Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Patent
1994-07-27
1996-04-09
Dees, Jose G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
514 45, A61K 3170
Patent
active
055062148
DESCRIPTION:
BRIEF SUMMARY
DESCRIPTION
TECHNICAL FIELD
This invention relates to therapeutic methods for treating multiple sclerosis. More particularly, this invention relates to the use of substituted adenine derivatives for treating multiple sclerosis.
BACKGROUND OF THE INVENTION
Multiple sclerosis (MS) is the result of demyelination in the brain and spinal cord (central nervous system). Symptoms resulting from this demyelination include weakness, visual impairment, incoordination, and paresthesia (abnormal tingling). The course of the disease is largely unpredictable, but often progresses through a cycle of exacerbation of symptoms followed by remission.
Conventional treatments presently employ therapy with ACTH or corticosteroids such as prednisone. Controlled studies suggest that such treatments induce more rapid clearing of acute symptoms and signs but leave the long-term outcome of the disease unaffected. Long-term maintenance therapy with ACTH or corticosteroids is contraindicated. Evidence indicates that immunosuppressant agents have no long-term benefit. (Cecil, Textbook of Medicine, Beeson et al., eds., 15th ed., W. B. Saunders Company, Philadelphia, (1979) page 847)
The etiology of multiple sclerosis is unknown but is linked to a variety of genetic and environmental factors. Both cell-mediated and humoral immune responses, triggered by extraneous or autoantigens may contribute to the pathogenesis of multiple sclerosis. Certain immune response genes may be associated with an increased susceptibility to the disease. The disease may be mediated by T cells that recognize an as yet unidentified autoantigen. For example, experimental allergic encephalomyelitis (EAE), an animal model of demyelinating diseases such as multiple sclerosis, can be induced by immunizing mice with whole myelin or specific myelin components such as myelin basic protein.
In humans with multiple sclerosis, exacerbations are correlated with high levels of neopterin in blood and cerebrospinal fluid. Neopterin is a factor released from monocytes and macrophages in the presence of activated T-cells, thereby implicating these cells as being involved in multiple sclerosis exacerbations. (Fredrickson et al. (1987), Acta Neurol. Scand., 75:352-355; Huber et al. (1984), J. Exp. Med., 160:310-316). At the microscopic level, monocytes, microglial cells (macrophages of the central nervous system), and activated T-cells are found within the demyelinated regions of the nerve cells during multiple sclerosis exacerbations. (Cecil, Textbook of Medicine (1979), Beeson et al. (eds.), W. B. Saunders Co., Philadelphia, Pa.).
Various conventional treatment methodologies have been employed to ameliorate the symptoms of multiple sclerosis. Many of these are directed to use of palliative, anti-inflammatory agents. No treatment to date has had any consistent positive effect on the course of the disease.
Recently, the art has described the use of specific deoxyribosides as anti-inflammatory agents. For instance, U.S. Pat. No. 4,481,197 (Rideout et al.) relates to the use of unsubstituted 3-deaza-2'-deoxyadenosine derivatives in the treatment of inflammation. U.S. Pat. No. 4,381,344 (Rideout et al.) relates to a process for the synthesis of deoxyribosides that utilizes a bacterial phosphorylase.
A deoxyriboside derivative, 2-chloro-2'-deoxyadenosine (CdA), has been found to be an effective agent for the treatment of chronic lymphocytic leukemia and some T cell malignancies. (Carson et al. (1984) Proc. Natl. Acad. Sci. U.S.A., 81:2232-2236; Piro et al. (1988), Blood 72:1069-1073) The pharmacokinetics of orally and subcutaneously administered 2-chloro-2'-deoxyadenosine in the treatment of chronic lymphocytic leukemia have been described and compared. (Liliemark et al. (1992) Journal of Clinical Oncology, 10, (10): 1514-1518; Juliusson et al. (1992) Blood, 80 (Suppl. 1): 1427) Chronic lymphocytic leukemia is a malignancy of B lymphocytes that bear the Leu-1 surface antigen.
The Leu-1 B cells represent a minor proportion of the normal pool of B lymphocytes, usually less than 20
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Dees Jos,e G.
Frazier Barbara S.
Lewis Donald G.
The Scripps Research Institute
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