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(12) Patent Application Publication (10) Pub. No.: US 2013/0197002 A1 Staubli Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2013/0197002 A1 Staubli Et Al US 2013 O1970O2A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0197002 A1 Staubli et al. (43) Pub. Date: Aug. 1, 2013 (54) BRIMONDINE FOR TREATING VISUAL Publication Classification DSORDERS MEDIATED BY CENTRAL VISUAL PROJECTIONS FROM THE EYE (51) Int. Cl. (71) Applicant: Allergan, Inc., Irvine, CA (US) A613 L/498 (2006.01) (52) U.S. Cl. (72) Inventors: Ursula Staubli, Laguna Beach, CA CPC .................................... A6 IK3I/498 (2013.01) (US); Alan C. Foster, San Diego, CA (US); Daniel W. Gil, Corona Del Mar, USPC .......................................................... S14/249 CA (US); John E. Donello, Dana Point, CA (US) (57) ABSTRACT (73) Assignee: ALLERGAN, INC. Irvine, CA (US) (21) Appl. No.: 13/752,871 The present invention relates to a method for treating visual (22) Filed: Jan. 29, 2013 disorders mediated by lateral geniculate nucleus, Superior Related U.S. Application Data colliculus and the visual cortex by administering to a patient (60) Provisional application No. 61/592,115, filed on Jan. in need of Such treatment, compounds acting at the alpha 2 30, 2012. adrenergic receptor. Patent Application Publication Aug. 1, 2013 Sheet 1 of 3 US 2013/O197002 A1 FIGURE 1 100 8 O 6 O 4. O 2 O Contro O.3 nM 3 nM 30 nM 300 nM 8 O 6 O 4. O 2 O 100 nM Atip 39 gig, 30 nM. Brimo Patent Application Publication Aug. 1, 2013 Sheet 2 of 3 US 2013/O197002 A1 FIGURE 2 p = 0.05 (paired t-test) Patent Application Publication Aug. 1, 2013 Sheet 3 of 3 US 2013/O197002 A1 FIGURE 3 : 22-23 weeks post Blue Light US 2013/O 197002 A1 Aug. 1, 2013 BRIMONDINE FORTREATINGVISUAL 0008 FIG. 2 shows that brimonidine counteracts the loss DISORDERS MEDIATED BY CENTRAL in signal power in Long Evans rats eight to nine weeks after a VISUAL PROJECTIONS FROM THE EYE 1 sec optic nerve crush (ONC) treatment. 0009 FIG. 3 shows that brimonidine restores the contrast RELATED APPLICATION sensitivity in treated Long Evans rats 22-23 weeks after blue 0001. This application claims the benefit of U.S. Provi light treatment. sional Application Ser. No. 61/592,115, filed Jan. 30, 2012, which is incorporated herein by reference in its entirety. SUMMARY OF THE INVENTION 0010 We have discovered that administering brimonidine FIELD OF THE INVENTION to visual cortex slices was found to produce a marked and 0002 The present invention relates to a method for treat dose-dependent enhancement of LTP, with a threshold dose ing visual disorders mediated by lateral geniculate nucleus, of 3 nM (FIG. 1, left panel), an effect that was fully sup Superior colliculus and the visual cortex by administering to a pressed in presence of the alpha 2 pan antagonistatipamezole patient in need of such treatment (5-bromo-quinoxalin-6-yl)- (FIG. 1, right panel). Atipamezole is a potent, selective and imidazolidin-2-ylidene-amine acting at the alpha 2 adrener specific antagonist of both centrally and peripherally located gic receptor. alpha 2-adrenoreceptors (Virtanen R. Savola J M. Saano V. Arch Int. Pharmacodyn. Ther. 297: 190-204, 1989). SUMMARY OF THE RELATED ART (0011 FIG. 1 shows Brimonidine given 8 weeks after ONC acutely reduced the loss in Sweep VEPamplitude measured in 0003. The compound (5-bromo-quinoxalin-6-yl)-imida visual cortex. Next brimonidine was tested in two different Zolidin-2-ylidene-amine (structure shown below) is generi animal models to assess its ability to reverse visual dysfunc cally known as brimonidine tartrate and is sold under the tion, as might be predicted from the above described in vitro trademark ALPHAGANRP (available from Allergan, Inc.). functional profile. First brimonidine was tested in a rat model of glaucoma consisting of a 1 sec unilateral optic nerve crush (ONC), a treatment that partially destroys retinal ganglion cells including their axonal projections to visual cortex. Fol lowing ONC, rats were found to exhibit a significant loss in visual acuity as measured by sweep VEP methodology. How Cry ever, when administered eight weeks after ONC via systemic route, brimonidine partially restored the power of the sVEP amplitude (see FIG. 2), in agreement with the Suggested Brimonidine therapeutic potential of alpha 2 adrenergic activation for visual dysfunction. 0004 Pharmacological activation of the alpha 2 adrener 0012 FIG. 2 shows that brimonidine counteracts the loss gic receptor by brimonidine is a well established treatment for in signal power in Long Evans rats eight to nine weeks after a various visual disorders of the eye. Alpha 2 adrenergicago 1 sec ONC treatment. Saline was used as a control. Half of the nists, such as brimonidine, have physiological effects beyond rats were injected with 0.3 mg/kg brimonidine and the other the eye in the central nervous system where they interact with half with saline in the first test; cross-overexposure took place the adrenergic central pathways. Thus, alpha 2 adrenergic one week later; the spatial frequencies were fixed at 0.2 cpd. agonists might also be beneficial for treating visual system The left and middle graphs show data from individual rats disorders mediated by central visual areas, including, but not collected 30 min before and after saline or brimonidine injec limited to the visual cortex. tion. The right graph compares individual changes (delta) in 0005. The visual cortex is one synapse removed from the power under control VS drug condition. Thus, brimonidine eye and integrates visual signals generated by the retina. It is reduced the deficit in visual performance in this model of thus essential for decoding, processing and transforming visual system degeneration. visual inputs originating in the eye, and proper visual cortical 0013 The ability of brimonidine to restore visual dysfunc function is necessary for normal vision. Noradrenaline tion was further confirmed in the blue light model. Blue-light released from the nerve terminals in visual cortex gates expe treatment damages photoreceptors in the retina, and has been rience dependent modification of visual responsiveness proposed as a model of age-related macular degeneration including ocular dominance shifts after monocular depriva (ARMD; Wielgus et al., Photochem. Photobiol. Sci., 2010, 9, tion (Imamura et al., Neuroscience 147 (2007) 508-521). 1505-1512). In blue-light treated Long-Evans rats, contrast 0006. The effect of bromonidine was investigated in the sensitivity, an important measure of visual performance, was visual cortex using brain slices prepared from primary visual significantly impaired, a deficit that was partially restored by cortex to determine possible drug interactions with visual acute brimonidine administration (FIG. 3). cortex plasticity mechanisms, in particular long-term poten 0014 FIG. 3 shows that brimonidine restores the contrast tiation (LTP). LTP serves as a cellular model for visual cortex sensitivity in rats 22-23 weeks after blue-light treatment. plasticity and has functional consequences on visual evoked Saline was used as a control. Half of the rats were injected responses (Cooke and Bear. The Journal of Neuroscience, with 0.3 mg/kg brimonidine and the other half with saline in Dec. 1, 2010, 30(48):16304-16313). the first test, cross-over exposure took place one week later; the spatial frequencies were fixed at 0.575 cpd. The left and BRIEF DESCRIPTION OF THE DRAWINGS middle graphs show data from individual rats collected 30 0007 FIG. 1 shows dose-dependent facilitation of LTP in min before and after saline or brimonidine injection. The right rat visual cortex by brimonidine and its reversal by alpha 2 graph illustrates the mean values of contrast sensitivities pan-antagonist atipamezole. shown in left and middle graph. The open bar indicates the US 2013/O 197002 A1 Aug. 1, 2013 contrast sensitivity measured in control rats using the same benign concentric maculopathy, Bietti's crystalline dystro spatial frequency. Thus, brimonidine half-way normalized phy, and pseudoxanthoma elasticum, retinal tears/holes Such the deficit in visual performance in this model of visual as retinal detachment, macular hole, and giant retinal tear; degenerative disease. tumors such as retinal disease associated with tumors, con 0015 These findings provide evidence that activation of genital hypertrophy of the retinal pigmented epithelium, pos alpha 2 adrenergic receptors by brimonidine is very effective terior uveal melanoma, choroidal hemangioma, retinitis pig at improving cortical synaptic plasticity, a strategy predicted mentosa, choroidal osteoma, choroidal metastasis, combined to have therapeutic benefits in disorders where central visual hamartoma of the retina and retinal pigmented epithelium, plasticity needs to be restored or increased. A prime example retinoblastoma, vasoproliferative tumors of the ocular fun of a visual disorder mediated by visual cortex is amblyopia. dus, retinal astrocytoma, and intraocular lymphoid tumors; Amblyopia is defined as poor or indistinct vision by an eye punctate inner choroidopathy, acute posterior multifocal pla that is physically normal. Amblyopia can be initiated by poor coid pigment epitheliopathy, myopic retinal degeneration, transmission of the visual image to the visual cortex during acute retinal pigement epitheliitis, retinitis pigmentosa, pro childhood. Abnormal visual processing may be caused by a liferative vitreal retinopathy (PVR), age-related macular form of deprivation (i.e. cataracts), anisometropia (different degeneration (ARMD), diabetic retinopathy, diabetic macu retinal image size, or magnification, in each eye), or Suppres lar edema, retinal detachment, retinal tear, uveitus, cytome sion resulting from Strabismus (misalignment of the eyes). A galovirus retinitis, glaucoma, amblyopia, stroke-induced prolonged transmission of poor quality visual images induces blindness, visual system disorder in Parkinson's disease, a physiological change within the visual cortex that alters the Alzheimer's disease and multiple Sclerosis, seizure-induced perception within the visual cortex. Briefly, the visual cortex cortical blindness, induced visual system disorder, epileptic will “ignore the poor vision from one eye. Hence amblyopes blindness, multiple sclerosis (MS)-induced visual system dis often lack visual acuity and stereopsis.
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