JPH05502434A - Pharmaceutical compositions and their uses - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Pharmaceutical compositions and their uses This invention relates to new medicinal uses of fundic acid and its derivatives, and more specifically, to the pathogenesis of fungic acid and its derivatives. Some immune inflammatory mediators (m6diators), especially cytokines, Prevention and/or treatment of relapses related to the production and/or function of Concerning applications. In particular, this invention relates to the use of fluoronic acid and its derivatives, Diabetes mellitus (type I) [insulin-dependent diabetes mellitus (DD, M): disease of the thyroid gland] associated with rheumatism, inflammatory rashes, skin diseases, and rejection of transferred substances. prevention and/or symptoms associated with oculopathy, endogenous uveitis, and eye cry involvement. is about treatment.

Background of the invention Many autoimmune diseases or disorders of the immune system, especially T-lymphocyte-mediated immunity, occur secondarily. There is growing clinical and experimental evidence that the drug is active. infectious diseases, inflammatory diseases, and , Many signs and symptoms of inducing diseases: They occur when cell-mediated immunity is stimulated. moreover Immune-competent cells: 1, not necessarily involved in the early stages, but with other appropriate 'a-receptors' Acute and chronic diseases result when the immune response is abnormally regulated.

The etiology of these diseases is generally unknown, and systemic rheumatic diseases [e.g. RA), organ-specific endocrine diseases [e.g. insulin-dependent RA 1 Urinary disease (IDDM): l, inflammatory diseases (e.g. Crohn's disease) and skin inflammation Include infectious diseases (e.g. contact dermatitis). (The disorders of cell-mediated immunity are as follows. As discussed in detail below, many of the immune-mediated diseases involved in immunoinflammatory and proliferative diseases. Ru.

Treatment 11 that can be used for the above diseases! Is the treatment usually symptomatic or? rP phase It is a medicine law. That is, most of the medications prescribed for these diseases or symptoms It is aimed at IfO and usually has no curative effect. Other treatments include: , because production in the body has decreased or is insufficient, such as hormones. There are so-called replacement therapies that involve providing a patient with such substances for a lifetime.

The above treatments are often unsatisfactory and have undesirable and often serious side effects. Cheer. l=r: There is a need for improved therapeutic methods and improved pharmaceutical compositions.

Fluoronic acid and its food derivatives are derived from Fusidiu conium. can be isolated from the fermentation broth of a strain of the species M. coccineum. has been known for many years as an efficient, medicinal and acceptable antibiotic. . Futunoic acid, i.e. 16-(acetyloxy)-3,11-dihydroxy- 29-Dammala-17(20), 24-diene 21-oic acid, (3α, 11 α, f6β-Tυhil-″Kokin-29-Noru8α19β, 13α, 14β- Danmara-tvc20'), 24-noene-21-oic acid L6 acetate ) is a tetracyclic triterpene acid having a Tesroid-like structure of the following formula 1. .

Fusidic acid inhibits bacterial protein synthesis, resulting in bacteriostatic and/or (superbacterial) It is known that there is. Nifsidic acid is an antibiotic that seems to be in the order of Beninoline. Seaphylococcus aureus (Seaphylococcus occus aureus). This medicine is in its acid form, Oyogo ζ, used clinically in both its sodium and noethanolamine salts. centre The sodium salt of cinonic acid has the action and uses of fusic acid. this salt in water It is more soluble and easily absorbed from the gastrointestinal tract. Also, this salt is used in preparations for opening. It is used. Severe grape-like bulb M! 1. Against G-staining disease. So, this antibiotic, for example It is administered intravenously as jetanolamine fluorofluoride.

A description of the chemical and microbiological modification of fundic acid can be found in 5structure-Ac tivi l: y ReLatt, on -5hip in Fusidic Ac1d-Type 8-ntibiomics (45), Humunonic acid and its derivatives are listed in the Pharmacopoeia and Martindale CExtra Pharmacop-oeia 28th edition (19 1982)].

Fusidic acid and its derivatives are disclosed in PCT Patent Application Publication No. WO36103966, Denma Park Patent Publication No. 148390 (U.S. Patent No. 4,119.717), Denmark Kupatent No. 96349 (British Patent No. 930786), Danish Patent No. 99802 (Austrian Patent No. 252466), Danish Patent No. 01687 (U.S. Patent No. No. 3,334.014), Danish Patent No. 104399 (U.S. Patent No. 3,230) 240), Danish Patent No. 105981 (U.S. Patent No. 3,230,240) , Danish Patent No. 107349 (UK Patent No. 999794), Danish Patent 116940 (US Patent No. 3499012), Danish Patent No. 131348 (U.S. Patent No. 3.867.413), Danish Patent No. 142852 (U.S. Patent No. No. 4100276, U.S. Patent No. 416259 and U.S. Patent No. 4315004), U.S. Pat. National Patent No. 3.376.324, National Patent No. 3.629,300, National Patent No. 3,920.817 No. 4.004.004, No. 4.025.620, No. 4.060.606 No. 4.315.004, British Patent No. 2.093.348, No. 98 7.042.

However, these prior art documents are limited to inhibiting specific immunological response mechanisms. Cytokine II (lymphins, interferons, interferons, etc.) - leukins, colony-stimulating hepta and/or monokines). Well, it looks like phosphoric acid! is not relevant to the use of functional derivatives; Nor is it relevant to treatments for symptoms associated with disorders of the cytokine system. specific sound For example, if you have diabetes or have a bacterial infection, you may be temporarily receiving fluorinated acid for a short period of time. Although sometimes found in the medical literature, it is not relevant to the teachings and embodiments of this invention. It is clear that there is no.

Summary of the invention This invention allows fungic acid and its derivatives to be used in the treatment of inflammatory diseases or inflammatory processes. prevention and protection of forms of infection, especially those related to the immune system and/or hormonal system. It has been discovered that it can be used therapeutically. About immunological mechanisms Its mechanism of action, as detailed below in the discussion of Inhibits the action of cytokines, especially monokines and lymphocytes. This is done by inhibiting the production of certain cytokines. inhibiting and/or suppressing the action and resulting in tissue damage. It is thought that it inhibits the physical process.

With a wide scope, this invention is applicable to the lymphin system, interleukine system, and monokine system. system, interferon system, and cytokine system such as colony stimulating factor system. Lymphukine, interleukin for the prevention and treatment of symptoms associated with the disorder , monokines, and interferons, which are biologically related to colony-stimulating factors. For applications using fluoronic acid or its derivatives to substantially inhibit the action of related. In addition, the broadest aspect of this invention is the functional induction of hutunoic acid. Disorders of the cytokine system in humans, consisting of administering to the subject an effective amount of the body Concerning the treatment of symptoms associated with. Therefore, the application of this invention is to or the use of its derivatives as antibiotics.

Detailed description of the invention General information on cytokines and immunoinflammatory diseases Many of the signs and symptoms of cancer and neoplastic regression result from stimulation of cellular immunity. Further exemption Disease-responsible cells are not necessarily involved in the early stages, but are involved in other appropriate cellular immune responses. are abnormally regulated, resulting in acute and chronic diseases. These diseases are generally caused by systemic rheumatism, e.g. rheumatoid arthritis (RA) L organ characteristics. Heterogeneous endocrine diseases [e.g. intuulin-dependent diabetes mellitus Wit (r　DDM)] ], and intestinal inflammatory diseases (e.g. Crohn's disease) and skin inflammation (e.g. contact skin). flame) or included. However, disorders of cell-mediated immunity are associated with many inflammatory and proliferative diseases. (see Table 1).

Table 1 Macrophage/nee lymphocytic immune responses are thought to be important in the pathogenesis some diseases.

Atopic dermatitis and contact dermatitis Psoriasis and psoriatic arthritis T-lymphocyte proliferative disorders such as fungiform syndrome and Cesar syndrome; Biten Healing erythema nodosum scleroderma Grapes @ flame noegren syndrome Rheumatism agency WB inflammation juvenile arthritis lighter syndrome gout osteoarthritis systemic lupus erythematosus Polymyositis and myocardial evidence Primary biliary cirrhosis crohn's disease 1 Ulcerative enterocolitis multiple sclerosis aplastic anemia Idiopathic thrombocytopenic purpura Dislocations such as multiple myeloma and some B-cell lymphoma multiple sclerosis Zinmonts panpituitarism Graves disease and Graves ophthalmopathy Subacute thyroiditis and Hashimoto disease anonan disease Intuulin-dependent wluria vera (type I) and others Vasculopathies (e.g., polyarteritis nodosa, Vento-Gener granulomatosis, giant arteritis) , fever, fatigue! , clinical symptoms associated with anxiety and anorexia (e.g. sexual and chronic Disseminated vasotropic coagulation (DIC) arteriosclerosis Shock (e.g. due to Gram-negative sepsis) Bad night (e.g. due to cancer, chronic and inflammatory disease) and chronic inflammatory diseases) transplant rejection and graft-versus-host disease T lymphocytes govern the induction and regulation of cellular immune responses, and T lymphocytes! (produces a ball) Tanobacteria and proteins (lymph proteins) initiate and control immune responses. +, 2). 1. Rudder 1. Antigen activation of T cells is similar to that of macrophages (Mφ). These cells require physical interaction of the cells in which the antigen is present [-1. production of mediator molecules that are critical for humans, followed by the attraction of B lymphocytes. The cells then undergo a process of development and become antibody-producing plasma cells. These mediators are The recruitment and activation of the many cell types that serve to increase the size of the inflammatory mass in the affected tissue Give 1) Lo (1-4).

Lymphokines and cell activation media produced by cells containing antigens The proteins are collectively called cytokines. Therefore, cytokines , in physiological and physical infectious processes, immunoinflammatory processes and proliferative processes. It is an essential transmitter for cell-to-cell communication. In many cases, these cytokines is a hormone that provides information between the immune system and the tissues and organs of the pond. It also works. Furthermore, many cytokines are produced by cells outside the immune system. (e.g. skin cells (5) and vascular cells), and therefore cytokines are Acts as an autocrine hormone without the need to remove immune-competent cells do.

Cytokines achieve polarization by binding to specific receptors on numerous target cells. Cains are active at low concentrations (+QlG~+O"M). It is thought that it probably acts near its production site, but as mentioned above, some Through the circulation of blood and lipophilic fluid, these mediators control the mechanisms of cells at distant sites. Mediates Noh. Figure 1 shows the production of cytokines during the immune response in blood cells and tissue. Demonstrates the dynamics of function.

macrophages Macrophages lli (Mφ) are central to defense against microbial diseases and neoplastic diseases. It plays an important role in a wide range of tissue repair processes (2).

For example, some functions of Mφ, such as removing red fastballs as the years pass, are continuous. will be implemented. Other WA functions are performed periodically, and these functions require Mφ in advance. It is necessary to activate it. Cells, for example, contain microorganisms and also endotoxins (lipopolyses contact with cell wall components such as microorganisms such as t-order) and muramyl peptides. This results in direct activation. ＼・■φ This direct means of activation: Yo, high In animals, activation is more likely to occur through an indirect form of activation than by lymphoids. (1-3). In other words, interferon α and γf, TF>jα and IF γ) are important activators of ~1φ, D\, and others. There is a lymph chi7 that activates ν1φ (+, ).

Phagocytosis itself and, perhaps more importantly, immunomimetic activity Due to sexual activation ~■φ or induced sako, prostaglanoa, tano Synthesizes and releases several biologically active molecules, including bacteriolytic enzymes and complement components. do. Four of these factors are interleukin 1α (tL-1 α8 interleukin lβ (IL-1β), interleukin 6 (jL-6) and and @tumor death factor-α (TNFa): i Widely affecting biological and disease physiology There is some scientific effect (+, -S).

Macrophage-derived polypeptide mediator Molecular biology; Recently, a wide range of topics have been summarized as 1 and 2 (2, 4.6-8),, This:) Hormones: All interferons and Members of a growing family of cytokines, including several growth factors. − is. Also: vlφ cytokines are produced during “stress” conditions and are , acute reactions, and chronic infections, inflammatory diseases, autoimmune diseases, and tumors. Important I: Mediator of cachexia caused by sexual diseases.

Production of IL-1α/β, [L-6 and TNFa IL-1α/β, UL-6 and and TNFα are mainly produced by activated Mφ, but these The ability to make molecules, especially [L-1α/β and IL-6; is limited to Aφ(2). do not have. Natural killer cells (NK cells, cells) and β-phosphorocytes produce [L-1α/β]. It is already known that fibroblasts produce IL-6 (=I A total of 1 cells known to produce FNβ2). In fact, all Nuclear alveoli are able to produce these peptides when triggered by appropriate stimuli. It is.

The mature mediator molecules are 169 (IL-1α), 1.53 (IL-1β), 1.84 (IL-6) and 157 (TNFa) amino acids It is Juhani Polybebutide. Native human rL-6 is glycosylated, and this protein The obtained molecular weight of the itokine species: ranged from 17 to 28 kD.

The TNFa and TNFβ genes are a combination of major human histocompatibility genes. The class ■ area, that is, the LA area area [7. According to recent research in , direct liquid mononuclei obtained from HLA-D R2 positive individuals Cells show a very low TNFα response in vitro (1). Tsute 0ru (9).

This means that) (L A - D R2 Sora has multiple sclerosis and Narco I/Pun- There is a positive relationship with eel disease, and a negative relationship with rheumatoid joint moxibustion and iDDM. is important.

Immunological functions of IL-1α/β, IL-6 - Clinical relevance IL-1α/β, -6 and TNFα receptors: more responsive to itokines Found in most known cell types. IL-1α and rL-1β are It is thought that these peptides bind to the same receptors on T lymphocytes and 8926 cells. can downregulate the expression of CD4 constructs in human T cells (10 ). This CD4 structure is probably in phase with MHC class II molecules on antigen-providing cells. Through interaction, it is directly involved in antigen presentation (Figure 1). Therefore, T lymphocytes [ The L-1 receptor binds to the primary receptor-associated IL-1 receptor (IL-1α) on antigen-providing cells. and this receptor physically appears to be connected to the DC4 molecule (Fig. 1 and Ref. 2). can be functionally related.

rL-6 is identical to B-cell stimulating factor 2 and is involved in plasma cell layer and B-cell hybridization. It has been shown to be a necessary factor for doma proliferation (2.7). IL-6 et al. It is a cofactor in cell activation. Perhaps the reason is that rL-6 is an IL-2 This is because it functions as a second knob for IL-2 production by inducing receptors for IL-2. (2).

Modification of immune response and tolerance induction Interference by IL-1 “second nognal” on T cell activation or antigen-specific tolerance It has been shown that it is clinically important to induce stress. Therefore, These characteristics subsequently occur when the T cell receptor is triggered by the treated antigen. while simultaneously preventing [L-1-induced activation of heteroreactive cells] , the selected clones were subsequently replicated both in vitro (II) and in vivo (12). prevents the body from responding to the same antigen.

IL-1α/β and IL-6 play a particularly important role in the activation of T lymphocytes and 8926 cells. The production of these mediators likely blocks immunological functions. The treatment is thought to suppress the entire cellular immune system. This is important to remember when receiving a transplant. It is particularly advantageous for the treatment of diseased sounds.

! Other functions of L-1, IL-6 and TNFα - clinically relevant TL-1α/β, IL-6 and TNFα1 exert many functions on many different cell types or multifaceted (2).

(= TNFβ), which seems to be an endogenous pyrogen, was first announced as a white blood cell pyrogen. It was revealed that this factor is the same as the hormone originating from the Shiramen method to prevent fever. It has become a crab (3). However, all of these cytokines do not induce fever. It is completely unknown whether they act in the same way in the brain.

acute rejection Fever (sat), usually associated with acute and chronic infectious and immunoinflammatory diseases and cancer. [L-1α/β and IL6 and low speciation TN Fα induces hepatocytes and serum amyloid A, C - Reactive proteins, fibrinogen, heptoglobin, complement components and blood clots Synthesize the somatic phase protein containing the factor. High levels of fibrinogen are especially When accompanied by anemia, the sedimentation rate of red blood cells I, that is, the clinical "inflammation" that is commonly used The above parameters will increase. IL-1α/β and TNFα are expressed in many cells, including hepatocytes. Because TL-6 is a strong inducer of IL-6 in cell types, IL-1α/ β and TN are the second mediators of the acute phase response induced by Fα. sell.

Cachexia, Dispersed Intravascular Consolidation (DTC) and Noyock Clinical Conditions Above It is often associated with carbohydrate, lipid and protein metabolism, and the last The person becomes sluggish (cachexia). Although rare, coagulopathy and shock occur There are things (6).

Products of microorganisms, especially endotoxins (ribopolypods) derived from the cell walls of Gram-negative bacteria (LP) S), these often life-threatening diseases when induced by bacterial infection It was thought by Kou that he would be directly involved in the incident. The second thing is right now I know it's not there. The reason is that LPS is MφIL-1α/β, [L -6 and Tt'JFα, and is a strong inducer of LPS-induced shock. All accompanying pathophysiological processes are associated with TNFα and, to a lesser extent, TL-1. This is because it can be reproduced by injection of α/β (2.6).

IL-1α also probably plays a role in metabolic syndrome, DIC, and cachexia. It is also involved in the pond phenomenon associated with S-induced diseases (2.6). these Some of the phenomena: It seems that IL-1α/β is caused by some (unknown) hormones in the pond. It appears to be mediated by TNFα-induced production of mon. r2 For example, TNFα: is a strong inducer of rL-1α/β in endothelial cells and is a potent inducer of rL-1α/β in endothelial cells; cytokines all induce the release of procoagulant factor from these cells. emanate. Therefore, the amount of both mediators varies regardless of whether there is a coagulopathy or not. It seems that there is a connection with the etiology of this pulse W disease.

1i Ulcerative disease also Unregulated production of IL-6 is associated with cardiac mucosal flM, as well as multiple t ! malignancies of various lymphocytes, such as II tumors and various T-cell and B-cell lymphomas. has been etiologically related to the symptoms of several human diseases, including the disease (6). bone marrow I cells essentially produce IL-6, express IL-6 receptors, and exhibit bone growth in vitro. The growth of myelin cells is likely to be inhibited by antibodies specific for human L-6. This is interesting (I3).

A tendency to dry up other proliferative diseases Additionally, IL-6 and possibly TNFα have been implicated in other proliferative disorders.

The development of this invention utilizes antibodies specific to human rTNFα and human rfL-6. Akira et al. recently demonstrated TNFα and IL-6 in skin biopsies (5 ．． 5A). The expression of both mediators was significantly increased by UV irradiation; High amounts of [L-6 and TNFα were found in psoriasis lesions.

Interestingly, topical treatment of psoriasis lesions with vitamin D3 analogues resulted in clinical The condition improved, and biopsies performed after treatment showed changes in the expression of TNFα. However, IL-6 expression in the upper epidermal layers was almost completely abolished. that Therefore, [L-6 is involved in the uncontrolled proliferation of keratinocytes seen in psoriasis]. There is a possibility that

rheumatic diseases TL-1α/β, IL-6 and TNF (!F are diseases that lead to rheumatic diseases) It has many biological effects of scientific importance (2.8). IL-1α and IL- The most relevant effect of β is probably its stimulatory effect on the following cell types: sand T cells and B cells (inflammatory lymphocytes and non-specific production of immunoglobulins) life), Mφ (e.g. expression of MHC class ■ antigens and production of eicosanoids), soft Osteocytes (production of collagen type ■), fibroblast 'i8-type (collagen) type and type ■ and eicosanoid production) and osteoclasts (+ resorption). Ru. If, -6! Will it cause bone resorption?TNFx and rL-6i 1, which together with IL-1 share many of these effects (Pedersen JG and Eendtzen K, unpublished work).

Some cells of Cytokinidae R: Yo, Mφ, Bl) Lymphocytes, myoblasts, and (2.8)0 rheumatoid arthritis present in arthritic joints, including vascular endothelial cells and vascular endothelial cells. Joint i? +L-1α/β has been demonstrated during the night. This suggests that [T-1 plays a particularly important role in the pathogenesis of arthritis and possibly osteoarthritis. (2.14). Immunocompetent cells, Mφ, NK cells or IL-1α /β, IL-6 and other inflammatory molecules such as prostagranones and leukotoxic molecules. It may cause continuous relapse. This is the arrogant fic like RA. It will be involved in sexuality.

[The arthritic activity of L-1β was determined from the highest in vivo rabbit arthritis model using a rabbit arthritis model. It is clearly seen (+5) that human r[LIβ was injected into the knee 24 hours later. This induces an increase in Mφ and neutrophils, which includes a decrease in proteoglycans from articular cartilage. This is accompanied by an increase in the glycosaminoglycan content of synovial fluid. cartilage by IL-1β The same symptoms of damage: Yo, by systemic administration of cytolodiene mustard, Found in the joints of rabbits previously depleted of polymorphonuclear leukocytes and Mφ. This means that IL '-1β itself can stimulate the unique cells of the joints, such as cartilage cells, and Suggested to remove rotoglycans. Furthermore, due to IL-1β Several effects suggest that pond thylocites, especially L-6 and IL-1α, -1β-induced production.

The fact that urate crystals are ~■φ[a strong activator of L-1 producers (16) is noteworthy. Therefore, [L-1 contributes to the symptoms of gout.

Intuulin-dependent urinary disease vera ([DD:’,・■) and thyroiditis recently, human I The predominant species of L-1, IL-1β is probably directly directed to pancreatic islet β-cells and Strong suppressor of intuulin production in vitro due to its selective cytotoxic action It turns out that it is r2 (17). Ma1ko [L-1α also produces inotyulin. However, the intensity is 10 @ less than that of IL-1β. [L-1β has two sets of actions. It is gender. This is because if the value of r+L-1β) is low (IO~200 p g/m1=3*l　0-13~l　O'''M), -tM has the production of inotyurin. On the other hand, high levels of rlL-1β probably lead to an increase in β cells. By direct and selective damaging effects on both extracellular and intracellular intuulin. The content of the latter decreases.

TNFα itself cannot affect β-cell function, but the suppressive effect of IL-1β is T' It is significantly increased by J Fα (3.8), and other thylocites are They themselves have no effect on TL-1β and β cells.

IL-6 increases the release of intuulin from islets of normal rats and TL-1 It is interesting that α and IL-1β induce IL-6 in the islets themselves. (17A). By increasing the production of IL-6 or inotyurin, this II Cain: i, β cell induces II structural changes similar to those caused by IL-1. wake up (17A). Therefore, local IL-1-induced IL-6 production is the biphasic intulin response observed with IL-1 of each species. Underly (17). Furthermore, i L-6) L-1 and B, and finally [ It is involved in the immunoinflammatory process leading to DDM.

Actions similar to those described above occur in the paraadenom glands. 　　　a　n　d　) During the surgery, human thyroid gland tissue was removed from normal thyroid tissue. obtained when testing IL-1β on cells (1.7A, 1.8L silo). Secretion of globulin, cA, and MP: t.

r[L-1β at is low (i, 5βg/m1.=10-”~[), 1)L <Suppressed. The second effect is further increased by T　N　Fα and by I〉ζFγ be done. Rhyroc-yte has no role in I-1β. However, in response to hormones that stimulate the thyroid gland, cells form and accumulate glycogen. performance is suppressed (18). As expected, the effect of stimulating thyroglobulin production is , [If the aI of L-1β is very low (1.5-1.50 fg/rnl = 10- 18-10-”M), and 1L-1β is always observed in thylocites. 6 (17A).

The above findings and considerations suggest that Mφ and perhaps the central role of <N+< cells, and some Their products in physiological and deaf physiological conditions [L~1α/β, T NFα and IL −(: Indicates the role of i (3.8). If cells are exposed to these cytokines for a long period of time, for example, for unknown reasons, Tamerin cells or as in the early stage of IDDM all 0M, produce thylocites. When surrounded by Mφ, NK cells and T lymphocytes and 8 lymphocytes, cells (For example, cells in IDDM) structure B (-< may damage the function. In such cases, IL Involved by incompatible producers of cytokine order such as -1α/〆rito r　L-6 do. Roughly low levels of [L-1α/β and (L-6), during conditions of stress, blood These cytokines diffuse from the fluid (diffuse, accumulate in the tissue, and therefore Under the environment, insulin and thyroid hormone secretion and possibly pituitary hormones and adrenal glands It has an important physiological function by increasing the secretion of cortical hormones ( Figure 1).

As mentioned above, the negative relationship between HLA-DR2 and TNFα production is due to tD DM! = Some like RA [(involved in LA-related diseases (3.8) . In IDDM and RA, HLA-DR2 is associated with disease resistance This suggests that TNFα is involved in the destruction of islet β cells in EDDM and in RA and deformation. It is directly or indirectly involved in the destruction of cartilage and bone in osteoarthritis. If so, it will be explained.

Therapeutic considerations Many predicted pathophysiological functions of IL-1α/β, IL-6 and TNFα Considering the above, the production-like effects of these hormones are likely to be mediated by a number of factors. Very beneficial against infectious and immunoinflammatory diseases, and possibly certain heel ulcer diseases Will. Ni et al. mediator production is induced by high doses of glucocorticoids. glucocorticoids directly suppress gene transcription; When the genes of This is the case for NFα (6.8).

The effects of [L-1α/β on T cells in vitro are Crosporin A) (+9), vitamin D.

(1,23(OH)tDff) and synthetic vitamins +:+sli body (20) This is prevented by Cyclosporine and vitamin D also [L-1α/β pond Although it is not completely clear whether some activities are prevented, pancreatic beta cell function These metabolic effects on cyclosporine (21) and vitamin D3 (B Unpublished paper by u s c h-ard K and Bendtzen K) Therefore, it is slightly inhibited.

Cyclosporine has many serious side effects, especially if treatment is prolonged. (34), alternative means of treating transplant rejection and immunoinflammatory diseases are highly recommended. is requested.

Sodium fluoronate (fluorofluoride) function of interleukin 1 and interleukin 6 inhibition by non).

As mentioned earlier, fusidic acid is a tetracyclic tricyclic compound with a steroid-like structure. It is a terpene acid. This medicine is available in acid form and sodium salt and jetanolamine Both salts, especially Staphylococcus arales (Staphylococcus It has been used clinically as an antibiotic active against (22) ) Does a-fluoronic acid have an inhibitory effect on T lymphocytes in a mouse model? It is shown that it is rare (23A). Fundic acid transfers RNA to lipolytic acid. Prokaryotic and eukaryotic cells by inhibiting binding to the 50S portion of the some. inhibits protein synthesis both in vitro and in vivo (23). Funno Even with long-term treatment, there are few or only minimal side effects.

According to this invention, 7-nononic acid acts as an immunosuppressant, and The mode of action of cyclosporin is very similar to that of cyclosporin (as explained below). (see Akira). Therefore, the possibility of treatment with phunone should be studied in all cases where treatment with cyclosporine is advocated.

As mentioned above, some of the main mediators of the human body's response to environmental factors are: Polypeptides produced by many cell types but most abundantly produced by Mφ It is a family of hormones (cytokines). The most distinctive feature of this family The characteristic members were recently announced as L-1α, rL-1β, and TNFα. IL-6(1,2). These cytokines are involved in inflammation, immunological responses and It participates in many types of acute and chronic reactions, including body and tissue damage. one In general, IL-1α/β activates cells (e.g., m-blasts, keratinocytes). cells and nerve cells) and/or increase their activity (e.g. Synthesis of prostaglandin E in fibroblasts, bone resorption by osteoclasts, and T already induced by a polyclonal activator, likely a specific antigen. activation of lymphocytes and B lymphocytes). However, in a small number of cases, IL-1 It seems to inhibit the ability of For example, fL-1 is associated with pancreatic islet β cells and thylocites, and is a potent inhibitor of melanoma cells (2.3.8.17.24). Also IL -1 is associated with fever, slow wave sleep, and traces of metals, albumin and fibrinogen. and changes in blood levels of acute phase reactants such as serum amyloid A. induce systemic changes (2.8.25). Therefore, IL-1α/β (and various Many, if not all, organisms respond to exogenous and perhaps endogenous stimuli. It is considered to be very important in response to changes.

Recently, IL-1α/β has been shown to share many activities with the Ike cytokine tL-6. I have come to understand that I am in charge of this (3.7).

Nevertheless, [L-6 and +L-1α/β show no sequence homology; These cytokines act on different receptors.

IL-6 is associated with B-cell stimulating factor 2 (7) and plasmacytoma and B-cell hybridization. It has been announced that this is the same factor (26-28) required for doma proliferation.

[Unregulated production of L-1α/β and IL-6 may occur in some cases, such as during prophase. Molecules that are involved as pathogens in the manifestation of human decline: Rheumatism, some of them many biological processes of pathological importance, leading to endocrine disorders and various skin diseases. (See Table 1).

Therefore, drugs that interfere with the functions of TL-1α/β and [L-6] are responsible for many human diseases. Very important for treatment.

As described in the examples, sodium hunonate (Fuzin) is a therapeutic, non-toxic concentration. When administered at high doses, it inhibits the function of various [L-[α/β] in vitro, and as a result, these was observed to prevent the lymphocyte co-stimulatory activity of human cytokines. Ru. Additionally, this drug may interfere with the hybridoma growth promoting activity of tL-6. was also found. Furthermore, this drug has an effect on the insulin producing body of pancreatic β cells. Prevents the "non-immunological" functions of cytokines, including the toxic effects of L-1α/β. Ta.

The above functional pattern of activity plays a role in the prevention of transplant rejection and in a number of inflammatory disorders. The activity is strikingly similar to that of cyclosporine, a drug widely used to treat ing. Therefore, KL-1α/β and probably <KL-6 are transmitted. Immune activation signals are activated by treatment with fusilic acid before and during transplantation. interference, the program will respond to the implant in the absence of this treatment. It is thought that specific and long-lasting paralysis of host lymphocytes, which have been previously treated, is induced. child By such treatment, all clones of lymphocytes in the receptor are removed long-term immunosuppressive treatment is no longer necessary.

Not possible. Therefore, treatment with fluoric acid and its derivatives according to the present invention; , life-threatening conditions dominated by DIC and the finer vessels of the pond. It is thought to be beneficial for both diseases (eg arteriosclerosis). IL-6 Aberrantly regulated R2 production and/or function, resulting in at least some lymphocytosis. This is important as a cause of reproductive harm. Therefore, interfering with cytokine function As for fluoronic acid, pharmaceuticals such as its derivatives are considered to be useful in clinical soil. Ru. In addition, the functions of 1L-1α/β and IL-6 are similar to those of Funjin. Interference with acid derivatives, therapeutic treatment for some inflammatory joint diseases and degenerative joint diseases! Essential It can be considered that

Uses of fluoronic acid of this invention According to this invention, fusidic acid and its derivatives can be used to treat pathogens under the above-mentioned siological conditions. 1. To prevent the effects of Cain order It has been found to be useful.

In this invention, the use of "fluorinic acid-like derivatives": The structure is the same as or more similar to fundic acid, and it has a similar structure to that of fundic acid, including derivatives of fundic acid. means a pharmaceutically active and acceptable compound that exhibits the appropriate biological effects of Taste, especially fluoronic acid, is a pharmaceutically acceptable salt of fucinonic acid. , meaning esters, solvates and conjugates.

Suitable salts are those with pharmaceutically acceptable bases, e.g. with alkaline earth metals. Ammonium salts include amine salts (especially noethanolamine salts).

Free esters are esters that can be easily hydrolyzed (e.g. Acid acetoxymethyl ester.

Suitable solvates include: hydrates, especially hemihydrates.

Suitable conjugates include those with glycine, especially taurine.

"Derivatives of fluoronic acid" in item 1 include, for example, the following compounds.

3-dehydrotunosic acid 1 3,11-nobuhydrofungic acid.

24, 25 Ichinohi and lofnononic acid, 17,20-24.25-Tetrahydrofluoronic acid, 17,20-24.23- Tetrahy}; Lofunononic acid and its corresponding 3-acetates (Special) N otsushiku; yo tau (conjugate with ノ/).

3-0-acetyl-l6-vidacetylfluoronic acid, this invention has a function Use of physiologically acceptable derivatives, including derivatives6. These derivatives,′ The patents and documents listed in the "Background of the Invention" section of this application, including the manufacturing method, etc. No. 4,004,004, for example. There's a body. Some of these derivatives are unsatisfactory as antibacterial agents. or its characteristics are advantageous for use according to the invention.

Of particular importance to this invention is the compound represented by the following general formula.

In the two formulas, eivt, c([3)-C(17) and C(1.7)-C(20) Under the condition that one of the bonds is a double bond, there is a double bond between the related atoms instead of a single bond. Indicates that there is a match.

A: Yo OH. OR’ and NHR. ” (where R is C. -C. Alkyl, phenyl C. -C. -Aralkyl group such as alkyl , and feninre also: earth. −, m−ζichishi<: earth p trill-like ary and R' is 10 HtC O O H or Or one CHI, CH.

SOzH): R: MaOH mako is keto oxygen (=O) (however, if R is OH, C(1.1)-R The bond is preferably: C(1.9) in the alpha configuration to the methyl group); R1 is hydrogen, halogen is a nitrile group, or R1 is 10R', -N}{R 3 and 1 from SR3 (where R, ': hydrogen, or anhydride). C. -C. -alkylcarbonyl, alkyl especially C. -C. alkyl, fu phenyl-C, -C.

Aralkyl group like alkyl, or phenyl like 0- like m- etc. or an aryl group such as p-1-lyl).

R7′MaOl{,C. -C. -Alkylsulfonyloxy is ke}・oxygen ( =O) (However, when R2 is OH, C(3)-R2 bond; preferably: yoC( 19) α-configuration relative to the methyl group), and R2 is hydrogen or halogen It seems to be a nitrile group, and the f2 consists of one OR3, -NHR' and -SR' selected from the group where R3 is hydrogen or anru, especially C, -C, -alkyl radical Rubonyl, alkyl especially C,-C,-alkyl, phenylC,-C.

-Aralkyl group like alkyl, seems to be [yo-phenyl-like: yo0-like] m-like is an organic group such as an aryl group such as p-tolyl] These are the compounds represented by and their salts.

Examples of C,-C,-alkyl are methyl, ethyl, propyl, isopropyl, butyl , isobutyl, 5ek-butyl and Cer-rlnibutyl. C above, -C,-alkyl groups and other groups, as appropriate, are referred to in the "Background of the Invention" section above. Any substitutions may be made as disclosed in the referenced patents and other documents.

Preferred compounds among the compounds of general formula There are double bonds at the C(20) and C(24)-C(25) positions, and C(9 ) is in the β configuration with respect to the C(19) methyl group, and R: yo C(+9) methyl group. R1 is a human quino group in α configuration with respect to the thyl group, and R1 is tC, - like an acetoquino group. C,-alkylcarbonyloxy group, 1st C,-C,-alkylcarbonyl group Arylcarbonylthio groups such as phenylcarnanylthio, phenylcarnanylthio, and seems to be methquino: it is a C, -C, -alcoquino group, like a yoethochino group, and and R1 is a nitrile group, a C,-C,-alkylsulfonyloxy group, and especially In particular, compounds with a hydroxyl group in the α-configuration relative to the C(19) methyl group are tunic acid and fluorinated salts such as the sodium salt (fluorone).

A specific example of an interesting derivative is VD1177.1178.1303 shown in Table 2 below. ．． 1360. +362.1460.1546, and an invitation called PR1089. It is a conductor.

＾　3 △4dv, Jppl, Microbio1ogy25.9+-146 (197 9X46) * s = 24.25 - single bond, d = 24.25 double bond ** Proposed The structure shown is 24.25 - single bond in this application: the following definitions are used.

“Cytopower Ino”: soil, specific stimulants such as specific antigens, alloantigens; or non-specific polyclonal activators such as gram-negative endotoxins or is primarily carried out by cell populations of the immune system in response to external cell wall components. Common uses for proteinaceous mediators that are released in a non-intrusive manner It is a word.

``Lymph talent'' refers to stimulants such as specific antigens and alloantigens. released by sensitized lymphocytes in response, or polyclonal Activating substances such as endotoxins of Gram-negative bacteria or: attacked by foreign cell wall components. Common uses for proteinaceous mediators released by lymphocytes This is Kogo.

“Interleukins” are stimulants such as specific antigens and alloantigens. As a response, macrophages, T cells, β cells, and NK cells also respond. is a polyclonal activator, such as endotoxin of Gram-negative bacteria. Released primarily but not exclusively by cells attacked by wall components A general term for proteinaceous mediators.

A “monokine” is a mononuclear phagocyte that acts in response to any stimulant. Monocytes are like macrophages, and Kutubah cells (liver) are like Langen. against proteinaceous mediators released by the skin) This is a term that

“Interferon” refers to an protein such as a virus or polynucleotide. A specific stimulant example by all cells in response to turferonoinducers For example, specific antigens may be alloantigens or nonspecific polyclonal activators, e.g. For example, gram-negative endotoxins appear to have a persistent immune response as a response to cell wall components. tanobacterial antivirals and/or monocytes/macroviruses released by cells of the system. A common term for lophage activators.

“Colony stimulating factor” is a specific stimulant, e.g. f-specific antigen, alloantigen Original: non-specific polyclonal activator, e.g. endotoxin of Gram-negative bacteria It is likely that the immune system is primarily responsible for the 'a-cloning group of the immune system in response to external cell wall components. A proteinaceous hematopoietic colony stimulating drug released as but not exclusively This is a general term for a mediator.

One of this invention? Mr. Lymphin, interleukin, monokine, and Interferons are associated with disorders of cytokine systems such as the colony-stimulating factor system. In order to prevent or treat the symptoms of Nocaine, like interferon, is a cytokine like colony-stimulating factor. Access to the production of pharmaceutical compositions that substantially inhibit the biological effects of Non-acid-like is the use of its functional derivatives. As used in this application, the term "pharmaceutical composition" The term refers to compositions suitable for human use.

This invention aims at the use of functional derivatives of funoic acid for the following purposes. Concerning business.

− Cytokine-related substantially inhibits biological effects in humans; and/or It seems to be a preventive measure for symptoms related to disorders of the 10-kine system. Substantially inhibits the biological effects on humans related to talin. and/ma People -Interleukin system therapy is used to prevent and treat symptoms related to interleukin disorders. - Substantially inhibits the biological effects of leukin on humans. and/ Mak is used for the prevention and treatment of symptoms related to monokine disorders. substantially inhibits the biological effects in humans associated with - Interferon therapy is used to prevent and treat symptoms related to interferon system disorders. - substantially inhibits the biological effects of feron in humans. and/ma or for the prevention of symptoms related to the colony-stimulating factor system [IF]. , which substantially inhibits the biological effects of colony-stimulating factors on humans.

This is the purpose of use.

As used herein, the term "substantially inhibits" the harmful effects of said mediator. means the therapeutically appropriate prevention of biological effects; ;Another derivative, a kind of legal effect on the effect of the mediator in question Based on the combination with other treatments/medications that give

Symptoms listed above or previously listed require treatment involvement. ``diseases that occur in humans'', This includes symptoms in which it is desirable to suppress the brain system. As mentioned in detail earlier, the relationship between shoes Clinically important interleukins: especially interleukin 1 (α or is β) and interleukin-6.

Most broadly, a further second invention provides substantially selective immunosuppressive agents and /Mafco may be affected by its action or by antagonism to the action of one or more Cykines. The invention relates to the use of its derivatives as medicaments that act as fluorophores.

Wherever systemic therapy is used, administration may be oral, direct, vol. It may be parenteral and its administration depends on the age and weight of the person, the specific condition being treated and It depends on the severity of the disease.

The active ingredients and their combinations are included in the composition in appropriate amounts and generally in the formulation. It is contained in an amount of 1 to 95% based on the total weight of. Composition (soil suitable standalone agent It can also be a shape.

Parenteral administration) For example, static injection, intramuscular injection, intraocular injection: injection after the main bulb. Appropriate injections, infusions, or administration devices such as injections, injections, or administration devices may be included.

Preparations for parenteral use may be prepared in unit dosage form, e.g. in ampoules, for proper storage. Add the drug and use it in two multi-dosing containers 1). Compositions include solutions, suspensions, and emulsions. Liquid! , < may be in the form of an implantable administration device, or may be used in other ways. In addition to the active pharmaceutical substance, it may be provided as a dry powder for reconstituting in a suitable solvent. , a composition of this invention: a suitable pharmaceutically acceptable carrier and/or a suitable pharmaceutically acceptable carrier; 3. It is good because it contains a sample agent. Saran, two compositions of this invention: It is convenient to contain a fixing agent, a PH reduction agent and/or a dispersing agent.

Compositions for oral or rectal use are formulated according to normal pharmaceutical practice and include Capsules, emulsions, powders, ampoules, granules, sugar-coated tablets, pastes, gels, suppositories, etc. 1. ＜は浣llJ! The effect of the first agent, and the second one is the 9 clouding agent (water is 1!41. for oil-based products) It may be a liquid preparation such as a solution, an elixir, or an emulsion. stomach.

Regarding auxiliary additives for pharmaceutical compositions, the following general pharmaceutical additives and carriers are used. Ru.

Cellulose derivatives (like starch, gelatin and polyvinylpyrrolidone) Binder, sugar, ma/di-ole, lactose, microcrystalline cellulose, balayodes 2. Excipients such as calcium phosphate, 2. Suitable absorption enhancers, 2. Valenoiodene. 3. Disintegrants like alginic acid, magnesium stearate, stearic acid, i'1iit agents like talc, 1nontin, sorbitano monooleate 1 tllll + 1 tsunotin, a humectant such as tensuoxyethylene ester forehead, Buffers: Buffers such as acetates, citrates, and phosphates.

In solid compositions, the active substance can be released, in particular by suitable t-coding methods. Before the composition is desired1. ＜The materials left behind to protect against chemical changes. 1. But that's fine. This coding can be used for example in controlled release formulations. In order to obtain the desired results, the active compound is released at a predetermined concentration. Good to have.

Dosage of fluoronic acid and its derivatives: method of administration, medical books, diseases, 7) Severe acne , IIg depends on everyone's weight and age. , for compositions suitable for oral administration, Dose: 3.3 mg to 1 g administered 2 to 6 times a day; For example, 0.5g x 5 times a day or 2 times every 2 days in some cases; or once every 3 days. 1g each.

Therefore, oral administration is approximately 1 mg to 75 mg per kilogram of body weight per day. It is likely to be between 1 and 20 mg (in appropriate cases). Preferred (, good dosage) The dosage is usually 0.5 g three times daily. In certain cases, e.g. When treating diseases, the dosage is usually 2@. Therefore, fluorosic acid When the derivative is administered rectally, about 1 mg to about 10 mg/kg body weight per day. Somewhat higher amounts, such as 0 mg, are generally preferred.

For parenteral administration, the dosage is approximately 0.1 mg per molar + kg body weight. Approximately 50m g7: Yes, most preferably approximately 1mg per 1kg body weight per day ~about 20 mg. When administering Fudgenoic acid intra-articularly, 1 body weight per day Amounts of about 0.1 mg to 20 mg per kg are usually preferred. For parenteral administration For example, if the active ingredient is, for example, 05 to 2%, water at 71 degrees and night exceeding two phases. is used.

When administering fluoronic acid and its derivatives to the eye: 1 kg body weight per day. Amounts from about 0.1 mg to about 50 mg per serving are usually preferred.

In either case, the dosage is such that it exhibits a specific effect on the cytokine system, i.e. should be carefully modified to achieve the optimal total dose, dosage form, and frequency of administration. If ζL1°, relatively high unit doses, i.e. Is it appropriate to administer an additional dose?

Topical pharmaceutical compositions, such as compositions suitable for application to the skin, according to the invention Appropriate products include creams, gels, ointments, lotions, and liniments. , suspensions, solutions, pastes, sticks, sprays, soaps, shampoos, powders , suppositories and intestinal shavings. Local administration is likely to cause pathological changes in the human body. If it's not close, it won't be ζ. This composition: suitable openings of the human body, such as rectum, urine A pot that is applied directly to the canal or vaginal opening should be properly configured to introduce the drug. It suffices if it is added as a second refining agent. This composition can be applied to relapsed areas such as skin. Simply apply directly to the mucous membranes. Examples of suitable formulations for eye application include e.g. The composition is suitable for administration as an ophthalmic rotary solution, ophthalmic ointment, eye drops, or eye drops. It is an X1 administration system that is suitable for dose control for wide eyes. In some cases, occlusive dressings Nong-like is an alternative plaster, bud, subonono, strip or pond form. It may also be applied with certain medical devices such as suitable flexible pieces of material.

The drug layer for topical administration is the base of ointments, such as ibarafin and polyethylene glyco. oils, Tween, Span, vegetable oil], suspending agents emulsifiers (e.g. lenotin, sorbitan monooleate, gelatin, methyl cellulose, gum arabic, solhitane monooleate derivative), gel forming agent ( e.g. carbobol, alginate, gelatin), preservatives (e.g. methyl etc.) (propyl p-hydroxyamino acid, fragrant acid, benzalkonium chloride), antioxidants (e.g. tocopherol, ascorbic acid, butylated hydroquinoanisole), Al11 (e.g. glycerin, propylene glycol, urea) and fragrances and Contains pharmaceutically acceptable carriers and/or excipients such as skin protectants. It's okay.

Formulations for topical administration to the eye may contain a pharmaceutically inert vehicle or a suitable suitable in the form of a carrier system. Pharmaceutically acceptable carriers used in the manufacture of eye drops The body and/or body may be used as an excipient, such as boric acid or a mild borate. pHyJI Section 4 for optimal stability and solubility of active pharmaceutical substances agents, tonicity-regulating agents such as sodium chloride or borates, hydroquinone Propylcellulose, methylcellulose, polyvinylpyrrolidone, polyvinyl cellulose Alcohols [viscosity modifiers such as earth polyacrylamide; peanut oil, castor] There are oil-based vehicles such as vehicles consisting of mineral oil and mineral oil. Like an emulsion Eye drops applied as a suspension: stabilizers, dispersants, iii! lubricant, emulsifier The agent and/or may contain @ or @ agent. Eye creams and eye softeners Ointments [like eye drop compositions, suitable topical compositions such as ointments, creams] Pharmaceutically acceptable carriers and/or carriers such as those used in formulations, formulations, etc. It may contain excipients.

Examples of common methods for manufacturing aqueous ophthalmic preparations containing active pharmaceutical substances include: . That is, a compound (preferably a soluble sodium salt) is added to sterile water at a predetermined concentration. An appropriate buffer solution is hydrochloric acid, but sodium hydroxide is used to adjust the pH. Arbitrarily adjust it to the desired value, and preserve it like chlorobutanol. optionally a viscosity-adjusting excipient such as methylcellulose; The final solution can be washed, e.g. Manufactured by sterilization by toclaving or filtration.

The topical composition used in this invention may contain, for example, 0001 to 60% w/w of the active ingredient. , preferably 0.1-20%, especially 0.5-10%, preferably 1-5%.

According to the invention, the composition is applied several times per day, e.g. It was applied 5 times, and this is the target symptom, number 11! In addition, the absorption conditions of the target area It depends.

In each case, the specific dosage should be determined by the amount and form of humonic acid that is most likely to induce The conductor is determined so that it is properly absorbed.

In each case, the above amounts and forms should be determined to have a specific effect on the cytokine system. must be adapted to. Therefore, if application to the skin is carried out, for example, It is very important that one insures that a relatively well-defined layer of the composition is applied.

In particular, this invention can prevent diabetes mellitus, especially intulin-dependent diabetes (type 1). or treatment, especially by first diagnosing and confirming diabetes mellitus (type 1), especially in most cases. How to immediately prevent the progression of the disease, and whether the child is at high risk of developing true 11i urine disease. Fluoronic acid seems to be an inducer to confirm that it is in the 0 group and to prevent it after F2. Concerning uses of conductors.

These uses and methods of this invention may be useful to doctors and/or patients. Instructions for use provided with the composition may include, as described herein, It is preferable to be specific and detailed.

Animal studies over the past few years have shown that cyclosporin [fungal ・Cyl 1ndrocarp-on lucidum and Trichoda Ring of T-richoderma polysporum peptide metabolites] specifically prevent diabetes in naturally occurring urinary BB rats. Performance is shown. Cyclos performed on diabetes and against the progression of diabetes Clinical research, including the study of the effects of cyclosporine, has shown that treatment with cyclosporine It has been shown that bedside remission has been obtained. This is due to improvement of functional β-cell mass. It is thought that Symptoms appeared and it was 6i! ! Hospitalized within 2 weeks and treated with intulin for 2 weeks The remission rate was greater in diabetics who underwent treatment than in those who were hospitalized later.

This finding suggests that cyclosporin therapy can be administered within a critical short time after clear onset of illness. Altering the acute process that drives beta cells by initiating immunosuppressive therapy If treatment continues, partial or complete remission can occur for at least one year. It has been proven that it is possible to maintain

As used in the specification and claims of this application, the term ``immediately'' refers to the term ``immediately''. There is a high risk of getting sick over a limited number of months or years. The period after diagnosis and initial confirmation of the disease, during which irreversible changes in the body's tissues occur. means a period that must be as short as possible in order to be able to interfere with the progress of The above-mentioned invention provides for the use of fusic acid and its derivatives. It was obtained by.

Administration of cyclosporine increases the remission rate of newly developed true M. and promotes β-cell function throughout the first year after diagnosis. It is speculated that this effect was induced by the immunosuppressive effects of cyclospodinone. follow Knowledge of levers (well, immune processes are involved in β! This strongly supports the hypothesis that there is.

Effect on early outcome of Wt stupor: Chronic immune hyperthermia that arouses β-cells. Therefore, long-term diagnosis is prioritized, but if an obvious disease occurs, it may be associated with it. The symptoms will be accelerated.

example'! From the above experiments, the possibility of recovery of In/Urino secretion: It was very painful, but by administering fluoronic acid and its derivatives, In many cases, the partial pressure and capacity will increase over a year, and the above immune suppression will bring it back to the appropriate range. I think you should wait.

Well, I don't want to use derivatives of futunoic acid as part of this invention. irreversible pathological damage to the pancreatic tissue leading to diabetes mellitus (diabetes mellitus). The treatment of this invention should be started as soon as possible to prevent (preferably i, shi), i.e., within a short period of time after the disease has developed, and also: Immediately after diagnosis of pathological overgrowth of pancreatic islets (e.g., clinical It is preferable to do this before any symptoms appear. Also, the treatment method of this invention: Applicable to 11 high-risk groups that have been confirmed. In other words, part 1! [Recognition For example, for pathological changes seen in diabetes mellitus and/or its preliminary stages (, relatively specific markers, particularly in individuals susceptible to disease (e.g., fHLA-D Screening using markers of ongoing pathological changes in 3/4 individuals with R odor be humiliated by the training program. The risk for a person is approximately lO~100%. For example, if about 50-100% of the time, the person is at risk of developing monourea vera (Ding type). It is considered to be in an extremely high group.

In particular, the second invention is for the prevention (or treatment) of diabetes mellitus (type 5). et al.1. < is l! Fluoronic acid used in the intestine is related to the use of its derivatives.

From Ike no I1tun, this invention: prevention and treatment of symptoms related to thyroid function. This invention relates to uses of fluorinated acid or its derivatives. This symptom usually occurs in the thyroid gland. Gland I+! Surplus Il! Since it is related to low function, for example, thyroiditis (acute, It seems to be subacute, but it is chronic. thyroiditis, Limbeian thyroiditis), Riedel's thyroiditis (invasive pharyngitis), de Kercha thyroiditis (subgrade 5 granulation 1 thyroiditis), subacute lymphocytic thyroiditis, grape Grapes disease, Grapes sub1. Includes thyroiditis, and Grape's eye disorder.

Inflammatory diseases, such as symptoms related to thyroid function, intestinal inflammatory pallor, uric acid arthritis, Multiple faeces (bacus disease, multiple myeloma, tB cell and T cell lymphoma) Treatment with tsunoic acid and its derivatives, 7-nonacid and its derivatives. Can treatment with derivatives of problem ○ prevent the recurrence of symptoms? However, during an illness that is not obvious, it is difficult to hear midtones. that Therefore, the term "treatment" seems to be used to prevent the recurrence of diseases and insects; means preventive treatment for the purpose of

From the point of view of Ike, this invention: i. Symptoms related to excessive function of the Kl kidney, especially Asonopathies. Apparently, it is also used for the prevention and treatment of non-mono-general hypopituitarism. Regarding the use of its derivatives, From the point of view of ponds, 2'01') Invention: i Fluorone for use in the treatment of endogenous uveitis Regarding acids, it relates to the uses of their derivatives. The term “endogenous uveitis”: Example: Non-infectious anterior uveitis and posterior uveitis. U@kko S which means inflammation) Invention Konoyo 2 composition, intraocular injection composition for retrobulbar elbow, diameter l:1 The present invention relates to the production of compositions essential for the treatment of the eye, such as M compositions.

Furthermore, from Ike's point i, this invention (i, 50 cataract surgeries seem to be 1) ~ The surgery 77 monoacid or its derivatives used to prevent inflammation after eye surgery such as Leave it for one use. Second treatment: Similar to the treatment for the symptoms of the pond, some In the example, ('i, the purpose of treatment h (to reduce inflammation)) In fact, it is a preventive method rather than a treatment of inflammation. Inventions: especially eye drop compositions, eye ointment compositions, eye lotion compositions, intraocular Preferably, an injection composition for retrobulbar elbow or an oral composition is suitable for the treatment of ffl. The present invention relates to a composition that is essential for medical treatment.

In another aspect, this invention (such as juvenile rheumatoid arthritis, dry W4 arthritis, etc.) Or, the progression of rheumatoid arthritis, including Rieter's arthritis, can be diagnosed as Seki'Ritis. It should be used for diagnosis almost immediately after first diagnosis. What is the use of the derivative? Regarding this. The treatment of this invention is coming (I'll start it soon) After onset of inflammatory disease, it occurs within a very short period of time. , preferably immediately after diagnosis of the pathological process (e.g. before clinical symptoms appear) It is preferable to do so. High-risk groups confirmed to be treated with this invention It can also be applied to i.e. confirming that arthritic changes and/or Relatively specific markers for the pre-O11 stage of arthritis, especially those that are susceptible to the disease. , especially specific i (individuals whose tissue type to L), 7) markers of ongoing pathological changes. The invention that was obtained through the cleaning program using For parenteral use: This invention relates to the production of a composition for intra-articular injection.

From another perspective, this invention: fluoronic acid and others used for the prevention and treatment of osteoarthritis. Or, be knowledgeable about the uses of its derivatives.

From the point of view of the pond, this invention is based on fluoronic acid used for the prevention and treatment of uric acid inflammation (gout). More specifically, it relates to the uses of its derivatives.

From a pond perspective, this invention relates to implant rejection, such as the implant-versus-host reaction. Symptoms, Matrix 1, LPI, bone marrow, cornea 2 (, < indicates other symptoms related to skin grafts) It seems to be used for the prevention of symptoms, and it is used for treatment. Fucinonic acid seems to be used for its derivatives. . This treatment often requires higher-than-normal doses of funnoic acid and In cases of transplant rejection, it is often performed as a preventive treatment to avoid transplant disease. stomach. In particular, the invention relates to compositions for oral or parenteral administration.

From another point of view, this invention can be used to prevent or treat symptoms associated with horn transplantation. Regarding the use of its derivatives, especially in compositions suitable for ocular treatment, e.g. For example, ophthalmic compositions, ophthalmic ointment compositions, ophthalmic lotion compositions, intraocular or ocular compositions, etc. An injectable composition for subsequent injection, and second relates to an oral composition. In addition, other From this point of view, the present invention is particularly useful for the treatment of Crohn's disease or ulcerative colitis. Crohn's disease seems to be 11 beak enteritis recurrence seems to be prevention of progression or worsening. Fluoronic acid, which is used to treat celiac disease for sexual anemia, is used for its derivatives. In particular, oral or colonic compositions may be used in the manufacture of parenteral compositions. Regarding the road.

From the point of view of the pond, this invention is effective in treating allergic/atopic skin as opposed to contact dermatitis. It seems to be a prevention of inflammation, but it seems to be a treatment for it. Regarding the uses of its derivatives, especially those for oral administration or those with contact properties, For use in the production of compositions for topical treatment of dermatitis, particularly for topical application to the skin. Ru.

From another aspect, the present invention provides treatment or prevention of demyelination, particularly multiple sclerosis; or hexosarcoidosus, Sjögren's syndrome, Reiter's syndrome, nodular Funri used to treat and prevent recurrence of erythema, scleroderma or Bechett's disease Regarding phosphoric acid, it concerns the use of its derivatives.

Furthermore, from Ike's point of view, this invention is effective in treating rheumatic polymuscular deficiency, myocarditis, and the like. Fluoronic acid is apparently used to treat and prevent recurrence of sexual lupus erythematosus. Uses of derivatives, especially for the production of compositions for oral or parenteral administration. related.

From the point of view of this invention: vasculitic phenomena, such as polyarteritis nodosa, Gunner's granulomatosis seems to be a treatment for symptoms related to giant cell arteritis, and prevention of recurrence. The fluoronic acid used for this purpose relates to the use of its derivatives.

From the point of view of Ike, this invention is useful for the treatment of active chronic hepatitis that appears to be primary biliary cirrhosis. First, it concerns the use of derivatives of fluorinated acid, which is used to prevent recurrence.

From the point of view of this invention, aplastic anemia seems to be an idiopathic thrombocytopenic plaque disease. treatment of neoplastic diseases such as or 11 neoplastic disorders of lymphoid tissue, e.g. Paratype or multiple myeloma, Mako is a proliferative disorder of T lymphocytes.Example: 2 Mushroom-shaped Fluorone acid is used to prevent recurrence of Cesar's disease, which seems to be a fungal disease. or uses of its derivatives. This invention is particularly useful for oral administration as well as for parenteral administration. The present invention relates to an eel composition.

From a pond perspective, this invention is useful for preventing septic poisoning caused by Gram-negative bacteria. It is concerned with the use of fluoronic acid and its derivatives for therapeutic purposes. Fucinon The acid is Staphylococcus aureus. It is traditionally used to treat infections caused by Durham-positive bacteria such as Prior to this invention, septic shock caused by fluoronic acid or gram-negative It was not known that it could be used for prevention or treatment. This invention The prevention or treatment of septic shock caused by gram-negative bacteria is urgently needed. Second, it can be used for oral or parenteral administration. related.

From another point of view, the present invention provides a method for preventing and treating disseminated vasotropic coagulation. Regarding non-acid, it relates to the use of its derivatives.

From the point of view of Ike, this invention is based on fluorosic acid, which is used to prevent arteriosclerosis. Concerning uses of conductors.

From the point of view of this invention: acute and chronic periodontal diseases, especially periodontitis and periodontitis. Fundic acid or its equivalent, which is used to prevent or treat periodontal injections, Concerning the use of derivatives of.

Furthermore, from other cereal studies, the present invention has developed a method for using humonic acid or Uses of its derivatives and other suitable applications such as cyclosporin and its derivatives. Concerning uses in combination with medicines.

In another aspect, the present invention provides cyclosporins (e.g. cyglosporin A and G). ), it should be used with its derivatives, and it should be used with its derivatives. do. Such combination therapy is effective against severe side effects and long-lasting effects of cyclosporin. It is designed to reduce the nephrotoxic effects of fluoronic acid and its derivatives. It utilizes the immunomodulatory effect of cyclosporin.

Appropriate dosage ranges include, for example:

Cyclosporin A (similar to other cyclosporins with the same potency).

Systemic administration: l-10mg/kg body weight - Topical administration: 1-20 mg/ml (ointment, solution, eye drops, etc.) (see) Also, this invention has revealed that fusic acid: other derivatives and cyclosporine (e.g. cyclosporin A and G) and their derivatives. provided.

From another point of view, the second invention provides non-steroidal anti-inflammatory drugs (NSAIDs) (e.g. 7) and acetylsalicylic acid) are similar and/or glucochemicals. Corticoids (e.g. hydrocortisone) and fluoronic acid or its Concerning uses of derivatives. Combination therapy like this can reduce serious side effects. At the same time, phuntunoic acid has the effect of its derivatives as well as the effects of drugs listed in n. Take advantage of action.

Suitable dosage ranges are, for example:

Acetylsalicylic acid (or NSA of the same potency) - Systemic administration: 5-100 mg/kg body weight.

-Local administration 10-100mg/ml (ointment, solution, eye drops, etc.) Reference IIQ).

Ike's glucocorticoid drug, which seems to have the same potency as hydrocortisone, Systemic administration: L-20mg/kg local administration/L-20mg/m I (See library information for ointments, solutions, eye drops, etc.)

From yet another point of view, the present invention provides fungic acid, its derivatives, and non-fungic acid. steroid anti-inflammatory agents (e.g. indomethacin and acetylsalicyl) de Regarding.

From another point of view, the present invention provides fluorinated acid or its derivatives such as FK-, )06 or its use in conjunction with its functional derivatives. This combination therapy (Yo, F t < - 5 0 6 is designed to reduce side effects! 1-sr,, same Sometimes fluoronic acid seems to be effective due to the effects of its derivatives and the effects of FK-5L6. Adjustment work This is for the person using the service.

In any case, the administration of the above additional single medicine X or additional medicine fij:L Achieving the optimal total dosage to have a specific effect on the cytokine system. The type and frequency of administration must be closely matched. , if S is 1i, relatively It may be appropriate to administer higher unit doses, so-called "booster doses".

〔Example〕

In vitro experiments Raw materials and methods Fuzzino, fundic acid derivatives and cyclospo? Non-fluoronic acid water-soluble sodium fucithalmic salts, fundic acid derivatives and fucithalmic points Eye drops and Fujin tablets are available from Leo Pharmaceur ical Produ. - Provided by CI:s (Ballerup, Denmark). Two derivatives (see below) The drug was added to oIMfk salted phosphate solution at pH 7.4 (PBS) except for It was dissolved at a degree of mc/m+ and stored at 4°C.

Heptanoic acid. W1 body VD1546Na and PR+089Na in 98% ethanol The solution was dissolved at a concentration of room mg/ml and stored at 4°C. In addition to each experiment center The compounds were ginseng (500E U / m +), streptominone ( 500 μg/ml), L-glutan ζ (2 mM) and 1-10% heat-inactivated human serum. Pool (, \4 I-IS-added 25rnM good trial aii for isosho (N . rd-va C C, Sj Tskholm, Sweden) RPM [ 1640 medium (Roswel I Park Memorial Institute te). Final a of ethanol: Normally 0.3% (T/v) or less. However, these levels do not affect the production and action of cytokines.

Cyclosporine was kindly provided by Sandoz (Basel, Switzerland). It was. Dissolve this powder in ethanol (50 mg/mI) and Diluted to μc/ml. This stock solution was stored at ~20°C until used.

Similar dilutions of ethanol were pooled and used in parallel experiments.

Cytokine rIL-1a is T. Submitted by Tsu b o i (Inu Nippon, Osaka, Japan) provided. r[L-1β is Cistron Bio-technology ( Pine, Plutsk, New Tsuya') State, USA) from lj! ! provided. f Purified natural human IL-6 and r[L-6 used in visceral β-cell experiments teeth. , J. van Da-mme (University of Leuffen, Leuffen, Berly) ( 26)'&Biri. A. Aa　r　de　n　(University of Amsterdam, Amstel Dam, Netherlands) (27). , used for pond research - 6 is T. Provided by Hirano (Osaka University, Osaka, Japan) (2B) 25 rTNFa is G. R. Ad　　　f　f(ErnSt　Boehrin ger [n. sl: itute.

Provided by Austria, Vienna. r[L-2 is Boehring er (Mannheim, Toysso) to Nagahama f2.

Cytokine activity was confirmed by bioassay (see below).

The cytokine was a temporary standard preparation of human cytokines (NBSB).

London, UK) and worldwide (certified by the World Health Organization (WHO). Entodoquinone content of itocaine preparations: home, Limulus (turnip) Test for pigment degradation products of migrating cells (Struers, Rodobre, Denma) lpg/1. It did not exceed OOOU.

Cytokine production Human mononuclear cell #i (MNC) (i, healthy ζ as described above (20.29-32) Ficoll-hyver in the blood (venous blood) of adult donors who are not receiving drug treatment. F　co　　　　-Hypa-qua) (Lympho-prep, Na Igaado, Osuguchi, Nono 1, Wii), add Hebarino, and centrifuge at an angle. It was separated to form a single layer. 2xl　O”/ml　’J)m RPMI164 Incubate in 0 medium, heat phenol-water, remove (Mλ1 1i nk-r odt Inc., St. Louis, MO, USA). E ・Collyendo) ・Quinone Oi55:B5 (LPS) 2μg/ml plus plant blood cells Agglutinin-P (PHA) (D-ifco. Detroit, Minnesota, USA) IO μg/m. Add l and shake at 37°C for 1 hour, then finely Cells are dissolved in Hanks' balanced salts. &coBss:+2 washes 1,,PHA not L Resuspend in the same medium containing 2 μg/mL of PS. In some experiments [Sat, The cytokine was indomethacin (S i gma).

St. Louis, Missouri, USA) produced in the presence of 1ag/ml (,, After 26 20 hours of culture, the supernatant was separated and [(BSS, i&RP 　M　　　/gutsu) Dialyze this trowel solution (20) at 4'C for at least 2 days. . These cells were collected using the trivan blue exclusion method for survival studies. . In parallel experiments, sodium 11β-1H-funnoate 20μg/ml , specific radioactivity 93μCi/mg (Leo Pharmaceut 1cal Co mpa-ny) at 0-10% (v/v) at the start of culture using NHS. added. X! After 1 liter, add the remaining 3H fucinonic acid to the supernatant using a non-tyrene counter. It was measured with

T cell increase induced by IC-2 Effect of funjin on supernatant IL-2 activity and IL-2 activity modification in vitro is rL-2-dependent CTLL-2 cells (American Type Cult ure Co11ec-tion, Rockwil, Maryland, USA) For the last 3 hours of culture (31), 3) 1-thymidine Shake at f2.

All experiments were conducted in three groups.

TNFa and IF\r'J) EL+S eight law T to existence of Fα: Yo, human rT,'JF Sandwich E as described above using a rabbit high titer monospecific antibody against α. LI SA's 1! ! It was measured by a small modification method.The ELISA method was used for biotin/ The Avinon system is used, and the detection limit is lpg/looμm. this minute The +Fr method is unaffected by serum and contains TNFβ (- lymphotoki 7)). There is no cross-reactivity with other cytokines. TNFa5) Recovery rate is usually 8 5% or more, and the coefficient of variation within the range of the Fr method is 10% or less. f2.

tFN7 was manufactured by Ho1land Biotechnology (Leiden, Oran). It was measured by the sandwich ELISA method purchased from DA).

The ELISA method uses [2M monoclonal antibody against FNγ and biotin/antiviral Use the ochin-phosphate alkaline method. The sensitivity of this analytical method is 15 pg/150 μm , and the variation frequency is rarely less than 10%. In initial experiments, human IFNγ , two monoclonal anti-human [FNγ antibodies (Centocor, Malvern) Immunolanoometric assay (IRMA) using measured by. The sensitivity I of this analytical method is approximately 0. lIU/ml.

Total IL-1 activity in the aqueous fluid on T cell proliferation induced by IL-1α/β 1) mouse T cells (thymocytes), 2) enriched human blood T lymphocytes) (both Both analytical methods [also detect L-6], or 3) mouse lymphoma cells (IL4) It was measured by the following three methods (r　L-6 detection system).

[Co-stimulatory factor analysis of L-1 breast vA cells: This was performed in the same manner as (29).

Briefly, Enodotocinus resistant C3H/SSI.

Female mice, 6-8I1M years old (Bomhol, Lee, Denmark) Thymocytes from 96-well microtiter plates (Nunc, Ro 10% (v / v) N HS and 5X10” in Skilde, Denmark) Medium containing M mercaptoethanol (10'H in 200 μm per well) cells) 3 sets of cells proliferated in 8 ways. Dilute the stock solution 2 times and add 10 μg of PHA at the beginning of culture. / Add ml. After 48 hours, cells were treated with 3H-thymidine (05 µCi/well), collected in agar, and counted with liquid I counted.

Purified human T lymphocytes were prepared from MNCs (29). Simply put, plus Becton Dickinson tissue culture dishes (Becton Dickinson, Oxnard, Cali) Fornia, USA) by incubating for 1 hour at 37°C. The MNCs from the attached cells were exhausted and became empty. Remove non-adherent cells and nylon The cell population generated when passing through the wool column contains over 80% T cells, 15% B cells, and MO of 1% or less.

Minute Fre for IL4 was performed similarly to (29).

This is 1.2 x, l O-'M calcium ionophore, ionomycin (Sigma) and mouse breast 111 cells in the presence of IL-1α or IL-1β. This is based on the generation of IL-2 from the system (IL4).

One simple sheet includes a test in which 3 sets of 2x105 EL4 cells/200 μl are diluted twice. Incubate with material for 18 hours. After 5 incubations, collect supernatant. We investigated IL-2 activity using rL-2-dependent CTLL-2 cells (3). . The activity was calculated using a computer program using the supernatant solution diluted twice serially. Performed by linear regression field of Lobit transformation data 7':.

! Hybridoma proliferation induced by L-6 [L-'66 activity is essentially +t, −61 & year mouse hybrids as described by Aarden et al. (27). cell, line B13.29 by incorporation of 3H-thymidine into clone B9. was measured. Briefly, triplicate samples each containing 5XIO'@ cells were tested twice in succession. Add the diluted test material and incubate at 37°C for 3 days. The last 5 hours of culture 3H-thymidine was added in between, the cells were harvested and fielded with liquid notyleazine. . A titration curve of the standard human R[L-61 Wi agent was prepared for each minute Fi- method. [ 1 unit/ml of L-6 activity is calculated using computer probit 9 is defined as the degree of 3H-thymidine incorporation that gives the maximum amount/2 of the laboratory standard ( fledge (=lpg of human rIL-6).

TNFa-induced cytotoxicity TNFy@-induced cytotoxicity ) was tested on IM mouse cilioblasts. il-like human rT The titration curve of the NFα preparation was first tested using a provisional W[(O)-related preparation, and Created. The activity was determined by using the supernatant liquid diluted three times serially. It was calculated by computer processing linear dumpling field of data.

Human mixed lymphocyte reaction Mixed lymphocyte culture (MLC) was performed using human blood from unrelated healthy sources, &MNc , 10'/100 μm to the same volume of blood MNC. RPM(1640 2xto’s cells in 200 μL of medium and IO% NHS for 5 days at 37 °C. Incubated. 2H-thymidine was incorporated 16 hours before the end of the culture and added to the liquid solution. It was measured by Nchinj/-Nunun.

Intuulin production by isolated rat pancreatic islets Wistar rat (90-120 g) obtained from r = isolated islets from collagenase digestion of pancreas @ tissue, essentially The islets were precultured for 7 days as described in (32) above, counted and pooled, and benin (500 IU/ml), streptomynon (+OOμg/ml) ), antenterinone B (2,5αg/ml), L-glutamine (2m~1), Good buffer reagent 25 mm, o1. /I2, glucose 1.　l　 mm　　　　　/　(!7h and add 0.59gNH3, rsR, PM If 640@ Underground washing twice (5 times).Culture: 3 groups were washed with 5% carbon dioxide gas. Rats were incubated for 5-7 days at 37°C in a humidified atmosphere. Measuring inotyurin by radioimmunoassay using innotuulin as a standard. For this purpose, 0, 2 m, and 1 of the medium were separated.

Bone resorption induced by IL-1α 2 days prior to subcutaneous injection of 5C, the calvaria of 5-day-old mice were excised and the upper S (32: z this one fights r two (this culture f2. Cut the bone of the wall C't'l into 4 pieces Two pieces were used as a control and two pieces were used for the experiment. Separation, 1. Place the bone fragments in TC-1991ml (GibcoBio-cult, Baseley, Stainless Steel). Kotsuland) 1 Kouno blood] Precious albumin component V3g/(! Support Anbinrin 4 Cultured in test tubes containing an additional 0 mg/Q.

Cultures were humidified with 5% carbon dioxide and incubated at 37"C in ambient air.48 After 3 hours, each calvaria piece was removed and dehydrated for 30 min at 90°C in 1 ml of 1N HCl. It turned into a stone. An aliquot of 250 μe of these solution-supported media was added to a standard liquid non-filter. H1) - Measure with a nozzle counter. Calcium release is found in the medium Calculated as % of the total amount of Ca (release of 5Ca from dead bone tissue is There was no).

The results are expressed as a ratio of treated bone to control bone.

Calculation and statistical evaluation of the effects of 7nonono and fudinoic acid derivatives Analysis 5 - Human natural cytokines are added to the cells before adding vA. Sodium 7nononoate (Fluonone) or fluoronic acid for 1.5 min. , Mafko is pre-cultured with the medium alone (for control).Add site Amount of kine: may vary depending on the sensitivity of various bioassays, or is usually Obtimal effect (subopcimal) (= Guaranteed to be 50% less than maximum activity) be chosen to do so.

To test the potential potentiation effect of cytokine action, add cyto-force ino. Minimal effect! (=10-20% of the maximum effective dose).

Blood'OV[X experiment to test the effect of Futsuno on 1nonjukaino production by NC In this case, the superna fluid containing t-horned Caine has a cytokine content of /! l+define It was then dialyzed (see above) to ensure the removal of fluorones.

Inhibitory effect of Fuunone or Fuunone rI & analogs) Usually, the formula.

It is expressed as a percent inhibition of CyI-kine activity change. The p-value is Mann-Hoy Sotony's rank sum test or Vircoso It was determined by the paired case test.

Example 1 Funnon-induced inhibition of interleukin I production by Hil-MO This test: i, : rhino]・Cain production: and = + L - t α / β 7 This was carried out according to the method described in ``Induced ra, nucleation''.

As shown in Figure 2, Futsuno has L P S - P I (7λ activity M\ The survival change of caries that inhibits the production of IL-1 from C is 11; After feeding, the production of Tokaino T\Fα exceeded 80%, and the MO-induced production of Tokaino T\Fα in the pond was completely Not affected (Figure 2).

Example 2 Fuunone-induced inhibition of lymphokine production by human T lymphocytes Second test: - Cytokine production - 1-1L - 21 T induced from this Cellular cough increase - ELISr method for overcoming TNFa and tNFr, as published by Seiko S. I went to sea urchin.

As shown in Figure 3, when the a degree of Funnon is gradually increased, +, ps-pHA inhibits the release of IL-2 and [FNγ by lingualized rkoM\C. do. 50% reduction in the production of these lymphokines; It was done at t. Under similar conditions, the maximum production amount/2 of these cytokines is Obtained and filtered with Crosporin I 5-50 ng/ml. As described above , compared to cyclosporin, the activity level of tefunone is relatively low in agricultural changes and scales. Considering that the toxicity of cycloborin is in the range of 1,000 x 77 m1 or more, I'm captivated by it and it's not a fault.

On the other hand) / non-1i, approximately 200 μK / m, significant at concentrations of 1 or more No toxicity was observed, and as a result, the curative* index of Fuunone was higher than that of cycloborin. Although it is small, it is five times larger. [L-2 and IFNγ are produced by T lipocytes. , these cells were treated with a polyclonal non-specific T-cell @activator. In many cases, IL-1 is required as a costimulatory factor. (See Figure 1 and References 1~・↓).

As shown above, fluorone has a positive effect on cells as judged by trypan blue exclusion method. On the other hand, the buoyancy of non-toxic 6 cells should normally exceed 80%.

important for bioassay systems, especially [L-2 bioassays] In order to rule out the possibility that radioactivity remains, the experiment was carried out in the presence of radioactive substances. Let's do it. In these experiments: in the presence of fluorone or 10% NH9 at 4 °C. So T for one day only! ! It's a leaf! Completely removed from the supernatant using the 1 sho method. I understand two things.

Example 3 Funnon induction effect on cytokine action 3.1. IL-1 This test was performed as described in rtt, -tα/β-induced T cell increase %li- Let's do it.

3.1. l Mouse thymocytes As shown in Figure 4, the amount of IL-1 activity in the second normal test is In this method, the costimulatory effects of rlL-1α and rfL-Lβ on thymocytes are inhibited. harm To reduce rL-1α support and IL-1β activity by 50%: Yo, Hunnong 1 Do this at 5-5 μg/ml. Under the same test conditions, the maximum amount / 2.7) [L] -1 response may require 15-50 ng/ml of cyclovorin.

Futsuno is a type of rL that binds to proteins extensively but reversibly. If it increases, it will interfere with the +L-1 inhibitory effect of the drug.

Therefore, experiments were carried out with 1%, 3% and 10% (v/v) blood at 13 degrees. rL. As shown in Table 3, high AT serum or IL inhibits -1N-induced breast cell activity. 5 drugs that slightly reduce the effects of drugs.

Table 3 Effect of serum JL on the efficacy of Funjin to interfere with IL-1-induced thymocyte activity. influence □ 10 and 30 U of rIL-1a or rlL-1β were added to the thymus with or without thymus. added to the cell assay. No difference was observed between the two types of IL-1. The result: yo , the average value of 4N experiments, using two types of degrees for each rlL-1α and rfL-1β. It is something that

312 Human T lymphocytes Figure 51. Illustrator of IL-1 costimulatory activity using enriched human T lymphocytes. This shows the effect of the A non-toxic variant of Funnon, especially PPD or T cell antigen. When used as a costimulatory factor to stimulate inductive activity, the work of Hunnong You can see the inhibitory effect.

3.1.3. Mouse Lipper species l1lliI (EL4) thymocytes (yo, T In addition to lymphocytes, it contains macrophages and dendritic cells, so it A drug that inhibits the activation of IL-1α induction in the thorax and phagocytosis system (EL4) As shown in Section 6, Fuunon studied the effects of EL-4 cells on EL-4 cells. r[L-1α-induced proliferation. Is it the effect of the drug (Funone)? Example 3.1. I and 3 L 2. The fact that IL -1 plus EL4 cells that require co-stimulation with calcium ionophores. This is thought to be due to cell enhancement. Another possibility is that EL-4 is a normal cell This is because they are transformed cells that cannot be compared with.

3.2. IL-2 and TNFα This experiment: T cell proliferation induced by rlL-2-□ and two TNFα Fibroblasts were induced as described in Section 2.

Compared to the effect on IL-1α and IL-1β action, the effect on IL-1α and IL-1β action is The ability of human L-2 to activate cytotoxic T lymphocytes (CTLL-2) or Mouse L [does not modify the ability of human T to kill fibroblasts (Fig. 7).

Example 4 [Effect of delayed addition of fucinone on L-1-induced thymocytes This experiment: r+t , -+α/β-induced T cell proliferation.

As shown in Figure 8, after the activation of thymocytes by IL-1 and PHA begins, Up to 48 hours, the addition of Funjin showed a decrease in the costimulatory effect of [L-1]. The impact becomes smaller as time goes by.

A similar response was obtained with the addition of 50 ng/m of cycloborin I: ,,This means that Hunon is the initial i! of T cell activation. It will affect me about 1 degree This is the one shown. Therefore, treatment of immune inflammatory inflammation with Funtuno or its derivatives It can be seen from its early stages that it is Tsutochi Aokari.

Example 5 Effect of fluoronic acid derivatives on IL-1-induced thoracic cell activation This experiment consisted of r+t, -+ α/β-induced cell proliferation.

It was performed as described.

As shown in Table 4, only three of the fluoronic acid derivatives, l　L　−1α and r　L It is effective in inhibiting the thymocyte co-stimulatory effect of -1β. Ineffective derivatives is characterized by the modification of substituents at the 16th and 21st positions of the molecule; As a result, these regions of humunonic acid are necessary for the IL-1 inhibitory effect of the drug. It is suggested.

Table 4 [To the fluoronic acid-induced inhibition rate of the thymocyte co-stimulatory effect of L-1 Funnon 70・, /-1o <0.05V D 1.177 21r/-19 ns, 1-/-9nsV D 1178 16+/-1,3ns 9-/-8 nsV D ■303 2-/-1i ns 7-/-3nsV D I 3 6 0’ 24=/-6<0.05 22-/-9<0.03V D I 3 6 2’ 59-/-10<0.05 61-/-15<0.0.1M D 1. 4 6 0” 46+/-f3<0.05 58-/-13<0. 05V Dl 546 3+/-9ns 14-/-7nsP RI O89 -10÷/4(lns 13-/-5nsResult: Yo, flat dog value-/-5EM1n = 6.

[, Koshichi, et al.'s wA is the same (Yo, the 16th position of the numerator and 2L are the same as Fuunon. .

2 In this order (hereinafter, whether the 16th and 21st stands are the same as Hunon, but (2, 1 It is O atom or S atom substituted at position 6.

Example 6 Funnon-induced inhibitory effect on mixed lymph 1illa conjugation (MLC) in 2 copies; This experiment was performed as described in ``Human matched lymphocyte reaction.''

MLC is correlated with graft rejection in vivo and in vitro. follow Therefore, if fugin has a role in inhibiting graft rejection, ~[[, C reaction et al. It should be suppressed. As shown in Figure 9, Funzino actually has two types of Hill-M-L Inhibits C.

Dose-response curve: i. Effect of IL-1 on thymocytes and PPD-activated human T cells. It is almost the same as the one that was humiliated when experimenting with the L-2 soil. Hunon The 50% inhibition factor I is 15-5 μg/ml. The same inhibition of MLC is caused by Icrosporin is obtained at 15-50 nK/ml.

Example 7 ■Hybridoma proliferation of L-6 (inhibitory effect on fluorone induction) This experiment was performed as described in rtL-6-induced f hybridoma proliferation. I did it.

[L-6 is Ike's MO-inducing peptide mediator and thymocyte activation (2 , 7, 8) has been reported to mediate several effects of IL-1. follow Therefore, it is interesting to see whether Fugino can inhibit the function of IL-6, as shown in Figure 03 IO. As shown, the growth of the 89 hybridoma cell line was inhibited by Funnon. child The dose-response of fluorophore in the IL-1-induced increase in normal (mouse) glandular cells. The results were very similar to those obtained when testing the effects of chlorine. IL-6 induction A 50% reduction in proliferation was obtained at approximately 10 μg/ml of funone. I'll show it in the next experiment. There is no explanation for the cytotoxicity induced by sea urchin.

As shown in Figure 11, [L-6-induced proliferation of B9 hybridoma cells] Fuunon's ability) The general toxic effects of cells and cells are not enough. That is, rIL-6 (5, pre-incubated with Funnon 30μg/m, l) The collected 89 cells are washed with a solvent and reconstituted with a fluorine. and Lr2 responded normally to the next challenge with +L-6.

Really! ! tej8 Failure to correct IL-1-induced activation of bone resorption in this experiment: More-induced bone resorption: was performed as described in.

As shown in Table 5, the radioactive drift induced by γIL-1α In biological systems, this does not affect the increase in release to C. Shows non-toxicity.

Table 5 r　[1-[lack of Fluorone effect on ductal bone resorption 45 Ca release (Kono]・Rho le%) Fugino rll, -1α average (direct +/-3DnP110ug,'ml -0 ,95+/-0,081,Ons:',10ug/ml 20ji/[ll [i, 4! l +/-0, 12' 9 <Q, QS, '1 and 2. of these values The difference is of no significance.

Example 9 1 I--1 j) Funnon-induced protection of pancreatic β-cells against inhibition/injury action This experiment: As described in ``Intuulin Production by Isolated Rat Pancreatic Islets.'' I went to

91 Fujin IL-1β is considered to be pathologically important for the development of U-DDM, and L-1β significantly stimulated glucose-induced insulin production by pancreatic β cells in vitro. Is it possible to restore normal tζβ cell function in vitro with Fugin to reduce the Experimenting with something: Interesting. As shown in Figure 12, a normal rat l-711\ Pancreatic islets isolated from J1 were co-incubated with increasing concentrations of phlegm. glucose induction in the presence of relatively high concentrations of rl and L-1β. Normalizes insulin production (5). At high concentrations of Nozine, the protective effects of the drug are A slight decrease was observed.

The reason for this is not clear, but it is probably due to the insulin mRNA translation effect (23). This seems to be due to the ability of the drug to inhibit this.

9.2 Fucinonic acid derivatives A protective effect similar to that of Funjin was observed after testing a number of fluoronic acid derivatives. . - Tennoethanolamine salt (3 experiments) gave similar results to fluorone . This indicates that, excluding derivatives such as salt formation at position 21, modification of the basic fusidic acid structure is possible. Decorations indicate that they are undesirable in relation to this effect.

Considerations regarding in vitro experiments Immunosuppressive effect of Fuunone The data presented in in vitro experiments support the use of fluorone in the process of lymphocyte activation. ! Represents dependence inhibiting effect. Induction of T and B lymphocytes 4i, MO or dendroid cells [(L, A class ■Antigen or allogen by positive cells) In addition to the recognition of n), it takes several hours. 1) Production and release of [L-1 and possibly L-6; 2) Characteristics of IL-1 and IL-6 Activation of T cells by these cytokines through different membrane receptors, 3) T phosphorylation Production and release of IL-2 by lymphocytes, 4) IL-2 receptors in T lymphocytes! iii; and 5) receptor-dependent endocytosis of the TL-2 receptor complex. addition Leverage cytokines include Hl, Aglff expression ([,8), -yt　o　 ! The T! Release from B vacuoles is important It is thought that.

Fuunone inhibits these early processes, much like cyclosporin (19). Be considered. First, a relatively high level of Hunnon is found in the LPS-PHA-activated human surface. inhibited the production/secretion of IL-1 from fluid MNCs. Second, perhaps this person or even more Is it important? 1, low-melting phthalate is associated with IL-1, IL-6, and T- and B-phosphorus. Activation of lymphocytes was restored in a double mutation using an MO-induced activator for lymphocytes. This conclusion As a result, antigens, mitogens, and after allogeneic (alterogeneic) activation, proteins probably Nunone inhibits the production of its own growth factor, IL-2, by T cells, begins to inhibit the growth of. rFNr secretes cytokines and promotes HL A class INFγ of the drug is an important activator of MO action that fosters the performance of molecules. The ability to inhibit the production of can be responsible for T cell suppression.

In all cases, the inhibitory effect is dose-dependent, and the effective degree of Funnon is It should be considered non-toxic. Furthermore, IL-2 induction in CTLL-2 cells was increased. Since proliferation is not affected by drugs, Fuunone has a general anti-proliferative effect. It doesn't work like that.

Futsuno has no serious side effects (at a therapeutic dose of 15-100 μg/m1). 33), this Jlf, which is effective in vitro, is said to be clinically appropriate. I can do it. However, since it binds extensively to proteins in vivo, it is difficult to detect drugs in vitro. In terms of efficacy, clinical efficacy will be reduced in vivo. However, this This may be due to increased concentrations of serum during thymocyte assays or due to fluorinated immunosuppression. It is not considered to be of much importance in the case of Funzino, since it has minimal effect on the action. I can't get it. Furthermore, some of the important clinical effects of Fuunone are serum proteins and total volume. It is thought that it occurs in squid or tissues that exist in very small amounts.

+L-1 activity when testing Funnon in mouse thymocyte co-stimulation assays. was almost completely eliminated by 15μmz/ml of drug, with 50% inhibition of 1 It was obtained at a concentration of 5-5 μg/ml. Funnon is a drug-free drug-free drug at all concentrations. We failed to reduce the survival changes of this thymocyte compared to thymocytes cultured in the conventional experiment.

The mechanism by which FUTSUNO inhibits the immunostimulatory effect of IL-[α/β is unknown. death However, it is known that fluorone inhibits protein synthesis at the translation stage (23). therefore, impairment of at least a portion of protein synthesis may explain the results. That will happen. However, our research results show that cytokine mRNA translation is Complete inhibition cannot be explained. In other words, it is activated by LPS+PHA and The production of TNFα by human blood MNC is even at 50μg/ml of Funnon. unaffected by r2. In addition, Funnon's cytokines, IL-2 & IFN The ability to inhibit γ production is due to the effect of fucinone on the translation of these lymphokines. It is thought that this is a combination of L-1α/β and IL-6 inhibitory effects. Therefore, especially I L-1 is essentially due to T lymphocyte activity including lymphokine (l=4) production. The first signal is thought to be the “second signal” of T cell receptor/CD31 binding. Antigen or mitogen-induced bartering of the body (l, 2.11.12) (Perturbat 1 on).

Fuunone's ability to inhibit mixed lymphocytes in vitro: Probably a second IL-1 inhibitory effect. It would be useful. In any case, in vitro correlation of human homologous M (allogeneic) graft rejection Futsuno's inhibitory effect on various substances is important. Because this hun Jin is a homologous transplant, such as kidney, FF@, heart, lung, skin, bone marrow, cornea, etc. This is because it is used to clinically inhibit the host's elimination of the virus.

1″ second signal of lymphocyte activation when host treatment of the graft with phunone is performed. The interference caused by ``specific tolerance'' to the transplanted tissue ance) (see above).

Funnon's ability to inhibit the proliferation-promoting effects of IL-1α/β and [L-6; It is important from a floor perspective. In other words, [L-1 and IL-6 are linked to several types of lymphoproliferation. Reproductive disease ρI, for example, one type of polyostosis and two traits 'aB, and B-support T- It means the occurrence of diseases such as cell cancer. (See above, see).

Anti-inflammatory effect of fujin rt, -tbi r　L-6 is a group of organisms among many cell types (1-4). It is known that it is scientifically active.

Therefore, Hunjin conducted a test [out of the many effects of L-1, some It is interesting that it inhibits the effects of the drug, but does not inhibit the entire effect.

For example, the drug (Funnon) does not affect 1L-1-induced bone resorption (2), whereas the drug (Fucidin) has been shown to affect the β-cells of pancreatic islets against the inhibitory/cytotoxic effects of IL-1β. Protected by crabs.

rL-1 and T1. , the apparent 1-inhibitory action of 7-nonone on the non-immunological effects of -6. Its use is of clinical interest. In other words, it is included in the lymphocyte activation reaction. Apart from this, probably in physiological and pathophysiological immune responses [L-1 and I L-6 is involved in many infectious and immunoinflammatory diseases, AIDS, autoimmune endocrine diseases, It is stored when rheumatism and other symptoms occur at some point (Table 1, ? Reference 2.3.8). Apart from being used as an antibiotic (5), The ability of IL-1α/β and IL-6 to cause fever and cause anorexia and cachexia Highlights the therapeutic role of fluoronic acid and its derivatives, along with the potential of IL-1α/β It's Shino.

@ Theory of in vitro experiments T lymphocytes, B lymphocytes: 40 cells and NK cells: against soil, microorganisms and tumors It plays an important role in human defense. On the other hand, the endocrine system, skin, gastrointestinal tract, and On the pathogenesis of rheumatoid arthritis, S. immune-inflammatory diseases involving many organs, and rheumatoid arthritis. However, the role of these cells has a powerful influence. These cells, especially TL-1α , a peptide hormone produced by IL-1β, IL-6 and TNFα. Ichadoin) is a powerful immunostimulant as well as hepatocytes, bone cells, endothelial cells, synovial tissue cells, pancreatic islet β-cells, thyroid cells, and numerous cells of T!! Monoyu 1 noter. +L-1α/β, IL-6 and s'T\town Fα production and Treatments that inhibit immune function and function inhibit the development of numerous immunoinflammatory and infectious diseases. Or improve symptoms. Such interventions may include continuous immunosuppressive therapy or Administered for periodic short-term treatment to induce specific tolerance in the transplanted tissue, It can be completely prevented. Fuunone was treated with appropriate treatment aI in vitro, [L- 1α/β and TL - 6 immunological growth-stimulating effects and inflammatory triggers (5) and the pattern of these responses is very similar to that of cyclosporine. Similar. Therefore, this discovery is a great example of human immunity! iInflammatory inflammation systemic and local It is important to consider that these side effects may be related to pathogenicity. . The diseases reported by Futami et al. include so-called autoimmune diseases (see Table 1), transplant rejection, and graft rejection. Transplant-related diseases, including host diseases, many infectious diseases, and 2-3 types of ulcers. Includes many diseases characterized by pathogenic cell proliferation.

Next, based on the obtained evidence, a large number of in-vivo experiments were carried out by et al. 1). As a guideline for experiments carried out in connection with specific uses of or derivatives thereof, III has been done. Pharmacologically, Fugin e-branches and their derivatives have been administered orally, parenterally, and It is clear from the scientifically-granted patent literature mentioned in section ``Background of the Invention'' that dermal and transdermal applications are possible. be. This document includes missing experiments that explain the penetration of this drug into the ocular chamber. (Experimental Example 10).

In vivo experiment pharmacological research Example 10 Fields from vitreous/I#i submembranous fluid Three days after the preoperative systemic treatment, the a. Measure K. Systemic treatment/Fuzin tablets (Leo, Copenhagen, Denmark) 500mg 3 times every 24 hours. Treatment will end at least 6 hours before surgery.

material 1 Vitreous hemorrhage stimulated by diabetes 1. Two related vitreous bodies Including 10 eyes that underwent surgery and are now f2.

2 Detachment surgery patient (retinal detachment), t! ! @ Retina of eye 10 [strains] related to surgery Lower liquid removal separation.

Preclinical (medical) research The following Examples 11 and 12 are based on ongoing research on animals. 1-0 Example 11 showing guidelines for preclinical research based on models Examples of in-vivo demonstration of the preventive effect of Fujin in two animal models of diabetes include B. B-rats and N0D-mice (type 2 of (intuurin-dependent) urinary disease) We plan to test the preventive effect of Fuunone in a naturally occurring T+ urine disease animal model. Painting (, ta.

I'm going to take a cold spring bath with 40 to 50 animals and treat them with a placebo. Contains the corresponding number of animals. He took care of couples who were bleeding, fostered experimental animals, and do. The animals were treated with drugs immediately after weaning and continued until the end of the study after 200 days. Now. Animals were observed daily, including weekends, and were weighed every 2 hours and urine tests were performed on a group basis. A course measurement is carried out for measurement. Occurrence of IL urine from animals and end of study The pancreas from the specimen was subjected to microscopic examination to determine whether 1) infiltration into the islets of Langerhans was possible; Find mononuclear cells and 2) measure the number of in7-ulin-producing instents. Zarani, Ren Measurement of cytokine content in serially removed serum samples to evaluate the relationship between disease occurrence and serum cytokines, IL levels.

Example 12 Fluorescence response to the acute phase response induced by IL-1 and IL-6 in mice effect of background Acute Phase Reactions: Usually during acute and chronic infectious and inflammatory diseases, and during cancer (this During this acute phase, administration of TNFα was recommended to support IL-1 and [L-6]. Regenerate reaction (8). tL-6 support and a small amount of IL-1 and TNFα) soil , serum amyloid A, C-reactive protein, fibrinogen, and haptoglobin in hepatocytes. The complement component induces the synthesis of acute-phase proteins, including coagulation factors. simultaneous , the blood level of albumin decreases, and the plasma concentration of Fe'' and Zn'' decreases. However, the concentration of Cu"" increases. Associated symptoms include fever and increased white blood cell count. It may induce symptoms and sleep. High levels of fibrinogen, especially when accompanied by anemia, can cause Increases the sedimentation rate of fluid, which is usually used as a clinical parameter for oral inflammation. It will be done.

The clinical symptoms mentioned above are often associated with carbohydrate-1 lipid-1 and protein-metabolic disorders. Associated and debilitating (cachexia). In rare cases, the acute phase reaction progresses and abnormal clotting occurs. resulting in death. First, it is caused by a bacterial infection. If so, microbial products such as entodoquinone may be directly responsible for these symptoms. It was thought to be the cause. This idea is now wrong, because Todoquinone is a potent inducer of MOIL~1, +L-6 and TNFα. , all pathophysiological AI associated with endotoquinone-induced noyoc are TNFα It can be reproduced by injection of a small amount of IL-1(2).

plan Preliminary experiment 121 using a mouse model (25) to answer interleukin lα induction. Fucidin 15 mg and solvent alone (control) were administered to BALB/C mice (female, 5 and 5 mice (8 to 10 weeks old) (administered intravenously to controlon. 30 minutes later) , human rIL-1α10 μg in 25 μQ of pyrogenic isotonic saline is injected intravenously. . After 24 hours, the mice are bled for measurement of butoglobin in the acute phase reactant.

These results indicate that the doses of Funnon and rlL-1α are effective in inducing IL-1 in mice. Induced acute phase responses vary to demonstrate the dose-response curve be able to.

12.2. Interleukin-6 induced response The experimental approach outlined above , human rTL-6, except when using 10 μg.

Again, a fucidin dose-response curve is established.

12.3 Feces in IL-1α- or +L-6-induced acute phase response in mice Effect of non-analogues Experiments similar to those described above were used, except that hunone analogues were used in place of hunone. I did it.

The following Examples 13-18 are based on the clinical experience gained by treating patients with Fuunone. controlled clinical experiments based on the evidence obtained from these preliminary experiments. guidelines.

clinical research Example 13 The next study will show that after eye surgery, fluoronic acid point ffl 荊 is used as a preventive treatment for inflammation. Designed to show the effectiveness of treatment.

131. Clinical trial on the anti-inflammatory effect of Futsuno during the period after cataract surgery Material: An artificial lens was implanted in the posterior chamber of the eye after cataract surgery to remove the lens6 Eyes 201 [1°] excluded for children over 0 years of age, eyes with circumference, glaucoma, retinal vascular hemorrhage, etc. or thrombosis, chorioretinal inflammation, and vision loss (sight, hreλten). ing diseases), urinary tract disease (type I), and collagen disease.

” Fujin the patient corresponding to the eye of 0? A group that treats children.

Patients corresponding to 10 eyes were treated with chloramphenicol-containing ultralanum (, Control group treated with ultr&lanum).

Method: Random treatment of two formulations in 20 eyes from 18th postoperative day to 3rd week .

Dosage: Ultralanum chloramphenicol eye drops four times a day.

Funosalminoku eye drops 4 times a day Parameters of the ox 1. Visual acuity: 1, 2 and 33 times a day after cataract surgery.

2. Biological microscopic examination (microscopic examination of live wood) will be performed on 2.5.14 and 21 days after surgery.

More detailed data should be recorded during the biopsy.

Intraocular pressure after surgery l, 2 and 31! ! Measured every time.

Examination of vitreous and central retinal status was performed every 1, 2 and 31111 after the examination, and Within the period! , f data: treatment with fussalmic/chloramphenicol This is recorded as an alarming evaluation of the ultralanum treatment.

For example, eye drops, eye pain, duration of eye pain, duration of decreased vision, if any, Postocular problems.

Eliminate urethral inflammation during the treatment period, (urinary vision disorder), obvious panophthalmia, and cannot be treated. Something that doesn't exist (non-compl 1ance).

13.2. The anti-inflammatory effect of funjin during the postoperative period after uncomplicated laser surgery floor test Materials: e.g. retinal loss, retinal biopsy (biopsy) or iI uretic omentum 'aA patient who underwent laser surgery due to inflammation.

t corresponding to 10 eyes! A group consisting of wealth. Usual treatment (glucocorticoid A control group consisting of patients corresponding to 10,121 eyes treated with .

Methods: Randomized treatment of the two formulations over a period of 3 weeks from the first postoperative day.

Dose/3 tablets of Punpun tablets 300mg within 21 days from the day of surgery Evaluation parameters: I Measured every 1, 2 and 3 weeks after optic crab laser surgery f=.

2. Biological microscopic examination will be performed on 2.5.14 and 21 after surgery. Living body w1. During the spout , more detailed data is recorded.

Examination of the vitreous body and @Lakuretinitis symptoms was performed every 1, 2, and 3 weeks postoperatively, and during the postoperative period. Interim data is recorded on patients' evaluations of treatment with Funnon.

Background of treatment with Funnon for non-infectious immunoinflammatory staphitis Severe uveal tube inflammation (uveitis) causes vision loss in developing and developed countries. It accounts for a large percentage of harmful stuttering cases. Most uveitis cases in developed countries are classified as idiopathic. and is assumed to have an underlying autoimmune cause. Treatment in these cases: It is mainly performed using glucocorticoids, cytotoxins or cyclosporine.

But from the start, treatment can slow down the side effects of vision loss (Kuhnung's syndrome). severe bone loss and nephropathy (cephalosporin) resulting in loss of vision. I had no choice but to request treatment.

141, Preliminary experiment Tables 5 and 6 below show results from two preliminary experiments. In the experiment [1], 3 people Include a secret number corresponding to the treatment of 5 eyes.

This treatment includes cephalosporin to phunone (0.5g tablets three times a day). changed to). In the second experiment, four secret numbers (Ui of 8) were included. this enemy Those who took an initial dose of Sephalosvorin and started taking Fuunone (3 to 30 tablets per day) ．． 5) was treated.

Table 6 Preliminary experiment Severe urgency vision uveitis 3 patients (5th eye) - cyclosporine (CyA) to 7nonone (Fus) convert to (nephropathy) Table 6 (continued): Note: All three practitioners were able to get effective results from Funnon treatment. one eye vision The deterioration in strength is due to the vitreous body and clouding, and vitrectomy is then performed. 2 pieces vitrectomy or during treatment with no further expansion of the disease's vitality. Ta. None of the patients were affected by Fuunone's side effects. Three patients had long-term @ Treatment with moderate/high doses of corticoids and CyA can reduce severe side effects. Affected by action.

Table 7 Preliminary experiment Grapes with severe urgency vision @ 4 moxibustion patients (8 (2) eyes) - 7 nonono ( Fus) treatment (cyclosporin) Table 7 (continued).

acute inflammation Note: In clinical evaluation, the response is restored by concurrent therapy with glucocorticoids. , patient 4 received treatment (ff1 of 8) or Fujin treatment was effective. That is, acute There was no evidence of chorioretinal inflammation, and two patients received lower doses of corticosteroids. I was able to However, attempts to completely discontinue 11M corticoid therapy Glucocorticoids were used in CyA-treated patients with severe uveitis due to recurrence in some patients. All N0 patients who experienced relapse when discontinuing treatment with Funjin did not experience any side effects from Funjin. Anti-inflammatory effect of Suna (r-614, 2 for patients with anterior uveitis)/Non! D Linsong experiment Materials, 20 eye-corresponding face area uveitis @ acute onset and: relapsed 1 1 Group 1 (treated with Fussalmink eye drops 6 times a day (applicable to 5 to 1° eyes) It consists of a secret number.

Group 2 received glucocorticoid topical ffl agents (e.g. ~ [a-xide X'', A., Inc., Texas, USA).

Consists of patients corresponding to individual eyes.

Both groups underwent eye removal with L% Atrobin twice daily (e.g., DAK, Copenhare). Gen, Denmark) and treatment.

Treatment period: 31 hours Clinical control: At least once on occasion.

Systemic treatment of uveitis and collagen diseases as a result of elimination and bacterial/viral infections If the patient's condition deteriorates during treatment for uveitis and cannot be treated.

143 The effectiveness of Futsuno on non-infectious immune inflammatory posterior uveal stria of urgent vision, l-・sexuality experiment (mul l l’, 1.Cen, Cer 5C-udy) Purpose of the experiment Regarding the treatment of perioptic cystitis, oral sonotsuno and conventional treatment (coral) are used. To compare efficacy, safety and tolerability with ticosteroids).

The parameters of the study are as follows: Continuous treatment is due to JII death, so a drug experiment was conducted. Canceled Ichitetsu count and visual acuity ・Anti-inflammatory activity parameters ・Fluorofluorescence angiography ・Number of recurrences ・Complete assessment of efficacy and tolerance capacity by researchers and patients ・Blood measurement of cytokines Immunological experiments.

Type of experiment A blindfolded ophthalmologist records unbiased information about uveitis mold. Parallel group experiment with multicentric, open randomized controls (Funtsuno and normal treatment). Iro Tetsugen, 20 early Chugu. At this stage, I am not sure whether to continue or not. make a decision.

the brightest standard Current unilateral one or f2 is bilateral - eyepiece improvement.

exclusion criteria A late stage of the disease with active lesions or irreversible retinal degeneration.

Exclude patients with miosis or cataracts that prevent the posterior pole of both eyes from being seen.

Progressive infectious diseases, liver dysfunction, such as ALAT, ASAT, hirirubin ( The upper limit of the positive f-value for all proteins is 2.5@ or more.

General experiment overview Patients on corticosteroids and/or cytostatics were randomized These drugs should be discontinued before treatment and before making a clear choice.

Patients will then be randomized to receive either Fucinon (monotherapy) or conventional therapy.

Two researchers should conduct the experiment. The researcher (1) knows the corresponding treatment. This point should be kept secret from researchers (2) (ophthalmologists). Should.

Researchers (1) should evaluate safety parameters, side effects, and should be administered. Researchers (2) should only evaluate the parameters of effectiveness. It is. He (researcher (2)) must not approach the pond data.

If no contraindications occur, corresponding treatment is recommended. Normal treatment f random Patients receiving treatment should start with corticosteroid monotherapy. Ru. If there is a response or non-conformance after a minimum of 4a, start the Funon Yakushi (with a small amount of code). (combined with ruticosteroids). More 4J! After 1 period, if the response is nonconforming, Futsuno should be replaced with cyclosporine treatment, and the patient should discontinue this experiment. It is a place where it is stopped.

Patients were studied at baseline, 1.2a, l, 2.3.4.6.9.12 months. and thereafter at intervals of six months during illness or hiatus, and: Acute attacks should be studied each time.

The first complete data analysis was conducted on six months of data for the first 20 legal entities. There should be an interval of 12 months thereafter.

For uveitis, the only concurrent medications allowed are glucocorticoids and ciliary muscle. It is a paralyzing eye drug. Subconjunctival injection of glucocorticoids is not allowed.

A) Experimental medication Fuunon 0.5g 3 times a day B)! legal treatment group Prednisolone 1.5 mg (e.g., DAK, Coben/1-Gen, Denomark) / to 4/days/week. The dose should be gradually reduced to 5-10 mg of prednisolone per day. Try to maintain 1 change. In case of recurrence, increase dose.

Contraindications for continuous treatment (for both treatment groups) Visual acuity at least up to 2 weeks After treatment, none of the inspector's eyes decreased from the initial baseline of treatment during the following two days. My eyesight deteriorates.・Inflammation: Measured by a second observer after at least 2 weeks of treatment. As expected, inflammatory activity worsens and visual acuity does not improve in either eye.

・As the symptoms of evening fever progress, the spots that appear appear in either eye, in the opinion of a second observer. can also cause permanent loss of vision.

Toxicity or side effects Y) Liver dysfunction, for example, the upper limit of normal value of 2.5@value b) Allergy to Futsuno lugie reaction C) Side effects that the patient perceives to be of such a nature that the man or woman cannot continue.

disease activity Patients completed baseline, 1.21st and 1.2.3.4.6.9.12 when the disease is quiescent: for at least 6 months in a year Patients should be evaluated at intervals or during acute attacks.

Concurrent Medications: Concurrent medications will be noted during both pretreatment evaluations and for each subsequent evaluation.

Ophthalmological evaluation by a blindfolded ophthalmologist.

a) Visual acuity b) Inflammation, anterior chamber, enlarged redness, vitreous haze and opacity C) Inflammation caused by other eyepieces sightseeing d) Fluoreracene angiography (when circumstances permit and at 3.6 and 12 months) ) laboratory experiments ! L (blood: hemoglobin, hematocrit (! [(red blood cell volume ratio), WBC count and differentiation, platelets, sedimentation rate changes, total protein, total bilirubin, alkaline phosphatase ze, ALAT, ASAT, potassium and creatinine b) Qualitative urine analysis (protein, sugar, sediment).

C) Participate in research only: Pregnancy test Immunological research (optional) Serum parameters a) Serum protein II! Katsunaga movement b) Ig (immunoglobulino) concentration C) Serum [NFr, IL-2, [L-2 receptor, iLlα/β, TNFα Cell parameters: a) Blood lymphocytes and mononuclear cell divisions - total loss and subsets b) Group #aa combination Flf -HLA-DR (IIJIO's !=1!t).

Autoimmune responsiveness.

2L) Antinuclear antibody b) Rheumatoid factor functional immune capacity &) LPS and P measured by proliferation reaction measurement method and support cytokine production method H.: Rini lighting response and bathok ground]・b) Self-cleansing for site power ino (ILIα and T:<　Fα) Discontinuation/Dropout Discontinuation means no further treatment due to reasons related to the drug experiment (specific contraindications). The patient is discontinued. They should be completely fielded and replaced with new alarms and people. It is possible. A complete evaluation should be made at the time of cancellation.

Dropout: refers to a patient who does not keep up with or is unable to respond. he etc.: You should be replaced (the next one is free).

Fuunone treatment for Crohn's disease background It is well established that cyrosporin can be effective in Crohn's disease (localized ileitis) (46). has been done. However, treatment is limited to small doses and for short periods of time due to dangerous side effects. It will be done.

Purpose of the experiment: Supporting absorption in the gastric field of Heungjin and possible efficacy of Funnon in treating Crohn's disease. fruit test Experiment D type: Open preliminary experiment patient The initial material consisted of a total of 6 patients with Crohn's disease.

Starting criteria ・Fluid treatment for active Rohn's disease is planned.

・Brnodnisolone treatment should not exceed 20 rng per day; At least 2a must remain unchanged and must remain 1゜ ・Salazovirino (SASP) or 5-aminosalicylic acid (5-AStλ) treatment No change and maintained for at least 2 weeks (if not 5, then 113 Overview of key experiments Continue taking Futsuno Tablets 0.5g three times a day for 41 days. -If the effect of - is not recorded, Patient 1, you must be removed from the experiment.

If an effect of - is recorded, treatment is continued for an additional 4a. Treatment of disease or worsening of ponds If necessary, the patient may be excluded from the experiment.

other treatments When the patient started the experiment, S A, S P (salicylazosulfapyridine)/ When receiving treatment with 3-ASA (5-aminosalicylic acid), the dose: unchanged Nii (Terasa, f': should.

Regarding Bu1/Donizolone, see below.

disease activity Disease activity is measured by a modified single-screen score, ja,m, (46). Osamu The effectiveness of treatment is defined as a total score of -fA. Prednisolone dose reduction Small should be defined as individual therapeutic objectives. The purpose of the second activity and (, then, P-olo Tumcoid concentration and "Crohn's disease activity 11" (CDAI) should be used.

Clinical controls with crude fluid samples were performed at 0, 2, 4, 8 and 12 intervals after treatment. It may be performed 4a after the end of treatment and depending on the clinical situation.

@Laboratory experiment Blood, sedimentation rate, oronomucoid, hemoglobin, hematocrit, pyrilpino , ALAT, , ASAT, alkaline phosphatase.

In addition, plasma measurements of fluorone concentration, cytokines, and cytokine autologous For determination, sample (5 mL of serum, 5 mL of EDTA-plasma and heparin Plasma 5 ml) is calculated as a coefficient.

Patients are not allowed to take their morning medication until a blood sample is taken.

Emperor's promotion Urgent i! 11. Background of Heunjin's treatment for graft-versus-host disease (acute GvHD) Acute Gv I-I D i, donor T-lymphocytes after isotopic allogeneic TA transplantation 8 to 40 days after surgery as a result of a reaction to host antigens in the anti-HLA system, especially in the transplanted locus. The symptoms appear within a period of 14 days (average of 14 days).

This occurs in 70% of alarms with HLA-identical progeny donors, but HL , A-incompatible strains (Pe donors or HLA-identical and unrelated voice donors) is often observed.

The following I)-IJ are valid reports of prognosis and treatment response.

grade! (Mild) rll or confluent rash.

Diarrhea: 500ml/24hrs or less.

Bilirubin 25μmol/L Gu I/-do ■ (moderate), rash and diarrhea 500-1000 ml / 24 h　rs　s and/or bilirubin〉23μm　o　1. / Q.

Grade ■ and ■ (severe) Rash and lower @ L OOOm! /24hrs, and/or bilirubin〉50　μmo　l/+! .

Middle school! ~ Is the occurrence of acute Gv HD in severe cases related to the same or different species? @ Increased after transplantation combined with the added mortality rate. Mortality is associated with infection, particularly as a result of delayed immunological reconstitution. It depends. This is due to GvHD itself and because these patients often patients receiving immunosuppressive treatment with prednisolone and/or antithymocyte globulin. This is due to the fact that Currently applicable treatment plan Zenichimiya is treated prophylactically for acute GvHD. This is due to the evolving acute Gv Due to the estimated risk of HD, cyclosporine (from day -1 to 180 days (up to 1 day), preferably methotrexate static pressure (1, 3, 6 and preferably 11 days) ).

Additional treatment for GvHD is given in the following symptoms: 1. Grade I (mild) subjectively GvHD is very bitter and the symptoms do not subside even after one week of observation.

2 Grade ■ (moderate) GvHD that progresses rapidly.

3 Grade I (severe) GvHD.

Antithymocyte globulin is used in addition to glucocorticoids whenever possible.

Increase the dose of cyclosporine.

Purpose and type of experiment Despite adequate prophylaxis with cyclosporine and optionally methotrexate , Acute CvHDh (1 sound, allogeneic bone N transplantation, Preliminary experiment to evaluate treatment effect. If Fuunone alleviates the worsening of GvHD symptoms, sugar The consumption of corticoids and cyclosporine is clinically significantly reduced and therefore It is possible to reduce side effects (e.g., infectious diseases and nephropathy), leukemia, and poor regeneration. Sexual anemia or life-tbreatening underwent an allogeneic bone marrow transplant for 10 r-girls.

exclusion criteria ・People under 18 years old - A person who is treated with glucocorticoids with alarm according to the above criteria.

glucocorticoids and/or antithymocyte globulin at or before transplantation Alarm receiving treatment.

Note S Koji Appropriate cyclosporine prophylaxis should be administered prior to Fucidin treatment.

(a) If the final concentration of cyclosporine is less than or equal to therapeutic A, the cyclosporin The Rosporin dose should be increased and its effect waited (24 hours).

(b) The results of the final 1-variant experiment of cyclosporin are at an appropriate concentration, but the alarm goes down. Cephalosporins are not absorbed while you begin to suffer from diarrhea and/or vomiting. , replace oral cephalosporin with intravenous injection and wait for its effect (24 hours). I can do it.

Outline of general studies (ii. See above) Patients suitable for treatment with Fluunone -cyclosporine # degree [low 1ji (va l l l ey-val ue ) Collect blood to measure the blood.

- Funnon tablets are a mixture; also: in symptoms of moderate/severe diarrhea, Funnon reduced injection, 12mg/kg 3 times daily for the first 2 days, then daily 3 times 8 mg/k g0 In cases where treatment with fluorone is considered to be effective. If this occurs, treatment is continued for 10 days and administration of Fluunone is discontinued after L.

Progress occurred despite treatment with Funnon. If so, stop the drug and start usual treatment (see above).

disease activity For each individual patient, the extent of the rash is recorded along with the amount of diarrhea and body temperature.

laboratory testing Blood/sedimentation rate, orosomucoid, hemoglobin, hirirubin, ALAT, AS AT, alkaline phosphatase; 5 ml blood, blue and 5 ml EDTA to support plasma. Collected to measure itokine and self-staking wood against site force ino.

Example 17 Funjin in the treatment of multiple myeloma Purpose of clinical efficacy study of Fluunone in early treatment of multiple myeloma Preliminary experience using Fucinon to treat patients with multiple myeloma. reactor.

The specific purpose is to confirm the following.

-Hunnon's administration skenor Safety and tolerability of Fucidin (jo 1erab i 1-ity) Effects of monofluorone on immunoinflammatory parameters.

The results of this pilot test will determine whether or not to start a controlled test. Should.

Class N of the test Uncontrolled pilot test glamor on release 1 adult male and female The diagnosis of multiple myeloma is made using the usual criteria. In other words, the classical three-tetsu method (Mr. fade): Bone marrow cytoplasmic ai (>1096), collapsed bone loss @ (lytic bone e1esion), and the M component of serum and/or urine, or the passage of time Plasmacytoma that remains in the expansion of M when trauma or trauma to the extramedullary mass occurs. carried out by

experimental drug treatment Fusidic acid tablet 0.5g 3 times per day for at least 3 days Test: First, record the following data.

-M component 1. Bone marrow biopsy, cranial radiation S East (lanogram) - accompanying disease and drug treatment laboratory test Blood: hemoglobin, RBC%WBC and differential count, platelets, creatinine Bilirubin, alkaline phosphatase, A, LA, T, ASAT, 1! solute , Se-calcium, [GA, [gG, IgM, M components.

Urine/24 hour proteinuria, glucose, M component.

Immunological tests.

Blood level of cytokines and in vitro production tracking test of IL-6.

This test is the highest [3i! One question and a maximum of three months. Data is for the first 3 weeks Collect the samples every 1 week, and then every 2 to 41 days.

One side effect caused by futsuno.

Single polymyeloma and associated disease symptoms and symptoms 1° - Full treatment details.

Laboratory parameters: creatinine, creatinine clearance, rod machine rejection test test, 1fIl fluidology, palliation (24-hour proteinuria), ~ ■ component.

Immunological test 1! , and must be returned at least once a month. Plasma levels (blood drawn the morning before the first dose of 7nodine) were measured at two-week intervals. Must be done.

Treatment discontinuation ceremony/Drop Ala]/Patient Treatment discontinuation declaration: A patient who discontinued treatment due to an inappropriate side effect. It is defined as These carriers must be thoroughly analyzed and safety and efficacy data available. It is necessary to discontinue treatment and soak 2 times.

Dropouts are those who fail to follow directions, fail to follow instructions, or fail to meet standards. It is Ki Miya who does not protect. These patients must be replaced with new Type 0 patients.

Example 18 Rheumatoid arthritis, juvenile rheumatoid arthritis, polymyalgia rheumatica and generalized Clinical efficacy of Fuunone for early treatment of lupus erythematosus (SLE) 18.1 Systemic lupus erythematosus when added to treatment with glucocorticoids (SLE) Effect of Futsuno on moderate tongue 11 cases.

background The use of glucocorticoids can cause systemic lupus erythematosus, especially if the kidneys are involved. - The result of Death (S　L　E　) was improved.

Adding immunosuppressive medications, including cytostatic medications, may be helpful in some cases. So it was claimed. However, for SLE, glucocorticoids are not recommended for the following reasons. I need a supplementary technique*.

& A strange habit that some patients, especially those with systemic vasculitis: corticosteroids It won't respond if you just ask.

b. Many patients: Yo, high dosage! (>l0mg blur]・Nizolone/day) corticosteroid Treatment with steroids is required. Key person around here: Gradually reduced home medicine 0 , the purpose of the study will be whether symptoms occur if treatment is discontinued. Low doses of glucocorticoids (<lom, gl prnodnisolone/day) are used (1 After long-term treatment, clinical and lingual ('clinical acj) Preliminary experience using fluoronic acid in the treatment of SLE patients with severe symptoms Obtain and collect items.One basic purpose: To remember the next thing. Dosing schedule call -Futsuno safety and tolerability - Uncontrolled pilot of release of effects of Funonone on immunoinflammatory parameters test patient 1 for men and women. 0 adults Inclusion group * (incl, usage criteria) Diagnosis of SLE is based on the diagnosis to American Rheum-a CI3171 A 390 Cl a Must satisfy four or more criteria for classifying l', l On S l-E. :Yonara-). <1. Omg of BuI/Donizolone was administered daily for more than 3 months. objective and/or subjective Sound the warning signs.

Exclusion Criteria - Supplementary treatment for 6LE Receive medical treatment: (1) alarm (e.g. cytostatic drugs) One Alarm Treated with Glucocorticoids - Implementing Effective Birth Control with Pregnant Women J, Tena 11 secret letter of childbearing age experimental drug treatment 1 Funonon tablet ¥110, 5 g 3 times daily for at least 3 weeks - Prednisolo (e.g., obtained from D, AK, Copenhagen, Denmark). Dosage should be Average daily exams given in the last 3 years First the following data must be recorded:

- The course of SLE and the subjective and objective aspects of SLE! Symptoms - Associated diseases and medicines treatment with Laboratory testing/ Blood, hemoglobin, RBCSWBC and differential counts, platelets, serum creatiny Bilirubin, alkaline phosphatase, ALAT, ASATS electrolytes.

Urine, 24-hour proteinuria, glucose Immunological blood test.

One anti-nuclear antibody and anti-DNA antibody -IgG, IgA, +gM - Rheumatoid arthritis test, rheumatoid factor - Level of B lymphocytes (immunoglobulin) - Level of T lymphocytes and sub-bodies Levels of resin-7in (CD4, CD-1) and IL-2, LT ( In vitro production of lymphotoquinone (TNFβ) and IF\γ - complement (comp element) C3 and C5a follow-up test This exam: A minimum of 3 weeks of questions and a maximum of 3 months. The data is for 31 rooms. Collect at intervals of 2 to 4 weeks.

A side effect of the cause - Signs and symptoms of 5LE and accompanying diseases - Full treatment details Laboratory parameters: creatinine, creatinine clearance, liver screening examination, hematology, wc (24 hour proteinuria).

Immunological tests must be repeated at least once a month.

- trough normal blood levels of Fucinone (before the first dose of Fucinon) (Blood drawn on the morning of) are taken at intervals of 2i11.

Patients under treatment/dropout patients Patients who discontinued treatment are defined as patients who discontinued treatment due to an inappropriate effect rather than a side effect. to justify These patients must be fully analyzed and safety and efficacy data available for treatment. It is necessary after treatment is discontinued.

Dropout patients are those who cannot be traced and who are phlegmatic, do not respond to instructions, or fail to meet criteria. This is unprotected stuttering. These patients must be replaced with new patients.

182. Administer immediately after diagnosis as an immune inflammatory monomodulator for rheumatoid arthritis. Background of the action of Funnon Rheumatoid arthritis is also a common medical condition whose cause is unknown. In rheumatoid arthritis The inflammatory process involves increased synovial fluid production, activation and proliferation of synovial cells, joint cartilage and Bone destruction and repair that occurs with fibrosis, ectopic calcification, and metaplastic bone formation process is included.

Polymorphonuclear leukocytes and macrophages (lφ) play important roles in all these processes. (35.36). Synovial tissue that is inflamed in severe cases due to the involvement of immunocompetent cells The tissue is composed of the ripper system, which is surrounded by T lymphocytes and has germinal centers of r and B lymphocytes, and the following. ing.

In general, the relatively thick T portion of infiltrating T cells is characterized by membrane markers characteristic of activated Ta retention. It is believed that such microorganisms are often found in the blood (35). Slippery In the membranous tissue, plate serum cells and immune tumor cells are present, and autoantibodies, especially anti-Fc-1gG rheumatoid arthritis, are present. Multifactor and hypergammaglobulinemia are commonly seen in antibody-mediated reactions. This suggests that this occurs during the disease process. However, these humoral responses The cellular infiltrate in the synovial tissue is dominated by activated T cells of the Hertzku phenotype. , these cells trigger B cells to produce fluid in an uncontrolled manner. It's showing. Many researchers believe that in rheumatoid arthritis (L), the host is exposed to exogenous antigens. Inappropriate cells respond to endogenous antigens or abnormally become immunogenic. It is believed to generate an immune response and a humoral immune response.

IL-1 and probably < + L-6 and TNFα; yo, rheumatoid arthritis and related rheumatoid arthritis It is said that medical care plays a central role in the process leading to organizational failure (8). Shi f2 Therefore, when IL-1 and TNFα were injected into the knee joint of normal rabbits, the initial stage of the knee joint was reduced. IL-1 causes biochemical changes similar to those seen in gossameritis (37), IL-1 The 1 m fluid level of tL-6 and tL-6 is similar to that of rheumatoid arthritis. closely parallels objective disease activity (38).

Cyclosporine has been used experimentally (39) and in clinical cases (40-43). ) In both cases, evidence that IL- 1 and/or IL-6 triggers the initial immune-inflammatory process and ultimately This supports the idea that it causes destruction of joints and bones. Unfortunately, cyclosporine Alternative treatments are sought after, as they are known to have significant side effects. There is.

Purpose of the exam When Fuunone is used to treat stuttering newly diagnosed as rheumatoid arthritis To gain preliminary experience.

The specific objectives were to evaluate the dosing schedule, the safety and tolerability of Fuunone, and To confirm the effect of medicines on immunoinflammatory parameters of rheumatoid arthritis It is.

Open uncontrolled pilot test stutter 10 male and female adults Inclusion criteria Diagnosis of rheumatoid arthritis is based on American Rheumatism at the time of diagnosis. Four or more criteria for classifying rheumatoid inflammation of As5ocation must satisfy 1, L).

Patients are advised to take non-steroidal anti-inflammatory drugs (NSAIDs), especially glucocorticoids, If you have already received drug treatment other than gold salts, beninolamine, or cytostatic drugs [ I can't go home. and active disease) period must not exceed 12 months.

exclusion criteria -NS A [Patients receiving treatment other than D- Implement effective birth control with pregnant women Persons of child-bearing age who are not allowed to do so. experimental drug treatment One Funonone tablet 0.5g 3 times daily, tested for at least 2 months First record the following data 3 The course of the rash and the subjective and objective features of rheumatoid arthritis - taking care of the accompanying diseases. One-product treatment laboratory experiments m fluid hemoglobin, R, BC, WBC5 and differential count, platelets: dish cleaning 1/ Anitino, hiriruhin, alkaline phosphatase, AL A, T, A S A, T, electrolyte.

urine, protein, glucose Immunological (fIL night test 4 Cough antibodies and anti-DNA antibodies ~+gG, [gA,! g:zo -Rheumatoid factor - 1 novel and service of 8 lymphocytes (III immunogucobrino) Bubohyurenoyon (CD 4. CD 1 size) Cain's 1 Nbel, and (Ko 1) In vitro production of L-2, LT and IFNr One complement 03 and C5 tracking experiment This exam will last for a minimum of 2 months and a maximum of 6 months. Data is for the first two months Ha, 2i! ! Collect every interval, then every 41 intervals.

A side effect of the cause Signs and Symptoms of Monorheumatoid Arthritis and Associated Diseases - Treatment Details Laboratory parameters creatinine, FF1i! ! function tests, hematology, urine (tan) protein, glucose) Immunological tests must be repeated at least once every two months.

- Trough plasma levels of Fugin (blood taken on the morning before the first dose of Fugin) Measurements in a) should be carried out every 2J for the first 2 months, and every 4 weeks thereafter. depression Treatment discontinuation alarm/dropout letter, person Patients discontinuing treatment: i, side effects, etc. (5) discontinuing treatment due to inappropriate effects (5) , is defined as a person. The living of the soul must be thoroughly analyzed and the safety and efficacy Data are required after treatment is discontinued.

Patients are patients who were lost to follow-up, did not respond to instructions, or did not meet criteria. patients who do not follow the guidelines. These patients must be replaced with new patients.

1.8.3 Connective tissue diseases in the pond 1) The term equine inflammatory disease is used for a syndrome of unknown cause; The etiology of synaptic tissue is markedly different from the associated and often severe clinical syndromes. It is difficult to confirm whether this will happen or not. Therefore, Ike's connective tissue medicine method, For example, juvenile rheumatoid arthritis, psoriatic arthritis, reactive arthritis (Reiter syndrome), Polymyalgia rheumatica, systemic sclerosis, and sarcoidosis are etiologically It's related. Likely similar disease mechanisms or some of these diseases: Patients with different types of connective tissue depigment are using T cell selection. This is reinforced by the fact that treatment with the immunosuppressive drug cyclosporine has been beneficial. (44) However, treatment for these diseases is often unsatisfactory and few There are always side effects.

Clinical trials related to these diseases are conducted in a manner similar to that described above. I have to become one.

Drawing description Figure 1. Cell pharyngeal reaction and site when antigen is given to T lymphocytes and B lymphocytes Cain production. Cytokines produced by immune and non-immune cells or surface fluid flow It enters the body and acts as a hormone that affects the function of distant tissues. Modified from (3) Correct.

~ [φ・macophage: Th: T helper lymphocytes, BB lymphocytes, Fl@fiber Blast cells, (; K. natural killer cells.

DR, MHC class ■molecule, [L-1-F interleukin l inducer.

Figure 2: Effect of funone on the production of [L-1 and T+-JFα. percent inhibition The rate is shown as a function of the final test concentration of fucinone. *P<0.01. n=12 ( IL-1) and n = 6 (TNFα) Figure 3. The origin of 1L-2 and IFNr Hunon's action against. Percentage of inhibition is shown as a function of final test concentration of fucinone. vinegar. *P<0.05, n-66 Figure 4: [Effect of Futsuno on L-1 (mouse cleansed cells).

The percentage of inhibition was calculated as a function of Hunnon's final test 1 degree and 1. Shown.

*: P<0.01. n=8゜ Figure 5. Effect of Fugin on IL-1 (human lymphocytes).

Percentage of inhibition is shown as a function of Hunon's final test, jIrt.

*: p<o, o 5, n=5, PPD tuberculin Wl protein'J t derivative (antigen), PHA/phytohemagglutinino C non-specific polyclonal T lymphocyte activator).

Figure 6: Effect of fucidin on IL-1 (mouse leprosy cell line, IL4). of inhibition Percentages are shown as a function of the final tested concentration of Fugin. *: P<0.05. n= 7゜Figure 7: Effect of funjin to inhibit the activities of IL-2 and TNFα.

Percentage of inhibition is shown as a function of Huunone's final test 1 degree.

n-4 (IL-2) and n=6 (IFNr), respectively.

Figure 8: PHA-activated mouse thymocytes were treated with 5 μg/ml of fluorone. Effect of late addition of

Figure 9: Effect of Funjin on the reaction of lymphocytes mixed in two ways. hundred of inhibitions The fraction is shown as a function of Fugin's final test 11'. *: p<o, ot, n= 10 Figure 10: Effect of fucidin on IL-6 (B9 cells). The percentage of inhibition is Final test of non, shown as a function of f11 degrees. human rlL-6 at IU/ml concentration to the test cells. *: P<0.02, =7゜ Figure 11: Reversibility of Fudgin-induced inhibition of L-6 activity (B9 (test). Test cells were treated as described below. Do as described (PRE) , 30 μg/ml of Futsuno was added to the cells, and then + Treated with 8 U/ml rtL-6. After 2 days, cells were washed three times and further described. 1) The power to add 30μg/ml of fluorone (POST)＼ Alternatively, culture for 2 days without addition. Assays for IL-6 activity are carried out at specified levels. The cells were cultured for 2 days in the presence or absence of rlL-6.

Figure 12. Inhibition of intuulin secretion by [L-1β. (vs. without @・tL-1 % of intuulin secretion of two cultures maintained in medium). given by fucidin protection. Rat pancreatic islets of Langerhans were precultured for 6 days. Then this The islets were washed and treated with 11 mmol/Q glucose and the indicated 1-mutant rIL-1β/ - Added to fresh medium containing Funjin.

Figure 13: Ability to protect against β-cell damage induced by +IL-1β Not found in the original substance. The culture conditions were tested for only one of the fluorone analogs. It was the same as FIG. 12 except that.

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Ann, Rhaum, DLs, 19811;47:127-133.43, τ uB;w@ll　P, BombardLar　C, Cane　M, Bsnn ee+: K, Luclwin D, Crac sword@E, 1suchanan　(JtJ,　Bsru 瞠n　JC,BalLamy　N , Murpby CF, Crafffenrl, ed@B von, , Low dose cyclosportn Ln rh@umaeoid arehr i, ei, s: A plLoe 5tzdyJ, RheumaeoL, L9 87;14:1108-L! 14゜(1m, 5chLndL@r　R(ad) , (:1cLosporin Ln^U seoiwun groan M++1s 榔i, 5 pt1. n, -ger-V@rLa5. BarLin He1delberz 1985゜45, von, Dashns! J, GodC: free 　O,Ra5oassn　P,R,,5truceure-Aceivkey RaLaeLoruh, Lpi Ln Fusidic Ac1d-Type Aneibi mouth eicg, AcLvancs+s Ln a drip fLisd microbLolag)r, vow, 25. 1979. 95-1.45. 46, ISryngkov @e al, N4ng1. J, He4.191 19.32L 11th unit at 845-850° 2pJL Rozuku 71st trial in ni Shusho Hayabusa 1 Pus ↓ and ~ Ro Ro Ro Ro TaFi4 prison 27z writer Suspicious P! L number student IFJL order C, P, M.

Kunito cool 4? .

pig, 12 NEET; -5- of - international search report In-〇”-”””””=　PCT/DK　891002541+dmnm -＾-pk11-Even N・l’l: T/DK 89100254 International search report

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[Claims] 1. Prevention or treatment of diabetes mellitus, especially insulin-dependent diabetes mellitus (type I) treatment, especially to prevent the progression of diabetes mellitus (type I), especially to confirm diabetes mellitus at initial diagnosis. almost immediately after diagnosis, or there is a high risk of developing diabetes mellitus (type I). Composition for preventing endogenous uveitis after confirming that the group compositions for treating, such as cataract surgery or laser surgery; Composition for preventing inflammation after eye surgery, rheumatoid arthritis, psoriatic Treatment of arthritic progressions such as arthritis or Reiter's arthritis at initial diagnosis Composition for almost immediate confirmation, Composition for preventing or treating uric acid arthritis; composition for treating osteoarthritis; composition, transplant rejection-related compositions, such as compositions for preventing or treating symptoms associated with corneal transplantation; compositions for preventing or treating associated symptoms; compositions for preventing or treating conditions associated with transplant-versus-host reactions; Treat Crohn's disease or ulcerative large intestine inflammation, especially Crohn's disease or ulcerative bowel inflammation. A composition for preventing the recurrence or progression of ulcerative colitis, Composition for treating pernicious anemia or peritoneal disease, prevention of contact dermatitis or is a composition for the treatment, prevention or treatment of allergic/atopic dermatitis. composition for performing therapy; Composition for treating pemphigus vulgaris or smallpox, related to thyroid function Symptoms, especially thyroid overfunction or underfunction, such as Hashimoto disease (lymphocyte hyperfunction). adenitis, lymphoid thyroiditis), Riedel's thyroiditis (chronic fibrotic thyroiditis), Kervain thyroiditis (submalignant granulomatous thyroiditis), subacute lymphocytic thyroiditis, gray Thyroiditis (including Greaves disease, Graves submalignant thyroiditis or Greaves eye disease) compositions for treating acute, submalignant or chronic Composition for treating Gimmonz panhypopituitarism, hypoadrenal gland function, especially a composition for treating symptoms associated with Addison's disease; A composition for treating or preventing recurrence of demyelinating diseases, especially multiple sclerosis; Sarcoidosis Beck, Siegren's syndrome, Reiter's syndrome, erythema nodosum , a composition for treating or preventing recurrence of scleroderma or Behcet's disease, Polymyositis, polymyalgia rheumatica, myocarditis or systemic lupus erythematosus Compositions for the treatment or prevention of recurrence of vasculitic phenomena, e.g. May treat symptoms associated with phlebitis, Wegener's granulomatosis, or giant cell arteritis. or a composition for preventing recurrence; For the treatment or prevention of recurrence of primary biliary cirrhosis or chronic active hepatitis. Composition, A composition for treating aplastic anemia or idiopathic thrombocytopenic purpura, Treatment of neoplastic disorders of lymphoid tissue, such as B-cell lymphoma or multiple myeloma or a composition for preventing recurrence, T lymphocyte proliferative disorders, such as mushroom-like Compositions and groups for treating or preventing recurrence of fungal diseases or Cesar syndrome A group for preventing or treating septic shock caused by rum-negative bacteria. product, Composition for preventing or treating disseminated intravascular coagulation, preventing arteriosclerosis Compositions for treatment of acute and chronic periodontal diseases, especially periodontitis and periodontitis. compositions for preventing or treating symptoms; Cytokines for the prevention or treatment of symptoms associated with disorders of the cytokine system, such as The aim is to produce compositions that substantially inhibit the biological effects in humans associated with Uses of dinic acid or its derivatives. 2. Prevention or treatment of diabetes mellitus, especially insulin-dependent diabetes mellitus (type I) treatment, especially to prevent the progression of diabetes mellitus (type I), especially to confirm diabetes mellitus at initial diagnosis. almost immediately after diagnosis, or there is a high risk of developing diabetes mellitus (type I). Fusidic acid to the production of compositions for prevention after confirming that the group or the use of its derivatives. 3. Arthritis progressions such as rheumatoid arthritis, psoriatic arthritis or Reiter's arthritis To prevent or treat arthritis almost immediately after first diagnosing arthritis. Use of fusidic acid or its derivatives for the manufacture of compositions. 4. To prevent or treat septic shock caused by Gram-negative teeth. Use of fusidic acid or its derivatives for the production of a composition for cooking. 5. Treat Crohn's disease or ulcerative large intestine inflammation, and prevent Samurai from developing Crohn's disease or provides a framework for the manufacture of compositions for preventing the recurrence or progression of ulcerative colitis. Uses of sidic acid or its derivatives. 6. Feedback for manufacturing compositions for preventing or treating symptoms associated with transplant rejection Uses of sidic acid or its derivatives. 7. Compositions for preventing or treating conditions associated with graft-versus-host reactions Use of fusidic acid or its derivatives in manufacturing. 8. Feedback for the manufacture of compositions for the prevention or treatment of conditions associated with corneal transplantation The use according to claim 6 of cisic acid or a derivative thereof. 9. Fusidic acid is apparently used in the manufacture of compositions for treating endogenous uveitis. Uses of derivatives of. 10. After eye surgery, such as cataract surgery and laser surgery. Use of fusidic acid or its derivatives for the production of a composition for preventing inflammation of . 11. fusidic acid or for the manufacture of compositions for the treatment or prevention of contact dermatitis. Uses of its derivatives. 12. Feedback for manufacturing compositions for treating or preventing recurrence of systemic lupus erythematosus Uses of sidic acid or its derivatives. 13. Neoplastic disorders of lymphoid tissue, such as B-cell lymphoma or multiple myeloma fusidic acid or its derivatives for the production of compositions for the treatment or prevention of recurrence of Purpose. 14. Use of fusidic acid or its derivatives as an immunosuppressive drug. 15. 15. According to any one of claims 1 to 14, the composition is a composition suitable for oral administration. Uses listed. 16. 15. According to any one of claims 1 to 14, the composition is a composition suitable for rectal administration. Uses listed. 17. Any one of claims 1 to 14, wherein the composition is suitable for parenteral administration. Uses listed in. 18. Any one of claims 1 to 14, wherein the composition is suitable for intra-articular administration. Uses listed in. 19. Any of claims 1 to 14, wherein the composition is a composition suitable for application to the skin. Uses listed in one of the above. 20. Any one of claims 1 to 14, wherein the composition is suitable for application to the eye. Uses listed in one. 21. 15. According to any one of claims 1 to 14, the composition is a composition suitable for transplant administration. Uses listed. 22. Fusidic acid for the production of compositions for the treatment of contact dermatitis, especially compositions for oral administration or the use of its derivatives. 23. Preparation of a composition for the topical treatment of contact dermatitis, especially for topical administration to the skin Uses of fusidic acid or its derivatives. 24. Compositions for treating Crohn's disease or ulcerative colon inflammation, especially if administered orally. or for the manufacture of compositions for rectal administration, or compositions for parenteral administration. is the use of its derivatives. 25. A composition for the treatment of arthritis almost immediately after the initial diagnosis of arthritis Fucidin for the manufacture of products, especially compositions for oral or parenteral or intraarticular injection. Uses of acids or their derivatives. 26. Compositions for the treatment of endogenous uveitis, especially ophthalmic compositions, ophthalmic ointment compositions, Eye lotion compositions or intraocular or intraocular injection or oral compositions Use of fusidic acid or its derivatives for the manufacture of compositions suitable for the treatment of the eye, such as On the way. 27. Compositions, especially oral compositions, for preventing inflammation after ophthalmic surgery of the eye, and is an ophthalmic composition, an ophthalmic ointment composition, an ophthalmic lotion composition or an intraocular or Fujiji for the production of compositions suitable for ocular treatment, such as injectable compositions for injection into the back of the eye. Applications of acid or its derivatives. 28. Compositions for the prevention or treatment of symptoms associated with transplant rejection, especially for oral administration The use of fusidic acid and its derivatives in the manufacture of compositions for parenteral administration. 29. Compositions for the prevention or treatment of conditions associated with graft-versus-host reactions, especially Use of fusidic acid or its derivatives for the manufacture of compositions for oral or parenteral administration On the way. 30. Compositions for the prevention or treatment of diabetes mellitus (type I), especially oral or rectal Use of fusidic acid or its derivatives for the manufacture of compositions for administration. 31. A combination for the prevention or treatment of septic shock caused by gram-negative bacteria. fusidic acid or the like for the manufacture of compositions, especially compositions for oral or parenteral administration. Uses of derivatives of. 32. A composition for treating systemic lupus erythematosus or preventing recurrence; Fusidic acid or its derivatives, especially for the production of compositions for oral or parenteral administration. Uses of. 33. Neoplastic disorders of lymphoid tissue, such as B-cell lymphoma or multiple myeloma Compositions for the treatment or prevention of recurrence, particularly for oral or parenteral administration Use of fusidic acid or its derivatives in the production of products. 34. Fusidic acid or its derivatives are known as cyclosporin (cyclosporin). Claims 1 to 33 used with A) or a derivative thereof or FK-506. Uses described in any one of the following. 35. Administering an effective amount of fusidic acid or its derivatives to a human in need of its therapy It consists of prevention or treatment of diabetes mellitus, especially insulin-dependent diabetes mellitus (type I); Particularly to prevent the progression of diabetes mellitus (type I), especially when diabetes mellitus is confirmed at initial diagnosis. almost immediately or with a high risk of developing diabetes mellitus (type I). preventive measures after confirming that it is a treat endogenous uveitis, Inflammation after eye surgery, such as cataract surgery or laser surgery prevent, of arthritic progressions like rheumatoid arthritis, psoriatic arthritis or Reiter's arthritis Treatment begins almost immediately after the initial diagnosis of arthritis; Prevent or treat uric acid arthritis, treat osteoarthritis, Conditions related to transplant rejection, such as the prevention or treatment of conditions related to corneal transplantation. to prevent or treat symptoms associated with transplant-versus-host reactions. to treat Crohn's disease or ulcerative large intestine inflammation, especially Crohn's disease or prevents the recurrence or progression of ulcerative colitis, Treat pernicious anemia or peritoneal disease, prevent or treat contact dermatitis, Prevent or treat allergic/atobic dermatitis and prevent pemphigus vulgaris or pemphigus vulgaris. treats pemphigus and treats symptoms related to thyroid function, especially thyroid overfunction or is caused by functional decline, such as Hashimoto disease (lymphocytic thyroiditis, lymphoid thyroiditis), De Quervain's thyroiditis (chronic fibrous thyroiditis), De Quervain's thyroiditis (subacute granulomatous thyroiditis) thyroiditis), subacute lymphocytic thyroiditis, Graves' disease, Graves' subacute thyroid Treats thyroiditis (acute, subacute or chronic) including inflammation or Graves' eye disease death, Treatment of Zinmontz panhypopituitarism and treatment of adrenal gland dysfunction, especially related to Addison's disease. Treat the associated symptoms and treat or prevent recurrence of demyelinating diseases, especially multiple sclerosis. sarcoidosis Beck, Siegren's syndrome, Reiter's syndrome, nodular Treatment or prevention of recurrence of erythema, scleroderma or Behcet's disease, Polymyositis, polymyalgia rheumatica, myocarditis or systemic lupus erythematosus Treat or prevent recurrence, and treat vasculitic phenomena such as polyarteritis nodosa, Treatment or prevention of recurrence of symptoms associated with Genner's granulomatosis or giant cell arteritis and Treat primary biliary cirrhosis or chronic active hepatitis or prevent recurrence, Treat aplastic anemia or idiopathic thrombocytopenic purpura, To treat or prevent recurrence of disorders such as B-cell lymphoma or multiple myeloma. Treatment of T-lymphocyte proliferative disorders such as mycosis or Cesar syndrome Or prevent recurrence and prevent septic shock caused by Gram-negative bacteria. Or treat prevent or treat disseminated intravascular coagulation, prevent arteriosclerosis, or Preventing or treating acute and chronic periodontal diseases, especially periodontitis and periodontitis symptoms. Ru, sites for the prevention or treatment of symptoms associated with disorders of the cytokine system such as A method of substantially inhibiting a biological effect in humans associated with Cain. 36. Administering an effective amount of fusidic acid or a derivative thereof to a human in need of such treatment Diabetes mellitus, especially insulin-dependent diabetes mellitus (type I), consisting of Treatment. 37. Administering an effective amount of fusidic acid or a derivative thereof to a human in need of such treatment Diabetes mellitus, especially insulin-dependent diabetes mellitus (type I), consisting of How to prevent progression. 38. Effective doses of fusidic acid or its derivatives are used to confirm diabetes mellitus at initial diagnosis. 38. The method of claim 37, wherein the method is administered substantially immediately upon recognition. 39. Confirm that the group is at high risk of developing diabetes mellitus (type I). A method for preventive treatment of diabetes mellitus (type I) after diagnosis. 40. Administering an effective amount of fusidic acid or a derivative thereof to a human in need of such treatment A method of treating or preventing inflammation after ophthalmic surgery, which consists of: 41. Administering an effective amount of fusidic acid or a derivative thereof to a human in need of such treatment A method of treating endogenous uveitis, consisting of: 42. Administering an effective amount of fusidic acid or a derivative thereof to a human in need of such treatment Identifying arthritis at initial diagnosis and treating arthritis almost immediately Method. 43. Administering an effective amount of fusidic acid or a derivative thereof to a human in need of such treatment A method of treating urate arthritis, which consists of: 44. Administering an effective amount of fusidic acid or a derivative thereof to a human in need of such treatment A treatment method for osteoarthritis that consists of: 45. Administering an effective amount of fusidic acid or a derivative thereof to a human in need of such treatment A method of treating symptoms related to transplant rejection, comprising: 46. Administering an effective amount of fusidic acid or a derivative thereof to a human in need of such treatment A method of treating symptoms associated with transplant-versus-host reactions, comprising: 47. Administering an effective amount of fusidic acid or a derivative thereof to a human in need of such treatment A method of treating symptoms associated with corneal transplants, comprising: 48. Administering an effective amount of fusidic acid or a derivative thereof to a human in need of such treatment Treatment or recurrence of Crohn's disease or ulcerative colitis, consisting of How to do prevention. 49. Administering an effective amount of fusidic acid or a derivative thereof to a human in need of such treatment A method of treating pernicious anemia or peritoneal disease, which consists of: 50. Administering an effective amount of fusidic acid or a derivative thereof to a human in need of such treatment A method of treating contact dermatitis, which consists of: 51. Administering an effective amount of fusidic acid or its derivatives to a human in need of its therapy A method of treating allergic/atopic dermatitis, which consists of: 52. Administering an effective amount of fusidic acid or a derivative thereof to a human in need of such treatment A method of treating pemphigus vulgaris or pemphigus, which consists of: 53. Administering an effective amount of fusidic acid or a derivative thereof to a human in need of such treatment Symptoms related to thyroid function, especially thyroid overfunction or is caused by functional decline, such as Hashimoto disease (lymphocytic thyroiditis, lymphoid thyroiditis), De Quervain's thyroiditis (chronic fibrous thyroiditis), De Quervain's thyroiditis (subacute granulomatous thyroiditis) thyroiditis), subacute lymphocytic thyroiditis, Graves' disease, Graves' subacute thyroid Thyroiditis (acute, subacute or chronic), including inflammation or Grace's eye disease; How to treat Zimmerz panhypopituitarism. 54. Administering an effective amount of fusidic acid or a derivative thereof to a human in need of such treatment Treat symptoms associated with adrenal insufficiency, especially Addison's disease, which consists of Method. 55. Administering an effective amount of fusidic acid or a derivative thereof to a human in need of such treatment To treat or prevent recurrence of demyelinating diseases, especially multiple sclerosis, Method. 56. Administering an effective amount of fusidic acid or a derivative thereof to a human in need of such treatment Sarcoidosis Beck, Siegren's Syndrome, Reiter syndrome, erythema nodosum, scleroderma, or Behcet's disease. How to do it. 57. Administering an effective amount of fusidic acid or a derivative thereof to a human in need of such treatment Polymyositis, polymyalgia rheumatica, myocarditis or systemic A method to treat or prevent recurrence of lupus erythematosus. 58. Administering an effective amount of fusidic acid or a derivative thereof to a human in need of such treatment vasculitic phenomena, such as polyarteritis nodosa, Wegener's granulation Methods for treating or preventing recurrence of symptoms associated with edema or giant cell arteritis . 59. Administering an effective amount of fusidic acid or a derivative thereof to a human in need of such treatment Treatment or relapse of primary biliary cirrhosis or chronic active hepatitis, consisting of How to prevent outbreaks. 60. Administering an effective amount of fusidic acid or a derivative thereof to a human in need of such treatment A method for treating aplastic anemia or idiopathic thrombocytopenic purpura, which comprises: 61. Administering an effective amount of fusidic acid or a derivative thereof to a human in need of such treatment neoplastic disorders of lymphoid tissue, such as B-cell lymphoma or Methods of treating multiple myeloma or preventing recurrence. 62. 63. The method of claim 62, wherein the disorder is multiple myeloma. 63. Administering an effective amount of fusidic acid or a derivative thereof to a human in need of such treatment T-lymphocyte proliferative disorders, such as mycosis or ceza Methods to treat or prevent recurrence of Hall syndrome. 64. Administering an effective amount of fusidic acid or a derivative thereof to a human in need of such treatment treatment of septic shock caused by gram-negative bacteria or is a method of prevention. 65. Administering an effective amount of fusidic acid or a derivative thereof to a human in need of such treatment A method of treating disseminated intravascular coagulation, comprising: 66. Administering an effective amount of fusidic acid or a derivative thereof to a human in need of such treatment A preventive treatment method for arteriosclerosis, which consists of: 67. Administering an effective amount of fusidic acid or a derivative thereof to a human in need of such treatment malignant and chronic periodontal disease, especially periodontitis and periodontitis-related How to treat symptoms. 68. Fusidic acid, preferably in an amount of about 1 mg to about 75 mg/kg body weight daily 69. The method according to any one of claims 36 to 68, wherein the method is administered orally. 69. Fusidic acid is preferably administered at a dose of about 1 mg to about 100 mg/kg body weight daily. 69. A method according to any one of claims 36 to 68, wherein the method is administered rectally in an amount. 70. Any of claims 36 to 68, wherein fusidic acid is topically administered to the skin in an effective amount. The method described in one. 71. Fusidic acid, preferably from about 0.1 mg to about 50 mg/kg body weight daily 69. A method according to any one of claims 36 to 68, wherein the method is administered to the eye in an amount of: 72. Fusidic acid, preferably from about 0.1 mg to about 50 mg/kg body weight daily parenterally, most preferably in an amount of about 1 mg to about 20 mg/kg body weight daily. 69. A method according to any one of claims 36 to 68, wherein the method of administering. 73. Fusidic acid, preferably from about 0.1 mg to about 20 mg/kg body weight daily 69. A method according to any one of claims 36 to 68, wherein the method is administered intra-articularly in an amount of . 74. A derivative of fusidic acid is dehydrofushidic acid; 3,11-didehydrofushidic acid; Dic acid; 24,25-dihydrofusidic acid; 17,20-24,25-tetrahydrofusidic acid; Dorofusidic acid; 17,20-24,25-tetrahydrofusidic acid and its Corresponding 3-acetates (especially those conjugated with glycine or taurine); selected from the group consisting of 36. Use according to any one of claims 1 to 35. 75. A derivative of fusidic acid is dehydrofushidic acid; 3,11-didehydrofushidic acid; Dic acid; 24,25-dihydrofusidic acid; 17,20-24,25-tetrahydrofusidic acid; Dorofusidic acid; 17,20-24,25-tetrahydrofusidic acid and its the corresponding 3-acetates (especially those conjugated with glycine or taurine); and 3-O-acetyl-16-evidacetylfusidic acid 39. A method according to any one of claims 36 to 38.