Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – 3,10-dihydroxy-2-naphthacene carboxamide or derivative doai
Reexamination Certificate
2001-05-03
2003-09-02
Cook, Rebecca (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
3,10-dihydroxy-2-naphthacene carboxamide or derivative doai
C514S903000
Reexamination Certificate
active
06613756
ABSTRACT:
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
BACKGROUND OF THE INVENTION
There is an urgent need for the development of new drugs or a new application of existing drugs to the treatment of multiple sclerosis and other incurable neurologic disorders. The application of tetracycline derivatives, such as minocycline or doxycycline, to the treatment of multiple sclerosis based on our data is an advance in the treatment of this disease, both as a primary therapy and in support of transplant-induced brain repair.
Multiple sclerosis is an inflammatory disease of the central nervous system (CNS) in which demyelination results in a variety of neurologic deficits. In many patients the disease relapses and remits while in others there is a progressive worsening with no remissions. At present, the only drugs that have been found to be effective in slowing or lessening the disease burden are &bgr;-interferon and copolymer-I. However, neither cures the disease and in many patients there is little or no effect. While T-cells are the early inflammatory cells found in areas of demyelination (plaques) in multiple sclerosis patients, microglia in these areas become activated and are thought to produce a number of cytotoxic cytokines. These cytokines are then thought to play a key role in the subsequent demyelination and oligodendrocyte death.
The best available model of multiple sclerosis is EAE (Experimental Allergic Encephalomyelitis). While there are differences between EAE and Multiple Sclerosis, EAE remains as the standard model in which to test therapeutic strategies. Indeed, some Phase I trials in multiple sclerosis patients have been based on experimental therapies of EAE. While EAE can be generated in both rats and mice and by using a number of protocols, we induce the disease in DA (Dark Agouti) rats by the injection of myelin-oligodendrocyte glycoprotein (MOG) in incomplete Freund's adjuvant. This creates a severe, often relapsing-remitting neurologic disease, like multiple sclerosis, with paralysis of the hind limbs 12-15 days after immunization. Histologically, there is scattered demyelination associated with inflammation and microglial activation.
BRIEF SUMMARY OF THE INVENTION
In one embodiment, the present invention is a method of treating multiple sclerosis comprising the step of treating a multiple sclerosis patient with a tetracycline derivative, wherein the derivative is lipid soluble, and wherein the multiple sclerosis symptoms of the patient are diminished.
In a preferred embodiment, the tetracycline derivative is selected from the group consisting of minocycline and doxycycline and the tetracycline derivative treatment is timed to prevent a relapse of multiple sclerosis symptoms.
In another embodiment of the invention, the treatment is at the time of a triggering event, typically a viral infection.
In another embodiment, the present invention is a method of treating multiple sclerosis patients wherein a multiple sclerosis patient is treated with a tetracycline derivative, wherein the tetracycline derivative is lipid soluble, prior to or at the same time as receiving a transplant of oligodendrocyte progenitor cells to repair chronic areas of the demyelination. Preferably, the tetracycline-derivative is supplied at least three days before transplantation of cells.
It is an object of the present invention to treat the symptoms of multiple sclerosis.
Other objects, features and advantages of the present invention will become apparent after one has examined the specification, claims and drawings.
REFERENCES:
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patent: 5919775 (1999-07-01), Amin et al.
patent: 00/64479 (2000-04-01), None
WPIDS Accession No. 1996-444664, Opdenakker, EP 736302, Oct. 9, 1996, abstract.*
Benveniste, Etty N., Role of Macrophages/Microglia in Multiple Sclerosis and Experimental Allergic Encephalomyelitis, J. of Mol. Med. (1997) 75:165-173.
Duncan, Ian D., Transplant Strategies in Myelin Disorders,Cell Transplantation for Neurological Disorders: Toward Reconstruction of the Human Central Nervous System, Ed. T.B. Freeman and H. Widner, Humana Press, 1996.
Duncan, Ian D. et al., Repair of Myelin Disease: Strategies and Progress in Animal Modes, Mol. Med. Today, Dec. 1997, 554-561.
Saivin, S. et al., Clinical Pharmacokinetics if Doxycycline and Minocycline, Clin. Pharm. 15:356-357 (1988).
Selkoe, S. et al., Translating Cell Biology into Therapeutic Advances in Alzheimer's Disease, Nature v. 39, Jun. 24, 1999, A23-A31.
Sriram, S. et al., Indictment of the Microglia as the Villain in Multiple Sclerosis, Neurology 48: Feb. 1997, 464-470.
Yrjänheikki, Juha et al., Tetracyclines Inhibit Microglial Activation and are Neuroprotective in Global Brain Ischemia, Proc. Natl. Acad. Sci. USA: v.95, 15769-15774, Dec. 1998.
Yrjänheikki, Juha et al., A Tetracycline Derivative, Minocycline, Reduces Inflammation and Protects Against Focal Cerebral Ischemia with a Wide Therapeutic Window, PNAS, v.96,n.23, Nov. 9, 1999.
Goodman & Gilman's:The Pharmacological Basis of, Therapeutics, Ninth Edition, Chapter 47, 1124-1129, 1996.
Duncan Ian D.
Zhang Su-Chun
Cook Rebecca
Quarles & Brady LLP
Wisconsin Alumni Research Foundation
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