Drug – bio-affecting and body treating compositions – Designated organic nonactive ingredient containing other... – Solid synthetic organic polymer
Reexamination Certificate
2001-07-25
2004-05-04
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Designated organic nonactive ingredient containing other...
Solid synthetic organic polymer
C514S215000, C514S220000
Reexamination Certificate
active
06730707
ABSTRACT:
TECHNICAL FIELD
This invention relates to a method for lowering intraocular pressure, treating ocular hypertension, and treating glaucoma, by administering indole analogues and pharmaceutical compositions.
BACKGROUND OF THE INVENTION
Glaucoma is a slowly progressive blinding disease usually associated with chronic elevation of intraocular pressure (IOP). Sufficiently high and persistent intraocular pressure is believed to result in damage to the optic disc at the juncture of the optic nerve and retina, resulting in degeneration of retinal ganglion cells and blindness characteristic of glaucoma. However, the mechanism whereby IOP elevation (also known as ocular hypertension) leads to glaucoma is not well understood. Additionally, a fraction of patients with typical visual field loss associated with glaucoma do not show abnormal elevated IOP levels (known as low-tension or normal-tension glaucoma).
Glaucoma is primarily classified as open-angle, closed-angle, or congenital, and further classified as primary and secondary. Glaucoma is treated with a variety of pharmacological and surgical approaches. In cases where glaucoma is associated with ocular hypertension, pharmacological treatment comprises adrenergic agonists (epinephrine, dipevefrin, apraclonidine), cholinergic agonists (pilocarpine), beta blockers (betaxolol, levobunolol, timolol), carbonic anhydrase inhibitors (acetazolamide) or more recently, prostaglandin analogues (latanoprost, bimatoprost (Lumigan™)) and alpha adrenergic agonists (brimonidine). These pharmacological approaches help restore the IOP to a normotensive state either by inhibiting the production of aqueous humor by the ciliary body, or facilitating trabecular or uveoscleral aqueous humor outflow. Anticholinergic agents reduce intraocular pressure in primary glaucoma, reducing the resistance to outflow of the aqueous humor outflow. Anticholinesterase inhibitors have been used to manage primary and certain forms of secondary glaucoma, such as aphakic glaucoma following cataract extraction. The congenital form of glaucoma rarely responds to therapy and is more commonly treated with surgery. In narrow angle glaucoma, the aqueous outflow is enhanced by freeing of the entrance to the trabecular space at the canal of Schlemm from blockade by the iris, as a result of the drug-induced contraction of the sphincter muscle of the iris. (Taylor, pp. 123-125, in The
Pharmacological Basis of Therapeutics
, 7
th
Ed, Eds., A. G. Gilman, L. S. Goodman, T. W. Rail, and F. Murad, MacMillan Publishing Company, New York, (1985)).
In wide-angle, or chronic simple glaucoma, the entry to the trabeculae is not physically obstructed; the trabeculae, a meshwork of pores of small diameter, lose their patency. Contraction of the sphincter muscle of the iris and the ciliary muscle enhances tone and alignment of the trabecular network to improve resorption and outflow of aqueous humor through the network to the canal of Schlemm (Watson,
Br. J. Opthalmol
. 56: 145-318 (1972); Schwartz,
N. Engl. J. Med.
, 290: 182-186 (1978); Kaufman, et al.,
Handbook of Experimental Pharmacology
69: 149-192 (1984)).
Acute congestive (narrow angle) glaucoma is nearly always a medical emergency in which the drugs are essential in controlling the acute attacks, but long-range management is usually based predominantly on surgery (peripheral or complete iridectomy). By contrast, chronic simple (wide-angle) glaucoma has a gradual, insidious onset and is not generally amenable to surgical improvement; and control of intraocular pressure depends upon permanent therapy.
Acute congestive glaucoma may be precipitated by the injudicious use of a mydriatic agent in patients over 40 years, or by a variety of factors that can cause pupillary dilatation or engorgement of intraocular vessels. Signs and symptoms include marked ocular inflammation, a semidilated pupil, severe pain, and nausea. The therapeutic objective is to reduce the intraocular pressure to the normal level for the duration of the attack. An anticholinesterase agent is instilled into the conjunctival sac in combination with a parasympathomimetic agent for greatest effectiveness. A commonly used combination consists of a solution of physostigmine and salicylate, 0.5%, plus pilocarpine nitrate, 4%. Adjunctive therapy includes the intravenous administration of a carbonic anhydrase inhibitor such as acetozolamide to reduce the secretion of aqueous humor, or of an osmotic agent such as mannitol or glycerin to induce intraocular dehydration. The long-acting organophosphorus compounds are not indicated in narrow-angle glaucoma because of vascular engorgement and increase in the angle block.
Therapy of chronic simple glaucoma and secondary glaucoma includes: (1) parasympathomimetic agents (e.g. pilocarpine nitrate, 0.5 to 0.6%); (2) anticholinesterase agents that are short-acting (e.g. physostigmine salicylate, 0.25 and 0.5%) or long-acting (demecarium bromide, 0.125 to 0.25%; echothiophate iodide, 0.03 to 0.25%; isoflurophate, 0.025%); (3) beta-adrenergic antagonists such as timolol maleate, a long-acting agent that is administered at 12-hour intervals, does not directly affect pupillary aperture, but reduces production of aqueous humor (Boger, et al.,
Am. J Opthalmol
. 86: 8-18 (1978); Lotti, et al.,
Handbook of Experimental Pharmacology
69: 249-278 (1984)) and avoids the partial block of accommodation and the untoward effects of the long-acting anticholinesterase agents; and, paradoxically, (4) sympathomimetic agents (e.g. epinephrine, 0.25 to 2%, phenylephrine, 10%), which are most effective when used in combination with anticholinesterase inhibitors or cholinergic agonists. They reduce intraocular pressure by decreasing secretion of the aqueous humor, and prevent engorgement of the small blood vessels.
Because the cholinergic agonists and cholinesterase inhibitors block accommodation, they induce transient blurring of far vision, usually after administration of relatively high doses over shorter duration. With long-term administration of the cholinergic agonists and anticholinesterase agents, the response diminishes due to a diminished number of acetylcholine receptors.
Despite the convenience of less frequent administration and the high potency of long-acting anticholinesterase agents, the use of long-acting anticholinesterase agents is associated with a greater risk of developing lenticular opacities and untoward autonomic effects. An organophosphorus agent, DFP, has the longest duration of action and is extremely potent when applied locally; solutions in peanut or sesame oil require installation from once daily to once weekly, and may control intraocular pressure in severe cases that are resistant to other drugs. Because the oily vehicle is unpleasant to most patients, DFP has been replaced by echothiophate.
Treatment of glaucoma with potent, long-acting anticholinesterase agents (including demecarium, echothiophate, and isoflurophate) for 6 months or longer is associated with a high risk of developing cataracts. (Axelsson, et al.,
Acta Opthalmol
. (
Kbh
.) 44: 421-429 (1966); de Roetth,
J.A.M.A
. 195: 664-666 (1966); Shaffer, et al.,
Am. J. Opthalmol
. 62: 613-618 (1966)) Although development of cataracts is common in untreated comparable age groups, the incidence of lenticular opacities under such circumstances can reach 50%, with the risk increasing in proportion to the strength of the solution, frequency of installation, duration of therapy, and age of patient. (Laties,
Am. J Opthalmol
. 68: 848-857 (1969); Kaufman, et al., pp. 149-192, in
Pharmacology of the Eye, Handbook of Experimental Pharmacology
, Vol. 69, Ed. M. L. Sears, Springer-Verlag, Berlin, (1984)).
Long-acting anticholinesterase agents are not recommended when glaucoma can be controlled by timolol, parasympathomimetic drugs, physostigmine, or other agents. Nevertheless, the long-acting cholinesterase inhibitors retain their therapeutic importance in situations where other agents are inadequate, since glaucoma may lead to irreversible blindness if not adequately controll
Brown Edward G.
Peral Maria A.
Peterson Ward M.
Pintor Jesus J.
Plourde, Jr. Robert
Fubara Blessing
Halluin Albert P.
Howrey Simon Arnold & White , LLP
Inspire Pharmaceuticals Inc.
Kung Viola T.
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