Lymphocytes include T cells, and B cells, which produce antibodies (immunoglobulins). T cells include helper T cells (CD4 antigen positive), which regulate immune response to antigens presented by monocytes or macrophages, and killer T cells (CD8 antigen positive), which destroy, for example, virus-infected cells. Helper T cells include Th1 cells (T helper 1 cells) and Th2 cells (T helper 2 cells). Whether Th1 cells (cellular immunity) or Th2 cells (humoral immunity) are dominant is determined by whether IL-12 or IL-4 is produced by antigen-presenting cells.
Thus, Th1 cells and Th2 cells respectively play an immunological role, and are involved in biological defense. However, it has been known to induce differentiation of T cells into Th1 cells and then excessive activation of Th1 cells may cause various diseases. Diseases known to be caused by excessive induction of Th1 cells include multiple sclerosis, type I diabetes, and rheumatoid arthritis.
Among these diseases, multiple sclerosis is a cryptogenic, intractable disease which is designated as a specified disease by the Japanese Ministry of Health, Labor and Welfare, and this disease involves central dysfunction due to cerebrospinal demyelination and causes sight problems, dyskinesia, etc. In Europe and the United States, the prevalence of multiple sclerosis is higher than that of any other neurological diseases affecting young adults, and is about 50 per 100,000 population. In Japan, the prevalence of multiple sclerosis is estimated to be about 8 or 9 per 100,000 population, and the number of multiple sclerosis patients is estimated to be about 12,000. In many cases, multiple sclerosis involves repeated remissions and relapses (relapsing-remitting multiple sclerosis). Particularly, the onset of multiple sclerosis often occurs around age 30, and relapse of the disease becomes less frequent with increasing age. However, some multiple sclerosis patients exhibit rapid progression of symptoms (chronic progressive multiple sclerosis). It has been shown that T cells or macrophages invade lesion sites of multiple sclerosis patients, and these cells are considered to break myelin protein and myelin sheath in central nerves, thereby causing neurological disorders (Non-Patent Document 1). Demyelinating lesions may be distributed throughout the central nervous system, but are located mainly in, for example, the optic nerves, the brain stem, the spinal cord, and the cerebellum. Multiple sclerosis causes a variety of symptoms (e.g., paralysis of the limbs, shivering, fatigue, optic nerve disorder, dysuria, and dyschezia), and these symptoms vary depending on the site where nerves are damaged.
In current therapy for multiple sclerosis, a steroid is used in the acute phase, whereas an interferon-β (IFN-β) pharmaceutical product or a glatiramer pharmaceutical product is used for prevention of relapse. However, the latter pharmaceutical product is not approved in Japan. An IFN-β pharmaceutical product acts on T cells, to thereby control the amount of interferon-γ produced, and to suppress antigen presentation by antigen-presenting cells (Non-Patent Document 2). Therefore, conceivably, an IFN-β pharmaceutical product suppresses enhancement of immune response, and contributes to delay of progression of multiple sclerosis symptoms or reduction in relapse frequency. However, even when such a pharmaceutical product is administered to multiple sclerosis patients, relapses of multiple sclerosis occur (average relapse frequency: about 0.8 a year), and a method for reliably preventing relapse of multiple sclerosis has not yet been developed (Non-Patent Document 3). In addition, such a pharmaceutical product requires frequent subcutaneous administration, which causes problematic side effects such as fever and subcutaneous ulcer, and imposes a considerable burden on patients in terms of compliance. Therefore, development of a pharmaceutical product which can be orally administered is considered very important for the treatment of multiple sclerosis. Meanwhile, although pulse therapy using cyclophosphamide (i.e., an immunosuppressive agent) has been reported to be effective for patients with severe progressive multiple sclerosis, this agent causes severe side effects (e.g., leukopenia and alopecia), and thus requires careful administration. Under such circumstances, keen demand has arisen for an effective therapeutic method for multiple sclerosis.
Statin compounds (i.e., HMG-Co reductase inhibitors) are known to exhibit various pharmacological effects. It has been known that, for example, atorvastatin and simvastatin are effective for an experimental autoimmune encephalomyelitis (EAE) model; exhibit the effect of inhibiting proliferation of T cells and the effect of inducing differentiation of T cells into Th2 cells; and thus are probably effective for multiple sclerosis (Non-Patent Documents 4 and 5).    Non-Patent Document 1: Noseworthy, et al.; N. Engl. J. Med. Vol. 343, No. 13, pp. 938-52 (2000)    Non-Patent Document 2: Joseph, et al.; J. Neuroimmunol. Vol. 20, No. 1, pp. 39-44 (1988)    Non-Patent Document 3: The IFNB Multiple Sclerosis Study Group; Neurology Vol. 43, No. 4, pp. 655-61 (1993)    Non-Patent Document 4: Nature, 420, 78-84, 2002    Non-Patent Document 5: Lancet, 363, 1607-1608, 2004
USPTO Backgrounds
USPTO Backgrounds