Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-03-17
2004-03-23
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S031000, C514S311000, C514S312000, C514S313000, C514S314000, C514S398000, C514S903000
Reexamination Certificate
active
06710033
ABSTRACT:
BACKGROUND OF THE INVENTION
Multiple Sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) in which the predominant pathologic findings are demyelination accompanied by disruption of underlying axons (Trapp et al., New Engl. J. Med. 338:278-285, 1998; Prineas, J. W., “Pathology of Multiple Sclerosis” in: Cook SD, ed. Handbook of Multiple Sclerosis. New York: Marcel Dekker, Inc, 1990:187-215). The disease affects young adults who usually present with a relapsing, remitting pattern of neurologic involvement and progress to a chronic phase with increasing difficulty in ambulation and coordination. The etiology of MS is not known, but there is considerable indirect evidence that argues for the role of an infectious agent(s) in the pathogenesis of the disease. Epidemiological studies strongly suggest that a CNS infection in early childhood is a key factor in the development of MS (Kurtzke, Clin. Microbiol. Rev. 6:382-427, 1993). Viral infections have long been thought to play a possible role in the pathogenesis of MS because viruses are known to cause demyelinating disease in experimental animals, often present clinically with relapsing, remitting symptoms, and can cause disease with long periods of latency (Cook and Dowling, Neurology 30:80-91, 1980; Johnson, R. T., Viral infections of the Nervous System. New York: Raven Press, 1982). Studies to date, however, have failed to identify any virus as playing a major role in MS, although activated human herpes virus 6 (HHV-6) has been identified recently in brains of MS patients (Sanders et al., J. Neurovirol. 2:249-258, 1996; Challoner et al., Proc. Natl. Acad. Sci. USA 92:7440-7444, 1995; Merelli, J. Neurol. 244:450-454, 1997). Although an immune response to this virus is seen during acute exacerbations, the role of HHV-6 infection in MS remains unclear (Soldan et al., Nature Med. 3:1394-1397, 1997).
Current opinion thus favors MS to be an autoimmune disease directed against self neural antigens (Martin et al., Annu. Rev. Immunol. 10:153-169, 1992). To reconcile the role of environment in the pathogenesis of MS as well as the absence of an identifiable infectious pathogen, it is believed that infectious agents may act to trigger an autoimmune process. Such an autoimmune response may result from structural similarities between an infectious agent and neural antigens (antigenic mimicry) or from an expansion of self autoreactive T cell clones in response to bacterial or viral superantigens (Brocke et al., Nature 65:642-646, 1993; Jahnke et al., Science 229:282-284, 1985; Marrack and Kappler, Science 248:325-329, 1998; Oldstone, J. Autoimmun. 2(S):187-194, 1989). Evidence that MS is a disease mediated by T cells that recognize neural antigens has been hard to justify, since measures directed at either eliminating or reducing helper T cell function have not changed the natural history of MS (Sriram and Rodriguez, Neurology 48:469-473, 1997). Improved methods of diagnosing MS would facilitate identification of treatable pathogens and expedite commencement of treatment.
Over the last few years, therapy with &bgr;-IFN has emerged as a means of reducing the morbidity of MS. Both &bgr;-IFNs (&bgr;-1a and &bgr;-1b) reduce the number of clinical relapses and slow the progression of the disease. In addition, magnetic resonance imaging (MRI) studies demonstrate a decrease in the number of new inflammatory cerebral lesions in patients receiving &bgr;-IFN. Although &bgr;-IFN was introduced as a therapeutic agent for MS based on its anti-viral properties, the reasons for the therapeutic benefit of &bgr;-IFN for MS remain unclear. Thus far, no viral agent has been consistently found to be associated with MS.
SUMMARY OF THE INVENTION
In a first aspect, the present invention features a method of diagnosing or monitoring multiple sclerosis in an individual, including assaying a test sample from the individual for the presence of Chlamydia, wherein the presence of Chlamydia in the sample indicates the presence of multiple sclerosis.
In preferred embodiments, the Chlamydia is selected from the group consisting of
Chlamydia pneumoniae, Chlamydia pecorum, Chlamydia psittacci
, and
Chlamydia trachomatis
, and the test sample is selected from the group consisting of blood, serum, peripheral blood mononuclear cells, cerebrospinal fluid, urine, nasal secretion, and saliva.
In one embodiment, the test sample is assayed for the presence of Chiamydia by contacting cultured chlamydia-free indicator cells (e.g., HL cells, H292 cells, HeLa cells, or Hep-2 cells) with the test sample; and then detecting the presence of Chlamydia in the cultured indicator cells. The presence of Chlamydia in the cultured indicator cells is indicative of the presence of Chlamydia in the test sample.
The presence of Chlamydia in the cultured indicator cells can be detected by detecting an antibody to Chlamydia (e.g, an antibody to a Chlamydia elementary body antigen), a Chlamydia gene, or a Chlamydia protein in the test sample. The presence of the antibody, gene, or protein is indicative of the presence of Chlamydia in the test sample. In one embodiment, the test sample is incubated under disulfide reducing conditions (e.g., incubating a disulfide reducing agent such as 2,3-dimercaptosuccinic acid, penicillamine, &bgr;-lactams, dithiotreitol, mercaptoethylamine, or N-acetylcysteine) prior to detecting the presence of Chlamydia.
In another aspect, the invention features a method of isolating elementary bodies from a receptacle containing elementary bodies. The method includes treating the receptable with trypsin/EDTA to release elementary bodies adhered to the receptacle; and then concentrating the elementary bodies by centrifugation or filtration.
In still another aspect, the invention features a method of releasing DNA from elementary bodies, the method including incubating the elementary bodies under disulfide reducing conditions and digesting the elementary bodies with a protease.
In yet another aspect, the invention features a method of treating an individual diagnosed to have multiple sclerosis, including administering to the individual an effective amount of at least one anti-chlamydial agent. In one embodiment, the individual is administered the anti-chlamydial agent until the individual tests negative for elementary body phase Chlamydia, replicating phase Chlamydia, and cryptic phase Chlamydia. In another aspect, the individual is administered the anti-chlamydial agent for at least 45 days. The adminstration can be continued for longer periods, and it may be preferable to continue the treatment for at least 90 days, at least 180 days, or even for one year or more.
Preferable anti-chlamydial agents include rifamycins, azalides, macrolides, ketolides, streptogramins, ampicillin, amoxicillin, nitroimidazoles, nitrofurans, quilolones, fluoroquinolones, sulfonamides, isonicotinic congeners, and tetracyclines.
In one embodiment, the individual is also administered an effective amount of an agent that increases inducible nitric oxide synthase (iNOS) activity, such as a type-1 interferon (e.g., &agr;-interferon or &bgr;-interferon), a synthetic type-1 interferon analog, or a hybrid type-1 interferon. Preferably, the type-1 interferon analog or hybrid binds to the same receptor as a naturally-occurring type-1 interferon. In another embodiment, the individual is administered at least two anti-chlamydial agents.
In yet another aspect, the invention features a method of treating an individual diagnosed to have multiple sclerosis, including administering to the individual (i) a rifamycin; and (ii) a compound selected from the group consisting of azalides, macrolides, ketolides, and streptogramins. In addition, the individual can optionally be administered ampicillin, amoxicillin, probenecid, a nitroimidazole, a nitrofuran, or any combination thereof.
In another aspect, the invention features a method of treating an individual diagnosed to have multiple sclerosis, including administering to the individual one of the following combinations: a rifamycin, ampicilli
Mitchell William M.
Sriram Subramaniam
Stratton Charles W.
Clark & Elbing LLP
Vanderbilt University
Weddington Kevin E.
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