Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2001-01-31
2003-08-12
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S912000, C424S669000
Reexamination Certificate
active
06605640
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a newly identified pharmacological treatment to treat age related diseases or disorders of the posterior segment of the eye. Specifically, the invention provides methods for restoring or alleviating visual acuity affected by retinal vascular diseases and choroidal vascular diseases and certain hereditary eye diseases by topical administration of acetylcholine esterase inhibitors.
BACKGROUND OF THE INVENTION
A diminished visual acuity or total loss of vision may result from a number of eye diseases or disorders caused by dysfunction of tissues or structures in the anterior region of the eye and/or posterior region of the eye. The eye is divided anatomically into an anterior and posterior segment. The anterior segment includes the cornea, anterior chamber, iris and ciliary body (anterior choroid), posterior chamber and crystalline lens. The posterior seqment includes the retina with optic nerve, choroid (posterior choroid) and vitreous. Some of the examples of eye disorders resulting from the pathologic conditions of structures in the anterior segment of the eye are dry eye syndrome, keratitis or corneal dystrophy, cataracts, and glaucoma. The disease or disorders of the posterior segment of the eye in general are retinal or choroidal vascular diseases or hereditary diseases such as Lebers Congenital Amaurosis. The posterior portion of the eyeball supports the retina, choroid and associated tissues.
So far certain treatments, including the topical application of acetylcholine esterase (ACHE) inhibitor, have been used with some success to treat ophthalmic disorders caused by dysfunction of eye muscles in the anterior region of the eye. Acetylcholine, when working on the eye or other smooth muscles of the body is regulated by the natural cholinesterase enzyme which breaks down acetylcholine and thus turns off its parasympathetic effect on muscles. The effect of acetylcholine on the muscles of the eye could be increased either by adding an acetylcholine like drug such as pilocarpine, or by blocking the breakdown of acetylcholine with an AChE drug which inhibits the natural cholinesterase (e.g., a cholinesterase inhibitor). However, the administration of acetylcholine (pilocarpine) results in the side effect of nearsightedness, thus acetylcholine treatment to correct presbyopia has not been effective.
A diminished visual activity may result due to pathologic conditions of tissues or structures located n the anterior segment of the eye or in the posterior region of the eye. Age related macular degeneration (AMD) is one of the specific diseases associated with the posterior portion of the eyeball and is the leading cause of blindness among older people. AMD results in damage to the macula, a small circular area in the center of the retina. Because the macular is the area which enables one to discern small details and to read or drive, its deterioration may bring about diminished visual acuity and even blindness. The retina contains two forms of light receiving cells, rods and cones, that change light into electrical signals. The brain then converts these signals into the images that we see. The macula is rich in cone cells, which give us our central vision. People with AMD suffer deterioration of central vision but usually retain peripheral sight.
There are several types of AMD. The “dry” (non-exudative) type accounts for about 90% of AMD cases. The wet (exudative) form afflicts only about 10% of AMD patients. However, the wet form is a more serious disease than the dry form and is responsible for about 90% of the instances of profound visual loss resulting from the disease. Wet AMD often starts abruptly with the development of tiny, abnormal, leaky blood vessels termed CNVs (chorodial new vessels), directly under the macula. In most patients, this leads to scarring and severe central vision loss, including distortion, blind spots, and functional blindness.
Signs of AMD such as drusen, which are abnormal yellow deposits under the retina, can be present even in patient with normal vision. Drusen look like specks of yellowish material under the retina. They are deposits of extracellular material that accumulate between retinal pigment epithelium (RPE) and Bruch's Membrane. The RPE is a specialized cell layer that ingests used-up outer tips of the rod and cone cells and provides them with essential nutrients (e.g. vitamin A derivatives). Bruch's membrane is a noncellular structure (made mostly of collagen) that separates the RPE from the choroidal circulation below. The choroidal circulation provides the blood supply to the rods, cones and RPE cells. A few small drusen normally form in the human eye, usually after age 40. AMD, in contrast, is almost always associated with a build-up of additional drusen. Drusen occur in two forms. Hard drusen are small, solid deposits that apparently do no harm when present in small numbers. Soft drusen are larger and may have indistinct borders. As soft drusen build up between the RPE and Bruch's membrane, they lift up the RPE and force the two layers apart.
Drusen develop long before the abnormal vessels of wet AMD. Three characteristics of soft drusen are risk factors for developing CNV: The presence of five or more drusen deposits; drusen size greater than 63 micrometers (about the thickness of a human hair); and, the clumping of the drusen deposits. Some evidence suggests soft drusen are instrumental in the spread of abnormal vessels, but whether they stimulate vessel growth (angiogenesis) or simply provide space for them by lifting up the RPE remains unclear.
Two networks of blood vessels nourish the retina, one located on the retinal surface and the other located deep in the retina, external to Bruch's membrane. The abnormal vessels of AMD originate in the lower network of vessels, called the choroidal circulation. These vessels make their way through Bruch's membrane and spread out under the RPE. Blood and fluids leak from them and cause the photoreceptor cells to degenerate and the macula to detach from the cells under it.
Slightly blurred or distorted vision is the most common early symptom of AMD. Visual loss with dry AMD usually progresses slowly while visual loss with wet AMD proceeds more rapidly and may occur over days or weeks. Patients who have wet AMD in one eye are at increased risk of developing CNVs in the other eye. The magnitude of the risk varies, depending on the appearance of the second eye. The risk is greater in eyes with numerous large drusen, with abnormal pigment changes in the macula, and in patients with a history of high blood pressure.
Presently, there are no effective treatments available for visually disabling retinal vascular disease or choroidal vascular disease such as diabetic retinopathy and age related macular degeneration (AMD). The therapeutic strategies for treating diminished or loss of vision caused by the vascular eye diseases vary. Laser photocoagulation is the first effective treatment found for wet AMD. The laser destroys abnormal blood vessels beneath the retinal and seals leaky areas but also destroys the overlying retina. This treatment can inhibit wet AMD's progression, but it cannot restore lost vision and the disease often progresses despite laser therapy. The use of the drug Visudyne (veteporfin) is another approach to treat AMD. This drug belongs to a class of drugs used in photodynamic therapy (PDT), a technique in which light-activated dyes destroy tissue. After an injection, the light-sensitive drug tends to localize in the new choroidal vessels. A low-intensity laser is then focused on the dye-containing CNVs, triggering a chemical reaction that destroys the abnormal vessels. The drug can stabilize vision for a time and slow retinal damage. Other PDT drugs for AMD are currently in clinical testing. However, even with the availability of PDT and conventional laser treatment, patients with the vascular diseases of the eye still have no known effective treatment option and remain vulnerable to sustaining perm
Fay Zohreh
Kumar Nanda P. B. A.
McNichol, Jr. William J.
ReedSmith LLP
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