Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Testing efficacy or toxicity of a compound or composition
Reexamination Certificate
2001-02-16
2003-06-10
Hartley, Michael G. (Department: 1619)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Testing efficacy or toxicity of a compound or composition
C514S562000
Reexamination Certificate
active
06576219
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to methods for reducing the intra-ocular pressure of the eye by enhancing aqueous humor outflow, and to a method for screening compounds that reduce intra-ocular pressure.
2. Description of Related Art
In glaucoma, a leading cause of blindness, the optic nerve is damaged through a poorly-understood interaction of elevated intra-ocular pressure (IOP) and patient predisposition to the disease. In the most common form of glaucoma the trabecular meshwork (TM), which plays a critical role in regulation of aqueous humor outflow and intra-ocular pressure in both health and disease, is thought to be defective in such a manner that resistance to outflow and IOP both rise.
The anterior chamber of the eye is bathed with aqueous humor, formed continuously by the ciliary body. Aqueous humor moves by bulk flow from its site of production in the posterior chamber through the pupillary aperture and into the anterior chamber. It subsequently exits the anterior chamber via one of two routes.
The majority of outflow in the healthy human eve occurs at the anterior chamber angle, where aqueous humor passes through the trabecular meshwork and into the Canal of Schlemm, from where it joins the general venous drainage of the eye. A second outflow pathway is via the uveoscleral route, although this appears to be a minor (≈20%) pathway in the normal human eve. A homeostatic balance of aqueous humor production and drainage allows intra-ocular pressure to be maintained within narrow limits in the normal eye (Caprioli, J.,
Adler's Physiology of the Eye: Clinical Application
, W. M. Hart, ed. 9th Ed., 7:228-247, 1992; Hart, W. M.,
Adler's Physiology of the Eye: Clinical Application
, W. M. Hart, ed. 9th Ed., 8:248-267, 1992).
Production of aqueous humor occurs along the surface of the ciliary processes (pars plicata), which is covered by a double layer of epithelial cells consisting of a pigmented and non-pigmented layer situated with their apical surfaces juxtaposed. These function in tandem to produce transepithelial secretion of NaCl and water in movement from the blood to the aqueous humor. Evidence has been provided that Na—K—Cl cotransport and the Na/K pump act in concert to bring about the vectorial transport (Dong, et al.,
Invest. Ophthalmol. Vis. Sci.,
35:1660, 1994). The rate of aqueous humor production is quite high relative to other types of epithelia that function in vectorial transport of water and electrolytes. Thus, a drainage pathway that can accommodate this rate of fluid production is essential for maintenance of normal intra-ocular pressure. The aqueous humor production and drainage mechanisms work to replace the entire volume of aqueous every 100 minutes (Caprioli, J., supra).
It is well recognized that regulation of aqueous humor outflow through the trabecular meshwork is critically important for maintenance of an appropriate intra-ocular pressure, and that in disease states such as ocular hypertension and glaucoma, this regulation appears to be defective. For instance. U.S. Pat. No. 4,757,089 teaches a method for increasing aqueous humor outflow by topical or intracameral administration of ethacrynic acid, or an analog, to treat glaucoma. It is also known that ethacrynic acid increases water flux across the walls of perfused microvessels (Brandt, et al.,
Invest. Ophthalmol. Vis. Sci.,
35(4[Suppl]): 1848, 1994) and inhibits Na
+
—K
+
—2Cl
−
cotransport activity of avian erythrocytes (Palfrey, et al.,
Am. J. Physiol.,
264:C1270-C1277, 1993), although the mechanisms by which these phenomena occur have not been elucidated. For instance, phenoxyacetic acids inhibit NaCl reabsorption in the thick ascending limb of the loop of Henle screening test, but its effect was exerted from both epithelial sides, rather than from the luminal side as with the class of loop diuretics, and it led to a depolarization of the membrane voltage. This effect is compatible with an inhibitory action at the level of mitochondrial ATP production rather than an inhibition of the Na
+
—K
+
—2Cl
−
cotransporter.
In contrast to the current level of knowledge regarding cellular processes responsible for aqueous humor production by the ciliary body, relatively little is known about the cellular mechanisms in the trabecular meshwork that determine the rate of aqueous outflow. Pinocytotic vesicles are observed in the juxtacanalicular meshwork and the inner wall of Schlemm's Canal. The function of these vesicles remains unknown, but some investigators have suggested that the bulk flow of aqueous humor through the meshwork cannot be accounted for by flow through the intercellular spaces and that these vesicles play a central role in outflow regulation. Evidence has been provided that cytoskeleton-mediated changes in trabecular meshwork cell shape modulate aqueous outflow (Erickson-Lamy and Nathanson,
Invest. Ophthalmol. Vis. Sci.,
33:2672-2678, 1992; Erickson-Lamy, Schroder, and Epstein,
Invest. Opthalmol. Vis. Sci.,
3263 1-2640. 1992). The extracellular matrix surrounding the trabeculae is thought to contribute to outflow resistance, perhaps by interactions with proteins contained in the aqueous humor (Freddo, T. F.,
Optometry Vis. Sci.,
70:263-270, 1993). Indeed. abnormalities in this extracellular matrix may contribute to the increased outflow resistance seen in corticosteroid-induced glaucoma (Partridge, et al.,
Invest. Ophthalmol. Vis. Sci.,
30:1843-1847, 1989; Polansky, et al.,
The Ocular Effects of Prostaglandins and Other Eicosanoids
, Alan R. Liss, Inc., pp. 113-138, 1989). Investigators evaluating both normal physiology and drug effects have provided evidence that changes in cell shape (as distinct from cell volume) may be involved in outflow regulation (Erickson-Lamy and Nathanson, supra; Erickson-Lamy, Schroder, and Epstein, supra). Trabecular meshwork cells have been shown to possess actin and myosin filaments (Clark, et al.,
Invest. Ophthalmol. Vis. Sci.,
35:281-294, 1994) and to contract in response to some agents (Coroneo, et al,
Exp. Eye Res.,
52:375-388, 1990; Lepple-Wienhues, et al.,
Exp. Eye Res.,
53:33-38, 1991; Wiederholt, et al.,
Invest. Ophthalmol. Vis. Sci.,
35:2515-2520, 1994). In a review of the existing literature at the time, Davson speculated that changes in trabecular meshwork cell volume (as distinct from cell shape) may participate in the regulation of aqueous outflow facility (Davson, H.,
Physiology of the Eye
, H. Davson, ed., 5th Ed., Macmillan Press, London, Chapter 1, pp. 9-81, 1990), but to date this hypothesis has not been specifically addressed by other investigators. An excellent review of trabecular meshwork physiology and morphology is found in P. L. Kaufman, “Pressure-dependent Outflow” in R. Pitch et al., ed.
The Glaucomas
, St. Louis, Mo.; C. V. Mosby Co., 1989, 219-240, Vol. 1.
In addition to regulation of aqueous outflow, trabecular meshwork cells are thought to serve an immunologic function as they phagocytize antigens in the anterior chamber of the eye as they pass through the trabecular meshwork (Epstein, et al.,
Invest. Opthalmol. Vis. Sci.,
27:387-395, 1986). It has been hypothesized that the cells then migrate out of the meshwork into the Canal of Schlemm to enter the systemic circulation and act as antigen presenting cells to trigger the production of antibodies to the phagocytized antigen. In at least one form of glaucoma (pigmentary), this phagocytotic function is thought to be overwhelmed, resulting in increased resistance to aqueous outflow (Epstein, et al., supra). The endothelial cells lining the Canal of Schlemm also appear to contribute to the resistance to outflow in the normal eye (Davson, H., supra; Hart, W. M., supra).
A number of hormones and neurotransmitters have been documented to decrease intra-ocular pressure by modulating aqueous production or outflow. Studies employing a human eye perfusion model have shown that epinephrine, via an apparent &bgr;-adrenergic effect upon the uveo-scler
Brandt James D.
Curry Fitz-Roy E.
O'Donnell Martha E.
Fish & Richardson P.C.
Hartley Michael G.
The Regents of the University of California
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