A NEW PHARMACEUTICAL USE OF FUSIDIC ACID AND DERIVATIVES THEREOF

Abstract: The use of fusidic acid or a derivative thereof for the manufacture of a composition for interfering with cytokines in a biological system, in particular for interfering with a cytokine such as a lymphokine, interleukine, monokine, interferon or colony-stimulating factor. Fusidic acid and derivatives thereof are useful for preventing effects of cytokines known to be pathogenetically involved in pathological conditions. Said conditions may e.g. be: insulin-dependent diabetes mellitus (Type 1), hyper- or hypo-functioning of the thyroid gland (e.g. thyroiditis), Addison's disease, endogenous uveitis, eye surgery such as cornea transplantation, cataract operation and laser surgery, transplant rejection, graft-versus-host disease, Crohn's disease or ulcerative colitis, pernicious anemia, celiac disease, contact dermatitis, allergic/atopic dermatitis, pemphigus vulgaris or pemphigoid, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica, conditions related to vasculitis phenomena, neoplastic diseases such as multiple myeloma, septic shock caused by gram-negative bacteria, DIC, arteriosclerosis, periodontal diseases, arthritis, osteoarthrosis or arthritis urica.

Description: A NEW PHARMACEUTICAL USE OF FUSIDIC ACID AND DERIVATIVES THEREOF The present invention relates to a new pharmaceutical use of fusidic acid and derivatives thereof, in particular the use for prevention and/or treatment of diseases, the pathogenesis of which is related to the production and/or function of certain immunoinflammatory media¬ tors, especially cytokines. In particular, the invention relates to the use of fusidic acid and derivatives thereof and to the prevention and/or treatment of diabetes mellitus (type 1) (insulin-dependent diabetes mellitus (IDDM)), thyroid diseases, rheumatoid diseases, inflammatory diseases of the gut, skin diseases, conditions related to transplant rejection, endogenous uveitis and conditions related to opthalmological interventions. BACKGROUND OF THE INVENTION There is increasing clinical and experimental evidence that many autoimmune diseases develop as as result of abnormalities in the immune system, especially in T lymphocyte-mediated immunity. Many signs and symptoms of infectious, inflammatory and neoplastic di¬ seases evolve as a result of stimulation of cellular immunity. In addition, although immunocompetent cells may not necessarily be involved at the initial stage, abnormal regulation of otherwise appropriate cellular immune reactions may lead to acute and chronic diseases. These diseases are generally of unknown etiology and in¬ clude systemic rheumatic diseases (e.g. rheumatoid arthritis (RA)) , organ-specific endocrine diseases (e.g. insulin-dependent diabetes mellitus (IDDM)) and inflammatory diseases of the gut (e.g. Crohn's disease) and skin (e.g. contact dermatitis). Disorders of cell-me¬ diated immunity, however, contribute to many other immunoinflammatory and proliferative diseases as will be described in further detail in the following. The treatments available in relation to said diseases are usually symptomatic or palliative treatments, i.e. most of the drugs pre¬ scribed in connection with said diseases are directed at the allaying of symptoms and usually have no curative effect. Other treatments are so-called substitution therapies which involve life-long supplying to SUBSTITUTE SHEET the patient of substances, e.g. hormones, needed due to a reduced/in¬ sufficient internal production of said substance. Said treatments are often unsatisfactory and imply unwanted and often serious side-ef¬ fects. Thus, improved methods of treatments and improved pharmaceuti¬ cal compositions are needed. Fusidic acid and certain derivatives thereof can be isolated from the fermentation broth of certain strains of Fusidium coccineum and have for a number of years been known as efficient and pharmaceutically acceptable antibiotics. Fusidic acid, Iβ-(acetyloxy)-3,11-dihydroxy- 29-dammara-17(20) ,24-dien-21-oic acid; (3α,llα,160-trihydroxy-29-nor- 8α,9 ,13α,14 -dammara-17(20),24-dien-21-oic acid 16-acetatate) , is a tetracyclic triterpenoic acid with a steroid-like primary structure of formula I: It is well-known that fusidic acid inhibits bacterial protein synthe¬ sis and it may be bacteriostatic and/or bactericidal. It is especial¬ ly active against Staphylococcus aureus, including strains that are resistant to the penicillins or to other antibiotics. The drug is used clinically both in its acid form, and as the sodium and di- ethanolamine salts. The sodium salt of fusidic acid has the actions and uses of fusidic acid. It is more soluble in water, and is readily absorbed from the gastro-intestinal tract. It is also used in topical preparations. For severe staphylococcal infections the antibiotic may be given intravenously as e.g. diethanolamine fusidate. A description of chemical and microbiological modifications of fusidic acid is given in Structure-Activity Relationship in Fusidic Acid-Type Anti¬ biotics (45) , and fusidic acid and derivatives thereof are described in Pharmacopoieas and in Martindale, The Extra Pharmacopoeia, 28th edition (1982). Fusidic acid and derivatives thereof are described in PCT application No. WO 86/03966, published examined Danish application No. 148390 (US 4,119,717), DK 96349 (GB 930786), DK 99802 (AT 252446), DK 101687 (US 3,334,014), DK 104399 (US 3230240), DK 105981 (US 3,230,240), DK 107349 (GB 999794), DK 116940 (US 3499012), DK 131348 (US 3,867,413), DK 142852 (US 4100276, US 4162259 and US 4315004), U.S. Patent Nos. 3,376,324, 3,629,300, 3,920,817, 4,004,004, 4,025,620, 4,060,606, 4,315,004 and U.K. Patent Nos. 2,093,348 and 987,042. However, none of these prior art documents are related to the use of fusidic acid or functional derivatives thereof for interfering with specific immunological response mechanisms or for interfering with cytokines (lymphokines, interferons, interleukins, colony-stimulating factors and/or monokines) , nor related to methods for treating conditions related to disturbances in the cytokine system. Occasional mentioning in the medical literature of specific patients, e.g. diabetics, receiving a short transitory fusidic acid medication due to a bac¬ terial infection is obviously irrelevant to the teaching and embodi- ments of the present invention. SUMMARY OF THE INVENTION According to the present invention it has been found that fusidic acid and derivatives thereof can be used for the prevention and/or treatment of certain forms of inflammatory diseases or processes, epecially forms related to the immune and/or hormone system. It is contemplated (as described in detail in the following description of immunological mechanisms) that the action mechanism is via inter¬ ference with the action of mediators of the immune system, in parti¬ cular cytokines such as monokines and lymphokines, i.e. that fusidic acid interferes with/suppresses the action of certain cytokines and thus inhibits pathological processes leading to tissue damage. In its broadest aspect the present invention relates to the use of fusidic acid or a derivative thereof for substantially inhibiting a biological effect related to a cytokine such as a lymphokine, inter- SUBSTITUTE SHEET ISA/SE leukin, monokine, interferon or colony-stimulating factor for the prophylaxis or treatment of a condition related to a disturbance of a cytokine system such as the ly phokine, interleukin, monokine, interferon or colony-stimulating factor system. The broadest aspect of the invention also relates to a method of treating in a human a condition related to a disturbance in a cytokine system which method comprises administering to the subject an effective amount of fusidic acid or a functional derivative thereof. Thus, the use according to the present invention is not based on the use of fusidic acid or functional derivatives thereof as antibiotics. DETAILED DESCRIPTION OF THE INVENTION General information on cytokines and immuno inflammatory diseases Many signs and symptoms of infectious, inflammatory and neoplastic diseases evolve as a result of stimulation of cellular immunity. In addition, although immunocompetent cells may not necessarily be involved at the initial stage, abnormal regulation of otherwise appropriate cellular immune reactions may lead to acute and chronic diseases. These diseases are generally of unknown etiology and in¬ clude systemic rheumatic diseases (e.g. rheumatoid arthritis (RA)), organ- specific endocrine diseases (e.g. insulin-dependent diabetes mellitus (IDDM)), and inflammatory diseases of the gut (e.g. Crohn's disease) and skin (e.g. contact dermatitis). Disorders of cellmedia- ted immunity, however, contribute to many other inflammatory and proliferative diseases (see Table 1) . SUBSTITUTE SHEET 1SA/SE TABLE 1 Some diseases where macrophages/T-lymphocyte-mediated immune reac¬ tions are considered pathogenetically important. Atopic dermatitis and contact dermatitis Psoriasis and psoriatic arthritis Mycosis fungoides, Sezary syndrome and other T lymphocyte prolifera- tive disorders Pemphigus vulgaris and pemphigoid Erythema nodosum Scleroderma Uveitis Bechet's disease Sarcoidosis Boeck Sjogren's syndrome Rheumatoid arthritis Juvenile arthritis Reiters syndrome Gout Osteoarthrosis Systemic lupus erythematosis Polymyositis and myocarditis Primary biliary cirrhosis Crohn's disease Ulcerative colitis Multiple sclerosis Aplastic anemia Idiopathic thrombocytopenic purpura Multiple myeloma and some B cell lymphomas Multiple sclerosis and other demyelinating diseases Simmonds' panhypopituitarism Graves' disease and Graves' opthalmopathy Subacute thyreoditis and Hashimoto's disease Addison's disease Insulin-dependent diabetes mellitus (type 1) SUBSTITUTE SHEET Miscellaneous Various clinical syndromes with vasculitis (e.g. polyarteritis nodosa, Wegener's granulomatosis, giant-cell arteritis, fever, malaise, anorexia (e.g. in acute and chronic inflammatory and infectious diseases) Disseminated intravascular coagulation (DIC) Arteriosclerosis Shock (e.g. in gram negative sepsis) Cachexia (e.g. in cancer, chronic infectious and chronic inflammatory diseases) Transplant re ection and graft-verus-host disease T lymphocytes govern the induction and regulation of cell-mediated Immune reactions, and proteins and glycoproteins produced by T lym- phocytes (lymphokines) initiate and control the immune response (1,2). However, antigen activation of T cells requires physical interaction with antigen-presenting cells such as macrophages (M0) , and these cells also produce mediator molecules crucial for T cell activation and the subsequent triggering of B lymphocytes to become antibody-producing plasma cells. These mediators are also responsible for the recruitment and activation of many other cell types which build up inflammatory infiltrates in the diseased tissues (1-4) . The lymphokines and the lymphocyte-activating mediators produced by antigen-presenting cells are collectively termed cytokines. Hence, cytokines are essential transmitters of cell-to-cell communication in both physiological and pathophysiological infectious, Immunoinflam¬ matory, and growth processes. In many cases they also function as hormones providing information between the immune system and other tissues and organs. Furthermore, many cytokines are produced by cells outside the Immune system (e.g. in the skin (5) and in blood vessels) , and cytokines may therefore act as autocrine or paracrine hormones without necessarily involving immunocompetent cells. Cytokines are active at extremely low concentrations (10 " - 1 - 0 to 10 ' -~~- M) via binding to specific receptors on a large number of target cells. Most cytokines probably act in the vicinity of the SUBSTITUTE SHEET production site but, as mentioned above, some of the mediators modu¬ late functions of cells at distant sites via blood and lymph cir¬ culation. Fig. 1 shows the dynamics of production and function of cytokines during an immune reaction in a vascularized tissue. Macrophages Macrophages (M0) play a central role in the defence against microbial and neoplastic diseases, and they are important in a wide variety of tissue repair processes (2) . Some M0 functions are performed continuously, such as removal of aged erythrocytes. Other functions are performed periodically, and these functions need prior activation of the M0. The cells may be activated directly, for instance by contact with microorganisms or their products, such as endotoxins (lipopolysaccharides) , muramyl peptides, and other cell wall components. This direct means of M0 activation is in higher animals improved considerably by a more indirect form of activation via lymphokines (1-3). Thus, interferon and -7 (IFNα and IFN7) are important activators of M0, but other M0 activating lymphokines exist (1) . Phagocytosis itself and, perhaps more importantly, immunecomplex- or lymphokine-mediated activation trigger the M0 to synthesize and release a number of biologically active molecules, including pros- taglandins, proteolytic enzymes, complement components, etc. Four of these factors, interleukin lα (IL-lα), interleukin β (IL-13), inter- leukin 6 (IL-6), and tumour necrosis factor-α (TNFα) , have far-reach- ing biological and pathophysiological significance (1-8) . Macrophage-derived polypeptide mediators The molecular biology of the best characterized human M0 hormones has recently been extensively reviewed (2,4,6-8). They are all members of a growing family of cytokines which includes the interferons and some hemopoietic growth factors. The M0 cytokines are also produced during conditions of "stress", and they are important mediators of fever, the acute-phase reaction, and the generation of cachexia as a result of chronic infectious, inflammatory, autoimmune, and neoplastic diseases. Production of TL-la/β , IL-6 and TNFα Although TL-la/β, IL-6 and TNFα are produced primarily by activated M0, the capacity to elaborate these molecules, particularly TL-la/β and IL-6, is not confined to M0 (2). Natural killer cells (NK cells) and B lymphocytes are already known to produce TL-la/β , and fibro- blasts were the cells originally shown to produce IL-6 (= IFNJ2) . In fact, it is likely that all nucleated cells may produce these peptides, provided they are triggered by an appropriate sti¬ mulus. The mature mediator molecules are single-chain polypeptides consist¬ ing of 169 (IL-lα), 153 (IL-L5) , 184 (IL-6), and 157 (TNFα) amino acids. Native human IL-6 is glycosylated, and the re- suiting molecular weight of this cytokine species range between 17 and 28 kD. The genes for TNFα and TNF3 are both located in the class III region of the major histocompatibility complex, i.e. the LA region in man. Recent studies in our laboratories show that blood mononuclear cells obtained from HIA-DR2 positive individuals exhibit a significantly diminished TNFα response in vitro (9) . This is important, because the HLA-DR2 type is positively associated with diseases such as multiple sclerosis and narcolepsy and negatively associated with rheumatoid arthritis and IDDM. Immunological functions of TL-la/β and IL-6 - clinical relevance Receptors for TL-la/β, IL-6 and TNFα have been found on most of the cell types known to respond to the cytokines. IL-lα and IL-l are thought to bind to the same receptor on T and B lymphocytes, and both peptides are capable of down-regulating the expression of the CD4 structure on human T cells (10) . The CD4 structure Is directly en¬ gaged in antigen presentation, possibly through interaction with MHC class II molecules on antigen-presenting cells (Fig. 1) . It is there- fore possible that the T lymphocyte IL-1 receptor binds to the major membrane-associated IL-1 species (IL-lα) on the antigen-presenting cell, and that this receptor is physically or functionally related to the CD4 molecule (Fig. 1 and ref. 2). IL-6 has been shown to be identical with B cell-stimulating factor 2 and a factor necessary for the growth of plasmacytomas and B cell hybridomas (2, 7). IL-6 is also a cof ctor in T cell activation, probably because it induces IL-2 receptors and functions as a second signal for IL-2 production (2) . Modulation of immune reactions and tolerance induction It may prove clinically important that interference with the IL-1- mediated "second signal" for T cell activation may lead to antigen- specific tolerance. Thus, triggering the T cell receptor by a proper¬ ly processed antigen, while at the same time preventing the ensuing IL-1-induced activation of these specifically reactive cells, pre¬ vents the selected clone(s) from responding to the same antigen at a later time, both in vitro (11) and in vivo (12). Because of the central importance of TL-la/β and IL-6 in T and B lymphocyte activation, any treatment that blocks the production or the immunological functions of these mediators would be expected to suppress the entire cellular immune system. This may be especially beneficial in the management of patients receiving transplants. Other functions of IL-1, IL-6 and TNFα - clinical relevance TL-la/β , IL-6 and TNFα are pleiotropic in that they exert multiple functions on many different cell types (2) . It has become clear that T -la/β , TNFα, IL-6 and lymphotoxin (=TNF ) are identical with the factors originally described as endogenous or leukocytic pyrogens; i.e., hormones of leukocytic origin which produced fever (3). It is not entirely clear, however, whether all these cytokines act in a similar fashion in the brain during fever induction. Acute-phase reaction Fever is often part of the acute-phase reaction usually seen in conjunction with acute and chronic infectious and immunoinflammatory diseases, and in cancer (2-4, 8). TL-la/β and IL6, and to a lesser extent TNFα, induce hepatocytes to synthesize acute-phase proteins, including serum amyloid A, C-reactive protein, fibrinogen, hapto- globin, complement components and clotting factors. The elevated level of fibrinogen, especially if accompanied by anemia, causes an increased erythrocyte sedimentation rate, a commonly used clinical parameter of "inflammation" Since TL-la/β and TNFα are potent in- ducers of IL-6 in many cell types, including hepatocytes, it is possible that IL-6 is a second mediator of the acute-phase response elicited by TL-la/β and TNFα. Cachexia, disseminated intravascular coagulation (DIC) and shock The above mentioned clinical picture is often associated with dis¬ turbances in carbohydrate-, lipid- and protein metabolism eventually resulting in wasting (cachexia). In rare situations, clotting ab¬ normalities and shock may occur (6). It was previously thought that microbial products, especially endo- toxin from the cell wall of gram-negative bacteria (lipopolysacchari- de (LPS)) were directly responsible for these often life-threatening symptoms, if triggered by bacterial infection. This is now known to be incorrect, because LPS is a potent inducer of M0 TL-la/β , IL-6 and TNFα, and all pathophysiological processes associated with LPS-in- duced shock can be reproduced by injection of TNFα and to a lesser extent by TL-la/β (2,6). TNFα is probably also responsible for other phenomena associated with LPS-induced disease, such as metabolic acidosis, DIC and cachexia (2,6). It is likely that some of these phenomena are mediated through TNFα-induced production of TL-la/β or IL-6, or one or several other (unknown) hormones. For example, TNFα is a potent inducer of TL-la/β in endothelial cells, and all three cytokines trigger the release of procoagulant factor(s) from these cells. It is therefore likely that both mediators may be involved in the pathogenesis of some vascular diseases with or without accompanying clotting ab¬ normalities. Neoplastic diseases Unregulated production of IL-6 may be pathogenetically involved in the manifestation of several human diseases, including cardiac myxoma and various lymphoid malignancies such as multiple myelomas and various T and B cell lymphomas (6). It is interesting, that myeloma cells constitutively produce IL-6 and express IL-6 receptors, and that the proliferation of myeloma cells in vitro is inhibited by specific antibodies to human IL-6 (13) . Other proliferative diseases - psoriasis IL-6 and, possibly, TNFα may also be involved in other proliferative disorders. Using specific antibodies to human rTNFα and human rIL-6, we have recently demonstrated TNFα and IL-6 in skin biopsies (5, 5A) . The expression of both mediators was considerably augmented by UV- irradiation, and relatively large amounts of IL-6 and TNFα were found in psoriatic lesions. Interestingly, local treatment of the psoriatic lesions with a vitamin D3 analogue resulted in clinical improvement, and biopsies performed after treatment showed unaltered expression of TNFα, but an almost complete elimination of the expression of IL-6 in the upper epidermal layers. It is therefore possible that IL-6 may be involved in the uncontrolled proliferation of keratinocytes seen in psoriasis. Rheumatic diseases TL-la/β, IL-6 and TNFα have many biological effects which qualify them as important in the pathology leading to rheumatic diseases (2,8). The most relevant actions of IL-lα and -β are most likely their stimulatory effects on T and B cells (nonspecific production of inflammatory lymphokines and immunoglobulins), M0 (e.g. MHC class II antigen expression and production of eicosanoids) , chondrocytes (production of collagen type II) , fibroblasts (production of collagen types I and II and eicosanoids) , and osteoclasts (bone resorption) . TNFα and IL-6 share many of these effects with IL-1, although IL-6 does not cause bone resorption (Pedersen JG & Bendtzen K, unpublis¬ hed) . Several cellular sources of the cytokines are present in the arth¬ ritic joint, including M0, B lymphocytes, fibroblasts and vascular endothelial cells (2,8). The demonstration of TL-la/β in synovial fluids from rheumatoid and osteoarthritic joints further suggests that IL-1 in particular may play an important role in the pathogene- sis of arthritis and, possibly, in osteoarthrosis (2, 14). An un¬ balanced reaction between immunocompetent cells and accessory cells such as M0, NK cells and polymorphonuclear leukocytes might continu¬ ally induce TL-la/β , IL-6 and other inflammatory molecules, for example prostaglandins and leukotrienes. This might contribute to the chronic nature of diseases such as RA. The arthritogenic activity of TL-lβ is most clearly seen from in vivo experiments using a rabbit arthritis model (15) . Human rIL-1/3 induces M0 and neutrophil accumulation 24 h after injection in the knee, and this is associated with depletion of proteoglycan from the articular cartilage and an increase in the glycosaminoglycan content of the joint fluid. The same signs of cartilage damage by TL-lβ are seen in joints of rabbits previously depleted of polymorphonuclear leukocytes and M0 by systemic administration of nitrogen mustard. This suggests that TL-lβ itself is capable of stimulating resident cells of the joint, such as the chondrocytes, to cause proteoglycan depletion. Again, it is possible that some of the effects ascribed to TL-lβ may be mediated via local, TL-lβ-induced production of other cytokines, particularly IL-6 and IL-lα. It is noteworthy that urate crystals are potent activators of M0 IL-1 production (16). Thus, IL-1 may contribute to the manifestations of gout. Insulin-dependent diabetes mellitus (IDDM) and thyroiditis Recently, the predominant species of human IL-1, IL-1?, was shown to be a potent suppressor of insulin production in vitro , possibly as a result of a direct and selective cytotoxic effect on pancreatic islet .-cells (17). IL-lα also reduces insulin production, but it is 10 times less potent than IL-1?. The effect of IL-1? is biphasic because increased insulin production is consistently observed at low con¬ centrations of τIL- lβ (10 - 200 pg/ml = 5*10 "13 - 10 "11 M) , whereas higher concentrations reduce both the extracellular and intracellular contents of insulin, probably by a direct and selective damaging effect on the /?-cells. Although TNFα itself fails to affect 3-cell function, the suppressive effect of IL-1/3 is augmented significantly by TNFα (3,8). Other cytokines, by themselves or in conjunction with TLlβ, fail to affect /3-cell function. It is interesting that IL-6 augments the release of insulin from normal rat islets and that IL-lα and IL-1/3 induce IL-6 in the islets themselves (17A) . Furthermore, even though IL-6 increases insulin production, this cytokine causes structural changes in /3-cells simi¬ lar to those caused by IL-1 (17A) . Thus, local IL-1-induced produc- tion of IL-6 may underly the biphasic insulin response observed with various concentrations of IL-1 (17). Furthermore, IL-6, in conjunc¬ tion with IL-1, may contribute to the immunoinflammatory processes eventually leading to IDDM. Similar effects as those described above have been obtained when testing IL-1/3 on human thyroid cells removed from normal thyroid tissue during surgery of paraadenomatous glands (17A, 18) . The secre¬ tion of thyroglobulin and cAMP is markedly suppressed even by low concentrations of rIL-1/3 (15 pg/ml = 10 "12 M) . The effect is aug¬ mented by TNFα and, in addition, by IFN7. The thyrocytes are not killed by TL- lβ , but their ability to form follicles and accumulate glycogen in response to thyroid stimulating hormone is suppressed (18) . Again, a stimulatory effect on thyroglobulin production is consistently observed at very low concentrations of TL-lβ (1.5 - 150 fg/ml = 10 "16 - 10 "14 M) (18), and TL-lβ is a very potent inducer of IL-6 in thyrocytes (17A) . SUBSTITUTE SHEET The above findings and considerations indicate a central role of M0 and perhaps NK cells, and their products TL-la/β , TNFα and IL-6 in a number of physiological and pathophysiological conditions (3,8). Prolonged exposure of cells to increased levels of these cytokines might lead to structural or functional damage to the cells (e.g., in IDDM) , for instance if the target cells for unknown reasons are surrounded by cytokine-producing M0, NK cells and' T and B lymphocy¬ tes, as is the case In the early stage of IDDM development. Endo- thelial cells, fibroblasts and other cells in the connective tissue may also contribute in these situations through an inappropriate production of cytokines such as TL-la/β and IL-6. Moreover, low concentrations of TL-la/β and IL-6 may accumulate in target tissues by diffusion from the blood during conditions of stress, and the cytokines may therefore have important physiological functions by potentiating the secretion of insulin, thyroid- and, possibly, pitui¬ tary- and adrenocortical hormones under these circumstances (Fig. 1) . As described above, the negative association between HLA-DR2 and the production of TNFα may be implicated in some HIA-associated diseases such as IDDM and RA (3,8). In the latter two, HIA-DR2 is associated with resistance to disease, and this might be explained if TNFα is involved, directly or indirectly, in the destruction of islet ?-cells in IDDM and of cartilage and bone in RA and osteoarthrosis. Therapeutic considerations Considering the many putative pathophysiological functions of IL- let//?, IL-6 and TNFα, intervention with the production or action of these hormones might be of great benefit in a number of infectious and immunoinflammatory diseases and, possibly, in certain neoplastic diseases. The production of the mediators is prevented by high doses of glucocorticoids, which directly suppress gene transcription and, If the genes have been transcribed, the mobilization of mRNA, at least in the case of TL-la/β and TNFα (6,8). The effect of TL-la/β on T cells in vitro is prevented by cyclosporin (=Cyclosporin A) (19), by vitamin D3 (1,25 (OH)2 D3) and a synthetic vitamin D3 analogue (20) . Whether cyclosporin and vitamin D3 also prevent some of the other activities of L-la/β is not completely clear, although their metabolic effect on pancreatic /3-cell function is slightly inhibited by both cyclosporin (21) and vitamin D3 (Buschard K & Bendtzen K, unpublished) . Since cyclosporin has many serious side-effects, especially during long-term treatment (34), alternative means of treating transplant rejection and immuninflammatory diseases are much needed. Inhibition of interleukin 1 and interleukin 6 functions by sodium fusidate (fusidin) Fusidic acid is a tetracyclic triterpenoic acid with a steroid-like primary structure as described above. The drug is used clinically both in its acid form and as the sodium and diethanolamine salts as an antibiotic particularly active against Staphylococcus aureus (22). It has been indicated that fusidic acid might have an inhibi¬ tory effect on T-lymphocytes in a mouse model (23A) . Fusidic acid inhibits in vivo and in vitro protein synthesis in both prokaryotic and eukaryotic cells by inhibiting the attachment of transfer RNA to the 50S part of the ribosomes (23). Fusidin has few and only trivial side-effects, even during long-term treatment. According to the present invention it has been found that fusidin acid act as an immunosuppressive agent and that its mode of action as an immunosuppressive agent closely mimicks that of cyclosporin (see the following). Hence, the potentials of fusidin therapy should be investigated in all situations where cyclosporin treatment is advoca¬ ted. As mentioned above, some of the key mediators of the body's response to environmental factors are a family of polypeptide hormones (cyto¬ kines) produced by many cell types but most abundantly by M0. The best characterized members of the family are IL-lα and IL-1/3, TNFα and the recently described IL-6 (1,2). These cytokines participate in many types of acute and chronic reactions involving inflammation, immunological reactions and tissue injury. Generally, IL- lα/β ac- SUBSTITUTE SHEET tivates cells to cell growth (e.g. fibroblasts, keratinocytes and glial cells) and/or increased activity (e.g. prostaglandin E£ syn¬ thesis in fibroblasts, bone resorption by osteoclasts and activation of T and B lymphocytes already triggered by specific antigens or polyclonal activators). In a few instances, however, IL-1 appears to inhibit cell function. For instance, IL-1 is a potent suppressor of pancreatic islet β-cells and thyrocytes, and of melanoma cells (2,3,8,17,24). IL-1 also induces a broad spectrum of systemic chan¬ ges, including fever, slow wave sleep, and changes in blood levels of trace metals, albumin and acute-phase reactants such as fibrinogen and serum amyloid A (2,8,25). TL-la/β are therefore considered of central importance in many if not all adaptive changes of the orga¬ nism in response to various exogenous and, possibly, endogenous stimuli. Recently, IL-lα//? have been recognized to share many activities with another cytokine, IL-6 (3,7). Despite this, IL-6 and TL-lα/β do not show any sequence homology, and the cytokines act on different recep¬ tors. IL-6 has been shown to be identical with B cell-stimulating factor 2 (7) and a factor necessary for the growth of plasmacytomas and B cell hybridomas (26-28) . Unregulated production of TL-lα/β and IL-6 may be pathogenetically involved in the manifestation of several human diseases as described above, and the molecules have many biological effects which qualify them as important in the pathology leading to rheumatic diseases, some endocrine disorders, and various skin diseases (see Table 1). Drugs that interfere with functions of IL-lα//3 and IL-6 are therefore of great interest in the management of many human diseases. As described in the examples, it has been observed that sodium fusi- date (fusidin) inhibited various TL-lα/β functions in vitro when administered in therapeutic and non-toxic concentrations and thus prevented the lymphocyte costimulatory activities of these human cytokines. The drug was also found to interfere with the hybridoma growth-promoting activity of IL-6. Furthermore, the drug prevented "non-immunological" functions of the cytokines, including the toxic effect of TL-la/β on insulin production by pancreatic /?-cells. The above described functional pattern of activity is strikingly similar to that of cyclosporin, a drug used extensively to prevent transplant rejection and in the management of several immunoinflamma¬ tory disorders. Thus, it is contemplated that interference with the immunoactivating signal delivered by TL-la/β and, possibly, IL-6 before and around transfer of a graft by fusidic acid treatment will induce specific and lasting paralysis of those host lymphocytes otherwise programmed to respond to the graft. Such treatment would spare all other clones of lymphocytes in the recipient, and life-long immunosuppressive therapy might no longer be needed. Treatment with fusidic acid or derivatives thereof is contemplated to be beneficial, according to the present invention in both the life-threatening situations dominated by DIC and in other more subtle vascular di¬ seases (e.g. arteriosclerosis). Also, a dysregulated production and/or function of IL-6 may be a key event in the pathogenesis of at least some lymphoid proliferative diseases. Drugs that interfere with the function of the cytokine such as fusidic acid or derivatives thereof are therefore contemplated to be clinically useful. It is also contemplated that interference with the functions of TL-la/β and IL-6 with fusidin or fusidic acid derivatives may be of therapeutic importance in several types of arthritic and degenerative joint diseases. Use of fusidic acid according to the present invention In accordance with the present invention it has been found that fusidic acid and derivatives thereof are useful for preventing effects of cytokines known to be pathogenetically involved in the previous described pathological conditions. In accordance with the present invention the term "fusidic acid or a derivative thereof" comprises any pharmaceutically active and acceptable compound being identical or structurally similar to fusidic acid and exhibiting relevant biological actions similar to those of fusidic acid, including derivatives of fusidic acid, especially pharmaceutically acceptable salts, esters and solvates as well as conjugates of fusidic acid or of the fusidic acid derivatives. Suitable salts are salts with pharmaceutically acceptable bases, such as alkaline earth metal salts, alkali metal salts (especially sodium salts) , ammonium salts or amine salts (especially the diethanolamine salts) . Suitable esters are easily hydrol sable esters, e.g. fusidic acid acetoxymethyl ester. Suitable solvates are e.g. hydrates, in particular hemihydrates. Suitable conjugates are especially conjugates with taurine or glyci- ne. "Derivatives of fusidic acid" comprise e.g. the following compounds: 3-dehydrofusidic acid; 3,11-didehydrofusidic acid; 24,25-dihydrofusidic acid; 17,20-24,25-tetrahydrofusidic acid; 17,20-24,25-tetrahydro usidic acid and their corresponding 3-acetates (especially conjugated with glycine or taurine) ; 3-0-acetyl-16-epideacetylfusidic acid. Also included in the present invention is the use of the physiologi¬ cally acceptable derivatives, including functional derivatives, which are disclosed, as well as their preparation, in the patents and the references listed above In the section "Background of the invention", e.g. the derivatives disclosed in U.S. Patent No. 4,004,004. Some of these derivatives are Insufficient as antibacterial agents - a feature which may be beneficial in the use according to the present invention. Of particular interest in connection with the present invention are compounds having the general formula II: wherein the dashed lines indicate the presence of either single or double bonds between the atoms in question, with the proviso that one of the bonds C(13-C(17) and C(17)-C(20) is a double bond, A is selected from the group consisting of OH, OR', and NHR", wherein R' is selected from the group consisting of C 1 -C -alkyl, aralkyl, such as phenyl-C* ] _-C -alkyl, and aryl, such as phenyl or o- , m- or p-tolyl, and R" is CH 2 COOH or CH 2 CH 2 S0 3 H, R is OH or a keto oxygen (=0), whereby, when R is OH, the C(ll)- R bond is preferably in the α configuration with respect to the C(19) methyl group, R-^ is hydrogen, halogen or a nitrile group, or R^- is selected from the group consisting of -OR 3 , -NHR 3 and -SR 3 , in which R 3 is hydrogen or is an organic group such as acyl, in particular C^-C^- alkylcarbonyl, alkyl, in particular C^-C^-alkyl, aralkyl, SUBSTITUTE SHEET such as phenyl-C^-C^alkyl, or aryl, such as phenyl or o-, m- or p-tolyl, R-~ is OH C-L-C -alk lsulfonyloxy or a keto oxygen (-=0), whereby, when B is OH, the C(3)-R^ bond is preferably in the α configuration with respect to the C(19) methyl group, or R 2 is hydrogen or halogen or a nitrile group or a group -OR 3 , -NHR 3 and -SR , in which R 3 Is hydrogen or is an organic group such as acyl, in particular C^-C^- alkylcarbonyl, alkyl, in particular 0^-0 -alkyl, aralkyl, such as phenyl- G__-C_^-alkyl, or aryl, such as phenyl or o-, m- or p-tolyl, and salts thereof. Examples of C^-C4-alk l are as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sek.butyl, and tert. butyl. C j _-C4-alk l and the other groups mentioned above may optionally be substituted where appropriate, such as disclosed in the patents and other literature referred to in the above section "Background of the invention" Among the compounds of the general formula II, preferred compounds of the general formula II are, e.g., compounds wherein A is OH, a double bond is present in the position C(17)-C(20) and in the position C(24)-C(25), the hydrogen atom at C(9) is in the β configuration with respect to the C(19) methyl group, R is a hydroxy group in the α configuration with respect to the C(19) methyl group, R 1 is a C^-C4-alkylcarbonyloxy group such as an acetoxy group or a C*L-C4-alkylcarbonylthio group, an arylcarbonylthio group such as a phenylcarbonylthio group, or a C^-C4~alkox group such as a methoxy or ethoxy group, and R 2 is a nitrile group, a C^-C4-alkylsulfonyloxy group, or, in particular, a hydroxy group In the α configuration with respect to the C(19) methyl group, in particular fusidic acid and fusidic acid salts such as the sodium salt (fusidin) . Specific examples of interesting derivatives are the derivates termed SUBSTITUTE SHEET ISA/SE VD 1177, 1178, 1303, 1360, 1362, 1460, 1546 and PR 1089 described in table 2 below. TABLE 2 Δ A v Appl. Microbi *ol ■ >ogy 2 ->-., 9955-1 l«46 (3979) (46) • > j ^S-inαl. bond. - - 24.25-doubl. bond ** Structure as indicated, but 24.25-single bond The following definitions are employed in the present text: "Cytokine" is a general term for a proteinaceous mediator released primarily but not exclusively by a cell population of the immune system as a response to a specific stimulating agent, e.g. a specific antigen or an alloantigen; or a nonspecific, polyclonal activator, e.g. an endotoxin or other cell wall components of a gram-negative bacteria; "lymphokine" is a general term for a proteinaceous mediator released by sensitized lymphocytes as a response to a stimulating agent, e.g. a specific antigen or an alloantigen; or by a lymphocyte challenged by a polyclonal activator, e.g. an endotoxin or other cell wall component of a gram-negative bacteria; "interleukin" is a general term for a proteinaceous mediator released primarily but not exclusively by a macrophage, T, B or NK cell as a response to a stimulating agent, e.g. a specific antigen or an al¬ loantigen or by a cell challenged by a polyclonal activator, e.g. an endotoxin or other cell wall component of a gram-negative bacteria; "monokine" is a general term for a proteinaceous mediator released by a mononuclear phagocyte (e.g. a monocyte or a macrophage or a Kupffer cell (liver) or a Langerhans' cell (skin)) as a response to any stimulating agent; "interferon" is a general term for a proteinaceous antiviral and/or monocyte/macrophage activating factor released by all cells as response to a virus or an interferon-inducer such as a polynucleotide; in particular cells of the immune system as a response to a specific stimulating agent, e.g. a specific antigen or an alloantigen, or a nonspecific, polyclonal activator, e.g. an endotoxin or other cell wall components of a gram-negative bacteria; "colony-stimulating factor" is a general term for a proteinaceous, haematopoietic colony-stimulating mediator released primarily but not exclusively by a cell population of the immune system as a response to a specific stimulating agent, e.g. a specific antigen or an al- SUBSTITUTE SHEET loantigen; or a nonspecific, polyclonal activator, e.g. an endotoxin or other cell wall components of a gram-negative bacteria. One aspect of the invention is the use of fusidic acid or a function¬ al derivative thereof for the manufacture of a pharmaceutical compo- sition for substantially inhibiting a biological effect in a human related to a cytokine, such as a lymphokine, interleukin, monokine, interferon or colony-stimulating factor, for the prophylaxis or treatment of a condition related to a disturbance of a cytokine system such as the lymphokine, interleukin, monokine, interferon or colony-stimulating factor system. As used herein the term "pharmaceu¬ tical composition" comprises any composition suitable for human use. The invention particularly relates to the use of fusidic acid or a functional derivative thereof for substantially inhibiting a biological effect in a human related to a cytokine for the prophylaxis or treatment of a condition related to a disturbance of a cytokine system; and/or for substantially inhibiting a biological effect in a human related to a lymphokine for the prophylaxis or treatment of a condition related to a disturbance of a lymphokine system; and/or for substantially inhibiting a biological effect in a human related to an interleukin for the prophylaxis or treatment of a condition related to a disturbance of a interleukin system; and/or - for substantially inhibiting a biological effect in a human related to a monokine for the prophylaxis or treatment of a condition related to a disturbance of a monokine system, and/or for substantially inhibiting a biological effect in a human related to an interferon for the prophylaxis or treatment of a condition related to a disturbance of a interferon system; and/or SUBSTITUTE SHEET for substantially inhibiting a biological effect in a human related to a colony-stimulating factor for the prophylaxis or treatment of a condition related to a disturbance of a colony- stimulating factor system. s used herein "substantially inhibiting" comprises a therapeutically relevant prevention of the harmful biological actions of said me¬ diator, said prevention being based on fusidic acid or derivatives thereof or combinations with other treatments/drugs exerting a form of antagonistic effect on the actions of the mediator in question. Said conditions have been described above, and the conditions descri¬ bed comprise diseases occuring in humans which diseases demand thera¬ peutical intervention as well as conditions in which a suppression of a cytokine system is desirable such as in connection with transplan¬ tation or eye surgery. As has been described in detail above, clini- cally important interleukins in this context are in particular inter¬ leukin 1 (α or β) , and interleukin 6. In one of its broadest aspects the invention further relates to the use of fusidic acid or its derivatives as a substantially selective immunosuppressive drug and/or as a drug the action of which is via an antagonistic effect on the action of one or more cytokines. whenever systemic treatments are employed, the administration may be orally, rectally and/or parenterall , the administration being depen¬ dent on the patient's age and weight and the particular condition being treated as well as the severity of the disease. The active ingredient or combinations thereof may be contained in any appropriate amount in a composition, and are generally contained in an amount of 1-95% by weight, based on the total weight of the pre¬ paration. The composition may be in any appropriate unit dosage form. Parenteral administration may comprise suitable injection, e.g. intraveneous, intramuscular, intraarticular, intraocular or retroocu- lar injection, infusion or implantation of e.g. suitable delivery devices. Formulations for parenteral use may be presented in unit dose forms, e.g. ampoules, or in multi-dose containers with an added suitable preservative. The composition may be in form of a solution, a suspen¬ sion, an emulsion or a delivery device for implantation or may be presented as a dry powder to be reconstituted with water or another suitable solvent before use. Apart from the active drug substance the compositions may comprise suitable pharmaceutically acceptable carri- ers and/or exipients. Furthermore the composition may, in addition, conveniently comprise suspending, stabilizing, pH-adjusting agents and/or dispersing agents. Compositions for oral or rectal use may be formulated according to conventional pharmaceutical practice and may be in the form of tab- lets, capsules, pills, powders, ampoules, granulates, dragees, pa¬ stes, gels, suppositories or enemas; or liquid formulations such as suspensions (oily or aqueous), solutions, elixirs, emulsions or drenches and the like. The auxiliary additives of the pharmaceutical compositions may be any conventional pharmaceutical additives and carriers: Binding agents such as cellulose derivatives, starch, gelatin and polyvinylpyrrolidine; fillers such as sugar, mannitol, lactose, microcrystalline cellulose, potato starch, calcium phosphate; sui¬ table absorption promotors; disintegrants such as potato starch, alginic acid; lubricants such as magnesium stearate, stearic acid, talc; emulsifying agents such as lecithin, sorbitan monooleate; wetting agents such as lecithin, polyoxyethylene esters; or buffering agents such as acetate, citrate, phosphate. The solid compositions may by means of specially adapted coating techniques be provided with a coating adapted to protect the composi¬ tion from unwanted chemical changes prior to the release of the active compound. The coating may be adapted to release the active compound in a predetermined pattern e.g. in order to achieve a con¬ trolled release formulation. The dosage of fusidic acid or its derivatives depend on the admini¬ stration method, the disease, the severity of the disease and of the weight and age of the patient. For compositions adapted for oral administration, the dosage is often 3.5 mg-1 g administered 2-6 times daily or for instance 0.5 g x 5 daily or in certain cases 1 g every second or third day. Thus, oral administration may comprise ranges from approximately 1 mg to 75 mg per kg body weight per day or in appropriate cases 0.1 mg to 20 mg per kg body weight per day. A preferred dosage regime is normally 0.5 g 3 times daily. In certain cases, e.g. in the treatment of graft-versus-host disease the dosage is normally doubled. When fusidic acid or a derivative thereof is administered rectally, a somewhat higher amount such as from about 1 mg to about 100 mg per kg body weight per day is usually preferred. For parenteral administration, a dosis of about 0.1 mg to about 50 mg per kg body weight per day, most preferably in an amount from about 1 mg to about 20 mg per kg body weight per day is convenient. When administering fusidic acid intraarticularly, an amount from about 0.1 mg to 20 mg per kg body weight per day is usually preferable. For parenteral administration, an aqueous solution of e.g. 0.5-2% or more of the active Ingredient may be employed. hen fusidic acid or a derivative thereof is administered to the eye, an amount from about 0.1 mg to about 50 mg per kg body weight per day is usually preferred. In every case, the dosage should be carefully adapted so as to imply the specific action in the cytokine system, i.e. attainment of op¬ timal total dosages, dosage forms and dosage frequency. In certain cases it is relevant to administer a relatively high unit dosis, a so-called "booster dosis". Pharmaceutical compositions for topical use such as compositions suitable for application to the skin according to the present in¬ vention are suitably creams, gels, ointments, lotions, liniments, suspensions, solutions, pastes, sticks, sprays, soaps, shampoos, powders, suppositories and enemas. The topical administration should be onto or close to the pathological changes in the body. The compo¬ sitions may be any suitable medicated mass adapted for direct appli- cation or for introduction into the relevant orifice of the body, e.g. the rectal, urethral or vaginal orifice. The compositions may simply be applied directly onto the diseased part, e.g. the skin or mucosa. Other relevant formulation adaptations for application to the eye may e.g. be eye lotions, eye ointments, eye-drops or drug deli- very systems adapted for administration to the eye such as compo¬ sitions suitable for implantation administration. In certain cases it may be applied by means of special medical devices such as dressings including occlusive dressings, or alternatively plasters, pads, sponges, strips, or other forms of suitable flexible pieces of ma- terial. Formulations for topical administration may comprise pharmaceutically acceptable carriers and/or exipients such as ointment bases (e.g. paraffin, polyethylene glycols, Tween®, Span® , vegetable oils), suspending or emulsifying agents (e.g. lecithin, sorbitan monooleate, gelatin, methyl cellulose, gum acacia, sorbitan monooleate derivati¬ ves), gelforming agents (e.g. Carbopol, alginates, gelatin), preser¬ vatives (e.g. methyl or propyl p-hydroxybenzoates, benzalkonium chloride), antioxidants (e.g. tocopherol, ascorbic acid, butylated hydroxy anisol) , humectants (e.g. glycerin, propylene glycol, urea), and perfumes and skin protective agents. Formulations for topical administration to the eye may comprise pharmaceutically inert vehicles or be in form of a suitable carrier system. Pharmaceutically acceptable carriers and/or exipients for the preparation of eyedrops include for example buffering agents such as boric acid or borates, pH adjusting agents to obtain optimal stabili¬ ty or solubility of the actuve drug substance, agents to adjust the tonicity such as sodium chloride or borates, viscosity altering agents such as hydroxypropyl cellulose, methylcellulose, polyvinyl- pyrrolidone, polyvinyl alcohols or polyacrylamide, oily vehicles such as vehicles comprising arachis oil, castor and mineral oils. Eyedrops presented as emulsions or suspensions may furthermore comprise stabi- lizing, dispersing, wetting, emulsifying and/or suspending agents. Eye lotions and eye ointments may comprise pharmaceutically accep¬ table carriers and/or exipients such as used in an eyedrop composi¬ tion or in other relevant topical composition, e.g. ointments, cre- ams, lotions and the like. An example of a general method for preparing aqueous eyedrops compri¬ sing an active drug substance is to dissolve the compound (preferably as the soluble sodium salt) in sterile water in a given concentra¬ tion, optionally adjust the pH to a suitable value with a suitable buffer or with hydrochloric acid or sodium hydroxide, optionally add a preservative like phenethanol or chlorobutanol, optionally add a viscous altering excipient like methylcellulose, and sterilize the final solution by e.g. autoclavation by use of one of the generally accepted cycles or by membrane filtration. The topical compositions for use according to the present invention comprise e.g. 0.001-60% w/w of the active ingredient, preferably 0.1- 20%, especially 0.5-10% or 1-5%. According to the invention the compositions may be applied several times a day, e.g. 1-5 times a day, depending on the condition in question and the severity thereof and furthermore on the absorption conditions on the site in question. In each case, the particular dosis will depend on obtaining an appro¬ priate absorption of the fusidic acid or derivative thereof in a sufficient form and amount. In each case, said amount and form should be adapted so as to exert its specific action in the cytokine system. Hence, it is very important - e.g. when application onto the skin is performed - to ensure that the patient applies a relatively well- defined layer of the composition. In particular, the invention relates to the use of fusidic acid or a derivative thereof for prophylaxis or treatment of diabetes mellitus, in particular insulin-dependent diabetes mellitus (type 1) , in particular for the prevention of progression of diabetes mellitus (type 1) , especially substantially immediately after the first diagnostic establishment of diabetes mellitus, or for prophylaxis after establishment of being in a high risk group of developing diabetes mellitus. These uses as well as other uses and methods of the invention will preferably be noted specifically and in detail as explained herein in instructions for use provided to the physician and/or to the patient together with the compositions to be used. During the last few years animal investigations have shown the capa¬ bility of cyclosporin (a cyclic peptide metabolite of the fungi cylindrocarpon lucidum and trichoderma polysporum) to prevent diabe¬ tes, first of all in the spontaneously diabetic BB rat. Clinical studies performed on diabetics and involving investigation of cyclosporin's effect on progression of diabetes have shown that clinical remission was obtained by means of the cyclosporin therapy; this seemed to be due to improvement of the functional j8-cell mass. The remission rate was greater in diabetic patients who entered after less than six weeks with symptoms and two weeks of insulin therapy, than in those who entered later. The findings demonstrate that an acute process affecting the β-cells can be modulated by initiation of the cyclosporin immunosuppressive therapy within a critically brief time interval after onset of overt disease, and that continued treat¬ ment can maintain partial or complete remission through a period of at least one year. As used in the present specification and claims, the term "substantially immediately after" comprises a period after the first diagnostic establishment of the disease or a high risk of developing the disease within a limited number of months or years which period should be as short as possible, so as to enable intervention with the progression of irreversible changes in the pathological body tissues, said invention being obtained by means of the use according to the invention of fusidic acid or derivatives thereof. The administration of cyclosporin increased the remission rate in diabetes mellitus (type 1) of recent onset, and enhanced and preser¬ ved /3-cell function through the first year after diagnosis. It is inferred that these effects were induced by virtue of the immunosup¬ pressive action of cyclosporin. Thus the findings strongly support the hypothesis that an immune process is involved in ^3-cell damage in the human disease. The effect of duration of diabetes on the early outcome suggests that although the immune processes affecting β-cells may be chronic and precede diagnosis through a long period of time, the development of overt disease is associated with an acceleration of events. From e.g. the above-described experiments it is inferred that the potentiality for recovery of Insulin secretion is greater than for¬ merly believed, and that by administration of fusidic acid or a derivative thereof, the secretory capacity can be maintained in the normal range through one year or more of immunosuppression in many patients. Thus, fusidic acid and derivatives thereof may be used according to the present invention for the prevention of progression of irrever¬ sible pathological processes in the pancreatic tissues which other¬ wise lead to diabetes mellitus (type 1) . The therapy of the invention is preferably instituted as soon as possible, i.e. very shortly after the onset of diabetes or, preferably, immediately after diagnosis of pathological processes in the islets of pancreas (e.g. before clini¬ cal manifestation of diabetes mellitus (type 1)) . The therapy of the invention may also apply to certain identified high risk groups the identification being e.g. obtained by means of a screening program employing markers relatively specific for pathological changes seen in diabetes mellitus and/or preliminary stages thereof, especially markers of ongoing pathological changes in predisposed individuals (e.g. in HIA-DR 3/4-positive individuals). A person is contemplated to be in a high risk group of developing diabetes mellitus (type 1) if his risk Is about 10-100%, such as about 50-100%. In particular, the present invention relates to the use of fusidic acid or a derivative thereof for prophylaxis or treatment of diabetes mellitus (type 1) for oral or rectal use. In another aspect, the invention relates to the use of fusidic acid or a derivative thereof for the prophylaxis or treatment of conditions related to the function of the thyroid gland, in particular hyper- or hypofunctioning of said gland, e.g. thyroiditis (acute, subacute or chronic), including Hashimoto's disease (lymphocytic thyroiditis; lymphoid thyroiditis), Riedel's thyroiditis (chronic fibrous thyroiditis), de Quervain's thyroiditis (subacute granulomatous thyroiditis) , subacute lymphocytic thyroiditis, Graves' disease, Graves' subacute thyroiditis and Graves' ophthalmopathy. For a plurality of diseases e.g. the conditions related to the func¬ tion of the thyroid gland, the inflammatory diseases of the gut, arthritis urica, multiple sclerosis, B and T cell lymphoma such as multiple myeloma treatment with fusidic acid or derivatives thereof can be beneficial to the patient also in a period of inapparant disease, in the way that the treatment with fusidic acid or derivati¬ ves thereof can prevent or postpone a relapse of the condition in question. By the term "treatment" is therefore generally also meant prophylactic treatment designated to prevent or postpone a relapse of the disease. In another aspect, the invention relates to the use of fusidic acid or a derivative thereof for the prophylaxis or treatment of a condition related to hypofunction of the adrenal glands, in particular Addison's disease or furthermore Simmonds' panhypopituitarism. In another aspect, the invention relates to the use of fusidic acid or a derivative thereof for the treatment of endogenous uveitis. By the term "endogenous uveitis" is meant e.g. non-infectious uveitis, such as non-infectious uveitis anterior and uveitis posterior. The present invention relates in particular to the manufacture of a composition suitable for treatment of the eye, such as an eye drop composition, an eye ointment composition, an eye lotion composition or an injectable composition for intraocular or retroocular injection, or an oral composition. SUBSTITUTE SHEET In yet another aspect, the invention relates to the use of fusidic acid or a derivative thereof for the prevention of the inflammation after eye surgery such as cataract operation or laser surgery. This treatment, as well as treatment in other conditions, can in some cases be prophylactic in the way the the goal of the treatment is to diminish or avoid an inflammation not to actually treat the condition. The present invention relates in particular to a composition suitable for treatment of the eye, such as an eye drop composition, an eye ointment composition, an eye lotion composition or an injectable composition for intraocular or retroocular injection or an oral composition. In another aspect, the invention relates to the use of fusidic acid or a derivative thereof for treatment of progression of arthritis such as rheumatoid arthritis including juvenile rheumatoid arthritis, psoriatic arthritis or Reiter arthritis substantially immediately after the first diagnostic establishment of arthritis. The therapy of the invention is preferably instituted as soon as possible, i.e. very shortly after the onset of arthritis or, preferably, immediately after diagnosis of pathological processes (e.g. before clinical manifestations) . The therapy of the invention may also apply to certain identified high risk groups the identification being e.g. obtained by means of a screening program employing markers relatively specific for arthritic changes and/or preliminary stages of arthritis, especially markers of ongoing pathological changes in predisposed Individuals, in particular individuals having specific HIA tissue types. The invention relates in particular to the manufacture of a composition for oral use or for use as parenteral or intraarticular injections. In another aspect, the Invention relates to the use of fusidic acid or a derivative thereof for the prophylaxis or treatment of osteoarthrosis. In another aspect, the invention relates to the use of fusidic acid or a derivative thereof for the prophylaxis or treatment of arthritis urica (gout) . SUBSTITUTE SHEET In another aspect, the invention relates to the use of fusidic acid or a derivative thereof for prophylaxis or treatment of a condition related to transplant rejection, such as a graft-versus-host reaction, or any other conditions related to e.g. marrow, cornea or skin trans¬ plantation. The treatment often requires higher doses of fusidic acid than usual and is often instituted as a prophylactic treatment to avoid transplant rejection or graft-versus-host disease. In parti¬ cular, the present invention relates to a such composition for oral or parenteral administration. In another aspect, the invention relates to the use of fusidic acid or a derivative thereof for the prophylaxis or treatment of a condition related to cornea transplantation, in particular to a composition suitable for treatment of the eye, such as an eye drop composition, an eye ointment composition, an eye lotion composition or an injectable composition for intraocular or retroocular injection, or an oral composition. In yet another aspect, the invention relates to the use of fusidic acid or a derivative thereof for the treatment of Crohn's disease or ulcerative colitis, especially for the prevention of relapse or progression of Crohn's disease or ulcerative colitis, or for the treatment of perniceous anemia or celiac disease, in particular to the manufacture of an oral or rectal composition, or a composition for parenteral administration. In another aspect, the invention relates to the use of fusidic acid or a derivative thereof for prophylaxis or treatment of contact dermatitis or allergic/atopic dermatitis, or for treatment of pemphigus vulgaris or pemphigoid, in particular to the manufacture of a composition for oral administration, or for topical treatment of contact dermatitis, in particular for topical administration to the skin. In another aspect, the invention relates to the use of fusidic acid or a derivative thereof for treatment or prevention of relapse of a demyelinating disease, in particular multiple sclerosis, or for SUBSTITUTE SHEET ISA/SE treatment or prevention of relapse of sarcoidosis Boeck, Sjogren's syndrome, Reiter's syndrome, erythema nodosum, scleroderma or Bechet's disease. In yet another aspect, the invention relates to the use of fusidic acid or a derivative thereof for treatment or prevention of relapse of polymyositis polymyalgia rheumatica, myocarditis or systemic lupus erythematosis, in particular to a the manufacture of a composition for oral or parenteral administration. In another aspect, the invention relates to the use of fusidic acid or a derivative thereof for treatment or prevention of relapse of a condition related to vasculitis phenomena, e.g. polyarteritis nodosa, Wegener's granulomatosis, or giant-cell arteritis. In another aspect, the invention relates to the use of fusidic acid or a derivative thereof for treatment or prevention of relapse of primary biliary cirrhosis or chronic active hepatitis. In another aspect, the invention relates to the use of fusidic acid or a derivative thereof for treatment of a neoplastic disease, such as aplastic anemia or idiopathic thrombocytopenic purpura, or for treatment or prevention of relapse of a neoplastic disorder of the lymphold tissue, e.g. B cell lymphoma or multiple myeloma, or a T lymphocyte proliferative disorder, e.g. mycosis fungoides or Sezary syndrome. The present invention relates in particular to a such composition for oral or parenteral administration. In another aspect, the invention relates to the use of fusidic acid or a derivative thereof for prophylaxis or treatment of septic shock caused by gram-negative bacteria. Fusidic acid has been used for treatment of infections caused by gram-positive bacteria such as Staphylococcus aureus, but prior to the present invention it was not known that fusidic acid could be used for prophylaxis or treatment of septic shock which is caused by gram-negative bacteria. The present invention relates in particular to the use of fusidic acid or a derivative thereof for " prophylaxis or treatment of septic shock caused by gram-negative bacteria for oral or parenteral administration. In another aspect, the invention relates to the use of fusidic acid or a derivative thereof for prophylaxis or treatment of disseminated intravascular coagulation. In another aspect, the invention relates to the use of fusidic acid or a derivative thereof for prophylaxis of arteriosclerosis. In another aspect, the invention relates to the use of fusidic acid or a derivative thereof for prophylaxis or treatment of a condition acute and chronic periodontal diseases, in particular periodontitis and periodontosis, in particular by means of periodontal injections. In yet another aspect, the invention relates to the use of fusidic acid or a derivative thereof for use as an immunosuppressive drug, and the use in combination with other relevant drugs, such as cyclosporin or a derivative thereof. In a further aspect, the invention relates to the use of fusidic acid or a derivative thereof together with a cyclosporin (e.g. Cyclosporin A and G) or a derivative thereof. Such combination therapy is designed so as to reduce the serious adverse effects of the cyclosporin, in particular the nephrotoxic effects, and at the same time utilizing the immunomodulating effects of the cyclosporin together with the effects of fusidic acid or its derivatives. Relevant dosage intervals may e.g. be: Cyclosporin A (or another cyclosporin of equivalent potency) : - Systemic administration: 1-10 mg/kg body weight; Topical administration: 1-20 mg/ml (ointments, solutions, eye drops etc., cf. above). Also provided by the present invention is a pharmaceutical composi¬ tion comprising fusidic acid or a derivative thereof together with a cyclosporin (e.g. Cyclosporin A and G) or a derivative thereof. In a further aspect, the invention relates to the use of fusidic acid or a derivative thereof together with a non-steroid antiinflammatory drug (NSAID) (e.g. indometacin and acetyl salicylic acid) or an analogue and/or a glucocorticoid (e.g. hydrocortisone). Such combination therapies are designed so as to reduce the serious adverse effects, and at the same time utilizing the effects of said drugs together with the effects of fusidic acid or its derivatives. Relevant dosage intervals may e.g. be: Acetyl salicylic acid (or another NSAID of equivalent potency) : - Systemic administration: 5-100 mg/kg body weight; Topical administration: 10-100 mg/ml (ointments, solutions, eye drops etc., cf. above). Hydrocortisone or another glucocorticoid drug of equivalent potency: Systemic administration: 1-20 mg/kg body weight; - Topical administration: 1-20 mg/ml (ointments, solutions, eye drops etc, cf. above). In yet a further aspect, the invention relates to use of a pharmaceutical composition comprising fusidic acid or a derivative together with a non-steroid antiinflammatory drug (e.g. indometacin and acetyl salicylic acid), and/or glucocorticoid (e.g. hydrocortisone) . In another aspect, the invention relates to the use of fusidic acid or a functional derivate thereof together with FK-506 or a functional derivative thereof. Such combination therapy is designed so as to reduce the serious adverse effects of FK-506, and at the same time utilizing the immunomodulating effects of the FK-506 together with the effects of fusidic acid or its derivatives. In every case, the dosage of the additional drug or drugs described above should be carefully adapted so as to imply the specific action in the cytokine system, i.e. attainment of optimal total dosages, dosage forms and dosage frequency. In certain cases it is relevant to administer a relatively high unit dosage, a so-called "booster do¬ sis". EXAMPLES IN VITRO EXPERIMENTS MATERIALS AND METHODS Fusidin, fusidic acid derivatives, and cyclosporin The water soluble sodium salts of fusidic acid and fusidic acid derivatives as well as the fucithalmic eyedrops and the fusidin tablets were gifts from Leo Pharmaceutical Products (Ballerup, Den- mark) . Except for 2 derivatives (see below) , the drugs were dissolved in 0.1 M phosphate buffered saline, pH 7.4 (PBS) at a concentration of 1 mg/ml and stored at 4°C. The fusidic acid derivatives VDl546Na and PR1089Na were dissolved at 100 mg/ml in 98% ethanol and stored at 4°C. Before each experiment, the compounds were further diluted in culture medium RPMI 1640 (Ros- well Park Memorial Institute) with 25 mM hepes-buffer (NordVacc, Stockholm, Sweden) supplemented with penicillin (500 IU/ml) , strep¬ tomycin (500 μg/ml) , L-glutamine (2 mM) , and 1 - 10% of a heat-in- activated human serum pool (NHS) . The final concentrations of ethanol were always less than 0.5 o/oo (v/v) , and these concentrations did not affect the production or function of the cytokines. Cyclosporin was kindly provided by Sandoz (Basel, Switzerland). The powder was dissolved in ethanol (50 mg/ml) and diluted to 20 μg/ml in sterile saline. This stock solution was stored at -20°C until use. A similar dilution of ethanol was stored and used in parallel experi¬ ments. Human cytokines rIL-lα was a gift from T. Tsuboi (Dainippon, Osaka, Japan). rIL-13 was from Cistron Biotechnology (Pine Brook, NJ, USA). Purified native human IL-6 and rIL-6 used for pancreatic /3-cell experiments were donated by J. van Damme (University of Leuven, Leuven, Belgium)(26) and L.A. Aarden (University of Amsterdam, Amsterdam, Holland)(27) . rIL-6 used for the other studies was a gift from T. Hirano (Osaka University, Osaka, Japan)(28). rTNFα was a gift from G.R. Adolf (Ernst Boehrlnger Institute, Vienna, Austria) . rIL-2 was from Boeh- ringer (Mannheim, FRG) . The activities of the cytokines were ascer¬ tained by bioassays (see below) . The cytokines were calibrated with WHO interim standard preparations of the human cytokines (NBSB, London, U.K.). The endotoxin contents of the cytokine preparations did not exceed 1 pg/1,000 U measured by a chromogenic Limulus Amebo- cyte Lysate assay (Struers, Rødovre, Denmark). Production of cytokines Human mononuclear cells (MNC) were Isolated from the blood of healt- hy, unmedicated adult donors by gradient centrifugation of heparini- zed venous blood on Ficoll-Hypaque (Lymphoprep, Nyegaard, Oslo, Norway), as previously described (20,29-32). Cells, 2xl0 6 /ml, were incubated in culutre medium RPMI 1640 and pulsed for lh at 37°C with 2 μg/ml of E. coli-endotoxin 055:B5 (LPS) extracted by the hot-phenol-water method (Mallinkrodt Inc. , St. Louis, MO, USA) plus 10 μg/ml of phytohemagglutinin-P (PHA)(Difco, Detroit, MI, USA). The cells were then washed two times with Hanks' balanced salt solution (HBSS) and resuspended in the same culture medium containing 2 μg/ml of LPS but not PHA. In some experiments, the production of cytokines were carried out in the presence of 1 μg/ml of indomethacin (Sigma, St. Louis, MO, USA). After 20 h of culture, the supernatants were isolated and dialyzed for minimum 2 days at 4°C against HBSS and, subsequently, RPMI/Hepes buffer (20) . The cells were collected for viability studies using trypan blue exclusion. In parallel experiments, 20 μg/ml of sodium-ll?--*H-fusi- date, specific activity 93 μCi/mg, (Leo Pharmaceutical Company) was added at the initiation of the cultures using 0-10% (v/v) NHS. After dialysis, the supernatants were tested for residual ^H fusidic acid by scintillation counting. T cell growth induced by IL-2 Supernatant IL-2 activity and the effect of fusidin on IL-2 activity in vitro were measured using IL-2-dependent CTLL-2 cells (American Type Culture Collection, Rockville, MD, USA) cultured for 20 h at 37°C and pulsed with -thymidine for the last 3 h of culture (31). All experiments were carried out in triplicate. ELISAs for TNFα and IFN7 The presence of TNFα was measured by a slight modification of a previously described sandwich ELISA, using high-titered, monospecific rabbit antisera to human rTNFα (30). The ELISA utilizes the biotin/a- vidin system, and the detection limit is 1 pg/100 μl. The assay is not influenced by serum, and there is no cross reaction with other cytokines, including TNF/9 (-lymphotoxin) . The recovery of TNFα: was always above 85% and the coefficient of variation within and between assays were less than 10%. IFN7 was measured by a sandwich ELISA purchased from Holland Biotech¬ nology (Leiden, Holland) . The ELISA utilizes two different monoclonal antibodies to IFN7 and the biotin/antibiotin-alkaline phosphatase method. The sensitivity of this assay was 15 pg per 150 μl, and the coefficient of variation was less than 10%. In the initial experi¬ ments, human IFN7 was tested by Immunoradiometric assay (IRMA) using two monoclonal antihuman IFN7 antibodies (Centocor, Malvern, PA, USA). The sensitivity of this assay is approximately 0.1 IU/ml. T cell proliferation induced by TL-la/β Total IL-1 activities in the supernatants were measured by 3 bio- assays using 1) murine T cells (thymocytes), 2) human enriched blood T lymphocytes (both assays also detect IL-6) , or 3) mouse lymphoma cells (EL 4) (do not detect IL-6) . The thymocyte co-stimulatory assay for IL-1 was carried out as pre- viously described (29). Briefly, thymocytes from endotoxin-resistant C3H/SSI, female mice, 6-8 weeks of age (Bomholtgaard, Ry, Denmark) were grown in triplicate In culture medium supplemented with 10% (v/v) NHS and 5xl0 * ^M mercaptoethanol in 96-wells microtiter plates (Nunc, Roskilde, Denmark), 10 6 cells/ 200 μl/well. Two-fold dilutions of test material and 10 μg/ml of PHA were added at the initiation of the cultures. After 48 h, the cells were pulsed with - -thymidine (0.5 μCi/well) for 24 h, harvested on paper filters and counted by liquid scintillation. Purified human T-lymphocytes were prepared from MNC as described (29A) . In brief, MNC were depleted of adherent cells by Incubation for 1 h at 37°C on plastic tissue culture dishes (Becton Dickinson, Oxnard, CA, U.S.A.). Nonadherent cells were removed and passed through a nylon wool column, and the resulting cell population con¬ sisted of more than 80% T cells, 15% B cells, and less than 1% MO. The EL 4 assay was carried out as described (29) . It is based on the production of IL-2 from the murine thymoma cell line (EL 4) in the presence of 1.2 x 10 " ' M of the calcium ionophore, inonomycin (Sig¬ ma), and IL-lα or TL-lβ . Briefly, 2 x 10 5 EL 4 cells/200 μl were incubated in triplicate for 18 h with 2- fold dilutions of test material. After incubation, the supernatants were collected and tested for IL-2 activity using IL-2-dependent CTLL-2 cells (31). Calculations of activities were carried out by a computerized linear regression analysis of probit-transformed data using serial 2-fold supernatant dilutions. Hybridoma growth induced by IL-6 IL-6 activity was determined by ^H-thymidine incorporation into IL-6- dependent mouse hybridoma cells, line B 13.29 clone B9, essentially as described by Aarden et al. (27). Briefly, triplicate samples each containing 5 x 10 * ^ B9 cells were added serial dilutions of test material and cultured for 3 days at 37°C. ■ -'H-Thymidine was added for the last 5 h of culture, and the cells were harvested and assayed by liquid scintillation. A titration curve of a standard human rIL-6 preparation was carried out in each assay. One unit/ml of IL-6 ac¬ tivity was defined as the concentration of the laboratory standard giving half maximal ^H-thymidine incorporation using computerized probit analysis (1 unit (») 1 pg of human rIL-6). Fibroblast toxicity induced by TNFα The TNF-induced cytotoxicity was tested on L-M mouse fibroblasts as previously described (30). A titration curve of a standard human rTNFα preparation, previously calibrated with a WHO interim reference preparation, was carried out in each assay. Calculations of activiti¬ es were carried out by a computerized linear regression analysis of probit-transformed data using serial 3-fold supernatant dilutions. Human mixed lymphocyte reaction The mixed lymphocyte cultures (MLC) were performed by adding human blood MNC, 10-yi00 *!- to the same amount of blood MNC from an un¬ related healthy donor. The cells, 2xl0 5 in 200 μl culture medium RPMI 1640 and 10% NHS, were then incubated at 37°C for 5 days. The in¬ corporation of - -thymidine, added 16 h before termination of the cultures, was determined by liquid scintillation. Insulin production by isolated rat islets Islets from collagenase-digests of pancreas tissues, obtained from Wistar rats (90-120 g) , were isolated and precultured for 7 days, essentially as previously described (32) . The islets were counted, pooled and washed two times in culture medium RPMI 1640, supplemented with penicillin (500 IU/ l) streptomycin (500 μg/ml) , amphotericin B (2.5 μg/ml), L-glutamine (2 mM), 25 mmol/1 Hepes buffer, 11 mmol/1 glucose, and 0.5% NHS. Islets, 25/1 ml, were distributed at random in 24-well culture plates (Nunc) . The cultures were performed in tripli- cate. After 5-7 days at 37 β C in a 5% CO2-humidified air atmosphere, 0.2 ml of culture medium were removed for insulin determination by a radioimmunoassay using rat insulin as standard. Bone resorption induced by IL-lα Calvaries from 5-day-old mice, injected subcutaneously 2 days before with ^Ca, were removed and cultured as previously described (32). The parietal bones were cut into 4 pieces, 2 acting as controls and 2 for experiments. The isolated bone pieces were cultured in test tubes containing 1 ml of medium TC-199 (Gibco Bio-cult, Paisley, Scotland), supplemented with 5 g/1 of bovine serum albumin fraction V and 40 mg/1 of ampicillin. The cultures were incubated at 37°C in 5% CO2-humidifled air atmosp¬ here. After 48 h, each calvarie-piece was removed and decalcified for 30 min at 90°C in 1 ml of IN HC1. Aliquots, 250 μl, from these solu¬ tions, and from the medium, were then assessed by standard liquid scintillation counting. The release of calcium was calculated as a percentage of the total amount of '*- > Ca found in the medium (the release of ^Ca from dead bone tissue was not subtracted) . The ef¬ fects were expressed as a ratio between the treated and control bones. CALCULATIONS AND STATISTICAL EVALUATIONS OF THE EFFECTS OF FUSIDIN AND FUSIDIC ACID DERIVATIVES The cells were always precultured for 15 min with sodium fusidate (fusidin), or fusidic acid analogues, or with the solvent alone (control) before adding the human natural or recombinant cytokine preparations to be assayed. The amounts of added cytokines varied in accordance with the sensitivities of the various bioassays, but they were always chosen to ensure suboptimal effects ((-) 50% of maximum activity) on their respective target cells. To test for possible enhancements of cytokine functions, experiments were also carried out with minimally effective amounts of added cytokines ((-=) 10-20% of maximum activity) . In experiments designed to test the effect of fusidin on lymphokine production by blood MNC, the lymphokine-containing supernatants were dialyzed to ensure removal of fusidin before they were measured for their cytokine contents (see above) . The inhibitory effects of fusidin or fusidic acid analogues were usually expressed as per cent inhibition of cytokine activity, accor¬ ding to the formula: median value (in the presence of fusidin) % Inhibition - x 100 median value (in medium alone) P values are determined by the Mann-Whitney rank sum test or Wil- coxon's test for paired differences. EXAMPLE 1 Fusidin- induced inhibition of interleukin 1 production by human M0 The test was performed as described in "Production of cytokines" and "T-cell proliferation induced by TL-lα/β" . As shown in Fig. 2, fusidin progressively inhibited IL-1 production from LPS-PHA-activated MNC in vitro. The viability of the cells always exceeded 80% after 1 day in culture, and the production of another Mø-derived cytokine, TNFα, was completely unaffected (Fig. 2). EXAMPLE 2 Fusidin- induced inhibition of lymphokine production by human T lym¬ phocytes The test was performed as described in "Production of Cytokines", "T cell growth induced by IL-2" and "ELISAs for TNFα and IFN7". As shown in Fig. 3, increased concentrations of fusidin progressively inhibited the release of IL-2 and IFN7 by LPS-PHA-activated MNC in vitro. Fifty % reduction in the production of these lymphokines were achieved with 5-15 μg/ml of fusidin. Under similar conditions, half maximal production of these cytokines was obtained with 15-50 ng/ml of cyclosporin. As noted above, the relatively lower concentration activity level of fusidin compared to cyclosporin Is not a disadvan¬ tage, considering that toxic concentrations of cyclosporine are in the range from 100 ng/ml and above. With fusidin, on the other hand, there is no significant toxicity in concentrations up to about 200 μg/ml, so that the therapeutic index of fusidin is at least 5 times higher than that of cyclosporin. IL-2 and IFN7 are produced by the T- lymphocytes, and these cells require IL-1 as a co-stimul tory signal even in the majority of cases where polyclonal, nonspecific T-cell activators are being used (see Fig. 1 and ref. 1-4). As indicated above, fusidin was not toxic to the cells, judged by trypan blue exclusion. The cellular viability always exceeded 80%. To rule out the possibility of carry-over of fusidin to the assay system, especially important in the case of the bioassay of IL-2, experiments were carried out in the presence of radiolabelled fusi¬ din. These experiments confirmed that fusidin was completely elimina- SUBSTITUTE SHEET ted from the supernatant material by the dialysis procedure, even in the presence of 10% NHS and with only 1 day of dialysis at 4°C. To test whether fusidin acted by an increased production of prostag- landins, some of which are known to suppress the production of cyto- kines (4) , experiments were carried out in the presence of indome- thacin throughout the culture period. Indomethacin is a cyclooxyge- nase inhibitor and therefore blocks the production of prostaglandins. However, in 4 different experiments indomethacin did not modify the suppression of lymphokine production afforded by fusidin. EXAMPLE 3 Fusidin- induced effects on cytokine functions 3.1.IL-1 The test was performed as described in "T cell proliferation induced by TL-la/β n . 3.1.1. Mouse thymocytes As shown in Fig. 4, fusidin inhibited the thymocyte co-stimulatory effect of rIL-lα and rIL-1/3 in a dose-related manner in this con¬ ventional test for IL-1 activity. A 50% reduction in IL-lα and TL-lβ activities was achieved at 1.5-5 μg/ml of fusidin. Under similar test conditions, half maximal IL-1 response required 15-50 ng/ml of cyclo¬ sporin. Since fusidin is bound extensively although reversibly to protein, increased concentrations of serum might nevertheless interfere with the IL-1 inhibitory function of the drug. Experiments were therefore carried out with serum concentrations of 1%, 3% and 10% (v/v) , re¬ spectively. As shown in Table 3, the highest serum concentration only slightly reduced the ability of the drug to interfere with IL-1- induced thymocyte activation. TABLE 3 Effect of various serum concentrations on the ability of fusidin to block IL-1-induced thymocyte activation Fusidin % inhibition cone, (μg/ml) 1% serum 3% serum 10% serum 10 89 93 87 30 96 95 87 10 and 30 U of rIL-lα or rIL-13 were added to the thymocyte assay with or without fusidin. There was no difference between the two species of IL-1. The results are means of 4 different experiments, each with the use of 2 different concentrations of rIL-lα and rIL-1/3. 3.1.2. Human T lymphocytes Fig. 5 shows the effect of fusidin on the IL-1 co-stimulatory aciti- vity using enriched human T lymphocytes. Significant inhibition was obtained at non-toxic concentrations of fusidin, especially when PPD was used as a co-stimulator to simulate antigen-induced activation of T cells. 3.1.3. Mouse lymphoma cells (EL 4) Because thymocytes contain a small number of macrophages and dendri¬ tic cells in addition to T lymphocytes, the ability of fusidin to inhibit IL-lα-induced activation of a mouse thymocyte cell line (EL 4) was next Investigated. As shown in Fig. 6, fusidin also appeared to inhibit rIL-lα-induced proliferation of EL 4 cells. The fact that the effect of the drug was much less pronounced than in Examples 3.1.1. and 3.1.2. can most likely be attributed to induction of EL 4 cell proliferation requiring co-stimulation with a calcium ionophore, in addition to IL-1. Another possibility could be that the EL-4 is a transformed cell line which is not comparable to a usual cell. SUBSTITUTE SHEET ISA/SE 3.2. IL-2 and TNFα The test was performed as described in "T cell growth induced by IL-2" and "Fibroblast toxicity induced by TNFα". In contrast to the effect on the function of IL-lα and TL-lβ , fusidin did not modify the ability of human IL-2 to activate mouse cytotoxic T lymphocytes (CTLL-2) or the ability of human TNFα to kill mouse L-M fibroblast (Fig. 7). EXAMPLE 4 Effect of delayed addition of fusidin to IL-1- induced thymocytes The test was performed as described in "T cell proliferation induced by IL-lα/0". As shown in Fig. 8, addition of fusidin 5 μg/ml up to 48 h after initiation of thymocyte activation by PHA plus IL-1 was progressively less effective in reducing the co-stimulatory effect of IL-1. A similar response pattern was obtained after addition of 50 ng/ml of cyclosporin. This indicates that fusidin affects the early processes leading to T cell activation. Early start of treatment of immunoin- flammatory diseases with fusidin or derivatives thereof is therefore most likely beneficial. EXAMPLE 5 Effect of fusidic acid derivatives on IL-1 -induced thymocyte activa¬ tion The test was performed as described in "T cell proliferation induced by IL-lα/β" . As shown in Table 4, only 3 fusidic acid derivatives were effective in inhibiting the thymocyte co-stimulatory effect of IL-lα and IL-1/3. The ineffective derivatives are characterized by modifications in the substituents at positions 16 and 21 of the molecule suggesting that these regions of fusidic acid are necessary for the IL-1-inhibitory effect of the drug. TABLE 4 Effect of fusidic acid derivatives on the thymocyte co-stimulatory function of IL-1 Results are means +/- SEM; n=6. 1 These analogues were identical with fusidin at the 16 and 21 posi¬ tions of the molecule 2 This analogue was also identical with fusidin at the 16 and 21 positions, except for substitution of oxygen with sulfur at position 16. EXAMPLE 6 Fusidin- induced inhibition of the human two-way mixed lymphocyte reaction (MLC) The test was performed as described in "Human mixed lymphocyte reac- tion". MLC is the in vitro correlate of a transplant rejection in vivo . Therefore, if fusidin has a role in preventing graft rejection, it should suppress the MLC reaction. As shown in Fig. 9, fusidin indeed inhibited the two-way human MLC. The dose-response was almost identi- cal to those obtained when testing the effects on IL-1 on thymocytes and PPD-activated human T cells as well as IL-2 production. The 50% inhibitory concentration of fusidin was 1.5-5 μg/ml. Similar suppres¬ sion of the MLC was obtained with 15-50 ng/ml of cyclosporin. EXAMPLE 7 Fusidin- induced inhibition the hybridoma growth- promoting effect of IL-6 The test was performed as described in "Hybridoma growth induced by IL-6". IL-6, another Mø-derived peptide mediator, has been reported to mediate several functions of IL-1, including thymocyte activation (2,7,8). It was therefore of interest to see whether fusidin inter¬ fered with the function of IL-6. As shown in Fig. 10, the growth of the B9 hybridoma cell line was inhibited by fusidin. The dose respon¬ se was very similar to the ones obtained when testing the effect of fusidin on the IL-1-induced growth of normal (mouse) thymocytes. Fifty % reduction in IL-6-induced growth was obtained at around 10 μg/ml of fusidin. Again, there was no evidence of fusidin-induced cytotoxicity, as demonstrated in the next experiments. As shown In Fig. 11, the ability of fusidin to prevent IL-6-induced proliferation of B9 hybridoma cells was not caused by a generalized toxic effect on the cells. Thus, B9 cells preincubated with 30 μg/ml of fusidin, with or without rIL-6, responded normally to a subsequent challenge by IL-6 after washing the cells with medium and reconstitu- tion without fusidin. EXAMPLE 8 Failure to modify IL-1- induced activation of bone resorption The test was performed as described in "Bone resorption induced by IL-lα". As shown in Table 5, fusidin did not affect the increased release of radiolabelled Ca induced by rIL-lα. This further demonstrates the non-toxicity of fusidin in biological systems. TABLE 5 Lack of effect of fusidin on rIL-lα-induced bone resorption -"Ca release (% of control) Fusidin rIL-lα mean +/- SD n (control) 0.08 10 ns 0.12 1 9 <0.05 0.10 2 8 <0.05 -- and ---. no significant difference between these values. EXAMPLE 9 Fusidin- induced protection of pancreatic β-cells against the inhibi¬ tion/damage afforded by IL-1 The tests were performed as described in "Insulin production by isolated rat islets". 9.1. Fusidin Since IL-1/3 is considered pathogenetically important for the develop¬ ment of IDDM, and since IL-1/3 significantly reduces glucose-induced insulin production by pancreatic /3-cells in vitro , it was of interest to test whether fusidin could restore normal /3-cell function in vitro . As shown in Fig. 12, co-incubation of pancreatic islets isola¬ ted from normal rats with increasing concentrations of fusidin pro¬ gressively normalized their glucose-induced insulin production, even in the presence of relatively high concentrations of rIL-1/3. At the highest concentration of fusidin, there appeared to be a slight reduction in the protective effect of the drug. The reason is not clear but is most likely caused by the drugs ability to inhibit insulin mRNA translation (23). 9.2. Fusidic acid derivatives A similar protective effect was not observed when testing a number of fusidic acid derivatives (Fig. 13) whereas the diethanolamine salt (3 experiments) gave similar results as fusidin. This indicates that modifications of the basic fusidic acid structure except for der¬ ivatives at the 21 position such as the salt formation are not de- sirable in connection with this effect. DISCUSSION RELATED TO THE IN VITRO EXPERIMENTS Immunosuppressive effects of fusidin The data presented from the in vitro experiments demonstrate a dose- dependent inhibitory effect of fusidin on processes involved in lymphocyte activation. Induction of T and B lymphocytes requires several steps in addition to antigen or allogen recognition by HLA class II positive cells such as M0 or dendritic cells: 1) production and release of IL-1 and, possibly, IL-6; 2) activation of T cells hy these cytokines through specific membrane receptors for IL-1 and IL- 6; 3) production and release of IL-2 by T lymphocytes; 4) acquisition of receptors for IL-2 on T lymphocytes, and 5) internalization of IL- 2-receptor complexes. In addition, the release from T cells of IFN7 is considered important, because this cytokine is a potent activator of M0 functions, including HIA class II expression (1,8). Like cyclosporin (19) , fusidin appears to interfere with some of these early processes. First, relatively high concentrations of fusidin Inhihited production/secretion of IL-1 from LPS-PHA-activated human blood MNC. Secondly, and probably more importantly, low thera¬ peutic concentrations of fusidin suppressed lymphocyte activation by IL-1 and IL-6, another Mø-derived activator of T- and B lymphocytes. Probably as a result of this, fusidin also inhibited the production by T cells of their own growth factor, IL-2, leading to impaired T cell proliferation after antigenic, mitogenic as well as allogeneic activation. Since IFN7 is an important activator of M0 functions, including their ability to secerete cytokines and express HLA class II molecules, the drugs ability to inhibit the elaboration of IFN7 might contribute to T cell suppression. In all cases, the inhibitory effects were dose-dependent, and the effective concentrations of fusidin appeared to be non-toxic to the target cells. Furthermore, fusidin did not function by a general antiproliferative effect, because the IL-2-induced proliferation of CTLL-2 cells were unaffected by the drug. The concentrations of fusidin which were shown to be effective in vitro seem to be clinically relevant, because therapeutic serum concentrations in the range 15-100 μg/ml may be obtained in man without significant side-effects (33). However, fusidin is bound extensively to protein in vivo , and this may contribute to a diminis¬ hed clinical efficacy if related to the effective concentrations of the drug in vitro . This, however, does not appear to be of major importance in the case of fusidin, because increased concentrations of serum in the thymocyte assay only marginally affected the fusidin- induced immunosuppressive function. Moreover, several important clinical effects of fusidin are expected to take place in tissues where serum proteins are absent or present in only small quantities. When testing fusidin in the mouse thymocyte co-stimulatory assay, the IL-1 activity was almost completely eliminated by 15 μg/ml of the drug, and a 50% inhibition was achieved at a concentration of 1.5-5 μg/ml. At all concentrations, fusidin failed to decrease the viabili¬ ty of the thymocytes compared with thymocytes cultured in parallel without the drug. The mechanism by which fusidin inhibits the immunostimulatory func- tions of TL-la/β is unknown. However, the drug is known to inhibit protein synthesis at the translational level (23) , and an impaired protein synthesis may therefore, at least in part, explain the re¬ sults. However, a complete inhibition of cytokine mRNA translation cannot by itself explain our findings. Thus, the production of TNFα by human blood MNC activated by LPS+PHA was unaffected even by 50 μg/ml of fusidin. Also, the ability of fusidin to inhibit production of the cytokines, IL-2 and IFN7, is most likely a consequence of the TL-la/β and the IL-6inhibitory effects of the drug rather than a direct effect on the translation of these lymphokines. Hence, IL-1 in particular is considered an essential 'second signal' for T lympho¬ cyte activation, including production of lymphokines (1-4) the first signal being antigen or mitogen-induced perturbation of the T cell receptor/CD3 complex (1,2,11,12). The ability of fusidin to inhibit a mixed lymphocyte reaction in vitro is probably also secondary to its IL-1-inhibitory effect. At any rate, the inhibitory effect of fusidin on this in vitro correlate of a human allograft rejection may be important, because it suggests that the drug may be used clinically to prevent the hosts elimination of allotransplants, such as kidneys, livers, hearts, lungs, skin, bone marrow, corneae, etc. Treatment of the host with fusidin at the time the transplant is performed, and thus interference with the 'second signal' of lymphocyte activation, may also lead to specific tolerance to the grafted tissue (see above) . The ability of fusidin to interfere with the growth-promoting effects of TL-la/β and IL-6 is also of clinical importance. Thus, IL-1 and particularly IL-6 have been implicated in the pathogenesis of several lymphoproliferative diseases, such as multiple myeloma and other plasma cell, and B- and T cell cancers (see above). Antiinflammatory effects of fusidin IL-1 and IL-6 are known to cause an array of biological activities in many cell types (1-4) . It is therefore interesting that fusidin interfered with some but not all the various functions of IL-1 that were tested. For example, the drug was unable to affect IL-1-induced bone resorp- tion. On the other hand, the drug clearly protected pancreatic islet 3-cells against the inhibitory/c totoxic action of IL-1/3. The apparent inhibitory effect of fusidin on non-immunological func¬ tions of IL-1 and, possibly, IL-6 is of clinical interest. Thus, apart from being involved in lymphocyte activation and thus presu- mably in physiological and pathophysiological immune reactions, IL-1 and IL-6 are involved in the development and manifestations of many infectious and immunoinflammatory diseases, including AIDS, auto- immune endocrine diseases, some rheumatic diseases, etc. (Table 1, ref. 2,3,8). This, along with the ability of TL-la/β and IL-6 to cause fever, and of TL-la/β to evoke anorexia and cachexia, emphasi¬ zes a therapeutic role of fusidic acid and deri atives thereof apart from their usage as antibiotics. CONCLUSIONS FOR THE IN VITRO EXPERIMENTS T- and B-lymphocytes, M0 and NK cells play important roles in man's defence against microorganisms and neoplastic diseases. On the other hand, there is strong evidence for a role of these cells in the pathogenesis of certain rheumatic diseases and immunoinflammatory diseases involving the endocrine system, the skin, the gut, and many other organs. The peptide hormones (cytokines) produced by these cells, particularly IL-lα, IL-13, IL-6 and TNFα, are potent immune stimulators as well as modulators of hepatocytes, bone cells, endot- helial cells, fibroblasts and synovial tissue cells, pancreatic islet ^-cells, thyrocytes, and many other cells. Treatment to prevent the production and/or function of IL-lα//3, IL-6 and TNFα may prevent the development, or ameliorate the symptoms, of many immunoinflammatory and infectious diseases. Such intervention may also prevent trans- plant rejection either if administered as a continuous, immunosup¬ pressive treatment or as a timed, short-term treatment to induce specific tolerance to the grafted tissue. Fusidin, in therapeutic relevant concentrations, inhibit several immunological, growth-pro¬ moting and pro-inflammatory functions of TL-la/β and IL-6 in vitro , and the patterns of these responses are strikingly similar to those caused by cyclosporin. The present discovery is therefore of impor¬ tance in the systemic and local treatment of several immunoinflamma¬ tory diseases in humans, where these cytokines are considered to be of pathogenetic relevance. These diseases include the so-called autoimmune diseases (see Table 1), diseases associated with trans¬ plantation, including graft rejection and graft-versus-host disease, many infectious diseases, and many diseases characterized by patholo¬ gical cell growth, including some neoplastic diseases. In the following, a number of in vivo experiments are described, either based upon evidence obtained or as guidelines for the experi¬ mental work to be performed in connection with specific uses of fusidic acid or derivatives thereof. With respect to pharmacology, the pharmacology of fusidic acid and derivatives thereof for oral, parenteral and topical application appears from the scientific and patent literature mentioned in the section of "Background of the Invention". This documentation is supplemented by the following example illustrating penetration of the drug into compartments of the eye (Example 10) . IN VIVO EXPERIMENTS PHARMACOLOGICAL STUDY EXAMPLE 10 Analyses From Corpus Vitreum/Subretinal Fluid The fusidin concentration in corpus vitreum/subretinal fluid is measured after 3 days of preceeding systemic therapy prior to opera¬ tion. Systemic therapy: Fusidin tablets (Leo, Copenhagen, Denmark) 500 mg 3 times every 24 hours. The therapy ends at least 6 hours before operation. Material 1. Corpus vltreum analyses include 10 eyes of patients who are subjected to a vitreous body operation In connection with bleed- ing in the vitreous body provoked by diabetes mellitus. 2. Amotio operation (detachment of the retina), removal of sub- retinal fluid of 10 eyes in connection with retina operations. PRE-CLINICAL STUDIES The following examples 11-12 are based upon ongoing studies and give guidelines for preclinical studies In animal models. SUBSTITUTE SHEET ISA/SE EXAMPLE 11 In vivo examination of the prophylactic effect of fusidin in two animal models of diabetes mellitus The following example is designed to examine the prophylactic effect of fusidin in BB-rats and NOD-mice (two spontaneously diabetic animal models for Type 1 (insulin-dependent) diabetes mellitus) . The study includes 40-50 animals treated with fusidin and a corre¬ sponding number of control animals treated with placebo. Breeding couples are procured and the experimental animals are supported and breed. The animals are treated with the drugs immediately after weaning and until the study is terminated after 200 days. The animals are observed daily, week-ends included, and once a week the animals are weighed and urine tests are carried out to determine glucose content. Pancreas from animals developing diabetes and from animals at the end of the study are subjected to microscopic examination to discover 1) possible infiltration of mononuclear cells in the islets of Langerhans (insulitis), and 2) to determine the number of cells producing insulin. Furthermore, the contents of insulin and cytokines in consecutively drawn serum samples are determined in order to evaluate a possible association between the development of the di¬ sease and the cytokine levels in serum. EXAMPLE 12 The effect of fusidin on the acute-phase response induced by IL-1 and IL-6 in mice Background The acute-phase reaction is usually seen during acute and chronic infectious and inflammatory diseases, and in cancer, and administra¬ tion of IL-1, IL-6 or TNFα reproduces this reaction (8). IL-6 and, to a lesser extent, IL-1 and TNFα induce hepatocytes to synthesize acute phase proteins, including serum amyloid A, C-reactive protein, fibri¬ nogen, haptoglobin, complement components and clotting factors. At the same time, the blood level of albumin decreases, as does the plasma concentrations of Fe 2+ and Zn 2+ , whereas the level of Cu 2+ increases. Associated phenomena are fever, leukocytosis and induction of sleep. The elevated level of fibrinogen, especially if accompanied by anemia, causes an increased sedimentation rate of the blood, a commonly used clinical parameter of 'inflammation' . The above mentioned clinical picture is often associated with di- sturbances in carbohydrate-, lipid- and protein metabolism resulting in wasting (cachexia). In rare situations, the acute-phase reaction may progress and lead to clotting abnormalities, shock, and death. It was previously thought that microbial products such as endotoxins were directly responsible for these symptoms, if triggered by bac- terial infection. This is now known to be incorrect, because endo¬ toxins are potent inducers of M0 IL-1, IL-6 and TNFα, and all patho¬ physiological processes associated with endotoxin-induced shock can be reproduced by injection of TNFα and, to a lesser extent, by IL-1 (2). Design Pilot study using a mouse model (25) . 12.1. Interleukin lα-induced response Fusidin, 15 mg, and solvent alone (control) are administered i.v. into 5 plus 5 (controls) female BALB/c mice (8-10 weeks old) . After 30 min, 10 μg of human rIL-lα in 25 μl pyrogen-free isotonic saline is given i.v. After 24 h, blood is drawn for measurements of the mouse acute phase reactant haptoglobin. Depending upon these results, the dosage of fusidin and rIL-lα will be altered in order to substantiate the dose-response curve of the effect of fusidin on the IL-1-induced acute-phase response in mice. 12.2. Interleukin 6-induced response The experimental approach outlined above will be used, except that human rIL-6, 10 μg, will be used. Again, the dose-response curve of the effect of fusidin will be established. 12.3. Effect of fusidin analogs on IL-lα- or IL6-induced acute-phase reactions in mice Similar experimental approach as above, except that fusidin analogs will be used instead of fusidin. The following examples 13-18 concern clinical experience gained by certain treatments of patients with fusidin and give guidelines for controlled clinical studies based upon the evidence gained from these pilot studies. CLINICAL STUDIES EXAMPLE 13 The following studies are designed to demonstrate the effect of fusidic acid eyedrop treatment as a prophylactic treatment against inflammation after eye surgery. 13.1. Clinical Examination of the Ant i inflammatory Effect of Fusidin in the Postoperative Period after Uncomplicated Operation for Ca- taract Material: Patients aged over 60 operated for cataract with extraction of the lens and subsequent implantation of an artificial lens in the posterior chamber of the eye corresponding to 20 eyes. Exclusion: Patients with eyes with trauma, glaucoma, retinovascular bleeding or thrombosis, corioretinal inflammatory and non-inflamma- tory sight-threatening diseases, diabetes mellitus (type I), collage- nosis. The group treated with fusidin includes patients corresponding to 10 eyes. The control group includes patients corresponding to 10 eyes treated with ultralanum with chloroamphenicol. Method: Randomized therapy between the two preparations of 20 eyes in a 3 week period postoperatively starting from the first postoperative day. Dosage: Ultralanum with chloroamphenicol eye drops 4 times daily. Fucithalmic eye drops 4 times daily. Evaluation parameters: 1. Visual acuity: Examined at weeks 1, 2 and 3 after the cataract operation. 2. Biomicroscopy is carried out at days 2, 5, 14 and 21 after operation. During biomicroscopy, a more detailed data recording would be carried out. Eye pressure is measured at weeks 1, 2 and 3 after operation. The examination of corpus vitreum and the corioretinal status is carried out at weeks 1, 2 and 3 after operation, and subjective data In the postoperative period are recorded including the patients' evaluation of the treatment with fucithalmic/ultralanum with chlor- ampfenicol, e.g. problems with dripping of eyes, eye pain, duration of eye pain, duration of sight reduction, if any, after dripping of eyes, etc. Exclusion during treatment: Increased intrabulbar Inflammation, (sight-threatening) , obvious panophthalmia, non-compliance. 13.2. Clinical examination of the ant i inflammatory effect of fusidin in the postoperative period after uncomplicated laser surgery Material Patients admitted for laser surgery due to e.g. loosening of the retina, retinal biopsy or diabetic retinopathy. The group treated with fusidin includes patients corresponding to 10 eyes. The control group includes patients corresponding to 10 eyes treated with conventional therapy (glucocorticoid) . Method: Randomized therapy between the two preparations in a 3 week period postoperatively starting from the first postoperative day. Dosage: Fusidin tablets 500 mg x 3 in 2 weeks starting at the day of the operation. Evaluation parameters: 1. Visual acuity: Examined at weeks 1, 2 and 3 after the laser surgery operation. 2. Biomicroscopy is carried out at days 2, 5, 14 and 21 after operation. During biomicroscopy, a more detailed data recording will be carried out. The examination of corpus vitreum and the corioretinal status is carried out at weeks 1, 2 and 3 after operation, and subjective data in the postoperative period are recorded including the patients' evaluation of the treatment with fusidin. EXAMPLE 14 Treatment with Fusidin of Non- infectious , Immuno inflammatory Uveitis Background Severe uveal tract inflammation (uveitis) is responsible for a large percentage of the visually handicapped patients in developing and developed countries. Most of the cases of uveitis in developed coun¬ tries are classified as idiopathic and are presumed to have an under¬ lying autoimmune cause. The treatment in these cases is mainly based on the use of glucocorticoids, cytotoxic drugs or cyclosporin. In many of the cases, however, the treatment only delays the loss of vision side-effects (Cushing's syndrome, and severe bone-marrow depression and nephropathy (cyclosporin) may force withdrawal of therapy with resulting loss of vision. 14.1. Pilot studies In the following Tables 6 and 7 are shown the results from two pilot studies. In the first study, three patients are included correspond¬ ing to treatment of ive eyes. The treatment was converted from cyclosporin to fusidin (0.5 g 3 times daily given as tablets). In the second study, four patients are included (8 eyes) . The patients were treated with fusidin (0.5 g 3 times daily given as tablets) without earlier cyclosporin medication. SUBSTITUTE SHEET ISA/SE TABLE 6 Pilot study: Severe, sight-threatening uveitis Three patients (5 eyes) conversion from cyclosporin (C A) to fusi- din (Fus) Prednisolone (mg/day) Id Case history CyA therm. (before - last) NJN One eye blind 5 years 10 7.5 JK Relapse on CyA + 1.5 years 0 0 pred. 7.5 mg/day 2 x relapse on pred.pulse Mb. Cushing MN 2.5 years 100 15 (nephropathy) TABLE 6 (continued) : Notes 2 x vitrectomy during Fus. thera¬ py without relapse Comments: All 3 patients (5 eyes) benefited from fusidin therapy. Deterioration in visual acuity in 1 eye was caused by vitreal haze secondary to a vitrectomy. Two vitrectomies were performed during Fus. therapy without flare-up of disease activity! None of the pati¬ ents had side-effects of Fus. All. 3 patients had severe side-ef¬ fects caused by the long-term treatment with moderate/high doses of glucocorticoids and CyA. TABLE 7 Pilot study: Severe, sight-threatening uveitis Four patients (8 eyes) - fusidin (Fus) treatment (no cyclosporin) Prednisolone (mg/day) Id Case history Fus therm. (before - last) BNJ 7 months 50 7.5/50 20 (relapse) VCK Relapse on pred. 7 months 30 10 30 mg/day Mb. Cushing FVT 7 months 60 10/60 0/30 20 (2 relapses) GHP Relapse on pred. 30 mg/day 3 months 60 10/40 25 (relapse) Comments: Even though the evalation of the clinical response is complicated by concomitant therapy with glucocorticoids, all 4 pa¬ tients (8 eyes) benefited from fusidin therapy. Thus, there were no signs of acute chorioretinal inflammation, and 2 patients were able to lower the dosage of glucocorticoid. However, attempts to complete¬ ly withdraw glucocorticoid treatment resulted in relapse in 3 pati¬ ents. Similar relapses are seen if glucocorticoid therapy is with¬ drawn from CyA-treated patients with severe uveitis. None of the patients had side-effects attributed to fusidin. 14.2. Clinical Examination of the Ant i inflammatory Efficacy of Fusi¬ din in Patients with Uveitis Anterior Material: Patients with acute onset or recurrence of uveitis anterior corresponding to 20 eyes. Group 1 includes patients corresponding to 10 eyes treated with fucithalmic eyedrops 6 times daily. Group 2 is treated with glucocorticoid eyedrops 6 times daily (e.g. Maxidex®, from Alcon, Texas, U.S.A.) Both groups are treated with atropine eyedrops (e.g. from DAK, Copen¬ hagen, Denmark) 1% twice daily. Duration of treatment: 3 weeks. Clinical control: At least once a week. Exclusion: Uveitis as a result of bacterial/viral infections, ongoing systemic therapy for collagenosis, aggravation of uveitis during actual treatment, and non-compliance. SUBSTITUTE SHEET ISA/SE 14.3. Multicenter study of the efficacy of fusidin in sight- hreate¬ ning, non- infectious , immuno inflamma tory _ posterior uveitis Aims of Study To compare efficacy, safety and tolerability of oral fusidin with conventional therapy (corticosteroids) for the treatment of sight-threatening uveitis. Study parameters are: Number of patients withdrawn from study medication because of contraindications to continued therapy - Visual acuity Parameters of inflammatory activity Fluorescein angiography Number of relapses Side-effects, safety parameters - Global evaluation of efficacy and tolerability by investigator and patient. Immunological studies, including measurements of blood levels of cytokines. Type of Study Multicenter, open, randomized, controlled, parallel-group study with "masked" opthalmologist for unbiased recording of symptoms in uveitis (comparison of fusidin vs. conventional therapy). SUBSTITUTE SHEET Patients Number: Initially 20 patients. At this stage, decision will be made whether to continue. Starting criteria Active uni- or bilateral ocular involvement. Exclusion criteria Terminal stage of disease with nonreversible degeneration of retina in which no active lesion is observed. Patients who are suffering from myosis or cataract which diseases made it impossible to note the posterior pole in both eyes will be excluded. Ongoing infectious disease, hepatic dysfunction, i.e. elevation 2.5 above upper limit of normal value of either ALAT, ASAT, bilirubin (direct and indirect) and total protein, non-compliance. General Study Outline Patients on corticosteroids and/or cytostatic agents should have these drugs withdrawn before definite selection and before randomiza¬ tion. In consecutive order, patients should be randomized to either fusidin (monotherapy) or conventional therapy. Two investigators should take part in the study. Investigator 1 should know the assigned treatment, whereas the investigator 2 (oph¬ thalmologist) should be masked in this respect. Investigator 1 should evaluate safety parameters, side-effects and should prescribe medica- tion. Investigator 2 should evaluate only the efficacy parameters. He should not have access to other data. The assigned therapy should be maintained unless contraindications occur. Patients randomized to conventional therapy should start on monotherapy with corticosteroids. If after a minimum of 4 weeks, the response is inadequate, fusidin therapy should be initiated (in combination with low-dose corticosteroids) . If, after further 4 weeks, the response is inadequate, fusidin should be replaced with cyclosporin therapy, and the patient should be withdrawn from the study. Patients should be investigated at baseline, at weeks 1, 2, months 1, 2, 3, 4, 6, 9 1 12 and thereafter at 6 monthly intervals if the di¬ sease is quiescent or at any time if acute attacks occur. First full analysis of data should be performed on 6-months data of the first 20 patients, and thereafter at 12 months intervals. The only concomitant medication for uveitis allowed are gluco- corticoids and cycloplegic eye drops. Subconjunctival glucocorticoid injections are not allowed. A) Test Medication Fusidin tablets 0.5 g 3 times daily B) Conventional Therapy-Group 1.5 mg prednisolone (e.g. from DAK, Copenhagen, Denmark) per kg per day for a week. The dose will be decreased gradually to reach a maintenance level of 5 to 10 mg prednisolone per day. In case of relapse, the dosage will be increased. Contraindications for Continued Therapy (for both treatment groups): - Visual acuity: If after maximum therapy of at least two weeks, the visual acuity falls two lines below baseline at the initia¬ tion of therapy) on two successive days in either affected eye. Inflammation: If, after maximum therapy of at least two weeks, the inflammatory activity as determined by a second observer, is worse and the visual acuity is not improved in either eye. If the disease process progresses into the macula which in the opinion of a second observer might lead to permanent loss of vision in either eye. Toxicity or side-effects a) Impaired hepatic function, such as any value 2.5 times that of the upper limit of normal b) Allergic reactions to fusidin c) Side-effects felt by the patient to be of such a nature that it is impossible for him/her to continue. Disease activity Patients will be evaluated at baseline and at weeks 1, 2 and months 1, 2, 3, 4, 6, 9, 12, and thereafter at 6-monthly intervals during at least 1 year if disease is quiscent or at any time if acute attack occur. Concomitant medications: Any concomitant medications will be listed during the pretreatment evalution and at each subsequent evaluation. Ophthalmological evaluations by "masked" ophthalmologist: a) Visual acuity b) Inflammation, anterior chamber flare, vitreal haze, and opacity c) Other ocular findings d) Flurorescein angiography (only to be done when media allows and at months 3, 6 and 12) Laboratory tests a) Blood: Hemoglobin, hematocrit, WBC count and differential, platelets, sedimentation rate, total protein, total bilirubin, alkaline phosphatase, AIAT, ASAT, potassium and creatinine. b) Qualitative urinalysis (protein, sugar, sediment). c) At entry to study only: Pregnancy test. Immunological Investigations (optional) : Serum parameters: a) Serum protein electrophoresis b) Ig levels c) Serum IFN7, IL-2, IL-2 receptor, TLla/β , TNFα Cellular parameters: a) Blood lymphocyte and monocyte analyses - total count and subsets b) Histocompatibllity antigens - HLA-DR (only at time 0) . Autoimmune responsiveness: a) Antinuclear antibodies b) Rheumatoid factor Functional immune capacities: a) Background levels and responses to LPS and PHA measured by proliferation assays and cytokine production b) Auto-antibodies for cytokines (ILlα and TNFα) SUBSTITUTE SHEET Withdrawals / Drop-outs Withdrawals are patients who for reasons related to test medication (contraindications as specified) stop further therapy. They should be fully analysed and should not be replaced by new patients. At time of Withdrawal, a complete evaluation should be performed. Drop-outs are patients lost to follow-up or non-complying to pro¬ tocol. They should be replaced (next free patient number). EXAMPLE 15 Fusidin treatment of Crohn 's disease Background It has been established that cyclosporin, is effective against Crohn's disease (46). However, the treatment can only be given in small doses and in short periods of time due to the risk of dangerous side-effects. Aims of study: Examination of the gastrointestinal absorption of fusidin and the possible effect of fusidin in the treatment of Crohn's disease. Type of study: Open pilot study Patients The initial material includes a total of 6 patients with Crohn's disease. Starting criteria Active Crohn's disease where medical treatment is planned. Any prednisolone treatment should not exceed 20 mg per day and must be kept unchanged for at least 2 weeks. Any salazopyrin (SASP) or 5-aminosalicylic acid (5-ASA) treat¬ ment should also be kept unchanged for at least 2 weeks. Exclusion criteria Patients receiving any other treatment of Crohn's disease. Patients having received cytostatic treatment within the last 2 weeks. Patients with a known hypersensitivity to fusidin. - Patients with known, serious liver diseases. Patients planning to become pregnant or being pregnant. General Study Outline Fucidin tablets 0.5 g 3 times daily for 4 weeks. If no positive effect is registered, the patient should be excluded from the test. If a positive effect is registered, treatment is carried on for another 4 week period. In case the disease is aggrevated and other treatment is needed, the patient can at any time be excluded from the test. Other treatment If the patient is receiving SASP (salicylazosulfapyridine) / 5-ASA (5-aminosalicylic acid) treatment by the start of the test, dosage should be kept unchanged. Concerning prednisolone, see below. Disease activity The disease activity is measured by means of the modified "Grading Score" a.m. (46) . The effect of the treatment is defined as a positi¬ ve total score. The reduction of the dosage of prednosolone can be included as an individual treatment aim. As secondary activity aims, P-orosomucoid concentration and "Crohn's Disease Activity Index" (CDAI) are used. Clinical control with blood sampling should be carried out after 0, 2, 4, 8 and 12 weeks of treatment and 4 weeks after ended therapy and at any other time depending upon clinical status. Laboratory tests Blood: Sedimentation rate, orosomucoid, hemoglobin, hematocrit, bilirubin, ALAT, ASAT, alkaline phosphatase. Furthermore, samples are taken (5 ml serum, 5 ml EDTA-plasma and 5 ml heparin plasma) for determining the fusidin concentration - the patient is not allowed to take his morning dosage until after the blood samples have been taken - and plasma levels of cytokines and cytokine autoantibodies. EXAMPLE 16 Fusidin in treatment of acute graft-versus-host disease (acute GvHD) . Background Acute GvHD is a symptom complex appearing 8-40 days (median 14 days) after allogeneic bone marrow transplantation as a consequence of the reaction of donor T-lymphocytes against recipient antigens, especial¬ ly transplantation antigens in the HLA-system. This occurs in 70% of the patients with HIA-identical sibling donors but is more frequently observed in HLA incompatible family donor or HIA-identical unrelated donor. The following grading is valuble interims of the prognosis and thera¬ peutic response: Grade I (slight grade): Macular or confluent exanthema. Diarrhoea not more than 500 ml per 24 hours. Bilirubin < 25 mikromol/liter. Grade II (moderate grade) : Exanthema as well as diarrhoea 500-1000 ml per 24 hours and/or bilirubin > 25 mikromol per liter Grade III and IV (heavy grade) : Exanthema and diarrhoea more than 1000 ml per 24 hours and/or bilirubin > 50 mikromol per liter. The occurence of acute GvHD in moderate to heavy grade is combined with increased lethality after allogeneic bone marrow transplanta¬ tion. Lethality is especially due to infections as a result of delay¬ ed immunological reconstitution. This is caused both by the GvHD itself and by the fact that these patients often receive further immunosuppressive treatment with prednisolone and/or anti-thymocyte globulin. Presently applied treatment strategy All patients are treated prophylactically against acute GvHD. This includes cyclosporin (day -1 to day +180) , possibly supplemented with methotrexate i.v. (day 1, 3, 6 and possibly 11), depending upon the estimated risk of developing acute GvHD. Supplementary treatment against GvHD is carried out in the following situations: 1. Grade I (slight) GvHD which is subjectively very annoying, or which is not reduced after app. one week's observation. 2. Quickly progressing grade II (moderate) GvHD. 3. Grade III (heavy) GvHD. Glucocorticoids are used, possibly supplemented with anti-thymocyte globulin. The dosage of cyclosporin is also Increased. Aim and type of study Pilot examination to evaluate the effect of fusidin in patients treated with allogeneic bone marrow transplantation who develop acute GvHD despite adequate prophylaxis with cyclosporin and, optionally, methotrexate. If fusidin reduces the development of GvHD, a clinical¬ ly important reduction in glucocorticoid and cyclosporin consumption and, hence, a reduction in side- effects can be obtained (e.g. infec¬ tions and nephropathy) . Patients: 10 patients receiving allogeneic bone marrow transplants because of leukemia, aplastic anemia, or other life-threatening marrow dysfunction Exclusion criteria Patients under 18 years of age. Patients who according to the above-mentioned criteria should be treated with glucocorticoid. Patients receiving glucocorticoid and/or anti-thymocyte globulin before or at the time of transplantation. Note: Before fusidin treatment is carried out, adequate cyclosporin pro- phylaxis should be carried out: a. If the results of the latest cyclosporin concentration test are below therapeutic level, the cyclosporin dosage should be in¬ creased and the effect should be awaited (24 hours) . b. If the results of the latest cyclosporin concentration test is at an adequeate level, but the patient is in the meantime be¬ ginning to suffer from diarrhoea and/or vomiting which can lead to non-absorption of cyclosporin, peroral cyclosporin must be substituted with intraveneous cyclosporin and the effect should be awaited (24 hours) . General study outline In patients eligable for treatment with fusidin (see above) : - ■ Blood samples are taken for measuring the cyclosporin concen¬ tration (valley-value) . - Fusidin tablets or mixture or, in cases of moderate/severe diarrhoea, fusidin for i.v. injection, 12 mg/kg 3 times daily in the first 2 days, thereafter 8 mg/kg 3 times daily. If the fusidin treatment is considered efficaceous, treatment is continued for 10 days whereafter fusidin is withdrawn. If progression occurs in spite of fusidin treatment, the drug is withdrwan and conventional therapy is instituted (see above) . Disease activity For each individual patient, the spread of the exanthema is recorded along with diarrhoea volume and body temperature Laboratory tests Blood: Sedimentation rate, orossomucoid, hemoglobin, bilirubin, ALAT, ASAT, alkaline phospatase. 5 ml serum and 5 ml EDTA-plasma are taken for measurements of cytokines and autoantibodies to cytokines. EXAMPLE 17 Fusidin in treatment of multiple myeloma Clinical effect of fusidin in early management of multiple myeloma Aim of study To gain preliminary experience with fusidin in the treatment of patients with multiple myeloma Specific aims are to etablish: Dosage schedule of fusidin. Safety and tolerability of fusidin. - Effects of fusidin on immunoinflammatory parameters. Depending upon the results of this pilot study, a decision should be made whether to start a controlled study. Type of study Open, uncontrolled pilot study. Patients 10 adults of both sexes. The diagnosis of multiple myeloma is established according to con¬ ventional criteria, i.e. the classic triade: Marrow plasmocytosis (>10 percent) , lytic bone lesions, and a serum and/or urine M component, or plasmocytosis associated with a progressive increase in the M component over time or if extramedullary mass lesions develop. Study medication Fucidin tablets 0.5 g three times daily for at least 3 weeks SUBSTITUTE SHEET ISA/SE Investigations: At entry, the following data are recorded: M component marrow biopsy, radiogram of the skull - concomitant disease(s) and medication Laboratory tests: Blood: Haemoglobin, RBC, WBC, and differential count, platelets; serum creatinine, bilirubin, alkaline phosphatase, ALAT, ASAT, elec¬ trolytes, se-calcium, IGA, IgG, IgM, M component. Urine: 24-h-proteinuria, glucose, M component. Immunological tests: Blood levels of cytokines and in vitro production of IL-6 Follow-up investigations: The study runs for minimum 3 weeks and maximum 3 months. Data which will be collected at weekly intervals during the first 3 weeks, and then at 2-4 weekly intervals: Side-effects which can be ascribed to fusidin. Symptoms and signs of multiple myeloma and concomitant di- sease(s) . - Details of all therapy. Laboratory parameters: Creatinine, creatinine clearance, liver func¬ tion tests, hematology, urine (24 h proteinuria), M component. The immunological tests should be repeated at least once monthly. True plasma levels of fusidin (blood drawn in the morning before first dosage of fusidin) should be performed at bi-weekly intervals. Withdrawals/drop-outs Withdrawals are defined as patients who discontinue therapy either because of side-effects or inadequate efficacy. These patients should be fully analysed and data safety and efficacy required also after withdrawal. Drop-outs are patients lost to follow-up, not complying to instruc- tions or otherwise violating the protocol. These patients should be replaced by new patients. EXAMPLE 18 Clinical effect of fusidin in early management of rheumatoid ar¬ thritis , juvenile rheumatoid arthritis , polymyalgia rheumatica and systemic lupus erythematosus (SLE) 18.1. Effect of fusidin in moderately active cases of systemic lupus erythematosus (SLE) as an adjunct to glucocorticoid therapy Background The use of glucocorticoids has improved the outcome of systemic lupus erythematosus (SLE) , particularly if accompanied by renal involve¬ ment. The addition of other immunosuppressive drugs, including cy- tostatic drugs, has been advocated in some cases. However, there is a need for a treatment complementary to glucocorticoids in SLE be¬ cause: a. Some patients, particularly patients with systemic vasculitis, do not respond to corticosteroids alone. SUBSTITUTE SHEET b. Many patients are in need of high dose (>10 mg prednisolone per day) corticosteroid treatment: They relapse as soon as the drug is progressively diminished or stopped. c. Severe side-effects of high dose glucocorticoid therapy. Aim of study To gain preliminary experience with fusidin in the treatment of SLE patients who, despite prolonged therapy with low doses of gluco¬ corticoids, (< 10 mg prednisolone per day) , show signs of clinical activity. Specific aims are to establish: Dosage schedule of fusidin. Safety and tolerability of fusidin. - Effects of fusidin on immunoinflammatory parameters. Open, uncontrolled pilot study. Patients 10 adults of both sexes. Inclusion criteria The SLE diagnosis should fulfil four or more of the American Rheuma¬ tism Association's criteria for the classification of SLE at the time of diagnosis. Patients who, despite receiving < 10 mg of prednisolon daily for ≥.3 months, present with subjective and/or objective signs of ongoing disease activity. Exclusion criteria Patients receiving complementary treatment (e.g. cytostatic drugs) for SLE. Patients who are not treated with glucocorticoids. Pregnancy and patients in child-bearing age not practising effective birth control. Study medication - Fucidin tablets 0.5 g three times daily for at least 3 weeks. Prednisolone (e.g. from DAK, Copenhagen, Denmark). The dosage should be the mean daily dosage (< 10 mg per day) given in the previous three months. This dosage must be kept unaltered throughout the study. Investigations At entry the following data should be recorded: History of SLE and subjective and objective signs of SLE. Concomitant disease(s) and medication. Laboratory tests: Blood: Haemoglobin, RBC, WBC, and differential count, platelets; serum creatinine, bilirubin, alkaline phosphatase, ALAT, ASAT, elec¬ trolytes. Urine: 24-h-proteinuria, glucose. Immunological blood tests: - Antinuclear and anti-DNA antibodies. IgG, IgA, IgM. Coombs'test, rheumatoid factor. B lymphocyte level (membrane immunoglobulin) . T lymphocyte level and subpopulations (CD4, CD8) . - Levels of cytokines and in vitro production of IL-2, LT (lympho- toxine (TNF/3) and IFN7. Complement C3 and C5a. Follow-up investigations: The study runs for minimum 3 weeks and maximum 3 months. Data which will be collected at weekly intervals during the first 3 weeks, and then at 2-4 weekly intervals: - Side-effects which can be acribed to fusidin. Symptoms and signs of SLE and concomitant disease(s). Details of all therapy. Laboratory parameters: Creatinine, creatinine clearance, liver func¬ tion tests, hematology, urine (24-h- proteinuria) . The immunological tests will be repeated at least once monthly. Trough plamas levels of fusidin (blood drawn in the morning before first dosage of fusidin) will be performed at bi-weekly intervals. Withdrawals/drop-outs Withdrawals are defined as patients who discontinue therapy either because of side-effects or inadequate efficacy. These patients will be fully analysed and data safety and efficacy required also after withdrawal. Drop-outs are patients lost to follow-up, not complying to instruc- tions or otherwise violating the protocol. These patiens will be replaced by new patients. 18.2: Effect of fusidin as an Immunoinflammatory modulator in rheuma¬ toid arthritis given immediately after diagnosis Background Rheumatoid arthritis is a common disease of unknown cause. The in¬ flammatory processes in rheumatoid arthritis include increased pro¬ duction of synovial fluid, activation and proliferation of cells in the synovial membrane, destruction of articular cartilage and bone, and repair processes resulting in fibrosis, ectopic calcification and metaplastic bone formation. Polymorphonuclear leukocytes and macrophages (M0) play a critical role in all these processes (35, 36). Immunocompetent cells are also involved, and in severe cases the inflamed synovial tissue may re¬ semble a lymphoid organ with germinal centers of B lymphocytes sur¬ rounded by T lymphocytes. Generally, a relatively large proportion of the infiltrating T cells bear membrane markers characteristic for activated T cells, and such cells are often found in the blood as well (35) . The presence of plasma cells and immune complexes in the synovial tissue and the frequent finding of autoantibodies, parti¬ cularly anti Fc-IgG rheumatoid factors, and hypergammaglobulinemia also suggests that antibody-mediated reactions are involved in the disease processes. However, these humoral reactions may reflect that the cellular infiltrate in the synovial tissue is dominated by ac¬ tivated T cells of the helper phenotype, and these cells may trigger B cells to produce antibodies in an uncontrolled manner. Many inves¬ tigators believe that in rheumatoid arthritis, the host responds to an exogenous antigen, or an endogenous antigen rendered immunogenie in an aberrant manner, to generate an inappropriate cellular as well as humoral immune response. IL-1 and, possibly, IL-6 and TNFα seem to play a central role in the processes leading to tissue damage in rheumatoid arthritis and rela- ted rheumatic diseases (8). Thus, injection of IL-1 and TNFα in knee joints of normal rabbits causes similar biochemical changes as those seen in early rheumatoid arthritis (37), and blood levels of IL-1 and IL-6 closely parallels subjective and objective disease activity in patients with rheumatoid arthritis (38) . The evidence that cyclosporin is effective in rheumatoid arthritis, both when experimentally induced (39) and in clinical cases (40-43) , further support the notion that IL-1 and/or IL-6 may trigger the initial immunoinflammatory processes which eventually causes joint and bone destruction. Unfortunately, significant adverse effects of cyclosporin have been noted, and alternative therapies are therefore advocated. Aim of study To gain preliminary experience with fusidin in the treatment of patients with newly diagnosed rheumatoid arthritis. Specific aims are to establish the dosage schedule, safety and to¬ lerability of fusidin and effects of the drug on immunoinflammatory parameters in rheumatoid arthritis. Open, uncontrolled pilot study. Patients 10 adults of both sexes Inclusion criteria The diagnosis should fulfil four or more of the American Rheumatism Association's criteria for the classification of rheumatoid arthritis at the time of diagnosis. Patients must not have received medication other than non-steroidal antiinflammatory drugs (NSAID) (In particu¬ lar glucocorticoids, gold salts, penicillamine, cytostatic drugs), and the duration of active disease should not exceed 12 months. Exclusion criteria - Patients receiving treatment other than NSAID. Pregnancy and patients in child-bearing age not practising effective birth control. Study medication Fucidin, tablets 0.5 g three times daily for at least 2 months. Investigations At entry the following data will be recorded: History of disease and subjective and objective signs of rheuma¬ toid arthritis. Concomitant disease(s) and medication. Laboratory tests Blood: Haemoglobin, RBC, WBC, and differential count, platelets; serum creatinine, bilirubin, alkaline phosphatase, ALAT, ASAT, elec¬ trolytes. Urine: protein, glucose. Immunological blood tests: Antinuclear and anti-DNA antibodies. IgG, IgA, IgM. Rheumatoid factor. B lymphocyte level (membrane immunoglobulin) . - T lymphocyte level and subpopulations (CD4, CD8) Levels of cytokines and in vitro production of IL-2, LT and IFN7. Complement C3 and C5a. Follow-up investigations: The study runs for minimum 2 months and maximum 6 months. Data which will be collected at bi-weekly intervals during the first 2 months, and then at 4 weekly intervals: Side-effects which can be ascribed to fusidin. Symptoms and signs of rheumatoid arthritis and concomitant disease(s) . Details of therapy. Laboratory parameters: Creatinine, liver function tests, hematology, urine (protein, glucose) . The immunological tests should be repeated at least once every second month. - Trough plasma levels of fusidin (blood drawn in the morning before first dosage of fusidin) should be performed at bi-weakly intervals during the first two months and then at four weeks intervals. Withdrawals/drop-outs Withdrawals are defined as patients who discontinue therapy either because of side-effects or inadequate efficacy. These patients should be fully analysed and data on safety and efficacy are required also after withdrawal. Drop-outs are patients lost to follow-up, not complying to instruc¬ tions or otherwise violating the protocol. These patients should be replaced by new patients. 18.3. Other connective tissue diseases: Since the term rheumatoid arthritis applies to a syndrome without known cause, it is difficult to ascertain whether the pathogenesis of this connective tissue disease differs markedly from related and often overlapping clinical syndromes. Thus, other connective tissue diseases, such as juvenile rheumatoid arthritis, psoriatic arthritis, reactive arthritis (Reiter's syndrome), polymyalgia rheumatica, systemic sclerosis, and sarcoidosis may be pathogenetically related. That similar disease mechanisms may be operative in several or all of these diseases is strengthened by the fact that patients with dif¬ ferent connective tissue diseases benefit from therapy with the T cell-selective immunosuppressive drug cyclosporin (44) . The treat¬ ment of these diseases, however, is often unsatisfactory, and almost always accompanied by side-effects. The clinical studies in connection with these diseases should be performed analogously to the protocols outlined above. LEGENDS TO FIGURES Fig. 1: Cellular interactions and cytokine production during antigen presentation to T- and B lymphocytes. The cytokines produced by both immune and non-immune cells may enter the blood stream and act as hormones which affect the functions of distant tissues. Modified from (3). M0: macrophage. Th: T helper lymphocyte. B: B lymphocyte. F: fibro¬ blast. NK: natural killer cell. DR: MHC class II molecule. IL-1 IF: interleukin 1-inducing factor. Fig. 2: Effect of fusidin on IL-1 and TNFα production. The percentage of inhibition is shown as a function of the final test concentration of fusidin. * : P<0.01, n-12 (IL-1) and n-6 (TNFα). Fig. 3: Effect of fusidin on IL-2 and IFN7 production. The percentage of inhibition Is shown as a function of the final test concentration of fusidin. * : P<0.05, n-6. Fig. 4: Effect of fusidin on IL-1 (mouse thymocytes) . The percentage of inhibition is shown as a function of the final test concentration of fusidin. * : P<0.01, n=8. Fig. 5: Effect of fusidin on IL-1 (human lymphocytes). The percentage of inhibition is shown as a function of the final test concentration of fusidin. * : P<0.05, n-=5. PPD: purified protein derivative of tuberculin (antigen). PHA: phytohemagglutinin (nonspecific, poly¬ clonal T lymphocyte activator) . Fig. 6: Effect of fusidin on IL-1 (mouse thymocyte cell line, EL 4). The percentage of inhibition is shown as a function of the final test concentration of fusidin. * : P<0.05, n=7. Fig. 7: Effect of fusidin to inhibit IL-2 and TNFα activities. The percentage of inhibition is shown as a function of the final test concentration of fusidin. n=4 (IL-2) and n=6 (IFN7) , respectively. Fig. 8: Effect of delayed addition of 5 μg/ml of fusidin to PHA-ac- tivated murine thymocytes. Fig. 9: Effect of fusidin on the two-way mixed lymphocyte reaction. The percentage of inhibition is shown as a function of the final test concentration of fusidin. * : P<0.01, n-10. Fig. 10: Effect of fusidin on IL-6 (B9 cells). The percentage of inhibition is shown as a function of the final test concentration of fusidin. Human rIL-6 was added to the test cells at a concentration of 1 U/ml. * : P<0.02, n-7. Fig. 11: Reversibility of fusidin-induced inhibition of IL-6 activity (B9 assay) . The test cells were treated as indicated. The cells were treated with 18 U/ml of rIL-6 with/without 30 μg/ml of fusidin, as indicated (PRE). After 2 days, the cells were washed three times and cultured further for 2 days with/without 30 μg/ml of fusidin, as indicated (POST). The assay for IL-6 activity was performed during the last 2 days of culture in the presence of the indicated levels of rIL-6. Fig. 12: IL-1/3 induced inhibition of insulin secretion (% of control: Insulin secretion in cultures kept in medium alone without IL-1) . Protection afforded by fusidin. The rat pancreatic islets of Lan- gerhans were precultured for 6 days. The islets were then washed and added fresh medium, containing 11 mmol/1 of glucose, and rIL-1/3 +/- fusidin at the indicated concentrations. Fig. 13: Inability of fusidin analogs to protect against IL-1/3 in- duced /3-cell damage. The culture conditions were the same as in Fig. 12, except that only one concentration of the fusidin analogs were tested. REFERENCES 1. Bendtzen K. Lymphokines in inflammation. Inflammation Basic Mecha¬ nisms Tissue Injuring Principles and Clinical Models (P Venge & A Lindbom eds ) 1985; Almqvist & Wiksell International. Stockholm: 187-217. 2. Bendtzen K. Interleukin 1, interleukin 6 and tumor necrosis factor in infection, inflammation and immunity. Immunol Lett 1988; 19: 183- 192. 3. Bendtzen K, Rasmussen AK, Bech K, Feldt-Rasmussen U, Buschard K. Pathogenic role of interleukin 1 and tumor necrosis factor in auto¬ immune endocrine diseases. Clin Immunol Newslett 1988; 9: 72-74. 4. 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T cell growth factor: parame¬ ters of production and a quantitative microassay for activity. J Immunol 1978; 120: 2027-2031. 32. Bendtzen K, Barington T, Mandrup-Poulsen T, Pedersen JG, Svenson M. Measurement of human IL-1 by LIF induction, pancreatic islet-cell cytotoxicity and bone resorption. Lymphokine Res 1986; 5.Suppl.1: 93-98. 33. Reeves DS. The pharmacokinetics of fusidic acid. J Antimicrob Chemother 1987; 20: 467-476. 34. von Graffenried B, Krupp P. Side-effects of cyclosporin (sandim- mun) in renal transplant recipients and In patients with autoimmune diseases. Tranpl Proc 1986; 18: 876-883. 35. Padula SJ, Clark RB, Korn JH. Cell-mediated immunity in rheumatic disease. Human Pathol.1986;17:254-263. 36. Bunning RAD, Richardson HJ, Crawford A, Skjødt H, Hughes D, Evans DB, Gowen M, Dobson PRM, Brown BL, Russell RGG. The effect of inter¬ leukin-1 on connective tissue metabolism and its relevance to ar- thritis. Agents Actions 1986;18:131-153. 37. Henderson B, Pettipher ER. Arthritogenic actions of recombinant IL-1 and tumour necrosis factor alpha in the rabbit: evidence for synergistic interactions between cytokines in vivo. Clin.Exp.Immuno 1.1989; 75:306-310. 38. Duff GW, 1988. Arthritis and interleukins. Br.J.Rheumatol. 1988;27:25. 39. Bowles CA, Wooley PH, Luthra HS, Handwerger BS. Therapeutic effect of cyclosporin A and indomethacin in collagen- induced ar¬ thritis in mice. Arthr.Rheumatol. 1983;S26-S52. 40. van Rijthoven AWAM, Dijkmans BAC, Goei The HS, Hermans J, Mont- nor-Beckers ZI.MB, Jacobs PCJ, Cats A. Cyclosporin treatment for rheumatoid arthritis: a placebo controlled, double blind, multicentre study. Ann. heum.Dis. 1986;45:726-731. 41. Førre 0, Bjerkhoel F, Salvesen CF, Berg KJ, Rugstad HE, Saelid G, Mellbye OJ, Ksess E. An open, controlled, randomized comparison of cyclosporin and azathioprine in the treatment of rheumatoid ar¬ thritis: a preliminary report. Arthr.Rheumatism 1987;30:88-92. 42. Dougados M, Awada H, Amor B. 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Claims: CLAIMS 1. The use of fusidic acid or a derivative thereof for the manufac¬ ture of a composition for substantially inhibiting a biological effect in a human related to a cytokine for prophylaxis or treatment of a condition related to disturbances of a cytokine system, such as for the manufacture of a composition for prophylaxis or treatment of diabetes mellitus, in particular insulin-dependent diabetes mellitus (type 1) , in particular for the prevention of progression of diabetes mellitus (type 1) , especially substantially immediately after the first diagnostic establishment of diabetes mellitus, or for pro¬ phylaxis after establishment of being in a high risk group of de¬ veloping diabetes mellitus (type 1) , or for the manufacture of a composition for the treatment of endogenous uveitis, or for the manufacture of a composition for the prevention of the in¬ flammation after eye surgery such as cataract operation or laser surgery, or for the manufacture of a composition for treatment of progression of arthritis such as rheumatoid arthritis, psoriatic arthritis or Reiter arthritis substantially immediately after the first diagnostic estab¬ lishment of arthritis, or for the manufacture of a composition for prophylaxis or treatment of arthritis urica, or for the manufacture of a composition for treatment of osteoarthrosis, or for the manufacture of a composition for prophylaxis or treatment of a condition related to transplant rejection, such as for the manufac¬ ture of a composition for prophylaxis or treatment of a condition related to cornea transplantation, or for the manufacture of a composition for prophylaxis or treatment of a condition related to a graft-versus-host reaction, or for the manufacture of a composition for the treatment of Crohn's disease or ulcerative colitis, especially for the prevention of relapse or progression of Crohn's disease or ulcerative colitis for the manufacture of a composition for the treatment of perniceous anemia or celiac disease, or for the manufacture of a composition for prophylaxis or treatment of contact dermatitis, or for the manufacture of a composition for prophylaxis or treatment of allergic/atopic dermatitis, or for the manufacture of a composition for treatment of pemphigus vulgaris or pemphigoid, or for the manufacture of a composition for treatment of a condition related to the function of the thyroid gland, in particular hyper- or hypofunctioning of said gland, e.g. thyroiditis (acute, subacute or chronic), including Hashimoto's disease (lymphocytic thyroiditis; lymphoid thyroiditis), Riedel's thyroiditis (chronic fibrous thyroi¬ ditis), de Quervain's thyroiditis (subacute granulomatous thyroidi- tis), subacute lymphocytic thyroiditis, Graves' disease, Graves'sub- acute thyroiditis or Graves' ophthalmopathy, or for the manufacture of a composition for treatment of Simmonds' parihypopituitarism or for the manufacture of a composition for treatment of a condition related to hypofunction of the adrenal glands, in particular Addi- son's disease, or for the manufacture of a composition for treatment or prevention of replapse of a demyelinating disease, in particular multiple sclero¬ sis, or for the manufacture of a composition for treatment or prevention of relapse of sarcoidosis Boeck, Sjogren's syndrome, Reiter's syndrome, erythema nodosum, scleroderma or Bechet's disease, or for the manufacture of a composition for treatment or prevention of relapse of polymyositis, polymyalgia rheumatica, myocarditis or systemic lupus erythematosis, or for the manufacture of a composition for treatment or prevention of relapse of a condition related to vasculitis phenomena, e.g. polyar- teritis nodosa, Wegener's granulomatosis, or giant-cell arteritis, or for the manufacture of a composition for treatment or prevention of relapse of primary biliary cirrhosis or chronic active hepatitis, or for the manufacture of a composition for treatment of aplastic anemia or idiopathic thrombocytopenic purpura, or for the manufacture of a composition for treatment or prevention of relapse of a neoplastic disorder of the lymphoid tissue, e.g. B cell lymphoma or multiple myeloma, or for the manufacture of a composition for treatment or prevention of relapse of a T lymphocyte proliferative disorder, e.g. mycosis fun¬ goides or Sezary syndrome, or for the manufacture of a composition for prophylaxis or treatment of septic shock caused by gram-negative bacteria, or for the manufacture of a composition for prophylaxis or treatment of disseminated intravascular coagulation, or for the manufacture of a composition for prophylaxis of arterio- sclerosis, or for the manufacture of a composition for prophylaxis or treatment of a condition acute and chronic periodontal diseases, in particular periodontitis and periodontosis. 2. The use of fusidic acid or a derivative thereof for the manufac¬ ture of a composition for prophylaxis or treatment of diabetes melli- tus, in particular insulin-dependent diabetes mellitus (type 1), in particular for the prevention of progression of diabetes mellitus (type 1) , especially substantially immediately after the first diag¬ nostic establishment of diabetes mellitus, or for prophylaxis after establishment of being in a high risk group of developing diabetes mellitus (type 1) . 3. The use of fusidic acid or a derivative thereof for the manufac¬ ture of a composition for prophylaxis or treatment of progression of arthritis such as rheumatoid arthritis, psoriatic arthritis or Reiter arthritis substantially immediately after the first diagnostic establishment of arthritis. 4. The use of fusidic acid or a derivative thereof for the manufac¬ ture of a composition for prophylaxis or treatment of septic shock caused by gram-negative bacteria. 5. The use of fusidic acid or a derivative thereof for the manufac- ture of a composition for treatment of Crohn's disease or ulcerative colitis, especially for the prevention of relapse or progression of Crohn's disease or ulcerative colitis. 6. The use of fusidic acid or a derivative thereof for the manufac¬ ture of a composition for prophylaxis or treatment of a condition related to transplant rejection. 7. The use of fusidic acid or a derivative thereof for the manufac¬ ture of a composition for prophylaxis or treatment of a condition related to a graft-versus-host reaction. 8. The use according to claim 6 of fusidic acid or a derivative thereof for the manufacture of a composition for prophylaxis or treatment of a condition related to cornea transplantation. 9. The use of fusidic acid or a derivative thereof for the manufac¬ ture of a composition for the treatment of endogenous uveitis. 10. The use of fusidic acid or a derivative thereof for the manufac- ture of a composition for the prevention of the inflammation after eye surgery such as cataract operation or laser surgery. 11. The use of fusidic acid or a derivative thereof for the manufac¬ ture of a composition for prophylaxis or treatment of contact der¬ matitis. 12. The use of fusidic acid or a functional derivate thereof for the manufacture of a composition for treatment or prevention of relapse of systemic lupus erythematosis. 13. The use of fusidic acid or a functional derivate thereof for the manufacture of a composition for treatment or prevention of relapse of a neoplastic disorder of the lymphoid tissue such as B cell lymp- homa or multiple myeloma. 14. The use of fusidic acid or a derivative thereof for use as an immunosuppressive drug. 15. The use according to any of claims 1-14 wherein the composition is a composition suitable for oral administration. 16. The use according to any of claims 1-14 wherein the composition is a composition suitable for rectal administration. 17. The use according to any of claims 1-14 wherein the composition is a composition suitable for parenteral administration. 18. The use according to any of claims 1-14 wherein the composition is a composition suitable for intraarticular administration. 19. The use according to any of claims 1-14 wherein the composition is a composition suitable for application to the skin. 20. The use according to any of claims 1-14 wherein the composition is a composition suitable for application to the eye. 21. The use according to any of claims 1-14 wherein the composition is a composition suitable for implantation administration. 22. The use of fusidic acid or a derivative thereof for the manufac¬ ture of a composition for the treatment of contact dermatitis, in particular for the manufacture of a composition for oral administra¬ tion. 23. The use of fusidic acid or a derivative thereof for the manufac- ture of a composition for the topical treatment of contact dermati¬ tis, in particular for the manufacture of a composition for topical administration to the skin. 24. The use of fusidic acid or a derivative thereof for the manufac¬ ture of a composition for treatment of Crohn's disease or colitis ulcerosa, in particular for the manufacture of an oral or rectal composition, or a composition for parenteral administration. 25. The use of fusidic acid or a derivative thereof for the manufac¬ ture of a composition for treatment of arthritis substantially imme¬ diately after the first diagnostic establishment of arthritis, in particular for the manufacture of a composition for oral use or for use as parenteral or intraarticular injections. 26. The use of fusidic acid or a derivative thereof for the manufac¬ ture of a composition for treatment of endogenous uveitis, in parti¬ cular for the manufacture of a composition suitable for treatment of the eye, such as an eye drop composition, an eye ointment composi¬ tion, an eye lotion composition or an injectable composition for intraocular or retroocular injection, or an oral composition. 27. The use of fusidic acid or a derivative thereof for the manufac¬ ture of a composition for the prevention of inflammation after eye surgery, in particular an oral composition, or a composition suitable for treatment of the eye, such as an eye drop composition, an eye ointment composition, an eye lotion composition or an injectable composition for intraocular or retroocular injection. 28. The use of fusidic acid or a derivative thereof for the manufac- ture of a composition for prophylaxis or treatment of a condition related to transplant rejection, in particular for the manufacture of a composition for oral or parenteral administration. 29. The use of fusidic acid or a derivative thereof for the manufac¬ ture of a composition for prophylaxis or treatment of a condition related to a graft-versus-host reaction, in particular for the manu¬ facture of a composition for oral or parenteral administration. 30. The use of fusidic acid or a derivative thereof for the manufac¬ ture of a composition for prophylaxis or treatment of diabetes melli¬ tus (type 1) , in particular for the manufacture of a composition for oral or rectal use. 31. The use of fusidic acid or a derivative thereof for the manufac¬ ture of a composition for prophylaxis or treatment of septic shock caused by gram-negative bacteria, in particular for the manufacture of a composition for oral or parenteral administration. 32. The use of fusidic acid or a derivative thereof for the manufac¬ ture of a composition for treatment or prevention of relapse of systemic lupus erythematosis, in particular for the manufacture of a composition for oral or parenteral administration. 33. The use of fusidic acid or a derivative thereof for the manufac- ture of a composition for treatment or prevention of relapse of a neoplastic disorder of the lymphoid tissue such as B cell lymphoma or multiple myeloma, in particular for the manufacture of a composition for oral or parenteral administration. 34. The use according to any of the preceding claims wherein the fusidic acid or a derivative is used together with a ciclosporin (Cyclosporin A) or a derivative thereof or together with FK-506. 35. A method for substantially inhibiting a biological effect in a human related to a cytokine for prophylaxis or treatment of a condition related to disturbances of a cytokine system, such as for prophylaxis or treatment of diabetes mellitus, in particular insulin-dependent diabetes mellitus (type 1), in particular for the prevention of progression of diabetes mellitus (type 1) , especially substantially immediately after the first diagnostic establishment of diabetes mellitus, or for prophylaxis after establishment of being in a high risk group of developing diabetes mellitus (type 1) , or for the treatment of endogenous uveitis, or for the prevention of the inflammation after eye surgery such as cataract operation or laser surgery, or for treatment of progression of arthritis such as rheumatoid arth- ritis, psoriatic arthritis or Reiter arthritis substantially immedia¬ tely after the first diagnostic establishment of arthritis, or for prophylaxis or treatment of arthritis urica, or for treatment of osteoarthrosis, or for prophylaxis or treatment of a condition related to transplant rejection, such as for prophylaxis or treatment of a condition rela¬ ted to cornea transplantation, or for prophylaxis or treatment of a condition related to a graft-ver¬ sus-host reaction, or for the treatment of Crohn's disease or ulcerative colitis, especial- ly for the prevention of relapse or progression of Crohn's disease or ulcerative colitis for the treatment of perniceous anemia or celiac disease, or for prophylaxis or treatment of contact dermatitis, or for prophylaxis or treatment of allergic/atopic dermatitis, or for treatment of pemphigus vulgaris or pemphigoid, or for treatment of a condition related to the function of the thyroid gland, in particular hyper- or hypofunctioning of said gland, e.g. thyroiditis (acute, subacute or chronic), including Hashimoto's disease (lymphocytic thyroiditis; lymphoid thyroiditis), Riedel's thyroiditis (chronic fibrous thyroiditis), de Quervain's thyroiditis (subacute granulomatous thyroiditis), subacute lymphocytic thyroid!- tis, Graves' disease, Graves'subacute thyroiditis or Graves' oph- thalmopathy, or for treatment of Simmonds' panhypopituitarism or for treatment of a condition related to hypofunction of the adrenal glands, in particular Addison's disease, or for treatment or prevention of replapse of a demyelinating disease, in particular multiple sclerosis, or for treatment or prevention of relapse of sarcoidosis Boeck, Sjo- gren's syndrome, Reiter's syndrome, erythema nodosu , scleroderma or Bechet's disease, or for treatment or prevention of relapse of polymyositis, polymyalgia rheumatica, myocarditis or systemic lupus erythematosis, or for treatment or prevention of relapse of a condition related to vasculitis phenomena, e.g. polyarteritis nodosa, Wegener's granuloma- tosis, or giant-cell arteritis, or for treatment or prevention of relapse of primary biliary cirrhosis or chronic active hepatitis, or for treatment of aplastic anemia or idiopathic thrombocytopenic purpura, or for treatment or prevention of relapse of a neoplastic disorder of the lymphoid tissue, e.g. B cell lymphoma or multiple myeloma, or for treatment or prevention of relapse of a T lymphocyte proliferati¬ ve disorder, e.g. mycosis fungoides or Sezary syndrome, or for prophylaxis or treatment of septic shock caused by gram-negative bacteria, or for prophylaxis or treatment of disseminated intravascular coagula- tion, or for prophylaxis of arteriosclerosis, or for prophylaxis or treatment of a condition acute and chronic perio¬ dontal diseases, in particular periodontitis and periodontosis, the method comprising administering to a human in need thereof an effective amount of fusidic acid or a derivative thereof. 36. A method of treating diabetes mellitus, in particular insulin- dependent diabetes mellitus (type 1) which method comprises admini¬ stering to a human in need of such treatment an effective amount of fusidic acid or a derivative thereof. 37. A method of preventing a progression of diabetes mellitus, in particular insulin-dependent diabetes mellitus (type 1) which method comprises administering to a human in need of such treatment an effective amount of fusidic acid or a derivative thereof. 38. A method according to claim 37 wherein the effective amount of fusidic acid or a derivative thereof is administered substantially immediately after the first diagnostic establishment of diabetes mellitus. 39. A method of prophylactic treatment of diabetes mellitus (type 1) after establishment of being in a high risk group of developing diabetes mellitus (type 1) . 40. A method of treatment or prevention of the inflammation after eye surgery, which method comprises administering to a human in need of such treatment an effective amount of fusidic acid or a derivative thereof. 41. A method of treating endogeneous uveitis, which method comprises administering to a human in need of such treatment an effective amount of fusidic acid or a derivative thereof. 42. A method of treating arthritis substantially immediately after the first diagnostic establishment of arthritis which method compri¬ ses administering to a human in need of such treatment an effective amount of fusidic acid or a derivative thereof. 43. A method of treating arthritis urica which method comprises administering to a human in need of such treatment an effective amount of fusidic acid or a derivative thereof. 44. A method of treating osteoarthrosis which method comprises ad¬ ministering to a human in need of such treatment an effective amount of fusidic acid or a derivative thereof. 45. A method of treating a condition related to transplant rejection which method comprises administering to a human in need of such treatment an effective amount of fusidic acid or a derivative there¬ of. 46. A method of treating a condition related to a graft-versus-host reaction which method comprises administering to a human in need of such treatment an effective amount of fusidic acid or a derivative thereof. 47. A method of treating a condition cornea transplantation, which method comprises administering to a human in need of such treatment an effective amount of fusidic acid or a derivative thereof. 48. A method of treating or preventing a relapse of Crohn's disease or ulcerative colitis which method comprises administering to a human in need of such treatment an effective amount of fusidic acid or a derivative thereof. 49. A method of treating pernicious anemia or celiac disease which method comprises administering to a human in need of such treatment an effective amount of fusidic acid or a derivative thereof. 50. A method of treating contact dermatitis which method comprises administering to a human in need of such treatment an effective amount of fusidic acid or a derivative thereof. 51. A method of treating allergic/atopic dermatitis which method comprises administering to a human in need of such treatment an effective amount of fusidic acid or a derivative thereof. 52. A method of treating pemphigus vulgaris or pemphigoid which method comprises administering to a human in need of such treatment an effective amount of fusidic acid or a derivative thereof. 53. A method of treating a condition which is related to the function of the thyroid gland, in particular hyper- or hypofunctioning of said gland, e.g. thyroiditis (acute, subacute or chronic), including Hashimoto's disease (lymphocytic thyroiditis; lymphoid thyroiditis), Riedel's thyroiditis (chronic fibrous thyroiditis), de Quervain's thyroiditis (subacute granulomatous thyroiditis), subacute lymphocy- tic thyroiditis, Graves' disease, Graves'subacute thyroiditis, Gra¬ ves' ophthal opathy or Simmond's panhypopituitarism which method comprises administering to a human in need of such treatment an effective amount of fusidic acid or a derivative thereof. 54. A method of treating a condition which is related to the hypo- function of the adrenal glands, in particular Addison's disease, which method comprises administering to a human in need of such treatment an effective amount of fusidic acid or a derivative there¬ of. 55. A method of treating or preventing relapse of a demyelinating disease, in particular multiple sclerosis, which method comprises administering to a human in need of such treatment an effective amount of fusidic acid or a derivative thereof. 56. A method of treating or preventing relapse of sarcoidosis Boeck, Sjδgren's syndrome, Reiter's syndrome, erythema nodosum, scleroderma or Bechet's disease which method comprises administering to a human in need of such treatment an effective amount of fusidic acid or a derivative thereof. 57. A method of treating or preventing relapse of polymyositis, polymyalgia rheumatica, myocarditis or systemic lupus erythematosis which method comprises administering to a human in need of such treatment an effective amount of fusidic acid or a derivative there¬ of. * 58. A method of treating or preventing a relapse of a condition related to vasculitis phenomena, e.g. polyarteritis nodosa, Wegener's granulomatosis, or giant-cell arteritis which method comprises ad- ministering to a human in need of such treatment an effective amount of fusidic acid or a derivative thereof. 59. A method of treating or preventing a relapse of primary biliary cirrhosis which method comprises administering to a human in need of such treatment an effective amount of fusidic acid or a derivative thereof. 60. A method of treating aplastic anemia or idiopathic thrombocyto- penic purpura which method comprises administering to a human in need of such treatment an effective amount of fusidic acid or a derivative thereof. 61. A method of treating or preventing a relapse of a neoplastic disorder of the lymphoid tissue, e.g. B-cell lymphoma or multiple myeloma, which method comprises administering to a human in need of such treatment an effective amount of fusidic acid or a derivative thereof. 62. A method according to claim 62 wherein disorder is multiple myeloma. 63. A method of treating or preventing a relapse of a T-lymphocyte proliferative disorder, e.g. mycosis fungoides or Sezary syndrome which method comprises administering to a human in need of such treatment an effective amount of fusidic acid or a derivative there- of. 64. A method of treating or preventing a condition of septic shock caused by gram-negative bacteria, which method comprises administer¬ ing to a human in need of such treatment an effective amount of fusidic acid or a derivative thereof. 65. A method of treating disseminated intravascular coagulation which method comprises administering to a human in need of such treatment an effective amount of fusidic acid or a derivative thereof. 66. A method of prophylactic treatment of arteriosclerosis which method comprises administering to a human in need of such treatment an effective amount of fusidic acid or a derivative thereof. 67. A method of treating a condition related to acute and chronic periodontal diseases, in particular periodontitis and periodontosis, which method comprises administering to a human in need of such treatment an effective amount of fusidic acid or a derivative there- of. 68. A method according to any of claims 36-68 wherein the fusidic acid is administered orally, preferably in an amount from about 1 mg to about 75 mg per kg body weight per day. 69. A method according to any of claims 36-68 wherein the fusidic acid is administered rectally, preferably in an amount from about 1 mg to about 100 mg per kg body weight per day. 70. A method according to any of claims 36-68 wherein the fusidic acid is administered topically to the skin in an effective amount. 71. A method according to any of claims 36-68 wherein the fusidic acid is administered to the eye, preferably in an amount from about 0.1 mg to about 50 mg per kg body weight per day. 72. A method according to any of claims 36-68 wherein the fusidic acid is administered parenterally, preferably in an amount from about 0.1 mg to about 50 mg per kg body weight per day, most preferably in an amount from about 1 mg to about 20 mg per kg body weight per day. 73. A method according to any of claims 36-68 wherein the fusidic acid is administered intraarticularly, preferably in an amount from about 0.1 mg to 20 mg per kg body weight per day. 74. The use according to any of claims 1-35 wherein the derivative of fusidic acid is selected from the group consisting of dehydrofusidic acid; 3,11-didehydrofusidic acid; 24,25-dihydrofusidic acid; 17,20- 24,25-tetrahydrofusidic acid; 17,20-24,25-tetrahydrofusidic acid and their corresponding 3-acetates (especially conjugated with glycine or taurine); and 3-0-acetyl-16-epideacetylfusidic acid. 75. A method according to any of claims 36-68 wherein the derivative of fusidic acid is selected from the group consisting of dehydrofusi¬ dic acid; 3,11-didehydrofusidic acid; 24,25-dihydrofusidic acid; 17,20-24,25-tetrahydrofusidic acid; 17,20-24,25-tetrahydrofusidic acid and their corresponding 3-acetates (especially conjugated with glycine or taurine); and 3-0-acetyl-16-epideacetylfusidic acid.

Inventors: BENDTZEN KLAUS, BENDTZEN, KLAUS
Applicants: BENDTZEN KLAUS, BENDTZEN, KLAUS
Application year: 1989
Main classification: A61K31
IPC codes: A61K31, A61P1, A61P3, A61P9, A61P17, A61P27, A61P29, A61P37, C07J13, C07J31, C07J41