoxifying, systemic (prednisone up to 20 mg / day, topical corticosteroids). Histological examination and immunophenotyping of a skin sample in UrNIIDViI of the Ministry of Health of the Russian Federation made it possible to establish a diagnosis : Malignant T-cell lymphoma of the skin Mushroom mycosis, erythrodermic form (stage III).

When examining a patient: skin in a state of erythroderma, reddish-cyanotic skin, severe infiltration, small-scaled flaking, excoriation on the skin of the trunk and upper extremities, hyperkeratosis of the palms and soles. Somatic: ischemic heart disease, atherosclerotic cardiosclerosis, NK 0-I; Chronical bronchitis. The liver is not enlarged, the spleen is not palpable.

Clinical and laboratory studies in the in-patient department of the URNIIDViI revealed abnormalities in the main immunological parameters: disimmunoglobulinemia, hyper-E-immunoglobulinemia, violation of the ratio of T-helper / T-suppressor populations, an increase in the level of CD19 (B cells), reduced by 1, 7 times the content of IFN-gamma in serum. In the peripheral blood - leukocytosis, lymphocytopenia, eosinophilia.

Was prescribed treatment with ridostin according to the traditional scheme in the form of a / m injection of 8 mg of the active substance, dissolved "ex tempore" in 2.0 ml of water for injection. Ridostin was prescribed from 1 week of general therapy of patients, was administered 2 times a week with an interval of 2-3 days, a total of 6 injections of the drug. At the same time, prednisone per os 30 mg / day was administered for 21 days, followed by a decrease of 2.5 mg in 3 days, antihistamines, and external ointment therapy. The treatment was carried out under the control of a hemogram 1 time in 5 days.

As a result of the therapy, after 2 injections of the drug ridostin (1 week of treatment), a significant decrease in the intensity of skin itching and burning was noted; after 4 injections (2 weeks of treatment) - a decrease in hyperemia and peeling of the skin was recorded, in the same period, skin infiltration and peeling significantly decreased. The resolution of erythrodermic manifestations occurred at 4 weeks of treatment. Adverse reactions and complications of therapy were not observed.

In the repeated immunogram after a course of therapy, a significant decrease in IgE level was observed, approaching normal IgG levels and the ratio of T-helper / T-suppressor populations. In the peripheral blood - normalization of the content of IFN-gamma, lymphocytes and eosinophils. The patient was discharged in a state of complete clinical remission, the duration of the course of therapy was 38 days.

Example 2. Patient B-a, 65 years old, was monitored at the clinic of the UrNIIDViI since 1999, after repeated histological studies in 2001, the diagnosis was verified: T-cell malignant lymphoma of the skin. Mushroom mycosis, ON stage. The patient repeatedly underwent inpatient treatment in the clinic with the use of desensitizing, detoxifying drugs, systemic therapy (prednisone 30 mg / day for 14-20 days) and external corticosteroid therapy, was prescribed with an improvement in maintenance therapy with glucocorticosgeroids. The skin process has become resistant to the therapy, frequent exacerbations combined with short periods of remission (2-3 months).

Clinical and laboratory studies in UrNIIDVi in the immunogram revealed dysimmunoglobulinemia, a moderate increase in IgE, a high content of IL-4. In the peripheral blood - moderate leukocytosis, eosinophilia.

Was prescribed treatment with ridostin according to the traditional scheme in the form of a / m injection of 8 mg of the active substance, dissolved "ex tempore" in 2.0 ml of water for injection. Ridostin was prescribed from 1 week of general therapy, the patient was administered 2 times a week with an interval of 2-3 days, a total of 6 injections of the drug. At the same time, prednisone per os 35 mg / day was administered for 21 days, followed by a decrease of 5 mg in 5 days, antihistamines, and external ointment therapy. The treatment was carried out under the control of a hemogram 1 time in 5 days.

As a result of the therapy, after 4 injections of the drug ridostin (2 weeks of treatment), there was a decrease in active hyperemia and infiltration in the area of plaques, and a decrease in itching at the rash sites. After 6 injections of the drug, spotted rashes almost regressed, and plaques significantly decreased in height, the itching completely disappeared. Within 3 weeks after the end of the administration of ridostine, the dose of prednisone slowly decreased until it was completely canceled. At discharge (total hospital stay 43 days), the process regressed by 50%, which characterizes the outcome of therapy as a partial remission of the process. Adverse reactions and complications during therapy were not noted.

A dynamic study of the immunological status revealed a downward trend in IgE in the peripheral blood, a decrease in leukocytosis, and eosinophilia.

The proposed method in the UrNIIDViI treated 13 patients with T-ZLK aged 39 to 70 years, including 3 women and 10 men. The duration of the disease ranged from 2 to 17 years, the diagnoses were histologically verified for the first time in the clinic of the UrNIIDViII. Previously, patients were treated using systemic and topical corticosteroids, which did not allow for complete clinical remission. After the course of therapy with ridostin and prednisone, a significant clinical improvement was achieved in 12 of 13 patients (92.4%), and in one patient (7.6%) - a minimal improvement in the process. The duration of remission ranged from 12 to 19 months.

Thus, a new method for the treatment of T-ZLK (fungal mycosis) was tested, including the appointment of an interferon inducer in combination with medium therapeutic doses of prednisone, which significantly increased the effectiveness of therapy while reducing the risk of complications.

Claims (1)

A method for the treatment of fungoid mycosis, including the use of immunotherapy and prednisone, characterized in that ridostin is used as an inducer of endogenous interferon in the form of intramuscular injections of 8 mg 2 times a week with a total course of 6 injections, and at the same time, prednisolone per os is prescribed at a dose of 0.5 mg / kg / day, followed by a dose reduction of 2.5 mg in 3 days.