US 20030199551A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0199551A1 Dreyer (43) Pub. Date: Oct. 23, 2003 (54) CALCIUM BLOCKERS TO TREAT (60) Provisional application No. 60/051,962, filed on Jun. PROLIFERATIVE WITREORETINOPATHY 30, 1997. (76) Inventor: Evan B. Dreyer, Pittsburgh, PA (US) Publication Classification Correspondence Address: (51) Int. Cl." ...................... A61K 31/445; A61K 31/455 ROBERT.J. BARAN Allergan, Inc. (T2-7H) (52) U.S. Cl. ............................................ 514/317; 514/355 2525 Dupont Drive Irvine, CA 926.12 (US) (57) ABSTRACT (21) Appl. No.: 10/436,902 Glutamate causes migration and proliferation of retinal (22) Filed: May 12, 2003 pigment epithelium and/or glial cells, and glutamate antago Related U.S. Application Data nists can prevent, treat or reduce retinal pigment epithelium and/or glial migration and the Subsequent development of (63) Continuation of application No. 10/038,215, filed on proliferative Vitreoretinopathy. Avoidance or management of Jan. 2, 2002, now Pat. No. 6,573,280, which is a continuation of application No. 09/445,832, filed on proliferative vitreoretinopathy can be achieved by adminis Dec. 13, 1999, now Pat. No. 6,380,261, filed as 371 tering to the patient a compound capable of reducing of international application No. PCT/US98/12414, glutamate-induced retinal cell migration in a concentration filed on Jun. 15, 1998. effective to reduce Such migration. US 2003/0199551A1 Oct. 23, 2003 CALCIUM BLOCKERS TO TREAT 0007. A third aspect of the invention features treating PROLIFERATIVE WITREORETINOPATHY preventing or reducing proliferative vitreoretinopathy in a patient by administering to the patient's retina an effective CROSS REFERENCE TO RELATED PATENT amount of a compound that reduces glutamate related retinal APPLICATIONS cell migration, proliferation, or both. 0001. This patent application is a continuation of U.S. 0008. The compound may be one of the so-called NMDA patent application Ser. No. 09/445,832 which was filed on antagonists-i.e., it reduces neuronal damage mediated by Dec. 13, 1999 as the U.S. National Patent Application of the NMDA receptor complex. Alternatively, the compound PCT/US98/12414, which was filed on Jun. 15, 1998 and was antagonizes neuronal damage mediated by the Voltage based on U.S. Provisional Application No. 60/051,962, dependent calcium channel. Other useful compounds are which was filed on Jun. 30, 1997 in the name of Dreyer. those which limit release of glutamate from cells or reduce BACKGROUND OF THE INVENTION the intracellular neurotoxic consequences of glutamate inter 0002 This application relates to preventing, controlling action with cell membrane glutamate receptorS. Preferably, reducing and/or treating proliferative vitreoretinopathy. Pro the compound crosses the blood-retinal barrier. liferative vitreoretinopathy (including epiretinal membrane 0009. The patient may be anyone who has experienced, formation) is a potentially devastating ophthalmic condition or is at risk for experiencing, penetrating trauma, retinal tear, that can lead to blindness. It can develop after any penetra traction detachment, Vitrectomy, or intraocular Surgery. The tion of the eye-Surgical or traumatic. Predisposing condi compound may be administered to the patient topically, tions therefore include, but are not limited to, penetrating orally, or intravitreally, as well as by other routes described trauma, retinal tears, traction detachments, vitrectomy, and below. It may be administered chronically, i.e., over an intraocular Surgery. Any ophthalmic condition that precipi extended period of a month or even six months or years. tates or permits migration of retinal pigment is epithelium or 0010) The invention preferably will be used to treat glial cells can lead to the development of proliferative patients having proliferative vitreoretinopathy or to treat vitreoretinopathy. See Machamer (1978) British J. Ophthal. patients prophylactically to avoid that condition. Preferably, 62:737; Hilton et al. (1983) Ophthalmology 90:121. the agent is administered over an extended period (e.g., at SUMMARY OF THE INVENTION least six-months and preferably at least one year). Those at 0003) 1 have discovered that glutamate causes migration risk for developing proliferative vitreoretinopathy include and proliferation of retinal pigment epithelium and/or glial patients who have experienced penetrating trauma, retinal cells. The invention features the use of glutamate antagonists tears, traction detachments, Vitrectomy, or intraocular Sur to reduce or control retinal pigment epithelium and/or glial gery. migration and the Subsequent development of proliferative 0011 Particularly preferred compounds are antagonists Vitreoretinopathy. Avoidance or management of proliferative of the NMDA receptor-channel complex. The term “NMDA Vitreoretinopathy can be achieved by administering to the receptor antagonists' includes several sub-types of NMDA patient a compound capable of reducing glutamate-induced antagonists including: a) channel blockers—i.e., antagonists retinal pigment epithelium and/or glial migration in a con that operate uncompetitively to block the NMDA receptor centration effective to reduce Such migration. channel; b) receptor antagonists-antagonists that compete 0004 While I do not wish to be bound to any specific with NMDA to act at the NMDA binding site; c) agents theory, I conclude that one or more of the Several types of acting at either the glycine co-agonist Site or any of Several calcium-permeable CNS ion channels mentioned below can modulation Sites Such as the Zinc Site, the magnesium site, be involved in controlling Such migration, including: a) the the redox modulatory site, or the polyamine site; d) agents various aspects of the NMDA (N-methyl-D-aspartate) which inhibit the downstream effects of NMDA receptor receptor channel complex; b) the voltage-dependent Ca" Stimulation, Such as agents that inhibit activation of protein channels; and c) other channels directly coupled to kinase C activation by NMDA stimulation, antioxidants, and glutamate (or excitatory amino acid) receptors. Such chan agents that decrease phosphatidylinositol metabolism. nels are reviewed in: Sommer, B. and Seeburg, P. H. 0012. Other compounds that are useful in the invention “Glutamate receptor channels: novel properties and new include Voltage-dependent calcium channel antagonists, e.g. clones'Trends Pharmacological Sciences 13:291-296 those which exert a Substantial direct effect on glutamate (1992); Nakanishi, S., “Molecular Diversity of glutamate toxicity mediated by the L-type voltage dependent Ca" receptors and implications for brain function”, Science channel in that they produce a Statistically significant result 248:597-603 (1992). in experiments measuring glutamate induced effects by the 0005 One aspect of the invention generally features a general method described in Karschian and Lipton, J. method of treating, preventing, or reducing proliferative Physiol. 418: 379-396 (1989) or by other techniques for Vitreoretinopathy in a patient by administering to the measuring antagonism of the L-type Ca" channel known to patient's retina an effective amount of a compound that those in the art. (We contrast the direct effect so measured reduces CNS neuronal damage incident to (associated with) with the secondary effects of excitoxicity mediated by other is calcium ion influx. channels, which in turn causes flow through the Voltage dependent Ca" channels.) Particular candidate compounds 0006 A second aspect of the invention features treating, include Class I Voltage dependent Ca" channel antagonists, preventing, or reducing proliferative vitreoretinopathy in a e.g., phenylalkylamines. patient by administering to the patient's retina an effective amount of at least one of the compounds listed in one or 0013 Preferably, the compounds used cross the blood more of Tables 2-5. below. retina barrier and can be administered chronically. Other US 2003/0199551A1 Oct. 23, 2003 useful agents act as antagonists of non-NMDA receptors tures antagonists having certain specific characteristics: the (glutamate receptor types other than the NMDA receptor ability to cross the blood-retina barrier; and the ability to be complex discussed above), and include agents which block administered chronically. Within those guidelines, any Suit inotropic glutamate receptorS or interact with metabotropic able antagonist of the glutamate induced excitotoxicity may glutamate receptors (Nakanishi, Supra). Still other agents act be used in accordance with the invention. AS mentioned, in to limit (reduce) release of glutamate from cells, thereby preferred embodiments, N-methyl-D-aspartate (NMDA) acting upstream from the glutamate receptors in the excita Subtype of glutamate receptor-channel complex may be used tory neurotoxicity process. Still other agents may act by to reduce or prevent proliferative vitreoretinopathy-related blocking downstream effects of glutamate receptor Stimula injury. Many antagonists of the NMDA receptor have been tion, e.g., the intracellular consequences of glutamate inter identified (Watkins et al., Trends in Pharmacological Sci. action with a cell membrane glutamate receptor, Such as 11:25, 1990, hereby incorporated by reference). There are agents (like dantrolene) that block the rise in intracellular Several recognized Sub-types of NMDA receptor including: calcium following Stimulation of membrane glutamate a) channel blockers—i.e., antagonists