Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – 3,10-dihydroxy-2-naphthacene carboxamide or derivative doai
Reexamination Certificate
2001-04-25
2003-01-07
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
3,10-dihydroxy-2-naphthacene carboxamide or derivative doai
C514S912000
Reexamination Certificate
active
06503892
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to methods of using matrix metalloproteinase inhibitors in glaucoma filtering surgery and in the treatment of ischemic damage to the retina and optic nerve.
BACKGROUND OF THE INVENTION
The retina is comprised of a network of light sensitive nerve cells that line the back of the eye. Located at the innermost cell layer are the ganglion cells. Long filamentous extensions from the axons of these cells wind their way across the retinal surface to a central location at the back of the eye, where they turn and bunch together to form the optic nerve leading to the brain. Light-induced signals are transmitted to produce our perception of sight. The place where the axons turn is called the optic nerve head. The term glaucoma describes a group of diseases that involve optic nerve damage at the level of the optic nerve head. Glaucoma results in a progressive loss of sight and may eventually lead to blindness.
Elevated intraocular pressure (IOP) is the major risk for patients who suffer from glaucoma. In a normal subject's eye, a fluid, known as the aqueous humor, circulates freely through the anterior chamber of the eye. This fluid, which is continuously produced by the eye's ciliary body, is drained from the eye, through the trabecular meshwork, back into the bloodstream. When the fluid drains properly, an appropriate fluid pressure is maintained in the anterior chamber, maintaining the shape of the cornea. Elevated IOP develops when the filtration mechanism of the trabecular meshwork is no longer adequate, leading to an increase in fluid within the anterior chamber. This increase in fluid, in turn, leads to an increase in the IOP. It is this increase in IOP that subsequently causes pressure on the optic nerve at the level of the optic nerve head. This causes damage to the optic nerve, which, in turn, may lead to blindness.
Ischemia is defined as an arrest of blood flow and reduction of oxygen supply to a tissue or organ. Ischemic damage to the retina is a common pathological factor in a number of diseases which cause blindness in humans, including central retinal artery and vein occlusions, diabetes, retinopathy of prematurity, and glaucoma, among others. Occlusion or damage to vessels that supply blood and oxygen to the retina results in ganglion cell death and irreversible blindness.
Management of glaucoma is directed at the control of IOP. However, therapy that prevents damage at the optic nerve head and the death of ganglion cells would constitute a more direct treatment. Present information supports the working hypothesis that ganglion cell death in glaucoma may result from a particular form of ischemia. Support for this view comes from the observation that ischemia induced by occlusion of the retinal artery due to acute elevation of IOP in animals produces damage at the optic nerve head similar to that seen in glaucoma.
Presently, glaucoma is not curable by any available treatment method. However, a variety of different treatment options are available to control, and, perhaps, to slow, the progression of the disease. The choice of a particular treatment is often dependent upon the degree of progression of the disease. Possible treatment options include medicinal therapy, laser eye surgery, and/or conventional surgical methods. Although many different surgical techniques have been employed in the past, glaucoma filtering surgery, also known as trabeculectomy, is principally performed today for the surgical (i.e., non-laser) management of glaucoma. Glaucoma filtration surgery, also known as glaucoma filtering surgery (“GFS”) is typically, but not necessarily, performed on patients in whom prior medicinal and laser therapies have failed to reduce the IOP to sufficiently lower levels.
Generally, GFS is performed to control the IOP when medical therapy or other measures fail. Filtration surgery lowers the IOP by creating a fistula between the anterior chamber and the subconjunctival space, creating a filtering bleb. The aqueous humor that percolates through the bleb can then either be absorbed through veins or conjunctival lymphatics or, in some cases where the conjunctiva is thin, pass directly into the tear film. The major determinant of glaucoma filtering surgery success is the conjunctival wound healing response, with excessive post-operative scarring leading to filtration failure. Late bleb leaks may compromise the ability of the bleb to regulate IOP, and can lead to bleb-related complications, such as infection and hypotony. Current modalities to treat bleb leaks include the use of aqueous suppressants (Pederson,. Ocular hypotony. St. Louis: Mosby; 1989), use of soft bandage contact lenses, pressure patching, glaucoma tamponade shell (Joiner et al., A modification of the use of the glaucoma tamponade shell, OPHTHAL SURG 1989;20:441-2), application of trichloroacetic acid (Gehring et al., Trichloroacetic acid treatment of filtering blebs following cataract extraction, AM J OPHTHALMOL 1972;74:622-4), cyanoacrylate glue (Awan et al., Use of isobutyl-2-cyanoacrylate tissue adhesive in the repair of conjunctival fistula in filtering procedures for glaucoma, ANN OPHTHALMOL 1974;6:851-3; Weber et al., The use of-cyanoacrylate adhesive with a collagen shield in leaking filtering blebs, OPHTHAL SURG 1989; 20:284-5), autologous blood injection (Wise, Treatment of chronic postfiltration hypotony by-intrableb injection of autologous blood, ARCH OPHTHALMOL 1993; 11:827-30.), application of argon laser (Hennis HL, Stewart WC. Use of the argon laser to close filtering bleb leaks, GRAEFES ARCH CLIN EXP OPHTHALMOL 1992;230:537-41), and suturing of the blebs. A variety of surgical procedures have also been used to repair leaking late-onset blebs, including conjunctival patch grafts (Wilson et al., Free conjunctival patch for repair of persistent late bleb leak, AM J OPHTHALMOL 1994; 117:569-74.), and scleral patch grafts in association with conjunctival advancement (Melamed et al., Donor scleral graft patching for persistent filtration bleb leak, OPHTHAL SURG 1991;22:164-5; Morris et al., Use of autologous Tenon's capsule and scleral patch grafts for repair of excessively draining fistulas with leaking filtering blebs, J GLAUCOMA 1998;7:417-9; O'Connor et al., A surgical method to repair leaking filtering blebs, OPHTHAL SURG 1992;23:336-8; Dunnington, Late fistulization of operative wounds. Diagnosis and treatment, ARCH.OPHTHALMOL.1950;43:407-418). Successful closure of late-onset bleb leaks often requires surgical revision of the bleb (Ritch et al., Cases in controversy: Management of the leaking filtration bleb, J GLAUCOMA 1993;2:114-118).
The filtration surgery technique is designed to provide an alternative pathway for the aqueous humor fluid to leave the eye. More specifically, during filtration surgery the filtering or conjunctival bleb is created which serves as an auxiliary “drain” on the outside of the eyeball, and which has direct communication to the inside of the eyeball. This alternate pathway has a lower resistance to fluid outflow than that of the failing, or irreversibly obstructed, trabecular meshwork found in the glaucoma patient. The desired result of this technique is to achieve a lower IOP that is compatible with normal optic nerve function.
Because the basic early events of GFS wound healing have not been well described in humans, animal models have been used to delineate the initial stages of wound healing process. Despite a number of studies using animal models and human tissues, however, the early events of wound healing after GFS are still not clearly understood. In the context of general wound healing, observations in animal models and after GFS in humans suggest a sequence of events in GFS wound healing that occur in early bleb failure. Wound healing has been shown to involve an orderly series of events, including ECM degradation, cell migration, matrix synthesis, and tissue remodeling. After surgical trauma to the conjunctiva, episclera, and iris, blood vessels-constrict, and leakage of plasma proteins
Chintala Shravan K.
Fini M. Elizabeth
Schuman Joel S.
Elrifi Ivor R.
Fay Zohreh
Marenberg Barry J.
Mintz Levin Cohn Ferris Glovsky and Popeo P.C.
New England Medical Center Hospitals Inc.
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