Hyperreactive inflammatory diseases are characterized in that the body hyperreacts to nonspecific stimuli with an uncontrolled inflammation reaction. This inflammatory reaction (hyperreactivity) causes pathological changes leading to the onset of the disease and its chronic establishment. Concerning a definition and examples of hyperreactive inflammatory diseases reference is made to EP-0 673 646, explicitly incorporated herein. Vasculitis is an example of such a hyperreactive inflammatory disease.
A general approach to vasculitis nomenclature and a set of definitions was agreed by consensus (Jennette et al., 1994, “Nomenclature of systemic vasculitides. Proposal of an international consensus conference” Arthritis and Rheumatism, 37, 187-92), and is incorporated herein by reference. According to this nomenclature, the distinction between the various forms of vasculitis depends principally on the size of vessel affected with recognition of characteristic features. Thus, the term vasculitis encompasses small vessel vasculitis (Wegener's granulomatosis, Churg-Strauss syndrome, microscopic poly-angiitis, Henoch-Schönlein purpura, essential cryoglobulin-aemic angiitis), medium-sized vessel vasculitis (cutaneous leucocytoclastic angiitis) and large vessel vasculitis (Poly-arteritis nodosa, Kawasaki's disease, Giant cell (temporal) arteritis, Takayasu's arteritis). The salient features are illustrated in: “Oxford Textbook of Clinical Nephrology”, 2nd edition (1998), Vol. 2, Chapter 4.5, incorporated herein by reference. See e.g. page 880, Table 1, for a short listing of the classification.
The clinical presentation of vasculitis is very diverse; it may be present as a primary disease or be associated with other diseases; vessels of different sizes may be affected in a single patient. The aetiology and pathogenesis are unknown in the vast majority of patients with vasculitis.
It was discovered that a certain spectrum of the diseases is associated with anti-neutrophil cytoplasmic antibodies, called ANCA. It is now clear that they are not only associated with Wegener's granulomatosis but also closely associated with microscopic polyangiitis and renal-limited vasculitis (i.e. isolated focal necrotizing glomerulonephritis), although these findings are more heterogenous than in Wegener's granulomatosis.
Autoimmune diseases are characterized by humoral, complement or cell-mediated immunity to constituents of the body's own tissues causing a clinical abnormality. As used herein, these tissues may also be allografts or xenografts, and graft-versus-host disease (GvHD) is considered an autoimmune disease for the purpose of this disclosure. Examples of autoimmune diseases are: collagenoses, vasculitides, arthritis, granulomatoses, organ specific autoimmunopathies as Morbus Crohn, ulcerative colitis and GvHD. In many diseases, autoimmune mechanisms are at least suspected as the molecular cause of disease. Various animal models of human autoimmune diseases exist and are used to test possible treatments. The diseases which may be treated according to the invention also encompass malignant diseases of the immune system as chronic immuno-proliferative syndrome, monoclonal gammopathies, Morbus Hodgkin and Non-Hodgkin-Lymphoma and chronic proliferative CD8-cell disease. The diseases which may be treated according to the invention generally encompass those mentioned in Peter/Pichler, “Klinische Immunologie”, 2nd ed., Urban & Schwarzenberg, 1996, p. X-XIV (Teil C Klinik).
Therapies for many hyperreactive inflammatory diseases and autoimmune diseases have to be regarded as insufficient. In many instances this is due to severe side effects of the medicaments used. For example, for hyperreactive inflammatory diseases as Alzheimer's disease, pancreatitis and sepsis, there are no adequate treatments.
Regarding vasculitis, early attempts of treatment include the use of oral corticosteroids (OCS). Later, cyclophosphamid was added in steroid-resistant disease. A standard treatment of Wegener's granulomatosis, a form of vasculits, is a combination of cyclophosphamide (CYC) and oral corticosteroids (OCS) Various therapeutic regimen including Prednisolone and cyclophosphamide or Azathioprine are disclosed in “Oxford Textbook for Clinical Nephrology, pp. 890”, referenced above. However, those therapies suffer from several drawbacks, including a relatively high number of therapy-resistant cases, a considerable relapse rate and side effects. For example, long-term treatment with CYC carries the risk of serious drug-related morbidity and mortality. Also, in some patients even short-time exposure to cyclophosphamide leads to overt CYC-toxicity, e.g. marrow suppression, toxic hepatitis or haemorrhagic cystitis and secondary cancers.
Similarly, efficient therapies for autoimmune diseases involving little or no side effects are rare or, in most cases, absent.
Therefore, there is a continued need for improved treatments of hyperreactive inflammatory diseases and autoimmune diseases.
It was now unexpectedly found that 15-deoxyspergualin (DSG) or analogues thereof show a high efficiency in the treatment of hyperreactive inflammatory diseases and autoimmune diseases when the treatment is performed in treatment cycles.
DSG is a synthetic derivative of spergualin, a natural product isolated from Bacillus laterosporus. It was originally described as having antitumor activity, and subsequently was found to possess immunosuppressive properties in experimental transplantation. In additional studies, DSG has demonstrated immunosuppressive activity in many animal models of transplant rejection. For clinical human transplantation, the safety and effectiveness of DSG treatment were proved in kidney graft recipients. Moreover, DSG showed an immunosuppressive effect in animal models of autoimmune diseases (C. Odaka et al., Immunology, 95, 370-376, 1998) and hyperreactive inflammatory diseases (EP-0 673 646).
USPTO Backgrounds
USPTO Backgrounds